JPWO2019088057A1 - Anilide derivatives and their pharmaceutical uses - Google Patents

Abstract

An object of the present invention is to provide a novel compound having retinoid-related orphan receptor γ antagonist activity and exerting a therapeutic effect or a preventive effect on autoimmune diseases such as psoriasis. The present invention provides an aniride derivative (I) represented by the following, a hydrate thereof, or a pharmacologically acceptable salt thereof.

Description

The present invention relates to anilide derivatives and their pharmaceutical uses.

Autoimmune disease is a general term for diseases in which an excessive immune response attacks one's normal cells and tissues to cause symptoms. For example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory disease. Examples include intestinal disease, ankylosing spondylitis, uveitis or rheumatoid arthritis.

Various mechanisms have been proposed for the onset and progression of autoimmune diseases, one of which is Th17 cells, which are one of a subset of helper T cells, and IL-17, which is an inflammatory cytokine produced by them. It is known to play an important role in the onset and progression of autoimmune diseases (Non-Patent Documents 1 and 2).

IL-17 acts on various cells such as fibroblasts, epithelial cells, vascular endothelial cells and macrophages, and is involved in the induction of inflammatory cytokines, chemokines, metalloprotease and other inflammatory mediators and the migration of neutrophils. ing. Therefore, it is considered that a strong anti-inflammatory effect is exhibited if the production or function of IL-17 can be suppressed, and clinical trials of anti-IL-17 antibody for various autoimmune diseases are conducted. Has been done.

In recent years, it has become clear that the nuclear receptor retinoid-related orphan receptor γ (hereinafter, RORγ) functions as a transcription factor essential for the differentiation and proliferation of Th17 cells and the expression of IL-17 (non-patented). Document 3), it was shown that by suppressing the expression or function of RORγ, the differentiation and activation of Th17 cells and the production of IL-17 are suppressed (Non-Patent Document 4).

It has been reported that in patients with autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus, etc.), the expression level of RORγ in peripheral blood mononuclear cells is higher than that in healthy subjects (Non-Patent Document 5). And 6). It has been reported that RORγ knockout mice suppress the pathophysiology of the mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, and suppress the symptoms of autoimmune diseases such as colitis. (Non-Patent Documents 3 and 7).

Furthermore, it has been suggested that binding of RORγ to a coactivator is necessary for RORγ to function as a transcription factor (Non-Patent Document 8). Therefore, RORγ antagonists, which are compounds that inhibit the binding of RORγ to coactivators, are expected to be useful as therapeutic or prophylactic agents for autoimmune diseases.

On the other hand, as a RORγ antagonist, N- (5- (N- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl) sulfamoyl) has been used so far. -4-Methylthiazole-2-yl) acetamide (Non-Patent Document 9) and 6- (2-chloro-4-methylphenyl) -3- (4-cyclopropyl-5- (3-neopentylcyclobutyl)) Substituted azole derivatives such as isooxazole-3-yl) -5-oxohexanoic acid (Patent Document 1) and N- (2-chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl). ] -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamido (Patent Document 2), 2- (4- (2- (4- (ethylsulfonyl) phenyl) acetamido) phenyl) -N- ( 4-Fluorophenyl) -2-methylpropanamide (Patent Document 3), N- (3-chloro-4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) ) Phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide (Patent Document 4) and 2- (4- (ethylsulfonyl) phenyl) -N- (4- (1,1,1,3,3) A sulfonylbenzene derivative such as 3-hexafluoro-2- (3-methylpiperidin-1-yl) propan-2-yl) phenyl) acetamide (Patent Document 5) and 1-acetyl-N- (2-chloro-2). Biaryl derivatives such as'-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidin-2-carboxamide have been reported (Patent Document 6).

Further, as a compound having an anilide structure such as 3-position substituted N- (4- (3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) acetamide, as a positive allosteric modulator of metabolic glutamate receptor type 1. , N- (3-Chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) -3-methylfuran-2-carboxamide, etc. have been reported (Non-Patent Document 10), 3-position substitution. Compounds having an anilide structure such as N- (4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) acetamide include fibroblast growth factor receptor 1 inhibitors and fibroblasts. As a growth factor receptor 2 inhibitor, N- (4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) -3- (trifluoromethyl) phenyl) -3- (isoquinolin-4-) Ilethynyl) -4-methylbenzamide and the like have been reported (Patent Document 7), and as a compound having an anilide structure such as 3-position substituted N- (4- (isoindoline-2-ylmethyl) phenyl) acetamide, fibroblast proliferation N- (4- (isoindoline-2-ylmethyl) -3- (trifluoromethyl) phenyl) -3- (isoquinolin-4-) as a factor receptor 1 inhibitor and a fibroblast proliferation factor receptor 2 inhibitor Ilethynyl) -4-methylbenzamide and the like have been reported (Patent Document 7), and as a compound having an anilide structure such as 3-position substituted N- (4- (indoline-1-ylmethyl) phenyl) acetamide, as a serine protease inhibitor. , 5'-Acetylamino-2'-(5-carbamimideyl-2,3-dihydro-indole-1-ylmethyl) -biphenyl-2-carboxylic acid and the like have been reported (Patent Document 8). No disclosure or suggestion has been made of the effects of these compounds on RORγ.

Japanese Unexamined Patent Publication No. 2012-236822 International Publication No. 2013/0293338 International Publication No. 2017/010399 International Publication No. 2015/082533 International Publication No. 2015/145371 International Publication No. 2017/131156 International Publication No. 2014/194667 International Publication No. 2004/094372

Chen et al., International Immunopharmacology, 2011, Vol. 11, p. 536-542 Hofmann et al., Currant Opinion in Allergy and Clinical Immunology, 2016, Vol. 16, p. 451-457 Ivanov et al., Cell, 2006, Vol. 126, p. 1121-1133 Jetten, Nuclear Receptor Signaling, 2009, Volume 7, e003 Hamzaoui et al., Medical Science Controller, 2011, Vol. 17, p. CR227-234 Ma et al., Journal of the European Journal of Dermatology and Venerology, 2014, Vol. 28, p. 1079-1086 Leppkes et al., Gastroenterology, 2009, Vol. 136, p. 257-267 Jin et al., Molecular Endocrinology, 2010, Vol. 24, p. 923-929 Salt et al., Nature, 2011, Vol. 472, p. 491-494 Garcia-Barrantes et al., Bioorganic & Medicinal Chemistry Letters, 2016, Vol. 26, p. 1869-1872

However, in the actual treatment of autoimmune diseases, steroids or immunosuppressants that act on the entire immune system are used as internal medicines, and sufficient efficacy is recognized due to concerns about serious side effects such as infectious diseases. At present, there are many clinical cases in which administration must be discontinued before it is administered. Therefore, the development of new drugs targeting molecules that play an important role in the onset and progression mechanism of autoimmune diseases is eagerly desired.

Therefore, an object of the present invention is to provide a novel compound having RORγ antagonist activity and exerting a therapeutic effect or a preventive effect on autoimmune diseases such as psoriasis.

As a result of intensive studies to solve the above problems, the present inventors have found a novel anilide derivative having RORγ antagonist activity, and have completed the present invention.

That is, the present invention provides an anilide derivative represented by the following general formula (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof.
[In the formula, R ¹ represents a halogen atom, and R ² is a hydrogen atom or a methyl group (the methyl group may have 1 to 3 arbitrary hydrogen atoms substituted with halogen atoms). , M represents 0 or 1, n represents 0 or 1, and p represents 1 or 2. ]

In the anilide derivative represented by the above general formula (I), R ¹ is a fluorine atom or a chlorine atom, and R ² is a hydrogen atom or a methyl group (the methyl group is any one to three hydrogen atoms). The atom may be substituted with a fluorine atom or a chlorine atom).

In this case, higher RORγ antagonist activity can be expected.

Further, in the anilide derivative represented by the above general formula (I), R ¹ is a fluorine atom or a chlorine atom, and R ² is a methyl group (the methyl group is an arbitrary hydrogen atom of 1 to 3). May be substituted with a fluorine atom.) Is more preferable.

In this case, higher RORγ antagonist activity can be expected, and further excellent therapeutic or preventive effect in autoimmune diseases such as psoriasis can be expected.

Further, in the anilide derivative represented by the above general formula (I), R ¹ is a fluorine atom or a chlorine atom, R ² is a trifluoromethyl group, n is 1, and p is 2. Is more preferable.

In this case, higher RORγ antagonist activity and stronger IL-17 production inhibitory action can be expected, and further excellent therapeutic or preventive effect in autoimmune diseases such as psoriasis can be expected.

The present invention also provides a pharmaceutical and a RORγ antagonist containing, as an active ingredient, an anilide derivative represented by the above general formula (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof.

The above-mentioned medicine is preferably a therapeutic agent or a preventive agent for an autoimmune disease, and more preferably a therapeutic agent or a preventive agent for psoriasis as the therapeutic agent or a preventive agent for the above-mentioned autoimmune disease.

Since the anilide derivative of the present invention or a hydrate thereof, or a pharmacologically acceptable salt thereof has RORγ antagonist activity, the function of RORγ can be effectively suppressed, and a therapeutic agent or prevention for autoimmune diseases can be achieved. Can be used as an agent.

It is a figure which shows the inhibitory effect of the compound of Example 4 on the increase of auricular thickness in the imiquimod-induced mouse psoriasis model.

The anilide derivative of the present invention is characterized by being represented by the following general formula (I).
[In the formula, R ¹ represents a halogen atom, and R ² is a hydrogen atom or a methyl group (the methyl group may have 1 to 3 arbitrary hydrogen atoms substituted with halogen atoms). , M represents 0 or 1, n represents 0 or 1, and p represents 1 or 2. ]

Unless otherwise noted, the following terms as used herein are as defined below.

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

"Methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom)" means that 1 to 3 arbitrary hydrogen atoms of the methyl group are substituted. Each independently means a group which may be substituted with the above-mentioned halogen atom, and examples thereof include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group or a trichloromethyl group.

"Methyl group (the methyl group may have 1 to 3 arbitrary hydrogen atoms substituted with a fluorine atom or a chlorine atom)" means 1 to 3 arbitrary hydrogen atoms of the methyl group. It means a group in which each atom may be independently substituted with a fluorine atom or a chlorine atom, and examples thereof include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group or a trichloromethyl group.

"Methyl group (the methyl group may have 1 to 3 arbitrary hydrogen atoms substituted with fluorine atoms)" means that 1 to 3 arbitrary hydrogen atoms of the methyl group are substituted. It means a group which may be substituted with a fluorine atom, and specifically, it means a methyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

The "anilide derivative represented by the general formula (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof" is an anilide derivative represented by the general formula (I), the general formula (I). Hydrate of the anilide derivative shown, pharmacologically acceptable salt of the anilide derivative represented by the general formula (I) or hydrate of the anilide derivative represented by the general formula (I) is pharmacologically acceptable. Means salt.

In the above-mentioned anilide derivative, in the general formula (I), R ¹ is preferably a fluorine atom or a chlorine atom.

R ² is a hydrogen atom or a methyl group (the methyl group, one to three arbitrary hydrogen atom of a fluorine atom or a chlorine atom may be substituted.) Is preferably a methyl group (the The methyl group is more preferably 1 to 3 arbitrary hydrogen atoms substituted with a fluorine atom), and even more preferably a trifluoromethyl group.

n is preferably 1.

p is preferably 2.

Examples of the combination of n and p include a combination in which n is 1 and p is 2 (tetrahydroisoquinoline ring), a combination in which n is 0 and p is 2 (indoline ring), or n is 1. The combination (isoquinoline ring) in which p is 1 is mentioned.

In the anilide derivative represented by the above general formula (I), when n is 1 and p is 2 (tetrahydroisoindoline ring), R ² is replaced with the 6-position or 7-position of the tetrahydroisoindoline ring. When n is 0 and p is 2 (isoindoline ring), R ² is preferably substituted at the 5-position of the indoline ring, n is 1 and p. When is 1 (isoindoline ring), R ² is preferably substituted at the 5-position of the isoindoline ring.

In the anilide derivative represented by the above general formula (I), any embodiment can be selected and combined with respect to the above-mentioned preferable R ¹ , the above-mentioned preferable R ² , the above-mentioned preferable n, and the above-mentioned preferable p.

Specific examples of preferable compounds of the anilide derivative represented by the above general formula (I) are shown in Table 1, but the present invention is not limited thereto.

The compounds listed in Table 1 also include their hydrates and their pharmacologically acceptable salts and mixtures thereof.

In the anilide derivative represented by the above general formula (I), when a stereoisomer is present, not only a single isomer but also a mixture such as a racemic mixture and a diastereomer mixture is also included in the above general formula (I). Included in the anilide derivative represented by.

"Stereoisomers" refer to compounds having the same chemical structure but different arrangements in three-dimensional space, such as constitutive isomers, rotational isomers, tautomers, optical isomers, and diastereomers. And so on.

Anilide derivative represented by the above general formula (I) may be labeled with one or more isotopes, as isotopes to be labeled, for ^{example, 2 H, 3 H, 13} C, 14 C, Examples include ¹⁵ N, ¹⁵ O, ¹⁸ O and / or ¹²⁵ I.

Examples of the "pharmacologically acceptable salt" of the anilide derivative represented by the above general formula (I) include a salt with an inorganic acid or a salt with an organic acid. Examples of the salt with the inorganic acid include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, and examples of the salt with the organic acid include oxalic acid. Salt, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbic acid Salt, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, asparagate, glutamate or cinnate Examples include acid salts. The same applies to the "pharmacologically acceptable salt" of the hydrate of the anilide derivative represented by the above general formula (I).

The anilide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof may be anhydrous or may form a solvate such as hydrate. Here, as the solvate, a pharmacologically acceptable solvate is preferable. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferred. Examples of the solvent constituting the solvent include alcohol-based solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO), and water.

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

The anilide derivative (I) and the intermediates and starting materials used in its production can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, reprecipitation, recrystallization or chromatography.

When the anilide derivative (I) contains a stereoisomer, each optical isomer or diastereomer can be obtained as a single optically active substance by a known method. Known methods include, for example, crystallization, enzymatic division or chiral chromatography.

Crystallization can be carried out according to a known method (for example, Brittain, HG, "Polymorphism in Physical Solids, Second Edition", CRC Press) or a method similar thereto.

Examples of the solvent used for crystallization of the anilide derivative (I) or its hydrate, or a pharmaceutically acceptable salt thereof include tetrahydrofuran (hereinafter, THF), 1,4-dioxane, diethyl ether, and the like. Ether-based solvents such as tert-butylmethyl ether or anisole, methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, n-propanol, 2-propanol, 2-methyl-1-propanol, n-butanol, 2-butanol , 3-Methyl-1-butanol, n-pentanol or ethylene glycol and other alcoholic solvents, toluene, xylene, cumene or tetralin and other aromatic hydrocarbon solvents, DMF, N, N-dimethylacetamide, formamide, N. -Aprotonic polar solvents such as methylpyrrolidone, DMSO or sulfolane, nitrile solvents such as acetonitrile or propionitrile, ester-based solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate or ethyl formate. Solvents, ketone solvents such as acetone, methyl ethyl ketone, methyl butyl ketone or methyl isobutyl ketone, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane or chlorobenzene, hexane, pentane, With hydrocarbon solvents such as heptane, cyclohexane or methylcyclohexane, nitro solvents such as nitromethane, pyridine solvents such as pyridine, carboxylic acid solvents such as acetic acid or formic acid, water or mixed solvents thereof, or their solvents. Examples thereof include a mixed solvent of the anilide derivative (I) and the solvent containing the base or acid forming the above-mentioned pharmacologically acceptable salt.

In each reaction of the production method described below, when the raw material compound has an amino group or a carboxyl group, a protecting group may be introduced into these groups, and the protecting group is deprotected as necessary after the reaction. By doing so, the target compound can be obtained.

Examples of the amino group protecting group include an alkylcarbonyl group having 2 to 6 carbon atoms (for example, an acetyl group), a benzoyl group, and an alkyloxycarbonyl group having 2 to 8 carbon atoms (for example, tert-butoxycarbonyl group or benzyloxy). Carbonyl group), aralkyl group having 7 to 10 carbon atoms (for example, benzyl group) or phthaloyl group.

Examples of the carboxyl-protecting group include an alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group or a tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group).

Protecting groups are deprotected according to known methods (eg, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or similar methods, depending on the type of protecting group. be able to.

The anilide derivative (I) can be obtained, for example, by a condensation reaction between the aniline derivative (II) and the phenylacetic acid derivative (III) in the presence of a condensing agent and a base, as shown in Scheme 1.
[In the formula, R ¹ , R ² , m, n and p are the same as in the above definition. ]

The amount of the phenylacetic acid derivative (III) used in the condensation reaction is preferably 0.1 to 10 equivalents, more preferably 0.5 to 3 equivalents, relative to the aniline derivative (II).

Examples of the condensing agent used in the condensation reaction include N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (hereinafter, EDC / HCl), and N, N'-carbodiimidazole. , {{[(1-Cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium hexafluorophosphate (COMU), O- (7-azabenzotriazole-) 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU) or O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyl Uronium hexafluorophosphate (hereinafter, HBTU) can be mentioned, but HATU or HBTU is preferable.

The amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aniline derivative (II).

Examples of the base used in the condensation reaction include an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydride or potassium carbonate, a metal hydride compound such as sodium hydride, potassium hydride or calcium hydride, and methyl lithium. Alternatively, alkyl lithium such as butyl lithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof can be mentioned, but an organic base such as triethylamine or diisopropylethylamine is preferable.

The amount of the base used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the aniline derivative (II).

The aniline derivative (II) used in the condensation reaction may be a free form or a salt such as hydrochloride.

The reaction solvent used for the condensation reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction. For example, tetrahydrofuran (hereinafter, THF), 1,4-dioxane, etc. Examples include ether solvents such as ethylene glycol dimethyl ether or dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotonic polar solvents such as DMF or DMSO, and nitrile solvents such as acetonitrile or propionitrile. However, halogen-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or aprotonic polar solvents such as DMF and DMSO are preferable.

The reaction temperature of the condensation reaction is preferably 0 to 200 ° C, more preferably 20 to 100 ° C.

The reaction time of the condensation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the aniline derivative (II) used in the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

The aniline derivative (II) and the phenylacetic acid derivative (III) used in the condensation reaction can be purchased, or can be produced by a known method or a method similar thereto.

Among the aniline derivatives (II) shown in Scheme 1, the aniline derivative (II-a) having m of 1 is, for example, a reduction reaction of the benzoic acid derivative (IV) as shown in Scheme 2 (first step). Subsequently, the oxidation reaction of the benzyl alcohol derivative (V) obtained in the first step (second step), followed by the benzaldehyde derivative (VI) obtained in the second step and the amine derivative (VII). It can be obtained by a reductive amination reaction (third step), followed by a reduction reaction (fourth step) of the nitrophenyl derivative (VIII) obtained in the third step in the presence of metal and acid.
[In the formula, R ¹ , R ² , n and p are the same as in the above definition. ]

(First step)
Examples of the reducing agent used in the reduction reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, lithium borohydride, lithium triethylborohydride or borane THF complex, and borane THF complex is preferable. ..

The amount of the reducing agent used in the reduction reaction is preferably 0.25 to 100 equivalents, more preferably 0.5 to 10 equivalents, relative to the benzoic acid derivative (IV).

The reaction solvent used for 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, THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxyethane Etc., and aromatic hydrocarbon solvents such as benzene and toluene can be mentioned, but ether solvents such as THF, 1,4-dioxane, ethylene glycol dimethyl ether and dimethoxyethane are preferable.

The reaction temperature of the reduction reaction is preferably −78 ° C. to 100 ° C., more preferably −30 ° C. to 50 ° C.

The reaction time of the reduction reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 10 minutes to 10 hours.

The concentration of the benzoic acid derivative (IV) used in the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

The benzoic acid derivative (IV) used in the reduction reaction may be a free form or a salt such as a sodium salt.

The benzoic acid derivative (IV) used in the reduction reaction can be purchased, or can be produced by a known method or a method similar thereto.

(Second step)
Examples of the oxidizing agent used in the oxidation reaction include sulfur trioxide-pyridine, activated dimethyl sulfoxide, desmartin reagent, manganese dioxide or 2,2,6,6-tetramethylpiperidine 1-oxyl (hereinafter, TEMPO). Be done.

The amount of the oxidizing agent used in the oxidation reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, relative to the benzyl alcohol derivative (V).

The reaction solvent used for the oxidation 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, an aromatic amine solvent such as pyridine, dichloromethane, chloroform or 1 , 2-Dichloroethane and other chlorine-based solvents, THF or 1,4-dioxane and other ether-based solvents, acetonitrile or propionitrile and other nitrile-based solvents, or mixed solvents thereof.

The reaction temperature of the oxidation reaction is preferably −78 ° C. to 100 ° C., more preferably −78 ° C. to 60 ° C.

The reaction time of the oxidation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 5 minutes to 72 hours, more preferably 0.5 to 48 hours.

The concentration of the benzyl alcoholic acid derivative (V) used in the oxidation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

(Third step)
The amount of the amine derivative (VII) used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the benzaldehyde derivative (VI).

The amine derivative (VII) used in the reductive amination reaction may be a free form or a salt such as hydrochloride.

Examples of the reducing agent used in the reductive amination reaction include sodium borohydride, sodium cyanoborohydride, and sodium borohydride triacetoxyborohydride, and sodium borohydride is preferred.

The amount of the reducing agent used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the benzaldehyde derivative (VI).

The reaction solvent used for the reductive amination 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, an alcohol solvent such as methanol or ethanol, diethyl ether, etc. , THF, dimethoxyethane or ether solvent such as 1,4-dioxane, chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane or a mixed solvent thereof, and examples thereof include dichloromethane, chloroform or 1,2-dichloroethane. Chloroform solvent such as is preferable.

The reaction temperature of the reductive amination reaction is preferably −78 ° C. to 200 ° C., more preferably −20 ° C. to 100 ° C.

The reaction time of the reductive amination reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 30 hours.

The concentration of the benzaldehyde derivative (VI) used in the reductive amination reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

The amine derivative (VII) used in the reductive amination reaction can be purchased, or can be produced by a known method or a method similar thereto.

(4th step)
Examples of the metal used in the reduction reaction include iron powder and tin (II) chloride, but iron powder is preferable.

The amount of metal used in the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, relative to the nitrophenyl derivative (VIII).

Examples of the acid used in the reduction reaction include acetic acid, hydrochloric acid, and an aqueous solution of ammonium chloride, and an aqueous solution of acetic acid or ammonium chloride is preferable.

The amount of the acid used in the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, relative to the nitrophenyl derivative (VIII).

The reaction solvent used for the reduction reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, diethyl ether, or THF is used. , Dimethoxyethane or ether solvent such as 1,4-dioxane, water or a mixed solvent thereof, and alcohol solvent such as methanol or ethanol and diethyl ether, THF, dimethoxyethane or 1,4-dioxane and the like. A mixed solvent of the ether solvent and water is preferable.

The reaction temperature of the reduction reaction is preferably 0 to 200 ° C, more preferably 50 to 150 ° C.

The reaction time of the reduction reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the nitrophenyl derivative (VIII) used in the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

Among the aniline derivatives (II) shown in Scheme 1, the aniline derivative (II-b) in which m is 0 is, for example, a fluorophenyl derivative (VII) of an amine derivative (VII) in the presence of a base, as shown in Scheme 3. It can be obtained by a nucleophilic substitution reaction (first step) with respect to IX), followed by a reduction reaction (second step) of the nitrophenyl derivative (X) obtained in the first step in the presence of metal and acid.
[In the formula, R ¹ , R ² , n and p are the same as in the above definition. ]

(First step)
The amount of the amine derivative (VII) used in the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the fluorophenyl derivative (IX).

The amine derivative (VII) used in the nucleophilic substitution reaction may be a free form or a salt such as hydrochloride.

Examples of the base used for the nucleophilic substitution reaction include organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine, inorganic bases such as sodium carbonate or potassium carbonate, and hydrogen such as sodium hydride, potassium hydride or calcium hydride. Examples include metal compounds, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, metal alkoxides such as tert-butyloxysodium or tert-butyloxypotassium, or mixtures thereof, including triethylamine, diisopropylethylamine or N-. Organic bases such as methylmorpholin or metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride are preferred.

The amount of the base used in the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the fluorophenyl derivative (IX).

The reaction solvent used for the nucleophilic substitution reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction. For example, THF, 1,4-dioxane, ethylene glycol dimethyl ether Alternatively, an ether solvent such as dimethoxyethane, a nitrile solvent such as acetonitrile or propionitrile, an aromatic hydrocarbon solvent such as benzene or toluene, an aprotonic polar solvent such as DMF or DMSO, water or a mixed solvent thereof may be used. Although mentioned, an aprotic polar solvent such as DMF or DMSO is preferable.

The reaction temperature of the nucleophilic substitution reaction is preferably −78 ° C. to 200 ° C., more preferably −20 ° C. to 160 ° C.

The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the fluorophenyl derivative (IX) used in the nucleophilic substitution reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

The fluorophenyl derivative (IX) and amine derivative (VII) used in the nucleophilic substitution reaction can be purchased or can be produced by a known method or a method similar thereto.

(Second step)
Examples of the metal used in the reduction reaction include iron powder and tin (II) chloride, but iron powder is preferable.

The amount of the metal used in the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, relative to the nitrophenyl derivative (X).

Examples of the acid used in the reduction reaction include acetic acid, hydrochloric acid, and an aqueous solution of ammonium chloride, and an aqueous solution of acetic acid or ammonium chloride is preferable.

The amount of acid used in the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, relative to the nitrophenyl derivative (X).

The reaction solvent used for the reduction reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, diethyl ether, or THF is used. , Dimethoxyethane or ether solvent such as 1,4-dioxane, water or a mixed solvent thereof, and alcohol solvent such as methanol or ethanol and diethyl ether, THF, dimethoxyethane or 1,4-dioxane and the like. A mixed solvent of the ether solvent and water is preferable.

The reaction temperature of the reduction reaction is preferably 0 to 200 ° C, more preferably 50 to 150 ° C.

The reaction time of the reduction reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the nitrophenyl derivative (X) used in the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

Among the amine derivatives (VII) shown in Schemes 2 and 3, the tetrahydroisoquinoline derivative (VII-a) having n of 1 and p of 2 is, for example, trifluoroacetic anhydride as shown in Scheme 4. Trifluoroacetylation reaction of phenethylamine derivative (XI) (first step), followed by cyclization reaction of trifluoroacetamide derivative (XII) obtained in first step in the presence of paraformaldehyde and acid (second step) ), Subsequently, it can be obtained by the hydrolysis reaction (third step) of the tetrahydroisoquinoline derivative (XIII) obtained in the second step.
[In the formula, R ² is the same as the above definition. ]

(First step)
The amount of trifluoroacetic anhydride used in the trifluoroacetylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the phenethylamine derivative (XI).

The reaction solvent used in the trifluoroacetylation 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, DMF, N, N-dimethylacetamide, N. -Aprotonic polar solvents such as methyl-2-pyrrolidone or DMSO, ether solvents such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or Examples thereof include a chlorine-based solvent such as 1,2-dichloroethane or a mixed solvent thereof, and a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane is preferable.

The reaction temperature of the trifluoroacetylation reaction is preferably −20 ° C. to 100 ° C., more preferably 0 to 50 ° C.

The reaction time of the trifluoroacetylation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the phenethylamine derivative (XI) used in the trifluoroacetylation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

The phenethylamine derivative (XI) used in the trifluoroacetylation reaction may be a free form or a salt such as hydrochloride.

The phenethylamine derivative (XI) used in the trifluoroacetylation reaction can be purchased, or can be produced by a known method or a method similar thereto.

(Second step)
The amount of paraformaldehyde used in the cyclization reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the trifluoroacetamide derivative (XII).

Examples of the acid used in the cyclization reaction include hydrochloric acid, acetic acid, trifluoroacetic acid, concentrated sulfuric acid, concentrated nitric acid, phosphoric acid and the like, and a mixed solution of acetic acid and concentrated sulfuric acid is preferable.

The amount of acid used in the cyclization reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 50 equivalents, relative to the trifluoroacetamide derivative (XII).

The reaction solvent used for the cyclization 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, DMF, N, N-dimethylacetamide, N-methyl- Aprotic polar solvents such as 2-pyrrolidone or DMSO, ether solvents such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixtures thereof. Solvents can be mentioned.

The reaction temperature of the cyclization reaction is preferably −20 ° C. to 100 ° C., more preferably 0 to 50 ° C.

The reaction time of the cyclization reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the trifluoroacetamide derivative (XII) used in the cyclization reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

(Third step)
Examples of the base used in the hydrolysis reaction include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide and potassium carbonate.

The amount of the base used in the hydrolysis reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 20 equivalents, relative to the tetrahydroisoquinoline derivative (XIII).

The reaction solvent used in the hydrolysis 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, an alcohol solvent such as methanol or ethanol, acetonitrile or pro. A nitrile solvent such as pionitrile, an aprotonic polar solvent such as DMF, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or DMSO, an ether such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane. Examples thereof include a system solvent, an ester solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof, and an alcohol solvent such as methanol or ethanol, DMF, N. , N-Dimethylacetamide, N-methyl-2-pyrrolidone, DMSO and other aprotonic polar solvents, or diethyl ether, THF, dimethoxyethane or 1,4-dioxane and other ether solvents are preferred.

The reaction temperature of the hydrolysis reaction is preferably −20 ° C. to 200 ° C., more preferably 0 to 150 ° C.

The reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the tetrahydroisoquinoline derivative (XIII) used in the hydrolysis reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

The medicament, the RORγ antagonist, and the therapeutic or prophylactic agent for autoimmune diseases of the present invention contain the anilide derivative (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient. It is characterized by that. The autoimmune disease described above is preferably psoriasis.

The "RORγ antagonist" means a compound having an action of suppressing the function of RORγ and eliminating or attenuating its activity.

"Autoimmune disease" is a general term for diseases in which an excessive immune reaction attacks one's normal cells and tissues, causing symptoms. For example, polysclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. , Inflammatory bowel disease, ankylosing spondylitis, uveitis, rheumatoid polymyositis, scleroderma, vasculitis, lupus, lupus or dermatomyositis. In addition, the autoimmune diseases of the present invention include acne, vitiligo or alopecia areata.

An "allergic disease" is a disease caused by an excessive immune response to a specific antigen, for example, allergic dermatitis, contact dermatitis, atopic dermatitis, allergic rhinitis (pollen). Diseases), allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma or food allergies.

"Psoriasis" is an inflammatory disease of the skin with infiltration and activation of immune cells and associated epidermal thickening. Typically, white scales are thickly attached to the red rash in various places throughout the body, causing the symptoms of desquamation. Examples of psoriasis include psoriasis vulgaris, pustular psoriasis, psoriatic arthritis, guttate psoriasis, and psoriatic erythroderma.

Anilide derivative (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof, is characterized by suppressing the function of RORγ by inhibiting the binding of RORγ to a coactivator. .. Since it is known that RORγ is involved in various diseases and that suppression of its function can be expected to improve the pathological condition or ameliorate the symptoms, anilide derivative (I) or its hydrate, or a drug thereof. Physiologically acceptable salts can be used as medicines for diseases that can be expected to improve the condition or relieve symptoms by suppressing the function of RORγ, especially as therapeutic or prophylactic agents for autoimmune diseases or allergic diseases. it can. The therapeutic or prophylactic agents for the above autoimmune diseases are preferably polysclerosis, psoriasis, rheumatoid arthritis, systemic erythematosus, inflammatory bowel disease, ankylosing spondylitis, vaginitis, rheumatoid polymyopathy. It can be used as a therapeutic or prophylactic agent for pemphigus, ankylosing spondylitis, vasculitis, pemphigus, pemphigus, dermatomyitis, acne, leukoplakia or alopecia, and more preferably a therapeutic or prophylactic agent for psoriasis. Can be used as.

The fact that the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof, has a RORγ antagonist activity that inhibits the binding of RORγ to a coactivator was evaluated using an in vitro test. it can. Examples of in vitro tests include a method for evaluating the binding between RORγ and an agonist (for example, cholesterol) (International Publication No. 2012/158784, International Publication No. 2013/018695), a ligand binding domain of RORγ and a coactivator. Methods for assessing binding to the beta include (International Publication No. 2012/064744, International Publication No. 2013/018695). In addition, the transcriptional activity inhibitory action of RORγ can be evaluated using various reporter gene assays (International Publication No. 2012/158784, International Publication No. 2012/064744, International Publication No. 2013/018695).

Anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof, suppresses the function of RORγ by using lymphocyte cells derived from various organs such as spleen or peripheral blood. The production of IL-17 or Th17 cell differentiation can be used as an index for evaluation. Examples of the method using IL-17 production as an index include a method of measuring IL-17 production stimulated by IL-23 using mouse splenocytes (The Journal of Biological Chemistry, 2003, Vol. 278). , No. 3, p. 1910-1914). As a method using Th17 cell differentiation as an index, for example, various cytokines (for example, IL-1β, IL-6, IL-23 and / or TGF) are used using mouse splenocytes or CD4-positive nive T cells derived from human PBMC. -Β) and various antibodies (eg, anti-CD3 antibody, anti-CD28 antibody, anti-IL-4 antibody, anti-IFN-γ antibody and / or anti-IL-2 antibody) to differentiate into Th17 and produce IL-17. Examples thereof include a method of measuring the amount or the proportion of IL-17-positive cells (International Publication No. 2012/158784, International Publication No. 2013/018695).

The effectiveness of the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof for the treatment or prevention of autoimmune diseases can be evaluated using a pathological model. Examples of the pathological model include an experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, Vol. 84, p.1225-1234), and an imikimod-induced psoriasis model (Journal of Immunology, 2009, 182). Volume, p.5836-5845), Collagen Arthritis Model (Annual Review of Immunology, 1984, Volume 2, p.199-218), Spontaneous Model of Systemic Lupus Erythematosus (Nature, 2000, Volume 404, p. 995-999), TNBS-induced colitis model (European Journal of Pharmacology, 2001, Vol. 431, p. 103-110), Scleroderma model (Artris Research & Therapy, 2012, Vol. 14, p. .253-265), Experimental Autoimmune Immunology Model (Journal of Immunology, 2006, Vol. 36, p. 3071-3081), Scleroderma Model (Journal of Investigative Dermatology, 1999, Vol. 112). , P.456-462), The Journal of Clinical Investment, 2002, Vol. 110, p.955-963), The Journal of Clinical Investment, 2000, Vol. 105, p. .625-631), Model of Scleroderma (Experimental Dermatology, 2012, Vol. 21, p.901-905), Model of Dermatitis (American Journal of Pathology, 1985, Vol. 120, p.323-325). , Scleroderma model of psoriasis (European Journal of Dermatology, 2005, Vol. 15, p.459-464), White spot model (Pigment Cell & Melanoma Research, 2014, Vol. 27, p.1075-185) or , Journal of Investigative Dermatology, 2015, Vol. 135, p. .. 2530-2532). The experimental autoimmune encephalomyelitis model is a common model for multiple sclerosis. In addition, the imiquimod-induced psoriasis model is a common model for psoriasis.

Moreover, it can be evaluated by using a pathological model that the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof is effective for the treatment or prevention of allergic diseases. Examples of the pathological condition model include a dinitrofluorobenzene (DNFB) -induced allergic dermatitis model (Pharmacological Reports, 2013, Vol. 65, p. 1237-1246), and an oxazolone-induced atopic dermatitis model (Journal of Investigative). Dermatology, 2014, Vol. 134, p.2122-2130), Egguloalbumin-induced allergic rhinitis model (Journal of Animal Science, 2010, Vol. 81, p.699-705), IgE-induced allergic conjunctivitis model ( British Journal of Ofthalmogy, 2012, Vol. 96, p.1332-1336), Allergic Gastroenteritis Model (Gastroenterology, 1997, Vol. 113, p.1560-1569), Eggerobalbumin-induced asthma model (American Journal). Respiratory and Critical Care Medicine, 1997, Vol. 156, p.766-775), or the egg white albumin-induced food allergy model (Clinical & Experimental Allergy, 2005, Vol. 35, p.461-466). .. The DNFB-induced allergic dermatitis model is common as a model for allergic dermatitis, especially as a contact dermatitis model. In addition, the oxazolone-induced atopic dermatitis model is common as a model of atopic dermatitis.

The efficacy of the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof, for the treatment or prevention of autoimmune or allergic diseases has been demonstrated using, for example, the in vitro test described above. , The decrease in the amount of binding between the ligand-binding domain of RORγ and the coactivator, or the decrease in the amount of IL-17 produced, which is an index of the function of RORγ, can be evaluated as an index. In addition, the effectiveness for the treatment or prevention of multiple sclerosis is determined by using the above experimental autoimmune encephalomyelitis model, for example, by using a decrease in the neurological symptom score, which is a characteristic index of multiple sclerosis, as an index. Can be evaluated. In addition, the effectiveness for the treatment or prevention of psoriasis can be evaluated using the above-mentioned imiquimod-induced psoriasis model, for example, by using the decrease in skin thickness such as the pinna, which increases as the symptoms of the psoriasis model progress, as an index. it can. In addition, the effectiveness for the treatment or prevention of allergic dermatitis, particularly contact dermatitis, is increased by using the above-mentioned DNFB-induced allergic dermatitis model, for example, in the pinna, etc., which increases with the progression of skin inflammatory conditions. The decrease in skin thickness can be evaluated as an index. In addition, the effectiveness for the treatment or prevention of atopic dermatitis is that the above-mentioned oxazolone-induced atopic dermatitis model is used to reduce the thickness of the skin such as the auricle, which increases as the skin inflammation progresses. It can be evaluated as an index.

Anilide derivatives (I) or hydrates thereof, or pharmacologically acceptable salts thereof, are mammals (eg, mice, rats, hamsters, rabbits, dogs, cats, monkeys, cows, sheep or humans). , Especially when administered to humans, can be used as a useful drug (particularly, a therapeutic or prophylactic agent for autoimmune diseases or allergic diseases). When the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof is used clinically as a medicine, the anilide derivative (I) or its hydrate, or a drug thereof The physically acceptable salt can be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier. The above-mentioned medicines include binders, excipients, lubricants, disintegrants, sweeteners, stabilizers, flavoring agents, fragrances, colorants, fluidizers, preservatives, buffers, and dissolution aids, as required. Additives such as agents, emulsifiers, surfactants, suspending agents, diluents or tonicity agents may be appropriately mixed. Pharmacologically acceptable carriers include these additives. In addition, the above-mentioned pharmaceuticals can be produced by a usual method using these pharmaceutical carriers as appropriate. Examples of the administration form of the above-mentioned pharmaceuticals include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or topical administration. Examples include ointments, creams or patches. Further, it may be a known long-acting preparation.

Binders include, for example, syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride or tragant.

Excipients include, for example, sugar, lactose, cornstarch, calcium phosphate, sorbitol or glycine.

Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc or silica.

Disintegrants include, for example, starch or calcium carbonate.

Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.

The above-mentioned pharmaceuticals preferably contain 0.00001 to 90% by weight, preferably 0.01 to 70% by weight, of the anilide derivative (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof. It is more preferable to do so. The dose is appropriately selected according to the patient's symptoms, age and body weight, and administration method, but the amount of active ingredient for adults is 0.1 μg to 1 g per day for injections and 1 for oral preparations. It is preferably 1 μg to 10 g per day, and in the case of a patch, 1 μg to 10 g per day is preferable, and each can be administered once or in several divided doses.

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

The present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited thereto.

Commercially available compounds were used for the compounds used in the synthesis of the compounds of Reference Examples and Examples, for which the synthesis method was not described. The "room temperature" in the following reference examples and examples usually indicates about 10 ° C to about 35 ° C. % Shows mol / mol% for yield,% by volume for solvents used in column chromatography and high performance liquid chromatography, and% by weight for others unless otherwise specified. 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.) or a JNM-ECS400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is expressed in δ (unit: ppm) with reference to tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), and quint, respectively. (Five-fold line), sept (seven-fold line), m (multiple line), br (wide), dd (double double line), dt (double triple line), ddd (double double double line) , Dq (double quadruple line), tt (triple double line), tt (triple triple line). If the protons such as hydroxyl groups and amino groups have very gentle peaks, they are not described. ESI-MS spectra were measured using Agilent Technologies 1200 Series, G6130A (Agilent Technologies). Silica gel 60 (Merck & Co., Ltd.) was used as silica gel, amine silica gel DM1020 (Fuji Silysia Chemical Ltd.) was used as amine silica gel, and YFLC W-prep2XY (Yamazen) was used for chromatography.

(Reference Example 1) Synthesis of 2-chloro-4-nitrobenzaldehyde:
2-Chloro-4-nitrobenzoic acid (10.0 g, 49.6 mmol) is dissolved in THF (99.2 mL) and borane THF complex-THF solution (0.95 M, 62.7 mL, 59.5 mmol) is 0. The mixture was added at ° C. and heated to room temperature. After stirring at 50 ° C. for 2 hours, the reaction solution was added to 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was used in the subsequent reaction without purification.
The above crude product was dissolved in chloroform (99.2 mL) and manganese dioxide (32.3 g, 372 mmol) was added at room temperature. After stirring at 50 ° C. for 24 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 1) (8.37 g, 45.1 mmol, 91%) as a pale yellow solid. It was.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.11 (d, J = 8.2 Hz, 1H), 8.23 (dd, J = 8.2, 1.8 Hz, 1H), 8.36 ( d, J = 1.8Hz, 1H), 10.55 (s, 1H).

(Reference Example 2) Synthesis of 2-fluoro-4-nitrobenzaldehyde:
2-Fluoro-4-nitrobenzoic acid (1.00 g, 5.40 mmol) is dissolved in THF (10.1 mL), and borane THF complex-THF solution (0.90 M, 9.00 mL, 8.10 mmol) is 0. Added at ° C. After stirring at room temperature for 2 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was used in the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (15.2 mL), saturated aqueous sodium hydrogen carbonate solution (15.2 mL), potassium bromide (0.181 g, 1.52 mmol), TEMPO (0.0048 g, 0.030 mmol). And a 6 wt% sodium hypochlorite aqueous solution (1.89 mL) was added at 0 ° C. After stirring at the same temperature for 3 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium thiosulfate solution, distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 90/10), and the title compound (hereinafter, the compound of Reference Example 2) (0.128 g, 0.757 mmol, 14) was purified. %) Was obtained as a yellow solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.07-8.11 (m, 2H), 8.14-8.17 (m, 1H), 10.45 (s, 1H).

(Reference Example 3) Synthesis of 2,2,2-trifluoro-N- (4-methylphenethyl) acetamide:
2- (4-Methylphenyl) ethylamine (0.532 mL, 3.70 mmol) was dissolved in dichloromethane (12.3 mL) and trifluoroacetic anhydride (0.575 mL, 4.07 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15), and the title compound (hereinafter, hereinafter, The compound of Reference Example 3) (0.525 g, 2.27 mmol, 61%) was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 2.34 (s, 3H), 2.85 (t, J = 6.9Hz, 2H), 3.60 (q, J = 6.6Hz, 2H) , 6.28 (brs, 1H), 7.08 (d, J = 8.2Hz, 2H), 7.15 (d, J = 7.8Hz, 2H).
ESI-MS: m / z = 232 (M + H) ⁺ .

(Reference Example 4) Synthesis of 2,2,2-trifluoro-1- (7-methyl-3,4-dihydroisoquinoline-2 (1H) -yl) ethane-1-one:
To a mixed solution of concentrated sulfuric acid (0.454 mL) and acetic acid (2.27 mL), the compound of Reference Example 3 (0.525 g, 2.27 mmol) and paraformaldehyde (0.102 g, 3.41 mmol) were added at 0 ° C. It was. After stirring at room temperature for 36 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 80/20), and the title compound (hereinafter, the compound of Reference Example 4) (0.335 g, 1.38 mmol, 61) was purified. %) Was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.33 (s, 3H), 2.91 (q, J = 5.8 Hz, 2H), 3.83 (t, J = 5.9 Hz, 1. 3H), 3.87 (t, J = 6.2Hz, 0.7H), 4.71 (s, 0.7H), 4.76 (s, 1.3H), 6.95 (d, J = 11.9Hz, 1H), 7.06 (d, J = 10.1Hz, 2H).

(Reference Example 5) Synthesis of 7-methyl-1,2,3,4-tetrahydroisoquinoline:
The compound of Reference Example 4 (0.335 g, 1.38 mmol) was dissolved in ethanol (4.17 mL), and a 2 M aqueous sodium hydroxide solution (3.79 mL) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 5) (0.185 g, 1.26 mmol, 91%). Obtained as a colorless oil.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 2.29 (s, 3H), 2.75 (t, J = 5.7Hz, 2H), 3.12 (t, J = 5.9Hz, 2H) , 3.98 (s, 2H), 6.83 (s, 1H), 6.95 (d, J = 7.3Hz, 1H), 6.99 (d, J = 7.8Hz, 1H).
ESI-MS: m / z = 148 (M + H) ⁺ .

(Reference Example 6) Synthesis of 2- (2-chloro-4-nitrobenzyl) -7-methyl-1,2,3,4-tetrahydroisoquinoline:
The compound of Reference Example 5 (0.184 g, 1.25 mmol) was dissolved in dichloromethane (3.75 mL), and the compound of Reference Example 1 (0.230 g, 1.25 mmol) and acetic acid (0.0354 mL) were added at room temperature. It was. After stirring at room temperature for 10 minutes, sodium borohydride triacetoxyboron (0.393 g, 1.86 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15), and the title compound (hereinafter, the compound of Reference Example 6) (0.349 g, 1.01 mmol, 89) was purified. %) Was obtained as a yellow solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.29 (s, 3H), 2.81 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 5.7 Hz, 2H) , 3.69 (s, 2H), 3.85 (s, 2H), 6.83 (s, 1H), 6.98 (d, J = 7.7Hz, 1H), 7.04 (d, J) = 7.7Hz, 1H), 7.84 (d, J = 8.6Hz, 1H), 8.11 (dd, J = 8.6, 2.3Hz, 1H), 8.26 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 317 (M + H) ⁺ .

(Reference Example 7) Synthesis of 3-chloro-4-((7-methyl-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) aniline:
The compound of Reference Example 6 (0.335 g, 1.06 mmol) was dissolved in THF (1.06 mL), and ethanol (1.06 mL), distilled water (1.06 mL), iron powder (0.295 g, 5.29 mmol) were dissolved. ) And acetic acid (0.303 mL, 5.29 mmol) were added at room temperature. After stirring at 50 ° C. for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 65/35), and the title compound (hereinafter, the compound of Reference Example 7) (0.271 g, 0.945 mmol, 89) was purified. %) Was obtained as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.27 (s, 3H), 2.76 (t, J = 5.7 Hz, 2H), 2.85 (t, J = 5.7 Hz, 2H) , 3.63 (s, 2H), 3.68 (s, 4H), 6.56 (dd, J = 8.4, 2.5Hz, 1H), 6.71 (d, J = 2.3Hz, 1H), 6.82 (s, 1H), 6.93 (d, J = 8.2Hz, 1H), 6.99 (d, J = 7.2Hz, 1H), 7.28 (d, J = 8.6Hz, 1H).
ESI-MS: m / z = 287 (M + H) ⁺ .

(Reference Example 8) Synthesis of 2- (4- (ethylsulfonyl) phenyl) ethyl acetate:
4-Mercaptophenylacetic acid (15.0 g, 89.2 mmol) was dissolved in DMF (111 mL) and potassium carbonate (49.3 g, 357 mmol) and bromoethane (20.0 mL, 268 mmol) were added at 0 ° C. After stirring at room temperature for 3 hours, distilled water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was used in the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (297 mL) and metachloroperbenzoic acid (46.2 g, 267 mmol) was added at 0 ° C. After stirring at room temperature for 16 hours, the reaction solution was filtered, the filtrate was washed with 1 M aqueous sodium hydroxide solution, distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was reprecipitated with n-hexane / ethyl acetate to give the title compound (hereinafter, the compound of Reference Example 8) (18.2 g, 71.1 mmol, 80%) as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.4Hz, 3H), 1.27 (t, J = 7.1Hz, 3H), 3.12 (q, J = 7.4Hz, 2H), 3.72 (s, 2H), 4.18 (q, J = 7.1Hz, 2H), 7.50 (d, J = 8.2Hz, 2H), 7.87 ( d, J = 8.2Hz, 2H).

(Reference Example 9) Synthesis of 2- (4- (ethylsulfonyl) phenyl) acetic acid:
The compound of Reference Example 8 (18.2 g, 71.1 mmol) was dissolved in ethanol (131 mL) and distilled water (131 mL), and sodium hydroxide (10.8 g, 270 mmol) was added at 0 ° C. After stirring at room temperature for 14 hours, concentrated hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether to give the title compound (hereinafter, the compound of Reference Example 9) (15.1 g, 66.0 mmol, 93%) as a white solid.
^{1 1} H-NMR (400MHz, DMSO-D ₆ ) δ: 1.09 (t, J = 7.5Hz, 3H), 3.28 (q, J = 7.5Hz, 2H), 3.74 (s, 2H), 7.54 (d, J = 8.6Hz, 2H), 7.82 (d, J = 8.6Hz, 2H).

(Example 1) N- (3-chloro-4-((7-methyl-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) Synthesis of acetamide:
The compound of Reference Example 7 (0.0400 g, 0.139 mmol) and the compound of Reference Example 9 (0.0382 g, 0.167 mmol) were dissolved in DMF (0.465 mL), and HATU (0.0636 g, 0.167 mmol) was dissolved. And diisopropylethylamine (0.0365 mL, 0.209 mmol) was added at room temperature. After stirring at the same temperature for 2 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 to 25/75), and the title compound (hereinafter, the compound of Example 1) (0.0375 g, 0.0754 mmol, 54) was purified. %) Was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5Hz, 3H), 2.27 (s, 3H), 2.76 (t, J = 5.7Hz, 2H) , 2.85 (t, J = 5.9Hz, 2H), 3.13 (q, J = 7.5Hz, 2H), 3.63 (s, 2H), 3.73 (s, 2H), 3 .81 (s, 2H), 6.81 (s, 1H), 6.95 (d, J = 8.7Hz, 1H), 7.00 (d, J = 7.8Hz, 1H), 7.16 (S, 1H), 7.50 (d, J = 8.7Hz, 1H), 7.56 (d, J = 8.2Hz, 2H), 7.66 (d, J = 2.3Hz, 1H) , 7.92 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 497 (M + H) ⁺ .

(Reference Example 10) Synthesis of 2,2,2-trifluoro-N- (4- (trifluoromethyl) phenethyl) acetamide:
2- (4-Trifluoromethylphenyl) ethylamine (1.68 mL, 10.6 mmol) is dissolved in dichloromethane (35.2 mL) and trifluoroacetic anhydride (1.64 mL, 11.6 mmol) is added at 0 ° C. It was. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 75/25), and the title compound (hereinafter, hereinafter, The compound of Reference Example 10) (2.60 g, 9.12 mmol, 86%) was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 2.97 (t, J = 7.1Hz, 2H), 3.65 (q, J = 6.7Hz, 2H), 6.30 (brs, 1H) , 7.32 (d, J = 8.2Hz, 2H), 7.60 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 284 (MH) ^- .

(Reference Example 11) Synthesis of 2,2,2-trifluoro-1- (7- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) ethane-1-one:
The compound of Reference Example 10 (1.00 g, 3.51 mmol) and paraformaldehyde (0.158 g, 5.26 mmol) were added to a mixed solution of concentrated sulfuric acid (6.54 mL) and acetic acid (5.02 mL) at 0 ° C. It was. After stirring at room temperature for 17 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25), and the title compound (hereinafter referred to as the compound of Reference Example 11) (0.961 g, 3.23 mmol, 92) was purified. %) Was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 3.00-3.04 (m, 2H), 3.88 (t, J = 5.7Hz, 1.3H), 3.93 (t, J = 6.2Hz, 0.7Hz), 4.81 (s, 0.7H), 4.85 (s, 1.3H), 7.31 (t, J = 9.1Hz, 1H), 7.42 ( d, J = 11.4Hz, 1H), 7.49 (t, J = 9.4Hz, 1H).

(Reference Example 12) Synthesis of 7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
The compound of Reference Example 11 (0.400 g, 1.35 mmol) was dissolved in ethanol (4.08 mL), and a 2 M aqueous sodium hydroxide solution (3.70 mL) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 12) (0.251 g, 1.25 mmol, 93%). Obtained as a colorless oil.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.7Hz, 2H), 3.16 (t, J = 5.9Hz, 2H), 4.06 (s, 2H) , 7.20 (d, J = 8.2Hz, 1H), 7.27 (s, 1H), 7.37 (d, J = 8.2Hz, 1H).
ESI-MS: m / z = 202 (M + H) ⁺ .

(Reference Example 13) Synthesis of 2- (2-chloro-4-nitrobenzyl) -7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
The compound of Reference Example 12 (10.0 g, 49.7 mmol) was dissolved in dichloromethane (148 mL), and the compound of Reference Example 1 (9.04 g, 49.7 mmol) and acetic acid (1.40 mL) were added at room temperature. After stirring at room temperature for 10 minutes, sodium borohydride triacetoxyboron (15.5 g, 73.1 mmol) was added at 0 ° C. After stirring at room temperature for 14 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was reprecipitated with n-hexane / ethyl acetate to give the title compound (hereinafter, the compound of Reference Example 13) (12.9 g, 34.8 mmol, 70%) as a yellow solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.7Hz, 2H), 3.00 (t, J = 5.5Hz, 2H), 3.76 (s, 2H) , 3.88 (s, 2H), 7.25 (d, J = 7.8Hz, 1H), 7.27 (s, 1H), 7.41 (d, J = 7.8Hz, 1H), 7 .80 (d, J = 8.7Hz, 1H), 8.13 (dd, J = 8.7, 2.3Hz, 1H), 8.27 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 371 (M + H) ⁺ .

(Reference Example 14) Synthesis of 3-chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) methyl) aniline:
The compound of Reference Example 13 (15.6 g, 42.1 mmol) was dissolved in THF (42.1 mL), and ethanol (42.1 mL), distilled water (42.1 mL), iron powder (11.8 g, 210 mmol) and iron powder (11.8 g, 210 mmol) were dissolved. Acetic acid (12.0 mL, 210 mmol) was added at room temperature. After stirring at 50 ° C. for 1.5 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 70/30), and the title compound (hereinafter, the compound of Reference Example 14) (13.9 g, 40.8 mmol, 97) was purified. %) Was obtained as a yellow oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.80 (t, J = 5.7 Hz, 2H), 2.94 (t, J = 5.7 Hz, 2H), 3.70 (d, J = 2.7Hz, 6H), 6.57 (dd, J = 8.5, 2.5Hz, 1H), 6.72 (d, J = 2.3Hz, 1H), 7.20 (d, J = 8) .2Hz, 1H), 7.25 (d, J = 8.7Hz, 2H), 7.26 (s, 1H), 7.36 (d, J = 7.8Hz, 1H).
ESI-MS: m / z = 341 (M + H) ⁺ .

(Example 2) N- (3-chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) methyl) phenyl) -2- (4- (ethyl) Synthesis of sulfonyl) phenyl) acetamide:
The compound of Reference Example 14 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 2) (0.0475 g, 0.0862 mmol, 65) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.5Hz, 3H), 2.80 (t, J = 5.7Hz, 2H), 2.94 (t, J = 5.7Hz, 2H), 3.13 (q, J = 7.5Hz, 2H), 3.71 (s, 2H), 3.77 (s, 2H), 3.81 (s, 2H), 7 .21 (d, J = 7.8Hz, 1H), 7.24 (s, 1H), 7.31 (dd, J = 8.7, 1.8Hz, 1H), 7.37 (d, J = 7.8Hz, 1H), 7.41 (brs, 1H), 7.46 (d, J = 8.2Hz, 1H), 7.54 (d, J = 8.2Hz, 2H), 7.69 ( d, J = 2.3Hz, 1H), 7.89 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 551 (M + H) ⁺ .

(Reference Example 15) Synthesis of 2- (2-fluoro-4-nitrobenzyl) -7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
The compound of Reference Example 2 is used instead of the compound of Reference Example 1, the compound of Reference Example 12 is used instead of the compound of Reference Example 5, and the title compound (hereinafter referred to as Reference) is otherwise followed in the same procedure as in Reference Example 6. The compound of Example 15) (0.126 g, 0.356 mmol, 79%) was obtained as a light brown solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.82 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 5.7 Hz, 2H), 3.73 (s, 2H) , 3.85 (s, 2H), 7.23 (d, J = 7.8Hz, 1H), 7.26 (s, 1H), 7.40 (d, J = 8.7Hz, 1H), 7 .73 (t, J = 7.8Hz, 1H), 7.95 (dd, J = 9.6, 2.3Hz, 1H), 8.04 (dd, J = 8.5, 1.6Hz, 1H) ).
ESI-MS: m / z = 355 (M + H) ⁺ .

(Reference Example 16) Synthesis of 3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) methyl) aniline:
The compound of Reference Example 15 was used instead of the compound of Reference Example 6, and the title compound (hereinafter referred to as the compound of Reference Example 16) (0.0695 g, 0.214 mmol, 61) was used in the same procedure as in Reference Example 7 except for the above. %) Was obtained as a yellow oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.77 (t, J = 5.9 Hz, 2H), 2.93 (t, J = 5.7 Hz, 2H), 3.66 (s, 4H) , 3.75 (brs, 2H), 6.39 (dd, J = 11.9, 2.3Hz, 1H), 6.44 (dd, J = 8.2, 2.3Hz, 1H), 7. 15 (t, J = 8.2Hz, 1H), 7.18 (d, J = 7.3Hz, 1H), 7.25 (s, 1H), 7.35 (dd, J = 8.2,1) .4Hz, 1H).
ESI-MS: m / z = 325 (M + H) ⁺ .

(Example 3) 2- (4- (ethylsulfonyl) phenyl) -N- (3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl)) Synthesis of methyl) phenyl) acetamide:
The compound of Reference Example 16 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 3) (0.0326 g, 0.0610 mmol, 66) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.3Hz, 3H), 2.77 (t, J = 5.9Hz, 2H), 2.93 (t, J = 5.7Hz, 2H), 3.13 (q, J = 7.5Hz, 2H), 3.66 (s, 2H), 3.71 (s, 2H), 3.82 (s, 2H), 7 .06 (dd, J = 8.2, 1.8Hz, 1H), 7.19 (d, J = 7.8Hz, 2H), 7.24 (s, 1H), 7.35-7.39 ( m, 2H), 7.51 (dd, J = 11.7, 2.1Hz, 1H), 7.56 (d, J = 8.2Hz, 2H), 7.92 (d, J = 8.2Hz) , 2H).
ESI-MS: m / z = 535 (M + H) ⁺ .

(Reference Example 17) Synthesis of 2,2,2-trifluoro-N- (3- (trifluoromethyl) phenethyl) acetamide:
2- (3-Trifluoromethylphenyl) ethylamine (1.67 mL, 10.6 mmol) is dissolved in dichloromethane (35.2 mL) and trifluoroacetic anhydride (1.64 mL, 11.6 mmol) is added at 0 ° C. It was. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 75/25), and the title compound (hereinafter, hereinafter, The compound of Reference Example 17) (2.52 g, 8.83 mmol, 84%) was obtained as a pale yellow solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.97 (t, J = 7.1 Hz, 2H), 3.65 (q, J = 6.7 Hz, 2H), 6.31 (brs, 1H) , 7.39 (d, J = 7.8Hz, 1H), 7.45 (s, 1H), 7.47 (t, J = 7.5Hz, 1H), 7.54 (d, J = 7. 8Hz, 1H).
ESI-MS: m / z = 284 (MH) ^- .

(Reference Example 18) Synthesis of 2,2,2-trifluoro-1- (6- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) ethane-1-one:
To a mixed solution of concentrated sulfuric acid (6.54 mL) and acetic acid (5.02 mL), the compound of Reference Example 17 (1.00 g, 3.51 mmol) and paraformaldehyde (0.158 g, 5.26 mmol) were added at 0 ° C. It was. After stirring at room temperature for 17 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25), and the title compound (hereinafter, the compound of Reference Example 18) (0.502 g, 1.69 mmol, 48) was purified. %) Was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 3.02 (q, J = 6.1Hz, 2H), 3.88 (t, J = 5.9Hz, 1.3H), 3.93 (t, J = 6.2Hz, 0.7Hz), 4.80 (s, 0.7H), 4.85 (s, 1.3H), 7.23-7.30 (m, 1H), 7.45 ( d, J = 9.6Hz, 1H), 7.50 (d, J = 8.7Hz, 1H).

(Reference Example 19) Synthesis of 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
The compound of Reference Example 18 (0.300 g, 1.01 mmol) was dissolved in ethanol (3.06 mL), and a 2 M aqueous sodium hydroxide solution (2.78 mL) was added at 0 ° C. After stirring at room temperature for 7 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (hereinafter referred to as Reference Example 19 compound) (0.185 g, 0.920 mmol, 91%). Obtained as a colorless oil.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.9Hz, 2H), 3.16 (t, J = 5.9Hz, 2H), 4.05 (s, 2H) , 7.11 (d, J = 7.8Hz, 1H), 7.35 (s, 1H), 7.36 (d, J = 8.7Hz, 1H).
ESI-MS: m / z = 202 (M + H) ⁺ .

(Reference Example 20) Synthesis of 2- (2-chloro-4-nitrobenzyl) -6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
The compound of Reference Example 19 (7.50 g, 37.3 mmol) was dissolved in dichloromethane (113 mL), and the compound of Reference Example 1 (6.92 g, 37.3 mmol) and acetic acid (1.07 mL) were added at room temperature. After stirring at room temperature for 15 minutes, sodium borohydride triacetoxyboron (11.9 g, 55.9 mmol) was added at 0 ° C. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-85 / 15), and the title compound (hereinafter, the compound of Reference Example 20) (12.1 g, 32.5 mmol, 87) was purified. %) Was obtained as a yellow solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.7 Hz, 2H), 3.00 (t, J = 5.7 Hz, 2H), 3.77 (s, 2H) , 3.88 (s, 2H), 7.12 (d, J = 7.8Hz, 1H), 7.39 (d, J = 8.7Hz, 1H), 7.40 (s, 1H), 7 .80 (d, J = 8.7Hz, 1H), 8.13 (dd, J = 8.7, 2.3Hz, 1H) 8.27 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 371 (M + H) ⁺ .

(Reference Example 21) Synthesis of 3-chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) methyl) aniline:
The compound of Reference Example 20 (11.5 g, 31.0 mmol) was dissolved in THF (38.8 mL), and ethanol (38.8 mL), distilled water (38.8 mL), iron powder (8.66 g, 155 mmol) and iron powder (8.66 g, 155 mmol) were dissolved. Acetic acid (8.88 mL, 155 mmol) was added at room temperature. After stirring at 50 ° C. for 2.5 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 70/30), and the title compound (hereinafter, the compound of Reference Example 21) (10.6 g, 40.8 mmol, quantified) was used. ) Was obtained as a yellow solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.80 (t, J = 5.7 Hz, 2H), 2.93 (t, J = 5.7 Hz, 2H), 3.70 (s, 6H) , 6.57 (dd, J = 8.2, 2.3Hz, 1H), 6.72 (d, J = 2.3Hz, 1H), 7.10 (d, J = 7.3Hz, 1H), 7.25 (d, J = 8.2Hz, 1H), 7.34 (d, J = 8.2Hz, 1H), 7.35 (s, 1H).
ESI-MS: m / z = 341 (M + H) ⁺ .

(Example 4) N- (3-chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) methyl) phenyl) -2- (4- (ethyl) Synthesis of sulfonyl) phenyl) acetamide:
The compound of Reference Example 21 (8.00 g, 23.5 mmol) and the compound of Reference Example 9 (5.41 g, 23.7 mmol) were dissolved in DMF (78.0 mL), and HATU (10.7 g, 28.2 mmol) was dissolved. And diisopropylethylamine (6.15 mL, 35.2 mmol) was added at room temperature. After stirring at the same temperature for 26 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether / ethanol (volume ratio 4: 1). The mixture was filtered and washed with diethyl ether. The obtained crystals were vacuum dried to give the title compound (hereinafter, the compound of Example 4) (9.73 g, 17.6 mmol, 75%) as white crystals.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5Hz, 3H), 2.80 (t, J = 5.9Hz, 2H), 2.94 (t, J = 6.2Hz, 2H), 3.13 (q, J = 7.3Hz, 2H), 3.70 (s, 2H), 3.76 (s, 2H), 3.82 (s, 2H), 7 .09 (d, J = 7.8Hz, 1H), 7.14 (s, 1H), 7.29 (dd, J = 8.0, 2.1Hz, 1H), 7.35 (d, J = 8.2Hz, 1H), 7.36 (s, 1H), 7.47 (d, J = 7.8Hz, 1H), 7.56 (d, J = 8.2Hz, 2H), 7.67 ( d, J = 1.8Hz, 1H), 7.93 (d, J = 8.7Hz, 2H).
ESI-MS: m / z = 551 (M + H) ⁺ .

(Reference Example 22) Synthesis of 1- (2-chloro-4-nitrobenzyl) indoline:
Indoline was used instead of the compound of Reference Example 5, and the title compound (hereinafter, the compound of Reference Example 22) (0.406 g, 1.41 mmol, 84%) was browned by the same procedure as in Reference Example 6 except for the above. Obtained as a solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.09 (t, J = 8.2 Hz, 2H), 3.49 (t, J = 8.2 Hz, 2H), 4.39 (s, 2H) , 6.33 (d, J = 7.8Hz, 1H), 6.74 (td, J = 7.3, 0.9Hz, 1H), 7.05 (td, J = 7.8, 1.4Hz) , 1H), 7.15 (d, J = 7.8Hz, 1H), 7.68 (d, J = 8.2Hz, 1H), 8.10 (dd, J = 8.7, 2.3Hz, 1H), 8.29 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 289 (M + H) ⁺ .

(Reference Example 23) Synthesis of 3-chloro-4- (indoline-1-ylmethyl) aniline:
Use the compound of Reference Example 22 instead of the compound of Reference Example 6, and follow the same procedure as in Reference Example 7 except for the title compound (hereinafter, the compound of Reference Example 23) (0.139 g, 0.537 mmol, 52). %) Was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.98 (t, J = 8.2 Hz, 2H), 3.36 (t, J = 8.2 Hz, 2H), 3.69 (brs, 2H) , 4.23 (s, 2H), 6.50 (d, J = 7.8Hz, 1H), 6.54 (dd, J = 8.2, 2.7Hz, 1H), 6.66 (td, J = 7.3, 0.9Hz, 1H), 6.73 (d, J = 2.3Hz, 1H), 7.05 (td, J = 7.8, 1.4Hz, 1H), 7.09 (D, J = 7.8 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H).
ESI-MS: m / z = 259 (M + H) ⁺ .

(Example 5) Synthesis of N- (3-chloro-4- (indoline-1-ylmethyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:
The compound of Reference Example 23 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 5) (0.0406 g, 0.0866 mmol, 75) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.3Hz, 3H), 3.01 (t, J = 8.2Hz, 2H), 3.13 (q, J = 7.5Hz, 2H), 3.39 (t, J = 8.2Hz, 2H), 3.81 (s, 2H), 4.28 (s, 2H), 6.41 (d, J = 7. 8Hz, 1H), 6.68 (t, J = 7.3Hz, 1H), 7.03 (t, J = 7.5Hz, 1H), 7.11 (d, J = 7.3Hz, 1H), 7.18 (brs, 1H), 7.23 (dd, J = 8.5, 2.1Hz, 1H), 7.39 (d, J = 8.2Hz, 1H), 7.56 (d, J) = 8.2Hz, 2H), 7.71 (d, J = 1.8Hz, 1H), 7.92 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 469 (M + H) ⁺ .

(Reference Example 24) Synthesis of 1- (2-chloro-4-nitrobenzyl) -5-methylindoline:
Use 5-methylindoline instead of the compound of Reference Example 5, and follow the same procedure as in Reference Example 6 except for the title compound (hereinafter, the compound of Reference Example 24) (0.407 g, 1.34 mmol, 90%). ) Was obtained as a brown solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.26 (s, 3H), 3.04 (t, J = 8.0 Hz, 2H), 3.44 (t, J = 8.2 Hz, 2H) , 4.34 (s, 2H), 6.24 (d, J = 8.2Hz, 1H), 6.85 (d, J = 7.8Hz, 1H), 6.99 (s, 1H), 7 .70 (d, J = 8.7Hz, 1H), 8.09 (dd, J = 8.7, 2.3Hz, 1H), 8.28 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 303 (M + H) ⁺ .

(Reference Example 25) Synthesis of 3-chloro-4-((5-methylindoline-1-yl) methyl) aniline:
Use the compound of Reference Example 24 instead of the compound of Reference Example 6, and follow the same procedure as in Reference Example 7 except for the title compound (hereinafter, the compound of Reference Example 25) (0.307 g, 1.13 mmol, 85). %) Was obtained as a white solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.24 (s, 3H), 2.93 (t, J = 8.4 Hz, 2H), 3.32 (t, J = 8.2 Hz, 2H) , 3.68 (brs, 2H), 4.18 (s, 2H), 6.41 (d, J = 7.7Hz, 1H), 6.54 (dd, J = 8.2, 2.3Hz, 1H), 6.73 (d, J = 2.3Hz, 1H), 6.85 (d, J = 8.2Hz, 1H), 6.93 (s, 1H), 7.20 (d, J = 8.2Hz, 1H).
ESI-MS: m / z = 273 (M + H) ⁺ .

(Example 6) Synthesis of N- (3-chloro-4-((5-methylindoline-1-yl) methyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:
The compound of Reference Example 25 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 6) (0.0303 g, 0.0627 mmol, 57) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.3Hz, 3H), 2.25 (s, 3H), 2.96 (t, J = 8.2Hz, 2H) , 3.13 (q, J = 7.5Hz, 2H), 3.35 (t, J = 8.2Hz, 2H), 3.81 (s, 2H), 4.23 (s, 2H), 6 .32 (d, J = 7.8Hz, 1H), 6.84 (d, J = 7.8Hz, 1H), 6.94 (s, 1H), 7.14 (s, 1H), 7.23 (Dd, J = 8.2, 2.3Hz, 1H), 7.40 (d, J = 8.7Hz, 1H), 7.56 (d, J = 8.2Hz, 2H), 7.71 ( d, J = 2.3Hz, 1H), 7.92 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 483 (M + H) ⁺ .

(Reference Example 26) Synthesis of 2- (2-chloro-4-nitrobenzyl) isoindoline:
Isoindoline was used instead of the compound of Reference Example 5, and the title compound (hereinafter referred to as the compound of Reference Example 26) (0.431 g, 1.49 mmol, 89%) was obtained by the same procedure as in Reference Example 6 except for the above. Obtained as a brown oil.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 4.05 (s, 4H), 4.12 (s, 2H), 7.22 (s, 4H), 7.83 (d, J = 8.2Hz) , 1H), 8.14 (dd, J = 8.7, 2.3Hz, 1H), 8.27 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 289 (M + H) ⁺ .

(Reference Example 27) Synthesis of 3-chloro-4- (isoindoline-2-ylmethyl) aniline:
Use the compound of Reference Example 26 instead of the compound of Reference Example 6, and follow the same procedure as in Reference Example 7 except for the title compound (hereinafter, the compound of Reference Example 27) (0.181 g, 0.700 mmol, 67). %) Was obtained as a brown solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.92 (s, 2H), 3.97 (s, 4H), 6.58 (dd, J = 8.2, 2.7 Hz, 1H), 6 .73 (d, J = 2.3Hz, 1H), 7.17 (s, 4H), 7.28 (d, J = 8.7Hz, 1H).
ESI-MS: m / z = 259 (M + H) ⁺ .

(Example 7) Synthesis of N- (3-chloro-4- (isoindoline-2-ylmethyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:
The compound of Reference Example 27 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 7) (0.0233 g, 0.0497 mmol, 43) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5Hz, 3H), 3.13 (q, J = 7.5Hz, 2H), 3.82 (s, 2H) , 3.98 (s, 4H), 3.99 (s, 2H), 7.18 (s, 5H), 7.31 (dd, J = 8.7, 2.3Hz, 1H), 7.50 (D, J = 8.2Hz, 1H), 7.56 (d, J = 8.2Hz, 2H), 7.67 (d, J = 2.3Hz, 1H), 7.93 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 469 (M + H) ⁺ .

(Reference Example 28) Synthesis of 2- (2-chloro-4-nitrobenzyl) -5- (trifluoromethyl) isoindoline:
Use 5- (trifluoromethyl) isoindoline instead of the compound of Reference Example 5, and follow the same procedure as in Reference Example 6 except for the title compound (hereinafter, the compound of Reference Example 28) (0.106 g, 0). .297 mmol, 79%) was obtained as a brown oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 4.09 (s, 4H), 4.13 (s, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.47 (s) , 1H), 7.50 (d, J = 7.8Hz, 1H), 7.80 (d, J = 8.2Hz, 1H), 8.15 (dd, J = 8.2, 2.3Hz, 1H), 8.28 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 357 (M + H) ⁺ .

(Reference Example 29) Synthesis of 3-chloro-4-((5- (trifluoromethyl) isoindoline-2-yl) methyl) aniline:
Use the compound of Reference Example 28 instead of the compound of Reference Example 6, and follow the same procedure as in Reference Example 7 except for the title compound (hereinafter, the compound of Reference Example 29) (0.0568 g, 0.174 mmol, 59). %) Was obtained as a brown oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.71 (s, 2H), 3.93 (s, 2H), 4.00 (s, 4H), 6.58 (dd, J = 8.2) , 2.3Hz, 1H), 6.73 (d, J = 2.3Hz, 1H), 7.25 (d, J = 8.2Hz, 1H), 7.27 (d, J = 7.3Hz, 1H), 7.43 (s, 1H), 7.44 (d, J = 8.2Hz, 1H).
ESI-MS: m / z = 327 (M + H) ⁺ .

(Example 8) Synthesis of N- (3-chloro-4-((5- (trifluoromethyl) isoindoline-2-yl) methyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:
The compound of Reference Example 29 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 8) (0.0115 g, 0.0214 mmol, 25) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5Hz, 3H), 3.13 (q, J = 7.3Hz, 2H), 3.82 (s, 2H) , 4.00 (s, 2H), 4.01 (s, 4H), 7.19 (brs, 1H), 7.28 (d, J = 7.8Hz, 1H), 7.32 (dd, J) = 8.5, 2.1Hz, 1H), 7.43-7.48 (m, 3H), 7.56 (d, J = 8.7Hz, 2H), 7.67 (d, J = 1. 8Hz, 1H), 7.93 (d, J = 8.7Hz, 2H).
ESI-MS: m / z = 537 (M + H) ⁺ .

(Reference Example 30) Synthesis of 2- (2-chloro-4-nitrophenyl) -1,2,3,4-tetrahydroisoquinoline:
1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g, 5.89 mmol) was dissolved in DMSO (11.8 mL), and 3-chloro-4-fluoronitrobenzene (1.04 g, 5.89 mmol) and N-Methylmorpholine (1.19 g, 11.8 mmol) was added at room temperature. After stirring at 110 ° C. for 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5), and the title compound (hereinafter, the compound of Reference Example 30) (1.05 g, 3.64 mmol, 62%) was yellowed. Obtained as a brown solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 3.07 (t, J = 5.7Hz, 2H), 3.62 (t, J = 5.7Hz, 2H), 4.43 (s, 2H) , 7.13 (t, J = 6.8Hz, 2H), 7.21-7.27 (m, 3H), 8.11 (td, J = 5.7, 2.7Hz, 1H), 8. 29 (d, J = 2.5Hz, 1H).
ESI-MS: m / z = 289 (M + H) ⁺ .

(Reference Example 31) Synthesis of 3-chloro-4- (3,4-dihydroisoquinoline-2 (1H) -yl) aniline:
Use the compound of Reference Example 30 instead of the compound of Reference Example 6, and follow the same procedure as in Reference Example 7 except for the title compound (hereinafter, the compound of Reference Example 31) (0.872 g, 3.37 mmol, 97). %) Was obtained as a light red oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 3.00 (t, J = 5.7 Hz, 2H), 3.27 (t, J = 5.9 Hz, 2H), 3.55 (s, 2H) , 4.17 (s, 2H), 6.56 (dd, J = 8.6, 2.7Hz, 1H), 6.78 (d, J = 2.7Hz, 1H), 6.96 (d, J = 8.6Hz, 1H), 7.09-7.11 (m, 1H), 7.15-7.20 (m, 3H).
ESI-MS: m / z = 259 (M + H) ⁺ .

(Example 9) Synthesis of N- (3-chloro-4- (3,4-dihydroisoquinoline-2 (1H) -yl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:
The compound of Reference Example 31 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 9) (0.0537 g, 0.114 mmol, 59) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.5Hz, 3H), 3.00 (t, J = 5.7Hz, 2H), 3.12 (q, J = 7.4Hz, 2H), 3.35 (t, J = 5.9Hz, 2H), 3.79 (s, 2H), 4.22 (s, 2H), 7.05 (d, J = 9. 1Hz, 1H), 7.07-7.10 (m, 1H), 7.15-7.18 (m, 3H), 7.30 (s, 1H), 7.33 (dd, J = 8. 6,2.3Hz, 1H), 7.54 (d, J = 8.6Hz, 2H), 7.60 (d, J = 2.7Hz, 1H), 7.89 (d, J = 8.6Hz) , 2H).
ESI-MS: m / z = 469 (M + H) ⁺ .

(Reference Example 32) Synthesis of 3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) aniline:
7- (Trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (0.500 g, 2.10 mmol) was dissolved in DMSO (10.5 mL) and 3-chloro-4-fluoronitrobenzene (0). .369 g, 2.10 mmol) and N-methylmorpholine (0.426 g, 4.21 mmol) were added at room temperature. After stirring at 110 ° C. for 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was used in the subsequent reaction without purification.
The above crude product was dissolved in THF (7.01 mL), ethanol (7.01 mL), distilled water (7.01 mL), iron powder (0.313 g, 5.61 mmol) and acetic acid (0.802 mL, 14). .0 mmol) was added at room temperature. After stirring at 70 ° C. for 3 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20), and the title compound (hereinafter, the compound of Reference Example 32) (0.389 g, 1.19 mmol, 57%) was orange. Obtained as a red oil.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 3.03 (t, J = 5.4Hz, 2H), 3.25 (t, J = 5.7Hz, 2H), 3.57 (s, 2H) , 4.15 (s, 2H), 6.54 (dd, J = 8.6, 2.7Hz, 1H), 6.76 (d, J = 2.7Hz, 1H), 6.92 (t, J = 4.1Hz, 1H), 7.24 (t, J = 4.1Hz, 1H), 7.32 (s, 1H), 7.40 (d, J = 7.7Hz, 1H).
ESI-MS: m / z = 327 (M + H) ⁺ .

(Example 10) N- (3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) phenyl) -2- (4- (ethylsulfonyl) phenyl ) Synthesis of acetamide:
The compound of Reference Example 32 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 10) (0.0571 g, 0.106 mmol, 69) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5Hz, 3H), 3.06 (t, J = 5.4Hz, 2H), 3.13 (q, J = 7.4Hz, 2H), 3.35 (t, J = 5.9Hz, 2H), 3.80 (s, 2H), 4.25 (s, 2H), 7.04 (d, J = 8. 6Hz, 1H), 7.27 (d, J = 6.3Hz, 1H), 7.29 (s, 1H), 7.33-7.35 (m, 2H), 7.42 (d, J = 8.2Hz, 1H), 7.54 (d, J = 8.6Hz, 2H), 7.63 (d, J = 2.7Hz, 1H), 7.89 (d, J = 8.2Hz, 2H) ).
ESI-MS: m / z = 537 (M + H) ⁺ .

(Reference Example 33) Synthesis of 2- (2-chloro-4-nitrophenyl) -6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Use 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, otherwise follow the same procedure as in Reference Example 30. , The title compound (hereinafter, the compound of Reference Example 33) (1.10 g, 3.08 mmol, 85%) was obtained as a yellowish brown oil.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 3.13 (t, J = 5.9Hz, 2H), 3.61 (t, J = 5.7Hz, 2H), 4.45 (s, 2H) , 7.13 (t, J = 8.7Hz, 1H), 7.24-7.27 (m, 1H), 7.45-7.47 (m, 2H), 8.13 (dd, J = 9.1, 2.7Hz, 1H), 8.30 (d, J = 2.7Hz, 1H).
ESI-MS: m / z = 357 (M + H) ⁺ .

(Reference Example 34) Synthesis of 3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) aniline:
Use the compound of Reference Example 33 instead of the compound of Reference Example 6, and follow the same procedure as in Reference Example 7 except for the title compound (hereinafter, the compound of Reference Example 34) (0.940 g, 2.88 mmol, 99). %) Was obtained as a yellowish brown oil.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 3.05 (t, J = 5.7Hz, 2H), 3.28 (t, J = 5.7Hz, 2H), 3.58 (s, 2H) , 4.19 (s, 2H), 6.57 (dd, J = 8.7, 2.7Hz, 1H), 6.79 (d, J = 2.7Hz, 1H), 6.94 (d, J = 8.7Hz, 1H), 7.18 (d, J = 7.8Hz, 1H), 7.38-7.42 (m, 2H).
ESI-MS: m / z = 327 (M + H) ⁺ .

(Example 11) N- (3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinoline-2 (1H) -yl) phenyl) -2- (4- (ethylsulfonyl) phenyl ) Synthesis of acetamide:
The compound of Reference Example 34 was used instead of the compound of Reference Example 7, and the title compound (hereinafter, the compound of Example 11) (0.0820 g, 0.153 mmol, quantification) was quantified by the same procedure as in Example 1 except for the compound. Was obtained as a yellow solid.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.3Hz, 3H), 3.05 (t, J = 5.7Hz, 2H), 3.12 (q, J = 7.5Hz, 2H), 3.34 (t, J = 5.7Hz, 2H), 3.78 (s, 2H), 4.24 (s, 2H), 7.03 (d, J = 8. 7Hz, 1H), 7.19 (d, J = 7.8Hz, 1H), 7.36 (dd, J = 8.7, 2.3Hz, 1H), 7.41 (d, J = 8.2Hz) , 1H), 7.42 (s, 1H), 7.52 (d, J = 8.7Hz, 2H), 7.54 (s, 1H), 7.62 (d, J = 2.7Hz, 1H) ), 7.85 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 537 (M + H) ⁺ .

(Reference Example 35) Synthesis of 2- (2-chloro-4-nitrobenzyl) -1,2,3,4-tetrahydroisoquinoline:
Use 1,2,3,4-tetrahydroisoquinoline instead of the compound of Reference Example 5, and follow the same procedure as in Reference Example 6 except for the title compound (hereinafter, the compound of Reference Example 35) (0.370 g, 1.22 mmol, 81%) was obtained as a yellow solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.83 (t, J = 5.7 Hz, 2H), 2.96 (t, J = 5.7 Hz, 2H), 3.73 (s, 2H) , 3.86 (s, 2H), 7.00-7.02 (m, 1H), 7.11-7.17 (m, 3H), 7.84 (d, J = 8.2Hz, 1H) , 8.11 (dd, J = 8.6, 2.3Hz, 1H), 8.26 (d, J = 2.3Hz, 1H).
ESI-MS: m / z = 303 (M + H) ⁺ .

(Reference Example 36) Synthesis of 3-chloro-4-((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) aniline:
Use the compound of Reference Example 35 instead of the compound of Reference Example 6, and follow the same procedure as in Reference Example 7 except for the title compound (hereinafter, the compound of Reference Example 36) (0.306 g, 1.12 mmol, 92). %) Was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 2.78 (t, J = 5.9Hz, 2H), 2.89 (t, J = 5.9Hz, 2H), 3.67 (brs, 4H) , 3.69 (s, 2H), 6.57 (dd, J = 8.2, 2.7Hz, 1H), 6.72 (d, J = 2.3Hz, 1H), 6.98-7. 01 (m, 1H), 7.07-7.12 (m, 3H), 7.28 (d, J = 8.2Hz, 1H).
ESI-MS: m / z = 273 (M + H) ⁺ .

(Example 12) Synthesis of N- (3-chloro-4-((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:
The compound of Reference Example 36 was used instead of the compound of Reference Example 7, and the title compound (hereinafter referred to as the compound of Example 12) (0.0293 g, 0.0607 mmol, 55) was used in the same procedure as in Example 1 except for the above. %) Was obtained as a white solid.
^{1 1} H-NMR (400MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5Hz, 3H), 2.78 (t, J = 5.7Hz, 2H), 2.90 (t, J = 5.7Hz, 2H), 3.13 (q, J = 7.5Hz, 2H), 3.68 (s, 2H), 3.75 (s, 2H), 3.81 (s, 2H), 6 .97-7.00 (m, 1H), 7.09-7.14 (m, 3H), 7.18 (s, 1H), 7.26-7.29 (m, 1H), 7.50 (D, J = 8.7Hz, 1H), 7.56 (d, J = 8.2Hz, 2H), 7.67 (d, J = 2.3Hz, 1H), 7.92 (d, J = 8.2Hz, 2H).
ESI-MS: m / z = 483 (M + H) ⁺ .

(Example 13) RORγ-coactivator binding inhibitory action:
The inhibitory effect of the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof on the binding of the ligand-binding domain of RORγ (hereinafter, RORγ-LBD) and the coactivator, to time. Evaluation was performed using the Invitrogen Lantha Screen ^TM TR-FRET Retinoid-Related Orphan Receptor (ROR) pharmacocoactivator Assay kit using decomposition fluorescence energy transfer (TR-FRET).

The test compound was dissolved in DMSO and then diluted with 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D (invitagen) so that the final concentration of DMSO was 1%. To each well of the 384-well black plate (Corning), 4 nmol / L GST fusion RORγ-LBD (invitogen) diluted with the above buffer and the test compound were added. Wells were provided for which no test compound was added and no GST fusion RORγ-LBD was added (background) and for which no test compound was added and GST fusion RORγ-LBD was added (control). Next, 150 nmol / L Flurescein-labeled TRAP220 / DRIP-2 (invitogen) diluted with the above buffer and 32 nmol / L terbium-labeled anti-GST antibody (invitogen) were added to each well. After incubating the plate at room temperature for 16 to 24 hours, the fluorescence at 495 nm and 520 nm when excited at 320 nm was measured for each well, and the ratio (fluorescence value at 520 nm / fluorescence value at 495 nm) was calculated.

Fold change when the test compound is added (Ratio when the test compound is added), Fold change for the control (Ratio for the control / Ratio for the background), and Fold change for the background (Ratio / background when the test compound is added). After calculating the ground ratio), the binding inhibition rate of RORγ-LBD and the coactivator (hereinafter, RORγ-coactivator binding inhibition rate) (%) was calculated from the following formula 1.

RORγ-coactivator binding inhibition rate (%) = (1-((Fold change when test compound added)-(Background Fold change)) / ((Control Fold change)-(Background Fold change)) )) × 100 ・ ・ ・ Equation 1

Table 2 shows the RORγ-coactivator binding inhibition rate (%) at 33 μmol / L of the test compound.

From this result, it was clarified that the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof, significantly inhibits the binding between RORγ-LBD and the coactivator.

(Example 14) IL-17 production inhibitory action in mouse splenocytes:
Using mouse splenocytes, the inhibitory effect of the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof on IL-23-stimulated IL-17 production, is shown in The Journal of Biological Chemistry. , 2003, Vol. 278, No. 3, p. The method described in 1910-1914 was evaluated with some modifications.

A single cell suspension was prepared from the spleen of C57BL / 6J mouse (male, 8-26 weeks old) (Charles River Japan, Ltd.), and splenocytes were prepared using Histopaque-1083 (Sigma). Culture medium was RPMI1640 medium (Gibco) with 10% FBS (Gibco), 50 U / mL penicillin, 50 μg / mL streptomycin (Gibco), 50 μmol / L 2-mercaptoethanol (Gibco) and 100 U / mL human IL-. 2 (Cell Science Laboratory Co., Ltd.) was added and used. The test compound was dissolved in DMSO and then diluted in a culture medium so that the final concentration of DMSO was 0.1%. Splenocytes (3 × 10 ⁵ cells / well) prepared in a culture medium were seeded in wells of a 96-well flat bottom plate (Corning Inc.), and the test compound and 10 ng / mL human IL-23 (R & D systems) were added. The cells were cultured at 37 ° C. and 5% CO ₂ for 3 days. Wells were provided with no human IL-23 added and no test compound added, and human IL-23 added and no test compound added. After completion of the culture, the culture supernatant was collected and the amount of IL-17 produced in the supernatant was quantified by an ELISA method (R & D systems).

The IL-17 production suppression rate (%) was calculated from the following formula 2.

IL-17 production suppression rate (%) = (1-((IL-17 production amount when IL-23 is added and test compound is added)-(IL-17 production amount when IL-23 is not added and test compound is not added) )) / ((IL-17 production amount when IL-23 is not added and test compound is not added)-(IL-17 production amount when IL-23 is not added and test compound is not added)))) × 100 ... 2

Table 3 shows the IL-17 production inhibition rate (%) at 5 μmol / L of the test compound.

Table 4 shows the IL-17 production inhibition rate (%) at 0.3 μmol / L of the test compound.

From these results, it was clarified that the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof suppresses IL-17 production.

(Example 15) Symptom-suppressing effect on imiquimod-induced mouse psoriasis model:
Using the increase in auricle thickness as an index of exacerbation of symptoms, the action of the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof in an imiquimod-induced mouse psoriasis model was evaluated. The imiquimod-induced mouse psoriasis model was prepared by partially modifying the method of Schaper et al. (The Journal of Dermatological Science, 2013, Vol. 71, No. 1, p. 29-36).

BALB / c mice (male, 7 weeks old) (Nippon Charles River Co., Ltd.) were used at 8 weeks of age after preliminary breeding. In order to induce psoriasis-like symptoms, 5% of Beselna Cream was applied once a day to the outside of the left and right auricles of mice for 8 days from the day of initial administration of imiquimod (hereinafter referred to as the day of induction) to the 7th day after induction. (Imiquimod dose 0.5 mg / body / day).

Mice were administered the test compound at a dose of 10 mg / kg once daily for 5 days from the 3rd day after the induction to the 7th day after the induction. As the test compound, the compound of Example 4 was used. The compound of Example 4 was suspended in a 0.5 w / v% methylcellulose solution and orally administered. The group in which the compound of Example 4 was administered to the mouse was designated as the compound administration group of Example 4. The solvent of each test compound (0.5 w / v% methylcellulose solution) was similarly administered to the solvent administration group.

The thickness of the left and right auricles before administration of imiquimod (before induction) on the day of induction and the thickness of the left and right auricles on the 8th day after induction were measured using a digital micrometer (Mitutoyo). The average value of the thickness of the left and right auricles was taken as the auricle thickness, and the change (auricle thickness on the 8th day after induction-auricle thickness before induction) was used as an index for drug efficacy evaluation.

The results are shown in FIG. The vertical axis shows the change in auricular thickness (mm) (mean ± standard error, n = 6). The “solvent” on the horizontal axis indicates the solvent administration group, and the “compound of Example 4” indicates the compound administration group of Example 4. The * mark indicates that it is statistically significant in comparison with the solvent-administered group (Student's t-test) (*: P <0.05).

Due to imiquimod induction, the auricle thickness of the solvent-administered group on the 8th day after induction increased by 0.26 mm from the auricle thickness before induction. This increase in auricular thickness was statistically significantly suppressed by administration of the compound of Example 4.

From this result, it was clarified that the anilide derivative (I) or its hydrate, or a pharmacologically acceptable salt thereof, shows a remarkable symptom-suppressing effect on psoriasis.

Since the anilide derivative (I) of the present invention or a hydrate thereof, or a pharmacologically acceptable salt thereof has excellent RORγ antagonist activity, the pathological condition can be improved or symptoms can be improved by suppressing the function of RORγ. It can be used as a drug for diseases that can be expected to be relieved. In particular, it can be used as a therapeutic or prophylactic agent for autoimmune diseases such as psoriasis.

Claims (8)

Anilide derivative represented by the following general formula (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof.
[In the formula, R ¹ represents a halogen atom, and R ² is a hydrogen atom or a methyl group (the methyl group may have 1 to 3 arbitrary hydrogen atoms substituted with halogen atoms). , M represents 0 or 1, n represents 0 or 1, and p represents 1 or 2. ] R ¹ is a fluorine atom or a chlorine atom,
R ² is a hydrogen atom or a methyl group (the methyl group, one to three arbitrary hydrogen atom may be substituted by a fluorine atom or a chlorine atom.) Is, anilide derivative according to claim 1, wherein Or its hydrate, or a pharmacologically acceptable salt thereof. R ¹ is a fluorine atom or a chlorine atom,
R ² is a methyl group (the methyl group, one to three arbitrary hydrogen atom may be substituted by fluorine atoms.) Is, anilide derivative or a hydrate thereof according to claim 1, Alternatively, these pharmacologically acceptable salts. R ¹ is a fluorine atom or a chlorine atom,
R ² is a trifluoromethyl group
n is 1,
p is 2, the anilide derivative according to claim 1 or a hydrate thereof, or a pharmacologically acceptable salt thereof. A medicament containing the anilide derivative according to any one of claims 1 to 4 or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient. A retinoid-related orphan receptor γ antagonist containing the anilide derivative according to any one of claims 1 to 4 or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient. A therapeutic or prophylactic agent for autoimmune diseases, which comprises the anilide derivative according to any one of claims 1 to 4 or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient. A therapeutic or prophylactic agent for psoriasis, which comprises the anilide derivative according to any one of claims 1 to 4 or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient.