KR20070031958A - Pyrazole derivatives - Google Patents

Abstract

[Formula I]

In the formula, Ar ₁ represents a phenyl group having 1 or 3 substituents or no unsubstituted 5 or 6 membered aromatic heterocyclic group; Ar ₂ is a phenyl group substituted with a lower alkyl group having 1 to 3 groups or atoms selected from (i) an unsubstituted phenyl group, (ii) a carbamoyl group, an amino group, a hydroxyl group, a lower alkoxy group and a halogen atom, or (iii 5 or 6 membered nitrogen aromatics substituted with 1 to 3 groups or atoms selected from lower alkyl groups, lower alkynyl groups, lower alkanoyl groups, carbamoyl groups, cyano groups, amino groups, hydroxyl groups, lower alkoxy groups and halogen atoms Heterocyclic group; X is formula II

[Formula II]

(The cyclic structure in the formula is a lower alkyl group, carbamoyl group, amino group, hydroxyl group, lower alkoxy group, which does not have one hetero atom selected from nitrogen atom, oxygen atom and sulfur atom as a member other than the nitrogen atom described in the above formula), And a 4-7 membered heterocyclic group which may be substituted with 1-4 groups or atoms selected from an oxo group, a lower alkanoyl group, a lower alkylsulfonyl group, and a halogen atom.).

Compounds represented by them, salts thereof or solvates thereof, and medicines.

Platelet aggregation inhibitory effect, pyrazole derivatives, COX-1, COX-2, solvates, medicines

Description

Pyrazole derivatives

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

Platelets aggregate during blood vessel damage and form a hemostatic thrombus, which plays an important role in preventing bleeding. On the other hand, platelets aggregate and clot in areas where blood vessel endothelium is damaged or narrowed. Or embolus. These blood clots and embolisms cause an ischemic disease such as myocardial infarction, angina pectoris, ischemic cerebrovascular disorder, or peripheral vascular disorder. Therefore, platelet aggregation inhibitor is used for the prevention and treatment of an ischemic disease. Among them, low-dose aspirin has been used as a platelet aggregation inhibitor for a long time, and its effect has been proved by APT (Antiplatelet Trialists' Collaboration) which meta-analyzes the results of a plurality of clinical trials administered to 100,000 patients. (See Nonpatent Literature 1).

However, aspirin is known to cause side effects such as gastrointestinal bleeding and so-called aspirin ulcers, and the side effects occur at a rate of 100 to 1 person, depending on the dose (see Non-Patent Document 2).

It is known that aspirin inhibits platelet aggregation due to the inhibitory effect of cyclooxygenase. Cyclooxygenases include cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Aspirin aggregates platelets by selectively and irreversibly inhibiting COX-1 at low doses. , But inhibiting COX-1 also causes aspirin ulcers (see Non-Patent Documents 3 and 4). In addition, it is known that nonsteroidal antiinflammatory drugs exhibit anti-inflammatory action by selectively inhibiting COX-2.

As mentioned above, although aspirin is useful as a platelet aggregation inhibitor, since a gastrointestinal disorder resulting from COX-1 inhibitory action which is its action mechanism is accompanied as a side effect, a platelet aggregation inhibitor without COX-1 inhibitory action is required. It is becoming.

On the other hand, compound (A) (refer patent document 1 and nonpatent literature 5) and compound (B) (refer patent document 2) are known as a pyrazole derivative which has an antithrombotic action so far.

Patent Document 1: Japanese Patent No. 2586713

Patent Document 2: International Publication No. 97/29774 Pamphlet

Non Patent Literature 1: BMJ, Vol. 308, pp. 81-106, 1994

Non-Patent Document 2: BMJ, Vol. 321, pp. 1183-1187, 2000

[Non-Patent Document 3] Neurology, 57, Suppl. 2, pages S5-S7, 2001

Non-Patent Document 4: Drugs Today, 35, 251-265, 1999

[Non-Patent Document 5] Chem. Pharm. Bull., Vol. 45, pp. 987-995, 1997

Disclosure of the Invention

Problems to be Solved by the Invention

However, the IC ₅₀ value for collagen-induced platelet aggregation of compound (A) is 5.3 × 10 ⁻⁶ M, which shows a stronger inhibitory activity for COX-2 (IC ₅₀ value 2.4 × 10 ⁻⁷ M). Similarly, the platelet aggregation inhibitory effect of Compound (B) is not as strong as its inhibitory activity against COX-2. As described above, since inhibition of COX-2 leads to anti-inflammatory action, having COX-2 inhibitory activity is not necessarily preferred as a platelet aggregation inhibitor. An object of the present invention is to provide a potent platelet aggregation inhibitor that does not inhibit COX-1 and COX-2.

Means to solve the problem

The present inventors have conducted extensive studies to obtain such platelet aggregation inhibitors, and have found that the pyrazole derivatives represented by the following general formula (I) exhibit potent platelet aggregation inhibitory activity without inhibiting COX-1 and COX-2. The present invention has been completed.

That is, the present invention is formula (I)

[Formula I

In the formula, Ar ₁ represents a phenyl group having 1 or 3 substituents or no unsubstituted 5 or 6 membered aromatic heterocyclic group; Ar ₂ has 1 to 3 groups or atoms selected from (i) an unsubstituted phenyl group, (ii) a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted amino group, a hydroxyl group, a lower alkoxy group and a halogen atom A phenyl group substituted with a lower alkyl group, or (iii) a substituted or unsubstituted lower alkyl group, lower alkynyl group, lower alkanoyl group, substituted or unsubstituted carbamoyl group, cyano group, substituted or unsubstituted amino group, hydroxyl group, substituted A 5- or 6-membered aromatic heterocyclic group substituted with 1 to 3 groups or atoms selected from optionally substituted lower alkoxy groups and halogen atoms; X is formula II

[Formula II]

(The cyclic structure in the formula is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted alkyl group, which does not or does not have one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom as a member other than the nitrogen atom described in the above formula. Substitution with 1 to 4 groups or atoms selected from den, substituted or unsubstituted carbamoyl groups, substituted or unsubstituted amino groups, hydroxyl groups, lower alkoxy groups, oxo groups, lower alkanoyl groups, lower alkylsulfonyl groups and halogen atoms 4-7 membered heterocyclic group which may be used.)]

Provided are compounds, salts thereof, or solvates thereof.

The present invention also provides a medicament comprising the above compounds, salts or solvates thereof as an active ingredient; Prophylactic and / or therapeutic agents for ischemic diseases comprising the above compounds, salts or solvates thereof as active ingredients; Platelet aggregation inhibitors comprising the above compounds, salts or solvates thereof as an active ingredient; The pharmaceutical composition containing the said compound, its salt, or their solvate is provided.

The present invention also provides a method for preventing and / or treating ischemic disease, characterized by administering an effective amount of the above compounds, salts or solvates thereof.

The present invention furthermore provides the use of the compounds, salts thereof or solvates thereof for the production of prophylactic and / or therapeutic agents for ischemic diseases.

Effects of the Invention

Compound (I), salts thereof, or solvates thereof of the present invention have a function of inhibiting platelet aggregation strongly without inhibiting COX-1 and COX-2, and inhibiting thrombus formation. Thus, myocardial infarction, angina (chronic stable angina, unstable angina, etc.), ischemic cerebrovascular disorders (transient cerebral ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disorders, obstruction after artificial blood vessel replacement, coronary artery intervention ( Thrombotic occlusion after coronary artery bypass grafting (CAGB), percutaneous transluminal coronary angioplasty (PTCA), stent placement, diabetic retinopathy, nephropathy, artificial It is useful as a prophylactic and / or therapeutic drug for ischemic diseases caused by thrombosis and embolism such as occlusion when replacing an artificial heart valve. It is also useful as a prophylactic and / or therapeutic agent for thrombosis and embolism associated with vascular surgery, extracorporeal blood circulation and the like. Moreover, it is also useful for improving hypotension symptoms such as ulcers, pain, and coldness associated with chronic arterial occlusion.

Best Mode for Carrying Out the Invention

Formula (I) is described below.

Ar ₁ represents a substituted or unsubstituted phenyl group or an unsubstituted 5 or 6 membered aromatic heterocyclic group.

Examples of the substituent for the phenyl group include an amino group, a hydroxyl group, a lower alkoxy group, and a halogen atom, which are unsubstituted or substituted with a lower alkyl group, cyano group, one or two lower alkyl groups which are the same or different. The number of substituents is one or two or three which are the same or different, and one is preferable. Moreover, the p position is preferable for the substitution position.

Lower alkyl group herein means a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, cyclopropyl group and cyclo A butyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclopentylmethyl group, etc. are mentioned. Among these, a methyl group, an ethyl group or n-propyl group is preferable, and a methyl group is especially preferable.

An amino group which is unsubstituted or substituted with one or the same or different two lower alkyl groups means an unsubstituted amino group or an amino group substituted with the lower alkyl group. Specifically, methylamino group, ethylamino group, n-propylamino group, dimethylamino group, diethylamino group, N-methyl-N-ethylamino group, etc. are mentioned.

Lower alkoxy group means the alkoxy group which contains the said lower alkyl group in the structure. Specifically, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentoxy group, cyclopentyloxy group, etc. are mentioned. Among these, a methoxy group or an ethoxy group is preferable and a methoxy group is particularly preferable.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Among them, fluorine or chlorine is preferable, and fluorine is particularly preferable.

When Ar ₁ is a phenyl group, it is preferable to have one substituent in the unsubstituted or p position.

Specifically as a 5 or 6 membered aromatic heterocyclic group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a furyl group, a tier And a silyl group, an oxazolyl group, an isoxazolyl group and a thiazolyl group. Among these, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, oxazolyl group, thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group are preferable, and especially pyrrolyl group and pyrazol group A zolyl group, imidazolyl group, thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group is preferable. Moreover, thiazolyl group, pyridyl group, pyridazinyl group or pyrimidinyl group is most preferable.

Next, Ar ₂ will be described.

When Ar <_2> is a phenyl group, unsubstituted may be sufficient and may be substituted by the lower alkyl group which has a substituent. The lower alkyl group having a substituent in this case means a lower alkyl group substituted with one or the same or different 2-3 groups or atoms selected from 1) to 5) described below. Here, the lower alkyl group is the same as the lower alkyl group defined as the substituent on Ar ₁ .

1) Carbamoyl group not substituted or substituted with one or the same or different two lower alkyl groups: The carbamoyl group means an unsubstituted carbamoyl group or a carbamoyl group substituted with 1-2 lower alkyl groups. . Specifically, methyl carbamoyl group, ethyl carbamoyl group, dimethyl carbamoyl group, N-methyl-N-ethyl carbamoyl group, etc. are mentioned. Among these, an unsubstituted carbamoyl group, methyl carbamoyl group or dimethyl carbamoyl group is preferable.

2) An amino group which is unsubstituted or substituted with one or the same or different two substituents selected from a lower alkyl group, a lower alkanoyl group and a lower alkylsulfonyl group: the amino group is an unsubstituted amino group or a lower alkyl group or a lower alkano. Amino group substituted with one or the same or different two substituents selected from diary and lower alkylsulfonyl groups.

Lower alkyl group means the lower alkyl group.

Lower alkanoyl group means a linear or branched alkanoyl group having 1 to 6 carbon atoms. Specifically, a formyl group, an acetyl group, n-propionyl group, n-butyryl group, isobutyryl group, etc. are mentioned.

Lower alkylsulfonyl group means a sulfonyl group substituted with the lower alkyl group. Specifically, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group , A cyclopropyl sulfonyl group, a cyclohexyl sulfonyl group, and the like.

Accordingly, the amino group selected from one or the same or different two substituents selected from the group consisting of lower alkyl group, lower alkanoyl group and lower alkylsulfonyl group includes methylamino group, ethylamino group, n-propylamino group, isopropylamino group, Cyclopropylamino group, n-butylamino group, isobutylamino group, cyclopentylmethylamino group, dimethylamino group, diethylamino group, di n-propylamino group, di n-butylamino group, N-methyl-N-ethylamino group, N-ethyl- Nn-propylamino group, N-methyl-N-cyclopentylmethylamino group, formylamino group, acetylamino group, n-propionylamino group, N-methyl-N-acetylamino group, N-ethyl-N-acetylamino group, methylsulfonyl Amino group, ethylsulfonylamino group, isopropylsulfonylamino group, n-butylsulfonylamino group, cyclopropylsulfonylamino group, cyclobutanesulfonylamino group, N-meth -N- and methyl sulfonyl amino group, N- ethyl -N- methyl sulfonylamino group.

3) hydroxyl

4) Lower Alkoxy Group: The lower alkoxy group means the same alkoxy group as the lower alkoxy group described as the substituent on Ar ₁ , that is, the lower alkyl group in its structure. Specifically, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, n-pentoxy group, cyclopentyloxy group, etc. are mentioned. Among these, a methoxy group or an ethoxy group is preferable and a methoxy group is particularly preferable.

5) Halogen atom: As a halogen atom, fluorine, chlorine, bromine, and iodine are mentioned similarly to the above. Among them, fluorine or chlorine is preferable, and fluorine is particularly preferable.

Therefore, when Ar ₂ is a phenyl group, typical examples of the substituent on the phenyl group include carbamoylmethyl group, methyl carbamoylmethyl group, dimethylcarbamoylmethyl group, N-methyl-N-ethylcarbamoylmethyl group, carbamoylethyl group, methylcarbamoylethyl group, Dimethylcarbamoylethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, ethylaminomethyl group, diethylaminomethyl group, N-methyl-N-ethylaminomethyl group, aminoethyl group, methylaminoethyl group, dimethylaminoethyl group, formylaminomethyl group , Acetylaminomethyl group, formylaminoethyl group, acetylaminoethyl group, N-methyl-N-acetylaminomethyl group, N-ethyl-N-acetylaminomethyl group, methylsulfonylaminomethyl group, ethylsulfonylaminomethyl group, isopropylsulfonyl Aminomethyl group, n-butylsulfonylaminomethyl group, cyclopropylsulfonylaminomethyl group, cyclobutanesulfonylaminomethyl group, N-methyl-N-methylsul Nylaminomethyl group, N-ethyl-N-methylsulfonylaminomethyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropionyl group, methoxymethyl group, methoxyethyl group, ethoxymethyl group, ethoxyethyl group, fluoromethyl group, Difluoromethyl group, a trifluoromethyl group, etc. are mentioned.

When Ar <_2> is a phenyl group, it is preferable that the said substituent is substituted in one p position with respect to the bond to an unsubstituted or pyrazole ring.

When Ar <_2> is a 5 or 6 membered aromatic heterocyclic group, this aromatic heterocyclic group is substituted by 1 or the same or different 2-3 group or atom selected from following (a)-(i). In this case, as a 5 or 6 membered aromatic heterocycle, a 5 or 6 membered nitrogen-containing aromatic heterocyclic group is preferable, and as a nitrogen-containing aromatic heterocyclic group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, an oxa A sleepy group, a thiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a furyl group, a thienyl group, an isoxazolyl group, etc. are mentioned. Among these, pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, oxazole group, thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group are preferable, and especially pyrrolyl group and pyrazol group A zolyl group, imidazolyl group, thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group is preferable.

(a) Lower alkyl group: As a lower alkyl group, the same thing as the above is mentioned. Among these, a methyl group, an ethyl group or n-propyl group is preferable, and a methyl group is especially preferable.

Here, the lower alkyl group may further be substituted with one to three atoms selected from 1) to 5) in the same manner as the lower alkyl group as the substituent in the case where Ar ₂ is a phenyl group.

(b) Lower alkynyl group: Lower alkynyl group means a C2-C6 linear, branched or cyclic alkynyl group. Specifically, an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 1-pentynyl group, 2-pentynyl group, etc. are mentioned. Among them, an ethynyl group, a 1-propynyl group or a 2-propynyl group is preferable, and an ethynyl group is particularly preferable.

(c) Lower alkanoyl group: Lower alkanoyl group means the same group as what was mentioned as a substituent in the case where said Ar <_1> is a phenyl group. Among these, an acetyl group or n-propionyl group is preferable, and an acetyl group is particularly preferable.

(d) Carbamoyl group unsubstituted or substituted with one or two lower alkyl groups: The carbamoyl group is the same as the carbamoyl group given as 1) of the substituent on the lower alkyl group when Ar ₂ is a phenyl group. Among these, an unsubstituted carbamoyl group, methyl carbamoyl group or ethyl carbamoyl group is preferable, and an unsubstituted carbamoyl group is particularly preferable.

(e) cyano groups

(f) an amino group which may be substituted with one or the same or different two groups selected from one or two lower alkyl groups, lower alkanoyl groups and lower alkylsulfonyl groups: the amino group is a lower group when Ar ₂ is a phenyl group It is the same as the amino group quoted as 2) of the substituent on the alkyl group. Among these, an unsubstituted amino group, dimethylamino group or diethylamino group is preferable, and an unsubstituted amino group or dimethylamino group is particularly preferable.

(g) hydroxyl group

(h) Substituted or unsubstituted lower alkoxy group: The lower alkoxy group in the substituted or unsubstituted lower alkoxy group is the same as the lower alkoxy group described as the substituent on Ar ₁ , that is, the lower alkyl group is included in its structure. It means an alkoxy group. Specifically, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, n-pentoxy group, cyclopentyloxy group, etc. are mentioned. Among these, a methoxy group or an ethoxy group is preferable and a methoxy group is particularly preferable.

Here, in the lower alkoxy group, a group selected from 1) to 5 or 1 to 3 atoms may be substituted in the same manner as the lower alkyl group as the substituent in the case where Ar ₂ is a phenyl group.

(i) Halogen atom: The above-mentioned thing is mentioned as a halogen atom. Among them, chlorine or fluorine is preferable, and fluorine is particularly preferable.

Specific examples of Ar ₂ which is a 5- or 6-membered nitrogen-containing heterocyclic group having a substituent include methylpyrrolyl group, carbamoylpyrrolyl group, dimethylcarbamoylpyrrolyl group, cyanopyrrolyl group, hydroxypyrrolyl group, methoxypyrrolyl group, Fluoropyrrolyl group, chloropyrrolyl group, aminopyrrolyl group, methylaminopyrrolyl group, dimethylaminopyrrolyl group, hydroxymethylpyrrolyl group, aminomethylpyrrolyl group, methylaminomethylpyrrolyl group, dimethylaminomethylpyrrolyl group, methylpyrazolyl group , Carbamoylpyrazolyl group, dimethylcarbamoylpyrazolyl group, cyanopyrazolyl group, hydroxypyrazolyl group, methoxypyrazolyl group, fluoropyrazolyl group, chloropyrazolyl group, aminopyrazolyl group, methylamino Pyrazolyl group, dimethylaminopyrazolyl group, hydroxymethylpyrazolyl group, aminomethylpyrazolyl group, methylaminomethylpyrazolyl group, dimethylaminomethylpyrazolyl group, methylimidazolyl , Carbamoyl imidazolyl group, dimethyl carbamoyl imidazolyl group, cyanoimidazolyl group, hydroxyimidazolyl group, methoxyimidazolyl group, fluoroimidazolyl group, chloroimidazolyl group, amino Imidazolyl group, methylaminoimidazolyl group, dimethylaminoimidazolyl group, hydroxymethylimidazolyl group, aminomethylimidazolyl group, methylaminomethylimidazolyl group, dimethylaminomethylimidazolyl group, Methyltriazolyl group, carbamoyltriazolyl group, dimethylcarbamoyltriazole group, cyanotriazole group, hydroxytriazole group, methoxytriazolyl group, fluorotriazolyl group, chlorotriazolyl group, aminotriazolyl group, methyl Aminotriazolyl group, dimethylaminotriazolyl group, hydroxymethyltriazolyl group, aminomethyltriazolyl group, methylaminomethyltriazolyl group, dimethylaminomethyltriazolyl group, methylpyri Dyl group, carbamoylpyridyl group, dimethyl carbamoylpyridyl group, cyanopyridyl group, hydroxypyridyl group, methoxypyridyl group, fluoropyridyl group, chloropyridyl group, aminopyridyl group, methylaminopyridyl group, dimethylaminopyridyl group , Hydroxymethylpyridyl group, aminomethylpyridyl group, methylaminomethylpyridyl group, dimethylaminomethylpyridyl group, fluoromethylpyridyl group, methoxymethylpyridyl group, ethynylpyridyl group, acetylpyridyl group, carbamoylmethoxypyrid Dyl group, methylpyridazinyl group, carbamoylpyridazinyl group, dimethylcarbamoylpyridazinyl group, cyanopyridazinyl group, hydroxypyridazinyl group, methoxypyridazinyl group, fluoropyridazinyl group , Chloropyridazinyl group, aminopyridazinyl group, methylaminopyridazinyl group, dimethylaminopyridazinyl group, hydroxymethylpyridazinyl group, aminomethylpyridazinyl group, methylaminomethylpi Dizinyl group, dimethylaminomethylpyridazinyl group, methylpyrimidinyl group, carbamoylpyrimidinyl group, dimethylcarbamoylpyrimidinyl group, cyanopyrimidinyl group, hydroxypyrimidinyl group, methoxypyrimidinyl group, fluoro Pyrimidinyl, chloropyrimidinyl, aminopyrimidinyl, methylaminopyrimidinyl, dimethylaminopyrimidinyl, hydroxymethylpyrimidinyl, aminomethylpyrimidinyl, methylaminomethylpyrimidinyl, dimethylaminomethylpyri Midinyl, methylpyrazinyl, carbamoylpyrazinyl, dimethylcarbamoylpyrazinyl, cyanopyrazinyl, hydroxypyrazinyl, methoxypyrazinyl, fluoropyrazinyl, chloropyrazinyl, Aminopyrazinyl, methylaminopyrazinyl, dimethylaminopyrazinyl, hydroxymethylpyrazinyl, aminomethylpyrazinyl, methylaminomethylpyrazinyl, dime Tylaminomethylpyrazinyl group, methyloxazole group, carbamoyloxazolyl group, dimethyl carbamoyloxazolyl group, cyanooxazolyl group, hydroxyoxazolyl group, methoxyoxazolyl group, fluorooxazolyl group, chlorooxa Zolyl group, aminooxazolyl group, methylaminooxazolyl group, dimethylaminooxazolyl group, hydroxymethyloxazolyl group, aminomethyloxazolyl group, methylaminomethyloxazolyl group, dimethylaminomethyloxazolyl group, methylthiazolyl Group, carbamoylthiazolyl group, dimethylcarbamoylthiazolyl group, cyanothiazolyl group, hydroxythiazolyl group, methoxythiazolyl group, fluorothiazolyl group, chlorothiazolyl group, aminothiazolyl group, methyl Aminothiazolyl group, dimethylaminothiazolyl group, hydroxymethylthiazolyl group, aminomethylthiazolyl group, methylaminomethylthiazolyl group, dimethylaminomethylthiazolyl group and the like.

Among them, especially methylpyrrolyl group, methylpyrazolyl group, methylimidazolyl group, methylpyridyl group, carbamoylpyridyl group, cyanopyridyl group, aminopyridyl group, hydroxypyridyl group, methoxypyridyl group, fluoropyripy Dyl group, chloropyridyl group, hydroxymethylpyridyl group, aminomethylpyridyl group, fluoromethylpyridyl group, methoxymethylpyridyl group, ethynylpyridyl group, acetylpyridyl group, carbamoylmethoxypyridyl group, methoxypyridazinyl Groups, methylpyrazinyl groups, carbamoylpyrazinyl groups or aminopyrazinyl groups are preferred.

Formula (II) means the 4-7 membered heterocyclic group which does not make one hetero atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom other than the nitrogen atom described in Formula (II) as a component.

As a 4-7 membered heterocyclic group, a saturated heterocyclic group is preferable, and an azetidino group, a pyrrolidino group, a piperidino group, a piperazino group, a hexahydropyridazino group, a hexahydropyrimidino group, a pyrazolidino group , Imidazolidino group, homopiperazino group, morpholino group, thiomorpholino group, and the like. Among these, especially an azetidino group, a pyrrolidino group, a piperidino group, a piperazino group, a homopiperazino group, a hexahydropyridazin-1-yl group, a pyrazolidino group or a morpholino group is preferable.

One or the same or different 2 to 4 groups or atoms selected from the substituents of (i) to (x) below may be further substituted on these heterocyclic groups. In addition, when several group or atom is substituted, you may substitute by the same element of the said heterocyclic group, and may substitute by a different element.

(i) Substituted or unsubstituted lower alkyl group: Substituted or unsubstituted lower alkyl group is a group or atom selected from 1) to 5), similarly to the lower alkyl group cited as a substituent when Ar ₂ is a phenyl group. 3 represents a lower alkyl group which may be substituted. In addition, an oxo group may be substituted independently by this lower alkyl group. As a lower alkyl group, the said lower alkyl group is mentioned, Among these, a methyl group or a cyclopropyl group is especially preferable. As group substituted by these lower alkyl groups, a halogeno group, an amino group, or a hydroxyl group is preferable, and a halogeno group or an amino group is more preferable. Therefore, as the substituted or unsubstituted lower alkyl group, in addition to the unsubstituted lower alkyl group, a halogeno lower alkyl group, an amino lower alkyl group, or a hydroxy lower alkyl group is preferable, and an unsubstituted lower alkyl group, halogeno lower alkyl group, amino lower alkyl group is preferable. More preferred. The halogeno lower alkyl group means the lower alkyl group substituted with the halogen atom. Specifically, a fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, etc. are mentioned, Among these, a fluoromethyl group, a difluoromethyl group, or a trifluoromethyl group is mentioned. Preference is given, especially fluoromethyl groups. An amino lower alkyl group means the said lower alkyl group substituted by the amino group, Specifically, an aminomethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-aminocyclopropyl group, etc. are mentioned, Among these, 1-amino is mentioned. Cyclopropyl groups are preferred. The hydroxy lower alkyl group means the lower alkyl group substituted with a hydroxyl group, and specifically, a hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, and 3-hydroxypropyl group. Etc. can be mentioned.

(ii) Substituted or unsubstituted alkylidene group: An alkylidene group means a linear, branched or cyclic alkylidene group having 1 to 6 carbon atoms. Specifically, methylene group, ethylidene group, isopropylidene group, cyclopropylidene group, cyclobutylidene group, cyclohexylidene group, etc. are mentioned. Among these, a methylene group and an ethylidene group are preferable, and a methylene group is especially preferable.

Here, the alkylidene group may be further substituted with one or the same or different two substituents selected from the halogeno group, lower alkanoyl group and lower alkylsulfonyl group.

(iii) Lower alkanoyl group: Lower alkanoyl group means a linear or branched alkanoyl group having 1 to 6 carbon atoms. Specifically, formyl group, acetyl group, n-propionyl group, n-butyryl group, isobutyryl group, pivaloyl group, etc. are mentioned, Among these, a formyl group is especially preferable.

(iv) Carbamoyl groups which are unsubstituted or substituted with one or two lower alkyl groups: the same ones as above. Among these, an unsubstituted carbamoyl group, methyl carbamoyl group or ethyl carbamoyl group is preferable, and an unsubstituted carbamoyl group is particularly preferable.

(v) an amino group which may be substituted with one or the same or different two groups selected from a lower alkyl group, a lower alkanoyl group and a lower alkylsulfonyl group: as the amino group, _two of the substituents on the lower alkyl group when Ar ₂ is a phenyl group The same amino group as e) when the amino group mentioned as) or Ar <_2> is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group. Among these, an unsubstituted amino group, dimethylamino group or diethylamino group is preferable, and an unsubstituted amino group or dimethylamino group is particularly preferable.

(vi) hydroxyl group

(vii) Lower alkoxy group: As a lower alkoxy group, the same thing as the above is mentioned, A methoxy group or an ethoxy group is preferable, Especially a methoxy group is preferable.

(viii) oxo groups

(ix) Lower alkylsulfonyl group: As a lower alkylsulfonyl group, the same thing as the above is mentioned. Among them, methylsulfonyl group, ethylsulfonyl group or n-propylsulfonyl group is preferable.

(x) Halogen atom: The same thing as the above is mentioned. Among them, fluorine or chlorine is preferable, and fluorine is particularly preferable.

One group may be substituted by these (i)-(x), and as long as it can substitute, 2-4 pieces which are the same or different may be substituted. In addition, when a some group is substituted, it may be substituted by the same element of the said heterocyclic group, and may be substituted by a different element.

As the general formula (II), for example, 3-aminoazetidin-1-yl group, 3-methylaminoazetidin-1-yl group, 3-dimethylaminoazetidin-1-yl group, 3,3-difluoroazetidine- 1-yl group, 3-methoxyazetidin-1-yl group, 2-fluoromethylpyrrolidino group, 3-fluoropyrrolidino group, 3-methoxypyrrolidino group, 2-hydroxymethylpyrrolidino Group, 2-methoxymethylpyrrolidino group, 2-carbamoyl pyrrolidino group, 2-methyl carbamoyl pyrrolidino group, 2-dimethyl carbamoyl pyrrolidino group, 3-carbamoyl pyrrolidino group, 3-methylcarbamoylpyrrolidino group, 3-dimethylcarbamoylpyrrolidino group, 2-methoxymethyl-5-methylpyrrolidino group, 3-aminopiperidino group, 4-aminopiperidino group, 3- Methylaminopiperidino group, 4-methylaminopiperidino group, 3-dimethylaminopiperidino group, 4-dimethylaminopiperidino group, 2-methylpiperidino group, 3-methylpiperidino group, 4-methylpiperidino group , 2,2- Methyl piperidino group, 3,3-dimethyl piperidino group, 4,4-dimethyl piperidino group, 4-fluoromethyl piperidino group, 2- (1-aminocyclopropyl) piperazino group, 2-carbamoyl pipe Lidino group, 3-carbamoyl piperidino group, 4-carbamoyl piperidino group, 2-methyl carbamoyl piperidino group, 3-methyl carbamoyl piperidino group, 4-methyl carbamoyl piperidino group, 2-dimethylcarba Moylpiperidino group, 3-dimethylcarbamoylpiperidino group, 4-dimethylcarbamoylpiperidino group, 3-fluoropiperidino group, 4-fluoropiperidino group, 4,4-difluoropiperidino group, 4,4-difluoro-2-carbamoyl piperidino group, 4-methylene piperidino group, 4- (difluoromethylene) piperidino group, 4-methoxy piperidino group, 4-methyl piperazino group, 4-cyclopropylpiperazino group, 2-carbamoyl-4-methylpiperazino group, 3-oxo-4-methylpiperazino group, 3-oxo-4-ethylpiperazino group, 4,6-di Methyl-3-oxopiperazino group, 3,5-dioxo-4-methylpiperazino group, morpholino group, 2,2-dimethylmorpholino group, 3,3-dimethylmorpholino group, hexahydropyridazino group , 2-carbamoylhexahydropyridazino group, pyrazolidino group, 2-methylpyrazolidinyl group, 2-formylpyrazolidinyl group, 3-methyl-4-oxo imidazolidino group, 4-methyl- 3-oxo homopiperazinyl group, the 4-methyl- 1, 2-dihydropyrazin- 3-one- 1-yl group, etc. are mentioned.

Below, the compound (I) of this invention is demonstrated in detail.

Regarding Ar ₁ , 2-thiazolyl group, 5-thiazolyl group, phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 2-pyrimidinyl group, 5- Pyrimidinyl group and 2-pyrazinyl group are preferable, and 2-thiazolyl group, 3-pyridyl group, 3-pyridazinyl group, 2-pyrazinyl group, and 2-pyrimidinyl group are especially preferable.

As for Ar ₂ is a phenyl group, a 4-amino-methylphenyl, 4-formyl-phenyl group, 4-acetyl phenyl group, a 4- (methylsulfonyl aminomethyl) phenyl, 4- (hydroxymethyl) phenyl, 4- ( Methoxymethyl) phenyl group, 4- (fluoromethyl) phenyl group, 4- (difluoromethyl) phenyl group, 4-trifluoromethyl-phenyl group, 1H-pyrrole-2-yl group, 1-methyl-1H-pyrrole- 2-yl group, 1H-pyrrole-1-yl group, 3-methyl-1H-pyrrole-1-yl group, 3-carbamoyl-1H-pyrrole-1-yl group, 3-hydroxymethyl-1H-pyrrole-1-yl group , 3-aminomethyl-1H-pyrrole-1-yl group, 3-methylaminomethyl-1H-pyrrole-1-yl group, 3-dimethylaminomethyl-1H-pyrrole-1-yl group, 1H-pyrrole-3-yl group, 1-methyl-1H-pyrrole-3-yl group, 1H-pyrazol-3-yl group, 1-methyl-1H-pyrazol-3-yl group, 1H-pyrazol-4-yl group, 1-methyl-1H-pyra Zol-4-yl group, 1H-imidazol-4-yl group, 1-methyl-1H-imidazol-4-yl group, thiazol-2-yl group, thiazol-3-yl group, thiazol-4-yl group, 2 -Pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-methoxy-2-pyridyl group, 3-methyl 2-pyridyl group, 3-fluoro-2-pyridyl group, 4-methyl-2-pyridyl group, 4-chloromethyl-2-pyridyl group, 4-ethyl-2-pyridyl group, 4-cyano-2 -Pyridyl, 4-carbamoyl-2-pyridyl, 4-methoxy-2-pyridyl, 4-ethoxy-2-pyridyl, 4-chloro-2-pyridyl, 4-amino-2-pyri Dyl group, 4-methylamino-2-pyridyl group, 4-dimethylamino-2-pyridyl group, 4-hydroxy-2-pyridyl group, 4-aminomethyl-2-pyridyl group, 4-methylaminomethylpyridyl group, 4-dimethylaminomethylpyridyl group, 5-methyl-2-pyridyl group, 5-ethynyl-2-pyridyl group, 5-hydroxy-2-pyridyl group, 5-methoxy-2-pyridyl group, 5-carba Molemethoxy-2-pyridyl group, 5-cyano-2-pyridyl group, 5-amino-2-pyridyl group, 5-methylamino-2-pyridyl group, 5-dimethylamino-2-pyridyl group, 5- Carbamoyl-2-pyridyl group, 5-methylcarbamoyl-2-pyridyl group, 5-dimethylcarbamoyl-2-pyridyl group, 5-chloro-2-pyridyl group, 5-fluoro-2-pyridyl group, 5 -Hydroxy-2-pyridyl group, 5-a Nomethyl-2-pyridyl group, 5-methylaminomethylpyridyl group, 5-dimethylaminomethylpyridyl group, 5-hydroxymethyl-2-pyridyl group, 5-aminomethyl-2-pyridyl group, 5-fluoromethyl 2-pyridyl group, 5-methoxymethyl-2-pyridyl group, 5-acetyl-2-pyridyl group, 6-methoxy-2-pyridyl group, 6-methyl-2-pyridyl group, 6-fluoro- 2-pyridyl group, 6-methoxy-3-pyridyl group, 3-pyridazinyl group, 6-methoxy-3-pyridazinyl group, 6-methyl-3-pyridazinyl group, 2-pyrimidinyl group , 5-methoxy-2-pyrimidinyl group, 5-methyl-2-pyrimidinyl group, 5-methoxy-2-pyrazinyl group, 5-methyl-2-pyrazinyl group, 5-amino-2-pyra Genyl group is preferable and especially 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-methoxyphenyl group, 4-hydroxyphenyl group, 4-hydroxymethylphenyl group, 4-aminomethylphenyl group, 4-methylaminomethylphenyl group, 4-dimethylaminomethylphenyl group, 1-methyl-1H-pyrazol-3-yl group, 1-methyl- 1H-imidazol-4-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 6-methoxy-3-pyridyl group, 6-methyl-3-pyridyl group, 6-methoxy-2- Pyridyl, 6-methyl-2-pyridyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyri Dyl, 5-methyl-2-pyridyl, 5-ethyl-2-pyridyl, 5-ethynyl-2-pyridyl, 5-methoxy-2-pyridyl, 5-carbamoylmethoxy-2-pyri Dyl, 5-cyano-2-pyridyl, 5-carbamoyl-2-pyridyl, 5-amino-2-pyridyl, 5-hydroxymethyl-2-pyridyl, 5-aminomethyl-2-pyri Dyl group, 5-fluoromethyl-2-pyridyl group, 5-methoxymethyl-2-pyridyl group, 5-acetyl-2-pyridyl group, 4-amino-2-pyridyl group, 4-pyrrolidinyl-2- Pyridyl group, 3-methoxy-2-pyridyl group, 3-meth 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, and 5-amino-2-pyrazinyl group are preferable.

As the formula (II),  Azetidine-1-yl group,  3-oxoazetidin-1-yl group,  2-oxoazetidin-1-yl group,  3-aminoazetidin-1-yl group,  3-methylaminoazetidin-1-yl group,  3-dimethylaminoazetidin-1-yl group,  2-methylazetidin-1-yl group,  3-methylazetidin-1-yl group,  2, 2-dimethylazetidin-1-yl group,  3, 3-dimethylazetidin-1-yl group,  2, 2-dimethyl-3-dimethylaminoazetidin-1-yl group,  2-hydroxymethylazetidin-1-yl group,  3-hydroxymethylazetidin-1-yl group,  2-fluoromethylazetidin-1-yl group,  3-fluoromethylazetidin-1-yl group,  3-methoxyazetidin-1-yl group,  2-carbamoylazetidin-1-yl group,  2-methylcarbamoylazetidin-1-yl group,  2-dimethylcarbamoylazetidin-1-yl group,  3-carbamoylazetidin-1-yl group,  3-methylcarbamoylazetidin-1-yl group,  3-dimethylcarbamoylazetidin-1-yl group;  Pyrrolidino Group,  2-oxopyrrolidino group,  3-oxopyrrolidino group,  2, 5-dioxopyrrolidino group,  3-aminopyrrolidino group,  3-methylaminopyrrolidino group,  2-dimethylaminomethylpyrrolidino group,  3-dimethylaminopyrrolidino group,  2-methylpyrrolidino group,  3-methylpyrrolidino group,  2, 2-dimethylpyrrolidino group,  3, 3-dimethylpyrrolidino group,  2, 2-dimethyl-3-dimethylaminopyrrolidino group,  2-hydroxymethylpyrrolidino group,  3-hydroxymethylpyrrolidino group,  3-methoxypyrrolidino group,  2-methoxymethylpyrrolidino group,  3-methoxymethylpyrrolidino group,  2-carbamoylpyrrolidino group,  2-methylcarbamoylpyrrolidino group,  2-dimethylcarbamoylpyrrolidino group,  3-carbamoylpyrrolidino group,  3-methylcarbamoylpyrrolidino group,  3-dimethylcarbamoylpyrrolidino group,  3-fluoropyrrolidino group,  2-fluoromethylpyrrolidino group;  Imidazolidin-1-yl group,  3-methylimidazolidin-1-yl group,  2-oxoimidazolidin-1-yl group,  4-oxoimidazolidin-1-yl group,  3-methyl-2-oxoimidazolidin-1-yl group,  3-methyl-4-oxoimidazolidin-1-yl group,  2, 2-dimethylimidazolin-1-yl group;  Pyrazolidin-1-yl group,  2-methylpyrazolidin-1-yl group,  3-oxopyrazolidin-1-yl group,  3, 5-dioxopyrazolidin-1-yl group,  2-formyl-pyrazolidin-1-yl group,  2-carbamoylpyrazolidin-1-yl group;  Piperidino,  2-oxopiperidino group,  3-oxopiperidino group,  4-oxopiperidino group,  2-hydroxypiperidino group,  3-hydroxypiperidino group,  4-hydroxypiperidino group,  2-methoxypiperidino group,  3-methoxypiperidino group,  4-methoxypiperidino group,  3-aminopiperidino group,  4-aminopiperidino group,  3-methylaminopiperidino group,  4-methylaminopiperidino group,  3-dimethylaminopiperidino group,  4-dimethylaminopiperidino group,  2-methylpiperidino group,  3-methylpiperidino group,  4-methylpiperidino group,  2, 2-dimethylpiperidino group,  3, 3-dimethylpiperidino group,  4, 4-dimethylpiperidino group,  3-fluoropiperidino group,  4-fluoropiperidino group,  4-chloropiperidino group,  3, 3-difluoropiperidino group,  4, 4-difluoropiperidino group,  3, 3-dichloropiperidino group,  4, 4-dichloropiperidino group,  4-fluoromethylpiperidino group,  2-hydroxymethylpiperidino group,  3-hydroxymethylpiperidino group,  4-hydroxymethylpiperidino group,  2- (1-aminocyclopropyl) piperidino group,  2-carbamoylpiperidino group,  3-carbamoylpiperidino group,  4-carbamoylpiperidino group,  2-methylcarbamoylpiperidino group,  3-methylcarbamoylpiperidino group,  4-methylcarbamoylpiperidino group,  2-dimethylcarbamoylpiperidino group,  3-dimethylcarbamoylpiperidino group,  4-dimethylcarbamoylpiperidino group,  2-methoxymethylpiperidino group,  3-methoxymethylpiperidino group,  4-methoxymethylpiperidino group,  2-aminomethylpiperidino group,  3-aminomethylpiperidino group,  4-aminomethylpiperidino group,  2-methylaminomethylpiperidino group,  3-methylaminomethylpiperidino group,  4-methylaminomethylpiperidino group,  2-dimethylaminomethylpiperidino group,  3-dimethylaminomethylpiperidino group,  4-dimethylaminomethylpiperidino group,  2-aminoethylpiperidino group,  3-aminoethylpiperidino group,  4-aminoethylpiperidino group,  2-methylaminoethylpiperidino group,  3-methylaminoethylpiperidino group,  4-methylaminoethylpiperidino group,  2-dimethylaminoethylpiperidino group,  3-dimethylaminoethylpiperidino group,  4-dimethylaminoethylpiperidino group,  4, 4-difluoro-2-carbamoylpiperidino group,  4-methylene piperidino group,  4- (difluoromethylene) piperidino group;  Piperazino,  2-oxopiperazino group,  3-oxopiperazino group,  2-oxo-4-methylpiperazino group,  3-oxo-4-methylpiperazino group,  3-oxo-4-ethylpiperazino group,  4-formyl piperazino group,  2, 3-dioxopiperazino group,  3, 5-dioxopiperazino group,  2, 6-Dioxopiperazino,  2, 3-dioxo-4-methylpiperazino group,  3, 5-dioxo-4-methylpiperazino group,  2, 6-dioxo-4-methylpiperazino group,  2-methylpiperazino group,  3-methylpiperazino group,  4-methylpiperazino group,  2-ethylpiperazino group,  3-ethylpiperazino group,  4-ethylpiperazino group,  2-isopropylpiperazino group,  3-isopropylpiperazino group,  4-isopropylpiperazino group,  2-cyclopropylpiperazino group,  3-cyclopropylpiperazino group,  4-cyclopropylpiperazino group,  4-cyclobutyl piperazino group,  2-cyclopropanespiroprazino group,  3-cyclopropanespiropiperazino group,  2, 2-dimethylpiperazino group,  3, 3-dimethylpiperazino group,  2, 3-dimethylpiperazino group,  2, 4-dimethylpiperazino group,  3, 4-dimethylpiperazino group,  3, 5-dimethylpiperazino group,  2, 6-dimethylpiperazino group,  2-ethyl-4-methylpiperazino group,  3-ethyl-4-methylpiperazino group,  2-isopropyl-4-methylpiperazino group,  3-isopropyl-4-methylpiperazino group,  2-cyclopropyl-4-methylpiperazino group,  3-cyclopropyl-4-methylpiperazino group,  One, 2, 6-trimethylpiperazino group,  3, 4, 5-trimethylpiperazino group,  2, 2, 4-trimethylpiperazino group,  3, 3, 4-trimethylpiperazino group,  4, 6-dimethyl-3-oxopiperazino group,  3, 3, 4-trimethyl-5-oxopiperazino group,  2, 2, 4-trimethyl-3-oxopiperazino group,  2-cyclopropanespiro-4-methylpiperazino group,  3-cyclopropanespiro-4-methylpiperazino group,  2-cyclopropanespiro-4-methyl-3-oxopiperazino group,  3-cyclopropanespiro-4-methyl-5-oxopiperazino group,  4-acetylpiperazino group,  4-acetyl-3-cyclopropanespiroprazino group,  2-hydroxymethylpiperazino group,  3-hydroxymethylpiperazino group,  4-methoxypiperazino group,  2-methoxymethylpiperazino group,  3-methoxymethylpiperazino group,  2-hydroxyethyl piperazino group,  3-hydroxyethyl piperazino group,  4-hydroxyethyl piperazino group,  2-hydroxymethyl-4-methylpiperazino group,  3-hydroxymethyl-4-methylpiperazino group,  2-methoxymethyl-4-methylpiperazino group,  3-methoxymethyl-4-methylpiperazino group,  2-hydroxyethyl-4-methylpiperazino group,  3-hydroxyethyl-4-methylpiperazino group,  2-methoxyethyl-4-methylpiperazino group,  3-methoxyethyl-4-methylpiperazino group,  2-carbamoyl piperazino group,  3-carbamoylpiperazino group,  4-carbamoyl piperazino group,  2-methylcarbamoylpiperazino group,  3-methylcarbamoylpiperazino group,  4-methylcarbamoylpiperazino group,  2-dimethylcarbamoylpiperazino group,  3-dimethylcarbamoylpiperazino group,  4-dimethylcarbamoylpiperazino group,  2-carbamoylmethylpiperazino group,  3-carbamoylmethylpiperazino group,  4-carbamoylmethylpiperazino group,  2-methylcarbamoylmethylpiperazino group,  3-methylcarbamoylmethylpiperazino group,  4-methylcarbamoylpiperazino group,  2-dimethylcarbamoylmethylpiperazino group,  3-dimethylcarbamoylmethylpiperazino group,  2-carbamoyl-4-methylpiperazino group,  3-carbamoyl-4-methylpiperazino group,  4-carbamoyl piperazino group,  2-methylcarbamoyl-4-methylpiperazino group,  3-methylcarbamoyl-4-methylpiperazino group,  4-methylcarbamoylpiperazino group,  2-dimethylcarbamoyl-4-methylpiperazino group,  3-dimethylcarbamoyl-4-methylpiperazino group,  4-dimethylcarbamoylpiperazino group,  2-carbamoylmethyl-4-methylpiperazino group,  3-carbamoylmethyl-4-methylpiperazino group,  4-carbamoylmethylpiperazino group,  2-methylcarbamoylmethyl-4-methylpiperazino group,  3-methylcarbamoylmethyl-4-methylpiperazino group,  4-methylcarbamoylpiperazino group,  2-dimethylcarbamoylmethyl-4-methylpiperazino group,  3-dimethylcarbamoylmethyl-4-methylpiperazino group,  2-aminomethylpiperazino group,  3-aminomethylpiperazino group,  2-methylaminomethylpiperazino group,  3-methylaminomethylpiperazino group,  2-dimethylaminomethylpiperazino group,  3-dimethylaminomethylpiperazino group,  2-aminoethylpiperazino group,  3-aminoethylpiperazino group,  4-aminoethylpiperazino group,  2-methylaminoethylpiperazino group,  3-methylaminoethylpiperazino group,  4-methylaminoethylpiperazino group,  2-dimethylaminoethyl piperazino group,  3-dimethylaminoethylpiperazino group,  4-dimethylaminoethylpiperazino group,  2-aminomethyl-4-methylpiperazino group,  3-aminomethyl-4-methylpiperazino group,  2-methylaminomethyl-4-methylpiperazino group,  3-methylaminomethyl-4-methylpiperazino group,  2-dimethylaminomethyl-4-methylpiperazino group,  3-dimethylaminomethyl-4-methylpiperazino group,  2-aminoethyl-4-methylpiperazino group,  3-aminoethyl-4-methylpiperazino group,  2-methylaminoethyl-4-methylpiperazino group,  3-methylaminoethyl-4-methylpiperazino group,  2-dimethylaminoethyl-4-methylpiperazino group,  3-dimethylaminoethyl-4-methylpiperazino group,  4-methanesulfonylpiperazino group;  One, 2-dihydropyrazin-3-one-1-yl group,  4-methyl-1, 2-dihydropyrazin-3-one-1-yl group;  Morpholino Group,  2-methylmorpholino group,  3-methylmorpholino group,  2-ethyl morpholino group,  3-ethyl morpholino group,  2-cyclopropanespiromorpholino group,  3-cyclopropanespiromorpholino group,  2, 2-dimethylmorpholino group,  3, 3-dimethylmorpholino group,  2-hydroxymethylmorpholino group,  3-hydroxymethylmorpholino group,  2-methoxymethylmorpholino group,  3-methoxymethylmorpholino group,  2-hydroxyethyl morpholino group,  3-hydroxyethyl morpholino group,  2-methoxyethyl morpholino group,  3-methoxyethyl morpholino group,  2-carbamoyl morpholino group,  3-carbamoyl morpholino group,  2-methylcarbamoyl morpholino group,  3-methylcarbamoylmorpholino group,  2-dimethylcarbamoyl morpholino group,  3-dimethylcarbamoylmorpholino group,  2-carbamoylmethylmorpholino group,  3-carbamoylmethylmorpholino group,  2-methylcarbamoylmethylmorpholino group,  3-methylcarbamoylmethylmorpholino group,  2-dimethylcarbamoylmethylmorpholino group,  3-dimethylcarbamoylmethylmorpholino group,  2-carbamoylethyl morpholino group,  3-carbamoylethyl morpholino group,  2-methylcarbamoylethyl morpholino group,  3-methylcarbamoylethyl morpholino group,  2-dimethylcarbamoylethyl morpholino group,  3-dimethylcarbamoylethyl morpholino group,  2-aminomethylmorpholino group,  3-aminomethylmorpholino group,  2-methylaminomethylmorpholino group,  3-methylaminomethylmorpholino group,  2-dimethylaminomethylmorpholino group,  3-dimethylaminomethylmorpholino group,  2-aminoethyl morpholino group,  3-aminoethyl morpholino group,  2-methylaminoethyl morpholino group,  3-methylaminoethyl morpholino group,  2-dimethylaminoethyl morpholino group,  3-dimethylaminoethyl morpholino group;  Thiomorpholino Group,  3-oxothiomorpholino group,  One, 1-dioxothiomorpholino group,  2-methylthiomorpholino group,  3-methylthiomorpholino group,  2-ethylthiomorpholino group,  3-ethylthiomorpholino group,  2-cyclopropanespirothiomorpholino group,  3-cyclopropanespirothiomorpholino group,  2, 2-dimethylthiomorpholino group,  3, 3-dimethylthiomorpholino group,  2-hydroxymethylthiomorpholino group,  3-hydroxymethylthiomorpholino group,  2-methoxymethylthiomorpholino group,  3-methoxymethylthiomorpholino group,  2-hydroxyethylthiomorpholino group,  3-hydroxyethylthiomorpholino group,  2-methoxyethylthiomorpholino group,  3-methoxyethylthiomorpholino group,  2-carbamoylthiomorpholino group,  3-carbamoylthiomorpholino group,  2-methylcarbamoylthiomorpholino group,  3-methylcarbamoylthiomorpholino group,  2-dimethylcarbamoylthiomorpholino group,  3-dimethylcarbamoylthiomorpholino group,  2-carbamoylmethylthiomorpholino group,  3-carbamoylmethylthiomorpholino group,  2-methylcarbamoylmethylthiomorpholino group,  3-methylcarbamoylmethylthiomorpholino group,  2-dimethylcarbamoylmethylthiomorpholino group,  3-dimethylcarbamoylmethylthiomorpholino group,  2-carbamoylethylthiomorpholino group,  3-carbamoylethylthiomorpholino group,  2-methylcarbamoylethylthiomorpholino group,  3-methylcarbamoylethylthiomorpholino group,  2-dimethylcarbamoylethylthiomorpholino group,  3-dimethylcarbamoylethylthiomorpholino group,  2-aminomethylthiomorpholino group,  3-aminomethylthiomorpholino group,  2-methylaminomethylthiomorpholino group,  3-methylaminomethylthiomorpholino group,  2-dimethylaminomethylthiomorpholino group,  3-dimethylaminomethylthiomorpholino group,  2-aminoethylthiomorpholino group,  3-aminoethylthiomorpholino group,  2-methylaminoethylthiomorpholino group,  3-methylaminoethylthiomorpholino group,  2-dimethylaminoethylthiomorpholino group,  3-dimethylaminoethylthiomorpholino group;  Hexahydropyridazin-1-yl group,  2-formylhexahydropyridazin-1-yl group,  2-acetylhexahydropyridazin-1-yl group,  3-oxohexahydropyridazin-1-yl group,  6-oxohexahydropyridazin-1-yl group,  4-aminohexahydropyridazin-1-yl group,  4-methylaminohexahydropyridazin-1-yl group,  4-dimethylaminohexahydropyridazin-1-yl group,  2-methylhexahydropyridazin-1-yl group,  3-methylhexahydropyridazin-1-yl group,  4-methylhexahydropyridazin-1-yl group,  2, 3-dimethylhexahydropyridazin-1-yl group,  3, 3-dimethylhexahydropyridazin-1-yl group,  4, 4-dimethylhexahydropyridazin-1-yl group,  3-hydroxymethylhexahydropyridazin-1-yl group,  4-hydroxymethylhexahydropyridazin-1-yl group,  5-hydroxymethylhexahydropyridazin-1-yl group,  6-hydroxymethylhexahydropyridazin-1-yl group,  2-carbamoylhexahydropyridazin-1-yl group,  3-carbamoylhexahydropyridazin-1-yl group,  4-carbamoylhexahydropyridazin-1-yl group,  5-carbamoylhexahydropyridazin-1-yl group,  6-carbamoylhexahydropyridazin-1-yl group,  2-methylcarbamoylhexahydropyridazin-1-yl group,  3-methylcarbamoylhexahydropyridazin-1-yl group,  4-methylcarbamoylhexahydropyridazin-1-yl group,  5-methylcarbamoylhexahydropyridazin-1-yl group,  6-methylcarbamoylhexahydropyridazin-1-yl group,  2-dimethylcarbamoylhexahydropyridazin-1-yl group,  3-dimethylcarbamoylhexahydropyridazin-1-yl group,  4-dimethylcarbamoylhexahydropyridazin-1-yl group,  5-dimethylcarbamoylhexahydropyridazin-1-yl group,  6-dimethylcarbamoylhexahydropyridazin-1-yl group,  3-methoxymethylhexahydropyridazin-1-yl group,  4-methoxymethylhexahydropyridazin-1-yl group,  5-methoxymethylhexahydropyridazin-1-yl group,  6-methoxymethylhexahydropyridazin-1-yl group,  2-aminoethylhexahydropyridazin-1-yl group,  3-aminoethylhexahydropyridazin-1-yl group,  4-aminoethylhexahydropyridazin-1-yl group,  5-aminoethylhexahydropyridazin-1-yl group,  6-aminoethylhexahydropyridazin-1-yl group,  2-methylaminoethylhexahydropyridazin-1-yl group,  3-methylaminoethylhexahydropyridazin-1-yl group,  4-methylaminoethylhexahydropyridazin-1-yl group,  5-methylaminoethylhexahydropyridazin-1-yl group,  6-methylaminoethylhexahydropyridazin-1-yl group,  3-aminomethylhexahydropyridazin-1-yl group,  4-aminomethylhexahydropyridazin-1-yl group,  5-aminomethylhexahydropyridazin-1-yl group,  6-aminomethylhexahydropyridazin-1-yl group,  3-methylaminomethylhexahydropyridazin-1-yl group,  4-methylaminomethylhexahydropyridazin-1-yl group,  5-methylaminomethylhexahydropyridazin-1-yl group,  6-methylaminomethylhexahydropyridazin-1-yl group,  3-dimethylaminomethylhexahydropyridazin-1-yl group,  4-dimethylaminomethylhexahydropyridazin-1-yl group,  5-dimethylaminomethylhexahydropyridazin-1-yl group,  6-dimethylaminomethylhexahydropyridazin-1-yl group,  2-dimethylaminoethylhexahydropyridazin-1-yl group,  3-dimethylaminoethylhexahydropyridazin-1-yl group,  4-dimethylaminoethylhexahydropyridazin-1-yl group,  5-dimethylaminoethylhexahydropyridazin-1-yl group,  6-dimethylaminoethylhexahydropyridazin-1-yl group;  Hexahydropyrimidin-1-yl group,  2-oxohexahydropyrimidin-1-yl group,  4-oxohexahydropyrimidin-1-yl group,  5-oxohexahydropyrimidin-1-yl group,  6-oxohexahydropyrimidin-1-yl group,  2-methylhexahydropyrimidin-1-yl group,  3-methylhexahydropyrimidin-1-yl group,  4-methylhexahydropyrimidin-1-yl group,  4-methylhexahydropyrimidin-1-yl group,  2, 2-dimethylhexahydropyrimidin-1-yl group,  4, 4-dimethylhexahydropyrimidin-1-yl group,  5, 5-dimethylhexahydropyrimidin-1-yl group,  6, 6-dimethylhexahydropyrimidin-1-yl group,  2-hydroxymethylhexahydropyrimidin-1-yl group,  4-hydroxymethylhexahydropyrimidin-1-yl group,  5-hydroxymethylhexahydropyrimidin-1-yl group,  6-hydroxymethylhexahydropyrimidin-1-yl group,  2-carbamoylhexahydropyrimidin-1-yl group,  3-carbamoylhexahydropyrimidin-1-yl group,  4-carbamoylhexahydropyrimidin-1-yl group,  5-carbamoylhexahydropyrimidin-1-yl group,  6-carbamoylhexahydropyrimidin-1-yl group,  2-methylcarbamoylhexahydropyrimidin-1-yl group,  3-methylcarbamoylhexahydropyrimidin-1-yl group,  4-methylcarbamoylhexahydropyrimidin-1-yl group,  5-methylcarbamoylhexahydropyrimidin-1-yl group,  6-methylcarbamoylhexahydropyrimidin-1-yl group,  2-dimethylcarbamoylhexahydropyrimidin-1-yl group,  3-dimethylcarbamoylhexahydropyrimidin-1-yl group,  4-dimethylcarbamoylhexahydropyrimidin-1-yl group,  5-dimethylcarbamoylhexahydropyrimidin-1-yl group,  6-dimethylcarbamoylhexahydropyrimidin-1-yl group,  3-methoxymethylhexahydropyrimidin-1-yl group,  4-methoxymethylhexahydropyrimidin-1-yl group,  5-methoxymethylhexahydropyrimidin-1-yl group,  6-methoxymethylhexahydropyrimidin-1-yl group,  2-aminoethylhexahydropyrimidin-1-yl group,  3-aminoethylhexahydropyrimidin-1-yl group,  4-aminoethylhexahydropyrimidin-1-yl group,  5-aminoethylhexahydropyrimidin-1-yl group,  6-aminoethylhexahydropyrimidin-1-yl group,  2-methylaminoethylhexahydropyrimidin-1-yl group,  3-methylaminoethylhexahydropyrimidin-1-yl group,  4-methylaminoethylhexahydropyrimidin-1-yl group,  5-methylaminoethylhexahydropyrimidin-1-yl group,  6-methylaminoethylhexahydropyrimidin-1-yl group,  2-dimethylaminoethylhexahydropyrimidin-1-yl group,  3-dimethylaminoethylhexahydropyrimidin-1-yl group,  4-dimethylaminoethylhexahydropyrimidin-1-yl group,  5-dimethylaminoethylhexahydropyrimidin-1-yl group,  6-dimethylaminoethylhexahydropyrimidin-1-yl group;  Homopiperazino,  2-oxo homopiperazino group,  3-oxo homopiperazino group,  5-oxo homopiperazino group,  6-Oxo Homopiperazino Group,  7-Oxo Homopiperazino Group,  2-oxo-4-methyl homopiperazino group,  3-oxo-4-methyl homopiperazino group,  5-oxo-4-methyl homopiperazino group,  6-oxo-4-methyl homopiperazino group,  7-oxo-4-methyl homopiperazino group,  2, 3-dioxohomopiperazino group,  2, 7-Dioxo Homopiperazino Group,  3, 5-dioxohomopiperazino group,  3, 7-Dioxo Homopiperazino Group,  2, 3-dioxo-4-methyl homopiperazino group,  2, 7-dioxo-4-methyl homopiperazino group,  3, 5-dioxo-4-methyl homopiperazino group,  3, 7-dioxo-4-methyl homopiperazino group,  2-methyl homopiperazino group,  3-methyl homopiperazino group,  4-methyl homopiperazino group,  5-methyl homopiperazino group,  6-methyl homopiperazino group,  7-methyl homopiperazino group,  2-ethyl homopiperazino group,  3-ethyl homopiperazino group,  4-ethyl homopiperazino group,  5-ethyl homopiperazino group,  6-ethyl homopiperazino group,  7-ethyl homopiperazino group,  4-cyclopropyl homopiperazino group,  2-cyclopropanespiro homopiperazino group,  3-cyclopropanespiro homopiperazino group,  5-cyclopropanespiro homopiperazino group,  6-cyclopropanespiro homopiperazino group,  7-cyclopropanespiro homopiperazino group,  2-cyclopropanespiro-4-methylhomopiperazino group,  3-cyclopropanespiro-4-methylhomopiperazino group,  5-cyclopropanespiro-4-methylhomopiperazino group,  6-cyclopropanespiro-4-methylhomopiperazino group,  7-cyclopropanespiro-4-methylhomopiperazino group,  2-cyclopropanespiro-4-methyl-3-oxo homopiperazino group,  2-cyclopropanespiro-4-methyl-5-oxo homopiperazino group,  2-cyclopropanespiro-4-methyl-7-oxo homopiperazino group,  3-cyclopropanespiro-4-methyl-2-oxo homopiperazino group,  3-cyclopropanespiro-4-methyl-5-oxohomopiperazino group,  3-cyclopropanespiro-4-methyl-7-oxo homopiperazino group,  5-cyclopropanespiro-4-methyl-2-oxo homopiperazino group,  5-cyclopropanespiro-4-methyl-3-oxo homopiperazino group,  5-cyclopropanespiro-4-methyl-7-oxo homopiperazino group,  6-cyclopropanespiro-4-methyl-2-oxo homopiperazino group,  6-cyclopropanespiro-4-methyl-3-oxo homopiperazino group,  6-cyclopropanespiro-4-methyl-5-oxo homopiperazino group,  6-cyclopropanespiro-4-methyl-7-oxo homopiperazino group,  7-cyclopropanespiro-4-methyl-2-oxo homopiperazino group,  7-cyclopropanespiro-4-methyl-3-oxo homopiperazino group,  7-cyclopropanespiro-4-methyl-5-oxo homopiperazino group,  2, 2-dimethyl homopiperazino group,  3, 3-dimethyl homopiperazino group,  5, 5-dimethyl homopiperazino group,  6, 6-dimethyl homopiperazino group,  7, 7-dimethyl homopiperazino group,  2, 3-dimethyl homopiperazino group,  2, 4-dimethyl homopiperazino group,  3, 4-dimethyl homopiperazino group,  3, 5-dimethyl homopiperazino group,  3, 4, 5-trimethyl homopiperazino group,  2-hydroxymethyl homopiperazino group,  3-hydroxymethyl homopiperazino group,  5-hydroxymethyl homopiperazino group,  6-hydroxymethyl homopiperazino group,  7-hydroxymethyl homopiperazino group,  2-hydroxymethyl-4-methyl homopiperazino group,  3-hydroxymethyl-4-methyl homopiperazino group,  5-hydroxymethyl-4-methyl homopiperazino group,  6-hydroxymethyl-4-methyl homopiperazino group,  7-hydroxymethyl-4-methyl homopiperazino group,  2-methoxymethyl homopiperazino group,  3-methoxymethyl homopiperazino group,  5-methoxymethyl homopiperazino group,  6-methoxymethyl homopiperazino group,  7-methoxymethyl homopiperazino group,  2-methoxymethyl-4-methyl homopiperazino group,  3-methoxymethyl-4-methyl homopiperazino group,  5-methoxymethyl-4-methyl homopiperazino group,  6-methoxymethyl-4-methyl homopiperazino group,  7-methoxymethyl-4-methyl homopiperazino group,  2-hydroxyethyl homopiperazino group,  3-hydroxyethyl homopiperazino group,  4-hydroxyethyl homopiperazino group,  5-hydroxyethyl homopiperazino group,  6-hydroxyethyl homopiperazino group,  7-hydroxyethyl homopiperazino group,  2-hydroxyethyl-4-methyl homopiperazino group,  3-hydroxyethyl-4-methyl homopiperazino group,  5-hydroxyethyl-4-methyl homopiperazino group,  6-hydroxyethyl-4-methyl homopiperazino group,  7-hydroxyethyl-4-methyl homopiperazino group,  2-methoxyethyl homopiperazino group,  3-methoxyethyl homopiperazino group,  4-methoxyethyl homopiperazino group,  5-methoxyethyl homopiperazino group,  6-methoxyethyl homopiperazino group,  7-methoxyethyl homopiperazino group,  2-methoxyethyl-4-methyl homopiperazino group,  3-methoxyethyl-4-methyl homopiperazino group,  5-methoxyethyl-4-methylhomopiperazino group,  6-methoxyethyl-4-methyl homopiperazino group,  7-methoxyethyl-4-methyl homopiperazino group,  2-carbamoyl homopiperazino group,  3-carbamoylhomopiperazino group,  4-Cavamoyl Homopiperazino Group,  5-carbamoyl homopiperazino group,  6-Cavamoilhopiperazinogi,  7-Cavamoilhopiferazinogi,  2-carbamoyl-4-methyl homopiperazino group,  3-carbamoyl-4-methyl homopiperazino group,  4-Cavamoyl Homopiperazino Group,  5-carbamoyl-4-methyl homopiperazino group,  6-carbamoyl-4-methyl homopiperazino group,  7-carbamoyl-4-methyl homopiperazino group,  2-methylcarbamoyl homopiperazino group,  3-methylcarbamoyl homopiperazino group,  4-methyl carbamoyl homopiperazino group,  5-methyl carbamoyl homopiperazino group,  6-methylcarbamoyl homopiperazino group,  7-methylcarbamoyl homopiperazino group,  2-methyl carbamoyl-4-methyl homopiperazino group,  3-methylcarbamoyl-4-methyl homopiperazino group,  5-methylcarbamoyl-4-methyl homopiperazino group,  6-methylcarbamoyl-4-methyl homopiperazino group,  7-methylcarbamoyl-4-methyl homopiperazino group,  2-dimethyl carbamoyl homopiperazino group,  3-dimethylcarbamoylhomopiperazino group,  4-dimethylcarbamoylhomopiperazino group,  5-dimethylcarbamoylhomopiperazino group,  6-dimethylcarbamoylhomopiperazino group,  7-dimethylcarbamoylhomopiperazino group,  2-dimethylcarbamoyl-4-methyl homopiperazino group,  3-dimethylcarbamoyl-4-methyl homopiperazino group,  5-dimethylcarbamoyl-4-methylhomopiperazino group,  6-dimethylcarbamoyl-4-methylhomopiperazino group,  7-dimethylcarbamoyl-4-methylhomopiperazino group,  2-carbamoylmethyl homopiperazino group,  3-carbamoylmethyl homopiperazino group,  4-carbamoylmethyl homopiperazino group,  5-carbamoylmethyl homopiperazino group,  6-carbamoylmethyl homopiperazino group,  7-carbamoylmethyl homopiperazino group,  2-carbamoylmethyl-4-methylhomopiperazino group,  3-carbamoylmethyl-4-methylhomopiperazino group,  5-carbamoylmethyl-4-methylhomopiperazino group,  6-carbamoylmethyl-4-methylhomopiperazino group,  7-carbamoylmethyl-4-methylhomopiperazino group,  2-methylcarbamoylmethyl homopiperazino group,  3-methylcarbamoylmethyl homopiperazino group,  4-methyl carbamoyl homopiperazino group,  5-methyl carbamoyl homopiperazino group,  6-methylcarbamoyl homopiperazino group,  7-methylcarbamoyl homopiperazino group,  2-methylcarbamoylmethyl-4-methylhomopiperazino group,  3-methylcarbamoylmethyl-4-methylhomopiperazino group,  5-methylcarbamoyl-4-methyl homopiperazino group,  6-methylcarbamoyl-4-methyl homopiperazino group,  7-methylcarbamoyl-4-methyl homopiperazino group,  2-dimethylcarbamoylmethylhomopiperazino group,  3-dimethylcarbamoylmethylhomopiperazino group,  4-dimethylcarbamoylmethylhomopiperazino group,  5-dimethylcarbamoylmethylhomopiperazino group,  6-dimethylcarbamoylmethylhomopiperazino group,  7-dimethylcarbamoylmethylhomopiperazino group,  2-dimethylcarbamoylmethyl-4-methylhomopiperazino group,  3-dimethylcarbamoylmethyl-4-methylhomopiperazino group,  5-dimethylcarbamoylmethyl-4-methylhomopiperazino group,  6-dimethylcarbamoylmethyl-4-methylhomopiperazino group,  7-dimethylcarbamoylmethyl-4-methylhomopiperazino group,  2-aminomethyl homopiperazino group,  3-aminomethylhomopiperazino group,  5-aminomethylhomopiperazino group,  6-aminomethyl homopiperazino group,  7-aminomethyl homopiperazino group,  2-aminomethyl-4-methyl homopiperazino group,  3-aminomethyl-4-methyl homopiperazino group,  5-aminomethyl-4-methyl homopiperazino group,  6-aminomethyl-4-methyl homopiperazino group,  7-aminomethyl-4-methyl homopiperazino group,  2-methylaminomethyl homopiperazino group,  3-methylaminomethyl homopiperazino group,  4-methylaminomethyl homopiperazino group,  5-methylaminomethyl homopiperazino group,  6-methylaminomethyl homopiperazino group,  7-methylaminomethyl homopiperazino group,  2-methylaminomethyl-4-methyl homopiperazino group,  3-methylaminomethyl-4-methyl homopiperazino group,  5-methylaminomethyl-4-methylhomopiperazino group,  6-methylaminomethyl-4-methyl homopiperazino group,  7-methylaminomethyl-4-methyl homopiperazino group,  2-dimethylaminomethyl homopiperazino group,  3-dimethylaminomethyl homopiperazino group,  4-dimethylaminomethyl homopiperazino group,  5-dimethylaminomethyl homopiperazino group,  6-dimethylaminomethyl homopiperazino group,  7-dimethylaminomethyl homopiperazino group,  2-dimethylaminomethyl-4-methyl homopiperazino group,  3-dimethylaminomethyl-4-methyl homopiperazino group,  5-dimethylaminomethyl-4-methyl homopiperazino group,  6-dimethylaminomethyl-4-methyl homopiperazino group,  7-dimethylaminomethyl-4-methyl homopiperazino 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-methyl homopiperazino group,  3-aminoethyl-4-methyl homopiperazino group,  5-aminoethyl-4-methyl homopiperazino group,  6-aminoethyl-4-methyl homopiperazino group,  7-aminoethyl-4-methyl homopiperazino group,  2-methylaminoethyl homopiperazino group,  3-methylaminoethyl homopiperazino group,  4-methylaminoethyl homopiperazino group,  5-methylaminoethyl homopiperazino group,  6-methylaminoethyl homopiperazino group,  7-methylaminoethyl homopiperazino group,  2-methylaminoethyl-4-methyl homopiperazino group,  3-methylaminoethyl-4-methyl homopiperazino group,  5-methylaminoethyl-4-methylhomopiperazino group,  6-methylaminoethyl-4-methyl homopiperazino group,  7-methylaminoethyl-4-methyl homopiperazino group,  2-dimethylaminoethyl homopiperazino group,  3-dimethylaminoethyl homopiperazino group,  4-dimethylaminoethyl homopiperazino group,  5-dimethylaminoethyl homopiperazino group,  6-dimethylaminoethyl homopiperazino group,  7-dimethylaminoethyl homopiperazino group,  2-dimethylaminoethyl-4-methyl homopiperazino group,  3-dimethylaminoethyl-4-methyl homopiperazino group,  5-dimethylaminoethyl-4-methyl homopiperazino group,  6-dimethylaminoethyl-4-methyl homopiperazino group,  7-dimethylaminoethyl-4-methyl homopiperazino group,  4-methanesulfonyl homopiperazino group,  4-methanesulfonylamino homopiperazino group,  4- (azetidin-1-yl) homopiperazino group;  4-pyrrolidinohomopiperazino group,  4-piperidino homopiperazino group;  One, 4-oxazepan-4-yl group etc. are mentioned as a representative example.

Among these, the following are preferable.

Azetidin-1-yl group, 3-dimethylaminoazetidin-1-yl group, 2-methylazetidin-1-yl group, 3-methylazetidin-1-yl group, 2,2-dimethylazetidin-1-yl group, 3,3-dimethylazetidin-1-yl group, 2,2-dimethyl-3-dimethylaminoazetidin-1-yl group, 2-hydroxymethylazetidin-1-yl group, 3-hydroxymethylazetidine-1 -Group, 2-carbamoylazetidin-1-yl group, 2-methylcarbamoylazetidin-1-yl group, 2-dimethylcarbamoylazetidin-1-yl group, 3-methoxyazetidin-1-yl group; Pyrrolidino group, 2-fluoropyrrolidino group, 3-fluoropyrrolidino group, 2-oxopyrrolidino group, 2-dimethylaminomethylpyrrolidino group, 3-dimethylaminomethylpyrrolidino group , 2,5-dioxopyrrolidino group, 2-methylpyrrolidino group, 3-methylpyrrolidino group, 2,2-dimethylpyrrolidino group, 3,3-dimethylpyrrolidino group, 2-hydride Hydroxymethylpyrrolidino group, 3-hydroxymethylpyrrolidino group, 3-methoxypyrrolidino group, 2-methoxymethylpyrrolidino group, 3-methoxymethylpyrrolidino group, 2-carbamoylpi Lolidino group, 2-methyl carbamoyl pyrrolidino group, 2-dimethyl carbamoyl pyrrolidino group, 2-fluoromethyl pyrrolidino group; 2-oxoimidazolidin-1-yl group, 4-oxoimidazolidin-1-yl group, 3-methyl-2-oxoimidazolidin-1-yl group, 3-methyl-4-oxoimidazoli Din-1-yl group; Pyrazolidino group, 2-methylpyrazolidin-1-yl group, 3-oxopyrazolidin-1-yl group, 3,5-dioxopyrazolidin-1-yl group, 2-formylpyrazolidine-1 -Group, 2-carbamoylpyrazolidin-1-yl group; Piperidino group, 2-oxo piperidino group, 3-oxo piperidino group, 4-oxo piperidino group, 2-hydroxymethyl piperidino group, 3-hydroxymethyl piperidino group, 4-hydroxymethyl piperididi No group, 2-methoxy piperidino group, 3-methoxy piperidino group, 4-methoxy piperidino group, 2-methyl piperidino group, 3-methyl piperidino group, 4-methyl piperidino group, 2,2 -Dimethylpiperidino group, 3,3-dimethylpiperidino group, 4,4-dimethylpiperidino group, 3-fluoropiperidino group, 4-fluoropiperidino group, 4-chloropiperidino group, 3,3 -Difluoropiperidino group, 4,4-difluoropiperidino group, 2-fluoromethylpiperidino group, 3-fluoromethylpiperidino group, 4-fluoromethylpiperidino group, 3,3- Dichloropiperidino group, 4,4-dichloropiperidino group, 4-fluoromethylpiperidino group, 2-hydroxymethylpiperidino group, 2- (1-aminocyclopropyl) piperidino group , 2-carbamoyl piperidino group, 2-methyl carbamoyl piperidino group, 2-dimethyl carbamoyl piperidino group, 2-methoxymethyl piperidino group, 4-methyl-4-methoxy piperidino group, 2- Aminomethylpiperidino group, 2-methylaminomethylpiperidino group, 2-dimethylaminomethylpiperidino group, 2-aminoethylpiperidino group, 2-methylaminoethylpiperidino group, 2-dimethylaminoethylpiperidino group, 4,4-difluoro-2-carbamoyl piperidino group, 4-methylene piperidino group, 4- (difluoromethylene) piperidino group; Piperazino group, 2-oxo-4-methyl piperazino group, 3-oxo-4-methyl piperazino group, 3-oxo-4-ethyl piperazino group, 4-formyl piperazino group, 2,3-di Oxo-4-methylpiperazino group, 3,5-dioxo-4-methylpiperazino group, 2,6-dioxo-4-methylpiperazino group, 4-methylpiperazino group, 4-ethylpiperazino group , 4-isopropyl piperazino group, 4-cyclopropyl piperazino group, 2,4-dimethylpiperazino group, 3,4-dimethylpiperazino group, 2-ethyl-4-methyl-piperazino group, 3-ethyl -4-methylpiperazino group, 2-isopropyl-4-methylpiperazino group, 3-isopropyl-4-methylpiperazino group, 2-cyclopropyl-4-methylpiperazino group, 3-cyclopropyl-4 -Methyl piperazino group, 3,4,5-trimethylpiperazino group, 2,2,4-trimethylpiperazino group, 3,3,4-trimethylpiperazino group, 4,6-dimethyl-3-oxopiperazin Nogi group, 3,3,4-trimethyl-5-oxo piperazino group, 2,2,4-trimethyl-3-oxo piperazino group , 2-cyclopropanespiro-4-methylpiperazino group, 3-cyclopropanespiro-4-methylpiperazino group, 2-cyclopropanespiro-4-methyl-3-oxopiperazino group, 3-cyclopropanespiro- 4-methyl-5-oxopiperazino group, 4-acetyl-3-cyclopropanespiroprazino group, 2-hydroxymethyl-4-methylpiperazino group, 3-hydroxymethyl-4-methylpiperazino group, 4-methoxypiperazino group, 2-methoxymethyl-4-methylpiperazino group, 3-methoxymethyl-4-methylpiperazino group, 2-hydroxyethyl-4-methylpiperazino group, 3-hydroxy Oxyethyl-4-methylpiperazino group, 2-methoxyethyl-4-methylpiperazino group, 3-methoxyethyl-4-methylpiperazino group, 2-carbamoyl-4-methylpiperazino group, 3- Carbamoyl-4-methyl piperazino group, 4-carbamoyl piperazino group, 2-methyl carbamoyl-4-methyl piperazino group, 3-methyl carbamoyl-4-methyl piperazino group, 4-methyl carbamoyl pipepe Lazino group, 2-dimethyl cover Mono-4-methylpiperazino group, 3-dimethylcarbamoyl-4-methylpiperazino group, 4-dimethylcarbamoylpiperazino group, 2-carbamoylmethyl-4-methylpiperazino group, 3-carbamoylmethyl- 4-methylpiperazino group, 4-carbamoylmethylpiperazino group, 2-methylcarbamoylmethyl-4-methylpiperazino group, 3-methylcarbamoylmethyl-4-methylpiperazino group, 4-methylcarbamoyl pipepe Lazino group, 2-dimethylcarbamoylmethyl-4-methylpiperazino group, 3-dimethylcarbamoylmethyl-4-methylpiperazino group, 2-aminomethyl-4-methylpiperazino group, 2-methylaminomethyl-4 -Methyl piperazino group, 2-dimethylaminomethyl-4-methylpiperazino group, 2-aminoethyl-4-methylpiperazino group, 2-methylaminoethyl-4-methylpiperazino group, 2-dimethylaminoethyl- 4-methylpiperazino group; Morpholino group, 2-methylmorpholino group, 3-methylmorpholino group, 2-ethylmorpholino group, 3-ethylmorpholino group, 2-cyclopropanespiromorpholino group, 3-cyclopropanespiromorpholino group, 2,2-dimethylmorpholino group, 3,3-dimethylmorpholino group, 3-hydroxymethylmorpholino group, 3-methoxymethylmorpholino group, 3-hydroxyethylmorpholino group, 3-methoxyethyl Morpholino group, 3-carbamoyl morpholino group, 3-methyl carbamoyl morpholino group, 3-dimethyl carbamoyl morpholino group, 3-carbamoyl methyl morpholino group, 3-methyl carbamoyl methyl morpholino group, 3 -Dimethyl carbamoyl methyl morpholino group, 3-carbamoyl ethyl morpholino group, 3-methyl carbamoyl ethyl morpholino group, 3-dimethyl carbamoyl ethyl morpholino group, 3-aminomethyl morpholino group, 3-methylamino Methyl morpholino group, 3-dimethylaminomethyl morpholino group, 3-aminoethyl morpholino group, 3-methylaminoethyl morpholino group, 3-dimethylaminoethyl morpholino group; Thiomorpholino group, 3-oxothiomorpholino group, 1,1-dioxothiomorpholino group, 2-methylthiomorpholino group, 3-methylthiomorpholino group, 2-ethylthiomorpholino group, 3- Ethylthiomorpholino group, 2-cyclopropanespirothiomorpholino group, 3-cyclopropanespirothiomorpholino group, 2,2-dimethylthiomorpholino group, 3,3-dimethylthiomorpholino group, 3-hydroxy Methylthiomorpholino group, 3-methoxymethylthiomorpholino group, 3-hydroxyethylthiomorpholino group, 3-methoxyethylthiomorpholino group, 3-carbamoylthiomorpholino group, 3-methyl carbamoyl Thiomorpholino group, 3-dimethylcarbamoylthiomorpholino group, 3-carbamoylmethylthiomorpholino group, 3-methylcarbamoylmethylthiomorpholino group, 3-dimethylcarbamoylmethylthiomorpholino group, 3-carba Moylethylthiomorpholino group, 3-methyl carbamoylethylthiomorpholino group, 3-dimethyl Carbamoyl ethyl thiomorpholinyl group, 3-methoxycarbonyl-thiomorpholinyl group, 3-methoxy-carbonyl-methyl-thiomorpholinyl group, ethoxycarbonyl methyl-3-thiomorpholinyl group; Hexahydropyridazin-1-yl group, 2-acetylhexahydropyridazin-1-yl group, 2-formylhexahydropyridazin-1-yl group, 2-methylhexahydropyridazin-1-yl group, 3-oxohexa Hydropyridazin-1-yl group, 6-oxohexahydropyridazin-1-yl group, 2,3-dimethylhexahydropyridazin-1-yl group, 3-hydroxymethylhexahydropyridazin-1-yl group, 5- Hydroxymethylhexahydropyridazin-1-yl group, 6-hydroxymethylhexahydropyridazin-1-yl group, 2-carbamoylhexahydropyridazin-1-yl group, 2-methylcarbamoylhexahydropyridazine-1 -Yl group, 2-dimethylcarbamoylhexahydropyridazin-1-yl group; 2-oxohexahydropyrimidin-1-yl group, 4-oxohexahydropyrimidin-1-yl group, 6-oxohexahydropyrimidin-1-yl group, 2-methylhexahydropyrimidin-1-yl group, 3- Methyl hexahydropyrimidin-1-yl group, 3-carbamoyl hexahydropyrimidin-1-yl group, 3-methyl carbamoyl hexahydropyrimidin-1-yl group, 3-dimethyl carbamoyl hexahydropyrimidin-1-yl group , 6-hydroxymethylpyrimidin-1-yl group; 2-oxo-4-methyl homopiperazino group, 3-oxo-4-methyl homopiperazino group, 5-oxo-4-methyl homopiperazino group, 6-oxo-4-methyl homopiperazino group, 7- Oxo-4-methyl homopiperazino group, 2,3-dioxohomopiperazino group, 2,7-dioxohomopiperazino group, 3,5-dioxohomopiperazino group, 3,7-dioxohomo Piperazino group, 2,3-dioxo-4-methyl homopiperazino group, 2,7-dioxo-4-methyl homopiperazino group, 3,5-dioxo-4-methyl homopiperazino group, 3 , 7-dioxo-4-methyl homopiperazino group, 4-methyl homopiperazino group, 4-ethyl homopiperazino group, 4-cyclopropyl homopiperazino group, 2-cyclopropanespiro homopiperazino group, 3 -Cyclopropanespiro homopiperazino group, 5-cyclopropanespiro homopiperazino group, 6-cyclopropanespiro homopiperazino group, 7-cyclopropanespiro homopiperazino group, 2,4-dimethyl homopiperazino group, 3 , 4-d Tyl homopiperazino group, 3,4,5-trimethyl homopiperazino group, 2-hydroxymethyl-4-methyl homopiperazino group, 7-hydroxymethyl-4-methyl homopiperazino group, 2-methoxy Methyl-4-methyl homopiperazino group, 3-methoxymethyl-4-methyl homopiperazino group, 5-methoxymethyl-4-methyl homopiperazino group, 6-methoxymethyl-4-methyl homopiperazin No group, 7-methoxymethyl-4-methyl homopiperazino group, 2-hydroxyethyl-4-methyl homopiperazino group, 7-hydroxyethyl-4-methyl homopiperazino group, 2-methoxyethyl- 4-methyl homopiperazino group, 3-methoxyethyl-4-methyl homopiperazino group, 5-methoxyethyl-4-methylhomopiperazino group, 6-methoxyethyl-4-methyl homopiperazino group, 7-methoxyethyl-4-methyl homopiperazino group, 2-carbamoyl-4-methylhomopiperazino group, 7-carbamoyl-4-methylhomopiperazino group, 2-methylcarbamoyl-4-methylhomo Piperazino groups, 7-methylcarbamoyl-4-methyl Piperazine large group, 2-dimethyl-carbamoyl homo piperazine large group, 7-dimethyl-carbamoyl homo piperazine large group; 1,4-oxazepan-4-yl group; 3-methyl-4-oxoimidazolidin-1-yl group.

Among these, the following are more preferable.

Azetidin-1-yl group, 3-dimethylaminoazetidin-1-yl group, 2,2-dimethyl-3-dimethylaminoazetidin-1-yl group, 2-hydroxymethylazetidin-1-yl group, 2-carba Moylazetidin-1-yl group, 2-methylcarbamoylazetidin-1-yl group, 2-dimethylcarbamoylazetidin-1-yl group, 3-methoxyazetidin-1-yl group; Pyrrolidino group, 2-oxopyrrolidino group, 2,5-dioxopyrrolidino group, 2-methylpyrrolidino group, 3-methylpyrrolidino group, 2,2-dimethylpyrrolidino group, 3 , 3-dimethylpyrrolidino group, 2-dimethylaminomethylpyrrolidino group, 3-dimethylaminomethylpyrrolidino group, 2-hydroxymethylpyrrolidino group, 3-methoxymethylpyrrolidino group, 2 -Carbamoyl pyrrolidino group, 2-methyl carbamoyl pyrrolidino group, 2-dimethyl carbamoyl pyrrolidino group, 2-fluoro pyrrolidino group, 3-fluoro pyrrolidino group, 2-fluoro Methylpyrrolidino group; 3-methyl-2-oxoimidazolidin-1-yl group, 3-methyl-4-oxoimidazolidin-1-yl group; Pyrazolidino group, 2-formyl-pyrazolidin-1-yl group, 2-carbamoylpyrazolidin-1-yl group; Piperidino group, 2-oxo piperidino group, 2-methoxy piperidino group, 3-methoxy piperidino group, 4-methoxy piperidino group, 2-hydroxymethyl piperidino group, 2- (1-amino Cyclopropyl) piperidino group, 2-carbamoylpiperidino group, 2-methylcarbamoylpiperidino group, 2-dimethylcarbamoylpiperidino group, 2-methoxymethylpiperidino group, 2-aminomethylpiperidino group, 2-methylaminomethylpiperidino group, 2-dimethylaminomethylpiperidino group, 2-aminoethylpiperidino group, 2-methylaminoethylpiperidino group, 2-dimethylaminoethylpiperidino group, 3-fluoropiperididi Furnace group, 4-fluoropiperidino group, 4-methylpiperidino group, 4-methoxypiperidino group, 3,3-difluoropiperidino group, 4,4-difluoropiperidino group, 3-fluoro Romethylpiperidino group, 4-fluoromethylpiperidino group, 4-methyl-4-methoxypiperidino group, 4,4-difluoro-2-carbamoyl Piperidino group, 4-methylene piperidino group, 4- (methylene-difluoro) piperidino group; Piperazino group, 2-oxo-4-methyl piperazino group, 3-oxo-4-methyl piperazino group, 3-oxo-4-ethyl piperazino group, 4-formyl piperazino group, 2,3-di Oxo-4-methylpiperazino group, 3,5-dioxo-4-methylpiperazino group, 2,6-dioxo-4-methylpiperazino group, 4-methylpiperazino group, 4-ethylpiperazino group , 4-isopropyl piperazino group, 4-cyclopropyl piperazino group, 2,4-dimethylpiperazino group, 3,4-dimethylpiperazino group, 2-ethyl-4-methylpiperazino group, 3-ethyl- 4-methylpiperazino group, 3,4,5-trimethylpiperazino group, 2,2,4-trimethylpiperazino group, 3,3,4-trimethylpiperazino group, 4,6-dimethyl-3-oxopipe Lazino group, 3,3,4-trimethyl-5-oxopiperazino group, 2,2,4-trimethyl-3-oxopiperazino group, 2-cyclopropanespiro-4-methylpiperazino group, 3-cyclopropane Spiro-4-methylpiperazino group, 2-cyclopropanespiro-4-methyl-3-oxopiperazino group, 3-hour Ropropanspiro-4-methyl-5-oxopiperazino group, 4-acetyl-3-cyclopropanespiroprazino group, 2-hydroxymethyl-4-methylpiperazino group, 3-hydroxymethyl-4- Methyl piperazino group, 4-methoxy piperazino group, 2-methoxymethyl-4-methyl- piperazino group, 3-methoxymethyl-4-methyl piperazino group, 2-hydroxyethyl-4-methyl pipepe Lazino group, 3-hydroxyethyl-4-methyl piperazino group, 2-methoxyethyl-4-methyl piperazino group, 3-methoxyethyl-4-methyl piperazino group, 2-carbamoyl-4-methyl Piperazino group, 2-methylcarbamoyl-4-methylpiperazino group, 2-dimethylcarbamoyl-4-methylpiperazino group, 2-carbamoylmethyl-4-methylpiperazino group, 2-methylcarbamoylmethyl- 4-methylpiperazino group, 2-dimethylcarbamoylmethyl-4-methylpiperazino group, 2-aminomethyl-4-methylpiperazino group, 2-methylaminomethyl-4-methylpiperazino group, 2-dimethylamino Methyl-4-methylpiperazino group, 2-a No ethyl 4-methylpiperazin-large group, a 2-methylamino-ethyl-4-methylpiperazin-large group, a 2-dimethylaminoethyl-4-methylpiperazin-large group; 1,2-dihydropyrazin-3-one-1-yl group; Morpholino group, 4-methyl-1,2-dihydropyrazin-3-one-1-yl group; Morpholino group, 3-methylmorpholino group, 2-cyclopropanespiromorpholino group, 3-cyclopropanespiromorpholino group, 2,2-dimethylmorpholino group, 3,3-dimethylmorpholino group, 3-hydride Hydroxymethyl morpholino group, 3-methoxymethyl morpholino group, 3-hydroxyethyl morpholino group, 3-methoxyethyl morpholino group, 3-carbamoyl morpholino group, 3-methyl carbamoyl morpholino group, 3-dimethylcarbamoyl morpholino group, 3-aminomethylmorpholino group, 3-methylaminomethylmorpholino group, 3-dimethylaminomethylmorpholino group, 3-aminoethyl morpholino group, 3-methylaminoethyl morpholi Furnace group, 3-dimethylaminoethyl morpholino group; Thiomorpholino groups, 3-oxothiomorpholino groups, 1,1-dioxothiomorpholino groups, 3-hydroxymethylthiomorpholino groups, 3-hydroxyethylthiomorpholino groups; Hexahydropyridazin-1-yl group, 2-acetylhexahydropyridazin-1-yl group, 2-formylhexahydropyridazin-1-yl group, 3-oxohexahydropyridazin-1-yl group, 2-methylhexa Hydropyridazin-1-yl groups, 2-carbamoylhexahydropyridazin-1-yl groups; 2-oxohexahydropyrimidin-1-yl group, 4-oxohexahydropyrimidin-1-yl group, 3-methylhexahydropyrimidin-1-yl group, 6-hydroxymethylhexahydropyrimidin-1-yl group; 2-oxo-4-methyl homopiperazino group, 3-oxo-4-methyl homopiperazino group, 5-oxo-4-methyl homopiperazino group, 7-oxo-4-methyl homopiperazino group, 2, 3-dioxo-4-methyl homopiperazino group, 2,7-dioxo-4-methyl homopiperazino group, 3,5-dioxo-4-methyl homopiperazino group, 3,7-dioxo- 4-methyl homopiperazino group, 4-methyl homopiperazino group, 4-ethyl homopiperazino group, 4-cyclopropyl homopiperazino group, 2-cyclopropanespiro-4-methyl homopiperazino group, 3-cyclo Propanespiro-4-methyl homopiperazino group, 5-cyclopropanespiro-4-methylhomopiperazino group, and 7-cyclopropanespiro-4-methylhomopiperazino group; 1,4-oxazepan-4-yl group; 3-methyl-4-oxoimidazolidin-1-yl group.

Among these, the following are especially preferable.

3-dimethylaminoazetidin-1-yl group, 2,2-dimethyl-3-dimethylaminoazetidin-1-yl group, 2-hydroxymethylazetidin-1-yl group, 2-carbamoylazetidin-1-yl group , 3-methoxyazetidin-1-yl group; 2-oxopyrrolidino group, 2-hydroxymethylpyrrolidino group, 2-carbamoylpyrrolidino group, 3-fluoropyrrolidino group, 2-fluoromethylpyrrolidino group, 2-fluoro Methylpyrrolidino group; Pyrazolidino group, 2-formyl-pyrazolidin-1-yl group, 2-carbamoylpyrazolidin-1-yl group; Piperidino group, 2-hydroxymethylpiperidino group, 2- (1-aminocyclopropyl) piperidino group, 2-carbamoylpiperidino group, 2-methylcarbamoylpiperidino group, 2-dimethylcarbamoylpiperididi Furnace group, 3-methoxypiperidino group, 3-fluoropiperidino group, 4-fluoropiperidino group, 4-methylpiperidino group, 4-methoxypiperidino group, 3,3-difluoropiperididi No group, 4,4-difluoropiperidino group, 4-fluoromethylpiperidino group, 4-methyl-4-methoxypiperidino group, 4,4-difluoro-2-carbamoylpiperidino group, 4-methylene piperidino group, 4- (difluoromethylene) piperidino group; 3-oxo-4-methyl piperazino group, 3-oxo-4-ethyl piperazino group, 4-methyl piperazino group, 4-ethyl piperazino group, 4-isopropyl piperazino group, 4-cyclopropyl piperazin No group, 2,4-dimethylpiperazino group, 3,4-dimethylpiperazino group, 3-cyclopropyl-4-methylpiperazino group, 3,4,5-trimethylpiperazino group, 2,2,4-trimethyl Piperazino group, 3,3,4-trimethylpiperazino group, 4,6-dimethyl-3-oxopiperazino group, 3,5-dioxo-4-methylpiperazino group, 4-methoxy piperazino group, 2-cyclopropanespiro-4-methylpiperazino group; Morpholino group, 3-carbamoyl morpholino group, 3-methyl morpholino group; 1,1-dioxothiomorpholino group, thiomorpholino group; 2-methylhexahydropyridazin-1-yl group, 3-methylhexahydropyridazin-1-yl group; 3-oxo-4-methyl homopiperazino group, 5-oxo-4-methyl homopiperazino group, 4-methyl homopiperazino group, 4-ethyl homopiperazino group, 4-cyclopropyl homopiperazino group; 1,4-oxazepan-4-yl group; Piperidino group, 4-methoxypiperidino group, 4,4-difluoropiperidino group, 3,3-difluoropiperidino group, 3-fluoropiperidino group, 4-fluoropiperidino group, 4-fluoromethylpiperidino group; 2-dimethylaminomethylpyrrolidino group, 3-dimethylaminopyrrolidino group, 3-methoxypyrrolidino group; 3-methyl-4-oxoimidazolidin-1-yl group; Hexahydropyridazin-1-yl group, 2-acetylhexahydropyridazin-1-yl group, 2-carbamoylhexahydropyridazin-1-yl group.

Among these, the following are most preferable.

3-dimethylaminoazetidin-1-yl group, 3-methoxyazetidin-1-yl group; 2-fluoromethylpyrrolidino group, 3-fluoropyrrolidino group; Pyrazolidino group, 2-formyl-pyrazolidino group; Piperidino group, 2- (1-aminocyclopropyl) piperidino group, 2-carbamoyl piperidino group, 2-methylcarbamoyl piperidino group, 2-dimethylcarbamoyl piperidino group, 3-methoxypiperidino group , 3-fluoropiperidino group, 4-fluoromethylpiperidino group, 4-methoxypiperidino group, 4-fluoropiperidino group, 4,4-difluoropiperidino group, 4-methyl-4 -Methoxypiperidino group, 4-methylene piperidino group, 4- (difluoromethylene) piperidino group; 4-cyclopropylpiperazino group, 3-oxo-4-methylpiperazino group, 3-oxo-4-ethylpiperazino group, 4-methylpiperazino group, 4,6-dimethyl-3-oxopiperazino group, 3,5-dioxo-4-methyl piperazino group; 4-methyl-3-oxo homopiperazino group; Hexahydropyridazin-1-yl group, 2-carbamoyl hexahydropyridazin-1-yl group; Morpholino group.

As the salt of the compound (I) of the present invention, not all compounds of the present invention form salts, but salts are formed when the compound has a carboxyl group, an amino group or the like, or when Ar ₁ or Ar ₂ is a pyridine ring or the like. Moreover, the salt may form solvate. Salts here are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid; Salts of 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 in the solvate of the compound (I) of the present invention or a salt thereof includes those formed by absorbing moisture in the air in addition to the solvate to which the solvent used for crystallization and the like is added. As an example of a solvent, organic solvents, such as lower alcohol, such as water, methanol, and ethanol, acetone, and acetonitrile, etc. are mentioned, for example.

Compound (I) of the present invention can be produced by the following method. Below, the typical manufacturing method of compound (I) of this invention is described.

(In said formula, Ar <_1> and Ar <_2> represent the same thing as the above, and R <^1> represents a methyl group or an ethyl group.)

Compound (2) can be obtained by treating aromatic ketone (1) and oxalic acid dialkyl ester in an alcohol (methanol or ethanol) solution in the presence of sodium alkoxide (sodium methoxide or sodium ethoxide). The reaction temperature is preferably -10 to 100 ° C.

In addition, compound (2) dissolves or suspends compound (1) and oxalic acid dialkyl ester in a suitable solvent such as N, N-dimethylformamide, and reacts with sodium hydride at -20 to 20 ° C under argon stream. It can manufacture.

Furthermore, compound (2) is also prepared by dissolving in an inert solvent such as tetrahydrofuran of compound (1), treating with a base such as lithium bis (trimethylsilyl) amide under cooling, and reacting with oxalic acid diethyl ester. can do. As for reaction time, -78-20 degreeC is preferable, and -78 degreeC is especially preferable.

In addition, you may use the compound (1) manufactured by the method as described in a commercial item or a reference example, or the method according to the method.

When compound (1) has functional groups, such as a hydroxyl group and an amino group, it is preferable to protect these functional groups previously with a suitable protecting group. Examples of the protecting group for the hydroxyl group include tert-butyl group and benzyl group, and examples of the protecting group for the amino group include trifluoroacetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group. These protecting groups can be deprotected under conditions suitable for each protecting group.

Subsequently, compound (2) is dissolved in alcohol (methanol or ethanol), hydrazine derivative (4) or a salt thereof is added thereto at room temperature, and then an appropriate amount of acetic acid is added and heated to reflux to prepare compound (5). can do. At that time, the position isomer 6 is by-produced, and the desired compound (5) can be easily separated and purified by silica gel column chromatography or the like.

The hydrazine derivative (4) or a salt thereof can be prepared by dissolving the aromatic amine (3) in concentrated hydrochloric acid, adding sodium nitrite under ice-cooling to guide the diazo body, and then treating with tin chloride (II). The reaction temperature is preferably -10 to 20 ° C.

The hydrazine derivative (4) may be used that prepared by the method according to the method or process of reacting a hydrazine in a halogenated Ar ₁ as set forth in one or a reference example of a commercially available. Moreover, aromatic amine (3) can be manufactured by the method as described in a commercially available compound, a reference example, or the method.

In the pyrazole ring forming reaction, an appropriate amount of triethylamine or concentrated hydrochloric acid may be added and heated to reflux instead of acetic acid, and in some cases, even if acetic acid, triethylamine or concentrated hydrochloric acid is not added, the compound (5 ) Can be obtained.

In the pyrazole ring formation reaction, a 4,5-dihydro-5-hydroxy-1H-pyrazole body may be obtained together with compound (5) as an intermediate, but the obtained mixture is dissolved in a solvent such as methylene chloride. Then, by adding and stirring methanesulfonyl chloride, triethylamine and 4-dimethylaminopyridine, the intermediate can be introduced into compound (5).

The compound (5) can be derived to the manufacturing intermediate (7) by hydrolysis of an ester using a base, Lewis acid, or the like, based on common knowledge of organic chemistry. As a base, the hydroxide of an alkali metal (for example, lithium, sodium, potassium, etc.) is mentioned. Moreover, as a Lewis' acid, boron tribromide is mentioned, for example. The reaction temperature is preferably -20 to 100 ° C, particularly preferably -5 to 50 ° C.

In addition, compound (5) can be converted into various derivatives by further modifying the formula, based on common knowledge of organic chemistry. For example, each derivative (5b-d) of alcohol, a triflate, and a nitrile can be manufactured from compound (5a).

(In formula, Ar <_1> shows the same thing as the above, Bn represents a benzyl group, and R <^1> represents a methyl group or an ethyl group.)

Specifically, the hydroxy body 5b can be produced by dissolving benzyloxy body 5a in ethanol or the like and contact reduction using 10% palladium-carbon as a catalyst. Compound (5c) can be prepared by dissolving the hydroxy compound (5b) in methylene chloride or the like and reacting with anhydrous trifluoromethanesulfonic acid at -50 to 50 ° C in the presence of a base such as pyridine. Furthermore, cyanobody 5d can be manufactured by dissolving compound (5c) in dichloroethane and the like and reacting with cyanotri n-butyltin and tetrakis (triphenylphosphine) palladium (O). As for reaction temperature, 10-100 degreeC is preferable. What is necessary is just to select conditions of this reaction, a reagent, etc. suitably based on the common knowledge of organic chemistry.

Moreover, as shown below, each derivative (5f-h) of carboxylic acid, an amide, an amine, etc. can be manufactured from compound (5e).

(In formula, Ar <_1> and R <^1> show the same thing as the above, and Boc shows a tert-butoxycarbonyl group.)

Specifically, carboxylic acid 5f can be produced by dissolving methylpyrazine 5e in pyridine or the like and heating and refluxing after adding selenium dioxide at room temperature. An amide (5 g) can be manufactured by condensing carboxylic acid (5f) with aqueous ammonia, ammonium chloride, etc. using a suitable condensing agent. The amine (5h) can be produced by dissolving carboxylic acid (5f) in dioxane or the like and heating and refluxing after addition of tert-butanol, triethylamine and diphenylphosphoryl azide at room temperature. What is necessary is just to select conditions of this reaction, a reagent, etc. suitably based on the common knowledge of organic chemistry.

As mentioned above, the compound (5) can hydrolyze the ester to lead to the production intermediate (7).

Compound (I) of the present invention can be obtained by condensation of the manufacturing intermediate (7) and the amine (8).

(In formula, Ar <_1> and Ar <_2> show the same thing as the above.)

What is necessary is just to apply the method generally used as said peptide synthesis method as said condensation reaction. As the peptide synthesis method, for example, the azide method, the acid chloride method, the acid anhydride method, the DCC (dicyclohexylcarbodiimide) method, the active ester method, the carbonyldiimidazole method, the DCC / HOBT (1-hydroxy) Benzotriazole) method, a method using water-soluble carbodiimide, a method using diethyl cyanophosphate, and the like, and their methods are described by M. Bodanszky, YS Klausner and MA Ondetti, "Peptide Synthesis" (A Wiley-interscience publication, New York, 1976), GR Pettit, "Synthetic Peptides" (Elsevier Scientific Publication Company, New York, 1976), Japanese Chemical Society, Vol. (Maruzen Kabushikiisha, 1992). As a solvent used for this condensation reaction, N, N- dimethylformamide, pyridine, chloroform, methylene chloride, tetrahydrofuran, dioxane, acetonitrile, or these mixed solvents are mentioned. -20-50 degreeC is preferable and -10-30 degreeC of reaction temperature is more preferable. The amine 8 may use a commercially available compound, or the one manufactured by the method as described in the literature, the method as described in a manufacturing example, or the method according to those methods.

In addition, in the said condensation reaction, when the amine body 8 has functional groups, such as a hydroxyl group, an amino group, and a carboxyl group, it is preferable to protect these functional groups previously using a suitable protecting group. In the case of a hydroxyl group, in the case of an amino group, such as a tert- butyl group and a benzyl group, in the case of an carboxyl group, such as a trifluoroacetyl group, tert-butoxycarbonyl group, and a benzyloxycarbonyl group, methyl ester, tert- butyl ester, etc. After induction, the condensation reaction may be provided.

The compound (I) of the present invention produced by the above method can be converted into a derivative of the compound (I) by further modifying the formula based on common knowledge of organic chemistry. For example, each derivative (Ib-Id) of alcohol, triflate, nitrile, and amide can be obtained from compound (Ia), and a methoxy derivative (If) can be obtained from alcohol (Ib).

(In formula, Ar <_1> represents the same thing as the above and Bn represents a benzyl group.)

Specifically, the alcohol (Ib) can be produced by dissolving the compound (Ia) in ethanol or the like and contact reduction using 10% palladium-carbon as a catalyst. Compound (Ic) can be prepared by dissolving alcohol (Ib) in methylene chloride or the like and reacting with trifluoromethanesulfonic anhydride at -50 to 50 ° C in the presence of a base such as pyridine. Nitrile (Id) can be manufactured by dissolving compound (Ic) in dichloroethane etc. and adding cyano tri n-butyltin and tetrakis (triphenylphosphine) palladium (O), and stirring. As for reaction temperature, 10-100 degreeC is preferable. The amide (Ie) can be obtained by dissolving nitrile (Id) in methanol, tetrahydrofuran, etc., and hydrolyzing using sodium hydroxide. As for reaction temperature, 0-100 degreeC is preferable. In addition, the amide (Ie) can be produced by inducing nitrile (Id) to a carboxylic acid and then condensing with ammonia water, ammonium chloride or the like using a suitable condensing agent.

A methoxy body (If) can be manufactured by dissolving alcohol (Ib) in a mixed solvent such as methanol, tetrahydrofuran, methylene chloride, and adding and stirring a hexane solution of (trimethylmethylsilyl) diazomethane at room temperature. . As for reaction temperature, 0-50 degreeC is preferable. When protection of a functional group is needed, the conditions of protection or deprotection may be suitably selected based on the common knowledge of organic chemistry.

In addition, the compounds (Ia to If) of the present invention can be converted to other derivatives of the present invention by further modifying the formulas based on common knowledge of organic chemistry.

Compound (I), salts thereof, or solvates thereof of the present invention have potent antiplatelet action and strongly inhibited thrombus formation even in high shear stress-induced thrombosis models. Accordingly, the compound (I) of the present invention, salts thereof, or solvates thereof may be used in mammals including humans for myocardial infarction, angina (chronic angina, unstable angina, etc.), ischemic cerebrovascular disorders (transient cerebral ischemic attack (TIA) ), Cerebral infarction, peripheral vascular disorders, occlusion after artificial vessel replacement, coronary artery intervention (coronary artery bypass grafting (CAGB), percutaneous transluminal coronary angioplasty (PTCA) Prevention of ischemic diseases caused by thromboembolism and / or embolism, such as thrombotic occlusion after diabetic stent placement, diabetic retinopathy, nephropathy, and obstruction when artificial heart valve is replaced. It is useful as a therapeutic agent. It is also useful as a prophylactic and / or therapeutic agent for thrombosis and embolism associated with vascular surgery, extracorporeal blood circulation and the like. Moreover, it is also useful for the improvement of hypotensive symptoms such as ulcers, pain and coldness associated with chronic arterial occlusion.

In the case of using the compound (I), salts thereof or solvates thereof of the present invention as a medicament, the dosage varies depending on the age, sex and symptoms of the patient, but the daily dose per adult is preferably 0.1 mg to 1 g. Especially, 0.5 mg-500 mg are preferable. In this case, the daily amount may be divided into several times, and if necessary, the daily amount may be exceeded.

A medicament comprising the compound (I), a salt thereof, or a solvate thereof of the present invention as an active ingredient can be used depending on the administration method and the dosage form as necessary, and the preparation method is a pharmaceutical preparation method according to the necessity. What is necessary is just to mix | blend an acceptable carrier, and to select the formulation suited to a dosage method, and a dosage form and a dosage form are not specifically limited.

Examples of oral preparations include liquid preparations such as liquids, syrups, elixirs, suspensions, and emulsions, in addition to solid preparations such as tablets, powders, granules, pills, and capsules. .

As an injection, compound (I), its salt, or its solvate may be melt | dissolved, and may be filled in a container, and also it may be made into the preparation of a preparation at the time of solid by lyophilization etc.

When preparing these preparations, pharmaceutically acceptable additives such as binders, disintegrating agents, dissolution accelerators, lubricants, fillers, excipients and the like can be selected and used as necessary.

Although an Example is given to the following and this invention is demonstrated in more detail, this invention is not limited to this.

Reference Example 1 3-Hydrazinopyridine

An aqueous solution of sodium nitrite (10.5 g) and water (39 mL) was added dropwise to a concentrated solution of 3-aminopyridine (13.0 g) in 5 mL or less over 30 minutes, followed by stirring for 15 minutes. . The reaction solution was added dropwise to a concentrated hydrochloric acid (59 ml) solution of tin chloride (II) dihydrate (109 g) over 5 minutes at 5 ° C. or lower, followed by stirring for 1 hour. Aqueous 6N sodium hydroxide solution (796 ml) was added dropwise to the reaction solution at the same temperature, methanol-chloroform (1:10) mixed solvent was added to the reaction solution for separation, and the organic layer solvent was distilled off under reduced pressure. The title compound (12.5 g, 83%) was obtained as a solid.

Reference Example 2 2-Hydrazinopyrazine

To a solution of 2-chloropyrazine (10.44 g) in ethanol (65 mL), hydrazine monohydrate (21.80 g) was added at room temperature and heated to reflux for 17 hours. After air cooling, benzene was added to the residue obtained by distilling off the reaction solvent under reduced pressure, and the insolubles were separated by decantation. The title compound (4.67 g, 47%) was obtained by adding hexane to the solid obtained by distilling a benzene solvent off under reduced pressure, and filtering.

Reference Example 3 2-Hydrazinopyrimidine

To a ethanol (60 mL) suspension of 2-chloropyrimidine (6.00 g) was added hydrazine monohydrate (20 mL) at room temperature and stirred for 80 minutes. Water (34 mL) was added to the residue obtained by distilling off the solvent of the reaction solution under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (2.30 g, 40%).

Reference Example 4 5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

4) 5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Ethanol (152 mL) suspension of 4- (5-benzyloxy-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (7.61 g) and 3-hydrazinopyridine (3.04 g) of Reference Example 1 To the mixture was added acetic acid (6.65 ml) at room temperature and heated to reflux for 64 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform) to give 5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (7.38 g, 79%) was obtained as a solid.

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

To the pyridine (83 mL) solution of 5-benzyloxy-2-methylpyridine (4.13 g), selenium dioxide (9.20 g) was added at room temperature and heated to reflux for 61 hours. After air cooling, water and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the residue was obtained by distilling off the solvent under reduced pressure, N, O-dimethylhydroxyamine hydrochloride (2.22 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.37 g), and Triethylamine (6.35 mL) was added to a N, N-dimethylformamide (95 mL) solution of 1-hydroxybenzotriazole (3.08 g) at room temperature, followed by stirring for 61 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to give 5-benzyloxypyridine-2-carboxylic acid N-methoxy-N-methylamide (3.75 g, 66%) was obtained as an oily substance (FAB-MS m / z: 273 (M + H) ⁺ .).

Methyllithium (1.10 M diethyl) in a tetrahydrofuran (75 ml) solution of 5-benzyloxypyridine-2-carboxylic acid N-methoxy-N-methyl amide (3.74 g) at 0 ° C. under argon atmosphere. Ether solution, 13.7 ml) was added dropwise and stirred for 40 minutes. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1- (5-benzyloxy-2-pyridyl) ethanone (1.47 g, 47%). Was obtained as an oil.

3) 4- (5-benzyloxy-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester

Diethyl oxalate (1.75 mL) and 1- (5-benzyloxy-2-pyridyl) ethanone (1.46 g) in ethanol (15 mL) solution of sodium ethoxide (0.874 g) under argon atmosphere. A solution (15 mL) was added and stirred at room temperature for 7 hours, followed by stirring at 60 ° C for 1 hour. After air cooling, sodium ethoxide (0.874 g) and diethyl oxalate (1.75 mL) were further added to the reaction solution, and the mixture was stirred at 60 ° C for 1 hour. After air cooling, water was added to the reaction solution, washed with diethyl ether, and saturated aqueous ammonium chloride solution and chloroform were added to the aqueous layer for separation. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (5-benzyloxy-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (1.38 g, 66%) as a solid.

4) 5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Ethanol (152 mL) suspension of 4- (5-benzyloxy-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (7.61 g) and 3-hydrazinopyridine (3.04 g) of Reference Example 1 To the mixture was added acetic acid (6.65 ml) at room temperature and heated to reflux for 64 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform) to give 5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (7.38 g, 79%) was obtained as a solid.

5) Title compound

5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl terter (5.16 g) in methanol (50 mL) and tetra To the hydrofuran (50 mL) mixed solution, 1N aqueous sodium hydroxide solution (32.2 mL) was added at room temperature, followed by stirring for 160 minutes. The reaction solvent was distilled off under reduced pressure, and chloroform and water were added to the residue, followed by dissolving. Then, 1N aqueous hydrochloric acid solution (33 ml) was added to neutralize. Water and methanol-chloroform (1: 5) mixed solvent were added to the reaction solution, the mixture was separated, and the organic layer solvent was distilled off under reduced pressure to obtain the title compound (4.61 g, 96%) as a solid.

Reference Example 5 5- (5-Chloro-2-pyridyl) -1- (3-pyridyl) -1 H-pyrazole-3-carboxylic acid

1) 2-bromo-5-chloropyridine

At 0 ° C., bromine (12 mL) is added to 47% hydrobromic acid solution (50 mL) of 2-amino-5-chloropyridine (5 g), and sodium nitrite (15 g) and water are further added to the reaction solution. An aqueous solution of (20 mL) was added dropwise and stirred for 1 hour. An aqueous solution of sodium hydroxide (32 g), water (80 ml) and ethyl acetate were added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 2-bromo-5-chloropyridine (6.8 g, 91%) as a solid.

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

N-butyllithium (1.56 M hexane solution, 27 ml) was added dropwise by cooling a diethyl ether (45 ml) solution of 2-bromo-5-chloropyridine (6.8 g) at -78 deg. -Dimethylacetamide (5 ml) was added dropwise and stirred for 30 minutes. A saturated ammonium chloride aqueous solution was added to the reaction solution, ethyl acetate was further added to the solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- (5-chloro-2-pyridyl) ethanone (3.26 g, 59%) as a solid. Obtained as.

3) 4- (5-chloro-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester

Diethyl oxalate (1.75 mL) was added to an ethanol (30 mL) solution of sodium ethoxide (0.88 g), followed by stirring for 5 minutes, followed by further 1- (5-chloro-2-pyridyl) ethanone (1.00 g). Was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, the mixture was washed with diethyl ether, the aqueous layer was made acidic with 1N aqueous hydrochloric acid solution, and chloroform was added thereto for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (5-chloro-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (2.59 g, quantitative) as a solid.

4) 5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

To the ethanol (100 mL) solution of 4- (5-chloro-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (2.59 g) and 3-hydrazinopyridine (1.2 g) of Reference Example 1 Acetic acid (5 mL) was added and heated to reflux for 16.5 hours. After air cooling, water and ethyl acetate were added to the reaction mixture for separation, 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 the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to give 5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H- Pyrazole-3-carboxylic acid ethyl ester (1.5 g) was obtained.

5) Title compound

Sodium methoxide in methanol (10 mL) solution of 5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (500 mg) (573 mg) was added and stirred for 17.5 hours at room temperature. An aqueous solution of 1N hydrochloric acid and chloroform were added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (348 mg, 76%) as a solid.

Reference Example 6 5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 5-Methylpyrazine-2-carboxylic acid N-methoxy-N-methylamide

5-Methylpyrazine-2-carboxylic acid (13.0 g), N, O-dimethylhydroxylamine hydrochloride (10.1 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (19.8 g) Triethylamine (28.9 mL) was added to a 1, hydroxybenzotriazole (14.0 g) N, N-dimethylformamide (130 mL) solution at room temperature, followed by stirring for 63 hours. Water and ethyl acetate were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give 5-methylpyrazine-2-carboxylic acid N-methoxy-N-methylamide (12.3 g, 72%) was obtained as a solid.

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

Under argon atmosphere, methyllithium (1.02 M) was cooled in a tetrahydrofuran (183 mL) solution of the 5-methylpyrazine-2-carboxylic acid N-methoxy-N-methylamide (12.2 g) at -78 ° C. Solution of diethyl ether, 72.6 ml) was added dropwise over 20 minutes, and then stirred for 130 minutes. Water and ethyl acetate were added and liquid-separated into the reaction liquid at 0 degreeC, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1- (5-methyl-2-pyrazinyl) ethanone (7.9 g, 86%) as an oil phase. Obtained as water.

3) 4- (5-methyl-2-pyrazinyl) -2,4-dioxobutanoic acid ethyl ester

To an aqueous solution of 1- (5-methyl-2-pyrazinyl) ethanone (7.89 g) in tetrahydrofuran (118 ml) under argon atmosphere, lithium bis (trimethylsilyl) amide (1.0 M tetra Hydrofuran solution, 63.7 ml) was added dropwise over 20 minutes, followed by further stirring for 30 minutes. Diethyl oxalate (11.8 ml) was added dropwise to the reaction solution, followed by stirring for 10 minutes. After stirring at 0 degreeC for 30 minutes, and also 1.5 hours at room temperature, water and diethyl ether were added and liquid-separated into the reaction liquid, and aqueous ammonium chloride aqueous solution and chloroform were added and liquid-separated. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (5-methyl-2-pyrazinyl) -2,4-dioxobutanoic acid ethyl ester (4.92 g, 36%) as a solid.

4) 5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

The ethanol (98 mL) solution of 4- (5-methyl-2-pyrazinyl) -2,4-dioxobutanoic acid ethyl ester (4.91 g) and 3-hydrazinopyridine (2.27 g) of Reference Example 1 was prepared. Heated to reflux for 40 minutes. Acetic acid (5.95 mL) was added to the reaction solution, and the mixture was further heated to reflux for 14 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was dissolved in ethanol (99 mL), concentrated hydrochloric acid (3.3 mL) was added to the reaction solution, and the mixture was heated and refluxed for 1 hour. After air cooling, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (acetone-toluene) to give 5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H- Pyrazole-3-carboxylic acid ethyl ester (3.16 g, 49%) was obtained as a solid.

5) Title compound

5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.60 g) with 1 N sodium hydroxide (4.85 mL) In the same manner as in 5) of the Reference Example 4, the title compound (0.525 g, 96%) was obtained as a solid.

Reference Example 7 5- (5-carbamoyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 5- (5-carboxy-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Pyridine (51 mL) of 5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (2.55 g) of Reference Example 6 ) To the solution was added selenium dioxide (3.66 g) at room temperature and heated to reflux for 67 hours. After air cooling, water and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solid obtained by distilling a solvent off under reduced pressure was washed with diethyl ether to give 5- (5-carboxy-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3- Carboxylic acid ethyl ester (2.51 g, 90%) was obtained.

2) 5- (5-carbamoyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Under argon atmosphere, the 5- (5-carboxy-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.70 g) and ammonium chloride (2.68 g) In the same manner as in 1) of Reference Example 6, 5- (5-carbamoyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.540 g, 32%) was obtained as a solid.

3) the title compound

To a tetrahydrofuran (11 mL) suspension of 5- (5-carbamoyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.530 g), At room temperature, an aqueous solution of lithium hydroxide monohydrate (72.3 mg) and water (5.5 mL) was added dropwise and stirred for 105 minutes. Aqueous 1 N hydrochloric acid solution (1.72 mL) was added to the reaction solution, and the precipitated solid was collected by filtration to obtain the title compound (0.445 g, 92%).

Reference Example 8 5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

A method)

1) 5- (5-hydroxy-2-pyridine) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Ethanol (463) of 5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (4.63 g) of Reference Example 4) 10% palladium-carbon (4.63 g) was added to the ethyl acetate (46 mL) solution and the mixture was stirred at room temperature for 6 hours in the presence of hydrogen. The catalyst was filtered off with the reaction solution, and the filtrate solvent was distilled off under reduced pressure to obtain 5- (5-hydroxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid. Ethyl ester (3.48 g, 97%) was obtained as a solid.

2) 1- (3-pyridyl) -5- (5-trifluoromethanesulfonyloxy-2-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Dichloromethane (69 mL) of 5- (5-hydroxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (3.47 g) under argon atmosphere Trifluoromethanesulfonic anhydride (2.26 ml) was added dropwise to the pyridine (23 ml) mixed solution at room temperature, followed by stirring for 85 minutes. Water and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain 1- (3-pyridyl) -5- (5-trifluoromethanesulfonyloxy 2-Pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (4.95 g, quantitative) was obtained as a solid.

3) the title compound

Under argon atmosphere, a suspension of dichloroethane (133 ml) of tri-cyanide cyanide (14.1 g) and tetrakis (triphenylphosphine) palladium (O) (19.4 g) was heated to reflux for 2 hours. Dichloroethane of 1- (3-pyridyl) -5- (5-trifluoromethanesulfonyloxy-2-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (4.94 g) to the reaction solution (109 ml) The solution was added dropwise and then heated to reflux for 13 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, filtered using celite, water and chloroform were added to the filtrate, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform) to give 5- (5-cyano-2-pyridyl) -1- (3-pyridyl)- 1H-pyrazole-3-carboxylic acid ethyl ester was obtained. An aqueous solution of lithium hydroxide monohydrate (0.470 g) and water (43 mL) was added dropwise to the tetrahydrofuran (87 mL) suspension of the obtained ethyl ester at room temperature, followed by stirring for 40 minutes. Water and chloroform were added to the reaction mixture for separation. Aqueous solution of 1 N hydrochloric acid (11.2 ml) was added to the aqueous layer, followed by neutralization. Then, a mixed solvent of methanol-chloroform (1:10) was added thereto to separate the solvent. Was obtained as a solid.

Method B)

1) 2-acetyl-5-cyanopyridine

To a mixture of 3-cyanopyridine (3.12 g), pyribic acid (6.23 mL) and silver nitrate (1.27 g) dichloromethane (150 mL) and water (150 mL), at room temperature, peroxo disulfide Ammonium (10.3 g) was added slowly. The reaction solution was cooled under ice and sulfuric acid (3.2 ml) was added gradually, and the mixture was stirred at 40 ° C for 1.5 hours. Under ice-cooling, 1M aqueous sodium hydroxide solution was added to the reaction solution to make it alkaline, and dichloromethane was added for extraction. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2-acetyl-5-cyanopyridine (903 mg, 21%) as a solid.

2) 4- (5-cyano-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester

4- (5-cyano-2-pyridyl) -2 in the same manner as in 3) of Reference Example 6 using 2-acetyl-5-cyanopyridine (900 mg) and diethyl oxalate (1.67 mL) , 4-dioxobutanoic acid ethyl ester (1.188 g, 78%) was obtained as a solid.

3) 5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Using 4- (5-cyano-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (1.72 g) and 3-hydrazinopyridine (0.92 g) of Reference Example 1, 5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.01 g, 45) in the same manner as in 3) of A method) %) Was obtained as a solid.

4) Title compound

5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (5.69 g) and lithium hydroxide monohydrate (823 mg) To obtain the title compound (5.19 g, quantitative) as a solid in the same manner as 3) of Reference Example 7.

Reference Example 9 5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

[A law]

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

To a solution of 2-bromo-5-picoline (5.0 g) in diethyl ether (100 ml) was added dropwise n-butyllithium (1.58 M hexane solution, 24 ml) over 5 minutes under -78 ° C cooling. And stirred for 5 minutes. N, N-dimethylacetamide (3.5 ml) was added dropwise to the reaction solution, followed by stirring for 2 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1- (5-methyl-2-pyridyl) ethanone (3.43 g, 87%) as an oil phase. Obtained as water.

2) 4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester

Diethyl oxalate (7 mL) was added dropwise to an ethanol (60 mL) solution of sodium ethoxide (3.5 g) at room temperature, and then 1- (5-methyl-2-pyridyl) ethanone (3.43 g) was added to the reaction solution. Ethanol (40 mL) solution was added and stirred for 2 hours. Water and diethyl ether were added to the reaction solution for separation. An aqueous solution of 1 N hydrochloric acid was added to the aqueous layer to make it acidic, and further, chloroform was added to separate the aqueous layer, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (6.8 g) as a solid.

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

To the ethanol (30 mL) solution of 4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (3.50 g), 3-hydrazinopyridine (2.0 g) of Reference Example 1 And concentrated hydrochloric acid (2 ml) were added, and the mixture was heated to reflux for 17.5 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-methanol) to give 5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H- Pyrazole-3-carboxylic acid ethyl ester (2.51 g, 55%) was obtained.

4) Title compound

Sodium ethoxy to the ethanol (80 ml) solution of the 5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (2.51 g) Seed (1.11 g) was added at room temperature and stirred for 19.5 hours. Water and diethyl ether were added to the reaction solution for separation. An aqueous solution of 1 N hydrochloric acid was added to the aqueous layer to make it acidic, chloroform was added to separate the aqueous layer, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (1.33 g, 58%).

[B method]

1) 4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid methyl ester

Dimethyl oxalate (10.4 g) was added to a methanol (200 mL) solution of sodium methoxide (4.74 g) at room temperature, followed by stirring for 5 minutes. 1- (5-methyl-2-pyridyl) ethanone (5.93 g) was added to the reaction solution at room temperature, followed by stirring for 5 hours. Water and diethyl ether were added to the reaction mixture for separation. The aqueous layer was made acidic with 1N aqueous hydrochloric acid solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid methyl ester (7.31 g, 75%) as a solid.

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

3-Hhydrazinopyridine (3.0 g) of Reference Example 1 to a methanol (250 mL) solution of 4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid methyl ester (4.0 g). And concentrated hydrochloric acid (4 mL) were added, and the mixture was heated and refluxed for 2.5 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to give 5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H- Pyrazole-3-carboxylic acid methyl ester (3.24 g, 61%) was obtained as a solid.

3) the title compound

To a tetrahydrofuran (100 ml) solution of 5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (3.24 g), room temperature Aqueous solution of 1N sodium hydroxide (16 ml) was added thereto, followed by stirring for 2 hours. An aqueous solution of 1 N hydrochloric acid and chloroform were added to the reaction mixture, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (2.0 g, 65%) as a solid.

Reference Example 10 5- (5-methyl-2-pyridyl) -1- (3-pyridazinyl) -1H-pyrazole-3-carboxylic acid

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

4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (5.56) of 6-chloro-3-hydrazinopyridazine (3.44 g) and 2) of method A of Reference Example 9 To the ethanol (60 mL) solution was added concentrated hydrochloric acid (1.2 mL) at room temperature, and the mixture was heated to reflux for 16 hours. After air cooling, 1N aqueous sodium hydroxide solution was added to the reaction solution to neutralize the mixture, and the precipitated solid was collected by filtration to obtain 1- (6-chloro-3-pyridazinyl) -5- (5-methyl-2-pyridyl). -1H-pyrazole-3-carboxylic acid ethyl ester (4.48 g, 55%) was obtained.

2) 5- (5-methyl-2-pyridyl) -1- (3-pyridazinyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Ethanol (70 mL) solution of 1- (6-chloro-3-pyridazinyl) -5- (5-methyl-2-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (2.58 g) To the mixture was added 10% palladium-carbon (1.27 g) and ammonium formate (2.615 g) at room temperature, followed by stirring at 75 ° C for 1 hour. After air cooling, the insoluble solid was filtered off, and the filtrate solvent was distilled off under reduced pressure. Water and chloroform were added and liquid-separated into the obtained residue, the aqueous layer was further extracted with chloroform, the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to give 5- (5-methyl-2-pyridyl) -1- (3-pyridazinyl) -1H. -Pyrazole-3-carboxylic acid ethyl ester (1.126 g, 49%) was obtained as a solid.

3) the title compound

Tetrahydrofuran (20 mL) of 5- (5-methyl-2-pyridyl) -1- (3-pyridazinyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.126 g), ethanol ( Lithium hydroxide monohydrate (0.173 g) was added to the aqueous solution of 10 ml) and water (20 ml) at room temperature, and it stirred for 2.5 hours. Aqueous 1N hydrochloric acid solution was added to the reaction solution to make acid (pH 5), and chloroform-methanol (15: 1) was added thereto to separate the solution. The aqueous layer was further extracted with chloroform-methanol (15: 1) and the combined organic layers were dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (0.688 g, 69%) as a solid.

Reference Example 11 4-methoxypiperidine trifluoro acetate

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

4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.00 g) in an N, N-dimethylformamide (20 mL) suspension of sodium hydride (60%, 0.477 g) at room temperature under argon atmosphere. N, N-dimethylformamide (20 mL) solution was added dropwise and stirred for 15 minutes. Methyl iodide (0.742 mL) was added dropwise to the reaction solution, and the mixture was stirred for 2 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, 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 purified by silica gel column chromatography (ethyl acetate-hexane) to give 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (1.43 g, 67% ) Was obtained as an oily substance.

2) the title compound

Trifluoroacetic acid (14 mL) was added to the dichloromethane (28 mL) solution of the 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (1.42 g) at room temperature, followed by stirring for 2.5 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain the title compound (2.65 g, quant.) As an oil.

Reference Example 12 4,4-difluoropiperidine hydrochloride

1) 1-benzyl-4,4-difluoropiperidine

Under argon atmosphere, diethylaminosulfur trifluoride (8.38 ml) was added dropwise to a benzene (200 ml) solution of 1-benzyl-4-piperidone (5.00 g) at 0 ° C, stirred for 30 minutes, and heated for 18 hours. It was refluxed. Under 0 degreeC cooling, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added and liquid-separated, 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 purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-benzyl-4,4-difluoropiperidine (4.67 g, 84%). Was obtained as an oil.

2) the title compound

To the dichloromethane (93 mL) solution of 1-benzyl-4,4-difluoropiperidine (4.66 g) was added dropwise chloroformic acid 1-chloroethyl (2.62 mL) at 0 ° C under argon atmosphere. It was heated to reflux for 2 hours. After air cooling, the methanol (93 ml) solution of the residue obtained by distilling off the reaction solvent under reduced pressure was heated to reflux for 4 hours. After air cooling, the reaction solvent was distilled off under reduced pressure to obtain the title compound (3.03 g, 87%) as a solid.

Reference Example 13 4-fluoropiperidine hydrochloride

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

Under argon atmosphere, cooled to -78 deg. C in dichloromethane (80 ml) solution of 4-hydroxy-1-piperidinecarboxylic acid tert-butyl ester (4.00 g) [bis (2-methoxyethyl) amino ] Sulfur trifluoride (7.33 mL) was added dropwise, stirred for 30 minutes, stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to give 4-fluoropiperidine-1-carboxylic acid tert-butyl ether (1.77 g). , 44%) was obtained as an oil.

2) the title compound

To a solution of 4-chloropiperidine-1-carboxylic acid tert-butyl ester (1.74 g) in dichloromethane (35 mL), 4N hydrochloric acid-dioxane solution (12 mL) was added at room temperature for 40 minutes. Stirred. Diethyl ether was added to the residue obtained by distilling off the solvent of the reaction solution under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (0.870 g, 73%) as a solid.

Reference Example 14 Hexahydropyridazine Hydrochloride

1) 3,6-dihydropyridazine-1,2-dicarboxylic acid = dibenzyl ester

1,2-Azodicarboxylic acid = 1,3-butadiene (14.2 g) was blown into a benzene (50 mL) solution of dibenzyl ester (10.28 g) under -10 ° C cooling, followed by stirring at room temperature for 16 hours. It was. The residue obtained by distilling off the reaction solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate -hexane) to give 3,6-dihydropyridazine-1,2-dicarboxylic acid = dibenzyl ester (2.57 g, 21 %) Was obtained as an oil.

2) hexahydropyridazine

To the methanol (25 ml) solution of the 3,6-dihydropyridazine-1,2-dicarboxylic acid-dibenzyl ester (2.57 g) was added 10% palladium-carbon (0.754 g) and hydrogen was present. The mixture was stirred for 19 hours. The catalyst was filtered off with the reaction solution, and then the filtrate solvent was distilled off under reduced pressure to obtain hexahydropyridazine (0.629 g, quantitative) as an oil.

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

A method)

To a methanol (20 mL) solution of hexahydropyridazine (0.72 g) was added di-tert-butoxydicarbonate (2.10 g) at room temperature and stirred for 15 hours. The residue obtained by distilling off the reaction solvent under reduced pressure was purified by silica gel column chromatography (acetone-chloroform) to give hexahydropyridazine-1-carboxylic acid tert-butyl ester (0.671 g, 43%) as an oil.

Method B)

10% in methanol (250 mL) solution of 2- (tert-butoxycarbonyl) hexahydropyridazine-1-carboxylic acid benzyl ester (Bioorg. Med. Chem., 2002, 10 , 953, 26.94 g) Palladium carbon (50% wet, 5.21 g) was added, and it stirred for 4 hours in hydrogen atmosphere. After filtration, the filtrate solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give hexahydropyridazine-1-carboxylic acid tert-butyl ester (18.24 g, 85%) as an oil phase. Obtained as water.

4) Title compound

To a dichloromethane (8 ml) solution of the hexahydropyridazine-1-carboxylic acid tert-butyl ester (0.6 ml) was added 4N hydrochloric acid-dioxane solution (4 ml) at room temperature and stirred for 1 hour. Diethyl ether and pentane were added to the reaction solution, and the supernatant was removed by decantation. The residue was dried under fitting to give the title compound (0.292 g, 66%) as a solid.

Reference Example 15 1-Methylpiperazin-2-one Hydrochloride

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

Triethylamine (3.83 mL) and di-tert-butoxydicarbonate (6.32 mL) were added to a mixture of piperazine-2-one (2.5 g) in tetrahydrofuran (50 mL) and methanol (50 mL) at room temperature. It was added and stirred for 4 hours. Water and ethyl acetate were added and liquid-separated into the residue obtained by distilling a reaction solvent under fitting. The organic layer was washed with water and brine in that order, and then the washed water layers were further combined and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was solidified with ethyl acetate-hexane to obtain 3-oxopiperazine-1-carboxylic acid tert-butyl ester (3.6 g, 72%).

2) 4-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester

To the N, N-dimethyl formamide (50 mL) solution of the 3-oxopiperazine-1-carboxylic acid tert-butyl ester (3.0 g) was added sodium hydride (60%, 960 mg) at 0 ° C. Then, methyl iodide (2.33 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added and liquid-separated the reaction liquid. The organic layer was washed with water and brine in that order, and the washed water layers were combined and extracted with ethyl acetate again. The combined organic layers were dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (2.32 g, 72%) as an oily substance.

3) the title compound

To the 4-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (2.06 g) was added 4N hydrochloric acid-dioxane solution (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure, toluene was added to the residue, and the residue obtained by azeotropic distillation of the solvent under reduced pressure was dried to obtain the title compound (1.44 g, 99%) as an oily substance.

Reference Example 16 1-methylpiperazin-2-one trifluoro acetate

Trifluoroacetic acid (3 mL) in a dichloromethane (6 mL) solution of 4-methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (0.308 g) of Reference Example 15 2). Was added and stirred for 1.5 hours. The residue obtained by distilling a reaction solvent off under reduced pressure was dried to obtain the title compound (0.485 g, quantitative).

Reference Example 17 1-Cyclopropylpiperazine Hydrochloride

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

In a solution of piperazine-1-carboxylic acid tert-butyl ester (1.87 g), [(1-ethoxycyclopropyl) oxy] trimethylsilane (8.05 ml) and methanol (60 ml) in acetic acid (5.72 ml), room temperature Sodium cyanohydride (1.89 g) was added thereto, followed by stirring for 5 days. Diethyl ether was added to the residue obtained by distilling a reaction solvent off under reduced pressure, and the insolubles were filtered out. An aqueous solution of 1N sodium hydroxide was added to the filtrate solvent for separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-cyclopropylpiperazine-1-carboxylic acid tert-butyl ester (1.62 g, 71%). Was obtained as a solid.

2) the title compound

Using the 4-cyclopropylpiperazine-1-carboxylic acid tert-butyl ester (1.61 g), the title compound (1.30 g, 93%) was obtained in the same manner as 3) of Reference Example 15 as a solid.

Reference Example 18 Azetidin-3-yl Dimethylamine Hydrochloride

1) 1-benzhydrylazetidin-3-one

To a triethylamine (27.9 ml) solution of 1-benzhydrazetidin-3-ol (4.79 g) was added dropwise a dimethyl sulfoxide (84 ml) solution of pyridinesulfonic acid (19.7 g) under ice-cooling, followed by Stirred for 40 min. Ice water and ethyl acetate were added to the reaction solution for separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-benzhydrylazetidin-3-one (2.85 g, 60%) as a solid. .

2) (1-benzhydrylazetidin-3-yl) dimethylamine

To the methanol (30 ml) solution of the 1-benzhydrazetidin-3-one (1.50 g) and 40% dimethylamine aqueous solution (4 ml), 5% palladium-carbon (1.5 g) was added to the hydrogen atmosphere. Then, contact reduction was performed overnight. After the catalyst was filtered off with the reaction solution, the filtrate solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain (1-benzhydrazetidin-3-yl) dimethylamine (1.55 g). , 92%) was obtained as a solid.

3) the title compound

20% palladium hydroxide-carbon (533 mg) was added to the ethanol (15 mL) solution of (1-benzhydrazetidin-3-yl) dimethylamine (533 mg), and the mixture was stirred for 18 hours under a hydrogen atmosphere. The catalyst was filtered off with the reaction solution, and then 1N hydrochloric acid-ethanol (4 mL) was added to the filtrate solvent. The reaction solution solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title compound (300 mg, 87%).

Reference Example 19 Piperidine-2-carboxylic Acid Amide

N-benzyloxycarbonylpiperidine-2-carboxylic acid (2.0 g), 1-hydroxybenzotriazole (1.6 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( Concentrated ammonia water (3 ml) and triethylamine (2 ml) were added to a 2.3 g) dichloromethane (20 ml) solution at room temperature, followed by stirring for 3 days. Water and dichloromethane were added to the reaction solution for separation. The organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, 10% palladium-carbon (1 g, 50% wet) was added to the methanol (30 mL) solution of the residue obtained by distilling off the solvent under reduced pressure, and stirred for 20 hours in the presence of hydrogen. The catalyst was filtered off with the reaction solution, and the filtrate solvent was distilled off under reduced pressure to obtain the title compound (970 mg, quant.) As a solid.

Reference Example 20 5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 2-acetyl-5-aminopyridine

To a tetrahydrofuran (200 mL) solution of 5-amino-2-cyanopyridine (10.13 g), methylmagnesium bromide (0.93 M tetrahydrofuran solution, 200 mL) was added over 25 minutes under nitrogen atmosphere and ice cooling. After dripping, it stirred at room temperature for 5 hours. Under ice-cooling, saturated aqueous ammonium chloride solution was added to the reaction solution, and further sulfuric acid (20 ml) was added dropwise, followed by stirring at room temperature for 80 minutes. Under ice-cooling, an aqueous solution of sodium hydroxide (20 g) and water (100 mL) was added dropwise to the reaction solution, and ethyl acetate was added to separate the solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to give 2-acetyl-5-aminopyridine (7.68 g, 66%) as a solid.

2) 2-acetyl-5- (tert-butoxycarbonylamino) pyridine

To a dichloromethane (150 mL) solution of 2-acetyl-5-aminopyridine (6.30 g) and 4- (dimethylamino) pyridine (5.65 g), dichloromethane of di-tert-butoxydicarbonate (11.10 g) under ice-cooling Methane (30 mL) solution was added and stirred at room temperature for 1 hour. The precipitated solid was filtered off, the filtrate solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-chloroform) to give 2-acetyl-5- (tert-butoxycarbonylamino) pyridine (8.04). g, 73%) was obtained as a solid.

3) 4- [5- (tert-butoxycarbonylamino) -2-pyridyl] -2,4-dioxobutanoic acid ethyl ester

Diethyl oxalate (9.2 mL) was added to an ethanol (340 mL) solution of sodium ethoxide (4.63 g). To the reaction solution at room temperature, an ethanol (60 mL) solution of 2-acetyl-5- (tert-butoxycarbonylamino) pyridine (8.04 g) was added, stirred for 45 minutes, and heated to reflux for 30 minutes. After air cooling, 5% citric acid solution and ethyl acetate were added to the residue obtained by distilling off the reaction solvent under reduced pressure, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to obtain 4- [5- (tert-butoxycarbonylamino) -2-pyridyl] -2, 4-Dioxobutanoic acid ethyl ester (1.70 g, 14.8%) was obtained as a solid.

4) 5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -4,5-dihydro-5-hydroxy-1- (3-pyridyl) -1H-pyrazole-3 Carboxylic acid ethyl ester

4- [5- (tert-butoxycarbonylamino) -2-pyridyl] -2,4-dioxobutanoic acid ethyl ester (1.59 g) and 3-hydrazinopyridine (0.52 g) of Reference Example 1 The ethanol (100 mL) solution was heated to reflux for 17 hours. After air cooling, the residue obtained by distilling off a reaction solvent under reduced pressure was purified by silica gel column chromatography (methanol-chloroform) to give 5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -4, 5-Dihydro-5-hydroxy-1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.382 g, 68%) was obtained as an amorphous material.

5) 5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -4,5-dihydro-5-hydroxy-1- (3-pyridyl) -1H-pyrazole-3-car To an N, N-dimethylformamide (30 mL) solution of acid ethyl ester (1.205 g) and 4- (dimethylamino) pyridine (344 mg), triethylamine (1.96 mL) and methanesulfonyl chloride at room temperature 327 μl) was added and stirred for 4 hours. Water and ethyl acetate were added and liquid-separated into the residue obtained by distilling a reaction solvent off under reduced pressure, and the organic layer was wash | cleaned with water and brine, and it dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), and further purified by silica gel thin layer chromatography (hexane-ethyl acetate) to obtain 5- [5- ( tert-butoxycarbonylamino) -2-pyridyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (506 mg, 43%) was obtained as a solid.

6) Title compound

Ethanol (20 mg) of 5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (505 mg) Ml) 1N aqueous sodium hydroxide solution (3.7 ml) was added to the suspension at room temperature, followed by heating to reflux for 10 minutes. After air cooling, water and ethyl acetate were added and liquid-separated into the residue obtained by distilling a solvent off under reduced pressure, and the aqueous layer was made acidic with 5% citric acid aqueous solution. The precipitated solid was collected by filtration to give the title compound (357 mg, 75.8%) as a solid.

Reference Example 21 5- [5- (tert-Butoxycarbonylamino) -2-pyridyl] -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid

1) 5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid ethyl ester

3) 4- [5- (tert-butoxycarbonylamino) -2-pyridyl] -2,4-dioxobutanoic acid ethyl ester (1.009 g) of Reference Example 20 and 2-hydrazino of Reference Example 2 A pyrazine (330 mg) solution of ethanol (30 mL) was heated to reflux for 88 hours. After air cooling, the residue obtained by distilling off the reaction solvent under reduced pressure was purified by silica gel column chromatography (methanol-chloroform), and further purified by silica gel thin layer chromatography (methanol-chloroform) to obtain 5- [5- (tert- Butoxycarbonylamino) -2-pyridyl] -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid ethyl ester (590 mg, 47%) was obtained as an amorphous material.

2) the title compound

Ethanol of 5- [5- (tert-butoxycarbonylamino) -2-pyridyl] -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid ethyl ester (589 mg) 10 mL) solution was added with 1 N aqueous sodium hydroxide solution (4.30 mL) at room temperature, followed by stirring for 2 hours. Water was added to the residue obtained by distilling off the reaction solvent under reduced pressure, and further acidified by adding 5% citric acid aqueous solution, and the precipitated solid was collected by filtration to obtain the title compound (441 mg, 80%).

Reference Example 22 5- (6-methoxy-3-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 3-acetyl-6-methoxypyridine

To a methanol (200 mL) solution of 6-methoxynicotinic acid methyl ester (20.07 g) was added 1N sodium hydroxide solution (140 mL) at room temperature and stirred for 16 hours. The reaction solution solvent was distilled off under reduced pressure to add 1N aqueous hydrochloric acid solution to make acidic (pH 4), and the precipitated solid was collected by filtration to give 6-methoxynicotinic acid (15.12 g, 82%) ( ESI-MS m / z: 154 (M + H) ⁺ ).

To the obtained 6-methoxynicotinic acid (15.0 g) solution of dichloromethane (600 ml), N, O-dimethylhydroxylamine hydrochloride (11.5 g) and 1- (3-dimethylaminopropyl) -3-ethylcarb at room temperature Bodyimide hydrochloride (41.0 g), 1-hydroxybenzotriazole (14.5 g) and triethylamine (54 mL) were added and stirred for 16 hours. Water and dichloromethane were added to the reaction solution for separation. The aqueous layer was further extracted with dichloromethane, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (acetone-chloroform) to give 6-methoxynicotinic acid N-methoxy-N-methylamide (19.2 g, quantitative) as an oil. Obtained as (ESI-MS m / z: 197 (M + H) ⁺ ).

To this tetrahydrofuran (400 ml) solution of 6-methoxynicotinic acid N-methoxy-N-methylamide (19.21 g), methyllithium (0.98 M diethyl ether solution, 135 ml) was cooled to -78 deg. After dripping over 30 minutes, it stirred for further 30 minutes. Aqueous solution of saturated ammonium chloride, water and ethyl acetate were added to the reaction solution, the mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, diethyl ether was added to the residue obtained by distilling off the solvent under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (10.86 g, 73%).

2) 4- (6-methoxy-3-pyridyl) -2,4-dioxobutanoic acid methyl ester

[A law]

To a methanol (15 mL) solution of 3-acetyl-6-methoxypyridine (0.309 g) and dimethyl oxalate (0.484 g) was added sodium methoxide (0.229 g) at room temperature, followed by stirring for 1.5 hours, further 45 ° C. Stir at 20 hours. After air cooling, the precipitated solid was collected by filtration, washed with diethyl ether, dissolved in chloroform and water, acidified with 1N aqueous hydrochloric acid, and separated. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (6-methoxy-3-pyridyl) -2,4-dioxobutanoic acid methyl ester (0.294 g, 61%) as a solid.

[B method]

To a N, N-dimethylformamide (6.0 mL) solution of 3-acetyl-6-methoxypyridine (0.321 g) was added sodium hydride (55%, 0.185 g) at 0 ° C and stirred for 25 minutes. Dimethyl oxalate (0.498 g) was added to the reaction liquid at 0 degreeC, and it stirred at room temperature for 1 hour. Water and diethyl ether were added to the reaction mixture for separation. The aqueous layer was made acidic (pH 4) with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (6-methoxy-3-pyridyl) -2,4-dioxobutanoic acid methyl ester (0.504 g, quantitative) as a solid.

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

To a methanol (120 mL) solution of 4- (6-methoxy-3-pyridyl) -2,4-dioxobutanoic acid methyl ester (6.80 g) at room temperature, 3-hydrazinopyridine (3.45) of Reference Example 1 g) was added and heated to reflux for 30 minutes. After air cooling, acetic acid (6.5 ml) was added, and the mixture was heated to reflux for 14 hours. After air-cooling, water and chloroform were added to the residue obtained by distilling a reaction liquid solvent off under reduced pressure, and it neutralized with 1N sodium hydroxide aqueous solution, and separated. Further, the aqueous layer was extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (acetone-chloroform) to give 5- (6-methoxy-3-pyridyl) -1- (3-pyridyl)- 1H-pyrazole-3-carboxylic acid methyl ester (4.53 g, 51%) was obtained as an oil.

4) Title compound

Tetrahydrofuran (30 mL) of 5- (6-methoxy-3-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (4.89 g), methanol ( Lithium hydroxide monohydrate (0.730 g) was added to the aqueous solution of 15 mL) and water (30 mL), and it stirred for 1.5 hours. The residue obtained by distilling off the reaction solvent under reduced pressure was made acidic (pH 5-6) with 1N aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration to obtain the title compound (3.278 g, 70%).

Reference Example 23 5- (6-Methyl-3-pyridazinyl) -1- (3-pyridyl) -1 H-pyrazole-3-carboxylic acid

1) 3-acetyl-6-methylpyridazine

Methylmagnesium iodide (2.0 M diethyl ether solution, 30 M) with 6-methyl-3-pyridazinecarbonitrile (6.00 g) diethyl ether (100 ml) and benzene (20 ml) mixed solution at -15 占 폚 cooling. Ml) was added dropwise and stirred for 1.5 hours. 1N aqueous hydrochloric acid solution (60 ml) was added to the reaction mixture, followed by stirring for 15 minutes, followed by separating an aqueous solution with saturated aqueous sodium hydrogencarbonate solution, making it alkaline and extracting with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 3-acetyl-6-methylpyridazine (4.84 g, 71%) as a solid.

2) 4- (6-methyl-3-pyridazinyl) -2,4-dioxobutanoic acid methyl ester

To a tetrahydrofuran (100 mL) solution of 3-acetyl-6-methylpyridazine (4.03 g), lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 33 mL) was added at -78 ° C. Stirred for 1 hour. A tetrahydrofuran (30 mL) solution of dimethyl oxalate (7.0 g) was added to the reaction solution at -78 ° C, followed by stirring at 0 ° C for 2 hours. Water and diethyl ether were added and liquid-separated into the reaction liquid, and the aqueous layer was made acidic (pH 4) with 1N aqueous hydrochloric acid, and extracted with chloroform. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (6-methyl-3-pyridazinyl) -2,4-dioxobutanoic acid methyl ester (5.42 g, 82%) as a solid.

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

To a methanol (140 mL) solution of 4- (6-methyl-3-pyridazinyl) -2,4-dioxobutanoic acid methyl ester (5.42 g) at room temperature, 3-hydrazinopyridine (3.00) of Reference Example 1 g) was added and heated to reflux for 30 minutes. After air cooling, acetic acid (5.6 mL) was added and heated to reflux for 14 h. In addition, concentrated hydrochloric acid (1.2 ml) was added, and the mixture was heated to reflux for 24 hours. After air cooling, an aqueous 1 N sodium hydroxide solution was poured into the reaction solution, the solution was brought to pH 4, and the reaction solvent was evaporated under reduced pressure. Chloroform and water were added and liquid-separated into the obtained residue, and the aqueous layer was further extracted with chloroform, the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to give 5- (6-methyl-3-pyridazinyl) -1- (3-pyridyl)- 1H-pyrazole-3-carboxylic acid methyl ester (2.98 g, 41%) was obtained as a solid.

4) Title compound

Tetrahydrofuran (20 mL) of 5- (6-methyl-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (2.98 g) and methanol ( 100 mL) 1N sodium hydroxide solution (25 mL) was added to the mixed suspension solution, followed by stirring at 40 ° C for 6 hours. After air cooling, the mixture was made acidic (pH 4) with 1 N aqueous hydrochloric acid, diethyl ether was added to the residue obtained by distilling off the reaction solvent under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (2.84 g, quant.). Obtained as a solid.

Reference Example 24 5- (5-methyl-2-pyridyl) -1- (2-pyridyl) -1H-pyrazole-3-carboxylic acid

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

4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (3.30 g) and 2-hydrazinopyridine (2.0 g) of 2) of method A of Reference Example 9 were used. , 5- (5-methyl-2-pyridyl) -1- (2-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.87) in the same manner as in 3) A method of Reference Example 9 g) was obtained.

2) the title compound

Using the 5- (5-methyl-2-pyridyl) -1- (2-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.86 g), In the same manner as in 4), the title compound (1.17 g, 30% in 2 steps) was obtained.

Reference Example 25 5- [5- (tert-Butoxycarbonylamino) -2-pyrazinyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 5- [5- (tert-butoxycarbonylamino) -2-pyrazinyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

1,4- of 5- (5-carboxy-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (5.34 g) of Reference Example 7 Triethylamine (2.41 mL), diphenylphosphoryl azide (3.73 mL) and tert-butanol (3.31 mL) were added to the dioxane (107 mL) suspension at room temperature, and the mixture was stirred at 100 ° C for 20 minutes. After air cooling, the residue obtained by distilling off a reaction solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform) to give 5- [5- (tert-butoxycarbonylamino) -2-pyrazinyl] -1. -(3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (4.63 g, 72%) was obtained as a solid.

2) the title compound

Methanol (6.7) of 5- [5- (tert-butoxycarbonylamino) -2-pyrazinyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.336 g) 1 N sodium hydroxide (2.05 mL) was added to the mixed suspension of mL) and tetrahydrofuran (6.7 mL) at room temperature, followed by stirring for 3 hours. Aqueous 1N hydrochloric acid solution (2.05 mL) was added to the reaction solution, the mixture was neutralized with water and methanol-chloroform (1:10), and the organic layer solvent was distilled off under reduced pressure to give the title compound (0.286 g, 91%). Was obtained as a solid.

Reference Example 26 5- (5-Methyl-2-pyridyl) -1- (2-pyrimidinyl) -1 H-pyrazole-3-carboxylic acid

1) 5- (5-methyl-2-pyridyl) -1- (2-pyrimidinyl) -1H-pyrazole-3-carboxylic acid ethyl ester

4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (2.14 g) in 2) of the A method of Reference Example 9 and 2-hydrazinopyrimidine (1.00 in Reference Example 3) To the ethanol (43 mL) suspension of g) was added acetic acid (2.60 mL) at room temperature and heated to reflux for 16 hours. After air cooling, concentrated hydrochloric acid (2.9 ml) was added, and the mixture was heated to reflux for 110 minutes. After air cooling, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (acetone-toluene) to give 5- (5-methyl-2-pyridyl) -1- (2-pyrimidinyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.22 g, 43%) was obtained as a solid.

2) the title compound

To a tetrahydrofuran (24 ml) solution of 5- (5-methyl-2-pyridyl) -1- (2-pyrimidinyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.21 g), At room temperature, an aqueous solution of lithium hydroxide monohydrate (0.181 g) and water (12 mL) was added dropwise and stirred for 3 hours. To the reaction solution, 1 N aqueous hydrochloric acid solution (4.30 mL) was added to neutralize, the mixture was separated by addition of water and a methanol-chloroform (1:10) mixed solvent, and the solid obtained by distilling off the solvent of the organic layer under reduced pressure was diethyl. Filtration with ether gave the title compound (1.01 g, 92%).

Reference Example 27 4-methoxypiperidine Hydrochloride

In a 1,4-dioxane (10 ml) solution of 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (5.34 g) of Reference Example 11), 4N hydrochloric acid-dioxane solution at room temperature (10 mL) was added and stirred for 30 minutes. Further 4N hydrochloric acid-dioxane solution (20 ml) was added and stirred for 30 minutes. The reaction solvent was distilled off under reduced pressure, and the obtained solid was collected by filtration with ethyl acetate to obtain the title compound (3.55 g).

Reference Example 28 (3S) -3-fluoropyrrolidine Hydrochloride

1) (3S) -fluoropyrrolidine-1-carboxylic acid tert-butyl ester

To dichloromethane (50 mL) solution of (3R) -hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.62 g), diethylaminosulfur trifluoride (2.22 mL) was added at -78 ° C. And stirred for 70 minutes at room temperature. The reaction solution was poured into iced water and liquid-separated, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give (3S) -fluoropyrrolidine-1-carboxylic acid tert-butyl ester (676 mg). , 26%) was obtained as an oily substance.

2) the title compound

To a solution of (3S) -3-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (600 mg) in dichloromethane (10 ml), 4N hydrochloric acid-dioxane (5 ml) was added at room temperature. And stirred for 1 hour. Diethyl ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain the title compound (341 mg, 86%).

Reference Example 29 4-Fluoromethylpiperidine Hydrochloride

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

To a solution of 4-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester (1.17 g) in dichloromethane (8 ml), ice-cooled [bis (2-methoxyethyl) amino] sulfur trifluoride ( 1.2 mL) and [bis (2-methoxyethyl) amino] sulfur trifluoride (50% of tetrahydrofuran solution, 3 mL) were added dropwise, followed by stirring at room temperature for 17 hours. Water, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-fluoromethylpiperidine-1-carboxylic acid tert-butyl ester (597 mg, 51 %) Was obtained as a solid.

2) the title compound

Using the 4-fluoromethylpiperidine-1-carboxylic acid tert-butyl ester (635 mg), the title compound (526 mg, quantitative) was obtained as a solid in the same manner as in Reference Example 28.

Reference Example 30 (3R) -3-Fluoropiperidine Hydrochloride

[A law]

(2S) -2-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (3.00 g) and diethylaminosulfur trifluoride (2.95 mL) were used, and were the same as in 1) of Reference Example 28. (3R) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (346 mg) was obtained as an oily product by the method. This ester was dissolved in dichloromethane (20 ml), 4N hydrochloric acid-dioxane (7 ml) was added at room temperature, and the mixture was stirred for 30 minutes. Diethyl ether was added to the reaction solution, and the precipitates were collected by filtration to obtain the title compound (162 mg, 8% in 2 steps) as a solid.

[B method]

To dichloromethane (300 ml) solution of (2S) -1-benzyl-2-hydroxymethylpyrrolidine (19.87 g), diethylaminosulfur trifluoride (20.6 ml) was added at 0 ° C, and at room temperature Stir for 90 minutes. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give (2S) -1-benzyl-2-fluoromethylpyrrolidine and (3R)-. A mixture of 1-benzyl-3-fluoropiperidine (14.56 g, 73%) was obtained as an oil. This mixture (7.25 g) and a dichloromethane (100 mL) solution of chloroformic acid 1-chloroethyl ester (4.50 mL) were heated to reflux for 1.5 hours. After air cooling, the residue obtained by distilling off the reaction solvent under reduced pressure was dissolved in methanol (50 mL) and heated to reflux for 45 minutes. After air cooling, the residue obtained by distilling off the reaction solvent under reduced pressure was crystallized from methanol-diethyl ether to obtain the title compound (1.582 g, 30%).

Reference Example 31 (2S) -2-fluoromethylpyrrolidine hydrochloride

1) (2S) -1-benzoyl-2-hydroxymethylpyrrolidine

To a mixed solution of (2S) -hydroxymethylpyrrolidine (3.00 mL), benzoyl chloride (6.92 mL), dichloromethane (100 mL) and water (100 mL) was added sodium hydrogencarbonate (7.51 g) at room temperature. And stirred for 1.5 hours. Dichloromethane was added to the reaction solution, the mixture was separated, 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 tetrahydrofuran (120 mL) and water (60 mL), and lithium hydroxide monohydrate (6.25 g) was added to the reaction solution at room temperature, followed by stirring overnight. . The reaction solution was separated and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain (2S) -1-benzoyl-2-hydroxymethylpyrrolidine (5.79 g, 95%) as an oil.

2) (2S) -1-benzoyl-2-fluoromethylpyrrolidine

To dichloromethane (50 ml) of (2S) -1-benzoyl-2-hydroxymethylpyrrolidine (1.50 g), diethylaminosulfur trifluoride (1.93 ml) under ice-cooling was added, and the mixture was stirred overnight. Then, the mixture was stirred at room temperature for 6.5 hours. Saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained product was purified by silica gel column chromatography (hexane-ethyl acetate) to give (2S) -1-benzoyl-2-fluoromethylpyrrolidine (772 mg, 51% ) Was obtained as an oily substance.

Reference Example 32 2- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] pyrazolidine-1-carboxylic acid tert Butyl ester

To a dichloromethane (10 ml) solution of 5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.372 g) of Reference Example 9, 1-hydroxybenzotriazole (0.123 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.580 g), triethylamine (0.739 mL) and pyrazolidine-1- at room temperature Carboxylic acid tert-butyl ester (0.349 g, Y. Endo et al., Bioorg. Med. Chem., 2002, 10, 953) was added and stirred for 4 days. Water and chloroform were added to the reaction solution for separation. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (0.459 g, 80%) as an oil.

Reference Example 33 4-methoxy-4-methylpiperidine Hydrochloride

1) 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester

Methyllithium (0.98 M diethyl ether solution) at -78 ° C in a diethyl ether (120 ml) suspension of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (12.0 g) under argon atmosphere 64.5 mL) was added dropwise over 15 minutes, stirred for 30 minutes, further stirred at 0 ° C. for 15 minutes, and stirred at room temperature for 30 minutes. Water, saturated brine and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester ( 12.2 g, 94%) was obtained as an oil.

2) 4-methoxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester

4-hydroxy-4-methylpiperidine-1-carboxylic acid tert at 0 ° C. in a suspension of N, N-dimethylformamide (86 mL) in sodium hydride (55%, 2.09 g) under argon atmosphere. A N, N-dimethylformamide (86 mL) solution of -butyl ester (8.61 g) was added dropwise over 15 minutes, and then stirred for 1 hour. A solution of methyl iodide (2.99 ml) of N, N-dimethylformamide (10 ml) was added dropwise to the reaction mixture, stirred for 15 minutes, and stirred at room temperature for 6 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 4-methoxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester ( 6.79 g, 74%) was obtained as an oil.

3) the title compound

In an argon atmosphere, a 4N hydrochloric acid-dioxane solution (at 0 ° C) was added to a dichloromethane (136 ml) solution of 4-methoxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (6.78 g) ( 45 mL) was added and stirred at room temperature for 5 hours. The reaction solution solvent was distilled off under reduced pressure, and the obtained solid was washed with diethyl ether, and then collected by filtration to obtain the title compound (4.04 g, 82%).

Reference Example 34 3-methoxypiperidine Hydrochloride

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

To methanol (50 mL) solution of 3-hydroxypiperidine (5.00 g) is added triethylamine (15.2 mL) and methanol (50 mL) solution of di-tert-butoxydicarbonate (11.9 g) at room temperature. And stirred for 15 hours. The residue obtained by distilling off the solvent of the reaction solution under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (9.86 g, 99%). ) Was obtained as a solid.

2) 3-methoxypiperidine-1-carboxylic acid tert-butyl ester

3-methoxypiperidine-1 in the same manner as in 2) of Reference Example 33 using 3-hydroxypiperidine-1-carboxylic acid tert-butylester (9.86 g) and methyl iodide (3.66 mL) -Carboxylic acid tert-butyl ester (9.24 g, 88%) was obtained as an oily substance.

3) the title compound

Using the 3-methoxypiperidine-1-carboxylic acid tert-butyl ester (9.24 g), the title compound (6.36 g, 98%) was obtained in the same manner as 3) of Reference Example 33 as a solid.

Reference Example 35 5- (5-methyl-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid

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

2-Hydrazinopyrazine (2.363 g) in Reference Example 2 and 4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (5.04 g) in 2) of method A of Reference Example 9 Ethanol (100 mL) solution was heated to reflux for 2 hours. After air cooling, concentrated hydrochloric acid (2.65 ml) was added to the reaction solution, and the mixture was heated to reflux for 1 hour. After air cooling, the reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and then extracted with chloroform. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (acetone-chloroform) to give 5- (5-methyl-2-pyridyl) -1- (2-pyrazinyl) -1H- Pyrazole-3-carboxylic acid ethyl ester (1.336 g, 22%) was obtained as an amorphous material.

2) the title compound

Tetrahydrofuran (20 mL) of 5- (5-methyl-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.470 g), ethanol (10 Lithium hydroxide monohydrate (0.222 g) was added to the mixed solution of mL) and water (5 mL) at room temperature, and stirred for 2.5 hours. Aqueous 1N hydrochloric acid was added to the reaction solution to make acidic (pH 5-6), and the mixture was separated by addition of a chloroform-methanol (15: 1) mixed solvent, and the aqueous layer was further mixed with chloroform-methanol (15: 1) solvent. Extraction was carried out and the combined organic layers were dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (1.315 g, 98%) as a solid.

Reference Example 36 5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 3-methoxypyridazine

Under a hydrogen atmosphere, 10% palladium-carbon (wet. 3.12 g) was added to a methanol (200 mL) solution of 3-chloro-6-methoxypyridazine (30.0 g) at room temperature, followed by stirring for 17 hours. After the reaction solution was filtered, the residue obtained by distilling off the filtrate solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate) to obtain 3-methoxypyridazine (16.3 g, 71%) as an oil.

2) 3-methoxypyridazine-1-oxide

To a solution of 3-methoxypyridazine (16.2 g) in dichloromethane (300 ml), m-chlorobenzoyl peroxide (44.0 g) was added at room temperature, followed by stirring for 16 hours. An aqueous solution of sodium bicarbonate (9.27 g) and water (100 mL) was added to the reaction solution, followed by stirring for 15 minutes. Further, an aqueous saturated sodium bicarbonate solution and chloroform were added for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 3-methoxypyridazine-1-oxide (15.8 g, 85%) as a solid.

3) 6-cyano-3-methoxypyridazine

A mixture of 3-methoxypyridazine-1-oxide (9.89 g) and dimethyl sulfuric acid (9.45 mL) was stirred at 80 ° C. for 1 hour. After air cooling, dioxane (100 mL) was added to the reaction solution, an aqueous solution of potassium cyanide (8.77 g) and water (30 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, and the organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6-cyano-3-methoxypyridazine (8.74 g, 72%) as a solid. Got it.

4) 3-acetyl-6-methoxypyridazine

Methylmagnesium iodide (0.84 M diethyl ether solution) under cooling at -10 ° C to a mixed solution of diethyl ether (100 ml) and benzene (20 ml) of 6-cyano-3-methoxypyridazine (5.61 g), 60 mL) was slowly added dropwise and stirred at the same temperature for 1 hour. An aqueous 1 N hydrochloric acid solution was added to the reaction solution at 0 ° C. to make acid (pH 4), followed by separation. The aqueous layer was made slightly alkaline (pH 9) with saturated aqueous sodium hydrogen carbonate solution, and then extracted with dichloromethane. The aqueous layer was further extracted with dichloromethane, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to give 3-acetyl-6-methoxypyridazine (3.82 g, 61%) as a solid.

5) 4- (6-methoxy-3-pyridazinyl) -2,4-dioxobutanoic acid methyl ester

To a tetrahydrofuran (100 mL) solution of 3-acetyl-6-methoxypyridazine (3.82 g), lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 27 mL) was added at -78 ° C. And stirred for 1 hour. A tetrahydrofuran (20 mL) solution of dimethyl oxalate (5.9 g) was added to the reaction solution at -78 ° C, and then stirred at 0 ° C for 2 hours. Water and diethyl ether were added to the reaction mixture for separation, and the aqueous layer was made acidic (pH 4) with 1N aqueous hydrochloric acid solution and extracted with chloroform. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (6-methoxy-3-pyridazinyl) -2,4-dioxobutanoic acid methyl ester (5.38 g, 90%) as a solid.

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

To a methanol (150 mL) solution of 4- (6-methoxypyridazin-3-yl) -2,4-dioxobutanoic acid methyl ester (5.38 g) at room temperature, 3-hydrazinopyridine of Reference Example 1 ( 2.82 g) was added and heated to reflux for 45 minutes. Acetic acid (5.2 mL) was added to the reaction solution, and the mixture was heated to reflux for 14 hours. After air cooling, the reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and the reaction solution solvent was distilled off under reduced pressure. Chloroform and water were added and liquid-separated into the obtained residue, and the aqueous layer was further extracted with chloroform, the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to give 5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (0.348 g, 5.0%) was obtained as a solid. Further, the second fractional solvent eluted with the same solvent was distilled off under reduced pressure, and 5-hydroxy-5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -4,5 -Dihydro-1H-pyrazole-3-carboxylic acid methyl ester (3.11 g, 44%) was obtained as an amorphous material.

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

5-hydroxy-5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester:

5-hydroxy-5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester ( Triethylamine (3.04 ml), methanesulfonyl chloride (1.35 ml) and 4- (dimethylamino) pyridine (0.111 g) were added to a 2.88 g) dichloromethane (80 ml) solution at room temperature, followed by stirring for 2.5 hours. . After adding methanol to the reaction liquid, chloroform and water were poured and added, and liquid-separated. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (acetone-chloroform) to give 5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (1.558 g, 57%) was obtained as a solid.

7) Title compound

Tetrahydrofuran (5 mL) of 5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid methyl ester (0.399 g), methanol Lithium hydroxide monohydrate (62 mg) was added to the mixed solution of (10 mL) and water (5 mL), and the mixture was stirred at 40 ° C for 1 hour. After air cooling, the reaction solution was neutralized with 1N aqueous hydrochloric acid solution, 1N hydrochloric acid aqueous solution was added to the residue obtained by distilling off the solvent of the reaction solution under reduced pressure to make acidic (pH 4), and the precipitated solid was collected by filtration. The title compound (0.303 g, 80%) was obtained as a solid.

Reference Example 37 5- (1-Methyl-1H-pyrrole-2-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 5- (1-Methyl-1H-pyrrole-2-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

A tetrahydrofuran (10 mL) solution of 1- (1-methyl-1H-pyrrole-2-yl) -1-ethanone (1.19 mL) was cooled to -78 ° C and lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 11.0 ml) was added and stirred for 30 minutes. Furthermore, oxalic acid dimethyl (2.05 mL) was added at the same temperature, and the mixture was stirred for 2 hours and half while gradually returning to room temperature. Ethanol (50 mL), 3-hydrazinopyridine (1.09 g) and 1 M hydrochloric acid-ethanol solution (11.0 mL) of Reference Example 1 were added thereto, and the resulting mixture was heated and refluxed for 16 hours and 30 minutes. Furthermore, 1 M hydrochloric acid-ethanol solution (11.0 mL) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. After air cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue obtained by distilling off the reaction solvent under reduced pressure, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (ethyl acetate-hexane) to give 5- (1-methyl-1H-pyrrol-2-yl) -1- (3-pyridine Dill) -1H-pyrazole-3-carboxylic acid ethyl ester (2.08 g, 70%) was obtained as an oil.

2) the title compound

To an ethanol (21 mL) solution of 5- (1-methyl-1H-pyrrole-2-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (2.08 g), Aqueous 1N sodium hydroxide solution (21.0 ml) was added at room temperature, followed by stirring for 4 hours. An aqueous solution of 1N hydrochloric acid (21.0 ml) and ethyl acetate were added to the reaction solution for separation. In addition, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. After filtration was fractionated, diethyl ether and hexane were added to the residue obtained by distilling off the solvent under reduced pressure, and the resulting solid was collected by filtration to obtain the title compound (1.63 g, 86%) as a solid.

Reference Example 38 5- (1-Methyl-1H-pyrrole-3-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid

1) 5- (1-Methyl-1H-pyrrole-3-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid ethyl ester

Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 11.1 ml) was added dropwise to a tetrahydrofuran (10 ml) solution of 3-acetyl-1-methylpyrrole (1.20 ml) under cooling at -78 ° C. . After stirring for 30 minutes, diethyl oxalate (2.06 ml) was added dropwise to the reaction solution, the temperature was raised to room temperature and the mixture was stirred at room temperature for 1 hour. 3-hydrazinopyridine (1.30 g), acetic acid (635 μl), and ethanol (50 mL) of Reference Example 1 were added to the reaction solution and heated to reflux for 16 hours. Furthermore, 3-hydrazinopyridine (650 mg) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. Concentrated hydrochloric acid (0.60 ml) was added to the reaction solution, and the mixture was heated to reflux for 24 hours. After air cooling, the reaction solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate aqueous solution (100 mL), water (50 mL), and ethyl acetate (100 mL) were added to the residue. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 5- (1-methyl-1H-pyrrole-3-yl) -1- (pyridine-3 -Yl) -1H-pyrazole-3-carboxylic acid ethyl ester (747 mg, 25%) was obtained as a solid.

2) the title compound

Tetrahydrofuran (10 mL) of 5- (1-methyl-1H-pyrrole-3-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (630 mg) ) To the suspension, 1M aqueous sodium hydroxide solution (2.8 ml) was added and stirred at room temperature for 2 hours, and 1M aqueous sodium hydroxide solution (1 ml) was further added and stirred for 19 hours. Water and diethyl ether were added to the reaction solution for separation, and hydrochloric acid was added to the aqueous layer, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the title compound (332 mg, 58%) was obtained by distilling off the solvent under reduced pressure.

Reference Example 39 1-Methyl-2,6-dioxopiperazin hydrochloride

1) 4-benzylpiperazine-2,6-dione

To a N, N-dimethylformamide (75 mL) solution of N-benzylimino diacetic acid (5.25 g), ammonium formate (4.5 g) was added at room temperature to reflux for 22 hours. After air cooling, water, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution for separation, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4-benzylpiperazine-2,6-dione (4.53 g, 94%) as an oil.

2) piperazine-2,6-dione hydrochloride

To an aqueous solution of 4-benzylpiperazine-2,6-dione (4.53 g) in methanol (120 mL) and water (50 mL), 1.0 M hydrochloric acid-ethanol (22 mL), 10% palladium carbon ( 1.45 g) was added, and it stirred for 20 hours in hydrogen atmosphere. After filtration fractionation, the solvent was distilled off under reduced pressure, and toluene was further added to the residue, and the solvent was distilled off under reduced pressure to obtain piperazine-2,6-dione hydrochloride (1.85 g, 51%) as a solid.

3) 4-tert-butoxycarbonylpiperazine-2,6-dione

To a tetrahydrofuran (15 mL), methanol (15 mL) and N, N-dimethylformamide (30 mL) suspension of piperazine-2,6-dione hydrochloride (1.58 g), triethylamine ( 3.21 ml) and di-tert-butyl dicarbonate ester (2.51 g) were added and the mixture was stirred for 17 hours. To the residue obtained by distilling off the reaction solvent under reduced pressure, water, a 1M aqueous hydrochloric acid solution, and ethyl acetate were added and separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4-tert-butoxycarbonylpiperazine-2,6-dione (1.75 g, 78%) as a solid.

4) 4-tert-butoxycarbonyl-1-methylpiperazine-2,6-dione

To a solution of 4-tert-butoxycarbonylpiperazine-2,6-dione (0.438 g) in N, N-dimethylformamide (10 ml), 60% sodium hydride (0.100 g) at 0 ° C. Methyl (0.190 mL) was added and stirred at room temperature for 1 hour. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was extracted with ethyl acetate further. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-acetone) to give 4-tert-butoxycarbonyl-1-methylpiperazine-2,6-dione (0.144 g, 31%) was obtained as an oil.

5) Title compound

To a 4-chloro tert-butoxycarbonyl-1-methylpiperazine-2,6-dione (0.144 g) dichloromethane (5.0 mL) solution, 4 M hydrochloric acid-dioxane solution (2.5 mL) at 0 ° C It was added and stirred at room temperature for 2 hours. Diethyl ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain the title compound (53.4 mg, 51%) as a solid.

Reference Example 40 1-ethyl-2-oxopiperazine Hydrochloride

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

To a solution of piperazine-2-one (5.07 g) in tetrahydrofuran (50 mL) and methanol (50 mL), triethylamine (7.76 mL) and di-tert-butyl dicarbonate (12.17 g) were added at room temperature. It was added and stirred for 4 hours. Diethyl ether was added to the residue obtained by distilling a reaction solvent off under reduced pressure, and the precipitated solid was collected by filtration and 3-oxopiperazine-1-carboxylic acid tert-butyl ester (9.36 g, 92%) was obtained as a solid. Got it.

2) 4-ethyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester

To the N, N-dimethylformamide (105 ml) solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (9.36 g) was added sodium hydride (1.361 g) at 0 ° C. and stirred for 25 minutes. It was. Ethyl iodide (4.48 mL) was added to the reaction solution, and the mixture was stirred at 40 ° C for 15 hours. After air cooling, water and ethyl acetate were added and liquid-separated, and the aqueous layer was extracted with ethyl acetate further. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-acetone) to give 4-ethyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (8.69 g, 81%) was obtained as an oil.

3) the title compound

In the same manner as in (5) of Reference Example 39, using tert-butyl 4-ethyl-3-oxopiperazine-1-carboxylic acid ester (8.69 g) and 4M hydrochloric acid-dioxane solution (60 ml). The title compound (5.88 g, 94%) was obtained as an oil.

Reference Example 41 3-methoxyazetidine Hydrochloride

1) 1-benzhydryl-3-methoxyazetidine

To a solution of 1, benzhydrazetidin-3-ol (4.60 g) in N, N-dimethylformamide (80 ml), 60% sodium hydride (0.852 g) and methyl iodide (1.43 ml) were added at 0 ° C. And stirred for 3 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was extracted with ethyl acetate further. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-benzhydryl-3-methoxyazetidine (4.27 g, 88%) as an oil. Got it.

2) the title compound

To a methanol (90 mL) solution of 1-benzhydryl-3-methoxyazetidine (4.27 g), a 1 M hydrochloric acid-ethanol solution (22 mL) and palladium hydroxide (20% wet, 2.11 g) at room temperature Was added and stirred for 18 hours under a hydrogen atmosphere. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether and hexane, and then the organic layer was removed by decantation, and the obtained residue was dried under reduced pressure to obtain the title compound (1.82 g, 88%) as an amorphous material.

Reference Example 42 5- (1-Methyl-1H-imidazol-4-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid ethyl ester

1) N-methoxy-N-methyl-1-methyl-1H-imidazole-4-carboxamide

1-Methyl-1H-imidazole-4-carboxylic acid (1.26 g), N, O-dimethylhydroxylamine hydrochloride (1.17 g), 1-hydroxybenzotriazole (1.84 g), triethylamine (2.09 ML) and a N, N-dimethylformamide (50 mL) solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.30 g) were stirred overnight at room temperature. The reaction solution was distilled off under reduced pressure, ethanol was added to the obtained residue, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (lower solvent of chloroform-methanol-water) to give N-methoxy-N-ethyl-1-methyl-1H-imidazole-4-carboxamide (1.08 g, 64%). Was obtained as a solid.

2) 4-acetyl-1-methyl-1H-imidazole

Methyl to tetrahydrofuran (30 ml) solution of the above-mentioned N-methoxy-N-methyl-1-methyl-1H-imidazole-4-carboxamide (1.08 g) under argon atmosphere and cooling at -78 deg. After dropping lithium (0.98 M diethyl ether solution, 6.84 ml), the mixture was stirred for 15 minutes and further stirred at 0 ° C for 75 minutes. Water and chloroform-methanol (10: 1) were added to the reaction mixture, the mixture was separated, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (chloroform-methanol-water lower solvent) to give 4-acetyl-1-methyl-1H-imidazole (309 mg, 39%). Obtained as a solid.

3) the title compound

To a tetrahydrofuran (100 mL) solution of 4-acetyl-1-methyl-1H-imidazole (1.41 g) under cooling at -78 ° C, lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 12.5 Ml) was added and stirred for 35 minutes. Diethyl oxalate (2.31 ml) was added to the reaction solution, followed by stirring for 15 minutes, followed by stirring at room temperature for 3 hours. Diethyl ether and water were added to the reaction mixture for separation. An aqueous 1 M hydrochloric acid solution (13 mL) was added to the aqueous layer, and extracted five times with a 10% methanol-dichloromethane mixed solvent, and the combined organic layers were dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain a crude product of 4- (1-methyl-1H-imidazol-4-yl) -2,4-dioxobutanoic acid ethyl ester (2.16 g, 85%). To this ethanol (50 mL) suspension of ethyl ester (2.16 g) was added an ethanol (50 mL) solution of 3-hydrazinopyridine (1.05 g) of Reference Example 1, followed by heating to reflux for 15 hours. After air cooling, dichloromethane and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted three times with dichloromethane and once with 10% methanol-dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-dichloromethane) to obtain the title compound (0.946 g, 33%) as a solid.

Reference Example 43 4-Methylene Piperidine Hydrochloride

To 4-methylene-1-piperidinecarboxylic acid tert-butyl ester (0.230 g), 4M hydrochloric acid-ethyl acetate solution (5 ml) was added and stirred at room temperature for 4 hours. The reaction solvent was distilled off under reduced pressure to obtain a crude product of the title compound.

Reference Example 44 (2S) -2,4-Dimethyl-5-oxo-1-piperazinecarboxylic acid tert-butyl ester

1) (1S) -1-methyl-2- (methylamino) -2-oxoethylcarbamic acid tert-butyl ester

N, N-dimethylform of (2S) -2-[(tert-butoxycarbonyl) amino] propionic acid (3.78 g) with methylamine hydrochloride (2.70 g), and 1-hydroxybenzotriazole (6.12 g) Triethylamine (11.1 mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.66 g) were added to an amide (100 mL) suspension at room temperature, followed by stirring for 17.5 hours. To the residue obtained by distilling off the reaction solvent under reduced pressure, ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added and liquid-separated. Furthermore, the aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain (1S) -1-methyl-2- (methylamino) -2-oxoethylcarbamic acid tert-butyl ester (4.33 g, quantitative) as a solid.

2) the title compound

To a tetrahydrofuran (140 ml) solution of the above (1S) -1-methyl-2- (methylamino) -2-oxoethylcarbamic acid tert-butyl ester (4.33 g), dimethyl sulfide borane (5.69) at room temperature. Ml) was added and stirred for 21.5 hours. After adding 3M aqueous hydrochloric acid solution (20 mL) to the reaction solution, tetrahydrofuran (200 mL), water (50 mL) and potassium hydroxide (8.00 g) were added and refluxed for 4.5 days. After air cooling, the organic solvent of the reaction solution was distilled off under reduced pressure, and the obtained aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain a crude product (3.00 g, 79%) of (1S) -1-methyl-2- (methylamino) ethylcarbamic acid tert-butylester as an oily substance. To a solution of ethyl acetate (50 mL) of this tert-butyl ester of carbamic acid (3.00 g) was cooled to 0 ° C, an aqueous 1 M sodium bicarbonate solution (47.8 mL) and chloroacetyl chloride (1.90 mL) were added. Stir at room temperature for 1.5 days. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was extracted with ethyl acetate further. The combined organic layers were dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (ethyl acetate-n-hexane) to give (1S) -2-[(2-chloroacetyl) (methyl) amino]- The crude product (2.29 g, 54%) of 1-methylethylcarbamic acid tert-butyl ester was obtained as a solid. Cesium carbonate (4.23 g) is added to this N, N- dimethylformamide (50 ml) solution of this methyl ethyl carbamic acid tert-butyl ester body (2.29 g) under 0 degreeC cooling, and it stirred at room temperature for 3.5 days. It was. To the residue obtained by distilling off the reaction solvent under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added and separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel flash column chromatography (ethyl acetate-n-hexane) to obtain the title compound (1.66 g, 84%) as an oil.

Reference Example 45 1- (3-Pyridyl) -5- {5- [2- (trimethylsilyl) ethynyl] -2-pyridyl} -1 H-pyrazole-3-carboxylic acid ethyl ester

2) 1- (3-pyridyl) -5- (5-trifluoromethanesulfonyloxy-2-pyridyl) -1H-pyrazole-3-carboxylic acid of 2) in A method of Reference Example 8) Trimethylsilylacetylene (0.630 mL) was added to a mixed solution of ester (1.85 g) N, N-dimethylformamide (10 mL) and triethylamine (3.6 mL) at room temperature, followed by stirring for 15 minutes. Bis (triphenylphosphine) palladium (II) dichloride (58.7 mg) was added to the reaction solution, and the mixture was stirred at 60 ° C for 1.5 days. After air cooling, water was added to the reaction solution, and the mixture was extracted five times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel flash column chromatography (ethyl acetate-n-hexane) to obtain the title compound (0.470 g, 28%) as a solid.

Reference Example 46 5- (5-Cyanopyridin-2-yl) -1-phenyl-1H-pyrazole-3-carboxylic acid

1) 5- (5-benzyloxy-2-pyridyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

4- (5-benzyloxy-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (3.14 g) and phenylhydrazine (1.16 ml) of Reference Example 4 were used. In the same manner as in 4), 5- (5-benzyloxy-2-pyridyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.95 g, 77%) was obtained as a solid.

2) 5- (5-hydroxy-2-pyridyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a ethanol (30 mL) and ethyl acetate (30 mL) solution of 5- (5-benzyloxy-2-pyridyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.83 g), 10% palladium-carbon (1.50 g) was added and stirred overnight under hydrogen atmosphere. The reaction solution was filtered, and the filtrate solvent was distilled off under reduced pressure to obtain 5- (5-hydroxy-2-pyridyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.98 g, 90 %) Was obtained as a solid.

3) 1-phenyl-5- (5-trifluoromethanesulfonyloxy-2-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Using 5- (5-hydroxy-2-pyridyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.98 g) and trifluoromethanesulfonic anhydride (1.29 mL), 1-phenyl-5- (5-trifluoromethanesulfonyloxy-2-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester in the same manner as 2) in the A method of Reference Example 8) 2.60 g, 92%) was obtained as an oil.

4) Title compound

Cyanide tri n-butyltin (7.42 g), tetrakis (triphenylphosphine) palladium (O) (10.17 g), and 1-phenyl-5- (5-trifluoromethanesulfonyloxy-2-pyridyl 5- (5-cyano-2-pyridyl) -1 in the same manner as 3) of method A of Reference Example 8 using 1H-pyrazole-3-carboxylic acid ethyl ester (2.59 g) -Phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.708 g) was obtained as a solid. Using this cyanomer (2.68 g) and lithium hydroxide monohydrate (369 mg), the title compound (951 mg, 56%) was obtained as a solid in the same manner as 3) of Method A of Reference Example 8.

Reference Example 47 5- (1-Methyl-1H-pyrazol-4-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid

1) 1-methyl-1H-pyrazole-4-carbaldehyde

Phosphorous oxychloride (65.3 ml) was added dropwise to N, N-dimethylformamide (54.2 ml) at 0 ° C. over 30 minutes under argon atmosphere, followed by stirring at room temperature for 1 hour. After stirring at 80 ° C for 10 minutes, 1-methylpyrazole (25.0 g) was added dropwise to the reaction solution over 30 minutes. The reaction solution was stirred at 85 ° C. for 1 hour, 100 ° C. for 3 hours, and further at 115 ° C. for 1 hour. After air cooling, the reaction solution was poured into ice water 11, and stirred for 20 hours. An aqueous 1 M sodium hydroxide solution (21) and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to give 1-methyl-1H-pyrazole-4-carbaldehyde (22.1 g, 66%) as an oil phase. Obtained as water.

2) 1- (1-methyl-1H-pyrazol-4-yl) ethanol

Tetrahydrofuran (220 ml) of the 1-methyl-1H-pyrazole-4-carbaldehyde (22.0 g) in an argon atmosphere, methyl magnesium bromide (0.84 M tetrahydrofuran solution) under cooling at -78 ° C. , 250 ml) was added dropwise over 50 minutes, and then stirred at the same temperature for 20 minutes and further at 0 ° C. for 50 minutes. Water and chloroform were added to the reaction solution, and after stirring, the insoluble matter in the reaction solution was filtered off using celite. To the obtained filtrate, water and chloroform were further added, liquid separation was carried out, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (methanol-chloroform) to give 1- (1-methyl-1H-pyrazol-4-yl) ethanol (20.2 g, 80% ) Was obtained as an oily substance.

3) 1- (1-methyl-1H-pyrazol-4-yl) ethanone

In an argon atmosphere, to a solution of 1- (1-methyl-1H-pyrazol-4-yl) ethanol (20.2 g) in dichloromethane (202 mL), manganese oxide (IV) (<5 micron, 209 g) was added and stirred at room temperature for 14 hours. After distilling off the solid in the reaction liquid by filtration, the solvent of the obtained filtrate was distilled off under reduced pressure to obtain 1- (1-methyl-1H-pyrazol-4-yl) ethanone (18.1 g, 91%) as a solid.

4) 4- (1-methyl-1H-pyrazol-4-yl) -2,4-dioxobutanoic acid ethyl ester

Diethyl oxalate (17.5 mL) was added to the ethanol (80 mL) solution of sodium ethoxide (8.77 g) in argon atmosphere, and it stirred at room temperature for 10 minutes. An ethanol (80 mL) solution of 1- (1-methyl-1H-pyrazol-4-yl) ethanone (8.00 g) was added to the reaction solution, which was stirred for 90 minutes at room temperature. Water and diethyl ether were added and liquid-separated the reaction liquid. Saturated ammonium chloride solution was added to the aqueous layer, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain 4- (1-methyl-1H-pyrazol-4-yl) -2,4-dioxobutanoic acid ethyl ester (11.4 g, 79%) as a solid.

5) 5- (1-Methyl-1H-pyrazol-4-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester

Ethanol (50 g) of 4- (1-methyl-1H-pyrazol-4-yl) -2,4-dioxobutanoic acid ethyl ester (2.8 g) and 3-hydrazinopyridine (2.8 g) of Reference Example 1 ML) solution was heated to reflux for 30 minutes. Acetic acid (3.6 mL) was added to the reaction solution, and the mixture was further heated to reflux for 13 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction mixture for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 5- (1-methyl-1H-pyrazol-4-yl) -1- (3- Pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (3.2 g, 86%) was obtained as a solid.

6) Title compound

Tetrahydrofuran (40 mL) of 5- (1-methyl-1H-pyrazol-4-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (3.2 g) ) And an aqueous solution of water (20 ml) were added lithium hydroxide monohydrate (500 mg) at room temperature and stirred for 17 hours. Water and ethyl acetate were added and liquid-separated the reaction liquid. An aqueous 1 M hydrochloric acid solution was added to the aqueous layer to make it acidic, and the precipitated solid was collected by filtration to obtain the title compound (2.2 g, 76%) as a solid.

Reference Example 48 5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester

1) 5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester

4- (5-methyl-2-pyridyl) -2,4-dioxobutanoic acid ethyl ester (1.18 g) and 2-hydrazino-1,3-thiazole (2) of Reference Example 9 (Fortuna Haviv, etc.) , J. Med. Chem., 1988, 31, 1719-1728, 0.576 g) ethanol (50 mL) solution was heated to reflux for 26.5 hours. A 1 M ethanol hydrochloride solution (2.50 mL) was added to the reaction solution, and the mixture was heated to reflux for 3 hours. After air cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution and the mixture was separated. Further, the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (ethyl acetate-n-hexane) to give 5- (5-methyl-2-pyridyl) -1- (1,3-thia Zol-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.734 g, 46%) was obtained as an oil.

2) the title compound

Ethanol (10 mL) of the 5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.734 g) To the solution was added 1M aqueous sodium hydroxide solution (3.50 ml) at room temperature and stirred for 85 minutes. Aqueous 1 M hydrochloric acid solution (3.50 mL) was added to the reaction solution, and the resulting solid was collected by filtration to obtain the title compound (0.493 g, 73%) as a solid.

Reference Example 49 1-Methyl-2-oxo [1.4] diazephan hydrochloride

1) [N- (3-benzyloxycarbonylaminopropyl)] aminoacetic acid benzyl ester

In an N, N-dimethylformamide (80 ml) suspension of N-benzyloxycarbonyl-1,3-diaminopropane hydrochloride (4.64 g), triethylamine (3.72 ml) and bromoacetic acid benzyl ester at room temperature (4.5 g) was added and stirred for 18 hours. The reaction solution was cooled to 0 ° C, and water, 1M aqueous hydrochloric acid solution and diethyl ether were added to the reaction solution. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and extracted with ethyl acetate. Further, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-methanol) to give [N- (3-benzyloxycarbonylaminopropyl)] aminoacetic acid benzyl ester (4.72 g, 67). %) Was obtained as an oil.

2) [N- (3-benzyloxycarbonylaminopropyl) -N- (tert-butoxycarbonyl)] aminoacetic acid benzyl ester

To a dichloromethane (100 mL) solution of the above-mentioned [N- (3-benzyloxycarbonylaminopropyl)] aminoacetic acid benzyl ester (4.72 g), triethylamine (2.23 mL) and di-tert-butyl dicarbonate at room temperature. Ester (3.19 g) was added and stirred for 24 hours. Water and chloroform were added to the reaction solution for separation. Furthermore, the aqueous layer was extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-acetone) to obtain [N- (3-benzyloxycarbonylaminopropyl) -N- (tert-butoxycarbonyl )] Amino acetate benzyl ester (4.77 g, 79%) was obtained as an oil.

3) [N- (3-aminopropyl) -N- (tert-butoxycarbonyl)] aminoacetic acid

To a methanol (10 mL) solution of the above-mentioned [N- (3-benzyloxycarbonylaminopropyl) -N- (tert-butoxycarbonyl)] aminoacetic acid benzyl ester (0.534 g), 10% palladium-carbon at room temperature (wet, 85.9 mg) was added and stirred under a hydrogen atmosphere for 24 hours. The insolubles were filtered off with the reaction solution, and the filtrate solvent was distilled off under reduced pressure to obtain [N- (3-aminopropyl) -N- (tert-butoxycarbonyl)] aminoacetic acid (WO 2004 037169, 0.270 g, 99). %) Was obtained as a solid.

4) Title compound

Using the above [N- (3-aminopropyl) -N- (tert-butoxycarbonyl)] aminoacetic acid (0.279 g), the title compound is used as a solid by the method described in WO 2004 037169 (BIFTU, Tesfaye et al.). Got it.

Reference Example 50 (1-piperidin-2-yl cyclopropyl) carbamic acid tert-butyl ester

1) 2- (1-aminocyclopropyl) pyridine

Titanium chloro triisopropoxide (10.3 mL) was added to a 2-hydro cyanopyridine (3.75 g) tetrahydrofuran (200 mL) solution at argon atmosphere, and it stirred for 7 minutes. Ethyl magnesium bromide (0.97 M tetrahydrofuran solution, 86 ml) was added dropwise to the reaction solution at room temperature over 5 minutes, followed by stirring for 55 minutes. The boron trifluoride diethyl ether complex (10.9 ml) was stirred for 55 minutes at room temperature in the reaction solution. After adding 1 M aqueous sodium hydroxide solution to the reaction solution to make it basic, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-methanol) to give 2- (1-aminocyclopropyl) pyridine (2.554 g, 53%) as an oil.

2) (1-pyridyl-2-yl cyclopropyl) carbamic acid tert-butyl ester

To the dichloromethane (50 mL) solution of 2- (1-aminocyclopropyl) pyridine (513 mg) and di-tert-butyl dicarbonate ester (1.25 g) was added triethylamine (1.06 mL) at room temperature. Stir for 3 days. The residue obtained by distilling off the reaction solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to give (1-pyridin-2-yl cyclopropyl) carbamic acid tert-butyl ester (563 mg, 63%). Was obtained as a solid.

3) the title compound

The suspension of (1-pyridin-2-yl cyclopropyl) carbamic acid tert-butyl ester (277 mg), 5% rhodium-alumina (200 mg), acetic acid (1 mL) and ethanol (10 mL) was added to a hydrogen atmosphere. Under stirring (6 atm), the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, and then, the solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate aqueous solution and a chloroform-methanol (10: 1) mixed solvent were added and distributed. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (297 mg, quant.) As a solid.

Example 1 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methylpiperazine

5- (5-Cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.350 g) and 1- (3-dimethylaminopropyl of Reference Example 8 N-methylpiperazine (0.200 ml) at room temperature in a solution of N, N-dimethylformamide (7 ml) of 1-3-hydroxycarbodiimide hydrochloride (0.253 g) and 1-hydroxybenzotriazole (0.179 g). ) And triethylamine (0.184 mL) were added and the mixture was stirred for 20 hours. Water and chloroform were added to the reaction solution, the mixture was separated, and the residue obtained by distilling off the solvent of the organic layer under reduced pressure was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (0.372 g, 81%) as a solid. .

Example 2 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-cyclopropylpiperazine

5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.30 g) of Reference Example 8 and 1-cyclopropyl of Reference Example 17 Using the piperazine hydrochloride (0.308 g), the title compound (0.316 g, 74%) was obtained in the same manner as in Example 1 as a solid.

Example 3 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-fluoropiperidine

5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.30 g) of Reference Example 8 and 4-fluoro of Reference Example 13 Using piperidine hydrochloride (0.216 g), the title compound (0.277 g, 71%) was obtained in the same manner as in Example 1 as a solid.

Example 4 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.60 g) of Reference Example 8 and 4-methoxy py of Reference Example 11 The title compound (0.300 g, 37%) was obtained in the same manner as Example 1 using ferridine trifluoro acetate (0.944 g).

Example 5 4- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] morpholine

5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.350 g) and morpholine (0.157 mL) in Reference Example 8 were used. In the same manner as in Example 1, the title compound (0.355 g, 82%) was obtained as a solid.

Example 6 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] piperidine

5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.350 g) and piperidine (0.178 mL) of Reference Example 8 were prepared. In the same manner as in Example 1, the title compound (0.353 g, 81%) was obtained as a solid.

Example 7 1- [5- (5-carbamoyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

5- (5-carbamoyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.215 g) of Reference Example 7 and 4,4- of Reference Example 12 Using difluoropiperidine hydrochloride (0.164 g), the title compound (0.238 g, 82%) was obtained in the same manner as in Example 1 as a solid.

Example 8 1- [5- (5-carbamoyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-fluoropiperidine

Example 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-fluoropiperidine (0.190 To the mixed solution of g) methanol (3.8 ml) and tetrahydrofuran (3.8 ml) was added 1 N sodium hydroxide solution (2.51 ml) at room temperature and stirred at 80 ° C for 15 minutes. After air cooling, water and methanol-chloroform (1:10) mixed solvent were added to the reaction solution and the mixture was separated. The residue obtained by distilling off the solvent of the organic layer under reduced pressure was purified by silica gel column chromatography (methanol-chloroform) to obtain the title. Compound (0.129 g, 64%) was obtained as a solid.

Example 9 1- [5- (5-carbamoyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

Example 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine (0.190 g ), The title compound (0.125 g, 63%) was obtained as a solid in the same manner as in Example 8.

Example 10 1- [5- (5-carbamoyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] piperidine

Example 1 using 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] piperidine (0.294 g) In the same manner as in Example 8, the title compound (0.197 g, 64%) was obtained as a solid.

Example 11 1- [5- (5-hydroxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

1) 1- [5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine

5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (1.93 g) of Reference Example 4 and 4,4- of Reference Example 12 1- [5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H in the same manner as in Example 1 using difluoropiperidine hydrochloride (0.980 g) -Pyrazole-3-carbonyl] -4,4-difluoropiperidine (2.34 g, 95%) was obtained as a solid.

2) the title compound

1- [5- (5-benzyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine (2.33 g 10% palladium-carbon (2.33 g) was added to a mixed solution of methanol (47 mL) and ethyl acetate (47 mL), and the mixture was stirred at room temperature under hydrogen stream for 1 hour and 30 minutes. After the catalyst was filtered off with the reaction solution, the filtrate solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (1.68 g, 89%) as a solid.

Example 12 1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

1) 1- [5- (5-trifluoromethanesulfonyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Lopiperidine

1- [5- (5-hydroxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi of Example 11 1- [5- (5-trifluoromethanesulfonyloxy-2- in the same manner as in 2) of Reference Example 8 using dean (1.27 g) and trifluoromethanesulfonic anhydride (0.665 mL). Pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine (1.67 g, 98%) was obtained as a solid.

2) the title compound

Under argon atmosphere, a suspension of dichloroethane (45 mL) of cyano tri n-butyltin (4.06 g) and tetrakis (triphenylphosphine) palladium (O) (5.56 g) was heated to reflux for 2 hours. 1- [5- (5-trifluoromethanesulfonyloxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-di A solution of fluoropiperidine (1.66 g) in dichloroethane (37 mL) was added dropwise, followed by heating to reflux for 22 hours. After air cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, filtered using Celite, water and chloroform were added to the filtrate, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (1.03 g, 80%) as a solid.

Example 13 1- [5- (5-carbamoyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

1- [5- (5-cyano-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi of Example 12 Using Dean (0.40 g), the title compound (0.109 g, 27%) was obtained in the same manner as in Example 8 as a solid.

Example 14 1- [5- (5-methoxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

1- [5- (5-hydroxy-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-di in Example 11 under argon atmosphere To a mixed solution of fluoropiperidine (0.40 g) in methanol (8 mL), tetrahydrofuran (8 mL) and dichloromethane (8 mL) at room temperature, (trimethylsilyl) diazomethane (2.0 M hexane solution, 0.623 mL) was added dropwise, followed by stirring for 3 hours. Furthermore, (trimethylsilyl) diazomethane (2.0 M hexane solution, 1.246 mL) was added to the reaction solution, and the mixture was stirred for 2.5 hours. The reaction solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate solution and chloroform were added to the residue, followed by separation. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain the title compound (0.194 g, 46%) as a solid.

Example 15 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (665 mg) in Reference Example 9 and 4,4-di in Reference Example 12 Using the fluoropiperidine hydrochloride (681 mg), the title compound (360 mg, 40%) was obtained in the same manner as in Example 1 as a solid.

Example 16 1- [5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (325 mg) of Reference Example 5 and 4,4-di in Reference Example 12 Using the fluoropiperidine hydrochloride (196 mg), the title compound (115 mg, 26%) was obtained in the same manner as in Example 1 as a solid.

Example 17 1- [5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.250 g) of Reference Example 6 and 4-methoxypiperi of Reference Example 27 Dean hydrochloride (0.150 g) was used to give the title compound (0.304 g, 88%) as a solid in the same manner as in Example 1.

Example 18 1- [5- (5-methyl-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

To a dichloromethane (8 ml) solution of 5- (5-methyl-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid (0.253 g) of Reference Example 35, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.374 g), 1-hydroxybenzotriazole (0.139 g), 4-methoxypiperidine hydrochloride (0.216 g) of Reference Example 27 at room temperature ) And triethylamine (0.565 mL) were added and stirred for 22 hours. Water and chloroform were added to the reaction solution for separation. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (0.149 g, 44%) as a solid.

Example 19 1- [5- (5-methyl-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

5- (5-methyl-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid (0.238 g) of Reference Example 35 and 4,4-di in Reference Example 12 Using the fluoropiperidine hydrochloride (0.200 g), the title compound (0.204 g, 63%) was obtained in the same manner as Example 18 as a solid.

Example 20 1- [5- (5-Chloro-2-pyridyl) -1- (3-pyridyl) -1 H-pyrazole-3-carbonyl] hexahydropyridazine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.288 g) of Reference Example 5 and hexahydropyridazine hydrochloride of Reference Example 14 Using (0.14 g), the title compound (0.204 g, 58%) was obtained as a solid in the same manner as in Example 18.

Example 21 1- [5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -2-carbamoylhexahydropyridazine

1, of 1- [5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] hexahydropyridazine (0.153 g) of Example 20, Trimethylsilyl isocyanate (1.20 mL) was added to the 4-dioxane (2.0 mL) solution at room temperature, and it stirred for 24 hours by heating at the outer temperature of 110 degreeC in a sealing pipe. After air cooling, methanol was added to the reaction solution, and the reaction solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate aqueous solution and a methanol-chloroform (1:20) mixed solvent were added and separated. The aqueous layer was further extracted with a methanol-chloroform (1:20) mixed solvent, the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to give the title compound (0.103 g, 61%) as a solid.

Example 22 1- [5- (5-amino-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

1) 1- [5- (5-tert-butoxycarbonylamino-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Lopiperidine

5- (5-tert-butoxycarbonylamino-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carboxylic acid (73 mg) and Reference Example 12 of Reference Example 20 1- [5- (5-tert-butoxycarbonylamino-2-pyridyl)-in the same manner as in Example 1 using 4,4-difluoropiperidine hydrochloride (90 mg) in 1- (2-pyrazinyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine (87 mg, 94%) was obtained as a solid.

2) the title compound

1- [5- (5-tert-butoxycarbonylamino-2-pyridyl) -1- (2-pyrazinyl) -1H-pyrazole-3-carbonyl] -4,4-difluoro To a solution of piperidine (85 mg) in dichloromethane (2 ml), trifluoroacetic acid (2 ml) was added at room temperature, followed by stirring for 30 minutes. The reaction solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate solution and ethyl acetate were added to the residue, followed by separation. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (72 mg, 97%) as a solid.

Example 23 1- [5- (5-Chloro-2-pyridyl) -1- (3-pyridyl) -1 H-pyrazole-3-carbonyl] -4-methylpiperazine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (300 mg) and N-methylpiperazine (100 mg) of Reference Example 5 Using the same method as in Example 1 to give the title compound (62 mg, 16%) as a solid.

Example 24 1- [5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methyl-3-oxopiperazine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (300 mg) in Reference Example 5 and 1-methylpiperazine in Reference Example 15 Using the 2-one hydrochloride (151 mg), the title compound (101 mg, 25.5%) was obtained in the same manner as in Example 1 as a solid.

Example 25 1- [5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -2-carbamoylpiperidine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (300 mg) in Reference Example 5 and piperidine-2 in Reference Example 19 Using the carboxylic acid amide (130 mg), the title compound (37 mg, 9%) was obtained in the same manner as in Example 1 as a solid.

Example 26 1- [5- (5-Chloro-2-pyridyl) -1- (3-pyridyl) -1 H-pyrazole-3-carbonyl] -3-dimethylaminoazetidine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (300 mg) in Reference Example 5 and azetidine-3- in Reference Example 18 Using the same dimethylamine hydrochloride (174 mg), the title compound (78 mg, 20%) was obtained in the same manner as in Example 1 as a solid.

Example 27 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-fluoromethylpiperidine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (350 mg) in Reference Example 9 and 4-fluoromethyl in Reference Example 29 Using piperidine hydrochloride (384 mg), the title compound (86 mg, 18%) was obtained in the same manner as in Example 18 as a solid.

Example 28 1- [5- (5-Chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (500 mg) in Reference Example 5 and 4-methoxypiperi in Reference Example 27 Dean hydrochloride (380 mg) was used to obtain the title compound (590 mg, 89%) as a solid in the same manner as in Example 18.

Example 29 1- [5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-fluoropiperidine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (300 mg) in Reference Example 5 and 4-fluoropyro in Reference Example 13 Using peridine hydrochloride (170 mg), the title compound (307 mg, 80%) was obtained in the same manner as in Example 18 as a solid.

Example 30 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (400 mg) of Reference Example 9 and 4-methoxypiperi of Reference Example 27 Dean hydrochloride (328 mg) was used to obtain the title compound (270 mg, 50%) as a solid in the same manner as in Example 18.

Example 31 4- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] morpholine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (400 mg) and morpholine (187 μl) of Reference Example 9 were used. In the same manner as in Example 18, the title compound (113 mg, 22%) was obtained as a solid.

Example 32 1- [5- (5-methyl-2-pyridyl) -1- (2-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

5- (5-methyl-2-pyridyl) -1- (2-pyridyl) -1H-pyrazole-3-carboxylic acid (556 mg) in Reference Example 24 and 4,4-di in Reference Example 12 Using the fluoropiperidine hydrochloride (313 mg), the title compound (270 mg, 36%) was obtained in the same manner as in Example 18 as a solid.

Example 33 1- [5- (5-methyl-2-pyridyl) -1- (2-pyridyl) -1H-pyrazole-3-carbonyl] -4-fluoropiperidine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (500 mg) in Reference Example 9 and 4-fluoropyro in Reference Example 13 Using peridine hydrochloride (324 mg), the title compound (264 mg, 41%) was obtained in the same manner as in Example 18 as a solid.

Example 34 4- [5- (6-methoxy-3-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] morpholine

5- (6-methoxy-3-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.262 g) and morpholine (0.235 mL) in Reference Example 22 were used. In the same manner as in Example 18, the title compound (0.189 g, 58%) was obtained as a solid.

Example 35 1- [5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] hexahydropyridazine

5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.256 g) of Reference Example 6 and hexahydropyridazine hydrochloride of Reference Example 14 Using (0.182 g), the title compound (0.132 g, 42%) was obtained in the same manner as in Example 18 as a solid.

Example 36 (2S) -1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -2-fluoromethyl Pyrrolidine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (280 mg) in Reference Example 9 and (2S) -2 in Reference Example 31. The title compound (29 mg, 8%) was obtained in the same manner as Example 18 using -fluoromethylpyrrolidine hydrochloride (154 mg).

Example 37 1- [5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.250 g) of Reference Example 6 and 4,4-di in Reference Example 12 Using the fluoropiperidine hydrochloride (0.168 g), the title compound (0.304 g, 89%) was obtained in the same manner as Example 1 as a solid.

Example 38 1- [5- (5-methyl-2-pyridyl) -1- (2-pyrimidinyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

5- (5-methyl-2-pyridyl) -1- (2-pyrimidinyl) -1H-pyrazole-3-carboxylic acid (0.250 g) of Reference Example 26 and 4,4- of Reference Example 12 Using difluoropiperidine hydrochloride (0.168 g), the title compound (0.270 g, 78%) was obtained in the same manner as Example 1 as a solid.

Example 39 1- [5- (5-methyl-2-pyridyl) -1- (2-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxy-4-methylpy Ferridine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.250 g) of Reference Example 9 and 4-methoxy- of Reference Example 33 Using the 4-methylpiperidine hydrochloride (0.192 g), the title compound (0.211 g, 60%) was obtained in the same manner as in Example 1 as a solid.

Example 40 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -3-methoxypiperidine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.250 g) of Reference Example 9 and 3-methoxypiperi of Reference Example 34 Dean hydrochloride (0.176 g) was used to give the title compound (0.133 g, 39%) as a solid in the same manner as in Example 1.

Example 41 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridazinyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

5- (5-methyl-2-pyridyl) -1- (3-pyridazinyl) -1H-pyrazole-3-carboxylic acid (0.227 g) of Reference Example 10 and 4,4- of Reference Example 12 Using the difluoropiperidine hydrochloride (0.194 g), the title compound (0.280 g, 92%) was obtained in the same manner as Example 18 as a solid.

Example 42 1- [5- (6-methyl-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

5- (6-methyl-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.226 g) of Reference Example 23 and 4,4- of Reference Example 12 Difluoropiperidine hydrochloride (0.226 g) was used to give the title compound (0.212 g, 58%) as a solid in the same manner as in Example 1.

Example 43 (3R) -1- [5- (5-Chloro-2-pyridyl) -1- (3-pyridyl) -1 H-pyrazole-3-carbonyl] -3-fluoropy Ferridine

5- (5-chloro-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (301 mg) of Reference Example 5 and (3R) -3 of Reference Example 30 Using -fluoropiperidine hydrochloride (154 mg), the title compound (135 mg, 35%) was obtained in the same manner as in Example 18 as a solid.

Example 44 (3R) -1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -3-fluoropy Ferridine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (302 mg) in Reference Example 9 and (3R) -3 in Reference Example 30 Using -fluoropiperidine hydrochloride (150.4 mg), the title compound (212 mg, 54%) was obtained in the same manner as Example 18 as a solid.

Example 45 1- [5- (5-amino-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

1) 1- [5- (5-tert-butoxycarbonylamino-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Lopiferidine

5- (5-tert-butoxycarbonylamino-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (381 mg) and Reference Example 12 of Reference Example 20 1- [5- (5-tert-butoxycarbonylamino-2-pyridyl)-in the same manner as in Example 18 using 4,4-difluoropiperidine hydrochloride (173 mg) in 1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine (466 mg, 96%) was obtained as an amorphous material.

2) the title compound

1- [5- (5-tert-butoxycarbonylamino-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy To a solution of ferridine (458 mg) in dichloromethane (30 ml) was added 4N hydrochloric acid-dioxane (10 ml) at room temperature and stirred for 30 minutes. The reaction solvent was distilled off under reduced pressure, neutralized by addition of saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform-methanol (10: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (methanol-chloroform) to obtain the title compound (254 mg, 70%) as a solid.

Example 46 (3S) -1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -3-fluoropy Lollidine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (280 mg) in Reference Example 9 and (3S) -3 in Reference Example 28 Using -fluoropyrrolidine hydrochloride (153 mg), the title compound (107 mg, 31%) was obtained in the same manner as in Example 18 as a solid.

Example 47 (2S) -1- [5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -2-fluoromethyl Pyrrolidine

5- (5-methyl-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (281 mg) in Reference Example 6 and (2S) -2 in Reference Example 31. The title compound (188 mg, 51%) was obtained in the same manner as Example 18 using -fluoromethylpyrrolidine hydrochloride (139 mg).

Example 48 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] pyrazolidine

2- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] pyrazolidine-1-carboxylic acid tert- of Reference Example 32 To a solution of butyl ester (0.459 g) in dichloromethane (13.5 ml) was added 4N hydrochloric acid-dioxane solution (4.5 ml) at 0 ° C and stirred for 1.5 hours. Aqueous solution of 1N sodium hydroxide was added to the reaction solution, followed by separation by addition of chloroform. The aqueous layer was further extracted with chloroform, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (0.284 g, 80%) as an amorphous material.

Example 49 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -2-formylpyrazolidine

N, N of 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] pyrazolidine (0.264 g) of Example 48 To the dimethylformamide (5.0 ml) solution was added 4- (dimethylamino) pyridine (0.186 g) and trifluoromethanesulfonic anhydride (0.199 ml) at 0 ° C and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, the mixture was further extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (0.156 g, 55%) as a solid.

Example 50 4- [5- (1-methyl-1H-pyrrol-2-yl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] morpholine

5- (1-Methyl-1H-pyrrole-2-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.209 g) and morpholine (0.123 mL) in Reference Example 37 Using the same method as in Example 1 to obtain the title compound (0.211 g, 80%) as a solid.

Example 51 1- [5- (1-Methyl-1H-pyrrol-2-yl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

5- (1-methyl-1H-pyrrol-2-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.209 g) of Reference Example 37 and 4- of Reference Example 27 Using methoxypiperidine hydrochloride (0.218 g), the title compound (0.247 g, 86%) was obtained in the same manner as Example 1 as an amorphous material.

Example 52 1- [5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Piperidine

5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.300 g) of Reference Example 36 and 4,4 of Reference Example 12 Using difluoropiperidine hydrochloride (0.235 g), the title compound (0.254 g, 66%) was obtained in the same manner as Example 1 as a solid.

Example 53 4- [5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] morpholine

5- (6-methoxy-3-pyridazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.259 g) and morpholine (0.145 mL) in Reference Example 36 were prepared. In the same manner as in Example 1, the title compound (0.118 g, 39%) was obtained as a solid.

Example 54 1- [5- (5-amino-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi Dean

1) 1- [5- (5-tert-butoxycarbonylamino-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Lopiferidine

Reference with 5- [5- (tert-butoxycarbonylamino) -2-pyrazinyl] -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.450 g) of Reference Example 25 1- [5- (5-tert-butoxycarbonylamino-2-pyrazinyl) in the same manner as in Example 1 using 4,4-difluoropiperidine hydrochloride (0.223 g) in Example 12. -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine (0.494 g, 87%) was obtained as a solid.

2) the title compound

1- [5- (5-tert-butoxycarbonylamino-2-pyrazinyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy To a solution of ferridine (0.486 g) in dichloromethane (9.7 mL), trifluoroacetic acid (4.9 mL) was added at room temperature, followed by stirring for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (0.342 g, 88%) as a solid.

Example 55 4- [5- (1-methyl-1H-pyrrol-3-yl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] morpholine

To a dichloromethane (10 mL) solution of (1-methyl-1H-pyrrole-3-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (165 mg) in Reference Example 38. At room temperature, 1-hydroxybenzotriazole (84 mg), morpholine (70 µl) and triethylamine (0.3 ml) were added. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (178 mg) was added to this reaction solution, and the mixture was stirred at room temperature for 23.5 hours. Water and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (146 mg, 70%) as a solid.

Example 56 1- [5- (1-Methyl-1H-pyrrol-3-yl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -4-methoxypiperidine

To a dichloromethane (10 mL) solution of (1-methyl-1H-pyrrole-3-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (165 mg) in Reference Example 38. At room temperature, 1-hydroxybenzotriazole (84 mg), 4-methoxypiperidine hydrochloride of Reference Example 27 (123 mg), and triethylamine (0.3 mL) were added. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (178 mg) was added to this reaction solution, and the mixture was stirred at room temperature for 23 hours. Water and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound as an oil.

Example 57 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] hexahydropyridazine

Dichloromethane (7.5 ml) and N of 5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (0.316 g) of Reference Example 9 1-hydroxybenzotriazole (0.167 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.462 g), tri, at room temperature in a N-dimethylformamide (3 mL) solution Ethylamine (0.944 mL) and hexahydropyridazine hydrochloride (0.269 g) in Reference Example 14 were added and stirred for 21 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.226 g, 58%) as a solid.

Example 58 2- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] hexahydropyridazine-1-carboxyl Acid amide

1 of 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] hexahydropyridazine (0.289 g) of Example 57 Trimethylsilyl isocyanate (1.35 mL) was added to the 4-4-dioxane (2.5 mL) solution at room temperature, and the mixture was heated to reflux for 2 days. After air cooling, methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.178 g, 55%) as a solid.

Example 59 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4-methyl-3,5- Dioxopiperazine

N, N-dimethylformamide of 5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (83.1 mg) of Reference Example 9 ( 1-hydroxybenzotriazole (49.5 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.127 g), triethylamine (0.165 ml), And 1-methyl 2,6-dioxopiperazine hydrochloride (52.5 mg) in Reference Example 39 were added and stirred for 20 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was extracted with ethyl acetate further. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (89.4 mg, 78%) as a solid.

Example 60 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -3-oxopiperazine

N, N-dimethylformamide of 5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (0.234 g) of Reference Example 9 ( 6.0 mL) solution, at room temperature, 1-hydroxybenzotriazole (0.125 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.342 g), triethylamine (0.350 mL), And piperazin-2-one (0.126 g) were added and stirred for 3 days. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was further extracted with the ethyl acetate-methanol (10: 1) mixed solvent. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (73.1 mg, 24%) as a solid.

Example 61 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -3-methoxyazetidine

To a dichloromethane (5.0 ml) solution of 5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (0.152 g) of Reference Example 9 , 1-hydroxybenzotriazole (0.0879 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.227 g), triethylamine (0.454 mL), and Reference Example 41 at room temperature. 3-methoxyazetidine hydrochloride (0.142 g) was added and stirred for 6 days. Water and chloroform were added to the reaction mixture for separation, and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (74.0 mg, 39%) as a solid.

Example 62 1- [5- (1-Methyl-1H-pyrrol-3-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4-methyl-3 -Oxopiperazine

N, N-dimethylformamide of 5- (1-methylpyrrole-3-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (0.242 g) of Reference Example 38 ( 5.0 ml) solution, at room temperature, 1-hydroxybenzotriazole (0.132 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.378 g), triethylamine (0.630 ml), And 1-methylpiperazin-2-one hydrochloride (0.200 g) in Reference Example 15 were added and stirred for 3 days. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was extracted with ethyl acetate further. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.243 g, 74%) as an amorphous material.

Example 63 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4-ethyl-3-oxopipe Razin

N, N-dimethylformamide of 5- (5-methylpyridin-2-yl) -5- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (0.247 g) of Reference Example 9 ( 5.0 ml) solution, at room temperature, 1-hydroxybenzotriazole (0.127 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.357 g), triethylamine (0.559 ml), And 1-ethylpiperazine-2-one hydrochloride (0.234 g) in Reference Example 40 were added and stirred for 18 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was extracted with ethyl acetate further. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.184 g, 53%) as a solid.

Example 64 1- [5- (5-aminomethylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Piperidine

1- [5- (5-cyanopyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy of Example 12 A 2 M ammonia-ethanol (30 mL) suspension of ferridine (500 mg) and nickel silica-alumina (˜65%, 280 mg) was stirred at 120 ° C. for 2 hours under a hydrogen (8 atmosphere) atmosphere. After air cooling, the residue obtained by distilling off the filtrate solvent under reduced pressure after filtration of celite was purified by silica gel thin layer chromatography (lower layer of chloroform-methanol-water) to obtain the title compound (259 mg, 51%) as a white solid.

Example 65 1- [5- (5-hydroxymethylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Lopiferidine

1- [5- (5-aminomethylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy of Example 64 Sodium nitrite (91 mg) was added to a solution of ferridine (105 mg) and acetic acid (1 mL) at room temperature, followed by stirring for 2 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and a chloroform-methanol (10: 1) mixed solvent were added thereto for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (46 mg, 44%) as a white solid.

Example 66 1- [5- (5-fluoromethylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Lopiferidine

5-[(5-hydroxymethylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoropiperi of Example 65 To a dichloromethane (30 mL) solution of dean (440 mg), bis (2-methoxyethyl) aminosulfur trifluoride (223 µl) was added under ice cooling, followed by stirring for 20 minutes. Saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) and NH silica gel thin layer chromatography (hexane-ethyl acetate) to give the title compound (130 mg, 29%) as a solid. Obtained as.

Example 67 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4-methylpiperazine

5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (280 mg) and 1-methylpiperazine (165 μl of Reference Example 9 ), 1-hydroxybenzotriazole (54 mg), triethylamine (697 μl), and dichloromethane (30 mL) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (288 mg) The solution was stirred overnight at room temperature. Water and dichloromethane were added to the reaction mixture for separation, and the organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (chloroform-methanol-water under layer) to obtain the title compound (90 mg, 25%) as a solid.

Example 68 1- [5- (5-aminomethylpyridin-2-yl) -1-phenyl-1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine

1) 1- [5- (5-cyanopyridin-2-yl) -1-phenyl-1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine

5- (5-cyanopyridin-2-yl) -1-phenyl-1H-pyrazole-3-carboxylic acid (1.0 g) of Reference Example 46 and 4,4-difluoropiperi of Reference Example 12 Dean hydrochloride (0.66 g) was used to give the title compound (1.1 g, 81%) as a solid in the same manner as in Example 1.

2) the title compound

Said 1- [5- (5-cyanopyridin-2-yl) -1-phenyl-1H-pyrazole-3-carbonyl] -4,4-difluoropiperidine (1.05 g) and nickel A 2 M ammonia-ethanol (30 mL) suspension of silica-alumina (˜65%, 730 mg) was stirred for 40 minutes at 120 ° C. under a hydrogen (8 atmosphere) atmosphere and then at room temperature overnight. The reaction solution was filtered through Celite, and the filtrate was distilled off under reduced pressure of the solvent. The residue was purified by silica gel thin layer chromatography (chloroform-methanol) to obtain the title compound (406 mg, 38%) as a solid.

Example 69 1- [5- (5-methoxymethylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Lopiferidine

1- [5- (5-hydroxymethylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoro of example 65 To a N, N-dimethylformamide (5 mL) solution of piperidine (60 mg) and methyl iodide (0.5 mL), sodium hydride (60% mineral oil suspension, 9.0 mg) was added under ice cooling and stirred for 1 hour. . The reaction solution was separated by adding water and ethyl acetate, and the organic layer was washed three times, and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (ethyl acetate) to obtain the title compound (33 mg, 53%) as a solid.

Example 70 1- [5- (1-Methyl-1H-imidazol-4-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4- Difluoropiperidine

Ethanol (5) of 5- (1-methyl-1H-imidazol-4-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.232 g) of Reference Example 42 Ml) and a tetrahydrofuran (5 ml) solution were added with 1 M aqueous sodium hydroxide solution (2.34 ml) and stirred at room temperature for 2.5 hours. After adding 1M hydrochloric acid (2.34 mL) to the reaction solution, the solvent was distilled off under reduced pressure. 4,4-difluoropiperidine hydrochloride (0.184 g) and 1-hydroxybenzotriazole (0.143 g) of Reference Example 12 in a suspension of the obtained residue in N, N-dimethylformamide (15 ml) at room temperature. , Triethylamine (0.330 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.179 g) were added, and the mixture was stirred at room temperature for 17.5 hours. The reaction solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate solution was added to the obtained residue, followed by extraction three times with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel flash column chromatography (dichloromethane-methanol) to obtain the title compound (0.234 g, 80%) as a solid.

Example 71 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4-methyl-3-oxopipe Razin

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.218 g) of Reference Example 9, 1-methyl-2 of Reference Example 15 In a N, N-dimethylformamide (15 mL) solution of piperazinone hydrochloride (176 mg) and 1-hydroxybenzotriazole (143 mg), triethylamine (0.330 mL) and 1- at room temperature (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (179 mg) was added, and the mixture was stirred at room temperature for 15.5 hours. The reaction solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue for separation, and the aqueous layer was further extracted with ethyl acetate four times. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (dichloromethane-methanol) to obtain the title compound (231 mg, 78%) as a solid.

Example 72 1- [5- (1-methyl-1H-imidazol-4-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4- (di Fluoromethylene) piperidine

Ethanol (5) of 5- (1-methyl-1H-imidazol-4-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.232 g) of Reference Example 42 Ml) and a tetrahydrofuran (5 ml) solution were added with 1 M aqueous sodium hydroxide solution (2.34 ml) and stirred at room temperature for 4 hours. After adding 1 M hydrochloric acid (2.34 mL) to the reaction solution, the reaction solvent was distilled off under reduced pressure, and the obtained residue was obtained from 4- (difluoromethylene) piperidine hydrochloride (Bioorganic & Medicinal Chemistry (2004), 12 ( 7), 1713-1730, 0.130 g), and 1-hydroxybenzotriazole (0.143 g) in a suspension of N, N-dimethylformamide (15 mL) at room temperature with triethylamine (0.330 mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.179 g) was added and the mixture was stirred for 2.5 days. The reaction solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue for separation, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration fractionation, the residue obtained by distillation under reduced pressure was purified by silica gel flash column chromatography (dichloromethane-methanol) to obtain the title compound (0.210 g, 67%) as a solid.

Example 73 1- [5- (1-Methyl-1H-imidazol-4-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4-methylenepy Ferridine

Methanol (5) of 5- (1-methyl-1H-imidazol-4-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester (0.232 g) of Reference Example 42 Ml) and a tetrahydrofuran (5 ml) solution were added with 1 M aqueous sodium hydroxide solution (2.34 ml) and stirred at room temperature for 4.5 hours. After adding 1M hydrochloric acid (2.34 mL) to the reaction solution, the residue obtained by distilling off a reaction solvent under reduced pressure, 4-methylene piperidine hydrochloride (0.156 g) of Reference Example 43, and 1-hydroxybenzotria In a suspension of N, N-dimethylformamide (25 ml) of sol (0.143 g), triethylamine (0.330 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.179 g) at room temperature ) Was added and stirred for 15.5 hours. The reaction solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue for separation, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (dichloromethane-methanol) to obtain the title compound (0.172 g, 62%) as a solid.

Example 74 1- [5- (5-ethynylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoro Piperidine

1- (3-pyridyl) -5- {5- [2- (trimethylsilyl) ethynyl] -2-pyridyl} -1H-pyrazole-3-carboxylic acid ethyl ester of Reference Example 45 (0.175 g To a mixed solution of ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1 M aqueous sodium hydroxide solution (1.35 mL) at room temperature, followed by stirring for 2 hours. After adding 1 M hydrochloric acid (1.35 ml) to the reaction solution, the residue obtained by distilling off the reaction solvent under reduced pressure, 4,4-difluoropiperidine hydrochloride (0.127 g) of Reference Example 12, and 1-hydride Triethylamine (0.187 mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.103) in an N, N-dimethylformamide (10 mL) suspension of oxybenzotriazole (82.4 mg). g) was added and stirred for 4.5 days at room temperature. The reaction solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (ethyl acetate-n-hexane) to obtain the title compound (0.132 g, 74%) as a solid.

Example 75 1- [5- (5-acetylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy Ferridine

1- [5- (5-ethynylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-difluoropy of Example 74 Sulfuric acid (0.0440 ml) was added to a 75% hydrous acetone (2 ml) suspension of ferridine (0.160 g) and dihydrogen sulfate (0.120 g), followed by heating to reflux for 2 hours. After air cooling, an aqueous potassium carbonate solution, methanol, and chloroform were added to the reaction solution, and the residue obtained by distilling off the reaction solvent under reduced pressure was purified by silica gel flash column chromatography (ethyl acetate -n-hexane) to obtain the title compound (59.2). Mg, 34%) was obtained as a solid.

Example 76 (-)-(6S) -1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl]- 4,6-dimethyl-3-oxopiperazine

To (2S) -2,4-dimethyl-5-oxo-1-piperazinecarboxylic acid tert-butyl ester (0.267 g) in Reference Example 44, 4M hydrochloric acid-dioxane solution (5 ml) was added at room temperature. And stirred for 4 hours. The residue obtained by distilling a reaction solvent under reduced pressure and 5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.218 g) of Reference Example 9 ), And triethylamine (0.330 mL) and 1- (3-dimethylaminopropyl) -3 at room temperature in a suspension of N, N-dimethylformamide (15 mL) of 1-hydroxybenzotriazole (143 mg). -Ethylcarbodiimide hydrochloride (179 mg) was added and stirred for 1.5 days. The reaction solvent was distilled off under reduced pressure, dichloromethane and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the aqueous layer was further extracted twice with a 10% methanol-dichloromethane mixed solvent. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel flash column chromatography (methanol-dichloromethane) to give the title compound (250 mg, 54%) as a solid.

Example 77 1- [5- (5-carbamoylmethoxypyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -4,4-di Fluoropiperidine

N, N-dimethylformamide of 5- (5-hydroxypyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carboxylic acid (300 mg) of Example 11 Potassium carbonate (215 mg) and bromoacetamide (129 mg) were added to the solution (5 ml), and the mixture was stirred at 50 ° C for 16 hours. After air cooling, water and ethyl acetate were added to the reaction solution for separation. The organic layer was washed twice with water and then dried over anhydrous magnesium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel thin layer chromatography (dichloromethane-methanol) to obtain the title compound (240 mg, 70%) as a solid.

Example 78 1- [5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carbonyl] -2-carbamoylpiperidine

5- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.250 g) of Reference Example 9, piperidine-2 of Reference Example 19 Dichloromethane (5 mL) of -carboxylic acid amide (0.126 g), 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (0.188 g) and 1-hydroxybenzotriazole (0.133 g) Triethylamine (0.137 mL) was added to the suspension at room temperature, followed by stirring for 15 hours. Water and chloroform were added to the reaction mixture for separation. The residue obtained by distilling off the solvent of the organic layer under reduced pressure was purified by silica gel column chromatography (methanol-chloroform) to obtain the title compound (0.229 g, 66%) as a solid.

Example 79 4-{[5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazol-3-yl] carbonyl}- 1-methyl-2-piperazinone

5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazole-3-carboxylic acid (0.160 g), 1-methyl of Reference Example 48 To a suspension of N, N-dimethylformamide (15 mL) of 2-piperazinone hydrochloride (0.126 g) and 1-hydroxybenzotriazole (0.103 g) at room temperature, triethylamine (0.235 mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.129 g) was added and the mixture was stirred for 16.5 hours. The reaction solution solvent was distilled off under reduced pressure, and a saturated sodium bicarbonate solution and 10% methanol-dichloromethane were added to the residue. In addition, the aqueous layer was extracted with 10% methanol-dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (methanol-dichloromethane) to give the title compound (0.185 g, 85%) as a solid.

Example 80 4-{[5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazol-3-yl] carbonyl} mor Pauline

(5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazole-3-carboxylic acid (0.160 g) and morpholine of Reference Example 48 (73.0 μl) was used to obtain the title compound (0.146 g, 73%) as a solid in the same manner as in Example 79.

Example 81 1-{[5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazol-3-yl] carbonyl}- 4-methoxypiperidine

5- (5-methyl-2-pyridyl) -1- (1,3-thiazol-2-yl) -1H-pyrazole-3-carboxylic acid (0.160 g) and Reference Example 11 of Reference Example 48 In the same manner as in Example 79 using 4-methoxypiperidine hydrochloride (0.127 g), the title compound (0.167 g, 78%) was obtained as a solid.

Example 82 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -3-oxo-4-methyl [ 1.4] diagen edition

N, N-dimethylformamide of 2- (5-methyl-2-pyridyl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (0.258 g) of Reference Example 9 (2 Ml) and 1-hydroxybenzotriazole (0.135 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.367 g), triethyl at room temperature in a dichloromethane (7.5 ml) solution Amine (0.621 mL) and 1-methyl-2-oxo [1.4] diazepane hydrochloride (0.210 g) in Reference Example 49 were added, and the mixture was stirred for 15 hours. Water and ethyl acetate were added and liquid-separated into the reaction liquid, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (0.185 g, 52%) as an amorphous material.

Example 83 (2S) -1- [5- (1-Methyl-1H-pyrazol-4-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl]- 2-fluoromethylpyrrolidine

1) Title compound

5- (1-Methyl-1H-pyrazol-4-yl) -1- (3-pyridyl) -1H-pyrazole-3-carboxylic acid (250 mg) and 3- (3- of Reference Example 47 To a dichloromethane (10 ml) solution of dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (270 mg) and 1-hydroxybenzotriazole (190 mg) at room temperature, (2S) -2- in Reference Example 31. Fluoromethylpyrrolidine hydrochloride (160 mg) and triethylamine (0.6 mL) were added, followed by stirring for 63 hours. Water and dichloromethane were added to the reaction mixture for separation, and the organic layer was dried over anhydrous magnesium sulfate. After filtration fractionation, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (dichloromethane-methanol) to obtain the title compound (290 mg, 88%) as an amorphous material.

2) hydrochloride of the title compound

To a mixture of ethanol (5 ml) and methanol (3 ml) of the title compound (290 mg) was added 1 M hydrochloric acid-ethanol (1 ml) at room temperature, followed by stirring for 30 minutes. The reaction solvent was distilled off under reduced pressure to obtain the hydrochloride (260 mg, 65%) of the title compound as a solid.

Example 84 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -2- (1-aminocyclopropyl Piperidine

1) 1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -2- [1- (N-tert-part Methoxycarbonylamino) cyclopropyl] piperidine

1- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-carboxylic acid (143 mg) in Reference Example 9 and (1-piperidine in Reference Example 50 1- [5- (5-methylpyridin-2-yl) -1- (pyridine-) in the same manner as in Example 78 using 2-yl cyclopropyl) carbamic acid tert-butylester (123 mg) 3-yl) -1H-pyrazole-3-carbonyl] -2- [1- (N-tert-butoxycarbonylamino) cyclopropyl] piperidine (225 mg, 88%) as amorphous Got it.

2) the title compound

1- [5- (5-methylpyridin-2-yl) -1- (pyridin-3-yl) -1H-pyrazole-3-carbonyl] -2- [1- (N-tert-butoxy Trifluoroacetic acid (7 mL) was added to a dichloromethane (20 mL) solution of carbonylamino) cyclopropyl] piperidine (224 mg), followed by stirring for 105 minutes. To the residue obtained by distilling off the reaction solvent under reduced pressure, a saturated sodium hydrogencarbonate aqueous solution and a chloroform-methanol (10: 1) mixed solvent were added and distributed. The organic layer was dried over anhydrous sodium sulfate. After filtration fractionation, the solvent was distilled off under reduced pressure to obtain the title compound (80 mg, 44%) as a solid.

Test Example 1 Inhibiting Platelet Aggregation

Human blood was collected using a 1/10 dose of 3.13% sodium citrate as a blood coagulation inhibitor and centrifuged at 180 g for 10 minutes to separate platelet rich plasma (PRP). After separating the upper PRP, the lower layer was centrifuged at 1600 g for 10 minutes to collect the platelet poor plasma (PPP) of the upper layer. 1 μL of the solution of the example compound was added to 200 μL of PRP and allowed to stand at 37 ° C. for 2 minutes, and then 2 μL of collagen was added to cause platelet aggregation. Platelet aggregation rate was measured using PAM-12C (SSR engineering). With the light transmittance of PPP as the 100% aggregation value, the aggregation rate at each concentration of the example compound was determined, and the IC ₅₀ value was calculated. The results are shown in Table 1.

[Test Example 2] Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) Inhibitory Activity

EXAMPLES The COX inhibitor screening assay kits (Catalog Nos. 560101 and 560121) of Cayman Chemical Company were used to measure the COX-1 and COX-2 inhibitory activity of the compounds.

Reaction buffer, heme, arachidonic acid, SnCl ₂ , EIA buffer, washing buffer, prostaglandin (PG) screening EIA standard, PG screening acetylcholine esterase (AchE), tracer (chromatase HRP conjugate), PG screening before measurement EIA antiserum was prepared.

Production of PGF _2α by COX-1 or COX-2

Example After the reaction solution containing the compound (50 μM) and COX-1 or COX-2 was allowed to stand at 37 ° C. for 10 minutes, 10 μL of arachidonic acid was added thereto and left at 37 ° C. for 2 minutes. After the reaction was stopped by adding 50 µL of 1 N-hydrochloric acid, 100 µL of SnCl ₂ solution was added, and the mixture was allowed to stand at room temperature for 5 minutes.

(2) Quantification of PGF _2α by ELISA

50 μL of antiserum (rabbit anti-PGF _2α antibody) was added to each well of a 96-well plate coated with mouse anti-rabbit IgG, and then 50 μL of a solution diluted 2000-fold of the PGF _2α production reaction solution and 50 μL of AchE tracer were sequentially added. It was left to stand for 18 hours at room temperature. Each well was washed five times with wash buffer to remove excess AchE tracer, and then 200 μL of Elman reagent was added. After standing in the dark for 60 minutes, the absorbance was measured at 405 nm.

(3) Calculation of Inhibitory Activity of Example Compound

A standard curve was prepared using PG screening EIA standard solution, and the yield of PGF _2α was determined from the absorbance. Example The inhibition rate of COX-1 or COX-2 in 50 µM of the compound was calculated. The results are shown in Table 1.

In addition, in calculation of inhibition rate, the production amount of PGF2 ( _alpha) obtained using the reaction liquid which does not contain an Example compound was made into 100%.

As is clear from Table 1, it was confirmed that the compound (I), salts thereof, or solvates thereof of the present invention have potent platelet aggregation inhibitory activity and do not exhibit COX-1 and COX-2 inhibitory effects.

Claims (14)

Formula I [Formula I]

In the formula, Ar ₁ represents a phenyl group having 1 or 3 substituents or no unsubstituted 5 or 6 membered aromatic heterocyclic group; Ar ₂ has 1 to 3 groups or atoms selected from (i) an unsubstituted phenyl group, (ii) a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted amino group, a hydroxyl group, a lower alkoxy group and a halogen atom A phenyl group substituted with a lower alkyl group, or (iii) a substituted or unsubstituted lower alkyl group, lower alkynyl group, lower alkanoyl group, substituted or unsubstituted carbamoyl group, cyano group, substituted or unsubstituted amino group, hydroxyl group, substituted A 5- or 6-membered aromatic heterocyclic group substituted with 1 to 3 groups or atoms selected from optionally substituted lower alkoxy groups and halogen atoms; X is formula II [Formula II]

(The cyclic structure in the formula is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted alkyl group, which does not or does not have one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom as a member other than the nitrogen atom described in the above formula. Substitution with 1 to 4 groups or atoms selected from den, substituted or unsubstituted carbamoyl groups, substituted or unsubstituted amino groups, hydroxyl groups, lower alkoxy groups, oxo groups, lower alkanoyl groups, lower alkylsulfonyl groups and halogen atoms Represents a 4 to 7 membered heterocyclic group which may be used. Compounds represented by them, salts thereof or solvates thereof. The compound, a salt thereof, or a solvate thereof according to claim 1, wherein Ar ₁ is an unsubstituted phenyl group. The compound, a salt thereof, or a solvate thereof according to claim 1, wherein Ar ₁ is an unsubstituted 5 or 6 membered aromatic heterocyclic group. The compound according to claim 3, wherein the 5 or 6 membered aromatic heterocyclic group is a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group, Salts or their solvates. Any one of claims 1 to 4, according to any one of items, Ar ₂ is a substituted or non-substituted lower alkyl group, a lower alkynyl group, a lower alkanoyl group, that is optionally substituted carbamoyl group, a cyano group, an optionally substituted And a 5 or 6 membered aromatic heterocyclic group substituted with 1 to 3 groups or atoms selected from an amino group, a hydroxyl group, a substituted or unsubstituted lower alkoxy group and a halogen atom. The compound according to claim 5, wherein the 5 or 6 membered aromatic heterocyclic group is a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group, a salt thereof or a solvate thereof . The substitution according to any one of claims 1 to 6, wherein the group represented by the formula (II) does not or does not have one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom as a member other than the nitrogen atom described in the formula (II). Or unsubstituted lower alkyl groups, substituted or unsubstituted alkylidene groups, substituted or unsubstituted carbamoyl groups, substituted or unsubstituted amino groups, hydroxyl groups, lower alkoxy groups, oxo groups, lower alkanoyl groups, lower alkylsulfonyl groups And an azetidino group, a pyrrolidino group, a pyrazolidino group, a piperidino group, a piperazino group, a morpholino group, a thiomorpholino group, which may be substituted with 1 to 4 groups or atoms selected from halogen atoms, A compound which is a homopiperazino group or a hexahydropyridazin-1-yl group, a salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 7, wherein X is 3-dimethylaminoazetidin-1-yl group, 3-methoxyazetidin-1-yl group, 2-fluoromethylpyrrolidino group, 3- Fluoropyrrolidino group, pyrazolidino group, 2-formyl-pyrazolidino group, piperidino group, 2- (1-aminocyclopropyl) piperidino group, 2-carbamoylpiperidino group, 2-methyl Carbamoylpiperidino group, 2-dimethylcarbamoylpiperidino group, 3-methoxypiperidino group, 3-fluoropiperidino group, 4-fluoromethylpiperidino group, 4-methoxypiperidino group, 4- Fluoropiperidino group, 4,4-difluoropiperidino group, 4-methyl-4-methoxypiperidino group, 4-methylene piperidino group, 4- (difluoromethylene) piperidino group, 4- Cyclopropylpiperazino group, 3-oxo-4-methylpiperazino group, 3-oxo-4-ethylpiperazino group, 4-methylpiperazino group, 4,6-dimethyl-3-oxopiperazino group, 3, 5-dioxo-4-methylpy A compound selected from a lazino group, a 4-methyl-3-oxo homopiperazinyl group, a hexahydropyridazin-1-yl group, a 2-carbamoylhexahydropyridazin-1-yl group, and a morpholino group, a salt thereof, or Their solvates. A pharmaceutical comprising the compound according to any one of claims 1 to 8, a salt thereof, or a solvate thereof as an active ingredient. An agent for the prevention and / or treatment of ischemic diseases comprising the compound of any one of claims 1 to 8, a salt thereof, or a solvate thereof as an active ingredient. A platelet aggregation inhibitor comprising the compound of any one of claims 1 to 8, a salt thereof, or a solvate thereof as an active ingredient. A pharmaceutical composition comprising the compound of any one of claims 1 to 8, a salt thereof, or a solvate thereof. A method for the prevention and / or treatment of ischemic diseases, characterized by administering an effective amount of the compound of any one of claims 1 to 8, salts thereof or solvates thereof. Use of the compound of any one of claims 1 to 8, salts thereof or solvates thereof for the production of a prophylactic and / or therapeutic agent for ischemic diseases.