WO2002092593A1 - 4-(4-pyridazinyl)pyrazole derivatives - Google Patents

Abstract

4-(4-Pyridazinyl)pyrazole derivatives represented by the following general formula or salts thereof have an excellent p38MAP kinase inhibitory activity, which makes them useful in preventing or treating tumor necrosis factor-α-associated diseases, interleukin-1-associated diseases, interleukin-6-associated diseases or cyclooxygenase II-associated diseases: (I) wherein Q represented optionally substituted aryl, etc.; R1 represents hydrogen, halogeno, etc.; R2 represents hydrogen, lower alkyl, etc.; and R3 represents hydrogen, -CH2-CH(R4)-(A)n-Y (wherein A represents lower alkylene; Y represents optionally substituted aryl; R4 represents hydrogen or lower alkyl; and n is 0 or 1), etc.

Description

 4- (4-Pyridazinyl) pyrazole derivative

TECHNICAL FIELD The present invention relates to a novel 4- (4-pyridazinyl) pyrazole derivative.

Background art

 TNF-, IL-1, IL-16 and COX-II are proteins produced mainly by immunocompetent cells such as macrophages and neutrophils. For example, they are important proteins involved in immunoregulatory functions and inflammatory symptoms. It is one of the factors. Moreover, TNF- and the like are known as factors involved in many biological reactions in the iL system, endocrine system, nervous system and the like. Therefore, production of TNF-α or the like in vivo in an excessive or uncontrolled manner is considered to be closely related to the occurrence or deterioration of related diseases such as TNF- ". On the other hand, in vivo It is known that p38 MAP kinase, which is present in various kinds of cells, specifically activates certain transcription factors, that is, transcription factors such as NF- / cB, AP-1, and CREB are It binds to DNA of a certain sequence common to TNF-, IL-1, IL-16, C0X-II, etc. and promotes transcription, but these transcription factors are activated in the cell nucleus by the action of p38MAP kinase. As a result, proteins such as TNF are synthesized from the transcribed mRNA, and mRNA that has gone out of the nucleus in the presence of calcium ions is not bound by binding to a protein having a specific sequence. It becomes active and is rapidly degraded, but activated by phosphorylation. When mRNA is present, mRNA is dissociated from the protein and becomes activated. In this pathway, proteins such as TNF-a, IL-1, IL-6, COX-II, etc. It is believed that synthesis is promoted.

Therefore, by inhibiting this p38MAP kinase, TNF-, IL- 1. It is thought that the production of IL-6, COX-II, etc. is considered to be inhibited. In line with this idea, p38 MAP kinase inhibitory activity and TNF-α :, IL-1, IL-6, COX-II Certain imidazole derivatives having a production inhibitory action have been proposed (see, for example, Bioorganic & Medicinal Chemistry, Vol. 5, No. 1, PP49-64, 1997 and PCT International Publication WO 93/14081 pamphlet). These TNF-production inhibitors, IL-11 production inhibitors, IL-6 production inhibitors or COX-II production inhibitors include TNF-related diseases, IL-1 related diseases, IL-6 related diseases or COX — II-related disorders, such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, psoriasis, HIV, asthma, Ml shock, inflammatory bowel disease, osteoporosis, Alzheimer's disease, diabetes, Cachexia, osteoporosis, graft-versus-host disease, adult respiratory distress syndrome, arteriosclerosis, gout, glomerulonephritis, congestive heart failure, ulcerative colitis, sepsis, cerebral malaria, restenosis ^ hepatitis, systemic Lupus erythematosus ヽ Thrombosis ヽ Bone resorption disease ヽ Chronic pulmonary inflammatory disease

(cronicpulmonary inflammation disease), cardiac reperfusion injury, renal reperfusion injury, cancer, Reita's syndrome, imminent preterm birth, eczema, allograft rejection, seizures, fever, Behcet's disease, neuralgia, meningitis, sunburn , Contact dermatitis, acute synovitis, spondylitis, muscle degeneration, angiogenesis, conjunctivitis, psoriatic arthritis, viral myocarditis, inflammation, glioblastoma, bleeding, arthritis, endotoxin shock, parasites Infection, tuberculosis, myocardial infarction, leprosy, diabetic retinopathy, irritable bowel syndrome (IBS), transplant rejection, burns, bronchitis, ischemic heart disease, eclampsia, pneumonia, remission of swelling. It is expected to be effective in treating or preventing diseases such as pharyngolaryngitis, Kawasaki disease, spinal cord disease and atopic dermatitis.

 On the other hand, recently, certain pyrazole derivatives having a p38 MAP kinase inhibitory action have been proposed (see PCT International Publications WO 98/52940 and WO 98/52941 Panfret).

The present inventors have also recently proposed certain substituted pyrazole derivatives that exhibit a very potent P38 MAP kinase inhibitory action (see WO 00/39116 and WO 0/75131 pamphlets). Disclosure of the invention

 This time, the 5- or 3-position of the pyrazole ring is substituted with an optionally substituted aryl or heteroaryl group and the 4-position is optionally substituted with a 4-pyridazinyl group. A series of substituted pyrazole derivatives have excellent p38 MAP kinase inhibitory activity, and based on it, have an inhibitory effect on the production of TNF- ", IL-1, IL-6, COX-II, etc. Was found.

 Thus, the present invention provides the formula

Where:

 Q represents an aryl group (this aryl group may be a halogen atom, a hydroxy group, a lower alkoxy group, an aralkyloxy group, a halogenated lower alkyl group, an octa-genated lower alkoxy group, a di-lower alkylamino group or a lower alkylenedioxy group; May be substituted with a group) or a heteroaryl group,

R ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, an amino group, an aralkylamino group, a lower alkylamino group, a di-lower alkylamino group or a lower alkylthio group,

R ² represents a hydrogen atom, a lower alkynyl group or a lower alkyl group optionally substituted with a hydroxy group, R ³ represents any of the following i) to vi i) 0 hydrogen atom ii) lower alkyl group iii) -CH (OH) -CH (R ⁴ )-(A) _n -Y iv) -CH = C (R ⁴ )-(A) _n- Y ν) — CH ₂ -CH (R ⁴ )-(Α) _η — Υ vi) — N (R ⁴ ) — CO— (Α) _η — Υ vii) A represents a lower alkylene group, Y represents an aryl group (this aryl group is optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group or a nitro group) R ⁴ represents a hydrogen atom or a lower alkyl group; n represents 0 or 1; and a 4- (4-pyridazinyl) pyrazole derivative represented by the formula or a salt thereof.

 As used herein, the term "lower" means that the group or compound to which this term is attached has at most 6, preferably at most 4, carbon atoms.

Thus, examples of the “lower alkyl group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. Examples of the “lower alkoxy group” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-hexyloxy and the like. Represents, for example, a methylthio, ethylthio, isopropylthio, n-butylthio group and the like. Examples of the “lower alkylene group” include, for example, one CH ₂ —, one CH (CH ₃ ) one, -CH (C ₂ H ₅ ) —, one (C H ₂ ) _2- , 1 CH ₂ -CH (CH ₃ )-, — CH ₂ -CH (C ₂ H ₅ ) 1,-(CH ₂ ) ₃ 1, 1 CH ₂ _ CH ₂ — CH (CH ₃ ) one, - (CH _{2) 4} one, - (CH _{2) 6} - or the like can Rukoto cited as the "lower alkylenedioxy O alkoxy group", for example, Mechirenjio alkoxy, Echirenjiokishi, propylene di O alkoxy group Can be mentioned. Further, examples of the “lower alkynyl group” include a propargyl group and the like, and examples of the “cycloalkyl group” include a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group.

 “Aryl group” is a monocyclic or polycyclic aromatic hydrocarbon group, for example, phenyl, indenyl, naphthyl group, etc., and “aralkyl group” is substituted by araryl group as defined above. Alkyl group, preferably an aryl-substituted lower alkyl group, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2- Examples include a naphthylmethyl group and a diphenylmethyl group.

 The aryl group represented by the symbol Q (this aryl group may be a halogen atom, a hydroxy group, a lower alkoxy group, an aralkyloxy group, a halogenated lower alkyl group, a halogenated lower alkoxy group, A phenyl group or a naphthyl group substituted by 1 to 3 halogen atoms; a hydroxy group, a lower alkoxy group, or a phenyl group substituted by 1 to 3 halogen atoms. And a phenyl group substituted by one substituent selected from a group selected from a group, an aralkyloxy group, a halogenated lower alkyl group, a halogenated lower alkoxy group, a di-lower alkylamino group and a lower alkylenedioxy group.

Examples of these substituted aryl groups include, for example, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, and 2-methylphenyl. Toxiphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-benzyloxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, '3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4 _ Dimethylaminophenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl Examples thereof include benzyl, 3-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-fluoronaphthyl, and 2,4-difluoronaphthyl.

 "Heteroaryl group" is a monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and one ring being a 5- or 6-membered ring. And the heterocyclic ring may form a condensed ring with a cyclic hydrocarbon group. Preferred among such heteroaryl groups are monocyclic or bicyclic heterocycles containing one or two heteroatoms selected from nitrogen, oxygen and sulfur atoms and one ring being a six-membered ring. May be a saturated heterocyclic group, optionally condensed with a phenyl group?ヽ Heterocyclic groups can be mentioned.

 Thus, these "heteroaryl groups" include, for example, pyrrolyl, furyl, chenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, viranyl, pyrimidinyl, pyridinyl, pyridinyl, pyridinyl Azepinyl, azocinyl, purinyl, naphthydinyl, pteridinyl, benzochenyl, benzofuranyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, chromenil, quinazolinyl, quinazolinyl Examples thereof include quinoxalinyl, quinolozinyl, phananthridinyl, acridinyl, and dibenzazepinyl groups.

 On the other hand, “halogen atom” includes fluorine, chlorine, bromine and iodine atoms. Examples of the “halogeno lower alkyl group” include, for example, trifluoromethyl, 2,2,2-trifluoroethyl and 2-chloroethyl groups.

The “lower alkyl group optionally substituted with a hydroxy group” represented by the symbol R ² includes, for example, a lower alkyl group substituted with one hydroxy group in addition to an unsubstituted lower alkynole group. And preferably methyl, ethyl, n-propyl Mouth pill, 2-hydroxyethyl, 4-hydroxybutyl group and the like can be mentioned.

 The “aryl group represented by the symbol Y (this aryl group may be optionally substituted with a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group or a nitro group)” is preferably unsubstituted. A substituted phenyl group; a phenyl group substituted with 1 to 3 halogen atoms; 1 or 2 substituents selected from a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, an amino group, and a nitro group. Examples thereof include a phenyl group substituted with a group, for example, 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 2-methylphenyl, 3-methylphenyl. , 4-Methylphenyl, 2-Methoxyphenyl, 4-Methoxyphenyl, 2-Aminophenyl, 4-Amiphenyl Phenyl, 2-ditrophenyl, 412-trophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl Examples include benzyl, 2-chloro-4-fluorophenyl, 2,5-dimethylphenyl, 2,4-dimethoxyphenyl, 4-amino-13-methylphenyl, and 3-methyl-4-nitrophenyl. it can.

 A preferred group of compounds in the present invention is a compound wherein Q is optionally a halogen atom, a hydroxy group, a methoxy group, a benzyloxy group, a trifluoromethyl group, a trifluoromethoxy group and a methylenedioxy group. And a compound represented by the formula (I) when Q represents a 4-fluorophenyl group, particularly a compound represented by the formula (I) wherein Q represents a 4-fluorophenyl group.

Another group of compounds preferred in the present invention are those of the formula (I) in which R ¹ represents a hydrogen atom, a lower alkoxy group or an amino group.

Other preferred group of compounds in the present invention are I匕合compound of formula (I) may represent R ² is a hydrogen atom, a methyl group, pro Parugiru group or 2-hydroxy E methyl group. Yet another group of compounds preferred in the present invention is that R ³ represents a hydrogen atom or a group of any of formulas iii) to vi), wherein A represents a methylene group, Y represents a fluorine group which may be optionally substituted by a halogen atom, R ⁴ represents a heptanium atom, and η represents 1, which is a compound of the formula (I).

In the compound of the formula (I) of the present invention, when R ² represents a hydrogen atom, the hydrogen atom is usually added to either of two nitrogen atoms constituting a pyrazole ring at a certain ratio depending on reaction conditions and the like. Because of the binding, the substitution position cannot be specified. Therefore, in the present specification, the expression of the substitution position of the substituent R ² in the chemical structural formula is as follows: `` When R ² represents a hydrogen atom, it is unknown which of two nitrogen atoms constituting the pyrazole ring is bonded. There is ". When R ² represents lower alkyl optionally substituted with a hydroxy group, the position of the substitution can be specified, and “R ² is optionally substituted with a hydroxy group. When it represents a alkyl group, it is bonded to a fixed position of one of the two nitrogen atoms constituting the pyrazole ring. "

In addition, in the description of the compound name in Examples and the like, when R ² represents a hydrogen atom, in which position are the substituents Q and R ^{3 at} the 3- and 5-positions bonded respectively? Since it cannot be specified, the substitution position is represented using the expression “3 (5) —” or “5 (3) one”.

 Representative examples of the compound of formula (I) provided by the present invention include the following in addition to those listed in Examples below.

 4-1 (4-pyridazinyl) -1 3 (5) -1 (4-trifluoromethylphenyl) pyrazole,

 3 (5) 1- (3,4-ethylenedioxyphenyl) -4--(4-pyridazinyl) pyrazole,

 3 (5) One (one naphthyl) one four one (4-pyridazinyl) pyrazole,

 4-1 (4-pyridazinyl) -1 3 (5)-(2-pyridyl) pyrazol,

 4 (4-pyridazinyl) 1 3 (5) 1 (4-pyridyl) pyrazole,

4- (4-pyridazinyl) -1 3 (5)-(5-pyrimidinyl) pyrazole, 4- [4- (3-cyclopyridazinyl)] 1-3 (5) 1- (4-fluorophenyl) pyrazole, 4- [5— (3-fluoropyridazinyl)] 1-3 (5) 1- (4-fluorophenyl) pyrazole,

 3 (5) — (4-Fluorophenyl) 1-41 [4- (3-hydroxypyridazinyl)] pyrazole,

 4— [5 .— (3-Aminobiridazinyl)] —3 (5)-(4-Monofluorophenyl) pyrazole,

 4— [5— (3-benzylaminopyridazinyl)] — 3 (5) _ (4-fluorophenyl) pyrazole,

 3 (5)-(4-Fluorophenyl) 1-4- [5- (4-Methylaminoviridazinyl)] pyrazole,

 4- [4- (3-dimethylaminopyridazinyl)]-3 (5) — (4-fluorophenyl) pyrazol,

 3 (5)-(4-Fluorophenyl) —4- [4- (3-methylthiopyridazinyl)] pyrazole,

 3- (4-fluorophenyl) -111-ethyl-1-41- (4-pyridazinyl) virazole,

 3- (4-fluorophenyl) 1-11-propyl-1-4-1 (4-pyridazinyl) pyrazole,

 3- (4-fluorophenyl) -1- (2-hydroxyethyl) _5_ (3-phenylpropyl) 1-4- (4-pyridazinyl) pyrazole,

 3- (4-fluorophenyl) 1-11 (2-hydroxyethyl) —5 -— (2—methoxyphenylacetylamino) 1-41 (4-pyridazinyl) pyrazole,

3 (5) 1- (4-fluorophenyl) -5 (3) 1- (1-hydroxy_3-phenylpropyl) 4- (4-pyridazinyl) pyrazole,

 3 (5) 1- (4-fluorophenyl)-5 (3) 1- (3-phenylpropyl) 1-41- (4-pyridazinyl) pyrazole,

3- (4-fluorophenyl) 1-1-methyl-5- (3-phenylbutyl) -1-4- (4-pyridazinyl) pyrazole, 3- (4-fluorophenyl) -1-methyl_5- (2-methyl-3-phenylpropyl) -4-1 (4-pyridazinyl) pyrazole,

 5- [3- (2-chlorophenyl) propyl] —3- (4-fluorophenyl) -1-methyl-14- (4-pyridazinyl) pyrazole,

 3- (4-fluorophenyl) _1-methyl-1-5-—3- (2-methylphenyl) propyl] —4 -— (4-pyridazinyl) pyrazole,

 3- (4-fluorophenyl) -1-5- (3- (3-methoxyphenyl) propyl] -1-methyl-1- (4-pyridazinyl) pyrazole,

 5— [3- (4-aminophenyl) propyl] —3- (4-fluorophenyl) _1-methyl-4_ (4-pyridazinyl) pyrazole,

 3- (4-fluorophenyl) — 1-methyl _5— [3- (4-nitrophenyl) propyl] —4— (4-pyridazinyl) pyrazol,

 5- [3- (2,4-dichlorophenyl) propyl] -3- (4-fluorophenyl) 1-1-methyl-4--1- (4-pyridazinyl) pyrazole and the like.

 The compound of the formula (I) of the present invention can also form a salt. Examples of the salt include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. And salts with organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid, and p-toluenesulfonic acid. Among them, pharmaceutically acceptable salts are preferable.

According to the present invention, the compound of the formula (I) is, for example, one of the following ( _a ) to (! 1) depending on the types of the substituents represented by R ² and R ³ . It can be manufactured by a method.

式中、 Q及び R¹は前記の意味を有する、 Method (a): The compound of the formula (I) in which R ³ represents a hydrogen atom in the above formula R (I) is represented by the formula

Wherein Q and R ¹ have the above-mentioned meaning,

Of the ethanony conjugate with N, N-dimethylformamide dimethyl acetal (DMF DMA)

H ₂ N-NHR ² (in)

Wherein R ² has the meaning described above,

By reacting the compound with a hydrazine compound or a hydrate thereof.

Method (b): Sengyo P, the compound of the formula (I) wherein R ² represents a hydrogen atom and R ³ represents a lower alkyl group or a lower cycloalkyl group in the formula (I)

式中、 R³¹は低級アルキル基又は低級シクロアルキル基を表わし、 MPMは 4—メトキシフエ二ルメチル基を表わし、 Qは前記の意味 を有する、

In the formula, R ³¹ represents a lower alkyl group or a lower cycloalkyl group, MPM represents a 4-methoxyphenylmethyl group, and Q has the above-mentioned meaning.

式中、 R¹は前記の意味を有する、 Of the formula

Wherein R ¹ has the meaning described above,

With the pyridazine compound of formula

I

式中、 Q、 R\ R³¹及び MP Mは前記の意味を有する、 の化合物を酸化反応に付し、 かくして得られる式

Wherein Q, R \ R ³¹ and MPM have the above-mentioned meanings.

式中、 Q、 R\ R³¹及び MP Mは前記の意味を有する、 の化合物を脱保護基反応に付することにより製造することができる。

Wherein, Q, R \ R ³¹ and MP M can be prepared by subjecting a compound of as defined above in deblocking reaction.

式中、 Q、 R¹及び R³¹は前記の意味を有する、 Method (c): In the above-mentioned P, in formula (I), R ² may be substituted with a lower alkynyl group or a hydroxy group, and represents a lower alkyl group, and R ³ represents a lower alkyl group or a lower cycloalkyl group. When the compound of the formula (I) is represented by the formula:

Wherein Q, R ¹ and R ³¹ have the meaning described above,

A compound of the formula

XR ²¹ (VIII)

In the formula, X represents a halogen atom, and R ²¹ represents a lower alkynyl group or a lower alkyl group optionally substituted with a hydroxy group,

By reacting with a lower alkynyl halide or a lower alkyl halide.

None (d): The compound of the formula (I) wherein R ² represents a hydrogen atom and R ³ represents a group of the formula iii) in the above-mentioned P, formula (I)

式中、 Q及び R¹は前記の意味を有する、

Wherein Q and R ¹ have the above-mentioned meaning,

A compound of the formula

Y- (A) _n -CH (R ⁴ ) -CHO (X) wherein A, Y, R ⁴ and η have the meaning described above, By reacting with an aldehyde compound.

Method (e): The above-mentioned P, in formula (I), R ² may be substituted with a lower alkynyl group or a hydroxy group, L represents a lower alkyl group, and R ³ represents a group of the formula iii) Wherein the compound of formula (I) is of the formula

式中、 Q、 R¹及び R²¹は前記の意味を有する、

Wherein Q, R ¹ and R ²¹ have the above-mentioned meaning,

Can be produced by reacting the compound of formula (X) with the aldehyde compound of formula (X).

Method (f): In the above formula (I), the compound of the formula (I) when R ³ represents a group of the formula iv) is a compound of the formula (I) wherein R ³ represents a group of the formula iii) The compound can be produced by subjecting the compound to a dehydration reaction.

Byon '(g): The compound of the formula (I) when R ³ represents a group of the formula V) in the preceding statement F », formula (I) is a formula when R ³ represents a group of the formula iv) The compound (I) can be produced by subjecting the compound to a reduction reaction.

Method (h): In the above formula (I), when R ³ represents a group of the formula vi), the compound of the formula (I) is represented by the formula:

式中、 Q及び R²は前記の意味を有する、

Wherein Q and R ² have the meaning described above,

Of the formula

Y-(A) _n -COOH (Xii)

 Wherein A, Y and n have the above-mentioned meanings,

With a carboxylic acid or a reactive derivative thereof of the formula

式中、 Q、 R²、 A、 Y及び nは前記の意味を有する、

Wherein Q, R ² , A, Y and n have the above-mentioned meanings,

Reacting the pyridazine compound of the formula (V) with the pyridazine compound of formula (V) to obtain a compound represented by the formula:

式中、 Q、 R\ R²、 A、 Y及び nは前記の意味を有する、 の化合物を酸化反応に付し、 さらに所望により、 得られるィ匕合物を低級アルキル ハライドで処理することにより製造することができる。

In the formula, Q, R \ R ² , A, Y and n have the above-mentioned meanings, and are subjected to an oxidation reaction, and further, if desired, the resulting compound is treated with a lower alkyl halide. Can be manufactured.

In the above method (a), the reaction between the ethanone compound of the formula (II) and DMFDMA is generally carried out in an inert organic solvent, for example, ethers such as tetrahydrofuran, dioxane and dimethoxyethane; and aromatics such as benzene and toluene. It can be performed in hydrocarbons and the like. The reaction temperature is usually in the range of from under ice-cooling to about 50 ° C., preferably around room temperature. The use ratio of DMF DMA to the ethanone compound of the formula (II) is as follows: "^ is at least 1 mole, preferably 1 to 5 moles, more preferably 1.5 moles of DMF DMA per mole of the ethanone compound of the formula (II). It can be in the range of ~ 2.5 mol.

 Thus, the expression

式中、 Q及び R¹は前記の意味を有する、

Wherein Q and R ¹ have the above-mentioned meaning,

The compound of the formula (XV) is usually reacted with the hydrazine-conjugated compound of the formula (III) or a hydrate thereof without isolation to obtain a compound of the formula (XV) In the case where R ^{3 in} the formula (I) represents a hydrogen atom, the compound can be changed to the compound of the formula (I).

 The reaction between the compound of the formula (XV) and the hydrazine compound of the formula (III) or a hydrate thereof is carried out in an inert solvent, for example, water; ethers such as tetrahydrofuran, dioxane, and diethyl ether; methanol, ethanol And alcohols such as propanol. The reaction temperature is usually from ice-cooling to the reflux temperature of the reaction mixture, and preferably from room temperature to around 50 ° C.

The use ratio of the hydrazine compound of the formula (III) or the hydrate thereof to the ethanone compound of the formula (II) is determined by the following formula per 1 mol of the ethanone compound of the formula (II): The hydrate can be in the range of at least 1 mole, preferably 1-5 moles, more preferably 1.5-2.5 moles. In the above method (b), the reaction between the pyrazole compound of the formula (IV) and the pyridazine conjugate of the formula (V) may be carried out by adding “^” in an inert solvent such as dichloromethane, Among the ethers such as dioxane, tetrahydrofuran, and dimethoxetane, etc., lower alkyl alkyl haloformate such as methyl carbonate, ethyl carbonate and isobutyl carbonate, etc. among ethers such as dioxane, tetrahydrofuran and dimethoxetane. Can be done below. The reaction temperature is usually from −20 ° C. to about 50 ° C., and preferably in the range from under ice-cooling to around room temperature.

 The proportion of the pyridazine compound of the formula (V) to the pyrazole compound of the formula (IV) is generally at least 1 mol, preferably 2 to 4 mols of the pyridazine compound of the formula (V) per mol of the pyrazole compound of the formula (IV). It can be within the range of 10 mol. '

 The obtained compound of the formula (V I) can then be converted to the compound of the formula (V I I) by subjecting it to an oxidation reaction.

 The oxidation reaction of the compound of the formula (VI) is generally carried out in an inert organic solvent, for example, in hydrocarbons such as decalin and tetralin; in halogenated hydrocarbons such as dichloromethane and chloroform, and the like. For example, the reaction can be performed in the presence of sulfur, manganese dioxide, or the like. The reaction temperature is usually in the range of from 40 ° C. to the reflux temperature of the reaction mixture, preferably from 100 ° C. to the reflux temperature of the reaction mixture.

Thus, the compound of the above formula (VII) is produced, and this compound is subsequently subjected to a deprotection group reaction, whereby in the formula (I) aimed at by the present invention, R ² represents a hydrogen atom. And R ³ represents a lower alkyl group or a lower cycloalkyl group.

 The deprotection reaction is generally carried out in an inert organic solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform, or an ether such as tetrahydrofuran, dioxane, or dimethoxyethane in a solvent such as trifluoroacetic acid or trifluoromethanesulfonic acid. It can be performed in the presence of a strong acid. The reaction temperature is usually from room temperature to the reflux temperature of the reaction mixture, preferably from 50 ° C. to the reflux temperature of the reaction mixture.

In the method (c), the reaction of the compound of the formula (I_1) with the lower alkyl halide or the lower alkynyl halide of the formula (VIII) is carried out in an inert organic solvent. For example, ethers such as dioxane, tetrahydrofuran, and dimethoxyethane; amides such as dimethylformamide and dimethylacetamide; aromatic hydrocarbons such as benzene and toluene; sodium hydride, sodium amide; The reaction can be performed in the presence of a base such as mu-butoxide. Examples of the lower alkyl halide or lower alkynyl halide that can be used in this reaction include methyl iodide, ethyl iodide, isopropyl iodide, 2-hydroxyethyl iodide, and propargyl iodide. Can be. The reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from ice-cooling to around room temperature.

 The use ratio of the lower alkyl halide or lower alkynyl halide of the formula (VIII) to the compound of the formula (I-1) is generally 1 mol per mole of the compound of the formula (I-11), The lower alkyl halide or lower alkynyl halide can be present in at least 1 mole, preferably in the range of 1.0 to 2 moles, more preferably in the range of 1.1 to 1.5 moles.

 In the above method (d), the reaction of the compound of the formula (IX) with the aldehyde compound of the formula (X) is generally carried out in an inert organic solvent, for example, ethers such as tetrahydrofuran, dioxane and dimethoxetane; benzene, toluene Among the aromatic hydrocarbons and the like, usually, first, a compound of the formula (IX) is first converted to, for example, n-butyllithium, tert-butyllithium, potassium tert-butoxide, lithium diisopropyl pyramide, lithium bis (trimethylsilyl). The treatment can be carried out by treating with a strong base such as amide and then reacting with an aldehyde compound of the formula (X). In general, the reaction temperature is preferably not more than 16 ° C. in the treatment with a strong base, and the subsequent reaction with the aldehyde compound of the formula (X) has a temperature in the range of −78 ° C. to room temperature. Are suitable.

The use ratio of the aldehyde compound of the formula (X) to the compound of the formula (IX) is generally at least 1 mol, preferably at least 1 mol of the aldehyde compound of the formula (X) per mol of the compound of the formula (IX). Can be in the range of 1 to 2 moles, more preferably 1.05 to 1.5 moles. The amount of the strong base used is generally the same as that of the compound 1 of the formula (IX). It can be at least 1 mole, preferably 1 to 2 moles, more preferably 1.05 to 1.5 moles per mole.

The reaction between the compound of formula (1-2) and the aldehyde compound of formula (X) in the method (e) can be carried out in the same manner as described in the method (d). A compound of the formula (I) wherein R ³ in the above method (f) represents a group of the formula iii), that is, a compound of the following formula (1-3)

式中、 Q、 R\ R A、 Y、 R⁴及び nは前記の意味を有する、 の化合物の脱水反応は、一般に、不活性有機溶媒中、例えばベンゼン、 トルエン、 キシレン等の芳香族炭化水素類；ジメチルスルホキシド等のスルホキシド類等の 中で、 必要に応じて脱水剤、 例えば 4—トルェンスルホン酸、 カンファ一スルホ ン酸等の存在下に処理することにより行うことができる。 反応温度は、通常、 室 温乃至反応混合物の還流温度、好ましくは 50 °C乃至反応混合物の還流温度の範 囲内の温度が適している。

Wherein, Q, dehydration of R \ RA, Y, R ⁴ and n are as defined above, the compound generally in an inert organic solvent, such as benzene, toluene, xylene and the like aromatic hydrocarbons It can be carried out in a sulfoxide such as dimethyl sulfoxide, if necessary, in the presence of a dehydrating agent, for example, 4-toluenesulfonic acid, camphorsulfonate and the like. The reaction temperature is usually from room temperature to the reflux temperature of the reaction mixture, preferably from 50 ° C. to the reflux temperature of the reaction mixture.

 In the dehydration reaction, the use ratio of the dehydrating agent to the compound of the formula (I-13) is generally at least 1 mol, preferably 1.

It can be in the range of 1 to 5 mol, more preferably 1.5 to 3 mol. In the above method (g), when R ³ represents a group of the formula iv), the reduction reaction of the compound of the formula (I) is represented by “^; alcohols such as methanol, ethanol, isopropanol and the like; tetrahydrofuran, dioxane, dimethoxetane Hydrogenation in a solvent such as an ester such as ethyl acetate in the presence of a catalyst such as palladium monocarbon, heptacene palladium monocarbon, and Raney Nigel under normal pressure or pressure. By Can be performed. The reaction temperature is usually in the range of 0 ° C. to 60 ° C., preferably around room temperature.

 In the above method (h), the amino acid conjugate of the formula (XI) and the carboxylic acid of the formula (XII) or a reactive derivative thereof (for example, acid chloride, acid anhydride, mixed acid anhydride, active amide, active ester, etc.) ) Is generally performed in an inert organic solvent, for example, ethers such as dioxane, tetrahydrofuran, and dimethoxetane; aromatic hydrocarbons such as benzene, toluene, and xylene; dimethylformamide, dimethylacetamide, and the like. Bases, for example, 1,8-diazabicyclo [5.4.0] amides; -Dene (DBU), triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine, N-methylmorpholine, etc. . The reaction temperature varies depending on the type of the carboxylic acid of the formula (XII) or its reactive derivative to be used, but it is usually in the range of 110 ° C to the reflux temperature of the reaction mixture, preferably from room temperature to the reflux temperature of the reaction mixture. Temperature is suitable. When a free carboxylic acid is used as the compound of the formula (XII), dicyclohexyl carbodiimide (DCC), 7j-soluble carbodiimide (WSC), diethyl cyanophosphate (DEPC), diphenylphosphoryl azide (DPPA) The reaction is preferably performed in the presence of a condensing agent such as

 The use ratio of the carboxylic acid of the formula (XII) or the reactive derivative thereof to the amino compound of the formula (XI) is as follows: "^ is the ratio of the carboxylic acid of the formula (XII) or The reactive derivative can be in the range of at least 1 mole, preferably 1-2 moles, more preferably 1-1.5 moles.

 The compound of the formula (XII I) obtained by the above reaction is then reacted with the pyridazine compound of the formula (V).

 The reaction between the compound of formula (XIII) and the pyridazine compound of formula (V) is described in the reaction of the compound of formula (IV) with the pyridazine compound of formula (V) in the method (b). Can be performed in the same manner as described above.

The subsequent oxidation reaction of the compound of formula (XIV) is also performed according to the method (b). The reaction can be carried out in the same manner as described in the oxidation reaction of the compound of formula (VI).

Thus, a compound of the formula (I) in which R ³ represents —NH—CO— (A) _N— Y in the formula (I) aimed at by the present invention is obtained.

The target compound obtained by this reaction is optionally treated with a lower alkyl halide to obtain a compound of the formula (I), wherein R ³ represents a group of the formula vi) and R ⁴ represents a lower alkyl halide. It can be changed to a compound of formula (I) when it represents a group.

 The treatment with a lower alkyl halide can be carried out in the same manner as described in the reaction of the compound (I-1) of the formula (VIII) with the lower alkyl halide or lower alkynyl halide of the formula (VIII) in the method (c). .

 Thus, the pyridazinyl virazole derivative of the formula (I), which is the object of the present invention, is produced.

 In the above reaction, most of the compound of the formula (II) used as a starting material is a novel compound which has not been described in the conventional literature.

式中、 R¹は前記の意味を有する、

Wherein R ¹ has the meaning described above,

With a pyridazine compound of the formula

QC 0 ₂ C ₂ H ₅ (XVII- 1)

Or

QC ON (CH ₃ ) (O CH ₃ ) (XVn-2)

 Wherein Q has the meaning described above,

Easy reaction with carboxylic acid ester or carboxylic acid amide derivative Can be manufactured. For details of the reaction conditions, see the step (a) of Example 1 and the step (a) of Example 4 described later.

 Further, the compound of the formula (IV), which is a starting material in the method (b), is also a novel compound which has not been described in the conventional literature.

Q-COCH ₂ COR ³¹ (XVIII)

Wherein Q and R ³¹ have the meaning described above,

By reacting the compound with hydrazine or a hydrate thereof, and treating the resulting pyrazole compound with 4-methoxybenzyl halide. For details of the reaction conditions, see the steps (a) to (c) of Example 51 described later. The compound of the formula (I) or a salt thereof produced as described above can be produced by a method known per se, for example, a method such as recrystallization, crystallization, distillation, column chromatography, and thin layer chromatography. It can be isolated and purified from the reaction mixture. The pyridazinyl virazole derivative represented by the formula (I) of the present invention described above or a salt thereof has excellent p38 MAP kinase inhibitory activity and TNF-, IL-11, IL-6 and COX- based thereon. It has an activity of inhibiting production of II and the like, and is useful as a therapeutic agent for TNF-related diseases, IL-11-related diseases, IL-6-related diseases, C0X-II-related diseases, and the like.

 The p38 MAP kinase (p38MAPK) inhibitory action and TNF-α release inhibitory action of the compound of formula (I) or a salt thereof of the present invention can be measured as follows.

 (1) Ρ 38Ρ 測定 Measurement of binding inhibitory activity

The Ρ38Κ binding inhibition activity was performed using the cytosol fraction of 単 Η-1 cells, which are human monocyte-derived cultured cells. That is, ΤΗΡ-1 spores were treated with cell lysis buffer (20 mM Tris salt solution (pH 7.4), 1 mM magnesium chloride, ImM PMSF (phenylmethylsulfonyl fluoride), lmM pepsatin A, ImM Putin, lOmgZml aprotinin) and sonicated in water. Then, ultracentrifuge at 100,00 OXg for 1 hour, and measure the protein concentration of the resulting supernatant (cytosol fraction). After diluting with Cell Rice Buffer to obtain a protein concentration of lm / m1, the solution was aliquoted and stored at -80 ° C until use.

The binding inhibitory activity was determined by incubating the cytosol fraction (100 g protein) of THP-1 cells and the test conjugate at 15 ° C for 30 minutes, and then using ³ H-SB 202190 (925 GB q / mmo) as a radioligand. 1, Amersham, UK) was added at 1.11 KB q and reacted at 15 ° C for 3 hours. Non-specific binding was determined by adding 20 μM of SB 203580. To separate free and bound ligand, add a charcoal solution (1% charcoal, 0.1% dextran T-70), cool on ice for 15 minutes, and centrifuge (3,000 rpm, 10 minutes, 4 ° C). The activity in the resulting supernatant was determined by adding liquid scintillation overnight and using a liquid scintillation counter.

The ³ H—SB 202190 used as the radioligand was 4- (4-fluorophenyl) -12- (4-hydroxy-13,5-di- ³ H-phenyl) 5-1— (4-pyridyl) SB 2 03580, which is imidazole and added for the measurement of non-specific binding, is 4- (4-fluorophenyl) 1-2- (4-methanesulfonylphenyl) 1-5- (4-pyridyl) imidazole. is there.

 The measurement results of the compound of the present invention are shown below. Compound I C50 (nM)

 Example 1 6.5

 Example 45 2.52

 Example 49 4.36

(2) Measurement of LPS-induced TNF_α release inhibitory action

A test compound, ヽ, was orally administered to a mouse, and after a lapse of a predetermined time, 5 g / kg of lipopolysaccharide (LPS) was administered from the tail vein. One hour later, the mice were thoracotomized under ether anesthesia, and blood was collected from the heart to obtain serum. Serum was stored at 120 ° C until measurement. The TNF-α concentration in serum samples was It was measured using a LISA kit. As a result, the compound of Example 1 of the present invention suppressed the release of TNF_ by 84% at 6 hours after administration at a dose of 30 mg / kg. In addition, release inhibition of 64% was observed even 9 hours after administration.

 As described above, the compound of the formula (I) or a salt thereof according to the present invention has an excellent ρ38ΡAΡΡ binding disorder activity, and is used as a p38MAP kinase inhibitor in humans and others. Can be administered orally or parenterally (eg, intramuscular, intravenous, rectal, transdermal, etc.) for the treatment and treatment of mammals.

 When the compound of the present invention is used as a drug, it may be in a solid form (for example, tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, troches, etc.) depending on the use. ), Semi-solid forms (eg, suppositories, ointments, etc.) or liquid forms (eg,

(E.g., pharmaceuticals, emulsions, suspensions, lotions, sprays, etc.). Non-toxic additives that can be used in the production of such preparations include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or the like. Salt, gum arabic, polyethylene glycol, alkyl ρ-hydroxybenzoate, syrup, ethanol, propylene glycol, cellulose, carboxyl, glycerin, sodium salt, sodium sulfite, sodium phosphate, citric acid and the like. The agent may also contain other therapeutically useful agents.

 The content of the compound of the present invention in the medicament can be varied depending on the dosage form and the like. However, in the case of solid and semi-solid forms, the concentration is in the range of 0.1 to 50% by weight. In the case of a liquid form, it is desirable to contain it at a concentration in the range of 0.05 to 10% by weight.

The dose of the compound of the present invention can be varied widely depending on the kind of human or other warm-blooded animals, the administration route, the severity of the symptoms, the diagnosis of a physician, etc. 0.02 to; LO mgZkg, preferably 0.1 to 2 mgZkg. However, depending on the severity of the patient's symptoms and the diagnosis of the physician, it is of course possible to administer a larger amount of M than the lower limit of the above range. You. The above dosage can be administered once or several times a day. Example

 Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1

 3 (5) — Synthesis of (4-fluorophenyl) 1-41 (4-pyridazinyl) pyrazole

 (a) Synthesis of 1-fluoro-4_ (4-pyridazinylacetyl) benzene

 Dissolve 3.83 g of 4-methylpyridazine in 40 ml of tetrahydrofuran (THF). After dropping a solution of 2.Omo 1/1 lithium diisopropylamide (LDA) heptane-THF-ethylbenzene with C, the mixture was stirred at room temperature for 30 minutes. Subsequently, 40 ml of a THF solution of 6.84 g of ethyl 4-fluorobenzoate was added dropwise at 170 ° C, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and insolubles were filtered and washed with ethyl acetate. The filtrate and the washing were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel gel chromatography (60 g, elution solvent, chloroform: methanol = 30: 1) to give 3.56 g (yield: 40%) of the title compound as yellow crystals. Obtained. Melting point: 114., 0 ~ 116.0 ° C

_{! H-NMR (CDC 1 3} ) S: 9. 20~ 9. 12 (m, 2H), 8. 05 (dd, J = 2. 4Hz, 5. 0Hz, 2H), 7. 41 (dd, J = 2.4 Hz, 5.0 Hz, 1H), 7.29 to 7.09 (m, 2H), 4.30 (s, 2H) Ma ss, m / e: 216 (M ⁺ ), 123 (base )

 (b) 3 (5) Synthesis of mono (4-fluorophenyl) -4- (4-monopyridazinyl) pyrazole

4 g of 1-fluoro-4- (4-pyridazinyl acetyl) benzene was dissolved in 80 ml of THF, 4.41 g of N, N-dimethylformamide dimethyl acetal was added, and the mixture was stirred at room temperature for 20 hours. Thereafter, the reaction solution was distilled off under reduced pressure. The obtained residue was dissolved in ethanol (60 ml), and hydrazine hydrate (1.85 g) was added. After stirring for 30 minutes at, the reaction solution was evaporated under reduced pressure, and 10% aqueous ammonia was added. The precipitated crystals were collected by filtration and washed with ether to give 3.53 g (yield: 79%) of the title compound as pale yellow crystals.

Melting point: 216.5 ~ 220.0 ° C

XH-NMR (DMS 0-d ₆ ) δ: 9.14 (dd, J = 1.3 Hz, 2.4 Hz, 1 H), 9.05 (dd, J = 1.3 Hz, 5.3 Hz, 1H) ), 8.42, 8.09 (s, 1H), 7.45 to 7.25 (m, 5H)

Ma s s, m / e: 240 (M +, ba s e)

Example 2

Synthesis of 3- (4-fluorophenyl) -1-methyl-41- (4-pyridazinyl) pyrazole

 584 mg of 1-fluoro-4- (4-pyridazinylacetyl) benzene was dissolved in 10 ml of THF, and 643 mg of N, N-dimethylformamide dimethyl acetal was added, followed by stirring at room temperature for 15 hours. After evaporating the reaction solution under reduced pressure, the residue was dissolved in 10 ml of ethanol, 249 mg of methylhydrazine was added, and the mixture was stirred at 50 ° C for 1.5 hours. After evaporating the reaction solution under reduced pressure, 10% aqueous ammonia was added, and the mixture was extracted with a porcine form. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ether and recrystallized from n-hexane-ethyl acetate to give 99 mg (yield: 14%) of the title compound.

Melting point: 107.5-: 110.0 ° C

_{^ -NMR (CDC 1 3) δ} 9. 15~9. 10 (m, 1 H), 9. 01 (dd, J = l. 3Hz, 5. 5Hz, 1H>, 7. 71 (s, 1H) , 7.53 to 6.95 (m, 5H), 4.01 (s, 3H)

Ma ss, m / e: 254 (M ⁺ , base)

Example 3

 Synthesis of 5- (4-fluorophenyl) 1-1-methyl-4- (4-pyridazinyl) pyrazole

The mother liquor obtained in Example 2 was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The mixture was applied to 25 g of Raffy (elution solvent, ethyl acetate: methanol = 6: 1). The yellow solid obtained from the low polar fraction was washed with ether to obtain 46 mg of 5- (4-fluorophenyl) -1-methyl-4- (4-pyridazinyl) pyrazole as a yellow powder. In addition, ether was added to the brown viscous substance obtained from the highly polar fraction and crystallized, and 3- (4-monofluorophenyl) -1-methyl-4- (4-pyridazinyl) pyrazole was obtained as a light brown solid. 154 mg were obtained. In addition, these structures were determined by the ¹ H-NM R spectrum (nuclear Oberhauser effect experiment).

Melting point: 158.5-16 IV

One _{NMR (CDC 1 3) ^:} . 9. 00 (dd, J = 1. 1 H z, 2. 4Hz, 1 H), 8. 95 (dd, J = l 1 Hz, 5. 6Hz, 1 H ), 7.91 (s, 1H), 7.35 to 7.21 (m, 4H), 7.13 (dd, J = 2.4 Hz, 5.6 Hz, 1H), 3.78 (s, 3H) )

Ma ss, m / e: 254 (M ⁺ , base)

Example 4

 3 (5) Synthesis of mono (3,4-difluorophenyl) -4--(4-pyridazinyl) pyrazole

 (a) Synthesis of 1,2-difluoro-4- (4-pyridazinyl acetyl) benzene 4-Methylpyridazine 47 Omg in THF 20m 1 under argon atmosphere at -60 ° C or lower 2. Omo 1 / 2. 75 ml of 1 LDA heptane_THF-ethylbenzene solution was added dropwise and stirred for 1 hour. Then, 1.11 g of THF solution 1 Om 1 of 3,4-difluoro-N-methoxy-1-N-methylbenzamide was added dropwise, and after stirring for 1 hour, 2. Omo 1/1 hydrochloric acid 2.75 ml was added dropwise. did. Further, the temperature was gradually raised, and when the temperature reached room temperature, 6 Oml of ethyl acetate was added, and the mixture was washed with 1 Oml of saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography 50 g (elution solvent, ethyl acetate: methanol = 9: 1) to give a yellow powder. 92 Omg (yield: 79%) of the compound was obtained.

Melting point: 136-139 ° C _{^{X H-NMR (CDC 1 3}} ) 5:. 9. 18 (dd, J = 1. 1 H z, 5. 1 Hz, 1H), 9. 19~9 09 (m, 1 H), 7. 90 Up to 7.76 (m, 2H), 7.41 (dd, J = 2.4 Hz, 5. lHz, 1H), 7.37 to 7.28 (m, 1H), 4.29 (s, 2H)

Ma ss, m / e: 234 (M ⁺ ), 141 (base)

 (b) Synthesis of 3 (5)-(3,4-difluorophenyl) -1-4- (4-pyridazinyl) pyrazol

 1,2-Difluoro-41- (4-pyridazinylacetyl)> The title compound was synthesized using benzene in the same manner as in Example 1 (b).

Melting point: 190.5-191.5 ° C

_{^ -NMR (CDC 1 3) δ} Q. 16 (dd, J = l. 2H z, 2. 5Hz, 1 H), 9. 10 (dd, J = 1. 2Hz, 5. 5Hz, 1 H>, 7.93 (s, 1H), 7.33 (dd, J = 2.5 Hz, 5.5 Hz, 1 H), 7.32 to 7.12 (m, 3H)

Ma ss, m / e: 258 (M ⁺ , base)

Example 5

 Synthesis of 3- (3,4-difluorophenyl) -1-methyl-4-1 (4-pyridazinyl) pyrazole

 The title compound was synthesized in the same manner as in Example 2.

Melting point: 150.5-151 ° C

_{^ - MR (CDC 1 3)} ^: 9. 13 (dd, J = 1. 2Hz, 2. 1 H z, 1H), 9. 06 (dd, J = 1. 2Hz, 5. 5Hz, 1 H) , 7.71 (s, 1H), 7.35 to 7.29 (m, 1H), 7.27 (J = 2.1 Hz, 5.5 Hz, 1H), 7.21 to 7.09 (m, 1H) 2H), 4.02 (s, 3H) Mass, m / e: 272 (M +, base) In the same manner as in Examples 1 and 2, the following Examples 6 to 21 and Examples 23 to 39 Was synthesized. Example 6

 3 (5) Monophenyl 4- (4-pyridazinyl) pyrazole

Melting point: 180.7-18.26 ° C

_{^{X H-NMR (CDC 1 3}} ) ^: 9. 16 (dd, J = 1. 1 Hz, 2. 4Hz, 1H), 9. 03 (. Dd, J = l 1Hz, 5. 5Hz, 1 H) , 7.92 (s, 1H), 7.44 (s, 5H), 7.33 (dd, J = 2.4 Hz, 5.5 Hz, 1H)

Ma ss, m / e: 222 (M ⁺ , base)

Example 7

 1-Methyl-3 _Phenyl-4-1- (4-pyridazinyl) pyrazole

_{^{X H-NMR (CDC 1 3}} ) δ 9. 14 (dd, J = l. 3Hz, 2. 4Hz, 1H), 8. 99 (dd, J = 1. 3Hz, 5. 5Hz, 1 H), 7 .71 (s, 1H), 7.40 (s, 5H), 7.30 to 7.21 (m, 1H), 4.02 (s, 3H)

Ma s s, m / e: 236 (M +, b a s e)

Example 8

 3 (5) — (2-fluorophenyl) 1 4- (4-pyridazinyl) pyrazole Melting point: 164.8-166.4 ° C

_{^{X H-NMR (CDC 1 3}} ) δ 11. 18 (bs, 1 H>, 9. 14 (dd, J = 1. 3H z, 2. 4Hz, 1 H), 9. 05 (dd, J = 1 3Hz, 5.4Hz, 1H), 7.97 (s, 1H), 7.58 to 704 (m, 5H) Ma ss, m / e: 240 (M ⁺ , base)

Example 9

 3- (2-fluorophenyl) -1-methyl-4- (4-pyridazinyl) pyrazole

Melting point: 136.8-140.4 ° C

_{^{X H-NMR (CDC 1 3}} ) δ 9. 09 (dd, J = 1. 1Hz, 2. 5Hz, 1H), 8. 98 (dd, J = l. LHz, 5. 5Hz, 1 H), 7 . 79 (s , 1 H), 7.6 1 to 6.98 (m, 5H), 4.04 (s, 3 H)

Ma ss, m / e: 254 (M ⁺ , base)

Example 10

 3 (5)-(3-Fluorophenyl) 1 4 _ (4-Pyridazinyl) pyrazole Melting point: 172.3-174.2 ° C

One _{NMR (CDC 1 3) δ:} . 9. 1 7 (dd, J = 1. 1 Η ζ, 2. 4H z, 1 H), 9. 07 (dd, J = l l H z, 5. 6H z, 1H), 7.93 (s, 1H), 7.47 to 7.12 (m, 5H)

Ma ss, m / e: 240 (M ⁺ , base)

Example 1 1

 3- (3-Fluorophenyl) 1-11-methyl-14- (4-pyridazinyl) pyrazole

Melting point: 96.6-: 101.8. C

_{^ -NMR (CDC 1 3) δ} 9. 14 (dd, J = 1. 3 H z, 2. 4H z, 1 H), 9. 03 (dd, J = l. 3H z, 5. 5H z, 1H), 7.70 (s, 1H), 7.3 1 to 7.00 (m, 5H), 4.02 (s, 3H)

Ma s s, m / e: 254 (M +, b a s e)

Example 1 2

 3 (5)-(2,4-difluorophenyl) 1-4- (4-pyridazinyl) pyrazole

Melting point: 203.3 ~ 205.6 ° C

_{^{X H-NMR (CDC 1 3}} ) δ 9. 1 5~ 9. 02 (m, 2H), 7. 98 (s, 1 H), 7. 58~6. 81 (m, 4H)

Ma ss, m / e: 258 (M ⁺ , base)

Example 13

 3- (2,4-difluorophenyl) 1-methyl-1 -4- (4-pyridazinyl) pyrazole

Melting point: 136.0-13.39.4 ° C _{^{X H-NMR (CDC 1 3}} ) 5:. 9. 1 1~ 8. 97 (m, 2H), 7. 78 (s, 1 H), 7. 56~6 74 (m, 4 H), 4 . 04 (s, 3 H)

Ma ss, m / e: 272 (M ⁺ , base)

Example 14

3 (5) — (4-chlorophenyl) 1-4 — (4-pyridazinyl) pyrazole Melting point: 173.0 to 174.5 ° C

One _{NMR (CDC 1 3) δ 9.} 0 9~ 9. 0 5 (m, 1 H), 8. 99 (dd, J = 1. 2H z, 5. 4H z, 1 H), 8. 04 ( s, 1H), 7.57 to 7.14 (m, 5H)

Ma ss, m / e: 256 (M ⁺ , base)

Example 15

 3- (4-chlorophenyl)-1-methyl-1- (4-pyridazinyl) pyrazole

Melting point: 152.0-15.5 ° C

One _{NMR (CDC 1 3) ^:} . 9. 06 (dd, J = 1. 3 H z, 2. 5H z, 1 H), 8. 94 (dd, J = l 0H z, 5. 4H z, 1H>, 7.86 (s, 1H), 7.48 to 7.45 (m, 2H), 7.43 to 7.35 (m, 2H), 7.07 (dd, J = 2 .5Hz, 5.4Hz, 1H), 4.06 (s, 3H)

Ma s s, m / e: 270 (M +, b a s e)

Example 16

 3 (5) — (4-Promophanil) 1 4 1 (4_pyridazinyl) pyrazole Melting point: 223.0 to 225.0 ° C

^X H-NMR (CD3OD) δ: 9.12 (dd, J = 1.2 Hz, 2.5 Hz, 1 H), 9.0 1 (dd, J = 1.3 Hz, 5.5 Hz) , LH) 8.20 (bs, 1 H), 7.63 (d, J = 6.8 Hz, 2H), 7.57 (dd, J = 2.5 Hz, 6.6 Hz, 1 H), 7.38 (d, J = 6.5Hz, 2H)

Ma ss, m / e: 302 (M ⁺ + 2), 300 (M ⁺ , base) Example 17

 3- (4-bromophenyl) 1-1-methyl- (4-pyridazinyl) pyrazole Melting point: 121.7-12.22.1 ° C

^ -NMR (CD ₃ OD) δ: 9.14 (m, 1 H), 9.04 (dd, J = 0.9 Hz, 5.3 Hz, iH), 7.72 (s, 1 H ), 7.53 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.27-7.25 (m, 1 H), 4 . 02 (s, 3H)

 Ma s s, m / e: 3 16 (M ++ 2), 3 14 (M +, b a se)

Example 18

3 (5)-(3,4-dichlorophenyl) 1-41 (4-pyridazinyl) pyrazole

Melting point: 176.5-17.5 ° C

-.. Negation _{R (CDC 1 3) δ 9.} 1 9 (dd, J = l 3Hz, 2. 6H z, 1 H>, 9. 1 2 (dd, J = l 3H z, 5. 5 H z , 1H), 7.96 (s, 1H), 7.63 (d, J-1.9Hz, 1H), 7.50 (d, J = 8.4Hz, 1H) , 7.35 (dd, 3 = 2.6 Hz, 5.5 Hz, 1 H), 7.2

4 (d d, J = 1.9Hz, 8.4Hz, 1H)

Ma ss, m / e: 290 (M ⁺ , base)

Example 19

 3- (3,4-dichloromouth phenyl) 1-methyl-4-1 (4-pyridazinyl) pyrazonole

Melting point: 147.0 ~ 15.0 ° C

_{^{X H-NMR (CDC 1 3}} ) 5: 9. 1 5 (dd, J = 1. 3 H z, 2. 6 H z, 1 H), 9. 08 (dd, J = 1. 3H z, 5 5Hz, 1H), 7.72 (s, 1H), 7.64 (d, J = l. 9Hz, 1H), 7.45 (d, J = 8.4Hz, 1 H), 7.28 (dd, J = 2.6 Hz, 5.5 Hz, IH), 7.22 (dd, J = l. 9 Hz, 8.4 Hz, 1 H), 4.04 ( s, 3H) Ma ss, m / e: 304 (M ⁺ , base) Example 20

 3 (5)-(4-Benzyloxyphenyl) 1-41 (4-pyridazinyl) pyrazole

Melting point: 174.5-176 ° C

XH-NMR (DMSO-d ₆ ) δ: 9.14 (dd, J = 1.3 Hz, 2.5 Hz, 1 H), 9.05 (dd, J = 1.3 Hz, 5.5 Hz, 1 H) ), 8.60 to 7.90 (bs, 1H), 7.53 to 7.30 (m, 8H), 7.11 (bs, 2H), 5.16 (s, 2H)

Ma s s, m / e: 328 (M +), 91 (ba s e)

Example 21

 3- (4-Benzyloxyphenyl) 1-11-Methyl _4-1 (4-Pyridazinyl) pyrazole

Melting point: 142-144 ° C

^ -NMR (DMSO-d ₆ ) δ: 9.09 (dd, J = 1.0 Hz, 2.3 Hz, 1H), 9.05 (dd, J = 1.0 Hz, 5.4 Hz, 1 H) , 8.33 (s, 1H), 7.52 to 7.25 (m, 8H), 7.06 (d, J = 8.8Hz, 2H), 5.13 (s, 2H), 3. 93 (s, 3H)

Ma ss, m / e: 342 (M ⁺ ), 91 (ba se)

Example 22

Synthesis of 3 (5) 1- (4-hydroxyphenyl) 1-41 (4-pyridazinyl) pyrazole

 3 (5) — (4-Benzyloxyphenyl) 1 4_ (4-pyridazinyl). Dissolve 5 mg of virazole in 30 ml of ethanol, add 50 mg of 5% palladium on carbon, and add 7] atmosphere The mixture was stirred at normal pressure and room temperature. After 24 hours, the mixture was filtered using celite, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for crystallization to obtain 26 mg (yield: 73%) of the title compound as a white powder.

— NMR (DMS 0-d ₆ ) δ 9.14 (dd, J = l. 1 Hz, 2.4 Hz, 1H), 9.03 (dd, J = 1.1 Hz, 5.5 Hz, 1 H) ), 8.18 (s, 1H), 7.46 (dd, J = 2.4 Hz, 5.5 Hz, 1 H), 7.2

2 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H) Ma s s, TO./e: 238 (M +, b a se)

Example 23

3- (4-Hydroxyphenyl) -1-methyl-4- (4-Pyridazinyl) virazole

^ -NMR (DMSO-d ₆ ) <^: 9.10 to 9.00 (m, 2H), 8.31 (s, 1H), 7.40 (dd, J = 2.5 Hz, 5.3 Hz, 1 H), 7.18 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H) '

Ma ss, mZ e: 252 (M ⁺ , base)

Example 24

 3 (5) 1- (4-methoxyphenyl) 1-41 (4-pyridazinyl) pyrazole Melting point: 182.5 to 185.8 ° C

NMR (DMSO-d ₆ ) δ: 9.14 (m, 1H), 9.05 (dd, J = l.2Hz, 5.3Hz, 1H), 8.40 (s, 0.5H), 8.07 (s, 0.5H), 7.49 to 7.43 (m, 1H), 7.36 (m, 2H), 7.03 (m, 2H), 3.82 (s, 1 5H), 3.80 (s, 1.5H) Ma ss, m / e: 252 (M +, base)

Example 25

 3- (4-Methoxyphenyl) _1-methyl-41- (4-pyridazinyl) pyrazole

Melting point: 154, 9 ~ 157.0 ° C

One _{NMR (CDC 1 3) 5:} 9. 14 (. Dd, J = l 1Hz, 2. 4Hz, 1H), 8. 99 (. Dd, J = l 3Hz, 5. 4Hz, 1H), 7. 70 (s, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.28 to 7.26 (m, 1H), 6.92 (d, J = 8.6 Hz, 2H), 4 . 00 (s, 3H), 3.84 (s, 3H) Ma ss, ./ e: 266 (M +, base)

Example 26

 3 (5) 1- (3-methoxyphenyl) _4-1- (4-pyridazinyl) pyrazole Melting point: 163.3-165.0 ° C

Chromatography Awakening: _{R (CDC 1 3):.} 9. 18 (dd, J = 1. 3H z, 2. 2H z, 1 H), 9. 0 5 (dd, J = l 3H z, 5. 4 H z , 1H), 7.93 (s, 1H), 7.39 to 7.32 (m, 3H), 7.00 to 6.95 (m, 3H), 3.79 (s, 3H)

Ma ss, m / e: 252 (M ⁺ , base)

Example 27 '

 3- (3-Methoxyphenyl) 1-1-Methinole 4- (4-Pyridazinyl) pyrazole

_{^ - MR (CDC 1 3)} 6:. 9. 1 5 (. Dd, J = l 1 H z, 2. 4H z, 1 H), 9. 00 (dd, J = l 1 H z, 5. 5Hz, 1H), 7.72 (s, 1H), 7.29 to 7.27 (m, 2H), 7000 to 6.92 (m, 3H), 4.03 (s, 3H) ), 3.78 (s, 3H)

M ss, m / e: 266 (M ⁺ ), 94 (base)

Example 28

 3 (5) 1- (2-methoxyphenyl) 1-41- (4-pyridazinyl) pyrazole Melting point: 194.6-19.6.4 ° C

_{! H-NMR (CDC 1 3} ) δ 9. 14 (dd, J = 1. 3H z, 2, 3H z, 1 H), 9. 04 (dd, J = 1. 3H z, 5. 5 H z , 1 H), 7.92 (s, 1 H), 7.46 to 7.42 (m, 1 H), 7.35 (dd, J = 2.3 Hz, 5.5 Hz, 1 H), 7.29 (m, 1H), 7.04 to 6.99 (m, 2H), 3.75 (s, 3H)

Ma ss, m / e: 252 (M ⁺ , base)

Example 29

3- (2-Methoxyphenyl) 1 1-Methyl-4 1- (4-pyridazinyl) pyrazo Rule

Melting point: 179.8-182.5 ° C

_{^{X H-NMR (CDC 1 3}} ) δ: 9. 07 (dd, J = 1. 3H z, 2. 2Hz, 1 H), 8. 94 (dd, J = 1. 1 H z, 5. 5 H z, 1H), 7.47 (dd, J = l. 7Hz, 7.4Hz, 1H), 7.41 (m, 1H), 7.15 (dd, 1 = 2. 4Hz, 5.5Hz, 2H), 7.09 to 7.05 (m, 1H), 6.90 (m, 1H), 4.03 (s, 3H), 3.46 (s , 3H) Ma ss, m / e: 266 (M ⁺ , base)

Example 30

4-(4-pyridazinyl) _ 3 (5) ― (3 _trifluoromethylphenyl) pyrazole

Melting point: 203.5-208.5 ° C

^X H-NMR (DMS 0-d ₆ ) δ: 9.15 (d, J = 1.0 Hz, 1 H), 9.07 (d, J = 5.4 Hz, 1 H), 8. 44, 8.13 (s, 1H), 7.76 to 7.68 (m, 4H), 7.45 (s, 1H)

Ma ss, m / e: 290 (M ⁺ , base)

Example 3 1

 1-Methyl-4-1 (4-Pyridazinyl) -1 3 _ (3-Trifluoromethylphenyl) pyrazole

Melting point: 108.0-10.9 ° C

_{- NMR (CDC 1 3) ^} : 9. 14 (dd, J = 1. 3H z, 2. 2H z, 1 H), 9. 04 (dd, J = 1. 3H z, 2. 2H z, 1 H), 7.82 (s, 1 H), 7.74 (s, 1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.55 (d, J = 7.6H z, 1 H), 7.49 (t, J = 7.6Hz, 1H), 7.25 (dd, J = 2.2Hz, 5.4Hz, 1H), 4.05 (s , 3H)

Ma ss, m / e: 304 (M ⁺ , base)

Example 32 3 (5)-(3,4-methylenedioxyphenyl) 1-41 (4-pyridazinyl) pyrazonole

Melting point: 200. 9 ~ 203.5 ° C

_{^{X H-NMR (CDC 1 3}} ) δ: 9. 17 (dd, J = 1. 3Hz, 2. 4Hz, 1H), 9. 05 (. Dd, J -l 3Hz, 5. 4Hz, 1 H), 7.90 (s, 1H), 7.37 (dd, J = 2.4 Hz, 5.4 Hz, 1 H), 6.89 to 6.86 (m, 3H), 6.04 (s, 2H )

Ma ss, m / e: 266 (M ⁺ , base)

Example 33

 1 _Methyl-1 3- (3,4-methylenedioxyphenyl) 1-4- (4-Pyridazininole) pyrazole

Melting point: 179.4-182.7 ° C

One _{NMR (CDC 1 3) ^:} 9. 13 (. Dd, J = l 3Hz, 2. 4Hz, 1H), 9. 01 (. Dd, J = l 3Hz, 5. 4Hz, 1H), 7. 68 (s, 1H), 7.33 to 7.27 (m, 1H), 6.94 to 6.74 (m, 3H), 5.99 (s, 2H), 4.00 (s, 3H)

Ma ss, m / e: 280 (M ⁺ , base)

Example 34

 3 (5) 1- (4-dimethylaminophenyl) 1 4- (4-pyridazinyl) pyrazole

Melting point: 195.4-199.9 ° C

_{^{X H-NMR (CDC 1 3}} ) δ 9. 22~ 9. 17 (m, 1 H), 9. 06~ 8. 97 (m, 1H), 7. 89 (s, 1 H), 7. 43 Up to 7.20 (m, 3H), 6.73 (d, J = 9.0Hz, 2H), 3.02 (s, 6H)

Ma s s, m / e: 265 (M +, b a s e)

Example 35

3- (4-dimethylaminophenyl) 1-1-methyl-4- (4-pyridazinyl) pyrazonole _{^ -NMR (CDC 1 3) ^} : 9. 16 (dd, J = 1. 3Hz, 2. 4Hz, 1H), 8. 97 (. Dd, J = l 3Hz, 5. 5Hz, 1 H), 7 . 66 (s

, 1H), 7.35 to 7.20 (m, 3H), 6.70 (d, J = 9.0 Hz, 2H), 3.99 (s, 3H), 2.98 (s, 6H)

Ma ss, m / e: 279 (M ⁺ , base)

Example 36

 3 (5) One [1— (4-Fluoronaphthyl)] —4— (4-Pyridazinyl) pyrazol

Melting point: 189.8-192.2 ° C

_{^ -NMR (CDC 1 3) δ} 9. 02 (dd, J = l. 1 Hz, 2. 5Hz,

1H), 8.84 (dd, J = l. 1Hz, 5.4Hz 1H), 8.28 to 8

• 14 (m, 2H), 7.69-7.12 (m, 5H) 7.03 (dd, J =

2.5Hz, 5.4Hz, 1H)

 Ma s s, m / e: 290 (M +, ba s e)

Example 37

 3-[1- (4-fluoronaphthyl)] 1-Methyl-4 _ (4-pyridazinyl) pyrazonole

_{^{X H-NMR (CDC 1 3}} ) ^:. 9. 02 (dd, J = 1. 1 H z, 2. 4H z, 1H), 8. 77 (dd, J = l lHz, 5. 5Hz, 1 H), 8.24 to 8.13 (m, 1H), 7.96 (s, 1H), 7.76 to 7.07 (m, 5H), 6.88 (dd, J = 2.4 Hz, 5.5Hz, 1H), 4.10 (s, 3H

)

 Ma s s, m / e: 304 (M +, ba s e)

Example 38

 4- (4-pyridazinyl) — 3 (5) One (3-pyridyl) pyrazole

Melting point: 195.4-199.8 ° C

Ichi匪_{R (CDC 1 3) 5:} 9. 18 (. Dd, J = l 1Hz, 2. 4Hz, 1H), 9. 08 (. Dd, J = l 1Hz, 5. 5Hz, 1 H), 8 . 77 (d d, J = 0.8 Hz, 2.3 Hz, 1H), 8.67 (dd, J = 1.8 Hz, 4.8 Hz, 1 H), 7.98 (s, 1 H), 7.83 ~ 7.70 (m, 1H), 7.43 to 7.28 (m, 2H)

Ma ss, m / e: 223 (M ⁺ , base)

Example 39

1-methyl-_ 4 i (4-pyridazinyl) Single 3- (3-pyridyl> pyrazol _{^{X H-NMR (CDC 1 3}} ) δ 9. 14 (dd, J = 1. 1Hz, 2. 4Hz, 1H), 9 04 (dd, J = l. 1 Hz, 5.4 Hz, 1H), 8.73 (dd, J = 0.9 Hz, 2.2 Hz, 1H), 8.64 (dd, J = l. 8 Hz, 4 8Hz, 1H), 7.81 to 7.68 (m, 2H), 7.39 to 7.20 (m, 2H), 4.04 (s, 3H)

Ma ss, m / e: 237 (M ⁺ , base)

Example 40

 3 Synthesis of (5)-(4-fluorophenyl) -1-4- [4- (3-methoxypyridazinyl)] pyrazole

 (a) Synthesis of 3-methoxy-4-methylpyridazine

 300 mg of 3-chloro-1-methylpyridazine (chem. Pharm. Bull., Vol. 5, 229 (1957)) was dissolved in 10 ml of methanol, 243 mg of sodium methoxide was added, and the mixture was heated under reflux for 15 hours. The reaction solution was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The dried form extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography 20 (eluent, solvent: chloroform: methanol = 50: 1) to give 263 mg (yield: 91%) of the title compound as a pale yellow oil.

_{XH-NMR (CDC 1 3)} δ 8. 64 (d, 1 = 4. 6Hz, 1H), 7. 5 (dd, J = 1. 0Hz, 4. 6Hz, 1H), 4. 15 (s, 3H ), 2.22 (d, J = l. 0, 3H)

Ma s s, m / e: 124 (M +), 65 (b a s e)

(b) 3 (5) 1- (4-fluorophenyl) 1-41 [4 (3-methoxypyrida Dinyl)] Synthesis of pyrazole

 The same procedure as in Example 1 was carried out using 3-methoxy-1-methylpyridazine to synthesize the title compound.

Melting point: 181.5-183.5 ° C

Marauder R (DMS O-d ₆ ) δ: 8.71 (d, J = 4.7 Hz, 1 H), 8.1 1, 7.80 (s, 1 H), 7.36 to 7. 1 2 (m, 5H), 3.50, 3.82 (s, 3H)

 Ma s s, m / e: 270 (M +, b a s e)

Example 4 1

3 (5) — Synthesis of (4-fluorophenyl) -14- [5- (3-methoxypyridazinyl)] pyrazole

 (a) Synthesis of 3-methoxy-5-methylpyridazine

 3-Chloro-5-methinolepyridazine 296 mg (Chem. Pharm. Bull., Vol. 5, 229 (1957)) was dissolved in methanol 10 ml, sodium methoxide 373 mg was added, and the mixture was heated under reflux for 1 hour. . The reaction solution was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying the extract in the form of black mouth with magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography 25 g (eluent, solvent: chloroform: methanol = 50: 1) to give 18 Omg (yield: 63%) of the title compound as a pale yellow oil. Obtained.

Over Keio _{R (CDC 1 3) δ:} S. 67 (d, J = 1. 6H z, 1 H), 6. 7 6 (dd, J = 0. 8 H z, 1. 6H z, 1 H) , 4.11 (s, 3H), 2.31 (d, J = 0.8 Hz, 3H)

Ma s s, mZ e: 1 24 (M +), 53 (b a s e)

 (b) Synthesis of 3 (5)-(4-fluorophenyl) 1-41- [5- (3-methoxypyridazinyl)] pyrazole

 The same procedure as in Example 1 was carried out using 3-methoxy-15-methylpyridazine to synthesize the title compound.

Melting point: 182.5 to 184.5 ° C _{^{X H-NMR (CDC 1 3}} ) ^:. 8. 76 (d, J = 1. 9Hz, 1 H), 7. 8 8 (s, 1H), 7. 45~7 40 (m, 2H), 7. 16-7. 11 (m, 2H), 6.83 (d, J = l. 9Hz, 1H), 4.13 (s, 3H)

Ma ss, m / e: 270 (M ⁺ ), 269 (base)

Example 42

 Synthesis of 3- (4-fluorophenyl) -1-1 (2-hydroxyethyl) -1-4- (4-pyridazinyl) pyrazol

 1-Fluoro-4- (4-pyridazinylacetyl) benzene 3131112 was dissolved in 8 ml of 11F, and 345 mg of, N-dimethylformamide dimethyl acetal was added, followed by stirring at room temperature for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in ethanol (8 ml), and 2-hydroxyethylhydrazine (22 Omg) was added thereto. The mixture was stirred at C for 30 minutes. The reaction solution was distilled off under reduced pressure, 10% aqueous ammonia was added, and the mixture was extracted with chloroform. The black-mouthed form extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by thin-layer chromatography (developing solvent, chloroform: methanol = 30: 1) to obtain 12 mg (yield: 3%) of the title compound as pale yellow crystals.

Melting point: 177.0 ~ 179.5 ° C

_{^ -NMR (CDC 1 3) 5} : 9. 13 (. Dd, J = l 0Hz, 2. 1 H z, 1 H), 9. 03 (dd, J = 1. 0Hz, 5. 4H z, 1 H), 7.82 (s, 1H), 7.42 (dd, J = 5.4Hz, 8.6Hz, 2H), 7.27 (dd, J = 2.lHz, 5.4Hz, 1H), 7.09 (t, J -8.6 Hz, 2H), 4.36 (t, J = 5.0, 2H), 4.12 (dd, J = 5.0 Hz, 9.4 Hz, 2H), 2 . 72 (t, J = 5.0Hz, 1H)

Ma s s, m / e: 294 (M +, b s e)

Example 43

 Synthesis of 3- (4-monofluorophenyl) -1-5_ (1-hydroxy-1-3-phenylpropyl) -1-1-methyl-4- (4-pyridazinyl) pyrazole

3- (4-Fluorophenyl) 1-1-methyl-14- (4-pyridazinyl) leaflets Solvent 203mg dissolved in THF 20m 1 under argon atmosphere-60. Under C, 0.59 ml of 1.56mo 1/1 butyllithium hexane solution was added dropwise and stirred for 1 hour. Then, 2 ml of a THF solution containing 139 mg of 3_phenylpropionaldehyde was added dropwise. The temperature was gradually raised, and when the temperature reached room temperature, 10 ml of water was added, followed by extraction with 5 Om1 of ether. The organic layer was washed with saturated saline 1 Om 1, dried over anhydrous 7_K magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (20 g, elution solvent: ethyl acetate) to give 159 mg (yield: 51%) of the title compound as a pale yellow powder.

Melting point: 186-17.5 ° C

Ichi匪_{R (CDC 1 3) δ 8.} 82 (m, 1 H), 8. 63 (m, 1 H), 7. 31~ 7. 12 (m, 7H), 7. 01~ 6. 93 ( m, 2H), 6.80 to 6.85 (m, 1H), 4.70 to 4.80 (m, 1H), 4.04 (s, 3H), 3.57 to 3.35 (bs, 1H), 2.90 to 2.65 (m, 2H), 2.47 to 2 · 34 (m, 1H), 2.05 to 1 · 94 (m, 1H)

Ma ss, m / e: 388 (M ⁺ ), 284 (base)

Example 44

 Synthesis of 3-(4-fluorophenyl) 1-1 -methyl 1-5-(3-phenyl-1-propyl) 1-4-(4-pyridazinyl) pyrazole

 3- (4-fluorophenyl) 15- (1-hydroxy-3-phenylpropyl), 11-methyl-4- (4-pyridazinyl) pyrazole 13 Omg and 4-toluenesulfonic acid-7j Then, the mixture was heated and refluxed for 24 hours, basified with a saturated aqueous solution of sodium bicarbonate, extracted twice with 20 ml of ethyl acetate, and the organic layers were combined and washed with 1 Oml of a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography 20 g (elution solvent, hexane: ethyl acetate = 1: 1) to obtain the obtained viscous material. The material was crystallized from ether-hexane to give 98 mg (yield: 78%) of the title compound as a light brown solid.

Melting point: 115-116 ° C _{^ - MR (CDC 1 3)} 5: 9. 04 (dd, J = 1. 1 Hz, 2. 2Hz, 1 H), 8. 99 (dd, J = 1. lHz, 5. 5Hz, 1 H) , 7.36 to 7.22 (m, 5H), 7.20 (dd, J = 2.2 Hz, 5.5 Hz, 1 H), 7.17 to 7.12 (m, 2H), 7.04 Up to 6.95 (m, 2H), 6.26 (dt, J = 1.5 Hz, 16.1 Hz, 1 H), 6.05 (dt, J = 6.6 Hz, 16. lHz, 1H), 3.94 (s, 3H), 3.53 (d, J = 6.6 Hz, 2H)

Ma ss, m / e: 370 (M ⁺ , base)

Example 45

3- (4-fluorophenyl) one 1-methyl-5- (3-phenylpropyl) one

Synthesis of 4- (4-pyridazinyl) pyrazole

 Dissolve 66 mg of 3- (4-fluorophenyl) -1-methyl-5- (3-phenyl_1-probenyl) -14- (4-pyridazinyl) virazole in 10 ml of ethanol, and add 5 Omg of 5% palladium carbon. The mixture was stirred under a hydrogen atmosphere at normal pressure and room temperature. After 18 hours, the mixture was filtered through celite, and the solvent was distilled off under reduced pressure to obtain 58 mg (yield: 73%) of the title compound as a solid.

_{^{X H-NMR (CDC 1 3}} ) δ 9. 00 (dd, J = 1. 1Ηζ, 5. 4H z, 1 H), 8. 95 (dd, J = 1. 3Hz, 2. 2Hz, 1 H) , 7.33-7.20 (m, 5H), 7.15-7.09 (m, 2H), 7.07 (dd, J = 2.2 Hz, 5.4 Hz, 1H), 7 .03 to 6.95 (m, 2H), 3.84 (s, 3H), 2.67 (t, J = 8.3Hz, 2H), 2.66 (t, J = 6 • 9Hz, 2H) , 1.97 to 1.86 (m, 2H)

Ma ss, m / e: 372 (M ⁺ ), 268 (base)

Example 46

Synthesis of 3- (4-fluorophenyl) -1-methyl-1-5-phenylacetylamino 4- (4-pyridazinyl) pyrazole

(a) Synthesis of 3- (4-fluorophenyl) -1-methyl-5-phenylacetylaminopyrazole 1.3 g of 5-amino-3- (4-fluorophenyl) -11-methylvirazole was dissolved in 20 ml of pyridine, and 2.6 ml of phenylacetyl chloride was added dropwise at room temperature. After stirring in an oil bath at 100 ° C. overnight, the reaction solution was concentrated, distilled water was added, and the mixture was extracted with a black hole form. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography 70 g (elution solvent, chloroform: methanol = 100: 1 to 30: 1), and the crystal residue was washed with getyl ether-hexane to give the title compound 1. 4 g (yield: 68%) were obtained.

Melting point: 176.3-177.0 ° C

_{iH- NMR (CDC 1 3) 5} : 7. 68 (dd, J = 5. 6H z, 8. 7Hz

, 2H), 7.46 to 7.36 (m, 5H), 7.04 (t, J = 8.7 Hz,

2H), 6.48 (s, 1H), 3.80 (s, 2H), 3.59 (s, 3H)

Ma s s, m / e: 309 (M +), 191 (b a s e)

 (b) Synthesis of 4- [4- (1,4-dihydro-1-1-ethoxycarbodirubidazinyl)]-3- (4-fluorophenyl) _1-methyl-15- (phenylacetylamino) pyrazole

 3- (4-Fluorophenyl) 1-1-methyl-1-5- (phenylacetylamino) pyrazole 250 mg and pyridazine 0.59 ml are dissolved in methylene chloride 20 ml, and the mixture is cooled under ice-cooling. After stirring at room temperature for 1.5 hours, water was added to the reaction solution, and the mixture was extracted with methylene chloride.The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography 30 g (elution solvent, hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain 295 mg (yield: 7996) of the title compound.

_{XH-NMR (CDC 1 3)} δ 7. 41~ 7. 28 (m, 7H), 7. 08 (t, J = 8. 7Hz, 2H), 6. 74 (t, J = 2. 4Hz, 1 H), 6.62 (s, 1H), 4.84 (dt, J = 2.9 Hz, 8.3 Hz, 1H), 4.44 (q, J = 7. 1 Hz, 2H), 4. 09 (dd, J = 2.2 Hz, 5.1 Hz, 1 H), 3.71 (s, 2H), 3.66 (s, 3H), 1.42 (t, (J = 7.1 Hz, 3H)

Ma ss, m / e: 461 (M ⁺ ), 388 (base)

 (c) Synthesis of 3- (4-fluorophenyl) 1-1-methyl-15-phenylacetylaminoamino 4- (4-pyridazinyl) pyrazole

 4- [4- (1,4-dihydro-11-ethoxycarbylviridazinyl)] 1-3- (4-fluorophenyl) _1-methyl-5- (phenylacetylamino) pyrazole 29 Omg, sulfur 14 lmg decalin 15m After suspending in 1, the mixture was refluxed under heating at 170 ° C for 2.5 hours. The residue was purified by silica gel column chromatography (50 g, eluting solvent, black form to black form: methanol = 20: 1) to obtain 183 mg (yield: 75%) of the title compound.

_{- NMR (CDC 1 3) δ} :. 8. 78-8 74 (m, 1Η), 8. 64~ 8. 63 (m, 1H), 8. 26~ 8. 10 (m, 1H), 7. 36 (s, 5H), 7.31 to 7.26 (m, 1H), 7.02 to 6.98 (m, 3H), 3.

85 (s, 2H), 3.74 (s, 3H), 1.68 (b s, 1H)

Mass, m / e: 387 (M ⁺ ), 91 (base) In the same manner as in Example 46, the following compounds of Examples 47 to 49 were synthesized.

Example 47

 5- (2-chloro phenylacetylamino)-3-(4-fluorophenyl) 1-1-methyl 1-4 (4-pyridazinyl) pyrazole

One _{NMR (CDC 1 3) δ:} . 8. 90 (m, 1H), 8. 79 (m, 1 H), 7. 49~7 · 38 (m, 2H), 7. 31~7 28 (m , 4H), 7.13 (dd, J = 2.4 Hz, 5.3 Hz, 1 H), 7.00 (m, 2H), 3.

96 (s, 2H), 3.81 (s, 3H), 1.61 (b s, 1 H)

Ma ss, m / e: 423 (M ⁺ +2), 421 (M ⁺ ), 269 (base) Example 48

1-methyl-3-phenyl 5-phenylphenylamino-4_ (4-pyridazinyl) pyrazole _{^{X H-NMR (CDC 1 3}} ) ^:. 8. 76 (dd, J = 1. 3H z, 5. 3 H z, 1 H), 8. 64~8 63 (m, 1 H), 7. 35 (s, 5H), 7.30 (s, 5H), 7.00 (dd, J = 2.4Hz, 5.3Hz, 1H), 3.84 (s, 2H), 3. 75 (s, 3H), 1.60 (bs, 1H)

Ma ss, m / e: 369 (M ⁺ ), 9 1 (base)

Example 49

 3- (4-chlorophenyl) 5- (2-chlorophenylacetyl) 1-1-methyl-4- (4-pyridazinyl) pyrazole

Melting point: 2 39.5-241.0 ° C

^ -NMR (DMS Od ₆ ) 5: 10.32 (s, 1 H), 9.13 (dd,

J = 1. l Hz, 5. l Hz, 1 H), 8.98 to 8.97 (m, 1 H), 7.

43 to 7.27 (m, 9H), 3.88 (s, 2H), 3.75 (s, 3H)

Ma s s, m / e: 441 (M ++ 4), 439 (M ++ 2), 437 (M +),

1 25 (b a s e)

Example 50

 Synthesis of 3- (4-fluorophenyl) 1-1-methyl-15- (N-methyl-N-phenylacetylamino) 4-14- (4-pyridazinyl) pyrazole

 7] Sodium iodide (60% mineral oil suspension) 14 mg of THF in 5 ml suspension under ice-cooling, 3- (4-fluorophenyl) -1-methyl-5-phenylacetylaminoamine 4- (4-pyridazinyl) 5) 1 ml of pyrazole 1 (39 mg) in THF was dropped and stirred for 30 minutes. At the same temperature, 0.022 ml of methyl iodide was added dropwise, and the mixture was stirred for 2 hours. After adding water, the reaction solution was extracted with getyl ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent, chloroform: methanol = 100: 1) to give 4 Omg of the title compound (yield: 28%).

_{^ -NMR (CDC 1 3) δ} 9. 0 5 (dd, J = 1. 3H z, 5. 4H z, 1 H), 8. 89 (dd, J = 1. 3H z, 2. 2H z, 1 H), 7.4 1 to 7.38 (m, 2H), 7.24 to 7.23 (m, 4H), 7.10 (t, J = 8.8 Hz, 2H), 7.01 (dd, J = 2.6 Hz, 5.4 Hz, 1 H), 6.92 to 6.90 (m, 1 H), 3.39 (s, 3H) , 3.37 (m, 2H), 3.25 (s, 3H)

 Ma s s, m / e: 401 (M +), 91 (b a s e)

Example 51

 3 (5) Synthesis of mono (4-fluorophenyl) -5 (3) -methyl-41- (4-pyridazinyl) pyrazole

 (a) Synthesis of 1 _ (4-fluorophenyl) -1,3-butanedione

 After washing 12.0 g of sodium hydrogen sulfide (60% mineral oil suspension) with 60 ml of hexane, 130 ml of THF was added. Under an argon atmosphere, add 29.3 ml of ethyl acetate, 5 drops of ethanol, 21.0 g of 4,1-fluoroacetophenone, 21.0 g of dibenzo-18-crown-16 (0.86 g) in this order, and add 50 minutes at room temperature. After stirring, the mixture was heated under reflux for 2 hours. 100 ml of a 10% aqueous sulfuric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained crystalline residue was recrystallized from getyl ether-hexane solvent to obtain 25.1 g (yield: 93%) of the title compound.

Melting point: 46.0-47.4 ° C

-. Negation _{R (CDC 1 3) δ S.} 00~ 7. 87 (m, 2H), 7. 16~ 7 10 (m, 2H), 6. 13 (s, 2H), 2. 19 (s, 3H)

Ma ss, mZ e: 176 (M ⁺ , base)

 (b) Synthesis of 3 (5) mono (4-monofluorophenyl)-5 (3)-methyl virazole

1- (4-Fluorophenyl) 1-1,3-butanedione and 63.0 neutral alumina were mixed. Under ice cooling, 68 ml of hydrazine monohydrate was added dropwise, and the mixture was stirred at room temperature for 4 hours. To the reaction residue was added chloroform and the mixture was filtered through celite, and the filtrate was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained crystalline residue was washed with getyl ether-hexane solvent to obtain 17.7 g (yield: 72%) of the title compound. Melting point: 1 10.6 ~ 1 12.1 ° C

^ ■ H-NMR (CDC 1 3): 7. 68 (dd, J = 5. 5H z, 8. 4H z,

2H), 7.06 (m, 2H), 6.29 (s, 1H), 2.32 (s, 3H)

Ma ss, / e: 1 76 (M ⁺ , base)

 (c) Synthesis of 3- (4-fluorophenyl) — 1- (4-methoxybenzyl) -1-5-methylpyrazol

 Hydrogen sodium (60% mineral oil suspension) 1.0 g of a 50 ml dimethylformamide suspension was added under ice-cooling to 3 (5) — (4-fluorophenyl) 1-5 (

3) 50 ml of a solution of 4.0 g of -methylvirazole in dimethylformamide was added dropwise, and the mixture was stirred for 30 minutes. Under ice cooling, 3.39 ml of 4-methoxybenzyl chloride was added dropwise, and the mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction solution, and extracted with getyl ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off and the title compound 6

.3 g (yield: 95%) were obtained.

Melting point: 7 1.6 to 5.9 degrees

_{XH-NMR (CDC 1 3)} o:. 7. 77~7 7 3 (m, 2H), 7. 1 0~7

• 03 (m, 4H), 6.86 to 6.82 (m, 2H), 6.30 (s, 1H)

, 5.25 (s, 2H), 3.77 (s, 3H), 2.2 1 (s, 3H)

Ma s s, m / e: 296 (M +), 1 2 1 (b a s e)

 (d) Synthesis of 3- (4-fluorophenyl) 1-1_ (4_methoxybenzyl) -1-5-methyl-1-4-1 (4-pyridazinyl) pyrazole

 The title compound was synthesized by treating 3- (4-monofluorophenyl) -1- (4-methoxybenzyl) -5-methylpyrazole in the same manner as in steps (b) and (c) of Example 46.

Melting point: 173.3-174.4 ° C

1H—NMR (CDC 13) 5: 9.09 (dd, j = l. 3 Hz, 5.4 Hz, 1 H)

3 Hz, 2. 6HZ, 1 H) , 7. 37〜7. 33 (m, 9.0 1 (dd,

3 Hz, 2.6HZ, 1H), 7.37 to 7.33 (m

6 Hz, 2H, 2H>, 7.23 to 7.20 (m, 3H), 7.02 (t,

6 Hz, 2H

), 6.90 (d, J = 8.6 Hz, 2H), 5.34 (s, 2H), 3.80 (s , 3H), 2.29 (s, 3H)

Ma ss, m / e: 374 (M ⁺ ), 1 2 1 (base)

 (e) 3 (5) ― (4-Monofluorophenyl) 1 5 (3) Synthesis of 1-methyl-4-1- (4-pyridazinyl) pyrazole

 3- (4-Fluorophenyl) 1-11- (4-methoxybenzyl) _5-methyl-14- (4-pyridazinyl) pyrazole 1 ml of trifluoromethanesulfonic acid was added, and the mixture was stirred in an oil bath at 65 ° C for 6 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the crystal residue was purified by TLC (developing solvent, chloroform: methanol = 50: 1) to give the title compound.

29 mg (yield: 28%) were obtained.

Melting point: 192.1-2.0.8 ° C

_{- NMR (CDC 1 3) 5} : 9. 1 6~ 9. 0 0 (m, 2H), 7. 58~ 6. 89 (m, 5H), 2. 42 (s, 3H)

Mass, m / e: 254 (M ⁺ , base) In the same manner as in Example 1 and Example 2, the following compound of Example 52-62 was synthesized.

Example 5 2 "

3 (5)-(3-Promophenyl) 1-4- (4-Pyridazinyl) pyrazole Melting point: 206.5-2 11.0 ° C

! H-NMR (DMS Od ₆ ) δ: 9.14 (s, 1 H), 9.07 (d, J = 5.4 Hz, 1 H), 8.41, 8.08 (s, 1 H ), 7.70 to 7.55 (m, 2H), 7.55 to 7.30 (m, 3H)

Ma s s, m / e: 300 (M +), 140 (b a s e)

Example 5 3

3-(3-Promopfanil) _ 1-methyl-41- (4-pyridazinyl) pyrazole _{! H-NMR (CDC 1 3} ) 5:. 9. 16-9 13 (m, 1 H), 9. 04 (d, J = 5. 5Hz, 1 H>, 7. 72 (s, 1 H) , 7.69 (t, J = l. 7Hz, 1H), 7.55 to 7.51 (m, 1H), 7.31 to 7.21 (m, 3H), 4.03 (s, 3H)

Ma ss, m / e: 314 (M ⁺ , base)

Example 54

 3 (5) ― (3-chlorophenyl) _4-one (4-pyridazinyl) pyrazole Melting point: 207-209 ° C

^ -NMR (DMS 0-d ₆ ) δ I S. 5 (bs, 1H), 9.14 (dd, J = 1.2 Hz, 2.5 Hz, 1H), 9.08 (dd, J = 1. 2Hz, 5.4Hz, 1H), 8.42 (bs, 0.8H), 8.09 (bs, 0.2H), 7.70 to 7.20 (m, 5H)

Ma s s, m / e: 256 (M +, b a s e)

Example 55

3- (3-chlorophenyl) 1-1-methyl-4-1 (4-pyridazinyl) pyrazole

_{- NMR (CDC 1 3) 5} : 9. 15 (dd, J = 1. 3Hz, 2. 5Hz, 1H), 9. 05 (dd, J = 1. 3H z, 5. 4Hz, 1 H>, 7 73 (s, 1H), 7.52 (m, 1H), 7.40 to 7.20 (m, 4H), 4.04 (s, 3H)

 Ma s s, m / e: 270 (M +, b a s e)

Example 56

 3 (5) ― (3-Chloro-4-monofluorophenyl) 1-4- (4-pyridazinyl) pyrazole

Melting point: 211.5 ~ 212.5 ° C

! H-NMR (DMS 0-d ₆ ) δ 13.6 (bs, 1H), 9.17 (dd, Jl. 0Hz, 2.4Hz, 1H), 9.08 (m, 1H), 8. 43, (s, 0.7H), 8.10 (bs, 0.3H), 7.80 to 7.30 (m, 4H) Ma ss, m / e: 274 (M +, base)

Example 57

 3- (3-Chloro-4-fluorophenyl) 111-methyl-14- (4-pyridazinyl) pyrazole

Melting point: 162.5-163.5 ° C

! H-NMR (DMSO— d ₆ ) δ: 9.13 (dd, J = 1.3 Hz, 2.5 Hz, 1H), 9.09 (dd, J = 1.3 Hz, 5.6 Hz) , 1 H), 8.36 (s, 1H), 7.60 (dd, 1 = 2.3 Hz, 7.3 Hz, 1H>, 7.44 (m, 2H), 7.36 (m, 1 H), 3.95 (s, 3H)

Ma s s, m / e: 288 (M +, b a s e)

Example 58

 3- (4-fluorophenyl) -1-propargyl-1- (4-pyridazinyl) pyrazole

Melting point: 103.6-107.4 ° C

_{^ - MR (CDC 1 3)} <5:. 9. 30~ 9. 00 (m, 2H), 7. 99 (s, 1Η), 7. 70 -6 90 (m, 5Η), 5. 04 ( d, J = 2.6 Hz, 2 H), 2.62 (t, J = 2.6 Hz, 1 H)

Ma s s, m / e: 278 (M +, b a s e)

Example 59

3 (5) I [5-(2-Methoxypyridyl)]-4- (4-pyridazinyl) virazole

Melting point: 178.5-180 ° C

! H-NMR (DMS 0-d ₆ ) δ: 13.60 (bs, 0.3H), 13.50 (bs, 0.7H), 9.18 (m, 1H), 9.07 (m , 1 H), 8.44 (d, J = 1.5 Hz, 0.7 H), 8.28 (d, J = 2.0 Hz, 0.3 H), 8.21 (d, 1 = 2.4 Hz) , 0.7H), 8.11 (d, J = l.5Hz, 0.3H), 7.76 (dd, J = 2.0Hz, 8.5Hz, 0.3H), 7.73 (dd , J = 2.4 Hz, 8.6 Hz, 0.7 H), 7.50 (dd, J = 2.4Hz, 5.4Hz, 0.3H), 7.45 (dd, 1 = 2.4Hz, 5.4Hz, 0.7H), 6.96 (d, J = 8.5Hz, 0.3H) , 6.88 (d, J = 8.6 Hz, 0.7H), 3.92 (s, 0.9H), 3.89 (s, 2.1H)

Ma s s, m / e: 253 (M +, b a s e)

Example 60

 3-[5- (2-Methoxypyridyl)]-1-methyl-4-1 (4-pyridazinyl) pyrazole

Melting point: 119-121 ° C

XH-NMR (DMS 0-d ₆ ) δ: 9.12 (dd, J = 1.3 Hz, 2.5 Hz, 1H), 9.08 (dd, J = l. 3 Hz, 5.4H) z, 1H), 8.37 (s, 1H), 8.18 (dd, J = 0.6 Hz, 2.2 Hz, 1H), 7.7

0 (dd, J = 2.2 Hz, 8.6 Hz, 1 H), 7.43 (dd, J = 2.5 Hz, 5.4 Hz, 1 H), 6.87 (dd, J = 0 6Hz, 8.6Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H)

Ma s s, m / e: 267 (M +, b a s e)

Example 61

 3 (5) ― (3-Trifluoromethoxyphenyl) 4- (4-Pyridazinyl) pyrazole

Melting point: 156.0-159.5 ° C

_{^ - MR (CDC 1 3)} δ 9. 18 (dd, J = 1. 3Hz, 2. 6Hz, 1 H), 9. 08 (. Dd, J = l 3Hz, 5. 5Hz, 1 H), 7 .95 (s, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.37 to 7.32 (m, 4 H)

Ma ss, m / e: 306 (M ⁺ , base)

Example 62

1-Methyl-1-41- (4-pyridazinyl) -1-3- (3-trifluoromethoxyphenyl) pyrazole _{! H-NMR (CDC 1 3} ) (5:. 9. 1 5 (dd, J = 1. 3H z, 2. 4H z, 1 H), 9. 08~9 03 (m, 1 H), 7 73 (s, 1H), to 7.45 7.23 (m, 5H), 4.04 (s, 3H)

Mass, m / e: 320 (M +, base) In the same manner as in Example 51, the following compounds of Examples 63 to 64 were synthesized. Example 63

 3 (5) -Cyclopropyl-5 (3)-(4-fluorophenyl) -4- (4-pyridazinyl) pyrazole

Melting point: 208.5 ~ 209.5 ° C

_{! H-NMR (CDC 1 3} ) δ: 9. 1 9 (dd, J = 1. 4H z, 2. 2H z, 1 H), 9. 1 0 (dd, J = 1. l H z, 5 lHz, 1H), 7.38 (dd, 1 = 2.2Hz, 5.3Hz, 1H), 7.32 (dd, J = 5.3Hz, 8.5Hz, 2H ), 7.06 (t, J = 8.5Hz, 2H), 1.95 to 1 · 91 (m, 1H), 1.67 (bs, 1H), 1.07 to 1. 02 (m, 2H), 0.90 to 0.86 (m, 2H)

Ma s s, m / e: 280 (M +, b a s e)

Example 64

 3 (5) —Ethyl-5 (3) 1- (4-fluorophenyl) —4- (4-pyridazinyl) pyrazole

Melting point: 172.2-173.3 ° C

_{^{X H-NMR (CDC 1 3}} ) δ 9. 1 9 (dd, J = 1. 3H z, 5. 3H z, 1 H), 9. 0 5 (dd, J = 1. 3H z, 2. 4H z, 1 H), 7.33-7.25 (m, 4H), 7.05 (t, J = 8.6 Hz, 2H), 2.80 (q, J = 7.7 Hz, 2H), 1.30 (t, 1 = 7.7Hz, 3H)

Ma ss, m / e: 268 (M +, base) then _c showing Formulation Examples of agents containing I匕合of the invention Formulation Example A: Tablet

Tablets:

 m g.

Active ingredient 3 0.0

Starch 5.0

Lactose 3 2.0

Carboxymethylcellulose calcium 10.0

Talc 0

Stearate_Magnet_Steam_2.

 180. 0 Mill the active ingredient to a particle size of 70 microns or less, add starch, lactose and calcium carboxymethylcellulose and mix well. 10% starch paste is added to the above mixed powder and mixed with stirring to produce granules. After drying, the particle size is adjusted to around 1000 micron, mixed with talc and magnesium stearate, and compressed.

Claims

Claim formula

Where:  Q is an aryl group (this aryl group is optionally substituted with a halogen atom, a hydroxy group, a lower alkoxy group, an aralkyloxy group, a halogenated lower alkyl group, a halogenated lower alkoxy group, a di-lower alkylamino group or a lower alkylenedioxy group) Or a heteroaryl group, R ¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, an amino group, an aralkylamino group, a lower alkylamino group, a di-lower alkylamino group or a lower alkylthio group, R ² represents a lower alkyl group which may be substituted with a hydrogen atom, a lower alkynyl group or a hydroxy group as the case may be; R ³ represents any of the following i) to vii)  i) hydrogen atom  ii) lower alkyl group iii) One CH (OH)-CH (R ⁴ ) — (A) _n —Y iv) -CH = C (R ⁴ )-(A) _n -Y v) — CH ₂ — CH (R ⁴ )-(A) _n — Y vi) —N (R ⁴ ) — CO— (A) _n -Y vii) Lower cycloalkynole group Here, A represents a lower alkylene group, and Y represents an aryl group (this aryl group may be optionally substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group or a nitro group). R ⁴ represents a hydrogen atom or a lower alkyl group; n represents 0 or 1; Or a salt thereof.  2. Q is a phenyl optionally substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group, a methoxy group, a benzyloxy group, a trifluoromethyl group, a trifluoromethoxy group and a methylenedioxy group. 2. The pyridazinyl bilazolyl derivative or a salt thereof according to claim 1, which represents a group or a pyridyl group. 3. The pyridazylpyrazole derivative or the salt thereof according to claim 1, wherein Q represents a 4-fluorophenyl group. 4. The pyridazinyl pyrazole derivative or a salt thereof according to claim ¹ , wherein R ¹ represents a hydrogen atom, a lower alkoxy group or an amino group. 5. The pyridazinyl pyrazole derivative or a salt thereof according to claim 1, wherein R ² represents a hydrogen atom, a methyl group, a propargyl group or a 2-hydroxyethyl group. 6. R ³ represents a hydrogen atom or a group represented by any of formulas Lii) to vi), wherein A represents a methylene group, and Y represents a phenyl optionally substituted by a halogen atom. A pyridazinylpyrazole derivative or a salt thereof according to claim 1, wherein R ⁴ represents a hydrogen atom, and n represents 1. 7. A medicament comprising the pyridazinyl virazole derivative of the formula (I) according to any one of claims 1 to 6 or a salt thereof as an active ingredient.  8. A pharmaceutical composition comprising the pyridazinyl virazole derivative according to any one of claims 1 to 6, or a salt thereof, and a pharmaceutically acceptable additive.  9. Inhibition of p38MAP kinase, comprising as an active ingredient the pyridazinyl virazole derivative of the formula (I) or a salt thereof according to any one of claims 1 to 6. Agent. 10. The cause of tumor necrosis comprising as an active ingredient a pyridazinylpyrazol derivative of the formula (I) or a salt thereof according to any one of claims 1 to 6. An agent for treating a child-related disease, an interleukin-1-related disease, an interleukin-16-related disease or a cyclooxygenase II-related disease.  1 1. Tumor necrosis factor-1 alpha-related disease, interleukin_1-related disease, interdickin-6-related disease or cyclooxygenase II-related disease, rheumatoid arthritis, multiple sclerosis, osteoarthritis , Psoriasis, Η IV, asthma, septic shock, inflammatory bowel disease, Crohn's disease., Alzheimer's disease, diabetes, cachexia, bone beta disease, graft-versus-host disease, adult respiratory distress syndrome, arteriosclerosis, gout, Glomerulonephritis, congestive heart failure, ulcerative colitis, sepsis, cerebral malaria, restenosis, hepatitis, systemic lupus erythematosus-des thrombosis, bone resorption disease (born respiration disease) ^ chronic pneumonia Disease (chxonic pulmonary inflammation disease) ヽ Cardiac reperfusion Renal reperfusion injury, cancer, Reita's syndrome, imminent preterm birth, eczema, allograft reaction, seizure, fever, Behcet's disease, neuralgia, meningitis, sunburn Contact dermatitis, acute synovitis, spondylitis, muscle degeneration, angiogenesis, conjunctivitis, psoriatic arthritis, viral myocarditis, phthitis, glioblastoma, bleeding, arthritis, endotoxin shock, parasitic Insect infection, tuberculosis, myocardial infarction, leprosy, diabetic retinopathy, irritable bowel syndrome (IBS), transplant rejection, burns, bronchitis, ischemic heart disease, eclampsia, pneumonia, remiss ion of swelling, The treatment agent according to claim 10, which is low back pain, pharyngolaryngitis, Kawasaki disease, spinal cord disease or atopic dermatitis.  1 2. Use of a pyridazinyl virazole derivative of the formula (I) or a salt thereof according to any one of claims 1 to 6 as a medicament.  1 3. Claims 1-6 for the prevention or treatment of tumor necrosis factor-α-related disease, interleukin-1 related disease, interleukin-1 6 related disease or cyclooxygenase II related disease Use of the pyridazinylpyrazole derivative of the formula (I) or a salt thereof according to any one of the above. 1 4. A human or other mammal comprising administering a pyridazinyl pyrazole derivative of the formula (I) or a salt thereof according to any one of claims 1 to 6 to a human or another mammal. Tumor necrosis factor-1 related disease in mammals, quinoa-leukin-1 related disease, interleukin-1 6 related disease X is a predictor of cyclooxygenase II related disease Prevention or treatment method.