Pharmaceutical composition comprising 3,4-dihydroquinolin-2(1H)-one compound

Abstract

To provide a pharmaceutical composition comprising a novel compound which has a thyroid-stimulating hormone receptor antagonist activity and is useful for the treatment of thyroid-related diseases.SOLUTION: There is provided a pharmaceutical composition comprising a 3,4-dihydroquinolin-2(1H)-one compound represented by a formula (I) or a pharmacologically acceptable salt thereof. A pharmaceutical composition comprising the compound or the pharmacologically acceptable salt thereof has an antagonist activity against thyroid-stimulating hormone receptors and is useful as a therapeutic agent or the like for thyroid-related diseases (for example, hyperthyroidism, Graves' disease, thyroid eye disease and thyroid cancer).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing a 3,4-dihydroquinolin-2(1H)-one compound useful as a pharmaceutical. More specifically, the present invention relates to a pharmaceutical composition containing a 3,4-dihydroquinolin-2(1H)-one compound or a pharmacologically acceptable salt thereof, which has antagonist activity against the thyroid-stimulating hormone receptor (TSHR) and is useful as a therapeutic agent for thyroid-related diseases.

Background Art

[0002] Thyroid hormones such as triiodothyronine (T3) and thyroxine (T4) play important roles in development, growth, and metabolism, and their synthesis and secretion are strictly regulated by thyroid-stimulating hormone (TSH) secreted from the pituitary gland.

[0003] In hyperthyroidism, these thyroid hormones are secreted excessively for some reason, and various unfavorable effects such as goiter, tachycardia, hypertension, fatigue, weight loss, palpitations, sleep disorders, and menstrual disorders appear in the mind and body due to the hormonal action.

[0004] Although there are various causes of hyperthyroidism, the most common one is Graves' disease. In Graves' disease, due to an autoimmune mechanism, the body regards its own thyroid as a foreign substance, and autoantibodies against the TSHR present on thyroid follicular cells, so-called TSHR antibodies (TRAb), are produced. It is considered that this TRAb acts as an agonist on the TSHR and excessively stimulates the TSHR, resulting in the secretion of more thyroid hormones than necessary and the onset of hyperthyroidism.

[0005] In addition, thyroid ophthalmopathy is also known as a disease associated with Graves' disease. Thyroid ophthalmopathy is an autoimmune inflammatory disease presenting various eye symptoms, and it is considered that the agonist action of TRAb on TSHR in orbital tissues is the main cause. It often develops almost simultaneously with hyperthyroidism, but it may also occur without thyroid dysfunction.

[0006] Currently, antithyroid drugs that inhibit the biosynthesis of thyroid hormones, such as thiamazole and propylthiouracil, are used for the drug treatment of Graves' disease. However, there are problems such as a low remission rate, a long treatment period until remission, and a high frequency of side effects. Therefore, a therapeutic agent for Graves' disease having a new mechanism of action is currently in demand.

[0007] Blocking TSHR or inhibiting the signal transduction induced via TSHR inhibits the production, secretion, and thyroid cell proliferation of thyroid hormones. Therefore, TSHR antagonists are considered to have a therapeutic effect on Graves' disease and thyroid ophthalmopathy caused by the agonist action of TRAb on TSHR (Patent Documents 1 and 2). As a TSHR antagonist, NCGC00242364 is known, and it has been clarified that it has an effect of decreasing the blood T4 concentration in mice administered with thyrotropin-releasing hormone (TRH) and in mice administered with thyroid-stimulating antibody M22 (Non-Patent Document 1).

[0008] Compounds having TSHR antagonist activity are described in Patent Documents 1 to 3 and Non-Patent Document 1. However, the 3,4-dihydroquinolin-2(1H)-one compound of the present invention is not described in any of Patent Documents 1 to 3 and Non-Patent Document 1.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Document

[0010]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide a pharmaceutical composition containing a novel compound having TSHR antagonist activity and useful for the treatment of thyroid-related diseases.

Means for Solving the Problems

[0012] The present invention relates to a pharmaceutical composition containing a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0013] That is, the present invention relates to the following [1] to

[14] and the like. [1] A compound represented by formula (I):

Chemical Formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[11] The pharmaceutical composition according to any one of [1] to [8] above, wherein: X is -CHR X -; R X has the same meaning as in [7] above; a compound or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

[12] The pharmaceutical composition according to any one of [1] to [8] and

[11] above, which is a compound selected from the group consisting of the following compounds: [Chem.] and [Chem.] or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

[13] The pharmaceutical composition according to any one of [1] to

[12] above, which is a pharmaceutical composition for treating thyroid-related diseases.

[14] The pharmaceutical composition according to

[13] above, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid ophthalmopathy.

[0014] In one embodiment, the present invention relates to a method for treating thyroid-related diseases, which comprises administering to a patient a therapeutically effective amount of the pharmaceutical composition according to any one of [1] to

[12] above.

[0015] In one embodiment, the present invention relates to the use of the pharmaceutical composition according to any one of [1] to

[12] above for the manufacture of a pharmaceutical composition for treating thyroid-related diseases.

[0016] In one embodiment of the compound represented by formula (I), for example, the compound represented by the following formula (V): [Chem.] 〔In the formula, ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl or C 3-8 cycloalkyl; X is -CHR X -, or -O-; R X is a hydrogen atom or C 1-6 alkyl; R V1 is a hydrogen atom, a halogen atom, a hydroxy group, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl or C 6-10 aryl C 1-6 alkoxy; R 1 is C 1-6 alkyl; R 2 is a halogen atom, a cyano group, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy; n is an integer from 0 to 3; When n is 2 or 3, each R 2 may be the same as or different from each other; R 4 is C 1-6 alkyl, halo C 1-6 alkyl, -NR 5 R 5' or C 3-8 cycloalkyl; R 5 and R 5' are each independently a hydrogen atom or C 1-6 alkyl〕 is exemplified.

Advantages of the Invention

[0017] The compounds of the present invention have excellent TSHR antagonist activity. Therefore, a pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for thyroid-related diseases.

Mode for Carrying Out the Invention

[0018] Hereinafter, embodiments of the present invention will be described in more detail.

[0019] In the present invention, each term has the following meaning unless otherwise specified.

[0020] The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. "C 1-6 alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. can be mentioned. "C 1-6 alkoxy" means a linear or branched alkoxy group having 1 to 6 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, etc. can be mentioned.

[0021] "HydroxyC 1-6 alkyl" means C 1-6 alkyl substituted with one or two hydroxy groups. For example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc. can be mentioned. "HaloC 1-6 alkyl" means C 1-6 alkyl substituted with 1 to 5 identical or different halogen atoms. For example, monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, pentafluoroethyl, etc. can be mentioned. "HaloC 1-6"Alkoxy" means C substituted with 1 to 5 identical or different halogen atoms 1-6 and represents alkoxy. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, etc. can be mentioned.

[0022] "C 6-10 aryl" means a phenyl group or a naphthyl group. "5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms in the ring. For example, pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, etc. can be mentioned. "C 3-8 cycloalkyl" means a saturated hydrocarbon group with a 3- to 8-membered ring, including those with a partially bridged structure. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, etc. can be mentioned. "3- to 8-membered heterocycloalkyl" means a cycloalkyl group in which the carbon atoms in the ring are substituted with 1 or 2 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, including those with a partially bridged structure. For example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[2.2.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyrrolidonyl, piperidonyl, oxiranyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, etc. can be mentioned.

[0023] "C 6-10 Aryl C 1-6 "Alkoxy" means a C 6-10 alkyl substituted with one C 1-6 aryl. For example, benzyloxy can be mentioned.

[0024] "C 6-10 Aryl C 1-6 "Alkyl" means a C 6-10 alkyl substituted with one C 1-6 aryl. For example, benzyl can be mentioned.

[0025] In the present text, the following abbreviations in the figures and tables respectively have the following meanings. Boc: tert-Butoxycarbonyl Boc2O: Di-tert-butyl dicarbonate DIPEA: N,N-Diisopropylethylamine DCM: Dichloromethane DMAP: 4-Dimethylaminopyridine DMF: N,N-Dimethylformamide DPPA: Diphenylphosphoryl azide HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate LDA: Lithium diisopropylamide MeCN: Acetonitrile MTBE: Methyl tert-butyl ether NMP: N-Methylpyrrolidone TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran Xphos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 10% Pd / C: 10% Palladium on carbon (about 55% water-wetted) 10% Pt / C: 10% Platinum on carbon (about 55% water-wetted) APS: Aminopropylated silica gel ODS: Octadecylsilylated silica gel Method A: Column chromatography with a silica gel column connected to the bottom of an aminopropylated silica gel column Ref. No.: Reference example number Str.: Structural formula Ex. No.: Example number Phys. data: Physical property value IC 50 : 50% inhibitory concentration 1 H-NMR: Proton nuclear magnetic resonance spectrum DMSO: Dimethyl sulfoxide DMSO-d6: Dimethyl sulfoxide-d6 CDCl3: Chloroform-d1 MS: Mass spectrometry (The measured values in the table were measured by the multi-ionization method of electrospray ionization-atmospheric pressure chemical ionization method.) cAMP: Adenosine 3',5'-cyclic monophosphate CHO: Chinese hamster ovary FBS: Fetal bovine serum HEPES: 2-(4-(2-Hydroxyethyl)-1-piperazinyl)ethanesulfonic acid IBMX: 3-Isobutyl-1-methylxanthine

[0026] In the compounds represented by formulas (I) to (V), when one or more asymmetric carbon atoms are present, the present invention also includes compounds in which each asymmetric carbon atom has an R configuration, compounds in which each asymmetric carbon atom has an S configuration, and compounds of any combination thereof. Further, their racemic compounds, racemic mixtures, single enantiomers, and diastereomer mixtures are also included in the scope of the present invention.

[0027] In the compounds represented by formulas (I) to (V), when cis-trans isomers are present, the present invention includes any of those cis-trans isomers.

[0028] In the case where tautomers exist in the compounds represented by formula (I) to (V), the present invention includes any of the tautomers.

[0029] In the present invention, the determination of stereochemistry can also be carried out by methods well-known in the art.

[0030] The compounds represented by formula (I) to (V) can also be converted into their pharmacologically acceptable salts according to conventional methods as necessary. Such salts include acid addition salts or salts with bases.

[0031] Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

[0032] Examples of salts with bases include salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, TEA, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

[0033] Unless otherwise specified, suffixes related to salts such as "hydrochloride" or "HCl" in chemical names or structural formulas of salts do not represent stoichiometric descriptions but merely mean salt forms.

[0034] When the compounds represented by formula (I) to (V) or their pharmacologically acceptable salts exist, for example, as crystals, the present invention includes any crystal forms. For example, pharmacologically acceptable salts include solvates with solvents acceptable as pharmaceuticals such as water or ethanol, and co-crystals with appropriate coformers.

[0035] In the compounds represented by formulas (I) to (V), some of the atoms may each be replaced with the corresponding isotope. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, and 35 isotopes of hydrogen atoms, carbon atoms, chlorine atoms, fluorine atoms, iodine atoms, nitrogen atoms, oxygen atoms, and sulfur atoms represented by S. As one embodiment, compounds in which some hydrogen atoms of the compounds represented by formulas (I) to (V) are 2 replaced with H (D: deuterium atom) are included.

[0036] In the compounds represented by formulas (I) to (V), compounds in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below using commercially available building blocks into which isotopes have been introduced. Also, they can be produced using the methods described in the literature (for example, see Journal of the Chemical Society of Japan, Vol. 65, No. 12, pp. 1179 - 1190, 2007 and RADIOISOTOPES, Vol. 56, No. 11, pp. 741 - 750, 2007).

[0037] The compounds represented by formulas (I) to (V) of the present invention can be produced, for example, according to the methods shown in Schemes 1 to 8 or methods analogous thereto, or according to the methods described in the literature or methods analogous thereto. In the Schemes, the compounds represented by formulas (I) to (V) correspond to the compounds represented by formulas (I - 1) to (I - 7).

[0038] The compounds represented by formulas (I) to (V) of the present invention can be produced by the methods shown below, but the following production methods are examples of general production methods and do not limit the production methods.

[0039] In the reactions of each step, when the raw material substances and reagents are commercially available, commercially available products can be used.

[0040] In the reactions of each step, the reaction time varies depending on the raw material substances, solvents, reaction temperature, etc. used. However, when not specifically described, it is usually 30 minutes to 3 days.

[0041] In the reactions of each step, the reaction temperature varies depending on the raw material substances and solvents used. However, when not specifically described, it is usually -78 °C to the reflux temperature.

[0042] In the reactions of each step, the pressure varies depending on the raw material substances, solvents, reaction temperature, etc. used. However, when not specifically described, it is usually 1 to 20 atmospheres.

[0043] In the reactions of each step, a microwave reactor such as the Initiator manufactured by Biotage may be used. When performing the reaction using a microwave reactor, although it varies depending on the raw material substances, solvents, and models used, the reaction can be carried out under the conditions of a pressure range: 1 to 30 bar, an output range: 1 to 400 W, a reaction temperature: room temperature to 300 °C, and a reaction time: 1 minute to 1 day.

[0044] The reactions of each step are carried out without solvent or using a suitable solvent when not specifically described. Examples of suitable solvents include solvents that are inert to the reaction. Specific examples of the solvents used include the solvents described in the reference examples or examples corresponding to each step, or the following solvents. The following solvents may be used by mixing two or more of them in an appropriate ratio. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, MTBE, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, n-pentane, etc.; Amides: DMF, N,N-dimethylacetamide, NMP, etc.; Halogenated hydrocarbons: DCM, 1,2-dichloroethane, carbon tetrachloride, etc.; Nitriles: MeCN, etc.; Sulfoxides: DMSO, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, TFA, methanesulfonic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0045] In the reaction of each step, when a base is used, the reaction is carried out using a base suitable for the reaction. Specific examples of the base used include the bases described in the reference examples or examples corresponding to each step, or the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.; Basic salts: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; Organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.; Organic magnesiums: isopropylmagnesium chloride, etc.; Organic lithiums: methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.

[0046] In the reaction of each step, when an acid is used, the reaction is carried out using an acid suitable for the reaction. Specific examples of the acid used include the acids described in the reference examples and examples corresponding to each step or the following acids. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, TFA, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0047] In the reaction of each step, when a condensing agent is used, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent used include the condensing agents described in the reference examples or examples corresponding to each step, or the following condensing agents. Carbodiimides: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, etc.; Imidazoles: carbonyldiimidazole, etc.; Uronium salts, phosphonium salts: HATU, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, etc.; Others: propylphosphonic anhydride (cyclic trimer), etc.

[0048] In the reaction of each step, when a reducing agent is used, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent used include the reducing agents described in the reference examples or examples corresponding to each step, or the following reducing agents. Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, etc.; Boranes: BH3-THF complex, picoline borane complex, decaborane, etc.

[0049] In the reaction of each step, when a carbonyl group-introducing reagent is used, the reaction is carried out using a carbonyl group-introducing reagent suitable for the reaction. Specific examples of the carbonyl group-introducing reagent used include the carbonyl group-introducing reagent described in the reference example or the example corresponding to each step, or the following carbonyl group-introducing reagent. Phosgene: phosgene, diphosgene, triphosgene, etc.; Chloroformates: 4-nitrophenyl chloroformate, etc.; Imidazoles: carbonyldiimidazole, etc.

[0050] In each step, when a protecting group is required depending on the type of functional group, it can also be carried out by appropriately combining the operations of introduction and removal according to conventional methods. Examples of the type of protecting group, protection, and deprotection include the methods described in, for example, "Greene's Protective Groups in Organic Synthesis" edited by Peter G. M. Wuts, fifth edition, Wiley-Interscience, 2014.

[0051] In each step, when a hydrolysis reaction is carried out, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base used include the above-mentioned examples.

[0052] In each step, when a catalytic reduction reaction is carried out, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst used include palladium carbon powder, Pearlman catalyst, platinum carbon powder, Raney nickel, etc. In addition, an acid may be used in the reaction as necessary.

[0053] In each step, when a reduction reaction is carried out, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent used include those described above.

[0054] In each step, when a metal reduction reaction is carried out, the reaction can be carried out in the presence of a metal or the like. Examples of the metal or the like used include iron powder, zinc powder, tin chloride, titanium trichloride, and the like. In addition, an acid may be used in the reaction as necessary.

[0055] In each step, when an amidation reaction is carried out, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and the base used include those described above. When carbodiimides are used as the condensing agent, additives such as 1-hydroxybenzotriazole and DMAP may be added to the reaction as necessary. In addition, the reaction can also be carried out using an acyl halide or an acid anhydride in the presence or absence of a base.

[0056] In each step, when a reductive amination reaction is carried out, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent used include those described above. In addition, the reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, and the like.

[0057] In each step, when an aromatic nucleophilic substitution reaction is carried out, the reaction can be carried out in the presence of a base. Examples of the base include those described above.

[0058] In each step, when a Negishi coupling reaction is carried out, the reaction can be carried out in the presence of an organozinc compound, a palladium catalyst, and a ligand. Examples of the palladium catalyst used include palladium(II) acetate, tris(dibenzylideneacetone)palladium(0), and the like. Examples of the ligand include Xphos, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, tris(2-methylphenyl)phosphine, and the like.

[0059] In each step, when performing the Suzuki-Miyaura cross-coupling reaction, the reaction can be carried out in the presence of a palladium catalyst and a base. Examples of the palladium catalyst used include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) 、 tetrakis(triphenylphosphine)palladium(0), etc. Examples of the base used include those described above.

[0060] In each step, when performing the Curtius rearrangement reaction, the reaction can be carried out in the presence of an azide source. Examples of the azide source used include sodium azide, DPPA, etc.

[0061] In each step, when performing a carbamation reaction or a urea formation reaction, the reaction can be carried out using a carbonyl group-introducing reagent in the presence or absence of a base. Examples of the carbonyl group-introducing reagent and the base used include those described above.

[0062] The compound represented by formula (I-1) can be produced, for example, according to the method described in Scheme 1.

[0063]

Chemical formula

[0064] Process 1-1 Compound (1-3) can also be produced by reacting compound (1-1) with compound (1-2) in the presence of a base.

[0065] Process 1-2 Compound (1-4) can also be produced by removing the protecting group of compound (1-3).

[0066] Process 1-3 Compound (I-1) can also be produced by the amidation reaction of compound (1-4).

[0067] The compound represented by formula (I-2) can be produced, for example, according to the method described in Scheme 2.

[0068]

Chemical formula

[0069] Process 2-1 Compound (2-1) can also be produced by reacting compound (1-1) with DPPA and Boc2O in the presence of a base.

[0070] Process 2-2 Compound (2-2) can be produced by removing the Boc group of compound (2-1).

[0071] Process 2-3 Compound (I-2a) can also be produced by reacting compound (2-2) with trimethylsilyl isocyanate. As another method, compound (I-2) can also be produced by reacting compound (2-2) with potassium cyanate or sodium cyanate etc. in the presence of an acid.

[0072] Process 2-4 Compound (I-2b) can also be produced by the ureation reaction of compound (2-2) and compound (2-3).

[0073] Process 2-5 Compound (I-2c) can also be produced by the amidation reaction of compound (2-2) and compound (2-4).

[0074] The compound represented by formula (3-10) can be produced, for example, according to the method described in Scheme 3.

[0075] [Chemical formula] The symbols in the formula have the same meaning as described above. PG 2 is a protecting group, and R 1P is C 1-6 alkyl, and R 3P is a halogen atom, or C 1-6 alkyl.

[0076] Process 3-1 Compound (3-3) can also be produced by the aromatic nucleophilic substitution reaction of compound (3-1) and compound (3-2).

[0077] Process 3-2 Compound (3-4) can also be produced by the metal reduction reaction of compound (3-3).

[0078] Process 3-3 Compound (3-6) can also be produced by reacting compound (3-4) and compound (3-5) in the presence of a palladium catalyst.

[0079] Process 3-4 Compound (3-7) can also be produced by the catalytic reduction reaction of compound (3-6). As another method, compound (3-7) can also be produced by reacting compound (3-6) with sodium borohydride in the presence of cobalt (II) chloride and copper (II) sulfate, and then reacting with a base.

[0080] Process 3-5 Compound (3-9) can also be produced by reacting compound (3-7) and compound (3-8) in the presence of a base.

[0081] Process 3-6 Compound (3-10) can also be produced by reacting compound (3-9) with a halogenating agent or an alkylating agent in the presence or absence of a base. As the halogenating agent, N-fluorobenzenesulfonimide, chlorosuccinimide, benzenesulfonyl chloride, etc. can be used. As the alkylating agent, methyl iodide, ethyl iodide, etc. can be used.

[0082] The compound represented by formula (I-3) can be produced, for example, according to the method described in Scheme 4.

[0083] [Chemical formula] The symbols in the formula have the same meaning as described above. X 2 is a bromine atom or an iodine atom, and PG 3 is a protecting group.

[0084] Process 4-1 Compound (4-2) can also be produced by reacting compound (3-4) with compound (4-1) in the presence of a base.

[0085] Process 4-2 Compound (4-4) can also be produced by the Negishi coupling reaction of compound (4-2) and compound (4-3).

[0086] Process 4-3 Compound (4-5) can also be produced by reacting compound (4-4) with an acid.

[0087] Process 4-4 Compound (I-3) can also be produced by reacting compound (4-5) with trimethylsilyl isocyanate. As another method, compound (I-3) can also be produced by reacting compound (4-5) with potassium cyanate or sodium cyanate, etc. in the presence of an acid.

[0088] The compound represented by formula (5-4) can be produced, for example, according to the method described in Scheme 5.

[0089]

Chemical formula

[0090] Process 5-1 Compound (5-3) can also be produced by the aromatic nucleophilic substitution reaction of compound (5-1) and compound (5-2).

[0091] Process 5-2 Compound (5-4) can also be produced by reacting compound (5-3) and compound (3-8) in the presence of a base.

[0092] The compound represented by formula (I-4) can be produced, for example, according to the method described in Scheme 6.

[0093]

Chemical formula

[0094] Process 6-1 Compound (6-3) can also be produced by reacting compound (6-1) and Grignard reagent (6-2).

[0095] Process 6-2 Compound (6-4) can also be produced by the metal reduction reaction of compound (6-3).

[0096] Process 6-3 Compound (6-5) can also be produced by reacting compound (6-4) with triethylsilane in the presence of an acid.

[0097] Process 6-4 Compound (6-6) can also be produced by reacting compound (6-5) with compound (4-1) in the presence of a base.

[0098] Process 6-5 Compound (6-7) can also be produced by the Negishi coupling reaction of compound (6-6) and compound (4-3).

[0099] Process 6-6 Compound (6-8) can also be produced by reacting compound (6-7) with an acid.

[0100] Process 6-7 Compound (I-4) can also be produced by reacting compound (6-8) with trimethylsilyl isocyanate. As another method, compound (I-4) can also be produced by reacting compound (6-8) with potassium cyanate or sodium cyanate etc. in the presence of an acid.

[0101] The compound represented by formula (I-6) can be produced, for example, according to the method described in Scheme 7.

[0102]

Chemical formula

[0103] Process 7-1 Compound (7-2) can also be produced by the aromatic nucleophilic substitution reaction of compound (7-1) and compound (3-2).

[0104] Process 7-2 Compound (7-3) can also be produced by the metal reduction reaction of compound (7-2).

[0105] Process 7-3 Compound (7-4) can also be produced by reacting compound (7-3) with compound (4-1) in the presence of a base.

[0106] Process 7-4 Compound (7-5) can also be produced by the Negishi coupling reaction of compound (7-4) and compound (4-3).

[0107] Process 7-5 Compound (7-6) can also be produced by reacting compound (7-5) with an acid.

[0108] Process 7-6 Compound (I-5) can also be produced by reacting compound (7-6) with trimethylsilyl isocyanate. As another method, compound (I-5) can also be produced by reacting compound (7-6) with potassium cyanate or sodium cyanate etc. in the presence of an acid.

[0109] Process 7-7 Compound (I-6) can also be produced by removing the protecting group of compound (I-5).

[0110] The compound represented by formula (I-7) can be produced, for example, according to the method described in Scheme 8.

[0111]

Chemical formula

[0112] Process 8-1 Compound (8-2) can also be produced by reacting compound (8-1) with Grignard reagent (6-2).

[0113] Process 8-2 Compound (8-3) can also be produced by the oxidation reaction of compound (8-2).

[0114] Process 8-3 Compound (8-5) can also be produced by reacting compound (8-3) with Grignard reagent (8-4).

[0115] Process 8-4 Compound (8-5) can also be produced by reacting compound (8-6) with Grignard reagent (6-2).

[0116] Process 8-5 Compound (8-7) can also be produced by reacting compound (8-5) with triethylsilane in the presence of an acid.

[0117] Process 8-6 Compound (8-8) can also be produced by reacting compound (8-7) with compound (4-1) in the presence of a base.

[0118] Process 8-7 Compound (8-9) can also be produced by the Negishi coupling reaction of compound (8-8) and compound (4-3).

[0119] Process 8-8 Compound (8-10) can also be produced by reacting compound (8-9) with an acid.

[0120] Process 8-9 Compound (8-11) can also be produced by reacting compound (8-10) with trimethylsilyl isocyanate. As another method, compound (8-11) can also be produced by reacting compound (8-10) with potassium cyanate or sodium cyanate etc. in the presence of an acid.

[0121] Process 8-10 Compound (I-7) can also be produced by the catalytic reduction reaction of compound (8-11).

[0122] Each of the above Schemes is an example of a method for producing a compound represented by formula (I) to (V) or an intermediate for its production. Each of the above Schemes can be variously modified into a Scheme that can be easily understood by those skilled in the art.

[0123] The compounds represented by formula (I) to (V) and their production intermediates can be isolated and purified, if necessary, by isolation and purification means well-known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.

[0124] Since the compounds of the present invention have excellent TSHR antagonist activity, they can be used as therapeutic agents for thyroid-related diseases. In the present invention, thyroid-related diseases include, for example, hyperthyroidism, Graves' disease, thyroid ophthalmopathy, and thyroid cancer. Preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism, Graves' disease, or thyroid ophthalmopathy (see Endocrinology, 2014, 155 (1), p.310-314). More preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism or Graves' disease.

[0125] Also, as one embodiment, hyperthyroidism includes, for example, hyperthyroidism caused by any of Graves' disease, thyroiditis, Plummer's disease, toxic multinodular goiter, TSH-producing pituitary adenoma, hyperemesis gravidarum, struma ovarii, gestational choriocarcinoma, or germ cell tumor. Preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism caused by Graves' disease.

[0126] In addition, as one embodiment, thyroid-related diseases are diseases and symptoms associated with abnormal thyroid hormone levels. Diseases and symptoms associated with abnormal thyroid hormone levels include, for example, diseases and symptoms caused by TRAb.

[0127] In the present invention, "treatment" includes the meaning of "prevention". For example, the treatment of hyperthyroidism, Graves' disease or thyroid ophthalmopathy includes the meaning of "prevention of relapse and recurrence" and "maintenance of remission". Also, as one embodiment, the compounds of the present invention can be used for the prevention of the onset of thyroid ophthalmopathy in patients with Graves' disease.

[0128] In the present invention, "antagonist" refers to a drug that inhibits or blocks the function of a target protein regardless of its binding site. For example, "antagonist" includes the meanings of "allosteric antagonist" and "negative allosteric modulator (NAM)".

[0129] The therapeutic effect of the compounds of the present invention on thyroid-related diseases can be confirmed according to methods well known in the art. For example, as a method for confirming the effect in model animals of hyperthyroidism or Graves' disease, the methods described in Endocrinology 2007, 148(5), p.2335-2344 etc. or methods analogous thereto can be mentioned.

[0130] The pharmaceutical compositions of the present invention are of various dosage forms depending on the usage. Such dosage forms can include, for example, powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, eye drops, and enemas.

[0131] The pharmaceutical compositions of the present invention contain, as an active ingredient, a compound represented by formula (I) to (V) or a pharmaceutically acceptable salt thereof.

[0132] The pharmaceutical composition of the present invention is prepared using a compound represented by formula (I) to (V) or a pharmacologically acceptable salt thereof, and at least one pharmaceutical additive. These pharmaceutical compositions can be appropriately mixed, diluted or dissolved with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizing agents, etc. by pharmaceutically known methods according to their dosage forms.

[0133] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) to (V) or a pharmacologically acceptable salt thereof is appropriately determined according to the patient's age, sex, weight, disease and degree of treatment, etc. The daily dosage may be administered once, twice, three times or four times. In the case of oral administration, the dosage for adults can be determined, for example, in the range of 0.1 to 5000 mg / day. As one embodiment, the oral dosage can also be determined in the range of 1 to 1500 mg / day, preferably in the range of 1 to 500 mg / day. In the case of parenteral administration, the dosage for adults can be determined, for example, at 0.01 to 5000 mg / day. As one embodiment, the parenteral dosage can also be determined in the range of 0.1 to 1500 mg / day, preferably in the range of 0.1 to 500 mg / day.

[0134] As one embodiment, the pharmaceutical composition of the present invention can also be used in combination with other drugs other than TSHR antagonists. Examples of other drugs that can be used in combination in the treatment of thyroid-related diseases include, for example, antithyroid drugs (such as thiamazole, propylthiouracil, etc.), inorganic iodine, lithium carbonate, thyroid hormone preparations, etc.

[0135] When using a compound represented by formula (I) to (V) or a pharmacologically acceptable salt thereof in combination with other drugs, it can be administered as a formulation containing these active ingredients together, or as a formulation in which these active ingredients are separately formulated. When separately formulated, these formulations can be administered separately or simultaneously. Also, the dosage of the compound represented by formula (I) to (V) or a pharmacologically acceptable salt thereof may be appropriately reduced according to the dosage of other drugs used in combination.

[0136] The compound represented by formula (I) to (V) may be appropriately converted into a prodrug for use. For example, a prodrug of the compound represented by formula (I) to (V) can also be produced by introducing a group constituting the prodrug using a prodrug reagent such as a corresponding halide and purifying it. Examples of the group constituting the prodrug include the groups described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Volume 7, pp. 163-198.

Examples

[0137] The present invention will be described in more detail below based on reference examples, examples and test examples, but the present invention is not limited to its content.

[0138] The compound names described in the following examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.

[0139] Reference Example A-1 2-Bromo-6-phenoxyaniline A mixture of 1-bromo-3-fluoro-2-nitrobenzene (4.01 g), phenol (1.89 g) and DMF (40 mL) was added with potassium carbonate (10.1 g), and stirred at 80 °C for 6 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain 1-bromo-2-nitro-3-phenoxybenzene (5.58 g). Iron powder (3.05 g) was added to a mixture of the obtained compound (5.58 g), ethanol (43 mL) and acetic acid (43 mL), and stirred at 91 °C for 11 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 94 / 6) to obtain the title compound (4.68 g).

[0140] Reference Example A-2 8-Phenoxy-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-1 (2.13 g), ethyl acrylate (2.42 g), palladium(II) acetate (0.181 g), tris(2-methylphenyl)phosphine (0.491 g), TEA (4.08 g) and MeCN (40 mL) was refluxed for 5 hours. After allowing the reaction mixture to cool to room temperature, it was added to water. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain ethyl (2E)-3-(2-amino-3-phenoxyphenyl)prop-2-enoate (2.08 g). A mixture of the obtained compound (2.08 g), 10% Pd / C (0.400 g) and methanol (30 mL) was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was suspended in water, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (1.53 g).

[0141] Reference Example A-3 1-Methyl-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one To a mixture of Reference Example A-2 (0.100 g), methyl iodide (0.119 g) and THF (2 mL), sodium hydride (about 60%) (0.022 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 74 / 26 to 57 / 43) to obtain the title compound (0.102 g).

[0142] Reference Example A-4 2-Bromo-6-(2-fluorophenoxy)aniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.00 g), 2-fluorophenol (0.561 g) and DMF (10 mL), potassium carbonate (1.57 g) was added, and the mixture was stirred at 100 °C for 1 hour. After the reaction mixture was cooled to room temperature, water was added, and the mixture was stirred at room temperature for 15 minutes. The insoluble material was collected by filtration, and the obtained solid was dissolved in ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue, a mixture of iron powder (0.762 g), ethanol (12 mL) and acetic acid (12 mL) was added, and the mixture was stirred at 90 °C for 1 hour. After the reaction mixture was allowed to cool to room temperature, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.32 g).

[0143] Reference Example A-5 8-(2-Fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-4 (1.23 g), benzyl acrylate (1.41 g), palladium(II) acetate (0.098 g), tris(2-methylphenyl)phosphine (0.265 g), TEA (1.77 g) and MeCN (10 mL) was stirred at 135 °C for 30 minutes under microwave irradiation. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to obtain benzyl 3-(2-amino-3-(2-fluorophenoxy)phenyl)prop-2-enoate (1.12 g). A mixture of the obtained compound (1.12 g), 10% Pd / C (0.100 g) and DMF (10 mL) was stirred at 60 °C for 1 hour under a hydrogen atmosphere. The reaction mixture was stirred at 80 °C for 1 hour under a hydrogen atmosphere. Ethanol (10 mL) was added to the reaction mixture, and it was stirred at 70 °C for 1 hour under a hydrogen atmosphere. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, 10% Pd / C (0.100 g) and acetic acid (10 mL) was stirred at 80 °C for 2 hours under a hydrogen atmosphere. Concentrated sulfuric acid (0.020 mL) was added to the reaction mixture, and it was stirred at 80 °C for 2 hours under a hydrogen atmosphere. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 67 / 33 to 37 / 63) to obtain 8-(2-fluorophenoxy)-1,2,3,4-tetrahydroquinolin-2-one (0.638 g). Sodium hydride (about 60%) (0.119 g) and methyl iodide (0.704 g) were added to a mixture of the obtained compound (0.638 g) and DMF (10 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 83 / 17 to 18 / 82) to obtain the title compound (0.672 g).

[0144] Reference Example A-6 2-Bromo-6-(3-fluorophenoxy)aniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.500 g), 3-fluorophenol (0.255 g) and DMF (5 mL), potassium carbonate (0.471 g) was added, and the mixture was stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (6 mL) and acetic acid (6 mL), iron powder (0.381 g) was added, and the mixture was stirred at 90 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.681 g).

[0145] Reference Example A-7 8-(3-Fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-6 (0.641 g), benzyl acrylate (0.737 g), palladium(II) acetate (0.051 g), tris(2-methylphenyl)phosphine (0.138 g), TEA (0.920 g) and MeCN (10 mL) was stirred at 130 °C for 1 hour under microwave irradiation. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 59 / 41) to obtain benzyl 3-(2-amino-3-(3-fluorophenoxy)phenyl)prop-2-enoate (0.382 g). A mixture of the obtained compound (0.382 g), 10% Pd / C (0.040 g), and acetic acid (5 mL) was stirred at 80 °C for 2 hours under a hydrogen atmosphere. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. The filtrate and a mixture of 10% Pd / C (0.040 g) were stirred at 80 °C for 1 hour and then at 100 °C for 3 hours under a hydrogen atmosphere. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 67 / 33 to 24 / 76) to obtain 8-(3-fluorophenoxy)-1,2,3,4-tetrahydroquinolin-2-one (0.135 g). Sodium hydride (about 60%) (0.025 g) was added to a mixture of the obtained compound (0.135 g), methyl iodide (0.149 g), and DMF (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. After the mixture was extracted with diethyl ether, the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 31 / 69) to obtain the title compound (0.156 g).

[0146] Reference Example A-8 Reference Example A-8 was synthesized in the same manner as Reference Example A-6, using 3-(trifluoromethyl)phenol instead of 3-fluorophenol.

[0147] Reference Example A-9 1-Methyl-8-(3-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-8 (1.27 g), benzyl acrylate (1.24 g), palladium(II) acetate (0.086 g), tris(2-methylphenyl)phosphine (0.233 g), TEA (1.55 g) and MeCN (10 mL) was stirred at 130 °C for 1 hour under microwave irradiation. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain benzyl 3-(2-amino-3-(3-(trifluoromethyl)phenoxy)phenyl)prop-2-enoate (1.48 g). A mixture of the obtained compound (1.48 g), 10% Pd / C (0.382 g) and acetic acid (18 mL) was stirred at 80 °C for 6 hours under a hydrogen atmosphere. After allowing the reaction mixture to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue. The mixture was extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 60 / 40 to 33 / 67) to obtain 8-(3-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-2-one (0.661 g). Sodium hydride (about 60%) (0.086 g) was added to a mixture of the obtained compound (0.661 g), methyl iodide (0.305 g) and DMF (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 38 / 62) to obtain the title compound (0.607 g).

[0148] Reference Example A-10 2-Bromo-6-(3-chlorophenoxy)aniline A mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.746 g), 3-chlorophenol (0.436 g) and DMF (10 mL) was added with potassium carbonate (0.937 g) and stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Iron powder (0.947 g) was added to a mixture of the residue, ethanol (12 mL) and acetic acid (12 mL), and the mixture was stirred at 90 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and ethyl acetate, 2 mol / L aqueous sodium hydroxide solution was added under ice-cooling. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (0.963 g).

[0149] Reference Example A-11 8-(3-Chlorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-10 (0.963 g), benzyl acrylate (1.05 g), palladium(II) acetate (0.072 g), tris(2-methylphenyl)phosphine (0.196 g), TEA (1.80 g) and MeCN (10 mL) was stirred at 130 °C for 1 hour under microwave irradiation. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain benzyl 3-(2-amino-3-(3-chlorophenoxy)phenyl)prop-2-enoate (0.955 g). To a mixture of the obtained compound (0.955 g), methanol (5 mL) and THF (5 mL), cobalt(II) chloride pentahydrate (0.002 g), copper(II) sulfate (0.012 g) and sodium borohydride (0.105 g) were added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, then 2 mol / L aqueous sodium hydroxide solution (3.77 mL) was added and the mixture was stirred at 50 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, 2 mol / L hydrochloric acid (3.77 mL) was added. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue and DMF (10 mL), methyl iodide (0.693 g) and sodium hydride (about 60%) (0.107 g) were added at room temperature and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with diethyl ether. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (0.345 g).

[0150] Reference Example A-12 Reference Example A-12 was synthesized in the same manner as Reference Example A-10, using 1-bromo-3,4-difluoro-2-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene and phenol instead of 3-chlorophenol.

[0151] Reference Example A-13 7-Fluoro-1-methyl-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one A mixture of Reference Example A-12 (1.20 g), benzyl acrylate (1.38 g), palladium(II) acetate (0.095 g), tris(2-methylphenyl)phosphine (0.259 g), TEA (2.15 g) and MeCN (10 mL) was stirred at 130 °C for 1 hour under microwave irradiation. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 92 / 8 - 43 / 57) to obtain benzyl 3-(2-amino-4-fluoro-3-phenoxyphenyl)prop-2-enoate (1.03 g). To a mixture of the obtained compound (0.998 g), methanol (7 mL) and THF (7 mL), cobalt(II) chloride pentahydrate (0.002 g), copper(II) sulfate (0.013 g) and sodium borohydride (0.229 g) were added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, then 2 mol / L hydrochloric acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes. 2 mol / L aqueous sodium hydroxide solution (0.5 mL) and DCM were added to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes and at 50 °C for 30 minutes. Concentrated hydrochloric acid (1 mL) was added to the reaction mixture at room temperature and stirred for 10 minutes. Ethyl acetate and water were added to the mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 65 / 35 - 26 / 74) to obtain 7-fluoro-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one (0.554 g). To a mixture of the obtained compound (0.554 g), methyl iodide (0.458 g) and DMF (6 mL), sodium hydride (about 60%) (0.103 g) was added and stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 - 35 / 65) to obtain the title compound (0.606 g).

[0152] Reference Example A-14 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-chloro-2-fluoro-3-nitrobenzene was used, and instead of 3-chlorophenol, phenol was used. Reference Example A-14 was synthesized in the same manner as Reference Example A-10.

[0153] Reference Example A-15 7-Chloro-1-methyl-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one To a mixture of Reference Example A-14 (1.17 g) and DCM (20 mL) under ice-cooling, pyridine (0.630 g) and 9-fluorenylmethyl chloroformate (1.65 g) were added, and the mixture was stirred at room temperature for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 44 / 56) to obtain N-(3-chloro-2-phenoxyphenyl)carbamic acid (9H-fluoren-9-yl)methyl (1.01 g). A mixture of the obtained compound (1.01 g), n-butyl acrylate (0.589 g), palladium(II) acetate (0.052 g), potassium peroxodisulfate (0.683 g), TFA (16 mL) and DCM (4 mL) was stirred at room temperature for 14 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture of the residue and ethyl acetate under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 43 / 57) to obtain butyl 3-(4-chloro-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenoxyphenyl)prop-2-enoate (0.271 g). To a mixture of the obtained compound (0.271 g) and DCM (2 mL), piperidine (0.203 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 68 / 32) to obtain butyl 3-(2-amino-4-chloro-3-phenoxyphenyl)prop-2-enoate (0.196 g). To a mixture of the obtained compound (0.196 g), methanol (5 mL) and THF (5 mL), cobalt(II) chloride pentahydrate (0.374 mg), copper(II) sulfate (2.71 mg) and sodium borohydride (0.024 g) were added, and the mixture was stirred at room temperature for 10 minutes. 2 mol / L aqueous sodium hydroxide solution (0.850 mL) was added to the reaction mixture, and the mixture was stirred at 50 °C for 30 minutes. After allowing the mixture to cool to room temperature, acetic acid (0.170 g) was added, and the mixture was concentrated under reduced pressure. Acetic acid (2 mL) was added to the residue, and the mixture was stirred at 50 °C for 30 minutes and then concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture of the residue and DCM. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 37 / 63) to obtain 7-chloro-8-phenoxy-1,2,3,4-tetrahydroquinolin-2-one (0.060 g). To a mixture of the obtained compound (0.060 g) and DMF (1 mL) under ice-cooling, methyl iodide (0.047 g) and sodium hydride (about 60%) (0.011 g) were added, and the mixture was stirred at room temperature for 30 minutes. Water and diethyl ether were added to the reaction mixture under ice-cooling. The mixture was extracted with diethyl ether. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 32 / 68) to obtain the title compound (0.061 g).

[0154] Reference Example A-16 1-Methyl-8-((3-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-2-one To a mixture of 8-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (0.200 g), NMP (5 mL) and 2-chloro-3-(trifluoromethyl)pyridine (0.289 g), potassium carbonate (0.508 g) was added and the mixture was stirred at 110 °C for 8 hours. After allowing the reaction mixture to cool to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 60 / 40 to 0 / 100) to obtain 8-((3-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-2-one (0.240 g). To a mixture of the obtained compound (0.240 g), DMF (2 mL) and methyl iodide (0.166 g) under ice-cooling, sodium hydride (about 60%) (0.047 g) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture under ice-cooling, saturated aqueous ammonium chloride solution, ethyl acetate and n-hexane were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to obtain the title compound (0.240 g).

[0155] Reference Example B-1 2-Bromo-N-methyl-6-(2-(trifluoromethyl)phenoxy)aniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.00 g), 2-(trifluoromethyl)phenol (0.737 g) and NMP (10 mL), potassium carbonate (1.26 g) was added and the mixture was stirred at 110 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of the residue, ethanol (15 mL) and water (5 mL), ammonium chloride (6.08 g) and iron powder (1.27 g) were added, and the mixture was stirred at 80 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, it was filtered through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain 2-bromo-6-(2-(trifluoromethyl)phenoxy)aniline (1.50 g). To a mixture of the obtained compound (0.300 g) and THF (3 mL), methyllithium (1.12 mol / L in diethyl ether) (0.887 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.154 g) and THF (2 mL) was added, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 2 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain the title compound (0.250 g).

[0156] Reference Example B-2 (3R)-3-Amino-1-methyl-8-(2-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-2-one To a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.285 g) and DMF (4 mL), zinc (0.104 g) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, Reference Example B-1 (0.250 g), palladium(II) acetate (0.008 g) and Xphos (0.034 g) were added, and the mixture was stirred at room temperature for 13 hours. An aqueous saturated ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (5 mL) was added TFA (1.65 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (3 mL) under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.084 g).

[0157] Reference Example B-3 2-Bromo-6-(2-methoxyphenoxy)-N-methylaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.612 g), 2-methoxyphenol (0.345 g) and DMF (10 mL) was added potassium carbonate (0.769 g), and the mixture was stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue, ethanol (6 mL) and acetic acid (3 mL) was added iron powder (0.777 g), and the mixture was stirred at 90 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, it was filtered through celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and ethyl acetate was added 2 mol / L aqueous sodium hydroxide solution under ice-cooling. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue and THF (10 mL) was added methyllithium (1.06 mol / L in diethyl ether) (2.72 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture at -78 °C was added a mixture of methyl iodide (0.375 g) and THF (1 mL), and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 30 minutes. To the reaction mixture under ice-cooling was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 55 / 45) to obtain the title compound (0.544 g).

[0158] Reference Example B-4 (3R)-3-Amino-8-(2-methoxyphenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.140 g) was added to a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.384 g) and DMF (5 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added Reference Example B-3 (0.300 g), palladium(II) acetate (0.011 g) and Xphos (0.046 g), and the mixture was stirred at room temperature for 14 hours. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to a mixture of the residue and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 50 / 50) to obtain the title compound (0.173 g).

[0159] Reference Example B-5 3-(3-Bromo-2-(methylamino)phenoxy)benzonitrile To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.01 g), 3-hydroxybenzonitrile (0.548 g) and DMF (10 mL) was added potassium carbonate (1.27 g), and the mixture was stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water was added. The insoluble material was collected by filtration, and the obtained solid was washed with DMF / water (1 / 2) and water, and then dried under reduced pressure to obtain 3-(3-bromo-2-nitrophenoxy)benzonitrile (1.33 g). To a mixture of the obtained compound (1.33 g), ethanol (15 mL) and water (5 mL) were added ammonium chloride (5.57 g) and iron powder (1.16 g), and the mixture was stirred at 80 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Toluene was added to the residue, and then the mixture was concentrated under reduced pressure to obtain 3-(2-amino-3-bromophenoxy)benzonitrile (1.22 g). Under an argon atmosphere, to a mixture of the obtained compound (1.17 g) and THF (12 mL) was added methyllithium (1.06 mol / L in diethyl ether) (4.2 mL) at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C was added a mixture of methyl iodide (0.687 g) and THF (7 mL), and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 2 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to obtain the title compound (1.24 g).

[0160] Reference Example B-6 3-(((3R)-3-Amino-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-8-yl)oxy)benzonitrile Under an argon atmosphere, zinc (0.527 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1.44 g) and DMF (8 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added a mixture of Reference Example B-5 (1.11 g) and DMF (3 mL), palladium(II) acetate (0.042 g), and Xphos (0.174 g), and the mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (11 mL) under ice-cooling, TFA (8.33 g) was added, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, 5 mol / L aqueous sodium hydroxide solution (13.2 mL) was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 85 / 15) to obtain the title compound (0.570 g).

[0161] Reference Example B-7 Reference Example B-7 was synthesized in the same manner as Reference Example B-3, using 3-methoxyphenol instead of 2-methoxyphenol.

[0162] Reference Example B-8 (3R)-3-Amino-8-(3-methoxyphenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.143 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.432 g) and DMF (5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a mixture of Reference Example B-7 (0.270 g) and DMF (0.5 mL), palladium(II) acetate (0.010 g), and Xphos (0.042 g), and the mixture was stirred at room temperature for 14 hours. A saturated aqueous ammonium chloride solution and diethyl ether were added to the reaction mixture. The mixture was filtered through Celite, and the filtrate was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (3 mL) was stirred under ice-cooling for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to a mixture of the residue and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to obtain the title compound (0.167 g).

[0163] Reference Example B-9 Reference Example B-9 was synthesized in the same manner as Reference Example B-3, using 2-ethylphenol instead of 2-methoxyphenol.

[0164] Reference Example B-10 Reference Example B-10 was synthesized in the same manner as Reference Example B-8, using Reference Example B-9 instead of Reference Example B-7.

[0165] Reference Example B-11 Reference Example B-11 was synthesized in the same manner as Reference Example B-3, using 3-ethylphenol instead of 2-methoxyphenol.

[0166] Reference Example B-12 (3R)-3-Amino-8-(3-ethylphenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.143 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.432 g) and DMF (5 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added a mixture of Reference Example B-11 (0.268 g) and DMF (1 mL), palladium(II) acetate (0.010 g), and Xphos (0.042 g), and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to a mixture of the residue and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was washed with water and then concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to obtain the title compound (0.110 g).

[0167] Reference Example B-13 2-Bromo-6-(2-chloro-5-fluorophenoxy)-N-methylaniline Potassium carbonate (0.377 g) was added to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.300 g), 2-chloro-5-fluorophenol (0.220 g), and DMF (10 mL), and the mixture was stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water and diethyl ether were added. The mixture was extracted with diethyl ether, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of residue, ethanol (9 mL) and water (3 mL), ammonium chloride (1.46 g) and iron powder (0.777 g) were added, and the mixture was stirred at 90 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, it was filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain 2-bromo-6-(2-chloro-5-fluorophenoxy)aniline (0.417 g). To a mixture of the obtained compound (0.417 g) and THF (7 mL), methyllithium (1.06 mol / L in diethyl ether) (1.37 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.224 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 30 minutes. Aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 77 / 23) to obtain the title compound (0.436 g).

[0168] Reference Example B-14 (3R)-3-Amino-8-(2-chloro-5-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, to a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.650 g) and DMF (7 mL), zinc (0.215 g) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, a mixture of Reference Example B-13 (0.435 g) and DMF (1 mL), palladium(II) acetate (0.015 g) and Xphos (0.063 g) were added, and the mixture was stirred at room temperature for 16 hours. Aqueous saturated ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4 - dioxane) (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture of the residue and ethyl acetate. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n - hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 71 / 29) to obtain the title compound (0.198 g).

[0169] Reference Example B - 15 2 - Bromo - N - methyl - 6-(2 - isopropylphenoxy)aniline Potassium carbonate (0.648 g) was added to a mixture of 1 - bromo - 3 - fluoro - 2 - nitrobenzene (0.516 g), 2 - isopropylphenol (0.351 g) and DMF (5 mL), and the mixture was stirred at 100 °C for 1 hour. Water and toluene were added to the reaction mixture under water cooling. The mixture was extracted with toluene, and the extract was washed with water. The extract was concentrated under reduced pressure to obtain 1 - bromo - 3-(2 - isopropylphenoxy)-2 - nitrobenzene (1.01 g). Ammonium chloride (3.00 g) and iron powder (0.638 g) were added to a mixture of the obtained compound (0.774 g), ethanol (8 mL) and water (2.7 mL), and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled with water and then filtered through celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n - hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 2 - bromo - 6-(2 - isopropylphenoxy)aniline (0.746 g). To a mixture of the obtained compound (0.672 g) and THF (7 mL), methyllithium (1.04 mol / L in diethyl ether) (2.5 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.374 g) and THF (4 mL) was added, and then the mixture was stirred for 1 hour under water cooling. An aqueous saturated ammonium chloride solution and water were added to the reaction mixture under ice cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.787 g).

[0170] Reference Example B-16 (3R)-3-Amino-1-methyl-8-(2-isopropylphenoxy)-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.312 g) was added to a mixture of Reference Example B-15 (0.685 g) and DMF (6 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.845 g), palladium(II) acetate (0.026 g) and Xphos (0.104 g) were added, and the mixture was stirred at room temperature for 14 hours. An aqueous saturated ammonium chloride solution, water and ethyl acetate were added to the reaction mixture. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure. Ethyl acetate, water and toluene were added to the residue. The mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue and DCM (7 mL) under ice cooling, TFA (4.88 g) was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture under ice cooling, 5 mol / L aqueous sodium hydroxide solution (8.5 mL) was added. The mixture was extracted with DCM, and the organic layer was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.357 g).

[0171] Reference Example B-17 2-Bromo-6-(2-(difluoromethyl)phenoxy)-N-methylaniline Potassium carbonate (0.660 g) was added to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.522 g), 2-hydroxybenzaldehyde (0.290 g) and DMF (5 mL), and the mixture was stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and toluene were added. An aqueous saturated ammonium chloride solution and 2 mol / L hydrochloric acid were added to the mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 55 / 45) to obtain 2-(3-bromo-2-nitrophenoxy)benzaldehyde (0.686 g). Bis(2-methoxyethyl)aminosulfur trifluoride (0.937 g) was added to a mixture of the obtained compound (0.682 g), DCM (3.4 mL) and ethanol (0.020 g), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was added to an ice-cooled aqueous saturated sodium hydrogen carbonate solution. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain 1-bromo-3-(2-(difluoromethyl)phenoxy)-2-nitrobenzene (0.674 g). Ammonium chloride (2.30 g) and iron powder (0.480 g) were added to a mixture of the obtained compound (0.588 g), ethanol (6 mL) and water (2 mL), and the mixture was stirred at 80 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, it was filtered through celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 2-bromo-6-(2-(difluoromethyl)phenoxy)aniline (0.488 g). To a mixture of the obtained compound (0.482 g) and THF (5 mL), methyllithium (1.04 mol / L in diethyl ether) (1.6 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.261 g) and THF (3 mL) was added, and then the mixture was stirred for 1 hour under ice-cooling. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.555 g).

[0172] Reference Example B-18 Instead of Reference Example B-15, Reference Example B-17 was used, and Reference Example B-18 was synthesized in the same manner as Reference Example B-16.

[0173] Reference Example B-19 1-Bromo-3,4-difluoro-2-nitrobenzene was used instead of 1-bromo-3-fluoro-2-nitrobenzene, and 2-chlorophenol was used instead of 2-chloro-5-fluorophenol. Reference Example B-19 was synthesized in the same manner as Reference Example B-13.

[0174] Reference Example B-20 Instead of Reference Example B-11, Reference Example B-19 was used, and Reference Example B-20 was synthesized in the same manner as Reference Example B-12.

[0175] Reference Example B-21 2-Chloro-4-fluorophenol was used instead of 2-chloro-5-fluorophenol, and Reference Example B-21 was synthesized in the same manner as Reference Example B-13.

[0176] Reference Example B-22 (3R)-3-Amino-8-(2-chloro-4-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.218 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.659 g) and DMF (7 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example B-21 (0.441 g) and DMF (1 mL), palladium(II) acetate (0.015 g) and Xphos (0.064 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. An aqueous saturated ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue and DCM (7 mL) under ice-cooling, TFA (3.04 g) was added, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a 5 mol / L aqueous sodium hydroxide solution (1.8 mL) was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 40 / 60 / 0 to 0 / 100 / 0 to 0 / 35 / 65) to obtain the title compound (0.295 g).

[0177] Reference Example B-23 2-Bromo-6-(5-fluoro-2-(trifluoromethyl)phenoxy)-N-methylaniline Potassium carbonate (0.188 g) was added to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.150 g), 5-fluoro-2-(trifluoromethyl)phenol (0.135 g) and NMP (2 mL), and the mixture was stirred at 110 °C for 6 hours. After allowing the reaction mixture to cool to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of residue, ethanol (3 mL) and water (1 mL), ammonium chloride (0.912 g) and iron powder (0.190 g) were added, and the mixture was stirred at 80 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 2-bromo-6-(5-fluoro-2-(trifluoromethyl)phenoxy)aniline (0.120 g). To a mixture of the obtained compound (0.120 g) and THF (1 mL), methyllithium (1.06 mol / L in diethyl ether) (0.356 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.058 g) and THF (1 mL) was added, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.094 g).

[0178] Reference Example B-24 Instead of Reference Example B-1, Reference Example B-23 was used, and Reference Example B-24 was synthesized in the same manner as Reference Example B-2.

[0179] Reference Example B-25 6-Bromo-3-chloro-2-(2-chlorophenoxy)-N-methylaniline To a mixture of 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (0.150 g), 2-chlorophenol (0.076 g) and NMP (2 mL), potassium carbonate (0.188 g) was added, and the mixture was stirred at 110 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of residue, ethanol (3 mL) and water (1 mL), ammonium chloride (0.788 g) and iron powder (0.165 g) were added, and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 6-bromo-3-chloro-2-(2-chlorophenoxy)aniline (0.110 g). To a mixture of the obtained compound (0.110 g) and THF (1 mL), methyllithium (1.06 mol / L in diethyl ether) (0.343 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.056 g) and THF (1 mL) was added, and then the mixture was stirred at the same temperature for 10 minutes and at room temperature for 1 hour. To the reaction mixture under ice-cooling, saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.100 g).

[0180] Reference Example B-26 Instead of Reference Example B-1, Reference Example B-25 was used, and Reference Example B-26 was synthesized in the same manner as Reference Example B-2.

[0181] Reference Example B-27 Instead of 2-chlorophenol, 2-fluorophenol was used, and Reference Example B-27 was synthesized in the same manner as Reference Example B-25.

[0182] Reference Example B-28 Instead of Reference Example B-1, Reference Example B-27 was used, and Reference Example B-28 was synthesized in the same manner as Reference Example B-2.

[0183] Reference Example B-29 2-Bromo-6-(3-(difluoromethoxy)phenoxy)-N-methylaniline A mixture of 3-(benzyloxy)phenol (1.01 g) and MeCN (25 mL) was added with a mixture of potassium hydroxide (5.62 g) and water (25 mL) at room temperature. To the mixture, under ice-cooling, diethyl (bromodifluoromethyl)phosphonate (2.69 g) was added and the mixture was stirred at room temperature for 10 minutes. After the mixture was extracted with DCM, the extract was washed with water and concentrated under reduced pressure. To the residue, ethanol (10 mL) and 10% Pd / C (0.204 g) were added and the mixture was stirred at room temperature for 13 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. To a mixture of the residue, 1-bromo-3-fluoro-2-nitrobenzene (0.630 g) and DMF (6 mL), potassium carbonate (0.794 g) was added and the mixture was stirred at 100 °C for 1 hour. After the reaction mixture was allowed to cool to room temperature, water, ethyl acetate and toluene were added. After the mixture was extracted with ethyl acetate, the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 1-bromo-3-(3-(difluoromethoxy)phenoxy)-2-nitrobenzene (0.871 g). To a mixture of the obtained compound (0.866 g), ethanol (9 mL) and water (3 mL), ammonium chloride (3.21 g) and iron powder (0.671 g) were added and the mixture was stirred at 80 °C for 2.5 hours. After the reaction mixture was cooled with water, it was filtered through celite. After adding water to the filtrate, it was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain 2-bromo-6-(3-(difluoromethoxy)phenoxy)aniline (0.758 g). To a mixture of the obtained compound (0.751 g) and THF (8 mL), methyllithium (1.04 mol / L in diethyl ether) (2.6 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.387 g) and THF (5 mL) was added, and then the mixture was stirred for 1 hour under water cooling. To the reaction mixture under water cooling, saturated aqueous ammonium chloride solution and water were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.687 g).

[0184] Reference Example B-30 Instead of Reference Example B-1, Reference Example B-29 was used, and Reference Example B-30 was synthesized in the same manner as Reference Example B-2.

[0185] Reference Example B-31 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-4-chloro-3-fluoro-2-nitrobenzene was used, and instead of 5-fluoro-2-(trifluoromethyl)phenol, 3-methoxyphenol was used. Reference Example B-31 was synthesized in the same manner as Reference Example B-23.

[0186] Reference Example B-32 Instead of Reference Example B-1, Reference Example B-31 was used, and Reference Example B-32 was synthesized in the same manner as Reference Example B-2.

[0187] Reference Example B-33 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-4-chloro-3-fluoro-2-nitrobenzene was used, and instead of 5-fluoro-2-(trifluoromethyl)phenol, 3-fluorophenol was used. Reference Example B-33 was synthesized in the same manner as Reference Example B-23.

[0188] Reference Example B-34 Instead of Reference Example B-1, Reference Example B-33 was used, and Reference Example B-34 was synthesized in the same manner as Reference Example B-2.

[0189] Reference Example B-35 6-Bromo-3-chloro-2-(2-(difluoromethyl)phenoxy)-N-methylaniline Potassium carbonate (0.217 g) was added to a mixture of 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (0.200 g), 2-hydroxybenzaldehyde (0.096 g) and NMP (2 mL), and the mixture was stirred at 110 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, 1 mol / L hydrochloric acid, ethyl acetate and n-hexane were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain 2-(3-bromo-6-chloro-2-nitrophenoxy)benzaldehyde (0.160 g). Bis(2-methoxyethyl)aminosulfur trifluoride (0.199 g) was added to a mixture of the obtained compound (0.160 g) and DCM (3 mL) under ice-cooling, and the mixture was stirred at 50 °C for 2 hours. Bis(2-methoxyethyl)aminosulfur trifluoride (0.496 g) was added to the reaction mixture, and the mixture was stirred at 50 °C for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 1-bromo-4-chloro-3-(2-(difluoromethyl)phenoxy)-2-nitrobenzene (0.130 g). To a mixture of the obtained compound (0.130 g), ethanol (3 mL) and water (1 mL), ammonium chloride (0.459 g) and iron powder (0.096 g) were added, and the mixture was stirred at 80 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 6-bromo-3-chloro-2-(2-(difluoromethyl)phenoxy)aniline (0.110 g). To a mixture of the obtained compound (0.110 g) and THF (1 mL), methyllithium (1.06 mol / L in diethyl ether) (0.327 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.054 g) and THF (1 mL) was added, and then the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. To the reaction mixture under ice-cooling, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.085 g).

[0190] Reference Example B-36 Instead of Reference Example B-1, Reference Example B-35 was used, and Reference Example B-36 was synthesized in the same manner as Reference Example B-2.

[0191] Reference Example B-37 2-Bromo-6-(2-(difluoromethyl)-5-fluorophenoxy)-N-methylaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.04 g), 4-fluoro-2-hydroxybenzaldehyde (0.701 g) and DMF (10 mL), potassium carbonate (1.30 g) was added, and the mixture was stirred at 100 °C for 4 hours. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and MTBE were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to obtain 2-(3-bromo-2-nitrophenoxy)-4-fluorobenzaldehyde (0.455 g). To a mixture of the obtained compound (0.361 g), DCM (4 mL) and ethanol (0.012 g), bis(2-methoxyethyl)aminosulfur trifluoride (0.587 g) was added, and the mixture was stirred at 50 °C for 2.5 hours. The reaction mixture was added to an ice-cooled 5 mol / L aqueous sodium hydroxide solution. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain 1-bromo-3-(2-(difluoromethyl)-5-fluorophenoxy)-2-nitrobenzene (0.359 g). To a mixture of the obtained compound (0.286 g), ethanol (3 mL) and water (1 mL), ammonium chloride (1.06 g) and iron powder (0.223 g) were added, and the mixture was stirred at 80 °C for 1 hour. After cooling the reaction mixture with water, it was filtered through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to obtain 2-bromo-6-(2-(difluoromethyl)-5-fluorophenoxy)aniline (0.256 g). To a mixture of the obtained compound (0.247 g) and THF (3 mL), methyllithium (1.04 mol / L in diethyl ether) (1.0 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.148 g) and THF (2 mL) was added, and then the mixture was stirred for 18 hours under water cooling. To the reaction mixture under water cooling, saturated aqueous ammonium chloride solution and water were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 65 / 35), and then by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to obtain the title compound (0.150 g).

[0192] Reference Example B-38 (3R)-3-Amino-8-(2-(difluoromethyl)-5-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.054 g) was added to a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.145 g) and DMF (1 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, a mixture of Reference Example B-37 (0.126 g) and DMF (2 mL), palladium(II) acetate (0.005 g) and Xphos (0.017 g) were added, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added to the reaction mixture. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL) under ice cooling, TFA (0.829 g) was added, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture under ice cooling, 5 mol / L aqueous sodium hydroxide solution (1.45 mL) was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.025 g).

[0193] Reference Example B-39 Instead of 4-fluoro-2-hydroxybenzaldehyde, 5-fluoro-2-hydroxybenzaldehyde was used, and Reference Example B-39 was synthesized in the same manner as Reference Example B-37.

[0194] Reference Example B-40 Instead of Reference Example B-37, Reference Example B-39 was used, and Reference Example B-40 was synthesized in the same manner as Reference Example B-38.

[0195] Reference Example B-41 Instead of 2-chloro-5-fluorophenol, 2-chloro-5-methoxyphenol was used, and Reference Example B-41 was synthesized in the same manner as Reference Example B-13.

[0196] Reference Example B-42 Instead of Reference Example B-21, Reference Example B-41 was used, and Reference Example B-42 was synthesized in the same manner as Reference Example B-22.

[0197] Reference Example B-43 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-3-fluoro-4-methyl-2-nitrobenzene was used, and instead of 2-chloro-5-fluorophenol, 2-chlorophenol was used, and Reference Example B-43 was synthesized in the same manner as Reference Example B-13.

[0198] Reference Example B-44 Instead of Reference Example B-21, Reference Example B-43 was used, and Reference Example B-44 was synthesized in the same manner as Reference Example B-22.

[0199] Reference Example B-45 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-(benzyloxy)-4-bromo-2-fluoro-3-nitrobenzene was used, and instead of 2-chloro-5-fluorophenol, 2-chlorophenol was used, and Reference Example B-45 was synthesized in the same manner as Reference Example B-13.

[0200] Reference Example B-46 Instead of Reference Example B-21, Reference Example B-45 was used, and Reference Example B-46 was synthesized in the same manner as Reference Example B-22.

[0201] Reference Example B-47 Instead of 2-chloro-5-fluorophenol, 2-chlorophenol was used, and instead of methyl iodide, ethyl iodide was used. Reference Example B-47 was synthesized in the same manner as Reference Example B-13.

[0202] Reference Example B-48 Instead of Reference Example B-21, Reference Example B-47 was used, and Reference Example B-48 was synthesized in the same manner as Reference Example B-22.

[0203] Reference Example B-49 2-Bromo-6-(2-chloro-4,5-difluorophenoxy)-N-methylaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.300 g), 2-chloro-4,5-difluorophenol (0.236 g) and NMP (3 mL), potassium carbonate (0.377 g) was added, and the mixture was stirred at 110 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL), ammonium chloride (1.82 g) and iron powder (0.381 g) were added, and the mixture was stirred at 80 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 2-bromo-6-(2-chloro-4,5-difluorophenoxy)aniline (0.160 g). To a mixture of the obtained compound (0.160 g) and THF (1 mL) was added methyllithium (1.04 mol / L in diethyl ether) (0.506 mL) at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C was added a mixture of methyl iodide (0.081 g) and THF (1 mL), and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.135 g).

[0204] Reference Example B-50 Instead of Reference Example B-1, Reference Example B-49 was used, and Reference Example B-50 was synthesized in the same manner as Reference Example B-2.

[0205] Reference Example B-51 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-3,4-difluoro-2-nitrobenzene was used, and instead of 2-chloro-4,5-difluorophenol, 2-(trifluoromethyl)phenol was used. Reference Example B-51 was synthesized in the same manner as Reference Example B-49.

[0206] Reference Example B-52 (3R)-3-Amino-7-fluoro-1-methyl-8-(2-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-2-one To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.347 g) and DMF (2 mL), zinc (0.126 g) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, Reference Example B-51 (0.320 g), palladium(II) acetate (0.010 g) and Xphos (0.042 g) were added, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL) under ice-cooling, TFA (2.00 g) was added, and the mixture was stirred at room temperature for 4 hours. Under ice-cooling, 2 mol / L aqueous sodium hydroxide solution (8.8 mL) was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 59 / 39 / 2 to 0 / 98 / 2), and then by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to obtain the title compound (0.099 g).

[0207] Reference Example B-53 Reference Example B-53 was synthesized in the same manner as Reference Example B-49, using 1-bromo-4-chloro-3-fluoro-2-nitrobenzene instead of 1-bromo-3-fluoro-2-nitrobenzene and 2-chloro-5-fluorophenol instead of 2-chloro-4,5-difluorophenol.

[0208] Reference Example B-54 Reference Example B-54 was synthesized in the same manner as Reference Example B-2, using Reference Example B-53 instead of Reference Example B-1.

[0209] Reference Example B-55 6-Bromo-2-(2-(difluoromethyl)phenoxy)-N,3-dimethylaniline A mixture of 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (0.306 g), 2-hydroxybenzaldehyde (0.167 g) and DMF (3 mL) was added with potassium carbonate (0.364 g) and stirred at 100 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 2-(3-bromo-6-methyl-2-nitrophenoxy)benzaldehyde (0.306 g). To a mixture of the obtained compound (0.306 g) and DCM (3 mL) were added bis(2-methoxyethyl)aminosulfur trifluoride (0.866 g) and ethanol (0.018 g), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was added to an ice-cooled aqueous potassium carbonate solution. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 65 / 35) to obtain 1-bromo-3-(2-(difluoromethyl)phenoxy)-4-methyl-2-nitrobenzene (0.298 g). To a mixture of the obtained compound (0.298 g), ethanol (4.5 mL) and water (1.5 mL) were added ammonium chloride (1.75 g) and iron powder (0.365 g), and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through celite. Water was added to the filtrate, followed by extraction with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 6-bromo-2-(2-(difluoromethyl)phenoxy)-3-methylaniline (0.237 g). To a mixture of the obtained compound (0.237 g) and THF (2 mL), methyllithium (1.04 mol / L in diethyl ether) (0.9 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.143 g) and THF (1 mL) was added, and then the mixture was stirred under ice-cooling for 2 hours. An aqueous saturated ammonium chloride solution and water were added to the reaction mixture under water-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.239 g).

[0210] Reference Example B-56 Instead of Reference Example B-5, Reference Example B-55 was used, and Reference Example B-56 was synthesized in the same manner as Reference Example B-6.

[0211] Reference Example B-57 6-Bromo-2-(2-chloro-5-fluorophenoxy)-N,3-dimethylaniline To a mixture of 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (0.305 g), 2-chloro-5-fluorophenol (0.200 g) and DMF (10 mL), potassium carbonate (0.360 g) was added, and the mixture was stirred at 100 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 55 / 45) to obtain 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene (0.439 g). To a mixture of the obtained compound (0.439 g), ethanol (4.5 mL) and water (1.5 mL), ammonium chloride (1.74 g) and iron powder (0.362 g) were added, and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-methylaniline (0.355 g). To a mixture of the obtained compound (0.355 g) and THF (3 mL), methyllithium (1.04 mol / L in diethyl ether) (1.3 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.214 g) and THF (1.5 mL) was added, and then the mixture was stirred under ice-cooling for 2 hours. Aqueous saturated ammonium chloride solution and water were added to the reaction mixture under water-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.349 g).

[0212] Reference Example B-58 (3R)-3-Amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, to a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.393 g) and DMF (3 mL), zinc (0.141 g) was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, a mixture of Reference Example B-57 (0.338 g) and DMF (1 mL), palladium(II) acetate (0.012 g) and Xphos (0.047 g) were added, and the mixture was stirred at room temperature for 13 hours. Aqueous saturated ammonium chloride solution, water and ethyl acetate were added to the reaction mixture. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. To a mixture of the residue and DCM (4 mL) was added TFA (2.24 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (3.9 mL) under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.135 g).

[0213] Reference Example B-59 Reference Example B-59 was synthesized in the same manner as Reference Example B-49, using 2-chlorophenol instead of 2-chloro-4,5-difluorophenol.

[0214] Reference Example B-60 Reference Example B-60 was synthesized in the same manner as Reference Example B-52, using Reference Example B-59 instead of Reference Example B-51.

[0215] Reference Example B-61 2-Bromo-6-(cyclohexyloxy)-N-methylaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.770 g), cyclohexanol (0.386 g) and DMF (5 mL) was added sodium hydride (about 60%) (0.280 g), and the mixture was stirred at room temperature for 1 hour. Water, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL) were added ammonium chloride (4.68 g) and iron powder (0.977 g) at room temperature, and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 2-bromo-6-(cyclohexyloxy)aniline (0.458 g). To a mixture of the obtained compound (0.458 g) and THF (8 mL), methyllithium (1.04 mol / L in diethyl ether) (1.8 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.385 g) and THF (2 mL) was added, and then the mixture was stirred at the same temperature for 10 minutes and at room temperature for 1 hour. Methyllithium (1.04 mol / L in diethyl ether) (1.8 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture under ice-cooling, saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to obtain the title compound (0.456 g).

[0216] Reference Example B-62 (3R)-3-Amino-8-(cyclohexyloxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.231 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.634 g) and DMF (10 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, Reference Example B-61 (0.456 g), palladium(II) acetate (0.018 g) and Xphos (0.077 g) were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was stirred at 80 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of the residue and DCM (5 mL) was added TFA (3.66 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (10 mL) under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 50 / 50) to obtain the title compound (0.016 g).

[0217] Reference Example B-63 2-Bromo-6-(cyclopentyloxy)-N-methylaniline To a mixture of cyclopentanol (0.196 g) and DMF (4 mL) was added sodium hydride (ca. 60%) (0.091 g), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1-bromo-3-fluoro-2-nitrobenzene (0.500 g), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture under ice-cooling were added saturated aqueous ammonium chloride solution, ethyl acetate and n-hexane. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30), then by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 1-bromo-3-(cyclopentyloxy)-2-nitrobenzene (0.462 g). To a mixture of the obtained compound (0.462 g), ethanol (5 mL) and water (2 mL) were added ammonium chloride (2.16 g) and iron powder (0.450 g), and the mixture was stirred at 90 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 0 / 100) to obtain 2-bromo-6-(cyclopentyloxy)aniline (0.382 g). To a mixture of the obtained compound (0.382 g) and THF (3 mL), methyllithium (1.04 mol / L in diethyl ether) (1.4 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a mixture of methyl iodide (0.284 g) and THF (1 mL) was added, and the mixture was stirred at the same temperature for 15 minutes and then under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 90 / 10) to obtain the title compound (0.218 g).

[0218] Reference Example B-64 Instead of Reference Example B-5, Reference Example B-63 was used, and Reference Example B-64 was synthesized in the same manner as Reference Example B-6.

[0219] Reference Example B-65 6-Bromo-2-(2-(difluoromethyl)phenoxy)-3-fluoro-N-methylaniline To a mixture of 1-bromo-3,4-difluoro-2-nitrobenzene (1.01 g), 2-hydroxybenzaldehyde (0.540 g) and DMF (10 mL), potassium carbonate (1.17 g) was added, and the mixture was stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. To a mixture of residue, DCM (10 mL) and ethanol (0.078 g), bis(2-methoxyethyl)aminosulfur trifluoride (3.76 g) was added, and the mixture was stirred at 40 °C for 3.5 hours. The reaction mixture was added to an ice-cooled aqueous sodium hydroxide solution. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ethyl acetate, MTBE and water were added to the residue. After the mixture was extracted with ethyl acetate, the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to obtain 1-bromo-3-(2-(difluoromethyl)phenoxy)-4-fluoro-2-nitrobenzene (1.07 g). To a mixture of the obtained compound (1.07 g), ethanol (10 mL) and water (3 mL), ammonium chloride (3.93 g) and iron powder (0.821 g) were added, and the mixture was stirred at 80 °C for 1.5 hours. After the reaction mixture was allowed to cool to room temperature, it was filtered through celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain 6-bromo-2-(2-(difluoromethyl)phenoxy)-3-fluoroaniline (0.963 g). Under an argon atmosphere, to a mixture of the obtained compound (0.957 g) and THF (12 mL), methyllithium (1.04 mol / L in diethyl ether) (3.6 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.573 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 30 minutes. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture under ice-cooling. After the mixture was extracted with ethyl acetate, the extract was washed with water and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5) to obtain the title compound (0.915 g).

[0220] Reference Example B-66 Instead of Reference Example B-21, Reference Example B-65 was used, and Reference Example B-66 was synthesized in the same manner as Reference Example B-22.

[0221] Reference Example B-67 6-Bromo-2-(2-chloro-5-fluorophenoxy)-3-fluoro-N-methylaniline To a mixture of 1-bromo-3,4-difluoro-2-nitrobenzene (1.02 g), 2-chloro-5-fluorophenol (0.651 g) and DMF (10 mL) was added potassium carbonate (1.17 g), and the mixture was stirred at 100 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and toluene were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. To a mixture of the residue, ethanol (15 mL) and water (5 mL) were added ammonium chloride (5.72 g) and iron powder (1.20 g), and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-fluoroaniline (0.916 g). To a mixture of the obtained compound (0.908 g) and THF (10 mL) was added methyllithium (1.04 mol / L in diethyl ether) (3.6 mL) at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C was added a mixture of methyl iodide (0.539 g) and THF (5 mL), and then the mixture was stirred for 1 hour under water cooling. To the reaction mixture under water cooling were added saturated aqueous ammonium chloride solution and water. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.633 g).

[0222] Reference Example B-68 Instead of Reference Example B-21, Reference Example B-67 was used, and Reference Example B-68 was synthesized in the same manner as Reference Example B-22.

[0223] Reference Example B-69 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-3-fluoro-4-methyl-2-nitrobenzene was used, and instead of 2-chloro-5-fluorophenol, 2-fluorophenol was used, and Reference Example B-69 was synthesized in the same manner as Reference Example B-13.

[0224] Reference Example B-70 (3R)-3-Amino-8-(2-fluorophenoxy)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.086 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.257 g) and DMF (4 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added a mixture of Reference Example B-69 (0.186 g) and DMF (1 mL), palladium(II) acetate (0.007 g), and Xphos (0.029 g), and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution and diethyl ether were added to the reaction mixture. The mixture was filtered through Celite, and the filtrate was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (4 mL) under ice-cooling, TFA (1.37 g) was added, and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, a 5 mol / L aqueous sodium hydroxide solution (2.5 mL) was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 40 / 60 / 0 to 0 / 100 / 0 to 0 / 60 / 40) to obtain the title compound (0.031 g).

[0225] Reference Example B-71 Instead of 1-bromo-3-fluoro-2-nitrobenzene, 1-bromo-3-fluoro-4-methyl-2-nitrobenzene was used, and instead of 2-chloro-5-fluorophenol, 3-fluorophenol was used. Reference Example B-71 was synthesized in the same manner as Reference Example B-13.

[0226] Reference Example B-72 Instead of Reference Example B-21, Reference Example B-71 was used, and Reference Example B-72 was synthesized in the same manner as Reference Example B-22.

[0227] Reference Example B-73 2-Bromo-N-methyl-6-(2-methylphenoxy)aniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.300 g), 2-methylphenol (0.147 g) and DMF (3 mL), potassium carbonate (0.377 g) was added and the mixture was stirred at 110 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, ethyl acetate, n-hexane and water were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL), ammonium chloride (1.46 g) and iron powder (0.381 g) were added and the mixture was stirred at 80 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 2-bromo-6-(2-methylphenoxy)aniline (0.370 g). To a mixture of the obtained compound (0.370 g) and THF (3 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.472 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture at -78 °C, a THF (1 mL) solution of methyl iodide (0.227 g) was added, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 2 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.390 g).

[0228] Reference Example B-74 (3R)-3-Amino-1-methyl-8-(2-methylphenoxy)-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.187 g) was added to a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.642 g) and DMF (3 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, Reference Example B-73 (0.380 g), palladium(II) acetate (0.015 g) and Xphos (0.062 g) were added, and the mixture was stirred at 40 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, an aqueous saturated ammonium chloride solution and ethyl acetate were added. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To a mixture of the residue and DCM (3 mL) under ice-cooling, TFA (2.97 g) was added, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture under ice-cooling, a 5 mol / L aqueous sodium hydroxide solution (5.2 mL) was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to obtain the title compound (0.290 g).

[0229] Reference Example B-75 Instead of 2-methylphenol, 5-fluoro-2-methylphenol was used, and Reference Example B-75 was synthesized in the same manner as Reference Example B-73.

[0230] Reference Example B-76 Instead of Reference Example B-73, Reference Example B-75 was used, and Reference Example B-76 was synthesized in the same manner as Reference Example B-74.

[0231] Reference Example B-77 Instead of 1-bromo-3-fluoronitrobenzene, 1-bromo-3-fluoro-4-methyl-2-nitrobenzene was used, and instead of 2-methylphenol, 2,5-difluorophenol was used, and Reference Example B-77 was synthesized in the same manner as Reference Example B-73.

[0232] Reference Example B-78 (3R)-3-Amino-8-(2,5-difluorophenoxy)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, a mixture of zinc (0.156 g) and DMF (1.4 mL) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoic acid methyl (0.537 g) and THF (0.7 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example B-77 (0.357 g) and THF (1.4 mL), palladium(II) acetate (0.012 g), and Xphos (0.052 g) were added to the reaction mixture, and the mixture was stirred at 40 °C for 2 hours. Saturated aqueous ammonium chloride solution, water, ethyl acetate, and n-hexane were added to the reaction mixture under ice-cooling. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate / n-hexane (1 / 1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.314 g) was added to a mixture of residue, toluene (1.7 mL) and ethanol (1.2 mL), and the mixture was stirred at 80 °C for 30 minutes. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.66 mL) under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to obtain the title compound (0.275 g).

[0233] Reference Example C-1 tert-Butyl 6-bromo-2-(2-fluorophenoxy)-3-(trifluoromethyl)benzoate A mixture of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (1.00 g), Boc2O (1.52 g), DMAP (0.043 g) and tert-butyl alcohol (10 mL) was stirred at room temperature for 13 hours. The reaction mixture was stirred at 50 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water and ethyl acetate were added. The mixture was extracted with ethyl acetate, and the extract was washed with 1 mol / L hydrochloric acid and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Potassium carbonate (0.403 g) was added to a mixture of the residue, 2-fluorophenol (0.163 g) and NMP (5 mL), and the mixture was stirred at 110 °C for 4 hours. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and n-hexane were added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.560 g).

[0234] Reference Example C-2 tert-Butyl N-(6-bromo-2-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl)-N-methylcarbamate A mixture of Reference Example C-1 (0.560 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was stirred at 60 °C for 3 hours. The reaction mixture was stirred at 70 °C for 14 hours. Hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was added to the reaction mixture, and the mixture was stirred at 80 °C for 6 hours. After allowing the reaction mixture to cool to room temperature, it was poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of the residue, toluene (3 mL) and tert-butyl alcohol (2 mL), DIPEA (0.171 g) and DPPA (0.365 g) were added, and the mixture was stirred at 100 °C for 3 hours. DPPA (0.912 g) and DIPEA (0.428 g) were added to the reaction mixture, and the mixture was stirred at 100 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, an aqueous saturated sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40), and then by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to obtain tert-butyl N-(6-bromo-2-(2-fluorophenoxy)-3-(trifluoromethyl)phenyl)carbamate (0.768 g). To a mixture of the obtained compound (0.497 g), DMF (10 mL) and methyl iodide (0.235 g) under ice-cooling, sodium hydride (about 60%) (0.066 g) was added, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, an aqueous saturated ammonium chloride solution, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 30 / 70) to obtain the title compound (0.248 g).

[0235] Reference Example C-3 (3R)-3-Amino-8-(2-fluorophenoxy)-1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.077 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.211 g) and DMF (2 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added Reference Example C-2 (0.248 g), palladium(II) acetate (0.006 g), and Xphos (0.025 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL) under ice-cooling was added TFA (1.22 g), and the mixture was stirred at room temperature for 15 hours. To the reaction mixture under ice-cooling was added 5 mol / L aqueous sodium hydroxide solution (5 mL). The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 50 / 50) to obtain the title compound (0.026 g).

[0236] Reference Example D-1 2-Bromo-6-((2-chlorophenyl)methyl)-N-methylaniline A mixture of 1-chloro-2-iodobenzene (1.12 g) and THF (5 mL) was added with isopropylmagnesium chloride (2 mol / L in THF) (2.4 mL) at -40 °C, and the mixture was stirred for 30 minutes under ice-cooling. A mixture of 3-bromo-2-nitrobenzaldehyde (0.540 g) and THF (5 mL) was added to the reaction mixture at -40 °C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain (3-bromo-2-nitrophenyl)(2-chlorophenyl)methanol (0.800 g). Ammonium chloride (3.12 g) and iron powder (0.652 g) were added to a mixture of the obtained compound (0.800 g), ethanol (6 mL) and water (2 mL), and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. Water was added to the filtrate, and the mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain (2-amino-3-bromophenyl)(2-chlorophenyl)methanol (0.670 g). TFA (2.44 g) and triethylsilane (0.498 g) were added to a mixture of the obtained compound (0.670 g) and DCM (5 mL), and the mixture was stirred at room temperature for 13 hours. A 5 mol / L aqueous sodium hydroxide solution (4.3 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 2-bromo-6-(2-chlorobenzyl)aniline (0.480 g). To a mixture of the obtained compound (0.480 g) and THF (5 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.574 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. Methyl iodide (0.276 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.460 g).

[0237] Reference Example D-2 (3R)-3-Amino-8-((2-chlorophenyl)methyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.213 g) was added to a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.731 g) and DMF (5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added Reference Example D-1 (0.460 g), palladium(II) acetate (0.017 g), and Xphos (0.071 g), and the mixture was stirred at 40 °C for 6 hours. After allowing the reaction mixture to cool to room temperature, an aqueous saturated ammonium chloride solution and ethyl acetate were added. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. TFA (3.38 g) was added to a mixture of the residue and DCM (5 mL), and the mixture was stirred at room temperature for 2 hours. A 5 mol / L aqueous sodium hydroxide solution (6.0 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to obtain the title compound (0.120 g).

[0238] Reference Example D-3 2-Bromo-6-((2-chloro-5-fluorophenyl)methyl)-N-methylaniline A mixture of 1-chloro-4-fluoro-2-iodobenzene (1.13 g) and THF (4.7 mL) was added with isopropylmagnesium chloride (2 mol / L in THF) (2.2 mL) at -40 °C, and the mixture was stirred for 30 minutes under ice-cooling. A mixture of 3-bromo-2-nitrobenzaldehyde (0.506 g) and THF (4.7 mL) was added to the reaction mixture at -40 °C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1.5 hours. An aqueous saturated ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain (3-bromo-2-nitrophenyl)(2-chloro-5-fluorophenyl)methanol (0.997 g). To a mixture of the obtained compound (0.997 g), ethanol (5.7 mL) and water (1.9 mL) were added ammonium chloride (2.94 g) and iron powder (0.615 g), and the mixture was stirred at 80 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was suspended in DCM. The supernatant of the suspension was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain (2-amino-3-bromophenyl)(2-chloro-5-fluorophenyl)methanol (0.106 g). The remaining insoluble matter of the suspension was washed with water and n-hexane and then dried under reduced pressure to obtain (2-amino-3-bromophenyl)(2-chloro-5-fluorophenyl)methanol (0.635 g). A mixture of (2-amino-3-bromophenyl)(2-chloro-5-fluorophenyl)methanol (0.740 g) and DCM (5.4 mL) was added with TFA (2.55 g) and triethylsilane (0.521 g), and stirred at room temperature for 24 h. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (4.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 10 min. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 - 85 / 15) to obtain 2-bromo-6-(2-chloro-5-fluorobenzyl)aniline (0.584 g). To a mixture of the obtained compound (0.584 g) and THF (5.7 mL) was added methyllithium (1.04 mol / L in diethyl ether) (1.96 mL) at -78 °C, and the mixture was stirred at the same temperature for 1 h. To the reaction mixture was added methyl iodide (0.316 g) at -78 °C, and then the mixture was stirred at the same temperature for 10 min and under ice-cooling for 30 min. To the reaction mixture were added saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 - 85 / 15) to obtain the title compound (0.517 g).

[0239] Reference Example D-4 (3R)-3-Amino-8-((2-chloro-5-fluorophenyl)methyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, a mixture of zinc (0.226 g) and DMF (2.0 mL) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.777 g) and THF (1.0 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a mixture of Reference Example D-3 (0.517 g) and THF (2.0 mL), palladium(II) acetate (0.018 g), and Xphos (0.075 g), and the mixture was stirred at room temperature for 21 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution, water, ethyl acetate, and n-hexane under ice-cooling. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate / n-hexane (1 / 1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.454 g) was added to a mixture of the residue, toluene (2.5 mL), and ethanol (1.6 mL), and the mixture was stirred at 70 °C for 2 hours. 5 mol / L aqueous sodium hydroxide solution (1.0 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate / methanol = 98 / 2 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.232 g).

[0240] Reference Example D-5 Reference Example D-5 was synthesized in the same manner as Reference Example D-1, using 1-iodo-2-(trifluoromethyl)benzene instead of 1-chloro-2-iodobenzene.

[0241] Reference Example D-6 Reference Example D-6 was synthesized in the same manner as Reference Example D-4, using Reference Example D-5 instead of Reference Example D-3.

[0242] Reference Example D-7 Reference Example D-7 was synthesized in the same manner as Reference Example D-1, using 1-iodo-2-methylbenzene instead of 1-chloro-2-iodobenzene.

[0243] Reference Example D-8 Instead of Reference Example D-3, Reference Example D-7 was used, and Reference Example D-8 was synthesized in the same manner as Reference Example D-4.

[0244] Reference Example D-9 Instead of 1-chloro-2-iodobenzene, 1-(difluoromethyl)-2-iodobenzene was used, and Reference Example D-9 was synthesized in the same manner as Reference Example D-1.

[0245] Reference Example D-10 (3R)-3-Amino-8-((2-(difluoromethyl)phenyl)methyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, a mixture of zinc (0.064 g) and DMF (0.6 mL) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.221 g) and THF (0.3 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a mixture of Reference Example D-9 (0.146 g) and THF (0.6 mL), palladium(II) acetate (0.005 g), and Xphos (0.021 g), and the mixture was stirred at room temperature for 12 hours and at 40 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, aqueous saturated ammonium chloride solution, water, ethyl acetate, and n-hexane were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate / n-hexane (1 / 1). The extract was washed with water and then concentrated under reduced pressure. Methanesulfonic acid (0.129 g) was added to a mixture of the residue, toluene (0.75 mL), and ethanol (0.45 mL), and the mixture was stirred at 70 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, it was partitioned between water and ethyl acetate. The aqueous layer was separated, ethyl acetate was added thereto, and while stirring, aqueous saturated sodium hydrogen carbonate solution was added. The organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (0.032 g).

[0246] Reference Example D-11 6-Bromo-2-((2-chloro-5-fluorophenyl)methyl)-3-fluoro-N-methylaniline A mixture of 1-chloro-4-fluoro-2-iodobenzene (0.620 g) and THF (3 mL) was added with isopropylmagnesium chloride (2 mol / L in THF) (1.21 mL) at -40 °C and stirred for 30 minutes under ice-cooling. A mixture of 3-bromo-6-fluoro-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) was added to the reaction mixture at -40 °C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain (3-bromo-6-fluoro-2-nitrophenyl)(2-chloro-5-fluorophenyl)methanol (0.424 g). Ammonium chloride (1.50 g) and iron powder (0.313 g) were added to a mixture of the obtained compound (0.424 g), ethanol (3 mL) and water (1 mL), and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain (2-amino-3-bromo-6-fluorophenyl)(2-chloro-5-fluorophenyl)methanol (0.328 g). Boron trifluoride diethyl ether complex (0.098 g) and triethylsilane (0.081 g) were added to a mixture of the obtained compound (0.161 g) and DCM (1.6 mL), and the mixture was stirred at room temperature for 15 hours. TFA (0.527 g) was added to the reaction mixture, and the mixture was refluxed for 8 hours. 5 mol / L aqueous sodium hydroxide solution (1 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to obtain 6-bromo-2-(2-chloro-5-fluorobenzyl)-3-fluoroaniline (0.073 g). To a mixture of the obtained compound (0.073 g) and THF (2 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.078 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.037 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.051 g).

[0247] Reference Example D-12 Instead of Reference Example D-9, Reference Example D-11 was used, and Reference Example D-12 was synthesized in the same manner as Reference Example D-10.

[0248] Reference Example D-13 6-Bromo-3-chloro-2-((2-chloro-5-fluorophenyl)methyl)-N-methylaniline To a mixture of 1-chloro-4-fluoro-2-iodobenzene (0.769 g) and THF (3.7 mL), isopropylmagnesium chloride (2 mol / L in THF) (1.5 mL) was added at -40 °C, and the mixture was stirred under ice-cooling for 30 minutes. A mixture of Reference Example E-1 (0.397 g) and THF (3.7 mL) was added to the reaction mixture at -40 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 30 minutes. An aqueous saturated ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of residue, ethanol (8.2 mL) and water (2.7 mL), ammonium chloride (2.01 g) and iron powder (0.419 g) were added, and the mixture was stirred at 80 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. DCM and n-hexane were added to the residue, and the insoluble material was filtered off. The obtained solid was washed with n-hexane and dried under reduced pressure to obtain (2-amino-3-bromo-6-chlorophenyl)(2-chloro-5-fluorophenyl)methanol (0.455 g). To a mixture of the obtained compound (0.455 g) and 1,2-dichloroethane (3 mL), TFA (1.42 g) and triethylsilane (0.290 g) were added, and the mixture was stirred at 50 °C for 30 minutes and at 70 °C for 2.5 hours. To the reaction mixture under ice-cooling, 5 mol / L aqueous sodium hydroxide solution (2.5 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 6-bromo-3-chloro-2-(2-chloro-5-fluorobenzyl)aniline as a mixture with impurities. n-Hexane was added to this product, and the mixture was stirred under ice-cooling. The insoluble material was filtered off, washed with n-hexane, and the filtrate and the washing solution were combined and concentrated under reduced pressure. n-Hexane was added to the residue, the supernatant was separated, and concentrated under reduced pressure to obtain 6-bromo-3-chloro-2-(2-chloro-5-fluorobenzyl)aniline (0.263 g). To a mixture of the obtained compound (0.262 g) and THF (2.1 mL), methyllithium (1.04 mol / L in diethyl ether) (0.718 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 45 minutes. To the reaction mixture at -78 °C, methyl iodide (0.116 g) was added, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 45 minutes. To the reaction mixture under ice-cooling, saturated aqueous ammonium chloride solution and water were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.228 g).

[0249] Reference Example D-14 Instead of Reference Example D-3, Reference Example D-13 was used, and Reference Example D-14 was synthesized in the same manner as Reference Example D-4.

[0250] Reference Example D-15 6-Bromo-2-((2-chlorophenyl)methyl)-N,3-dimethylaniline Isopropylmagnesium chloride (2 mol / L in THF) (1.64 mL) was added to a mixture of 1-chloro-2-iodobenzene (0.782 g) and THF (4 mL) at -40°C, and the mixture was stirred for 30 minutes under ice-cooling. A mixture of Reference Example E-2 (0.400 g) and THF (4 mL) was added to the reaction mixture at -40°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ammonium chloride (2.19 g) and iron powder (0.458 g) were added to a mixture of the residue, ethanol (9 mL), and water (3 mL), and the mixture was stirred at 80°C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain (2-amino-3-bromo-6-methylphenyl)(2-chlorophenyl)methanol (0.390 g). TFA (1.26 g) and triethylsilane (0.256 g) were added to a mixture of the obtained compound (0.360 g) and 1,2-dichloroethane (5 mL), and the mixture was stirred at 70°C for 4 hours. A 5 mol / L aqueous sodium hydroxide solution (2.2 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain 6-bromo-2-(2-chlorobenzyl)-3-methylaniline (0.350 g). To a mixture of the obtained compound (0.350 g) and THF (3 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.4 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. Methyl iodide (0.192 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. Aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.330 g).

[0251] Reference Example D-16 (3R)-3-Amino-8-((2-chlorophenyl)methyl)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, zinc (0.146 g) was added to a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.502 g) and DMF (2 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example D-15 (0.330 g) and DMF (2 mL), palladium(II) acetate (0.011 g), and Xphos (0.048 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. Aqueous saturated ammonium chloride solution and ethyl acetate were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. TFA (2.32 g) was added to a mixture of the residue and 1,2-dichloroethane (5 mL), and the mixture was stirred at 70 °C for 2 hours. 5 mol / L aqueous sodium hydroxide solution (4.1 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to obtain the title compound (0.009 g).

[0252] Reference Example D-17 6-Bromo-2-((2-chloro-5-fluorophenyl)methyl)-N,3-dimethylaniline To a mixture of 1-chloro-4-fluoro-2-iodobenzene (1.05 g) and THF (5 mL) was added isopropylmagnesium chloride (2 mol / L in THF) (2.05 mL) at -40 °C, and the mixture was stirred for 30 minutes under ice-cooling. To the reaction mixture was added a mixture of Reference Example E-2 (0.500 g) and THF (5 mL) at -40 °C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1.5 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, ethanol (9 mL) and water (3 mL) were added ammonium chloride (2.74 g) and iron powder (0.572 g), and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to give (2-amino-3-bromo-6-methylphenyl)(2-chloro-5-fluorophenyl)methanol (0.540 g). To a mixture of the obtained compound (0.540 g) and 1,2-dichloroethane (5 mL) were added TFA (1.79 g) and triethylsilane (0.364 g), and the mixture was stirred at 70 °C for 10 hours. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (4.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give 6-bromo-2-(2-chloro-5-fluorobenzyl)-3-methylaniline (0.580 g). To a mixture of the obtained compound (0.580 g) and THF (5 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.559 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. Methyl iodide (0.268 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.410 g).

[0253] Reference Example D-18 Instead of Reference Example D-15, Reference Example D-17 was used, and Reference Example D-18 was synthesized in the same manner as Reference Example D-16.

[0254] Reference Example D-19 6-Bromo-2-((2-chlorophenyl)methyl)-3-fluoro-N-methylaniline To a mixture of 1-chloro-2-iodobenzene (0.577 g) and THF (3 mL), isopropylmagnesium chloride (2 mol / L in THF) (1.21 mL) was added at -40 °C, and the mixture was stirred under ice-cooling for 30 minutes. A mixture of 3-bromo-6-fluoro-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) was added to the reaction mixture at -40 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue, ethanol (3 mL) and water (1 mL), ammonium chloride (1.62 g) and iron powder (0.338 g) were added, and the mixture was stirred at 80 °C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then filtered through celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue and DCM (4 mL), TFA (1.38 g) and triethylsilane (0.281 g) were added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was refluxed overnight. To the reaction mixture under ice-cooling, 5 mol / L aqueous sodium hydroxide solution (2.42 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 92 / 8) to obtain 6-bromo-2-(2-chlorobenzyl)-3-fluoroaniline (0.192 g). To a mixture of the obtained compound (0.192 g) and THF (2 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.217 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture at -78 °C, methyl iodide (0.104 g) was added, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. To the reaction mixture under ice-cooling, saturated aqueous ammonium chloride solution and water were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 92 / 8) to obtain the title compound (0.178 g).

[0255] Reference Example D-20 Instead of Reference Example D-9, Reference Example D-19 was used, and Reference Example D-20 was synthesized in the same manner as Reference Example D-10.

[0256] Reference Example D-21 Instead of 1-chloro-2-iodobenzene, 1-iodo-2-(trifluoromethyl)benzene was used, and Reference Example D-21 was synthesized in the same manner as Reference Example D-19.

[0257] Reference Example D-22 Instead of Reference Example D-9, Reference Example D-21 was used, and Reference Example D-22 was synthesized in the same manner as Reference Example D-10.

[0258] Reference Example D-23 Instead of 3-bromo-6-fluoro-2-nitrobenzaldehyde, Reference Example D-23 was synthesized in the same manner as Reference Example D-19 using Reference Example E-1.

[0259] Reference Example D-24 Instead of Reference Example D-9, Reference Example D-24 was synthesized in the same manner as Reference Example D-10 using Reference Example D-23.

[0260] Reference Example D-25 6-Bromo-3-fluoro-N-methyl-2-((2-methylphenyl)methyl)aniline Isopropylmagnesium chloride (2 mol / L in THF) (1.21 mL) was added to a mixture of 1-iodo-2-methylbenzene (0.527 g) and THF (3 mL) at -40°C, and the mixture was stirred for 30 minutes under ice-cooling. A mixture of 3-bromo-6-fluoro-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) was added to the reaction mixture at -40°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Aqueous saturated ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ammonium chloride (1.62 g) and iron powder (0.337 g) were added to a mixture of the residue, ethanol (3 mL) and water (1 mL), and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then filtered through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL), TFA (0.669 g) and triethylsilane (0.136 g) were added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (1.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain 6-bromo-3-fluoro-2-(2-methylbenzyl)aniline (0.149 g). To a mixture of the obtained compound (0.149 g) and THF (2 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.180 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, methyl iodide (0.086 g) was added at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. To the reaction mixture, saturated aqueous ammonium chloride solution and water were added under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.138 g).

[0261] Reference Example D-26 Instead of Reference Example D-9, Reference Example D-25 was used, and Reference Example D-26 was synthesized in the same manner as Reference Example D-10.

[0262] Reference Example D-27 6-Bromo-3-chloro-2-((2-fluorophenyl)methyl)-N-methylaniline To a mixture of 1-fluoro-2-iodobenzene (0.666 g) and THF (3.7 mL), isopropylmagnesium chloride (2 mol / L in THF) (1.50 mL) was added at -40 °C, and the mixture was stirred under ice-cooling for 50 minutes. To the reaction mixture, a mixture of Reference Example E-1 (0.397 g) and THF (3.7 mL) was added at -40 °C, and the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 30 minutes. To the reaction mixture, saturated aqueous ammonium chloride solution and water were added under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of residue, ethanol (8.2 mL) and water (2.7 mL), ammonium chloride (2.01 g) and iron powder (0.419 g) were added, and the mixture was stirred at 80 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain (2-amino-3-bromo-6-chlorophenyl)(2-fluorophenyl)methanol (0.471 g). To a mixture of the obtained compound (0.470 g) and DCM (1.4 mL), TFA (1.62 g) and triethylsilane (0.331 g) were added, and the mixture was refluxed for 1.5 hours. To the reaction mixture under ice-cooling, 5 mol / L aqueous sodium hydroxide solution (2.9 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 6-bromo-3-chloro-2-(2-fluorobenzyl)aniline (0.298 g). To a mixture of the obtained compound (0.297 g) and THF (2.9 mL), methyllithium (1.04 mol / L in diethyl ether) (0.999 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 45 minutes. To the reaction mixture at -78 °C, methyl iodide (0.161 g) was added, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 45 minutes. To the reaction mixture under ice-cooling, saturated aqueous ammonium chloride solution and water were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.297 g).

[0263] Reference Example D-28 Instead of Reference Example D-3, Reference Example D-27 was used, and Reference Example D-28 was synthesized in the same manner as Reference Example D-4.

[0264] Reference Example D-29 6-Bromo-3-chloro-2-(3-fluorobenzyl)-N-methylaniline To a mixture of 1-fluoro-3-iodobenzene (0.666 g) and THF (3.7 mL) was added isopropylmagnesium chloride (2 mol / L in THF) (1.50 mL) at -40°C, and the mixture was stirred for 50 minutes under ice-cooling. To the reaction mixture was added a mixture of Reference Example E-1 (0.397 g) and THF (3.7 mL) at -40°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 30 minutes. To the reaction mixture were added saturated aqueous ammonium chloride solution and water under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, ethanol (8.2 mL) and water (2.7 mL) were added ammonium chloride (2.01 g) and iron powder (0.419 g), and the mixture was stirred at 80°C for 30 minutes. After allowing the reaction mixture to cool to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to give (2-amino-3-bromo-6-chlorophenyl)(3-fluorophenyl)methanol (0.471 g). To a mixture of the obtained compound (0.470 g) and DCM (1.4 mL) were added TFA (1.62 g) and triethylsilane (0.331 g), and the mixture was refluxed for 2 hours. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (2.9 mL) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give 6-bromo-3-chloro-2-(3-fluorobenzyl)aniline as a mixture with impurities. n-Hexane was added to this product, and the mixture was allowed to stand under ice-cooling. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give 6-bromo-3-chloro-2-(3-fluorobenzyl)aniline (0.369 g). To a mixture of the obtained compound (0.369 g) and THF (3.6 mL), methyllithium (1.04 mol / L in diethyl ether) (1.24 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 45 minutes. Methyl iodide (0.200 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 45 minutes. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.272 g).

[0265] Reference Example D-30 Instead of Reference Example D-3, using Reference Example D-29, Reference Example D-30 was synthesized in the same manner as Reference Example D-4.

[0266] Reference Example D-31 Instead of Reference Example E-1, using Reference Example E-2, Reference Example D-31 was synthesized in the same manner as Reference Example D-27.

[0267] Reference Example D-32 Instead of Reference Example D-3, using Reference Example D-31, Reference Example D-32 was synthesized in the same manner as Reference Example D-4.

[0268] Reference Example D-33 Instead of 1-fluoro-2-iodobenzene, using 1-fluoro-3-iodobenzene, and instead of Reference Example E-1, using Reference Example E-2, Reference Example D-33 was synthesized in the same manner as Reference Example D-27.

[0269] Reference Example D-34 Instead of Reference Example D-3, using Reference Example D-33, Reference Example D-34 was synthesized in the same manner as Reference Example D-4.

[0270] Reference Example D-35 2-Bromo-6-(5-fluoro-2-methylbenzyl)-N-methylaniline A mixture of 4-fluoro-2-iodo-1-methylbenzene (0.677 g) and THF (3 mL) was added with isopropylmagnesium chloride (2 mol / L in THF) (1.44 mL) at -40 °C and stirred for 30 minutes under ice-cooling. A mixture of 3-bromo-2-nitrobenzaldehyde (0.330 g) and THF (3 mL) was added to the reaction mixture at -40 °C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1.5 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ammonium chloride (1.92 g) and iron powder (0.401 g) were added to a mixture of the residue, ethanol (6 mL) and water (2 mL), and the mixture was stirred at 80 °C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 - 80 / 20) to obtain (2-amino-3-bromophenyl)(5-fluoro-2-methylphenyl)methanol (0.550 g). TFA (1.64 g) and triethylsilane (0.334 g) were added to a mixture of the obtained compound (0.550 g) and DCM (5 mL), and the mixture was stirred at room temperature for 13 hours. 5 mol / L aqueous sodium hydroxide solution (3.0 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 - 85 / 15) to obtain 2-bromo-6-(5-fluoro-2-methylbenzyl)aniline (0.480 g). To a mixture of the obtained compound (0.480 g) and THF (5 mL), methyllithium (3.1 mol / L in diethoxymethane) (0.510 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.245 g) was added to the reaction mixture at -78 °C, and then the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. An aqueous saturated ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.520 g).

[0271] Reference Example D-36 Instead of Reference Example D-15, Reference Example D-35 was used, and Reference Example D-36 was synthesized in the same manner as Reference Example D-16.

[0272] Reference Example E-1 3-Bromo-6-chloro-2-nitrobenzaldehyde To a mixture of 5-bromo-2-chlorobenzaldehyde (6.00 g) and concentrated sulfuric acid (41.6 g), a mixture of 70% nitric acid (4.92 g) and concentrated sulfuric acid (51.1 g) was slowly added under ice-cooling. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was slowly added to ice water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), n-hexane (30 mL) was added, and the mixture was stirred at room temperature for 30 minutes and under ice-cooling for 30 minutes. The insoluble material was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (3.10 g).

[0273] Reference Example E-2 Instead of 5-bromo-2-chlorobenzaldehyde, 5-bromo-2-methylbenzaldehyde was used, and Reference Example E-2 was synthesized in the same manner as Reference Example E-1.

[0274] Reference Example F-1 1-Bromo-4-chloro-3-fluoro-2-nitrobenzene was used instead of 1-bromo-3-fluoro-2-nitrobenzene, and 2,5-difluorophenol was used instead of 2-methylphenol. Reference Example F-1 was synthesized in the same manner as Reference Example B-73.

[0275] Reference Example F-2 (3R)-3-Amino-7-chloro-8-(2,5-difluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, a mixture of zinc (0.089 g) and DMF (0.8 mL) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.306 g) and DMF (0.4 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a mixture of Reference Example F-1 (0.216 g) and DMF (0.8 mL), palladium(II) acetate (0.007 g), and Xphos (0.030 g), and the mixture was stirred at 40 °C for 3 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution, water, ethyl acetate, and n-hexane under ice-cooling. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate / n-hexane (1 / 1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.179 g) was added to a mixture of the residue, toluene (1.0 mL), and ethanol (0.7 mL), and the mixture was stirred at 80 °C for 0.5 hour. 5 mol / L aqueous sodium hydroxide solution (0.375 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to obtain the title compound (0.084 g).

[0276] Reference Example F-3 1-Bromo-3-fluoro-4-methyl-2-nitrobenzene was used instead of 1-bromo-3-fluoro-2-nitrobenzene, and 4-fluoro-2-hydroxybenzaldehyde was used instead of 2-hydroxybenzaldehyde. Reference Example F-3 was obtained in the same manner as Reference Example B-17.

[0277] Reference Example F-4 Using Reference Example F-3 instead of Reference Example F-1, Reference Example F-4 was obtained in the same manner as Reference Example F-2.

[0278] Reference Example F-5 (4-Bromo-2-(2-chloro-5-fluorophenoxy)-3-(methylamino)phenyl)methanol To a mixture of 4-bromo-2-fluorobenzyl alcohol (3.00 g) and DMF (30 mL) was added sodium hydride (about 60%) (0.761 g) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 4-methoxybenzyl chloride (2.75 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated aqueous ammonium chloride solution, water, ethyl acetate and n-hexane under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain 4-bromo-2-fluoro-1-(((4-methoxyphenyl)methoxy)methyl)benzene (4.96 g). A mixture of the obtained compound (4.76 g) and THF (50 mL) was added dropwise with LDA (1.07 mol / L in n-hexane / THF) (22 mL) at -78 °C, and the mixture was stirred at the same temperature for 1 hour. DMF (3.21 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 0.5 hour. 2 mol / L hydrochloric acid (40 mL) was added to the reaction mixture at -20 °C, and then the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with n-hexane, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Potassium carbonate (4.05 g) was added to a mixture of the residue, NMP (40 mL) and 2-chloro-5-fluorophenol (2.25 g), and the mixture was stirred at 110 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, water, ethyl acetate and n-hexane were added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-(((4-methoxyphenyl)methoxy)methyl)benzaldehyde (5.00 g). To a mixture of the obtained compound (5.00 g), MeCN (22.5 mL) and DMSO (0.977 g) was added concentrated sulfuric acid (0.613 g) under a salt-ice bath. To the mixture was added a mixture of sodium chlorite (80%) (1.41 g) and water (7.5 mL) under a salt-ice bath, and the mixture was stirred at the same temperature for 0.5 h. To the reaction mixture was added an aqueous saturated sodium bisulfite solution (1.5 mL) under a salt-ice bath, and the mixture was stirred at room temperature for 10 min. Water was added to the mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DMF (25 mL) were added TEA (2.11 g) and DPPA (4.31 g), and the mixture was stirred at room temperature for 2 h. To the mixture was added 5 mol / L aqueous sodium hydroxide solution (8.3 mL) under water cooling, and the mixture was stirred at room temperature for 0.5 h. The mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with an aqueous saturated ammonium chloride solution, water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-(((4-methoxyphenyl)methoxy)methyl)aniline (2.80 g). To a mixture of the obtained compound (2.80 g) and ethyl acetate (28 mL), pyridine (0.617 g) and trifluoroacetic anhydride (1.64 g) were added under a salt-ice bath, and the mixture was stirred at the same temperature for 0.5 hour. Methanol (0.192 g) and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DMF (14 mL), methyl iodide (1.28 g) and potassium carbonate (1.66 g) were added, and the mixture was stirred at room temperature for 3 hours. Water, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. To a mixture of the residue, methanol (14 mL) and THF (14 mL), 5 mol / L aqueous sodium hydroxide solution (2.4 mL) was added, and the mixture was stirred at 60 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-(((4-methoxyphenyl)methoxy)methyl)-N-methylaniline (2.50 g). To a mixture of the obtained compound (1.50 g), DCM (15 mL) and water (0.15 mL), 2,3-dichloro-5,6-dicyano-p-benzoquinone (0.779 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to obtain the title compound (0.920 g).

[0279] Reference Example F-6 Using Reference Example F-5 instead of Reference Example F-1, Reference Example F-6 was obtained in the same manner as Reference Example F-2.

[0280] Reference Example F-7 6-Bromo-2-(2-chloro-5-fluorophenoxy)-3-(difluoromethyl)-N-methylaniline To a mixture of 4-bromo-1-(difluoromethyl)-2-fluorobenzene (0.800 g) and THF (8 mL) was added LDA (1.07 mol / L in n-hexane / THF) (5.5 mL) at -78°C, and the mixture was stirred at the same temperature for 1 hour. DMF (0.780 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 0.5 hour. Aqueous saturated ammonium chloride solution was added to the reaction mixture at -78°C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with n-hexane, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue, a mixture of NMP (5 mL) and 2-chloro-5-fluorophenol (0.535 g) was added potassium carbonate (0.721 g), and the mixture was stirred at 110°C for 2 hours. The reaction mixture was allowed to cool to room temperature, water, ethyl acetate and n-hexane were added, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-(difluoromethyl)benzaldehyde (0.790 g). To a mixture of the obtained compound (0.790 g), MeCN (3.6 mL) and DMSO (0.195 g) was added concentrated sulfuric acid (0.122 g) under a salt-ice bath. To the mixture was added a mixture of sodium chlorite (80%) (0.282 g) and water (1.2 mL) under a salt-ice bath, and the mixture was stirred at the same temperature for 0.5 hour. To the reaction mixture was added an aqueous solution of saturated sodium bisulfite (0.24 mL) under a salt-ice bath, and the mixture was stirred at room temperature for 10 minutes. Water was added to the mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DMF (4 mL) were added TEA (0.420 g) and DPPA (0.856 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added 5 mol / L aqueous sodium hydroxide solution (1.7 mL) under water cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with n-hexane / ethyl acetate (1 / 1), and the extract was washed with an aqueous solution of saturated ammonium chloride, water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-(difluoromethyl)aniline (0.330 g). To a mixture of the obtained compound (0.330 g) and ethyl acetate (3 mL) was added pyridine (0.093 g) and trifluoroacetic anhydride (0.246 g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Methanol (0.029 g) and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DMF (1.5 mL) were added methyl iodide (0.192 g) and potassium carbonate (0.249 g), and the mixture was stirred at room temperature for 1 hour. Water, ethyl acetate and n-hexane were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. To a mixture of the residue, methanol (1.5 mL) and THF (1.5 mL) was added 5 mol / L aqueous sodium hydroxide solution (0.36 mL), and the mixture was stirred at 60 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain the title compound (0.300 g).

[0281] Reference Example F-8 (3R)-3-Amino-8-(2-chloro-5-fluorophenoxy)-7-(difluoromethyl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.389 g) was added to a mixture of zinc (0.113 g) and DMF (1 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a mixture of Reference Example F-7 (0.300 g) and DMF (1 mL), palladium(II) acetate (0.009 g), and Xphos (0.038 g), and the mixture was stirred at 40 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, an aqueous saturated ammonium chloride solution, water, ethyl acetate, and n-hexane were added to the reaction mixture. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine. After drying the extract over anhydrous sodium sulfate, it was concentrated under reduced pressure. Methanesulfonic acid (0.227 g) was added to a mixture of the residue, toluene (1 mL), and ethanol (0.5 mL), and the mixture was stirred at 70 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. Water, toluene, and ethyl acetate were added to the residue for partitioning. The aqueous layer was separated, ethyl acetate was added thereto, and then an aqueous saturated sodium hydrogen carbonate solution was added with stirring. The organic layer was separated and washed with saturated brine. After drying the organic layer over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain the title compound (0.050 g).

[0282] Reference Example F-9 Reference Example F-9 was obtained in the same manner as Reference Example F-7, using 4-bromo-2-fluoro-1-(fluoromethyl)benzene instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene.

[0283] Reference Example F-10 Reference Example F-10 was obtained in the same manner as Reference Example F-2, using Reference Example F-9 instead of Reference Example F-1.

[0284] Reference Example F-11 Reference Example F-11 was obtained in the same manner as Reference Example F-7, using 4-bromo-2-fluoro-1-(trifluoromethyl)benzene instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene.

[0285] Reference Example F-12 (3R)-3-Amino-8-(2-chloro-5-fluorophenoxy)-1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-one Under an argon atmosphere, methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate (0.997 g) was added to a mixture of zinc (0.256 g) and DMF (3 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added a mixture of Reference Example F-11 (0.710 g) and DMF (1.5 mL), palladium(II) acetate (0.020 g), and Xphos (0.085 g), and the mixture was stirred at 40 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride solution, water, ethyl acetate, and n-hexane were added. The mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.514 g) was added to a mixture of the residue, toluene (3.5 mL), and ethanol (2 mL), and the mixture was stirred at 70 °C for 2 hours. After allowing the reaction mixture to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.400 g).

[0286] Reference Example F-13 Reference Example F-13 was obtained in the same manner as Reference Example F-7, using 4-bromo-1-(1,1-difluoroethyl)-2-fluorobenzene instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene.

[0287] Reference Example F-14 Reference Example F-14 was obtained in the same manner as Reference Example F-12, using Reference Example F-13 instead of Reference Example F-11.

[0288] Reference Example F-15 Using 4-bromo-1-ethyl-2-fluorobenzene instead of 4-bromo-1-(difluoromethyl)-2-fluorobenzene, Reference Example F-15 was obtained in the same manner as Reference Example F-7.

[0289] Reference Example F-16 Using Reference Example F-15 instead of Reference Example F-11, Reference Example F-16 was obtained in the same manner as Reference Example F-12.

[0290] Reference Example G-1 2-Bromo-6-(1-(2-chlorophenyl)ethenyl)-N-methylaniline To a mixture of 1-chloro-2-iodobenzene (0.715 g) and THF (3.7 mL) was added isopropylmagnesium chloride (2.0 mol / L in THF) (1.5 mL) at -40°C, and the mixture was stirred at 0°C for 45 minutes. To the reaction mixture was added a mixture of 3-bromo-2-nitrobenzaldehyde (0.345 g) and THF (3.7 mL) at -40°C, and the mixture was stirred at the same temperature for 10 minutes and at 0°C for 30 minutes. To the reaction mixture were added saturated aqueous ammonium chloride solution and water at 0°C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, ethanol (8.2 mL), and water (2.7 mL) were added iron powder (0.419 g) and ammonium chloride (2.01 g), and the mixture was stirred at 80°C for 2 hours and then allowed to stand at room temperature for 13 hours. The reaction mixture was stirred at 80°C for 1 hour. After allowing the reaction mixture to cool to room temperature, water and DCM were added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in n-hexane, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain (2-amino-3-bromophenyl)(2-chlorophenyl)methanol (0.351 g). To a mixture of the obtained compound (0.250 g) and DCM (7.3 mL) was added manganese dioxide (0.348 g), and the mixture was stirred at room temperature for 2.5 hours and at 35°C for 17 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through celite. The filtrate was concentrated under reduced pressure to obtain 2-bromo-6-(2-chlorobenzoyl)aniline (0.247 g). Under an argon atmosphere, methylmagnesium bromide (3.0 mol / L in diethyl ether) (0.52 mL) was added to a mixture of the obtained compound (0.231 g) and diethyl ether (2.5 mL) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes and then at room temperature for 1 hour. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 1-(2-amino-3-bromophenyl)-1-(2-chlorophenyl)ethan-1-ol (0.247 g). To a mixture of the obtained compound (0.195 g) and 1,2-dichloroethane (3 mL), boron trifluoride diethyl ether complex (0.127 g) and triethylsilane (0.174 g) were added, and the mixture was stirred at 70 °C for 2 hours and then at 50 °C for 15 hours. 5 mol / L aqueous sodium hydroxide solution (0.18 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 2-bromo-6-(1-(2-chlorophenyl)ethenyl)aniline (0.171 g). To a mixture of the obtained compound (0.171 g) and THF (1.7 mL) at -78 °C, methyllithium (1.04 mol / L in diethyl ether) (0.59 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.094 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 10 minutes and then at 0 °C for 1.5 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.168 g).

[0291] Reference Example G-2 Reference Example G-1 was used instead of Reference Example F-1, and Reference Example G-2 was obtained in the same manner as Reference Example F-2.

[0292] Reference Example G-3 2-Bromo-N-methyl-6-(1-(2-(trifluoromethyl)phenyl)ethenyl)aniline Isopropylmagnesium chloride (2.0 mol / L in THF) (1.3 mL) was added to a mixture of 1-iodo-2-(trifluoromethyl)benzene (0.710 g) and THF (3 mL) at -40°C, and the mixture was stirred at 0°C for 30 minutes. A mixture of 3-bromo-2-nitrobenzaldehyde (0.300 g) and THF (3 mL) was added to the reaction mixture at -40°C, and the mixture was stirred at the same temperature for 10 minutes and then at 0°C for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Iron powder (0.365 g) and ammonium chloride (1.75 g) were added to a mixture of the residue, ethanol (3 mL), and water (1 mL), and the mixture was stirred at 80°C for 1.5 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. Water was added to the filtrate, and then the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain (2-amino-3-bromophenyl)(2-(trifluoromethyl)phenyl)methanol (0.286 g). Manganese dioxide (0.359 g) was added to a mixture of the obtained compound (0.286 g) and 1,2-dichloroethane (6 mL), and the mixture was stirred at 50°C for 3 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to obtain 2-bromo-6-(2-(trifluoromethyl)benzoyl)aniline (0.224 g). To a mixture of the obtained compound (0.224 g) and THF (3 mL) was added methylmagnesium bromide (3.0 mol / L in THF) (0.65 mL) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. Methylmagnesium bromide (3.0 mol / L in THF) (0.65 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hours. Methylmagnesium bromide (3.0 mol / L in THF) (0.65 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 10 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain 1-(2-amino-3-bromophenyl)-1-(2-(trifluoromethyl)phenyl)ethan-1-ol (0.187 g). To a mixture of the obtained compound (0.187 g) and 1,2-dichloroethane (3 mL) were added TFA (0.592 g) and triethylsilane (0.121 g), and the mixture was stirred at 60 °C for 1 hour. 5 mol / L aqueous sodium hydroxide solution (1.0 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 2-bromo-6-(1-(2-(trifluoromethyl)phenyl)ethenyl)aniline (0.138 g). To a mixture of the obtained compound (0.138 g) and THF (3 mL) was added methyllithium (3.1 mol / L in diethoxymethane) (0.14 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.069 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 10 minutes and then at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.102 g).

[0293] Reference Example G-4 Reference Example G-3 was used instead of Reference Example D-9, and Reference Example G-4 was obtained in the same manner as Reference Example D-10.

[0294] Reference Example G-5 2-Bromo-6-(1-(2-chloro-5-fluorophenyl)ethenyl)-N-methylaniline Isopropylmagnesium chloride (2.0 mol / L in THF) (1.4 mL) was added to a mixture of 1-chloro-4-fluoro-2-iodobenzene (0.719 g) and THF (3 mL) at -40 °C, and the mixture was stirred at 0 °C for 0.5 h. A mixture of 1-(2-amino-3-bromophenyl)ethan-1-one (0.300 g) and THF (3 mL) was added to the reaction mixture at -40 °C, and the mixture was stirred at 0 °C for 1 h and at room temperature for 12 h. Aqueous saturated ammonium chloride solution and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain 1-(2-amino-3-bromophenyl)-1-(2-chloro-5-fluorophenyl)ethan-1-ol (0.360 g). TFA (1.19 g) and triethylsilane (0.243 g) were added to a mixture of the obtained compound (0.360 g) and 1,2-dichloroethane (4 mL), and the mixture was stirred at room temperature for 1 h and at 70 °C for 3 h. 5 mol / L aqueous sodium hydroxide solution (2.2 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 10 min. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain 2-bromo-6-(1-(2-chloro-5-fluorophenyl)ethenyl)aniline (0.320 g). To a mixture of the obtained compound (0.320 g) and THF (5 mL) was added methyllithium (3.1 mol / L in diethoxymethane) (0.35 mL) at -78 °C, and the mixture was stirred at the same temperature for 0.5 hour. Methyl iodide (0.167 g) was added to the mixture at -78 °C, and the mixture was stirred at the same temperature for 10 minutes and then at 0 °C for 1 hour. After adding saturated aqueous ammonium chloride solution and water to the reaction mixture at 0 °C, the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.244 g).

[0295] Reference Example G-6 Using Reference Example G-5 instead of Reference Example D-15, Reference Example G-6 was obtained in the same manner as Reference Example D-16.

[0296] The structural formulas of the reference examples are shown in the following table.

[0297] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

Table 10

Table 11

Table 12

[0298] Example 1 2-(1-Methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)acetamide To a mixture of Reference Example A-3 (0.040 g) and THF (2 mL), LDA (1.09 mol / L in THF / n-hexane) (0.188 mL) was added at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. tert-Butyl bromoacetate (0.062 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes and then under ice-cooling for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 2 / 98) to obtain tert-butyl 2-(1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)acetate (0.032 g). A mixture of the obtained compound (0.032 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL), TEA (0.045 g), HATU (0.044 g), and ammonia (2 mol / L in methanol) (0.090 mL) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 90 / 10 / 0 to 0 / 100 / 0 to 0 / 49 / 51) to obtain the title compound (0.016 g).

[0299] Example 2 (1-Methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-3 (0.100 g) and THF (2 mL) was added LDA (1.09 mol / L in THF / n-hexane) (0.905 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. DPPA (0.272 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of Boc2O (0.172 g) and THF (0.5 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes and then under ice-cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 66 / 34) to obtain tert-butyl (1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.125 g). A mixture of the obtained compound (0.125 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 3-amino-1-methyl-8-phenoxy-3,4-dihydroquinolin-2(1H)-one hydrochloride (0.114 g). To a mixture of the obtained compound (0.025 g) and THF (1 mL) were added TEA (0.017 g) and trimethylsilyl isocyanate (0.057 g), and the mixture was stirred at room temperature for 1 hour. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.010 g).

[0300] Example 3 (8-(2-Fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-5 (0.050 g) and THF (2 mL) was added LDA (1.09 mol / L in THF / n-hexane) (0.220 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. DPPA (0.127 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of Boc2O (0.080 g) and THF (0.5 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes and then under ice-cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 76 / 24 to 41 / 59) to obtain tert-butyl (8-(2-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.065 g). A mixture of the obtained compound (0.065 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL) were added a mixture of potassium cyanate (0.018 g) and water (0.1 mL) and methanesulfonic acid (0.018 g), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 90 / 10 / 0 to 0 / 100 / 0 to 0 / 62 / 38) to obtain the title compound (0.028 g).

[0301] Example 4 (8-(3-Fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea A mixture of Reference Example A-7 (0.075 g) and THF (2 mL) was added dropwise with LDA (1.09 mol / L in THF / n-hexane) (0.330 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. DPPA (0.190 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of Boc2O (0.121 g) and THF (0.5 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes and then under ice-cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 41 / 59) to obtain tert-butyl (8-(3-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.039 g). A mixture of the obtained compound (0.039 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL) were added a mixture of potassium cyanate (0.010 g) and water (0.1 mL) and methanesulfonic acid (0.010 g), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. A mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.016 g).

[0302] Example 5 (1-Methyl-2-oxo-8-(3-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl)urea A mixture of Reference Example A-9 (0.607 g) and THF (2 mL) was stirred at -78 °C, and LDA (1.09 mol / L in THF / n-hexane) (2.25 mL) was added thereto. The mixture was stirred at the same temperature for 30 minutes. DPPA (1.04 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of Boc2O (0.825 g) and THF (0.5 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 30 minutes and then under ice-cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, a saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 67 / 33) to obtain tert-butyl (1-methyl-2-oxo-8-(3-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.830 g). A mixture of the obtained compound (0.050 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL) were added a mixture of potassium cyanate (0.012 g) and water (0.1 mL) and methanesulfonic acid (0.011 g), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. A mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to obtain the title compound (0.030 g).

[0303] Example 6 (8-(3-Chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-11 (0.345 g) and THF (5 mL) was added LDA (1.09 mol / L in THF / n-hexane) (1.32 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added DPPA (0.660 g) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a mixture of Boc2O (0.523 g) and THF (0.5 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes and then under ice-cooling for 30 minutes. The reaction mixture was stirred at room temperature for 15 minutes and at 50 °C for 30 minutes. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 73 / 27) to obtain tert-butyl N-(8-(3-chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.378 g). A mixture of the obtained compound (0.065 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The mixture of the residue and methanol was passed through APS, and the eluate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL) were added a mixture of potassium cyanate (0.017 g) and water (0.1 mL) and methanesulfonic acid (0.017 g), and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in diethyl ether, and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.028 g).

[0304] Example 7 Instead of Reference Example A-5, Reference Example A-13 was used, and Example 7 was synthesized in the same manner as in Example 3.

[0305] Example 8 Instead of Reference Example A-11, Reference Example A-15 was used, and Example 8 was synthesized in the same manner as in Example 6.

[0306] Example 9 (1-Methyl-2-oxo-8-((3-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example A-16 (0.240 g) and THF (2 mL) was added LDA (1.09 mol / L in THF / n-hexane) (1.7 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. DPPA (0.512 g) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 1 hour. A mixture of Boc2O (0.325 g) and THF (1 mL) was added to the reaction mixture at -78 °C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water (3 mL) was added to the reaction mixture under ice-cooling, and then the mixture was stirred at 50 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride solution and ethyl acetate were added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to obtain tert-butyl (1-methyl-2-oxo-8-((3-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.091 g). To a mixture of the obtained compound (0.090 g) and DCM (1 mL) was added TFA (0.469 g) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. 1 mol / L aqueous sodium hydroxide solution (5 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, water (0.037 g) and THF (1 mL) were added potassium cyanate (0.022 g) and methanesulfonic acid (0.022 g), and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble material was collected by filtration, and the obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.045 g).

[0307] Example 10 ((3R)-1-Methyl-2-oxo-8-(2-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-2 (0.080 g) and THF (1 mL) were added potassium cyanate (0.029 g), water (0.043 g) and methanesulfonic acid (0.025 g), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14), and then by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.040 g).

[0308] Example 11 ((3R)-8-(2-Methoxyphenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-4 (0.173 g) and THF (1 mL) were added a mixture of potassium cyanate (0.061 g) and water (0.1 mL) and methanesulfonic acid (0.061 g), and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution and diethyl ether were added to the reaction mixture. The insoluble matter was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.109 g).

[0309] Example 12 ((3R)-8-(3-Cyanophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-6 (0.504 g), THF (5 mL) and water (0.5 mL), potassium cyanate (0.184 g) and acetic acid (0.108 g) were added, and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was suspended in DCM, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.068 g).

[0310] Examples 13 to 15 Instead of Reference Example B-4, using the corresponding raw materials respectively, Examples 13 to 15 were synthesized in the same manner as Example 11.

[0311] Example 16 ((3R)-8-(2-Chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-14 (0.050 g) and THF (2 mL), a mixture of potassium cyanate (0.016 g) and water (0.1 mL) and methanesulfonic acid (0.018 g) were added, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution and diethyl ether were added to the reaction mixture. The insoluble matter was filtered off, and the obtained solid was dried under reduced pressure to obtain the title compound (0.031 g).

[0312] Example 17 ((3R)-1-Methyl-2-oxo-8-(2-(propan-2-yl)phenoxy)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-16 (0.273 g), THF (3 mL) and water (0.3 mL), potassium cyanate (0.095 g) and acetic acid (0.055 g) were added, and the mixture was stirred at room temperature for 1.5 hours. Water and diethyl ether were added to the reaction mixture. The mixture was extracted with diethyl ether, and the extract was concentrated under reduced pressure. The residue was suspended in diethyl ether, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.233 g).

[0313] Example 18 ((3R)-8-(2-(Difluoromethyl)phenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-18 (0.108 g), THF (1 mL) and water (0.1 mL), potassium cyanate (0.037 g) and acetic acid (0.021 g) were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture. The insoluble matter was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.091 g).

[0314] Example 19 ((3R)-8-(2-Chlorophenoxy)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-20 (0.278 g) and THF (2 mL), a mixture of potassium cyanate (0.098 g) and water (0.1 mL) and acetic acid (0.062 g) were added, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Diethyl ether was added to the residue. The insoluble matter was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.209 g).

[0315] Example 20 ((3R)-8-(2-Chloro-4-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-22 (0.295 g) and THF (2 mL), a mixture of potassium cyanate (0.104 g) and water (0.1 mL) and acetic acid (0.066 g) were added, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.220 g).

[0316] Example 21 ((3R)-8-(5-Fluoro-2-(trifluoromethyl)phenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-24 (0.038 g) and THF (0.5 mL) were added potassium cyanate (0.011 g), water (0.019 g) and methanesulfonic acid (0.011 g), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14), then by APS column chromatography (elution solvent: ethyl acetate / methanol = 98 / 2 to 88 / 12) to obtain the title compound (0.013 g).

[0317] Example 22 ((3R)-7-Chloro-8-(2-chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-26 (0.038 g) and THF (0.5 mL) were added potassium cyanate (0.012 g), water (0.020 g) and methanesulfonic acid (0.011 g), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.018 g).

[0318] Example 23 ((3R)-7-Chloro-8-(2-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-28 (0.044 g) and THF (0.5 mL) were added potassium cyanate (0.014 g), water (0.025 g), and methanesulfonic acid (0.014 g), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution, water, and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.042 g).

[0319] Example 24 ((3R)-8-(3-(Difluoromethoxy)phenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-30 (0.188 g), THF (2 mL), and water (0.2 mL) were added potassium cyanate (0.060 g) and acetic acid (0.036 g), and the mixture was stirred at room temperature for 1.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.175 g).

[0320] Example 25 Instead of Reference Example B-28, B-32 was used, and Example 25 was synthesized in the same manner as in Example 23.

[0321] Example 26 ((3R)-7-Chloro-8-(3-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-34 (0.043 g) and THF (0.5 mL) were added potassium cyanate (0.014 g), water (0.024 g) and methanesulfonic acid (0.014 g), and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.042 g).

[0322] Example 27 ((3R)-7-Chloro-8-(2-(difluoromethyl)phenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-36 (0.027 g) and THF (0.5 mL) were added potassium cyanate (0.008 g), water (0.014 g) and methanesulfonic acid (0.008 g), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14), and then by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.015 g).

[0323] Example 28 ((3R)-8-(2-(Difluoromethyl)-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-38 (0.025 g), THF (1 mL), and water (0.1 mL), potassium cyanate (0.008 g) and acetic acid (0.005 g) were added, and the mixture was stirred at room temperature for 15 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.011 g).

[0324] Example 29 Instead of Reference Example B-30, using Reference Example B-40, Example 29 was synthesized in the same manner as Example 24.

[0325] Example 30 ((3R)-8-(2-Chloro-5-methoxyphenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-42 (0.133 g) and THF (2 mL), a mixture of potassium cyanate (0.045 g) and water (0.1 mL) and acetic acid (0.029 g) were added, and the mixture was stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.056 g).

[0326] Example 31 ((3R)-8-(2-Chlorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-44 (0.074 g) and THF (2 mL), a mixture of potassium cyanate (0.027 g) and water (0.1 mL) and acetic acid (0.017 g) were added, and the mixture was stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. The insoluble matter was filtered off, and the obtained solid was dried under reduced pressure to obtain the title compound (0.031 g).

[0327] Example 32 ((3R)-7-(Benzyloxy)-8-(2-chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-46 (0.100 g) and THF (2 mL) was added a mixture of potassium cyanate (0.028 g) and water (0.1 mL) and acetic acid (0.018 g), and the mixture was stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. The insoluble material was collected by filtration, and the obtained solid was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.042 g).

[0328] Example 33 ((3R)-8-(2-Chlorophenoxy)-7-hydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Example 32 (0.034 g), THF (0.5 mL) and methanol (0.5 mL) was added 10% Pd / C (0.008 g), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.016 g).

[0329] Example 34 ((3R)-8-(2-Chlorophenoxy)-1-ethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-48 (0.138 g) and THF (2 mL) was added a mixture of potassium cyanate (0.053 g) and water (0.1 mL) and acetic acid (0.037 g), and the mixture was stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.036 g).

[0330] Example 35 ((3R)-8-(2-Chloro-4,5-difluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-50 (0.068 g) and THF (1 mL) were added potassium cyanate (0.021 g), water (0.036 g) and methanesulfonic acid (0.020 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified successively by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14), APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) and ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.018 g).

[0331] Example 36 Example 36 was synthesized in the same manner as Example 10 using Reference Example B-52 instead of Reference Example B-2.

[0332] Example 37 ((3R)-7-Chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-54 (0.003 g) and THF (0.2 mL) were added potassium cyanate (0.001 g), water (0.002 g) and methanesulfonic acid (0.001 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.003 g).

[0333] Example 38 ((3R)-8-(2-(Difluoromethyl)phenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-56 (0.080 g), THF (1 mL) and water (0.1 mL) were added potassium cyanate (0.027 g) and acetic acid (0.017 g), and the mixture was stirred at room temperature for 3.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble material was filtered off. The resulting solid was dried under reduced pressure to obtain the title compound (0.070 g).

[0334] Example 39 ((3R)-8-(2-Chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-58 (0.118 g), THF (1 mL) and water (0.1 mL) were added potassium cyanate (0.039 g) and acetic acid (0.025 g), and the mixture was stirred at room temperature for 3.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble material was filtered off. The resulting solid was dried under reduced pressure to obtain the title compound (0.062 g).

[0335] Example 40 ((3R)-8-(2-Chlorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-60 (0.370 g) and THF (2.5 mL), potassium cyanate (0.129 g), water (0.220 g) and methanesulfonic acid (0.123 g) were added, and the mixture was stirred at room temperature for 2 hours. An aqueous saturated sodium hydrogen carbonate solution, water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.390 g).

[0336] Example 41 Instead of Reference Example B-28, Reference Example B-62 was used, and Example 41 was synthesized in the same manner as Example 23.

[0337] Example 42 ((3R)-8-(Cyclopentyloxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-64 (0.100 g) and THF (1 mL), potassium cyanate (0.041 g), water (0.069 g) and methanesulfonic acid (0.039 g) were added, and the mixture was stirred at room temperature for 2 hours. An aqueous saturated sodium hydrogen carbonate solution, water, DCM and ethyl acetate were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ethyl acetate and water were added to the residue. The insoluble matter was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.076 g).

[0338] Example 43 ((3R)-8-(2-(Difluoromethyl)phenoxy)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-66 (0.035 g) and THF (2 mL) was added a mixture of potassium cyanate (0.013 g) and water (0.1 mL) and acetic acid (0.009 g), and the mixture was stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. The insoluble matter was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.030 g).

[0339] Example 44 ((3R)-8-(2-Chloro-5-fluorophenoxy)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-68 (0.070 g) and THF (2 mL) was added a mixture of potassium cyanate (0.025 g) and water (0.1 mL) and acetic acid (0.017 g), and the mixture was stirred at room temperature for 14 hours. Water and MTBE were added to the reaction mixture. The insoluble matter was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.052 g).

[0340] Example 45 ((3R)-8-(2-Fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-70 (0.031 g) and THF (2 mL) was added a mixture of potassium cyanate (0.013 g) and water (0.1 mL) and acetic acid (0.009 g), and the mixture was stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.030 g).

[0341] Example 46 ((3R)-8-(3-Fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-72 (0.065 g) and THF (2 mL), a mixture of potassium cyanate (0.026 g), water (0.1 mL), and acetic acid (0.018 g) were added, and the mixture was stirred at room temperature for 14 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.027 g).

[0342] Example 47 ((3R)-1-Methyl-8-(2-methylphenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-74 (0.290 g) and THF (3 mL), potassium cyanate (0.108 g), water (0.185 g), and methanesulfonic acid (0.104 g) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.210 g).

[0343] Example 48 ((3R)-8-(5-Fluoro-2-methylphenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-76 (0.220 g) and THF (2 mL), potassium cyanate (0.077 g), water (0.132 g), and methanesulfonic acid (0.074 g) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.190 g).

[0344] Example 49 ((3R)-8-(2-Fluorophenoxy)-1-methyl-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example C-3 (0.026 g) and THF (1 mL) were added potassium cyanate (0.008 g), water (0.013 g) and methanesulfonic acid (0.007 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.025 g).

[0345] Example 50 ((3R)-8-(2,5-Difluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example B-78 (0.274 g), THF (1.5 mL) and methanol (1.0 mL) were added potassium cyanate (0.094 g), water (0.278 g) and acetic acid (0.065 g), and the mixture was stirred at room temperature for 1 hour. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.242 g).

[0346] Example 51 ((3R)-8-((2-Chlorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-2 (0.120 g) and THF (1 mL) were added potassium cyanate (0.042 g), water (0.072 g), and methanesulfonic acid (0.040 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water, and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the insoluble material was collected by filtration. The resulting solid was dried under reduced pressure to obtain the title compound (0.096 g).

[0347] Example 52 ((3R)-8-((2-Chloro-5-fluorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-4 (0.100 g), THF (0.8 mL), and water (0.057 mL) were added potassium cyanate (0.033 g) and methanesulfonic acid (0.032 g), and the mixture was stirred at room temperature for 2.5 hours. Methanesulfonic acid (0.003 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution, water, and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the insoluble material was collected by filtration. The resulting solid was dried under reduced pressure to obtain the title compound (0.055 g).

[0348] Example 53 ((3R)-1-Methyl-2-oxo-8-((2-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-6 (0.100 g), THF (0.8 mL) and water (0.054 mL), potassium cyanate (0.032 g) and methanesulfonic acid (0.030 g) were added, and the mixture was stirred at room temperature for 2.5 hours. Methanesulfonic acid (0.003 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: DCM / methanol = 100 / 0 to 90 / 10). 2 mol / L hydrochloric acid was added to the obtained target compound, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue. The resulting solid was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.026 g).

[0349] Example 54 ((3R)-1-Methyl-8-((2-methylphenyl)methyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-8 (0.046 g), THF (0.5 mL) and water (0.030 mL), potassium cyanate (0.017 g) and methanesulfonic acid (0.017 g) were added, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.012 g).

[0350] Example 55 ((3R)-8-((2-(Difluoromethyl)phenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-10 (0.032 g), THF (1 mL) and water (0.018 mL), potassium cyanate (0.011 g) and methanesulfonic acid (0.010 g) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate / n-hexane (1 / 1), and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.018 g).

[0351] Example 56 ((3R)-8-((2-Chloro-5-fluorophenyl)methyl)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-12 (0.006 g), THF (1 mL) and water (0.003 mL), potassium cyanate (0.002 g) and methanesulfonic acid (0.002 g) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.004 g).

[0352] Example 57 ((3R)-7-Chloro-8-((2-chloro-5-fluorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-14 (0.036 g), THF (0.3 mL) and methanol (0.2 mL), potassium cyanate (0.012 g), water (0.035 mL) and acetic acid (0.008 g) were added, and the mixture was stirred at room temperature for 1.5 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue. The resulting solid was collected by filtration, and the obtained solid was dried under reduced pressure to obtain the title compound (0.004 g).

[0353] Example 58 ((3R)-8-((2-Chlorophenyl)methyl)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-16 (0.009 g), THF (0.3 mL) and water (0.005 mL) were added potassium cyanate (0.003 g) and methanesulfonic acid (0.003 g), and the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.004 g).

[0354] Example 59 ((3R)-8-((2-Chloro-5-fluorophenyl)methyl)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-18 (0.008 g), THF (0.3 mL) and water (0.004 mL) were added potassium cyanate (0.003 g) and methanesulfonic acid (0.002 g), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.002 g).

[0355] Example 60 ((3R)-8-((2-Chlorophenyl)methyl)-7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-20 (0.049 g), THF (1 mL), and water (0.028 mL) were added potassium cyanate (0.016 g) and methanesulfonic acid (0.016 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water, and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate / n-hexane (1 / 1), and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.018 g).

[0356] Example 61 ((3R)-7-Fluoro-1-methyl-2-oxo-8-((2-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-22 (0.028 g), THF (1 mL), and water (0.014 mL) were added potassium cyanate (0.008 g) and methanesulfonic acid (0.008 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water, and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate / n-hexane (1 / 1), and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.014 g).

[0357] Example 62 ((3R)-7-Chloro-8-((2-chlorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-24 (0.026 g), THF (1 mL), and water (0.014 mL) were added potassium cyanate (0.008 g) and methanesulfonic acid (0.008 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water, and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate / n-hexane (1 / 1), and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.013 g).

[0358] Example 63 ((3R)-7-Fluoro-1-methyl-8-((2-methylphenyl)methyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-26 (0.040 g), THF (1 mL) and water (0.024 mL) were added potassium cyanate (0.014 g) and methanesulfonic acid (0.014 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate / n-hexane (1 / 1), and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.026 g).

[0359] Example 64 ((3R)-7-Chloro-8-((2-fluorophenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-28 (0.097 g), THF (0.9 mL) and methanol (0.6 mL) were added potassium cyanate (0.037 g), water (0.110 mL) and acetic acid (0.026 g), and the mixture was stirred at room temperature for 17.5 hours. Water was added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was suspended in MTBE, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.073 g).

[0360] Examples 65 to 67 Examples 65 to 67 were synthesized in the same manner as in Example 64, using the corresponding raw materials instead of Reference Example D-28.

[0361] Example 68 ((3R)-8-((5-Fluoro-2-methylphenyl)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example D-36 (0.030 g), THF (0.3 mL) and water (0.018 mL), potassium cyanate (0.011 g) and methanesulfonic acid (0.010 g) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble material was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.026 g).

[0362] Example 69 ((3R)-7-Chloro-8-(2,5-difluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-2 (0.084 g), THF (0.48 mL) and methanol (0.32 mL), potassium cyanate (0.030 g), water (0.089 g) and acetic acid (0.021 g) were added, and the mixture was stirred at room temperature for 2 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM / methanol = 100 / 0 to 95 / 5) to obtain the title compound (0.013 g).

[0363] Example 70 ((3R)-8-(2-(Difluoromethyl)-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-4 (0.005 g), THF (0.3 mL) and methanol (0.2 mL), potassium cyanate (0.002 g), water (0.005 g) and acetic acid (0.001 g) were added, and the mixture was stirred at room temperature for 2 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.002 g).

[0364] Example 71 ((3R)-8-(2-Chloro-5-fluorophenoxy)-7-(hydroxymethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-6 (0.270 g) and THF (3.0 mL) were added potassium cyanate (0.081 g), water (0.139 g) and acetic acid (0.049 g), and the mixture was stirred at room temperature for 21 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 78 / 22) to obtain the title compound (0.210 g).

[0365] Example 72 ((3R)-8-(2-Chloro-5-fluorophenoxy)-7-(difluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-8 (0.050 g) and THF (1 mL) were added potassium cyanate (0.014 g), water (0.024 g) and acetic acid (0.009 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.035 g).

[0366] Example 73 ((3R)-8-(2-Chloro-5-fluorophenoxy)-7-(fluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-10 (0.100 g) and THF (1 mL) were added potassium cyanate (0.030 g), water (0.051 g), and acetic acid (0.018 g), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution, water, methanol, and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.090 g).

[0367] Example 74 ((3R)-8-(2-Chloro-5-fluorophenoxy)-1-methyl-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-12 (0.400 g), methanol (1.2 mL), and THF (1.8 mL) were added potassium cyanate (0.109 g), water (0.371 g), and acetic acid (0.068 g), and the mixture was stirred at room temperature for 3 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.390 g).

[0368] Example 75 ((3R)-8-(2-Chloro-5-fluorophenoxy)-7-(1,1-difluoroethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-14 (0.250 g), methanol (0.75 mL), and THF (1.1 mL) were added potassium cyanate (0.069 g), water (0.234 g), and acetic acid (0.043 g), and the mixture was stirred at room temperature for 2 hours. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.200 g).

[0369] Example 76 ((3R)-8-(2-Chloro-5-fluorophenoxy)-7-ethyl-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example F-16 (0.480 g), methanol (1.4 mL) and THF (2.2 mL) were added potassium cyanate (0.145 g), water (0.496 g) and acetic acid (0.091 g), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.473 g).

[0370] Example 77 ((3R)-8-(1-(2-Chlorophenyl)ethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-2 (0.024 g), THF (0.3 mL) and methanol (0.2 mL) were added potassium cyanate (0.009 g), water (0.027 g) and acetic acid (0.006 g), and the mixture was stirred at room temperature for 45 minutes. Water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain ((3R)-8-(1-(2-chlorophenyl)ethenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (0.015 g). To a mixture of the obtained compound (0.014 g) and THF (1 mL) was added platinum(IV) oxide (0.003 g), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. Platinum(IV) oxide (0.009 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.005 g).

[0371] Example 78 ((3R)-1-Methyl-2-oxo-8-(1-(2-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-4 (0.013 g), THF (1 mL) and water (0.007 mL) were added potassium cyanate (0.004 g) and methanesulfonic acid (0.004 g), and the mixture was stirred at room temperature for 10 hours. A saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM / methanol = 100 / 0 to 90 / 10) to obtain ((3R)-1-methyl-2-oxo-8-(1-(2-(trifluoromethyl)phenyl)ethenyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (0.012 g). To a mixture of the obtained compound (0.012 g) and methanol (1 mL) was added 10% Pd / C (0.001 g), and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: DCM / methanol = 100 / 0 to 95 / 5), and then by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.005 g).

[0372] Example 79 ((3R)-8-(1-(2-Chloro-5-fluorophenyl)ethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-6 (0.038 g), THF (0.3 mL) and water (0.021 g) were added potassium cyanate (0.012 g) and methanesulfonic acid (0.012 g), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution, water and DCM were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, methanol (0.5 mL) and THF (0.5 mL) was added 10% Pt / C (0.010 g), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.005 g).

[0373] Example 80 1-((3R)-8-(2-Chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-3-methylurea To a mixture of Reference Example B-58 (0.036 g), carbonyldiimidazole (0.017 g) and DCM (1 mL) was added DIPEA (0.069 g), and the mixture was stirred at room temperature for 1 hour. Methylamine (2 mol / L in THF) (0.11 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Water and DCM were added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to obtain the title compound (0.026 g).

[0374] Example 81 N-((3R)-8-(2-Chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide To a mixture of Reference Example B-58 (0.100 g), DIPEA (0.077 g) and DCM (1 mL) under water cooling, acetyl chloride (0.030 g) was added, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to obtain the title compound (0.079 g).

[0375] Example 82 Example 82 was obtained in the same manner as in Example 81, using cyclopropanecarbonyl chloride instead of acetyl chloride.

[0376] Example 83 Example 83 was obtained in the same manner as in Example 81, using dichloroacetyl chloride instead of acetyl chloride.

[0377] Example 84 Example 84 was obtained in the same manner as in Example 81, using Reference Example B-14 instead of Reference Example B-58 and cyclopropanecarbonyl chloride instead of acetyl chloride.

[0378] Example 85 N-((3R)-8-(2-Chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-3,3,3-trifluoropropanamide A mixture of Reference Example B-58 (0.100 g), 3,3,3-trifluoropropionic acid (0.042 g), HATU (0.125 g), and MeCN (1 mL) was added with DIPEA (0.046 g) and stirred at room temperature for 1 hour. Water and DCM were added to the reaction mixture, and it was stirred at room temperature for 5 minutes. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 20 / 80 / 0 to 0 / 100 / 0 to 0 / 70 / 30), and then by ODS column chromatography (elution solvent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.074 g).

[0379] The structural formulas, physical property values, and TSHR antagonist activities (see Test Example 1) of the examples are shown in the following table.

[0380] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

Table 23

Table 24

Table 25

Table 26

Table 27

[0381] Test Example 1 Measurement of antagonist activity using TSH-induced cAMP production in human TSHR stably expressing CHO cells as an index

[0382] The gene sequence of human TSHR (reference number NM_000369.2) was inserted into the multiple cloning site of pcDNA3.1(+). The prepared plasmid vector was introduced into CHO cells using the lipofection method to establish human TSHR stably expressing CHO cells. The obtained cells were seeded at 5 x 10 in a 96-well poly-D-lysine coated plate 4Seeded at a density of cells per well and cultured in F12 medium containing 10% FBS, 400 μg / mL of G418, 50 U / mL of penicillin and 50 μg / mL of streptomycin at 37 °C under 5% CO2 for 1 day. After removing the medium, the cells were washed twice with 100 μL of assay buffer (Hanks' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX) per well. 30 μL of assay buffer containing the test compound was added to the well and incubated at room temperature for 15 minutes. Then, 30 μL of assay buffer containing human TSH (R&D Systems, Inc., final concentration 50 ng / mL) was added and incubated at 37 °C for 1 hour. The supernatant was removed, and cell lysates were prepared by adding Lysis and Detection Buffer 2 (Cisbio) and incubating at room temperature for 1 hour. According to the instructions of the cAMP Gs HiRange kit (Cisbio), the cell lysates were reacted with d2-labeled cAMP and anti-cAMP Europium Cryptate labeled antibody (Cisbio) in a 384-well white microplate. Then, the fluorescence intensity ratio (measurement wavelengths 665 nm / 620 nm) was measured using a multiplate reader (PHERAstar FSX, BMG LABTECH Japan). The fluorescence intensity ratio of each sample was converted to cAMP content using a standard curve. The cAMP content was converted as a percentage of the control value, and the cAMP production rate was calculated. Prism (Graph Pad Software Inc.) was used to plot the cAMP production rate against the test compound concentration, and the IC 50 value was calculated. The IC 50 of each test compound is shown in the above table. In the table, IC 50 <0.5 μM: A, 0.5 μM ≤ IC 50 <3.0 μM: B, 3.0 μM ≤ IC 50 <30 μM: C was denoted as such.

[0383] As shown in the above table, it was revealed that the compounds of the present invention have human TSHR antagonist activity.

Industrial Applicability

[0384] Since the compound of the present invention or a pharmacologically acceptable salt thereof has TSHR antagonist activity, the pharmaceutical composition of the present invention is useful as a therapeutic agent for thyroid-related diseases.

Claims

1. A compound represented by formula (I): 【Chemical 1】 〔wherein, Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; X is -CHR X -, or -O-; R X is a hydrogen atom or C 1-6 alkyl; V 1 is =CR V1 -, or =N-; V 2 is =CR V2 -, or =N-; V 3 is =CR V3 -, or =N-; R V1 、R V2 、R V3 are each independently a hydrogen atom, a halogen atom, a hydroxy group, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl, or C 6-10 aryl C 1-6 alkoxy; W is -CH 2 -, or -NH-; R 1 is a hydrogen atom or a C 1-6 alkyl; R 2 is a halogen atom, cyano group, hydroxy group, amino group, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 6-10 arylC 1-6 alkyl or C 6-10 arylC 1-6 alkoxy; n is an integer from 0 to 3; When n is 2 or 3, each R 2 may be the same as or different from each other; R 3 is a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 4 is C 1-6 alkyl, halo C 1-6 alkyl, -NR 5 R 5' or C 3-8 cycloalkyl; R 5 and R 5' each independently represents a hydrogen atom or a C 1-6 alkyl]] or a pharmaceutically acceptable salt thereof, comprising a pharmaceutical composition.

2. A compound selected from the group consisting of the following compounds: 【Chemical 2】 【Chemical Formula 3】 and 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof, comprising a pharmaceutical composition.

3. A compound selected from the group consisting of the following compounds: 【Chemical Formula 5】 and 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof, comprising a pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, which is for the treatment of thyroid-related diseases.

5. The pharmaceutical composition according to claim 4, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid ophthalmopathy.

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