WO2019088057A1

WO2019088057A1 - Anilide derivative and medicinal use thereof

Info

Publication number: WO2019088057A1
Application number: PCT/JP2018/040211
Authority: WO
Inventors: 雄輝松村; 英喜高橋; 新之助林; マーシャルバレット; 真幸星; 拓実青木; 和也大角; 慎也横坂; 目黒　裕之; こずえ高垣; 戒能　美枝
Original assignee: 東レ株式会社
Priority date: 2017-10-31
Filing date: 2018-10-30
Publication date: 2019-05-09
Also published as: JPWO2019088057A1; TW201922700A

Abstract

The purpose of the present invention is to provide a novel compound which has retinoid-related orphan receptor γ antagonistic activity and exhibits a remedial effect or prophylactic effect on autoimmune diseases including psoriasis. The present invention provides the anilide derivative (I) shown below or a hydrate thereof or a pharmacologically acceptable salt of either.

Description

Anilide derivative and its pharmaceutical use

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

Autoimmune disease is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient. For example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory Intestinal diseases, ankylosing spondylitis, uveitis or polymyalgia rheumatica can be mentioned.

Various mechanisms have been proposed for the onset and progression of autoimmune diseases, and one of them is Th17 cells, which is a subset of helper T cells, and IL-17, which is an inflammatory cytokine that it produces. 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 induction of inflammatory cytokines, chemokines, metalloproteases and other inflammatory mediators and neutrophil migration. ing. Therefore, if it is possible to suppress the production or function of IL-17, a strong anti-inflammatory effect is considered to be exerted, and clinical trials of anti-IL-17 antibodies with indications for various autoimmune diseases are conducted. It is done.

In recent years, it has been clarified that the nuclear receptor retinoid-related orphan receptor γ (hereinafter referred to as RORγ) functions as a transcription factor essential for differentiation and proliferation of Th17 cells and expression of IL-17 (non-patent) Reference 3), it was shown that suppressing the expression or function of RORγ suppresses the differentiation and activation of Th17 cells and the production of IL-17 (Non-patent Document 4).

In patients with autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus etc.), it has been reported that the expression level of RORγ in peripheral blood mononuclear cells shows a high value as compared with healthy people (Non-patent Document 5) And 6). It is reported that in RORγ knockout mice, the pathological condition of mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, is suppressed, and symptoms of autoimmune diseases such as colitis are suppressed. (Non-Patent Documents 3 and 7).

Furthermore, it has been suggested that in order for RORγ to function as a transcription factor, binding between RORγ and a coactivator is necessary (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 RORγ antagonists, N- (5- (N- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl) sulfamoyl) has hitherto been described. -4-methylthiazol-2-yl) acetamide (Non-patent Document 9), 6- (2-chloro-4-methylphenyl) -3- (4-cyclopropyl-5- (3-neopentylcyclobutyl) Substituted azole derivatives such as isoxazol-3-yl) -5-oxohexanoic acid (Patent Document 1), N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl ]-4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (Patent Document 2), 2- (4- (4- (4- (ethylsulfonyl) phenyl) acetamide) phenyl (Nyl) -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- (1,1,6) Sulfonylbenzene derivatives such as 1,3,3,3-hexafluoro-2- (3-methylpiperidin-1-yl) propan-2-yl) phenyl) acetamide (Patent Document 5), 1-acetyl-N- Biaryl derivatives such as (2-chloro-2 '-(trifluoromethoxy)-[1, 1'-biphenyl] -4-yl) piperidine-2-carboxamide have been reported (US Pat. No. 5,677,859).

Moreover, as a compound having an anilide structure such as 3-substituted N- (4- (3,4-dihydroisoquinolin-2 (1H) -yl) acetamide, etc., as a positive allosteric modulator of metabotropic glutamate receptor type 1 And N- (3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) -3-methylfuran-2-carboxamide etc. (Non-patent document 10), 3-substituted Examples of compounds having anilide structure such as N- (4-((3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) acetamide include fibroblast growth factor receptor 1 inhibitors and fibroblasts N- (4-((3,4-Dihydroisoquinolin-2 (1H) -yl) methyl) -3- (trifluoro) as a growth factor receptor 2 inhibitor (Thyl) phenyl) -3- (isoquinolin-4-ylethynyl) -4-methylbenzamide and the like have been reported (Patent Document 7), such as 3-substituted N- (4- (isoindoline-2-ylmethyl) phenyl) acetamide and the like. As compounds having anilide structure, N- (4- (isoindoline-2-ylmethyl) -3- (trifluoro) as a fibroblast growth factor receptor 1 inhibitor and a fibroblast growth factor receptor 2 inhibitor (Methyl) phenyl) -3- (isoquinolin-4-ylethynyl) -4-methylbenzamide and the like have been reported (Patent Document 7), and anilide such as 3-substituted N- (4- (indoline-1-ylmethyl) phenyl) acetamide and the like As a compound having a structure, 5'-acetylamino-2 '-(5-carbamimidiine) as a serine protease inhibitor 2,3-dihydro - indol-1-ylmethyl) - but-2-carboxylic acid and the like have been reported (Patent Document 8), are not disclosed or suggested about the effect on RORγ of these compounds.

JP 2012-236822 A International Publication No. 2013/029338 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

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 has been recognized due to concerns about serious side effects such as infections. At present, there are a large number of cases where the administration must be discontinued before being taken. For this reason, development of new medicines targeting molecules that play an important role in the onset and progression mechanism of autoimmune diseases is desired.

Then, this invention aims at providing the novel compound which has ROR (gamma) antagonist activity and exhibits a therapeutic effect or a preventive effect with respect to autoimmune diseases, such as psoriasis.

As a result of intensive studies to solve the above problems, the present inventors have found novel anilide derivatives 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.

[Wherein, R ¹ represents a halogen atom, and R ² represents a hydrogen atom or a methyl group (in this methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom)] And m represents 0 or 1; n represents 0 or 1; 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, R ² is a hydrogen atom or a methyl group (wherein the methyl group is any one to three hydrogen atoms) Preferably, the atom is 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 optional hydrogen atom of 1 to 3) Is more preferably substituted by a fluorine atom).

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

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 It is further preferred that

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

The present invention also provides medicaments and RORγ antagonists comprising, as an active ingredient, the 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 as a therapeutic agent or a preventive agent for the above-mentioned autoimmune disease, a therapeutic agent or a preventive agent for psoriasis is more preferable.

The anilide derivative of the present invention or a hydrate thereof, or a pharmacologically acceptable salt thereof can effectively suppress the function of RORγ because it has RORγ antagonist activity, and can be used as a therapeutic agent or agent for autoimmune diseases It can be used as an agent.

It is a figure which shows the inhibitory effect of the compound of Example 4 on the increase in the auricle 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).

The following terms used herein are as defined below unless otherwise indicated.

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

The “methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom)” means that one to three arbitrary hydrogen atoms of the methyl group are Each independently represents a group which may be substituted by 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.

The “methyl group (in the methyl group, any one to three optional hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)” means any one to three hydrogens of the methyl group. Each of the atoms independently represents a group which may be 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 and a trichloromethyl group.

The “methyl group (in the methyl group, any one to three optional hydrogen atoms may be substituted with a fluorine atom)” means that one to three optional hydrogen atoms of the methyl group are It means a group which may be substituted by a fluorine atom, and specifically 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” refers to the anilide derivative represented by the general formula (I), a compound represented by the general formula (I) The pharmacologically acceptable hydrate of the anilide derivative shown, the pharmacologically acceptable salt of the anilide derivative shown by the general formula (I) or the pharmacologically acceptable hydrate of the anilide derivative shown by the general formula (I) Mean salt.

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

R ² is preferably a hydrogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom), and a methyl group (the above-mentioned methyl group) The methyl group is more preferably 1 to 3 arbitrary hydrogen atoms which may be substituted with a fluorine atom), and still more preferably a trifluoromethyl group.

N is preferably 1.

P is preferably 2.

As a combination of n and p, for example, 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 And p is 1 (isoindoline ring).

In the anilide derivative represented by the above general formula (I), when n is 1 and p is 2 (tetrahydroisoquinoline ring), R ² is substituted at the 6- or 7-position of the tetrahydroisoquinoline ring When n is 0 and p is 2 (indoline ring), R ² is preferably substituted at the 5-position of the indoline ring, n is 1 and p is 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 aspect can be selected and combined for the preferred R ¹ , the preferred R ² , the preferred n described above, and the preferred p described above.

Specific examples of preferred 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), not only a single isomer but also a mixture of a racemate and a mixture of diastereomers as well as a single isomer when the stereoisomer exists is also represented by the above general formula (I) It includes in the anilide derivative shown by these.

"Stereoisomer" refers to a compound having the same chemical structure but different arrangement in three-dimensional space, such as, for example, conformer, rotamer, tautomer, optical isomer, diastereomer Etc.

The anilide derivative represented by the above general formula (I) may be labeled with one or more isotopes, and the isotopes to be labeled include, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁵ O, ¹⁸ O and / or ¹²⁵ I can be mentioned.

Examples of the "pharmaceutically acceptable salt" of the anilide derivative represented by the above general formula (I) include salts with inorganic acids or salts with organic acids. Examples of salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides or phosphates, and salts with organic acids include, for example, 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, aspartate, glutamate or cinnamate An acid salt etc. are mentioned. The same applies to "pharmacologically acceptable salts" 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 an anhydride, or may form a solvate such as a hydrate. Here, as a solvate, a pharmacologically acceptable solvate is preferable. The pharmacologically acceptable solvate may be either hydrate or non-hydrate, but hydrate is preferred. Examples of the solvent constituting the solvate include alcohol solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO) or 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. Starting materials and reagents used for producing these compounds can be generally purchased or can be produced by known methods.

The anilide derivative (I) and the intermediates and starting materials used for its preparation 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 and diastereomer can be obtained as a single optically active substance by a known method. Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.

The crystallization can be carried out according to a known method (for example, Brittain, H. G., "Polymorphism in Pharmaceutical Solids, Second Edition", CRC Press) or a method analogous thereto.

As a solvent used for crystallization of the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof, for example, tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane, diethyl ether, Ether solvents such as tert-butyl methyl ether or anisole, methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, n-propanol, 2-propanol, 2-methyl-1-propanol, n-butanol, 2-butanol Alcohol solvents such as 3-methyl-1-butanol, n-pentanol or ethylene glycol, aromatic hydrocarbon solvents such as toluene, xylene, cumene or tetralin DMF, N, N-dimethylacetamide, formamide, N -Methyl pyrrolidone, D Aprotic polar solvents such as SO or sulfolane, nitrile solvents such as acetonitrile or propionitrile, ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate or ethyl formate, acetone, Ketone solvents such as methyl ethyl ketone, methyl butyl ketone or methyl isobutyl ketone, halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethene, 1,1,2-trichloroethene or chlorobenzene, hexane, pentane, heptane, cyclohexane or Hydrocarbon solvents such as 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 A mixed solvent of these solvents and anilide derivative (I) and a solvent containing a base or acid to form the pharmacologically acceptable salts thereof.

In each reaction of the production method described below, when the raw material compound has an amino group or a carboxyl group, a protective group may be introduced into these groups, and after the reaction, the protective group is optionally deprotected. The target compound can be obtained by

As a protecting group of an amino group, for example, an alkylcarbonyl group having 2 to 6 carbon atoms (eg, acetyl group), benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy) And a carbonyl group), an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group) or a phthaloyl group.

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

The deprotection of the protective group varies depending on the type of protective group, but is carried out according to known methods (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method according thereto. be able to.

The anilide derivative (I) can be obtained, for example, by condensation reaction of an aniline derivative (II) with a phenylacetic acid derivative (III) in the presence of a condensing agent and a base as shown in Scheme 1.

[Wherein, R ¹ , R ² , m, n and p are as defined above. ]

The amount of 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 aniline derivative (II).

Examples of the condensing agent used for the condensation reaction include N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (hereinafter referred to as EDC.HCl), N, N'-carbodiimidazole {{[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethyl ammonium hexafluorophosphate (hereinafter COMU), O- (7-azabenzotriazole- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter HATU) or O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Although uronium hexafluorophosphate (following, HBTU) is mentioned, HATU or HBTU is preferred

The amount of the condensing agent used for 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 for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.

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

The aniline derivative (II) used for 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 according to the type of reagent used, etc., and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran (hereinafter, THF), 1,4-dioxane, Ether solvents such as ethylene glycol dimethyl ether or dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile However, preferred are halogen-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO.

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

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

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

The aniline derivative (II) and the phenylacetic acid derivative (III) used for the condensation reaction can be purchased or can be produced by known methods or methods analogous thereto.

Among the aniline derivatives (II) shown in Scheme 1, an aniline derivative (II-a) in which m is 1 is, for example, as shown in Scheme 2, a reduction reaction of benzoic acid derivative (IV) (step 1) Then, the oxidation reaction (the second step) of the benzyl alcohol derivative (V) obtained in the first step, and subsequently, the benzaldehyde derivative (VI) obtained in the second step and the amine derivative (VII) It can be obtained by a reductive amination reaction (step 3), followed by a reduction reaction (step 4) of the nitrophenyl derivative (VIII) obtained in the third step in the presence of a metal and an acid.

[Wherein, R ¹ , R ² , n and p are as defined above. ]

(Step 1)
Examples of the reducing agent used for the reduction reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, lithium borohydride, lithium triethylborohydride or borane THF complex, but a borane THF complex is preferable .

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

The reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxyethane And ethereal solvents such as benzene and toluene; 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, and more preferably -30 ° C to 50 ° C.

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

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

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

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

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

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

The reaction solvent used for the oxidation reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aromatic amine solvents such as pyridine, dichloromethane, chloroform or Chlorinated solvents such as 2-dichloroethane, ether solvents such as THF or 1,4-dioxane, nitrile solvents such as acetonitrile or propionitrile, or mixed solvents thereof.

The reaction temperature of the oxidation reaction is preferably −78 ° C. to 100 ° C., and 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, and more preferably 0.5 to 48 hours.

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

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

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

As the reducing agent used for the reductive amination reaction, for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride can be mentioned, and sodium triacetoxyborohydride is preferable.

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

The reaction solvent used for the reductive amination reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol and ethanol, diethyl ether And ether solvents such as THF, dimethoxyethane or 1,4-dioxane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixed solvents thereof, but dichloromethane, chloroform or 1,2-dichloroethane Chlorinated solvents such as are preferred.

The reaction temperature of the reductive amination reaction is preferably −78 ° C. to 200 ° C., and 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) at the start of the reaction used for the reductive amination reaction is preferably 1 mmol / L to 1 mol / L.

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

(Step 4)
Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.

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

Examples of the acid used for the reduction reaction include acetic acid, hydrochloric acid or an aqueous solution of ammonium chloride, with preference given to acetic acid or an aqueous solution of ammonium chloride.

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

The reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl ether, THF And ether solvents such as dimethoxyethane or 1,4-dioxane, water, or mixed solvents thereof, but alcohol solvents such as methanol or ethanol and diethyl ether, THF, dimethoxyethane or 1,4-dioxane A mixed solvent of an ether-based solvent and water is preferred.

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

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

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

Among aniline derivatives (II) shown in Scheme 1, aniline derivative (II-b) in which m is 0 is, for example, a fluorophenyl derivative of amine derivative (VII) in the presence of a base as shown in Scheme 3. This can be obtained by the nucleophilic substitution reaction (step 1) for IX), followed by the reduction reaction (step 2) of the nitrophenyl derivative (X) obtained in the first step in the presence of a metal and an acid.

[Wherein, R ¹ , R ² , n and p are as defined above. ]

(Step 1)
The amount of the amine derivative (VII) used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the fluorophenyl derivative (IX).

The amine derivative (VII) used for the nucleophilic substitution reaction may be in free form or may be 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, hydrogen such as sodium hydride, potassium hydride or calcium hydride Metal oxides, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, metal alkoxides such as tert-butyloxy sodium or tert-butyloxy potassium, or mixtures thereof, but triethylamine, diisopropylethylamine or N- Organic bases such as methyl morpholine or sodium hydride, metal hydride compounds such as potassium hydride or calcium hydride are preferred.

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

The reaction solvent used for the nucleophilic substitution reaction is appropriately selected according to the type of the reagent used, etc., 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 an ether solvent such as dimethoxyethane, a nitrile solvent such as acetonitrile or propionitrile, an aromatic hydrocarbon solvent such as benzene or toluene, an aprotic polar solvent such as DMF or DMSO, water or a mixed solvent thereof Although non-polar polar solvents such as DMF or DMSO are preferred.

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

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

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

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

(Step 2)
Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.

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

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

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

Among the amine derivatives (VII) shown in Schemes 2 and 3, tetrahydroisoquinoline derivatives (VII-a) in which n is 1 and p is 2 are, for example, trifluoroacetic anhydride as shown in Scheme 4. Trifluoroacetylation reaction of phenethylamine derivative (XI) according to (Step 1), followed by cyclization reaction of trifluoroacetamide derivative (XII) obtained in Step 1 in the presence of paraformaldehyde and acid (Step 2) ), Followed by hydrolysis reaction (third step) of the tetrahydroisoquinoline derivative (XIII) obtained in the second step.

[Wherein, R ² is as defined above. ]

(Step 1)
The amount of trifluoroacetic anhydride used for the trifluoroacetylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, with respect to phenethylamine derivative (XI).

The reaction solvent used for the trifluoroacetylation reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, for example, DMF, N, N-dimethylacetamide, N -Aprotic 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 Chlorinated solvents such as 1,2-dichloroethane or mixed solvents thereof may be mentioned, and chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferable.

The reaction temperature of the trifluoroacetylation reaction is preferably -20 ° C to 100 ° C, and 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 phenethylamine derivative (XI) used for the trifluoroacetylation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

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

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

(Step 2)
The amount of paraformaldehyde used for 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 for the cyclization reaction include hydrochloric acid, acetic acid, trifluoroacetic acid, concentrated sulfuric acid, concentrated nitric acid, and phosphoric acid, but a mixed solution of acetic acid and concentrated sulfuric acid is preferable.

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

The reaction solvent used for the cyclization reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and, 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, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixtures thereof A solvent is mentioned.

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

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

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

(Third step)
As a base used for a hydrolysis reaction, inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or potassium carbonate, are mentioned, for example.

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

The reaction solvent used for the hydrolysis reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol and ethanol, acetonitrile or pro Nitrile solvents such as piononitrile, aprotic polar solvents such as DMF, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or DMSO, ethers such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane Examples of the solvent include ester solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, and mixed solvents thereof, and alcohol solvents such as methanol or ethanol, DMF, N , N-dimeth Acetamide, N- methyl-2-pyrrolidone or aprotic polar solvents or diethyl ether such as DMSO, THF, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

The reaction temperature of the hydrolysis reaction is preferably -20 ° C to 200 ° C, and 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 for the hydrolysis reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

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

The “RORγ antagonist” means a compound having the function of suppressing the function of RORγ to abolish or attenuate its activity.

"Autoimmune disease" is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient, and includes, for example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus Inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, scleroderma, vasculitis, pemphigus, pemphigus or dermatomyositis. The autoimmune diseases of the present invention also include acne, vitiligo or alopecia areata.

"Allergic disease" is a disease derived from the occurrence of excessive immune reaction against a specific antigen, such as allergic dermatitis, contact dermatitis, atopic dermatitis, allergic rhinitis (pollen Disease, allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma or food allergy.

"Psoriasis" is an inflammatory disease of the skin associated with infiltration and activation of immune cells and concomitant epidermal hyperplasia. Typically, white scales adhere thickly on a red rash in various places throughout the body, causing symptoms of scaling that may fall off. Psoriasis includes, for example, psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, psoriatic psoriasis, psoriatic erythroderma.

The anilide derivative (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof is characterized in that the function of RORγ is suppressed by inhibiting the binding of RORγ to a coactivator. . RORγ is involved in various diseases, and it is known that improvement in the condition or amelioration of symptoms can be expected by suppression of its function. Therefore, the anilide derivative (I) or a hydrate thereof or these drugs Physiologically acceptable salts may be used as medicaments for diseases for which improvement of the pathological condition or amelioration of symptoms can be expected by suppressing the function of RORγ, particularly as a therapeutic agent or preventive agent for autoimmune diseases or allergic diseases it can. The therapeutic agent or prophylactic agent for the above-mentioned autoimmune diseases is preferably multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica Can be used as a therapeutic or preventive agent for atrophy, scleroderma, vasculitis, pemphigus, pemphigus, dermatomyositis, acne, vitiligo or alopecia areata, more preferably a therapeutic or preventive agent for psoriasis It can be used as

Evaluation of the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof having RORγ antagonist activity for inhibiting the binding of RORγ to a coactivator using an in vitro test it can. As an in vitro test, for example, a method of evaluating the binding of RORγ to an agonist (eg, cholesterol) (WO 2012/158784, WO 2013/018695), a ligand binding domain of RORγ and a coacti Methods for assessing binding to beta can be mentioned (WO 2012/064744, WO 2013/018695). In addition, the transcriptional activity inhibitory action of RORγ can be evaluated using various reporter gene assays (WO 2012/158784, WO 2012/064744, WO 2013/018695).

That the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof suppresses the function of RORγ can be obtained by using lymphocyte cells derived from various organs such as spleen or peripheral blood. Production of IL-17 or Th17 cell differentiation can be evaluated as an index. As a method using IL-17 production as an index, for example, a method of measuring IL-17 production by IL-23 stimulation using mouse splenocytes can be mentioned (The Journal of Biological Chemistry, 2003, 278) , No. 3, p. 1910-1914). As a method using Th17 cell differentiation as an index, for example, various cytokines (eg, IL-1β, IL-6, IL-23 and / or TGF are used, using CD4 positive naive T cells derived from mouse splenocytes or human PBMC). Stimulate with -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 to Th17 and produce IL-17 The method includes measuring the amount or the proportion of IL-17 positive cells etc. (WO 2012/158784, WO 2013/018695).

The effectiveness of the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof for the treatment or prevention of an autoimmune disease can be evaluated using a pathological model. As a pathological model, for example, experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, 84, pages 1225-1234), imiquimod-induced psoriasis model (Journal of Immunology, 2009, 182) , P. 5836-5845), collagen arthritis model (Annual Review of Immunology, 1984, Volume 2, 199-218), spontaneous lupus erythematosus model (Nature, volume 404, p. 2000). .995-999), TNBS-induced colitis model (European Journal of Pharmacology, 2001, 431, p. 103-110), ankylosing spondylitis Dell (Arthritis Research & Therapy, 2012, 14, p. 253-265), experimental autoimmune uveitis model (Journal of Immunology, 2006, 36, p. 3071-3081), strong Dermatosis model (Journal of Investigative Dermatology, 1999, 112, p. 456-462), vasculitis model (The Journal of Clinical Investigation, 2002, 110, p. 955-963), pemphigus model (The Journal of Clinical Investigation, 2000, 105, p. 625-631), pemphigoid model (Expe imental Dermatology, 2012, Vol. 21, p. 901-905), Dermatomyositis model (American Journal of Pathology, 1985, Vol. 120, p. 323-325), spontaneous onset model of acne (European Journal of Europe) Dermatology, 2005, vol. 15, p. 459-464, vitiligo model (Pigment Cell & Melanoma Research, 2014, vol. 27, p. 1075-1085), or alopecia areata model (Journal of Investigative Dermatology, Vol. 2015, Volume 135, pp. 2530-2532). The experimental autoimmune encephalomyelitis model is common as a model of multiple sclerosis. In addition, the imiquimod-induced psoriasis model is common as a model of psoriasis.

Further, the effectiveness of the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof for treating or preventing allergic disease can be evaluated using a pathological model. As a pathological model, for example, dinitrofluorobenzene (hereinafter, DNFB) -induced allergic dermatitis model (Pharmacological Reports, 2013, 65, p. 1237-1246), oxazolone-induced atopic dermatitis model (Journal of Investigative) Dermatology, 2014, vol. 134, p. 2122-2130), ovalbumin-induced allergic rhinitis model (Journal of Animal Science, 2010, vol. 81, p. 699-705), IgE-induced allergic conjunctivitis model (vol. British Journal of Ophthalmology, 2012, Vol. 96, p. 1332-1336), allergic gastroenteritis Dell (Gastroenterology, 1997, 113, p. 1560-1569), ovalbumin-induced asthma model (American Journal of Respiratory and Critical Care Medicine, 1997, 156, p. 766-775), or egg white An albumin-induced food allergy model (Clinical & Experimental Allergy, 2005, 35, 461-466) can be mentioned. The DNFB-induced allergic dermatitis model is common as a model of allergic dermatitis, in particular 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 a hydrate thereof or a pharmacologically acceptable salt thereof for treating or preventing autoimmune diseases or allergic diseases can be determined, for example, using the in vitro test described above, for example 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 indicator of the function of RORγ, can be evaluated as an indicator. In addition, the efficacy for treatment or prevention of multiple sclerosis can be evaluated using, for example, a decrease in neurological symptom score, which is a characteristic index of multiple sclerosis, using the above-mentioned experimental autoimmune encephalomyelitis model. It can be evaluated. In addition, the efficacy for treatment or prevention of psoriasis may be evaluated using, for example, the reduction in thickness of skin such as auricle or the like, which increases with the progression of symptoms of the psoriasis model, using the imiquimod-induced psoriasis model described above as an indicator. it can. Moreover, the efficacy for treatment or prevention of allergic dermatitis, particularly contact dermatitis, is increased using, for example, the above-mentioned DNFB-induced allergic dermatitis model, such as the auricle, etc., along with the progress of skin inflammation. The decrease in skin thickness can be evaluated as an index. Moreover, the efficacy for the treatment or prevention of atopic dermatitis is, for example, using the above-mentioned oxazolone-induced atopic dermatitis model to decrease the thickness of the skin such as the auricle that increases with the progress of skin inflammation. It can be evaluated on indicators.

The anilide derivative (I) or a hydrate thereof, or a pharmacologically acceptable salt thereof is a mammal (eg, mouse, rat, hamster, rabbit, dog, cat, monkey, cow, sheep or human) In particular, when it is administered to humans, it can be used as a useful medicament (in particular, a therapeutic or preventive agent for autoimmune diseases or allergic diseases). When the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof is clinically used as a medicament, the anilide derivative (I) or a hydrate thereof or a drug thereof The physiologically acceptable salt can be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier. The above-mentioned medicines, if necessary, binders, excipients, lubricants, disintegrants, sweeteners, stabilizers, flavoring agents, flavors, coloring agents, fluidizers, preservatives, buffers, solution aids Additives such as an agent, an emulsifying agent, a surfactant, a suspending agent, a diluent or an isotonic agent may be appropriately mixed. Pharmaceutically acceptable carriers include these additives. Also, the above-mentioned medicament can be manufactured by a usual method using appropriately these pharmaceutical carriers. The dosage form of the above-mentioned medicine includes, for example, oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or solutions, or topical administration. An ointment, a cream or a patch may be mentioned. Also, it may be a known sustained release preparation.

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

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

As the lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, talc or silica can be mentioned.

Disintegrants include, for example, starch or calcium carbonate.

Sweetening agents include, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.

The above-mentioned medicament preferably contains 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. The dose is appropriately selected according to the patient's condition, age and body weight, and administration method, but as an active ingredient amount for adults, 0.1 μg to 1 g per day for injections and 1 for oral preparations The amount is preferably 1 μg to 10 g per day, and in the case of a patch, 1 μg to 10 g per day, each of which can be administered once or several times.

The above-mentioned medicines may be used together with other medicines in appropriate amounts or in combination for complementation or enhancement of their therapeutic or preventive effects or reduction of dosage.

The present invention will be described in more detail by the following reference examples and examples, but the present invention is not limited thereto.

The compounds used for the synthesis of the compounds of Reference Examples and Examples were commercially available compounds that were not described in the synthesis method. The “room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates mol / mol% for yield, volume% for solvents used in column chromatography and high performance liquid chromatography, and weight% unless otherwise specified. The solvent name shown in the NMR data indicates the solvent used for the measurement. In addition, the 400 MHz NMR spectrum was measured using a JNM-AL400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.) or a JNM-ECS400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.). Chemical shifts are expressed in δ (unit: ppm) relative to tetramethylsilane, and signals are s (singlet), d (doublet), t (triplet), q (quadruple), quint respectively (Quaternion), sept (seven), m (multiple), br (wide), dd (double double), dt (double triple), ddd (double double) , Dq (double quadruple), td (triple doublet), tt (triple triple). When protons such as a hydroxyl group and an amino group are very mild peaks, they are not described. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technologies). Silica gel used silica gel 60 (Merck), amine silica gel used amine silica gel DM 1020 (Fuji Silysia Chemical Ltd.), and chromatography used YFLC W-prep 2 XY (Yamazen Co.).

(Reference Example 1) Synthesis of 2-chloro-4-nitrobenzaldehyde:

Dissolve 2-chloro-4-nitrobenzoic acid (10.0 g, 49.6 mmol) in THF (99.2 mL), add borane THF complex-THF solution (0.95 M, 62.7 mL, 59.5 mmol) to 0. Add at ° C and warm to room temperature. After stirring for 2 hours at 50 ° C., the reaction solution was added to 1 M 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 crude product obtained was used for 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 is filtered, and the filtrate is 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. The
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.11 (d, J = 8.2 Hz, 1 H), 8.23 (dd, J = 8.2, 1.8 Hz, 1 H), 8.36 ( d, J = 1.8 Hz, 1 H), 10. 55 (s, 1 H).

Reference Example 2 Synthesis of 2-Fluoro-4-nitrobenzaldehyde:

Dissolve 2-fluoro-4-nitrobenzoic acid (1.00 g, 5.40 mmol) in THF (10.1 mL) and add borane THF complex-THF solution (0.90 M, 9.00 mL, 8.10 mmol) to 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 crude product obtained was used for the subsequent reaction without purification.
The above crude product is 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 6 wt% aqueous sodium hypochlorite solution (1.89 mL) were added at 0.degree. After stirring for 3 hours at the same temperature, distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated aqueous sodium thiosulfate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 90/10) to give the title compound (hereinafter referred to as the compound of Reference Example 2) (0.128 g, 0.757 mmol, 14 %) As a yellow solid.
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.degree. After stirring at room temperature for 2 hours, the reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15) to give the title compound (below) The compound of Reference Example 3 (0.525 g, 2.27 mmol, 61%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.34 (s, 3 H), 2.85 (t, J = 6.9 Hz, 2 H), 3. 60 (q, J = 6.6 Hz, 2 H) , 6.28 (brs, 1 H), 7.08 (d, J = 8.2 Hz, 2 H), 7.15 (d, J = 7.8 Hz, 2 H).
ESI-MS: m / z = 232 (M + H) ⁺ .

Reference Example 4 Synthesis of 2,2,2-trifluoro-1- (7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one:

The compound of Reference Example 3 (0.525 g, 2.27 mmol) and paraformaldehyde (0.102 g, 3.41 mmol) are added to a mixture of concentrated sulfuric acid (0.454 mL) and acetic acid (2.27 mL) at 0 ° C. The 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, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-80 / 20) to give the title compound (hereinafter referred to as the compound of Reference Example 4) (0.335 g, 1.38 mmol, 61) %) As a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.33 (s, 3 H), 2.91 (q, J = 5.8 Hz, 2 H), 3.83 (t, J = 5.9 Hz, 1. 3H), 3.87 (t, J = 6.2 Hz, 0.7 H), 4.71 (s, 0.7 H), 4.76 (s, 1.3 H), 6.95 (d, J = 11.9 Hz, 1 H), 7.06 (d, J = 10.1 Hz, 2 H).

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 2M 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 is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 5) (0.185 g, 1.26 mmol, 91%) Obtained as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.29 (s, 3 H), 2.75 (t, J = 5.7 Hz, 2 H), 3. 12 (t, J = 5.9 Hz, 2 H) , 3.98 (s, 2H), 6.83 (s, 1 H), 6.95 (d, J = 7.3 Hz, 1 H), 6.99 (d, J = 7.8 Hz, 1 H).
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) is 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) are added at room temperature. The After stirring for 10 minutes at room temperature, sodium triacetoxyborohydride (0.393 g, 1.86 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate 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 resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15) to give the title compound (hereinafter referred to as the compound of Reference Example 6) (0.349 g, 1.01 mmol, 89) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.29 (s, 3 H), 2.81 (t, J = 5.9 Hz, 2 H), 2.91 (t, J = 5.7 Hz, 2 H) , 3.69 (s, 2H), 3.85 (s, 2H), 6.83 (s, 1H), 6.98 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1 H), 7.84 (d, J = 8.6 Hz, 1 H), 8.11 (dd, J = 8.6, 2.3 Hz, 1 H), 8. 26 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 317 (M + H) ⁺ .

Reference Example 7 Synthesis of 3-chloro-4-((7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:

The compound of Reference Example 6 (0.335 g, 1.06 mmol) is dissolved in THF (1.06 mL), ethanol (1.06 mL), distilled water (1.06 mL), iron powder (0.295 g, 5.29 mmol) ) And acetic acid (0.303 mL, 5.29 mmol) were added at room temperature. After stirring at 50 ° C. for 2 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate 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 resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 65/35) to give the title compound (hereinafter, the compound of Reference Example 7) (0.271 g, 0.945 mmol, 89) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.27 (s, 3 H), 2.76 (t, J = 5.7 Hz, 2 H), 2.85 (t, J = 5.7 Hz, 2 H) , 3.63 (s, 2H), 3.68 (s, 4H), 6.56 (dd, J = 8.4, 2.5 Hz, 1 H), 6.71 (d, J = 2.3 Hz, 1H), 6.82 (s, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.99 (d, J = 7.2 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 1 H).
ESI-MS: m / z = 287 (M + H) ^<+> .

Reference Example 8 Synthesis of Ethyl 2- (4- (ethylsulfonyl) phenyl) 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 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 crude product obtained was used for 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 is filtered, and the filtrate is washed with 1 M aqueous sodium hydroxide solution, distilled water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate is 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 H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.4 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 3.12 (q, J =) 7.4 Hz, 2 H), 3.72 (s, 2 H), 4. 18 (q, J = 7.1 Hz, 2 H), 7. 50 (d, J = 8.2 Hz, 2 H), 7.87 ( d, J = 8.2 Hz, 2 H).

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 H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.09 (t, J = 7.5 Hz, 3 H), 3.28 (q, J = 7.5 Hz, 2 H), 3.74 (s, 2H), 7.54 (d, J = 8.6 Hz, 2 H), 7.82 (d, J = 8.6 Hz, 2 H).

Example 1 N- (3-Chloro-4-((7-methyl-3,4-dihydroisoquinolin-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) are dissolved in DMF (0.465 mL), and HATU (0.0636 g, 0.167 mmol) is dissolved. And diisopropylethylamine (0.0365 mL, 0.209 mmol) were added at room temperature. After stirring for 2 hours at the same temperature, distilled water was added to the reaction solution, 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 resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 to 25/75) to give the title compound (compound of Example 1 below) (0.0375 g, 0.0754 mmol, 54) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5 Hz, 3 H), 2.27 (s, 3 H), 2.76 (t, J = 5.7 Hz, 2 H) , 2.85 (t, J = 5.9 Hz, 2 H), 3. 13 (q, J = 7.5 Hz, 2 H), 3.63 (s, 2 H), 3.73 (s, 2 H), 3 .81 (s, 2 H), 6.81 (s, 1 H), 6. 95 (d, J = 8.7 Hz, 1 H), 7.00 (d, J = 7.8 Hz, 1 H), 7.16 (S, 1 H), 7. 50 (d, J = 8.7 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7. 66 (d, J = 2.3 Hz, 1 H) , 7.92 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 497 (M + H) ⁺ .

Reference Example 10 Synthesis of 2,2,2-trifluoro-N- (4- (trifluoromethyl) phenethyl) acetamide:

Dissolve 2- (4-trifluoromethylphenyl) ethylamine (1.68 mL, 10.6 mmol) in dichloromethane (35.2 mL) and add trifluoroacetic anhydride (1.64 mL, 11.6 mmol) at 0 ° C. The After stirring at room temperature for 4 hours, the reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 75/25) to give the title compound (below) The compound of Reference Example 10 (2.60 g, 9.12 mmol, 86%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.97 (t, J = 7.1 Hz, 2 H), 3.65 (q, J = 6.7 Hz, 2 H), 6.30 (brs, 1 H) , 7.32 (d, J = 8.2 Hz, 2 H), 7. 60 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 284 (M-H) ^- .

Reference Example 11 Synthesis of 2,2,2-trifluoro-1- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) ethan-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 mixture of concentrated sulfuric acid (6.54 mL) and acetic acid (5.02 mL) at 0 ° C. The 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, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25) to give the title compound (hereinafter referred to as the compound of Reference Example 11) (0.961 g, 3.23 mmol, 92) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.00 to 3.04 (m, 2 H), 3.88 (t, J = 5.7 Hz, 1.3 H), 3.93 (t, J =) 6.2 Hz, 0.7 Hz), 4.81 (s, 0.7 H), 4.85 (s, 1.3 H), 7.31 (t, J = 9.1 Hz, 1 H), 7.42 ( d, J = 11.4 Hz, 1 H), 7.49 (t, J = 9.4 Hz, 1 H).

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 2M 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 is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 12) (0.251 g, 1.25 mmol, 93%) Obtained as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.7 Hz, 2 H), 3.16 (t, J = 5.9 Hz, 2 H), 4.06 (s, 2 H) , 7.20 (d, J = 8.2 Hz, 1 H), 7. 27 (s, 1 H), 7. 37 (d, J = 8.2 Hz, 1 H).
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 for 10 minutes at room temperature, sodium triacetoxyborohydride (15.5 g, 73.1 mmol) was added at 0 ° C. After stirring at room temperature for 14 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate 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 H-NMR (400 MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.7 Hz, 2 H), 3.00 (t, J = 5.5 Hz, 2 H), 3.76 (s, 2 H) , 3.88 (s, 2 H), 7. 25 (d, J = 7.8 Hz, 1 H), 7. 27 (s, 1 H), 7.41 (d, J = 7.8 Hz, 1 H), 7 80 (d, J = 8.7 Hz, 1 H), 8.13 (dd, J = 8.7, 2.3 Hz, 1 H), 8.27 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

Reference Example 14 Synthesis of 3-chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:

The compound of Reference Example 13 (15.6 g, 42.1 mmol) is dissolved in THF (42.1 mL), ethanol (42.1 mL), distilled water (42.1 mL), iron powder (11.8 g, 210 mmol) and Acetic acid (12.0 mL, 210 mmol) was added at room temperature. After stirring at 50 ° C. for 1.5 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate 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) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.80 (t, J = 5.7 Hz, 2 H), 2.94 (t, J = 5.7 Hz, 2 H), 3.70 (d, J = 2.7 Hz, 6 H), 6.57 (dd, J = 8.5, 2.5 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 7.20 (d, J = 8 2 Hz, 1 H), 7. 25 (d, J = 8.7 Hz, 2 H), 7. 26 (s, 1 H), 7. 36 (d, J = 7.8 Hz, 1 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

Example 2 N- (3-Chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) -2- (4- (ethyl) Synthesis of sulfonyl) phenyl) acetamide:

Using the compound of Reference Example 14 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except for the above, the title compound (the compound of Example 2 below) (0.0475 g, 0.0862 mmol, 65) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.5 Hz, 3 H), 2.80 (t, J = 5.7 Hz, 2 H), 2.94 (t, J = 5.7 Hz, 2 H), 3. 13 (q, J = 7.5 Hz, 2 H), 3.7 1 (s, 2 H), 3.77 (s, 2 H), 3.81 (s, 2 H), 7 .21 (d, J = 7.8 Hz, 1 H), 7.24 (s, 1 H), 7.31 (dd, J = 8.7, 1.8 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.41 (brs, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 2 H), 7.69 ( d, J = 2.3 Hz, 1 H, 7.89 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 551 (M + H) ⁺ .

Reference Example 15 Synthesis of 2- (2-fluoro-4-nitrobenzyl) -7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:

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

Reference Example 16 Synthesis of 3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:

Using the compound of Reference Example 15 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 16) (0.0695 g, 0.214 mmol, 61) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.77 (t, J = 5.9 Hz, 2 H), 2.93 (t, J = 5.7 Hz, 2 H), 3.66 (s, 4 H) , 3.75 (brs, 2H), 6.39 (dd, J = 11.9, 2.3 Hz, 1 H), 6.44 (dd, J = 8.2, 2.3 Hz, 1 H), 7. 15 (t, J = 8.2 Hz, 1 H), 7. 18 (d, J = 7.3 Hz, 1 H), 7. 25 (s, 1 H), 7. 35 (dd, J = 8.2, 1 .4 Hz, 1 H).
ESI-MS: m / z = 325 (M + H) ⁺ .

Example 3 2- (4- (ethylsulfonyl) phenyl) -N- (3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) Synthesis of methyl) phenyl) acetamide:

Using the compound of Reference Example 16 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except the above, the title compound (the compound of Example 3 below) (0.0326 g, 0.0610 mmol, 66) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.3 Hz, 3 H), 2.77 (t, J = 5.9 Hz, 2 H), 2.93 (t, J = 5.7 Hz, 2 H), 3. 13 (q, J = 7.5 Hz, 2 H), 3. 66 (s, 2 H), 3.7 1 (s, 2 H), 3.82 (s, 2 H), 7 .06 (dd, J = 8.2, 1.8 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 2 H), 7.24 (s, 1 H), 7.35-7.39 ( m, 2H), 7.51 (dd, J = 11.7, 2.1 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.92 (d, J = 8.2 Hz) , 2H).
ESI-MS: m / z = 535 (M + H) ⁺ .

Reference Example 17 Synthesis of 2,2,2-trifluoro-N- (3- (trifluoromethyl) phenethyl) acetamide:

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

Reference Example 18 Synthesis of 2,2,2-trifluoro-1- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one:

The compound of Reference Example 17 (1.00 g, 3.51 mmol) and paraformaldehyde (0.158 g, 5.26 mmol) were added to a mixture of concentrated sulfuric acid (6.54 mL) and acetic acid (5.02 mL) at 0 ° C. The 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, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25) to give the title compound (hereinafter referred to as the compound of Reference Example 18) (0.502 g, 1.69 mmol, 48) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.02 (q, J = 6.1 Hz, 2 H), 3.88 (t, J = 5.9 Hz, 1.3 H), 3.93 (t, J = 6.2 Hz, 0.7 Hz), 4.80 (s, 0.7 H), 4.85 (s, 1.3 H), 7.23-7.30 (m, 1 H), 7.45 ( d, J = 9.6 Hz, 1 H), 7. 50 (d, J = 8.7 Hz, 1 H).

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 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 is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 19) (0.185 g, 0.920 mmol, 91%) Obtained as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.9 Hz, 2 H), 3.16 (t, J = 5.9 Hz, 2 H), 4.05 (s, 2 H) , 7.11 (d, J = 7.8 Hz, 1 H), 7. 35 (s, 1 H), 7. 36 (d, J = 8.7 Hz, 1 H).
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 for 15 minutes at room temperature, sodium triacetoxyborohydride (11.9 g, 55.9 mmol) was added at 0 ° C. After stirring at room temperature for 4 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate 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 20) (12.1 g, 32.5 mmol, 87) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.85 (t, J = 5.7 Hz, 2 H), 3.00 (t, J = 5.7 Hz, 2 H), 3.77 (s, 2 H) , 3.88 (s, 2H), 7.12 (d, J = 7.8 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.40 (s, 1 H), 7 80 (d, J = 8.7 Hz, 1 H), 8.13 (dd, J = 8.7, 2.3 Hz, 1 H) 8.27 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

Reference Example 21 Synthesis of 3-chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:

The compound of Reference Example 20 (11.5 g, 31.0 mmol) is dissolved in THF (38.8 mL), ethanol (38.8 mL), distilled water (38.8 mL), iron powder (8.66 g, 155 mmol) and 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 mixture, 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, quantitative) ) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.80 (t, J = 5.7 Hz, 2 H), 2.93 (t, J = 5.7 Hz, 2 H), 3.70 (s, 6 H) , 6.57 (dd, J = 8.2, 2.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 7. 10 (d, J = 7.3 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 7. 35 (s, 1 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

Example 4 N- (3-Chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-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) are dissolved in DMF (78.0 mL), and HATU (10.7 g, 28.2 mmol) And diisopropylethylamine (6.15 mL, 35.2 mmol) were added at room temperature. After stirring at the same temperature for 26 hours, distilled water was added to the reaction solution, and 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 with diethyl ether / ethanol (volume ratio 4: 1). The mixture was filtered and washed with diethyl ether. The obtained crystals were dried under vacuum to give the title compound (hereinafter, the compound of Example 4) (9.73 g, 17.6 mmol, 75%) as white crystals.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5 Hz, 3 H), 2.80 (t, J = 5.9 Hz, 2 H), 2.94 (t, J = 6.2 Hz, 2 H), 3. 13 (q, J = 7.3 Hz, 2 H), 3. 70 (s, 2 H), 3. 76 (s, 2 H), 3.82 (s, 2 H), 7 .09 (d, J = 7.8 Hz, 1 H), 7.14 (s, 1 H), 7. 29 (dd, J = 8.0, 2.1 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.36 (s, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.67 ( d, J = 1.8 Hz, 1 H, 7.93 (d, J = 8.7 Hz, 2 H).
ESI-MS: m / z = 551 (M + H) ⁺ .

Reference Example 22 Synthesis of 1- (2-chloro-4-nitrobenzyl) indoline:

The title compound (hereinafter, the compound of Reference Example 22) (0.406 g, 1.41 mmol, 84%) was browned by using indoline instead of the compound of Reference Example 5 and using the same procedure as in Reference Example 6 except the above. Obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.09 (t, J = 8.2 Hz, 2 H), 3.49 (t, J = 8.2 Hz, 2 H), 4.39 (s, 2 H) , 6.33 (d, J = 7.8 Hz, 1 H), 6. 74 (td, J = 7.3, 0.9 Hz, 1 H), 7.05 (td, J = 7.8, 1.4 Hz , 1 H), 7.15 (d, J = 7.8 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 8. 10 (dd, J = 8.7, 2.3 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 289 (M + H) ⁺ .

Reference Example 23 Synthesis of 3-chloro-4- (indoline-1-ylmethyl) aniline:

Using the compound of Reference Example 22 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except the above, the title compound (hereinafter, the compound of Reference Example 23) (0.139 g, 0.537 mmol, 52 %) As a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.98 (t, J = 8.2 Hz, 2 H), 3.36 (t, J = 8.2 Hz, 2 H), 3.69 (brs, 2 H) , 4.23 (s, 2 H), 6.50 (d, J = 7.8 Hz, 1 H), 6.54 (dd, J = 8.2, 2.7 Hz, 1 H), 6.66 (td, J = 7.3, 0.9 Hz, 1 H, 6.73 (d, J = 2.3 Hz, 1 H), 7.05 (td, J = 7.8, 1.4 Hz, 1 H), 7.09 (D, J = 7.8 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 1 H).
ESI-MS: m / z = 259 (M + H) ⁺ .

Example 5 Synthesis of N- (3-Chloro-4- (indoline-1-ylmethyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:

Using the compound of Reference Example 23 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except for the above, the title compound (the compound of Example 5 below) (0.0406 g, 0.0866 mmol, 75) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.3 Hz, 3 H), 3.01 (t, J = 8.2 Hz, 2 H), 3.13 (q, J = 7.5 Hz, 2 H), 3. 39 (t, J = 8.2 Hz, 2 H), 3.81 (s, 2 H), 4.28 (s, 2 H), 6.41 (d, J = 7. 8 Hz, 1 H), 6.68 (t, J = 7.3 Hz, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 7.1 1 (d, J = 7.3 Hz, 1 H), 7.18 (brs, 1 H), 7.23 (dd, J = 8.5, 2.1 Hz, 1 H), 7. 39 (d, J = 8.2 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.71 (d, J = 1.8 Hz, 1 H), 7. 92 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 469 (M + H) ^<+> .

Reference Example 24 Synthesis of 1- (2-chloro-4-nitrobenzyl) -5-methylindoline:

The title compound (hereinafter, the compound of Reference Example 24) (0.407 g, 1.34 mmol, 90%) was prepared by using 5-methylindoline instead of the compound of Reference Example 5 and using the same procedure as in Reference Example 6 except the above. ) As a brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.26 (s, 3 H), 3.04 (t, J = 8.0 Hz, 2 H), 3.44 (t, J = 8.2 Hz, 2 H) , 4. 34 (s, 2 H), 6. 24 (d, J = 8.2 Hz, 1 H), 6. 85 (d, J = 7.8 Hz, 1 H), 6.99 (s, 1 H), 7 70 (d, J = 8.7 Hz, 1 H), 8.09 (dd, J = 8.7, 2.3 Hz, 1 H), 8.28 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 303 (M + H) ⁺ .

Reference Example 25 Synthesis of 3-chloro-4-((5-methylindoline-1-yl) methyl) aniline:

Using the compound of Reference Example 24 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 25) (0.307 g, 1.13 mmol, 85 %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.24 (s, 3 H), 2.93 (t, J = 8.4 Hz, 2 H), 3.32 (t, J = 8.2 Hz, 2 H) , 3.68 (brs, 2H), 4.18 (s, 2H), 6.41 (d, J = 7.7 Hz, 1 H), 6.54 (dd, J = 8.2, 2.3 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.93 (s, 1 H), 7.20 (d, J = 8.2 Hz, 1 H).
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:

Using the compound of Reference Example 25 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except the above, the title compound (the compound of Example 6 below) (0.0303 g, 0.0627 mmol, 57) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.3 Hz, 3 H), 2.25 (s, 3 H), 2.96 (t, J = 8.2 Hz, 2 H) , 3.13 (q, J = 7.5 Hz, 2 H), 3. 35 (t, J = 8.2 Hz, 2 H), 3.81 (s, 2 H), 4.23 (s, 2 H), 6 .32 (d, J = 7.8 Hz, 1 H), 6.84 (d, J = 7.8 Hz, 1 H), 6.94 (s, 1 H), 7.14 (s, 1 H), 7.23 (Dd, J = 8.2, 2.3 Hz, 1 H), 7.40 (d, J = 8.7 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.71 (d d, J = 2.3 Hz, 1 H), 7.92 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 483 (M + H) ⁺ .

Reference Example 26 Synthesis of 2- (2-chloro-4-nitrobenzyl) isoindoline:

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

Reference Example 27 Synthesis of 3-chloro-4- (isoindoline-2-ylmethyl) aniline:

Using the compound of Reference Example 26 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 27) (0.181 g, 0.700 mmol, 67 %) As a brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.92 (s, 2 H), 3.97 (s, 4 H), 6.58 (dd, J = 8.2, 2.7 Hz, 1 H), 6 73 (d, J = 2.3 Hz, 1 H), 7.17 (s, 4 H), 7. 28 (d, J = 8.7 Hz, 1 H).
ESI-MS: m / z = 259 (M + H) ⁺ .

Example 7 Synthesis of N- (3-Chloro-4- (isoindoline-2-ylmethyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:

Using the compound of Reference Example 27 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except the above, the title compound (the compound of Example 7 below) (0.0233 g, 0.0497 mmol, 43) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5 Hz, 3 H), 3.13 (q, J = 7.5 Hz, 2 H), 3.82 (s, 2 H) , 3.98 (s, 4 H), 3.99 (s, 2 H), 7. 18 (s, 5 H), 7.3 1 (dd, J = 8.7, 2.3 Hz, 1 H), 7.50 (D, J = 8.2 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.67 (d, J = 2.3 Hz, 1 H), 7.93 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 469 (M + H) ^<+> .

Reference Example 28 Synthesis of 2- (2-chloro-4-nitrobenzyl) -5- (trifluoromethyl) isoindoline:

Using 5- (trifluoromethyl) isoindoline instead of the compound of Reference Example 5 and using the same procedure as in Reference Example 6 except for this, the title compound (hereinafter, the compound of Reference Example 28) (0.106 g, 0 .297 mmol, 79%) were obtained as a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.09 (s, 4 H), 4. 13 (s, 2 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.47 (s , 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7. 80 (d, J = 8.2 Hz, 1 H), 8. 15 (dd, J = 8.2, 2.3 Hz, 1H), 8.28 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 357 (M + H) ⁺ .

Reference Example 29 Synthesis of 3-chloro-4-((5- (trifluoromethyl) isoindolin-2-yl) methyl) aniline:

Using the compound of Reference Example 28 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except the above, the title compound (hereinafter, the compound of Reference Example 29) (0.0568 g, 0.174 mmol, 59) %) As a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.71 (s, 2 H), 3.93 (s, 2 H), 4.00 (s, 4 H), 6.58 (dd, J = 8.2 , 2.3 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 7. 25 (d, J = 8.2 Hz, 1 H), 7.27 (d, J = 7.3 Hz, 1H), 7.43 (s, 1 H), 7.44 (d, J = 8.2 Hz, 1 H).
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:

Using the compound of Reference Example 29 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except the above, the title compound (the compound of Example 8 below) (0.0115 g, 0.0214 mmol, 25) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5 Hz, 3 H), 3.13 (q, J = 7.3 Hz, 2 H), 3.82 (s, 2 H) , 4.00 (s, 2 H), 4.01 (s, 4 H), 7.19 (brs, 1 H), 7. 28 (d, J = 7.8 Hz, 1 H), 7.32 (dd, J = 8.5, 2.1 Hz, 1 H), 7.43-7. 48 (m, 3 H), 7.56 (d, J = 8.7 Hz, 2 H), 7.67 (d, J = 1. 8 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 2 H).
ESI-MS: m / z = 537 (M + H) ⁺ .

Reference Example 30 Synthesis of 2- (2-chloro-4-nitrophenyl) -1,2,3,4-tetrahydroisoquinoline:

Dissolve 1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g, 5.89 mmol) in DMSO (11.8 mL), 3-chloro-4-fluoronitrobenzene (1.04 g, 5.89 mmol) and N-methyl morpholine (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 H-NMR (400 MHz, CDCl ₃ ) δ: 3.07 (t, J = 5.7 Hz, 2 H), 3.62 (t, J = 5.7 Hz, 2 H), 4.43 (s, 2 H) , 7.13 (t, J = 6.8 Hz, 2 H), 7.21-7. 27 (m, 3 H), 8.11 (td, J = 5.7, 2.7 Hz, 1 H), 8. 29 (d, J = 2.5 Hz, 1 H).
ESI-MS: m / z = 289 (M + H) ⁺ .

Reference Example 31 Synthesis of 3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) aniline:

Using the compound of Reference Example 30 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 31) (0.872 g, 3.37 mmol, 97 %) As a pale red oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.00 (t, J = 5.7 Hz, 2 H), 3.27 (t, J = 5.9 Hz, 2 H), 3.55 (s, 2 H) , 4.17 (s, 2 H), 6.56 (dd, J = 8.6, 2.7 Hz, 1 H), 6.78 (d, J = 2.7 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 1 H), 7.09-7.11 (m, 1 H), 7.15-7.20 (m, 3 H).
ESI-MS: m / z = 259 (M + H) ⁺ .

Example 9 Synthesis of N- (3-Chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:

Using the compound of Reference Example 31 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except the above, the title compound (the compound of Example 9 below) (0.0537 g, 0.114 mmol, 59) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.5 Hz, 3 H), 3.00 (t, J = 5.7 Hz, 2 H), 3.12 (q, J = 7.4 Hz, 2 H), 3. 35 (t, J = 5.9 Hz, 2 H), 3.79 (s, 2 H), 4.22 (s, 2 H), 7.05 (d, J = 9. 1 Hz, 1 H), 7.07-7. 10 (m, 1 H), 7.15-7. 18 (m, 3 H), 7. 30 (s, 1 H), 7.33 (dd, J = 8. 6, 2.3 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 2 H), 7. 60 (d, J = 2.7 Hz, 1 H), 7.89 (d, J = 8.6 Hz , 2H).
ESI-MS: m / z = 469 (M + H) ^<+> .

Reference Example 32 Synthesis of 3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) aniline:

Dissolve 7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (0.500 g, 2.10 mmol) in DMSO (10.5 mL), 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 crude product obtained was used for the subsequent reaction without purification.
The above crude product is 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, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate 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 H-NMR (400 MHz, CDCl ₃ ) δ: 3.03 (t, J = 5.4 Hz, 2 H), 3.25 (t, J = 5.7 Hz, 2 H), 3.57 (s, 2 H) , 4.15 (s, 2H), 6.54 (dd, J = 8.6, 2.7 Hz, 1 H), 6.76 (d, J = 2.7 Hz, 1 H), 6.92 (t, J = 4.1 Hz, 1 H), 7.24 (t, J = 4.1 Hz, 1 H), 7.32 (s, 1 H), 7.40 (d, J = 7.7 Hz, 1 H).
ESI-MS: m / z = 327 (M + H) ⁺ .

Example 10 N- (3-Chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) -2- (4- (ethylsulfonyl) phenyl ) Synthesis of acetamide:

Using the compound of Reference Example 32 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except the above, the title compound (the compound of Example 10) (0.0571 g, 0.106 mmol, 69) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5 Hz, 3 H), 3.06 (t, J = 5.4 Hz, 2 H), 3.13 (q, J = 7.4 Hz, 2 H), 3. 35 (t, J = 5.9 Hz, 2 H), 3. 80 (s, 2 H), 4. 25 (s, 2 H), 7.04 (d, J = 8). 6 Hz, 1 H), 7. 27 (d, J = 6.3 Hz, 1 H), 7. 29 (s, 1 H), 7.33-7. 35 (m, 2 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 2 H), 7.63 (d, J = 2.7 Hz, 1 H), 7.89 (d, J = 8.2 Hz, 2 H ).
ESI-MS: m / z = 537 (M + H) ⁺ .

Reference Example 33 Synthesis of 2- (2-chloro-4-nitrophenyl) -6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:

A procedure similar to Reference Example 30 is used except that 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride is used instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride. The title compound (hereinafter, the compound of Reference Example 33) (1.10 g, 3.08 mmol, 85%) was obtained as a yellow-brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.13 (t, J = 5.9 Hz, 2 H), 3.61 (t, J = 5.7 Hz, 2 H), 4.45 (s, 2 H) , 7.13 (t, J = 8.7 Hz, 1 H), 7.24-7. 27 (m, 1 H), 7.45-7.47 (m, 2 H), 8.13 (dd, J = 9.1, 2.7 Hz, 1 H), 8.30 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 357 (M + H) ⁺ .

Reference Example 34 Synthesis of 3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) aniline:

Using the compound of Reference Example 33 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 34) (0.940 g, 2.88 mmol, 99) %) As a tan oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.05 (t, J = 5.7 Hz, 2 H), 3.28 (t, J = 5.7 Hz, 2 H), 3.58 (s, 2 H) , 4.19 (s, 2 H), 6.57 (dd, J = 8.7, 2.7 Hz, 1 H), 6.79 (d, J = 2.7 Hz, 1 H), 6.94 (d, 7 J = 8.7 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H), 7.38-7.42 (m, 2 H).
ESI-MS: m / z = 327 (M + H) ⁺ .

Example 11 N- (3-Chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) -2- (4- (ethylsulfonyl) phenyl ) Synthesis of acetamide:
Using the compound of Reference Example 34 instead of the compound of Reference Example 7, and according to the same procedure as Example 1 except the above, the title compound (the compound of Example 11 below) (0.0820 g, 0.153 mmol, quantitative) ) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.3 Hz, 3 H), 3.05 (t, J = 5.7 Hz, 2 H), 3.12 (q, J = 7.5 Hz, 2 H), 3.34 (t, J = 5.7 Hz, 2 H), 3.78 (s, 2 H), 4.24 (s, 2 H), 7.03 (d, J = 8. 7 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7. 36 (dd, J = 8.7, 2.3 Hz, 1 H), 7.41 (d, J = 8.2 Hz , 1 H), 7.42 (s, 1 H), 7.52 (d, J = 8.7 Hz, 2 H), 7.54 (s, 1 H), 7.62 (d, J = 2.7 Hz, 1 H) ), 7.85 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 537 (M + H) ⁺ .

Reference Example 35 Synthesis of 2- (2-chloro-4-nitrobenzyl) -1,2,3,4-tetrahydroisoquinoline:

The title compound (hereinafter, the compound of Reference Example 35) (0.370 g), using 1,2,3,4-tetrahydroisoquinoline instead of the compound of Reference Example 5, and using the same procedure as in Reference Example 6 except the above. 1.22 mmol, 81%) were obtained as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.83 (t, J = 5.7 Hz, 2 H), 2.96 (t, J = 5.7 Hz, 2 H), 3.73 (s, 2 H) , 3.86 (s, 2 H), 7.00-7.02 (m, 1 H), 7.1 1-7. 17 (m, 3 H), 7.8 4 (d, J = 8.2 Hz, 1 H) , 8.11 (dd, J = 8.6, 2.3 Hz, 1 H), 8.26 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 303 (M + H) ⁺ .

Reference Example 36 Synthesis of 3-chloro-4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:

Using the compound of Reference Example 35 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 36) (0.306 g, 1.12 mmol, 92 %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.78 (t, J = 5.9 Hz, 2 H), 2.89 (t, J = 5.9 Hz, 2 H), 3.67 (brs, 4 H) , 3.69 (s, 2 H), 6.57 (dd, J = 8.2, 2.7 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 6.98-7. 01 (m, 1 H), 7.07-7. 12 (m, 3 H), 7. 28 (d, J = 8.2 Hz, 1 H).
ESI-MS: m / z = 273 (M + H) ⁺ .

Example 12 Synthesis of N- (3-Chloro-4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide:

Using the compound of Reference Example 36 instead of the compound of Reference Example 7, and using the same procedure as Example 1 except the above, the title compound (the compound of Example 12 below) (0.0293 g, 0.0607 mmol, 55) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.5 Hz, 3 H), 2.78 (t, J = 5.7 Hz, 2 H), 2.90 (t, J = 5.7 Hz, 2 H), 3. 13 (q, J = 7.5 Hz, 2 H), 3. 68 (s, 2 H), 3. 75 (s, 2 H), 3.81 (s, 2 H), 6 .97-7.00 (m, 1 H), 7.09-7. 14 (m, 3 H), 7. 18 (s, 1 H), 7. 26-7. 29 (m, 1 H), 7. 50 (D, J = 8.7 Hz, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.67 (d, J = 2.3 Hz, 1 H), 7.92 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 483 (M + H) ⁺ .

(Example 13) RORγ-coactivator binding inhibitory action:
The inhibitory effect of the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof on the binding of the ligand binding domain of RORγ (hereinafter referred to as RORγ-LBD) to a coactivator It was evaluated using the resolved fluorescence energy transfer LanthaScreen ^TM of (TR-FRET) invitrogen company using the TR-FRET Retinoid-Related Orphan Receptor (ROR) gamma Coactivator Assay kit.

The test compound was dissolved in DMSO and then diluted with a 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D (invitogen) to a final DMSO concentration of 1%. To each well of a 384 well black plate (Corning), 4 nmol / L GST-fused RORγ-LBD (invitogen) diluted with the above buffer and a test compound were added. A test compound-free and GST-fused RORγ-LBD-free (background), and a test compound-free and GST-fused RORγ-LBD-added (control) wells were provided. 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 at 520 nm / fluorescence at 495 nm) was calculated.

Fold change at the time of test compound addition (Ratio at the time of test compound addition / Ratio of background), Fold change of control (Ratio of control / Ratio of background), and Fold change of background (Ratio of background / background) After calculating the ratio of the ground, 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 upon addition of test compound) − (Fold change)) / ((Fold change) − (Fold change) )) × 100 ... Formula 1

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

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

Example 14 Inhibitory Effect on IL-17 Production in Mouse Splenocytes:
The suppressive effect of anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof on IL-23 production by IL-23 stimulation using mouse splenocytes, The Journal of Biological Chemistry 2003, 278, No. 3, p. The method described in 1910-1914 was partially modified and evaluated.

A single cell suspension was prepared from the spleen of a C57BL / 6J mouse (male, 8 to 26 weeks old) (Nihon Charles River Co., Ltd.), and splenocytes were prepared using Histopaque-1083 (Sigma). The culture medium is RPMI 1640 medium (Gibco), 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 Research Institute, Inc.) was added and used. The test compound was dissolved in DMSO and then diluted to a final concentration of 0.1% in culture medium. Splenocytes (3 × 10 ⁵ cells / well) prepared in culture medium are seeded in wells of a 96 well flat bottom plate (Corning Co.), and a test compound and 10 ng / mL of human IL-23 (R & D systems) are added. Te, 37 ° C., and cultured for 3 days under the conditions of 5% CO _2. In addition, a human IL-23 non-added and a test compound non-added, and a human IL-23 added and test compound non-added well were provided. After completion of the culture, the culture supernatant was collected, and the amount of IL-17 produced in the supernatant was quantified by ELISA (R & D systems).

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

IL-17 production suppression rate (%) = (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) )) / ((The amount of IL-17 produced with addition of IL-23 and no test compound)-(the amount of IL-17 produced without addition of IL-23 and no test compound))) × 100 ··· Formula 2

The inhibition ratio (%) of IL-17 production at 5 μmol / L of the test compound is shown in Table 3.

The inhibition ratio (%) of IL-17 production at 0.3 μmol / L of the test compound is shown in Table 4.

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

Example 15 Suppressive effect on imiquimod-induced mouse psoriasis model:
The effect of the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof in an imiquimod-induced mouse psoriasis model was evaluated using an increase in auricle thickness as an indicator of symptom deterioration. The imiquimod-induced mouse psoriasis model was prepared by partially modifying the method of Schaper et al. (The Journal of Dermatological Science, 2013, 71, No. 1, p. 29-36).

BALB / c mice (male, 7 weeks old) (Nihon Charles River Co., Ltd.) were used at 8 weeks of age after preliminary breeding. In order to induce psoriasis-like symptoms, 5 mg of Becelna cream was applied once a day on the outside of the left and right auricle of the mouse for 8 days from the first day of imiquimod administration (hereinafter, induction day) to 7 days after induction. (Imikimod dose 0.5 mg / body / day).

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

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

The results are shown in FIG. The vertical axis represents the change in ear thickness (mm) (mean value ± standard error, n = 6). The “solvent” on the horizontal axis represents a solvent administration group, and the “compound of Example 4” represents a compound administration group of Example 4. * Indicates statistically significant (*: P <0.05) in comparison with the vehicle administration group (Student's t-test).

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

From this result, it has become clear that the anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof exhibits a remarkable symptom suppressing effect on psoriasis.

The anilide derivative (I) or a hydrate thereof or a pharmacologically acceptable salt thereof according to the present invention has excellent RORγ antagonist activity, so that the improvement or symptoms of the pathological condition by suppressing the function of RORγ It can be used as a medicine for diseases in which a remission of In particular, it can be used as a therapeutic or preventive agent for autoimmune diseases such as psoriasis.

Claims

Anilide derivatives represented by the following general formula (I) or hydrates thereof, or pharmacologically acceptable salts thereof.

[Wherein, R 1 represents a halogen atom, and R 2 represents a hydrogen atom or a methyl group (in this methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom)] And m represents 0 or 1; n represents 0 or 1; p represents 1 or 2; ]
R 1 is a fluorine atom or a chlorine atom,
The anilide derivative according to claim 1, wherein R 2 is a hydrogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom). Or a hydrate thereof, or a pharmacologically acceptable salt thereof.
R 1 is a fluorine atom or a chlorine atom,
The anilide derivative or the hydrate thereof according to claim 1, wherein R 2 is a methyl group (in the methyl group, any one to three hydrogen atoms may be substituted with a fluorine atom). Or, these pharmacologically acceptable salts.
R 1 is a fluorine atom or a chlorine atom,
R 2 is a trifluoromethyl group,
n is 1 and
The anilide derivative according to claim 1, wherein p is 2, or a hydrate thereof, or a pharmacologically acceptable salt thereof.
A medicine comprising 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 gamma antagonist comprising 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 preventive agent for an autoimmune disease, comprising 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 preventive 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.