HK1087402B - Pyrazole derivative - Google Patents

Description

Pyrazole derivatives

Technical Field

The present invention relates to a pyrazole derivative having a platelet aggregation inhibitory action.

Background

Platelets aggregate when a blood vessel is damaged to form a hemostatic thrombus, which plays an important role in preventing bleeding, but, on the other hand, as seen in arteriosclerosis, aggregation occurs when a blood vessel endothelium is damaged or a blood vessel is narrowed to induce thrombus and embolism, resulting in ischemic diseases such as myocardial infarction, angina pectoris, ischemic cerebrovascular disorder, peripheral vascular disorder, and the like. Therefore, platelet aggregation-inhibiting drugs are administered to patients in the prevention and treatment of ischemic diseases. Among them, aspirin has been used as a platelet aggregation inhibitor since a long time, and its effect has been demonstrated by meta-analysis APT (platelet aggregation) of the results of a plurality of clinical trials given to 10 ten thousand people (BMJ, volume 308, pages 81 to 106, 1994). However, aspirin is known to cause side effects of gastrointestinal bleeding, called aspirin ulcer, which is not dependent on the dose, and this phenomenon occurs in 1 out of 100 persons (BMJ, 321 Vol, 1183-1187 p., 2000).

It is well known that the inhibition of platelet aggregation by aspirin is based on the inhibition of cyclooxygenase (cyclooxygenase). Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), low doses of aspirin selectively inhibit COX-1, thereby inhibiting platelet aggregation, but COX-1 inhibition is also responsible for the development of aspirin ulcers (Neurology, 57, supply.2, S5-S7, 2001, Drugs Today, 35, 251-265, 1999). In addition, it is known that non-steroidal anti-inflammatory drugs selectively inhibit COX-2, exhibiting anti-inflammatory effects.

As described above, aspirin is useful as a platelet aggregation inhibitor, but since a COX-1 inhibitory action, which is a mechanism of its action, is accompanied by side effects such as gastrointestinal damage, it is desired to obtain a platelet aggregation inhibitor free from the COX-1 inhibitory action.

On the other hand, as a pyrazole derivative having an antithrombotic action at present, there have been known a compound (A) (Japanese patent No. 2586713, chem. pharm. Bull., vol. 45, p. 995 987-propan, 1997) or a compound (B) (BMJ, vol. 321, p. 1183-1187, 2000).

Disclosure of The Invention

However, IC of Compound (A) against collagen-induced platelet aggregation ₅₀A value of 5.3X 10^-6M, shows stronger inhibitory activity (IC) to COX-2₅₀Value 2.4X 10^-7M). Also, in the same manner as above,the inhibitory activity of compound (B) on platelet aggregation is inferior to that of COX-2, and since the inhibitory activity of COX-2 is related to the anti-inflammatory activity as described above, substances having COX-2 inhibitory activity are not necessarily suitable as platelet aggregation-inhibiting drugs. Accordingly, an object of the present invention is to provide a potent platelet aggregation-inhibiting drug which does not inhibit COX-1 and COX-2.

The present inventors have conducted extensive studies on the platelet aggregation inhibitory drugs and have found that pyrazole derivatives represented by the following general formulae (1) and (II) exhibit potent platelet aggregation inhibitory activity without COX-1 and COX-2 inhibitory activity, and have completed the present invention.

That is, the present invention provides a compound of the formula (I)

A compound represented by the formula (I), a salt thereof or a solvate thereof,

in the formula, Ar₁Represents a 5-or 6-membered aromatic heterocyclic group having 1 to 3 substituents, Ar₂Represents a 5-or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents or a phenyl group which may have 1 to 3 substituents, R1 is represented by the following general formula (1)

Wherein the cyclic structure A represents a 4-to 7-membered ring which may have 1 hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom as a constituent atom in addition to the nitrogen atom described in the above formula, X represents a carbonyl group, a thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups, R3 represents a cyclic structure A having a substituent selected from a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a sulfo group, a lower alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituents, an amino group which may have 1 or 2 substituents, a carbamoyl group which may have 1 or 2 substituents, a lower acyl group, an aminosulfonyl group which may have 1 or 2 substituents, an oxo group, a hydroxyiminocarbonyl group, a lower alkoxyiminocarbonyl group, an arylalkyl group which may have 1 to 3 substituents, a 4-to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents, a heterocyclic group, a salt thereof, a, Phenyl which may have 1 to 3 substituents, 5-or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents, 1 to 4 groups of 3-to 6-membered substituted or unsubstituted spirocyclic alicyclic alkyl group and 4 to 6-membered substituted or unsubstituted spirocyclic alicyclic heterocyclic group, and R2 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkoxy group, lower alkyl which may have 1 or 2 substituents, amino which may have 1 or 2 substituents, carbamoyl which may have 1 or 2 substituents, or acyl which may have 1 or 2 substituents.

Furthermore, the present invention provides compounds of the general formula (II)

A compound represented by (1), a salt thereof or a solvate thereof,

wherein the cyclic structure B represents a 5-7 membered ring which may contain 1-2 hetero atoms of the same or different species selected from nitrogen atom, oxygen atom and sulfur atom, and the cyclic structure Ar₃Represents a 5-or 6-membered aromatic heterocyclic ring which may have 1 to 3 substituents or a benzene ring which may have 1 to 3 substituents, Ar₄Represents a 5-or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents or a phenyl group which may have 1 to 3 substituents, R4 is represented by the following general formula (2)

Wherein the cyclic structure C represents a 4-to 7-membered ring which may have 1 hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom as a constituent atom in addition to the nitrogen atom described in the above formula, Y represents a carbonyl group, a thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups, R7 represents a cyclic structure C having a substituent selected from a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a sulfo group, a lower alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituents, an amino group which may have 1 or 2 substituents, a carbamoyl group which may have 1 or 2 substituents, a lower acyl group, an aminosulfonyl group which may have 1 or 2 substituents, an oxo group, a hydroxyiminocarbonyl group, a lower alkoxyiminocarbonyl group, an arylalkyl group which may have 1 to 3 substituents, a 4-to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents, a heterocyclic group, a salt thereof, phenyl group which may have 1 to 3 substituents, 5-or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents, 1 to 4 groups of 3-to 6-membered substituted or unsubstituted spirocyclic alicyclic alkyl group and 4-to 6-membered substituted or unsubstituted spirocyclic alicyclic heterocyclic group, and R5 and R6 each independently represent a group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group which may have 1 or 2 substituents, a lower alkyl group which may have 1 or 2 substituents and an oxo group.

The present invention also provides a pharmaceutical containing the compound represented by the general formula (I) or (II), a salt thereof, or a solvate thereof.

The present invention also provides an agent for preventing and/or treating ischemic diseases, which comprises a compound represented by the general formula (I) or (II), a salt thereof, or a solvate thereof.

The invention also provides a pharmaceutical composition containing the compound represented by the general formula (I) or (II), a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier.

The invention also provides the application of the compound represented by the general formula (I) or (II), the salt thereof or the solvate thereof in the preparation of medicaments.

The present invention also provides a method for treating ischemic diseases, which comprises administering an effective amount of a compound represented by the general formula (I) or (II), a salt thereof or a solvate thereof.

The compounds (I) and (II), salts thereof or solvates of salts thereof of the present invention have no inhibitory effect on COX-1 and COX-2, strongly inhibit aggregation of platelets, and have a strong inhibitory effect on thrombosis. Therefore, the compound is useful as a prophylactic and/or therapeutic agent for ischemic diseases that cause thrombosis and embolism, such as myocardial infarction, angina (chronic stable angina, unstable angina, and the like), ischemic cerebrovascular disorders (transient ischemic attack (TIA), cerebral infarction, and the like), peripheral vascular disorders, occlusion after artificial vascular replacement, thrombotic occlusion after coronary intervention (coronary artery bypass (CAGB), Percutaneous Transluminal Coronary Angioplasty (PTCA), stent placement, and the like), diabetic retinopathy and nephropathy, and occlusion at the time of artificial valve replacement. Alternatively, the compound is useful as a prophylactic and/or therapeutic agent for thrombosis and embolism accompanying, for example, vascular surgery, extracorporeal circulation of blood, or the like.

Best Mode for Carrying Out The Invention

The substituents and cyclic structures in the general formulae (I) and (II) will be described below.

Aromatic heterocyclic radical Ar₁And Ar₄The 5-or 6-membered aromatic heterocyclic group may, for example, be a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group or a pyrazolyl group.

The aromatic heterocyclic group Ar₁And Ar₄Examples of the substituent(s) in (b) include a lower alkyl group, a halogen atom, a hydroxyl group, an amino group, a lower alkoxy group, an aralkyloxy group, a lower thioalkoxy group, a lower alkoxycarbonyl group, a carboxyl group, a lower alkylsulfonyl group, an amino group which may have 1 or 2 substituents, a carbamoyl group which may be substituted by 1 or 2 lower alkyl groups, an aminosulfonyl group which may be substituted by 1 or 2 lower alkyl groups, and a 4-to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents. These substituents are explained below.

As aromatic heterocyclic radicals Ar₁And Ar₄The lower alkyl group as the substituent(s) represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclopentylmethyl group and the like.

Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.

The lower alkoxy group represents an alkoxy group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentyloxy group, a cyclopentyloxy group and the like.

The aralkyl group in the aralkyloxy group represents a group formed of the above-mentioned lower alkyl group and an aryl group having 6 to 20 carbon atoms, and specific examples of the aralkyloxy group include a benzyloxy group, a phenethyloxy group and the like.

The lower thioalkoxy group represents a thioalkoxy group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group, a cyclopentylthio group and the like.

The lower alkoxycarbonyl group represents an alkoxycarbonyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a primary to tertiary butoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, a cyclopentylmethoxycarbonyl group and the like.

The lower alkylsulfonyl group represents an alkylsulfonyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methylsulfonyl group, an ethylsulfonyl group, and a trifluoromethanesulfonyl group.

Amino which may have 1 or 2 substituents represents, in addition to unsubstituted amino, amino which may be substituted by 1 or 2 of the above-mentioned lower alkyl groups, lower alkanoylamino, lower alkoxycarbonylamino and ureido which may be substituted by 1 or 2 of the above-mentioned lower alkyl groups. Specific examples of the amino group which may be substituted by 1 or 2 of the above-mentioned lower alkyl groups include methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, isobutylamino, cyclopentylmethylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-cyclopentylmethylamino and the like. The lower alkanoylamino group represents an amino group substituted with a linear or branched alkanoyl group having 2 to 6 carbon atoms, and specific examples thereof include acetylamino group, propionylamino group and the like. The lower alkoxycarbonylamino group represents an amino group substituted with a linear or branched lower alkoxycarbonyl group having 2 to 6 carbon atoms, and specific examples thereof may include methoxycarbonylamino group and ethoxycarbonylamino group. Specific examples of the ureido group which may be substituted by 1 or 2 of the above lower alkyl groups include aminocarbonylamino, N1-methylaminocarbonylamino, N1-ethylaminocarbonylamino, N3-methylaminocarbonylamino, N1, N1-dimethylaminocarbonylamino, N1, N3-dimethylaminocarbonylamino, N1-methyl-N3-ethylaminocarbonylamino and the like.

Carbamoyl which may be substituted by 1 or 2 lower alkyl groups means carbamoyl which is substituted by 1 or 2 lower alkyl groups mentioned above in addition to unsubstituted carbamoyl, and specific examples thereof include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and methylethylcarbamoyl.

Aminosulfonyl which may be substituted by 1 or 2 lower alkyl groups means aminosulfonyl which may be substituted by 1 or 2 lower alkyl groups as described above in addition to unsubstituted aminosulfonyl, and specific examples thereof include methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, primary to tertiary butylaminosulfonyl, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, cyclohexylaminosulfonyl, cyclopentylmethylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl and the like.

Examples of the 4-to 7-membered alicyclic heterocyclic group in the 4-to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidyl, pyrazolidinyl, imidazolidinyl, homopiperazinyl, morpholinyl, and thiomorpholinyl. Examples of the substituents of these alicyclic heterocyclic groups being substituted with 1 or 2 substituents are exemplified by 3-aminoazetidin-1-yl, 3-methylaminoazetidin-1-yl, 3-dimethylaminoazetidin-1-yl, 2-carbamoylazetidin-1-yl, 2-methylcarbamoylazetidin-1-yl, 2-dimethylcarbamoylazetidin-1-yl, 3-carbamoylazetidin-1-yl, 3-methylcarbamoylazetidin-1-yl, 3-dimethylcarbamoylazetidin-1-yl, 3-hydroxypyrrolidinyl, 3-methoxymethylpyrrolidinyl, p-tolyl-N-oxide, p-tolyl-acetyl-N-methyl-ethyl-n-1-yl, p-tolyl-acetyl-n-yl, p-tolyl-acetyl, 2-carbamoylpyrrolidinyl, 2-methylcarbamoylpyrrolidinyl, 2-dimethylcarbamoylpyrrolidinyl, 3-carbamoylpyrrolidinyl, 3-methylcarbamoylpyrrolidinyl, 3-dimethylcarbamoylpyrrolidinyl, 3-aminopiperidinyl, 4-aminopiperidinyl, 3-methylaminopiperidinyl, 4-methylaminopiperidinyl, 3-dimethylaminopiperidinyl, 4-dimethylaminopiperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, 2-dimethylpiperidinyl, 3-dimethylpiperidinyl, 4-dimethylpiperidinyl, 2-carbamoylpiperidinyl, 3-carbamoylpyrrolidinyl, 3-methylaminopiperidinyl, 4-methylaminopiperidinyl, 3-dimethylaminopiperidinyl, 4-carbamoylpiperidyl, 2-methylcarbamoylpiperidyl, 3-methylcarbamoylpiperidyl, 4-methylcarbamoylpiperidyl, 2-dimethylcarbamoylpiperidyl, 3-dimethylcarbamoylpiperidyl, 4-methylpiperazinyl, 4-cyclopropylpiperazinyl, 4-carbamoylpiperazinyl, 2-dimethylmorpholinyl, 3-dimethylmorpholinyl and the like.

Aromatic heterocyclic radical Ar₁The substituent(s) is preferably substituted at a position para to the pyrazole ring.

Ar₄The substituent on the phenyl group which may have 1 to 3 substituents may be mentioned, for example, the above-mentioned aromatic heterocyclic group Ar₄The substituents in (1) are the same as those in (1). Further, Ar₄The 5-or 6-membered aromatic heterocyclic group represented also includes heterocyclic groups having no substituent.

Aromatic heterocyclic radical Ar₂The heterocyclic group may be a 5-or 6-membered aromatic heterocyclic group having 1 to 3 substituents or a phenyl group, and specific examples of the aromatic heterocyclic group include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyrazolyl group and the like.

Aromatic heterocyclic ring Ar₃The aromatic heterocyclic ring may have 1 to 3 substituents and may be a 5-or 6-membered aromatic heterocyclic ring or a benzene ring, and specific examples of the aromatic heterocyclic ring may include a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a triazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, and a pyrazole ring.

Aromatic heterocyclic radical Ar₂And aromatic heterocyclic ring Ar₃The substituent (C) may be the same as those mentioned for Ar₁And Ar₄The substituents in (1) are the same as those in (1).

Aromatic heterocyclic radical Ar ₁When the substituent(s) is (are) substituted at the para-position of the pyrazole ring, an aromatic heterocyclic group or phenyl Ar₂The substituents on (a) are preferably absent or substituted at a position meta to the pyrazole ring.

The cyclic structures a and C are 4 to 7-membered rings which may have 1 heteroatom, which may be the same or different, selected from a nitrogen atom, an oxygen atom and a sulfur atom, as a constituent atom in addition to the nitrogen atom described in the above general formulae (1) and (2), and specific examples thereof include saturated heterocycles such as an azetidine ring, a pyrrolidine ring, an imidazolidine ring, a pyrazoline ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, a hexahydropyridazine ring, a hexahydropyrimidine ring, a homopiperazine ring and an azepin ring, and unsaturated heterocycles such as a pyrrole ring, a dihydropyrrole ring, an imidazole ring, a dihydroimidazole ring, a pyrazole ring, a dihydropyridine ring, a dihydropyrimidine ring and a dihydropyrazine ring.

The cyclic structure B represents a 5-7 membered ring which may contain 1-2 hetero atoms which may be the same or different selected from a nitrogen atom, an oxygen atom and a sulfur atom, for example, Ar₃Condensed with a pyrazole ring to form 1, 4-dihydroindeno [1, 2-c ]]Pyrazole ring, 1, 4-dihydro-4-oxoindeno [1, 2-c]Pyrazole ring, 4, 5-dihydro-1H-benzo [ g]Indazole ring, 1, 4-dihydrochromene [4, 3-c ]Pyrazole rings, and the like.

The substituents R2, R3, R5, R6 and R7 are explained below.

Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.

The lower alkoxy group represents an alkoxy group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a primary to tertiary butoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cyclopentylmethoxy group and the like.

The lower alkoxycarbonyl group represents an alkoxycarbonyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a primary to tertiary butoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, a cyclopentylmethoxycarbonyl group and the like.

The lower alkylsulfonyl group represents a sulfonyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a primary-tertiary butylsulfonyl group, a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, and a cyclopentylmethylsulfonyl group.

The lower alkyl group which may have 1 or 2 substituents represents a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms which may be substituted by a group selected from a hydroxyl group, a halogen atom, a carboxyl group, a sulfo group, a linear, branched or cyclic alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, an amino group which may be substituted by a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, a carbamoyl group which may be substituted by a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, a ureido group which may be substituted by 1 group of a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms or 2 groups which may be the same or different.

Specific examples thereof may include methyl, ethyl, propyl, isopropyl, primary to tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-fluoroethyl, 3-fluoropropyl, 2-fluorocyclopropyl, 2-chloroethyl, 3-chloropropyl, 2-chloropropyl, trifluoromethyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxypropyl, sulfomethyl, 2-sulfoethyl, 1-sulfoethyl, 3-sulfopropyl, 2-sulfopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, 2-methoxyethyl, isopropyl, 3-methoxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-propoxycarbonylethyl, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 2-aminopropyl, methylaminomethyl, 2- (methylamino) ethyl, 1- (methylamino) ethyl, 3- (methylamino) propyl, 2- (methylamino) propyl, dimethylaminomethyl, 2- (dimethylamino) ethyl, 1- (dimethylamino) ethyl, 3- (dimethylamino) propyl, 2- (methylethylamino) ethyl, 1- (methylethylamino) ethyl, 2- (methylamino) ethyl, methyl-ethyl, ethyl-propyl, isopropyl, carbamoylmethyl, methylcarbamoylmethyl, ethylcarbamoylmethyl, dimethylcarbamoylmethyl, methylethylcarbamoylmethyl, carbamoylethyl, methylcarbamoylethyl, ethylcarbamoylethyl, dimethylcarbamoylethyl, methylethylcarbamoylethyl, carbamoylpropyl, 2-carbamoylcyclopropyl, ureidomethyl, N3-methylureidomethyl, N3-ethylureidomethyl, N3, N3-dimethylureidomethyl, N3-methyl-N3-ethylureidomethyl, 2- (ureido) ethyl, 2- (N3-methylureido) ethyl, 2- (N3-ethylureido) ethyl, 2- (N3, N3-dimethylureido) ethyl, 2- (N3-methyl-N3-ethylureido) ethyl, 3- (ureido) propyl, 2- (ureido) cyclopropyl, N1-methylureidomethyl, N1-ethylureidomethyl, N1, N1-dimethylureidomethyl, N1-methyl-N1-ethylureidomethyl, 2- (ureido) ethyl, 2- (N1-methylureido) ethyl, 2- (N1-ethylureido) ethyl, 2- (N1, N1-dimethylureido) ethyl, 2- (N1-methyl-N1-ethylureido) ethyl, N1, N3-dimethylureidomethyl, N1-methyl-N3-ethylureidomethyl, 2- (N3-methyl-N1-ethyl) ureidoethyl, 2- (N1, N3-diethylureido) ethyl, 1-carbamoyl-2-hydroxyethyl, 1, 2-dicarbamoylethyl and the like.

The amino group which may have 1 or 2 substituents represents an amino group which may be substituted by a linear, branched or cyclic alkyl group having 1 or 2 carbon atoms and 1 to 6 carbon atoms, and specific examples thereof include, in addition to an unsubstituted amino group, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a primary to tertiary butylamino group, a pentylamino group, a hexylamino group, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a cyclopropylmethylamino group, a cyclopentylmethylamino group, a dimethylamino group, a methylethylamino group, a diethylamino group, a methylpropylamino group, a methylisopropylamino group, a methylcyclopropylamino group, a methyl tert-butoxycarbonylamino group, and the like.

Carbamoyl which may have 1 or 2 substituents represents carbamoyl which may be substituted with a linear, branched or cyclic alkyl group having 1 or 2 carbon atoms of 1 to 6, and specific examples thereof include, in addition to unsubstituted carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, primary to tertiary butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl and cyclopentylcarbamoyl, cyclohexylcarbamoyl group, cyclopropylmethylcarbamoyl group, cyclopentylmethylcarbamoyl group, dimethylcarbamoyl group, methylethylcarbamoyl group, diethylcarbamoyl group, methylpropylcarbamoyl group, methylisopropylcarbamoyl group, methylcyclopropylcarbamoyl group, methylcyclopropylmethylcarbamoyl group and the like.

The lower acyl group represents an acyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a formyl group, an acetyl group, a propionyl group, a primary to secondary butyryl group, a pivaloyl group, a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, a cyclopropylmethylcarbonyl group, a cyclobutylmethylcarbonyl group, a cyclopentylmethylcarbonyl group and the like.

The aminosulfonyl group which may have 1 or 2 substituents represents an aminosulfonyl group which may be substituted by an alkyl group having 1 to 3 carbon atoms in number of 1 or 2, and specific examples thereof include an aminosulfonyl group, a methylaminosulfonyl group, an ethylaminosulfonyl group, a propylaminosulfonyl group, an isopropylaminosulfonyl group, a cyclopropylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, a methylethylaminosulfonyl group, a methylpropylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group and the like, in addition to an unsubstituted aminosulfonyl group.

The lower alkoxyiminocarbonyl group represents an iminocarbonyl group substituted with an alkoxy group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methoxyiminocarbonyl group, an ethoxyiminocarbonyl group, a propoxyiminocarbonyl group, an isopropoxyiminocarbonyl group, a primary to tertiary butoxyiminocarbonyl group, a cyclobutoxyiminocarbonyl group, a cyclopentyloxyiminocarbonyl group, a cyclohexyloxyiminocarbonyl group, and a cyclopentylmethoxyiminocarbonyl group.

The aralkyl group which may have 1 to 3 substituents represents an aralkyl group which may have 1 to 3 substituents and is formed from a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and an aryl group having 6 to 20 carbon atoms, and specific examples thereof include a benzyl group and a phenethyl group.

Examples of the substituent for these groups include a hydroxyl group, a carboxyl group, a sulfo group, a cyano group, and a nitro group. Examples of the substituent of the phenyl group which may have 1 to 3 substituents include the same substituents.

Specific examples of the 5-or 6-membered aromatic heterocyclic group which may have 1 to 3 substituents include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl and the like.

The substituents for these groups may be exemplified by the aforementioned Ar₁And Ar₄The substituents in (1) are the same as those in (1).

Specific examples of the 4-to 7-membered alicyclic heterocyclic group which may have 1 or 2 substituents include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidyl, pyrazolidinyl, imidazolidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl and the like.

These groups may be substituted, and the substituents thereof may include, in addition to a hydroxyl group, an oxo group, a carboxyl group, a sulfo group, a cyano group, and a nitro group, the above-mentioned halogen atom, a lower alkoxy group, an alkylsulfonyl group, a lower alkyl group which may have 1 or 2 substituents, an amino group which may have 1 or 2 substituents, a carbamoyl group which may have 1 or 2 substituents, a lower acyl group, and an aminosulfonyl group which may have 1 or 2 substituents.

Specific examples of the 3 to 6-membered substituted or unsubstituted spiro alicyclic alkyl group include cyclopropane spiro group, cyclobutane spiro group, cyclopentane spiro group and cyclohexane spiro group.

These groups may be substituted, and the substituents thereof may include, in addition to hydroxy and oxo, the above-mentioned lower alkoxy group, lower alkyl group which may have 1 or 2 substituents, amino group which may have 1 or 2 substituents, carbamoyl group which may have 1 or 2 substituents, lower acyl group, aminosulfonyl group which may have 1 or 2 substituents.

The 4-to 6-membered substituted or unsubstituted spirocyclic alicyclic heterocyclic group represents a spirocyclic heterocyclic group which may have 1 double bond, and specific examples thereof include azetidine spiro group, pyrrolidine spiro group, piperidine spiro group, piperazine spiro group, pyrazolidine spiro group, imidazoline spiro group, morpholine spiro group, thiomorpholine spiro group and the like.

The substituent for these groups may be exemplified by hydroxy, oxo, carboxy, the above-mentioned lower alkoxy, lower alkyl which may have 1 or 2 substituents, amino which may have 1 or 2 substituents, carbamoyl which may have 1 or 2 substituents, acyl which may have 1 or 2 substituents, aminosulfonyl which may have 1 or 2 substituents.

The compounds (I) and (II) of the present invention are described in more detail below.

Ar in the general formula (I)₁A6-membered aromatic heterocyclic group having 1 to 3 substituents is preferred. Ar (Ar)₁More preferably a pyridyl group having 1 to 3 substituents, a pyridazinyl group having 1 to 3 substituents, a pyrazinyl group having 1 to 3 substituents, particularly preferably a pyridyl group having 1 to 3 substituents or a pyridazinyl group having 1 to 3 substituents.

Ar in the general formula (I)₄Preferably a 6-membered aromatic heterocyclic group which may have 1 to 3 substituents or a phenyl group which may have 1 to 3 substituents. Ar (Ar)₄More preferred are a pyridyl group which may have 1 to 3 substituents, a pyridazinyl group which may have 1 to 3 substituents, a pyrazinyl group which may have 1 to 3 substituents, and a phenyl group which may have 1 to 3 substituents.

From Ar₁Or Ar₄The aromatic heterocyclic group represented by (1-3) substituents are more preferably C_1-6Alkyl, halogen atom, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, and the like.

Ar in the general formula (I)₂More preferred are a pyridyl group which may have 1 to 3 substituents, a pyridazinyl group which may have 1 to 3 substituents, a pyrazinyl group which may have 1 to 3 substituents, a pyrrolyl group which may have 1 to 3 substituents, and a phenyl group which may have 1 to 3 substituents.

Ar in the general formula (II)₃Preferably a 6-membered aromatic heterocyclic ring which may have 1 to 3 substituents, or a benzene ring which may have 1 to 3 substituents. Ar (Ar)₃More preferably a pyridyl group which may have 1 to 3 substituents, a benzene ring which may have 1 to 3 substituents.

Ar in the general formula (I)₁And Ar in the general formula (II)₄Preferred are 3-pyridyl group, 6-methoxy-3-pyridyl group, 6-methyl-3-pyridyl group, 6-ethyl-3-pyridyl group, 6-chloro-3-pyridyl group, 6-ethoxy-3-pyridyl group, 6-isopropoxy-3-pyridyl group, 6-methylamino-3-pyridyl group, 6-cyclopropylamino-3-pyridyl group, 5-methoxy-2-pyridyl group, 6-methoxy-3-pyridazinyl group, 6-methyl-3-pyridazinyl group, 5-methoxy-2-pyrimidinyl group, 5-methyl-2-pyrimidinyl group, 2-methoxy-5-pyrimidinyl group, 2-methyl-5-pyrimidinyl, 5-methoxy-2-pyrazinyl, preferably 6-methoxy-3-pyridinyl, 6-methyl-3-pyridinyl, 5-methoxy-2-pyridinyl, 6-methoxy-3-pyridazinyl, 6-methyl-3-pyridazinyl, 5-methoxy-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 5-methoxy-2-pyrazinyl, 5-methyl-2-pyrazinyl, particularly preferably 6-methoxy-3-pyridinyl, 6-methyl-3-pyridinyl, 5-methoxy-2-pyridinyl, and the like, 6-methoxy-3-pyridazinyl.

Ar₂Preferred is a phenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 2-methylphenyl group, 2-methoxyphenyl group, 2-hydroxyphenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 3-hydroxyphenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-methoxyphenyl group, 4-hydroxyphenyl group, 4-trifluoromethylphenyl group, 4-benzyloxyphenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 6-methoxy-2-pyridyl group, 6-methyl-2-pyridyl group, 6-methoxy-3-pyridyl group, 6-methyl-2-pyridyl group, 2-chlorophenyl group, 3-methoxyphenyl group, 3-pyridyl group, 4-pyridyl group, 6-methoxy-2-pyridyl group, 2-methoxyphenyl group, 2-, 6-methoxy-2-pyridyl group, 6-methyl-2-pyridyl group, 3-methoxy-2-pyridyl group, 3-methyl-2-pyridyl group, 3-fluoro-2-pyridyl group, 4-fluoro-2-pyridyl group, 5-fluoro-2-pyridyl group, 6-fluoro-2-pyridyl group, 4-methyl-2-pyridyl group, 4-ethyl-2-pyridyl group, 4-methoxy-2-pyridyl group, 4-ethoxy-2-pyridyl group, 4-cyano-2-pyridyl group, 4-carbamoyl-2-pyridyl group, 4-pyrrolidinyl-2-pyridyl group, 4-methoxy-2-pyridyl group, 4-ethoxy-2-pyridyl group, 4-cyano-2-pyridyl group, 4-carbamoyl-2-pyridyl group, 4, 4-methylthio-2-pyridyl4-methanesulfonyl-2-pyridyl group, 4-carboxy-2-pyridyl group, 6-methoxy-3-pyridazinyl group, 6-methyl-3-pyridazinyl group, 5-methoxy-2-pyrimidinyl group, 5-methyl-2-pyrimidinyl group, 5-methoxy-2-pyrazinyl group, 5-methyl-2-pyrazinyl group, pyrrol-1-yl group, pyrrol-2-yl group, pyrrol-3-yl group, 1-methylpyrrol-2-yl group, 1-methylpyrrol-3-yl group, 1-ethylpyrrol-2-yl group, 1-ethylpyrrol-3-yl group, more preferably phenyl group, 2-fluorophenyl group, p-tolyl group, p-butyl group, 2-chlorophenyl group, 2-methylphenyl group, 2-methoxyphenyl group, 2-hydroxyphenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 3-hydroxyphenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-hydroxyphenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 6-methoxy-3-pyridyl group, 6-methyl-3-pyridyl group, 6-methoxy-2-pyridyl group, 6-methyl-2-pyridyl group, 3-fluoro-2-pyridyl group, 4-fluoro-2-pyridyl group, 5-fluoro-2-pyridyl group, 2-methylphenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-methylphenyl group, 4, 6-fluoro-2-pyridyl group, 4-methyl-2-pyridyl group, 4-ethyl-2-pyridyl group, 4-methoxy-2-pyridyl group, 4-cyano-2-pyridyl group, 4-carbamoyl-2-pyridyl group, 4-pyrrolidinyl-2-pyridyl group, 3-methoxy-2-pyridyl group, 3-methyl-2-pyridyl group, 6-methoxy-3-pyridazinyl group, 6-methyl-3-pyridazinyl group, 5-methoxy-2-pyrimidinyl group, 5-methyl-2-pyrimidinyl group, 5-methoxy-2-pyrazinyl group, 5-methyl-2-pyrazinyl group, 4-methoxy-2-pyridyl group, 4-methyl-2-pyridyl group, 3, Pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methylpyrrol-2-yl, 1-methylpyrrol-3-yl, 1-ethylpyrrol-2-yl, 1-ethylpyrrol-3-yl.

Ar₃Preferably a benzene ring and a pyridine ring, more preferably a benzene ring.

R1 is represented by the following general formula (1)

When X is a carbonyl group, a thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups, preferably a carbonyl group, a methylene group which may be substituted by 1 or 2 lower alkyl groups, more preferably a carbonyl group.

R4 is represented by the following general formula (2)

When Y is a carbonyl group, a thiocarbonyl group or a methylene group which may be substituted by 1 or 2 lower alkyl groups, preferably a carbonyl group, a methylene group which may be substituted by 1 or 2 lower alkyl groups, more preferably a carbonyl group.

Examples of the cyclic structures a and C in the general formulae (1) and (2) include saturated heterocycles such as an azetidine ring, a pyrrolidine ring, an imidazolidine ring, a pyrazoline ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, a hexahydropyridazine ring, a hexahydropyrimidine ring, a homopiperazine ring and a azepin ring, and unsaturated heterocycles such as a pyrrole ring, a dihydropyrrole ring, an imidazole ring, a dihydroimidazole ring, a pyrazole ring, a dihydropyridine ring, a dihydropyrimidine ring and a dihydropyrazine ring. Among them, preferred are saturated heterocycles such as an azetidine ring, a pyrrolidine ring, an imidazolidine ring, a pyrazoline ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, a hexahydropyridazine ring, a hexahydropyrimidine ring, a homopiperazine ring, and an azepin ring.

In the general formula (1) or (2)

Representative substituents of the groups are shown below.

Examples thereof may include azetidin-1-yl, 3-oxoazetidin-1-yl, 2-oxoazetidin-1-yl, 3-aminoazetidin-1-yl, 3-methylaminoazetidin-1-yl, 3-dimethylaminoazetidin-1-yl, 2-methylazetidin-1-yl, 3-methylazetidin-1-yl, 2-dimethylazetidin-1-yl, 3-dimethylazetidin-1-yl, 2-dimethyl-3-dimethylaminoazetidin-1-yl, 3-dimethylaminomethylazetidin-1-yl, and the like, 3-methoxyazetidin-1-yl, 2-hydroxymethylazetidin-1-yl, 3-hydroxyazetidin-1-yl, 2-carboxyazetidin-1-yl, 3-carboxyazetidin-1-yl, 2-carbamoylazetidin-1-yl, 2-methylcarbamoylazetidin-1-yl, 2-dimethylcarbamoylazetidin-1-yl, 3-carbamoylazetidin-1-yl, 3-methylcarbamoylazetidin-1-yl, 3-dimethylcarbamoylazetidin-1-yl, and mixtures thereof, Pyrrolidinyl, 2-oxopyrrolidinyl, 3-oxopyrrolidinyl, 2, 5-dioxopyrrolidinyl, 3-aminopyrrolidinyl, 3-methylaminopyrrolidinyl, 2-dimethylaminomethylpyrrolidinyl, 3-dimethylaminopyrrolidinyl, 2-methylpyrrolidinyl, 3-methylpyrrolidinyl, 2-dimethylpyrrolidinyl, 3-dimethylpyrrolidinyl, 2-dimethyl-3-dimethylaminopyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-methoxypyrrolidinyl, 2-methoxymethylpyrrolidinyl, 3-methoxymethylpyrrolidinyl, 2-carboxypyrrolidinyl, 3-carboxypyrrolidinyl, and the use thereof, 2-carbamoylpyrrolidinyl, 2-methylcarbamoylpyrrolidinyl, 2-dimethylcarbamoylpyrrolidinyl, 3-carbamoylpyrrolidinyl, 3-methylcarbamoylpyrrolidinyl, 3-dimethylcarbamoylpyrrolidinyl, imidazolidin-1-yl, 3-methylimidazolidin-1-yl, 2-oxoimidazolidin-1-yl, 4-oxoimidazolidin-1-yl, 3-methyl-2-oxoimidazolidin-1-yl, 3-methyl-4-oxoimidazolidin-1-yl, 2-dimethylimidazolidin-1-yl, pyrazolidin-1-yl, 2-methylpyrazolidin-1-yl, pyrazolidin-1-yl, and mixtures thereof, 3-oxopyrazolidin-1-yl, 3, 5-dioxopyrazolin-1-yl, piperidinyl, 2-oxopiperidinyl, 3-oxopiperidinyl, 4-oxopiperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 2-hydroxyiminopiperidinyl, 3-hydroxyiminopiperidinyl, 4-hydroxyiminopiperidinyl, 2-methoxypiperidinyl, 3-methoxypiperidinyl, 4-methoxypiperidinyl, 2-methoxyiminopiperidinyl, 3-methoxyiminopiperidinyl, 4-methoxyiminopiperidinyl, 3-aminopiperidinyl, 4-aminopiperidinyl, 3-methylaminopiperidinyl, 4-methylaminopiperidinyl, 3-dimethylaminopiperidinyl, 3-oxopyrazolyl, piperidine-4-oximinopiperidinyl, piperidine-piperidinyl, piperidine-, 4-dimethylaminopiperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, 2-dimethylpiperidinyl, 3-dimethylpiperidinyl, 4-dimethylpiperidinyl, 4-fluoropiperidinyl, 4-chloropiperidinyl, 3-difluoropiperidinyl, 4-difluoropiperidinyl, 3-dichloropiperidinyl, 4-dichloropiperidinyl, 2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl, 4-hydroxymethylpiperidinyl, 2-carboxypiperidinyl, 3-carboxypiperidinyl, 4-carboxypiperidinyl, 2-carbamoylpiperidinyl, 3-carbamoylpiperidinyl, 4-carbamoylpiperidinyl, 2-methylcarbamoylpiperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-fluoropiperidinyl, 3-chloropiperidinyl, 3, 4-difluoropiperidinyl, 3-, 3-methylcarbamoylpiperidinyl group, 4-methylcarbamoylpiperidinyl group, 2-dimethylcarbamoylpiperidinyl group, 3-dimethylcarbamoylpiperidinyl group, 4-dimethylcarbamoylpiperidinyl group, 2-carboxymethylpiperidinyl group, 3-carboxymethylpiperidinyl group, 4-carboxymethylpiperidinyl group, 2-methoxymethylpiperidinyl group, 3-methoxymethylpiperidinyl group, 4-methoxymethylpiperidinyl group, 2-aminomethylpiperidinyl group, 3-aminomethylpiperidinyl group, 4-aminomethylpiperidinyl group, 2-methylaminomethylpiperidinyl group, 3-methylaminomethylpiperidinyl group, 4-methylaminomethylpiperidinyl group, 2-dimethylaminomethylpiperidinyl group, 3-dimethylaminome, 4-dimethylaminomethylpiperidinyl, 2-aminoethylpiperidinyl, 3-aminoethylpiperidinyl, 4-aminoethylpiperidinyl, 2-methylaminoethylpiperidinyl, 3-methylaminoethylpiperidinyl, 4-methylaminoethylpiperidinyl, 2-dimethylaminoethylpiperidinyl, 3-dimethylaminoethylpiperidinyl, 4-dimethylaminoethylpiperidinyl, piperazinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, 2-oxo-4-methylpiperazinyl, 3-oxo-4-methylpiperazinyl, 4-formylpiperazinyl, 2, 3-dioxopiperazinyl, 3, 5-dioxopiperazinyl, 2, 6-dioxopiperazinyl, 2, 3-dioxo-4-methylpiperazinyl, N-acetylpiperazinyl, N-acetylpiperazin, 3, 5-dioxo-4-methylpiperazinyl, 2, 6-dioxo-4-methylpiperazinyl, 2-methylpiperazinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 2-ethylpiperazinyl, 3-ethylpiperazinyl, 4-ethylpiperazinyl, 2-isopropylpiperazinyl, 3-isopropylpiperazinyl, 4-isopropylpiperazinyl, 2-cyclopropylpiperazinyl, 3-cyclopropylpiperazinyl, 4-cyclobutylpiperazinyl, 2-cyclopropanespiropiperazinyl, 3-cyclopropanespiropiperazinyl, 2-dimethylpiperazinyl, 3-dimethylpiperazinyl, 2, 4-dimethylpiperazinyl, 2, 6-dioxo-4-methylpiperazinyl, 2-isopropylpiperazinyl, 3-isopropylpiperazinyl, 4-isopropylpiperazinyl, 2-cyclopropylpiperazinyl, 3-cyclopropylpiperazinyl, 4-cyclobutylpiperazinyl, 2-cyclopropanespiropiperazinyl, 3, 4-dimethylpiperazinyl group, 3, 5-dimethylpiperazinyl group, 2, 6-dimethylpiperazinyl group, 2-ethyl-4-methylpiperazinyl group, 3-ethyl-4-methylpiperazinyl group, 2-isopropyl-4-methylpiperazinyl group, 3-isopropyl-4-methylpiperazinyl group, 2-cyclopropyl-4-methylpiperazinyl group, 3-methyl-4-benzylpiperazinyl group, 4-phenylpiperazinyl group, 4- (2-pyridyl) piperazinyl group, 1, 2, 6-trimethylpiperazinyl group, 3, 4, 5-trimethylpiperazinyl group, 2, 4-trimethylpiperazinyl group, 3, 4-trimethylpiperazinyl group, 4-dimethylpiperazinyl group, 2, 6-dimethylpiperazinyl group, 3, 3, 3, 4-trimethyl-5-oxopiperazinyl, 2, 4-trimethyl-3-oxopiperazinyl, 2-cyclopropanespiro-4-methylpiperazinyl, 3-cyclopropanespiro-4-methylpiperazinyl, 2-cyclopropanespiro-4-methyl-3-oxopiperazinyl, 3-cyclopropanespiro-4-methyl-5-oxopiperazinyl, 4-acetylpiperazinyl, 4-acetyl-3-cyclopropanespiro piperazinyl, 2-hydroxymethylpiperazinyl, 3-hydroxymethylpiperazinyl, 2-methoxymethylpiperazinyl, 3-methoxymethylpiperazinyl, 2-hydroxyethylpiperazinyl, 3-hydroxyethylpiperazinyl, 2-methoxypiperazinyl, 3-methoxypiperazinyl, 4-isopropylpiperazinyl, 2-isopropylpiperazinyl, 4-hydroxyethylpiperazinyl, 2-hydroxymethyl-4-methylpiperazinyl, 3-hydroxymethyl-4-methylpiperazinyl, 2-methoxymethyl-4-methylpiperazinyl, 3-methoxymethyl-4-methylpiperazinyl, 2-hydroxyethyl-4-methylpiperazinyl, 3-hydroxyethyl-4-methylpiperazinyl, 2-methoxyethyl-4-methylpiperazinyl, 3-methoxyethyl-4-methylpiperazinyl, 2-carbamoylpiperazinyl, 3-carbamoylpiperazinyl, 4-carbamoylpiperazinyl, 2-methylcarbamoylpiperazinyl, 3-methylcarbamoylpiperazinyl, 4-methylcarbamoylpiperazinyl, methyl-carbamoylpiperazinyl, methyl-4-piperazinyl, methyl-, 2-dimethylcarbamoylpiperazinyl, 3-dimethylcarbamoylpiperazinyl, 4-dimethylcarbamoylpiperazinyl, 2-carbamoylmethylpiperazinyl, 3-carbamoylmethylpiperazinyl, 4-carbamoylmethylpiperazinyl, 2-methylcarbamoylmethylpiperazinyl, 3-methylcarbamoylmethylpiperazinyl, 4-methylcarbamoylpiperazinyl, 2-dimethylcarbamoylmethylpiperazinyl, 3-dimethylcarbamoylmethylpiperazinyl, 2-carbamoyl-4-methylpiperazinyl, 3-carbamoyl-4-methylpiperazinyl, 4-carbamoylpiperazinyl, 2-methylcarbamoyl-4-methylpiperazinyl, 3-methylcarbamoyl-4-methylpiperazinyl, 4-methylcarbamoylpiperazinyl, 2-dimethylcarbamoyl-4-methylpiperazinyl, 3-dimethylcarbamoyl-4-methylpiperazinyl, 4-dimethylcarbamoylpiperazinyl, 2-carbamoylmethyl-4-methylpiperazinyl, 3-carbamoylmethyl-4-methylpiperazinyl, 4-carbamoylmethylpiperazinyl, 2-methylcarbamoylmethyl-4-methylpiperazinyl, 3-methylcarbamoylmethyl-4-methylpiperazinyl, 4-methylcarbamoylpiperazinyl, 2-dimethylcarbamoylmethyl-4-methylpiperazinyl, 3-dimethylcarbamoylmethyl-4-methylpiperazinyl, 2-carboxypiperazinyl, 3-carboxypiperazinyl, 2-methoxycarbonylcarboxypiperazinyl, 3-methoxycarbonylcarboxypiperazinyl, 2-ethoxycarboxypiperazinyl, 3-ethoxycarboxypiperazinyl, 2-carboxymethylpiperazinyl, 3-carboxymethylpiperazinyl, 4-carboxymethylpiperazinyl, 2-carboxyethylpiperazinyl, 3-carboxyethylpiperazinyl, 4-carboxy-tert-butylpiperazinyl, 2-methoxycarbonylmethylpiperazinyl, 3-methoxycarbonylmethylpiperazinyl, 4-methoxycarbonylmethylpiperazinyl, 2-ethoxycarbonylmethylpiperazinyl group, 3-ethoxycarbonylmethylpiperazinyl group, 4-ethoxycarbonylmethylpiperazinyl group, 2-carboxy-4-methylpiperazinyl group, 3-carboxy-4-methylpiperazinyl group, 2-carboxymethyl-4-methylpiperazinyl group, 3-carboxymethyl-4-methylpiperazinyl group, 2-methoxycarbonylmethyl-4-methylpiperazinyl group, 3-methoxycarbonylmethyl-4-methylpiperazinyl group, 2-ethoxycarbonylmethyl-4-methylpiperazinyl group, 3-ethoxycarbonylmethyl-4-methylpiperazinyl group, 2-aminomethyl piperazinyl group, 3-aminomethyl piperazinyl group, 2-methylaminomethylpiperazinyl group, 2-ethoxycarbonylmethylpiperazinyl group, 4-ethoxycarbonylmethylpiperazinyl group, 2-aminomethyl piperazinyl, 3-methylaminomethylpiperazinyl group, 2-dimethylaminomethylpiperazinyl group, 3-dimethylaminomethylpiperazinyl group, 2-aminoethylpiperazinyl group, 3-aminoethylpiperazinyl group, 4-aminoethylpiperazinyl group, 2-methylaminoethylpiperazinyl group, 3-methylaminoethylpiperazinyl group, 4-methylaminoethylpiperazinyl group, 2-dimethylaminoethylpiperazinyl group, 3-dimethylaminoethylpiperazinyl group, 4-dimethylaminoethylpiperazinyl group, 2-aminomethyl-4-methylpiperazinyl group, 3-aminomethyl-4-methylpiperazinyl group, 2-methylaminomethyl-4-methylpiperazinyl group, 3-methylaminomethyl-4-methylpiperazinyl group, 2-dimethylaminomethyl-4-methylpiperazinyl group, 2-dimethylaminomethylpiperazinyl group, 3-methylaminomethylpiperazinyl group, 3-methylaminomethyl-4, 3-dimethylaminomethyl-4-methylpiperazinyl, 2-aminoethyl-4-methylpiperazinyl, 3-aminoethyl-4-methylpiperazinyl, 2-methylaminoethyl-4-methylpiperazinyl, 3-methylaminoethyl-4-methylpiperazinyl, 2-dimethylaminoethyl-4-methylpiperazinyl, 3-dimethylaminoethyl-4-methylpiperazinyl, 4-methylsulfonylpiperazinyl, 4-aminosulfonylpiperazinyl, 4- (azetidin-1-yl) piperazinyl, 4-pyrrolidinylpiperazinyl, 4-piperidinylpiperazinyl, morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl, 2-ethylmorpholinyl, methyl-piperazinyl, methyl-4-morpholinyl, methyl-4, 3-ethylmorpholinyl, 2-cyclopropanespiromorpholinyl, 3-cyclopropanespiromorpholinyl, 2-dimethylmorpholinyl, 3-dimethylmorpholinyl, 2-hydroxymethylmorpholinyl, 3-hydroxymethylmorpholinyl, 2-methoxymethylmorpholinyl, 3-methoxymethylmorpholinyl, 2-hydroxyethylmorpholinyl, 2-methoxyethylmorpholinyl, 3-methoxyethylmorpholinyl, 2-carbamoylmorpholinyl, 3-carbamoylmorpholinyl, 2-methylcarbamoylmorpholinyl, 3-methylcarbamoylmorpholinyl, 2-dimethylcarbamoylmorpholinyl, 3-dimethylcarbamoylmorpholinyl, 2-carbamoylmethylmorpholinyl, 2-dimethylcarbamoylmorpholinyl, 2-carbamoylmethylmorpholinyl, 3-dimethylcarbamoylmorpholinyl, 2-carbamoylmethylmorpholinyl, 3-dimethyl, 3-carbamoylmethylmorpholinyl, 2-methylcarbamoylmethylmorpholinyl, 3-methylcarbamoylmethylmorpholinyl, 2-dimethylcarbamoylmethylmorpholinyl, 3-dimethylcarbamoylmethylmorpholinyl, 2-carbamoylethylmorpholinyl, 3-carbamoylethylmorpholinyl, 2-methylcarbamoylethylmorpholinyl, 3-methylcarbamoylethylmorpholinyl, 2-dimethylcarbamoylethylmorpholinyl, 3-dimethylcarbamoylethylmorpholinyl, 2-carboxymorpholinyl, 3-carboxymorpholinyl, 2-methoxycarbonylmorpholinyl, 3-methoxycarbonylmorpholinyl, 2-carboxymethylmorpholinyl, 3-carboxymethylmorpholinyl, 2-methoxycarbonylmethylmorpholinyl, 3-methoxycarbonylmethylmorpholinyl, 2, 3-methoxycarbonylmethylmorpholinyl, 2-ethoxycarbonylmethylmorpholinyl, 3-ethoxycarbonylmethylmorpholinyl, 2-aminomethylmorpholinyl, 3-aminomethylmorpholinyl, 2-methylaminomethylmorpholinyl, 3-methylaminomethylmorpholinyl, 2-dimethylaminomethylmorpholinyl, 3-dimethylaminomethylmorpholinyl, 2-aminoethylmorpholinyl, 3-aminoethylmorpholinyl, 2-methylaminoethylmorpholinyl, 3-methylaminoethylmorpholinyl, 2-dimethylaminoethylmorpholinyl, 3-dimethylaminoethylmorpholinyl, thiomorpholinyl, 3-oxothiomorpholinyl, 1-dioxothiomorpholinyl, 2-methylthiomorpholinyl, 3-methylthiomorpholinyl, 2-methoxycarbonylmethylmorpholinyl, 3-methylthiomorpholinyl, methylthiom, 2-ethylthiomorpholinyl, 3-ethylthiomorpholinyl, 2-cyclopropanespirothiomorpholinyl, 3-cyclopropanespirothiomorpholinyl, 2-dimethylthiomorpholinyl, 3-dimethylthiomorpholinyl, 2-hydroxymethylthiomorpholinyl, 3-hydroxymethylthiomorpholinyl, 2-methoxymethylthiomorpholinyl, 3-methoxymethylthiomorpholinyl, 2-hydroxyethylthiomorpholinyl, 3-methoxyethylthiomorpholinyl, 2-carbamoylthiomorpholinyl, 3-carbamoylthiomorpholinyl, 2-methylcarbamoylthiomorpholinyl, 3-dimethylcarbamoylthiomorpholinyl, 2-dimethylthiomorpholinyl, 2-dimethylthiomorpholin, 2-dimethylcarbamoylthiomorpholinyl, 3-dimethylcarbamoylthiomorpholinyl, 2-carbamoylmethylthiomorpholinyl, 3-carbamoylmethylthiomorpholinyl, 2-methylcarbamoylmethylthiomorpholinyl, 3-methylcarbamoylmethylthiomorpholinyl, 2-dimethylcarbamoylmethylthiomorpholinyl, 3-dimethylcarbamoylmethylthiomorpholinyl, 2-carbamoylethylthiomorpholinyl, 3-carbamoylethylthiomorpholinyl, 2-methylcarbamoylethylthiomorpholinyl, 3-methylcarbamoylethylthiomorpholinyl, 2-dimethylcarbamoylethylthiomorpholinyl, 3-dimethylcarbamoylmethylthiomorpholinyl, 2-, 2-carboxythiomorpholinyl, 3-carboxythiomorpholinyl, 2-methoxycarbonylthiomorpholinyl, 3-methoxycarbonylthiomorpholinyl, 2-carboxymethylthiomorpholinyl, 3-carboxymethylthiomorpholinyl, 2-methoxycarbonylmethylthiomorpholinyl, 3-methoxycarbonylmethylthiomorpholinyl, 2-ethoxycarbonylmethylthiomorpholinyl, 3-ethoxycarbonylmethylthiomorpholinyl, 2-aminomethylthiomorpholinyl, 3-aminomethylthiomorpholinyl, 2-methylaminomethylthiomorpholinyl, 3-methylaminomethylthiomorpholinyl, 2-dimethylaminomethylthiomorpholinyl, 3-dimethylaminomethylthiomorpholinyl, 2-aminoethylthiomorpholinyl, 2-aminocarbonylthiomorpholinyl, 2-aminocarbonylmethylthiomorpholinyl, 2-aminocarbonylthiomorpholinyl, 3-aminoethylthiomorpholinyl, 2-methylaminoethylthiomorpholinyl, 3-methylaminoethylthiomorpholinyl, 2-dimethylaminoethylthiomorpholinyl, 3-dimethylaminoethylthiomorpholinyl, hexahydropyridazin-1-yl, 2-acetylhexahydropyridazin-1-yl, 2-formylhexahydropyridazin-1-yl, 3-oxophexahydropyridazin-1-yl, 6-oxopiperazin-1-yl, 4-aminopiperazin-1-yl, 4-methylaminohexahydropyridazin-1-yl, 4-dimethylaminepyridazin-1-yl, 2-methylhexahydropyridazin-1-yl, 3-methylhexahydropyridazin-1-yl, 4-methylhexahydropyridazin-1-yl, 2, 3-dimethylhexahydropyridazin-1-yl, 3-dimethylhexahydropyridazin-1-yl, 4-dimethylhexahydropyridazin-1-yl, 3-hydroxymethylhexahydropyridazin-1-yl, 4-hydroxymethylhexahydropyridazin-1-yl, 5-hydroxymethylhexahydropyridazin-1-yl, 6-hydroxymethylhexahydropyridazin-1-yl, 2-carbamoylhexahydropyridazin-1-yl, 3-carbamoylhexahydropyridazin-1-yl, 4-carbamoylhexahydropyridazin-1-yl, 5-carbamoylhexahydropyridazin-1-yl, 6-carbamoyl-hexahydropyridazin-1-yl, 2-methylcarbamoyl-hexahydropyridazin-1-yl, 3-methylcarbamoyl-hexahydropyridazin-1-yl, 4-methylcarbamoyl-hexahydropyridazin-1-yl, 5-methylcarbamoyl-hexahydropyridazin-1-yl, 6-methylcarbamoyl-hexahydropyridazin-1-yl, 2-dimethylcarbamoyl-hexahydropyridazin-1-yl, 3-dimethylcarbamoyl-hexahydropyridazin-1-yl, 4-dimethylcarbamoyl-hexahydropyridazin-1-yl, 5-dimethylcarbamoyl-hexahydropyridazin-1-yl, 6-dimethylcarbamoyl-hexahydropyridazin-1-yl, 2-dimethylcarbamoyl-hexahydropyridazin-1-yl, 3-dimethylcarbamoyl-hexahydropyridazin-1-yl, 2-methylcarbamoyl-hexahydropyridazin-1-yl, 3-dimethylcarbamoyl-hexahydro, 3-carboxypiperidin-1-yl, 4-carboxypiperidin-1-yl, 5-carboxypiperidin-1-yl, 6-carboxypiperidin-1-yl, 2-carboxymethylhexahydropyridazin-1-yl, 3-carboxymethylhexahydropyridazin-1-yl, 4-carboxymethylhexahydropyridazin-1-yl, 5-carboxymethylhexahydropyridazin-1-yl, 6-carboxymethylhexahydropyridazin-1-yl, 3-methoxycarbonylhexahydropyridazin-1-yl, 4-methoxycarbonylhexahydropyridazin-1-yl, 5-methoxycarbonylhexahydropyridazin-1-yl, 6-methoxycarbonylhexahydropyridazin-1-yl, 2-methoxycarbonylmethylhexahydropyridazin-1-yl, 3-methoxycarbonylmethylhexahydropyridazin-1-yl, 4-methoxycarbonylmethylhexahydropyridazin-1-yl, 5-methoxycarbonylmethylhexahydropyridazin-1-yl, 6-methoxycarbonylmethylhexahydropyridazin-1-yl, 3-methoxymethylhexahydropyridazin-1-yl, 4-methoxymethylhexahydropyridazin-1-yl, 5-methoxymethylhexahydropyridazin-1-yl, 6-methoxymethylhexahydropyridazin-1-yl, 2-aminoethyl hexahydropyridazin-1-yl, 3-aminoethyl hexahydropyridazin-1-yl, 4-aminoethyl hexahydropyridazin-1-yl, 3-methoxycarbonylmethylhexahydropyridazin-1-yl, 4-methoxycarbonylmethyl-hexahydropyridazin-1-yl, 4-methoxymethyl-methyl-1, 5-aminoethylhexahydropyridazin-1-yl, 6-aminoethylhexahydropyridazin-1-yl, 2-methylaminoethylhexahydropyridazin-1-yl, 3-methylaminoethylhexahydropyridazin-1-yl, 4-methylaminoethylhexahydropyridazin-1-yl, 5-methylaminoethylhexahydropyridazin-1-yl, 6-methylaminoethylhexahydropyridazin-1-yl, 3-aminomethylhexahydropyridazin-1-yl, 4-aminomethylhexahydropyridazin-1-yl, 5-aminomethylhexahydropyridazin-1-yl, 6-aminomethylhexahydropyridazin-1-yl, 3-methylaminomethylhexahydropyridazin-1-yl, N-methylaminoethylhexahydropyridazin, 4-methylaminomethylhexahydropyridazin-1-yl, 5-methylaminomethylhexahydropyridazin-1-yl, 6-methylaminomethylhexahydropyridazin-1-yl, 3-dimethylaminomethylhexahydropyridazin-1-yl, 4-dimethylaminomethylhexahydropyridazin-1-yl, 5-dimethylaminomethylhexahydropyridazin-1-yl, 6-dimethylaminomethylhexahydropyridazin-1-yl, 2-dimethylaminoethylhexahydropyridazin-1-yl, 3-dimethylaminoethylhexahydropyridazin-1-yl, 4-dimethylaminoethylhexahydropyridazin-1-yl, 5-dimethylaminoethylhexahydropyridazin-1-yl, 6-dimethylaminoethyl-hexahydropyridazin-1-yl, hexahydropyrimidin-1-yl, 2-oxohexahydropyrimidin-1-yl, 4-oxohexahydropyrimidin-1-yl, 5-oxohexahydropyrimidin-1-yl, 6-oxohexahydropyrimidin-1-yl, 2-methylhexahydropyrimidin-1-yl, 3-methylhexahydropyrimidin-1-yl, 4-methylhexahydropyrimidin-1-yl, 2-dimethylhexahydropyrimidin-1-yl, 4-dimethylhexahydropyrimidin-1-yl, 5-dimethylhexahydropyrimidin-1-yl, 6-dimethylhexahydropyrimidin-1-yl, 2-oxopiperidin-1-yl, 2-dimethylhexahydropyrimidin-1-yl, 2-oxopiperidine-1-yl, 2-methylhexahydropyrimidin-1-yl, 4-dimethyl, 2-hydroxymethylhexahydropyrimidin-1-yl, 4-hydroxymethylhexahydropyrimidin-1-yl, 5-hydroxymethylhexahydropyrimidin-1-yl, 6-hydroxymethylhexahydropyrimidin-1-yl, 2-carboxyhexahydropyrimidin-1-yl, 4-carboxyhexahydropyrimidin-1-yl, 5-carboxyhexahydropyrimidin-1-yl, 6-carboxyhexahydropyrimidin-1-yl, 2-carbamoylhexahydropyrimidin-1-yl, 3-carbamoylhexahydropyrimidin-1-yl, 4-carbamoylhexahydropyrimidin-1-yl, 5-carbamoylhexahydropyrimidin-1-yl, 6-carbamoylhexahydropyrimidin-1-yl, 2-methylcarbamoylhexahydropyrimidin-1-yl, 3-methylcarbamoylhexahydropyrimidin-1-yl, 4-methylcarbamoylhexahydropyrimidin-1-yl, 5-methylcarbamoylhexahydropyrimidin-1-yl, 6-methylcarbamoylhexahydropyrimidin-1-yl, 2-dimethylcarbamoylhexahydropyrimidin-1-yl, 3-dimethylcarbamoylhexahydropyrimidin-1-yl, 4-dimethylcarbamoylhexahydropyrimidin-1-yl, 5-dimethylcarbamoylhexahydropyrimidin-1-yl, 6-dimethylcarbamoylhexahydropyrimidin-1-yl, 2-carboxymethylhexahydropyrimidin-1-yl, 3-dimethylcarbamoylhexahydropyrimidin-1-yl, 3-carboxymethylhexahydropyrimidin-1-yl, 3-methylcarbamoylhexahydropyrimidin-1-yl, 3-carboxymethylhexahydropyrimidin-1-yl, 4-carboxymethylhexahydropyrimidin-1-yl, 5-carboxymethylhexahydropyrimidin-1-yl, 6-carboxymethylhexahydropyrimidin-1-yl, 2-methoxycarbonylmethylhexahydropyrimidin-1-yl, 3-methoxycarbonylmethylhexahydropyrimidin-1-yl, 4-methoxycarbonylmethylhexahydropyrimidin-1-yl, 5-methoxycarbonylmethylhexahydropyrimidin-1-yl, 6-methoxycarbonylmethylhexahydropyrimidin-1-yl, 3-methoxymethylhexahydropyrimidin-1-yl, 4-methoxymethylhexahydropyrimidin-1-yl, 5-methoxymethylhexahydropyrimidin-1-yl, 6-methoxymethylhexahydropyrimidin-1-yl, 2-aminoethyl hexahydropyrimidin-1-yl, 3-aminoethyl hexahydropyrimidin-1-yl, 4-aminoethyl hexahydropyrimidin-1-yl, 5-aminoethyl hexahydropyrimidin-1-yl, 6-aminoethyl hexahydropyrimidin-1-yl, 2-methylaminoethyl hexahydropyrimidin-1-yl, 3-methylaminoethyl hexahydropyrimidin-1-yl, 4-methylaminoethyl hexahydropyrimidin-1-yl, 5-methylaminoethyl hexahydropyrimidin-1-yl, 6-methylaminoethyl hexahydropyrimidin-1-yl, 2-dimethylaminoethyl hexahydropyrimidin-1-yl, and mixtures thereof, 3-dimethylaminoethyl hexahydropyrimidin-1-yl, 4-dimethylaminoethyl hexahydropyrimidin-1-yl, 5-dimethylaminoethyl hexahydropyrimidin-1-yl, 6-dimethylaminoethyl hexahydropyrimidin-1-yl, homopiperazinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, 5-oxopiperazinyl, 6-oxopiperazinyl, 7-oxopiperazinyl, 2-oxo-4-methylpiperazinyl, 3-oxo-4-methylpiperazinyl, 5-oxo-4-methylpiperazinyl, 6-oxo-4-methylpiperazinyl, 7-oxo-4-methylpiperazinyl, 2, 3-dioxohomopiperazinyl, 2, 7-dioxohomopiperazinyl, 3, 5-dioxohomopiperazinyl, 3, 7-dioxohomopiperazinyl, 2, 3-dioxo-4-methylpiperazinyl, 2, 7-dioxo-4-methylpiperazinyl, 3, 5-dioxo-4-methylpiperazinyl, 3, 7-dioxo-4-methylpiperazinyl, 2-methylpiperazinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 5-methylpiperazinyl, 6-methylpiperazinyl, 7-methylpiperazinyl, 2-ethylpiperazinyl, 3-ethylpiperazinyl, 4-ethylpiperazinyl, 5-ethylpiperazinyl, 6-ethylpiperazinyl, 7-ethylpiperazino, 4-cyclopropylhomopiperazino, 2-cyclopropanespirohomopiperazino, 3-cyclopropanespirohomopiperazino, 5-cyclopropanespirohomopiperazino, 6-cyclopropanespirohomopiperazino, 7-cyclopropanespirohomopiperazino, 2-cyclopropanespiro-4-methylpiperazino, 3-cyclopropanespiro-4-methylpiperazino, 5-cyclopropanespiro-4-methylpiperazino, 6-cyclopropanespiro-4-methylpiperazino, 7-cyclopropanespiro-4-methylpiperazino, 2-cyclopropanespiro-4-methyl-3-oxohomopiperazino, 2-cyclopropanespiro-4-methyl-5-oxohomopiperazino, 2-cyclopropanespiro-4-methyl-7-oxohomopiperazinyl, 3-cyclopropanespiro-4-methyl-2-oxohomopiperazinyl, 3-cyclopropanespiro-4-methyl-5-oxohomopiperazinyl, 3-cyclopropanespiro-4-methyl-7-oxohomopiperazinyl, 5-cyclopropanespiro-4-methyl-2-oxohomopiperazinyl, 5-cyclopropanespiro-4-methyl-3-oxohomopiperazinyl, 5-cyclopropanespiro-4-methyl-7-oxohomopiperazinyl, 6-cyclopropanespiro-4-methyl-2-oxohomopiperazinyl, 6-cyclopropanespiro-4-methyl-3-oxohomopiperazinyl, thiopiperazinyl, and the like, 6-cyclopropanespiro-4-methyl-5-oxohomopiperazinyl group, 6-cyclopropanespiro-4-methyl-7-oxohomopiperazinyl group, 7-cyclopropanespiro-4-methyl-2-oxohomopiperazinyl group, 7-cyclopropanespiro-4-methyl-3-oxohomopiperazinyl group, 7-cyclopropanespiro-4-methyl-5-oxohomopiperazinyl group, 2-dimethylhomopiperazinyl group, 3-dimethylhomopiperazinyl group, 5-dimethylhomopiperazinyl group, 6-dimethylhomopiperazinyl group, 7-dimethylhomopiperazinyl group, 2, 3-dimethylhomopiperazinyl group, 2, 4-dimethylhomopiperazinyl group, 3, 4-dimethylhomopiperazinyl group, 2, 4-dimethylhomopiperazinyl group, 6-dimethylhomopiperazinyl group, 7-dimethylhomopiperazinyl group, 3, 5-dimethylpiperazino group, 3, 4, 5-trimethylpiperazino group, 2-hydroxymethylhomopiperazino group, 3-hydroxymethylhomopiperazino group, 5-hydroxymethylhomopiperazino group, 6-hydroxymethylhomopiperazino group, 7-hydroxymethylhomopiperazino group, 2-hydroxymethyl-4-methylpiperazino group, 3-hydroxymethyl-4-methylpiperazino group, 5-hydroxymethyl-4-methylpiperazino group, 6-hydroxymethyl-4-methylpiperazino group, 7-hydroxymethyl-4-methylpiperazino group, 2-methoxymethylpiperazino group, 3-methoxymethylpiperazino group, 5-methoxymethylpiperazino group, 6-methoxymethylpiperazino group, homopiperazino group, 2-methoxymethylpiperazino group, 3-methoxymethylpiperazino group, homopiperazino, 7-methoxymethyl homopiperazinyl group, 2-methoxymethyl-4-methylpiperazinyl group, 3-methoxymethyl-4-methylpiperazinyl group, 5-methoxymethyl-4-methylpiperazinyl group, 6-methoxymethyl-4-methylpiperazinyl group, 7-methoxymethyl-4-methylpiperazinyl group, 2-hydroxyethyl homopiperazinyl group, 3-hydroxyethyl homopiperazinyl group, 4-hydroxyethyl homopiperazinyl group, 5-hydroxyethyl homopiperazinyl group, 6-hydroxyethyl homopiperazinyl group, 7-hydroxyethyl homopiperazinyl group, 2-hydroxyethyl-4-methylpiperazinyl group, 3-hydroxyethyl-4-methylpiperazinyl group, 5-hydroxyethyl-4-methylpiperazinyl group, 6-hydroxyethyl-4-methylpiperazino group, 7-hydroxyethyl-4-methylpiperazino group, 2-methoxyethylpiperazino group, 3-methoxyethylpiperazino group, 4-methoxyethylpiperazino group, 5-methoxyethylpiperazino group, 6-methoxyethylpiperazino group, 7-methoxyethylpiperazino group, 2-methoxyethyl-4-methylpiperazino group, 3-methoxyethyl-4-methylpiperazino group, 5-methoxyethyl-4-methylpiperazino group, 6-methoxyethyl-4-methylpiperazino group, 7-methoxyethyl-4-methylpiperazino group, 2-carbamoyl homopiperazino group, 3-carbamoyl homopiperazinyl group, 4-carbamoyl homopiperazinyl group, 5-carbamoyl homopiperazinyl group, 6-carbamoyl homopiperazinyl group, 7-carbamoyl homopiperazinyl group, 2-carbamoyl-4-methyl homopiperazinyl group, 3-carbamoyl-4-methyl homopiperazinyl group, 4-carbamoyl homopiperazinyl group, 5-carbamoyl-4-methyl homopiperazinyl group, 6-carbamoyl-4-methyl homopiperazinyl group, 7-carbamoyl-4-methyl homopiperazinyl group, 2-methylcarbamoyl homopiperazinyl group, 3-methylcarbamoyl homopiperazinyl group, 4-methylcarbamoyl homopiperazinyl group, 5-methylcarbamoyl homopiperazinyl group, 4-methyl carbamoyl homopiperazinyl group, methyl piperazine group, methyl, 6-methylcarbamoyl homopiperazinyl, 7-methylcarbamoyl homopiperazinyl, 2-methylcarbamoyl-4-methyl homopiperazinyl, 3-methylcarbamoyl-4-methyl homopiperazinyl, 5-methylcarbamoyl-4-methyl homopiperazinyl, 6-methylcarbamoyl-4-methyl homopiperazinyl, 7-methylcarbamoyl-4-methyl homopiperazinyl, 2-dimethylcarbamoyl homopiperazinyl, 3-dimethylcarbamoyl homopiperazinyl, 4-dimethylcarbamoyl homopiperazinyl, 5-dimethylcarbamoyl homopiperazinyl, 6-dimethylcarbamoyl homopiperazinyl, 7-dimethylcarbamoyl homopiperazinyl, methyl-substituted homopiperazinyl, methyl-, 2-dimethylcarbamoyl-4-methylpiperazino group, 3-dimethylcarbamoyl-4-methylpiperazino group, 5-dimethylcarbamoyl-4-methylpiperazino group, 6-dimethylcarbamoyl-4-methylpiperazino group, 7-dimethylcarbamoyl-4-methylpiperazino group, 2-carboxypiperazino group, 3-carboxypiperazino group, 5-carboxypiperazino group, 6-carboxypiperazino group, 7-carboxypiperazino group, 2-carboxy-4-methylpiperazino group, 3-carboxy-4-methylpiperazino group, 5-carboxy-4-methylpiperazino group, 6-carboxy-4-methylpiperazino group, 7-carboxy-4-methylpiperazino group, 2-carboxymethyl homopiperazino group, 3-carboxymethyl homopiperazino group, 4-carboxymethyl homopiperazino group, 5-carboxymethyl homopiperazino group, 6-carboxymethyl homopiperazino group, 7-carboxymethyl homopiperazino group, 2-carboxymethyl-4-methyl homopiperazino group, 3-carboxymethyl-4-methyl homopiperazino group, 5-carboxymethyl-4-methyl homopiperazino group, 6-carboxymethyl-4-methyl homopiperazino group, 7-carboxymethyl-4-methyl homopiperazino group, 2-methoxycarbonylmethyl homopiperazino group, 3-methoxycarbonylmethyl homopiperazino group, 4-methoxycarbonylmethyl homopiperazino group, 5-methoxycarbonylmethyl homopiperazino group, 2-carboxymethyl homopiperazino group, 6-methoxycarbonylmethyl homopiperazinyl, 7-methoxycarbonylmethyl homopiperazinyl, 2-methoxycarbonylmethyl-4-methyl homopiperazinyl, 3-methoxycarbonylmethyl-4-methyl homopiperazinyl, 5-methoxycarbonylmethyl-4-methyl homopiperazinyl, 6-methoxycarbonylmethyl-4-methyl homopiperazinyl, 7-methoxycarbonylmethyl-4-methyl homopiperazinyl, 2-ethoxycarbonylmethyl homopiperazinyl, 3-ethoxycarbonylmethyl homopiperazinyl, 4-ethoxycarbonylmethyl homopiperazinyl, 5-ethoxycarbonylmethyl homopiperazinyl, 6-ethoxycarbonylmethyl homopiperazinyl, 7-ethoxycarbonylmethyl homopiperazinyl, 2-ethoxycarbonylmethyl-4-methyl homopiperazinyl, methyl homopiperazinyl, 3-ethoxycarbonylmethyl-4-methylpiperazinyl, 5-ethoxycarbonylmethyl-4-methylpiperazinyl, 6-ethoxycarbonylmethyl-4-methylpiperazinyl, 7-ethoxycarbonylmethyl-4-methylpiperazinyl, 2-carbamoylmethyl homopiperazinyl, 3-carbamoylmethyl homopiperazinyl, 4-carbamoylmethyl homopiperazinyl, 5-carbamoylmethyl homopiperazinyl, 6-carbamoylmethyl homopiperazinyl, 7-carbamoylmethyl homopiperazinyl, 2-carbamoylmethyl-4-methylpiperazinyl, 3-carbamoylmethyl-4-methylpiperazinyl, 5-carbamoylmethyl-4-methylpiperazinyl, methyl-4-piperazinyl, methyl-4-pipera, 6-carbamoylmethyl-4-methylpiperazino-group, 7-carbamoylmethyl-4-methylpiperazino-group, 2-methylcarbamoylmethyl homopiperazino-group, 3-methylcarbamoylmethyl homopiperazino-group, 4-methylcarbamoylhomopiperazino-group, 5-methylcarbamoylhomopiperazino-group, 6-methylcarbamoylhomopiperazino-group, 7-methylcarbamoylhomopiperazino-group, 2-methylcarbamoylmethyl-4-methylpiperazino-group, 3-methylcarbamoylmethyl-4-methylpiperazino-group, 5-methylcarbamoyl-4-methylpiperazino-group, 6-methylcarbamoyl-4-methylpiperazino-group, 7-methylcarbamoyl-4-methylpiperazino-group, 2-dimethylcarbamoylmethyl homopiperazinyl group, 3-dimethylcarbamoylmethyl homopiperazinyl group, 4-dimethylcarbamoylmethyl homopiperazinyl group, 5-dimethylcarbamoylmethyl homopiperazinyl group, 6-dimethylcarbamoylmethyl homopiperazinyl group, 7-dimethylcarbamoylmethyl homopiperazinyl group, 2-dimethylcarbamoylmethyl-4-methyl homopiperazinyl group, 3-dimethylcarbamoylmethyl-4-methyl homopiperazinyl group, 5-dimethylcarbamoylmethyl-4-methyl homopiperazinyl group, 6-dimethylcarbamoylmethyl-4-methyl homopiperazinyl group, 7-dimethylcarbamoylmethyl-4-methyl homopiperazinyl group, 2-aminomethyl homopiperazinyl group, 2-dimethylcarbamoylmethyl homopiperazinyl group, methyl group, 3-aminomethyl homopiperazinyl group, 5-aminomethyl homopiperazinyl group, 6-aminomethyl homopiperazinyl group, 7-aminomethyl homopiperazinyl group, 2-aminomethyl-4-methyl homopiperazinyl group, 3-aminomethyl-4-methyl homopiperazinyl group, 5-aminomethyl-4-methyl homopiperazinyl group, 6-aminomethyl-4-methyl homopiperazinyl group, 7-aminomethyl-4-methyl homopiperazinyl group, 2-methylaminomethyl homopiperazinyl group, 3-methylaminomethyl homopiperazinyl group, 4-methylaminomethyl homopiperazinyl group, 5-methylaminomethyl homopiperazinyl group, 6-methylaminomethyl homopiperazinyl group, 7-methylaminomethyl homopiperazinyl group, 2-methylaminomethyl-4-methyl homopiperazinyl group, 6-aminomethyl homopiperazinyl group, 7-methylaminomethyl homopiperazinyl group, 2-methylaminomethyl-4-methyl homop, 3-methylaminomethyl-4-methylpiperazinyl group, 5-methylaminomethyl-4-methylpiperazinyl group, 6-methylaminomethyl-4-methylpiperazinyl group, 7-methylaminomethyl-4-methylpiperazinyl group, 2-dimethylaminomethyl homopiperazinyl group, 3-dimethylaminomethyl homopiperazinyl group, 4-dimethylaminomethyl homopiperazinyl group, 5-dimethylaminomethyl homopiperazinyl group, 6-dimethylaminomethyl homopiperazinyl group, 7-dimethylaminomethyl homopiperazinyl group, 2-dimethylaminomethyl-4-methylpiperazinyl group, 3-dimethylaminomethyl-4-methylpiperazinyl group, 5-dimethylaminomethyl-4-methylpiperazinyl group, methyl-4-methylp, 6-dimethylaminomethyl-4-methylpiperazino-group, 7-dimethylaminomethyl-4-methylpiperazino-group, 2-aminoethyl homopiperazino-group, 3-aminoethyl homopiperazino-group, 4-aminoethyl homopiperazino-group, 5-aminoethyl homopiperazino-group, 6-aminoethyl homopiperazino-group, 7-aminoethyl homopiperazino-group, 2-aminoethyl-4-methylpiperazino-group, 3-aminoethyl-4-methylpiperazino-group, 5-aminoethyl-4-methylpiperazino-group, 6-aminoethyl-4-methylpiperazino-group, 7-aminoethyl-4-methylpiperazino-group, 2-methylaminoethyl homopiperazino-group, 3-methylaminoethyl homopiperazino-group, methyl homopiperazin, 4-methylaminoethyl homopiperazinyl group, 5-methylaminoethyl homopiperazinyl group, 6-methylaminoethyl homopiperazinyl group, 7-methylaminoethyl homopiperazinyl group, 2-methylaminoethyl-4-methyl homopiperazinyl group, 3-methylaminoethyl-4-methyl homopiperazinyl group, 5-methylaminoethyl-4-methyl homopiperazinyl group, 6-methylaminoethyl-4-methyl homopiperazinyl group, 7-methylaminoethyl-4-methyl homopiperazinyl group, 2-dimethylaminoethyl homopiperazinyl group, 3-dimethylaminoethyl homopiperazinyl group, 4-dimethylaminoethyl homopiperazinyl group, 5-dimethylaminoethyl homopiperazinyl group, 6-dimethylaminoethyl homopiperazinyl group, 7-dimethylaminoethyl homopiperazinyl, 2-dimethylaminoethyl-4-methylpiperazinyl, 3-dimethylaminoethyl-4-methylpiperazinyl, 5-dimethylaminoethyl-4-methylpiperazinyl, 6-dimethylaminoethyl-4-methylpiperazinyl, 7-dimethylaminoethyl-4-methylpiperazinyl, 4-methanesulfonyl homopiperazinyl, 4-methanesulfonyl aminopiperazinyl, 4- (azetidin-1-yl) homopiperazinyl, 4-pyrrolidinyl homopiperazinyl, 4-piperidinyl homopiperazinyl, 1, 4-oxazepan-4-yl, spiro [ azetidin-3, 2 '-1' -methylazetidin ] -1-yl, spiro (N-methyl-3, 2 '-1' -methyl-azetidinyl), Spiro [ piperidine-4, 2 '-1' -methylazetidin ] -1-yl, spiro [ piperidine-2, 3 '-1' -methylpyrrolidine ] -1-yl, spiro [ morpholine-3, 3 '-1' -methylazetidin ] -4-yl, spiro [ morpholine-3, 3 '-1' -methylpyrrolidine ] -4-yl, spiro [ piperazine-3-cyclopropane ] -1-yl, spiro [ 4-methylpiperazin-3-cyclopropane ] -1-yl and the like are typical examples.

Preferable groups among these groups are as follows.

Preferable examples of the group include azetidin-1-yl, 3-dimethylaminoazetidin-1-yl, 2-methylazetidin-1-yl, 3-methylazetidin-1-yl, 2-dimethylazetidin-1-yl, 3-dimethylazetidin-1-yl, 2-dimethyl-3-dimethylaminoazetidin-1-yl, 2-hydroxymethylazetidin-1-yl, 3-hydroxymethylazetidin-1-yl, 2-carbamoylazetidin-1-yl, 2-methylcarbamoylazetidin-1-yl, and, 2-dimethylcarbamoylazetidin-1-yl, pyrrolidinyl, 2-oxopyrrolidinyl, 2-dimethylaminomethylpyrrolidinyl, 3-dimethylaminomethylpyrrolidinyl, 2, 5-dioxopyrrolidinyl, 2-methylpyrrolidinyl, 3-methylpyrrolidinyl, 2-dimethylpyrrolidinyl, 3-dimethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3-methoxypyrrolidinyl, 2-methoxymethylpyrrolidinyl, 3-methoxymethylpyrrolidinyl, 2-carbamoylpyrrolidinyl, 2-methylcarbamoylpyrrolidinyl, 2-dimethylcarbamoylpyrrolidinyl, 2-oxoimidazolidin-1-yl, methyl-2-oxopyrrolidinyl, methyl-1-yl, methyl-2-oxopyrrolidin, 4-oxoimidazolidin-1-yl, 3-methyl-2-oxoimidazolidin-1-yl, 3-methyl-4-oxoimidazolidin-1-yl, 2-methylpyrazolidin-1-yl, 3-oxopyrazolidin-1-yl, 3, 5-dioxopyrazolidin-1-yl, piperidinyl, 2-oxopiperidinyl, 3-oxopiperidinyl, 4-oxopiperidinyl, 2-hydroxyiminopiperidinyl, 3-hydroxyiminopiperidinyl, 4-hydroxyiminopiperidinyl, 2-methoxypiperidinyl, 3-methoxypiperidinyl, 4-methoxypiperidinyl, 2-methoxyiminopiperidinyl, 3-methoxyiminopiperidinyl, 4-methoxyiminopiperidinyl group, 2-methylpiperidinyl group, 3-methylpiperidinyl group, 4-methylpiperidinyl group, 2-dimethylpiperidinyl group, 3-dimethylpiperidinyl group, 4-dimethylpiperidinyl group, 4-fluoropiperidinyl group, 4-chloropiperidinyl group, 3-difluoropiperidinyl group, 4-difluoropiperidinyl group, 3-dichloropiperidinyl group, 4-dichloropiperidinyl group, 2-hydroxymethylpiperidinyl group, 2-carbamoylpiperidinyl group, 2-methylcarbamoylpiperidinyl group, 2-dimethylcarbamoylpiperidinyl group, 2-carboxymethylpiperidinyl group, 2-methoxymethylpiperidinyl group, 2-aminomethylpiperidinyl group, 2-dimethylaminomethylpiperidinyl group, 3-dimethylpiperidinyl group, 4-dimethylpiperidinyl group, 2-aminoethylpiperidinyl, 2-methylaminoethylpiperidinyl, 2-dimethylaminoethylpiperidinyl, 2-oxo-4-methylpiperidinyl, 3-oxo-4-methylpiperidinyl, 4-formylpiperazinyl, 2, 3-dioxo-4-methylpiperazinyl, 3, 5-dioxo-4-methylpiperazinyl, 2, 6-dioxo-4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 2, 4-dimethylpiperazinyl, 3, 4-dimethylpiperazinyl, 2-ethyl-4-methyl-piperazinyl, 3-ethyl-4-methylpiperazinyl, 2-isopropyl-4-methylpiperazinyl, N-methyl-piperidinyl, N-ethyl-4-methylpiperazinyl, N-methyl-piperidinyl, N-methyl-piperazinyl, 3-isopropyl-4-methylpiperazinyl, 2-cyclopropyl-4-methylpiperazinyl, 3, 4, 5-trimethylpiperazinyl, 2, 4-trimethylpiperazinyl, 3, 4-trimethyl-5-oxopiperazinyl, 2, 4-trimethyl-3-oxopiperazinyl, 2-cyclopropanespiro-4-methylpiperazinyl, 3-cyclopropanespiro-4-methylpiperazinyl, 2-cyclopropanespiro-4-methyl-3-oxopiperazinyl, 3-cyclopropanespiro-4-methyl-5-oxopiperazinyl, 4-acetyl-3-cyclopropanespiro piperazinyl, 3-cyclopropanespiro-4-methyl-5-oxopiperazinyl, 4-acetyl-3-piperazinyl, 2-hydroxymethyl-4-methylpiperazinyl, 3-hydroxymethyl-4-methylpiperazinyl, 2-methoxymethyl-4-methylpiperazinyl, 3-methoxymethyl-4-methylpiperazinyl, 2-hydroxyethyl-4-methylpiperazinyl, 3-hydroxyethyl-4-methylpiperazinyl, 2-methoxyethyl-4-methylpiperazinyl, 3-methoxyethyl-4-methylpiperazinyl, 2-carbamoyl-4-methylpiperazinyl, 3-carbamoyl-4-methylpiperazinyl, 4-carbamoyl-piperazinyl, 2-methylcarbamoyl-4-methylpiperazinyl, 3-methylcarbamoyl-4-methylpiperazinyl, 2-methylcarbamoyl-4-methylpiperazinyl, methyl-4, 4-methylcarbamoylpiperazinyl, 2-dimethylcarbamoyl-4-methylpiperazinyl, 3-dimethylcarbamoyl-4-methylpiperazinyl, 4-dimethylcarbamoylpiperazinyl, 2-carbamoylmethyl-4-methylpiperazinyl, 3-carbamoylmethyl-4-methylpiperazinyl, 4-carbamoylmethylpiperazinyl, 2-methylcarbamoylmethyl-4-methylpiperazinyl, 3-methylcarbamoylmethyl-4-methylpiperazinyl, 4-methylcarbamoylpiperazinyl, 2-dimethylcarbamoylmethyl-4-methylpiperazinyl, 3-dimethylcarbamoylmethyl-4-methylpiperazinyl, 2-carboxy-4-methylpiperazinyl, 2-carboxymethyl-4-methylpiperazinyl, 2-methoxycarbonylmethyl-4-methylpiperazinyl, 3-methoxycarbonylmethyl-4-methylpiperazinyl, 2-ethoxycarbonylmethyl-4-methylpiperazinyl, 3-ethoxycarbonylmethyl-4-methylpiperazinyl, 2-aminomethyl-4-methylpiperazinyl, 2-methylaminomethyl-4-methylpiperazinyl, 2-dimethylaminomethyl-4-methylpiperazinyl, 2-aminoethyl-4-methylpiperazinyl, 2-methylaminoethyl-4-methylpiperazinyl, 2-dimethylaminoethyl-4-methylpiperazinyl, methyl piperazine, methyl, Morpholinyl, 2-methylmorpholinyl, 3-methylmorpholinyl, 2-ethylmorpholinyl, 3-ethylmorpholinyl, 2-cyclopropanespiromorpholinyl, 3-cyclopropanespiromorpholinyl, 2-dimethylmorpholinyl, 3-dimethylmorpholinyl, 3-hydroxymethylmorpholinyl, 3-methoxymethylmorpholinyl, 3-hydroxyethylmorpholinyl, 3-methoxyethylmorpholinyl, 3-carbamoylmorpholinyl, 3-methylcarbamoylmorpholinyl, 3-dimethylcarbamoylmorpholinyl, 3-carbamoylmethylmorpholinyl, 3-methylcarbamoylmethylmorpholinyl, 3-dimethylcarbamoylmethylmorpholinyl, 3-carbamoylethylmorpholinyl, 3-methylcarbamoylethylmorpholinyl, 3-dimethylcarbamoylmethylmorpholinyl, 3-carbamoylethylmorpholinyl, 3-methylcarbamoylethylmorpholinyl, 3-dimethylcarbamoylethylmorpholinyl, 3-methoxycarbonylmorpholinyl, 3-methoxycarbonylmethylmorpholinyl, 3-ethoxycarbonylmethylmorpholinyl, 3-aminomethylmorpholinyl, 3-methylaminomethylmorpholinyl, 3-dimethylaminomethylmorpholinyl, 3-aminoethyl morpholinyl, 3-methylaminoethylmorpholinyl, 3-dimethylaminoethylmorpholinyl, thiomorpholinyl, 3-oxothiomorpholinyl, 1-dioxothiomorpholinyl, 2-methylthiomorpholinyl, 3-methylthiomorpholinyl, 2-ethylthiomorpholinyl, 3-ethylthiomorpholinyl, 2-cyclopropanespirothiomorpholinyl, 3-cyclopropanespirothiomorpholinyl, 2-dimethylthiomorpholinyl, 2-methoxycarbonylmethylmorpholinyl, 3-ethoxycarbonylmethylmorpholinyl, 3-dimethylaminoethylmorpholinyl, 2-, 3, 3-dimethylthiomorpholinyl, 3-hydroxymethylthiomorpholinyl, 3-methoxymethylthiomorpholinyl, 3-hydroxyethylthiomorpholinyl, 3-methoxyethylthiomorpholinyl, 3-carbamoylthiomorpholinyl, 3-methylcarbamoylthiomorpholinyl, 3-dimethylcarbamoylthiomorpholinyl, 3-carbamoylmethylthiomorpholinyl, 3-methylcarbamoylmethylthiomorpholinyl, 3-dimethylcarbamoylmethylthiomorpholinyl, 3-methylcarbamoylethylthiomorpholinyl, 3-dimethylcarbamoylethylthiomorpholinyl, 3-methoxycarbonylthiomorpholinyl, 3-methoxycarbonylmethylthiomorpholinyl, and, 3-ethoxycarbonylmethylthiomorpholinyl, 2-acetylhexahydropyridazin-1-yl, 2-formylhexahydropyridazin-1-yl, 3-oxohexahydropyridazin-1-yl, 6-oxohexahydropyridazin-1-yl, 2, 3-dimethylhexahydropyridazin-1-yl, 3-hydroxymethylhexahydropyridazin-1-yl, 5-hydroxymethylhexahydropyridazin-1-yl, 6-hydroxymethylhexahydropyridazin-1-yl, 2-carbamoylhexahydropyridazin-1-yl, 2-methylcarbamoylhexahydropyridazin-1-yl, 2-dimethylcarbamoylhexahydropyridazin-1-yl, 2-oxohexahydropyrimidin-1-yl, 4-oxohexahydropyrimidin-1-yl, 6-oxohexahydropyrimidin-1-yl, 2-methylhexahydropyrimidin-1-yl, 3-carbamoylhexahydropyrimidin-1-yl, 3-methylcarbamoylhexahydropyrimidin-1-yl, 3-dimethylcarbamoylhexahydropyrimidin-1-yl, 2-oxo-4-methylpiperazino, 3-oxo-4-methylpiperazino, 5-oxo-4-methylpiperazino, 6-oxo-4-methylpiperazino, 7-oxo-4-methylpiperazino, 2, 3-dioxohomopiperazino, 2-dioxohomopiperazino, and, 2, 7-dioxohomopiperazinyl, 3, 5-dioxohomopiperazinyl, 3, 7-dioxohomopiperazinyl, 2, 3-dioxo-4-methylpiperazinyl, 2, 7-dioxo-4-methylpiperazinyl, 3, 5-dioxo-4-methylpiperazinyl, 3, 7-dioxo-4-methylpiperazinyl, 4-ethylpiperazinyl, 4-cyclopropylhomopiperazinyl, 2-cyclopropanespirohomopiperazinyl, 3-cyclopropanespirohomopiperazinyl, 5-cyclopropanespirohomopiperazinyl, 6-cyclopropanespirohomopiperazinyl, 7-cyclopropanespirohomopiperazinyl, 2, 4-dimethylpiperazinyl, 3, 4-dimethylpiperazinyl, homopiperazinyl, 3, 4, 5-trimethyl homopiperazinyl, 2-hydroxymethyl-4-methyl homopiperazinyl, 7-hydroxymethyl-4-methyl homopiperazinyl, 2-methoxymethyl-4-methyl homopiperazinyl, 3-methoxymethyl-4-methyl homopiperazinyl, 5-methoxymethyl-4-methyl homopiperazinyl, 6-methoxymethyl-4-methyl homopiperazinyl, 7-methoxymethyl-4-methyl homopiperazinyl, 2-hydroxyethyl-4-methyl homopiperazinyl, 7-hydroxyethyl-4-methyl homopiperazinyl, 2-methoxyethyl-4-methyl homopiperazinyl, 3-methoxyethyl-4-methyl homopiperazinyl, methyl homopiperazin, 5-methoxyethyl-4-methylpiperazinyl group, 6-methoxyethyl-4-methylpiperazinyl group, 7-methoxyethyl-4-methylpiperazinyl group, 2-carbamoyl-4-methylpiperazinyl group, 7-carbamoyl-4-methylpiperazinyl group, 2-methylcarbamoyl-4-methylpiperazinyl group, 7-methylcarbamoyl-4-methylpiperazinyl group, 2-dimethylcarbamoyl-homopiperazinyl group, 7-dimethylcarbamoyl-homopiperazinyl group, 2-carboxy-homopiperazinyl group, 7-carboxy-homopiperazinyl group, 2-carboxy-4-methylpiperazinyl group, 7-carboxy-4-methylpiperazinyl group, 2-carboxymethyl-4-methylpiperazino group, 7-carboxymethyl-4-methylpiperazino group, 1, 4-oxazepan-4-yl group and the like.

Among them, more preferable groups are as follows.

More preferred groups are azetidin-1-yl, 3-dimethylaminoazetidin-1-yl, 2-dimethyl-3-dimethylaminoazetidin-1-yl, 2-hydroxymethylazetidin-1-yl, 2-carbamoylazetidin-1-yl, 2-methylcarbamoylazetidin-1-yl, 2-dimethylcarbamoylazetidin-1-yl, pyrrolidinyl, 2-oxopyrrolidinyl, 2, 5-dioxopyrrolidinyl, 2-methylpyrrolidinyl, 3-methylpyrrolidinyl, 2-dimethylpyrrolidinyl, 3-dimethylpyrrolidinyl, 2-dimethylaminomethylpyrrolidinyl, p, 3-dimethylaminomethylpyrrolidinyl group, 2-hydroxymethylpyrrolidinyl group, 3-methoxymethylpyrrolidinyl group, 2-carbamoylpyrrolidinyl group, 2-methylcarbamoylpyrrolidinyl group, 2-dimethylcarbamoylpyrrolidinyl group, 3-methyl-2-oxoimidazolidin-1-yl group, 3-methyl-4-oxoimidazolidin-1-yl group, piperidinyl group, 2-oxopiperidinyl group, 2-methoxypiperidinyl group, 3-methoxypiperidinyl group, 4-methoxypiperidinyl group, 2-hydroxymethylpiperidinyl group, 2-carbamoylpiperidinyl group, 2-methylcarbamoylpiperidinyl group, 2-dimethylcarbamoylpiperidinyl group, 2-methoxymethylpiperidinyl group, 3-methylcarbamoylpyrrolidinyl group, 2-dimethylcarbamoylpiperidinyl group, 2-methoxymethylp, 2-aminomethylpiperidinyl, 2-methylaminomethylpiperidinyl, 2-dimethylaminomethylpiperidinyl, 2-aminoethylpiperidinyl, 2-methylaminoethylpiperidinyl, 2-dimethylaminoethylpiperidinyl, 4-fluoropiperidinyl, 3-difluoropiperidinyl, 4-difluoropiperidinyl, 2-oxo-4-methylpiperazinyl, 3-oxo-4-methylpiperazinyl, 4-formylpiperazinyl, 2, 3-dioxopiperazinyl, 3, 5-dioxopiperazinyl, 2, 6-dioxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-cyclopropylpiperazinyl, 2, 4-dimethylpiperazinyl, piperazine, piperidine, 3, 4-dimethylpiperazinyl group, 2-methyl-4-methylpiperazinyl group, 3, 4, 5-trimethylpiperazinyl group, 2, 4-trimethylpiperazinyl group, 3, 4-trimethyl-5-oxopiperazinyl group, 2, 4-trimethyl-3-oxopiperazinyl group, 2-cyclopropanespiro-4-methylpiperazinyl group, 3-cyclopropanespiro-4-methylpiperazinyl group, 2-cyclopropanespiro-4-methyl-3-oxopiperazinyl group, 3-cyclopropanespiro-4-methyl-5-oxopiperazinyl group, 4-acetyl-3-cyclopropanespiro piperazinyl group, 3-cyclopropanespiro-4-methyl-5-oxopiperazinyl group, 3, 4-methyl-4-oxopiperazinyl group, 2-hydroxymethyl-4-methylpiperazinyl, 3-hydroxymethyl-4-methylpiperazinyl, 2-methoxymethyl-4-methyl-piperazinyl, 3-methoxymethyl-4-methylpiperazinyl, 2-hydroxyethyl-4-methylpiperazinyl, 3-hydroxyethyl-4-methylpiperazinyl, 2-methoxyethyl-4-methylpiperazinyl, 3-methoxyethyl-4-methylpiperazinyl, 2-carbamoyl-4-methylpiperazinyl, 2-methylcarbamoyl-4-methylpiperazinyl, 2-dimethylcarbamoyl-4-methylpiperazinyl, 2-carbamoylmethyl-4-methylpiperazinyl, 2-methylcarbamoylmethyl-4-methylpiperazinyl, 2-dimethylcarbamoylmethyl-4-methylpiperazinyl, 2-methoxycarbonylmethyl-4-methylpiperazinyl, 2-ethoxycarbonylmethyl-4-methylpiperazinyl, 2-aminomethyl-4-methylpiperazinyl, 2-methylaminomethyl-4-methylpiperazinyl, 2-dimethylaminomethyl-4-methylpiperazinyl, 2-aminoethyl-4-methylpiperazinyl, 2-methylaminoethyl-4-methylpiperazinyl, 2-dimethylaminoethyl-4-methylpiperazinyl, morpholinyl, 2-cyclopropanespiromorpholinyl, 3-cyclopropanespiromorpholinyl, 2, 2-dimethylmorpholinyl, 3-dimethylmorpholinyl, 3-hydroxymethylmorpholinyl, 3-methoxymethylmorpholinyl, 3-hydroxyethylmorpholinyl, 3-methoxyethylmorpholinyl, 3-carbamoylmorpholinyl, 3-methylcarbamoylmorpholinyl, 3-dimethylcarbamoylmorpholinyl, 3-aminomethylmorpholinyl, 3-methylaminomethylmorpholinyl, 3-dimethylaminomethylmorpholinyl, 3-aminoethylmorpholinyl, 3-methylaminoethylmorpholinyl, 3-dimethylaminoethylmorpholinyl, thiomorpholinyl, 3-oxothiomorpholinyl, 1-dioxothiomorpholinyl, 3-hydroxymethylthiomorpholinyl, 3-hydroxyethylthiomorpholinyl, methylthiomorpholinyl, 2-acetylhexahydropyridazin-1-yl, 2-formylhexahydropyridazin-1-yl, 3-oxohexahydropyridazin-1-yl, 2-methylhexahydropyridazin-1-yl, 2-carbamoylhexahydropyridazin-1-yl, 2-oxohexahydropyrimidin-1-yl, 4-oxohexahydropyrimidin-1-yl, 3-methylhexahydropyrimidin-1-yl, 6-hydroxymethylhexahydropyrimidin-1-yl, 2-oxo-4-methylpiperazinyl, 3-oxo-4-methylpiperazinyl, 5-oxo-4-methylpiperazinyl, 7-oxo-4-methylpiperazinyl, 2-formylhexahydropyridazin-1-yl, 3-oxohexahydropyridazin-1-yl, 2-oxopiperazinyl, 4-methylpiperazinyl, 2-oxopiperazinyl, 4-methylpiperazinyl, 2, 3-dioxohomopiperazinyl, 2, 7-dioxohomopiperazinyl, 3, 5-dioxohomopiperazinyl, 3, 7-dioxohomopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-cyclopropylhomopiperazinyl, 2-cyclopropanespiro-4-methylpiperazinyl, 3-cyclopropanespiro-4-methylpiperazinyl, 5-cyclopropanespiro-4-methylpiperazinyl, 7-cyclopropanespiro-4-methylpiperazinyl, 1, 4-oxazepan-4-yl and the like.

Particularly preferred are 3-dimethylaminoazetidin-1-yl, 2-dimethyl-3-dimethylaminoazetidin-1-yl, 2-hydroxymethylazetidin-1-yl, 2-carbamoylazetidin-1-yl, 2-oxopyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 2-carbamoylpyrrolidinyl, 2-hydroxymethylpiperidinyl, 2-carbamoylpiperidinyl, 2-methylcarbamoylpiperidinyl, 2-dimethylcarbamoylpiperidinyl, 3-oxo-4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-cyclopropylpiperazinyl, 2-hydroxymethylazetidinyl-1-yl, 2-oxopyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-cyclopropylpiperazinyl, 2, 4-dimethylpiperazinyl, 3-cyclopropyl-4-methylpiperazinyl, 3, 4, 5-trimethylpiperazinyl, 2, 4-trimethylpiperazinyl, 3, 4-trimethylpiperazinyl, 2-cyclopropanespiro-4-methylpiperazinyl, morpholinyl, 3-carbamoylmorpholinyl, 1-dioxothiomorpholinyl 2-methylhexahydropyridazin-1-yl, 3-oxo-4-methylpiperazinyl, 5-oxo-4-methylpiperazinyl, 4-ethylhomopiperazinyl, 4-cyclopropylhomopiperazinyl, 1, 4-Oxazacycloheptan-4-yl, piperidyl, 4-methoxypiperidinyl, thiomorpholinyl, 4-difluoropiperidyl, 3-difluoropiperidyl, 4-fluoropiperidinyl, 2-dimethylaminomethylpyrrolidinyl, 3-dimethylaminopyrrolidinyl, 3-methyl-4-oxoimidazolidin-1-yl, 3-methoxypyrrolidinyl, 2-acetylhexahydropyridazin-1-yl, 2-carbamoylhexahydropyridazin-1-yl and the like.

The salts of the compounds (I) and (II) of the present invention are not limited to all of the salts formed by the compounds of the present invention, and may have a carboxyl group, an amino group and/or Ar₁、Ar₂、Ar₃Or Ar₄A pyridine ring or the like may form a salt, and the salt may form a solvate in some cases. The salts herein include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acidExamples thereof may include salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, and trifluoroacetic acid, and salts with ions of alkali metals or alkaline earth metals such as sodium, potassium, and calcium.

The solvate of the solvates of the compounds (I) and (II) or the solvate of the salt thereof of the present invention includes a solvate formed by absorbing moisture in the air, in addition to a solvate formed by adding a solvent used for precipitation of crystals or the like. Examples of the solvent include lower alcohols such as methanol and ethanol, organic solvents such as acetone and acetonitrile, and water.

The compound (I) of the present invention can be produced by the following method.

In the above formula, Ar₁、Ar₂And R2 is as previously described, R₁₀Represents a methyl group or an ethyl group.

The compound (4) can be obtained by dissolving or suspending the compound (3) and dialkyl oxalate in an appropriate solvent such as N, N-dimethylformamide, adding sodium hydride under argon flow at-20 to 20 ℃, and stirring.

Compound (4) can also be produced by treating compound (3) and a dialkyl oxalate in an alcohol (methanol or ethanol) solution in the presence of sodium alkanol (methanol or ethanol). The reaction temperature is preferably-10 to 100 ℃.

Then, compound (4) is dissolved in an alcohol (methanol or ethanol), and after hydrazine derivative (6) or a salt thereof is added at room temperature, an appropriate amount of acetic acid is added, followed by heating and refluxing to obtain compound (7). At this time, the positional isomer (8) is by-produced, but the compound (7) can be easily isolated and purified by silica gel column chromatography.

In the above-mentioned pyrazole ring-forming reaction, a suitable amount of triethylamine or concentrated hydrochloric acid may be added, instead of the step of adding acetic acid, and the compound (7) may be obtained without adding acetic acid, triethylamine or concentrated hydrochloric acid according to circumstances.

The hydrazine derivative (6) or a salt thereof to be used in the above-mentioned pyrazole ring-forming reaction can be obtained by dissolving the aromatic amine (5) in concentrated hydrochloric acid, adding sodium nitrite under ice-cooling to form a diazo, and treating with tin dichloride. The reaction temperature is preferably-10 to 20 ℃.

The hydrazine derivative (6) may be a commercially available product, or may be a product obtained by halogenating Ar as described in reference example₁A method of reacting with hydrazine or a method based on the method.

The aromatic amine (5) can be obtained by using a commercially available compound, or by the method described in the reference example or the method based on the method.

Compound (7) produced by the above production method can be treated as follows to obtain compound (I) of the present invention.

Wherein R2, R3 and R₁₀、Ar₁、Ar₂And ring structure A is as previously described.

The carboxylic acid (9) can be obtained by hydrolyzing the compound (7) by a conventional method, and the compound (I) of the present invention can be obtained by condensation with the amine compound (10).

The above hydrolysis reaction may be carried out in the presence of a base or a lewis acid. The base may, for example, be a hydroxide of an alkali metal (e.g., lithium, sodium, potassium, etc.). The lewis acid may be boron tribromide. The reaction temperature is preferably-20 to 100 ℃ and more preferably-5 to 50 ℃.

Ar is reacted with₁The compound (7) having a halogen atom as a substituent(s) such as chlorine or bromine is dissolved in methanol, and sodium methoxide is added thereto, followed by reflux under heating or dissolution in methanol and tolueneAdding catalyst such as sodium methoxide and cuprous bromide, etc., heating and refluxing to obtain Ar₁Compound (7) (R) wherein the substituent(s) is (are) substituted with methoxy group₁₀Is methyl).

The condensation reaction can be carried out by a conventional method as a peptide synthesis method. Examples of the conventional peptide synthesis methods include an azide method, an acid chloride method, an acid anhydride method, a DCC (dicyclohexylcarbodiimide) method, an active ester method, a carbodiimide method, a DCC/HOBT (1-hydroxybenzotriazole) method, a method using a water-soluble carbodiimide, and a method using diethylcyanophosphate. These methods are described in M.Bodanszky, Y.S.Klausner, and M.A.Ondetti, Peptide Snthesis (A Wiley-Interscience Publication, New York, 1976), G.R.Pettit, Synthetic Peptides (Elsevier scientific Publication Company, New York, 1976), Japan chemical society, ed, volume 4, laboratory chemistry lecture 22, organic Synthesis IV (pill-type society, 1991), and the like. Examples of the solvent used in the condensation reaction include solvents such as N, N-dimethylformamide, pyridine, chloroform, dichloromethane, tetrahydrofuran, dioxane and acetonitrile, and mixed solvents thereof. The reaction temperature is preferably-20 to 50 ℃ and more preferably-10 to 30 ℃. As the amine compound (10), a commercially available compound can be used, and a product obtained by the method described in the literature or the method described in the preparation examples or the method based on the above method can be used.

In the above condensation reaction, when the amine compound (10) has a functional group such as a hydroxyl group, an amino group, or a carboxyl group, it may be necessary to protect the functional group with an appropriate protecting group in advance. Examples of the protecting group for a hydroxyl group include a tert-butyl group and a benzyl group, and examples of the protecting group for an amino group include a trifluoroacetyl group, a tert-butoxycarbonyl group and a benzyloxycarbonyl group. When the functional group is a carboxyl group, it can be used for condensation reaction after formation of a methyl ester or a tert-butyl ester. These protecting groups may be cleaved under conditions suitable for each protecting group.

The compound (II) of the present invention can be prepared by the following method.

In the above formula, Ar₃、Ar₄R5, R6, ring structure Ar₃And cyclic structure B is as previously described, R₁₀Represents a methyl group or an ethyl group.

The compound (12) can be obtained by dissolving or suspending a commercially available compound (11) and dialkyl oxalate in an appropriate solvent such as N, N-dimethylformamide, adding sodium hydride under argon flow at-20 to 20 ℃, and stirring.

Compound (12) can also be obtained by treating compound (11) and diethyl oxalate with lithium bis (trimethylsilyl) amide in an inert solvent such as tetrahydrofuran. The reaction temperature is-78-50 ℃.

Then, compound (12) is dissolved in ethanol, and after hydrazine derivative (14) or a salt thereof is added at room temperature, an appropriate amount of acetic acid is added, followed by heating and refluxing to obtain compound (15).

In the above-mentioned pyrazole ring-forming reaction, instead of the step of adding acetic acid, an appropriate triethylamine may be added and heated under reflux, and the compound (15) may be obtained without adding acetic acid or triethylamine depending on the case.

The hydrazine derivative (14) or a salt thereof used in the above-mentioned pyrazole ring-forming reaction can be obtained by dissolving the aromatic amine (13) in concentrated hydrochloric acid, adding sodium nitrite under ice-cooling to form a diazo, and treating with tin dichloride. The reaction temperature is-10 to 20 ℃.

As the hydrazine derivative (14), commercially available hydrazine derivatives can be used, or Ar can be halogenated by the use of the same as described in reference example₁A method of reacting with hydrazine or a method based on the method.

Further, as the aromatic amine (13), a commercially available compound can be used, and a product obtained by the method described in reference example or a method based on the method can be used.

Compound (15) produced by the above production method can be treated as follows to obtain compound (II) of the present invention.

Wherein R5, R6, R7 and R₁₀、Ar₄Ar of cyclic structure₃The cyclic structure B and the cyclic structure C are as described above.

The carboxylic acid (16) can be obtained by hydrolyzing the compound (15) according to a conventional method, and the compound (II) of the present invention can be obtained by condensation with the amine compound (17).

The conditions of the hydrolysis reaction and the condensation reaction are the same as those of the preparation of the compound (I).

The compound (I) of the present invention can also be prepared by the following method.

Wherein R2, R3 and R₁₀、Ar₁、Ar₂And cyclic structure A is as previously described, and Z is a leaving group.

The compound (I) of the present invention can be obtained by reducing the ester (7) to obtain an alcohol (18), then forming a compound (19) in which the Z group is a leaving group (for example, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, chlorine atom, bromine atom or iodine atom), and reacting it with an amine body (10).

The reduction reaction of the ester (7) to form the alcohol (18) is carried out by treatment with lithium aluminum hydride, lithium borohydride or the like in an inert solvent such as tetrahydrofuran at-78 to 50 ℃ and preferably-20 to 30 ℃.

The alcohol (18) can be prepared by treating the carboxylic acid (9) with lithium aluminum hydride, borane-tetrahydrofuran complex or the like in an inert solvent such as tetrahydrofuran or the like at-78 to 50 ℃, preferably-20 to 30 ℃.

When the Z group is a methanesulfonyloxy group, the alcohol (18) is reacted with methanesulfonyl chloride in the presence of a base such as pyridine at-50 to 50 ℃ to convert the alcohol (18) into the compound (19). When the Z group is a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or the like, it can be converted into the compound (19) under the same conditions. When the Z group is a chlorine atom, a bromine atom, an iodine atom or the like, a chlorine derivative (19) or a bromine derivative (19) can be formed by thionyl chloride, thionyl bromide or the like, and then they are treated with sodium iodide to obtain an iodine derivative (19). The conditions, reagents and the like of these reactions can be appropriately selected in accordance with the common knowledge of organic chemistry.

Compound (19) can be converted into compound (I) of the present invention by reacting compound (19) with amine (10) in an appropriate solvent such as tetrahydrofuran or N, N-dimethylformamide with a base such as triethylamine or diisopropylethylamine or an inorganic base such as potassium carbonate and a base such as sodium hydride. The reaction temperature varies depending on the kind of the Z group, and is preferably-79 to 100 ℃.

In the above reaction, the functional group may be protected as necessary. The protecting group and the cleavage conditions thereof may be appropriately selected in accordance with common knowledge of organic chemistry.

Further, another compound (I) of the present invention can be obtained by modifying the compound (I) of the present invention prepared by the above 3 methods according to the common general knowledge of organic chemistry.

The compounds (I) and (II), salts thereof or solvates thereof, or solvates of the salts thereof of the present invention have a potent antiplatelet effect and are also effective for a model of thrombosis induced by high shear stress. Therefore, the compounds (I) and (II), salts thereof or solvates thereof, or solvates of salts thereof of the present invention are useful as a prophylactic and/or therapeutic agent for ischemic diseases that cause thrombosis and embolism, such as myocardial infarction, angina pectoris (chronic stable angina pectoris, unstable angina pectoris, and the like), ischemic cerebrovascular disorders (transient ischemic attack (TIA), cerebral infarction, and the like), peripheral vascular disorders, occlusion after artificial blood vessel replacement, thrombotic occlusion after coronary intervention (coronary artery bypass graft (CAGB), Percutaneous Transluminal Coronary Angioplasty (PTCA), stent, and the like), diabetic retinopathy and nephropathy, and occlusion at the time of artificial valve replacement, and the like, in mammals including humans. Alternatively, the compound is useful as a prophylactic and/or therapeutic agent for thrombosis and embolism accompanying, for example, vascular surgery, extracorporeal circulation of blood, or the like.

When the compounds (I) and (II), salts thereof or solvates of salts thereof of the present invention are used as a pharmaceutical, the dosage thereof varies depending on the age, sex, symptoms and the like of a patient, but is preferably 0.1mg to 1g, more preferably 0.5mg to 500mg per 1 day of an adult. In this case, the 1 day dose may be administered several times, and if necessary, an amount of administration exceeding the 1 day dose may be administered.

The pharmaceutical preparation containing the compounds (I) and (II) of the present invention, a salt thereof or a solvate thereof can be used according to the desired administration method and dosage form, and the preparation can be prepared by a common preparation method of various preparations, can be incorporated with pharmaceutically acceptable carriers according to need, can be selected in a dosage form suitable for the administration method, and is not particularly limited in the administration method and dosage form.

Examples of the oral preparations include solid dosage forms such as tablets, powders, granules, pills and capsules, and liquid preparations such as solutions, syrups, elixirs, suspensions and emulsions.

The injection may be prepared by dissolving the compound (I), a salt thereof, a solvate thereof, or a solvate of the salt thereof in a container, or by freeze-drying the solution to form a solid, and then preparing the solid at the time of use.

When the above preparation is prepared, pharmaceutically acceptable additives such as binders, disintegrants, solubilizers, lubricants, fillers and excipients may be optionally used.

Examples

The following description will discuss a method for producing specific compounds of the present invention, and the non-inhibitory effect on COX-1 and COX-2 and the potent platelet aggregation inhibitory effect exhibited by these compounds in a specific test.

[ reference example 1] 5-hydrazino-2-methoxypyridine hydrochloride

A solution of sodium nitrite (3.795g) in water (20ml) was added dropwise to a concentrated hydrochloric acid (50ml) solution of 5-amino-2-methoxypyridine (6.21g) under ice cooling for 60 minutes, and the mixture was stirred at the same temperature for 30 minutes. A solution of tin dichloride 2 hydrate (39.5g) in concentrated hydrochloric acid (30ml) was added dropwise to the reaction mixture over 30 minutes at an internal temperature of about 10 ℃ and then stirred at room temperature for 2 hours. Under ice-cooling, a solution of sodium hydroxide (75g) in water (300ml) and diethyl ether were added to the reaction mixture to separate the mixture. The aqueous layer was extracted 2 times with ether. Then, the aqueous layer was saturated with sodium chloride, extracted with diethyl ether, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, a 1M hydrochloric acid-ethanol solution (50ml) was added to the filtrate, and the resulting mixture was stirred, and the precipitated solid was collected by filtration, washed with ether, and dried to obtain the title compound (5.02g, 57%).

¹H-NMR(400MHz，DMSO-d₆)δ：3.81(3H，s)，6.82(1H，d，J＝8.8Hz)，7.57(1H，dd，J＝8.8，2.9Hz)，7.97(1H，d，J＝2.9Hz)，8.55-9.20(1H，br)，10.13-10.50(3H，br).

MS(ESI)m/z：140(M+H)⁺.

[ reference example 2] 5-hydrazino-2-methoxypyridine

A solution of sodium nitrite (3.795g) in water (20ml) was added dropwise to a concentrated hydrochloric acid (50ml) solution of 5-amino-2-methoxypyridine (6.207g) over 80 minutes under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. A solution of tin dichloride 2 hydrate (39.5g) in concentrated hydrochloric acid (30ml) was added dropwise to the reaction mixture over 60 minutes at an internal temperature of about 10 ℃ and then stirred at room temperature for 12.5 hours. Under ice-cooling, a water (200ml) solution of sodium hydroxide (54g) and chloroform were added to the reaction mixture to remove insoluble matter, followed by liquid separation. The aqueous layer was extracted with chloroform 2 times, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (4.23g, 60%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：3.50-3.68(2H，br)，3.88(3H，s)，4.86-5.03(1H，br)，6.66(1H，d，J＝8.8Hz)，7.20(1H，dd，J＝8.8，2.9Hz)，7.77(1H，d，J＝2.9Hz).

MS(ESI)m/z：140(M+H)⁺.

[ reference example 3]5- (4-chlorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

1)4- (4-chlorophenyl) -2, 4-dioxobutyric acid ethyl ester

Sodium hydride (0.474 g after washing with benzene and drying) was added to a solution of 4' -chloroacetophenone (1.535g) in N, N-dimethylformamide (25ml) at 0 ℃ and stirred at room temperature for 0.5 hour. Diethyl oxalate (2.6ml) was added to the reaction solution, which was stirred at room temperature for 17 hours. Water and ether were added to the reaction solution to separate the solution. The aqueous layer was made acidic (pH3) with 1M aqueous hydrochloric acid and extracted with ether. Then, the aqueous layer was extracted with diethyl ether, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 4- (4-chlorophenyl) -2, 4-dioxobutyrate (1.952g, 77%).

¹H-NMR(400MHz，CDCl₃) δ: 1.41(3H, t, J ═ 7.0Hz), 4.40(2H, q, J ═ 7.0Hz), 7.03(1H, s), 7.48(2H, d-like, J ═ 8.6Hz), 7.94(2H, d-like, J ═ 8.6Hz).

MS(ESI)m/z：255(M+H)⁺.

2) The title Compound

To a solution of ethyl 4- (4-chlorophenyl) -2, 4-dioxobutyrate (0.930g) in ethanol (20ml) was added hydrazine (0.250g) of reference example 2 at room temperature, and the mixture was refluxed for 12 hours. After air-cooling, the solvent was evaporated under reduced pressure, and chloroform and water were added to the obtained residual component to separate the components. The aqueous layer was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate: 17 to 50%) to obtain the title compound (0.543g, 85%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 1.42(3H, t, J ═ 7.1Hz), 3.94(3H, s), 4.45(2H, q, J ═ 7.1Hz), 6.75(1H, d, J ═ 8.8Hz), 7.03(1H, s), 7.15(2H, d-like, J ═ 8.3Hz), 7.32(2H, d-like, J ═ 8.3Hz), 7.57(1H, dd, J ═ 8.8, 2.9Hz), 8.08(1H, d, J ═ 2.9Hz).

MS(FAB)m/z：358(M+H)⁺.

[ reference example 4]5- (4-chlorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

Lithium hydroxide monohydrate (69.4g) was added to a solution of 2) pyrazole-3-carboxylic acid ethyl ester (0.543g) of reference example 3 in tetrahydrofuran (6ml) -water (2ml) and methanol (1.5ml) at room temperature, followed by stirring for 2 hours. After the solvent was evaporated under reduced pressure, water and ether were added to the residue to separate the solution. The aqueous layer was made acidic (pH3) with 1N-hydrochloric acid aqueous solution, and the precipitated solid was filtered off after stirring at 0 ℃. The solid was washed with water, isopropanol and diethyl ether and dried to give the title compound as a solid (0.240g, 48%).

¹H-NMR(400MHz，CDCl₃) δ: 3.95(3H, s), 6.77(1H, d, J ═ 8.8Hz), 7.09(1H, s), 7.17(2H, d-, J ═ 8.6Hz), 7.34(2H, d-, J ═ 8.6Hz), 7.56(1H, dd, J ═ 8.8, 2.9Hz), 8.09(1H, d, J ═ 2.9Hz).

MS(ESI)m/z：330(M+H)⁺.

[ reference example 5]5- (4-ethylphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

1)4- (4-ethylphenyl) -2, 4-dioxobutyric acid ethyl ester

Ethyl 4- (4-ethylphenyl) -2, 4-dioxobutyrate (2.577g, 97%) was obtained in the same manner as in 1) of reference example 3 using 4' -ethylacetobenzene (1.599g) and diethyl oxalate (2.9 ml).

¹H-NMR(400MHz，CDCl₃) δ: 1.27(3H, t, J ═ 7.5Hz), 1.41(3H, t-like, J ═ 7.4Hz), 2.73(2H, q, J ═ 7.4Hz), 4.30-4.50(2H, m), 7.05(1H, s), 7.32(2H, d-like, J ═ 7.1Hz), 7.92(2H, d-like, J ═ 7.1Hz).

MS(ESI)m/z：249(M+H)⁺.

2) The title Compound

The title compound (0.589g, 83%) was obtained as an oil in the same manner as in 2) of reference example 3 using the above ethyl 4- (4-ethylphenyl) -2, 4-dioxobutyrate (1.012g) and 5-hydrazino-2-methoxypyridine (0.280g) of reference example 2.

¹H-NMR(400MHz，CDCl₃)δ：1.22(3H，t，J＝7.6Hz)，1.41(3H，t，J＝7.0Hz)，2.63(2H，q，J＝7.6Hz)，3.92(3H，s)，4.44(2H，q，J＝7.0Hz)，6.73(1H，d，J＝8.8Hz)，7.01(1H，s)，7.08-7.20(4H，m)，7.57(1H，dd，J＝8.8，2.7Hz)，8.12(1H，d，J＝2.7Hz).

MS(FAB)m/z：352(M+H)⁺.

[ reference example 6]5- (4-ethylphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.457g, 84%) was obtained as a solid by the same method as in reference example 4 using the ethyl pyrazole-3-carboxylate (0.589g) obtained in 2) of reference example 5.

¹H-NMR(400MHz，CDCl₃)δ：1.23(3H，t，J＝7.6Hz)，2.64(2H，q，J＝7.6Hz)，3.94(3H，s)，6.75(1H，d，J＝8.8Hz)，7.07(1H，s)，7.10-7.20(5H，m)，7.60(1H，dd，J＝8.8，2.7Hz)，8.15(1H，d，J＝2.7Hz)，10.20(1H，br).

MS(FAB)m/z：324(M+H)⁺.

[ reference example 7]1- (6-methoxy-3-pyridyl) -5- (3-methylphenyl) pyrazole-3-carboxylic acid ethyl ester

1)4- (3-Methylphenyl) -2, 4-dioxobutyric acid ethyl ester

Ethyl 4- (3-methylphenyl) -2, 4-dioxobutyrate (2.71g, quantitative) was obtained in the same manner as in 1) of reference example 3 using 3' -methylacetophenone (1.557g) and diethyl oxalate (3.1 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.41(3H，t，J＝7.1Hz)，2.43(3H，s)，4.40(2H，q，J＝7.1Hz)，7.06(1H，s)，7.35-7.45(2H，m)，7.75-7.82(2H，m).

MS(ESI)m/z：235(M+H)⁺.

2) The title Compound

To a solution of ethyl 4- (3-methylphenyl) -2, 4-dioxobutyrate (1.014g) in ethanol (20ml) was added 5-hydrazino-2-methoxypyridine hydrochloride (0.380g) of reference example 1 and triethylamine (0.30ml) at room temperature, and the mixture was refluxed for 14 hours. After air-cooling, the solvent was evaporated under reduced pressure, and chloroform and water were added to the resulting residue to separate the mixture. The aqueous layer was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was eluted with silica gel column chromatography (hexane-ethyl acetate: 20%) to obtain the title compound (0.451g, 62%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.1Hz)，2.30(3H，s)，3.92(3H，s)，4.45(2H，q，J＝7.1Hz)，6.68-6.76(1H，m)，6.92-7.25(4H，m)，7.02(1H，s)，7.53-7.61(1H，m)，8.08-8.15(1H，m).

MS(FAB)m/z：338(M+H)⁺.

[ reference example 8]1- (6-methoxy-3-pyridyl) -5- (3-methylphenyl) pyrazole-3-carboxylic acid

The title compound (0.353g, 86%) was obtained as a solid by the same method as in reference example 4 using the ethyl pyrazole-3-carboxylate (0.451g) obtained in 2) of reference example 7.

¹H-NMR(400MHz，CDCl₃) δ: 2.31(3H, s), 3.94(3H, s), 6.74(1H, d, J ═ 8.8Hz), 6.96(1H, d-, J ═ 7.3Hz), 7.05-7.25(4H, m), 7.60(1H, dd, J ═ 8.8, 2.7Hz), 8.14(1H, d, J ═ 2.7Hz), 9.65(1H, br).

[ reference example 9]1- (6-methoxy-3-pyridyl) -5- (2-methylphenyl) pyrazole-3-carboxylic acid ethyl ester

1)4- (2-Methylphenyl) -2, 4-dioxobutyric acid ethyl ester

Ethyl 4- (2-methylphenyl) -2, 4-dioxobutyrate (2.54g, 95%) was obtained as an oil in the same manner as in 1) of reference example 3 using 2' -methylacetophenone (1.543g) and diethyl oxalate (3.1 ml).

¹H-NMR(400MHz，CDCl₃) δ: 1.39(3H, t-like, J ═ 7.1Hz), 2.55(3H, s), 4.38(2H, q-like, J ═ 7.1Hz), 6.83(1H, s), 7.20-7.30(2H, m), 7.41(1H, t-like, J ═ 7.6Hz), 7.62(1H, d-like, J ═ 7.6Hz).

LC-MSm/z：235(M+H)⁺.

2) The title Compound

The title compound (0.542g, 69%) was obtained as an oil in the same manner as in 2) of reference example 7 using ethyl 4- (2-methylphenyl) -2, 4-dioxobutyrate (1.074g) and 5-hydrazino-2-methoxypyridine hydrochloride (0.407g) of reference example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.1Hz)，2.04(3H，s)，3.86(3H，s)，4.45(2H，q，J＝7.1Hz)，6.65(1H，d，J＝8.8Hz)，6.94(1H，s)，7.10-7.35(4H，m)，7.56(1H，dd，J＝8.8，2.2Hz)，8.01(1H，d，J＝2.2Hz).

MS(FAB)m/z：338(M+H)⁺.

[ reference example 10]1- (6-methoxy-3-pyridyl) -5- (2-methylphenyl) pyrazole-3-carboxylic acid

The title compound (0.479g, 96%) was obtained as a solid by the same method as in reference example 4 using the ethyl pyrazole-3-carboxylate (0.542g) of 2) of reference example 9.

¹H-NMR(400MHz，CDCl₃)δ：2.06(3H，s)，3.91(3H，s)，6.68(1H，d，J＝9.0Hz)，7.00(1H，s)，7.15-7.38(4H，m)，7.50-7.60(1H，m)，8.03(1H，d，J＝2.5Hz).

MS(ESI)m/z：310(M+H)⁺.

[ reference example 11]5- (3-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

1)4- (3-fluorophenyl) -2, 4-dioxobutyric acid ethyl ester

Ethyl 4- (3-fluorophenyl) -2, 4-dioxobutyrate (2.26g, 86%) was obtained as a solid by the same method as in 1) of reference example 3 using 3' -fluoroacetophenone (1.530g) and diethyl oxalate (3.0 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.39(3H，t，J＝7.1Hz)，4.38(2H，q，J＝7.1Hz)，7.01(1H，s)，7.20-7.32(1H，m)，7.40-7.50(1H，m)，7.60-7.68(1H，m)，7.70-7.77(1H，m).

MS(ESI)m/z：239(M+H)⁺.

2) The title Compound

The title compound (0.362g, 52%) was obtained as an oil by the same method as in 2) of reference example 7 using the above ethyl 4- (3-fluorophenyl) -2, 4-dioxobutyrate (0.978g) and 5-hydrazino-2-methoxy-pyridine hydrochloride (0.358g) of reference example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.1Hz)，3.94(3H，s)，4.45(2H，q，J＝7.1Hz)，6.76(1H，d，J＝8.8Hz)，6.92-7.10(3H，m)，7.06(1H，s)，7.58(1H，dd，J＝8.8，2.9Hz)，8.09(1H，d，J＝2.9Hz).

MS(FAB)m/z：342(M+H)⁺.

[ reference example 12]5- (3-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.302g, 91%) was obtained as a solid by the same method as in reference example 4 using the ethyl pyrazole-3-carboxylate (0.362g) of 2) of reference example 11.

¹H-NMR(400MHz，CDCl₃)δ：3.95(3H，s)，6.78(1H，d，J＝8.8Hz)，6.93-7.12(3H，m)，7.12(1H，s)，7.28-7.38(1H，m)，7.60(1H，dd，J＝8.8，2.7Hz)，8.12(1H，d，J＝2.7Hz).

MS(ESI)m/z：314(M+H)⁺.

[ reference example 13]5- (4-Benzyloxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

1)4- (4-Phenylmethoxyphenyl) -2, 4-dioxobutyric acid ethyl ester

Ethyl 4- (4-benzyloxyphenyl) -2, 4-dioxobutyrate (3.18g, quantitative) was obtained as an oil in the same manner as in 1) of reference example 3 using 4' -benzyloxyacetophenone (2.07g) and diethyl oxalate (2.5 ml).

MS(ESI)m/z：327(M+H)⁺.

2) The title Compound

The title compound (1.026g, 35%) was obtained as a solid by the same method as in 2) of reference example 3 using ethyl 4- (4-benzyloxyphenyl) -2, 4-dioxobutyrate (3.21g) and 5-hydrazino-2-methoxypyridine hydrochloride (0.952g) of reference example 2.

¹H-NMR(400MHz，CDCl₃) δ: 1.42(3H, t, J ═ 7.3Hz), 3.94(3H, s), 4.44(2H, q, J ═ 7.3Hz), 5.05(2H, s), 6.73(1H, d, J ═ 8.8Hz), 6.92(2H, d-like, J ═ 8.6Hz), 6.97(1H, s), 7.13(2H, d-like, J ═ 8.6Hz), 7.30-7.46(5H, m), 7.56(1H, dd, J ═ 8.8, 2.7Hz), 8.10(1H, d, J ═ 2.7Hz).

MS(FAB)m/z：430(M+H)⁺.

[ reference example 14]5- (4-Benzyloxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.973g, quantitative) was obtained as an oil by the same method as in reference example 4 using ethyl 5- (4-benzyloxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylate (0.991g) of reference example 13.

¹H-NMR(400MHz，CDCl₃) δ: 3.94(3H, s), 5.05(2H, s), 6.74(1H, d, J ═ 8.8Hz), 6.93(2H, d-like, J ═ 8.8Hz), 7.02(1H, s), 7.12(2H, d-like, J ═ 8.8Hz), 7.30-7.45(5H, m), 7.56(1H, dd, J ═ 8.8, 2.7Hz), 8.12(1H, d, J ═ 2.7Hz).

MS(FAB)m/z：402(M+H)⁺.

[ reference example 15] 4-methoxypyridine-2-carbonitrile

Triethylamine (17.8ml) was added to an acetonitrile (160ml) solution of 4-methoxypyridine-N-oxide (8.0g) at room temperature under an argon atmosphere, followed by dropwise addition of trimethylsilylnitrile (24.1ml), and the mixture was stirred for 20 minutes and then at 95 ℃ for 14 hours. After air-cooling, the solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the obtained residue to separate the mixture. The organic layer was dried with anhydrous sodium hydrogen sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.57g, 18%).

¹H-NMR(400MHz，CDCl₃)δ：3.91(3H，s)，7.00-7.02(1H，m)，7.22(1H，d，J＝2.4Hz)，8.51(1H，d，J＝6.0Hz).

MS(EI)m/z：134(M⁺).

[ reference example 16]1- (4-methoxy-2-pyridyl) ethanone

After a 0.93M-methylmagnesium bromide solution (13.8ml) was added dropwise to a tetrahydrofuran (31ml) solution of 4-methoxypyridine-2-carbonitrile (1.56g) at-78 ℃ under argon, the reaction mixture was stirred for 15 minutes, at 0 ℃ for 15 minutes and at room temperature for 5 hours. After water was added dropwise to the reaction mixture, water and ethyl acetate were added thereto to separate the mixture. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.30g, 73%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.72(3H，s)，3.91(3H，s)，6.97-6.99(1H，m)，7.57-7.58(1H，m)，8.48-8.50(1H，m).

MS(ESI)m/z：152(M+H)⁺.

[ reference example 17] Ethyl 4- (4-methoxy-2-pyridyl) -2, 4-dioxobutyrate

The title compound (0.713g, 33%) was obtained as a solid by the same method as in 1) of reference example 3 using 1- (4-methoxy-2-pyridyl) ethanone (1.28g) and diethyl oxalate (2.30 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.39-1.43(3H，m)，3.96(3H，s)，4.37-4.42(2H，m)，7.03-7.05(1H，m)，7.72(1H，d，J＝2.8Hz)，8.02(1H，s)，8.50(1H，d，J＝5.6Hz).

MS(EI)m/z：251(M⁺).

[ reference example 18] ethyl 1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylate

The title compound (0.472g, 49%) was obtained as a solid by the same method as 2) of reference example 3 using ethyl 4- (4-methoxy-2-pyridyl) -2, 4-dioxobutyrate (0.691g) of reference example 17 and 5-hydrazino-2-methoxypyridine (0.383g) of reference example 2.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.44(3H，m)，3.82(3H，s)，3.95(3H，s)，4.43-4.48(2H，m)，6.75-6.78(2H，m)，6.89(1H，d，J＝2.4Hz)，7.25(1H，s)，7.68(1H，dd，J＝8.8，2.4Hz)，8.11(1H，d，J＝2.4Hz)，8.33(1H，d，J＝5.6Hz).

MS(FAB)m/z：355(M+H)⁺.

[ reference example 19]1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylic acid

To a mixed solution of ethyl 1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylate (0.416g) in referential example 18 and methanol (6.3ml) in tetrahydrofuran (6.3ml) was added an aqueous 1N sodium hydroxide solution (2.23ml) at room temperature, followed by stirring for 5 hours. After the reaction mixture was neutralized by adding 1N hydrochloric acid aqueous solution (2.23ml), water and chloroform were added to separate the reaction mixture. The aqueous layer was extracted with chloroform 2 times, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (0.353g, 92%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：3.86(3H，s)，3.89(3H，s)，6.88(1H，d，J＝8.8Hz)，6.93(1H，dd，J＝5.6，2.7Hz)，7.29(1H，d，J＝5.6Hz)，7.37(1H，s)，7.69-7.72(1H，m)，8.14(1H，d，J＝2.8Hz)，8.24(1H，d，J＝5.6Hz)，13.05(1H，br).

MS(FAB)m/z：327(M+H)⁺.

[ reference example 20] 2-bromo-6-methoxypyridine

Sodium methoxide (1.82g) was added to a toluene (120ml) solution of 2, 6-dibromopyridine (8.0g) under an argon atmosphere, and the mixture was stirred at 120 ℃ for 13 hours. Then, sodium methoxide (0.728g) was added thereto, and the mixture was stirred at 120 ℃ for 6 hours. After air cooling, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (5.64g, 89%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：3.93(3H，s)，6.68(1H，d，J＝8.0Hz)，7.05(1H，d，J＝7.2Hz)，7.39-7.42(1H，m).

[ reference example 21] 6-methoxypyridine-2-carbonitrile

Cuprous cyanide (2.68g) was added to a solution of 2-bromo-6-methoxypyridine (5.62g) in N, N-dimethylformamide (112ml) at room temperature, and the mixture was stirred at 165 ℃ for 15 hours. After air-cooling, water and ethyl acetate were added, and the resulting insoluble matter was filtered through celite, and water and ethyl acetate were added to the obtained filtrate to separate the filtrate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was eluted with silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.78g, 44%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.96(3H，s)，6.95-6.98(1H，m)，7.29-7.31(1H，m)，7.64-7.67(1H，m).

MS(EI)m/z：134(M⁺).

[ reference example 22]1- (6-methoxy-2-pyridyl) ethanone

The title compound (0.819g, 42%) was obtained as a solid by the same method as in reference example 16 using 6-methoxypyridine-2-carbonitrile (1.75 g).

¹H-NMR(400MHz，CDCl₃)δ：2.68(3H，s)，4.00(3H，s)，6.92-6.94(1H，m)，7.62-7.72(2H，m).

MS(ESI)m/z：152(M+H)⁺.

[ reference example 23] Ethyl 4- (6-methoxy-2-pyridyl) -2, 4-dioxobutyrate

The title compound (1.16g, 87%) was obtained as an oil by the same method as in 1) of preparation example 3 using 1- (6-methoxy-2-pyridyl) ethanone (0.80g) and diethyl oxalate (1.44 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.40-1.43(3H，m)，4.03(3H，s)，4.38-4.43(2H，m)，6.95-6.98(1H，m)，7.63(1H，m)，7.74-7.76(1H，m)，8.02(1H，s).

MS(EI)m/z：251(M⁺).

[ reference example 24] ethyl 1- (6-methoxy-3-pyridyl) -5- (6-methoxy-2-pyridyl) pyrazole-3-carboxylate

The title compound (0.740g, 46%) was obtained as an oil by the same method as in 2) of reference example 3 using ethyl 4- (6-methoxy-2-pyridyl) -2, 4-dioxobutyrate (1.15g) of reference example 23 and 5-hydrazino-2-methoxypyridine (0.637g) of reference example 2.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.45(3H，m)，3.43(3H，s)，3.95(3H，s)，4.44-4.49(2H，m)，6.64-6.67(1H，m)，6.77-6.79(1H，m)，7.08-7.10(1H，m)，7.27(1H，s)，7.56-7.60(1H，m)，7.64-7.66(1H，m)，8.16-8.17(1H，m).

MS(EI)m/z：354(M⁺).

[ reference example 25]1- (6-methoxy-3-pyridyl) -5- (6-methoxy-2-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.584g, 91%) was obtained as a solid by the same method as in referential example 19 using the ethyl pyrazole-3-carboxylate (0.694g) of referential example 24.

¹H-NMR(400MHz，CDCl₃)δ：3.44(3H，s)，3.96(3H，s)，6.66-6.69(1H，m)，6.80(1H，d，J＝8.8Hz)，7.10-7.12(1H，m)，7.33(1H，s)，7.57-7.61(1H，m)，7.66-7.68(1H，m)，8.19(1H，m).

MS(FAB)m/z：327(M+1)⁺.

[ reference example 26] 6-methylpyridine-2-carbonitrile

The title compound (2.81g, 41%) was obtained as a solid by the same method as in reference example 21 using 2-bromo-6-methylpyridine (9.87g) and copper (I) cyanide (5.14 g).

¹H-NMR(400MHz，CDCl₃)δ：2.62(3H，s)，7.39(1H，d，J＝8.0Hz)，7.52(1H，d，J＝7.6Hz)，7.70-7.74(1H，m).

MS(EI)m/z：118(M⁺).

[ reference example 27]1- (6-methyl-2-pyridyl) ethanone

The title compound (1.04g, 33%) was obtained as an oil by the same method as in reference example 16 using 6-methylpyridine-2-carbonitrile (2.80g) and a 0.93M-methylmagnesium bromide solution in tetrahydrofuran (28.0 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.62(3H，s)，2.71(3H，s)，7.30-7.32(1H，m)，7.68-7.71(1H，m)，7.82-7.85(1H，m).

MS(FAB)m/z：136(M+H)⁺.

[ reference example 28] ethyl 4- (6-methyl-2-pyridyl) -2, 4-dioxobutyrate

The title compound (0.443g, 25%) was obtained as an oil by the same method as in 1) of reference example 3 using 1- (6-methyl-2-pyridyl) ethanone (1.03g) and diethyl oxalate (2.07 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.2Hz)，2.67(3H，s)，4.41(2H，q，J＝7.2Hz)，7.39(1H，d，J＝7.6Hz)，7.49(1H，br)，7.79-7.83(1H，m)，8.00(1H，d，J＝7.6Hz).

MS(EI)m/z：235(M⁺).

[ reference example 29]1- (6-methoxy-3-pyridyl) -5- (6-methyl-2-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (0.491g, 79%) was obtained as an oil by the same method as in 2) of reference example 3 using ethyl 4- (6-methyl-2-pyridyl) -2, 4-dioxobutyrate (0.431g) of reference example 28 and 5-hydrazino-2-methoxypyridine (0.255g) of reference example 2.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.44(3H，m)，2.41(3H，s)，3.95(3H，s)，4.43-4.48(2H，m)，6.75-6.77(1H，m)，7.07-7.14(2H，m)，7.27(1H，s)，7.53-7.57(1H，m)，7.66-7.69(1H，m)，8.10-8.11(1H，m).

MS(FAB)m/z：339(M⁺).

[ reference example 30]1- (6-methoxy-3-pyridyl) -5- (6-methyl-2-pyridyl) pyrazole-3-carboxylic acid

The same procedures used in referential example 19 were repeated except for using the ethyl pyrazole-3-carboxylate (0.444g) obtained in referential example 29 to obtain a compound (0.342g, 84%) in the form of a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：2.25(3H，s)，3.90(3H，s)，6.90(1H，d，J＝8.8Hz)，7.20(1H，d，J＝7.6Hz)，7.32(1H，s)，7.46(1H，d，J＝7.6Hz)，7.71-7.75(2H，m)，8.14(1H，d，J＝2.4Hz)，13.05(1H，br).

MS(FAB)m/z：311(M+H)⁺.

[ reference example 31] Ethyl 4- (2-pyridyl) -2, 4-dioxobutyrate

2-Acetylpyridine (1.39ml) and diethyl oxalate (3.36ml) were obtained as a solid by the same method as in 1) of reference example 3 (1.12g, 41%).

¹H-NMR(400MHz，CDCl₃)δ：1.40-1.43(3H，m)，4.38-4.43(2H，m)，7.51-7.54(1H，m)，7.62(1H，s)，7.89-7.93(1H，m)，8.18(1H，d，J＝8.0Hz)，8.73(1H，d，J＝4.4Hz).

MS(EI)m/z：221(M⁺).

[ reference example 32]1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid ethyl ester

1) 5-hydroxy-1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -4, 5-dihydropyrazole-3-carboxylic acid ethyl ester

A solution of ethyl 4- (2-pyridyl) -2, 4-dioxobutyrate (1.10g) of referential example 31 and 5-hydrazino-2-methoxypyridine (0.692g) of referential example 2 in ethanol (22ml) was refluxed for 14 hours. After air-cooling, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) and again by silica gel column chromatography (toluene-acetone), whereby ethyl 5-hydroxy-1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -4, 5-dihydropyrazole-3-carboxylate (0.575g, 34%) was obtained as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.37-1.40(3H，m)，3.47-3.64(2H，m)，3.81(3H，s)，4.35-4.40(2H，m)，6.57-6.59(1H，m)，6.85(1H，m)，7.34-7.38(1H，m)，7.45-7.48(1H，m)，7.52-7.59(2H，m)，7.79-7.83(1H，m)，8.55-8.57(1H，m).

2) The title Compound

Acetic acid (0.456ml) was added to an ethanol (11ml) solution of the ethyl 5-hydroxy-1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) -4, 5-dihydropyrazole-3-carboxylate (0.546g) obtained above, and the mixture was stirred at 105 ℃ for 4 hours. After air cooling, a saturated aqueous sodium bicarbonate solution, water and ethyl acetate were added to the reaction mixture to separate the mixture. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (0.516g, 100%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.2Hz)，3.95(3H，s)，4.46(2H，q，J＝7.2Hz)，6.76-6.78(1H，m)，7.22-7.28(2H，m)，7.35-7.37(1H，m)，7.66-7.71(2H，m)，8.11(1H，m)，8.52-8.54(1H，m).

MS(FAB)m/z：325(M+H)⁺.

[ reference example 33]1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.344g, 86%) was obtained as a solid by the same method as in reference example 19 using the ethyl pyrazole-3-carboxylate (0.438g) of 2) of reference example 32.

¹H-NMR(400MHz，DMSO-d₆)δ：3.89(3H，s)，6.89(1H，d，J＝8.8Hz)，7.33-7.37(2H，m)，7.67-7.73(2H，m)，7.85-7.89(1H，m)，8.14(1H，d，J＝2.4Hz)，8.44-8.46(1H，m)，13.06(1H，br).

MS(FAB)m/z：297(M+H)⁺.

[ reference example 34] Ethyl 4- (4-methylphenyl) -2, 4-dioxobutyrate

The title compound (1.68g, 64%) was obtained as an oil by the same method as in 1) of reference example 3 using 4' -methylacetophenone (1.50g) and diethyl oxalate (3.04 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.40-1.43(3H，m)，2.44(3H，s)，4.37-4.43(2H，m)，7.06(1H，s)，7.30-7.32(2H，m)，7.89-7.91(2H，m).

MS(EI)m/z：234(M⁺).

[ reference example 35]1- (6-methoxy-3-pyridyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (1.52g, 63%) was obtained as an oil by the same method as in 2) of reference example 3 using ethyl 4- (4-methylphenyl) -2, 4-dioxobutyrate (1.67g) of reference example 34 and 5-hydrazino-2-methoxypyridine (0.992g) of reference example 2.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.44(3H，m)，2.35(3H，s)，3.94(3H，s)，4.43-4.48(2H，m)，6.72-6.75(1H，m)，7.01(1H，s)，7.09-7.15(4H，m)，7.56-7.59(1H，m)，8.11(1H，m).

MS(EI)m/z：337(M⁺).

[ reference example 36]1- (6-methoxy-3-pyridyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid

The title compound (1.24g, 90%) was obtained in an amorphous state in the same manner as in reference example 19 using the ethyl pyrazole-3-carboxylate (1.50g) of reference example 35.

¹H-NMR(400MHz，CDCl₃)δ：2.36(3H，s)，3.95(3H，s)，6.75(1H，d，J＝8.8Hz)，7.07(1H，s)，7.11-7.16(4H，m)，7.59(1H，dd，J＝8.8，2.8Hz)，8.13(1H，d，J＝2.8Hz).

MS(EI)m/z：309(M⁺).

[ reference example 37] Ethyl 4- (2-fluorophenyl) -2, 4-dioxobutyrate

The title compound (0.256g, 37%) was obtained as a solid by the same method as in 1) of reference example 3 using 2' -fluoroacetophenone (0.40g) and diethyl oxalate.

¹H-NMR(400MHz，CDCl₃)δ：1.39-1.43(3H，m)，4.37-4.43(2H，m)，6.96-7.32(3H，m)，7.54-7.59(1H，m)，7.90-7.99(1H，m).

MS(FAB)m/z：239(M+H)⁺.

[ reference example 38]5- (2-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (0.231g, 65%) was obtained as an oil by the same method as in 2) of reference example 7 using ethyl 4- (2-fluorophenyl) -2, 4-dioxobutyrate (0.248g) of reference example 37 and 5-hydrazino-5-methoxypyridine hydrochloride (0.219g) of reference example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.45(3H，m)，3.91(3H，s)，4.43-4.48(2H，m)，6.71-6.73(1H，m)，7.03-7.41(5H，m)，7.60-7.63(1H，m)，8.04-8.06(1H，m).

MS(EI)m/z：341(M⁺).

[ reference example 39]5- (2-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.199g, 98%) was obtained in an amorphous state in the same manner as in referential example 19 using the ethyl pyrazole-3-carboxylate (0.222g) of referential example 38.

¹H-NMR(400MHz，CDCl₃)δ：3.93(3H，s)，6.75(1H，d，J＝8.8Hz)，7.03-7.43(5H，m)，7.63(1H，dd，J＝8.8，2.8Hz)，8.07(1H，d，J＝2.8Hz).

MS(EI)m/z：313(M⁺).

[ reference example 40]1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid ethyl ester

Ethyl 4-phenyl-2, 4-dioxobutyrate (22.96g, quantitative) was obtained as an oil in the same manner as in 1) of reference example 3 using acetophenone (9.85g) and diethyl oxalate (23.97 g). Then, using the obtained ethyl 4-phenyl-2, 4-dioxobutyrate and 5-hydrazino-2-methoxypyridine (11.39g) of reference example 2, the title compound (16.37g, 61%) was obtained as an oil by the same method as in 2) of reference example 3.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.0Hz)，3.93(3H，s)，4.45(2H，q，J＝7.0Hz)，6.73(1H，d，J＝8.8Hz)，7.04(1H，s)，7.19-7.26(2H，m)，7.30-7.37(3H，m)，7.57(1H，dd，J＝8.8，2.6Hz)，8.11(1H，d，J＝2.6Hz).

MS(ESI)m/z：324(M+H)⁺.

[ reference example 41]1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid

The title compound (13.88g, 92%) was obtained as crystals by the same method as in reference example 19 using the ethyl pyrazole-3-carboxylate (16.37g) of reference example 40.

¹H-NMR(400MHz，CDCl₃)δ：3.94(3H，s)，6.75(1H，d，J＝8.8Hz)，7.10(1H，s)，7.21-7.27(2H，m)，7.32-7.39(3H，m)，7.58(1H，dd，J＝8.8，2.6Hz)，8.12(1H，d，J＝2.6Hz).

MS(ESI)m/z：296(M+H)⁺.

[ reference example 42]1- (6-chloro-3-pyridazinyl) -5-phenylpyrazole-3-carboxylic acid ethyl ester

The title compound (1.93g, 65%) was obtained in an amorphous state in the same manner as 2) in referential example 3 using 3-chloro-6-hydrazinopyridazine (1.31g) and ethyl 4-phenyl-2, 4-dioxobutyrate (2.20g) prepared in the same manner as in referential example 40.

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.0Hz)，4.46(2H，q，J＝7.0Hz)，7.04(1H，s)，7.29-7.39(5H，m)，7.64(1H，d，J＝9.1Hz)，8.06(1H，d，J＝9.1Hz).

LC-MSm/z：329(M+H)⁺.

[ reference example 43]1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carboxylic acid

28% sodium methoxide in methanol (0.6ml) was added to a solution of pyrazole-3-carboxylic acid ethyl ester (329mg) in reference example 42 in methanol (10ml), and the mixture was refluxed for 2 hours. After air-cooling, tetrahydrofuran (5ml) and water (5ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Then, 1N hydrochloric acid aqueous solution (4ml) was added to the reaction mixture, and water and ethyl acetate were added to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and diethyl ether was added to the obtained residue to collect a precipitated solid by filtration, followed by drying to obtain the title compound (218mg, 74%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：4.03(3H，s)，7.12(1H，s)，7.28-7.31(2H，m)，7.37-7.40(3H，m)，7.51(1H，d，J＝9.2Hz)，8.01(1H，d，J＝9.2Hz)，13.18(1H，br).

LC-MSm/z：297(M+H)⁺.

[ reference example 44]5- (4-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

To a solution of 4-methoxyacetophenone (300mg) in N, N-dimethylformamide (4ml), 60% sodium hydride (160mg) was added at 0 ℃ and the mixture was stirred at room temperature for 0.5 hour. Diethyl oxalate (542. mu.l) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 14 hours. To the reaction solution was added 5-hydrazino-2-methoxypyridine hydrochloride (406mg) of reference example 1, and the mixture was stirred at 80 ℃ for 3 hours. After air-cooling, water and ethyl acetate were added to the reaction mixture to separate the mixture, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was eluted with silica gel column chromatography (hexane-ethyl acetate) to give the title compound (517mg, 73%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 1.42(3H, t, J ═ 7.0Hz), 3.80(3H, s), 3.93(3H, s), 4.44(2H, q, J ═ 7.0Hz), 6.73(1H, d, J ═ 8.8Hz), 6.84(2H, d-like, J ═ 8.8Hz), 6.97(1H, s), 7.13(2H, d-like, J ═ 8.8Hz), 7.56(1H, dd, J ═ 8.8, 2.7Hz), 8.10(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：354(M+H)⁺.

[ reference example 45]5- (4-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

To a methanol (10ml) solution of the ethyl pyrazole-3-carboxylate (515mg) prepared in referential example 44 was added a 1M aqueous sodium hydroxide solution (3.64ml), and the mixture was refluxed for 1 hour. The reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. To the aqueous layer was added 1M aqueous hydrochloric acid (4.5ml) to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (453mg, 95%) as crystals.

¹H-NMR(400MHz，CDCl₃) δ: 3.81(3H, s), 3.95(3H, s), 6.75(1H, d, J ═ 8.8Hz), 6.86(2H, d-, J ═ 8.8Hz), 7.03(1H, s), 7.15(2H, d-, J ═ 8.8Hz), 7.57(1H, dd, J ═ 8.8, 2.7Hz), 8.12(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：326(M+H)⁺.

[ reference example 46]5- (3-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (495mg, 70%) was obtained as an oil by the same method as in referential example 44 using 3-methoxyacetophenone (300mg) and diethyl oxalate (542. mu.l) and further using 5-hydrazino-2-methoxypyridine hydrochloride (406mg) of referential example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.1Hz)，3.72(3H，s)，3.93(3H，s)，4.45(2H，q，J＝7.0Hz)，6.73(1H，d，J＝8.8Hz)，6.73-6.80(2H，m)，6.85-6.91(1H，m)，7.03(1H，s)，7.20-7.27(1H，m)，7.58(1H，dd，J＝8.8，2.7Hz)，8.11(1H，d，J＝2.7Hz).

MS(ESI)m/z：354(M+H)⁺.

[ reference example 47]5- (3-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

The title compound (472mg, 94%) was obtained as crystals by the same method as in reference example 45 using the ethyl pyrazole-3-carboxylate (490mg) of reference example 46.

¹H-NMR(400MHz，CDCl₃)δ：3.74(3H，s)，3.94(3H，s)，6.75(1H，d，J＝8.8Hz)，6.75-6.82(2H，m)，6.88-6.93(1H，m)，7.09(1H，s)，7.22-7.29(1H，m)，7.58(1H，dd，J＝8.8，2.7Hz)，8.13(1H，d，J＝2.7Hz).

MS(ESI)m/z：326(M+H)⁺.

[ reference example 48]5- (2-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (476mg, 67%) was obtained as crystals by the same method as in referential example 44 using 2-methoxyacetophenone (300mg) and diethyl oxalate (542. mu.l) and further using 5-hydrazino-2-methoxypyridine hydrochloride (421mg) of referential example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.41(3H，t，J＝7.1Hz)，3.49(3H，s)，3.89(3H，s)，4.44(2H，q，J＝7.1Hz)，6.67(1H，d，J＝8.8Hz)，6.81(1H，d，J＝8.3Hz)，6.95-7.01(1H，m)，6.97(1H，s)，7.22-7.29(1H，m)，7.33-7.40(1H，m)，7.58(1H，dd，J＝8.8，2.7Hz)，8.03(1H，d，J＝2.7Hz).

MS(ESI)m/z：354(M+H)⁺.

[ reference example 49]5- (2-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

The title compound (454mg, quantitative) was obtained as a solid by the same method as in reference example 45 using the ethyl pyrazole-3-carboxylate (473mg) of reference example 48.

¹H-NMR(400MHz，CDCl₃)δ：3.50(3H，s)，3.91(3H，s)，6.70(1H，d，J＝8.8Hz)，6.83(1H，d，J＝8.3Hz)，6.97-7.03(1H，m)，7.04(1H，s)，7.23-7.30(1H，m)，7.35-7.42(1H，m)，7.58(1H，dd，J＝8.8，2.7Hz)，8.05(1H，d，J＝2.7Hz).

MS(ESI)m/z：326(M+H)⁺.

[ reference example 50]5- [4- (trifluoromethyl) phenyl ] -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (332mg, 42%) was obtained as an oil by the same method as in reference example 44 using 4' - (trifluoromethyl) acetophenone (376mg) and diethyl oxalate (542. mu.l) and further using 5-hydrazino-2-methoxypyridine hydrochloride (421mg) of reference example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.1Hz)，3.94(3H，s)，4.46(2H，q，J＝7.1Hz)，6.77(1H，d，J＝8.8Hz)，7.10(1H，s)，7.34(2H，d，J＝8.0Hz)，7.56-7.64(3H，m)，8.07(1H，d，J＝2.7Hz).

MS(ESI)m/z：392(M+H)⁺.

[ reference example 51]5- [4- (trifluoromethyl) phenyl ] -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

The title compound (309mg, quantitative) was obtained as crystals by the same method as in reference example 45 using the ethyl pyrazole-3-carboxylate (332mg) of reference example 50.

¹H-NMR(400MHz，CDCl₃)δ：3.96(3H，s)，6.79(1H，d，J＝8.8Hz)，7.15(1H，s)，7.37(2H，d，J＝8.5Hz)，7.58(1H，dd，J＝8.8，2.7Hz)，7.62(2H，d，J＝8.5Hz)，8.09(1H，d，J＝2.7Hz).

MS(ESI)m/z：364(M+H)⁺.

[ reference example 52] 3-hydrazinopyridine

An aqueous solution (20ml) of sodium nitrite (4.28g) was added dropwise to a concentrated hydrochloric acid (54ml) solution of 3-aminopyridine (5.15g) over 30 minutes at an internal temperature of 0 to 5 ℃ and stirred for 5 minutes. The reaction solution was dropped into a concentrated hydrochloric acid (30ml) solution of tin (II) chloride 2 hydrate (43.68g) over 1 hour at an internal temperature of 0 to 10 ℃ and stirred for 0.5 hour. The precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain the title compound (16.38g, quantitative).

¹H-NMR(400MHz，DMSO-d₆) δ: 7.93(1H, dd, J ═ 8.8, 5.6Hz), 8.09(1H, dd, J ═ 8.8, 2.7Hz), 8.43(1H, d, J ═ 5.6Hz), 8.51(1H, d-like, J ═ 2.7Hz).

MS(ESI)m/z：109(M)⁺.

[ reference example 53] 4-methyl-5-phenyl-1- (3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

1) 3-methyl-4-phenyl-2, 4-dioxobutyric acid ethyl ester

A solution of propiophenone (4.0g) in diethyl ether (5ml) was added to a 1.0M solution of lithium-bis (trimethylsilyl) amide in tetrahydrofuran (30ml) at-78 ℃ and stirred for 30 minutes. Then, a solution of diethyl oxalate (4.35g) in diethyl ether (5ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Subsequently, the mixture was stirred at room temperature for 16 hours, and the precipitated solid was collected by filtration, washed with diethyl ether and dried to obtain a lithium salt of ethyl 3-methyl-4-phenyl-2, 4-dioxobutyrate (3.23g, 47%) as a solid.

MS(FAB)m/z：235(M+H)⁺.

2) The title Compound

To a solution of the above lithium salt of ethyl 3-methyl-4-phenyl-2, 4-dioxobutyrate (1.502g) in ethanol (30ml) were added a 1M-hydrochloric acid-ethanol solution (8ml) and 3-hydrazinopyridine (1.977g) of reference example 52, and the mixture was refluxed for 2.5 hours. After air cooling, an aqueous sodium hydroxide solution was added to the reaction mixture to make it basic (pH10), and then chloroform and water were added to separate the mixture. The aqueous layer was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetone) to obtain the title compound (1.428g, 34%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.44(3H，t，J＝7.1Hz)，2.32(3H，s)，4.47(2H，q，J＝7.1Hz)，7.13-7.20(2H，m)，7.22-7.30(1H，m)，7.35-7.42(3H，m)，7.60-7.68(1H，m)，8.46-8.53(2H，m).

MS(FAB)m/z：308(M+H)⁺.

[ reference example 54] 4-methyl-5-phenyl-1- (3-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.892g, 69%) was obtained as a solid by the same method as in referential example 45 using the ethyl pyrazole-3-carboxylate (1.428g) of referential example 53.

¹H-NMR(400MHz，DMSO-d₆) δ: 2.20(3H, s), 7.20-7.30(2H, m), 7.37-7.50(m, 4H), 7.66-7.74(1H, m), 8.41(1H, d, J ═ 2.7Hz), 8.52(1H, d-like, J ═ 4.7Hz), 12.91(1H, br).

LC-MSm/z：280(M+H)⁺.

[ reference example 55] 4-methyl-1, 5-diphenylpyrazole-3-carboxylic acid ethyl ester

The title compound (1.897g, 62%) was obtained as an oil by the same method as in 2) of reference example 53 using the lithium salt (3.04g) of ethyl 3-methyl-4-phenyl-2, 4-dioxobutyrate of 1) of reference example 53 and phenylhydrazone (1.671 g).

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.3Hz)，2.32(3H，s)，4.46(2H，q，J＝7.3Hz)，7.10-7.18(2H，m)，7.20-7.31(5H，m)，7.32-7.40(3H，m).

MS(FAB)m/z：307(M+H)⁺.

[ reference example 56] 4-methyl-1, 5-diphenylpyrazole-3-carboxylic acid

The title compound (1.38g, 80%) was obtained as a solid by the same method as in reference example 4 using the ethyl pyrazole-3-carboxylate (1.897g) of reference example 55.

¹H-NMR(400MHz，DMSO-d₆)δ：2.20(3H，s)，7.15-7.25(4H，m)，7.30-7.45(6H，m)，12.80(H，br).

MS(FAB)m/z：279(M+H)⁺.

[ reference example 57] alpha-fluoroacetophenone

A suspension of potassium fluoride (3.091g) and 18-crown-6-ether (0.341g) in acetonitrile (25ml) was stirred at 55 ℃ for 1 hour, and α -bromoacetophenone (5.12g) was added to the reaction mixture and stirred for 20 hours. Then, diethyl ether was added to the reaction mixture, and the insoluble matter precipitated was filtered off. The filtrate was separated by adding water, and the organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a residue.

The reaction was repeated in an equal amount to the above reaction, and the obtained residue was combined with the residue of the above reaction and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (4.7g, 45%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 5.53(2H, d, J ═ 47.0Hz), 7.50(2H, t-like, J ═ 7.9Hz), 7.62(1H, t-like, J ═ 7.9Hz), 7.89(2H, d-like, J ═ 7.9Hz).

MS(ESI)m/z：139(M+H)⁺.

[ reference example 58] 4-fluoro-1, 5-diphenylpyrazole-3-carboxylic acid ethyl ester

1) 3-fluoro-4-phenyl-2, 4-dioxobutyric acid ethyl ester

A1.0M tetrahydrofuran solution (13ml) of lithium-bis (trimethylsilyl) amide was added dropwise to a tetrahydrofuran (35ml) solution of α -fluoroacetophenone (1.64g) at-78 ℃ and stirred for 45 minutes. Diethyl oxalate (1.77ml) was added to the reaction mixture, followed by stirring for 30 minutes and then stirring at 0 ℃ for 1 hour. The reaction mixture was neutralized with 1M-hydrochloric acid aqueous solution, and water and chloroform were added to separate the reaction mixture. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 3-fluoro-4-phenyl-2, 4-dioxobutyrate (0.753g, 27%) as an oil.

2) The title Compound

The title compound (0.208g, 15%) was obtained in the same manner as in 2) of reference example 53 using the lithium salt of ethyl 3-fluoro-4-phenyl-2, 4-dioxobutyrate (0.753g) and phenylhydrazine (0.350 g).

¹H-NMR(400MHz，CDCl₃) δ: 1.27(3H, t, J ═ 7.1Hz), 4.30(2H, q, J ═ 7.1Hz), 7.33-7.52(8H, m), 7.93(2H, d-like, J ═ 7.4Hz).

MS(FAB)m/z：311(M+H)⁺.

[ reference example 59] 4-fluoro-1, 5-diphenylpyrazole-3-carboxylic acid

The title compound (0.169g, 90%) was obtained as a solid by the same method as in reference example 4 using the ethyl pyrazole-3-carboxylate (0.208g) of reference example 58.

¹H-NMR(400MHz，DMSO-d₆) δ: 7.45(1H, t-like, J ═ 7.6Hz), 7.48-7.60(7H, m), 7.83(1H, d-like, J ═ 7.3Hz).

[ reference example 60] Ethyl 1, 4-dihydro-1- (6-methoxy-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylate

To a solution of 1-indanone (661mg) in N, N-dimethylformamide (10ml) was added 60% sodium hydride (400mg) at 0 ℃ and the mixture was stirred at room temperature for 0.5 hour. Diethyl oxalate (1.36ml) was added to the reaction mixture at 0 ℃ and stirred at room temperature for 16 hours. After adding 1M aqueous hydrochloric acid (11ml) to the reaction mixture to make it acidic, water and ethyl acetate were added to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 2-oxo-2- (1-oxoindan-2-yl) acetate (1.441g, quantitative) as an oil. To a solution of the obtained ethyl 2-oxo-2- (1-oxoindan-2-yl) acetate in ethanol (25ml) was added 5-hydrazino-2-methoxypyridine (696ml) of reference example 2, and the mixture was refluxed for 16 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the obtained residue to separate the liquid. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (890mg, 53%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：1.45(3H，t，J＝7.0Hz)，3.84(2H，s)，4.04(3H，s)，4.47(2H，q，J＝7.0Hz)，6.93(1H，d，J＝8.8Hz)，7.27-7.34(2H，m)，7.36-7.41(1H，m)，7.57(1H，d，J＝6.6Hz)，7.96(1H，dd，J＝8.8，2.9Hz)，8.54(1H，d，J＝2.9Hz).

MS(ESI)m/z：336(M+H)⁺.

[ reference example 61]1, 4-dihydro-1- (6-methoxy-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylic acid

The title compound (791mg, 97%) was obtained as crystals by the same method as in referential example 45 using ethyl 1, 4-dihydro-1- (6-methoxy-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylate (890mg) of referential example 60.

¹H-NMR(400MHz，CDCl₃)δ：3.89(2H，s)，4.05(3H，s)，6.95(1H，d，J＝8.8Hz)，7.28-7.36(2H，m)，7.38-7.42(1H，m)，7.58(1H，d，J＝6.6Hz)，7.96(1H，dd，J＝8.8，2.6Hz)，8.56(1H，d，J＝2.6Hz).

MS(ESI)m/z：308(M+H)⁺.

[ reference example 62] 2-oxo-2- (1-oxoindan-2-yl) acetic acid ethyl ester

The title compound (3.39g, 97%) was obtained as crystals by the same method as in 1) of reference example 3 using 1-indanone (1.982g) and diethyl oxalate (4.07 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.0Hz)，3.99(2H，s)，4.42(2H，q，J＝7.0Hz)，7.44(1H，dd，J＝7.3，7.1Hz)，7.55(1H，d，J＝7.3Hz)，7.64(1H，dd，J＝7.3，7.1Hz)，7.87(1H，d，J＝7.3Hz).

MS(ESI)m/z：233(M+H)⁺.

[ reference example 63] Ethyl 1, 4-dihydro-1- (6-methyl-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylate

A solution of 5-tert-butoxycarbonylamino-2-methylpyridine (625mg) in concentrated hydrochloric acid (3ml) was stirred at room temperature for 50 minutes. An aqueous solution (1ml) of sodium nitrite (228mg) was added dropwise to the reaction mixture over 10 minutes under ice-common salt cooling, followed by stirring for 10 minutes. Then, a solution of tin dichloride 2 hydrate (2.37g) in concentrated hydrochloric acid (1.6ml) was added dropwise to the reaction mixture over 10 minutes, and the mixture was stirred under ice cooling for 3 hours. Subsequently, a solution of ethyl 2-oxo-2- (1-oxoindan-2-yl) acetate (696mg) obtained in referential example 62 in ethanol (20ml) was added to the reaction mixture, and the mixture was refluxed for 39 hours. After the reaction mixture was made alkaline with an aqueous sodium hydroxide solution under ice-cooling, ethyl acetate and the aqueous solution were added, and the organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetone) to obtain the title compound (340mg, 35%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：1.46(3H，t，J＝7.0Hz)，2.69(3H，s)，3.85(2H，s)，4.48(2H，q，J＝7.0Hz)，7.24-7.35(2H，m)，7.37(1H，d，J＝8.3Hz)，7.46(1H，dd，J＝6.8，1.3Hz)，7.58(1H，d，J＝7.3Hz)，8.00(1H，dd，J＝8.3，2.4Hz)，8.92(1H，d，J＝2.4Hz).

MS(ESI)m/z：320(M+H)⁺.

[ reference example 64]1, 4-dihydro-1- (6-methyl-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylic acid

The title compound (287mg, 95%) was obtained as a solid by the same method as in reference example 45 using ethyl 1, 4-dihydro-1- (6-methyl-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylate (331mg) of reference example 63.

¹H-NMR(400MHz，DMSO-d₆)δ：2.62(3H，s)，3.81(2H，s)，7.31-7.39(3H，m)，7.56(1H，d，J＝8.1Hz)，7.60-7.68(1H，m)，8.10(1H，dd，J＝8.1，2.4Hz)，8.85(1H，d，J＝2.4Hz)，13.02-13.16(1H，br).

MS(ESI)m/z：292(M+H)⁺.

[ reference example 65] 5-Nitro-2-vinylpyridine

Tributyl (vinyl) tin (6.658g) and tetrakis (triphenylphosphine) palladium (0) (1.155g) were added to a tetrahydrofuran (40ml) solution of 2-chloro-5-nitropyridine (3.171g) and 2, 6-di-tert-butyl-p-cresol (44mg) under argon atmosphere, and the mixture was refluxed for 14 hours. After air-cooling, a solution of ethyl acetate and sodium fluoride (2.52g) in water (60ml) was added to the reaction mixture at room temperature, and the mixture was stirred for 7 hours. After insoluble matter was filtered off, the aqueous solution was added to the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.519g, 50%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：5.74(1H，dd，J＝10.8，1.0Hz)，6.45(1H，dd，J＝17.4，1.0Hz)，6.90(1H，dd，J＝17.4，10.8Hz)，7.47(1H，d，J＝8.8Hz)，8.43(1H，dd，J＝8.8，2.4Hz)，9.38(1H，d，J＝2.4Hz).

MS(ESI)m/z：151(M+H)⁺.

[ reference example 66] 5-amino-2-ethylpyridine

To a solution of 5-nitro-2-vinylpyridine (450mg) in ethanol (30ml) was added 10% palladium-carbon (50% wet, 90mg), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure to obtain the title compound (359mg, 98%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.25(3H，t，J＝7.5Hz)，2.71(2H，q，J＝7.5Hz)，3.32-3.78(2H，br)，6.91-6.98(2H，m)，8.02-8.05(1H，m)。MS(ESI)m/z：1 23(M+H)⁺.

[ reference example 67] ethyl 1- (6-ethyl-3-pyridyl) -1, 4-dihydroindeno [1, 2-c ] pyrazole-3-carboxylate

A solution of sodium nitrite (228mg) in concentrated hydrochloric acid (3ml) was added dropwise to a solution of 5-amino-2-ethylpyridine (359mg) in water (1ml) over 10 minutes under cooling with ice-common salt, and the mixture was stirred at the same temperature for 10 minutes. A solution of tin dichloride 2 hydrate (2.37g) in concentrated hydrochloric acid (1.6ml) was added dropwise to the reaction mixture over 10 minutes, and the mixture was stirred under ice cooling for 3 hours. A solution of ethyl 2-oxo-2- (1-oxoindan-2-yl) acetate (696mg) in ethanol (20ml) according to reference example 62 was added to the reaction mixture, which was then refluxed for 39 hours. Then, an aqueous sodium hydroxide solution was added to the reaction mixture under ice-cooling to make it alkaline, ethyl acetate and the aqueous solution were added, and the organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetone) to obtain the title compound (372mg, 37%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：1.39(3H，t，J＝7.0Hz)，1.45(3H，t，J＝7.0Hz)，2.94(2H，q，J＝7.0Hz)，3.85(2H，s)，4.48(2H，q，J＝7.0Hz)，7.25-7.35(2H，m)，7.38(1H，d，J＝8.3Hz)，7.46(1H，dd，J＝6.3，1.7Hz)，7.58(1H，d，J＝6.8Hz)，8.02(1H，dd，J＝8.3，2.4Hz)，8.94(1H，d，J＝2.4Hz).

MS(ESI)m/z：334(M+H)⁺.

[ reference example 68]1- (6-Ethyl-3-pyridinyl) -1, 4-dihydroindeno [1, 2-c ] pyrazole-3-carboxylic acid

The title compound (302mg, 91%) was obtained as crystals by the same method as in reference example 45 using ethyl 1- (6-ethyl-3-pyridyl) -1, 4-dihydroindeno [1, 2-c ] pyrazole-3-carboxylate (360mg) of reference example 67.

¹H-NMR(400MHz，DMSO-d₆)δ：1.33(3H，t，J＝7.5Hz)，2.91(2H，q，J＝7.5Hz)，3.81(2H，s)，7.32-7.40(3H，m)，7.57(1H，d，J＝8.3Hz)，7.62-7.69(1H，m)，8.13(1H，dd，J＝8.3，2.4Hz)，8.89(1H，d，J＝2.4Hz)，13.05-13.13(1H，br)。

MS(ESI)m/z：306(M+H)⁺.

[ reference example 69] Ethyl 1, 4-dihydro-1- (2-methoxypyridin-5-yl) -4-oxoindeno [1, 2-c ] pyrazole-3-carboxylate

A1.1M hexane solution (3ml) of lithium bis (trimethylsilyl) amide was added dropwise to a tetrahydrofuran (15ml) solution of 1, 3-indandione (438mg) under cooling at-78 ℃ for 10 minutes under argon atmosphere, and the mixture was stirred for 45 minutes. To the reaction mixture was added a solution of ethyl glyoxylate (450mg) in tetrahydrofuran (3ml), and the mixture was stirred at 0 ℃ for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethanol (15ml), followed by addition of 5-hydrazino-2-methoxypyridine (417mg) of reference example 2 and heating under reflux for 14 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed successively with a 5% citric acid aqueous solution, water, a saturated sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (22mg, 2%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.47(3H，t，J＝7.0Hz)，4.04(3H，s)，4.49(2H，q，J＝7.0Hz)，6.94(1H，d，J＝8.8Hz)，7.08-7.15(1H，m)，7.32-7.40(2H，m)，7.63-7.71(1H，m)，7.93(1H，dd，J＝8.8，2.9Hz)，8.51(1H，d，J＝2.9Hz).

MS(ESI)m/z：350(M+H)⁺.

[ reference example 70]1, 4-dihydro-1- (6-methoxy-3-pyridyl) -4-oxoindeno [1, 2-c ] pyrazole-3-carboxylic acid

The title compound (16mg, 80%) was obtained as a solid by the same method as in referential example 45 using ethyl 1, 4-dihydro-1- (6-methoxy-3-pyridyl) -4-oxoindeno [1, 2-c ] pyrazole-3-carboxylate (22mg) of referential example 69.

¹H-NMR(400MHz，CDCl₃)δ：4.05(3H，s)，6.96(1H，d，J＝8.8Hz)，7.15-7.20(1H，m)，7.36-7.43(2H，m)，7.67-7.73(1H，m)，7.95(1H，dd，J＝8.8，2.7Hz)，8.52(1H，d，J＝2.7Hz).

MS(ESI)m/z：322(M+H)⁺.

[ reference example 71] Ethyl 4, 5-dihydro-1- (6-methoxy-3-pyridyl) -1H-benzo [ g ] indazole-3-carboxylate

A1.1M hexane solution (5ml) of lithium bis (trimethylsilyl) amide was added dropwise to a tetrahydrofuran (10ml) solution of α -tetralone (731mg) over 10 minutes under cooling at-78 ℃ under argon atmosphere, followed by stirring for 0.5 hour. A solution of diethyl oxalate (1.461g) in tetrahydrofuran (5ml) was added to the reaction mixture, and the mixture was stirred at 0 ℃ for 2 hours and then at room temperature for 14 hours. Then, 1M-hydrochloric acid aqueous solution (10ml) was added to the reaction solution to make it acidic, and water and ethyl acetate were added to separate the solution. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 2- (1, 2, 3, 4-tetrahydro-1-oxonaphthalen-2-yl) -2-oxoacetate (1.516g, quantitative) as an oil. To a solution of the obtained ethyl ester in ethanol (20ml), 5-hydrazino-2-methoxypyridine (696mg) of reference example 2 was added, and the mixture was refluxed for 18 hours. After air-cooling, the solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed with a 5% citric acid aqueous solution, water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.093g, 62%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 1.42(3H, t, J ═ 7.1Hz), 2.96-3.13(4H, m), 4.01(3H, s), 4.44(2H, q, J ═ 7.0Hz), 6.77(1H, d-like, J ═ 7.1Hz), 6.85(1H, d, J ═ 8.8Hz), 7.00-7.06(1H, m), 7.15-7.21(1H, m), 7.30(1H, d-like, J ═ 7.6Hz), 7.70(1H, dd, J ═ 8.8, 2.7Hz), 8.33(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：350(M+H)⁺.

[ reference example 72]4, 5-dihydro-1- (6-methoxy-3-pyridyl) -1H-benzo [ g ] indazole-3-carboxylic acid

The title compound (745mg, 79%) was obtained as crystals by the same method as in reference example 45 using ethyl 4, 5-dihydro-1- (6-methoxy-3-pyridyl) -1H-benzo [ g ] indazole-3-carboxylate (1.015g) of reference example 71.

¹H-NMR(400MHz，DMSO-d₆)δ：2.96(4H，s)，3.96(3H，s)，6.68(1H，d，J＝7.6Hz)，7.03(1H，d，J＝8.8Hz)，7.08(1H，dd，J＝7.6，7.6Hz)，7.21(1H，dd，J＝7.6，7.6Hz)，7.36(1H，d，J＝7.6Hz)，7.90(1H，dd，J＝8.8，2.7Hz)，8.36(1H，d，J＝2.7Hz)，12.92(1H，s).

MS(ESI)m/z：322(M+H)⁺.

[ reference example 73] Ethyl 1, 4-dihydro-1- (6-methoxy-3-pyridyl) chromeno [4, 3-c ] pyrazole-3-carboxylate

A1.1M hexane solution (3ml) of lithium bis (trimethylsilyl) amide was added dropwise to a tetrahydrofuran (10ml) solution of 4-chromanone (444mg) under cooling at-78 ℃ for 10 minutes under argon, followed by stirring for 0.5 hour. A solution of diethyl oxalate (877mg) in tetrahydrofuran (3ml) was added to the reaction mixture, which was stirred at 0 ℃ for 2 hours. Then, 1M-hydrochloric acid aqueous solution (6ml) was added to the reaction solution to make it acidic, and water and ethyl acetate were added to separate the solution. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 2-oxo-2- (4-oxochroman-3-yl) acetate (855mg, quantitative) as a semi-solid. To a solution of the obtained ethyl ester in ethanol (30ml), 5-hydrazino-2-methoxypyridine (417mg) of reference example 2 was added, and the mixture was refluxed for 14 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the obtained residue to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the obtained crystals were recrystallized from ethyl acetate-hexane to obtain the title compound (267mg) as crystals. Then, the solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (hexane-ethyl acetate) to obtain the title compound (28 mg). Combined with the previously obtained crystals to obtain the title compound (295mg, 27%).

¹H-NMR(400MHz，CDCl₃) δ: 1.42(3H, t, J ═ 7.1Hz), 4.03(3H, s), 4.44(2H, q, J ═ 7.0Hz), 5.55(2H, s), 6.72-6.80(2H, m), 6.88(1H, d, J ═ 8.8Hz), 7.01(1H, d-like, J ═ 8.8Hz), 7.16-7.22(1H, m), 7.70(1H, dd, J ═ 8.8, 2.7Hz), 8.34(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：352(M+H)⁺.

[ reference example 74]1, 4-dihydro-1- (6-methoxy-3-pyridyl) chromeno [4, 3-c ] pyrazole-3-carboxylic acid

The title compound (226mg, 93%) was obtained as crystals by the same method as in reference example 45 using ethyl 1, 4-dihydro-1- (2-methoxypyridin-5-yl) chromeno [4, 3-c ] pyrazole-3-carboxylate (265mg) of reference example 73.

¹H-NMR(400MHz，DMSO-d₆)δ：3.97(3H，s)，5.48(2H，s)，6.67(1H，dd，J＝7.8，1.3Hz)，6.84(1H，dd，J＝7.8，7.8Hz)，7.02(1H，d，J＝8.3Hz)，7.06(1H，d，J＝8.8Hz)，7.22(1H，dd，J＝8.3，7.6Hz)，7.97(1H，dd，J＝8.8，2.7Hz)，8.43(1H，d，J＝2.7Hz)，13.26(1H，br s).

MS(ESI)m/z：324(M+H)⁺.

[ reference example 75] [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methanol

A tetrahydrofuran solution (9.2ml) of 1.08M-borane-tetrahydrofuran complex was added dropwise to a tetrahydrofuran (20ml) solution of 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (1.181g) in referential example 41 over 10 minutes under ice-cooling under argon atmosphere, followed by stirring at room temperature for 7 hours. Water and ethyl acetate were added to the reaction mixture, followed by stirring, and insoluble substances precipitated were filtered off to separate an organic layer. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (682mg, 60%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：3.92(3H，s)，4.79(2H，s)，6.52(1H，s)，6.72(1H，d，J＝8.5Hz)，7.18-7.27(2H，m)，7.29-7.37(3H，m)，7.52(1H，dd，J＝8.5，2.7Hz)，8.07(1H，d，J＝2.7Hz).

MS(ESI)m/z：282(M+H)⁺.

[ reference example 76] methanesulfonic acid [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methyl ester

Triethylamine (61. mu.l) and methanesulfonyl chloride (34. mu.l) were added to a solution of [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methanol (112mg) in dichloromethane (4ml) of referential example 75 at room temperature, and stirred for 15 minutes. Then, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (138mg, 96%) as an oil.

MS(ESI)m/z：360(M+H)⁺.

[ reference example 77] tert-butyl 2- (2-hydroxyethyl) piperidine-1-carboxylate

To a solution of 2-piperidineethanol (1.292g) and triethylamine (1.393ml) in dichloromethane (40ml) was added a solution of di-tert-butyl dicarbonate (2.182g) in dichloromethane (40ml) at room temperature, followed by stirring for 1 hour. The reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed with a 5% citric acid aqueous solution, water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (2.182g, 95%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.33-1.81(7H，m)，1.49(9H，s)，1.88-2.00(1H，br m)，2.63-2.73(1H，m)，3.25-3.47(1H，br)，3.56-3.66(1H，brm)，3.75-4.08(2H，br)，4.35-4.54(1H，br).

[ reference example 78] methanesulfonic acid 2- (N-tert-butoxycarbonylpiperidin-2-yl) ethyl ester

Methanesulfonyl chloride (116. mu.l) was added to a solution of tert-butyl 2- (2-hydroxyethyl) piperidine-1-carboxylate (229mg) of reference example 77 and triethylamine (209. mu.l) in dichloromethane (5ml) at room temperature, followed by stirring for 30 minutes. The reaction solvent was distilled off under reduced pressure, and water and methylene chloride were added to the resulting residue to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (288mg, 93%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：1.34-1.70(6H，m)，1.46(9H，s)，1.75-1.86(1H，m)，2.16-2.27(1H，m)，2.71-2.81(1H，br m)，3.01(3H，s)，3.92-4.08(1H，br)，4.20(2H，t，J＝6.8Hz)，4.34-4.48(1H，br).

[ reference example 79] tert-butyl 2- (2-azidoethyl) piperidine-1-carboxylate

To a solution of the methanesulfonate (288mg) of referential example 78 in N, N-dimethylformamide (10ml) was added sodium azide (325mg), and the mixture was stirred at 80 ℃ for 15 hours. Then, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (217mg, 91%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.32-1.70(7H，m)，1.46(9H，s)，1.98-2.09(1H，m)，2.68-2.80(1H，br m)，3.22-3.31(2H，m)，3.91-4.09(1H，br)，4.28-4.39(1H，br).

[ reference example 80]2- (2-azidoethyl) piperidine

Trifluoroacetic acid (1ml) was added to a dichloromethane (3ml) solution of the azide (215mg) in referential example 79 at room temperature, and the mixture was stirred for 30 minutes. Then, the reaction solvent was distilled off under reduced pressure, and a saturated aqueous sodium bicarbonate solution and methylene chloride were added to the obtained residue to separate. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (62mg) as an oil. The aqueous layer after separation was saturated with common salt, extracted 2 times with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (39mg) as an oil in a total amount of 101mg (yield: 77%).

¹H-NMR(400MHz，CDCl₃)δ：1.04-1.17(1H，m)，1.30-1.45(2H，m)，1.53-1.71(5H，m)，1.75-1.86(1H，m)，2.56-2.69(2H，m)，3.02-3.11(1H，m)，3.32-3.44(2H，m).

MS(ESI)m/z：155(M+H)⁺.

[ reference example 81]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2- (2-azidoethyl) piperidine

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (186mg) was added to a solution of 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (191mg) of referential example 41, 2- (2-azidoethyl) piperidine (100mg) of referential example 80, 1-hydroxybenzotriazole (88mg) and triethylamine (316. mu.l) in methylene chloride (10ml) at room temperature, followed by stirring for 14 hours. The reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (hexane-ethyl acetate) to obtain the title compound (227mg, 81%) as an oil.

¹H-NMR(400MHz，CDCl₃) [2 mixture of isomers]δ: 1.51-1.87(7H, m), 2.13-2.28(1H, br), 2.76-2.89(0.5H, br m), 3.13-3.27(0.5H, br m), 3.30-3.49(2H, m), 3.94(3H, s), 4.67 and 4.70(1H, br s), 4.99-5.19(1H, br m), 6.71(1H, d, J ═ 8.8Hz), 6.86 and 6.88 (0.5H each, br s), 7.20-7.27(2H, m), 7.30-7.37(3H, m), 7.48(1H, dd, J ═ 8.8, 2,7Hz), 8.12(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：432(M+H)⁺.

[ reference example 82] tert-butyl 3-methylpiperazine-1-carboxylate

2-methylpiperazine (3.19g) was added to a tetrahydrofuran (100ml) solution of 2- (tert-butylcarbonyloxyimino) -2-phenylacetonitrile (7.87g) at 0 ℃ and stirred for 2 hours. The reaction solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-7N ammonia/methanol solution) to obtain the title compound (5.70g, 89%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.05(3H，d，J＝6.4Hz)，1.46(9H，s)，2.40(1H，br)，2.65-2.84(3H，m)，2.90-3.00(1H，br)，3.94(2H，br).MS(ESI)m/z：201(M+H)⁺.

[ reference example 83] tert-butyl 3, 4-dimethylpiperazine-1-carboxylate

To a methanol (100ml) solution of tert-butyl 3-methylpiperazine-1-carboxylate (5.70g) of referential example 82 was added 10% palladium-carbon (0.59g) and a 35% formalin aqueous solution (9.7ml) and a 1M-hydrochloric acid-ethanol solution (31.3ml) at room temperature, and the mixture was stirred for 15 hours under a hydrogen atmosphere. After the nitrogen substitution, insoluble matter was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, chloroform-methanol (9%) was added to the residue, and an aqueous sodium hydroxide solution was added thereto to make the residue alkaline, followed by liquid separation. Subsequently, the aqueous layer was extracted with chloroform-methanol (9%), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (3.10g, 51%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.04(3H，d，J＝6.3Hz)，1.46(9H，s)，1.95-2.20(2H，m)，2.28(3H，s)，2.50-2.78(2H，br)，2.90-3.05(1H，br)，3.88(1H，br).

MS(ESI)m/z：215(M+H)⁺.

[ reference example 84]1, 2-dimethylpiperazine trifluoroacetate

Trifluoroacetic acid (15ml) was added to a solution of tert-butyl 3, 4-dimethylpiperazine-1-carboxylate (3.10g) in dichloromethane (30ml) in referential example 83 at room temperature, and the mixture was stirred for 1 hour. The reaction solvent was evaporated under reduced pressure, and the obtained residue was crystallized from chloroform-ether and then filtered to obtain the title compound (2.756g, 56%).

¹H-NMR(400MHz，DMSO-d₆)δ：1.24(3H，d，J＝6.4Hz)，2.30-3.70(10H，br).

MS(ESI)m/z：115(M+H)⁺.

[ reference example 85] 1-benzyl-2-methylpiperazine trifluoroacetate

1) N-benzyl compound

Benzaldehyde (0.405ml), acetic acid (0.230ml) and sodium cyanoborohydride (0.164g) were added to a solution of tert-butyl 3-methylpiperazine-1-carboxylate (0.530g) in ethanol (10ml) of referential example 82 at room temperature, and the mixture was stirred for 19 hours. After cooling at 0 ℃, a saturated aqueous sodium bicarbonate solution and chloroform were added thereto, followed by liquid separation. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetone) to obtain N-benzyl base (0.547g, 71%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.12(3H，d，J＝6.1Hz)，1.44(9H，s)，2.07(1H，br)，2.35-2.47(1H，m)，2.56-2.69(1H，m)，2.97-3.23(2H，m)，3.57-3.65(1H，m)，3.90-4.01(1H，m)，4.69(2H，s)，7.15-7.45(5H，m).

LC-MSm/z：291(M+H)⁺.

2) The title Compound

Trifluoroacetic acid (1.5ml) was added to a solution of the above N-benzyl base (0.547g) in dichloromethane (10ml) at room temperature, and the mixture was stirred for 2 hours. The reaction solvent was distilled off under reduced pressure, and then toluene was added thereto, followed by azeotropic distillation under reduced pressure. The obtained residue was crystallized from chloroform-ether, filtered and dried to obtain the title compound (0.610g, 55%).

¹H-NMR(400MHz，DMSO-d₆)δ：1.35(3H，d，J＝6.3Hz)，2.5-4.5(9H，m)，7.30-7.60(5H，m)，9.00(1H，br).

MS(ESI)m/z：191(M+H)⁺.

[ reference example 86] (4' -Phenylmethoxy) acetophenone

To a solution of 4' -hydroxyacetophenone (3.00g) in N, N-dimethylformamide (60ml) were added potassium carbonate (6.15g) and benzyl bromide (2.75ml) at room temperature, and the mixture was stirred at 80 ℃ for 3 hours. After air cooling, water and ethyl acetate were added for liquid separation. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (4.49g, 90%) as a solid.

¹H-NMR(400MHz，CDCl₃) δ: 2.55(3H, s), 5.13(2H, s), 7.00(2H, d-like, J ═ 9.1Hz), 7.30-7.50 (5)H, m), 7.93(2H, d-like, J ═ 9.1Hz).

MS(FAB)m/z：227(M+H)⁺

[ reference example 87] tert-butyl 3, 5-dimethylpiperazine-1-carboxylate

Cis-2, 6-dimethylpiperazine (5.08g) was added to a solution of 2- (tert-butoxycarbonylimino) -2-phenylacetonitrile (11.35g) in tetrahydrofuran (150ml) at 0 ℃ and stirred for 2 hours. The reaction solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-7N ammonia/methanol solution) to obtain the title compound (15.36g, 72%).

¹H-NMR(400MHz，CDCl₃)δ：1.16(6H，d，J＝6.5Hz)，1.47(9H，s)，2.50(2H，br)，2.90(2H，br)，4.02(2H，br).

MS(ESI)m/z：214(M+H)⁺.

[ reference example 88] tert-butyl 3, 4, 5-trimethylpiperazine-1-carboxylate

To a methanol (50ml) solution of tert-butyl 3, 5-dimethylpiperazine-1-carboxylate (3.31g) of referential example 87 was added 10% palladium-carbon (0.504g), a 35% formalin aqueous solution (1.85ml) and a 1M-hydrochloric acid-ethanol solution (15.4ml) at room temperature, and the mixture was stirred for 19 hours under a hydrogen atmosphere. Then, 10% palladium-carbon (0.95g), 35% formalin aqueous solution (1.8ml), and 1M-hydrochloric acid-ethanol solution (15ml) were added again, and stirred for 23 hours under a hydrogen atmosphere. After replacement with nitrogen, the mixture was neutralized with an aqueous sodium hydroxide solution, and insoluble matter was filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-7N ammonia/methanol) to obtain the title compound (2.28g, 65%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.08(6H，d，J＝6.1Hz)，1.45(9H，s)，2.00-2.20(2H，m)，2.25(3H，s)，2.60(2H，br)，3.85(2H，br).

MS(FAB)m/z：229(M+H)⁺.

[ reference example 89]1, 2, 6-Trimethylpiperazine trifluoroacetate

The title compound (3.579g, quantitative) was obtained as a solid by the same method as in reference example 84 using tert-butyl 3, 4, 5-trimethylpiperazine-1-carboxylate (2.28g) of reference example 88.

¹H-NMR(400MHz，DMSO-d₆)δ：1.28(6H，d，J＝6.6Hz)，2.71(3H，br)，2.90-3.60(6H，br)。

MS(ESI)m/z：128(M+H)⁺.

[ reference example 90] 4-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester

1) 3-Oxopiperazine-1-carboxylic acid tert-butyl ester

Triethylamine (3.9ml) and di-tert-butyl dicarbonate (6.31g) were added to a mixed solution of 2-oxopiperazine (2.61g) in tetrahydrofuran (40ml) and methanol (50ml) at room temperature, and the mixture was stirred for 3 hours. After the solvent was evaporated under reduced pressure, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration to obtain tert-butyl 3-oxopiperazine-1-carboxylate (4.54g, 87%).

¹H-NMR(400MHz，DMSO-d₆)δ：1.40(9H，s)，3.15(2H，br)，3.45(2H，br)，3.81(2H，br)，8.03(1H，br).

LC-MSm/z：201(M+H)⁺.

2) The title Compound

Sodium hydride (44.3 mg of a reagent obtained by washing with benzene and drying) was added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.303g) in N, N-dimethylformamide (12ml) at 0 ℃ and the mixture was stirred for 10 minutes. Methyl iodide (0.141ml) was added to the reaction solution, and the mixture was stirred at room temperature for 20 hours. Then, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (0.308mg, 95%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 1.46(9H, s), 2.99(3H, s), 3.34(2H, t-like, J ═ 5.3Hz), 3.65(2H, t-like, J ═ 5.3Hz), 4.07(2H, s).

MS(FAB)m/z：215(M+H)⁺.

[ reference example 91] 1-methylpiperazin-2-one trifluoroacetate

The title compound (0.485g, quantitative) was obtained in the same manner as in reference example 84 using tert-butyl 3-oxopiperazine-1-carboxylate (0.308g) obtained in reference example 90.

¹H-NMR(400MHz，CDCl₃-CD₃OD (15: 1)) delta: 2.98(3H, s), 3.39(2H, t-like, J ═ 6.1Hz), 3.54(2H, t-like, J ═ 6.1Hz), 3.72(2H, s).

MS(EI)m/z：114(M)⁺.

[ reference example 92] tert-butyl 2- (2-dimethylaminoethyl) -piperidine-1-carboxylate

A methanol solution (5ml) of 2M-dimethylamine was added to a methanol solution (5ml) of the methanesulfonate (292mg) of reference example 78 under ice cooling, and the mixture was stirred at room temperature for 87 hours. After the solvent was evaporated under reduced pressure, water and chloroform were added to the resulting residue to separate the mixture. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (172mg, 70%) as an oil.

MS(ESI)m/z：257(M+H)⁺.

[ reference example 93] ethyl 2- (piperidin-2-yl) acetate

Platinum (IV) oxide (15mg) was added to a solution of ethyl 2- (2-pyridyl) acetate (1.652g) in water (1.25ml) and concentrated hydrochloric acid (1.25ml) in methanol (15ml), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off, the solvent was evaporated under reduced pressure, and ethanol was added to the obtained residue, which was again evaporated under reduced pressure. To the resulting residue were added a small amount of water, diethyl ether (about 100ml) and an excess of potassium carbonate, followed by stirring and filtration. The solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (1.322g, 77%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.08-1.23(1H，m)，1.25(3H，t，J＝7.0Hz)，1.29-1.47(2H，m)，1.53-1.67(2H，m)，1.73-1.82(1H，m)，2.30-2.40(2H，m)，2.60-2.71(1H，m)，2.84-2.94(1H，m)，2.98-3.08(1H，m)，4.13(3H，t，J＝7.0Hz).

MS(ESI)m/z：172(M+H)⁺.

[ reference example 94] tert-butyl 1-isopropylpiperazine-4-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (1.862g) in methanol (20ml) were added acetone (1.47ml) and 10% palladium-carbon (50% wet, 186mg), and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. Acetone (1.47ml) was added thereto, and the mixture was stirred at room temperature for 36 hours under a hydrogen atmosphere. The catalyst was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (2.253g, 98%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 1.03(6H, d, J ═ 6.6Hz), 1.45(9H, s), 2.45(4H, t, J ═ 5.1Hz), 2.68(1H, seventy, J ═ 6.6Hz), 3.42(4H, t, J ═ 5.1Hz).

MS(ESI)m/z：229(M+H)⁺.

[ reference example 95] 1-isopropylpiperazine hydrochloride

To tert-butyl 1-isopropylpiperazine-4-carboxylate (2.253g) in referential example 94 was added a 1M-hydrochloric acid-ethanol solution (40ml), and the mixture was stirred at room temperature for 17 hours and then refluxed for 1 hour. After the solvent was distilled off under reduced pressure, ethanol was added to the obtained residue, and an insoluble solid was collected by filtration to obtain the title compound (824mg, 41%).

¹H-NMR(400MHz，DMSO-d₆)δ：1.29(6H，d，J＝6.3Hz)，3.26-3.63(9H，br)，9.47-10.02(2H，br)，11.60-12.00(1H，br).

MS(ESI)m/z：129(M+H)⁺.

[ reference example 96]1- (2-methoxyethyl) -piperazine-4-carboxylic acid tert-butyl ester

To a suspension of piperazine-4-carboxylic acid tert-butyl ester (1.87g) and potassium carbonate (1.38g) in N, N-dimethylformamide (20ml) was added dropwise 2-bromoethyl methyl ether (0.94ml) at room temperature, and the mixture was stirred at 60 ℃ for 24 hours. The reaction mixture was added with ice water and ethyl acetate to separate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (1.39g, 57%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.46(9H，s)，2.42-2.45(4H，m)，2.58(2H，t，J＝5.6Hz)，3.36(3H，s)，3.44-3.47(4H，m)，3.51(2H，t，J＝5.6Hz).

MS(ESI)m/z：245(M+H)⁺.

[ reference example 97]1- (2-methoxyethyl) piperazine hydrochloride

A solution of tert-butyl 1- (2-methoxyethyl) piperazine-4-carboxylate (1.39g) in 4N hydrochloric acid-dioxane (20ml) as in reference example 96 was stirred at room temperature for 3 hours. The reaction solution was distilled off under reduced pressure, and ethanol was added to the resulting residue, followed by distillation under reduced pressure. Ethanol and diethyl ether were added to the resulting residue, and the precipitated solid was collected by filtration to obtain the title compound (900mg, 74%).

¹H-NMR(400MHz，DMSO-d₆)δ：3.36-3.38(2H，m)，3.45(8H，br)，3.73-3.76(2H，m)，10.00(2H，br).LC-MSm/z：145(M+H)⁺.

[ reference example 98] 1-Cyclopropylpiperazine-4-carboxylic acid tert-butyl ester

Sodium cyanoborohydride (1.89g) was added to a solution of tert-butyl piperazine-1-carboxylate (1.87g), [ (1-ethoxycyclopropyl) oxy ] trimethylsilane (8.05ml) and acetic acid (5.72ml) in methanol (60ml) at room temperature, and the mixture was stirred for 5 days. The reaction solvent was evaporated under reduced pressure, and diethyl ether was added to the resulting residue to filter insoluble substances. The filtrate was added with a 1N aqueous solution of sodium hydroxide and separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.62g, 71%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：0.41-0.48(4H，m)，1.46(9H，s)，2.54-2.56(4H，m)，3.37-3.44(4H，m).

MS(ESI)m/z：268(M+MeCN)⁺.

[ reference example 99] 1-Cyclopropylpiperazine hydrochloride

The title compound (1.30g, 93%) was obtained as a solid by the same method as in reference example 97 using tert-butyl 1-cyclopropylpiperazine-4-carboxylate (1.61g, 7.11mmol) of reference example 98.

¹H-NMR(400MHz，DMSO-d₆)δ：0.79-0.81(2H，m)，1.14(2H，br s)，3.52(8H，br s)，9.94(2H，br).

LC-MSm/z：127(M+H)⁺.

[ reference example 100] 1-Benzylmethylazetidin-3-one

A solution of pyridine sulfonic acid (19.7g) in dimethyl sulfoxide (84ml) was added dropwise to a triethylamine (27.9ml) solution of 1-benzhydrylazetidin-3-ol (4.79g) under ice cooling, followed by stirring at 50 ℃ for 40 minutes. Then, ice water and ethyl acetate were added to the reaction solution to separate the solution. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (2.85g, 60%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：4.00(4H，s)，4.59(1H，s)，7.19-7.49(10H，m).

[ reference example 101] (1-Diphenylmethylazetidin-3-yl) dimethylamine

5% Palladium-carbon (1.5g) was added to a solution of 1-benzhydrylazetidin-3-one (1.50g) of referential example 100 and 40% aqueous dimethylamine solution (4ml) in methanol (30ml), and catalytic reduction was carried out overnight in a hydrogen atmosphere. The catalyst was filtered off, the solvent of the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (1.55g, 92%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.08(6H，s)，2.80-2.87(3H，m)，3.36-3.42(2H，m)，4.37(1H，s)，7.15-7.41(10H，m).

MS(ESI)m/z：267(M+H)⁺.

[ reference example 102] azetidin-3-yldimethylamine hydrochloride

To a solution of (1-benzhydrylazetidin-3-yl) dimethylamine (533mg) in referential example 101 in ethanol (15ml) was added 20% palladium hydroxide-carbon (533mg), and catalytic reduction was carried out for 18 hours in a hydrogen atmosphere. After the catalyst was filtered off, 1N hydrochloric acid-ethanol (4ml) was added to the filtrate solvent, the solvent was distilled off under reduced pressure, ether was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title compound (300mg, 87%).

¹H-NMR(400MHz，DMSO-d₆)δ：2.70(6H，m)，4.05-4.10(2H，m)，4.25-4.31(1H，m)，4.38-4.43(2H，m).

LC-MSm/z：101(M+H)⁺.

[ reference example 103] methanesulfonic acid (1-benzhydrylazetidin-3-yl) ester

Methanesulfonyl chloride (0.68ml) was added dropwise to a pyridine (12ml) solution of 1-benzhydrylazetidin-3-ol (1.50g) under ice cooling, and stirred overnight at room temperature. Ice water was added to the reaction mixture, and the precipitated precipitate was collected by filtration to obtain the title compound (890mg, 45%).

LC-MSm/z：318(M+H)⁺.

[ reference example 104] 3-azido-1-benzhydrylazetidine

To a mixed solution of methanesulfonate (890mg) of referential example 103, N-dimethylformamide (17.8ml) and water (1.8ml) was added sodium azide (237mg), and the mixture was stirred at 70 ℃ for 3 hours. Water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (635mg, 86%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：3.01-3.05(2H，m)，3.47-3.51(2H，m)，3.96-4.01(1H，m)，4.34(1H，s)，7.17-7.40(10H，m).

LC-MSm/z：265(M+H)⁺.

[ reference example 105] 3-amino-1-benzhydrylazetidine

5% Palladium-carbon (200mg) was added to a solution of 3-azido-1-benzhydrylazetidine (630mg) in ethyl acetate (12ml) in referential example 104, and catalytic reduction was carried out for 15 hours in a hydrogen atmosphere. The catalyst was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (410mg, 65%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.45(2H，br)，2.62-2.67(2H，m)，3.51-3.54(2H，m)，3.59-3.66(1H，m)，4.28(1H，s)，7.16-7.40(10H，m).

LC-MSm/z：239(M+H)⁺.

[ reference example 106] 1-Diphenylmethyl-3-methoxyazetidine

A solution of 1-benzhydrylazetidin-3-ol (718mg) in tetrahydrofuran (8ml) was added dropwise to a suspension of 60% sodium hydride (144mg) in N, N-dimethylformamide (8ml) under ice-cooling, and the mixture was stirred for 20 minutes. Then, methyl iodide (0.23ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a cold saturated aqueous ammonium chloride solution and ethyl acetate to separate the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (680mg, 90%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：2.89-2.93(2H，m)，3.23(3H，s)，3.47-3.51(2H，m)，4.04-4.07(1H，m)，4.35(1H，s)，7.16-7.41(10H，m).LC-MSm/z：254(M+H)⁺.

[ reference example 107] 3-Methoxyazetidine hydrochloride

The title compound (287mg, 87%) was obtained as a solid by the same method as in reference example 102 using 1-benzhydryl-3-methoxyazetidine (680mg) of reference example 106.

¹H-NMR(400MHz，DMSO-d₆)δ：2.17(3H，s)，3.75-3.79(2H，m)，4.06-4.11(2H，m)，4.21-4.27(1H，m)，9.28(2H，br).

[ reference example 108] 3-Hydroxyazetidine hydrochloride

The title compound (190mg, 83%) was obtained as a solid by the same method as in reference example 102 using 1-benzhydrylazetidin-3-ol (500 mg).

¹H-NMR(400MHz，DMSO-d₆)δ：3.73(2H，br)，3.93-4.03(2H，m)，4.47-4.55(1H，m)，6.21(1H，d，J＝6.3Hz)，9.12(2H，br).

[ reference example 109] tert-butyl 1-cyclobutyl piperazine-4-carboxylate

Sodium cyanoborohydride (1.89g) was added to a solution of tert-butyl piperazine-4-carboxylate (3.74g), cyclobutanone (3.00ml) and acetic acid (1.15ml) in methanol (100ml) at room temperature, followed by stirring for 3 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the resulting residue to separate the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (4.43g, 92%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.46(9H，s)，1.61-1.73(2H，m)，1.82-1.85(2H，m)，1.87-1.94(2H，m)，2.25-2.27(4H，m)，2.62-2.73(1H，m)，3.42-3.44(4H，m).

[ reference example 110] 4-Cyclobutylpiperazine hydrochloride

The title compound (3.24g, 83%) was obtained as a solid by the same method as in reference example 97 using tert-butyl 1-cyclobutylpiperazine-4-carboxylate (4.40g) of reference example 109.

¹H-NMR(400MHz，DMSO-d₆)δ：1.65-1.80(2H，m)，2.13-2.19(2H，m)，2.33-2.42(2H，m)，3.49(8H，br s)，3.70-3.73(1H，m)，9.83(2H，br)，12.38(1H，br).

LC-MSm/z：141(M+H)⁺.

[ reference example 111] (1-Benzylmethylazetidin-3-yl) -N, N-dimethylmethylamine

A solution of 1-benzhydrylazetidine-3-carbonitrile (880mg) in tetrahydrofuran (10ml) was added dropwise to a suspension of lithium aluminum hydride (134mg) in tetrahydrofuran (20ml) at 0 ℃ and the mixture was refluxed for 40 minutes. After cooling at 0 ℃, water (134. mu.l) and a 15% aqueous solution (134. mu.l) of sodium hydroxide were added dropwise to the reaction mixture, followed by addition of water (387. mu.l) and stirring for 20 minutes. The reaction solution was filtered, and water and ethyl acetate were added to the filtrate to separate the solution. Then, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine 2 times, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and methanol (20ml) was added to the resulting residue, followed by addition of sodium cyanoborohydride (1.11g) and 37% aqueous formaldehyde solution (1.48ml) at room temperature and stirring for 24 hours. The solvent was evaporated under reduced pressure, and water and chloroform were added to the resulting residue to separate the mixture. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (161mg, 16%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：2.16(6H，s)，2.45(2H，d，J＝6.8Hz)，2.67(1H，m)，2.74(2H，t，J＝7.6Hz)，3.39(2H，t，J＝7.6Hz)，4.32(1H，s)，7.14-7.18(2H，m)，7.23-7.27(4H，m)，7.38(4H，dd，J＝1.5，8.3Hz).

LC-MSm/z：281(M+H)⁺.

[ reference example 112] 3-dimethylaminomethylazetidine hydrochloride

The title compound (47mg, 44%) was obtained as a solid by the same method as in reference example 102 using (1-benzhydrylazetidin-3-yl) -N, N-dimethylmethylamine (160mg) of reference example 111.

¹H-NMR(400MHz，DMSO-d₆)δ：2.67(6H，s)，3.28-3.40(3H，m)，3.85-3.89(2H，m)，4.01-4.06(2H，m).

[ reference example 113] 4-chloropyridine-2-carbonitrile

The title compound (5.89g, 92%) was obtained as a solid by the same method as in reference example 15 using 4-chloropyridine-N-oxide (6.00g) and trimethylsilylnitrile (17.5 ml).

¹H-NMR(400MHz，CDCl₃)δ：7.54-7.56(1H，m)，7.72(1H，m)，8.63-8.87(1H，m).

MS(EI)m/z：138(M⁺).

[ reference example 114] 4-methylthiopyridine-2-carbonitrile

Sodium thiomethoxide (1.01g) was added to a solution of 4-chloropyridine-2-carbonitrile (2.00g) of referential example 113 in N, N-dimethylformamide (20ml) at 0 ℃ and stirred for 2 hours. Water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.96g, 90%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.53(3H，s)，7.26-7.27(1H，m)，7.45-7.46(1H，m)，8.45-8.46(1H，m).

MS(EI)m/z：150(M⁺).

[ reference example 115]1- (4-methylthio-2-pyridyl) ethanone

The same procedures used in referential example 16 were repeated except for using 4-methylthiopyridine-2-carbonitrile (1.94g) of referential example 114 to give a compound (1.77g, 82%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.53(3H，s)，2.71(3H，s)，7.25-7.27(1H，m)，7.83-7.84(1H，m)，8.44-8.45(1H，m).

MS(EI)m/z：167(M⁺).

[ reference example 116] Ethyl 4- (4-methylsulfanyl-2-pyridyl) -2, 4-dioxobutyrate

The title compound (1.64g, 58%) was obtained as a solid by the same method as in reference example 17 using 1- (4-methylsulfanyl-2-pyridyl) ethanone (1.76g) and diethyl oxalate (2.86 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.39-1.43(3H，m)，2.56(3H，s)，4.37-4.42(2H，m)，7.30(1H，d，J＝5.2，2.0Hz)，7.51(1H，br)，7.97(1H，d，J＝2.0Hz)，8.46(1H，d，J＝5.2Hz).

MS(EI)m/z：267(M⁺).

[ reference example 117] Ethyl 1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carboxylate

The title compound (0.366g, 16%) was obtained as a solid by the same method as in 2) of reference example 3 using ethyl 4- (4-methylsulfanyl-2-pyridyl) -2, 4-dioxobutyrate (1.62g) and 5-hydrazino-2-methoxypyridine of reference example 2 (0.843 g).

₁H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.2Hz)，2.42(3H，s)，3.95(3H，s)，4.46(2H，q，J＝7.2Hz)，6.77(1H，d，J＝8.8Hz)，7.01-7.03(1H，m)，7.16(1H，d，J＝1.6Hz)，7.26(1H，s)，7.68(1H，dd，J＝8.8，2.8Hz)，8.11(1H，d，J＝2.8Hz)，8.28(1H，d，J＝5.6Hz).

MS(FAB)m/z：371(M+H)⁺.

[ reference example 118]1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carboxylic acid

The title compound (0.312g, quantitative) was obtained as a solid by the same method as in reference example 19 using ethyl 1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carboxylate (0.326 g).

¹H-NMR(400MHz，CDCl₃)δ：2.43(3H，s)，3.95(3H，s)，6.78(1H，d，J＝8.8Hz)，7.05-7.07(1H，m)，7.17(1H，d，J＝1.6Hz)，7.31(1H，s)，7.69(1H，d，J＝8.8，2.8Hz)，8.13(1H，d，J＝2.8Hz)，8.33(1H，d，J＝5.2Hz).

MS(FAB)m/z：343(M+H)⁺.

[ reference example 119]1-Phenylmethylhexahydro-1H-1, 4-diaza-5-ketones

Concentrated sulfuric acid (25ml) was added to a solution of 1-benzyl-4-piperidone (10.14g) in acetic acid (50ml) at room temperature, and sodium azide (3.880g) was added at 0 ℃ over 2 hours, followed by stirring at 5 ℃ for 25 hours. An aqueous sodium hydroxide solution was added to the reaction solution to make it alkaline, and chloroform was added thereto for liquid separation. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (5.081g, 47%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.50-2.70(6H，m)，3.20-3.35(2H，m)，3.60(2H，s)，6.07(1H，br)，7.20-7.40(5H，m).

MS(ESI)m/z：205(M+H)⁺.

[ reference example 120]hexahydro-1H-1, 4-diazepines-5-keto hydrochloride

At room temperature, under the action of 1-phenylmethylhexahydro-1H-1, 4-diazaTo a methanol (10ml) solution of (E) -5-ketone (1.490g) were added a 1M-hydrochloric acid-ethanol solution (7.2ml) and 10% palladium-carbon (0.34g), and the mixture was stirred for 4 hours under a hydrogen atmosphere. The gas in the reaction system was replaced with nitrogen, and insoluble matter was filtered off. The filtrate was evaporated under reduced pressure, ether was added to the resulting residue, and the precipitated solid was collected by filtration to obtain the title compound (1.045g, 96%).

¹H-NMR(400MHz，CD₃OD)δ：2.75-2.85(2H，m)，3.25-3.40(6H，m)，3.48-3.56(2H，m).

MS(ESI)m/z：115(M+H)⁺.

[ reference example 121] (2, 2-Dimethylazetidin-3-yl) dimethylamine hydrochloride

1) 3-bromo-3-methylbutan-2-one

3 drops of bromine were added dropwise at 60 ℃ while irradiating a solution of potassium chloride (2.1g) and 3-methylbutan-2-one (30ml) in water (20ml) with a 250W incandescent lamp. After confirming that the color disappeared, bromine (7.6ml) was added dropwise at an internal temperature of 40 to 45 ℃ for 1 hour while irradiating with a 100W incandescent lamp, and then the mixture was stirred at 40 ℃ for 2 hours. After air cooling, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine and then dried over anhydrous calcium chloride. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was distilled (boiling point: 120 to 130 ℃ C.) to obtain 3-bromo-3-methylbutan-2-one (5.88g, 13%) as an oily substance.

¹H-NMR(400MHz，CDCl₃)δ：1.86(6H，s)，2.44(3H，s).

2)3- (benzhydrylamino) -3-methylbutan-2-one

To a solution of the above 3-bromo-3-methylbutan-2-one (5.88g) in methanol (30ml) were added benzhydrylamine (5.0ml) and triethylamine (7.5ml), and the mixture was stirred at 70 ℃ for 24 hours. After air cooling, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained solid was added with ether to remove insoluble matter. The mother liquor was concentrated under reduced pressure to a dry solid, which was then purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3- (benzhydrylamino) -3-methylbutan-2-one (3.3g, 34%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.18(6H，s)，2.09(3H，s)，4.76(1H，s)，7.17(2H，m)，7.25-7.29(4H，m)，7.37-7.39(4H，m).

LC-MSm/z：268(M+H)⁺.

3) 1-benzhydryl-2, 2-dimethyl azetidin-3-one

Hydrochloric acid gas was blown into a solution of 3- (benzhydrylamino) -3-methylbutan-2-one (6.5g) in acetic acid (20ml) to saturate the solution, and then bromine (1.25ml) was added dropwise and stirred for 3 hours. The reaction solution was adjusted to pH 14 or more by adding 20% aqueous sodium hydroxide solution, and then separated by adding carbon tetrachloride. The organic layer was washed with water. The solvent was distilled off under reduced pressure, and to the resulting residue were added N, N-dimethylformamide (30ml) and a saturated aqueous sodium hydrogencarbonate solution (7ml), and the mixture was stirred for 3 minutes. Water and carbon tetrachloride were added to the reaction solution to separate the solution. The organic layer was washed with saturated brine 2 times and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 1-benzhydryl-2, 2-dimethylazetidin-3-one (754mg, 12%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.20(6H，s)，3.95(2H，s)，4.85(1H，s)，7.18(2H，m)，7.26-7.31(4H，m)，7.52-7.54(4H，m).

4) The title Compound

To a suspension of 1-benzhydryl-2, 2-dimethyl azetidin-3-one (265mg) in methanol (4ml) was added a 2M-dimethylamine solution in tetrahydrofuran (3ml) and 10% palladium on carbon (50% wet, 250mg), and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. Then, the reaction solution was filtered, the solvent was evaporated under reduced pressure, and ethanol (4ml) was added to the resulting residue, followed by addition of 20% palladium hydroxide (50% wet, 265mg) and stirring at room temperature for 22 hours under a hydrogen atmosphere. Subsequently, the reaction mixture was filtered, and a 1N hydrochloric acid-ethanol solution (2.2ml) was added to the solvent, followed by stirring for 10 minutes. The reaction solution was evaporated under reduced pressure, and the resulting residue was solidified with ethyl ether-ethyl acetate and collected by filtration to obtain the title compound (60mg, 30%).

¹H-NMR(400MHz，DMSO-d₆)δ：1.62(3H，s)，1.81(3H，s)，2.57(6H，m)，3.89(2H，m)，4.06(1H，m).

LC-MSm/z：129(M+H)⁺.

[ reference example 122]4, 7-diazaspiro [2.5] octane hydrochloride

A tetrahydrofuran solution (24.7ml) of 1.04M-borane-tetrahydrofuran complex was added dropwise to a tetrahydrofuran (30ml) solution of 4, 7-diazaspiro [2.5] octane-5, 8-dione (1.2g) at 0 ℃ over 30 minutes, followed by thermal refluxing for 13 hours. Methanol (4ml) and a 4N hydrochloric acid-dioxane solution (8ml) were added to the reaction solution at 0 ℃ and heated under reflux for 1 hour. After air-cooling, the precipitated solid was collected by filtration and washed with tetrahydrofuran to obtain a mixture (1.86g) containing the title compound.

To a solution of the obtained mixture (1.4g) in water (25ml) was added triethylamine (3.16ml), and to the reaction solution was added a solution of N-benzyloxysuccinimide (4.7g) in acetonitrile (15ml), and the mixture was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain N-benzyloxycarbonyl (1.4g) as an oily substance.

To a solution of the obtained oily substance (1.4g) in ethanol (10ml) was added 10% palladium-carbon (50% wet, 100mg), and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The reaction mixture was filtered, and a 1N hydrochloric acid-ethanol solution (5.78ml) was added to the solvent at 0 ℃ and stirred for 1 hour. The reaction solution was distilled under reduced pressure, and the obtained residue was solidified with ethanol and ethyl acetate and filtered to obtain the title compound (315mg, 26%).

¹H-NMR(400MHz，DMSO-d₆)δ：0.96-1.03(2H，m)，1.18-1.21(2H，m)，3.30(2H，s)，8.36(4H，m).

LC-MSm/z：113(M+H)⁺.

[ reference example 123]1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid

1) 4-phenyl-2, 4-dioxobutyric acid ethyl ester

After washing 60% sodium hydride (1.50g) with hexane, it was suspended in tetrahydrofuran (60 ml). After acetophenone (4.20g) was added to the reaction mixture under stirring at room temperature, diethyl oxalate (5.0ml) was added. Subsequently, N-dimethylformamide (50ml) was added thereto, and the mixture was stirred at an external temperature of 60 ℃ for 3 hours. After air cooling, the reaction solution was acidified with a 1N aqueous hydrochloric acid solution, and water and ethyl acetate were added to separate the solution. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 4-phenyl-2, 4-dioxobutyrate as an oil.

2)5- (2-Chloropyridyl) hydrazine

Concentrated hydrochloric acid (40ml) was added to 5-amino-2-chloropyridine (5.22g) under ice cooling, and the mixture was stirred. A solution of sodium nitrite (3.20g) in water (20ml) was added dropwise to the reaction mixture at an internal temperature of 5 ℃ or lower. After completion of the dropwise addition, the mixture was stirred under ice-cooling for another 1 hour to obtain a diazo solution.

Tin dichloride 2 hydrate (40g) was dissolved in concentrated hydrochloric acid (25ml), stirred under ice cooling, and the diazonium solution was added dropwise at an internal temperature of 10 ℃ or lower. After the completion of the dropwise addition, stirring was continued for 1 hour under ice-cooling, and then the precipitate was collected by filtration and washed with diethyl ether to obtain a crude tin salt of 5- (2-chloropyridyl) hydrazine.

3)1- (6-chloro-3-pyridinyl) -5-phenylpyrazole-3-carboxylic acid ethyl ester

The crude ethyl 4-phenyl-2, 4-dioxobutyrate and the crude 5- (2-chloropyridyl) hydrazine (tin salt) were refluxed with heating in ethanol (150ml) for 2 hours. After the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed with a 30% aqueous solution of potassium hydroxide, water (2 times) and saturated brine in this order, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain crystalline ethyl 1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carboxylate (6.01g, 52%).

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7Hz)，4.46(2H，q，J＝7Hz)，7.05(1H，s)，7.21-7.23(2H，m)，7.35-7.42(4H，m)，7.70(1H，dd，J＝9,3Hz)，8.34(1H，d，J＝3Hz).

Elemental analysis value: c₁7H₁₄ClN₃O₂

Theoretical value: c, 62.30%; h, 4.31%; n, 12.81 percent.

Measured value: c, 62.20%; h, 4.25%; and N, 12.60%.

4) The title Compound

To ethyl 1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carboxylate (3.01g) were added methanol (50ml), tetrahydrofuran (40ml) and a 1N aqueous solution (20ml) of sodium hydroxide, and the mixture was stirred at room temperature for 6 hours. The reaction solvent was distilled off under reduced pressure, and to the resulting residue were added water (50ml) and a 1N aqueous solution (30ml) of sodium hydroxide, followed by washing with diethyl ether 2 times. The resulting solution was acidified with a 1N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration and washed with water. The crystals were dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (2.66g, 97%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：7.13(1H，s)，7.21-7.25(2H，m)，7.35-7.42(4H，m)，7.74(1H，dd，J＝9,3Hz)，8.38(1H，d，J＝3Hz).

Elemental analysis value: c₁₅H₁₀ClN₃O₂

Theoretical value: c, 60.11%; h, 3.36%; n, 14.02 percent.

Measured value: c, 60.06%; h, 3.30%; n, 13.84 percent.

[ reference example 124] [1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1-succinimide

Chloroform (50ml) and triethylamine (6.5ml) were added to 1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (2.56g), and the mixture was stirred under ice-cooling. To this was added bis (N-succinimidyl) carbonate (4.70g) and the mixture was stirred overnight. Chloroform was added to the reaction solution for liquid separation. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water, a 1N aqueous hydrochloric acid solution and water in this order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and diethyl ether-hexane was added to the obtained residue to collect the precipitated powder by filtration to obtain the title compound (3.33 g).

¹H-NMR(400MHz，CDCl₃)δ：2.93(4H，s)，7.20-7.25(3H，m)，7.35-7.44(4H，m)，7.71(1H，dd，J＝9Hz，3Hz)，8.35(1H，d，J＝3Hz).

[ reference example 125]1- (6-ethoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid

A solution of ethyl 1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carboxylate (207mg) and sodium ethoxide (500mg) of 3) of reference example 123 in ethanol (15ml) was heated overnight at 90 ℃ in a sealed tube. The reaction solvent was distilled off under reduced pressure, and 1N sodium hydroxide (50ml) and ether were added to the resulting residue to separate a liquid. The aqueous layer was acidified with 1N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the solid of the obtained residue was recrystallized from ether-hexane to obtain the title compound (120mg, 71%).

¹H-NMR(400MHz，CDCl₃)δ：1.39(3H，t，J＝7Hz)，4.36(2H，q，J＝7Hz)，6.72(1H，d，J＝9Hz)，7.10(1H，s)，7.22-7.25(2H，m)，7.32-7.36(3H，m)，7.56(1H，dd，J＝9,3Hz)，8.11(1H，d，J＝3Hz).

Elemental analysis value: c₁₇H₁₅N₃O₃

Theoretical value: c, 66.01%; h, 4.89%; and N, 13.58%.

Measured value: c, 65.65%; h, 4.85%; and N, 13.44 percent.

[ reference example 126] [1- (6-ethoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1-succinimide

Triethylamine (0.30ml) and bis (N-succinimidyl) carbonate (200mg) were added to a chloroform (5ml) solution of 1- (6-ethoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (110mg) in referential example 125 under ice-cooling, and the mixture was stirred overnight, followed by addition of bis (N-succinimidyl) carbonate (500mg) and stirring for 7 hours. Water and chloroform were added to the reaction solution to separate the solution. The organic layer was washed with a 10% citric acid aqueous solution, water, a 5% potassium carbonate aqueous solution and water in this order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (232mg, quantitative) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.38(3H，t，J＝7Hz)，2.83(4H，s)，4.38(2H，q，J＝7Hz)，6.71(1H，d，J＝9Hz)，7.17(1H，s)，7.21-7.26(2H，m)，7.33-7.36(3H，m)，7.54(1H，dd，J＝9,3Hz)，8.10(1H，d，J＝3Hz).

[ reference example 127]1- (6-isopropoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid

The title compound (840mg, 81%) was obtained as a powder by the same method as in reference example 125 using ethyl 1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carboxylate (1.05g) of 3) of reference example 123 and isopropanol.

¹H-NMR(400MHz，CDCl₃)δ：1.34(6H，d，J＝6Hz)，5.28(1H，sep，J＝6Hz)，6.66(1H，d，J＝9Hz)，7.10(1H，s)，7.23-7.27(2H，m)，7.33-7.38(3H，m)，7.53(1H，dd，J＝9,3Hz)，8.11(1H，d，J＝3Hz).

Elemental analysis value: c₁₈H₁₇N₃O₃

Theoretical value: c, 66.86%; h, 5.30 percent; n, 13.00 percent.

Measured value: c, 66.62%; h, 5.25%; and N, 13.03 percent.

[ reference example 128] [1- (6-isopropoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1-succinimide

The title compound (1.11g, quantitative) was obtained as a foamy substance in the same manner as in reference example 126 using 1- (6-isopropoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.80g) and bis (N-succinimidyl) carbonate (1.9g) of reference example 127.

¹H-NMR(400MHz，CDCl₃)δ：1.33(6H，d，J＝6Hz)，2.91(4H，s)，5.27(1H，sep，J＝6Hz)，6.66(1H，d，J＝9Hz)，7.17(1H，s)，7.22-7.26(2H，m)，7.33-7.38(3H，m)，7.52(1H，dd，J＝9,3Hz)，8.11(1H，d，J＝3Hz).

[ reference example 129] [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1-succinimid e

The title compound (1.22g, 92%) was obtained by the same method as in reference example 126 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (1.00g) and bis (N-succinimidyl) carbonate (1.88g) of reference example 41.

¹H-NMR(400MHz，CDCl₃)δ：2.93(4H，s)，3.94(3H，s)，6.75(1H，d，J＝9Hz)，7.18-7.26(3H，m)，7.34-7.39(3H，m)，7.57(1H，dd，J＝9,3Hz)，8.12(1H，d，J＝3Hz).

[ reference example 130]1, 3, 3-trimethylpiperazine-2, 5-dione

1) N- [ alpha, alpha-dimethyl- (9H-fluoren-9-ylmethoxy) carbamoyl ] acetylsarcosine ethyl ester

To a solution of N- [ (9H-fluoren-9-ylmethoxy) carbonyl ] - α -aminoisobutyric acid (976mg) in N, N-dimethylformamide (15ml) were added diisopropylethylamine (1.25ml), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.25 g). After stirring at room temperature for 10 minutes, sarcosine ethyl ester hydrochloride (553mg) was added. After stirring at room temperature for 14 hours, the solvent was evaporated under reduced pressure, and chloroform and water were added to the resulting residue to separate the mixture. The aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl N- [ α, α -dimethyl- (9H-fluoren-9-ylmethoxy) carbamoyl ] acetylsarcosinate (824mg, 67%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.26(3H，t，J＝7.08Hz)，1.59(6H，s)，3.10(3H，s)，4.05(2H，br s)，4.17-4.21(4H，m)，4.47(2H，m)，5.56(1H，br s)，7.31(2H，t，J＝7.57Hz)，7.40(2H，t，J＝7.57Hz)，7.60(2H，d，J＝7.57Hz)，7.76(2H，d，J＝7.57Hz).

2) The title Compound

Piperidine (867ml) was added to a solution of ethyl N- [ α, α -dimethyl- (9H-fluoren-9-ylmethoxy) carbamoyl ] acetylsarcosinate (743mg) in N, N-dimethylformamide (20ml), and the mixture was stirred at room temperature for 1 hour. Then, N-dimethylformamide (60ml) was added thereto, and the mixture was stirred at 80 ℃ for 14 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, followed by addition of hexane to collect the formed crystals by filtration to obtain the title compound (162mg, 59%).

¹H-NMR(400MHz，DMSO-d₆)δ：1.30(6H，s)，2.82(3H，s)，3.95(2H，s)，8.32(1H，br s).

[ reference example 131] piperidine-2-carboxamide

Concentrated aqueous ammonia (3ml) and triethylamine (2ml) were added to a solution of N-benzyloxypiperidine-2-carboxylic acid (2.0g), 1-hydroxybenzotriazole (1.6g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.3g) in dichloromethane (20ml) at room temperature, and the mixture was stirred for 3 days. Water and methylene chloride were added to the reaction mixture to separate the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and 10% palladium-carbon (1g, 50% wet) was added to a methanol (30ml) solution of the obtained residue, followed by stirring in the presence of hydrogen for 20 hours. After filtering the catalyst, the solvent was distilled off under reduced pressure, and the obtained oil was dried to obtain the title compound (970mg, quantitative) as a solid.

MS(ESI)m/z：128(M⁺).

[ reference example 132] piperidine-2-carboxylic acid methylamide

The title compound (970mg, quantitative) was obtained as an oil by the same method as in reference example 131 using N-benzyloxypiperidine-2-carboxylic acid (2.0g) and 1.0M-methylamine in tetrahydrofuran (4 ml).

MS(ESI)m/z：142(M⁺).

[ reference example 133] piperidine-2-carboxylic acid dimethylamide

The title compound (3.8g, quantitative) was obtained as an oil by the same method as in reference example 131 using N-benzyloxypiperidine-2-carboxylic acid (6.4g) and dimethylamine hydrochloride (2 g).

MS(ESI)m/z：156(M⁺).

[ reference example 134] Ethyl 4- (4-fluorophenyl) -2, 4-dioxobutyrate

The title compound (3.12g, 60%) was obtained as a solid by the same method as in 1) of reference example 3 using 4' -fluoroacetophenone (3.0g) and diethyl oxalate (5.9 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.41(3H，t，J＝7.1Hz)，4.40(2H，q，J＝7.1Hz)，7.02(1H，s)，7.17(2H，t，J＝8.8Hz)，8.02(2H，dd，J＝8.8，5.4Hz).

MS(ESI)m/z：239(M+1)⁺.

[ reference example 135]5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (2.12g, 86%) was obtained as an oil by the same method as in 2) of reference example 3 using 5-hydrazino-2-methoxypyridine (1.0g) of reference example 2 and ethyl 4- (4-fluorophenyl) -2, 4-dioxobutyrate (1.88g) of reference example 134.

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.1Hz)，3.94(3H，s)，4.46(2H，q，J＝7.1Hz)，6.75(1H，d，J＝8.8Hz)，7.02(1H，s)，7.02(2H，t，J＝8.5Hz)，7.21(2H，dd，J＝8.5，5.1Hz)，7.57(1H，dd，J＝8.8，2.7Hz)，8.09(1H，d，J＝2.7Hz).

MS(EI)m/z：341(M⁺).

[ reference example 136]5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid

To a solution of ethyl 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylate (164g) in methanol (1.6L) was added a 1N aqueous sodium hydroxide solution (1.2L), and the mixture was stirred at room temperature for 5 hours. The reaction solvent was evaporated under reduced pressure, and water and ether were added to the resulting residue to separate a liquid. The pH was adjusted to 2 by adding 1N aqueous hydrochloric acid (1.5L) to the aqueous layer, the precipitated crystals were dissolved in chloroform, a saturated saline solution was added thereto for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the precipitated crystal was collected by ether filtration to obtain the title compound (132.0g, 88%).

¹H-NMR(400MHz，CDCl₃)δ：3.95(3H，s)，6.76(1H，d，J＝8.8Hz)，7.02-7.09(3H，m)，7.18-7.26(2H，m)，7.56(1H，dd，J＝8.8，2.7Hz)，8.09(1H，d，J＝2.7Hz).

[ reference example 137]1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carboxylic acid

1) 5-amino-2-chloropyridines

Concentrated hydrochloric acid (1ml) was added to a mixed solution of 2-chloro-5-nitropyridine (20g) in ethanol (160ml) and water (40ml), and reduced iron (70.5g) was added in small amounts at room temperature, followed by stirring at 90 ℃ for 1 hour. After air-cooling, the reaction mixture was filtered through celite, the mother liquor solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain an amine compound (15.2g, 94%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.71(2H，br s)，6.96(1H，dd，J＝8.3，2.9Hz)，7.08(1H，d，J＝8.3Hz)，7.85(1H，d，J＝2.9Hz).

LC-MSm/z：129(M+H)⁺.

2) 5-acetoxy-2-chloropyridine

To a solution of the above 5-amino-2-chloropyridine (18g) in ethanol (360ml) was added a 48% aqueous tetrafluoroboric acid solution (40.5ml), and tert-butyl nitrite (23.5ml) was added dropwise under cooling at-5 ℃ and then stirred for 20 minutes. Diethyl ether was added to the reaction mixture to filter a precipitate, which was dried to obtain 6-chloropyridine-3-diazonium tetrafluoroborate (32g, quantitative). A solution of the diazonium salt (32g) in acetic anhydride (160ml) was slowly warmed to 90 ℃ and stirred for 45 minutes. After air-cooling, the reaction solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the obtained residue to separate the mixture. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5-acetoxy-2-chloropyridine (10g, 42%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，7.34(1H，d，J＝8.8Hz)，7.47(1H，dd，J＝8.8，2.9Hz)，8.21(1H，d，J＝2.9Hz).

LC-MSm/z：172(M+H)⁺.

3) 2-chloro-5-hydroxypyridine

To a solution of the above 5-acetoxy-2-chloropyridine (10g) in methanol (200ml) was added potassium carbonate (400mg), and the mixture was stirred at room temperature for 20 hours. The reaction solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2-chloro-5-hydroxypyridine (6.86g, 91%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：7.24(1H，dd，J＝8.8，2.9Hz)，7.29(1H，d，J＝8.8Hz)，7.91(1H，d，J＝2.9Hz)，10.22(1H，br).

LC-MSm/z：130(M+H)⁺.

4) 2-chloro-5-methoxypyridine

28% sodium methoxide-methanol solution (2.0ml) was added dropwise to a solution of the above 2-chloro-5-hydroxypyridine (1.30g) and methyl iodide (1.25ml) in N, N-dimethylformamide (26ml) at room temperature, followed by stirring for 1.5 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture to separate the solution, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-chloro-5-methoxypyridine (1.40g, 98%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.85(3H，s)，7.17-7.25(2H，m)，8.05(1H，d，J＝2.9Hz).

LC-MSm/z：144(M+H)⁺.

5) 2-hydrazino-5-methoxypyridine

A solution of the above 2-chloro-5-methoxypyridine (4.0g) in hydrazine monohydrate (30ml) was stirred at 100 ℃ for 24 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, chloroform and a 1N aqueous solution of sodium hydroxide were added to the obtained residue to separate the mixture, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 2-hydrazino-5-methoxypyridine (705mg, 18%) as an oil.

LC-MSm/z：140(M+H)⁺.

6)1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carboxylic acid ethyl ester

A solution of the above-mentioned 2-hydrazino-5-methoxypyridine (705mg) and ethyl 2, 4-dioxo-4-phenylbutyrate (1.12g) of 1) of referential example 123 in ethanol (25ml) was heated under reflux for 19 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue to separate the mixture, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain amorphous ethyl 1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carboxylate (705mg, 43%).

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.1Hz)，3.88(3H，s)，4.45(2H，q，J＝7.1Hz)，7.03(1H，s)，7.22-7.32(6H，m)，7.45(1H，d，J＝6.8Hz)，8.05(1H，d，J＝3.1Hz).

LC-MSm/z：324(M+H)⁺.

7) The title Compound

To a solution of the above ethyl 1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carboxylate (700mg) in methanol (7ml) and tetrahydrofuran (7ml) was added a 1N aqueous solution (3.5ml) of sodium hydroxide, and the mixture was stirred at room temperature for 2 hours. After a 1N aqueous hydrochloric acid solution (3.6ml) was added to the reaction mixture under ice cooling, water and ethyl acetate were added to separate the mixture, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (602mg, 94%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.89(3H，s)，7.09(1H，s)，7.23-7.35(6H，m)，7.46(1H，d，J＝6.9Hz)，8.08(1H，d，J＝3.1Hz).

LC-MSm/z：296(M+H)⁺.

[ reference example 138]1- (5-methoxy-2-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid

1) 5-bromo-2-hydrazinopyridines

Hydrazine monohydrate (10ml) was added to a pyridine (100ml) solution of 2, 5-dibromopyridine (10.0g) at room temperature, and the mixture was refluxed for 13 hours. After cooling with air, the reaction solvent was evaporated under reduced pressure, and to the resulting residue were added 0.5N aqueous sodium hydroxide solution and chloroform for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-hydrazinopyridine (7.61g, 96%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：6.67(1H，d，J＝9.0Hz)，7.55(1H，dd，J＝9.0，2.4Hz)，7.64(1H，s)，8.00(1H，d，J＝2.4Hz).

EI-MSm/z：188(M⁺).

2)1- (5-bromo-2-pyridinyl) -5- (2-pyridinyl) pyrazole-3-carboxylic acid ethyl ester

To a suspension of the above 5-bromo-2-hydrazinopyridine (7.12g) and ethyl 4- (2-pyridyl) -2, 4-dioxobutyrate (8.38g) of reference example 31 in ethanol (126ml) was added acetic acid (8.67ml), and the mixture was refluxed for 12 hours at room temperature. After air-cooling, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a dihydropyrazole. Concentrated hydrochloric acid (4.9ml) was added to an ethanol (146ml) solution of the dihydropyrazole at room temperature, and the mixture was refluxed for 3 hours. After air-cooling, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 1- (5-bromo-2-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylate (11.6g, 82%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.2Hz)，4.45(2H，q，J＝7.2Hz)，7.20(1H，s)，7.23-7.25(1H，m)，7.49(1H，dd，J＝7.8，0.7Hz)，7.72-7.75(2H，m)，7.95-7.97(1H，m)，8.26(1H，d，J＝2.2Hz)，8.45-8.46(1H，m).

EI-MSm/z：373(M⁺).

3) The title Compound

Sodium methoxide (1.74g) and cuprous bromide (0.231g) were added to a mixed solution of ethyl 1- (5-bromo-2-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylate (3.00g) in methanol (30ml) and toluene (30ml) at room temperature under argon atmosphere, and the mixture was refluxed for 47 hours. After air-cooling, water (50ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Then, a mixed solvent of water, acetic acid (10ml) and methanol-chloroform (1: 10) was added to the reaction mixture to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (1.68g, 71%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：4.17(3H，s)，7.56-8.71(8H，m)，13.35(1H，s).

FAB-MSm/z：297(M+H)⁺.

[ reference example 139]1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid

A method)

1)1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid ethyl ester

After 3-chloro-6-hydrazinopyridazine (1.59g) and a solution of ethyl 4- (2-pyridyl) -2, 4-dioxobutyrate (2.45g) of referential example 31 in ethanol (60ml) were refluxed for 6 hours, concentrated hydrochloric acid (1ml) was added to the reaction mixture, and the reflux was continued for 1 hour. After air-cooling, the reaction solvent was evaporated under reduced pressure, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue to separate the mixture, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain ethyl 1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (1.50g, 41%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.44(3H，t，J＝7.0Hz)，4.46(2H，q，J＝7.0Hz)，7.23(1H，s)，7.24-7.27(1H，m)，7.62-7.65(1H，m)，7.69(1H，d，J＝9.0Hz)，7.76-7.81(1H，m)，8.10(1H，d，J＝9.0Hz)，8.40(1H，d，J＝4.6Hz).

LC-MSm/z：330(M+H)⁺.

2)1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid methyl ester

To a solution of the above ethyl 1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (1.50g) in methanol (45ml) was added a 28% sodium methoxide-methanol solution (3ml), and the mixture was refluxed for 2 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the obtained residue to separate the mixture, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give methyl 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (480mg, 34%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.99(3H，s)，4.10(3H，s)，7.15(1H，d，J＝9.3Hz)，7.21-7.23(1H，m)，7.24(1H，s)，7.58-7.61(1H，m)，7.73-7.78(1H，m)，7.93(1H，d，J＝9.3Hz)，8.40-8.41(1H，m).

LC-MSm/z：312(M+H)⁺.

3) The title Compound

To a solution of methyl 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (475mg) in ethanol (10ml) and tetrahydrofuran (10ml) was added a 1N aqueous solution (3ml) of sodium hydroxide, and the mixture was stirred at room temperature for 20 hours. After the reaction mixture was neutralized with 1N aqueous hydrochloric acid (3ml) under ice-cooling, a chloroform-methanol (10: 1) mixed solvent was added to the reaction mixture to separate the solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (300mg, 66%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：4.04(3H，s)，7.32-7.35(1H，m)，7.41(1H，s)，7.49(1H，d，J＝9.3Hz)，7.80-7.82(1H，m)，7.87-7.91(1H，m)，7.99(1H，d，J＝9.3Hz)，8.35-8.36(1H，m).

LC-MSm/z：298(M+H)⁺.

B method)

1)4- (2-pyridinyl) -2, 4-dioxobutyric acid methyl ester

A methanol (26ml) solution of 2-acetylpyridine (2.56g) was added to a methanol (26ml) solution of dimethyl oxalate (5.00g) and sodium methoxide (2.29g) under argon atmosphere at room temperature, followed by stirring at 60 ℃ for 45 minutes after 15 minutes. After air cooling, water was added to the reaction solution, and the mixture was washed with diethyl ether. Then, a saturated aqueous ammonium chloride solution and chloroform were added to the aqueous layer to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain methyl 4- (2-pyridyl) -2, 4-dioxobutyrate (3.44g, 79%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.94(3H，s)，7.54-7.50(1H，m)，7.64(1H，s)，7.93-7.89(1H，m)，8.19-8.16(1H，m)，8.74-8.72(1H，m).

EI-MSm/z：207(M⁺).

2)1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid methyl ester

A solution of the above methyl 4- (2-pyridyl) -2, 4-dioxobutanoate (4.143g) and 3-chloro-6-hydrazinopyridine (2.891g) in methanol (100ml) was refluxed for 109 hours. Concentrated hydrochloric acid (2ml) was added to the reaction solution, and the mixture was heated under reflux for 6 hours. After air-cooling, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture to separate the mixture, and the organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain methyl 1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (3.169g, 50%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：4.00(3H，s)，7.24-7.28(1H，m)，7.24(1H，s)，7.64(1H，dt，J＝7.8，1.2Hz)，7.70(1H，d，J＝9.0Hz)，7.79(1H，td，J＝7.8，1.7Hz)，8.09(1H，d，J＝9.0Hz)，8.38-8.41(1H，m).

ESI-MSm/z：316(M+H)⁺.

3)1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid methyl ester

Sodium methoxide (1.530g) was added to a solution of methyl 1- (6-chloro-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (2.981g) in methanol (190ml) at room temperature, and the mixture was stirred for 19 hours. To the reaction mixture was added 1N aqueous hydrochloric acid (19ml), methanol was distilled off under reduced pressure, and the obtained residue was added water to filter out an insoluble solid, which was then dried to obtain methyl 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (2.571g, 87%) as a solid.

[ reference example 140]1- (6-methoxy-3-pyridazinyl) -5- (4-dimethylaminophenyl) pyrazole-3-carboxylic acid

1)4- (4-dimethylaminophenyl) -2, 4-dioxobutyric acid methyl ester

Methyl 4- (4-dimethylaminophenyl) -2, 4-dioxobutyrate (742mg, 39%) was obtained as a solid in the same manner as in 1) of method B of reference example 139 using 4' -dimethylaminoacetophenone (1.224g), dimethyl oxalate (1.771g) and sodium methoxide (180 mg).

¹H-NMR(400MHz，CDCl₃)δ：3.10(6H，s)，3.93(3H，s)，6.69(2H，d，J＝9.0Hz)，7.01(1H，s)，7.92(2H，d，J＝9.0Hz).

ESI-MSm/z：250(M+H)⁺.

2)1- (6-chloro-3-pyridazinyl) -5- (4-dimethylaminophenyl) pyrazole-3-carboxylic acid methyl ester

A solution of the above methyl 4- (4-dimethylaminophenyl) -2, 4-dioxobutyrate (742mg) and 3-chloro-6-hydrazinopyridazine (473mg) in methanol (30ml) was heated under reflux for 18 hours. After cooling with air, the reaction solvent was evaporated under reduced pressure, a saturated aqueous sodium bicarbonate solution and chloroform were added to the resulting residue to separate a liquid, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain methyl 1- (6-chloro-3-pyridazinyl) -5- (4-dimethylaminophenyl) pyrazole-3-carboxylate (679mg, 63%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.98(6H，s)，3.98(3H，s)，6.65(2H，d，J＝8.8Hz)，6.97(1H，s)，7.16(2H，d，J＝8.8Hz)，7.62(1H，d，J＝9.0Hz)，7.90(1H，d，J＝9.0Hz).

ESI-MSm/z：358(M+H)⁺.

3) The title Compound

The title compound (592mg, 91%) was obtained as a solid by the same method as in 7) of reference example 137 using the above methyl 1- (6-chloro-3-pyridazinyl) -5- (4-dimethylaminophenyl) pyrazole-3-carboxylate (679 mg).

¹H-NMR(400MHz，CDCl₃)δ：2.97(6H，s)，4.16(3H，s)，6.64(2H，d，J＝8.8Hz)，7.01(1H，s)，7.07(1H，d，J＝9.0Hz)，7.15(2H，d，J＝8.8Hz)，7.60(1H，d，J＝9.0Hz).

ESI-MSm/z：340(M+H)⁺.

[ reference example 141]5- (5-chloro-2-pyridyl) -1- (6-methoxy-3-pyridazinyl) pyrazole-3-carboxylic acid

1) 2-bromo-5-chloropyridine

After bromine (12ml) was added to a 47% hydrobromic acid solution (50ml) of 2-amino-5-chloropyridine (5g) at 0 ℃, a water (20ml) solution of sodium nitrite (15g) was added dropwise to the reaction solution, and the mixture was stirred for 1 hour. To the reaction mixture were added a solution of sodium hydroxide (32g) in water (80ml) and ethyl acetate to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 2-bromo-5-chloropyridine (6.8g, 91%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：7.44(1H，d，J＝8.42Hz)，7.54(1H，m)，8.36(1H，s).

2)1- (5-chloro-2-pyridyl) ethanone

After a 1.56M hexane solution (27ml) of N-butyllithium was added dropwise to a solution of 2-bromo-5-chloropyridine (6.8g) in diethyl ether (45ml) at-78 ℃ under cooling, N-dimethylacetamide (5ml) was added dropwise, and the mixture was stirred for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by addition of ethyl acetate for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1- (5-chloro-2-pyridyl) ethanone (3.26g, 59%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.70(3H，s)，7.80(1H，dd，J＝8.42，2.32Hz)，8.00(1H，d，J＝8.42Hz)，8.62(1H，d，J＝2.32Hz).

3)4- (5-chloro-2-pyridinyl) -2, 4-dioxobutyric acid ethyl ester

Dimethyl oxalate (5g) was added to a solution of sodium methoxide (2.26g) in ethanol (100ml), and after stirring for 5 minutes, 1- (5-chloro-2-pyridyl) ethanone (3.26g) was added and stirred at room temperature for 45 minutes. Then, water was added to the reaction solution, and the reaction solution was washed with ether, and then the aqueous layer was acidified with a 1N aqueous hydrochloric acid solution, followed by addition of chloroform for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 4- (5-chloro-2-pyridyl) -2, 4-dioxobutyrate (4.12g, 77%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.08Hz)，4.41(2H，q，J＝7.08Hz)，7.64(1H，s)，7.87(1H，dd，J＝8.42，2.44Hz)，8.11(1H，d，J＝8.42Hz)，8.67(1H，d，J＝2.44Hz).

EI-MSm/z：256(M+H)⁺.

4)1- (6-chloro-3-pyridazinyl) -5- (5-chloro-2-pyridinyl) pyrazole-3-carboxylic acid ethyl ester

Using the above ethyl 4- (5-chloro-2-pyridyl) -2, 4-dioxobutyrate (1g) and 3-chloro-6-hydrazinopyridazine (735mg), according to the same method as in A) of reference example 139, ethyl 1- (6-chloro-3-pyridazinyl) -5- (5-chloro-2-pyridyl) pyrazole-3-carboxylate (500mg, 35%) was obtained as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝3.52Hz)，4.47(2H，q，J＝3.52Hz)，7.28(1H，s)，7.58(1H，d，J＝8.30Hz)，7.76(1H，d，J＝8.30Hz)，7.93(1H，d，J＝9.28Hz)，8.11(1H，d，J＝9.28Hz)，8.34(1H，s).

5) The title Compound

To a solution of the above ethyl 1- (6-chloro-3-pyridazinyl) -5- (5-chloro-2-pyridyl) pyrazole-3-carboxylate (500mg) in methanol (10ml) was added sodium methoxide (150mg), and the mixture was stirred at room temperature for 15 hours. To the reaction mixture, 1N aqueous hydrochloric acid solution and chloroform were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (483mg, > 100%) as an amorphous form.

¹H-NMR(400MHz，CDCl₃)δ：4.12(3H，s)，7.15(1H，d，J＝9.28Hz)，7.19(1H，s)，7.57(1H，dd，J＝8.42，2.81Hz)，7.75(1H，dt，J＝8.42，2.81Hz)，7.97(1H，d，J＝9.28Hz)，8.40(1H，s).

EI-MSm/z：332(M+H)⁺.

[ reference example 142]1- (5-methoxy-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid

1) 5-chloro-2-hydrazinopyrazines

A solution of 5-chloro-2-hydroxypyrazine (1.84g) in phosphorus oxychloride (28ml) synthesized from aminopyrazine by the method of Palamimidesi et al (J.org.chem., 29 vol., 2491-2492 p., 1964) was stirred at an external temperature of 130 ℃ for 6 hours in a sealed tube. After air-cooling, ice water and methylene chloride were added to the reaction mixture to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and hydrazine monohydrate (1.39ml) was added to an ethanol (14ml) solution of the obtained residue, followed by stirring at room temperature for 150 minutes and at 80 ℃ for 15 minutes. After air-cooling, the solvent of the reaction mixture was evaporated under reduced pressure, and a mixed solvent of water and chloroform-methanol (1: 10) was added to the obtained residue to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 5-chloro-2-hydrazinopyrazine (0.325g, 16%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：4.32(2H，br s)，7.92(1H，s)，7.99(1H，s)，8.13(1H，s).

EI-MSm/z：144(M⁺).

2)1- (5-chloro-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid methyl ester

Using methyl 4- (2-pyridyl) -2, 4-dioxobutyrate (0.414g) obtained in 1) of method B) of reference example 139 and the above-mentioned 5-chloro-2-hydrazinopyrazine (0.289g), methyl 1- (5-chloro-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (0.260g, 41%) was obtained as a solid in the same manner as in 2) of method B) of reference example 139.

¹H-NMR(400MHz，CDCl₃)δ：4.00(3H，s)，7.25-7.28(2H，m)，7.59-7.61(1H，m)，7.77-7.81(1H，m)，8.25-8.25(1H，m)，8.39-8.41(1H，m)，8.85-8.84(1H，m).

FAB-MSm/z：316(M+H)⁺.

3) The title Compound

The title compound (0.237g, 99%) was obtained as a solid in the same manner as in 7) of reference example 137 using the above methyl 1- (5-chloro-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (0.254 g).

¹H-NMR(400MHz，DMSO-d₆)δ：3.98(3H，s)，7.29-7.32(1H，m)，7.37(1H，s)，7.74-7.87(2H，m)，8.11(1H，s)，8.33-8.34(1H，m)，8.52(1H，s)，13.15(1H，br s).

FAB-MSm/z：298(M+H)⁺.

[ reference example 143]1- (6-methyl-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The title compound (0.459g, 15%) was obtained as an oil in the same manner as in 2) of reference example 3 using 5-hydrazino-2-methylpyridine (1.20g) of reference example 63 and ethyl 4- (2-pyridyl) -2, 4-dioxobutyrate (3.48g) of reference example 31.

¹H-NMR(400MHz，CDCl₃) δ: 1.43(3H, t-like, J ═ 7.3Hz), 2.60(3H, s), 4.46(2H, q, J ═ 7.3Hz), 7.20-7.50(4H, m), 7.67-7.80(2H, m), 8.39(1H, br), 8.51(1H, br).

FAB-MSm/z：309(M+H)⁺.

[ reference example 144] lithium 1- (6-methoxy-3-pyridyl) -5- (3-pyridazinyl) pyrazole-3-carboxylate

1)4- (3-pyridazinyl) -2, 4-dioxobutanoic acid methyl ester

A1.0M tetrahydrofuran solution (19ml) of lithium-bis (trimethylsilyl) amide was added dropwise to a tetrahydrofuran (50ml) solution of 3-acetylpyridazine (2.097g) under cooling at-78 ℃ under argon atmosphere, and the mixture was stirred for 1 hour. A solution of dimethyl oxalate (4.055g) in tetrahydrofuran (35ml) was added dropwise to the reaction mixture, followed by stirring at 0 ℃ for 2 hours. The reaction solvent was evaporated under reduced pressure, the obtained residue was washed with ether and water, the aqueous layer was made weakly acidic with 1N aqueous hydrochloric acid solution, ethyl acetate was added thereto for extraction, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain methyl 4- (3-pyridazinyl) -2, 4-dioxobutyrate (2.63g, 73%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.97(3H，s)，7.73(1H，dd，J＝8.5，5.1Hz)，7.96(1H，s)，8.28(1H，dd，J＝8.5，1.8Hz)，9.38(1H，dd，J＝5.1，1.8Hz).

ESI-MSm/z：209(M+H)⁺.

2)1- (6-methoxy-3-pyridyl) -5- (3-pyridazinyl) pyrazole-3-carboxylic acid methyl ester

Using methyl 4- (3-pyridazinyl) -2, 4-dioxobutyrate (1.086g) and 5-hydrazino-2-methoxypyridine (726mg) in reference example 2, methyl 1- (6-methoxy-3-pyridyl) -5- (3-pyridazinyl) pyrazole-3-carboxylate (309mg, 19%) as a solid was obtained in the same manner as in 2) in reference example 140.

¹H-NMR(400MHz，CDCl₃)δ：3.95(3H，s)，4.00(3H，s)，6.80(1H，d，J＝8.8Hz)，7.43(1H，s)，7.51(2H，d，J＝3.4Hz)，7.70(1H，dd，J＝8.8，2.7Hz)，8.11(1H，d，J＝2.7Hz)，9.15(1H，t，J＝3.4Hz).

ESI-MSm/z：312(M+H)⁺.

3) The title Compound

To a solution of methyl 1- (6-methoxy-3-pyridyl) -5- (3-pyridazinyl) pyrazole-3-carboxylate (309mg) in methanol (20ml) was added lithium hydroxide monohydrate (42mg), which was then refluxed for 18 hours. After air-cooling, the reaction solvent was distilled off under reduced pressure to obtain the title compound (322mg, > 100%) in an amorphous state.

ESI-MSm/z：298(M+H)⁺.

[ reference example 145]1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carboxylic acid

1) 4-methylpyridine-2-carbonitrile

Using 4-methylpyridine-N-oxide (6.00g), 4-methylpyridine-2-carbonitrile (4.65g, 72%) was obtained as a solid in the same manner as in reference example 15.

¹H-NMR(400MHz，CDCl₃)δ：2.44(3H，s)，7.33-7.35(1H，m)，7.53(1H，s)，8.57(1H，d，J＝4.8Hz).

EI-MSm/z：118(M⁺).

2)1- (4-methyl-2-pyridyl) ethanone

The same procedures used in referential example 16 were repeated except for using the above-mentioned 4-methylpyridine-2-carbonitrile (4.46g) to give 1- (4-methyl-2-pyridyl) ethanone (4.38g, 86%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：2.43(3H，s)，2.72(3H，s)，7.28-7.29(1H，m)，7.87(1H，m)，8.54(1H，d，J＝5.2Hz).

EI-MSm/z：135(M⁺).

3)4- (4-methyl-2-pyridinyl) -2, 4-dioxobutyric acid ethyl ester

After diethyl oxalate (4.42ml) was added to a solution of sodium ethoxide (2.22g) in ethanol (22ml) and stirred for 10 minutes, a solution of the above 1- (4-methyl-2-pyridyl) ethanone (2.20g) in ethanol (22ml) was added and stirred at room temperature for 20 minutes. After washing the reaction mixture with ether, a saturated aqueous ammonium chloride solution and chloroform were added to the aqueous layer to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain ethyl 4- (4-methyl-2-pyridyl) -2, 4-dioxobutyrate (2.84g, 74%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.41(3H，t，J＝7.2Hz)，2.47(3H，s)，4.40(2H，q，J＝7.2Hz)，7.34-7.35(1H，m)，7.52(1H，br)，8.01(1H，s)，8.57(1H，d，J＝5.2Hz).

EI-MSm/z：235(M⁺).

4)1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The same procedures used in 2) of reference example 138 were repeated except for using ethyl 4- (4-methyl-2-pyridyl) -2, 4-dioxobutyrate (2.83g) and 5-hydrazino-2-methoxypyridine (1.67g) of reference example 2 to give ethyl 1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carboxylate (1.66g, 41%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.43(3H，t，J＝7.2Hz)，2.34(3H，s)，3.94(3H，s)，4.46(2H，q，J＝7.2Hz)，6.76(1H，d，J＝8.8Hz)，7.05-7.06(1H，m)，7.23-7.24(2H，m)，7.66-7.69(1H，m)，8.10(1H，d，J＝2.8Hz)，8.36(1H，d，J＝4.8Hz).

EI-MSm/z：338(M⁺).

5) The title Compound

The title compound (0.944g, 99%) was obtained as a solid in the same manner as in 7) of reference example 137 using the above ethyl 1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carboxylate (1.04 g).

¹H-NMR(400MHz，DMSO-d₆)δ：2.43(3H，s)，3.89(3H，s)，6.87(1H，d，J＝8.8Hz)，7.17-7.19(1H，m)，7.30(1H，s)，7.59(1H，s)，7.68-7.71(1H，m)，8.13(1H，d，J＝2.8Hz)，8.27-8.30(1H，m)，13.04(1H，br).

EI-MSm/z：310(M⁺).

[ reference example 146]1- (6-methoxy-3-pyridyl) -5- (5-methyl-2-pyridyl) pyrazole-3-carboxylic acid

1)1- (5-methyl-2-pyridyl) ethanone

The same procedures used in 2) of referential example 141 were repeated except for using 2-bromo-5-methylpyridine (10.0g), to give 1- (5-methyl-2-pyridinyl) ethanone (6.71g, 85%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：2.42(3H，s)，2.71(3H，s)，7.61-7.64(1H，m)，7.95(1H，d，J＝8.0Hz)，8.50(1H，m).

EI-MSm/z：135(M⁺).

2)4- (5-methyl-2-pyridinyl) -2, 4-dioxobutyric acid ethyl ester

Using the above-mentioned 1- (5-methyl-2-pyridyl) ethanone (6.7g) and diethyl oxalate (13.5ml), ethyl 4- (5-methyl-2-pyridyl) -2, 4-dioxobutyrate (8.99g, 77%) was obtained as a solid in the same manner as in 3) of reference example 146.

¹H-NMR(400MHz，CDCl₃)δ：1.41(3H，t，J＝7.2Hz)，2.45(3H，s)，4.40(2H，q，J＝7.2Hz)，7.56(1H，br)，7.69-7.71(1H，m)，8.08(1H，d，J＝8.0Hz)，8.54(1H，m).

EI-MSm/z：235(M⁺).

3)1- (6-methoxy-3-pyridyl) -5- (5-methyl-2-pyridyl) pyrazole-3-carboxylic acid ethyl ester

The same procedures used in 2) of reference example 138 were repeated except for using ethyl 4- (5-methyl-2-pyridyl) -2, 4-dioxobutyrate (8.98g) and 5-hydrazino-2-methoxypyridine (5.31g) of reference example 2 to give ethyl 1- (6-methoxy-3-pyridyl) -5- (5-methyl-2-pyridyl) pyrazole-3-carboxylate (7.31g, 57%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.42(3H，t，J＝7.2Hz)，2.34(3H，s)，3.95(3H，s)，4.45(2H，q，J＝7.2Hz)，6.76(1H，d，J＝8.8Hz)，7.23-7.30(2H，m)，7.47-7.50(1H，m)，7.66-7.69(1H，m)，8.10(1H，d，J＝2.4Hz)，8.36(1H，m).

FAB-MSm/z：339(M+H)⁺.

4) The title Compound

The title compound (0.789g, 86%) was obtained as a solid in the same manner as in 7) of reference example 137 using the above ethyl 1- (6-methoxy-3-pyridyl) -5- (5-methyl-2-pyridyl) pyrazole-3-carboxylate (1.00 g).

¹H-NMR(400MHz，DMSO-d₆)δ：2.29(3H，s)，3.89(3H，s)，6.87-6.90(1H，m)，7.26(1H，s)，7.55-7.57(1H，m)，7.67-7.72(2H，m)，8.13(1H，d，J＝2.8Hz)，8.30(1H，m)，13.04(1H，br).

FAB-MSm/z：311(M+H)⁺.

[ reference example 147] 1-tert-Butoxycarbonylpiperazine-3-carboxylic acid ethyl ester

1)1, 4-di-tert-butoxycarbonylpiperazine-3-carboxylic acid ethyl ester

Triethylamine (10.7ml) and a 6N aqueous solution (1ml) of sodium hydroxide were added to a solution of piperazine-2-carboxylic acid hydrochloride (5.0g) and di-t-butoxycarbonate (11.8g) in tetrahydrofuran (50ml), and the mixture was stirred at room temperature for 6 hours. Dichloromethane was added to the reaction solution to separate the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 1, 4-di-tert-butoxycarbonylpiperazine-3-carboxylic acid (5.45g, 67%). Using the obtained 1, 4-di-tert-butoxycarbonylpiperazine-3-carboxylic acid product and ethanol (2ml), ethyl 1, 4-di-tert-butoxycarbonylpiperazine-3-carboxylate (5.5g, 62%) was obtained in the same manner as in reference example 81.

EI-MSm/z：358(M⁺).

2) The title Compound

Concentrated hydrochloric acid (5ml) was added to a solution of the above ethyl 1, 4-di-tert-butoxycarbonylpiperazine-3-carboxylate (5.5g) in ethanol (50ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was evaporated under reduced pressure to obtain piperazine-2-carboxylic acid ethyl ester hydrochloride (3.4g, 95.7%). To a solution of the obtained piperazine-2-carboxylic acid ethyl ester hydrochloride (3.4g) in tetrahydrofuran (30ml) were added triethylamine (5ml) and 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (4.0g) under ice cooling, and the mixture was stirred at room temperature for 16 hours. Dichloromethane was added to the reaction solution to separate the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain the title compound (3.14g, 49%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.28(3H，t，J＝7.3Hz)，1.47(9H，s)，2.70-2.80(1H，m)，3.00-3.15(3H，m)，3.40-3.45(1H，m)，3.68-3.75(1H，m)，4.20(2H，q，J＝7.3Hz).

EI-MSm/z：258(M⁺).

[ reference example 148] (3S) -morpholine-3-carboxylic acid methyl ester

1) (2S) -2- (N-benzyloxycarbonyl) amino-3- (2-chloroethoxy) propionic acid methyl ester

2-chloroethanol (3ml) and a catalytic amount of boron trifluoride-diethyl ether complex (3 drops) were added dropwise to a chloroform (10ml) solution of (S) - (-) -1, 2-azetidinedicarboxylic acid 1-benzyl ester 2-methyl ester (1g) at room temperature, and the mixture was stirred for 4 hours. Water and chloroform were added to the reaction mixture to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl (2S) -2- (N-benzyloxycarbonyl) amino-3- (2-chloroethoxy) propionate (1.09g, 81%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：3.56(2H，t，J＝5.74Hz)，3.69(2H，m)，3.77(3H，s)，3.85(1H，m)，3.95(1H，dd，J＝9.40，3.17Hz)，4.51(1H，dt，J＝8.67，3.17Hz)，5.13(2H，s)，5.67(1H，br)，7.36(5H，m).

EI-MSm/z：316(M+H)⁺.

2) (2S) -2-amino-3- (2-chloroethoxy) propionic acid methyl ester

To a solution of the above-mentioned methyl (2S) -2- (N-benzyloxycarbonyl) amino-3- (2-chloroethoxy) propionate (1.09g) in methanol (15ml) was added 5% palladium-carbon (170mg), and the mixture was stirred at room temperature for 16.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain methyl (2S) -2-amino-3- (2-chloroethoxy) propionate (608mg, 97%) as an oil.

¹H-NMR(400MHz，CD₃OD)δ：3.62(2H，m)，3.70(5H，m)，3.74(3H，s)，3.84(1H，m)，3.90(1H，m).

EI-MSm/z：182(M+H)⁺.

3) The title Compound

Triethylamine (1.2ml) was added to a solution of the above methyl (2S) -2-amino-3- (2-chloroethoxy) propionate (726mg) in methanol (10ml), and the mixture was refluxed for 3 hours. After air-cooling, the reaction solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting solid residue, insoluble materials were filtered, and the filtrate solvent was evaporated under reduced pressure to obtain the title compound (467mg, 80%) as an oil.

¹H-NMR(400MHz，D₂O)δ：2.70(1H，m)，2.88(1H，m)，3.50-3.70(4H，m)，3.65(3H，s)，3.87(1H，dd，J＝11.60，3.05Hz).

[ reference example 149]1, 4-Oxazacycloheptane hydrochloride

1)1, 4-oxazepan-5-ones

Sodium azide (17.8g) was added to a concentrated hydrochloric acid (50ml) solution of tetrahydro-4H-pyran-4-one (9.80g) under ice cooling for 40 minutes, followed by stirring for 30 minutes and then stirring at room temperature for 16 hours. Under ice-cooling, sodium carbonate is added to the reaction solution, the pH is adjusted to 8-9, and chloroform is added for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 1, 4-oxazepan-5-one (5.34g, 47.4%) as a solid.

¹H-NMR(300MHz，CDCl₃)δ：2.70-2.74(2H，m)，3.32-3.37(2H，m)，3.75-3.83(4H，m)，6.31(1H，br s).

FAB-MSm/z：116(M+H)⁺.

2)1, 4-Oxazacycloheptane-4-carboxylic acid tert-butyl ester

Under a nitrogen stream, the above 1, 4-oxazepan-5-one (3.041g) was added to a 1.0M tetrahydrofuran solution (40ml) of a borane-tetrahydrofuran complex under ice cooling for 30 minutes, stirred at room temperature for 30 minutes, and then refluxed for 2.5 hours. After air-cooling, a 4N hydrochloric acid-dioxane solution (25ml) and methanol (12ml) were added to the reaction solution, and the mixture was refluxed for 1 hour. After air-cooling, a 1N aqueous solution (80ml) of sodium hydroxide was added to the reaction mixture, and a solution of di-t-butoxydicarbonate (8.849g) in tetrahydrofuran (25ml) and methanol (20m1) were further added thereto at room temperature, followed by stirring for 17 hours. Water and chloroform were added to the reaction mixture to separate the mixture, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 1, 4-oxazepan-4-carboxylate (2.68g, 50%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.46(9H，s)，1.82-1.95(2H，m)，3.45-3.58(4H，m)，3.66-3.77(4H，m).

3) The title Compound

To a solution of the above tert-butyl 1, 4-oxazepan-4-carboxylate (0.468g) in dichloromethane (9.2ml) was added a 4N dioxane-hydrochloric acid solution (4.6ml) at 0 ℃, and the mixture was stirred at room temperature for 0.5 hours. The reaction solvent was distilled off under reduced pressure to obtain the title compound (0.263g, 82%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.22-2.33(2H，m)，3.27-3.43(4H，m)，3.82-3.90(2H，m)，3.92-4.01(2H，m)，9.89(1H，br).

ESI-MSm/z：102(M+H)⁺.

[ reference example 150] 1-Methylhexahydropyridazine

1) Hydrazine-1, 2-dicarboxylic acid phenylmethyl ester-ethyl ester

Triethylamine (100ml) and benzyl chloroformate (103ml) were added to a solution of ethyl carbazate (50.0g) in methylene chloride (400ml) under cooling at 0 ℃ and stirred at room temperature for 18 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution and chloroform were added for liquid separation, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl hydrazine-1, 2-dicarboxylate-ethyl ester (31.7g, 27.7%) as an oil.

¹H-NMR(300MHz，CDCl₃)δ：1.25(3H，t，J＝7.16Hz)，4.12(2H，q，J＝7.16Hz)，5.16(2H，s)，7.28-7.36(5H，m).

2) Azo-1, 2-dicarboxylic acid benzyl ester-ethyl ester

Tert-butyl hypochlorite (19.1ml) was added to an ethyl acetate (150ml) solution of the above hydrazine-1, 2-dicarboxylic acid benzyl ester-ethyl ester (31.0g) and stirred at room temperature for 3 hours. A saturated aqueous sodium carbonate solution and water were added to the reaction mixture to separate the mixture. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain azo-1, 2-dicarboxylic acid benzyl ester-ethyl ester (28.7g, 93.4%) as an oil.

¹H-NMR(300MHz，CDCl₃)δ：1.39(3H，t，J＝7.16Hz)，4.46(2H，q，J＝7.16Hz)，5.41(2H，s)，7.30-7.53(5H，m).

3)1, 2, 3, 6-Tetrahydropyridazine-1, 2-dicarboxylic acid 1-benzyl ester-2-ethyl ester

1, 3-butadiene (64.0g) gas was introduced into a benzene (100ml) solution of the above-mentioned azo-1, 2-dicarboxylic acid benzyl ester-ethyl ester (28.0g) under cooling at-10 ℃ and then stirred at room temperature for 18 hours. The reaction solvent was distilled off under reduced pressure to obtain 1, 2, 3, 6-tetrahydropyridazine-1, 2-dicarboxylic acid 1-benzyl ester-2-ethyl ester (32g) containing impurities as an oil.

FAB-MSm/z：291(M+H)⁺.

4) Hexahydropyridazine-1-carboxylic acid ethyl ester

To a solution of the above 1, 2, 3, 6-tetrahydropyridazine-1, 2-dicarboxylic acid 1-benzyl ester-2-ethyl ester (32g) in ethanol (100ml) was added 10% palladium on carbon (3.2g), and the mixture was stirred under a hydrogen atmosphere at 40 ℃ for 24 hours. After air-cooling, the reaction mixture was filtered, the solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was purified by distillation (boiling point: 81 ℃/1mmHg), whereby ethyl hexahydropyridazine-1-carboxylate (5.96g, 31.1% in the 2-step) was obtained as an oil.

¹H-NMR(300MHz，CDCl₃)δ：1.29(3H，t，J＝7.16Hz)，1.65(4H，Brs)，2.92(2H，t，J＝5.69Hz)，3.57(2H，t，J＝5.69Hz)，4.19(2H，q，J＝7.16Hz).

5) The title Compound

A solution of the above ethyl hexahydropyridazine-1-carboxylate (5.5g) in diethyl ether (20ml) was added dropwise to a suspension of lithium aluminum hydride (2.64g) in diethyl ether (50ml) at room temperature over 1 hour, followed by heating and refluxing for 4 hours. After 40% potassium hydroxide aqueous solution (100ml) was slowly dropped into the reaction mixture at-10 ℃ under cooling, ether was added for liquid separation, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (1.75g, 50.3%) as an oil.

¹H-NMR(300MHz，CDCl₃)δ：1.42(2H，br s)，1.73-1.81(2H，m)，2.38(3H，s)，2.48(2H，br s)，3.02(2H，t，J＝5.51Hz).

[ reference example 151] 4-methoxypiperidine trifluoroacetate

1) 4-Methoxypiperidine-1-carboxylic acid tert-butyl ester

Using tert-butyl 4-hydroxy-1-piperidinecarboxylate (2.0g), tert-butyl 4-methoxypiperidine-1-carboxylate (1.43g, 67%) was obtained as an oil in the same manner as in reference example 106.

¹H-NMR(400MHz，CDCl₃)δ：1.39-1.54(2H，m)，1.46(9H，s)，1.81-1.84(2H，m)，3.05-3.12(2H，m)，3.31-3.39(1H，m)，3.35(3H，s)，3.74-3.77(2H，m).

2) The title Compound

The title compound (2.65g, quantitative) was obtained as an oil in the same manner as in 2) of reference example 85 using tert-butyl 4-methoxypiperidine-1-carboxylate (1.42 g).

¹H-NMR(400MHz，CDCl₃)δ：1.98-2.02(4H，m)，3.19-3.23(2H，m)，3.30-3.42(2H，m)，3.37(3H，s)，3.54-3.60(1H，m).

[ reference example 152]4, 4-Difluoropiperidine hydrochloride

1) N-benzyl-4, 4-difluoropiperidine

Diethylaminosulfur trifluoride (8.38ml) was added dropwise to a solution of 1-benzyl-4-piperidone (5.00g) in benzene (200ml) at 0 ℃ under an argon atmosphere, and the mixture was stirred for 30 minutes and then refluxed for 18 hours. After cooling at 0 ℃, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to separate the solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain N-benzyl-4, 4-difluoropiperidine (4.67g, 84%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.93-2.04(4H，m)，2.53-2.55(4H，m)，3.54(2H，s)，7.24-7.34(5H，m).

EI-MSm/z：211(M⁺).

2) The title Compound

1-chloroethyl chloroformate (2.62ml) was added dropwise to a solution of the above N-benzyl-4, 4-difluoropiperidine (4.66g) in methylene chloride (93ml) at 0 ℃ under an argon atmosphere, followed by stirring at 55 ℃ for 2 hours. After air-cooling, the reaction solvent was distilled off under reduced pressure, and the resulting methanol (93ml) solution of the residue was heated under reflux for 4 hours. After air-cooling, the reaction solvent was distilled off under reduced pressure to obtain the title compound (3.03g, 87%) as a solid.

FAB-MSm/z：122(M+H)⁺.

[ reference example 153]3, 3-Difluoropiperidine hydrochloride

1) N-benzyl-3, 3-difluoropiperidine

The same procedures used in 1) of referential example 152 were repeated except for using 1-benzyl-3-piperidone hydrochloride (4.00g) to obtain N-benzyl-3, 3-difluoropiperidine (1.09g, 31%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.73-1.92(4H，m)，2.45(2H，t，J＝5.4Hz)，2.63(2H，t，J＝11.4Hz)，3.60(2H，s)，7.24-7.37(5H，m).

FAB-MSm/z：212(M+H)⁺.

2) The title Compound

The title compound (0.764g, 95%) was obtained as a solid in the same manner as in 2) of reference example 152 using the above-mentioned N-benzyl-3, 3-difluoropiperidine (1.08 g).

¹H-NMR(400MHz，D₂O)δ：1.85-1.91(2H，m)，2.01-2.11(2H，m)，3.12(2H，t，J＝5.2Hz)，3.40(2H，t，J＝11.5Hz).

FAB-MSm/z：122(M+H)⁺.

[ reference example 154] 4-Fluoropiperidine hydrochloride

1) 4-Fluoropiperidine-N-carboxylic acid tert-butyl ester

[ bis (2-methoxyethyl) amino ] sulfur trifluoride (7.33ml) was added dropwise to a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (4.00g) in methylene chloride (80ml) at-78 ℃ under an argon atmosphere, followed by stirring at 0 ℃ for 30 minutes, then at 0 ℃ for 30 minutes, and then at room temperature for 2 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution and chloroform were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain tert-butyl 4-fluoropiperidine-N-carboxylate (1.77g, 44%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.45(9H，s)，1.86-1.76(4H，m)，3.41-3.54(4H，m)，4.70-4.87(1H，m).

EI-MSm/z：203(M⁺).

2) The title Compound

The title compound (0.870g, 73%) was obtained as a solid in the same manner as in 2) of reference example 85 using the above tert-butyl 4-fluoropiperidine-N-carboxylate (1.74 g).

¹H-NMR(400MHz，DMSO-d₆)δ：2.13-1.92(4H，m)，3.01-3.12(4H，m)，4.83-4.97(1H，m).

FAB-MSm/z：104(M+H)⁺.

[ reference example 155] (3R) -3-Methoxypyrrolidine-1-carboxylic acid tert-butyl ester

The title compound (0.899g, 89%) was obtained as an oil in the same manner as in reference example 106 using tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (0.955g) and methyl iodide (0.47 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.46(9H，s)，1.88-2.03(2H，m)，3.33-3.50(4H，m)，3.33(3H，s)，3.92(1H，br s).

ESI-MSm/z：146(M-Bu+H)⁺.

[ reference example 156] Hexahydropyridazine

1)1, 2, 3, 6-tetrahydropyridazine-1, 2-dicarboxylic acid diphenylmethyl ester

The same procedures used in 3) of referential example 151 were repeated using 1, 2-azobisdimethyldicarboxylate (10.28g) to give 1, 2, 3, 6-tetrahydropyridazine-1, 2-dicarboxylic acid diphenylmethyl ester (2.57g, 21%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：3.70-3.85(2H，br)，4.35-4.52(2H，br)，5.05-5.25(4H，br)，5.78(2H，br)，7.03-7.40(10H，m).

FAB-MSm/z：353(M+H)⁺.

2) The title Compound

The title compound (0.629g, quantitative) was obtained as an oil in the same manner as in 4) of reference example 151 using diphenylmethyl 1, 2, 3, 6-tetrahydropyridazine-1, 2-dicarboxylate (2.57 g).

¹H-NMR(400MHz，DMSO-d₆)δ：1.67-1.75(2H，m)，1.96-2.05(2H，m)，2.60-3.10(4H，m).

ESI-MSm/z：87(M+H)⁺.

[ reference example 157] 1-methylpiperazin-2-one hydrochloride

To tert-butyl 3-oxopiperazine-1-carboxylate (2.06g) in referential example 90 was added a 4N hydrochloric acid-dioxane solution (20ml), and the mixture was stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure to obtain the title compound (1.44g, 99%) as an oil.

¹H-NMR(400MHz，DMSO-d₆)δ：2.86(3H，s)，3.34(2H，br m)，3.50(2H，m)，3.64(2H，m).

ESI-MSm/z：115(M+H)⁺.

[ reference example 158]1- (6-methoxy-3-pyridazinyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylic acid

1)1- (6-chloro-3-pyridazinyl) -5- (4-methoxy-2-pyridinyl) pyrazole-3-carboxylic acid ethyl ester

The same procedures used in method 1) of method A of reference example 139 were repeated except for using ethyl 4- (4-methoxy-2-pyridyl) -2, 4-dioxobutyrate (4.94g and 3-chloro-6-hydrazinopyridazine (2.84g) obtained in reference example 17 to obtain ethyl 1- (6-chloro-3-pyridazinyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylate (2.02g, 29%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.44(3H，m)，3.88(3H，s)，4.43-4.49(2H，m)，6.75(1H，dd，J＝5.9，2.4Hz)，7.15(1H，d，J＝2.4Hz)，7.19(1H，s)，7.66-7.68(1H，m)，8.07(1H，d，J＝9.0Hz)，8.19(1H，d，J＝5.9Hz).

EI-MSm/z：359(M⁺).

2) The title Compound

To a mixed solution of ethyl 1- (6-chloro-3-pyridazinyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylate (2.01g) in methanol (40ml) and tetrahydrofuran (40ml) was added a 1N aqueous solution (14ml) of sodium hydroxide and the mixture was stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure, the resulting residue was washed with chloroform by adding water, a mixed solvent of acetic acid (20ml) and methanol-chloroform (1: 5) was added to the aqueous layer to separate the solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in methanol (14ml), and sodium methoxide (0.332g) was added thereto under argon atmosphere at room temperature and stirred for 3 hours, followed by heating and refluxing for 2 hours. After air-cooling, the reaction mixture was added with acetic acid (10ml), water and a mixed solvent of methanol and chloroform (1: 10) for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (0.626g, 34%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：3.87(3H，s)，4.03(3H，s)，6.87-6.89(1H，m)，7.40-7.45(3H，m)，7.92(1H，d，J＝9.3Hz)，8.12(1H，d，J＝5.9Hz)，13.09(1H，br s).

EI-MSm/z：327(M⁺).

[ reference example 159]1- (6-methoxy-3-pyridyl) -5- (pyrrol-2-yl) pyrazole-3-carboxylic acid

Diethyl oxalate (3.10ml) and 1- [1- (benzenesulfonyl) pyrrol-2-yl ] -1-ethanone (2.49g) were added to a solution of sodium ethoxide (1.63g) in ethanol (20ml) under ice-cooling, and stirred at room temperature for 5 hours. To the reaction solution were added 5-hydrazino-2-methoxypyridine hydrochloride (2.52g) of reference example 1 and ethanol (20ml), and the mixture was refluxed for 14 hours and 30 minutes. After air-cooling, the reaction solvent was evaporated under reduced pressure, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the obtained residue to separate the mixture, and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain ethyl 1- (6-methoxy-3-pyridyl) -5- [1- (benzenesulfonyl) pyrrol-2-yl ] pyrazole-3-carboxylate (3.28g, 72%) as an oil. To a solution of the ethyl ester (3.28g) in ethanol (22ml) was added a 1N aqueous solution (22ml) of sodium hydroxide, and the mixture was stirred at room temperature for 2 days. Then, a 1N aqueous hydrochloric acid solution was added to the reaction solution, and the resulting solid was collected by filtration to obtain the title compound (1.40g, 68%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：3.94(3H，s)，5.49-5.51(1H，m)，5.98-6.00(1H，m)，6.87-6.89(1H，m)，6.98(1H，dd，J＝8.8，0.5Hz)，7.08(1H，s)，7.80(1H，dd，J＝8.8，2.7Hz)，8.25(1H，dd，J＝2.7，0.5Hz)，11.39(1H，br s).

ESI-MSm/z：285(M+H)⁺.

[ reference example 160]1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid

To a mixed solution of methyl 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylate (2.20g) obtained in method 3) of reference example 139, in methanol (30ml) and tetrahydrofuran (30ml) was added a 1N aqueous solution (15ml) of sodium hydroxide at room temperature, and the mixture was stirred for 2.5 hours. Under ice-cooling, a 1N aqueous hydrochloric acid solution (15ml) and a chloroform-methanol (10: 1) mixed solvent were added to the reaction mixture to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title compound (1.42g, 47.6%).

¹H-NMR(400MHz，DMSO-d₆)δ：4.04(3H，s)，7.32-7.35(1H，m)，7.41(1H，s)，7.49(1H，d，J＝9.3Hz)，7.80-7.82(1H，m)，7.87-7.91(1H，m)，7.99(1H，d，J＝9.3Hz)，8.35-8.36(1H，m).

LC-MSm/z：298(M+H)⁺.

[ reference example 161]1- (6-methoxy-3-pyridyl) -5- (1-methylpyrrol-2-yl) pyrazole-3-carboxylic acid

To a solution of 1- (1-methylpyrrol-2-yl) -1-ethanone (1.19ml) in tetrahydrofuran (10ml) was added a solution of 1.0M lithium-bis (trimethylsilyl) amide in tetrahydrofuran (10.4ml) with cooling at-78 ℃ and stirred for 35 minutes. Diethyl oxalate (2.05ml) was added to the reaction mixture, and the temperature was gradually returned to room temperature, followed by stirring at room temperature for 2 and half hours. Triethylamine (1.64ml), 5-hydrazino-2-methoxypyridine hydrochloride (2.52g) obtained in reference example 1 and ethanol (50ml) were added to the reaction mixture, and the mixture was refluxed for 2 days and a half. Then, acetic acid (5ml) was added to the reaction solution, and the mixture was refluxed for 3 days. After air-cooling, the reaction solvent was evaporated under reduced pressure, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the obtained residue to separate the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain ethyl 1- (6-methoxy-3-pyridyl) -5- (1-methylpyrrol-2-yl) pyrazole-3-carboxylate (2.70g, 82%) as an oil. To a solution of the ethyl ester (2.70g) in ethanol (20ml) was added a 1N aqueous solution (21ml) of sodium hydroxide, and the mixture was stirred at room temperature for 26 hours. A1N aqueous hydrochloric acid solution and ethyl acetate were added to the reaction mixture to separate the reaction mixture, and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (2.57g, quantitative) as an amorphous solid. This was used in the following reaction without purification.

[ example 1]1- [5- (4-chlorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

1-hydroxybenzotriazole (0.110g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.303g), triethylamine (0.255ml) and N-methylpiperazine (0.240ml) were added to a solution of 5- (4-chlorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.237g) in N, N-dimethylformamide (5.0ml) of referential example 4 at room temperature, and the mixture was stirred for 21 hours. Water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. Then, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.261g, 88%).

¹H-NMR(400MHz，CDCl₃) δ: 2.33(3H, s), 2.40-2.60(4H, m), 3.84(2H, br), 3.94(3H, s), 4.11(2H, br), 6.74(1H, d-like, J-8.7 Hz), 6.91(1H, s), 7.17(2H, d-like, J-8.8 Hz), 7.31(2H, d-like, J-8.8 Hz), 7.49(1H, dd, J-8.7 Hz), 8.09(1H, d-like, J-2.7 Hz).

MS(ESI)m/z：412(M+H)⁺.

2) Hydrochloride salt of the title compound

To a chloroform (1.0ml) solution of the title compound (0.261g) was added a 1M-hydrochloric acid-ethanol solution (0.635ml) and the mixture was stirred. To the reaction mixture were added diethyl ether and pentane, and the precipitated solid was collected by filtration, washed with diethyl ether and dried to obtain the hydrochloride of the title compound (0.223g, 75%).

¹H-NMR(400MHz，DMSO-d₆)δ：2.79(3H，s)，3.00-3.70(6H，m)，3.88(3H，s)，4.60(1H，br)，4.95(1H，br)，6.92(1H，d，J＝8.8Hz)，7.05(1H，s)，7.32(2H，d，J＝8.5Hz)，7.47(2H，d，J＝8.5Hz)，7.71(1H，dd，J＝8.8，2.9Hz)，8.21(1H，d，J＝2.9Hz)，10.60(1H，br).

MS(ESI)m/z：412(M+H)⁺.

[ example 2]1- [5- (4-ethylphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.294g, 87%) was obtained as an oil in the same manner as in 1) of example 1 using 5- (4-ethylphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.269g) and N-methylpiperazine (0.275ml) of reference example 6.

¹H-NMR(400MHz，CDCl₃)δ：1.23(3H，t，J＝7.8Hz)，2.32(3H，s)，2.40-2.60(4H，m)，2.64(2H，q，J＝7.8Hz)，3.84(2H，br)，3.93(3H，s)，4.12(2H，br)，6.72(1H，d，J＝8.7Hz)，6.88(1H，s)，7.10-7.20(4H，m)，7.49(1H，dd，J＝8.7，2.4Hz)，8.13(1H，d，J＝2.4Hz).

MS(ESI)m/z：406(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above title compound (0.294g), the same procedure as in 2) of example 1 was followed to obtain the hydrochloride salt of the title compound (0.276g, 81%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：1.17(3H，t，J＝7.6Hz)，2.60(2H，q，J＝7.6Hz)，2.79(3H，s)，3.00-3.75(6H，m)，3.88(3H，s)，4.65(1H，br)，5.00(1H，br)，6.91(1H，d，J＝9.1Hz)，6.97(1H，s)，7.17-7.28(4H，m)，7.70(1H，dd，J＝9.1，2.7Hz)，8.21(1H，d，J＝2.7Hz).

LC-MSm/z：406(M+H)⁺.

Elemental analysis: c₂₃H₂₇N₅O₂ 1.0HCl 1.5H₂O

Theoretical value: c, 58.90; h, 6.66; cl, 7.56; n, 14.93.

Measured value: c, 58.65; h, 6.51; cl, 7.63; n, 14.84.

[ example 3]1- [1- (6-methoxy-3-pyridyl) -5- (3-methylphenyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.471, quantitative) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (3-methylphenyl) pyrazole-3-carboxylic acid (0.353g) and N-methylpiperazine (0.380ml) of reference example 8.

¹H-NMR(400MHz，CDCl₃) δ: 2.31(3H, s), 2.33(3H, s), 2.40-2.60(4H, m), 3.84(2H, br), 3.94(3H, s), 4.12(2H, br), 6.71(1H, d, J ═ 8.8Hz), 6.88(1H, s), 6.97(1H, d-like, J ═ 7.3Hz), 7.08-7.25(3H, m), 7.48(1H, dd, J ═ 8.8, 2.6Hz), 8.12(1H, d, J ═ 2.6Hz).

MS(ESI)m/z：392(M+H)⁺.

2) Hydrochloride salt of the title compound

The same procedure as in 2) of example 1 was repeated using the above-mentioned title compound (0.471g) to obtain a hydrochloride (0.356g, 70%) of the title compound as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：2.28(3H，s)，2.79(3H，s)，2.95-3.70(6H，m)，3.7(3H，s)，4.60(1H，br)，4.99(1H，br)，6.90(1H，d，J＝8.7Hz)，6.95-7.03(2H，m)，7.17-7.30(3H，m)，7.68(1H，dd，J＝8.7，2.0Hz)，8.19(1H，d，J＝2.0Hz)，10.79(1H，br).

LC-MSm/z：392(M+H)⁺.

[ example 4]1- [1- (6-methoxy-3-pyridyl) -5- (2-methylphenyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.335g, 86%) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-methylphenyl) pyrazole-3-carboxylic acid (0.307g) and N-methylpiperazine (0.330ml) of reference example 10.

¹H-NMR(400MHz，CDCl₃)δ：2.04(3H，s)，2.34(3H，s)，2.50(4H，m)，3.85(2H，br)，3.89(3H，s)，4.17(2H，br)，6.64(1H，d，J＝9.1Hz)，6.83(1H，s)，7.15-7.35(5H，m)，7.42(1H，dd，J＝9.1，2.7Hz)，8.03(1H，d，J＝2.7Hz).

MS(ESI)m/z：392(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above-mentioned title compound (0.335g), a hydrochloride (0.30g, 81%) of the title compound was obtained as a solid in the same manner as in 2) of example 1.

¹H-NMR(400MHz，DMSO-d₆)δ：2.04(3H，s)，2.80(3H，s)，3.00-3.80(6H，m)，3.82(3H，s)，4.60(1H，br)，5.02(1H，br)，6.83(1H，d，J＝9.0Hz)，6.90(1H，s)，7.18-7.40(4H，m)，7.62(1H，dd，J＝9.0，2.7Hz)，8.07(1H，d，J＝2.7Hz).

MS(ESI)m/z：392(M+H)⁺.

[ example 5]1- [5- (3-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.314g, 83%) was obtained as an oil in the same manner as in 1) of example 1 using 5- (3-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.302g) of reference example 12 and N-methylpiperazine (0.320 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.31(3H，s)，2.40-2.60(4H，m)，3.82(2H，br)，3.93(3H，s)，4.09(2H，br)，6.72(1H，d，J＝8.8Hz)，6.90(1H，s)，6.90-7.10(3H，m)，7.25-7.35(1H，m)，7.47(1H，dd，J＝8.8，2.7Hz)，8.08(1H，d，J＝2.7Hz).

MS(ESI)m/z：396(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above title compound (0.314g), the same procedure as in 2) of example 1 was repeated to obtain the hydrochloride salt of the title compound (0.282g, 79%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：2.79(3H，s)，3.00-3.75(6H，m)，3.88(3H，s)，4.60(1H，br)，4.95(1H，br)，6.92(1H，d，J＝8.8Hz)，7.05-7.13(1H，m)，7.09(1H，s)，7.18-7.30(2H，m)，7.39-7.50(1H，m)，7.72(1H，dd，J＝8.8，2.7Hz)，8.22(1H，d，J＝2.7Hz)，10.50(1H，br).

LC-MSm/z：396(M+H)⁺.

Elemental analysis: c₂₁H₂₂FN₅O₂ 1.0HCl 1.0H₂O

Theoretical value: c, 56.06; h, 5.60; cl, 7.88; f, 4.22; n, 15.57.

Measured value: c, 55.97; h, 5.60; cl, 8.01; f, 4.20; n, 15.36.

[ example 6]4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] morpholine

The title compound (0.126g, 66%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.155g) of reference example 41 and morpholine (0.137 ml).

¹H-NMR(400MHz，CDCl₃)δ：3.65-4.05(6H，m)，3.94(3H，s)，4.10-4.30(2H，m)，6.72(1H，d，J＝8.8Hz)，6.95(1H，s)，7.15-7.40(5H，m)，7.47(1H，dd，J＝8.8，2.7Hz)，8.12(1H，d，J＝2.7Hz).

MS(FAB)m/z：365(M+H)⁺.

[ example 7]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -3, 4-dimethylpiperazine

1) The title Compound

The title compound (0.268g, 84%) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.241g) of reference example 41 and 1, 2-dimethylpiperazine trifluoroacetate (0.838g) of reference example 84.

¹H-NMR(400MHz，CDCl₃) δ: 1.09 and 1.15(3H, d each, J6.1 each)Hz)，2.10-2.40(1.5H，m)，2.33(3H，s)，2.70-2.95(2H，m)，3.08-3.20(1H，m)，3.45-3.60(0.5H，m)，3.93(3H，s)，4.45-4.85(2H，m)，6.71(1H，d，J＝8.8Hz)，6.91(1H，s)，7.20-7.60(6H，m)，8.12(1H，s).

LC-MSm/z：392(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above title compound (0.268g), the same method as in 2) of example 1 was performed to obtain a hydrochloride salt of the title compound (0.173g, 54%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：1.15-1.45(3H，m)，2.0-4.0(5H，m)，2.79(3H，s)，3.86(3H，s)，4.60(1H，br)，4.95(1H，br)，6.89(1H，d，J＝8.7Hz)，7.00(1H，s)，7.20-7.45(5H，m)，7.68(1H，dd，J＝8.7，2.5Hz)，8.18(1H，d，J＝2.5Hz).

LC-MSm/z：392(M+H)⁺.

[ example 8]1- [ 4-methyl-5-phenyl- (3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.596g, 61%) was obtained as an oil in the same manner as in 1) of example 1 using 4-methyl-5-phenyl-1- (3-pyridyl) pyrazole-3-carboxylic acid (0.752g) and N-methylpiperazine (0.90ml) of reference example 54.

¹H-NMR(400MHz，CDCl₃)δ：2.18(3H，s)，2.34(3H，s)，2.45-2.59(4H，m)，3.87(4H，br)，7.15-7.30(3H，m)，7.35-7.43(3H，m)，7.51-7.57(1H，m)，8.47(1H，dd，J＝4.7Hz，J＝1.5Hz)，8.49(1H，d，J＝2.2Hz).

MS(ESI)m/z：362(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above-mentioned title compound (0.596g), a hydrochloride salt of the title compound (0.565g, 84%) was obtained as a solid in the same manner as in 2) of example 1.

¹H-NMR(400MHz，DMSO-d₆) δ: 2.11(3H, s), 2.82(3H, s), 3.00-3.65(6H, m), 4.55-4.80(2H, m), 7.21-7.32(2H, m), 7.40-7.50(3H, m), 7.63-7.70(1H, m), 8.48(1H, d, J ═ 2.4Hz), 8.52(1H, d-type, J ═ 4.8Hz), 10.45(1H, br).

MS(ESI)m/z：362(M+H)⁺.

[ example 9]1- [ 4-methyl-1, 5-diphenylpyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.818g, 90%) was obtained as an oil in the same manner as in 1) of example 1 using 4-methyl-1, 5-diphenylpyrazole-3-carboxylic acid (0.70g) of reference example 56 and N-methylpiperazine (0.840 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.18(3H，s)，2.34(3H，s)，2.45-2.60(4H，m)，3.80-3.96(4H，m)，7.10-7.50(10H，m).

MS(ESI)m/z：361(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above-mentioned title compound (0.818g), a hydrochloride salt of the title compound (0.685g, 56%) was obtained as a solid in the same manner as in 2) of example 1.

¹H-NMR(400MHz，DMSO-d₆) δ: 2.10(3H, s), 2.81(3H, s-like), 3.00-3.65(6H, m), 4.55-4.80(2H, m), 7.16-7.30(4H, m), 7.30-7.50(6H, m), 10.57(1H, br).

MS(ESI)m/z：361(M+H)⁺.

Elemental analysis: c₂₂H₂₄N₄O 1.1HCl 1.0H₂O

Theoretical value: c, 63.13; h, 6.53; cl, 9.32; n, 13.38.

Measured value: c, 63.32; h, 6.42; cl, 9.11; and N, 13.45.

[ example 10]1- [ 4-fluoro-1, 5-diphenylpyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.124g, 49%) was obtained as an oil in the same manner as in 1) of example 1 using 4-fluoro-1, 5-diphenylpyrazole-3-carboxylic acid (0.169g) of reference example 59 and N-methylpiperazine (0.20 ml).

¹H-NMR(400MHz，CDCl₃) δ: 2.08-2.18(2H, m), 2.24(3H, s), 2.32-2.43(2H, m), 3.30-3.45(2H, m), 3.68-3.82(2H, m), 7.32-7.68(8H, m), 7.93(2H, d-like, J ═ 7.8Hz).

MS(ESI)m/z：365(M+H)⁺.

2) Hydrochloride salt of the title compound

The title compound (0.124g) was obtained as a solid in the same manner as in 2) of example 1 using the above title compound (0.108g, 79%).

¹H-NMR(400MHz，DMSO-d₆)δ：2.80(3H，s)，2.80-3.65(6H，m)，4.08-4.22(1H，m)，4.40-4.55(1H，m)，7.35-7.60(8H，m)，7.86(2H，d，J＝7.4Hz)，11.09(1H，br).

MS(ESI)m/z：365(M+H)⁺.

[ example 11]4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1, 1-dioxothiomorpholine

The title compound (0.185g, 51%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.250g) of reference example 41 and thiomorpholine-1, 1-dioxide (0.126 g).

¹H-NMR(400MHz，CDCl₃)δ：3.17-3.21(4H，m)，3.96(3H，s)，4.29(2H，m)，4.66(2H，m)，6.74(1H，d，J＝8.8Hz)，7.02(1H，s)，7.22-7.39(5H，m)，7.42-7.45(1H，m)，8.12(1H，d，J＝2.8Hz).

MS(EI)m/z：412(M⁺).

[ example 12]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

To a solution of ethyl 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylate (2.1g) in methanol (20ml) in referential example 135 was added a 1M aqueous sodium hydroxide solution (15.4ml) at 0 ℃ and the mixture was stirred at room temperature for 4.5 hours. Cooling at 0 deg.C again, slowly adding concentrated hydrochloric acid into the reaction solution to adjust pH to 3, adding chloroform to dissolve the resultant solid, evaporating under reduced pressure to remove the solvent, and adding a mixed solvent of water and chloroform-methanol (9: 1) into the obtained residue to separate the liquid. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in a mixed solvent of N, N-dimethylformamide (50ml) and methylene chloride (30ml), and N-methylpiperazine (1.37ml), triethylamine (3.4ml), 1-hydroxybenzotriazole (1.66g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.36g) were added at room temperature. After stirring at room temperature for 62 hours, a saturated aqueous sodium bicarbonate solution and chloroform were added to the reaction mixture to separate the mixture. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (2.421g, 99.5%).

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.49(4H，dt，J＝14.0，4.9Hz)，3.84(2H，br s)，3.94(3H，s)，4.12(2H，br s)，6.74(1H，d，J＝8.8Hz)，6.89(1H，s)，7.04(2H，t，J＝8.8Hz)，7.22(2H，dd，J＝8.8，5.1Hz)，7.48(1H，dd，J＝8.8，2.9Hz)，8.10(1H，d，J＝2.9Hz).

MS(EI)m/z：395(M⁺).

2) Hydrochloride salt of the title compound

1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine (1.12g) was dissolved in diethyl ether (10ml), and a 1M-hydrochloric acid-ethanol solution (8.5ml) was added at room temperature under an argon stream. After stirring at the same temperature for 4 hours, ethanol was added to the reaction mixture, the solvent was evaporated under reduced pressure, ether and hexane were added to the resulting residue, and the precipitated solid was washed and filtered. The filtered solid was recrystallized from ethanol to obtain the title compound (715mg, 57%) as a solid.

MS(EI)m/z：395(M⁺).

Elemental analysis: c₂₁H₂₂FN₅O₂ 1.0HCl 0.5H₂O

Theoretical value: c, 57.21; h, 5.49; n, 15.88; f, 4.31; cl, 8.04.

Measured value: c, 57.28; h, 5.37; n, 16.22; f, 4.19; cl, 8.06.

[ example 13]4- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] morpholine

The title compound (0.386g, 86%) was obtained as a solid in the same manner as in 1) of example 1 using 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.368g) of referential example 136 and morpholine (0.310 ml).

¹H-NMR(400MHz，CDCl₃) δ: 3.70-3.90(6H, m), 3.93(3H, s), 4.18(2H, br), 6.74(1H, d, J ═ 8.8Hz), 6.94(1H, s), 7.04(2H, t-like, J ═ 8.6Hz), 7.18-7.29(2H, m), 7.49(1H, dd, J ═ 8.6, 2.2Hz), 8.10(1H, d, J ═ 2.2Hz).

[ example 14]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-benzyl-3-methylpiperazine

The title compound (0.462g, quantitative) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid of reference example 41 (0.290g) and 1-benzyl-2-methylpiperazine trifluoroacetate (0.609g) of 2) of reference example 85.

¹H-NMR(400MHz，CDCl₃) δ: 1.16 and 1.22(3H, each d, each J ═ 6.1Hz), 2.00-4.60(9H, m), 3.89 and 3.91(3H, each s), 6.65-6.74(1H, m), 6.92 and 6.93(1H, each s), 7.15-7.55(11H, m), 8.08 and 8.14(1H, each d, each J ═ 2.5Hz). 468(M + H)⁺.

[ example 15]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -3-methylpiperazine

1) The title Compound

To a solution of 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-benzyl-3-methylpiperazine (0.459g) in ethanol (10ml) of example 14 were added 1M-hydrochloric acid-ethanol (0.980ml) and 10% palladium on carbon (123mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 5.5 hours. After the replacement with nitrogen, the mixture was neutralized with a 1M aqueous sodium hydroxide solution (pH8), and insoluble materials were filtered off. The filtrate was evaporated under reduced pressure, and water and chloroform were added to the resulting residue to separate the mixture. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.250g, 67%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 2.51(0.5H, t-like, J ═ 11.0Hz), 2.80-3.30(4.5H, m), 3.93(3H, s), 4.59-4.87(2H, m), 6.71(1H, d, J ═ 8.7Hz), 6.90(1H, s), 7.20-7.60(6H, m), 8.12(1H, s-like).

MS(ESI)m/z：378(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above compound (0.250g), the hydrochloride of the title compound (0.201g, 68%) was obtained as a solid in the same manner as in 2) of example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.20-1.34(3H，br)，3.00-3.75(5H，m)，4.40-4.53(1H，m)，4.70-4.90(1H，m)，6.91(1H，d，J＝8.8Hz)，7.01(1H，s)，7.25-7.45(5H，m)，7.70(1H，dd，J＝8.8，3.0Hz)，8.18(1H，d，J＝2.7Hz)，9.10-9.50(2H，br).

MS(ESI)m/z：378(M+H)⁺.

Elemental analysis: c₂₁H₂₃N₅O₂ 1.2H₂O 1.5HCl

Theoretical value: c, 56.27; h, 6.12; cl, 9.49; n, 15.62.

Measured value: c, 56.12; h, 6.00; cl, 9.84; n, 15.45.

[ example 16]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine

1)1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-4-carboxylic acid tert-butyl ester

Using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.407g) of reference example 41 and tert-butyl piperazine-1-carboxylate, tert-butyl 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-4-carboxylate (0.772g, quantitative) was obtained as an oil in the same manner as in 1) of example 1.

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，3.53(4H，br)，3.79(2H，br)，3.94(3H，s)，4.10(2H，br)，6.72(1H，d，J＝8.8Hz)，6.94(1H，s)，7.20-7.40(5H，m)，7.47(1H，dd，J＝8.8，2.7Hz)，8.12(1H，d，J＝2.7Hz).

MS(ESI)m/z：464(M+H)⁺.

2) The title Compound

Trifluoroacetic acid (2.4ml) was added to a solution of tert-butyl 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-4-carboxylate (0.639g) in methylene chloride (15ml) at room temperature, and the mixture was stirred for 0.7 hours. The reaction solvent was evaporated under reduced pressure, and chloroform and a saturated aqueous sodium bicarbonate solution were added to the resulting residue to separate the mixture. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.446g, 89%) as an oil.

¹H-NMR(400MHz，CDCl₃) δ: 2.90-3.02(4H, m), 3.80(2H, br), 3.94(3H, s), 4.07(2H, br), 6.72(1H, d-like, J ═ 8.7Hz), 6.90(1H, s), 7.20-7.38(5H, m), 7.48(1H, dd, J ═ 8.7, 2.2Hz), 8.12(1H, d-like, J ═ 2.2Hz).

MS(FAB)m/z：364(M+H)⁺.

[ example 17]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-isopropylpiperazine

1) The title Compound

To a solution of 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine (0.446g) in N, N-dimethylformamide (7.5ml) prepared in example 16 was added potassium carbonate (0.505g) and isopropyl bromide (0.30ml) at room temperature, and the mixture was stirred at 60 ℃ for 16 hours. After air cooling, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. Then, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.283g, 57%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.06(6H，d，J＝6.5Hz)，2.50-2.81(5H，m)，3.83(2H，br)，3.93(3H，s)，4.10(2H，br)，6.71(1H，d，J＝8.8Hz)，6.90(1H，s)，7.19-7.38(5H，m)，7.47(1H，dd，J＝8.8，2.7Hz)，8.11(1H，d，J＝2.7Hz).

MS(ESI)m/z：406(M+H)⁺.

2) Hydrochloride salt of the title compound

The title compound (0.226g, 73%) was obtained as a solid in the same manner as in 2) of example 1 using the above title compound (0.283 g).

¹H-NMR(400MHz，DMSO-d₆)δ：1.26(6H，d，J＝6.4Hz)，2.95-3.60(6H，m)，3.67(1H，br)，3.86(3H，s)，4.63(1H，br)，5.03(1H，br)，6.89(1H，d，J＝8.8Hz)，7.00(1H，s)，7.25-7.43(5H，m)，7.68(1H，dd，J＝8.8，2.7Hz)，8.17(1H，d，J＝2.7Hz)，10.49(1H，br).

MS(ESI)m/z：406(M+H)⁺.

[ example 18]1- [5- (4-Benzyloxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (0.802g, 72%) was obtained as an oil in the same manner as in 1) of example 1 using 5- (4-benzyloxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.926g) and N-methylpiperazine (0.765ml) of reference example 14.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.42-2.60(4H，m)，3.84(2H, br), 3.94(3H, s), 4.12(2H, br), 6.72(1H, d, J ═ 9.0Hz), 6.84(1H, s), 6.93(2H, d-like, J ═ 8.7Hz), 7.15(2H, d-like, J ═ 8.7Hz), 7.30-7.45(5H, m), 7.48(1H, dd, J ═ 9.0, 2.7Hz), 8.13(1H, d, J ═ 2.7Hz).

MS(FAB)m/z：484(M+H)⁺.

[ example 19]1- [5- (4-hydroxyphenyl) -1- (6-methoxy-5-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

To a solution of 1- [5- (4-benzyloxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine (0.802g) in example 18 in ethanol (15ml) were added 10% palladium-carbon (0.466g) and 1M-hydrochloric acid-ethanol (1.65ml), and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. After completion of the reaction, the reaction mixture was replaced with nitrogen, the reaction mixture was neutralized with an aqueous sodium hydroxide solution, insoluble materials were filtered, and the residue was washed with methanol. The filtrate was evaporated under reduced pressure, and water and chloroform were added to the resulting residue to separate the mixture. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.493g, 69%) as a foamy substance.

¹H-NMR(400MHz，CDCl₃)δ：2.34(3H，s)，2.45-2.60(4H，m)，3.85(2H，br)，3.94(3H，s)，4.13(2H，br)，6.71(1H，d，J＝8.8Hz)，6.77(2H，d，J＝8.8Hz)，6.80(1H，s)，7.05(2H，d，J＝8.8Hz)，7.47(2H，dd，J＝8.8，2.2Hz)，8.12(1H，d，J＝2.2Hz).

MS(ESI)m/z：394(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above-mentioned title compound (0.493g), the hydrochloride of the title compound (0.436g, 72%) as a solid was obtained in the same manner as in 2) of example 1.

¹H-NMR(400MHz，DMSO-d₆) δ: 2.77(3H, s-like), 3.00-3.70(6H, m), 3.86(3H, s), 4.60(1H, br), 4.97(1H, br), 6.75(2H, d-like, J ═ 6.6Hz), 6.86(1H, s), 6.89(1H, d, J ═ 8.8Hz), 7.66(1H, dd, J ═ 8.8, 2.7Hz), 8.16(1H, d, J ═ 2.7Hz), 9.85(1H, br), 10.85(1H, br).

MS(ESI)m/z：394(M+H)⁺.

[ example 20]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

1-hydroxybenzotriazole (0.341g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.971g), triethylamine (1.61ml) and N-methylpiperazin-2-one trifluoroacetate (1.06g) of reference example 91 were added to a dichloromethane (15ml) solution of 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.695g) of reference example 41 at room temperature, and stirred for 26 hours. After the reaction mixture was made acidic (pH4) with 1M aqueous hydrochloric acid, water and chloroform were added to separate the mixture. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-acetone) to obtain the title compound (0.707g, 79%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：3.40-3.60(2H，m)，3.94(3H，s)，4.04(1H，br)，4.25-4.50(2H，m)，4.83(1H，s)，6.73(1H，d，J＝8.7Hz)，7.18-7.40(5H，m).

MS(ESI)m/z：392(M+H)⁺.

[ example 21]4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1, 2, 6-trimethylpiperazine

1) The title Compound

The title compound (0.351g, 76%) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.337g) of reference example 41 and 1, 2, 6-trimethylpiperazine trifluoroacetate (1.178g) of reference example 89.

¹H-NMR(400MHz，CDCl₃) δ: 1.09(3H, d, J ═ 6.1Hz), 1.16(3H, d, J ═ 6.1Hz), 2.20-2.30(2H, m), 2.28(3H, s), 2.65(1H, t-like, J ═ 13.2Hz), 3.03(1H, t-like, J ═ 13.2Hz), 3.92(3H, s), 4.51-4.61(1H, m), 4.68-4.79(1H, m), 6.69(1H, d, J ═ 8.8Hz), 6.88(1H, s), 7.17-7.36(5H, m), 7.43(1H, dd, J ═ 8.8, 2.7Hz), 8.10(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：406(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above-mentioned title compound (0.335g), a hydrochloride (0.277g, 71%) of the title compound was obtained as a solid in the same manner as in 2) of example 1.

¹H-NMR(400MHz，DMSO-d₆)δ：1.30-1.45(6H，br)，3.86(3H，s)，4.62(1H，br)，4.97(1H，br)，6.90(1H，d，J＝8.8Hz)，7.00(1H，s)，7.25-7.50(5H，m)，7.69(1H，dd，J＝8.8，2.7Hz)，8.18(1H，d，J＝2.7Hz)，10.61(1H，br).

MS(ESI)m/z：406(M+H)⁺.

[ example 22]4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2, 6-dimethylpiperazine

The title compound (0.312g, 94%) was obtained as a solid in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.278g) and 2, 6-dimethylpiperazine (0.214g) of reference example 41.

¹H-NMR(400MHz，CDCl₃) δ: 1.08(3H, d, J ═ 6.4Hz), 1.14(3H, d, J ═ 6.4Hz), 2.40(1H, t-like, J ═ 9.0Hz), 2.76(1H, t-like, J ═ 10.7Hz), 2.85-3.02(2H, m), 3.93(3H, s), 4.67(1H, d-like, J ═ 12.6Hz), 4.76(1H, d-like, J ═ 12.6Hz), 6.71(1H, d, J ═ 8.7Hz), 6.89(1H, s), 7.20-7.37(5H, m), 7.46(1H, dd, J ═ 8.7, 2.5Hz), 8.12(1H, d, J ═ 2.5Hz).

LC-MSm/z：392(M+H)⁺.

[ example 23]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

The title compound (0.213g, 94%) was obtained as a foamy substance in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.171g) of reference example 33 and N-methylpiperazin-2-one trifluoroacetic acid (0.251g) of reference example 91.

¹H-NMR(400MHz，CDCl₃) δ: 3.02(3H, s), 3.47(2H, br), 3.95(3H, s), 4.04(1H, br), 4.42(2H, s-like), 4.84(1H, s-like), 6.76(1H, d, J ═ 8.8Hz), 7.15-7.28(2H, m), 7.37-7.48(1H, m), 7.55-7.75(2H, m), 8.05-8.17(1H, m), 8.51(1H, d, J ═ 4.1Hz).

MS(FAB)m/z：393(M+H)⁺.

Elemental analysis: c₂₀H₂₀N₆O₃ 1.5H₂O

Theoretical value: c, 57.27; h, 5.53; and N, 20.04.

Measured value: c, 57.03; h, 5.06; n, 19.66.

[ example 24]4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -1, 2, 6-trimethylpiperazine

1) The title Compound

The title compound (0.272g, quantitative) was obtained as a foamy substance in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.197g) of reference example 33 and 1, 2, 6-trimethylpiperazine trifluoroacetic acid (0.477g) of reference example 89.

¹H-NMR(400MHz，CDCl₃)δ：1.10(3H，d，J＝6.1Hz)，1.18(3H，d，J＝6.1Hz)，2.15-2.30(2H，m)，2.29(3H，s)，2.69(1H，dd，J＝13.0，11.2Hz)，3.06(1H，dd，J＝13.0，11.2Hz)，3.95(3H，s)，4.55-4.74(2H，m)，6.75(1H，d，J＝8.8Hz)，7.11(1H，s)，7.21-7.27(1H，m)，7.43(1H，d，J＝7.8Hz)，7.57(1H，dd，J＝8.8，2.7Hz)，7.63-7.75(1H，m)，8.12(1H，d，J＝2.7Hz)，8.51(1H，br d，J＝4.4Hz).

MS(SEI)m/z：407(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above title compound (0.272g), the same procedure as in 2) of example 1 was carried out to obtain the hydrochloride salt of the title compound (0.222g, 67%) as a solid.

¹H-NMR(400MHz，DMSO-d₆) δ: 1.33(3H, br), 1.39(3H, br), 2.80(3H, d, J ═ 4.4Hz), 2.80-3.80(4H, m), 3.87(3H, s), 4.64(1H, br), 4.94(1H, br), 6.88(1H, d, J ═ 8.8Hz), 7.26(1H, s), 7.33-7.40(1H, m), 7.67-7.75(2H, m), 7.88(1H, dt, J ═ 7.8, 1.9Hz), 8.20(1H, d, J ═ 2.7Hz), 8.44(1H, d-like, J ═ 4.9Hz), 10.23(1H, br).

MS(ESI)m/z：407(M+H)⁺.

[ example 25]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-phenylpiperazine

The title compound (0.372g, 85%) was obtained as a foamy substance in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.296g) and N-phenylpiperazine (0.305ml) of reference example 41.

¹H-NMR(400MHz，CDCl₃)δ：3.20-3.35(4H，m)，3.94(3H，s)，3.99(2H，br)，4.30(2H，br)，6.72(1H，d，J＝8.8Hz)，6.82-7.00(4H，m)，7.20-7.37(7H，m)，7.48(1H，dd，J＝8.8，2.7Hz)，8.13(1H，d，J＝2.7Hz).

MS(FAB)m/z：440(M+H)⁺.

[ example 26]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4- (2-pyridyl) piperazine

The title compound (0.393g, 90%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (0.299g) and N- (pyridin-2-yl) piperazine (0.275ml) of reference example 41.

¹H-NMR(400MHz，CDCl₃)δ：3.60-3.70(4H，m)，3.90-3.95(2H，m)，3.93(3H，s)，4.24(2H，br)，6.62-6.73(3H，m)，6.94(1H，s)，7.20-7.37(5H，m)，7.43-7.52(2H，m)，8.11(1H，dd，J＝2.7，0.8Hz)，8.16-8.23(1H，m).

MS(FAB)m/z：441(M+H)⁺.

[ example 27]1- [1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (0.140g, 65%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylic acid (0.171g) and N-methylpiperazine (0.0639ml) of reference example 19.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.44-2.52(4H，m)，3.83(3H，s)，3.85(2H，m)，3.95(3H，s)，4.09(2H，m)，6.74-6.77(2H，m)，6.95(1H，d，J＝2.8Hz)，7.09(1H，s)，7.59(1H，dd，J＝8.8，2.8Hz)，8.12(1H，d，J＝2.8Hz)，8.32(1H，d，J＝6.0Hz).

MS(EI)m/z：408(M⁺).

[ example 28]4- [1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carbonyl ] morpholine

The title compound (0.132g, 62%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylic acid (0.171g) of reference example 19 and morpholine (0.0502 ml).

¹H-NMR(400MHz，CDCl₃)δ：3.73-3.75(2H，m)，3.81-3.84(4H，m)，3.84(3H，s)，3.95(3H，s)，4.14(2H，m)，6.74-6.78(2H，m)，6.96(1H，d，J＝2.4Hz)，7.13(1H，s)，7.57-7.60(1H，m)，8.12(1H，d，J＝2.8Hz)，8.32(1H，d，J＝6.0Hz).

MS(FAB)m/z：396(M+H)⁺.

Elemental analysis: c₂₀H₂₁N₅O₄ 0.5H₂O

Theoretical value: c: 59.40%, H: 5.48%, N: 17.32 percent.

Measured value: c: 59.64%, H: 5.31%, N: 17.19 percent.

[ example 29]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-ethylpiperazine

1) The title Compound

The title compound (0.265g, quantitative) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.20g) of reference example 33 and N-ethylpiperazine (0.0942 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.09-1.13(3H，m)，2.43-2.55(6H，m)，3.86(2H，m)，3.95(3H，s)，4.10(2H，m)，6.75(1H，d，J＝8.8Hz)，7.12(1H，s)，7.22-7.25(1H，m)，7.41(1H，d，J＝7.6Hz)，7.57-7.60(1H，m)，7.68-7.73(1H，m)，8.11(1H，d，J＝2.8Hz)，8.51(1H，d，J＝4.8Hz).

MS(EI)m/z：392(M⁺).

2) Hydrochloride salt of the title compound

To a solution of the above-mentioned title compound (0.249g) in diethyl ether (10ml) was added dropwise 1N hydrochloric acid-ethanol (1.27ml) at 0 ℃ and the mixture was stirred for 10 minutes. The precipitated crystal was collected by filtration, washed with diethyl ether and dried to obtain the hydrochloride of the title compound (0.257g, 81%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：(1.04-1.11(3/4H，m，for0.25EtOH))，1.26-1.29(3H，m)，3.06-3.72(8H，m，(2/4H，m，for0.25EtOH))，3.89(3H，s)，4.60(1H，m)，4.99(1H，m)，6.89(1H，d，J＝8.8Hz)，7.27(1H，s)，7.37-7.40(1H，m)，7.69-7.73(2H，m)，7.88-7.92(1H，m)，8.21(1H，d，J＝2.8Hz)，8.48(1H，d，J＝4.8Hz).

MS(EI)m/z：392(M⁺).

[ example 30]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3, 4-dimethylpiperazine

1) The title Compound

The title compound (0.234g, 88%) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.20g) of reference example 33 and 1, 2-dimethylpiperazine trifluoroacetate (0.254g) of reference example 84.

¹H-NMR(400MHz，CDCl₃)δ：1.07-1.17(3H，m)，2.20(2H，m)，2.33(3H，s)，2.71-3.52(3H，m)，3.95(3H，s)，4.50-4.76(2H，m)，6.76(1H，d，J＝8.8Hz)，7.12(1H，m)，7.23-7.27(1H，m)，7.40-7.44(1H，m)，7.56-7.61(1H，m)，7.69-7.73(1H，m)，8.12(1H，m)，8.52(1H，d，J＝4.8Hz).

MS(EI)m/z：392(M⁺).

2) Hydrochloride salt of the title compound

Using the above title compound (0.223g), the same method as in 2) of example 29 was performed to obtain a hydrochloride salt of the title compound (0.192g, 67%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：1.04-1.11((3/2H，m，for0.5EtOH))，1.23-1.39(3H，m)，2.73-3.89(5H，m，(2/2H，for0.5EtOH))，3.89(3H，s)，4.58-4.62(1H，m)，4.90-5.00(1H，m)，6.89(1H，d，J＝8.8Hz)，7.27(1H，s)，7.37-7.40(1H，m)，7.69-7.74(2H，m)，7.88-7.92(1H，m)，8.21(1H，d，J＝2.8Hz)，8.48(1H，d，J＝4.8Hz).

MS(EI)m/z：392(M⁺).

[ example 31]1- [1- (6-methoxy-3-pyridyl) -5- (6-methoxy-2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.217g, 96%) was obtained as an oil in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (6-methoxy-2-pyridyl) pyrazole-3-carboxylic acid (0.180g) and N-methylpiperazine (0.0673ml) of reference example 25.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.46-2.52(4H，m)，3.43(3H，s)，3.85(2H，m)，3.95(3H，s)，4.12(2H，m)，6.63-6.66(1H，m)，6.76-6.78(1H，m)，7.10-7.12(1H，m)，7.14(1H，s)，7.56-7.59(2H，m)，8.16-8.17(1H，m).

MS(EI)m/z：408(M⁺).

2) Hydrochloride salt of the title compound

Using the above title compound (0.290g), the same procedure as in 2) of example 29 was carried out to obtain the hydrochloride salt of the title compound (0.185g, 78%) as a solid.

¹H-NMR(400MHz，CD₃OD)δ：2.95(3H，s)，3.30-3.60(8H，m)，3.38(3H，s)，3.95(3H，s)，6.71(1H，d，J＝8.4Hz)，6.88(1H，d，J＝8.8Hz)，7.25(1H，s)，7.29-7.30(1H，m)，7.68-7.72(2H，m)，8.16(1H，d，J＝2.8Hz).

MS(EI)m/z：408(M⁺).

Elemental analysis: c₂₁H₂₄N₆O₃ HCl H₂O

Theoretical value: c: 54.49%, H: 5.88%, N: 18.15%, Cl: 7.66 percent.

Measured value: c: 54.46%, H: 5.94%, N: 18.01%, Cl: 7.75 percent.

[ example 32]4- [1- (6-methoxy-3-pyridyl) -5- (6-methoxy-2-pyridyl) pyrazole-3-carbonyl ] morpholine

The title compound (0.176g, 80%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (6-methoxy-2-pyridyl) pyrazole-3-carboxylic acid (0.180g) and morpholine (0.0529ml) of reference example 25.

¹H-NMR(400MHz，CDCl₃)δ：3.43(3H，s)，3.73-3.82(6H，m)，3.95(3H，s)，4.17(2H，m)，6.64-6.66(1H，m)，6.76-6.78(1H，m)，7.10-7.13(1H，m)，7.17(1H，s)，7.55-7.60(2H，m)，8.16-8.17(1H，m).

MS(EI)m/z：395(M⁺).

[ example 33]1- [1- (6-methoxy-3-pyridyl) -5- (6-methyl-2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (0.148g, 72%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (6-methyl-2-pyridyl) pyrazole-3-carboxylic acid (0.162g) and N-methylpiperazine (0.0637ml) of reference example 30.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.41(3H，s)，2.43-2.52(4H，m)，3.85(2H，m)，3.95(3H，s)，4.08(2H，m)，6.75(1H，d，J＝8.8Hz)，7.09(1H，d，J＝8.0Hz)，7.11(1H，s)，7.19(1H，d，J＝8.0Hz)，7.56-7.62(2H，m)，8.12(1H，d，J＝2.8Hz).

MS(EI)m/z：392(M⁺).

[ example 34]4- [1- (6-methoxy-3-pyridyl) -5- (6-methyl-2-pyridyl) pyrazole-3-carbonyl ] morpholine

The title compound (0.156g, 78%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (6-methyl-2-pyridyl) pyrazole-3-carboxylic acid (0.162g) of reference example 30 and morpholine (0.050 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.40(3H，s)，3.72-3.82(6H，m)，3.95(3H，s)，4.14(2H，m)，6.74-6.77(1H，m)，7.09(1H，d，J＝7.6Hz)，7.14(1H，s)，7.19(1H，d，J＝8.0Hz)，7.56-7.61(2H，m)，8.11-8.12(1H，m).

MS(EI)m/z：379(M⁺).

Elemental analysis: c₂₀H₂₁N₅O₃ 0.25H₂O

Theoretical value: c: 62.57%, H: 5.64%, N: 18.24 percent.

Measured value: c: 62.61%, H: 5.53%, N: 17.98 percent.

[ example 35]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.132g, 63%) was obtained in an amorphous state in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.164g) and N-methylpiperazine (0.0675ml) of reference example 33.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.45-2.53(4H，m)，3.85(2H，m)，3.95(3H，s)，4.09(2H，m)，6.76(1H，d，J＝8.8Hz)，7.12(1H，s)，7.22-7.27(1H，m)，7.42(1H，d，J＝7.6Hz)，7.59(1H，dd，J＝8.8，2.8Hz)，7.69-7.73(1H，m)，8.12(1H，d，J＝2.8Hz)，8.52(1H，d，J＝4.4Hz).

MS(EI)m/z：378(M⁺).

2) Hydrochloride salt of the title compound

The title compound (0.135g, 45%) was obtained as a solid in the same manner as in 2) of example 29 using the above title compound (0.241 g).

¹H-NMR(400MHz，DMSO-d₆)δ：(1.06-1.11(3/4H，m，for0.25EtOH))，2.79-2.80(3H，m)，3.06-3.66(6H，m，(2/4H，m，for0.25EtOH))，3.89(3H，s)，4.60-4.63(1H，m)，4.96-5.00(1H，m)，6.89(1H，d，J＝8.8Hz)，7.27(1H，s)，7.36-7.40(1H，m)，7.69-7.74(2H，m)，7.88-7.92(1H，m)，8.21(1H，d，J＝2.8Hz)，8.47(1H，d，J＝4.4Hz).

MS(EI)m/z：378(M⁺).

[ example 36]4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine

The title compound (0.171g, 83%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.164g) of reference example 33 and morpholine (0.053 ml).

¹H-NMR(400MHz，CDCl₃)δ：3.74-3.83(6H，m)，3.95(3H，s)，4.15(2H，m)，6.75-6.77(1H，m)，7.16(1H，s)，7.22-7.27(1H，m)，7.41-7.43(1H，m)，7.57-7.60(1H，m)，7.69-7.73(1H，m)，8.11-8.12(1H，m)，8.51-8.53(1H，m).

MS(EI)m/z：365(M⁺).

[ example 37]1- [1- (6-methoxy-3-pyridyl) -5- (4-methylphenyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.912g, quantitative) was obtained in an amorphous state in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid (0.70g) and N-methylpiperazine (0.276ml) of reference example 36.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.35(3H，s)，2.46-2.52(4H，m)，3.85(2H，m)，3.95(3H，s)，4.13(2H，m)，6.71-6.74(1H，m)，6.88(1H，s)，7.11-7.16(4H，m)，7.48-7.50(1H，m)，8.13(1H，d，J＝2.8Hz).

MS(EI)m/z：391(M⁺).

2) Hydrochloride salt of the title compound

Using the above-mentioned title compound (0.493g), the hydrochloride salt of the title compound (0.425g, 75%) as a solid was obtained in the same manner as in 2) of example 29.

¹H-NMR(400MHz，CD₃OD)δ：2.35(3H，s)，2.95(3H，s)，3.39(8H，m)，3.93(3H，s)，6.81-6.84(1H，m)，6.95(1H，s)，7.15-7.25(4H，m)，7.61-7.64(1H，m)，8.08-8.09(1H，m).

MS(EI)m/z：391(M⁺).

[ example 38]1- [5- (2-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (0.238g, 97%) was obtained as an oil in the same manner as in 1) of example 1 using 5- (2-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.195g) of reference example 39 and N-methylpiperazine (0.076 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.34(3H，s)，2.47-2.52(4H，m)，3.85(2H，m)，3.92(3H，s)，4.13(2H，m)，6.70-6.73(1H，m)，6.95(1H，s)，7.03-7.41(4H，m)，7.51-7.54(1H，m)，8.06(1H，m).

MS(EI)m/z：395(M⁺).

2) Hydrochloride salt of the title compound

Using the above title compound (0.224g), the same procedure as in 2) of example 29 was carried out to obtain the hydrochloride salt of the title compound (0.125g, 51%) as a solid.

¹H-NMR(400MHz，CD₃OD)δ：2.96(3H，s)，3.41(8H，m)，3.91(3H，s)，6.80-6.82(1H，m)，7.03(1H，s)，7.12-7.51(4H，m)，7.63-7.65(1H，m)，8.06(1H，m).

MS(EI)m/z：395(M⁺).

[ example 39]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2- (2-aminoethyl) piperidine hydrochloride

To a methanol (5ml) solution of 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2- (2-azidoethyl) piperidine (179mg) in referential example 81 were added 1M aqueous hydrochloric acid (415. mu.l) and 10% palladium on carbon (50% wet, 36mg), and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. The catalyst was filtered off, the filtrate solvent was evaporated under reduced pressure, and the resulting residue was dissolved in water to obtain the title compound (172mg, 89%) as a solid by lyophilization.

¹H-NMR(400MHz，DMSO-d₆) [2 mixture of isomers]δ: 1.31-1.85(7H, brm), 2.14-2.32(1H, br m), 2.64-2.92(2.5H, br m), 3.10-3.24(0.5H, br m), 3.91(3H, s), 4.41-4.53(1H, br m), 4.75-4.85(1H, br m), 6.85-6.93(2H, m), 7.25-7.32(2H, m), 7.35-7.42(3H, m), 7.64-7.74(1H, br m), 7.80-8.00(3H, br), 8.12 and 8.18(1H, br s).

MS(ESI)m/z：406(M+H)⁺.

[ example 40]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2- (2-dimethylaminoethyl) piperidine

1) The title Compound

Trifluoroacetic acid (1ml) was added to a solution of tert-butyl 2- (2-dimethylaminoethyl) piperidine-1-carboxylate (172mg) in referential example 92 in methylene chloride (3ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in methylene chloride (10ml), to which 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (198mg), 1-hydroxybenzotriazole (90mg), triethylamine (467. mu.l) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (192mg) of referential example 41 were added, followed by stirring at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (100mg, 34%) as an oil.

¹H-NMR(400MHz，CDCl₃) [2 mixture of isomers]δ：1.50-1.85(6H，m)，1.95-2.43(10H，m)，2.79-2.92(0.5H，m)，3.15-3.28(0.5H，m)，3.93(3H，s)，4.53-4.74(1H，br)，4.81-5.04(1H，br)，6.71(1H，d，J＝8.8Hz)，6.84(1H，s)，7.15-7.39(5H，m)，7.49(1H，dd，J＝8.8，2.7Hz)，8.11(1H，d，J＝2.7Hz).

MS(ESI)m/z：434(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above title compound (100mg), the hydrochloride (109mg, 93%) of the title compound was obtained as a solid in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆) δ: [2 mixture of isomers]1.32-1.80(6H, m), 1.86-2.01(1H, br), 2.22-2.40(1H, br m), 2.63-2.81(0.5H, br m), 2.67 and 2.70(6H, br s), 2.86-3.01(1H, br m), 3.03-3.16(1H, br m), 3.18-3.29(0.5H, br), 3.87(3H, s), 4.40-4.57(1H, br m), 4.73-4.82(1H, br), 6.85-6.94(2H, m), 7.25-7.33(2H, m), 7.35-7.42(3H, br), 7.62-7.78(1H, br m), 10.08-10.47(1H, 47H).

MS(ESI)m/z：434(M+H)⁺.

EXAMPLE 41 1- [1, 4-dihydro-1- (6-methoxy-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (281mg, 72%) was obtained in an amorphous state in the same manner as in example 20 using 1, 4-dihydro-1- (6-methoxy-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylic acid (307mg) and N-methylpiperazine (166 μ l) of reference example 61.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.44-2.56(4H，br m)，3.82(2H，s)，3.80-3.90(2H，br)，4.03(3H，s)，4.19-4.29(2H，br)，6.93(1H，d，J＝8.8Hz)，7.24-7.32(2H，m)，7.37-7.42(1H，m)，7.53-7.58(1H，m)，7.91(1H，dd，J＝8.8，2.7Hz)，8.53(1H，d，J＝2.7Hz).

MS(ESI)m/z：390(M+H)⁺.

[ example 42]1- [4, 5-dihydro-1- (6-methoxy-3-pyridyl) benzo [ g ] indazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (281mg, 93%) was obtained as a solid in the same manner as in example 20 using 4, 5-dihydro-1- (6-methoxy-3-pyridyl) benzo [ g ] indazole-3-carboxylic acid (241mg) and N-methylpiperazine (125 μ l) of reference example 72.

2) Hydrochloride salt of the title compound

Using the above title compound (278mg), the hydrochloride of the title compound (259mg, 83%) was obtained as crystals in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：2.79(3H，s)，2.81-2.90(2H，m)，2.92-3.00(2H，m)，3.00-3.68(6H，br m)，3.96(3H，s)，4.53-4.68(1H，br)，4.77-4.91(1H，br)，6.74(1H，d，J＝7.8Hz)，7.04(1H，d，J＝8.8Hz)，7.10(1H，dd，J＝7.8，7.6Hz)，7.23(1H，dd，J＝7.6，7.3Hz)，7.38(1H，d，J＝7.3Hz)，7.92(1H，dd，J＝8.8，2.7Hz)，8.41(1H，d，J＝2.7Hz)，10.81-11.01(1H，br).

MS(ESI)m/z：404(M+H)⁺.

Elemental analysis: c₂₃H₂₅N₅O₂ HCl 0.5H₂O

Theoretical value: c, 61.53; h, 6.06; n, 15.60; cl, 7.90.

Measured value: c, 61.70; h, 6.06; n, 15.57; cl, 8.06.

[ example 43]1- [1, 4-dihydro-1- (6-methoxy-3-pyridyl) chromeno [4, 3-c ] pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (187mg, 76%) was obtained as crystals in the same manner as in example 20 using 1, 4-dihydro-1- (6-methoxy-3-pyridyl) chromeno [4, 3-c ] pyrazole-3-carboxylic acid (194mg) and N-methylpiperazine (100 μ l) of reference example 74.

¹H-NMR(400MHz，CDCl₃) δ: 2.32(3H, s), 3.42-3.54(4H, m), 3.76-3.85(2H, br), 4.03(3H, s), 4.19-4.29(2H, br), 5.51(2H, s), 6.72-6.80(2H, m), 6.89(1H, d, J ═ 8.8Hz), 7.00(1H, d-like, J ═ 7.8Hz), 7.12-7.20(1H, m), 7.68(1H, dd, J ═ 8.8, 2.7Hz), 8.33(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：406(M+H)⁺.

Elemental analysis: c₂₂H₂₃N₅O₃

Theoretical value: c, 65.17; h, 5.72; n, 17.27.

Measured value: c, 65.02; h, 5.64; n, 17.19.

EXAMPLE 44 1- [1, 4-dihydro-1- (6-methoxy-3-pyridyl) -4-oxoindeno [1, 2-c ] pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (12mg, 60%) was obtained as an oil in the same manner as in example 20 using 1, 4-dihydro-1- (6-methoxy-3-pyridyl) -4-oxoindeno [1, 2-c ] pyrazole-3-carboxylic acid (16mg) and N-methylpiperazine (11 μ l) of referential example 70.

¹H-NMR(400MHz，CDCl₃)δ：2.34(3H，s)，2.41-2.60(4H，br m)，3.69-3.93(4H，br m)，4.04(3H，s)，6.94(1H，d，J＝8.8Hz)，7.11-7.20(1H，m)，7.31-7.40(2H，m)，7.60-7.68(1H，m)，7.92(1H，dd，J＝8.8，2.4Hz)，8.50(1H，d，J＝2.4Hz).

MS(ESI)m/z：404(M+H)⁺.

EXAMPLE 45 1- [1, 4-dihydro-1- (6-methyl-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (108mg, 57%) was obtained as crystals in the same manner as in example 20 using 1, 4-dihydro-1- (6-methyl-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylic acid (145mg) and N-methylpiperazine (66 μ l) of reference example 64.

¹H-NMR(400MHz，CDCl₃)δ：2.34(3H，s)，2.43-2.60(4H，m)，2.69(3H，s)，3.83(2H，s)，3.78-3.93(2H，br)，4.18-4.30(2H，br)，7.23-7.34(2H，m)，7.37(1H，d，J＝8.0Hz)，7.46(1H，dd，J＝6.3，1.7Hz)，7.57(1H，d，J＝6.3Hz)，7.94(1H，dd，J＝8.0，2.4Hz)，8.91(1H，d，J＝2.4Hz).

MS(ESI)m/z：374(M+H)⁺.

Elemental analysis: c₂₂H₂₃N₅O 0.25H₂O

Theoretical value: c, 69.91; h, 6.27; n, 18.53.

Measured value: c, 69.79; h, 6.10; and N, 18.24.

EXAMPLE 46 1- [1, 4-dihydro-1- (6-ethyl-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (163mg, 84%) was obtained as crystals in the same manner as in example 20 using 1, 4-dihydro-1- (6-ethyl-3-pyridyl) indeno [1, 2-c ] pyrazole-3-carboxylic acid (152mg) of referential example 68 and N-methylpiperazine (66 μ l).

¹H-NMR(400MHz，CDCl₃)δ：1.40(3H，t，J＝7.5Hz)，2.34(3H，s)，2.42-2.58(4H，m)，2.96(2H，q，J＝7.0Hz)，3.84(2H，s)，3.78-3.93(2H，br)，4.17-4.30(2H，br)，7.25-7.35(2H，m)，7.38(1H，d，J＝8.3Hz)，7.47(1H，dd，J＝6.3，1.9Hz)，7.57(1H，d，J＝6.3Hz)，7.96(1H，dd，J＝8.3，2.4Hz)，8.94(1H，d，J＝2.4Hz).

MS(ESI)m/z：388(M+H)⁺.

Elemental analysis: c₂₃H₂₅N₅O

Theoretical value: c, 71.29; h, 6.50; and N, 18.07.

Measured value: c, 71.06; h, 6.49; n, 17.73.

[ example 47] tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate

The title compound (0.379g, 84%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carboxylic acid (0.305g) and piperidine-1-carboxylic acid tert-butyl ester (0.180g) of reference example 118.

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，2.44(3H，s)，3.51-3.52(4H，m)，3.79(2H，m)，3.95(3H，s)，4.08(2H，m)，6.76(1H，d，J＝8.8Hz)，7.02-7.04(1H，m)，7.13(1H，s)，7.22(1H，d，J＝1.6Hz)，7.59(1H，dd，J＝8.8，2.8Hz)，8.12(1H，d，J＝2.4Hz)，8.27(1H，d，J＝5.2Hz).

MS(EI)m/z：510(M⁺).

[ example 48] tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- (4-methanesulfonyl-2-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate

To a solution of tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate (0.366g) in methylene chloride (7.3ml) in example 47 was added 3-chloroperbenzoic acid (0.260g) at 0 ℃ and the mixture was stirred for 20 minutes and then at room temperature for 2 hours. Then, 3-chloroperbenzoic acid (0.124g) was added at 0 ℃ and stirred for 2 hours. To the reaction mixture were added a saturated aqueous solution (10ml) of sodium thiosulfate and a saturated aqueous solution (10ml) of sodium hydrogencarbonate, followed by stirring. Subsequently, water and chloroform were added to the reaction solution for liquid separation. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.387g, 99%) in an amorphous state.

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，3.08(3H，s)，3.53-3.54(4H，m)，3.80(2H，m)，3.97(3H，s)，4.09(2H，m)，6.80(1H，d，J＝8.8Hz)，7.31(1H，s)，7.60-7.63(1H，m)，7.70-7.72(1H，m)，7.94(1H，d，J＝0.8Hz)，8.10(1H，d，J＝2.4Hz)，8.75-8.77(1H，m).

MS(EI)m/z：542(M⁺).

[ example 49]1- [5- (4-ethoxy-2-pyridyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1)4- [5- (4-ethoxy-2-pyridinyl) -1- (6-methoxy-3-pyridinyl) pyrazole-3-carbonyl ] piperazine-1-carboxylic acid tert-butyl ester

Sodium ethoxide (28.4ml) was added to a solution of tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- (4-methanesulfonyl-2-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate (0.189g) in tetrahydrofuran (3.8ml) of example 48 at room temperature under an argon atmosphere, and after stirring for 1 hour, the mixture was stirred at 80 ℃ for 90 minutes. Then, sodium ethoxide (85.2mg) was added, and stirred at 80 ℃ for 2 hours and 20 minutes. After cooling the air, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain tert-butyl 4- [5- (4-ethoxy-2-pyridyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate (0.139g, 79%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.44(3H，m)，1.48(9H，s)，3.51-3.53(4H，m)，3.79(2H，m)，3.95(3H，s)，4.03-4.13(4H，m)，6.73-6.77(2H，m)，6.94(1H，d，J＝2.0Hz)，7.10(1H，s)，7.26-7.27(1H，m)，7.58(1H，dd，J＝8.8，2.8Hz)，8.12(1H，d，J＝2.8Hz)，8.30(1H，d，J＝5.6Hz).

MS(EI)m/z：508(M⁺).

2) The title Compound

Trifluoroacetic acid (1.4ml) was added to a solution of tert-butyl 4- [5- (4-ethoxy-2-pyridyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate (0.135g) in dichloromethane (2.7ml) at room temperature, and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in ethanol (2.7ml), to which were added 35% aqueous formalin (0.114g), acetic acid (0.076ml) and sodium cyanoborohydride (50.0 mg). After stirring at room temperature for 100 minutes, sodium cyanoborohydride (33.3mg) was added thereto and the mixture was stirred for 50 minutes. Then, a saturated aqueous sodium bicarbonate solution and chloroform were added to the reaction solution to separate the mixture. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), and the obtained residue was purified by silica gel thin layer chromatography (chloroform-methanol), whereby the title compound (86.9mg, 78%) was obtained as an oil.

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.44(3H，m)，2.33(3H，s)，2.44-2.52(4H，m)，3.85(2H，m)，3.95(3H，s)，4.03-4.08(4H，m)，6.72-6.76(2H，m)，6.94(1H，d，J＝2.4Hz)，7.07(1H，s)，7.57-7.61(1H，m)，8.12-8.13(1H，m)，8.30(1H，d，J＝6.0Hz).

MS(EI)m/z：422(M⁺).

[ example 50] tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- [4- (pyrrolidin-1-yl) -2-pyridyl ] pyrazole-3-carbonyl ] piperazine-1-carboxylate

A solution of tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- (4-methanesulfonyl-2-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate (0.186g) from example 48 in pyrrolidine (3.7ml) was stirred at 100 ℃ for 17 hours. After air cooling, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.176g, 96%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，1.84-2.07(4H，m)，2.05(3H，s)，3.25-3.51(8H，m)，3.79(2H，m)，3.94(3H，s)，4.07(2H，m)，6.31-6.33(1H，m)，6.53(1H，d，J＝2.0Hz)，6.73(1H，d，J＝8.8Hz)，7.05(1H，s)，7.60(1H，dd，J＝8.8，2.8Hz)，8.09(1H，d，J＝6.0Hz)，8.16(1H，d，J＝2.8Hz).

MS(EI)m/z：533(M⁺).

[ example 51]1- [1- (6-methoxy-3-pyridyl) -5- [4- (pyrrolidin-1-yl) -2-pyridyl ] pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (70.1mg, 50%) was obtained as a solid in the same manner as in 2) of example 49 using tert-butyl 1- [1- (6-methoxy-3-pyridyl) -5- [4- (pyrrolidin-1-yl) -2-pyridyl ] pyrazole-3-carbonyl ] piperazine-4-carboxylate (0.167g) of reference example 50.

¹H-NMR(400MHz，CDCl₃)δ：1.19-2.05(4H，m)，2.33(3H，s)，2.45-2.50(4H，m)，3.25-3.28(4H，m)，3.84(2H，m)，3.93(3H，s)，4.08(2H，m)，6.31(1H，dd，J＝6.0，2.8Hz)，6.53(1H，d，J＝2.4Hz)，6.72(1H，d，J＝8.8Hz)，7.02(1H，s)，7.59-7.62(1H，m)，8.09(1H，d，J＝6.0Hz)，8.16(1H，d，J＝2.8Hz).

MS(EI)m/z：447(M⁺).

Elemental analysis: c₂₄H₂₉N₇O₂ 0.25H₂O

Theoretical value: c: 63.77%, H: 6.58%, N: 21.69 percent.

Measured value: c: 63.93%, H: 6.67%, N: 21.31 percent.

[ example 52] Ethyl 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidin-2-ylacetate

The title compound (331mg, 98%) was obtained as an oil in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (221mg) of reference example 41 and ethyl piperidin-2-ylacetate (154mg) of reference example 93.

¹H-NMR(400MHz，CDCl₃) [2 mixture of isomers]δ: 1.19 and 1.26 (0.5 × 3H each, t each, J7.0 Hz each), 1.48-1.85(6H, br m), 2.64-2.95(2.5H, m), 3.15-3.29(0.5H, m), 3.93(3H, s), 4.01-4.19(2H, br), 4.62-4.75(1H, br), 5.32-5.41(1H, br), 6.70(1H, d, J8.8 Hz), 6.84 and 6.87 (0.5 × 1H each, br s), 7.18-7.28(2H, m), 7.30-7.37(3H, m), 7.45-7.57(1H, br m), 8.11(1H, d, J2.7 Hz).

MS(ESI)m/z：449(M+H)⁺.

[ example 53]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidin-2-ylacetic acid

To a solution of ethyl 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidin-2-ylacetate (330mg) in methanol (4ml) in example 52 was added 1M aqueous sodium hydroxide solution (1.84ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The aqueous layer was acidified with 1M-hydrochloric acid aqueous solution (2ml), followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (311mg, 98%) as an amorphous product.

¹H-NMR(400MHz，CDCl₃)δ：1.48-1.90(6H，br m)，2.67-3.00(2.5H，brm)，3.12-3.28(0.5H，br)，3.92(3H，s)，4.65-4.82(1H，br)，5.23-5.43(1H，br)，6.70(1H，d，J＝8.8Hz)，6.90(1H，br s)，7.19-7.28(2H，m)，7.30-7.38(3H，m)，7.48(1H，dd，J＝8.8，2.7Hz)，8.13(1H，br s).

MS(ESI)m/z：421(M+H)⁺.

Elemental analysis: c₂₃H₂₄N₄O₄ 0.5H₂O

Theoretical value: c, 64.32; h, 5.87; and N, 13.05.

Measured value: c, 64.11; h, 5.90; n, 12.75.

[ example 54]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-isopropylpiperazine

1) The title Compound

The title compound (251mg, 82%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (222mg) of reference example 33 and 1-isopropylpiperazine hydrochloride (181mg) of reference example 95.

¹H-NMR(400MHz，CDCl₃)δ：1.06(6H，d，J＝6.6Hz)，2.56(2H，t，J＝4.9Hz)，2.61(2H，t，J＝4.9Hz)，2.73(1H，Seventy-high, J ═ 6.6Hz), 3.83(2H, t, J ═ 4.9Hz), 3.95(3H, s), 4.07(2H, t, J ═ 4.9Hz), 6.71(1H, dd, J ═ 8.8, 0.7Hz), 7.11(1H, s), 7.23(1H, ddd, J ═ 7.8, 4.9, 1.2Hz), 7.41(1H, ddd, J ═ 7.8, 1.2, 1.0Hz), 7.59(1H, dd, J ═ 8.7 Hz), 7.70(1H, ddd, J ═ 7.8, 7.8, 1.2Hz), 8.12(1H, ddd, J ═ 2.7, 0.7, 1.7, 1.51, 1H, 1.9, 1.51 Hz).

MS(ESI)m/z：407(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above title compound (251mg), the hydrochloride (235mg, 73%) of the title compound was obtained as crystals in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：1.30(6H，d，J＝6.6Hz)，3.01-3.20(2H，br)，3.33-3.56(4H，br m)，3.69-3.74(1H，br m)，3.89(3H，s)，4.60-4.73(1H，br m)，5.03-5.17(1H，br m)，6.88(1H，d，J＝8.8Hz)，7.27(1H，s)，7.35-7.41(1H，m)，7.64-7.74(2H，m)，7.85-7.94(1H，m)，8.20(1H，d，J＝2.7Hz)，8.47(1H，dd，J＝4.9，0.7Hz)，10.84-11.04(1H，br).

MS(ESI)m/z：407(M+H)⁺.

Elemental analysis: c₂₂H₂₆N₆O₂ 2HCl 2H₂O

Theoretical value: c, 51.27; h, 6.26; n, 16.30; cl, 13.76.

Measured value: c, 51.30; h, 6.18; n, 15.97; cl, 13.36.

[ example 55]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-cyclopropylpiperazine

The title compound (253mg, 83%) was obtained as crystals by the same method as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (222mg) of reference example 33 and N-cyclopropylpiperazine hydrochloride (179mg) of reference example 99.

¹H-NMR(400MHz，CDCl₃)δ：0.41-0.51(4H，m)，1.60-1.69(1H，m)，2.66(2H，t，J＝4.9Hz)，2.71(2H，t，J＝4.9Hz)，3.79(2H，br t，J＝4.9Hz)，3.95(3H，s)，4.02(2H，br t，J＝4.9Hz)，6.75(1H，d，J＝8.8Hz)，7.11(1H，s)，7.23(1H，ddd，J＝7.8，4.9，1.2Hz)，7.41(1H，d，J＝7.8Hz)，7.59(1H，dd，J＝8.8，2.7Hz)，7.71(1H，ddd，J＝7.8，7.8，1.7Hz)，8.12(1H，d，J＝2.7Hz)，8.52(1H，ddd，J＝4.9，1.7，1.0Hz).

MS(ESI)m/z：404(M+H)⁺.

Elemental analysis: c₂₂H₂₄N₆O₂

Theoretical value: c, 65.33; h, 5.98; n, 20.78.

Measured value: c, 64.97; h, 5.92; n, 20.53.

[ example 56]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2- (2-hydroxyethyl) piperidine

The title compound (82mg, 39%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (148mg) and 2- (piperidin-2-yl) ethanol (78mg) of reference example 41.

¹H-NMR(400MHz，CDCl₃) [2 mixture of isomers]δ：1.53-1.80(5H, m), 1.84-1.95(0.5H, br), 2.04-2.13(0.5H, m), 2.25-2.36(0.5H, m), 2.74-2.85(0.5H, m), 2.98-3.08(0.5H, m), 3.43-3.53(0.5H, m), 3.57-3.79(2H, m), 3.92 and 3.94 (3H each, s each), 4.00-4.09(0.5H, m), 4.62-4.78(1H, m), 4.88-5.04(1H, m), 5.10-5.17(0.5H, m), 6.71 and 6.75 (0.5 x 1H each, d each, 8.8Hz), 6.88 and 6 x 1.96 (0.96H, 7.7H, 7.47H, 7.51H, 7.8H, 7.47H, 7.8H, 7.1H, 7.51H, 7.1H, 7.47H, 7.8H, 7.1H, 7.47H, 7.1H, 7.51H, 7.7H, 7.47H, 7.7.7.7.7.7.7H, 7H, 7.7.1H, 7H, 7.1H, 7H, 7.51H, 7., each J ═ 2.7Hz).

MS(ESI)m/z：407(M+H)⁺.

Elemental analysis: c₂₃H₂₆N₄O₃ 0.5H₂O

Theoretical value: c, 66.49; h, 6.55; and N, 13.48.

Measured value: c, 66.68; h, 6.53; n, 13.31.

[ example 57]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidine

The title compound (137mg, 75%) was obtained as crystals in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (148mg) of reference example 41 and piperidine (59 μ l).

¹H-NMR(400MHz，CDCl₃)δ：1.56-1.75(6H，br m)，3.71-3.78(2H，br)，3.89-3.97(2H，br)，3.93(3H，s)，6.71(1H，d，J＝8.8Hz)，6.84(1H，s)，7.21-7.27(2H，m)，7.30-7.37(3H，m)，7.48(1H，dd，J＝8.8，2.7Hz)，8.11(1H，d，J＝2.7Hz).

MS(ESI)m/z：363(M+H)⁺.

Elemental analysis: c₂₁H₂₂N₄O₂

Theoretical value: c, 69.59; h, 6.12; n, 15.46.

Measured value: c, 69.43; h, 6.09; and N, 15.20.

[ example 58]1- [5- (4-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (237mg, 77%) was obtained as crystals in the same manner as in example 20 using 5- (4-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (244mg) of reference example 45 and N-methylpiperazine (125 μ l).

¹H-NMR(400MHz，CDCl₃) δ: 2.33(3H, s), 2.42-2.54(4H, m), 3.78-3.88(2H, br), 3.81(3H, s), 3.94(3H, s), 4.07-4.17(2H, br), 6.71(1H, d, J ═ 8.8Hz), 6.84(1H, s), 6.85(2H, d-like, J ═ 8.8Hz), 7.15(2H, d-like, J ═ 8.8Hz), 7.48(1H, dd, J ═ 8.8, 2.7Hz), 8.12(1H, d, J ═ 2.7Hz).

MS(ESI)m/z：408(M+H)⁺.

Elemental analysis: c₂₂H₂₅N₅O₃

Theoretical value: c, 64.85; h, 6.18; n, 17.19.

Measured value: c, 64.66; h, 6.20; and N, 17.06.

[ example 59]1- [5- (3-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (243mg, 79%) was obtained as an oil in the same manner as in example 20 using 5- (3-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (244mg) of reference example 47 and N-methylpiperazine (125 μ l).

2) Hydrochloride salt of the title compound

Using the above title compound, a hydrochloride (253mg, 92%) of the title compound was obtained as crystals in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：2.79(3H，s)，2.98-3.73(6H，br m)，3.70(3H，s)，3.88(3H，s)，4.53-4.70(1H，br)，4.92-5.08(1H，br)，6.80(1H，d，J＝7.5Hz)，6.85-6.98(3H，m)，7.02(1H，s)，7.23-7.32(1H，m)，7.70(1H，dd，J＝8.8，2.7Hz)，8.19(1H，d，J＝2.7Hz)，10.78-10.94(1H，br).

MS(ESI)m/z：408(M+H)⁺.

Elemental analysis: c₂₂H₂₅N₅O₃ HCl H₂O

Theoretical value: c, 57.20; h, 6.11; n, 15.16; cl, 7.67.

Measured value: c, 57.12; h, 6.09; n, 15.08; cl, 7.74

[ example 60]1- [5- (2-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (263mg, 84%) was obtained as crystals in the same manner as in example 20 using 5- (2-methoxyphenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (244mg) of reference example 49 and N-methylpiperazine (125 μ l).

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.43-2.56(4H，br)，3.48(3H，s)，3.78-3.92(2H，br)，3.90(3H，s)，4.11-4.22(2H，br)，6.67(1H，d，J＝8.8Hz)，6.82(1H，d，J＝8.3Hz)，6.86(1H，s)，6.95-7.03(1H，m)，7.27-7.32(1H，m)，7.34-7.40(1H，m)，7.48(1H，dd，J＝8.8，2.7Hz)，8.06(1H，d，J＝2.7Hz).

MS(ESI)m/z：408(M+H)⁺.

[ example 61]1- [1- (6-methoxy-3-pyridyl) -5- (4-trifluoromethylphenyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (272mg, 81%) was obtained as crystals in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (4-trifluoromethylphenyl) pyrazole-3-carboxylic acid (272mg) and N-methylpiperazine (125 μ l) of reference example 51.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.42-2.57(4H，m)，3.79-3.91(2H，br)，3.95(3H，s)，4.07-4.18(2H，br)，6.76(1H，d，J＝8.8Hz)，6.98(1H，s)，7.36(2H，d，J＝8.0Hz)，7.49(1H，dd，J＝8.8，2.4Hz)，7.60(2H，d，J＝8.0Hz)，8.09(1H，d，J＝2.4Hz).

MS(ESI)m/z：446(M+H)⁺.

Elemental analysis: c₂₂H₂₂F₃N₅O₂

Theoretical value: c, 59.32; h, 4.98; n, 15.72; f, 12.80.

Measured value: c, 58.95; h, 4.93; n, 15.71; f, 12.57.

[ example 62]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (6.23g, 66%) was obtained as an oil in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (7.38g) of reference example 41 and N-methylpiperazine (3.32 ml).

2) Hydrochloride salt of the title compound

To a methanol (200ml) solution of the above-mentioned title compound (6.23g) was added a 1M-hydrochloric acid aqueous solution (17ml) and the mixture was stirred. The solvent was evaporated under reduced pressure, and the residue was added with ethanol and evaporated under reduced pressure again. The obtained residue was crystallized from ethanol-diethyl ether, and collected by filtration to obtain the hydrochloride of the title compound (5.04g, 72%) as crystals.

¹H-NMR(400MHz，DMSO-d₆)δ：2.80(3H，s)，3.00-3.73(6H，br m)，3.88(3H，s)，4.53-4.72(1H，br)，4.94-5.10(1H，br)，6.89(1H，d，J＝8.8Hz)，7.00(1H，s)，7.25-7.32(2H，m)，7.36-7.43(3H，m)，7.68(1H，dd，J＝8.8，2.6Hz)，8.18(1H，d，J＝2.6Hz)，10.71-10.87(1H，br).

MS(ESI)m/z：378(M+H)⁺.

Elemental analysis: c₂₁H₂₃N₅O₂ HCl 0.5H₂O

Theoretical value: c, 59.64; h, 5.96; n, 16.56; cl, 8.38.

Measured value: c, 59.60; h, 6.17; n, 16.43; cl, 8.56.

[ example 63]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-thiocarbonyl ] -4-methylpiperazine

To a solution of 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine (173mg) in toluene (10ml) obtained in example 62 was added 2, 4-bis (4-methoxyphenyl) -1, 3, 2, 4-dithiadiphosphetane-2, 4-disulfide (ロ - ソン reagent, 222mg), and the mixture was refluxed for 14 hours. Water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (61mg, 33%) in an amorphous state.

¹H-NMR(400MHz，CDCl₃)δ：2.37(3H，s)，2.50-2.71(4H，m)，3.93(3H，s)，4.09-4.20(2H，br)，4.42-4.55(2H，br)，6.70(1H，d，J＝8.8Hz)，6.90(1H，s)，7.22-7.28(2H，m)，7.30-7.39(3H，m)，7.47(1H，dd，J＝8.8，2.7Hz)，8.10(1H，d，J＝2.7Hz).

MS(ESI)m/z：394(M+H)⁺.

[ example 64] tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-1-carboxylate

To a solution of 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (295mg), piperazine-1-carboxylic acid tert-butyl ester (186mg), 1-hydroxybenzotriazole (135mg) and triethylamine (488. mu.l) in reference example 41 in dichloromethane (5ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288mg), and the mixture was stirred at room temperature for 13 hours. The reaction solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from ethyl acetate-hexane to obtain the title compound (225mg) as crystals. Then, the filtrate solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (hexane-ethyl acetate) to obtain the title compound (154 mg). The crystals obtained previously were combined to obtain 379mg (81%).

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，3.48-3.57(4H，br)，3.75-3.82(2H，br)，3.94(3H，s)，4.06-4.14(2H，br)，6.72(1H，d，J＝8.8Hz)，6.93(1H，s)，7.21-7.27(2H，m)，7.31-7.38(3H，m)，7.47(1H，dd，J＝8.8，2.7Hz)，8.12(1H，d，J＝2.7Hz).

MS(ESI)m/z：464(M+H)⁺.

[ example 65]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine hydrochloride

To a solution of tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-1-carboxylate (332mg) in referential example 64 in dichloromethane (2ml) were added anisole (0.4ml) and trifluoroacetic acid (1.6ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solvent was evaporated under reduced pressure, and water and ether were added to the resulting residue to separate a liquid. After the aqueous layer was made alkaline by adding a saturated aqueous sodium bicarbonate solution, it was extracted 4 times with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, the obtained residue was dissolved in a mixed solvent of ether and a small amount of methanol, 1M-hydrochloric acid-ethanol (0.78ml) was added thereto, and the precipitated crystal was collected by filtration and recrystallized from methanol-ether to obtain the title compound (229mg, 76%).

¹H-NMR(400MHz，DMSO-d₆)δ：3.12-3.23(4H，br)，3.83-3.94(2H，br)，3.87(3H，s)，4.23-4.33(2H，br)，6.89(1H，d，J＝8.8Hz)，6.99(1H，s)，7.26-7.32(2H，m)，7.36-7.42(3H，m)，7.68(1H，dd，J＝8.8，2.4Hz)，8.17(1H，d，J＝2.4Hz)，9.26-9.40(2H，br).

MS(ESI)m/z：364(M+H)⁺.

Elemental analysis: c₂₀H₂₁N₅O₂ HCl H₂O

Theoretical value: c, 57.48; h, 5.79; n, 16.76; cl, 8.48.

Measured value: c, 57.11; h, 5.70; n, 16.58; cl, 8.81.

[ example 66] tert-butyl 4- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate

To a solution of 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (313mg), piperidine-1-carboxylic acid tert-butyl ester (186mg), 1-hydroxybenzotriazole (135mg) and triethylamine (488. mu.l) in referential example 136 in methylene chloride (5ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288mg), and the mixture was stirred at room temperature for 13 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting solid was recrystallized from ethyl acetate-hexane to obtain the title compound (241 mg). Then, the solvent of the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (hexane-ethyl acetate) to obtain the title compound (170mg) as crystals. The crystals obtained previously were combined to yield 411mg (85%).

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，3.48-3.57(4H，br)，3.74-3.82(2H，br)，3.95(3H，s)，4.07-4.13(2H，br)，6.74(1H，d，J＝8.8Hz)，6.92(1H，s)，7.00-7.08(2H，m)，7.18-7.25(2H，m)，7.47(1H，dd，J＝8.8，2.7Hz)，8.09(1H，d，J＝2.7Hz).

MS(ESI)m/z：482(M+H)⁺.

Elemental analysis: c₂₅H₂₈FN₅O₄ 0.5H₂O

Theoretical value: c, 61.21; h, 5.96; n, 14.28; f, 3.87.

Measured value: c, 61.41; h, 5.76; n, 14.18; f, 3.95.

[ example 67]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperazine hydrochloride

The title compound (278mg, 81%) was obtained as crystals in the same manner as in example 65 using tert-butyl 4- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate (363mg) of example 66.

¹H-NMR(400MHz，DMSO-d₆)δ：3.10-3.22(4H，br)，3.82-3.96(2H，br)，3.88(3H，s)，4.22-4.32(2H，br)，6.90(1H，d，J＝8.8Hz)，7.00(1H，s)，7.20-7.28(2H，m)，7.31-7.40(2H，m)，7.69(1H，dd，J＝8.8，2.7Hz)，8.19(1H，d，J＝2.4Hz)，9.30-9.43(2H，br).

MS(ESI)m/z：382(M+H)⁺.

[ example 68]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methoxyethylpiperazine

1) The title Compound

The title compound (285mg, quantitative) was obtained in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (200mg) of reference example 41 and N- (2-methoxyethyl) piperazine hydrochloride (175mg) of reference example 97.

2) Hydrochloride salt of the title compound

Using the above title compound (285mg), the hydrochloride of the title compound (255mg, 82%) was obtained as a solid in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：3.13(2H，br)，3.30-3.32(2H，br)，3.33(3H，s)，3.56(3H，br)，3.72-3.73(3H，m)，4.58(1H，br)，4.99(1H，br)，6.90(1H，d，J＝8.8Hz)，7.00(1H，s)，7.29-7.31(2H，m)，7.39-7.41(3H，m)，7.70(1H，dd，J＝8.8，2.7Hz)，8.20(1H，d，J＝2.7Hz)，10.85(1H，br).

MS(FAB)m/z：422(M+H)⁺.

Elemental analysis: c₂₃H₂₇N₅O₃ HCl

Theoretical value: c, 60.45; h, 6.18; n, 15.33; cl, 7.76.

Measured value: c, 60.15; h, 6.14; n, 15.01; cl, 7.63.

[ example 69]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-cyclopropylpiperazine

The title compound (180mg, 66%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid of reference example 41 (200mg) and N-cyclopropylpiperazine hydrochloride of reference example 99 (160 mg).

¹H-NMR(400MHz，DMSO-d₆)δ：0.34-0.36(2H，m)，0.41-0.44(2H，m)，1.64-1.67(1H，m)，2.58(4H，br)，3.61(2H，br)，3.87(3H，s)，3.89(2H，br)，6.90(1H，d，J＝8.8Hz)，6.92(1H，s)，7.28-7.32(2H，m)，7.37-7.40(3H，m)，7.70(1H，dd，J＝8.8，2.2Hz)，8.14(1H，d，J＝2.2Hz).

MS(EI)m/z：403(M⁺).

Elemental analysis: c₂₃H₂₅N₅O₂

Theoretical value: c, 68.47; h, 6.25; n, 17.36.

Measured value: c, 68.45; h, 6.29; n, 17.23.

[ example 70]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -3-dimethylaminoazetidine

1) The title Compound

The title compound (185mg, 95%) was obtained in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (150mg) of reference example 41 and azetidin-3-yldimethylamine hydrochloride (106mg) of reference example 102.

2) Hydrochloride salt of the title compound

Using the above title compound (185mg), the hydrochloride (155mg, 74%) of the title compound was obtained as a solid in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：2.75(6H，s)，3.88(3H，s)，4.14(1H，br)，4.24-4.33(2H，m)，4.70-4.81(2H，m)，6.90(1H，d，J＝8.8Hz)，7.04(1H，s)，7.29-7.32(2H，m)，7.38-7.41(3H，m)，7.67(1H，dd，J＝8.8，2.9Hz)，8.22(1H，d，J＝2.9Hz)，11.47(1H，br).

MS(EI)m/z：377(M⁺).

Elemental analysis: c₂₃H₂₇N₅O₃ HCl H₂O

Theoretical value: c, 58.40; h, 6.07; n, 16.21; cl, 8.21.

Measured value: c, 58.08; h, 6.02; n, 15.97; cl, 8.23.

[ example 71]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -3-methoxyazetidine

The title compound (140mg, 76%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid of reference example 41 (150mg) and 3-methoxyazetidine hydrochloride of reference example 107 (75.6 mg).

¹H-NMR(400MHz，CDCl₃)δ：3.37(3H，s)，3.95(3H，s)，4.08-4.11(1H，m)，4.25-4.31(1H，m)，4.36-4.40(1H，m)，4.46-4.50(1H，m)，4.78-4.82(1H，m)，6.71(1H，d，J＝8.8Hz)，6.92(1H，s)，7.22-7.24(2H，m)，7.32-7.35(3H，m)，7.46(1H，dd，J＝8.8，2.9Hz)，8.15(1H，d，J＝2.9Hz).

LC-MSm/z：365(M+H)⁺.

Elemental analysis: c₂₀H₂₀N₄O₃ 0.25H₂O

Theoretical value: c, 65.12; h, 5.60; n, 15.19.

Measured value: c, 65.12; h, 5.44; and N, 15.13.

[ example 72]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -3-hydroxyazetidine

The title compound (135mg, 76%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid of reference example 41 (150mg) and 3-hydroxyazetidine hydrochloride of reference example 108 (67.0 mg).

¹H-NMR(400MHz，CDCl₃)δ：3.94(3H，s)，4.07-4.12(1H，m)，4.45-4.50(2H，m)，4.73(1H，br)，4.86-4.90(1H，m)，6.70(1H，d，J＝8.8Hz)，7.01(1H，s)，7.20-7.23(2H，m)，7.30-7.37(3H，m)，7.46(1H，dd，J＝8.8，2.8Hz)，8.12(1H，d，J＝2.8Hz).

LC-MSm/z：351(M+H)⁺.

Elemental analysis: c₁₉H₁₈N₄O₃ 0.25H₂O

Theoretical value: c, 64.31; h, 5.25; n, 15.79.

Measured value: c, 64.19; h, 5.15; and N, 15.60.

[ example 73]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-cyclobutylpiperazine

1) The title Compound

The title compound (283mg, quantitative) was obtained in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (200mg) of reference example 41 and 4-cyclobutylpiperazine hydrochloride (173mg) of reference example 110.

2) Hydrochloride salt of the title compound

Using the above title compound (283mg), the hydrochloride (254mg, 83%) of the title compound was obtained as a solid in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：1.69-1.79(2H，m)，2.17(2H，br)，2.37(2H，br)，2.91(2H，br)，3.35-3.37(3H，m)，3.66-3.73(2H，m)，3.88(3H，s)，4.62(1H，br d，J＝13.4Hz)，5.03(1H，br d，J＝13.4Hz)，6.91(1H，d，J＝8.8Hz)，7.02(1H，s)，7.29-7.32(2H，m)，7.39-7.41(3H，m)，7.70(1H，dd，J＝8.8，2.7Hz)，8.19(1H，d，J＝2.7Hz)，10.46(1H，br).

LC-MSm/z：418(M+H)⁺.

Elemental analysis: c₂₄H₂₇N₅O₂ HCl 0.25H₂O

Theoretical value: c, 62.87; h, 6.27; n, 15.28; cl, 7.73.

Measured value: c, 63.05; h, 6.25; n, 15.05; cl, 7.69.

[ example 74]1- [1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (150mg, 78%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carboxylic acid (150mg) of reference example 43 and N-methylpiperazine (0.068 ml).

¹H-NMR(400MHz，DMSO-d₆)δ：2.21(3H，s)，2.35-2.38(4H，m)，3.66(2H，br s)，3.89(2H，br s)，4.02(3H，s)，6.96(1H，s)，7.29-7.31(2H，m)，7.37-7.39(3H，m)，7.48(1H，d，J＝9.3Hz)，7.99(1H，d，J＝9.3Hz).

LC-MSm/z：379(M+H)⁺.

Elemental analysis: c₂₀H₂₂N₆O₂ 0.25H₂O

Theoretical value: c, 62.73; h, 5.92; and N, 21.95.

Measured value: c, 62.69; h, 5.81; n, 21.66.

[ example 75]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-ethylpiperazine hydrochloride

Using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (100mg) of reference example 41 and N-ethylpiperazine (52 μ l), according to the same method as 1) of example 1, 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-ethylpiperazine was obtained, and then the title compound (111mg, 76%) was obtained as a solid from the compound according to the same method as 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：1.27(3H，t，J＝7.1Hz)，3.05(2H，br m)，3.13(2H，br m)，3.33(3H，s)，3.33(1H，br m)，3.54(2H，br m)，3.71(1H，br m)，3.88(3H，s)，4.60(1H，d，J＝12.5Hz)，5.03(1H，J＝13.5Hz)，6.90(1H，d，J＝8.8Hz)，7.01(1H，s)，7.27-7.31(2H，m)，7.38-7.41(3H，m)，7.70(1H，dd，J＝8.8，2.7Hz)，8.19(1H，d，J＝2.7Hz)，11.13(1H，br s).

LC-MSm/z：392(M+H)⁺.

Elemental analysis: c₂₂H₂₅N₆O₂ HCl 0.75H₂O

Theoretical value: c, 59.86; h, 6.28; n, 15.87; cl, 8.03.

Measured value: c, 59.89; h, 6.20; n, 15.81; cl, 8.08.

[ example 76]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-ethylpiperazine hydrochloride

Using 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (150mg) and N-ethylpiperazine (73 μ l) of reference example 136, according to the same method as in 1) of example 1, 1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] -4-ethylpiperazine was obtained, and then according to the same method as in 2) of example 29, the title compound (96mg, 45%) was obtained as a solid from the compound.

¹H-NMR(400MHz，DMSO-d₆)δ：1.26(3H，t，J＝7.1Hz)，3.04(2H，br m)，3.12(2H，br m)，3.33(3H，s)，3.33(1H，br m)，3.53(2H，br m)，3.71(1H，br m)，3.88(3H，s)，4.60(1H，br m)，5.00(1H，br m)，6.91(1H，d，J＝8.8Hz)，7.02(1H，s)，7.25(2H，t，J＝8.8Hz)，7.34-7.37(2H，m)，7.70(1H，dd，J＝8.8，2.7Hz)，8.21(1H，d，J＝2.7Hz)，11.10(1H，br s).

LC-MSm/z：410(M+H)⁺.

Elemental analysis: c₂₂H₂₄FN₅O₂ HCl 0.5H₂O

Theoretical value: c, 58.08; h, 5.76; n, 15.39; f, 4.18; cl, 7.79.

Measured value: c, 57.90; h, 5.82; n, 15.12; f, 4.07; cl, 7.64.

EXAMPLE 77 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -3-dimethylaminomethylazetidine

The title compound (17mg, 22%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid of reference example 41 (60mg) and 3-dimethylaminomethylazetidine hydrochloride of reference example 112 (40 mg).

¹H-NMR(400MHz，CDCl₃)δ：2.23(6H，s)，2.52(1H，dd，J＝12.2，6.8Hz)，2.60(1H，dd，J＝12.2，8.3Hz)，2.86(1H，m)，3.85(1H，dd，J＝10.3，5.6Hz)，3.94(3H，s)，4.28-4.33(2H，m)，4.74(1H，t，J＝8.3Hz)，6.71(1H，d，J＝8.8Hz)，7.01(1H，s)，7.21-7.25(2H，m)，7.32-7.35(3H，m)，7.46(1H，dd，J＝8.8，2.7Hz)，8.12(1H，d，J＝2.7Hz).

MS(ESI)m/z：392(M+H)⁺.

Elemental analysis: c₂₀H₂₂N₆O₂ 0.5H₂O

Theoretical value: c, 65.98; h, 6.54; n, 17.48.

Measured value: c, 65.92; h, 6.36; n, 17.37.

EXAMPLE 78N- [1- [1- (6-methoxy-3-pyridinyl) -5-phenylpyrazole-3-carbonyl ] azetidin-3-yl ] -N-methylcarbamic acid tert-butyl ester

The title compound (453mg, 96%) was obtained in an amorphous state in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (300mg) of reference example 41 and tert-butyl azetidin-3-yl-N-methylcarbamate (250 mg).

¹H-NMR(400MHz，CDCl₃)δ：1.47(9H，s)，1.56(9H，s)，2.95(3H，s)，3.95(3H，s)，4.24(1H，m)，4.41(1H，m)，4.64(1H，m)，4.84(1H，m)，6.72(1H，d，J＝8.8Hz)，7.03(1H，s)，7.22-7.24(2H，m)，7.33-7.35(3H，m)，7.46(1H，dd，J＝8.8，2.5Hz)，8.13(1H，d，J＝2.7Hz).

MS(ESI)m/z：464(M+H)⁺.

EXAMPLE 79 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -3-methylaminoazetidine

The title compound (255mg, 72%) was obtained as a solid in the same manner as in 2) of example 49 using tert-butyl N- [1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] azetidin-3-yl ] -N-methylcarbamate (450mg) of the above example 78.

¹H-NMR(400MHz，CDCl₃)δ：3.51(3H，s)，3.66(1H，m)，3.92(1H，m)，3.95(3H，s)，4.32(1H，dd，J＝10.6，4.9Hz)，4.39(1H，dd，J＝10.6，7.4Hz)，4.79(1H，dd，J＝9.5，7.3Hz)，6.71(1H，d，J＝8.8Hz)，7.02(1H，s)，7.21-7.25(2H，m)，7.32-7.35(3H，m)，7.45(1H，dd，J＝8.8，2.7Hz)，8.14(1H，d，J＝2.2Hz).

MS(FAB)m/z：364(M+H)⁺.

[ example 80] tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate

The title compound (0.407g, quantitative) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.252g) and piperazine-1-carboxylic acid tert-butyl ester (0.311g) of reference example 33.

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，3.52(4H，br)，3.79(2H，br)，3.94(3H，s)，4.08(2H，br)，6.75(1H，d，J＝8.7Hz)，7.15(1H，s)，7.20-7.30(1H，m)，7.42(1H，d，J＝7.8Hz)，7.58(1H，dd，J＝8.7，2.6Hz)，7.71(1H，dt，J＝7.8，1.5Hz)，8.12(1H，d，J＝2.6Hz)，8.45-8.55(1H，m).

MS(FAB)m/z：465(M+H)⁺.

[ example 81]4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine

1) The title Compound

The title compound (0.281g, 91%) was obtained as an oil in the same manner as in 2) of example 49 using tert-butyl 4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine-1-carboxylate (0.396g) of example 80.

¹H-NMR(400MHz，CDCl₃)δ：2.85-3.02(4H，m)，3.79(2H，br)，3.94(3H，s)，4.03(2H，br)，6.75(1H，d，J＝8.8Hz)，7.11(1H，s)，7.20-7.30(1H，m)，7.40(1H，d，J＝7.8Hz)，7.59(1H，dd，J＝7.8，2.7Hz)，7.70(1H，dt，J＝7.8，1.7Hz)，8.11(1H，d，J＝2.7Hz)，8.45-8.55(1H，m).

LC-MSm/z：365(M+H)⁺.

2) Hydrochloride salt of the title compound

Using the above title compound (0.281g), a hydrochloride (0.237g, 69%) of the title compound was obtained as a solid in the same manner as in 2) of example 1.

¹H-NMR(400MHz，DMSO-d₆)δ：3.18(4H，br)，3.88(3H，s)，3.89(2H，br)，4.25(2H，br)，6.88(1H，d，J＝9.1Hz)，7.26(1H，s)，7.32-7.40(1H，m)，7.65-7.75(2H，m)，7.86(1H，dt，J＝7.8，2.5Hz)，8.19(1H，d，J＝2.5Hz)，8.42-8.50(1H，m)，9.25(2H，br).

LC-MSm/z：365(M+H)⁺.

[ example 82]4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -2-oxopiperazine

The title compound (0.210g, 66%) was obtained as a solid in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.248g) and piperazin-2-one (0.129g) of reference example 33.

¹H-NMR(400MHz，CDCl₃)δ：3.45-3.60(2H，m)，3.96(3H，s)，4.03(1H，br)，4.35(2H，br)，4.88(1H，br)，6.25-6.40(1H，br)，6.72-6.80(1H，br)，7.15-7.30(2H，m)，7.37-7.75(3H，m)，8.05-8.16(1H，br)，8.51(1H，d，J＝4.4Hz).

MS(ESI)m/z：379(M+H)⁺.

Elemental analysis: c₁₉H₁₈N₆O₃ 0.3H₂O

Theoretical value: c, 59.46; h, 4.88; and N, 21.90.

Measured value: c, 59.35; h, 4.71; n, 21.57.

[ example 83]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3, 5-dimethylpiperazine

The title compound (0.142g, 72%) was obtained as a solid in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.150g) and 2, 6-dimethylpiperazine (91.4mg) of reference example 33.

¹H-NMR(400MHz，CDCl₃) δ: 1.05(3H, d, J ═ 6.1Hz), 1.14(3H, d, J ═ 6.1Hz), 2.40(1H, t-like, J ═ 12.7Hz), 2.76(1H, t-like, J ═ 12.7Hz), 2.85-3.00(2H, m), 3.95(3H, s), 4.67(2H, d-like, J ═ 8.8Hz), 7.09(1H, s), 7.20-7.30(1H, m), 7.41(1H, d, J ═ 8.1Hz), 7.57(1H, dd, J ═ 8.8, 2.7Hz), 7.70(1H, dt, J ═ 8.1, 2.0Hz), 8.11(1H, d, J ═ 8.8, 49H, 49-m).

MS(ESI)m/z：393(M+H)⁺.

[ example 84]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-dimethylaminoazetidine

The title compound (0.248g, 90%) was obtained as a solid in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.216g) of reference example 33 and 3-dimethylaminoazetidine hydrochloride (0.252g) of reference example 102.

¹H-NMR(400MHz，CDCl₃)δ：2.21(6H，s)，3.05-3.25(1H，m)，3.96(3H，s)，4.00-4.10(1H，m)，4.17-4.28(1H，m)，4.35-4.47(1H，m)，4.60-4.72(1H，m)，6.74(1H，d，J＝8.9Hz)，7.17-7.30(2H，m)，7.44(1H，d，J＝7.3Hz)，7.50-7.60(1H，m)，7.67-7.78(1H，m)，8.15(1H，d，J＝2.5Hz)，8.50(1H，br d，J＝3.5Hz).

MS(ESI)m/z：379(M+H)⁺.

Elemental analysis: c₂₀H₂₂N₆O₂

Theoretical value: c, 63.48; h, 5.86; n, 22.21.

Measured value: c, 63.34; h, 5.84; n, 22.31.

[ example 85]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-4-carboxylic acid ethyl ester

The title compound (262mg, 90%) was obtained as an oil in the same manner as in example 20 using 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.2g) of reference example 136 and ethyl hexahydroisonicotinite (0.1 g).

¹H-NMR(400MHz，CDCl₃)δ：1.27(3H，t，J＝7.3Hz)，1.75-1.90(2H，m)，1.90-2.10(2H，m)，2.58-2.66(1H，m)，2.98-3.10(1H，m)，3.32-3.43(1H，m)，3.95(3H，s)，4.16(2H，q，J＝7.3Hz)，4.52-4.60(1H，m)，4.70-4.80(1H，m)，6.73(1H，d，J＝8.8Hz)，6.87(1H，s)，7.02-7.26(2H，m)，7.48(1H，dd，J＝8.8，2.7Hz)，8.09(1H，d，J＝2.7Hz).

MS(EI)m/z：452(M⁺).

[ example 86]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-4-carboxylic acid

The title compound (170mg, 69%) was obtained in an amorphous state in the same manner as in reference example 4 using ethyl 1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-4-carboxylate (262mg) of example 85.

¹H-NMR(400MHz，CDCl₃)δ：1.77-1.94(2H，m)，2.00-2.16(2H，m)，2.65-2.75(1H，m)，3.05-3.15(1H，m)，3.35-3.45(1H，m)，3.95(3H，s)，4.55-4.60(1H，m)，4.72-4.76(1H，m)，6.74(1H，d，J＝8.8Hz)，6.88(1H，s)，7.02-7.07(2H，m)，7.19-7.24(2H，m)，7.48(1H，dd，J＝8.8，2.4Hz)，8.11(1H，d，J＝2.4Hz).

MS(EI)m/z：424(M⁺).

Elemental analysis: c₂₂H₂₁FN₄O₄ 0.75H₂O

Theoretical value: c, 60.36; h, 5.18; and N, 12.80.

Measured value: c, 60.24; h, 5.01; n, 12.47.

[ example 87]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-3-carboxylic acid ethyl ester

The title compound (280mg, 97%) was obtained as an oil in the same manner as in example 20 using 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.2g) of reference example 136 and ethyl hexahydropyridine-3-carboxylate (0.1 g).

¹H-NMR(400MHz，CDCl₃)δ：1.21-1.30(3H，m)，2.13-2.20(1H，m)，2.56-2.75(1H，m)，2.94-3.10(1H，m)，3.21-3.30(0.5×1H，m)，3.42-3.50(0.5×1H，m)，3.94(3H，s)，4.10-4.20(2H，m)，4.47-4.55(0.5×1H，m)，4.67-4.75(0.5×1H，m)，4.80-4.93(1H，m)，6.73(1H，d，J＝8.8Hz)，6.87(1H，s)，7.05(2H，t，J＝8.8Hz)，7.20-7.27(2H，m)，7.47-7.55(1H，m)，8.10(1H，d，J＝2.7Hz).

MS(EI)m/z：452(M⁺).

[ example 88]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-3-carboxylic acid

The title compound (150mg, 57%) was obtained in an amorphous state in the same manner as in reference example 4 using ethyl 1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-3-carboxylate (280mg) of example 87.

¹H-NMR(400MHz，CDCl₃)δ：3.94(3H，s)，6.73(1H，d，J＝8.8Hz)，6.88(1H，s)，7.01-7.07(2H，m)，7.20-7.26(2H，m)，7.48(1H，dd，J＝8.8，2.9Hz)，8.11(1H，d，J＝2.9Hz).

MS(EI)m/z：424(M⁺).

Elemental analysis: c ₂₂H₂₁FN₄O₄ 0.75H₂O

Theoretical value: c, 60.36; h, 5.18; and N, 12.80.

Measured value: c, 60.49; h, 5.04; n, 12.47.

[ example 89]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-2-carboxylic acid ethyl ester

The title compound (270mg, 93%) was obtained as an oil in the same manner as in example 20 using 5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carboxylic acid (0.2g) of reference example 136 and ethyl hexahydropyridine-2-carboxylate (0.1 g).

¹H-NMR(400MHz，CDCl₃)δ：1.24(0.5×3H，t，J＝7.1Hz)，1.30(0.5×3H，t，J＝7.1Hz)，2.26-2.40(1H，m)，2.95-3.05(0.5×1H，m)，3.32-3.40(0.5×1H，m)，3.94(0.5×3H，s)，3.95(0.5×3H，s)，4.19-4.28(2H，m)，4.67-4.73(0.5×1H，m)，4.80-4.85(0.5×1H，m)，5.51(0.5×1H，d，J＝4.6Hz)，5.81(0.5×1H，d，J＝4.6Hz)，6.71(0.5×1H，d，J＝7.1Hz)，6.72(0.5×1H，d，J＝7.1Hz)，6.89(0.5×1H，s)，6.92(0.5×1H，s)，7.00-7.07(2H，m)，7.17-7.21(2H，m)，7.44(0.5×1H，dd，J＝8.8，2.7Hz)，7.50(0.5×1H，dd，J＝8.8，2.7Hz)，8.05(0.5×1H，d，J＝2.7Hz)，8.10(0.5×1H，d，J＝2.7Hz).

MS(EI)m/z：452(M⁺).

[ example 90]1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-2-carboxylic acid

The title compound (130mg, 51%) was obtained in an amorphous state in the same manner as in reference example 4 using ethyl 1- [5- (4-fluorophenyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine-2-carboxylate (270mg) of example 89.

¹H-NMR(400MHz，CDCl₃)δ：3.95(3H，s)，4.67-4.92(1H，m)，5.47-5.65(1H，m)，6.73-6.75(1H，m)，6.91-7.24(5H，m)，7.42-7.53(1H，m)，8.08-8.11(1H，m).

MS(EI)m/z：424(M⁺).

Elemental analysis: c₂₂H₂₁FN₄O₄ H₂O

Theoretical value: c, 59.74; h, 5.24; n, 12.67.

Measured value: c, 59.85; h, 5.00; and N, 12.26.

[ example 91]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2-hydroxymethylpiperidine

The title compound (220mg, 48%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (300mg) and 2-hydroxymethylpiperidine (234mg) of reference example 41.

¹H-NMR(400MHz，CDCl₃)δ：1.55-1.90(6H，m)，3.93(0.5×3H，s，and0.5×3H，s)，6.72(1H，d，J＝8.8Hz)，6.92(1H，br s)，7.31-7.36(3H，m)，7.46(1H，dd，J＝8.8，2.4Hz)，8.09(1H，br s).

MS(FAB)m/z：393(M+H)⁺.

[ example 92]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -2-hydroxymethylpiperidine

The title compound (250mg, 55%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (300mg) and 2-hydroxymethylpiperidine (234mg) of reference example 33.

¹H-NMR(400MHz，CDCl₃)δ：1.52-1.88(6H，m)，3.95(3H，s)，6.75(1H，dd，J＝8.8，0.7Hz)，7.12(1H，br s)，7.22-7.26(1H，m)，7.42(1H，d，J＝8.1Hz)，7.57(1H，dd，J＝8.8，2.7Hz)，7.69-7.73(1H，m)，8.09(1H，brs)，8.51-8.53(1H，m).

MS(FAB)m/z：394(M+H)⁺.

[ example 93]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidine-2-carboxamide

The title compound (270mg, 58%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (300mg) of reference example 41 and piperidine-2-carboxamide (131mg) of reference example 131.

¹H-NMR(400MHz，CDCl₃)δ：1.50-1.95(6H，m)，2.30-2.47(1H，m)，2.80-2.91(0.5×1H，m)，3.15-3.28(0.5×1H，m)，3.94(3H，s)，4.68-4.88(2H，m)，5.30-5.65(2H，m)，6.40(0.5×1H，br s)，6.70-6.74(1H，m)，6.93(1H，d，J＝14Hz)，8.09(0.5×1H，br s)，8.13(0.5×1H，br s).

MS(EI)m/z：405(M⁺).

[ example 94]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidine-2-carboxylic acid methylamide

The title compound (150mg, 32%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (300mg) of reference example 41 and piperidine-2-carboxylic acid methylamide (145mg) of reference example 132.

¹H-NMR(400MHz，CDCl₃)δ：1.50-1.95(6H，m)，2.33-2.48(1H，m)，2.83(0.5×3H，s)，2.84(0.5×3H，s)，3.10-3.20(0.5×1H，m)，3.94(3H，s)，4.60-4.82(1H，m)，5.30-5.40(1H，m)，6.42(0.5×1H，br s)，6.72(1H，d，J＝8.8Hz)，6.92(1H，d，J＝9.0Hz)，8.06(0.5×1H，br s)，8.14(0.5×1H，br s).

MS(EI)m/z：419(M⁺).

Elemental analysis: c₂₃H₂₅N₅O₃ 0.3CHCl₃

Theoretical value: c, 61.46; h, 5.60; n, 15.38.

Measured value: c, 61.06; h, 5.68; and N, 15.08.

[ example 95]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidine-2-carboxylic acid dimethylamide

The title compound (194mg, 42%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (300mg) of reference example 41 and piperidine-2-carboxylic acid dimethylamide (159mg) of reference example 133.

¹H-NMR(400MHz，CDCl₃)δ：1.52-2.15(7H，m)，2.98(3H，s)，3.12(3H，s)，3.55-3.70(1H，m)，3.94(3H，s)，4.70-4.85(1H，m)，6.72(1H，d，J＝8.8Hz)，6.88(1H，s)，7.20-7.40(4H，m)，7.49(1H，dd，J＝8.8，2.7Hz)，8.10-8.13(1H，m).

MS(EI)m/z：433(M⁺).

Elemental analysis: c₂₄H₂₇N₅O₃ 0.75H₂O

Theoretical value: c, 64.48; h, 6.43; n, 15.67.

Measured value: c, 64.11; h, 6.09; n, 15.58.

[ example 96]1- [1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carbonyl ] piperidine

The title compound (0.870g, 91%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methylsulfanyl-2-pyridyl) pyrazole-3-carboxylic acid (0.80g) and piperidine (0.254ml) of reference example 118.

¹H-NMR(400MHz，CDCl₃)δ：1.64-1.69(6H，m)，2.44(3H，s)，3.75-3.76(2H，m)，3.89-3.92(2H，m)，3.95(3H，s)，6.75(1H，d，J＝8.8Hz)，7.02-7.04(1H，m)，7.05(1H，s)，7.22(1H，d，J＝1.6Hz)，7.59-7.62(1H，m)，8.12(1H，d，J＝2.4Hz)，8.27(1H，d，J＝5.6Hz).

MS(EI)m/z：409(M⁺).

[ example 97]1- [5- (4-methanesulfonyl-2-pyridyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine

The title compound (0.935g, quantitative) was obtained as a solid in the same manner as in example 48 using 1- [1- (6-methoxy-3-pyridyl) -5- (4-methylthio-2-pyridyl) pyrazole-3-carbonyl ] piperidine (0.869g) and 3-chloroperbenzoic acid (1.10g) of example 96.

¹H-NMR(400MHz，CDCl₃)δ：1.64-1.70(6H，m)，3.08(3H，s)，3.76(2H，m)，3.92(2H，m)，3.96(3H，s)，6.80(1H，d，J＝8.8Hz)，7.22(1H，s)，7.63(1H，dd，J＝8.8，2.8Hz)，7.69-7.71(1H，m)，7.92-7.93(1H，m)，8.10(1H，d，J＝2.8Hz)，8.76(1H，d，J＝5.2Hz).

MS(EI)m/z：441(M⁺).

Elemental analysis: c₂₁H₂₃N₅O₄S 0.25H₂O

Theoretical value: c: 56.55%, H: 5.31%, N: 15.70%, S: 7.19 percent.

Measured value: c: 56.73%, H: 5.05%, N: 15.68%, S: 7.30 percent.

[ example 98]1- [5- (4-cyano-2-pyridyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine

To a solution of 1- [5- (4-methanesulfonyl-2-pyridyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine (0.60g) in N, N-dimethylformamide (12ml) prepared in example 97 was added potassium cyanide (97.3mg) at room temperature, and after stirring at 120 ℃ for 37 hours, potassium cyanide (97.3mg) was further added, followed by stirring at 120 ℃ for 4 hours. After air cooling, saturated brine and ethyl acetate were added to the reaction mixture to separate the mixture. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain the title compound (0.441g, 84%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.63-1.70(6H，m)，3.75(2H，m)，3.91(2H，m)，3.97(3H，s)，6.79(1H，d，J＝8.8Hz)，7.17(1H，s)，7.43-7.45(1H，m)，7.58-7.61(1H，m)，7.65(1H，m)，8.10(1H，d，J＝2.4Hz)，8.66-8.68(1H，m).

MS(EI)m/z：388(M⁺).

[ example 99]2- [1- (6-methoxy-3-pyridyl) -3- (piperidine-1-carbonyl) pyrazol-5-yl ] isonicotinic acid

To a mixed solution of 1- [5- (4-cyano-2-pyridyl) -1- (6-methoxy-3-pyridyl) pyrazole-3-carbonyl ] piperidine (0.418g) prepared in example 98 in methanol (8.4ml) and tetrahydrofuran (8.4ml) was added 1N aqueous sodium hydroxide solution (5.38ml) at room temperature, followed by stirring at 80 ℃ for 7 hours. After air cooling, water and chloroform were added to the reaction mixture to separate the mixture. The aqueous layer was neutralized with 1N aqueous hydrochloric acid (pH6), and chloroform was added thereto for liquid separation. The aqueous layer was then extracted with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain the title compound (0.239g, 52%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.73(6H，m)，3.84(2H，m)，3.95(3H，s)，4.04-4.06(2H，m)，6.75(1H，d，J＝8.8Hz)，7.39(1H，s)，7.58-7.61(1H，m)，7.80-7.82(1H，m)，8.14(1H，d，J＝2.4Hz)，8.26(1H，m)，8.58(1H，d，J＝4.8Hz).

MS(EI)m/z：407(M⁺).

[ example 100]2- [1- (6-methoxy-3-pyridyl) -3- (piperidine-1-carbonyl) pyrazol-5-yl ] isonicotinamide

The title compound (52.0mg, 42%) was obtained as a solid in the same manner as in 1) of example 1 using 2- [1- (6-methoxy-3-pyridyl) -3- (piperidine-1-carbonyl) pyrazol-5-yl ] isonicotinic acid (0.120g) of example 99 and 28% aqueous ammonia (53.7 ml).

¹H-NMR(400MHz，DMSO-d₆)δ：1.57-1.66(6H，m)，3.63(2H，m)，3.86(2H，m)，3.89(3H，s)，6.87(1H，d，J＝8.8Hz)，7.25(1H，s)，7.69-7.72(2H，m)，7.78(1H，s)，8.15-8.17(2H，m)，8.29-8.30(1H，m)，8.56(1H，d，J＝4.8Hz).

MS(EI)m/z：406(M⁺).

[ example 101] N- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methyl-2-oxopyrrolidine

60% sodium hydride (26mg) was added to a tetrahydrofuran (5ml) solution of 2-pyrrolidone (55mg) at room temperature, and the mixture was stirred for 30 minutes. Then, N-dimethylformamide (2ml) was added to the reaction solution, and the mixture was stirred for 30 minutes. Subsequently, a solution of [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methyl methanesulfonate (195mg) in reference example 76 in tetrahydrofuran (3ml) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Then, the solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the resulting residue to separate the mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (140mg, 74%) as an oil.

¹H-NMR(400MHz，CDCl₃)δ：2.04(2H，tt，J＝7.8，7.1Hz)，2.45(2H，t，J＝7.8Hz)，3.48(2H，t，J＝7.1Hz)，3.93(3H，s)，4.56(2H，s)，6.44(1H，s)，6.72(1H，d，J＝8.8Hz)，7.17-7.23(2H，m)，7.28-7.34(3H，m)，7.51(1H，dd，J＝8.8，2.7Hz)，8.07(1H，d，J＝2.7Hz).

MS(ESI)m/z：349(M+H)⁺.

[ example 102] 3-methyl-1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methyl-2-oxoimidazolidine

The title compound (167mg, 77%) was obtained as crystals in the same manner as in example 101 using 1-methylimidazolidin-2-one (71mg) and [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methyl methanesulfonate (214mg) of reference example 76.

¹H-NMR(400MHz，CDCl₃)δ：2.83(3H，s)，3.26-3.41(4H，m)，3.92(3H，s)，4.47(2H，s)，6.48(1H，s)，6.71(1H，d，J＝8.8Hz)，7.17-7.23(2H，m)，7.27-7.33(3H，m)，7.51(1H，dd，J＝8.8，2.7Hz)，8.06(1H，d，J＝2.7Hz).

MS(ESI)m/z：364(M+H)⁺.

Elemental analysis: c₂₀H₂₁N₅O₂

Theoretical value: c, 66.10; h, 5.82; n, 19.27.

Measured value: c, 65.76; h, 5.80; and N, 18.97.

[ example 103]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methyl-2, 5-dioxopyrrolidine

To a solution of [1- (6-methoxy-3-pyridyl) -5-phenylpyrazol-3-yl ] methyl methanesulfonate (194mg) and succinimide (53mg) in N, N-dimethylformamide (5ml) in referential example 76 was added potassium carbonate (373mg), and the mixture was stirred at 60 ℃ for 16 hours at room temperature. After air cooling, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (151mg, 75%) as crystals.

¹H-NMR(400MHz，CDCl₃)δ：2.77(4H，s)，3.91(3H，s)，4.81(2H，s)，6.44(1H，s)，6.69(1H，d，J＝8.8Hz)，7.14-7.22(2H，m)，7.27-7.33(3H，m)，7.50(1H，dd，J＝8.8，2.7Hz)，8.03(1H，d，J＝2.7Hz).

MS(ESI)m/z：363(M+H)⁺.

Elemental analysis: c ₂₀H₁₈N₄O₃ 0.5H₂O

Theoretical value: c, 64.68; h, 5.16; and N, 15.09.

Measured value: c, 64.74; h, 4.96; n, 14.85.

[ example 104]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2, 2-dimethyl-3-dimethylaminoazetidine

The title compound (48mg, 47%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid of reference example 41 (74mg) and (2, 2-dimethylazetidin-3-yl) dimethylamine hydrochloride of reference example 121 (50 mg).

¹H-NMR(400MHz，CDCl₃)δ：1.67(3H，s)，1.70(3H，s)，2.14(6H，s)，2.69(1H，dd，J＝7.9，15.4Hz)，3.94(3H，s)，4.21(1H，dd，J＝7.6，10.0Hz)，4.60(1H，dd，J＝7.8，10.0Hz)，6.71(1H，d，J＝8.8Hz)，7.00(1H，s)，7.20-7.23(2H，m)，7.31-7.34(3H，m)，7.42(1H，dd，J＝2.7，8.8Hz)，8.17(1H，d，J＝2.7Hz).

MS(ESI)m/z：406(M+H)⁺.

Elemental analysis: c₂₃H₂₇N₅O₂ 0.25H₂O

Theoretical value: c, 67.38; h, 6.76; and N, 17.08.

Measured value: c, 67.27; h, 6.67; and N, 17.03.

[ example 105]7- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4, 7-diazaspiro [2.5] octane

The title compound (224mg, 71%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid of reference example 41 (240mg) and 4, 7-diazaspiro [2.5] octane hydrochloride of reference example 122 (150 mg).

¹H-NMR(400MHz，DMSO-d₆)δ：0.48(2H，m)，0.53(2H，m)，2.82(2H，t，J＝5.1Hz)，3.12(2H，s)，3.42-3.55(2H，m)，3.94(3H，s)，6.87(2H，m)，7.29-7.32(2H，m)，7.38-7.40(3H，m)，7.65(1H，m)，8.12(1H，br s).

MS(ESI)m/z：390(M+H)⁺.

Elemental analysis: c₂₂H₂₃N₅O₂

Theoretical value: c, 67.85; h, 5.95; and N, 17.98.

Measured value: c, 67.62; h, 5.96; n, 17.94.

[ example 106] 4-methyl-7- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4, 7-diazaspiro [2.5] octane hydrochloride

To a solution of 7- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4, 7-diazaspiro [2.5] octane (120mg) in methanol (4ml) of example 105 were added sodium cyanoborohydride (78mg) and 37% aqueous formalin (26. mu.l) at room temperature, and the mixture was stirred for 41.5 hours. Then, sodium cyanoborohydride (78mg) and 37% formalin aqueous solution (26. mu.l) were added to the reaction solution, and the mixture was stirred for 4 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the resulting residue to separate the mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 4-methyl-7- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4, 7-diazaspiro [2.5] octane. This compound was dissolved in diethyl ether (4ml), and 1N hydrochloric acid-ethanol solution (372. mu.l) was added thereto at 0 ℃ and stirred for 10 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was crystallized from ether-hexane to obtain the title compound (101mg, 74%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：0.94(2H，m)，1.24(2H，m)，2.85(3H，br s)，3.25-3.40(4H，m)，3.88(3H，s)，4.06(2H，m)，6.88(1H，d，J＝8.8Hz)，6.96(1H，s)，7.29(2H，m)，7.38(3H，m)，7.67(1H，dd，J＝9.0，2.5Hz)，8.14(1H，s).

MS(ESI)m/z：404(M+H)⁺.

Elemental analysis: c₂₃H₂₅N₅O₂ HCl 0.25H₂O

Theoretical value: c, 62.16; h, 6.01; n, 15.76; cl, 7.98.

Measured value: c, 62.17; h, 5.90; n, 15.79; cl, 7.98.

[ example 107]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-acetylpiperazine

Triethylamine (0.205ml) and acetyl chloride (0.0477ml) were added to a solution of 4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine hydrochloride (0.185g) in methylene chloride (5.0ml) of example 81 at 0 ℃ and the mixture was stirred at room temperature for 1 hour. Then, water and chloroform were added to the reaction solution to separate the reaction solution. The aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.147g, 87%) in an amorphous state.

¹H-NMR(400MHz，CDCl₃) δ: 2.13(3H, br), 3.56(2H, br), 3.65-3.90(2H, br), 3.95(3H, s), 4.06-4.25(2H, m), 6.76(1H, d, J ═ 8.6Hz), 7.13-7.20(2H, m), 7.42(1H, br), 7.58(1H, br), 7.71(1H, t-like, J ═ 7.8Hz), 8.10(1H, br), 8.51(1H, d, J ═ 4.1Hz).

LC-MSm/z：407(M+H)⁺.

[ example 108]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -5-oxo-1, 4-diazepan

1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.223g) of referential example 33 and hexahydro-1H-1, 4-diaza-ne of referential example 120 were used -5-Ketone hydrochloride (0.227g), according to the same method as in example 20, the title compound (0.223g, 76%) was obtained as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.70-2.85(2H，m)，3.39-3.49(2H，m)，3.87-4.02(2H，m)，3.94(3H，s)，4.16-4.25(2H，m)，6.76(1H，d，J＝8.8Hz)，7.17(1H，s)，7.44(1H，d，J＝7.8Hz)，7.48(1H，br)，7.58(1H，br)，7.65-7.76(1H，m)，8.11(1H，d，J＝2.5Hz)，8.51(1H，br d，J＝3.0Hz).

LC-MS m/z：393(M+H)⁺.

Elemental analysis: c₂₀H₂₀N₆O₃

Theoretical value: c, 61.22; h, 5.14; n, 21.42.

Measured value: c, 61.01; h, 5.05; n, 21.23.

[ example 109]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methyl-5-oxo-1, 4-diazepan

To a solution of 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -5-oxo-1, 4-diazepan (0.253g) in N, N-dimethylformamide (5.0ml) prepared in example 108 was added sodium hydride (washed with pentane, dried, 20.4mg) at 0 ℃ and the mixture was stirred for 15 minutes. Then, methyl iodide (0.0602ml) was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. Subsequently, water and chloroform-methanol (5%) were added to the reaction solution for liquid separation. The aqueous layer was extracted with chloroform-methanol (5%), and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.231g, 88%) in an amorphous state.

¹H-NMR(400MHz，CDCl₃)δ：2.81(2H，br)，3.00-3.14(3H，m)，3.51-3.70(2H，m)，3.90-4.05(2H，m)，3.95(3H，s)，4.10-4.27(2H，m)，6.76(1H，d，J＝8.9Hz)，7.15(1H，br d，J＝10.0Hz)，7.22-7.30(1H，m)，7.45(1H，br)，7.57(1H，br)，7.71(1H，br t，J＝7.6Hz)，8.10(1H，br)，8.53(1H，br).

LC-MSm/z：407(M+H)⁺.

[ example 110]1- [1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine

N-methylpiperazine (1.80ml) was added to a chloroform (30ml) solution of 1- [1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1-succinimide (3.20g) of referential example 124 at room temperature, and the mixture was stirred for 2 hours. Then, water and chloroform were added to the reaction solution to separate the reaction solution. The organic layer was washed with water, a 1N aqueous sodium hydroxide solution and water in this order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ether-hexane to obtain the title compound (2.60g, 80%).

¹H-NMR(400MHz，CDCl₃)δ：2.34(3H，s)，2.46-2.52(4H，m)，3.83-3.86(2H，m)，4.07-4.12(2H，m)，6.92(1H，s)，7.22-7.41(6H，m)，7.58(1H，dd，J＝9,3Hz)，8.35(1H，d，J＝3Hz).

Elemental analysis: c₂₀H₂₀ClN₅O

Theoretical value: c, 62.91%; h, 5.28%; n, 18.34 percent.

Measured value: c, 62.67%; h, 5.22%; n, 18.29 percent.

[ example 111]1- [1- (6-ethoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine hydrochloride

The same procedures used in example 110 were repeated except for using 1- [1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1-succinimide (232mg) and N-methylpiperazine (0.14ml) obtained in referential example 126 to give 1- [1- (6-ethoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine, which was dissolved in ethanol, and then added with 1N aqueous hydrochloric acid (0.07ml) and stirred. The solvent was distilled off under reduced pressure, and the resulting solid was recrystallized from ether-hexane to obtain the title compound (25mg, 16%).

¹H-NMR(400MHz，CDCl₃)δ：1.40(3H，t，J＝7Hz)，2.82(3H，s)，2.80-3.05(2H，m)，3.45-3.80(m，3H)，3.98-4.15(1H，m)，4.36(2H，q，J＝7Hz)，4.75-4.99(1H，m)，5.23-5.52(1H，m)，6.70(1H，d，J＝9Hz)，6.99(1H，s)，7.21-7.43(6H，m)，8.08(1H，d，J＝3Hz)，13.49(1H，br s).

Elemental analysis: c₂₂H₂₆ClN₅O₂ 0.25H₂O

Theoretical value: c, 61.11%; h, 6.18%; n, 16.20 percent.

Measured value: c, 61.10%; h, 6.15%; and N, 16.02 percent.

[ example 112]1- [1- (6-isopropoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine hydrochloride

To a solution of 1- [1- (6-chloro-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1-succinimide (1.11g) in dichloromethane (20ml) of referential example 128 was added N-methylpiperazine (0.64ml) at room temperature, and the mixture was stirred overnight. Chloroform and water were added to the reaction solution to separate the reaction solution. The organic layer was washed with water, a 1N aqueous solution of sodium hydroxide and water in this order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1- [1- (6-isopropoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine. This was dissolved in ethanol, and a 1N aqueous hydrochloric acid solution (2.9ml) was added thereto and stirred. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from ether-ethanol to obtain the title compound (25g, 16%).

¹H-NMR(400MHz，CDCl₃)δ：1.35(6H，d，J＝6Hz)，2.85(3H，s)，2.80-3.05(2H，m)，3.50-3.78(m，3H)，4.00-4.15(1H，m)，4.85-4.95(1H，m)，5.29(1H，sep，J＝6Hz)，5.35-5.45(1H，m)，6.65(1H，d，J＝9Hz)，6.99(1H，s)，7.22-7.42(6H，m)，8.07(1H，d，J＝3Hz)，13.43(1H，br s).

Elemental analysis: c₂₃H₂₈ClN₅O₂ 0.25H₂O

Theoretical value: c, 61.88%; h, 6.43%; n, 15.69 percent.

Measured value: c, 61.98%; h, 6.40%; n, 15.62 percent.

[ example 113]1- [1- (6-methylamino-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine

To a solution of 1- [1- (2-chloro-5-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine (300mg) in N, N-dimethylformamide (1.5ml) obtained in example 110 was added 40% methylamine-methanol solution (0.6ml), and the mixture was stirred at 85 ℃ for 3 days in a sealed tube. After the air cooling, a 1N aqueous solution (30ml) of sodium hydroxide and ethyl acetate were added to the reaction mixture to separate the mixture. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and water in this order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in dimethyl sulfoxide (1ml), which was purified by preparative reverse phase high performance liquid chromatography (eluent: water-acetonitrile) and crystallized from ether-hexane to obtain the title compound (11.7mg, 4%).

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.47-2.51(4H，m)，2.93(3H，d，J＝5Hz)，3.83-3.86(2H，m)，4.09-4.14(2H，m)，4.70(1H，q，J＝5Hz)，6.33(1H，d，J＝9Hz)，6.89(1H，s)，7.25-7.34(6H，m)，8.05(1H，d，J＝3Hz).

Element classificationAnd (3) analysis: c₂₁H₂₄N₆O 0.25H₂O

Theoretical value: c, 66.21%; h, 6.48%; and N, 22.06%.

Measured value: c, 66.21%; h, 6.39%; and N, 21.86%.

[ example 114]1- [1- (6-cyclopropylamino-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine

Cyclopropylamine (1.0ml) was added to a dioxane (1.0ml) solution of 1- [1- (2-chloro-5-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine (200mg) obtained in example 110, and the mixture was stirred at 100 ℃ for 3 days in a sealed tube. After air cooling, water and ethyl acetate were added to the reaction mixture to separate the reaction mixture. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution in this order and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in dimethyl sulfoxide (1ml), which was purified by preparative reverse phase high performance liquid chromatography (eluent: water-acetonitrile) to obtain the title compound (19.6mg, 9%) as an oil.

MS(ESI)m/z：403(M+H)⁺.

[ example 115]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2, 2, 4-trifluoromethylpiperazine

To a tetrahydrofuran (2ml) solution of 1, 3, 3-trimethyl-piperazine-2, 5-dione (162mg) of referential example 130 was added a tetrahydrofuran solution (3ml) of 1.0M-borane-tetrahydrofuran complex, and the mixture was refluxed for 14 hours. After air-cooling, the solvent was evaporated under reduced pressure, and a 1N aqueous hydrochloric acid solution (4ml) was added to the resulting residue, followed by heating at 100 ℃ for 30 minutes. After air-cooling, tetrahydrofuran (3ml) and an anion exchange resin (Amberlite, 3.29g) washed with ethanol were added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. The reaction solution was filtered, and the solvent was distilled off under reduced pressure to obtain a mixture (71.0mg) of 1, 3, 3-trimethylpiperazine and 1-fluorenylmethylpiperidine as an oil. This mixture and 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxy ] -1-succinimid (66.4mg) of referential example 129 were dissolved in methylene chloride (2ml), and diisopropylethylamine (185. mu.l) was added to stir at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure to 1ml, which was purified by preparative high performance liquid chromatography (acetonitrile-water (0.1% formic acid added, 12-50% v/v)) to obtain the title compound (11.8mg, 15%) as an oil.

MS(FAB)m/z：406(M+H)⁺.

[ example 116]4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -1, 2, 6-trimethylpiperazine

To a solution of 4- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -2, 6-dimethylpiperazine (29.7mg) in ethanol (2.0ml) of example 22 were added 35% aqueous formalin (0.0325ml), acetic acid (0.0217ml) and sodium cyanoborohydride (9.2mg) at room temperature, and the mixture was stirred for 1.5 hours. An aqueous sodium bicarbonate solution and chloroform were added to the reaction mixture at 0 ℃. The aqueous layer was extracted with chloroform, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dried to obtain the title compound (40mg, quantitative).

LC-MSm/z：406(M+H)⁺.

[ example 117]1- [1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (130mg, 68%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carboxylic acid (150mg) of reference example 137 and N-methylpiperazine (0.068 ml).

¹H-NMR(400MHz，DMSO-d₆)δ：2.20(3H，s)，2.35(4H，br)，3.65(2H，br)，3.87(3H，s)，3.92(2H，br)，6.91(1H，s)，7.21-7.23(2H，m)，7.33-7.35(3H，m)，7.60-7.63(2H，m)，8.08-8.09(1H，m).

LC-MSm/z：378(M+H)⁺.

Elemental analysis: c₂₁H₂₃N₅O₂

Theoretical value: c, 66.77; h, 6.15; n, 18.63.

Measured value: c, 66.83; h, 6.14; n, 18.55.

[ example 118] (2S) -1- [1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carbonyl ] pyrrolidine-2-carboxamide

The title compound (270mg, 81%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carboxylic acid (250mg) and L-prolinamide (116mg) of reference example 137.

¹H-NMR(400MHz，CDCl₃) δ: 1.99-2.46(4H, m), 3.87(3H, s), 4.13(1H, m), 4.88(1H, br), 5.35(1H, s), 7.04(1H, s), 7.23-7.48(7H, m), 7.96 and 8.08(1H, s each).

FAB-MSm/z：392(M+H)⁺.

[ example 119]1- [1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperidine-2-carboxamide

The title compound (229mg, 66%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (5-methoxy-2-pyridyl) -5-phenylpyrazole-3-carboxylic acid (250mg) of reference example 137 and piperidine-2-carboxamide (119mg) of reference example 131.

¹H-NMR(400MHz，CDCl₃)δ：1.62-1.91(6H，m)，2.28-2.40(1H，m)，2.81-3.21(1H，m)，3.88(3H，s)，4.71-4.80(1H，m)，5.37(1H，br s)，5.46(1H，br s)，6.39(1H，s)，6.91(1H，d，J＝26.4Hz)，7.22-7.33(6H，m)，8.06(1H，d，J＝9.8Hz).

EI-MSm/z：405(M⁺).

[ example 120]1- [1- (5-methoxy-2-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (264mg, 69%) was obtained as an oil in the same manner as in 1) of example 1 using 1- (5-methoxy-2-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (300mg) and N-methylpiperazine (0.247ml) of reference example 138.

¹H-NMR(400MHz，CDCl₃)δ：2.31(3H，s)，2.42-2.51(4H，m)，3.84(2H，m)，3.86(3H，s)，4.08(2H，m)，7.06(1H，s)，7.17-7.21(1H，m)，7.32(1H，dd，J＝8.8，2.9Hz)，7.40-7.42(1H，m)，7.55(1H，d，J＝8.8Hz)，7.66-7.70(1H，m)，7.93(1H，d，J＝2.9Hz)，8.44-8.46(1H，m).

EI-MSm/z：378(M⁺).

2) Hydrochloride salt of the title compound

Using the above title compound (254mg), the hydrochloride of the title compound (187mg, 64%) was obtained as a solid in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：2.78(3H，m)，3.10-3.67(4H，m)，3.86(3H，s)，4.60-5.32(4H，m)，7.18(1H，s)，7.34-7.37(1H，m)，7.55-7.60(2H，m)，7.66-7.68(1H，m)，7.84-7.88(1H，m)，7.97(1H，d，J＝2.9Hz)，8.43(1H，d，J＝4.9Hz)，11.08(1H，br s).

EI-MSm/z：378(M⁺).

[ example 121]4- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine

The title compound (85mg, 69%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (100mg) and morpholine (0.035ml) of reference example 139.

¹H-NMR(400MHz，DMSO-d₆)δ：3.62(2H，br)，3.66(4H，br s)，3.96(2H，br)，4.03(3H，s)，7.27(1H，s)，7.32-7.36(1H，m)，7.47(1H，d，J＝9.3Hz)，7.79(1H，d，J＝7.8Hz)，7.89(1H，dt，J＝7.8，1.5Hz)，7.99(1H，d，J＝9.3Hz)，8.37(1H，d，J＝4.0Hz).

LC-MSm/z：367(M+H)⁺.

Elemental analysis: c₁₈H₁₈N₆O₃ 0.5H₂O

Theoretical value: c, 58.29; h, 5.03; n, 22.66.

Measured value: c, 58.59; h, 4.89; n, 22.57.

[ example 122]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperidine

The title compound (87mg, 71%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (100mg) of reference example 139 and piperidine (0.040 ml).

¹H-NMR(400MHz，DMSO-d₆)δ：1.55(4H，br)，1.65(2H，br)，3.64(2H，br)，3.80(2H，br)，4.03(3H，s)，7.21(1H，s)，7.32-7.35(1H，m)，7.47(1H，d，J＝9.2Hz)，7.77(1H，d，J＝7.8Hz)，7.88(1H，dt，J＝7.8，1.5Hz)，7.97(1H，d，J＝9.2Hz)，8.37(1H，d，J＝4.1Hz).

LC-MSm/z：365(M+H)⁺.

Elemental analysis: c₁₉H₂₀N₆O₂

Theoretical value: c, 62.62; h, 5.53; and N, 23.06.

Measured value: c, 62.46; h, 5.43; and N, 23.01.

[ example 123]4- [1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carbonyl ] morpholine

The title compound (170mg, 69%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carboxylic acid (200mg) of reference example 43 and morpholine (0.071 ml).

¹H-NMR(400MHz，DMSO-d₆)δ：3.63(2H，br)，3.67(4H，br s)，3.96(2H，br)，4.03(3H，s)，7.00(1H，s)，7.29-7.31(3H，m)，7.36-7.39(2H，m)，7.49(1H，d，J＝9.2Hz)，7.99(1H，d，J＝9.2Hz).

LC-MSm/z：366(M+H)⁺.

[ example 124]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

The title compound (54mg, 43%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (90mg) of reference example 139 and N-methylpiperazin-2-one hydrochloride (57mg) of reference example 157.

¹H-NMR(400MHz，CDCl₃) δ: 3.03(3H, s), 3.47(2H, t, J ═ 5.8Hz), 4.07(1H, m), 4.11 and 4.13(3H, each s), 4.40 and 4.44(2H, each brm), 4.87(1H, br s), 7.14-7.24(3H, m), 7.59(1H, d, J ═ 7.8Hz), 7.70 and 7.86(1H, each d, J ═ 9.0Hz), 7.75(1H, td, J ═ 7.8, 1.7Hz), 8.40(1H, s).

ESI-MSm/z：394(M+H)⁺.

[ example 125]1- [1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

The title compound (125mg, 63%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carboxylic acid (151mg) of reference example 43 and N-methylpiperazin-2-one trifluoroacetate (128mg) of reference example 91.

¹H-NMR(400MHz，DMSO-d₆)δ：2.89(3H，s)，3.43(2H，br s)，3.91(1H，br)，4.03(3H，s)，4.21(2H，br s)，4.62(1H，br)，7.04(1H，s)，7.31-7.52(5H，m)，7.50(1H，d，J＝9.3Hz)，7.96-8.04(1H，m)

LC-MSm/z：393(M+H)⁺.

[ example 126] (2S) -1- [1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carbonyl ] -2-hydroxymethylpyrrolidine

To a solution of 1- [1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carboxylic acid (237mg) in N, N-dimethylformamide (4ml) in referential example 43 were added diphenylphosphoryl azide (0.19ml), triethylamine (0.245ml) and (S) -2-pyrrolidinemethanol (0.181ml), and the mixture was stirred at room temperature for 17 hours. Water and chloroform were added to the reaction mixture to separate the mixture, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.166g, 47%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.60-2.20(4H，m)，3.55-4.60(5H，m)，4.12(3H，s)，4.83-4.98(1H，m)，7.03(1H，s)，7.08(1H，d，J＝9.2Hz)，7.25-7.42(5H，m)，7.61(1H，d，J＝9.2Hz).

ESI-MSm/z：380(M+H)⁺.

[ example 127]1- [1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carbonyl ] piperidine-2-carboxamide

The title compound (213mg, 65%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5-phenylpyrazole-3-carboxylic acid (151mg) of reference example 43 and piperidine-2-carboxamide (154mg) of reference example 131.

¹H-NMR(400MHz，CDCl₃)δ：1.50-1.87(6H，m)，2.30-2.43(1H，m)，2.83-2.92(1/2×1H，m)，3.15-3.26(1/2×1H，m)，4.13(3H，s)，4.70-4.78(1H，m)，5.34-5.50(1H，m)，5.52(1/2×1H，bs)，6.36(1/2×1H，bs)，7.05-7.12(2H，m)，7.26-7.38(5H，m)，7.50(1/2×1H，d，J＝9.3Hz)，7.63(1/2×1H，d，J＝9.3Hz).

ESI-MSm/z：407(M+H)⁺.

Elemental analysis: c₂₁H₂₂N₆O₃

Theoretical value: c, 62.06; h, 5.46; and N, 20.68.

Measured value: c, 62.16; h, 5.52; and N, 20.59.

[ example 128]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] pyrrolidine

The title compound (226mg, 77%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 139 and pyrrolidine (0.084 ml).

¹H-NMR(400MHz，DMSO-d₆)δ：1.85(2H，q，J＝6.59Hz)，1.91(2H，q，J＝6.59Hz)，3.53(2H，t，J＝6.59Hz)，3.88(2H，t，J＝6.59Hz)，4.03(3H，s)，7.30(1H，s)，7.33(1H，dt，J＝4.27，1.59Hz)，7.47(1H，d，J＝9.28Hz)，7.79(1H，d，J＝7.81Hz)，7.89(1H，dt，J＝7.81，1.59Hz)，7.99(1H，d，J＝9.28Hz)，8.37(1H，d，J＝4.27Hz).

FAB-MSm/z：351(M+H)⁺.

Elemental analysis: c₁₈H₁₈N₆O₂

Theoretical value: c, 61.70; h, 5.18; and N, 23.99.

Measured value: c, 61.42; h, 5.01; n, 23.87.

[ example 129]4- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -1, 4-oxazepan

The title compound (77.5mg, 25%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 139 and 1, 4-oxazepan hydrochloride (363mg) of reference example 149.

¹H-NMR(400MHz，CDCl₃)δ：2.01-2.11(2H，m)，3.79-3.91(6H，m)，4.05-4.15(2H，m)，4.11(3H，s)，7.13(1/2×1H，s)，7.14(1H，d，J＝9.3Hz)，7.14(1/2×1H，s)，7.20-7.24(1H，m)，7.59(1H，d，J＝7.8Hz)，7.73-7.78(1H，m)，7.79(1H，d，J＝9.3Hz)，8.40-8.43(1H，m).

ESI-MSm/z：381(M+H)⁺.

[ example 130]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methoxypiperidine

The title compound (130mg, 39%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 139 and 4-methoxypiperidine trifluoroacetate (386mg) of reference example 151.

¹H-NMR(400MHz，CDCl₃)δ：1.65-1.72(2H，m)，1.90-1.95(2H，m)，3.38(3H，s)，3.48-3.57(1H，m)，3.69-3.74(1H，m)，4.11(3H，s)，4.22-4.24(1H，m)，7.07(1H，s)，7.13(1H，d，J＝9.2Hz)，7.21-7.24(1H，m)，7.71(1H，d，J＝8.4Hz)，7.72-7.83(2H，m)，8.41-8.42(1H，m).

EI-MSm/z：394(M⁺).

Elemental analysis: c₁₉H₂₀N₆O₃

Theoretical value: c, 60.90; h, 5.62; n, 21.31.

Measured value: c, 60.72; h, 5.38; and N, 21.15.

[ example 131]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -2-methylhexahydropyridazine

The title compound (16.5mg, 5%) was obtained in an amorphous state in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (251mg) of reference example 139 and 1-methylhexahydropyridazine (143mg) of reference example 150.

¹H-NMR(400MHz，CDCl₃)δ：1.35-1.48(1H，m)，1.65-2.05(3H，m)，2.75(3H，s)，2.85-2.95(1H，m)，3.10-3.23(1H，m)，4.07(3H，s)，4.42-4.60(1H，m)，7.07(1H，s)，7.12(1H，d，J＝9.3Hz)，7.17-7.25(1H，m)，7.52(1H，d，J＝7.8Hz)，7.72(1H，dt，J＝7.8，1.9Hz)，8.03(1H，d，J＝9.3Hz)，8.46(1H，d，J＝4.7Hz).

ESI-MSm/z：380(M+H)⁺.

[ example 132]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (215mg, 71%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (238mg) and N-methylpiperazine (122mg) of reference example 139.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.40-2.57(4H，m)，3.81-3.92(2H，m)，4.03-4.11(2H，m)，4.11(3H，s)，7.10(1H，s)，7.13(1H，d，J＝9.3Hz)，7.22(1H，dd，J＝7.8，4.9Hz)，7.58(1H，d，J＝7.8Hz)，7.75(1H，dt，J＝7.8，1.7Hz)，7.80(1H，d，J＝9.3Hz)，8.41(1H，d，J＝4.9Hz).

ESI-MSm/z：380(M+H)⁺.

Elemental analysis: c₁₉H₂₁N₇O₂

Theoretical value: c, 60.15; h, 5.58; n, 25.84.

Measured value: c, 59.95; h, 5.40; n, 25.71.

[ example 133]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine

1)1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine-4-carboxylic acid tert-butyl ester

The same procedures used in 1) of example 1 were repeated except for using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (237mg) and N-tert-butoxycarbonylpiperazine (223mg) of reference example 139 to obtain tert-butyl 1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine-4-carboxylate (349mg, 94%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.48(9H，s)，1.56(6H，s)，3.48-3.57(4H，m)，3.77-3.82(2H，m)，4.03-4.09(2H，m)，4.12(3H，s)，7.13(1H，s)，7.14(1H，d，J＝9.0Hz)，7.22(1H，ddd，J＝7.8，4.9，1.1Hz)，7.59(1H，dt，J＝7.8，1.1Hz)，7.75(1H，dt，J＝7.8，1.8Hz)，7.77(1H，d，J＝9.0Hz)，8.41(1H，ddd，J＝4.9，1.8，1.1Hz).

ESI-MSm/z：466(M+H)⁺.

2) The title Compound

The title compound (242mg, 88%) was obtained as a solid in the same manner as in 2) of example 16 using tert-butyl 1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine-4-carboxylate (349 mg).

¹H-NMR(400MHz，CDCl₃)δ：2.86-3.06(4H，m)，3.76-3.88(2H，m)，4.00-4.08(2H，m)，4.11(3H，s)，7.10(1H，s)，7.13(1H，d，J＝9.0Hz)，7.22(1H，dd，J＝7.8，4.9Hz)，7.58(1H，d，J＝7.8Hz)，7.75(1H，dt，J＝7.8，1.3Hz)，7.79(1H，d，J＝9.0Hz)，8.38-8.45(1H，m).

ESI-MS m/z：366(M+H)⁺.

[ example 134]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-oxopiperidine

1) Piperidin-3-one hydrochloride

To a solution of tert-butyl 3-oxopiperidine-1-carboxylate (400mg) in methylene chloride (5ml) was added a 4N hydrochloric acid-dioxane solution (3ml), and the mixture was stirred at room temperature for 3 hours. The reaction solvent was distilled off under reduced pressure to obtain piperidin-3-one hydrochloride.

¹H-NMR(400MHz，CD₃OD)δ：1.85(2H，m)，3.04(2H，m)，3.66(2H，br)，4.88(2H，br).

2) The title Compound

The title compound (53mg, 10%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (400mg) of reference example 139 and the above-mentioned piperidin-3-one hydrochloride (272 mg).

¹H-NMR(400MHz，CDCl₃)δ：2.13(2H，br)，2.58(2H，t，J＝6.47Hz)，3.97(1H，br)，4.12(3H，br)，4.23(1H，br)，4.39(1H，br)，4.74(1H，br)，7.15(2H，m)，7.22(1H，m)，7.59(1H，d，J＝7.81Hz)，7.79(2H，m)，8.41(1H，d，J＝3.91Hz).

FAB-MSm/z：379(M+H)⁺.

[ example 135]1- [1- (6-methoxy-3-pyridazinyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (226mg, 60%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylic acid (300mg) of reference example 158 and N-methylpiperazine (0.244 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.32(3H，s)，2.42-2.51(4H，m)，3.83-3.92(2H，m)，3.86(3H，s)，4.06-4.14(2H，m)，4.10(3H，s)，6.73(1H，dd，J＝5.9，2.4Hz)，7.06(1H，s)，7.10-7.12(2H，m)，7.76-7.79(1H，m)，8.20(1H，d，J＝5.9Hz).

EI-MSm/z：409(M⁺).

Elemental analysis: c₂₀H₂₃N₇O₃ 0.25H₂O

Theoretical value: c, 58.03; h, 5.72; n, 23.69.

Measured value: c, 58.07; h, 5.64; n, 23.47.

[ example 136] 4-cyclopropyl-1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperazine

The title compound (271mg, 79%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 139 and N-cyclopropylpiperazine hydrochloride (284mg) of reference example 99.

¹H-NMR(400MHz，CDCl₃)δ：0.41-0.50(4H，m)，1.61-1.67(1H，m)，2.63-2.72(4H，m)，3.79(2H，t，J＝4.9Hz)，3.99(2H，t，J＝4.9Hz)，4.10(3H，s)，7.08(1H，s)，7.11-7.13(1H，m)，7.19-7.23(1H，m)，7.56-7.58(1H，m)，7.71-7.81(2H，m)，8.39-8.41(1H，m).

EI-MSm/z：405(M⁺).

Elemental analysis: c₂₁H₂₃N₇O₂ 0.25H₂O

Theoretical value: c, 61.51; h, 5.78; n, 23.92.

Measured value: c, 61.51; h, 5.54; n, 23.94.

[ example 137]4- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -1, 1-dioxothiomorpholine

The title compound (235mg, 72%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 139 and thiomorpholine-1, 1-dioxide (136 mg).

¹H-NMR(400MHz，DMSO-d₆)δ：3.28(4H，br)，4.03(3H，s)，4.07(2H，br)，4.35(2H，br)，7.32(1H，s)，7.34(1H，dd，J＝7.81，4.88Hz)，7.47(1H，d，J＝9.28Hz)，7.77(1H，d，J＝7.81Hz)，7.89(1H，dt，J＝7.81，1.59Hz)，7.99(1H，d，J＝9.28Hz)，8.37(1H，d，J＝4.88Hz).

FAB-MSm/z：415(M+H)⁺.

[ example 138]4- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] thiomorpholine

The title compound (236mg, 92%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (200mg) of reference example 139 and thiomorpholine (0.081 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.74(4H，br)，4.07(2H，m)，4.11(3H，s)，4.27(2H，br)，7.09(1H，s)，7.14(1H，d，J＝9.16Hz)，7.23(1H，ddd，J＝7.57，4.88，1.10Hz)，7.58(1H，d，J＝7.81Hz)，7.74(1H，dd，J＝7.57，1.71Hz)，7.78(1H，d，J＝9.16Hz)，8.41(1H，d，J＝4.88Hz).

FAB-MSm/z：383(M+H)⁺.

[ example 139]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4, 4-difluoropiperidine

The title compound (574mg, 85%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (500mg) of reference example 139 and 4, 4-difluoropiperidine hydrochloride (398mg) of reference example 152.

¹H-NMR(400MHz，CDCl₃)δ：2.07(4H，m)，3.92(2H，m)，4.11(3H，s)，4.17(2H，m)，7.12-7.15(2H，m)，7.20-7.23(1H，m)，7.58(1H，d，J＝7.8Hz)，7.72-7.77(2H，m)，8.40(1H，d，J＝4.6Hz).

EI-MSm/z：400(M⁺).

[ example 140]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3, 3-difluoropiperidine

The title compound (403mg, 74%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (400mg) of reference example 139 and 3, 3-difluoropiperidine hydrochloride (233mg) of reference example 153.

¹H-NMR(400MHz，CDCl₃)δ：1.88(2H，m)，2.12-2.09(2H，m)，3.79(1H，m)，4.06(1H，m)，4.11(3H，s)，4.30-4.36(1H，m)，7.14-7.26(3H，m)，7.60-7.61(1H，m)，7.73-7.84(2H，m)，8.41(1H，d，J＝3.9Hz).

EI-MSm/z：400(M⁺).

[ example 141]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-fluoropiperidine

The title compound (403mg, 74%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (400mg) of reference example 139 and 4-fluoropiperidine hydrochloride (207mg) of reference example 154.

¹H-NMR(400MHz，CDCl₃)δ：1.91-2.01(4H，m)，3.69-3.72(1H，m)，3.92-4.21(3H，m)，4.11(3H，s)，4.86-4.99(1H，m)，7.10(1H，s)，7.14(1H，d，J＝9.3Hz)，7.20-7.24(1H，m)，7.57-7.59(1H，m)，7.73-7.80(2H，m)，8.40-8.42(1H，m).

FAB-MSm/z：383(M+H)⁺.

Elemental analysis: c₁₉H₁₉FN₆O₂

Theoretical value: c, 59.68; h, 5.01; n, 21.98; f, 4.97.

Measured value: c, 59.65; h, 4.96; n, 22.04; f, 4.91.

[ example 142]1- [1- (6-methoxy-3-pyridazinyl) -5- (4-dimethylaminophenyl) pyrazole-3-carbonyl ]

The title compound (200mg, 76%) was obtained in an amorphous state in the same manner as in example 20 using 1- (6-methoxy-3-pyridazinyl) -5- (4-dimethylaminophenyl) pyrazole-3-carboxylic acid (203mg) and N-methylpiperazine (0.067ml) of reference example 140.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.43-2.54(4H，m)，2.96(6H，s)，3.82-3.88(2H，m)，4.06-4.12(2H，m)，4.15(3H，s)，6.64(2H，d，J＝8.8Hz)，6.81(1H，s)，7.02(1H，d，J＝9.3Hz)，7.16(2H，d，J＝8.8Hz)，7.47(1H，d，J＝9.3Hz).

ESI-MSm/z：422(M+H)⁺.

Elemental analysis: c₂₂H₂₇N₇O₂ 0.75H₂O

Theoretical value: c, 60.74; h, 6.60; n, 22.54.

Measured value: c, 60.62; h, 6.68; n, 22.54.

[ example 143]1- [5- (5-chloro-2-pyridyl) -1- (6-methoxy-3-pyridazinyl) pyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

The title compound (45mg, 7%) was obtained as a solid in the same manner as in example 20 using 5- (5-chloro-2-pyridyl) -1- (6-methoxy-3-pyridazinyl) pyrazole-3-carboxylic acid (483mg) of reference example 141 and N-methylpiperazin-2-one hydrochloride (440mg) of reference example 157.

¹H-NMR(400MHz，CDCl₃)δ：3.01(3H，s)，3.45(3H，m)，4.04(1H，br)，4.11(3H，br)，4.36(1H，br)，4.84(1H，s)，7.15(1H，d，J＝9.03Hz)，7.16(1H，s)，7.53(1H，d，J＝8.30Hz)，7.71(1.5H，dd，J＝8.30，2.20Hz)，7.85(0.5H，d，J＝9.03Hz)，8.34(1H，s).

FAB-MSm/z：428(M+H)⁺.

[ example 144]1- [1- (5-methoxy-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (251mg, 61%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (5-methoxy-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (320mg) of referential example 142 and N-methylpiperazine (0.179 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.32(3H，s)，2.44-2.52(4H，m)，3.85(2H，m)，4.01(3H，s)，4.10(2H，m)，7.12(1H，s)，7.22-7.19(1H，m)，7.52-7.54(1H，m)，7.70-7.75(1H，m)，7.91(1H，d，J＝1.0Hz)，8.40-8.41(2H，m).

EI-MSm/z：379(M⁺).

[ example 145]1- [1- (5-methoxy-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

The title compound (287mg, 64%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (5-methoxy-2-pyrazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (329mg) of reference example 142 and N-methylpiperazin-2-one hydrochloride (333mg) of reference example 157.

¹H-NMR(400MHz，CDCl₃)δ：3.02(3H，s)，3.47(2H，m)，4.01-4.03(4H，m)，4.44(2H，m)，4.87(1H，m)，7.16-7.23(2H，m)，7.52-7.54(1H，m)，7.73(1H，m)，7.92(1H，d，J＝8.8Hz)，8.44-8.38(2H，m).

FAB-MSm/z：394(M+H)⁺.

Elemental analysis: c₁₉H₁₉N₇O₃

Theoretical value: c, 56.71; h, 5.01; n, 24.36.

Measured value: c, 56.77; h, 5.16; and N, 24.40.

[ example 146]1- [1- (6-methyl-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

Lithium hydroxide monohydrate (40.1mg) was added to a mixed solution of ethyl 1- (6-methyl-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylate (245mg) in tetrahydrofuran (2ml), ethanol (0.5ml) and water (1ml) of referential example 143 at room temperature, and the mixture was stirred for 1 hour. Then, 1N aqueous hydrochloric acid (0.191mg) was added to the reaction mixture, and the reaction solvent was distilled off under reduced pressure to obtain 1- (6-methyl-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid lithium salt. 1-hydroxybenzotriazole (153mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (238mg) and N-methylpiperazine (0.265ml) were added to an N, N-dimethylformamide (4.0ml) solution of the obtained lithium salt at room temperature, and the mixture was stirred for 3 days. Then, water and a chloroform-methanol (15: 1) solvent were added to the reaction solution to separate the solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (66.5mg, 25%) in an amorphous state.

¹H-NMR(400MHz，CDCl₃) δ: 2.33(3H, s), 2.45-2.55(4H, m), 2.59(3H, s), 3.85(2H, br), 4.09(2H, br), 7.12(1H, s), 7.19(1H, d, J ═ 8.3Hz), 7.21-7.27(1H, m), 7.44(1H, d, J ═ 7.8Hz), 7.62(1H, dd, J ═ 8.3, 2.7Hz), 7.72(1H, t, J ═ 7.8Hz), 8.40(1H, d, J ═ 2.7Hz), 8.47-8.53(1H, m).

ESI-MSm/z：362(M+H)⁺.

[ example 147]1- [1- (6-methoxy-3-pyridyl) -5- (3-pyridazinyl) pyrazole-3-carbonyl ] -4-methylpiperazine hydrochloride

The same procedures used in 1) of example 1 were repeated except for using 1- (6-methoxy-3-pyridyl) -5- (3-pyridazinyl) pyrazole-3-carboxylic acid lithium salt (160mg) and N-methylpiperazine (0.088ml) of reference example 144 to obtain 1- [1- (6-methoxy-3-pyridyl) -5- (3-pyridazinyl) pyrazole-3-carbonyl ] -4-methylpiperazine, and using the same, the same procedures used in 2) of example 29 were repeated to obtain the title compound (123mg, 50%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：2.81(3H，s)，3.01-3.78(6H，m)，3.90(3H，s)，4.57-4.70(1H，br m)，4.93-5.07(1H，br m)，6.90(1H，d，J＝8.8Hz)，7.45(1H，s)，7.75-7.84(2H，m)，7.98-8.03(1H，m)，8.25(1H，d，J＝2.7Hz)，9.17-9.21(1H，m)，11.07-11.22(1H，br).

ESI-MSm/z：380(M+H)⁺.

[ example 148]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1)4- (2-pyrazinyl) -2, 4-dioxobutyric acid ethyl ester

The same procedures used in referential example 71 were repeated except for using 1- (2-pyrazinyl) -1-ethanone (1.22g) and diethyl oxalate (2.05ml) to obtain ethyl 4- (2-pyrazinyl) -2, 4-dioxobutyrate (1.83g, 82%) as a solid. The reaction mixture was used in the following reaction without purification.

2)1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carboxylic acid ethyl ester

The same procedures used in 2) of reference example 138 were repeated except for using ethyl 4- (2-pyrazinyl) -2, 4-dioxobutyrate (1.58g) and 5-hydrazino-2-methoxypyridine hydrochloride (1.50g) obtained in reference example 1 to give ethyl 1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carboxylate (1.05g, 45%) as a solid.

3)1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carboxylic acid

Using the above ethyl 1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carboxylate (1.05g), in the same manner as in 7) of reference example 137, 1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carboxylic acid (0.883g, 92%) was obtained as a solid.

4) The title Compound

The title compound (145mg, 48%) was obtained as a solid in the same manner as in 1) of example 1 using the above-mentioned 1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carboxylic acid (0.232g) and N-methylpiperazine (0.156 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.45-2.53(4H，m)，3.84-3.87(2H，m)，3.97(3H，s)，4.09-4.12(2H，m)，6.79(1H，d，J＝8.8Hz)，7.26(1H，d，J＝2.7Hz)，7.60(1H，dd，J＝8.8，2.7Hz)，8.12(1H，d，J＝2.7Hz)，8.47(1H，dd，J＝2.4，1.7Hz)，8.51(1H，d，J＝2.4Hz)，8.73(1H，d，J＝1.5Hz).

ESI-MSm/z：380(M+H)⁺.

Elemental analysis: c₁₉H₂₁N₇O₂

Theoretical value: c, 60.15; h, 5.58; n, 25.83.

Measured value: c, 60.00; h, 5.52; n, 25.57.

[ example 149] (2S) -1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -2-dimethylaminomethylpyrrolidine

1) (2S) -2-dimethylaminomethylpyrrolidine

A solution of sulfonyl chloride (0.409ml) in methylene chloride (30ml) was added dropwise to a solution of (2S) -2-pyrrolidinemethanol (0.498ml) and triethylamine (1.39ml) in methylene chloride (30ml) over 10 minutes while cooling at-78 ℃ to gradually return the temperature to room temperature, followed by stirring for 20 hours. Then, 1N aqueous hydrochloric acid solution and methylene chloride were added to the reaction mixture to separate the mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and a 2.0M tetrahydrofuran solution (25ml) of dimethylamine was added to the obtained residue, followed by stirring at an external temperature of 100 ℃ for 14 hours and half hours in a sealed tube. After air cooling, trifluoroacetic acid (1 drop) was added and then stirred in a sealed tube at an external temperature of 100 ℃ for 21 hours. After air-cooling, the solvent was distilled off under normal pressure, and a 2N aqueous solution (50ml) of sodium hydroxide was added to the resulting residue, followed by stirring at 100 ℃ for 15 hours. After air-cooling, ether was added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under normal pressure to obtain (2S) -2-dimethylaminomethylpyrrolidine.

2) The title Compound

The title compound (116mg, 5.1%) was obtained as a solid in the same manner as in 1) of example 1 using the above-mentioned (2S) -2-dimethylaminomethylpyrrolidine and 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (231mg) of reference example 33.

¹H-NMR(400MHz，CDCl₃)δ：2.03-2.11(2H，m)，2.27-2.37(1H，m)，2.48-2.55(1H，m)，2.87-3.08(7H，m)，3.48(1H，d，J＝12.3Hz)，3.96-4.04(4H，m)，4.11-4.17(1H，m)，4.60-4.65(1H，m)，6.76(1H，d，J＝8.8Hz)，7.21(1H，s)，7.24-7.27(1H，m)，7.42(1H，d，J＝7.8Hz)，7.58(1H，dd，J＝8.8，2.7Hz)，7.72(1H，dd，J＝7.7，7.6，1.7Hz)，8.12(1H，d，J＝2.5Hz)，8.52(1H，d，J＝4.2Hz).

ESI-MSm/z：407(M+H)⁺.

[ example 150]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-dimethylaminopyrrolidine

The title compound (250mg, 80%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (231mg) of reference example 33 and 3-dimethylaminopyrrolidine (0.148 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.77-1.95(1H，m)，2.11-2.21(1H，m)，2.29(3H，s)，2.32(3H，s)，2.69-2.84(1H，m)，3.43(1/2×1H，dd，J＝11.7，9.0Hz)，3.59-3.72(1H，m)，3.88-3.97(1H，m)，3.96(3H，s)，4.05(1/2×1H，dd，J＝12.0，6.8Hz)，4.27-4.39(1H，m)，6.75(1H，d，J＝8.8Hz)，7.21-7.25(2H，m)，7.46(1H，d，J＝7.8Hz)，7.56-7.60(1H，m)，7.69-7.74(1H，m)，8.12-8.14(1H，m)，8.52-8.49(1H，m).

ESI-MSm/z：393(M+H)⁺.

[ example 151]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -2-methyl-3-oxopyrazolidine

1)1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-oxopyrazolidine

The same procedures used in 1) of example 1 were repeated except for using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (231mg) and 3-oxopyrazolidine (115mg) of reference example 33 to give 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-oxopyrazolidine (141mg, 48%) as a solid.

¹H-NMR(400MHz，DMSO-d₆)δ：2.70(2H，t，J＝8.4Hz)，3.89(3H，s)，4.48(2H，br s)，6.89(1H，d，J＝8.8Hz)，7.33(1H，s)，7.37(1H，dd，J＝7.6，4.9Hz)，7.71-7.75(2H，m)，7.89(1H，ddd，J＝7.8，7.8，1.2Hz)，8.19(1H，d，J＝2.7Hz)，8.47(1H，d，J＝4.6Hz)，11.35(1H，br s).

ESI-MSm/z：365(M+H)⁺.

2) The title Compound

To a solution of the above 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-oxopyrazolidine (0.542g) in N, N-dimethylformamide (5ml) was added 60% sodium hydride (142.4mg) at room temperature, followed by stirring for 15 minutes, followed by addition of methyl iodide (0.828ml) and stirring for 10 days. Then, potassium carbonate (0.614g) and methyl iodide (0.276ml) were added to the reaction solution, and the mixture was stirred at 60 ℃ for 2 hours. After air-cooling, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (89.8mg, 15%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：2.93(2H，t，J＝9.6Hz)，3.94(3H，s)，3.96(3H，s)，4.28(2H，t，J＝9.5Hz)，6.75(1H，dd，J＝8.8，0.7Hz)，7.21-7.24(1H，m)，7.33(1H，d，J＝7.8Hz)，7.42(1H，s)，7.65-7.71(2H，m)，8.11(1H，d，J＝2.7Hz)，8.55(1H，d，J＝4.2Hz).

ESI-MSm/z：379(M+H)⁺.

[ example 152]1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine-2-carboxamide

1) 4-tert-Butoxycarbonyl-1- [1- (6-methoxy-3-pyridinyl) -5-phenylpyrazole-3-carbonyl ] piperazine-2-carboxylic acid ethyl ester

The same procedures used in example 20 were repeated except for using 1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carboxylic acid (540mg) of reference example 41 and ethyl 4-tert-butoxycarbonylpiperazine-2-carboxylate (500mg) of reference example 147 to give amorphous ethyl 4-tert-butoxycarbonyl-1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-2-carboxylate (992mg, 95%).

¹H-NMR(400MHz，CDCl₃)δ：1.23(1/2×3H，t，J＝7.1Hz)，1.31(1/2×3H，t，J＝7.1Hz)，1.47(9H，s)，3.94(1/2×3H，s)，3.95(1/2×3H，s)，6.69-6.74(1H，m)，6.72(1/2×1H，s)，6.74(1/2×1H，s)，7.22-7.50(6H，m)，8.08(1/2×1H，d，J＝2.7Hz)，8.13(1/2×1H，d，J＝2.7Hz).

FAB-MSm/z：536(M+H)⁺.

2)1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine-2-carboxylic acid ethyl ester

The same procedures used in 2) of example 16 were repeated except for using the above ethyl 4-tert-butoxycarbonyl-1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-2-carboxylate (992mg) and trifluoroacetic acid (2ml) to obtain ethyl 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] piperazine-2-carboxylate, and to a solution of the compound in dichloromethane (27ml), 37% aqueous formalin (0.36ml) and sodium triacetoxyborohydride (1.4g) were added and the mixture was stirred at room temperature for 1 hour. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and dried to obtain amorphous ethyl 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine-2-carboxylate (702mg, 84%).

¹H-NMR(400MHz，CDCl₃)δ：1.23(1/2×3H，t，J＝7.1Hz)，1.30(1/2×3H，t，J＝7.1Hz)，2.06-2.19(1H，m)，2.301(1/2×3H，s)，2.304(1/2×3H，s)，2.76-2.90(1H，m)，3.27-3.68(2H，m)，3.94(1/2×3H，s)，3.94(1/2×3H，s)，4.20-4.33(2H，m)，4.58(1/2×1H，d，J＝13.4Hz)，4.95(1/2×1H，d，J＝13.4Hz)，5.38-5.39(1/2×1H，m)，5.85-5.86(1/2×1H，m)，6.72(1H，t，J＝8.3Hz)，6.96(1/2×1H，s)，6.99(1/2×1H，s)，7.22-7.51(6H，m)，8.07(1/2×1H，d，J＝2.7Hz)，8.14(1/2×1H，d，J＝2.7Hz).

EI-MSm/z：449(M⁺).

3) The title Compound

To a solution of the above ethyl 1- [1- (6-methoxy-3-pyridyl) -5-phenylpyrazole-3-carbonyl ] -4-methylpiperazine-2-carboxylate (702mg) in tetrahydrofuran (33ml) and water (7ml) was added lithium hydroxide monohydrate (66mg), and the mixture was stirred at room temperature for 41 hours. Then, the reaction mixture was neutralized with concentrated hydrochloric acid, followed by addition of dichloromethane for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a carboxylic acid body. Triethylamine (0.5ml) was added to a solution of the resulting carboxylic acid compound, 1-hydroxybenzotriazole (422mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (600mg) and 28% aqueous ammonia (1.0ml) in methylene chloride (10ml) at room temperature, and the mixture was stirred for 1 day. Then, water was added to the reaction solution to separate the solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (dichloromethane-methanol) to obtain the title compound (430mg, 65%) in an amorphous state.

¹H-NMR(400MHz，CDCl₃)δ：2.10-2.20(2H，m)，2.33(3H，s)，2.75-2.93(1H，m)，3.15-3.60(2H，m)，3.94(3H，s)，4.65-5.00(1H，m)，6.70-6.75(1H，m)，6.98-7,01(1H，m)，7.22-7.27(2H，m)，7.33-7.38(3H，m)，7.33-7.47(1H，m)，8.08(1/2×1H，br s)，8.14(1/2H×1H，br s).

FAB-MSm/z：421(M+H)⁺.

[ example 153] (3S) -4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine-3-carboxamide

1) (3S) -4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine-3-carboxylic acid methyl ester

The same procedures used in example 20 were repeated except for using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (250mg) obtained in referential example 33 and methyl morpholine-3-carboxylate (190mg) obtained in referential example 148 to obtain amorphous methyl (3S) -4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine-3-carboxylate (387mg, quantitative).

¹H-NMR(400MHz，CDCl₃)δ：3.57-4.02(5H，m)，3.76(3H，s)，3.96(3H，s)，4.45(1H，d，J＝12.09Hz)，5.00(0.5H，m)，5.25(0.2H，s)，5.89(0.3H，s)，6.74(1H，d，J＝8.79Hz)，7.23(1H，d，J＝4.52Hz)，7.27(1H，d，J＝3.78Hz)，7.46(1H，m)，7.59(1H，dd，J＝8.79，2.69Hz)，7.79(1H，m)，8.13(1H，dd，J＝5.13，2.69Hz)，8.50(1H，d，J＝4.88Hz).

EI-MSm/z：424(M+H)⁺.

2) (3S) -4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine-3-carboxylic acid

A1N aqueous sodium hydroxide solution (3ml) was added dropwise to a tetrahydrofuran (5ml) solution of methyl (3S) -4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine-3-carboxylate (387mg) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Then, a 1N aqueous hydrochloric acid solution (3.5ml) and chloroform were added to the reaction mixture to separate a liquid, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain amorphous (3S) -4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine-3-carboxylic acid (338mg, 90%).

¹H-NMR(400MHz，CDCl₃)δ：3.57-3.80(3H，m)，3.76(3H，s)，4.45(1H，d，J＝12.09Hz)，4.93(0.5H，m)，5.25(0.2H，s)，5.79(0.3H，s)，6.76(1H，m)，7.24-7.78(5H，m)，8.13(1H，m)，8.50(1H，m).

EI-MSm/z：410(M+H)⁺.

3) The title Compound

The title compound (58mg, 17%) was obtained in an amorphous state in the same manner as in example 20 using the above-mentioned (3S) -4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] morpholine-3-carboxylic acid (338mg) and ammonium chloride (221 mg).

¹H-NMR(400MHz，CDCl₃)δ：3.23(0.5H，m)，3.65(2.5H，m)，3.91(1H，m)，3.95(3H，s)，4.61(1.5H，m)，4.96(0.5H，m)，5.17(0.5H，br)，5.46(1.5H，br)，6.27(0.5H，br)，6.76(1.5H，br)，7.26(2H，m)，7.42(1H，m)，7.55(1H，m)，7.73(1H，m)，8.09(1H，m)，853(1H，m).

FAB-MSm/z：409(M+H)⁺.

[ example 154]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-methyl-4-oxoimidazolidine

1)1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-oxoimidazolidine

The same procedures used in 1) of example 1 were repeated except for using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (231mg) and 4-imidazolidinone (80.5mg) obtained in reference example 33 to give 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-oxoimidazolidine (200mg, 70%) as a solid.

2) The title Compound

The title compound (141mg, 68%) was obtained as a solid in the same manner as in 1) of referential example 152 using the above-mentioned 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-oxoimidazolidine (200mg) and methyl iodide (0.052 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.98(1H，s)，3.02(2H，s)，3.97(2H，s)，3.98(1H，s)，4.29(2/3H，s)，4.71(4/3H，s)，5.09(4/3H，s)，5.45(2/3H，s)，6.76-6.80(1H，m)，7.24-7.27(1H，m)，7.32(2/3H，s)，7.33(1/3H，s)，7.43-7.48(1H，m)，7.55(1/3H，dd，J＝8.9，2.8Hz)，7.62(2/3H，dd，J＝8.9，2.8Hz)，7.71-7.76(1H，m)，8.08(2/3H，d，J＝2.7Hz)，8.19(1/3H，d，J＝2.4Hz)，8.50-8.54(1H，m).

ESI-MSm/z：379(M+H)⁺.

[ example 155] (3R) -1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -3-methoxypyrrolidine

1) (3R) -3-methoxypyrrolidine hydrochloride

To tert-butyl (3R) -3-methoxypyrrolidine-1-carboxylate (899mg) in referential example 155 was added a 4N hydrochloric acid-dioxane solution (10ml), and the mixture was stirred at room temperature for 18 hours and half hours. The reaction mixture was evaporated to dryness under reduced pressure to obtain (3R) -3-methoxypyrrolidine hydrochloride (0.637g, quantitative).

2) The title Compound

The title compound (267mg, 88%) was obtained as an oil in the same manner as in 1) of example 1 using the above-mentioned (3R) -3-methoxypyrrolidine hydrochloride (0.20g) and 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.231g) of reference example 33.

¹H-NMR(400MHz，CDCl₃)δ：1.95-2.18(2H，m)，3.34(3H，s)，3.37(3H，s)，3.71-4.08(4H，m)，3.96(3H，s)，4.15-4.25(1H，m)，6.75(1H，d，J＝8.8Hz)，7.21-7.27(2H，m)，7.44-7.48(1H，m)，7.57-7.61(1H，m)，7.69-7.74(1H，m)，8.13-8.15(1H，m)，8.50(1H，d，J＝3.7Hz).

ESI-MSm/z：380(M+H)⁺.

Elemental analysis: c₂₀H₂₁N₅O₃ 0.5H₂O

Theoretical value: c, 61.84; h, 5.71; and N, 18.03.

Measured value: c, 61.69; h, 5.60; n, 17.74.

[ example 156]1- [1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (265mg, 82%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carboxylic acid (250mg) and N-methylpiperazine (0.0983ml) of reference example 145.

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.36(3H，s)，2.46-2.51(4H，m)，3.85(2H，m)，3.95(3H，s)，4.09(2H，m)，6.73-6.75(1H，m)，7.05-7.07(1H，m)，7.08(1H，s)，7.27-7.28(1H，m)，7.57-7.60(1H，m)，8.11(1H，d，J＝2.4Hz)，8.36(1H，d，J＝4.8Hz).

EI-MSm/z：392(M⁺).

Elemental analysis: c₂₁H₂₄N₆O₂ 0.5H₂O

Theoretical value: c, 62.83; h, 6.28; and N, 20.93.

Measured value: c, 63.09; h, 6.18; n, 20.67.

[ example 157]1- [1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

The title compound (204mg, 57%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methyl-2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 145 and N-methylpiperazin-2-one trifluoroacetate (313mg) of reference example 91.

¹H-NMR(400MHz，CDCl₃)δ：2.37(3H，s)，3.03(3H，s)，3.48(2H，m)，3.96(3H，s)，4.05(1H，m)，4.44(2H，m)，4.85(1H，m)，6.76(1H，d，J＝8.0Hz)，7.07(1H，m)，7.16(1H，m)，7.27-7.30(1H，m)，7.56-7.62(1H，m)，8.02-8.14(1H，m)，8.35(1H，d，J＝4.8Hz).

EI-MSm/z：406(M⁺).

Elemental analysis: c₂₁H₂₂N₆O₃ 0.5H₂O

Theoretical value: c, 60.71; h, 5.58; n, 20.23.

Measured value: c, 60.83; h, 5.55; n, 20.19.

[ example 158]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] piperidine-2-carboxamide

The title compound (198mg, 59%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (231mg) of reference example 33 and piperidine-2-carboxamide (150mg) of reference example 131.

¹H-NMR(400MHz，CDCl₃)δ：1.49-1.88(5H，m)，2.36(1H，dd，J＝30.0，13.6Hz)，2.80-2.87(1/2×1H，m)，3.15-3.22(1/2×1H，m)，3.96(3H，s)，4.70-4.79(1H，m)，5.33-5.44(2H，m)，6.37(1/2×1H，br s)，6.76(1H，dd，J＝8.6，4.9Hz)，7.12(1/2×1H，br s)，7.15(1H，d，J＝15.7Hz)，7.24-7.27(1H，m)，7.42(1H，dd，J＝12.0，7.8Hz)，7.56(1H，dd，J＝25.6，8.7Hz)，7.70-7.75(1H，m)，8.11(1H，d，J＝17.4Hz)，8.54(1H，s).

ESI-MSm/z：407(M+H)⁺.

[ example 159]1- [1- (6-methoxy-3-pyridyl) -5- (5-methyl-2-pyridyl) pyrazole-3-carbonyl ] -4-methyl-3-oxopiperazine

The title compound (156mg, 46%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (5-methyl-2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 146 and N-methylpiperazin-2-one trifluoroacetate (313mg) of reference example 91.

¹H-NMR(400MHz，CDCl₃)δ：2.34(3H，s)，3.02(3H，s)，3.47(2H，m)，3.96(3H，s)，4.04(1H，m)，4.43(2H，m)，4.84(1H，m)，6.76(1H，d，J＝8.8Hz)，7.15(1H，m)，7.27(1H，m)，7.51-7.62(2H，m)，8.08-8.13(1H，m)，8.35(1H，m).

EI-MSm/z：406(M⁺).

[ example 160]4- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -1, 4-oxazepan

The title compound (215mg, 66%) was obtained as a solid in the same manner as in example 20 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 33 and 1, 4-oxazepan hydrochloride (173mg) of reference example 149.

¹H-NMR(400MHz，DMSO-d₆)δ：1.86(2H，br)，3.70(6H，m)，3.87(3H，s)，3.96(2H，m)，6.87(1H，d，J＝8.67Hz)，7.19(1H，s)，7.35(1H，m)，7.68(2H，m)，7.87(1H，t，J＝7.81Hz)，8.15(1H，s)，8.45(1H，d，J＝4.64Hz).

FAB-MSm/z：380(M+H)⁺.

Elemental analysis: c₂₀H₂₁N₅O₃ 0.5H₂O

Theoretical value: c, 61.84; h, 5.71; and N, 18.03.

Measured value: c, 62.12; h, 5.49; and N, 17.89.

[ example 161]1- [1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carbonyl ] -4-methylpiperazine

1) The title Compound

The title compound (136mg, 42%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (4-methoxy-2-pyridyl) pyrazole-3-carboxylic acid (250mg) of reference example 158 and N-methylpiperazine (0.105 ml).

¹H-NMR(400MHz，CDCl₃)δ：1.99-2.07(2H，m)，2.39(1/2×3H，s)，2.41(1/2×3H，s)，2.61-2.67(2H，m)，2.76-2.77(2H，m)，3.80-4.10(10H，m)，6.73-6.77(2H，m)，6.96-6.99(1H，m)，7.09(1/2×1H，s)，7.11(1/2×1H，s)，7.55-7.60(1H，m)，8.13(1H，d，J＝2.8Hz)，8.32-8.34(1H，m).

EI-MSm/z：422(M⁺).

2) Hydrochloride salt of the title compound

Using the above title compound (132mg), the hydrochloride of the title compound (140mg, 82%) was obtained as a solid in the same manner as in 2) of example 29.

¹H-NMR(400MHz，DMSO-d₆)δ：2.14-2.34(2H，m)，2.78-2.80(3H，m)，3.18-3.26(1.5H，m)，3.35-3.95(5H，m)，3.88(3H，s)，4.06-4.19(1H，m)，4.50-4.54(0.5H，m)，6.87(1H，dd，J＝8.9，3.5Hz)，7.04-7.06(1H，m)，7.28-7.33(2H，m)，7.70-7.72(1H，m)，8.20(1H，dd，J＝17.1，2.7Hz)，8.33-8.36(1H，m).

EI-MSm/z：422(M⁺).

[ example 162]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] hexahydropyridazine

The title compound (1.61g, 87%) was obtained in an amorphous state in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (1.495g) of reference example 33 and hexahydropyridazine (0.629g) of reference example 156.

¹H-NMR(400MHz，CDCl₃)δ：1.60-1.90(4H，m)，2.95-3.10(2H，m)，3.80-3.90(1/3×1H，m)，3.95(2/3×3H，s)，3.97(1/3×3H，s)，4.20-4.27(2/3×1H，m)，6.75(1H，d，J＝8.8Hz)，7.17(1H，s)，7.20-7.75(5H，m)，8.12(1H，br)，8.5(1H，br).

FAB-MSm/z：365(M+H)⁺.

[ example 163]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -2-acetylhexahydropyridazine

Triethylamine (0.210ml), acetyl chloride (0.0807ml) and 4-dimethylaminopyridine (13.5mg) were added to a solution of 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] hexahydropyridazine (0.275g) prepared in example 162 in methylene chloride (6.0ml) at room temperature, and the mixture was stirred for 20 minutes. Then, water and chloroform were added to the reaction mixture to separate the mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.149g, 59%) in an amorphous state.

¹H-NMR(400MHz，CDCl₃)δ：1.65-1.90(3H，m)，2.13(3H，s)，2.52(1H，br)，2.84-3.02(2H，m)，3.93(3H，s)，4.60-4.85(7/8×2H，m)，5.20-5.40(1/8×2H，m)，6.76(1H，d，J＝8.8Hz)，7.15-7.80(5H，m)，8.02(1H，br)，8.53(1H，br).

ESI-MSm/z：407(M+H)⁺.

[ example 164]1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] hexahydropyridazine-2-carboxamide

Trimethylsilyl isocyanate (0.920ml) was added to a solution of 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] hexahydropyridazine (0.397g) in 1, 4-dioxane (3ml) in example 162 at room temperature, and the mixture was stirred in a sealed tube at an external temperature of 110 ℃ for 4 days. After air-cooling, methanol was added to the reaction mixture, the reaction solvent was evaporated under reduced pressure, a saturated aqueous sodium bicarbonate solution and a chloroform-methanol (20: 1) mixed solvent were added to the obtained residue to separate the mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.122g, 25%) as a solid.

¹H-NMR(400MHz，CDCl₃) δ: 1.60-1.90(4H, m), 2.84-3.13(2H, m), 3.93(3H, s), 4.42(1H, d-like, J ═ 12.4Hz), 4.62-4.73(1H, br), 5.51(2H, br), 6.73(1H, d, J ═ 8.7Hz), 7.08(1H, s), 7.20-7.26(1H, m), 7.33(1H, d-like, J ═ 7.8Hz), 7.62(1H, dd, J ═ 8.8, 2.7Hz), 7.65-7.72(1H, m), 8.06(1H, d, J ═ 2.4Hz), 8.48-8.54(1H, m).

ESI-MSm/z：408(M+H)⁺.

[ example 165]1- [1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -4-formylpiperazine

The title compound (0.249g, 77%) was obtained as a solid in the same manner as in example 20 using 1- (6-methoxy-3-pyridazinyl) -5- (2-pyridyl) pyrazole-3-carboxylic acid (0.246g) of referential example 139 and N-formylpiperazine (0.185 ml).

¹H-NMR(400MHz，CDCl₃)δ：3.42-3.55(2H，m)，3.61-3.72(2H，m)，3.80-3.90(2H，m)，4.10-4.24(2H，m)，4.12(3H，s)，7.12-7.27(3H，m)，7.59(1H，d，J＝8.1Hz)，7.70-7.81(2H，m)，8.13(1H，br)，8.40(1H，d，J＝4.6Hz).

ESI-MSm/z：394(M+H)⁺.

EXAMPLE 166 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] -2-formyl hexahydropyridazine

To a solution of 1- [1- (6-methoxy-3-pyridyl) -5- (2-pyridyl) pyrazole-3-carbonyl ] hexahydropiperazine (0.203g) in N, N-dimethylformamide (4.0ml) obtained in example 162 were added 4-dimethylaminopyridine (0.142g) and trifluoromethanesulfonic anhydride (0.140ml) at 0 ℃ and the mixture was stirred for 20 minutes. Then, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture to separate the mixture, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (65.5mg, 30%) as a solid.

¹H-NMR(400MHz，CDCl₃)δ：1.65-2.00(4H，m)，2.86-3.10(1H，m)，3.94(3H，s)，4.41-4.51(1H，br)，4.85(1H，br)，6.76(1H，d，J＝8.8Hz)，7.12-7.30(2H，m)，7.47(1H，d，J＝8.8Hz)，7.52-7.63(1H，m)，7.67-7.76(1H，m)，8.02(1H，br)，8.34(1H，br)，8.50-8.55(1H，m).

FAB-MSm/z：393(M+H)⁺.

[ example 167]1- [1- (6-methoxy-3-pyridyl) -5- (pyrrol-2-yl) pyrazole-3-carbonyl ] -4-methylpiperazine

The title compound (218mg, 76%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (pyrrol-2-yl) pyrazole-3-carboxylic acid (222mg) of reference example 159 and N-methylpiperazine (0.156 ml).

¹H-NMR(400MHz，CDCl₃)δ：2.33(3H，s)，2.44-2.52(4H，m)，3.83-3.85(2H，m)，3.99(3H，s)，4.11-4.14(2H，m)，5.91-5.93(1H，m)，6.15-6.17(1H，m)，6.80(1H，d，J＝8.8Hz)，6.82-6.84(1H，m)，6.93(1H，s)，7.57(1H，dd，J＝8.8，2.7Hz)，8.26(1H，d，J＝2.7Hz)，8.66(1H，br s).

ESI-MSm/z：367(M+H)⁺.

Elemental analysis: c₁₉H₂₂N₆O₂

Theoretical value: c, 62.28; h, 6.05; n, 22.94.

Measured value: c, 62.08; h, 6.08; n, 22.73.

[ example 168]4- [1- (6-methoxy-3-pyridyl) -5- (pyrrol-2-yl) pyrazole-3-carbonyl ] morpholine

The title compound (212mg, 76%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (pyrrol-2-yl) pyrazole-3-carboxylic acid (222mg) of reference example 159 and morpholine (0.123 ml).

¹H-NMR(400MHz，CDCl₃)δ：3.72-3.75(2H，m)，3.79-3.83(4H，m)，3.99(3H，s)，4.16-4.19(2H，m)，5.92-5.94(1H，m)，6.16-6.18(1H，m)，6.81(1H，d，J＝8.8Hz)，6.82-6.84(1H，m)，6.94(1H，s)，7.56(1H，dd，J＝8.8，2.7Hz)，8.25(1H，d，J＝2.4Hz)，8.50(1H，br s).

ESI-MSm/z：354(M+H)⁺.

[ example 169]4- [1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carbonyl ] morpholine

The title compound (141mg, 55%) was obtained as a solid in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (2-pyrazinyl) pyrazole-3-carboxylic acid (195mg) of example 148 and morpholine (0.123 ml).

¹H-NMR(400MHz，CDCl₃)δ：3.73-3.76(2H，m)，3.79-3.86(4H，m)，3.97(3H，s)，4.15-4.17(2H，m)，6.79(1H，d，J＝8.8Hz)，7.29(1H，s)，7.59(1H，dd，J＝8.9，2.8Hz)，8.12(1H，d，J＝2.7Hz)，8.47-8.48(1H，m)，8.51(1H，d，J＝2.4Hz)，8.73(1H，d，J＝1.5Hz).

ESI-MSm/z：367(M+H)⁺.

[ example 170]1- [1- (6-methoxy-3-pyridyl) -5- (1-methylpyrrol-2-yl) pyrazole-3-carbonyl ] -4-methylpyrazine

The title compound (258mg, 81%) was obtained as a viscous substance in the same manner as in 1) of example 1 using 1- (6-methoxy-3-pyridyl) -5- (1-methylpyrrol-2-yl) pyrazole-3-carboxylic acid (232mg) and N-methylpyrazine (0.156ml) of reference example 161.

¹H-NMR(400MHz，CDCl₃)δ：2.34(3H，s)，2.47-2.53(4H，m)，3.39(3H，s)，3.84-3.86(2H，m)，3.94(3H，s)，4.13-4.16(2H，m)，6.07(1H，dd，J＝3.7，1.7Hz)，6.14(1H，dd，J＝3.7，2.9Hz)，6.69-6.71(2H，m)，6.88(1H，s)，7.42(1H，dd，J＝8.8，2.7Hz)，8.13(1H，d，J＝2.7Hz).

ESI-MSm/z：381(M+H)⁺.

[ test example 1] platelet aggregation inhibitory Effect

As a blood coagulation inhibitor, platelet-rich plasma (PRP) was isolated by collecting human blood using 1/10 volumes of 3.13% sodium citrate and centrifuging at 180g for 10 minutes. After the PRP in the upper layer was separated, the lower layer was centrifuged at 1600g for 10 minutesThe upper Platelet Poor Plasma (PPP) was removed in minutes. Mu.l of a solution of the compound of example was added to 200. mu.l of PRP, and after standing at 37 ℃ for 2 minutes, 2. mu.l of collagen was added to initiate platelet aggregation. The platelet aggregation rate was determined using PAM-12C (SSR engineering). The light transmittance of PPP was defined as 100% of the aggregation value, and the aggregation ratios at each concentration of the example compounds were determined to calculate IC₅₀The value is obtained. The results are shown in Table 1.

[ test example 2] inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)

In the determination of COX-1 and COX-2 inhibitory activity of the compounds of the examples, COX inhibitor screening kits from the cayman chemical Company (Cat. No. 560101, 560121) were used.

Before the measurement, reaction buffer, hemoglobin, arachidonic acid, and SnCl were prepared₂EIA buffer, wash buffer, EIA standard for Prostaglandin (PG) screening, acetylcholinesterase (AchE) for PG screening, tracer (chromogenic enzyme HRP conjugate), EIA antiserum for PG screening.

(1) PGF production Using COX-1 or COX-2₂α

After allowing the reaction solution containing the compound of example (50. mu.M) and COX-1 or COX-2 to stand at 37 ℃ for 10 minutes, 10. mu.l of arachidonic acid was added and allowed to stand at 37 ℃ for 2 minutes. After the reaction, 50. mu.l of 1N-hydrochloric acid was added to stop the reaction, and 100. mu.l of SnCl was added₂The solution was allowed to stand at room temperature for 5 minutes.

(2) PGF Using ELISA₂Quantification of alpha

50 μ l of antiserum (rabbit anti-PGF) was added to each well of a 96-well microplate coated with mouse anti-rabbit IgG₂Alpha antibody), the above PGF-producing compounds are added sequentially₂The reaction solution of α was diluted to 50 μ l of a 2000-fold solution and 50 μ l of an AchE tracer, and allowed to stand at room temperature for 18 hours. After 5 washes of each well with wash buffer to remove excess AchE tracer, 200 μ l Ellman's reagent was added. After standing in a dark room for 60 minutes, absorbance at 405nm was measured.

(3) Calculation of inhibitory Activity of the Compounds of the examples

The EIA standard solution used for PG screening was used to prepare a calibration curve, and PGF was determined from the absorbance₂Alpha production. The inhibition rate of COX-1 or COX-2 was calculated at 50. mu.M of the example compounds. The results are shown in Table 1.

In the calculation of the inhibition ratio, PGF calculated using the reaction solution not containing the compound of example₂The amount of α produced was taken as 100%.

TABLE 1

Compound (I)	Inhibition of collagen-induced platelet aggregation IC(μM)	COX-1 inhibitory Effect at 50. mu.M (% inhibition)	COX-2 inhibitory Effect at 50. mu.M (% inhibition)
				23	0.17	-1.2	3.4
27	0.27	0.5	-0.1
				36	0.14	ND	ND
55	0.035	ND	ND
				62	0.12	-2.4	-2.6
70	0.26	ND	ND
				122	0.75	1	4.5
132	0.4	2.7	10.5
				139	0.042	7.6	3.4
140	0.11	ND	ND
				144	0.44	9.7	8.8
148	0.09	ND	ND
				160	0.17	ND	ND
163	0.09	ND	ND
				167	0.029	ND	ND
168	0.017	ND	ND

ND: not determined

As is apparent from Table 1, the compounds (I) and (II) of the present invention, their salts or solvates of their salts have potent platelet aggregation inhibitory effects, and do not exhibit COX-1 and COX-2 inhibitory effects.

Claims (11)

1. General formula (I)

The compound represented by (I), or a salt thereof,

in the formula, Ar₁Represents having a structure selected from C_1～6Alkyl, halogen atom, C_1～6Alkoxy and C_1～6Pyridyl, pyridazinyl or pyrazinyl with 1 to 3 substituents in the alkylamino radical, Ar₂Represents unsubstituted or has a substituent selected from C_1～6Alkyl, halogen, hydroxy, cyano, C_1～6Alkoxy, benzyloxy, C_1～6Alkylthio, carboxyl, C_1～6Alkylsulfonyl radical, C_1～6Alkylamino radical, di (C)_1～6Alkyl) amino, carbamoyl, C_1～6A pyridyl group, a pyridazinyl group, a pyrazinyl group, a pyrrolyl group or a phenyl group having 1 to 3 substituents of a haloalkyl group and a 4-to 7-membered alicyclic heterocyclic group, wherein R1 is represented by the following general formula (1)

Wherein the cyclic structure A represents an azetidine ring, a pyrrolidine ring, an imidazolidine ring, a pyrazoline ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, a hexahydropyridazine ring, a hexahydropyrimidine ring, a homopiperazine ring, or an azepin ring, X represents a carbonyl group, R3 represents that the cyclic structure A has a structure selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, and C_1～6Alkoxy radical, C_1～6Alkoxycarbonyl, carboxyl, C_1～6Alkyl, amino, having 1 or 2C atoms_1～6Alkyl-substituted amino, carbamoyl, optionally having 1 or 2C_1～6Alkyl-substituted carbamoyl, C _1～6Acyl, oxo, 3-6 membered spiro alicyclic alkyl or phenyl, amino, C_1～6Alkylamino, hydroxy or C_1～6C of 1 or 2 substituents of alkoxy_1～6Alkyl, R2 represents a hydrogen atom, a halogen atom, C_1～6Alkyl, or C having 1 or 2 or less substituents_1～6Alkyl groups: phenyl, amino, C_1～6Alkylamino, hydroxy or C_1～6An alkoxy group.

2. The compound according to claim 1, or a salt thereof, wherein Ar is Ar₁Is selected from C_1～6Alkyl, halogen atom, C_1～6Alkoxy and C_1～6Pyridyl or pyridazinyl having 1 to 3 substituents on the alkylamino group.

3. A compound according to claim 1 or 2, or a salt thereof, wherein Ar is₂Is unsubstituted or has a substituent selected from C_1～6Alkyl, halogen, hydroxy, cyano, C_1～6Alkoxy, benzyloxy, C_1～6Alkylthio, carboxyl, C_1～6Alkylsulfonyl radical, C_1～6Alkylamino radical, di (C)_1～6Alkyl) amino, carbamoyl, C_1～6A halogenated alkyl group and a pyridyl group having 1 to 3 substituents in a 4 to 7-membered alicyclic heterocyclic group.

4. A compound according to claim 1 or 2, or a salt thereof, of the formula

The group represented is a group selected from the group consisting of 3-dimethylaminoazetidin-1-yl, 2-dimethyl-3-dimethylaminoazetidin-1-yl, 2-hydroxymethylazetidin-1-yl, 2-carbamoylazetidin-1-yl, 2-oxopyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 2-carbamoylpyrrolidinyl, 2-hydroxymethylpiperidinyl, 2-carbamoylpiperidinyl, 2-methylcarbamoylpiperidinyl, 2-dimethylcarbamoylpiperidinyl, 3-oxo-4-methylpiperidinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-isopropylpiperazinyl, 4-cyclopropylpiperazinyl, methyl-piperazinyl, methyl-1-yl, methyl-2-pyrrolidinyl, methyl-1-yl, methyl-2-piperidinyl, methyl-4-, 2, 4-dimethylpiperazinyl, 3-cyclopropyl-4-methylpiperazinyl, 3, 4, 5-trimethylpiperazinyl, 2, 4-trimethylpiperazinyl, 3, 4-trimethylpiperazinyl, 2-cyclopropanespiro-4-methylpiperazinyl, morpholinyl, 3-carbamoylmorpholinyl, 1-dioxothiomorpholinyl, 2-methylhexahydropyridazin-1-yl, 3-oxo-4-methylpiperazinyl, 5-oxo-4-methylpiperazinyl, 4-ethylhomopiperazinyl, 4-cyclopropylhomopiperazinyl, 1, 4-oxazepan-4-yl, piperidinyl, 4-methoxypiperidinyl, thiomorpholinyl, 4-difluoropiperidinyl, 3-difluoropiperidinyl, 4-fluoropiperidinyl, 2-dimethylaminomethylpyrrolidinyl, 3-dimethylaminopyrrolidinyl, 3-methyl-4-oxoimidazolidin-1-yl, 3-methoxypyrrolidinyl, 2-acetylhexahydropyridazin-1-yl and 2-carbamoylhexahydropyridazin-1-yl.

5. A compound represented by any one of the following formulae (1) to (17), or a salt thereof,

6. a compound represented by the following formula (18) or a salt thereof,

7. a pharmaceutical comprising the compound according to any one of claims 1 to 6, or a salt thereof.

8. An agent for preventing and/or treating ischemic diseases, which comprises the compound according to any one of claims 1 to 6 or a salt thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a salt thereof and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 6, or a salt thereof, in the preparation of a medicament.

11. The use according to claim 10, further characterized in that the medicament is for the treatment of ischemic diseases.