JPWO2017057695A1 - Diphenylpyrazole derivatives and their pharmaceutical use - Google Patents

Abstract

An object of the present invention is to provide a compound having a diphenylpyrazole skeleton that inhibits the protease activity of MALT1 and exhibits a therapeutic or preventive effect on autoimmune diseases such as psoriasis. The present invention provides a diphenylpyrazole derivative represented by the following formula or a pharmacologically acceptable salt thereof.

Description

  The present invention relates to a diphenylpyrazole derivative and a pharmaceutical use thereof.

  Mucosa-associated lymphoid tissue transcription protein 1 (hereinafter referred to as MALT1) is a cysteine protease. By degrading proteins such as A20 and CYLD, NF-κB signaling is activated (Non-patent Documents 1 and 2).

  The NF-κB signal controls immune responses such as survival, differentiation, and activation of B cells and T cells. However, when the NF-κB signal is excessively activated due to increased protease activity of MALT1, various autoimmune diseases It is known that it can develop. For example, in MALT lymphoma and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), the protease activity of MALT1 is enhanced and is involved in the development of diseases accompanied by immune abnormalities (non-patented) Reference 3).

  In addition, in an experimental autoimmune encephalomyelitis model, which is a typical animal model of multiple sclerosis, when a MALT1 gene (Mucosa-associated lympholipid transcription gene 1; hereinafter referred to as MALT1 gene) is deleted, Has been reported to be completely suppressed. For this reason, there is a report that inhibition of the protease activity of MALT1 is effective in the treatment and prevention of multiple sclerosis (Non-patent Document 4).

  Furthermore, the relationship between proteins such as A20 and CYLD that are degraded and inactivated by MALT1 and autoimmune diseases has also been reported. For example, in mice lacking the gene encoding A20, rheumatism, psoriasis, colitis It has been reported that autoimmune disease-like pathologies such as these occur spontaneously (Non-patent Document 5).

  Examples of compounds that inhibit the protease activity of MALT1 include oligopeptide compounds Z-VRPR-fmk (Non-patent Document 6), phenylfuran derivatives (Patent Document 1), phenothiazine derivatives (Patent Document 2), and triazole derivatives ( Non-patent document 7) is known.

  On the other hand, as a compound having a diphenylpyrazole skeleton, for example, as a compound having cannabinoid 1 receptor antagonistic action, rimonabant (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N— (Piperidin-1-yl) -1H-pyrazole-3-carboxamide) (Patent Document 3) is a compound having a cyclooxygenase inhibitory action as celecoxib (4- (1- (p-tolyl) -3- (trifluoromethyl). ) -1H-pyrazol-5-yl) benzenesulfonamide) (Non-patent Document 8) is a diphenylpyrazol-3-ylcarbonylguanidine derivative (Patent Document 4) as a compound having a sodium ion / proton exchange transporter 1 inhibitory action. ) Has been reported.

International Publication No. 2009/065897 International Publication No. 2013/017637 US Pat. No. 5,624,941 International Publication No. 1999/043663

Beyaert et al., Nature Immunology, 2008, Vol. 9, p. 263-271 Beyaert et al., The EMBO Journal, 2011, volume 30, p. 1742-1752 Staudt et al., Nature, 2006, vol. 441, p. 106-110 Mak et al., The Journal of Clinical Investigation, 2012, Vol. 122, p. 4698-4709 Ma et al., Science, 2000, 289, p. 2350-2354 Thomas et al., Nature Immunology, 2008, Vol. 9, p. 272-281 Melnick et al., Cancer Cell, 2012, Vol. 22, p. 812-824 Akiyuki Kimoto et al., Japanese Pharmacology Journal, 2008, 131, p. 127-136

  However, Patent Documents 1 to 4 and Non-Patent Documents 1 to 8 do not describe that a compound having a diphenylpyrazole skeleton inhibits the protease activity of MALT1, and do not suggest its possibility.

  Therefore, the present invention aims to provide a compound having a diphenylpyrazole skeleton that inhibits the protease activity of MALT1 and exhibits a therapeutic or preventive effect on autoimmune diseases such as multiple sclerosis and psoriasis. .

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found a diphenylpyrazole derivative having an action of inhibiting the protease activity of MALT1.

That is, the present invention provides a diphenylpyrazole derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
[Wherein, R ¹ and R ² each independently represents a halogen atom or an alkoxy group having 1 to 3 carbon atoms, and R ³ represents one or two hydrogen atoms each independently a halogen atom. Represents an atom, an aryl group which may be substituted with an alkoxy group having 1 to 3 carbon atoms or a cyano group, or a heteroaryl group, and R ⁴ represents a hydrogen atom, a hydroxyl group, an amino group or 1 to 3 carbon atoms. Represents an alkyl group. ]

In the diphenylpyrazole derivative represented by the above general formula (I), R ¹ and R ² are each independently a chlorine atom or a methoxy group, and R ³ is a hydrogen atom, a carbon atom or a carbon atom. It is a phenyl group, a 2-thienyl group or a 2-pyridyl group which may be substituted with an alkoxy group of 1 to 3 or a cyano group, and R ⁴ is a hydrogen atom, a hydroxyl group, an amino group or a methyl group. Is preferred.

  In this case, high MALT1 inhibitory activity can be expected.

In the diphenylpyrazole derivative represented by the general formula (I), R ¹ and R ² are each independently a chlorine atom or a methoxy group, and R ³ is a halogen atom at the 3-position. , A phenyl group optionally substituted with a methoxy group or a cyano group, a 2-thienyl group or a 2-pyridyl group, and R ⁴ is preferably a hydrogen atom, a hydroxyl group, an amino group or a methyl group.

  In this case, a high MALT1 inhibitory activity can be expected, and an excellent therapeutic effect or preventive effect in an autoimmune disease can be expected.

  The present invention also provides a medicament and a MALT1 inhibitor containing the diphenylpyrazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

  The medicament is preferably a therapeutic or prophylactic agent for autoimmune diseases, and the therapeutic or prophylactic agent for autoimmune diseases is preferably a therapeutic or prophylactic agent for multiple sclerosis or psoriasis. More preferred.

  The diphenylpyrazole derivative of the present invention or a pharmacologically acceptable salt thereof has an action of strongly inhibiting the protease activity of MALT1, and has a therapeutic effect or prophylaxis against autoimmune diseases such as multiple sclerosis and psoriasis. The effect can be demonstrated.

It is a figure which shows the effect | action of the compound of Example 1 with respect to the thickness of the pinna in the imiquimod induced psoriasis model mouse.

The diphenylpyrazole derivative of the present invention is characterized by being represented by the following general formula (I).
[Wherein, R ¹ and R ² each independently represents a halogen atom or an alkoxy group having 1 to 3 carbon atoms, and R ³ represents one or two hydrogen atoms each independently a halogen atom. Represents an atom, an aryl group which may be substituted with an alkoxy group having 1 to 3 carbon atoms or a cyano group, or a heteroaryl group, and R ⁴ represents a hydrogen atom, a hydroxyl group, an amino group or 1 to 3 carbon atoms. Represents an alkyl group. ]

  The following terms used in this specification are defined as follows unless otherwise specified.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  “Alkoxy group having 1 to 3 carbon atoms” means a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group.

  The “aryl group” means a monocyclic or bicyclic aromatic hydrocarbon group containing only carbon atoms, and examples thereof include a phenyl group and a naphthyl group (for example, a 1-naphthyl group or a 2-naphthyl group). Can be mentioned.

  The “heteroaryl group” is a 4-membered to containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to carbon atoms as ring-constituting atoms. A 7-membered monocyclic aromatic heterocyclic group or a condensed aromatic heterocyclic group can be mentioned. Examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5-membered or 6-membered aromatic group containing 1 or 2 nitrogen atoms. 1 or 2 rings selected from heterocycles (eg pyrrole, imidazole, pyrazole, pyrazine, pyridine or pyrimidine), 5-membered aromatic heterocycles containing one sulfur atom (eg thiophene) and benzene rings And a group derived from a condensed ring. For example, furyl group (for example, 2-furyl group or 3-furyl group), thienyl group (for example, 2-thienyl group or 3-thienyl group), pyridyl group (for example, 2-pyridyl group, 3-pyridyl group, or 4 -Pyridyl group), pyrimidinyl group (for example, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group or 6-pyrimidinyl group), pyridazinyl group (for example, 3-pyridazinyl group or 4-pyridazinyl group), pyrazinyl group ( For example, 2-pyrazinyl group), pyrrolyl group (for example, 1-pyrrolyl group, 2-pyrrolyl group or 3-pyrrolyl group), imidazolyl group (for example, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group or 5 -Imidazolyl group), pyrazolyl group (for example, 1-pyrazolyl group, 3-pyrazolyl group or 4-pyrazolyl group), thi Zolyl group (for example, 2-thiazolyl group, 4-thiazolyl group or 5-thiazolyl group), isothiazolyl group (for example, 3-isothiazolyl group, 4-isothiazolyl group or 5-isothiazolyl group), oxazolyl group (for example, 2-oxazolyl group) Group, 4-oxazolyl group or 5-oxazolyl group), isoxazolyl group (for example, 3-isoxazolyl group, 4-isoxazolyl group or 5-isoxazolyl group), oxadiazolyl group (for example, 1,2,4-oxadiazole-5) -Yl group or 1,3,4-oxadiazol-2-yl group), thiadiazolyl group (for example, 1,3,4-thiadiazol-2-yl group), triazolyl (for example, 1,2,4-triazole) -1-yl group, 1,2,4-triazol-3-yl group, 1,2,3-tria Ol-1-yl group, 1,2,3-triazol-2-yl group or 1,2,3-triazol-4-yl group), tetrazolyl group (for example, tetrazol-1-yl group or tetrazol-5) -Yl group), triazinyl group (for example, 1,2,4-triazin-1-yl group or 1,2,4-triazin-3-yl group) and the like, and quinolyl group (For example, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group or 6-quinolyl group), isoquinolyl group (for example, 3-isoquinolyl group), quinazolyl group (for example, 2-quinazolyl group or 4-quinazolyl group) Quinoxalyl group (for example, 2-quinoxalyl group or 6-quinoxalyl group), benzofuryl group (for example, 2-benzofuryl group or 3-benzofuryl group), benzothienyl group (for example, 2- Benzothienyl group or 3-benzothienyl group), benzoxazolyl group (for example, 2-benzoxazolyl group), benzisoxazolyl group (for example, 7-benzisoxazolyl group), benzothiazolyl group ( For example, 2-benzothiazolyl group), benzimidazolyl group (for example, benzimidazol-1-yl group, benzimidazol-2-yl group or benzimidazol-5-yl group), benzotriazolyl group (for example, 1H-1 , 2,3-benzotriazol-5-yl group), indolyl group (for example, indol-1-yl group, indol-2-yl group, indol-3-yl group or indol-5-yl group), indazolyl group (For example, 1H-indazol-3-yl group), pyrrolopyrazinyl group (for example, 1H-pyrrolo [2,3-b Pyrazin-2-yl group or 1H-pyrrolo [2,3-b] pyrazin-6-yl group), imidazopyridyl group (for example, 1H-imidazo [4,5-b] pyridin-2-yl group, 1H- Imidazo [4,5-c] pyridin-2-yl group or 2H-imidazo [1,2-a] pyridin-3-yl group), imidazopyrazinyl group (for example, 1H-imidazo [4,5-b ] Pyrazin-2-yl group), pyrazolopyridyl group (for example, 1H-pyrazolo [4,3-c] pyridin-3-yl group), pyrazolothienyl group (for example, 2H-pyrazolo [3,4-b] thiophene) -2-yl group), pyrazolotriazinyl group (for example, pyrazolo [5,1-c] [1,2,4] triazin-3-yl group) and the like.

  “Alkyl group having 1 to 3 carbon atoms” means a methyl group, an ethyl group, a propyl group, or an isopropyl group.

  The diphenylpyrazole derivative represented by the above general formula (I) may have optical isomers or diastereomers, but the diphenylpyrazole derivative represented by the above general formula (I) has only a single isomer. Also included are racemic and diastereomeric mixtures.

Further, in the diphenylpyrazole derivative represented by the above general formula (I), other tautomers and geometric isomers may exist depending on the type of the substituent. In this specification, although it may describe only with one form of those isomers, these isomers are also included in this invention, and what isolate | separated the isomer, or a mixture is also included. For example, in the sulfonylguanidine moiety of the diphenylpyrazole derivative represented by the above general formula (I), there can exist three isomers having different double bond positions as shown in Scheme 1 below. Furthermore, in each isomer, there can be E-isomers and Z-isomers based on the geometry of the double bond. The present invention includes all these isomers.
(The structure in the formula is a partial representation of the sulfonylguanidine moiety of the diphenylpyrazole derivative represented by the above general formula (I). The bond indicated by the wavy line takes either E or Z configuration. Indicates that

  The present invention also includes a prodrug of the diphenylpyrazole derivative represented by the above general formula (I). The prodrug of the diphenylpyrazole derivative represented by the above general formula (I) is a compound that is enzymatically or chemically converted into the diphenylpyrazole derivative represented by the above general formula (I) in vivo. The active body of the prodrug of the diphenylpyrazole derivative represented by the above general formula (I) is a diphenylpyrazole derivative represented by the above general formula (I), but the diphenylpyrazole represented by the above general formula (I) The derivative prodrug itself may have activity.

  Examples of the group that forms a prodrug of the diphenylpyrazole derivative represented by the above general formula (I) include known literature (for example, “Drug Development”, Hirokawa Shoten, 1990, Vol. 7, p.163-198 and (Progress in Medicine, Vol. 5, 1985, p. 2157-2161).

  Examples of the “pharmacologically acceptable salt” of the diphenylpyrazole derivative represented by the above general formula (I) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphorus. Inorganic acid salts such as acid salts or oxalates, malonates, citrates, fumarate, lactates, malates, succinates, tartrate, acetates, trifluoroacetates, maleates, Gluconate, benzoate, ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate Organic salts such as aspartate, glutamate or cinnamate, but hydrochloride, sulfate, hydrobromide, maleate, benzoate or methanesulfonate Preferred.

  The diphenylpyrazole derivative represented by the above general formula (I) may be a crystal, and the diphenylpyrazole represented by the above general formula (I) may be a single crystal form or a crystal form mixture. Included in the derivative.

  The diphenylpyrazole derivative represented by the above general formula (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a known cocrystallization method.

  The diphenylpyrazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof may form an anhydride, hydrate or solvate.

The diphenylpyrazole derivative represented by the above general formula (I) may be labeled with a radioisotope, and examples of the radioisotope to be labeled include ³ H, ¹⁴ C or ¹²⁵ I.

  Further, the diphenylpyrazole derivative represented by the above general formula (I) may be a deuterium converter.

  The diphenylpyrazole derivative represented by the above general formula (I) can be produced by an appropriate method based on characteristics derived from the basic skeleton and the type of substituent. The starting materials and reagents used for the production of these compounds can be generally purchased or can be produced by known methods.

  The diphenylpyrazole derivative represented by the above general formula (I) and the intermediates and starting materials used for the production thereof can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.

  When the diphenylpyrazole derivative represented by the above general formula (I) contains an optical isomer or a stereoisomer, each isomer can be obtained as a single compound by a known method. Known methods include, for example, crystallization, enzyme resolution, or chiral chromatography.

The diphenylpyrazole derivative represented by the above general formula (I) (hereinafter, diphenylpyrazole derivative (I)) can be obtained by, for example, the method described in Scheme 2.
[Wherein, R ⁵ represents a protecting group for a carboxyl group, X independently represents a leaving group, and other symbols are as defined above. ]

Examples of the protecting group for the carboxyl group represented by R ⁵ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, and a benzyl group.

  Examples of the leaving group represented by X include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group or a dodecylthio group, and a phenoxy group. An alkylsulfonylamino group such as an arylsulfonyl group, a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonylamino group, or an alkylsulfonyloxy group or a trifluoromethanesulfonylamino group in which a hydrogen atom may be substituted with a halogen atom Group or an azolyl group such as imidazol-1-yl group or pyrazol-1-yl group.

(First step)
The diphenylpyrazole-3-carboxylic acid ester derivative (IV) can be obtained by a dehydration condensation reaction between the diketone derivative (II) and the hydrazine derivative (III).

  The amount of the hydrazine derivative (III) used for the dehydration condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the diketone derivative (II).

  The reaction solvent used in the dehydration condensation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc. Alcohol solvents, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane or the like Although a mixed solvent is mentioned, alcohol solvents, such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol, are preferable.

  The reaction temperature of the dehydration condensation reaction is preferably −30 ° C. to 300 ° C., more preferably 0 ° C. to 150 ° C.

  The reaction time of the dehydration condensation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

  The diketone derivative (II) and hydrazine derivative (III) used in the dehydration condensation reaction can be purchased, or can be produced by a known method or a method analogous thereto.

(Second step)
The diphenylpyrazol-3-ylmethanol derivative (V) can be obtained by a reduction reaction of the diphenylpyrazole-3-carboxylic acid ester derivative (IV).

  Examples of the reducing agent used in the reduction reaction include aluminum-based reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride, and boron-based reducing agents such as sodium borohydride or lithium borohydride. Aluminum-based reducing agents such as aluminum or diisobutylaluminum hydride are preferred.

  The amount of the reducing agent used in the reduction reaction is preferably from 0.3 to 100 equivalents, more preferably from 0.5 to 20 equivalents, based on the diphenylpyrazole-3-carboxylic acid ester derivative (IV).

  The reaction solvent used in the reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc. Alcohol solvents, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, toluene or xylene An aromatic hydrocarbon solvent such as the above or a mixed solvent thereof is preferable, and an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane is preferable.

  The reaction temperature of the reduction reaction is preferably −100 ° C. to 200 ° C., more preferably −50 ° C. to 50 ° C.

  The reaction time of the reduction reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

(Third step)
The pyrazole derivative (VI) can be obtained by a sulfonylation reaction of a diphenylpyrazol-3-ylmethanol derivative (V). Alternatively, it can also be obtained by a halogenation reaction of diphenylpyrazol-3-ylmethanol derivative (V).

  Examples of the sulfonylating agent used in the sulfonylation reaction include methanesulfonyl chloride, toluenesulfonyl chloride, and trifluoromethanesulfonic anhydride, and methanesulfonyl chloride is preferable.

  The amount of the sulfonylating agent used in the sulfonylation reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 10 equivalents, relative to the diphenylpyrazol-3-ylmethanol derivative (V).

  In the sulfonylation reaction, a base may be used if desired. Examples of the base to be used include organic bases such as triethylamine, N-ethyldiisopropylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, or mixtures thereof, but triethylamine, N-ethyldiisopropylamine or pyridine and the like. The organic base is preferred.

  The reaction solvent used for the sulfonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc. Alcohol solvents, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, toluene or An aromatic hydrocarbon solvent such as xylene, a basic solvent such as pyridine or 2,6-lutidine, or a mixed solvent thereof may be mentioned, and a basic solvent such as pyridine or 2,6-lutidine is preferable.

  The reaction temperature of the sulfonylation reaction is preferably -100 ° C to 200 ° C, more preferably -50 ° C to 50 ° C.

  The reaction time of the sulfonylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

  Examples of the halogenating agent used in the halogenation reaction include thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus pentachloride, and phosphoryl chloride, with thionyl chloride being preferred.

  The amount of the halogenating agent used in the halogenation reaction is preferably 0.5 to 1000 equivalents, more preferably 0.8 to 100 equivalents, relative to the diphenylpyrazol-3-ylmethanol derivative (V).

  In the halogenation reaction, a base may be used if desired. Examples of the base to be used include organic bases such as triethylamine, N-ethyldiisopropylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, or mixtures thereof, but triethylamine, N-ethyldiisopropylamine or pyridine and the like. The organic base is preferred.

  In the halogenation reaction, a reaction solvent may be used if desired. The reaction solvent to be used is appropriately selected depending on the type of reagent to be used, but is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, and aromatics such as toluene or xylene Group hydrocarbon solvents, basic solvents such as pyridine or 2,6-lutidine, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof.

  The reaction temperature of the halogenation reaction is preferably −100 ° C. to 200 ° C., more preferably −20 ° C. to 150 ° C.

  The reaction time of the halogenation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

(4th process)
The N- (diphenylpyrazol-3-ylmethyl) phthalimide derivative (VIII) can be obtained by a substitution reaction between the pyrazole derivative (VI) and phthalimide potassium (VII).

  The amount of potassium phthalimide (VII) used for the substitution reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 10 equivalents, relative to the pyrazole derivative (VI).

  The reaction solvent used for the substitution reaction is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol, N, N-dimethylformamide, N, Aprotic polar solvents such as N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, aromatic hydrocarbon solvents such as toluene or xylene, or a mixed solvent thereof An aprotic polar solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide is preferable.

  The reaction temperature of the substitution reaction is preferably −30 ° C. to 300 ° C., more preferably 0 ° C. to 150 ° C.

  The reaction time for the substitution reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

(5th process)
The diphenylpyrazol-3-ylmethylamine derivative (IX) can be obtained by deprotecting the N- (diphenylpyrazol-3-ylmethyl) phthalimide derivative (VIII) in the presence of hydrazine monohydrate.

  The amount of hydrazine monohydrate used for the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 10 equivalents with respect to the N- (diphenylpyrazol-3-ylmethyl) phthalimide derivative (VIII). .

  The reaction solvent used in the deprotection reaction is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, isopropyl alcohol or tert-butyl alcohol, N, N-dimethylformamide, N Aprotic polar solvents such as N, dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, aromatic hydrocarbon solvents such as toluene or xylene, or mixtures thereof Examples of the solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butyl alcohol.

  The reaction temperature of the deprotection reaction is preferably -30 ° C to 300 ° C, more preferably 0 ° C to 150 ° C.

The reaction time for the deprotection reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
(6th process)
The guanidine derivative (XI) can be obtained by a guanidination reaction between a diphenylpyrazol-3-ylmethylamine derivative (IX) and a guanidinating agent (X).

The amount of the guanidinating agent (X) used for the guanidination reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the diphenylpyrazol-3-ylmethylamine derivative (IX).

  In the guanidinolation reaction, a base may be used if desired. Examples of the base to be used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, or mixtures thereof, but triethylamine, N, N-diisopropylethylamine or Organic bases such as pyridine are preferred.

  The reaction solvent used in the guanidinolation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, a nitrile solvent such as acetonitrile or propionitrile, N , N-dimethylformamide, aprotic polar solvents such as N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Solvent, chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane or a mixed solvent thereof, but ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane are preferred. .

  The reaction temperature of the guanidinolation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.

  The reaction time of the guanidination reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

  The guanidinating agent (X) used for the guanidination reaction can be purchased, or can be produced by a known method or a method analogous thereto.

(Seventh step)
The diphenylpyrazole derivative (I) can be obtained by a sulfonylation reaction of a guanidine derivative (XI) and a sulfonylating agent (XII).

  0.5-10 equivalent is preferable with respect to guanidine derivative (XI), and, as for the quantity of the sulfonylation agent (XII) used for a sulfonylation reaction, 1-3 equivalent is more preferable.

  In the sulfonylation reaction, a base may be used if desired. Examples of the base used include organic bases such as triethylamine, N, N-diisopropylethylamine and pyridine, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, sodium hydrogen carbonate and potassium hydrogen carbonate, etc. Alkali metal carbonates such as sodium carbonate, sodium carbonate and potassium carbonate, or a mixture thereof, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide are preferred.

  The reaction solvent used in the sulfonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, nitrile solvents such as acetonitrile or propionitrile, N , N-dimethylformamide, aprotic polar solvents such as N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Examples thereof include a system solvent, a ketone system solvent such as acetone or methyl ethyl ketone, water, or a mixed solvent thereof, and a mixed solvent of water and an ether system solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane is preferable.

  The reaction temperature of the sulfonylation reaction is preferably -78 ° C to 100 ° C, more preferably -20 ° C to 50 ° C.

  The reaction time of the sulfonylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

  The sulfonylating agent (XII) used for the sulfonylation reaction can be purchased, or can be produced by a known method or a method analogous thereto.

(8th step)
The guanidine derivative (XIV) can be obtained by a guanidination reaction between a diphenylpyrazol-3-ylmethylamine derivative (IX) and a guanidinating agent (XIII).

The amount of the guanidinating agent (XIII) used for the guanidination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the diphenylpyrazol-3-ylmethylamine derivative (IX).

  In the guanidinolation reaction, a base may be used if desired. Examples of the base to be used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, or mixtures thereof, but triethylamine, N, N-diisopropylethylamine or Organic bases such as pyridine are preferred.

  The reaction solvent used in the guanidinolation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, a nitrile solvent such as acetonitrile or propionitrile, N , N-dimethylformamide, aprotic polar solvents such as N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Solvent, chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane or a mixed solvent thereof, but ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane are preferred. .

  The reaction temperature of the guanidinolation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.

  The reaction time of the guanidination reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

  The guanidinating agent (XIII) used for the guanidination reaction can be purchased, or can be produced by a known method or a method analogous thereto.

(9th step)
The diphenylpyrazole derivative (I) can be obtained by deprotecting the guanidine derivative (XIV) in the presence of an acid.

  Examples of the acid used for the deprotection reaction include hydrochloric acid, 10 wt% hydrogen chloride / methanol solution, 4 mol / L hydrogen chloride / ethyl acetate solution, trifluoroacetic acid or hydrofluoric acid, but 4 mol / L hydrochloric acid / Ethyl acetate solution or trifluoroacetic acid is preferred.

  0.5-1000 equivalent is preferable with respect to the guanidine derivative (XIV), and, as for the quantity of the acid used for deprotection reaction, 1-100 equivalent is more preferable.

  The reaction solvent for the deprotection reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane. An ether solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, an alcohol solvent such as methanol or ethanol, or a mixed solvent thereof. Preference is given to ester solvents such as ethyl acetate or propyl acetate or chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane.

  The reaction temperature for the deprotection reaction is preferably -78 ° C to 200 ° C, more preferably -20 ° C to 100 ° C.

  The reaction time for the deprotection reaction varies depending on the reaction conditions, but is preferably 1 to 50 hours.

(10th step)
The carbamic imido acid derivative (XVI) can be obtained by a carbamimidation reaction of a diphenylpyrazol-3-ylmethylamine derivative (IX) and a carboximidic acid derivative (XV).

  0.5-10 equivalent is preferable with respect to the diphenylpyrazol-3-ylmethylamine derivative (IX), and, as for the quantity of the carbonimido acid derivative (XV) used for carbamimidation reaction, 1-3 equivalent is more preferable.

  In the carbamimidation reaction, a base may be used if desired. Examples of the base to be used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, or mixtures thereof, but triethylamine, N, N-diisopropylethylamine or Organic bases such as pyridine are preferred.

  The reaction solvent used for the carbamimidation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, nitrile solvents such as acetonitrile or propionitrile, N , N-dimethylformamide, aprotic polar solvents such as N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Solvent, chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane or a mixed solvent thereof, and ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane are preferred. Arbitrariness.

  The reaction temperature of the carbamimidation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.

  The reaction time of the carbamimidation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

  The carbonimidic acid derivative (XV) used for the carbamimidation reaction can be purchased, or can be produced by a known method or a method analogous thereto.

(11th step)
The diphenylpyrazole derivative (I) can be obtained by a guanidinolation reaction of a carbamimic acid derivative (XVI) and an amine derivative (XVII).

  The amount of the amine derivative (XVII) used for the guanidinolation reaction is preferably 0.5 to 100 equivalents, and more preferably 1 to 20 equivalents, relative to the carbamimic acid derivative (XVI).

  The reaction solvent used in the guanidinolation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, a nitrile solvent such as acetonitrile or propionitrile, N , N-dimethylformamide, aprotic polar solvents such as N, N-dimethylacetamide or dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, esters such as ethyl acetate or propyl acetate Examples of the solvent include chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or mixed solvents thereof, and nitrile solvents such as acetonitrile or propionitrile are preferable.

  The reaction temperature of the guanidinolation reaction is preferably 0 ° C to 300 ° C, more preferably 30 ° C to 200 ° C.

  The reaction time of the guanidination reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

  The amine derivative (XVII) used for the guanidinolation reaction can be purchased, or can be produced by a known method or a method analogous thereto.

  The medicament and MALT1 inhibitor of the present invention are characterized by containing a diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient.

  “MALT1 inhibition” means inhibiting the protease activity of MALT1.

  The “MALT1 inhibitor” means a compound having an action of inhibiting the protease activity of MALT1 to eliminate or attenuate the activity.

  “Autoimmune disease” is a general term for diseases that cause symptoms when the immune system responds excessively to normal cells and tissues and attacks them. For example, psoriasis, multiple sclerosis Disease, rheumatism, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, uveitis or rheumatic polymyalgia.

  The diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof is characterized by suppressing the function of MALT1 by inhibiting the protease activity of MALT1, ie, the substrate cleavage activity. Therefore, the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof is a medicament for a disease for which improvement of the disease state or amelioration of symptoms can be expected by inhibiting the protease activity of MALT1, particularly for the treatment of autoimmune diseases. It can be used as an agent or a preventive agent.

  It can be evaluated using an in vitro test that the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof has an action of inhibiting the protease activity of MALT1. Examples of the in vitro test include a method for evaluating cleavage of a substrate (for example, BCL10 protein) by MALT1 (Cancer Cell, 2012, Vol. 22, p. 825-837). Moreover, the NF-κB transcription activity inhibitory action caused by inhibiting the protease activity of MALT1 can be evaluated using a reporter gene assay (International Publication No. 2009/065897).

  The diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof suppresses the function of MALT1 using IL-2 (interleukin-2) using a lymphocyte cell line (for example, Jurkat T cell). ) Production amount can be evaluated as an index. As a method using IL-2 production as an index, for example, Jurkat T cell is co-stimulated with Phorbol 12-myristate 13-acetate and Ionomycin, or co-stimulated with CD3 and CD28, and is dependent on MALT1. A method for measuring the induced IL-2 production (Cancer Cell, 2012, Vol. 22, p. 825-837).

  The effectiveness of the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof for the treatment or prevention of an autoimmune disease can be evaluated using a disease state model. Examples of pathological models include the imiquimod-induced psoriasis model (The Journal of Dermatological Science, 2013, Vol. 71, No. 1, p. 29-36), an experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research). 2006, 84, p. 1225-1234), collagen arthritis model (Annual Review of Immunology, 1984, 2, p. 199-218), dextran sulfate sodium induced colitis model (Laboratory Investigation, 1993). , 69, p.238-249), spontaneous onset model of systemic lupus erythematosus (Nature, 2000, 404, p.995) 999), ankylosing spondylitis model (Arthritis Research & Therapy, 2012, 14, 253-265) or experimental autoimmune uveitis model (Journal of Immunology, 2006, 36), p. .3071-3081).

  The effectiveness of the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof for the treatment or prevention of an autoimmune disease can be determined by, for example, reducing the protease activity of MALT1, using the above in vitro test, or It can be evaluated using a decrease in NF-κB transcriptional activity caused by inhibiting the protease activity of MALT1 or a decrease in the production amount of IL-2 that is an index of the function of MALT1. In addition, the effectiveness of treating or preventing psoriasis, one of the autoimmune diseases, can be reduced by using the above-mentioned imiquimod-induced psoriasis model, for example, by reducing the thickness of the auricle that increases with the progression of symptoms in the psoriasis model. It can be evaluated as an indicator.

  When the diphenylpyrazole derivative (I) or a pharmaceutically acceptable salt thereof is administered to a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human), particularly human In addition, it can be used as a useful medicament (in particular, a therapeutic or prophylactic agent for autoimmune diseases). When the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof is used clinically as a pharmaceutical, the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof may be used as it is. Additives such as excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents or tonicity agents may be mixed as appropriate. Moreover, said pharmaceutical can be manufactured by a normal method using these pharmaceutical carriers as appropriate. Examples of the above-mentioned pharmaceutical administration forms include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or topical administration. , Ointments, creams or patches. Further, it may be a known continuous preparation.

  The medicament preferably contains 0.00001 to 90% by weight, more preferably 0.01 to 70% by weight, of the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof. The dose is appropriately selected according to the patient's symptoms, age and body weight, and administration method. The daily active ingredient amount for adults is 0.1 μg to 1 g for injections and 1 μg to 10 g for oral preparations. In the case of a patch, 1 μg to 10 g is preferable, and can be administered once or divided into several times.

  Examples of the pharmacologically acceptable carrier or diluent of the above-mentioned pharmaceutical include, for example, binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, calcium phosphate, etc. Sorbitol, glycine, etc.) or lubricants (magnesium stearate, polyethylene glycol, talc, silica, etc.).

  The above medicines may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic effect or preventive effect or to reduce the dose.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail using an Example, this invention is not limited to these.

In addition, the commercially available compound was used about the compound which is not described in the synthesis method by the compound used for the synthesis | combination of an Example compound. “Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruplex line), quint, respectively. (Quintet), sept (sevent), m (multiple line), br (wide), dd (double double line), dt (double triple line), ddd (double double line) , Dq (double quadruple line), td (triple double line), and tt (triple triple line). ^{In 1} H-NMR, the case where protons such as a hydroxyl group, an amino group, and a carboxyl group are very gentle peaks is not described. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technologies). The amine silica gel used was amine silica gel DM1020 (Fuji Silysia Chemical Co.), and the flash chromatography used YFLC W-prep2XY (Yamazen Co., Ltd.). As the microwave synthesizer, Monowave 300 (Anton Paar) was used.

Reference Example 1 Synthesis of ethyl 4- (4-chlorophenyl) -2,4-dioxobutanoate:
1- (4-Chlorophenyl) ethanone (100 g) and diethyl oxalate (95 g) were dissolved in ethanol (400 mL), 20 wt% sodium ethoxide in ethanol (142 mL) was added, and the mixture was stirred at 70 ° C. for 5 hours 30 hours. Stir for minutes. After the reaction mixture was cooled to room temperature, 1 mol / L hydrochloric acid was added. The precipitated solid was collected by filtration and washed with ethanol / water (= 1/1, v / v, 200 mL × 2) to obtain the title compound (153 g).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 7.04 (1H, s), 7 .47-7.51 (2H, m), 7.93-7.96 (2H, m).

Reference Example 2 Synthesis of ethyl 1,5-bis (4-chlorophenyl) -1H-pyrazole-3-carboxylate:
After dissolving ethyl 4- (4-chlorophenyl) -2,4-dioxobutanoate (5.0 g) and (4-chlorophenyl) hydrazine hydrochloride (3.5 g) synthesized in Reference Example 1 in ethanol (50 mL) , Heated to reflux overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the crude product, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate), and the obtained solid was washed with hexane to obtain the title compound (4.2 g).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 4.46 (2H, q, J = 7.1 Hz), 7.03 (1H, s), 7 .13-7.16 (2H, m), 7.25-7.36 (6H, m).
MS (ESI) [M + H] ⁺ : 361.

Reference Example 3 Synthesis of (1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methanol:
Lithium aluminum hydride (2.5 g) was suspended in tetrahydrofuran (50 mL), cooled to 4 ° C., and then 1,5-bis (4-chlorophenyl) -1H-pyrazole-3-carbon synthesized in Reference Example 2. A solution of ethyl acid (10.0 g) in tetrahydrofuran (50 mL) was added slowly. The reaction mixture was stirred for 4 hours, sodium sulfate decahydrate was added, and the mixture was further stirred for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (8.8 g).
¹ H-NMR (CDCl ₃ ) δ: 2.11 (1H, t, J = 5.9 Hz), 4.78 (2H, d, J = 5.9 Hz), 6.52 (1H, s), 7 .13-7.23 (4H, m), 7.29-7.34 (4H, m).
MS (ESI) [M + H] ⁺ : 319.

Reference Example 4 Synthesis of 2-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) isoindoline-1,3-dione:
(1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methanol (6.0 g) synthesized in Reference Example 3 was dissolved in pyridine (30 mL), cooled to 4 ° C., and then methane chloride. Sulfonyl (2.9 mL) was added slowly. The reaction mixture was warmed to room temperature and stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product (3.0 g) and potassium phthalimide (1.7 g) were dissolved in N, N-dimethylformamide (15 mL), and then stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate), and the obtained solid was recrystallized (hexane-ethyl acetate) to give the title compound (2.6 g).
¹ H-NMR (CDCl ₃ ) δ: 4.99 (2H, s), 6.47 (1H, s), 7.08-7.11 (2H, m), 7.17-7.20 (2H M), 7.25-7.30 (4H, m), 7.72-7.74 (2H, m), 7.88-7.90 (2H, m).
MS (ESI) [M + H] ⁺ : 448.

Reference Example 5 Synthesis of (1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methanamine:
2-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) isoindoline-1,3-dione (2.5 g) synthesized in Reference Example 4 was added to methanol (15 mL). After dissolving and adding hydrazine monohydrate (0.81 mL), the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was cooled to room temperature, insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the obtained crude product, and insoluble matters were removed by filtration. The filtrate was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.7 g).
¹ H-NMR (DMSO-D ₆ ) δ: 1.80 (2H, brs), 3.74 (2H, s), 6.65 (1H, s), 7.23-7.27 (4H, m ), 7.44-7.49 (4H, m).
MS (ESI) [M + H] ⁺ : 318.

Reference Example 6 Synthesis of 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine:
(1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methanamine (0.10 g) synthesized in Reference Example 5 was dissolved in tetrahydrofuran (1 mL), and then triethylamine (0.11 mL) and 1-Amidinopyrazole hydrochloride (51 mg) was added. The reaction mixture was stirred at room temperature overnight, 1 mol / L aqueous sodium hydroxide solution (0.35 mL) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was recrystallized (hexane-ethyl acetate) to obtain the title compound (0.030 g).
¹ H-NMR (CD ₃ OD) δ: 4.48 (2H, s), 6.62 (1H, s), 7.22-7.28 (4H, m), 7.37-7.44 ( 4H, m).
MS (ESI) [M + H] ⁺ : 360.

Example 1 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) benzenesulfonamide:
1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.030 g) synthesized in Reference Example 6 was dissolved in tetrahydrofuran (0.5 mL), An 8 mol / L aqueous sodium hydroxide solution (0.021 mL) and benzenesulfonyl chloride (8.5 μL) were added. The reaction mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (hereinafter, the compound of Example 1) (0.015 g).
¹ H-NMR (DMSO-D ₆ ) δ: 4.36 (2H, d, J = 5.9 Hz), 6.38 (1H, s), 6.82 (2H, brs), 7.15-7 .31 (4H, m), 7.41-7.51 (7H, m), 7.76-7.78 (2H, m).
MS (ESI) [M + H] ⁺ : 500.

Example 2 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-methoxybenzenesulfonamide:
Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.050 g) synthesized in Reference Example 6 and 3-methoxybenzenesulfonyl chloride (39 μL), In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 2) (0.030 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.74 (3H, s), 4.40 (2H, brs), 6.37 (1H, s), 6.66 (2H, brs), 6.98 ( 1H, dd, J = 8.2, 2.7 Hz), 7.05-7.08 (2H, m), 7.11-7.15 (2H, m), 7.25-7.32 (5H , M), 7.39-7.46 (2H, m).
MS (ESI) [M + H] ⁺ : 530.

Example 3 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-chlorobenzenesulfonamide:
Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.050 g) and 3-chlorobenzenesulfonyl chloride (29 μL) synthesized in Reference Example 6 In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 3) (0.030 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 4.41 (2H, brs), 6.38 (1H, s), 6.65 (2H, brs), 7.07-7.16 (4H, m), 7.29-7.35 (5H, m), 7.41-7.44 (1H, m), 7.76 (1H, d, J = 7.7 Hz), 7.85 (1H, s).
MS (ESI) [M + H] ⁺ : 534.

Example 4 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-cyanobenzenesulfonamide:
Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.10 g) synthesized in Reference Example 6 and 3-cyanobenzenesulfonyl chloride (84 mg), In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 4) (0.067 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 4.42 (2H, s), 6.39 (1H, s), 6.80 (1H, brs), 7.08-7.17 (4H, m), 7.29-7.34 (4H, m), 7.54 (1H, t, J = 7.7 Hz), 7.72 (1H, d, J = 7.7 Hz), 8.09-8.13 (2H, m).
MS (ESI) [M + H] ⁺ : 525.

Example 5 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) -3-fluorobenzenesulfonamide:
Using 1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.10 g) synthesized in Reference Example 6 and 3-fluorobenzenesulfonyl chloride (55 μL), In the same manner as in Example 1, the title compound (hereinafter, the compound of Example 5) (0.068 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 4.40 (2H, s), 6.37 (1H, s), 6.76 (1H, s), 7.06-7.16 (5H, m), 7.28-7.39 (5H, m), 7.53-7.58 (1H, m), 7.64-7.67 (1H, m).
MS (ESI) [M + H] ⁺ : 518.

Example 6 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) pyridine-2-sulfonamide:
1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.050 g) and pyridine-2-sulfonyl chloride (0.037 g) synthesized in Reference Example 6 were used. The title compound (hereinafter, the compound of Example 6) (0.043 g) was obtained in the same manner as in Example 1.
¹ H-NMR (CDCl ₃ ) δ: 4.44 (2H, d, J = 5.4 Hz), 6.46 (1H, s), 6.81 (2H, brs), 7.10-7.21 (4H, m), 7.27-7.41 (5H, m), 7.84 (1H, dt, J = 8.0, 1.5 Hz), 8.04 (1H, d, J = 8. 0 Hz), 8.60 (1H, d, J = 4.1 Hz).
MS (ESI) [M + H] ⁺ : 501.

Example 7 Synthesis of N- (amino (((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) thiophene-2-sulfonamide:
1-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) guanidine (0.056 g) synthesized in Reference Example 6 and thiophene-2-sulfonyl chloride (0.037 g) The title compound (hereinafter, the compound of Example 7) (0.031 g) was obtained in the same manner as in Example 1.
¹ H-NMR (CDCl ₃ ) δ: 4.42 (2H, brs), 6.43 (1H, s), 6.98 (1H, dd, J = 5.0, 3.8 Hz), 7.11 −7.15 (4H, m), 7.30−7.33 (4H, m), 7.42 (1H, dd, J = 5.0, 1.2 Hz), 7.55 (1H, dd, J = 3.8, 1.2 Hz).
MS (ESI) [M + H] ⁺ : 506.

Reference Example 7 Synthesis of ethyl 5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate:
Using ethyl 4- (4-chlorophenyl) -2,4-dioxobutanoate (5.0 g) and (4-methoxyphenyl) hydrazine hydrochloride (3.4 g) synthesized in Reference Example 1 in the same manner as Reference Example 2. To give the title compound (5.0 g).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 3.83 (3H, s), 4.45 (2H, q, J = 7.1 Hz), 6 .85-6.89 (2H, m), 7.02 (1H, s), 7.12-7.16 (2H, m), 7.21-7.30 (4H, m).
MS (ESI) [M + H] ⁺ : 357.

Reference Example 8 Synthesis of (5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanol:
The title compound was prepared in the same manner as in Reference Example 3 using ethyl 5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (1.8 g) synthesized in Reference Example 7. (1.6 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.41 (1H, t, J = 5.9 Hz), 3.81 (3H, s), 4.77 (2H, d, J = 5.9 Hz), 6 .49 (1H, s), 6.84-6.88 (2H, m), 7.12-7.20 (4H, m), 7.25-7.28 (2H, m).
MS (ESI) [M + H] ⁺ : 315.

Reference Example 9 Synthesis of 2-((5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) isoindoline-1,3-dione:
(5- (4-Chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanol (1.4 g) synthesized in Reference Example 8 was dissolved in dichloromethane (15 mL), and then chlorinated. Thionyl (0.9 mL) was added slowly. The reaction mixture was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. The obtained crude product and potassium phthalimide (0.87 g) were dissolved in N, N-dimethylformamide (15 mL) and stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was recrystallized (hexane-ethyl acetate) to obtain the title compound (1.6 g).
¹ H-NMR (CDCl ₃ ) δ: 3.80 (3H, s), 4.99 (2H, s), 6.45 (1H, s), 6.81-6.85 (2H, m), 7.07-7.11 (2H, m), 7.14-7.18 (2H, m), 7.21-7.24 (2H, m), 7.70-7.75 (2H, m) ), 7.86-7.91 (2H, m).
MS (ESI) [M + H] ⁺ : 444.

Reference Example 10 Synthesis of (5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanamine:
2-((5- (4-Chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) isoindoline-1,3-dione (1.6 g) synthesized in Reference Example 9 In the same manner as in Reference Example 5, the title compound (0.30 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.82 (3H, s), 3.96 (2H, s), 6.43 (1H, s), 6.84-6.88 (2H, m), 7.13-7.20 (4H, m), 7.25-7.28 (2H, m).
MS (ESI) [M + H] ⁺ : 314.

Reference Example 11 Synthesis of S-methylisothiourea hydroiodide:
Thioamide (10 g) was dissolved in methanol (100 mL), and methyl iodide (19 g) was added. The reaction mixture was heated to reflux for 1 hour and then concentrated under reduced pressure to obtain the title compound (27.6 g).
_{^{1 H-NMR (DMSO-D}} 6) δ: 2.57 (3H, s), 8.89 (4H, s).

Reference Example 12 Synthesis of N- (tert-butoxycarbonyl) -S-methylisothiourea:
S-methylisothiourea hydroiodide synthesized in Reference Example 11 (28 g) and triethylamine (18 mL) were dissolved in dichloromethane (250 mL), and di-tert-butyl dicarbonate (28 mL) was added. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (24 g).
¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 2.46 (3H, s).

Reference Example 13 Synthesis of N- (phenylsulfonyl) -N ′-(tert-butoxycarbonyl) -S-methylisothiourea:
Sodium hydride (55% by weight in mineral oil, 2.5 g) was suspended in N, N-dimethylformamide (100 mL), and then N- (tert-butoxycarbonyl) -S-methylisothio synthesized in Reference Example 12 was used. Urea (10 g) was added. After cooling to 4 ° C., benzenesulfonyl chloride (8.1 mL) was added slowly. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was added to ice water / ethyl acetate / hexane (100 mL / 50 mL / 50 mL) and subjected to liquid separation operation. The aqueous layer was extracted with ethyl acetate / hexane (1/1, v / v), the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (4.8 g).
¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 2.29 (3H, s), 7.50-7.62 (3H, m), 7.93-7.96 (2H , M), 10.33 (1H, s).

Reference Example 14 2-Benzenesulfonyl-3-((5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) -1- (tert-butoxycarbonyl) Synthesis of guanidine:
(5- (4-Chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanamine (0.10 g) synthesized in Reference Example 10 was dissolved in tetrahydrofuran (1 mL). N- (phenylsulfonyl) -N ′-(tert-butoxycarbonyl) -S-methylisothiourea (0.12 g) synthesized in Example 13 was added. The reaction mixture was stirred at 50 ° C. overnight and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (0.15 g).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 3.81 (3H, s), 4.59 (2H, d, J = 5.4 Hz), 6.29 (1H, s ), 6.84-6.87 (2H, m), 7.02-7.05 (2H, m), 7.12-7.16 (2H, m), 7.23-7.26 (2H) , M), 7.41-7.51 (3H, m), 7.93-7.96 (2H, m), 8.96 (1H, t, J = 5.4 Hz), 10.00 (1H , S).
MS (ESI) [M + H] ⁺ : 596.

Example 8 Synthesis of N- (amino ((((5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) benzenesulfonamide:
2-Benzenesulfonyl-3-((5- (4-chlorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) -1- (tert-butoxycarbonyl) synthesized in Reference Example 14 ) After guanidine (0.14 g) was dissolved in ethyl acetate (2 mL), a 4 mol / L hydrogen chloride / ethyl acetate solution (2.0 mL) was added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The obtained crude product was washed with hexane / ethyl acetate (2/1, v / v) to obtain the title compound (hereinafter, the compound of Example 8) (0.082 g).
¹ H-NMR (DMSO-D ₆ ) δ: 3.77 (3H, s), 4.35 (2H, d, J = 5.9 Hz), 6.35 (1H, s), 6.83 (1H , Brs), 6.94-6.98 (2H, m), 7.13-7.17 (4H, m), 7.33-7.52 (6H, m), 7.77-7.79. (2H, m).
MS (ESI) [M + H] ⁺ : 496.

Reference Example 15 Synthesis of ethyl 4- (4-methoxyphenyl) -2,4-dioxobutanoate:
The title compound (41 g) was obtained in the same manner as in Reference Example 1 using (4-methoxyphenyl) ethanone (50 g).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0 Hz), 3.90 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 6 97-7.00 (2H, m), 7.04 (1H, s), 7.98-8.01 (2H, m).

Reference Example 16 Synthesis of ethyl 1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate:
Using ethyl 4- (4-methoxyphenyl) -2,4-dioxobutanoate (10 g) synthesized in Reference Example 15, the title compound (8.7 g) was obtained in the same manner as Reference Example 2.
¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 3.82 (3H, s), 4.45 (2H, q, J = 7.1 Hz), 6 84-6.87 (2H, m), 6.97 (1H, s), 7.11-7.15 (2H, m), 7.27-7.34 (4H, m).
MS (ESI) [M + H] ⁺ : 357.

Reference Example 17 Synthesis of (1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanol:
Using ethyl 1,5-bis (4-chlorophenyl) -1H-pyrazole-3-carboxylate (2.5 g) synthesized in Reference Example 16, the title compound (1.9 g) was prepared in the same manner as in Reference Example 3. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.23 (1H, t, J = 5.9 Hz), 3.81 (3H, s), 4.77 (2H, d, J = 5.9 Hz), 6 .45 (1H, s), 6.83-6.87 (2H, m), 7.11-7.15 (2H, m), 7.20-7.24 (2H, m), 7.28 −7.32 (2H, m).
MS (ESI) [M + H] ⁺ : 315.

Reference Example 18 Synthesis of 2-((1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) isoindoline-1,3-dione:
Using (1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanol (1.8 g) synthesized in Reference Example 17, the title was prepared in the same manner as in Reference Example 9. Compound (2.0 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.79 (3H, s), 4.98 (2H, s), 6.40 (1H, s), 6.79-6.82 (2H, m), 7.07-7.10 (2H, m), 7.19-7.22 (2H, m), 7.25-7.28 (2H, m), 7.70-7.75 (2H, m) ), 7.86-7.91 (2H, m).
MS (ESI) [M + H] ⁺ : 444.

Reference Example 19 Synthesis of (1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanamine:
2-((1- (4-Chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) isoindoline-1,3-dione (2.0 g) synthesized in Reference Example 18 In the same manner as in Reference Example 5, the title compound (1.4 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.81 (3H, s), 3.95 (2H, s), 6.39 (1H, s), 6.83 to 6.86 (2H, m), 7.12-7.15 (2H, m), 7.21-7.24 (2H, m), 7.28-7.31 (2H, m).
MS (ESI) [M + H] ⁺ : 314.

Reference Example 20 2-Benzenesulfonyl-3-((1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) -1- (tert-butoxycarbonyl) Synthesis of guanidine:
Using (1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methanamine (0.10 g) synthesized in Reference Example 19, the title was prepared in the same manner as in Reference Example 14. Compound (0.17 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 3.82 (3H, s), 4.59 (2H, d, J = 5.4 Hz), 6.25 (1H, s ), 6.81-6.85 (2H, m), 7.02-7.06 (2H, m), 7.17-7.21 (2H, m), 7.27-7.31 (2H) M), 7.41-7.50 (3H, m), 7.93-7.95 (2H, m), 8.99 (1H, t, J = 5.4 Hz), 10.00 (1H , S).
MS (ESI) [M + H] ⁺ : 596.

Example 9 Synthesis of N- (amino (((1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) amino) methylene) benzenesulfonamide:
2-Benzenesulfonyl-3-((1- (4-chlorophenyl) -5- (4-methoxyphenyl) -1H-pyrazol-3-yl) methyl) -1- (tert-butoxycarbonyl) synthesized in Reference Example 20 ) Using guanidine (0.14 g), the title compound (hereinafter, the compound of Example 9) (0.10 g) was obtained in the same manner as in Example 8.
¹ H-NMR (DMSO-D ₆ ) δ: 3.77 (3H, s), 4.35 (2H, d, J = 5.4 Hz), 6.29 (1H, s), 6.82 (1H , Brs), 6.93-6.96 (2H, m), 7.06-7.09 (2H, m), 7.22-7.25 (2H, m), 7.32-7.53. (6H, m), 7.76-7.79 (2H, m).
MS (ESI) [M + H] ⁺ : 496.

(Reference Example 21) Synthesis of diphenyl phenylsulfonylcarbonimidate:
After dichlorodiphenoxymethane (5.7 g) and benzenesulfonamide (7.3 g) were suspended in ethyl acetate (25 mL), the reaction mixture was heated to reflux for 25 hours. The reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was suspended in dichloromethane, and insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate), and the resulting solid was recrystallized (hexane-ethyl acetate) to give the title compound (2. 4 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.07-7.09 (m, 4H), 7.27-7.29 (m, 2H) 7.35-7.39 (m, 4H), 7. 46-7.50 (m, 2H), 7.55-7.59 (1H, m), 7.94-7.96 (m, 2H).
MS (ESI) [M + H] ⁺ : 354.

Reference Example 22 Synthesis of phenyl N-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) -N ′-(phenylsulfonyl) carbamimidate:
Phenyl synthesized in Reference Example 21 was prepared by dissolving (1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methanamine (0.50 g) synthesized in Reference Example 5 in tetrahydrofuran (3 mL). Diphenyl sulfonylcarbonimidate (0.58 g) was added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (0.90 g).
¹ H-NMR (CDCl ₃ ) δ: 4.73 (2H, d, J = 5.4 Hz), 6.45 (1H, s), 6.98-7.01 (2H, m), 7.14 -7.17 (2H, m), 7.20-7.25 (3H, m), 7.30-7.40 (8H, m), 7.46-7.50 (1H, m), 7 .77-7.80 (2H, m), 8.12 (1H, t, J = 5.4 Hz).
MS (ESI) [M + H] ⁺ : 577.

Example 10 Synthesis of N-((((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) (methylamino) methylene) benzenesulfonamide:
N-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) -N ′-(phenylsulfonyl) carbamic imidophenyl (0.050 g) synthesized in Reference Example 22 was added to acetonitrile (0.050 g). 2 mL), a tetrahydrofuran solution of methylamine (2 mol / L, 0.22 mL) was added, and the mixture was stirred at 150 ° C. for 30 minutes using a microwave synthesizer. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (hereinafter, the compound of Example 10) (0.040 g).
¹ H-NMR (CDCl ₃ ) δ: 2.85 (3H, d, J = 5.0 Hz), 4.48 (2H, brs), 6.37 (1H, s), 7.07-7.11 (2H, m), 7.14-7.18 (2H, m), 7.29-7.35 (4H, m), 7.40-7.49 (3H, m), 7.92-7 .94 (2H, m).
MS (ESI) [M + H] ⁺ : 514.

Example 11 Synthesis of N-((((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) amino) (hydroxyamino) methylene) benzenesulfonamide:
N-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) -N ′-(phenylsulfonyl) carbamic imidophenyl (0.050 g) synthesized in Reference Example 22 was added to acetonitrile (0.050 g). After dissolving in 2 mL), triethylamine (0.24 mL) and hydroxylamine hydrochloride (120 mg) were added and stirred at 80 ° C. for 10 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (hereinafter referred to as the compound of Example 11) (0.011 g).
¹ H-NMR (CDCl ₃ ) δ: 4.51 (2H, d, J = 5.4 Hz), 6.35 (1H, s), 6.62 (1H, brs), 7.03-7.07 (2H, m), 7.11-7.16 (2H, m), 7.27-7.31 (4H, m), 7.37-7.49 (3H, m), 7.91 (2H) , D, J = 8.2 Hz).
MS (ESI) [M + H] ⁺ : 516.

Example 12 Synthesis of N-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) -N ′-(phenylsulfonyl) hydrazinecarboximide
N-((1,5-bis (4-chlorophenyl) -1H-pyrazol-3-yl) methyl) -N ′-(phenylsulfonyl) carbamic imidophenyl (0.050 g) synthesized in Reference Example 22 was added to acetonitrile (0.050 g). 2 mL), hydrazine monohydrate (0.021 mL) was added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with diisopropyl ether to obtain the title compound (hereinafter, the compound of Example 12) (0.039 g).
¹ H-NMR (DMSO-D ₆ ) δ: 4.40 (2H, d, J = 5.9 Hz), 4.61 (2H, s), 6.35 (1H, s), 7.12-7 .16 (2H, m), 7.22-7.26 (2H, m), 7.37-7.41 (2H, m), 7.45-7.51 (5H, m), 7.75 −7.78 (2H, m), 7.86 (1H, t, J = 5.4 Hz), 8.21 (1H, s).
MS (ESI) [M + H] ⁺ : 515.

(Example 13) Evaluation of inhibition of protease activity of MALT1:
The diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof inhibits the protease activity of MALT1 according to the method described in the literature (Cancer Cell, 2012, Vol. 22, p.825-837). Similarly, evaluation was performed in an in vitro experimental system. That is, it was evaluated by measuring the degree of decrease of the fluorescence value by the compound with respect to the increase of the fluorescence value caused by cleaving the artificial peptide substrate fluorescently labeled by the recombinant MALT1.

A) Production of recombinant GST-fused MALT1:
A vector in which the full-length cDNA of the human MALT1 gene (GenBank accession number: AB02618.1) amplified by PCR is incorporated into the SalI site downstream of the GST gene of the pGEX6P3 vector (GE Healthcare) (hereinafter referred to as “in frame”) PGEX6P3-MALT1 vector). Next, after transforming the pGEX6P3-MALT1 vector into E. coli for protein expression (BL21-RIL-codon plus-DE3, Agilent), ampicillin resistance screening and analysis by colony PCR were performed, and an E. coli strain expressing recombinant GST-fused MALT1 Got. Induction of protein expression was performed with isopropyl-β-thiogalactopyranoside. After induction of expression, the E. coli precipitate was recovered from the E. coli culture solution by centrifugation, and the E. coli precipitate was disrupted and centrifuged to obtain a supernatant. The supernatant was purified using a GSTrap FF column (GE Health Care) to obtain a recombinant GST-fused MALT1.

B) Evaluation of inhibition of protease activity of MALT1:
89 μL of enzyme solution per specimen (4.8 μg / mL GST-fused MALT1, 50 mmol / L MES, 150 mmol / L NaCl, 10% sucrose, 0.1% CHAPS, 10 mmol / L dithiothreitol, 1 mol / L tri- 1 μL of each concentration of the test compound (DMSO diluted solution) was added to each (ammonium citrate) to prepare a mixed solution. The mixture was incubated at room temperature for 30 minutes, and then the fluorescence value of the mixture was measured (fluorescence value of the first measurement) (Ex: 380 nm, Em: 460 nm; Envision (Perkin Elmer)). Next, 10 μL of 200 μmol / L substrate (Ac-LRSR-AMC, SM Biochemicals) was added to the mixed solution (final concentration: 20 μmol / L), and incubated at 30 ° C. for 80 minutes to react. (The fluorescence value of the second measurement) (Ex: 380 nm, Em: 460 nm; Envision (Perkin Elmer)). In addition, “wells for which no test compound was added (DMSO only was added), enzyme was not added and the substrate was added” and “test compound was not added (DMSO only was added), enzyme was added and the substrate was added” were provided.

The fluorescence value of the first measurement was “F1”, and the fluorescence value of the second measurement was “F2”. F2-F1 of “test compound non-added (DMSO only added), enzyme-free and substrate-added well” is “Fback”, and “test compound non-added (DMSO only added), enzyme-added and substrate-added well” F2-F1 is “Fpositive”, F2-F1 of “well of test compound addition, enzyme addition and substrate addition” is “Fsample”, and the protease activity inhibition rate (%) of MALT1 by the test compound was calculated by the following formula: .
Inhibition rate (%) = 100 × (1− (Fsample−Fback) / (Fpositive−Fback))

The IC ₅₀ value of each test compound is shown in Table 1. As is clear from the results in Table 1, it was shown that the diphenylpyrazole derivative (I) of the present invention or a pharmacologically acceptable salt thereof has an action of inhibiting the protease activity of MALT1.

(Example 14) Inhibitory effect of pinna thickening in imiquimod-induced psoriasis model mice:
The fact that the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof exerts a therapeutic effect on psoriasis, which is one of autoimmune diseases, is described in the literature (The Journal of Dermatological Science, 2014, No. 1). 76, No. 2, p. 96-103), and evaluated in an in vivo experimental system using an imiquimod-induced psoriasis model mouse. That is, it evaluated by verifying the inhibitory effect by the compound with respect to the thickening of the auricle, using the thickness of the auricle as the symptom progression of the imiquimod-induced psoriasis model as an index.

  Seven-week-old BALB / c male mice (Nihon Charles River) were used at 8 weeks of age after preliminary breeding. For the induction of psoriasis-like symptoms, once a day for 6 days from the first administration date of imiquimod (hereinafter referred to as the induction date) to the fifth day after the induction, and further once a day on the 7th and 9th days after the induction. Each time, 5 mg of Beselna cream 5% (imiquimod dose 0.25 mg / body / day) was applied to both ears of the mouse. The test compound was suspended in a 0.5% methylcellulose-0.025% Tween 20 solution to prepare an administration drug solution. The administered drug solution was orally administered twice a day in the morning and afternoon for 3 days from the 7th day to the 9th day after the induction (dose volume was 10 mL / kg). In addition, the group which similarly administered 0.5% methylcellulose-0.025% Tween20 solution was provided as a solvent administration group.

  The thickness of the auricle before administration of imiquimod on the induction day (before induction) and the thickness of the auricle on the 10th day after the induction were measured using a digital micrometer (Mitutoyo), and the change (10 days after the induction) The thickness of the auricle—the thickness of the auricle before induction) was used as an index for evaluating drug efficacy. For statistical analysis, Steel test was performed using statistical analysis software EXSAS (ver. 7.6).

  The evaluation results of the compound of Example 1 are shown in FIG. The vertical axis in the figure shows the change in thickness of the pinna (μm), and the horizontal axis shows each administration group. “*” In the figure indicates a statistically significant (P <0.05) difference compared to the solvent administration group.

  The thickness of the pinna of the solvent administration group increased by 153 μm. In contrast, the thickness of the auricles of the groups in which the compound of Example 1 was orally administered at 15 mg / kg (twice a day), 30 mg / kg (twice a day), or 60 mg / kg (twice a day). The changes remained at 98 μm, 87 μm, and 68 μm, respectively, and were significantly reduced compared to changes in the thickness of the pinna in the solvent administration group.

  Thereby, it was shown that the diphenylpyrazole derivative (I) of the present invention or a pharmacologically acceptable salt thereof exhibits a therapeutic effect on psoriasis.

  Since the diphenylpyrazole derivative (I) or a pharmacologically acceptable salt thereof of the present invention has an action of strongly inhibiting the protease activity of MALT1, it can be used as a therapeutic or preventive agent for autoimmune diseases such as psoriasis. .

Claims (7)

A diphenylpyrazole derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
[Wherein, R ¹ and R ² each independently represents a halogen atom or an alkoxy group having 1 to 3 carbon atoms, and R ³ represents one or two hydrogen atoms each independently a halogen atom. Represents an atom, an aryl group which may be substituted with an alkoxy group having 1 to 3 carbon atoms or a cyano group, or a heteroaryl group, and R ⁴ represents a hydrogen atom, a hydroxyl group, an amino group or 1 to 3 carbon atoms. Represents an alkyl group. ] R ¹ and R ² are each independently a chlorine atom or a methoxy group,
R ³ is a phenyl group, a 2-thienyl group or a 2-pyridyl group in which one hydrogen atom may be substituted with a halogen atom, an alkoxy group having 1 to 3 carbon atoms or a cyano group,
The diphenylpyrazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ is a hydrogen atom, a hydroxyl group, an amino group or a methyl group. R ¹ and R ² are each independently a chlorine atom or a methoxy group,
R ³ is a phenyl group, a 2-thienyl group or a 2-pyridyl group in which the hydrogen atom at the 3-position may be substituted with a halogen atom, a methoxy group or a cyano group;
The diphenylpyrazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ is a hydrogen atom, a hydroxyl group, an amino group or a methyl group.   The pharmaceutical which contains the diphenylpyrazole derivative or its pharmacologically acceptable salt as described in any one of Claims 1-3 as an active ingredient.   A Mucosa-associated lymphoid tissue phosphotranslation protein 1 inhibitor comprising the diphenylpyrazole derivative according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.   The therapeutic agent or preventive agent of an autoimmune disease containing the diphenylpyrazole derivative as described in any one of Claims 1-3, or its pharmacologically acceptable salt as an active ingredient.   A therapeutic or prophylactic agent for psoriasis comprising the diphenylpyrazole derivative according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.