Tetrahydroquinoline derivatives and their pharmaceutical uses

Abstract

To provide a compound having a tetrahydroquinoline skeleton that exhibits ferroptosis inhibitory activity and exerts therapeutic or preventive effects on diseases, disorders, or syndromes related to ferroptosis inhibition, such as multiple sclerosis. [Solution] The present invention provides tetrahydroquinoline derivatives or pharmaceutically acceptable salts thereof, as represented below. [Formula 1] JPEG2026083313000325.jpg2154

Description

[Technical Field]

[0001] This invention relates to tetrahydroquinoline derivatives and their pharmaceutical applications. [Background technology]

[0002] In recent years, various forms of regulatory cell death have been identified, and ferroptosis has been reported as a new type of cell death that takes the form of iron-dependent regulatory cell death (Non-Patent Literature 1). Ferroptosis is a reaction in which various stimuli lead to a decrease in antioxidant function, such as a decrease in intracellular glutathione levels and glutathione peroxidase 4 (GPX4), and as a result of the iron-dependent reaction, intracellular lipid peroxides rise to lethal levels, leading to cell death.

[0003] To date, a relationship between ferroptosis inhibitory effects and therapeutic effects on renal disease, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, Friedreich's ataxia, cardiomyopathy, and multiple sclerosis has been reported (Non-patent Literature 2-6).

[0004] For example, multiple sclerosis, in which a decrease in GPX4 has been reported in the brains of patients and a link to ferroptosis has been suggested, is a disease characterized by demyelination, in which the myelin sheath covering nerve fibers in the brain, spinal cord, and optic nerves is destroyed, and the disability progresses with repeated relapses and remissions. Symptoms vary depending on the site of the lesion, and it is known to present with a variety of neurological symptoms such as visual impairment, paralysis of the limbs, sensory impairment, and gait disturbances (Non-patent documents 7, 8).

[0005] Aniline derivatives such as Ferrostatin-1 are known to exhibit ferroptosis inhibitory activity (Non-Patent Documents 1, 9). In addition, tetrahydroquinoxaline derivatives and 3,4-dihydro-2H-benzo-[1,4]oxazine derivatives have also been disclosed to have ferroptosis inhibitory activity (Patent Documents 1, 2).

[0006] It has been reported that radical scavenging activity is important for the expression of ferroptosis inhibitory activity (Non-Patent Document 10). Furthermore, it has been disclosed that the tetrahydroquinoxaline derivative described in Patent Document 1 has potent radical scavenging activity and consequently exhibits ferroptosis inhibitory activity (Non-Patent Documents 11, 12).

[0007] On the other hand, Patent Documents 3 to 7 disclose tetrahydroquinoline derivatives that have antiviral, antitumor, pain-relieving, or immune response-modifying effects. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Chinese Patent Application Publication No. 110372614 Specification [Patent Document 2] Chinese Patent Application Publication No. 110464727 Specification [Patent Document 3] Japanese Patent Application Publication No. 56-051456 [Patent Document 4] International Publication No. 2007 / 054138 [Patent Document 5] Japanese Patent Application Publication No. 5-125052 [Patent Document 6] International Publication No. 2005 / 063735 [Patent Document 7] German Patent Application Publication No. 10236910 [Non-patent literature]

[0009] [Non-Patent Document 1] Dixon et al., Cell, 2012, Vol. 149, pp. 1060-1072. [Non-Patent Document 2] Friedmann et al., Nature Cell Biology, 2014, Vol. 16, pp. 1180-1191. [Non-Patent Document 3] Masaldan et al., Free Radical Biology and Medicine, 2019, Vol. 133, pp. 221-233. [Non-Patent Document 4] Tsurusaki et al., Cell Death and Disease, 2019, Vol. 10, 449. [Non-Patent Document 5] Yoshida et al., Nature Communications, 2019, Vol. 10 [Non-Patent Document 6] Xuexian et al., Proceedings of the National Academy of Sciences of the United States of America, 2019, Vol. 116, pp. 2672-2680. [Non-Patent Document 7] Madeline et al., International Journal of Molecular Sciences, 2020, Vol. 21, 4312. [Non-Patent Document 8] Che-Lin et al., Journal of Neurochemistry, 2019, Vol. 148, pp. 426-439. [Non-Patent Document 9] Lars et al., Journal of Medicinal Chemistry, 2018, Vol. 61, pp. 10126-10140. [Non-Patent Document 10] Jennifer Yinus Cao et al., Cellular and Molecular Life Science, 2016, Vol. 73, pp. 2195-2209. [Non-Patent Document 11] Yu-Zhen Li et al., Frontiers in Chemistry, 2019, Vol. 7, p. 850. [Non-Patent Document 12] Hong-Xu Lei et al., Journal of Molecular Structure, 2021, Vol. 1228, pp. 129485. [Overview of the project] [Problems that the invention aims to solve]

[0010] However, Patent Documents 1-7 and Non-Patent Documents 1-12 do not disclose or even suggest the possibility of ferroptosis inhibitory activity of tetrahydroquinoline derivatives.

[0011] Therefore, the present invention aims to provide a compound that has ferroptosis inhibitory activity and exhibits therapeutic or preventive effects against diseases, disorders, or syndromes related to ferroptosis inhibition, such as multiple sclerosis. [Means for solving the problem]

[0012] The inventors of this invention conducted extensive research to solve the above-mentioned problems and, as a result, discovered that compounds having a tetrahydroquinoline skeleton have ferroptosis inhibitory activity and pharmacological activity based thereon, thus completing the present invention.

[0013] In other words, the present invention encompasses the following: [1] A tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacoposly acceptable salt thereof.

[0014] [ka]

[0015] [In the formula, R 1x This represents a hydrogen atom, a phenyl group (the phenyl group may be substituted with the following substituents and may form the following fused ring group), or a 5 or 6-membered heteroaryl group selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, and pyridyl group (the heteroaryl group may be substituted with the following substituents), R 1yrepresents a hydrogen atom, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl (provided that when R 1x is a hydrogen atom, R 1y is a substituent other than a hydrogen atom, and when R 1x is a substituent other than a hydrogen atom, R 1y is a hydrogen atom), R 2 , R 4 and R 5 combination is that R 2 , R 4 and R 5 are all hydrogen atoms, or R 2 and R 4 is such that one of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted by a hydroxy group, and the other and R 5 are hydrogen atoms, or R 2 and R 4 are both hydrogen atoms, and R 5 is a fluorine atom or a chlorine atom, R 3 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which any one to three hydrogen atoms may be independently substituted by a hydroxy group or a fluorine atom, a 3-hydroxyoxetan-3-yl group, a hydroxy group, an alkoxy group having 1 to 3 carbon atoms in which any one to three hydrogen atoms may be substituted by a fluorine atom, a methoxycarbonyl group, -NR 9 R 10 , -CH2NR 11 R 12 or -CH2CONR 13 R 14 represents, R v represents a hydrogen atom, R w represents a hydrogen atom, Here, R 1xHowever, a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, a C1-C3 alkyl group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a C1-C3 alkoxy group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a cyano group, a methoxycarbonyl group, and -NHCOR 8 It may be substituted with one substituent selected from the group consisting of (except for the m-cyanophenyl group and the p-trifluoromethoxyphenyl group), or it may represent a 5- or 6-membered ring heteroaryl group (where any one hydrogen atom of the 5- or 6-membered ring heteroaryl group may be substituted with a C1- to C3 alkyl group or a C1- to C3 alkoxy group, except for the 1-methyl-1H-pyrazole-4-yl group and the 6-methoxypyridine-3-yl group), R 3 This includes C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms, C1-C3 alkyl groups in which 1 arbitrary hydrogen atom is substituted with a hydroxyl group, ethyl groups, propyl groups, isopropyl groups, 3-hydroxyoxetane-3-yl groups, methoxy groups, methoxycarbonyl groups, and -NR groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms. 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 (However, R 2 and R 4 Both are hydrogen atoms, and R 5 If R is a fluorine atom or a chlorine atom, 3 R may be a hydrogen atom or a fluorine atom, 2 and R 5 Both are hydrogen atoms, and R 4 If R is a fluorine atom or a chlorine atom, 3 R may be a fluorine atom, 2 However, a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and R 4 and R 5 If all of them are hydrogen atoms, then R 3 (This may be a hydrogen atom) R 8 This represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 This represents a hydrogen atom, R 10 is a hydrogen atom, -COR 15 Or it represents an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 (CH2) n - represents, n represents 4 or 5, R 11 and R 12 They become one - (CH2) m - represents, m represents 4 or 5, where any one methylene group may be substituted with an oxygen atom. R 13 This represents a hydrogen atom or a methyl group. R 14 This represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a C3 or C4 cycloalkyl group in which any one carbon atom may be substituted with an oxygen atom, or a methyl group in which any one carbon atom may be substituted with a C3 or C4 cycloalkyl group in which any one carbon atom may be substituted with a nitrogen atom or an oxygen atom, or R 13 and R 14 Together with the nitrogen atoms bonded to them, they may form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a piperazinone ring, or an azetidine ring in which two arbitrary hydrogen atoms are substituted with methyl groups or fluorine atoms, or one arbitrary hydrogen atom is substituted with a hydroxyl group or a methoxy group. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 This represents, R 16 This represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Or, R 1xHowever, hydrogen atoms, phenyl groups (any one hydrogen atom of the phenyl group is a C1-C3 alkyl group in which any one hydrogen atom is substituted with a hydroxyl group, -CONR 6 R 7 (substituted with an aminosulfonyl group, a methylsulfonylamino group, an aminosulfonylamino group, or an alkylsulfonyl group having 1 to 3 carbon atoms, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group), represents a 1-methyl-1H-pyrazole-4-yl group or a 6-methoxypyridine-3-yl group, or R 1x However, when representing a fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (where any one hydrogen atom of the fused ring group may be substituted with a methyl group), R 3 This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, and -NR 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 This represents, R 6 and R 7 Each of these independently represents either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atoms bonded to them. R 9 This represents a hydrogen atom, R 10 is a hydrogen atom, -COR 15represents an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 are combined together to represent -(CH2) n -, n represents 4 or 5, R 11 and R 12 are combined together to represent -(CH2) m -, m represents 4 or 5, where any one methylene group may be substituted with an oxygen atom, R 13 represents a hydrogen atom or a methyl group, R 14 represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a cycloalkyl group having 3 or 4 carbon atoms where any one carbon atom may be substituted with an oxygen atom, or a methyl group substituted with a cycloalkyl group having 3 or 4 carbon atoms where any one carbon atom may be substituted with a nitrogen atom or an oxygen atom, or R 13 and R 14 together with the nitrogen atom to which they are attached may form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a piperazinone ring, or an azetidine ring where any two hydrogen atoms may be substituted with a methyl group or a fluorine atom or any one hydrogen atom may be substituted with a hydroxy group or a methoxy group, R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or -NHR 16 and R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms (however, methyl 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate and 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline are excluded).]

[0016] [2]R 1xThis is a phenyl group (the phenyl group may be substituted with the following substituents and may form the following fused ring group), or a 5 or 6-membered heteroaryl group selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group and pyridyl group (the heteroaryl group may be substituted with the following substituents), R 2 , R 4 and R 5 The combination is R 2 , R 4 and R 5 Are they all hydrogen atoms, or R 2 and R 4 One of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other and R 5 Is it a hydrogen atom, or R 2 and R 4 Both are hydrogen atoms, and R 5 is a fluorine atom or a chlorine atom, R v It is a hydrogen atom, R w It is a hydrogen atom, Here, R 1x However, a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, a C1-C3 alkyl group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a C1-C3 alkoxy group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a cyano group, a methoxycarbonyl group, and -NHCOR 8 It may be substituted with one substituent selected from the group consisting of (except for the m-cyanophenyl group and the p-trifluoromethoxyphenyl group), or if it is a 5 or 6-membered ring heteroaryl group (any one hydrogen atom of the 5 or 6-membered ring heteroaryl group may be substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group, except for the 1-methyl-1H-pyrazole-4-yl group and the 6-methoxypyridine-3-yl group), R 3This includes C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms, C1-C3 alkyl groups in which 1 arbitrary hydrogen atom is substituted with a hydroxyl group, ethyl groups, propyl groups, isopropyl groups, 3-hydroxyoxetane-3-yl groups, methoxy groups, methoxycarbonyl groups, and -NR groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms. 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 (However, R 2 and R 4 Both are hydrogen atoms, and R 5 If R is a fluorine atom or a chlorine atom, 3 R may be a hydrogen atom or a fluorine atom, 2 and R 5 Both are hydrogen atoms, and R 4 If R is a fluorine atom or a chlorine atom, 3 R may be a fluorine atom, 2 However, a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and R 4 and R 5 If all of them are hydrogen atoms, then R 3 (This may be a hydrogen atom) R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 It is a hydrogen atom, R 10 is a hydrogen atom, -COR 15 Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 (CH2) n -and, n is either 4 or 5. R 11 and R 12 They become one - (CH2) m -and, m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R 13 It is a hydrogen atom, R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R 13 and R 14 These may form an azetidine ring with the nitrogen atom bonded to them, in which any one hydrogen atom may be substituted with a hydroxyl group. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 And, R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Or, R 1x However, a phenyl group (where any one hydrogen atom of the phenyl group is replaced by a C1-C3 alkyl group, -CONR) 6 R 7 (substituted with an aminosulfonyl group or an alkylsulfonyl group having 1 to 3 carbon atoms, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group), a 1-methyl-1H-pyrazole-4-yl group or a 6-methoxypyridine-3-yl group, or R 1x However, if it is a fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (where any one hydrogen atom of the fused ring group may be substituted with a methyl group), R 3 This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, and -NR 9 R 10 -CH2NR 11R 12 or -CH2CONR 13 R 14 And, R 6 and R 7 Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 6 and R 7 These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atoms bonded to them. R 9 It is a hydrogen atom, R 10 is a hydrogen atom, -COR 15 Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 (CH2) n -and, n is either 4 or 5. R 11 and R 12 They become one - (CH2) m -and, m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R 13 It is a hydrogen atom, R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R 13 and R 14 These may form an azetidine ring with the nitrogen atom bonded to them, in which any one hydrogen atom may be substituted with a hydroxyl group. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 And, R 16is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms (except for 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate methyl and 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline), the tetrahydroquinoline derivative described in [1] or a pharmaceutically acceptable salt thereof.

[0017] [3] A tetrahydroquinoline derivative described in [1] or [2], or a pharmaceutically acceptable salt thereof, selected from the following group: (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanol, (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate tert-butyl, 2-phenyl-1,2,3,4-tetrahydroquinoline-6-amine, 2-(benzo[d][1,3]dioxol-5-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline, (2-phenyl-1,2,3,4-tetrahydroquinoline-7-yl)methanol, 2-Phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline, 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline, (2-phenyl-1,2,3,4-tetrahydroquinoline-5-yl)methanol, (2-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, (3-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, (4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, N-methyl-3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzonitrile, 6-Isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline, 2-(1-methyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline, 2-(6-methoxypyridine-3-yl)-1,2,3,4-tetrahydroquinoline, 4-((2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)propan-2-ol, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)oxetan-3-ol, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, 2-phenyl-6-(piperidine-1-yl)-1,2,3,4-tetrahydroquinoline, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanesulfonamide, 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, 2-(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)propan-2-ol, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 2-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)pivaramide, 1-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, 1,2,3,3',4,4'-Hexahydro-[2,6'-Biquinoline]-2'(1'H)-one, 1'-Methyl-1,2,3,3',4,4'-Hexahydro-[2,6'-Biquinoline]-2'(1'H)-one, N,N-diethyl-4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, N-ethyl-4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 5-(1,2,3,4-tetrahydroquinoline-2-yl)isoindorin-1-one, (4-methylpiperazine-1-yl)(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, Piperidine-1-yl(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, and Morphorino(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, or a pharmacoposityal salt thereof.

[0018] [4] A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof, selected from the following group, as described in any of [1] to [3]: (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate tert-butyl, (4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-((2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanesulfonamide, 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)pivaramide, 1-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, and 5-(1,2,3,4-tetrahydroquinoline-2-yl)isoindorin-1-one, or a pharmacopositically acceptable salt thereof.

[0019] [5] R 1x is a phenyl group (the phenyl group may be substituted with the following substituents), R 1yIt is a hydrogen atom, R 2 , R 4 and R 5 The combination is R 2 , R 4 and R 5 Are they all hydrogen atoms, or R 2 and R 4 One is a fluorine atom, a chlorine atom, or a methyl group, and the other is R 5 That is a hydrogen atom, R v It is a hydrogen atom. R w It is a hydrogen atom, Here, R 1x However, if it is a phenyl group (the hydrogen atom at the para position of the phenyl group may be substituted with one substituent selected from the group consisting of a fluorine atom, a trifluoromethyl group, a cyano group, and an acetamide group), R 3 is a trifluoromethoxy group, a hydroxymethyl group, or -CH2CONR 13 R 14 (However, R 2 is a methyl group, and R 4 and R 5 If all of them are hydrogen atoms, then R 3 (This may be a hydrogen atom) R 13 is a hydrogen atom or a methyl group, R 14 is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, or an oxetane-3-yl group, or R 13 and R 14 These may form a piperazine ring, a piperazine-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, a 3-hydroxyazetidine ring, or a 3-methoxyazetidine ring together with the nitrogen atoms to which they are bonded. Or, R 1xHowever, if it is a phenyl group (the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group, an aminocarbonyl group, an aminosulfonyl group, a methylsulfonylamino group, or a methylsulfonyl group), R 3 This includes hydrogen atoms, fluorine atoms, chlorine atoms, methyl groups, hydroxymethyl groups, trifluoromethoxy groups, or -CH2CONR 13 R 14 And, R 13 is a hydrogen atom or a methyl group, R 14 is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, or an oxetane-3-yl group, or R 13 and R 14 The tetrahydroquinoline derivatives or pharmaceutically acceptable salts thereof described in [1] or [2] may, together with the nitrogen atoms to which they are bonded, form a piperazine ring, a piperazine-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, a 3-hydroxyazetidine ring, or a 3-methoxyazetidine ring, respectively.

[0020] [6] A tetrahydroquinoline derivative described in [1] or a pharmaceutically acceptable salt thereof, selected from the following group: 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, 4-(6-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(5-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(5-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 1-(3-methoxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3,3-difluoroazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(2-hydroxyethyl)-N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(azetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-Cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-Cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-1-(piperazine-1-yl)ethane-1-one, and 4-(1,2,3,4-tetrahydroquinoline-3-yl)benzenesulfonamide, or a pharmacoposityal salt thereof.

[0021] [7] A pharmaceutical product containing a tetrahydroquinoline derivative represented by the following general formula (I) (hereinafter also referred to as tetrahydroquinoline derivative (I)) or a pharmacokinetically acceptable salt thereof as an active ingredient.

[0022] [ka]

[0023] [In the formula, R 1x This refers to a 5 or 6-membered ring heteroaryl group containing one or two heteroatoms selected from a hydrogen atom, an aryl group, or a nitrogen atom, an oxygen atom, and a sulfur atom (the aryl group and one or two of the 5 or 6-membered ring heteroaryl group may each be independently substituted with a halogen atom, a C1-C3 alkyl group in which one to three of the hydrogen atoms may each be independently substituted with a hydroxyl group or a fluorine atom, a C1-C3 alkoxy group in which one to three of the hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, or -CONR 6 R 7 , -NHCOR 8 (which may be substituted with an aminosulfonyl group, a C1-C3 alkylsulfonylamino group, an aminosulfonylamino group, or a C1-C3 alkylsulfonyl group), or R 1xIn this case, if the aryl group is a phenyl group (the phenyl group may form the following fused ring group), the phenyl group may be fused with one ring selected from the group consisting of 5 and 6-membered lactam rings and 5 and 6-membered saturated heterorings containing one or two oxygen atoms as constituent atoms of the ring, forming a fused ring group (one of the hydrogen atoms of the fused ring group may be substituted with a methyl group). R 1y R represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group (however, R 1x and R 1y (Except that both are hydrogen atoms), R 2 , R 4 and R 5 The combination is R 2 , R 4 and R 5 Are they all hydrogen atoms? Or, R 2 , R 4 and R 5 One of them is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other two are hydrogen atoms. R 3 This includes hydrogen atoms, halogen atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may each be independently substituted with hydroxyl groups or fluorine atoms, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, C1-C3 alkoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, and -NR. 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 This represents, R 6 and R 7 Each of these independently represents either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R6 and R 7 They become one - (CH2) h - represents, h represents an integer between 3 and 5, where any one methylene group may be substituted with an oxygen atom, -NH-, or -N(CH3)-. R 8 This represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 and R 10 These are, independently, hydrogen atoms and -COR 15 Or it represents an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 They become one - (CH2) n - represents, n represents an integer between 3 and 6. R 11 and R 12 They become one - (CH2) m - represents, m represents an integer between 3 and 5, where any one methylene group may be substituted with an oxygen atom. R 13 and R 14 Each of these independently represents a hydrogen atom, a C1-C5 alkyl group, a 2-hydroxyethyl group, a C3 or C4 cycloalkyl group in which one of the carbon atoms may be replaced by an oxygen atom, or a methyl group in which one of the carbon atoms may be replaced by a C3 or C4 cycloalkyl group, or R 13 and R 14 This may be a compound in which one or two arbitrary hydrogen atoms are substituted with a fluorine atom, a methyl group, a hydroxyl group, or a methoxy group, or one arbitrary CH2 group is substituted with an oxygen atom, a nitrogen atom, or -CONH- -(CH2) k - represents, k represents an integer between 3 and 5. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 This represents, R 16 This represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R v This represents a hydrogen atom, a methyl group in which any one hydrogen atom may be substituted with a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group. R w This represents a hydrogen atom, a methyl group, a hydroxymethyl group, or a methoxycarbonyl group (excluding 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydroquinoline).

[0024] [8] R 1x This includes a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, an alkyl group having 1 to 3 carbon atoms where any 1 to 3 hydrogen atoms may be substituted with a fluorine atom or an alkyl group having 1 to 3 carbon atoms where any 1 to 3 hydrogen atoms may be substituted with a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms where any 1 to 3 hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, and -CONR 6 R 7 , -NHCOR 8 (which may be substituted with an aminosulfonyl group or a C1-C3 alkylsulfonyl group), or a 5 or 6-membered ring heteroaryl group selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group and pyridyl group (any one hydrogen atom of the 5 or 6-membered ring heteroaryl group may be substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group), or R 1x This may form a fused ring group in which a phenyl group is fused with one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (any one hydrogen atom of the fused ring group may be substituted with a methyl group), R 1y It is a hydrogen atom, R 2 , R 4 and R 5The combination is R 2 , R 4 and R 5 Are they all hydrogen atoms, or R 2 and R 4 One of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other and R 5 Is it a hydrogen atom, or R 2 and R 4 Both are hydrogen atoms, and R 5 is a fluorine atom or a chlorine atom, R 3 This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, and -NR 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 And, R 6 and R 7 Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 6 and R 7 These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atom bonded to them. R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 It is a hydrogen atom, R 10 is a hydrogen atom, -COR 15 Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 They become one - (CH2) n -and, n is either 4 or 5. R 11 and R 12 They become one - (CH2) m -and, m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R 13 It is a hydrogen atom, R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R 13 and R 14 These may form an azetidine ring with the nitrogen atom bonded to them, in which any one hydrogen atom may be substituted with a hydroxyl group. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 And, R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R v It is a hydrogen atom, R w A pharmaceutical product containing a tetrahydroquinoline derivative described in [7] or a pharmacopoeia thereof as an active ingredient, wherein the active ingredient is a hydrogen atom (except for 2-phenyl-1,2,3,4-tetrahydroquinoline).

[0025] [9] R 1x This is a phenyl group (the phenyl group may have the following substituents and may form the following fused ring group), or a 5 or 6-membered heteroaryl group selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group and pyridyl group (the heteroaryl group may have the following substituents), R 1y It is a hydrogen atom, R 2 , R 4 and R 5 The combination is R 2 , R4 and R 5 Are they all hydrogen atoms, or R 2 and R 4 One of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other and R 5 Is it a hydrogen atom, or R 2 and R 4 Both are hydrogen atoms, and R 5 is a fluorine atom or a chlorine atom, R v It is a hydrogen atom, R w It is a hydrogen atom, Here, R 1x However, a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, a C1-C3 alkyl group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a C1-C3 alkoxy group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a cyano group, a methoxycarbonyl group, and -NHCOR 8 It may be substituted with one substituent selected from the group consisting of (except for the m-cyanophenyl group and the p-trifluoromethoxyphenyl group), or if it is a 5 or 6-membered ring heteroaryl group (any one hydrogen atom of the 5 or 6-membered ring heteroaryl group may be substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group, except for the 1-methyl-1H-pyrazole-4-yl group and the 6-methoxypyridine-3-yl group), R 3 This includes C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms, C1-C3 alkyl groups in which 1 arbitrary hydrogen atom is substituted with a hydroxyl group, ethyl groups, propyl groups, isopropyl groups, 3-hydroxyoxetane-3-yl groups, methoxy groups, methoxycarbonyl groups, and -NR groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms. 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 (However, R2 and R 4 Both are hydrogen atoms, and R 5 If R is a fluorine atom or a chlorine atom, 3 R may be a hydrogen atom or a fluorine atom, 2 and R 5 Both are hydrogen atoms, and R 4 If R is a fluorine atom or a chlorine atom, 3 R may be a fluorine atom, 2 However, a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and R 4 and R 5 If all of them are hydrogen atoms, then R 3 (This may be a hydrogen atom) R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 It is a hydrogen atom, R 10 is a hydrogen atom, -COR 15 Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 (CH2) n -and, n is either 4 or 5. R 11 and R 12 They become one - (CH2) m -and, m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R 13 It is a hydrogen atom, R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R 13 and R 14 These may form an azetidine ring with the nitrogen atom bonded to them, in which any one hydrogen atom may be substituted with a hydroxyl group. R 15This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 And, R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Or, R 1x However, a phenyl group (where any one hydrogen atom of the phenyl group is replaced by a C1-C3 alkyl group, -CONR) 6 R 7 (substituted with an aminosulfonyl group or an alkylsulfonyl group having 1 to 3 carbon atoms, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group), a 1-methyl-1H-pyrazole-4-yl group or a 6-methoxypyridine-3-yl group, or R 1x However, if it is a fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (where any one hydrogen atom of the fused ring group may be substituted with a methyl group), R 3 This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, and -NR 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 And, R 6 and R 7 Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 6 and R 7These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atoms bonded to them. R 9 It is a hydrogen atom, R 10 is a hydrogen atom, -COR 15 Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 (CH2) n -and, n is either 4 or 5. R 11 and R 12 They become one - (CH2) m -and, m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R 13 It is a hydrogen atom, R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R 13 and R 14 These may form an azetidine ring with the nitrogen atom bonded to them, in which any one hydrogen atom may be substituted with a hydroxyl group. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 And, R 16 A pharmaceutical product containing, as an active ingredient, a tetrahydroquinoline derivative described in [7] or [8], which is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or a pharmacoposly acceptable salt thereof.

[0026]

[10] The pharmaceutical product according to any one of [7] to [9], wherein the above-mentioned tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group described in [3].

[0027]

[11] The pharmaceutical product according to any one of [7] to

[10] , wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group described in [4].

[0028]

[12] R 1x This is a phenyl group (the hydrogen atom at the para position of the phenyl group may be substituted with a fluorine atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetamide group, an aminosulfonyl group, a methylsulfonylamino group, or a methylsulfonyl group), R 1y It is a hydrogen atom, R 2 , R 4 and R 5 The combination is R 2 , R 4 and R 5 Are they all hydrogen atoms, or R 2 and R 4 One is a fluorine atom, a chlorine atom, or a methyl group, and the other is R 5 That is a hydrogen atom, R 3 This includes hydrogen atoms, fluorine atoms, chlorine atoms, methyl groups, hydroxymethyl groups, trifluoromethoxy groups, or -CH2CONR 13 R 14 And, R 13 is a hydrogen atom or a methyl group, R 14 is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, or an oxetane-3-yl group, or R 13 and R 14 These may form a piperazine ring, a piperazine-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, a 3-hydroxyazetidine ring, or a 3-methoxyazetidine ring together with the nitrogen atoms to which they are bonded. R v It is a hydrogen atom, R wA pharmaceutical product containing a tetrahydroquinoline derivative described in any of [7] to [9] or a pharmacopoecilistically acceptable salt thereof as an active ingredient, wherein the active ingredient is a hydrogen atom (except for 2-phenyl-1,2,3,4-tetrahydroquinoline).

[0029]

[13] The pharmacopoeia according to [7] or [8], wherein the tetrahydroquinoline derivative or a pharmacopositically acceptable salt thereof is selected from the group described in [6].

[0030]

[14] A pharmaceutical product according to any one of [7] to

[13] for the treatment or prevention of a disease, disorder or syndrome associated with ferroptosis inhibition.

[0031]

[15] The medicine described in

[14] , wherein the above disease, disorder or syndrome is multiple sclerosis.

[0032] In another embodiment, the present invention includes a ferroptosis inhibitor containing a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0033] [ka]

[0034] [In the formula, R 1x This refers to a 5 or 6-membered ring heteroaryl group containing one or two heteroatoms selected from a hydrogen atom, an aryl group, or a nitrogen atom, an oxygen atom, and a sulfur atom (the aryl group and one or two of the 5 or 6-membered ring heteroaryl group may each be independently substituted with a halogen atom, a C1-C3 alkyl group in which one to three of the hydrogen atoms may each be independently substituted with a hydroxyl group or a fluorine atom, a C1-C3 alkoxy group in which one to three of the hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, or -CONR 6 R 7 , -NHCOR 8(which may be substituted with an aminosulfonyl group, a C1-C3 alkylsulfonylamino group, an aminosulfonylamino group, or a C1-C3 alkylsulfonyl group), or R 1x In this case, if the aryl group is a phenyl group (the phenyl group may form the following fused ring group), the phenyl group may be fused with one ring selected from the group consisting of 5 and 6-membered lactam rings and 5 and 6-membered saturated heterorings containing one or two oxygen atoms as constituent atoms of the ring to form a fused ring group (any one hydrogen atom of the fused ring group may be substituted with a methyl group). R 1y R represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group (however, R 1x and R 1y (Except that both are hydrogen atoms), R 2 , R 4 and R 5 The combination is R 2 , R 4 and R 5 Are they all hydrogen atoms? Or, R 2 , R 4 and R 5 One of them is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other two are hydrogen atoms. R 3 This includes hydrogen atoms, halogen atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may each be independently substituted with hydroxyl groups or fluorine atoms, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, C1-C3 alkoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, and -NR. 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R14 This represents, R 6 and R 7 Each of these independently represents either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 They become one - (CH2) h - represents, h represents an integer between 3 and 5, where any one methylene group may be substituted with an oxygen atom, -NH-, or -N(CH3)-. R 8 This represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 and R 10 These are, independently, hydrogen atoms and -COR 15 Or it represents an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 They become one - (CH2) n - represents, n represents an integer between 3 and 6. R 11 and R 12 They become one - (CH2) m - represents, m represents an integer between 3 and 5, where any one methylene group may be substituted with an oxygen atom. R 13 and R 14 Each of these independently represents a hydrogen atom, a C1-C5 alkyl group, a 2-hydroxyethyl group, a C3 or C4 cycloalkyl group in which one of the carbon atoms may be replaced by an oxygen atom, or a methyl group in which one of the carbon atoms may be replaced by a C3 or C4 cycloalkyl group, or R 13 and R 14 This may be a compound in which one or two arbitrary hydrogen atoms are substituted with a fluorine atom, a methyl group, a hydroxyl group, or a methoxy group, or one arbitrary CH2 group is substituted with an oxygen atom, a nitrogen atom, or -CONH- -(CH2) k - represents, k represents an integer between 3 and 5. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 This represents, R 16 This represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R v This represents a hydrogen atom, a methyl group in which any one hydrogen atom may be substituted with a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group. R w [This represents a hydrogen atom, a methyl group, a hydroxymethyl group, or a methoxycarbonyl group.]

[0035] In another embodiment, the present invention includes the use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof in the production of a ferroptosis inhibitor.

[0036] In yet another aspect, the present invention includes the use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical, preferably the use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment or prevention of a disease, disorder or syndrome associated with ferroptosis inhibition, more preferably the use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment or prevention of multiple sclerosis.

[0037] In yet another embodiment, the present invention includes the tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases, disorders or syndromes related to ferroptosis inhibition, preferably the tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of multiple sclerosis.

[0038] In yet another aspect, the present invention includes a method for treating or preventing a disease, disorder, or syndrome related to ferroptosis inhibition, comprising administering an effective amount of the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof to a subject in need, preferably a method for treating or preventing multiple sclerosis, comprising administering an effective amount of the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof to a subject in need. [Effects of the Invention]

[0039] The tetrahydroquinoline derivative or a pharmacopositically acceptable salt thereof, which is the active ingredient of the pharmaceutical product of the present invention, has ferroptosis inhibitory activity and pharmacological activity based thereon. Therefore, the pharmaceutical product of the present invention is effective in treating or preventing diseases, disorders, or syndromes related to ferroptosis inhibition, such as multiple sclerosis. [Brief explanation of the drawing]

[0040] [Figure 1] This figure shows the inhibitory effect of the compound from Example 1 on the elevation of neurological symptom scores in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model. [Figure 2] This figure shows the inhibitory effects of the compounds from Example 11, Example 32, and Example 36 on the elevation of neurological symptom scores in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model. [Figure 3] This figure shows the inhibitory effects of the compounds from Example 144, Example 171, and Example 172 on the elevation of neurological symptom scores in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model. [Figure 4] This figure shows the inhibitory effects of the compounds from Example 38 and Example 119 on the elevation of neurological symptom scores in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model. [Figure 5]This figure shows the inhibitory effect of Example 33 on the elevation of neurological symptom scores in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model. [Figure 6] This figure shows the inhibitory effects of the compounds from Example 108 and Example 117 on the elevation of neurological symptom scores in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model. [Modes for carrying out the invention]

[0041] The tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof, which is the active ingredient of the pharmaceutical product of the present invention, is characterized by being represented by the following general formula (I).

[0042] [ka]

[0043] [In the formula, R 1x This refers to a 5 or 6-membered ring heteroaryl group containing one or two heteroatoms selected from a hydrogen atom, an aryl group, or a nitrogen atom, an oxygen atom, and a sulfur atom (the aryl group and one or two of the 5 or 6-membered ring heteroaryl group may each be independently substituted with a halogen atom, a C1-C3 alkyl group in which one to three of the hydrogen atoms may each be independently substituted with a hydroxyl group or a fluorine atom, a C1-C3 alkoxy group in which one to three of the hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, or -CONR 6 R 7 , -NHCOR 8 (which may be substituted with an aminosulfonyl group, a C1-C3 alkylsulfonylamino group, an aminosulfonylamino group, or a C1-C3 alkylsulfonyl group), or R 1xIn this case, if the aryl group is a phenyl group (the phenyl group may form the following fused ring group), the phenyl group may be fused with one ring selected from the group consisting of 5 and 6-membered lactam rings and 5 and 6-membered saturated heterorings containing one or two oxygen atoms as constituent atoms of the ring to form a fused ring group (any one hydrogen atom of the fused ring group may be substituted with a methyl group). R 1y R represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group (however, R 1x and R 1y (Except that both are hydrogen atoms), R 2 , R 4 and R 5 The combination is R 2 , R 4 and R 5 Are they all hydrogen atoms? Or, R 2 , R 4 and R 5 One of them is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other two are hydrogen atoms. R 3 This includes hydrogen atoms, halogen atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may each be independently substituted with hydroxyl groups or fluorine atoms, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, C1-C3 alkoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, and -NR. 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 This represents, R 6 and R 7 Each of these independently represents either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R6 and R 7 They become one - (CH2) h - represents, h represents an integer between 3 and 5, where any one methylene group may be substituted with an oxygen atom, -NH-, or -N(CH3)-. R 8 This represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 and R 10 These are, independently, hydrogen atoms and -COR 15 Or it represents an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 They become one - (CH2) n - represents, n represents an integer between 3 and 6. R 11 and R 12 They become one - (CH2) m - represents, m represents an integer between 3 and 5, where any one methylene group may be substituted with an oxygen atom. R 13 and R 14 Each of these independently represents a hydrogen atom, a C1-C5 alkyl group, a 2-hydroxyethyl group, a C3 or C4 cycloalkyl group in which one of the carbon atoms may be replaced by an oxygen atom, or a methyl group in which one of the carbon atoms may be replaced by a C3 or C4 cycloalkyl group, or R 13 and R 14 This may be a compound in which one or two arbitrary hydrogen atoms are substituted with a fluorine atom, a methyl group, a hydroxyl group, or a methoxy group, or one arbitrary CH2 group is substituted with an oxygen atom, a nitrogen atom, or -CONH- -(CH2) k - represents, k represents an integer between 3 and 5. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 This represents, R 16 This represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R v This represents a hydrogen atom, a methyl group in which any one hydrogen atom may be substituted with a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group. R w This represents a hydrogen atom, a methyl group, a hydroxymethyl group, or a methoxycarbonyl group (excluding 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydroquinoline).

[0044] Furthermore, among the tetrahydroquinoline derivative (I) or its pharmaceutically acceptable salt, which is the active ingredient of the pharmaceutical product of the present invention, the tetrahydroquinoline derivative or its pharmaceutically acceptable salt described in [1] above is a novel compound. The tetrahydroquinoline derivative or its pharmaceutically acceptable salt described in [1] above is encompassed within the tetrahydroquinoline derivative (I) or its pharmaceutically acceptable salt.

[0045] Unless otherwise specified, the following terms used in this specification have the definitions set forth below.

[0046] "Halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom.

[0047] "Alkyl group with 1 to 3 carbon atoms" refers to a methyl group, ethyl group, propyl group, or isopropyl group.

[0048] "C1-C5 alkyl group" refers to a linear or branched hydrocarbon group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, or neopentyl group.

[0049] "A C1-C3 alkyl group in which 1 to 3 arbitrary hydrogen atoms may each be independently substituted with a hydroxyl group or a fluorine atom" means a group in which 1 to 3 arbitrary hydrogen atoms of the above-mentioned "C1-C3 alkyl group" may each be independently substituted with a hydroxyl group or a fluorine atom, for example, methyl group, hydroxymethyl group, ethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1,2-dihydroxyethyl group, propyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl Examples include the 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, isopropyl group, 2-hydroxypropan-2-yl group, 1-hydroxypropan-2-yl group, 1,2-dihydroxy-1-methylethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoropropyl group, 2,2-difluoropropyl group, 3,3,3-trifluoropropyl group, 2-fluoropropan-2-yl group, or 1,1,1-trifluoropropan-2-yl group.

[0050] "A C1-C3 alkyl group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms" means a group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, and examples include a methyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, ethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, propyl group, 1,1-difluoropropyl group, 2,2-difluoropropyl group, 3,3,3-trifluoropropyl group, isopropyl group, 2-fluoropropan-2-yl group, or 1,1,1-trifluoropropan-2-yl group.

[0051] "A C1-C3 alkyl group in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms" refers to a group in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms, such as fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoropropyl group, 2,2-difluoropropyl group, 3,3,3-trifluoropropyl group, 2-fluoropropan-2-yl group, or 1,1,1-trifluoropropan-2-yl group.

[0052] "A C1-C3 alkyl group in which one arbitrary hydrogen atom may be substituted with a hydroxyl group" means a C1-C3 alkyl group in which one arbitrary hydrogen atom may be substituted with a hydroxyl group, and examples include a methyl group, hydroxymethyl group, ethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, propyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, isopropyl group, 2-hydroxypropan-2-yl group, or 1-hydroxypropan-2-yl group.

[0053] "A C1-C3 alkyl group in which one arbitrary hydrogen atom is substituted with a hydroxyl group" refers to a group in which one arbitrary hydrogen atom of the above-mentioned "C1-C3 alkyl group" is substituted with a hydroxyl group. Examples include the hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxypropan-2-yl group, or 1-hydroxypropan-2-yl group.

[0054] "A C1-C3 alkyl group in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group" means the above-mentioned "a C1-C3 alkyl group in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms" or the above-mentioned "a C1-C3 alkyl group in which 1 arbitrary hydrogen atom may be substituted with a hydroxyl group".

[0055] "A methyl group in which one hydrogen atom may be replaced by a hydroxyl group" means a methyl group or a hydroxymethyl group.

[0056] "Alkoxy groups with 1 to 3 carbon atoms" refers to methoxy groups, ethoxy groups, propoxy groups, or isopropoxy groups.

[0057] "Alkoxy groups having 1 to 5 carbon atoms" refers to monovalent substituents in which a linear or branched hydrocarbon group having 1 to 5 carbon atoms is bonded to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, sec-pentyloxy, tert-pentyloxy, or neopentyloxy groups.

[0058] "A C1-C3 alkoxy group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms" means a C1-C3 alkoxy group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, and examples include methoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, 1,1-difluoroethoxy group, 2,2,2-trifluoroethoxy group, propoxy group, 1,1-difluoropropoxy group, 2,2-difluoropropoxy group, 3,3,3-trifluoropropoxy group, isopropoxy group, (2-fluoropropan-2-yl)oxy group, or (1,1,1-trifluoropropan-2-yl)oxy group.

[0059] "A methoxy group in which 1 to 3 arbitrary hydrogen atoms are replaced by fluorine atoms" refers to a fluoromethoxy group, a difluoromethoxy group, or a trifluoromethoxy group.

[0060] "A methoxy group in which 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms" means the above-mentioned "methoxy group in which 1 to 3 arbitrary hydrogen atoms are substituted with fluorine atoms" or a methoxy group.

[0061] "Alkyl sulfonyl groups with 1 to 3 carbon atoms" refers to methyl sulfonyl groups, ethyl sulfonyl groups, propyl sulfonyl groups, or isopropyl sulfonyl groups.

[0062] An "aryl group" refers to a monocyclic or bicyclic aromatic hydrocarbon group, such as a phenyl group or a naphthyl group (1-naphthyl group or 2-naphthyl group).

[0063] "A 5- or 6-membered heteroaryl ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur atoms" means a 5- or 6-membered monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur atoms in addition to carbon atoms as constituent atoms of the ring, such as a furyl group (e.g., 2-furyl or 3-furyl group), a thienyl group (e.g., 2-thienyl or 3-thienyl group), a pyrrolyl group (e.g., 1-pyrrolyl, 2-pyrrolyl, or 3-pyrrolyl group), an imidazolyl group (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, or 5-imidazolyl group), a pyrazolyl group (e.g., 1-pyrrolyl, 3-pyrrolyl, or 4-pyrrolyl group), a thiazolyl group (e.g., Examples include 2-thiazolyl group, 4-thiazolyl group, or 5-thiazolyl group), isothiazolyl group (e.g., 3-isothiazolyl group, 4-isothiazolyl group, or 5-isothiazolyl group), oxazolyl group (e.g., 2-oxazolyl group, 4-oxazolyl group, or 5-oxazolyl group), or isoxazolyl group (e.g., 3-isoxazolyl group, 4-isoxazolyl group, or 5-isoxazolyl group), pyridyl group (e.g., 2-pyridyl group, 3-pyridyl group, or 4-pyridyl group), pyrimidinyl group (e.g., 2-pyridyl group, 4-pyridyl group, 5-pyridinyl group, or 6-pyridinyl group), pyridazinyl group (e.g., 3-pyridazinyl group or 4-pyridazinyl group), and pyrazinyl group (e.g., 2-pyridyl group).

[0064] "5- and 6-membered lactam rings" refers to pyrrolidine-2-one rings and piperidine-2-one rings.

[0065] "5- and 6-membered saturated heterocycles containing one or two oxygen atoms as constituent atoms of the ring" refers to 5- and 6-membered monocyclic saturated heterocycles that contain one or two oxygen atoms in addition to carbon atoms as constituent atoms of the ring. Examples include tetrahydrofuran rings, 1,3-dioxolane rings, tetrahydro-2H-pyran rings, 1,2-dioxane rings, 1,3-dioxane rings, and 1,4-dioxane rings.

[0066] "A fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of a 5- and 6-membered lactam ring and a 5- and 6-membered saturated heterocycle containing one or two oxygen atoms as constituent atoms of the ring" means a bicyclic fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of the above-mentioned "5- and 6-membered lactam ring" and the above-mentioned "5- and 6-membered saturated heterocycle containing one or two oxygen atoms as constituent atoms of the ring," for example, 3-oxoisoindolin-4-yl group, 3-oxoisoindolin-5-yl group, 1-oxoisoindolin-5-yl group, 1-oxoiso 1-oxo-indolin-4-yl group, 2-oxoindolin-4-yl group, 2-oxoindolin-5-yl group, 2-oxoindolin-6-yl group, 2-oxoindolin-7-yl group, 2,3-dihydrobenzofuran-4-yl group, 2,3-dihydrobenzofuran-5-yl group, 2,3-dihydrobenzofuran-6-yl group, 2,3-dihydrobenzofuran-7-yl group, benzo[d][1,3]dioxol-4-yl group, benzo[d][1,3]dioxol-5-yl group, 1-oxo- 1,2,3,4-tetrahydroisoquinoline-5-yl group, 1-oxo- 1,2,3,4-tetrahydroisoquinoline-6-yl group, 1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl group, 1-oxo-1,2,3,4-tetrahydroisoquinoline-8-yl group, 2-oxo-1,2,3,4-tetrahydroisoquinoline-5-yl group, 2-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl group, 2-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl group, 2-oxo-1,2,3,4-tetrahydroisoquinoline-8-yl group, 3-oxo-1,2,3,4-tetrahydroisoquinoline n-5-yl group, 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl group, 3-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl group, 3-oxo-1,2,3,4-tetrahydroisoquinoline-8-yl group, chroman-5-yl group, chroman-6-yl group, chroman-7-yl group, chroman-8-yl group, isochroman-5-yl group, isochroman-6-yl group, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl group, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl group, 4H-benzo[d][1,Examples of bicyclic fused ring groups include the 3]dioxin-5-yl group, the 4H-benzo[d][1,3]dioxin-6-yl group, the 4H-benzo[d][1,3]dioxin-7-yl group, the 4H-benzo[d][1,3]dioxin-8-yl group, the 3,4-dihydrobenzo[c][1,2]dioxin-5-yl group, the 3,4-dihydrobenzo[c][1,2]dioxin-6-yl group, the 3,4-dihydrobenzo[c][1,2]dioxin-7-yl group, the 3,4-dihydrobenzo[c][1,2]dioxin-8-yl group, the 1,4-dihydrobenzo[d][1,2]dioxin-5-yl group, or the 1,4-dihydrobenzo[d][1,2]dioxin-6-yl group.

[0067] "A fused ring group formed by the fusion of a phenyl group with one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane" refers to, for example, a 3-oxisoindolin-4-yl group, a 3-oxisoindolin-5-yl group, a 1-oxisoindolin-5-yl group, a 1-oxisoindolin-4-yl group, a 2-oxisoindolin-4-yl group, and a 2 -Oxoindolin-5-yl group, 2-Oxoindolin-6-yl group, 2-Oxoindolin-7-yl group, benzo[d][1,3]dioxol-4-yl group, benzo[d][1,3]dioxol-5-yl group, 1-Oxo-1,2,3,4-tetrahydroisoquinolin-5-yl group, 1-Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl group, 1-Oxo- 1,2,3,4-tetrahydroisoquinoline-7-yl group, 1-oxo-1,2,3,4-tetrahydroisoquinoline-8-yl group, 2-oxo-1,2,3,4-tetrahydroisoquinoline-5-yl group, 2-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl group, 2-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl group, 2-oxo-1,2,3 Examples include bicyclic condensed ring groups such as ,4-tetrahydroisoquinoline-8-yl group, 3-oxo-1,2,3,4-tetrahydroisoquinoline-5-yl group, 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl group, 3-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl group, or 3-oxo-1,2,3,4-tetrahydroisoquinoline-8-yl group.

[0068] "R 2 , R 4 and R 5 "One of them is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other two are hydrogen atoms" means R 2 R is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and 4 and R 5 Are all of them hydrogen atoms, or R 4R is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and 2 and R 5 Either all of them are hydrogen atoms, or R 5 R is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and 2 and R 4 This means that all of them are hydrogen atoms.

[0069] "R 2 and R 4 One of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other and R 5 "It is a hydrogen atom" means that R 2 R is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and 4 and R 5 Either all of them are hydrogen atoms, or R 4 R is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and 2 and R 5 This means that all of them are hydrogen atoms.

[0070] "R 6 and R 7 They become one - (CH2) h - represents a value, where h represents an integer between 3 and 5, and where any one methylene group may be substituted with an oxygen atom, -NH- or -N(CH3)-. 6 and R 7 This means that together with the nitrogen atom to which they are bonded, they form an azetidine ring (h=3), a pyrrolidine ring (h=4), or a piperidine ring (h=5), where one arbitrary methylene group may be substituted with an oxygen atom, -NH-, or -N(CH3)-, for example, an azetidine ring (h=3), a pyrrolidine ring (h=4), a piperidine ring (h=5), a morpholine ring (h=5), a piperazine ring (h=5), or a 1-methylpiperazine ring (h=5).

[0071] "R 9 and R 10 They become one - (CH2) n "- represents an integer, and n represents an integer between 3 and 6" is R 9 and R 10 This means that together with the nitrogen atoms bonded to them, they form an azetidine ring (n=3), pyrrolidine ring (n=4), piperidine ring (n=5), or azepane ring (n=6).

[0072] "R 11 and R 12 They become one - (CH2) m - represents a value where m is an integer between 3 and 5, and where any one methylene group may be substituted with an oxygen atom. 11 and R 12 This means that together with the nitrogen atom to which they are bonded, they form an azetidine ring (m=3), a pyrrolidine ring (m=4), or a piperidine ring (m=5), where one arbitrary methylene group may be substituted with an oxygen atom, for example, an azetidine ring (m=3), a pyrrolidine ring (m=4), a piperidine ring (m=5), a morpholine ring (m=5), a piperazine ring (m=5), or a 1-methylpiperazine ring (m=5).

[0073] "R 13 and R 14 This may be a combination in which one arbitrary hydrogen atom is substituted with a hydroxyl group - (CH2) k - represents, and k represents 3 or 4" means R 13 and R 14 This means that together with the nitrogen atom bonded to them, they form an azetidine ring (k=3) or a pyrrolidine ring (k=4), where one arbitrary hydrogen atom may be substituted with a hydroxyl group, for example, an azetidine ring (k=3), a 3-hydroxyazetidine ring (k=3), a pyrrolidine ring (k=4), or a 3-hydroxypyrrolidine ring (k=4).

[0074] "R 13 and R 14This may be a compound in which one or two arbitrary hydrogen atoms are substituted with a fluorine atom, a methyl group, a hydroxyl group, or a methoxy group, or one arbitrary CH2 group is substituted with an oxygen atom, a nitrogen atom, or -CONH- -(CH2) k "- represents and k represents an integer between 3 and 5" is R 13 and R 14This means that together with the nitrogen atom bonded to them, one or two arbitrary hydrogen atoms may be substituted with a fluorine atom, a methyl group, a hydroxyl group or a methoxy group, or one arbitrary CH2 group may be substituted with an oxygen atom, a nitrogen atom or -CONH-, forming an azetidine ring (k=3), a pyrrolidine ring (k=4), or a piperidine ring (k=5), for example, an azetidine ring (k=3), a 3-fluoroazetidine ring (k=3), a 3,3-difluoroazetidine ring (k=3), a 2-methylazetidine ring (k=3), a 3-methylazetidine ring (k= 3) 4-methylazetidine ring (k=3), 2,2-dimethylazetidine ring (k=3), 2,3-dimethylazetidine ring (k=3), 2,4-dimethylazetidine ring (k=3), 3,3-dimethylazetidine ring (k=3), 3-hydroxyazetidine ring (k=3), 3-methoxyazetidine ring (k=3), pyrrolidine ring (k=4), 3-fluoropyrrolidine ring (k=4), 3,3-difluoropyrrolidine ring (k=4), 3,4-difluoropyrrolidine ring (k=4), 2-methylpyrrolidine ring (k=4), 3-methylpyrrolidine ring (k=4), 2,2-dimeth Lupyrrolidine ring (k=4), 2,3-dimethylpyrrolidine ring (k=4), 2,4-dimethylpyrrolidine ring (k=4), 2,5-dimethylpyrrolidine ring (k=4), 3,3-dimethylpyrrolidine ring (k=4), 3,4-dimethylpyrrolidine ring (k=4), 3,5-dimethylpyrrolidine ring (k=4), 3-hydroxypyrrolidine ring (k=4), 3,4-dihydroxypyrrolidine ring (k=4), 3-methoxypyrrolidine ring (k=4), 3,4-dimethoxypyrrolidine ring (k=4), tetrahydropyrimidine-2(1H)-one ring (k=4), piperazine-2-one Ring (k=4), piperidine ring (k=5), 3-fluoropiperidine ring (k=5), 4-fluoropiperidine ring (k=5), 3,3-difluoropiperidine ring (k=5), 3,4-difluoropiperidine ring (k=5), 3,5-difluoropiperidine ring (k=5), 4,4-difluoropiperidine ring (k=5), 4,5-difluoropiperidine ring (k=5), 2-methylpiperidine ring (k=5), 3-methylpiperidine ring (k=5), 4-methylpiperidine ring (k=5), 5-methylpiperidine ring (k=5), 2,2-dimethylpiperidine ring (k=5), 2,Examples include 3-dimethylpiperidine rings (k=5), 2,4-dimethylpiperidine rings (k=5), 2,5-dimethylpiperidine rings (k=5), 3,3-dimethylpiperidine rings (k=5), 3,4-dimethylpiperidine rings (k=5), 3,5-dimethylpiperidine rings (k=5), 3-hydroxypiperidine rings (k=5), 4-hydroxypiperidine rings (k=5), 3,4-dihydroxypiperidine rings (k=5), 3,5-dihydroxypiperidine rings (k=5), morpholine rings (k=5), piperazine rings (k=5), 1,3-diazepan-2-one rings (k=5), 1,4-diazepan-2-one rings (k=5), or 1,4-diazepan-5-one rings (k=5).

[0075] "R 13 and R 14 An azetidine ring in which any one hydrogen atom may be substituted with a hydroxyl group along with the nitrogen atom to which it is bonded includes, for example, an azetidine ring or a 3-hydroxyazetidine ring.

[0076] "An azetidine ring in which two arbitrary hydrogen atoms are substituted with methyl groups or fluorine atoms, or one arbitrary hydrogen atom is substituted with a hydroxyl group or a methoxy group" includes azetidine rings, 2,2-dimethylazetidine rings, 2,3-dimethylazetidine rings, 2,4-dimethylazetidine rings, 3,3-dimethylazetidine rings, 3,3-difluoroazetidine rings, 3-hydroxyazetidine rings, or 3-methoxyazetidine rings.

[0077] "A C3 or C4 cycloalkyl group in which one arbitrary carbon atom may be substituted with an oxygen atom" refers to, for example, a cyclopropyl group, a cyclobutyl group, an oxiran-2-yl group, or an oxetane-3-yl group.

[0078] "A methyl group substituted with a C3 or C4 cycloalkyl group in which one arbitrary carbon atom may be substituted with a nitrogen atom or an oxygen atom" refers to, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, an oxiran-2-ylmethyl group, an oxetane-2-ylmethyl group, an oxetane-3-ylmethyl group, an aziridine-2-ylmethyl group, an azetidine-2-ylmethyl group, or an azetidine-3-ylmethyl group.

[0079] "A methyl group in which any one hydrogen atom may be substituted with a hydroxyl group or a methoxycarbonyl group" refers, for example, to a methyl group, a hydroxymethyl group, or a methoxycarbonylmethyl group.

[0080] R 1x This includes a phenyl group (where any one hydrogen atom of the phenyl group may be a fluorine atom, a chlorine atom, a C1-C3 alkyl group in which 1-3 of the hydrogen atoms may be substituted with a fluorine atom or 1 of the hydrogen atoms may be substituted with a hydroxyl group, a C1-C3 alkoxy group in which 1-3 of the hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, and -CONR 6 R 7 , -NHCOR 8 Preferably, the group is an aminosulfonyl group, a C1-C3 alkylsulfonylamino group, an aminosulfonylamino group, or a C1-C3 alkylsulfonyl group, a pyrazolyl group, a 1-oxoisoindolin-5-yl group, a 2-oxo-1,2,3,4-tetrahydroquinoline-6-yl group, or a benzo[d][1,3]dioxol-5-yl group, and preferably a phenyl group (any one hydrogen atom of the phenyl group may be a fluorine atom, a trifluoromethyl group, a hydroxymethyl group, a 2-hydroxypropane-2-yl group, a methoxy group, a trifluoromethoxy group, a cyano group, a methoxycarbonyl group, or a -CONR group). 6 R 7 , -NHCOR 8It is more preferably a phenyl group (where any one hydrogen atom of the phenyl group may be substituted with a fluorine atom, a hydroxymethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetamide group, an aminosulfonyl group, a methylsulfonylamino group, or a methylsulfonyl group), and even more preferably a phenyl group (where any one hydrogen atom of the phenyl group may be substituted with a fluorine atom, a hydroxymethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetamide group, an aminosulfonyl group, a methylsulfonylamino group, or a methylsulfonyl group).

[0081] R 1x When it is a substituted phenyl group, it is preferable that the hydrogen atom at the para position is substituted.

[0082] In the case of a novel compound, such as the tetrahydroquinoline derivative described in [1] above or a pharmaceutically acceptable salt thereof, R 1x This includes phenyl groups (where any one hydrogen atom of the phenyl group may be a halogen atom, a C1-C3 alkyl group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a C1-C3 alkoxy group in which 1-3 of the hydrogen atoms may be substituted with fluorine atoms, a cyano group, a methoxycarbonyl group, and -NHCOR 8 It is preferable that the group is substituted with one substituent selected from the group consisting of the following (except for the m-cyanophenyl group and the p-trifluoromethoxyphenyl group), or a 5- or 6-membered ring heteroaryl group (one of the hydrogen atoms of the 5- or 6-membered ring heteroaryl group may be substituted with a C1- to C3 alkyl group or a C1- to C3 alkoxy group, except for the 1-methyl-1H-pyrazole-4-yl group and the 6-methoxypyridine-3-yl group).

[0083] Furthermore, in the case of a novel compound, such as the tetrahydroquinoline derivative described in [1] above or a pharmaceutically acceptable salt thereof, R 1xThis is a hydrogen atom, a phenyl group (any one hydrogen atom of the phenyl group is a C1-C3 alkyl group in which any one hydrogen atom is substituted with a hydroxyl group, -CONR 6 R 7 Preferably, the phenyl group is substituted with an aminosulfonyl group, a methylsulfonylamino group, an aminosulfonylamino group, or an alkylsulfonyl group having 1 to 3 carbon atoms, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or one hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group), represents a 1-methyl-1H-pyrazole-4-yl group, or a 6-methoxypyridine-3-yl group, or is a fused ring group formed by the fusion of a phenyl group with one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (any one hydrogen atom of the fused ring group may be substituted with a methyl group).

[0084] R 1y It is preferably a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl group; more preferably a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl group; and even more preferably a 4-aminocarbonylphenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl group.

[0085] However, R 1x and R 1y It is impossible for both to be hydrogen atoms.

[0086] R 1x and R 1y The combination is R 1x is a hydrogen atom and R 1y is a substituent other than a hydrogen atom, or R 1x R is a substituent other than a hydrogen atom 1y It is preferably a hydrogen atom, R 1xR is a substituent other than a hydrogen atom 1y It is more preferable that it be a hydrogen atom.

[0087] R 2 It is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxymethyl group, or a methyl group, and more preferably a hydrogen atom.

[0088] R 3 This includes a hydrogen atom, a fluorine atom, a chlorine atom, a C1-C3 alkyl group in which any one hydrogen atom may be substituted with a hydroxyl group, a trifluoromethoxy group, and -CH2NR 11 R 12 or -CH2CONR 13 R 14 Preferably, it is a hydrogen atom, fluorine atom, chlorine atom, methyl group, hydroxymethyl group, trifluoromethoxy group or -CH2CONR 13 R 14 It is more preferable that it be a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group.

[0089] R 4 It is preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group, and more preferably a hydrogen atom.

[0090] R 5 It is preferable that it be a hydrogen atom.

[0091] R 6 and R 7 Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 It is preferable that together with the nitrogen atoms bonded to them, they form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring, R 6 and R 7 It is more preferable that all of these are hydrogen atoms.

[0092] R 8It is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group.

[0093] R 9 R is a hydrogen atom, 10 is a hydrogen atom, -COR 15 Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 They become one, -(CH2) n - and n is preferably 4 or 5, R 9 R is a hydrogen atom, 10 ha-COR 15 It is preferable that it be so.

[0094] R 11 and R 12 They become one, -(CH2) m - and preferably m is 4 or 5 (where any one methylene group may be substituted with an oxygen atom).

[0095] R 13 R is a hydrogen atom or a methyl group, 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, an oxetane-3-yl group, a cyclopropylmethyl group, a cyclobutylmethyl group, or an oxetane-3-ylmethyl group, or R 13 and R 14 Preferably, together with the nitrogen atoms bonded to them, these rings form a pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, azetidine ring, 3,3-dimethylazetidine ring, 3,3-difluoroazetidine ring, 3-hydroxyazetidine ring, or 3-methoxyazetidine ring.

[0096] R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 It is preferable that this be the case.

[0097] R16 It is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0098] R v It is preferable that it be a hydrogen atom.

[0099] R w It is preferable that it be a hydrogen atom.

[0100] The above-mentioned tetrahydroquinoline derivatives (I) or their pharmacopositically acceptable salts include not only single stereoisomers but also mixtures of stereoisomers such as racemates and diastereomers (e.g., mixtures of enantiomers).

[0101] "Stereoisomers" are compounds that have the same chemical structure but differ in their arrangement in three-dimensional space. Examples include conformational isomers, rotational isomers, tautomers, enantiomers, or diastereomers.

[0102] The above tetrahydroquinoline derivative (I) may also be of the following general formulas (I-1) to (I-8).

[0103] [ka]

[0104] [In the formula, R 1x , R 1y , R 2 , R 3 , R 4 , R 5 , R v and R w This is synonymous with the definition above.

[0105] In the above tetrahydroquinoline derivative (I), the preferred R 1x , R 1y , R 2 ~R 16 , R v , R wFurthermore, any preferred mode of h, k, m, and n described above can be selected and combined. For example, the following combinations are possible, but are not limited to them.

[0106] For example, in the above tetrahydroquinoline derivative (I), R 1x This includes a phenyl group (where any one hydrogen atom of the phenyl group may be a fluorine atom, a chlorine atom, a C1-C3 alkyl group in which 1-3 of the hydrogen atoms may be substituted with a fluorine atom or 1 of the hydrogen atoms may be substituted with a hydroxyl group, a C1-C3 alkoxy group in which 1-3 of the hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, and -CONR 6 R 7 , -NHCOR 8 , an aminosulfonyl group, a C1-C3 alkylsulfonylamino group (may be substituted with an aminosulfonylamino group or a C1-C3 alkylsulfonyl group), a pyrazolyl group, a 1-oxoisoindolin-5-yl group, a 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl group, or a benzo[d][1,3]dioxol-5-yl group, R 1y It is a hydrogen atom, R 2 It is a hydrogen atom, R 3 This includes hydrogen atoms, fluorine atoms, chlorine atoms, C1-C3 alkyl groups in which any one hydrogen atom may be substituted with a hydroxyl group, methoxy groups, and -NR 9 R 10 -CH2NR 11 R 12 or -CH2CONR 13 R 14 And, R 4 is a hydrogen atom or a methoxy group, R 5 It is a hydrogen atom, R 6 and R 7 Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atom bonded to them. R 8 This is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R 9 R is a hydrogen atom, 10 is a hydrogen atom, -COR 15 Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 They become one, -(CH2) n -and, n is either 4 or 5. R 11 and R 12 They become one, -(CH2) m -and, m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R 13 R is a hydrogen atom or a methyl group, 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, an oxetane-3-yl group, a cyclopropylmethyl group, a cyclobutylmethyl group, or an oxetane-3-ylmethyl group, or R 13 and R 14 These may form a pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, azetidine ring, 3,3-dimethylazetidine ring, 3,3-difluoroazetidine ring, 3-hydroxyazetidine ring, or 3-methoxyazetidine ring together with the nitrogen atom bonded to them. R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 And, R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R v It is a hydrogen atom, R wIt is preferably a hydrogen atom (except for 2-phenyl-1,2,3,4-tetrahydroquinoline).

[0107] In the above-mentioned tetrahydroquinoline derivative (I), one embodiment is, for example, a tetrahydroquinoline derivative represented by the following general formula (II-a) or a pharmaceutically acceptable salt thereof.

[0108] [ka]

[0109] [In the formula, A is a hydrogen atom or -CONH2, and R 9 and R 10 These are, independently, hydrogen atoms and -COR 15 Or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 They become one - (CH2) n - where n is an integer from 3 to 6, R 15 This refers to an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 And R 16 This is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0110] In the tetrahydroquinoline derivative represented by the above general formula (II-a) (hereinafter also referred to as tetrahydroquinoline derivative (II-a)), R 9 R is a hydrogen atom, 10 ha-COR 15 And R 15 It is preferably an alkoxy group having 1 to 5 carbon atoms, A is a hydrogen atom, and R 9 R is a hydrogen atom, 10 ha-COR 15 And R 15 It is more preferably an alkoxy group having 1 to 5 carbon atoms, A is a hydrogen atom, and R 9 R is a hydrogen atom, 10 ha-COR 15 And R 15It is even more preferable that it be a tert-butoxy group.

[0111] For pharmacologically acceptable salts of the above-mentioned tetrahydroquinoline derivative (II-a), the description of pharmacologically acceptable salts of tetrahydroquinoline derivative (I), as described later, can be applied.

[0112] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacoagulably acceptable salt thereof can be used as a pharmaceutical product containing the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacoagulably acceptable salt thereof as an active ingredient, and more preferably as a pharmaceutical product for treating or preventing diseases, disorders, or syndromes related to ferroptosis inhibition.

[0113] Diseases, disorders, or syndromes related to the above-mentioned ferroptosis inhibition will be discussed later.

[0114] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacopositably acceptable salt thereof can be used as a ferroptosis inhibitor containing the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacopositably acceptable salt thereof as an active ingredient.

[0115] The ferroptosis inhibitors mentioned above will be discussed later.

[0116] In the above-mentioned tetrahydroquinoline derivative (I), one embodiment is, for example, a tetrahydroquinoline derivative represented by the following general formula (II-b) or a pharmaceutically acceptable salt thereof.

[0117] [ka]

[0118] [In the formula, R 1yR is a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group. 3 is a hydrogen atom or a halogen atom, and R 4 This is a hydrogen atom or a halogen atom (except for 3-phenyl-1,2,3,4-tetrahydroquinoline).

[0119] In the tetrahydroquinoline derivative represented by the above general formula (II-b) (hereinafter also referred to as tetrahydroquinoline derivative (II-b)), R 1y R is a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl group. 3 is a hydrogen atom, a fluorine atom, or a chlorine atom, and R 4 It is preferably a hydrogen atom, a fluorine atom, or a chlorine atom, R 1y R is a 4-aminocarbonylphenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl group. 3 R is a hydrogen atom, 4 It is more preferable that it be a hydrogen atom.

[0120] For pharmacologically acceptable salts of the above-mentioned tetrahydroquinoline derivative (II-b), the description of pharmacologically acceptable salts of tetrahydroquinoline derivative (I), as described later, can be applied.

[0121] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacoagulably acceptable salt thereof can be used as a pharmaceutical product containing the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacoagulably acceptable salt thereof as an active ingredient, and more preferably as a pharmaceutical product for treating or preventing diseases, disorders, or syndromes related to ferroptosis inhibition.

[0122] Diseases, disorders, or syndromes related to the above-mentioned ferroptosis inhibition will be discussed later.

[0123] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacopositably acceptable salt thereof can be used as a ferroptosis inhibitor containing the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacopositably acceptable salt thereof as an active ingredient.

[0124] The ferroptosis inhibitors mentioned above will be discussed later.

[0125] Specific examples of preferred compounds of the above-mentioned tetrahydroquinoline derivative (I) are shown in Tables 1-1 to 1-7, but the present invention is not limited to these.

[0126] [Table 1-1]

[0127] [Table 1-2]

[0128] [Table 1-3]

[0129] [Table 1-4]

[0130] [Table 1-5]

[0131] [Table 1-6]

[0132] [Table 1-7]

[0133] The compounds listed in Tables 1-1 to 1-7 include their stereoisomers, solvates thereof, and pharmacokinetically acceptable salts thereof, as well as mixtures thereof.

[0134] Furthermore, the present invention includes a prodrug of the above-mentioned tetrahydroquinoline derivative (I). The above-mentioned prodrug of the tetrahydroquinoline derivative (I) is a compound that is converted to the above-mentioned tetrahydroquinoline derivative (I) enzymatically or chemically in vivo. The active component of the above-mentioned prodrug of the tetrahydroquinoline derivative (I) is the above-mentioned tetrahydroquinoline derivative (I), but the above-mentioned prodrug of the tetrahydroquinoline derivative (I) itself may also be active.

[0135] The groups that form the prodrug of the above-mentioned tetrahydroquinoline derivative (I) include those described in the publicly available literature (for example, "Pharmaceutical Development," Hirokawa Shoten, 1990, Vol. 7, pp. 163–198 and Progress in Medicine, Vol. 5, 1985, pp. 2157–2161).

[0136] Examples of "pharmacologically acceptable salts" of the above-mentioned tetrahydroquinoline derivative (I) include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, or phosphate, or organic salts such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate, or cinnamate.

[0137] The above-mentioned tetrahydroquinoline derivative (I) may be crystalline, and is encompassed whether it is a single crystalline form or a mixture of crystalline forms.

[0138] The tetrahydroquinoline derivative (I) described above may be a pharmaceutically acceptable cocrystal or cocrystalline salt. Here, a cocrystal or cocrystalline salt means a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, or stability). Cocrystals or cocrystalline salts can be produced according to known cocrystallization methods.

[0139] The tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof may be in an anhydrous form or may form a solvate such as a hydrate.

[0140] The above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof can be converted into solvates such as hydrates by known methods. Known methods include, for example, treating the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof with water, other solvents (e.g., alcoholic solvents such as methanol, ethanol, or n-propanol, N,N-dimethylformamide (hereinafter DMF), dimethyl sulfoxide (hereinafter DMSO)), or mixed solvents thereof.

[0141] The above tetrahydroquinoline derivative (I) may be labeled with one or more isotopes, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 15 O, 17 O, 18 O and / or 125 I is one example.

[0142] The above-mentioned tetrahydroquinoline derivative (I) can be produced by appropriate methods based on its characteristics derived from its basic skeleton and the types of substituents. The starting materials and reagents used in the production of these compounds can generally be purchased or produced by known methods.

[0143] The above-mentioned tetrahydroquinoline derivative (I), as well as the intermediates and starting materials used in its production, can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization, or chromatography.

[0144] If the above-mentioned tetrahydroquinoline derivative (I) contains optical isomers or stereoisomers, each isomer can be obtained as a single compound by known methods or similar methods. Known methods include, for example, crystallization, enzymatic resolution, or chiral chromatography.

[0145] The following is an example of a general method for producing the above-mentioned tetrahydroquinoline derivative (I). Note that the compounds in the following scheme include cases where a salt is formed, and such a salt is, for example, similar to the salt used for the above-mentioned tetrahydroquinoline derivative (I). The production method of the present invention is not limited to the examples shown below.

[0146] Manufacturing method 1 In the above tetrahydroquinoline derivative (I), R 1y , R v and R w All of them are hydrogen atoms, R 3 However, tetrahydroquinoline derivatives (Ia) which are a hydrogen atom, a halogen atom, a C1-C3 alkyl group in which 1-3 arbitrary hydrogen atoms may each be independently substituted with a hydroxyl group or a fluorine atom, a hydroxyl group, a C1-C3 alkoxy group or methoxycarbonyl group in which 1-3 arbitrary hydrogen atoms may each be substituted with a fluorine atom, can be obtained, for example, by the method described in Scheme 1.

[0147] [ka]

[0148] [In the formula, X represents a halogen atom, R 3a This represents a hydrogen atom, a halogen atom, a C1-C3 alkyl group in which 1-3 arbitrary hydrogen atoms may each be independently substituted with a hydroxyl group or a fluorine atom, a hydroxyl group, a C1-C3 alkoxy group in which 1-3 arbitrary hydrogen atoms may each be substituted with a fluorine atom, or a methoxycarbonyl group, and each symbol in the formula has the same meaning as the definition above.

[0149] (Process 1-1) The quinoline derivative (IX) can be obtained by a coupling reaction between the 2-haloquinoline derivative (III) and the boronic acid derivative (IV) in the presence of a metal catalyst and a base.

[0150] The amount of boronic acid derivative (IV) used in the coupling reaction is preferably 0.5 to 10 equivalents, and more preferably 0.8 to 4 equivalents, relative to the 2-haloquinoline derivative (III).

[0151] Examples of metal catalysts used in the coupling reaction include 1,1'-bis(diphenylphosphin)ferrocenedichloropalladium(II)dichloromethane adduct, palladium(II) chloride, palladium(II) acetate, bis(dibenzylideneacetone)palladium(O), tetrakistriphenylphosphinepalladium(O), or dichlorobistriphenylphosphinepalladium(O), but tetrakistriphenylphosphinepalladium(O) is preferred.

[0152] The amount of metal catalyst used in the coupling reaction is preferably 0.01 to 5 equivalents, and more preferably 0.025 to 1 equivalent, relative to the 2-haloquinoline derivative (III).

[0153] The coupling reaction may also involve the use of ligands. Examples of ligands include triphenylphosphine, tert-butylphosphine, or 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl.

[0154] Examples of bases used in the coupling reaction include organic bases such as triethylamine or N,N-diisopropylethylamine, inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, or mixtures thereof, but inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate are preferred.

[0155] The amount of base used in the coupling reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 4 equivalents, relative to the 2-haloquinoline derivative (III).

[0156] The reaction solvent used in the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether-based solvents such as tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane, or 1,2-dimethoxyethane (hereinafter referred to as DME), nitrile-based solvents such as acetonitrile or propionitrile, aromatic hydrocarbon-based solvents such as benzene or toluene, aprotic polar solvents such as DMF, N,N-dimethylacetamide (hereinafter referred to as DMA), or DMSO, water, or mixed solvents thereof. However, ether-based solvents such as THF, 1,4-dioxane, or DME, aprotic polar solvents such as DMF, DMA, or DMSO, or water and mixed solvents thereof are preferred.

[0157] The reaction temperature for the coupling reaction is preferably 0 to 200°C, and more preferably 50 to 150°C.

[0158] The reaction time for the coupling reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 30 hours is preferred.

[0159] The 2-haloquinoline derivative (III) and boronic acid derivative (IV) used in the coupling reaction can be purchased or produced by known or similar methods.

[0160] (Step 1-2) The quinoline derivative (IX) can be obtained by a cycloaddition reaction between a 2-aminobenzyl alcohol derivative (V) and a ketone derivative (VI) in the presence of a base. For example, this can be carried out according to the method described in (Tetrahedron Letters, 2008, pp. 6893-6895) or a similar method.

[0161] The amount of ketone derivative (VI) used in the cycloaddition reaction is preferably 0.5 to 10 equivalents, and more preferably 0.8 to 5 equivalents, relative to the 2-aminobenzyl alcohol derivative (V).

[0162] Examples of bases used in the cycloaddition reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, or cesium hydroxide; metal alkoxides such as sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; metal hydride compounds such as sodium hydride, potassium hydride, or calcium hydride; or mixtures thereof. However, metal alkoxides such as sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide are preferred.

[0163] The amount of base used in the cycloaddition reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the 2-aminobenzyl alcohol derivative (V).

[0164] The reaction solvent used in the cycloaddition reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether solvents such as THF, 1,4-dioxane, or DME; aromatic hydrocarbon solvents such as benzene or toluene; aprotic polar solvents such as DMF, DMA, or DMSO; or mixed solvents thereof. However, ether solvents such as THF, 1,4-dioxane, or DME are preferred.

[0165] The reaction temperature for the cycloaddition reaction is preferably 0 to 200°C, and more preferably 50 to 150°C.

[0166] The reaction time for the cycloaddition reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 24 hours is preferred.

[0167] The 2-aminobenzyl alcohol derivative (V) and ketone derivative (VI) used in the cycloaddition reaction can be purchased or produced by known or similar methods.

[0168] (Step 1-3) Quinoline derivative (IX) can be obtained by an oxidative cyclization reaction of aniline derivative (VII) with allyl alcohol derivative (VIII-a) or α,β unsaturated aldehyde derivative (VIII-b) under an oxygen atmosphere and in the presence of a metal catalyst. For example, this can be carried out according to the method described in (RSC Advances, 2017, pp. 36242-36245) or a similar method.

[0169] The amount of allyl alcohol derivative (VIII-a) or α,β-unsaturated aldehyde derivative (VIII-b) used in the oxidative cyclization reaction is preferably 0.5 to 10 equivalents, and more preferably 0.8 to 2 equivalents, relative to the aniline derivative (VII).

[0170] Examples of metal catalysts used in oxidative cyclization reactions include palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) chloride, and dichlorobis(acetonitrile)palladium(II), but palladium(II) acetate is preferred.

[0171] The amount of metal catalyst used in the oxidative cyclization reaction is preferably 0.01 to 5 equivalents, and more preferably 0.025 to 1 equivalent, relative to the aniline derivative (VII).

[0172] The oxygen pressure used in the oxidative cyclization reaction is preferably about 1 to about 20 atmospheres, and more preferably about 1 to about 5 atmospheres.

[0173] The reaction solvent used in the oxidative cyclization reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether-based solvents such as THF, 1,4-dioxane, or DME; aromatic hydrocarbon-based solvents such as benzene or toluene; aprotic polar solvents such as DMF, DMA, or DMSO; or mixed solvents thereof. Aprotic polar solvents such as DMF, DMA, or DMSO are preferred.

[0174] The reaction temperature for the oxidative cyclization reaction is preferably 0 to 300°C, and more preferably 70 to 200°C.

[0175] The reaction time for the oxidative cyclization reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 24 hours is preferred.

[0176] The aniline derivative (VII), allyl alcohol derivative (VIII-a), and α,β unsaturated aldehyde derivative (VIII-b) used in the oxidative cyclization reaction can be purchased or produced by known or similar methods.

[0177] (Step 1-4) Tetrahydroquinoline derivative (Ia) can be obtained by hydrogenation of quinoline derivative (IX) in a hydrogen atmosphere and in the presence of a metal catalyst. Alternatively, it can be obtained by hydrogen transfer reduction reaction between 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative and quinoline derivative (IX).

[0178] Examples of metal catalysts used in the hydrogenation reaction include palladium compounds such as palladium-carbon, palladium(II) hydroxide-carbon, or palladium(II) oxide; nickel compounds such as nickel developing catalysts; platinum compounds such as platinum(IV) oxide or platinum-carbon; and rhodium compounds such as rhodium-carbon, but platinum(IV) oxide is preferred.

[0179] The amount of metal catalyst used in the hydrogenation reaction is preferably 0.001 to 1 equivalent, and more preferably 0.01 to 0.5 equivalents, relative to the quinoline derivative (IX).

[0180] The hydrogen pressure used in the hydrogenation reaction is preferably about 1 to 30 atmospheres, and more preferably about 1 to 10 atmospheres.

[0181] The reaction solvent used in the hydrogenation reaction can be appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include alcoholic solvents such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol; aromatic hydrocarbon solvents such as toluene or xylene; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; ether-based solvents such as diethyl ether, THF, DME, or 1,4-dioxane; ester-based solvents such as ethyl acetate or propyl acetate; aprotic polar solvents such as DMF, DMA, or DMSO; carboxylic acid-based solvents such as formic acid or acetic acid; water; or mixed solvents thereof. However, a mixed solvent of an alcoholic solvent such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol and a carboxylic acid-based solvent such as formic acid or acetic acid is preferred.

[0182] The reaction temperature for the hydrogenation reaction is preferably 0 to 200°C, and more preferably 10 to 100°C.

[0183] The reaction time for the hydrogenation reaction is appropriately selected depending on conditions such as the reaction temperature, but 0.5 to 40 hours is preferred.

[0184] Examples of 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivatives used in the hydrogen transfer reduction reaction include dimethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, and didodecyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, but diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid is preferred.

[0185] The amount of 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid derivative used in the hydrogen transfer reduction reaction is preferably 1 to 10 equivalents, and more preferably 1.7 to 3 equivalents, relative to the quinoline derivative (IX).

[0186] The reaction solvent used in the hydrogen transfer reduction reaction can be appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include alcoholic solvents such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol; aromatic hydrocarbon solvents such as toluene or xylene; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; ether-based solvents such as diethyl ether, THF, DME, or 1,4-dioxane; ester-based solvents such as ethyl acetate or propyl acetate; aprotic polar solvents such as DMF, DMA, or DMSO; or mixed solvents thereof. However, chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or ether-based solvents such as diethyl ether, THF, DME, or 1,4-dioxane are preferred.

[0187] The reaction temperature for the hydrogen transfer reduction reaction is preferably 0 to 100°C, and more preferably 10 to 50°C.

[0188] The reaction time for the hydrogen transfer reduction reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 24 hours is preferred.

[0189] Manufacturing method 2 In the above tetrahydroquinoline derivative (I), R 1y , R v and R w All of them are hydrogen atoms, R 3 ga-NR 9 R 10 And R 9 and R 10 (CH2) n -The tetrahydroquinoline derivative (Ib) can be obtained, for example, by the method described in Scheme 2.

[0190] [ka]

[0191] [In the formula, each symbol has the same meaning as the definition above.]

[0192] (Process 2-1) The aminoquinoline derivative (XI) can be obtained by a coupling reaction between a 6-haloquinoline derivative (IX-a) and a secondary amine derivative (X) in the presence of a metal catalyst and a base.

[0193] The amount of secondary amine derivative (X) used in the coupling reaction is preferably 0.5 to 20 equivalents, and more preferably 0.8 to 10 equivalents, relative to the 6-haloquinoline derivative (IX-a).

[0194] Examples of metal catalysts used in the coupling reaction include 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II)dichloromethane adduct, palladium(II) chloride, palladium(II) acetate, bis(dibenzylideneacetone)palladium(O), tris(dibenzylideneacetone)dipalladium(O), tetrakistriphenylphosphinepalladium(O), or dichlorobistriphenylphosphinepalladium(O), but palladium(II) acetate is preferred.

[0195] The amount of metal catalyst used in the coupling reaction is preferably 0.001 to 5 equivalents, and more preferably 0.02 to 0.5 equivalents, relative to the 6-haloquinoline derivative (IX-a).

[0196] The coupling reaction may also involve the use of ligands. Examples of ligands include triphenylphosphine, tert-butylphosphine, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl, or 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

[0197] When a ligand is used in the coupling reaction, the amount of ligand is preferably 0.001 to 5 equivalents, and more preferably 0.02 to 1 equivalent, relative to the 6-haloquinoline derivative (IX-a).

[0198] Examples of bases used in the coupling reaction include organic bases such as triethylamine or N,N-diisopropylethylamine, inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, or mixtures thereof, but inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate are preferred.

[0199] The amount of base used in the coupling reaction is preferably 0.8 to 10 equivalents, and more preferably 1 to 5 equivalents, relative to the 6-haloquinoline derivative (IX-a).

[0200] The reaction solvent used in the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include alcoholic solvents such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol; etheric solvents such as THF, 1,4-dioxane, or DME; aromatic hydrocarbon solvents such as benzene or toluene; nitrile solvents such as acetonitrile or propionitrile; aprotic polar solvents such as DMF, DMA, or DMSO; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; or mixed solvents thereof. However, etheric solvents such as THF, 1,4-dioxane, or DME are preferred.

[0201] The reaction temperature for the coupling reaction is preferably 0 to 200°C, and more preferably 50 to 150°C.

[0202] The reaction time for the coupling reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 30 hours is preferred.

[0203] The 6-haloquinoline derivative (IX-a) used in the coupling reaction can be purchased or manufactured by the methods described in steps 1-1 to 1-3, known methods, or similar methods.

[0204] The secondary amine derivative (X) used in the coupling reaction can be purchased or produced by known or similar methods.

[0205] (Step 2-2) Tetrahydroquinoline derivative (Ib) can be obtained by hydrogenation or hydrogen transfer reduction of aminoquinoline derivative (XI). The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in steps 1-4.

[0206] Manufacturing method 3 In the above tetrahydroquinoline derivative (I), R 1y , R v and R w All of them are hydrogen atoms, R 3 NR 9 R 10 And R 9 is a hydrogen atom, R 10 ga-COR 15 And R 15 A tetrahydroquinoline derivative (Ic) in which is an alkoxy group having 1 to 5 carbon atoms can be obtained, for example, by the method described in Scheme 3.

[0207] [ka]

[0208] [In the formula, Y represents an alkyl group having 1 to 5 carbon atoms, and the other symbols have the same meaning as defined above.]

[0209] (Step 3-1) The quinoline-6-carboxylic acid derivative (XII) can be obtained by the hydrolysis reaction of the quinoline-6-carboxylic acid ester derivative (IX-b) in the presence of a base.

[0210] Examples of bases used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, or sodium tert-butoxide, but potassium hydroxide or sodium hydroxide are preferred.

[0211] The amount of base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, and more preferably 0.8 to 30 equivalents, relative to the quinoline-6-carboxylic acid ester derivative (IX-b).

[0212] The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether-based solvents such as THF, 1,4-dioxane, or DME; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aromatic hydrocarbon-based solvents such as benzene or toluene; aprotic polar solvents such as DMF, DMA, or DMSO; ketone-based solvents such as acetone or methyl ethyl ketone; alcohol-based solvents such as methanol, ethanol, or 2-propanol; water; or a mixture thereof. A mixture of an alcohol-based solvent such as methanol, ethanol, or 2-propanol and water is preferred.

[0213] The reaction temperature for the hydrolysis reaction is preferably -50°C to 150°C, and more preferably -20°C to 100°C.

[0214] The reaction time for the hydrolysis reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 30 hours is preferred.

[0215] The quinoline-6-carboxylic acid ester derivative (IX-b) used in the hydrolysis reaction can be purchased or produced by the methods described in steps 1-1 to 1-3, known methods, or similar methods.

[0216] (Step 3-2) The quinoline-6-carbamate ester derivative (XIV) can be obtained by the alcohol decomposition reaction of an isocyanate derivative produced by the rearrangement reaction of an acid azide generated by using diphenyl phosphate azide with the quinoline-6-carboxylic acid derivative (XII).

[0217] The amount of diphenyl phosphate azide used in the rearrangement reaction is preferably 1 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the quinoline-6-carboxylic acid derivative (XII).

[0218] Examples of bases used in the rearrangement reaction include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide, or organic bases such as triethylamine or N,N-diisopropylethylamine, but organic bases such as triethylamine or N,N-diisopropylethylamine are preferred.

[0219] The amount of base used in the rearrangement reaction is preferably 1 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the quinoline-6-carboxylic acid derivative (XII).

[0220] The reaction solvent used in the rearrangement reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether solvents such as THF, 1,4-dioxane, or DME; ester solvents such as ethyl acetate or propyl acetate; chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aromatic hydrocarbon solvents such as benzene or toluene; nitrile solvents such as acetonitrile or propionitrile; aprotic polar solvents such as DMF, DMA, or DMSO; or mixtures thereof.

[0221] Examples of alcohols (XIII) used in the alcohol decomposition reaction include methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol.

[0222] The amount of alcohol (XIII) used in the alcohol decomposition reaction may be 1 to 20 equivalents relative to the quinoline-6-carboxylic acid derivative (XII), or it may be used as a reaction solvent instead of the reaction solvent used in the rearrangement reaction.

[0223] The reaction temperature for the rearrangement reaction and the alcohol decomposition reaction is preferably 30 to 200°C, and more preferably 50 to 150°C.

[0224] The reaction time for the rearrangement reaction and the alcohol decomposition reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 30 hours is preferred.

[0225] Furthermore, quinoline-6-carbamate ester derivative (XIV) can also be obtained by using an acid azide produced by converting the carboxyl group of quinoline-6-carboxylic acid derivative (XII) to a reactive functional group and reacting it with a metal azide (e.g., sodium azide).

[0226] Examples of the reactive functional groups mentioned above include acid chlorides, mixed acid anhydrides with chlorocarbonates (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate), symmetric acid anhydrides, and activated amides with imidazoles.

[0227] (Step 3-3) Tetrahydroquinoline derivatives (Ic) can be obtained by hydrogenation or hydrogen transfer reduction of quinoline-6-carbamate derivatives (XIV). The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those for steps 1-4.

[0228] Manufacturing method 4 In the above tetrahydroquinoline derivative (I), R 1y , R v and R w All of them are hydrogen atoms, R 3 ga-NR 9 R 10 And R 9 is a hydrogen atom, R 10 ga-COR 15 Or an alkylsulfonyl group having 1 to 3 carbon atoms, R 15 This refers to alkyl groups with 1 to 5 carbon atoms or -NHR 16 And R 16 Tetrahydroquinoline derivatives (Id) to (If), which consist of a hydrogen atom and an alkyl group having 1 to 5 carbon atoms, can be obtained, for example, by the method described in Scheme 4.

[0229] [ka]

[0230] [In the formula, L independently represents a leaving group, Z represents an alkyl group having 1 to 3 carbon atoms, and all other symbols have the same meaning as defined above.]

[0231] Examples of leaving groups represented by L include halogen atoms such as fluorine, chlorine, bromine, or iodine; C1-C12 alkylthio groups such as methylthio, ethylthio, or dodecylthio; aryloxy groups such as phenoxy; alkylsulfonyloxy groups in which hydrogen atoms may be substituted with halogen atoms, such as methanesulfonyloxy, ethanesulfonyloxy, or trifluoromethanesulfonyloxy; alkylsulfonylamino groups such as trifluoromethanesulfonylamino; or azolyl groups such as imidazole-1-yl or pyrazole-1-yl.

[0232] (Step 4-1) Diphenylmethaneimine derivative (XV) can be obtained by a coupling reaction of 6-haloquinoline derivative (IX-a) and diphenylmethaneimine in the presence of a metal catalyst and a base. The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in step 2-1.

[0233] The 6-haloquinoline derivative (IX-a) used in the coupling reaction can be purchased or manufactured by the methods described in steps 1-1 to 1-3, known methods, or similar methods.

[0234] (Step 4-2) The aminoquinoline derivative (XVI) can be obtained by the deprotection reaction of the diphenylmethaneimine derivative (XV).

[0235] Examples of acids used in the deprotection reaction include hydrochloric acid, 10% by weight hydrogen chloride / methanol solution, 4 mol / L hydrogen chloride / ethyl acetate solution, trifluoroacetic acid, or hydrofluoric acid, but hydrochloric acid is preferred.

[0236] The amount of acid used in the deprotection reaction is preferably 0.5 to 100 equivalents, and more preferably 1 to 10 equivalents, relative to the diphenylmethaneimine derivative (XV).

[0237] The reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether-based solvents such as diethyl ether, THF, DME, or 1,4-dioxane; ester-based solvents such as ethyl acetate or propyl acetate; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; alcohol-based solvents such as methanol or ethanol; or mixed solvents thereof. However, ester-based solvents such as ethyl acetate or propyl acetate, or chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane are preferred.

[0238] The reaction temperature for the deprotection reaction is preferably 0 to 200°C, and more preferably 0 to 100°C.

[0239] The reaction time for the deprotection reaction varies depending on the reaction conditions, but 1 to 48 hours is preferred.

[0240] (Step 4-3) Amidoquinoline derivatives (XVIII) can be obtained by an acylation reaction between aminoquinoline derivative (XVI) and an acylating agent (XVII).

[0241] The amount of acylating agent (XVII) used in the acylation reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).

[0242] The acylation reaction may optionally use a base. Examples of bases that can be used include organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; alkali metal carbonates such as sodium carbonate or potassium carbonate; or mixtures thereof. However, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide are preferred.

[0243] The reaction solvent used in the acylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include nitrile solvents such as acetonitrile or propionitrile, aprotic polar solvents such as DMF, DMA, or DMSO, ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, ketone solvents such as acetone or methyl ethyl ketone, water, or a mixture thereof. A mixture of an ether solvent such as diethyl ether, THF, DME, or 1,4-dioxane and water is preferred.

[0244] The reaction temperature for the acylation reaction is preferably -78°C to 100°C, and more preferably -20°C to 50°C.

[0245] The reaction time for the acylation reaction varies depending on the reaction conditions, but 1 to 30 hours is preferable.

[0246] The acylating agent (XVII) used in the acylation reaction can be purchased or manufactured by known or similar methods.

[0247] (Step 4-4) Tetrahydroquinoline derivatives (Id) can be obtained by hydrogenation or hydrogen transfer reduction of amidequinoline derivatives (XVIII). The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those for steps 1-4.

[0248] (Step 4-5) Ureaquinoline derivatives (XX) can be obtained by a ureation reaction between an aminoquinoline derivative (XVI) and a urea-forming agent (XIX).

[0249] The amount of ureating agent (XIX) used in the ureation reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).

[0250] The ureation reaction may optionally use a base. Examples of bases that can be used include organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; alkali metal carbonates such as sodium carbonate or potassium carbonate; or mixtures thereof. However, organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine are preferred.

[0251] The reaction solvent used in the urea reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include nitrile solvents such as acetonitrile or propionitrile, aprotic polar solvents such as DMF, DMA, or DMSO, ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, ketone solvents such as acetone or methyl ethyl ketone, water, or mixtures thereof, but ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane are preferred.

[0252] The reaction temperature for the urea formation reaction is preferably -78°C to 100°C, and more preferably -20°C to 50°C.

[0253] The reaction time for the urea conversion reaction varies depending on the reaction conditions, but 1 to 30 hours is preferable.

[0254] The ureating agent (XIX) used in the ureation reaction can be purchased or manufactured by known or similar methods.

[0255] (Step 4-6) Tetrahydroquinoline derivatives (Ie) can be obtained by hydrogenation or hydrogen transfer reduction of ureaquinoline derivatives (XX). The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in steps 1-4.

[0256] (Step 4-7) Sulfonylamide quinoline derivatives (XXII) can be obtained by a sulfonylation reaction between an aminoquinoline derivative (XVI) and a sulfonylating agent (XXI).

[0257] The amount of sulfonylating agent (XXI) used in the sulfonylation reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).

[0258] The sulfonylation reaction may optionally use a base. Examples of bases that can be used include organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; alkali metal carbonates such as sodium carbonate or potassium carbonate; or mixtures thereof. However, organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine are preferred.

[0259] The reaction solvent used in the sulfonylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include nitrile solvents such as acetonitrile or propionitrile, aprotic polar solvents such as DMF, DMA, or DMSO, ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, ketone solvents such as acetone or methyl ethyl ketone, water, or mixtures thereof, but ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane are preferred.

[0260] The reaction temperature for the sulfonylation reaction is preferably -78°C to 100°C, and more preferably -20°C to 50°C.

[0261] The reaction time for the sulfonylation reaction varies depending on the reaction conditions, but 1 to 30 hours is preferred.

[0262] The sulfonylation agent (XXI) used in the sulfonylation reaction can be purchased or manufactured by known or similar methods.

[0263] (Step 4-8) Tetrahydroquinoline derivatives (If) can be obtained by hydrogenation or hydrogen transfer reduction of sulfonylamide quinoline derivatives (XXII). The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in steps 1-4.

[0264] Manufacturing method 5 In the above tetrahydroquinoline derivative (I), R 1y , R v and R w All of them are hydrogen atoms, R 3 -CH2NR 11 R 12 The tetrahydroquinoline derivative (Ig) can be obtained, for example, by the method described in Scheme 5.

[0265] [ka]

[0266] [In the formula, each symbol has the same meaning as the definition above.]

[0267] (Step 5-1) Methoxycarbonyltetrahydroquinoline derivative (XXIII) can be obtained by hydrogenation or hydrogen transfer reduction of quinoline-6-carboxylic acid ester derivative (IX-b). The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those for steps 1-4.

[0268] The quinoline-6-carboxylic acid ester derivative (IX-b) used in the hydrogenation reaction or hydrogen transfer reduction reaction can be purchased or produced by the methods described in steps 1-1 to 1-3, known methods, or similar methods.

[0269] (Step 5-2) Hydroxymethyltetrahydroquinoline derivative (XXIV) can be obtained by the reduction reaction of methoxycarbonyltetrahydroquinoline derivative (XXIII).

[0270] Examples of reducing agents used in the reduction reaction include aluminum-based reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride, and boron-based reducing agents such as sodium borohydride or lithium borohydride, but aluminum-based reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride are preferred.

[0271] The amount of reducing agent used in the reduction reaction is preferably 0.3 to 100 equivalents, and more preferably 0.5 to 20 equivalents, relative to the methoxycarbonyltetrahydroquinoline derivative (XXIII).

[0272] The reaction solvent used in the reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include alcoholic solvents such as methanol, ethanol, isopropyl alcohol, or tert-butyl alcohol; aprotic polar solvents such as DMF, DMA, or DMSO; etheric solvents such as diethyl ether, THF, DME, or 1,4-dioxane; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aromatic hydrocarbon solvents such as toluene or xylene; or mixed solvents thereof. However, etheric solvents such as diethyl ether, THF, DME, or 1,4-dioxane, or aromatic hydrocarbon solvents such as toluene or xylene are preferred.

[0273] The reaction temperature for the reduction reaction is preferably -100°C to 200°C, and more preferably -50°C to 50°C.

[0274] The reaction time for the reduction reaction varies depending on the reaction conditions, but 1 to 30 hours is preferable.

[0275] (Step 5-3) Tetrahydroquinoline derivatives (Ig) can be obtained by a substitution reaction between a hydroxymethyltetrahydroquinoline derivative (XXIV) and a secondary amine derivative (XXV) in the presence of a phosphine derivative and iodine.

[0276] The amount of secondary amine derivative (XXV) used in the substitution reaction is preferably 0.5 to 100 equivalents, and more preferably 1 to 20 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0277] Examples of phosphine derivatives used in the substitution reaction include triphenylphosphine, trimethylphosphine, or tri-n-butylphosphine, but triphenylphosphine is preferred.

[0278] The amount of phosphine derivative used in the substitution reaction is preferably 0.5 to 20 equivalents, and more preferably 1 to 5 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0279] The amount of iodine used in the substitution reaction is preferably 0.5 to 20 equivalents, and more preferably 1 to 5 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0280] The reaction solvent used in the substitution reaction is not particularly limited as long as it does not inhibit the reaction. Examples include aprotic polar solvents such as DMF, DMA, or DMSO; ketone solvents such as acetone or methyl ethyl ketone; ester solvents such as ethyl acetate or propyl acetate; ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane; chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aromatic hydrocarbon solvents such as toluene or xylene; or mixed solvents thereof. However, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane are preferred.

[0281] The reaction temperature for the substitution reaction is preferably 0 to 150°C, and more preferably 10 to 70°C.

[0282] The reaction time for substitution reactions varies depending on the reaction conditions, but 1 to 24 hours is preferable.

[0283] Manufacturing method 6 In the above tetrahydroquinoline derivative (I), R 1y , R v and R w All of them are hydrogen atoms, R 3 -CH2CONR 13 R 14 The tetrahydroquinoline derivatives (Ih) and (Ii) can be obtained, for example, by the method described in Scheme 6.

[0284] [ka]

[0285] [In the formula, each symbol has the same meaning as the definition above.]

[0286] (Step 6-1) Nitrile derivatives (XXVI) can be obtained by the Mitsunobu reaction of hydroxymethyltetrahydroquinoline derivative (XXIV) and acetone cyanohydrin using an azodicarboxylic acid ester derivative in the presence of a phosphine derivative.

[0287] Examples of azodicarboxylic acid ester derivatives used in the Mitsunobu reaction include diethyl azodicarboxylic acid, diisopropyl azodicarboxylic acid, and 1,1'-(azodicarbonyl)dipiperidine, but 1,1'-(azodicarbonyl)dipiperidine is preferred.

[0288] The amount of azodicarboxylic acid ester derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, and more preferably 1 to 10 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0289] Examples of phosphine derivatives used in the Mitsunobu reaction include triphenylphosphine, trimethylphosphine, or tri-n-butylphosphine, with tri-n-butylphosphine being preferred.

[0290] The amount of phosphine derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, and more preferably 1 to 10 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0291] The amount of acetone cyanohydrin used in the Mitsunobu reaction is preferably 0.5 to 50 equivalents, and more preferably 1 to 20 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0292] The reaction solvent used in the Mitsunobu reaction is not particularly limited as long as it does not inhibit the reaction. Examples include aprotic polar solvents such as DMF, DMA, or DMSO; ketone solvents such as acetone or methyl ethyl ketone; ester solvents such as ethyl acetate or propyl acetate; ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane; chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aromatic hydrocarbon solvents such as toluene or xylene; or mixed solvents thereof. However, ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane are preferred.

[0293] The reaction temperature for the Mitsunobu reaction is preferably -20°C to 200°C, and more preferably -10°C to 100°C.

[0294] The reaction time for the Mitsunobu reaction varies depending on the reaction conditions, but 1 to 12 hours is preferable.

[0295] (Step 6-2) Tetrahydroquinoline derivatives (Ih) can be obtained by hydrolysis reaction with nitrile derivatives (XXVI) in the presence of hydrogen peroxide and a base.

[0296] The amount of hydrogen peroxide solution used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, and more preferably 1 to 30 equivalents, relative to the nitrile derivative (XXVI).

[0297] Examples of bases used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, or sodium tert-butoxide, but potassium hydroxide or sodium hydroxide are preferred.

[0298] The amount of base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, and more preferably 0.8 to 20 equivalents, relative to the nitrile derivative (XXVI).

[0299] The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether-based solvents such as THF, 1,4-dioxane, or DME; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aromatic hydrocarbon-based solvents such as benzene or toluene; aprotic polar solvents such as DMF, DMA, or DMSO; ketone-based solvents such as acetone or methyl ethyl ketone; alcohol-based solvents such as methanol, ethanol, or 2-propanol; or mixed solvents thereof. However, a mixed solvent of an aprotic polar solvent such as DMF, DMA, or DMSO and an ether-based solvent such as THF, 1,4-dioxane, or DME is preferred.

[0300] The reaction temperature for the hydrolysis reaction is preferably -50°C to 150°C, and more preferably -20°C to 100°C.

[0301] The reaction time for the hydrolysis reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 30 hours is preferred.

[0302] (Step 6-3) The carboxylic acid derivative (XXVII) can be obtained by the hydrolysis reaction of the tetrahydroquinoline derivative (Ih) in the presence of a base.

[0303] Examples of bases used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, or sodium tert-butoxide, but potassium hydroxide or sodium hydroxide are preferred.

[0304] The amount of base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, and more preferably 0.8 to 30 equivalents, relative to the tetrahydroquinoline derivative (Ih).

[0305] The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether-based solvents such as THF, 1,4-dioxane, or DME; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aromatic hydrocarbon-based solvents such as benzene or toluene; aprotic polar solvents such as DMF, DMA, or DMSO; ketone-based solvents such as acetone or methyl ethyl ketone; alcohol-based solvents such as methanol, ethanol, or 2-propanol; water; or a mixture thereof. A mixture of an alcohol-based solvent such as methanol, ethanol, or 2-propanol and water is preferred.

[0306] The reaction temperature for the hydrolysis reaction is preferably 0 to 200°C, and more preferably 20 to 100°C.

[0307] The reaction time for the hydrolysis reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 30 hours is preferred.

[0308] (Step 6-4) Tetrahydroquinoline derivatives (Ii) can be obtained by a condensation reaction between a carboxylic acid derivative (XXVII) and an amine derivative (XXVIII) in the presence of a coupling agent.

[0309] The amount of amine derivative (XXVIII) used in the condensation reaction is preferably 0.1 to 10 equivalents, and more preferably 0.5 to 5 equivalents, relative to the carboxylic acid derivative (XXVII).

[0310] Examples of condensing agents used in the condensation reaction include N,N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride, N,N'-carbodimidazole, {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, but O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is preferred.

[0311] The amount of condensing agent used in the condensation reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 3 equivalents, relative to the carboxylic acid derivative (XXVII).

[0312] Examples of bases used in the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium bicarbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, alkyllithium compounds such as methyllithium or butyllithium, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but organic bases such as triethylamine or diisopropylethylamine are preferred.

[0313] The amount of base used in the condensation reaction is preferably 0.5 to 10 equivalents, and more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XXVII).

[0314] Furthermore, the amine derivative (XXVIII) may be used as the base in the condensation reaction. When the amine derivative (XXVIII) is used as the base in the condensation reaction, the amount of the amine derivative (XXVIII) is preferably 0.6 to 20 equivalents, and more preferably 1 to 10 equivalents, relative to the carboxylic acid derivative (XXVII).

[0315] The reaction solvent used in the condensation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. Examples include ether-based solvents such as THF, 1,4-dioxane, or DME; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; aprotic polar solvents such as DMF or DMSO; or nitrile-based solvents such as acetonitrile or propionitrile. However, chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or aprotic polar solvents such as DMF or DMSO are preferred.

[0316] The reaction temperature for the condensation reaction is preferably 0 to 200°C, and more preferably 20 to 100°C.

[0317] The reaction time for the condensation reaction is appropriately selected depending on conditions such as the reaction temperature, but 1 to 30 hours is preferred.

[0318] The amine derivative (XXVIII) used in the condensation reaction may be in its free form or as a salt such as a hydrochloride salt.

[0319] The amine derivative (XXVIII) used in the condensation reaction can be purchased or produced by known or similar methods.

[0320] Manufacturing method 7 In the above tetrahydroquinoline derivative (I), R 1y , R v and R w The optically active forms (I-j') and (I-j'') of the tetrahydroquinoline derivative, which are all hydrogen atoms, can be obtained, for example, by the method described in Scheme 7.

[0321] [ka]

[0322] [In the formula, each symbol has the same meaning as the definition above.]

[0323] (Step 7-1) The optically active derivatives (I-j') and (I-j'') of the tetrahydroquinoline derivative (I) can be obtained by an asymmetric hydrogen transfer reduction reaction between a 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid derivative and a quinoline derivative (XXIX) in the presence of an asymmetric phosphoric acid catalyst. For example, this can be carried out according to the method described in (Tetrahedron: Asymmetry, 2015, pp. 1174-1179) or a similar method.

[0324] The quinoline derivative (XXIX) used in the asymmetric hydrogen transfer reduction reaction can be purchased or manufactured by the methods described in steps 1-1 to 1-3, 2-1, 3-1, 3-2, 4-1 to 4-3, 4-5, and 4-7, known methods, or similar methods.

[0325] Examples of asymmetric phosphoric acid catalysts used in asymmetric hydrogen transfer reduction reactions include (S)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, (R)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, (S)-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (S)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (S)-3,3'-bis( Examples include 9-phenanthryl)-1,1'-binaphthalene-2,2'-diyl, hydrogen phosphate (R)-3,3'-bis(9-phenanthryl)-1,1'-binaphthalene-2,2'-diyl, hydrogen phosphate (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl, or hydrogen phosphate (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl, but hydrogen phosphate (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl and hydrogen phosphate (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl.

[0326] Manufacturing method 8 In the above tetrahydroquinoline derivative (I), R 1x , R v and R w A tetrahydroquinoline derivative (Ik), in which all atoms are hydrogen atoms, can be obtained, for example, by the method described in Scheme 8.

[0327] [ka]

[0328] [In the formula, X represents a halogen atom, and each symbol in the formula has the same meaning as defined above.]

[0329] (Step 8-1) The quinoline derivative (XXXII) can be obtained by a coupling reaction between a 3-haloquinoline derivative (XXX) and a boronic acid derivative (XXXI) in the presence of a metal catalyst and a base. The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in step 1-1.

[0330] The 3-haloquinoline derivative (XXX) and boronic acid derivative (XXXI) used in the coupling reaction can be purchased or manufactured by known or similar methods.

[0331] (Step 8-2) Tetrahydroquinoline derivative (Ik) can be obtained by hydrogenation or hydrogen transfer reduction of quinoline derivative (XXXII). The selection conditions for reagents, catalysts, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in steps 1-4.

[0332] Manufacturing method 9 In the above tetrahydroquinoline derivative (I), R 1x , R v and R w The optically active derivatives (I-k') and (I-k'') of the tetrahydroquinoline derivative (Ik), which consists entirely of hydrogen atoms, can be obtained, for example, by the method described in Scheme 9.

[0333] [ka]

[0334] [In the formula, each symbol has the same meaning as the definition above.]

[0335] (Step 9-1) The optically active derivatives (I-k') and (I-k'') of the tetrahydroquinoline derivative (Ik) can be obtained by HPLC preparative separation using a chiral column.

[0336] One embodiment of the present invention is a pharmaceutical product that can be used to treat or prevent diseases, disorders, or syndromes related to ferroptosis inhibition.

[0337] "Ferroptosis inhibition" means inhibiting ferroptosis (iron-dependent cell death). The ferroptosis inhibitor of the present invention can be used for diseases, disorders, or syndromes in which improvement of the pathological condition or remission of symptoms can be expected by inhibiting ferroptosis.

[0338] "Diseases, disorders, or syndromes associated with ferroptosis inhibition" refers to diseases, disorders, or syndromes in which improvement of the condition or remission of symptoms can be expected through the above-mentioned ferroptosis inhibition. Examples of diseases, disorders, or syndromes associated with ferroptosis inhibition include renal disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, Friedreich's ataxia, or multiple sclerosis, with multiple sclerosis being preferred.

[0339] Multiple sclerosis (MS) is a disease characterized by demyelination, the destruction of the myelin sheath covering nerve fibers in the brain, spinal cord, and optic nerves, with progressive impairment occurring through repeated relapses and remissions. The symptoms vary depending on the site of the lesion and include a variety of neurological symptoms such as visual impairment, paralysis of the limbs, sensory disturbances, and gait disturbances. Examples of multiple sclerosis include relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis.

[0340] Furthermore, the tetrahydroquinoline derivative (I) or its pharmaceutically acceptable salt or pharmaceutical product of the present invention can also be used as a ferroptosis inhibitor containing the tetrahydroquinoline derivative (I) or its pharmaceutically acceptable salt as an active ingredient. Here, as the ferroptosis inhibitor, the tetrahydroquinoline derivative (I) or its pharmaceutically acceptable salt or 2-phenyl-1,2,3,4-tetrahydroquinoline or its pharmaceutically acceptable salt can be used.

[0341] "Ferroptosis inhibitor" refers to a compound that inhibits ferroptosis, thereby improving cell viability, enhancing and maintaining cell function, or a composition containing such a compound as an active ingredient.

[0342] Incidentally, it has been reported that having radical scavenging activity is important for exhibiting ferroptosis inhibitory activity, as described in Non-Patent Document 10. Furthermore, Patent Document 1 and Non-Patent Document 11 disclose that tetrahydroquinoxaline derivatives have strong radical scavenging activity. On the other hand, Non-Patent Document 11 reports that tetrahydroquinoline derivatives have extremely weak radical scavenging activity. Nevertheless, since the tetrahydroquinoline derivative (I) of the present invention or a pharmacopoecitable salt thereof exhibits ferroptosis inhibitory activity, it can be used as a novel pharmaceutical for treating or preventing diseases, disorders, or syndromes related to ferroptosis inhibition.

[0343] The ferroptosis inhibitory effect of tetrahydroquinoline derivatives (I) or their pharmacologically acceptable salts can be evaluated using in vitro tests. For example, the inhibitory effect on cell death induced by treating ferroptosis-inducing agents such as Erastin, RSL3, FIN56, or butionine sulfoximine in ferroptosis-inducing agents such as human fibrosarcoma cells (HT-1080 cells), primary cultured cells, or iPS cells can be used as an indicator for evaluation.

[0344] The radical scavenging activity of a test compound can be evaluated using in vitro tests. For example, it can be evaluated using a method with the stable radical 1,1-Diphenyl-2-picrylhydrazyl (DPPH) (Antioxidants, 2019, Vol. 258).

[0345] The effectiveness of tetrahydroquinoline derivatives (I) or their pharmacologically acceptable salts in treating or preventing diseases, disorders, or syndromes associated with ferroptosis inhibition can be evaluated using disease models. Examples of disease models include the experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, Vol. 84, pp. 1225-1234; International Immunology, 1997, Vol. 9, pp. 1243-1251). The experimental autoimmune encephalomyelitis model is an animal model in which neurological disorders such as hind limb paralysis due to demyelination of the central nervous system are induced by immunizing experimental animals with myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein or partial peptides thereof. Due to the similarity of its symptoms and pathological findings to those of humans, this disease model is widely used in evaluating the efficacy of therapeutic or prophylactic agents for multiple sclerosis. The effectiveness of the treatment or prevention of multiple sclerosis can be evaluated using the experimental autoimmune encephalomyelitis model described above, for example, by a reduction in the neurological symptom score, which is a characteristic indicator of multiple sclerosis.

[0346] Tetrahydroquinoline derivatives (I) or their pharmacoagulably acceptable salts have ferroptosis inhibitory activity and can therefore be used as useful pharmaceuticals for mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, or humans) (particularly for the treatment or prevention of diseases, disorders, or syndromes associated with ferroptosis inhibition, such as multiple sclerosis).

[0347] When tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof is used clinically as a pharmaceutical, it can be administered orally, parenterally, or topically, either as is or in combination with a pharmacologically acceptable carrier. The pharmaceutical may, as necessary, contain additives such as excipients, binders, lubricants, disintegrants, sweeteners, stabilizers, flavoring agents, fragrances, colorants, fluidizers, preservatives, buffers, solubilizers, emulsifiers, surfactants, suspending agents, diluents, or isotonic agents. Examples of pharmacologically acceptable carriers include these additives. Furthermore, the pharmaceutical may be manufactured by conventional methods using these pharmacologically acceptable carriers as appropriate. Examples of the above-mentioned forms of administration include oral preparations such as tablets, pills, capsules, granules, powders, syrups, emulsions, or suspensions; parenteral preparations such as inhalants, injections, suppositories, or liquids; or ointments, creams, or patches for topical administration. It is also effective to combine the above-mentioned pharmaceuticals with a suitable base (for example, polymers of butyric acid, polymers of glycolic acid, copolymers of butyric acid and glycolic acid, mixtures of polymers of butyric acid and glycolic acid, or polyglycerol fatty acid esters) to create sustained-release formulations.

[0348] The preparation of the above-mentioned formulations containing the above-mentioned tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof can be carried out according to known manufacturing methods commonly used in the pharmaceutical field. For example, tablets can be prepared by including excipients, binders, disintegrants, lubricants, etc., pills and granules can be prepared by including excipients, binders, disintegrants, etc., capsules and powders can be prepared by including excipients, etc., syrups can be prepared by including sweeteners, etc., and emulsions and suspensions can be prepared by including surfactants, suspending agents, emulsifiers, etc.

[0349] Examples of the above-mentioned excipients include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, or calcium sulfate.

[0350] Examples of the binders mentioned above include starch paste, gum arabic, gelatin, tragacanth, carboxymethylcellulose, sodium alginate, or glycerin.

[0351] Examples of the disintegrants mentioned above include starch or calcium carbonate.

[0352] Examples of the above-mentioned lubricants include magnesium stearate, calcium stearate, polyethylene glycol, purified talc, or silica.

[0353] Examples of the sweeteners mentioned above include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, or simple syrup.

[0354] Examples of the surfactants mentioned above include sodium lauryl sulfate, polysorbate 80, sorbitan mono fatty acid ester, or polyoxyl stearate 40.

[0355] Examples of the suspending agents mentioned above include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, or bentonite.

[0356] Examples of the emulsifiers mentioned above include gum arabic, tragacanth, gelatin, or polysorbate 80.

[0357] Furthermore, when preparing a pharmaceutical product containing a tetrahydroquinoline derivative (I) or a pharmacokinetically acceptable salt thereof in the above dosage form, colorants, preservatives, fragrances, flavoring agents, stabilizers, viscosity modifiers, etc., which are commonly used in the pharmaceutical field, may be added as appropriate.

[0358] The above-mentioned pharmaceutical product preferably contains 0.00001 to 90% by weight of a tetrahydroquinoline derivative (I) or a pharmacopositically acceptable salt thereof, and more preferably 0.01 to 70% by weight. The daily dose of the above-mentioned pharmaceutical product is appropriately selected depending on the patient's condition, weight, age, and route of administration, but for example, for an adult (weighing approximately 60 kg), the amount of active ingredient is preferably 1 mg to 1000 mg for oral preparations and 0.01 to 100 mg for injectable preparations, and these can be administered in one dose or in several divided doses.

[0359] The above-mentioned pharmaceuticals may be used in combination with other drugs in appropriate amounts to complement or enhance their therapeutic or preventive effects, or to reduce the dosage. The above-mentioned pharmaceuticals may be administered simultaneously with other drugs, or in any order and sequence. Other drugs may, but are not limited to, those listed below, for use in combination with drugs that treat multiple sclerosis or drugs that treat symptoms such as convulsions and spasticity in patients with multiple sclerosis.

[0360] Other drugs used to treat multiple sclerosis include, for example, corticosteroids (prednisolone, methylprednisolone, etc.), interferon preparations (interferon α, interferon β-1b, interferon β-1a, PEG-interferon β-1a, etc.), glatiramer acetate, fumarate compounds (dimethyl fumarate, diloxymethyl fumarate, monomethyl fumarate), teriflunomide, S1P receptor agonists (fingolimod, siponimod, ozanimod, ponesimod), anti-α4 integrin antibodies (natalizumab), and anti-CD20 antibodies (occre). Examples include relizumab (relizumab, ofatumumab), anti-CD52 antibodies (aremzumab), cladribine, mitoxantrone, Bruton's tyrosine kinase inhibitors, immunomodulators (methotrexate, azathioprine, cyclophosphamide, cyclosporine A, tacrolimus, mizoribine, leflunomide, etc.), copolymer I, immunoglobulins, T-cell receptor vaccines, adhesion molecule inhibitors, analgesics (indomethacin, diclofenac, etc.), or muscle relaxants (tizanidine, eperisone, afloquarone, baclofen, diazepam, dantrolene sodium, etc.).

[0361] Examples of medications used to treat symptoms such as seizures and spasticity in patients with multiple sclerosis include anticonvulsants (carbamazepine, phenytoin, clonazepam, amitriptyline, etc.). [Examples]

[0362] The present invention will be described in detail below with reference to examples and embodiments, but the present invention is not limited thereto.

[0363] For compounds used in the synthesis of the compounds in the Reference Examples and Examples, where the synthesis method is not described, commercially available compounds were used. In the following Examples and Reference Examples, "room temperature" usually refers to approximately 10 to 35°C. The solvent names shown in the NMR data indicate the solvent used for measurement. The 400 MHz NMR spectra were measured using a JNM-ECS400 or JNM-ECZ400S nuclear magnetic resonance spectrometer (JEOL Ltd.). Chemical shifts were expressed in δ (unit: ppm) with tetramethylsilane as the reference, and the signals were expressed as s (singular), d (double), t (triple), q (quadruple), quint (quintruple), sept (septuple), m (multiple), br (broad), dd (double double), dt (double triple), ddd (double double double), dq (double quadruple), td (triple double), and tt (triple triple). 1 In 1H-NMR, peaks with very gentle protons, such as hydroxyl groups, amino groups, and carboxyl groups, are not included. ESI-MS spectra were measured using Agilent Technologies 1200 Series, G6130A (Agilent Technologies). Silica gel 60 (Merck) was used, amino silica gel (Fuji Silysia Chemical Co.) was used, and flash chromatography was performed using YFLCW-prep2XY (Yamazen). Preparative thin-layer chromatography (hereinafter, preparative TLC) was performed using silica gel 60 (Merck).

[0364] (Example 1) Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinoline hydrochloride:

[0365] [ka]

[0366] 2-phenyl-1,2,3,4-tetrahydroquinoline (7.48 g, 35.7 mmol) was dissolved in ethyl acetate (100 mL), and a 4 mol / L hydrogen chloride / ethyl acetate solution (17.8 mL, 71.5 mmol) was added. The mixture was stirred at room temperature under an argon atmosphere for 16 hours. After the reaction was complete, the precipitated solid was filtered off and washed with ethyl acetate to obtain the title compound (hereinafter referred to as the compound of Example 1) (8.07 g, 32.9 mmol, yield 92%) as a white solid. 1 H-NMR(DMSO-d6)δ:7.40-7.34(4H,m),7.28(1H,t,J=6.8Hz),6.94(2H,t,J=7.9Hz),6.67(1H,d,J=6.8Hz),6.56(1H,s),4.4 4(1H,dd,J=8.6,3.2Hz),2.81(1H,dt,J=17.8,6.1Hz),2.55(1H,ddd,J=25.0,12.3,8.7Hz),2.03-1.99(1H,m),1.91(1H,s). MS(ESI)[M+H] + :210.

[0367] (Example 2) Synthesis of (R)-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0368] [ka]

[0369] 2-phenylquinoline (0.100 g, 0.487 mmol) and hydrogen(S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (7.3 mg, 0.0097 mmol) were suspended in diethyl carbonate (5 mL), and 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (0.296 g, 1.17 mmol) was added. The mixture was stirred under an argon atmosphere at -10°C for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 2) (95.0 mg, 0.457 mmol, yield 95%, enantiomeric excess 98.5% ee) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.37(4H,ddt,J=16.0,8.9,2.8Hz),7.28(1H,tt,J=7.0,2.2Hz),7.01(2H,t,J=7.2Hz),6.65(1H,td,J=7.4,1.1Hz),6.54(1H,dd ,J=8.4,1.1Hz),4.44(1H,dd,J=9.3,3.4Hz),4.04(1H,s),2.97-2.89(1H ,m),2.74(1H,dt,J=16.3,4.8Hz),2.16-2.09(1H,m),2.05-1.94(1H,m). MS(ESI)[M+H] + :210. Retention time (hereinafter referred to as Rt): 18.40 minutes HPLC analysis conditions: Column: DaicelChiralcelOD-H chiral column (Inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 5:95 Flow rate: 0.6mL / min Detection: UV (254nm)

[0370] (Example 3) Synthesis of (S)-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0371] [ka]

[0372] Using 2-phenylquinoline (50.0 mg, 0.243 mmol) and hydrogen phosphate (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (3.7 mg, 0.0048 mmol), the title compound (hereinafter referred to as the compound of Example 3) (49.0 mg, 0.236 mmol, yield 97%, enantiomeric excess 97.2% ee) was obtained as a colorless, transparent oil in the same manner as in Example 2. 1 H-NMR(CDCl3)δ:7.41-7.32(4H,m),7.31-7.25(1H,m),7.01(2H,t,J=7.2Hz),6.65(1H,td,J=7.4,1.2Hz),6.55(1H,dd,J=7.2,1.4H z),4.44(1H,dd,J=9.3,3.4Hz),4.04(1H,s),2.97-2.89(1H,m),2.74(1H,dt,J=16.5,4.9Hz),2.16-2.09(1H,m),2.04-1.94(1H,m). MS(ESI)[M+H] + :210. Rt:14.28 minutes HPLC analysis conditions: Column: DaicelChiralcelOD-H chiral column (Inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 5:95 Flow rate: 0.6mL / min Detection: UV (254nm)

[0373] (Example 4) Synthesis of 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0374] [ka]

[0375] 2-(4-methoxyphenyl)quinoline (40.0 mg, 0.170 mmol) was dissolved in THF / methanol (1 / 1, v / v, 3.0 mL), acetic acid (0.029 mL, 0.51 mmol) and platinum(IV) oxide (3.8 mg, 0.017 mmol) were added, and the mixture was stirred at room temperature under atmospheric pressure and hydrogen for 6 hours. After the reaction was complete, the mixture was purged with nitrogen, and the reaction mixture was filtered using Celite. The residue was washed with chloroform, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 4) (26.9 mg, 0.113 mmol, yield 66%) as a white solid. 1 H-NMR(CDCl3)δ:7.31(2H,dt,J=9.2,2.5Hz),7.00(2H,dd,J=7.2,6.3Hz),6.89(2H,td,J=5.8,3.5Hz),6.64(1H,td,J=7.4,1.2Hz),6.54-6.51(1H ,m),4.38(1H,dd,J=9.5,3.2Hz),3.99(1H,s),3.81(3H,s),2.97-2.89(1 H,m),2.74(1H,dt,J=16.3,4.5Hz),2.11-2.05(1H,m),2.01-1.91(1H,m). MS(ESI)[M+H] + :240.

[0376] (Reference Example 1) Synthesis of 2-(3-methoxyphenyl)quinoline:

[0377] [ka]

[0378] 2-chloroquinoline (0.120 g, 0.734 mmol) and 3-methoxyphenylboronic acid (0.111 g, 0.734 mmol) were dissolved in DME (4.0 mL), and 1.5 mL of 1 mol / L aqueous sodium carbonate solution and tetrakistriphenylphosphine palladium (0) (8.5 mg, 0.0073 mmol) were added. The mixture was stirred at 100 °C for 4 hours under an argon atmosphere. After the reaction was complete, water was added to the reaction mixture and extracted with hexane / ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (0.165 g, 0.702 mmol, yield 95%) as a white solid. 1 H-NMR(CDCl3)δ:8.23(1H,d,J=8.6Hz),8.18(1H,t,J=4.8Hz),7.85(2H,dt,J=12.5,5.5Hz),7.77 -7.69(3H,m),7.56-7.51(1H,m),7.44(1H,t,J=7.9Hz),7.02(1H,tt,J=5.4,2.4Hz),3.94(3H,s). MS(ESI)[M+H] + :236.

[0379] (Example 5) Synthesis of 2-(3-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0380] [ka]

[0381] Using 2-(3-methoxyphenyl)quinoline (60.0 mg, 0.255 mmol) synthesized in Reference Example 1, the title compound (hereinafter referred to as the compound of Example 5) (23.7 mg, 0.0991 mmol, yield 39%) was obtained as a white solid by the same method as in Example 4. 1H-NMR(CDCl3)δ:7.27(1H,dd,J=8.8,7.0Hz),7.03-6.96(4H,m),6.83(1H,dq,J=8.2,1.2Hz),6.65(1H,td,J=7.4,1.1Hz),6.54(1H,d,J=7.7Hz), 4.42(1H,dd,J=9.3,3.4Hz),4.01(1H,brs),3.81(3H,s),2.97-2.88(1H ,m),2.74(1H,dt,J=16.3,4.8Hz),2.15-2.09(1H,m),2.05-1.94(1H,m). MS(ESI)[M+H] + :240.

[0382] (Reference Example 2) Synthesis of 2-(2-methoxyphenyl)quinoline:

[0383] [ka]

[0384] Using 2-chloroquinoline (0.100 g, 0.611 mmol) and 2-methoxyphenylboronic acid (92.8 mg, 0.611 mmol), the title compound (0.157 g, 0.668 mmol, 99% yield) was obtained as a white solid by the same method as in Reference Example 1. 1 H-NMR(CDCl3)δ:8.16(2H,t,J=8.8Hz),7.89(1H,d,J=8.2Hz),7.84(2H,dq,J=7.7,1.8Hz),7.73-7.69(1H,m),7 .55-7.51(1H,m),7.43(1H,td,J=7.9,1.5Hz),7.13(1H,td,J=7.5,1.1Hz),7.04(1H,t,J=4.3Hz),3.87(3H,s). MS(ESI)[M+H] + :236

[0385] (Example 6) Synthesis of 2-(2-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0386] [ka]

[0387] Using 2-(2-methoxyphenyl)quinoline (60.0 mg, 0.255 mmol) synthesized in Reference Example 2, the title compound (hereinafter referred to as the compound of Example 6) (35.5 mg, 0.148 mmol, yield 58%) was obtained as a white solid by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.43(1H,dd,J=7.7,1.8Hz),7.28-7.22(1H,m),7.05-6.85(4H,m),6.63(1H,td,J=7.4,1.2Hz),6.56(1H,d,J=7.7Hz),4.87(1H,dd ,J=8.2,3.6Hz),4.04(1H,s),3.85(3H,s),2.92-2.84(1H,m),2.69(1H,t d,J=10.8,5.4Hz),2.14(1H,dtd,J=13.4,5.0,2.9Hz),2.01-1.92(1H,m). MS(ESI)[M+H] + :240.

[0388] (Reference Example 3) Synthesis of 2-(benzo[d][1,3]dioxol-5-yl)-6-methoxyquinoline:

[0389] [ka]

[0390] Using 2-chloro-6-methoxyquinoline (0.130 g, 0.671 mmol) and benzo[d][1,3]dioxol-5-ylphenylboronic acid (0.111 g, 0.671 mmol), the title compound (0.128 g, 0.459 mmol, yield 68%) was obtained as a pale yellow solid by the same method as in Reference Example 1. 1H-NMR(CDCl3)δ:8.08(1H,d,J=8.6Hz),8.02(1H,d,J=8.6Hz),7.75(1H,d,J=8.6Hz),7.70(1H,d,J=1.8Hz),7.62(1H,dd,J= 8.2,1.8Hz),7.37(1H,dd,J=9.1,2.7Hz),7.08(1H,d,J=2.7Hz),6.94(1H,d,J=4.1Hz),6.04(2H,d,J=5.0Hz),3.95(3H,s). MS(ESI)[M+H] + :280.

[0391] (Example 7) Synthesis of 2-(benzo[d][1,3]dioxol-5-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline (novel compound):

[0392] [ka]

[0393] Using 2-(benzo[d][1,3]dioxol-5-yl)-6-methoxyquinoline (60.0 mg, 0.215 mmol) synthesized in Reference Example 3, the title compound (hereinafter referred to as the compound of Example 7) (24.3 mg, 0.0859 mmol, yield 99%) was obtained as a white solid by the same method as in Example 4. 1 H-NMR(CDCl3)δ:6.91(1H,d,J=1.8Hz),6.84(1H,dd,J=8.2,1.8Hz),6.77(1H,d,J=7.7Hz),6.62(2H,td,J=7.4,2.7Hz),6.49(1H,d,J=8.6Hz), 5.95(2H,s),4.28(1H,dd,J=9.7,2.9Hz),3.74(3H,s),2.97-2.88(1H, m),2.72(1H,dt,J=16.5,4.5Hz),2.09-2.03(1H,m),1.98-1.88(1H,m). MS(ESI)[M+H] + :284.

[0394] (Reference Example 4) Synthesis of 7-methoxy-2-(4-methoxyphenyl)quinoline:

[0395] [ka]

[0396] Using 2-chloro-7-methoxyquinoline (0.130 g, 0.671 mmol) and 4-methoxyphenylboronic acid (0.102 g, 0.671 mmol), the title compound (0.155 g, 0.585 mmol, yield 87%) was obtained as a white solid by the same method as in Reference Example 1. 1 H-NMR(CDCl3)δ:8.13-8.09(3H,m),7.69(2H,dd,J=8.6,5.0Hz),7.47(1H,d,J=2.7Hz ),7.16(1H,dd,J=8.8,2.5Hz),7.04(2H,td,J=6.0,3.5Hz),3.98(3H,s),3.89(3H,s). MS(ESI)[M+H] + :266.

[0397] (Example 8) Synthesis of 7-methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0398] [ka]

[0399] Using 7-methoxy-2-(4-methoxyphenyl)quinoline (62.0 mg, 0.234 mmol) synthesized in Reference Example 4, the title compound (hereinafter referred to as the compound of Example 8) (62.3 mg, 0.234 mmol, yield 99%) was obtained as a white solid by the same method as in Example 4. 1H-NMR(CDCl3)δ:7.30(2H,td,J=5.8,3.5Hz),6.91-6.87(3H,m),6.24(1H,dd,J=8.4,2.5Hz),6.10(1H,d,J=2.3Hz),4.36(1H,dd,J=9.5 ,3.2Hz),4.00(1H,s),3.81(3H,s),3.75(3H,s),2.89-2.81(1H,m),2.67(1H,dt,J=16.2,4.6Hz),2.10-2.03(1H,m),1.99-1.89(1H,m). MS(ESI)[M+H] + :270.

[0400] (Reference Example 5) Synthesis of 2-(benzo[d][1,3]dioxol-5-yl)quinoline:

[0401] [ka]

[0402] Using 2-chloroquinoline (0.150 g, 0.917 mmol) and benzo[d][1,3]dioxol-5-ylphenylboronic acid (0.167 g, 1.01 mmol), the title compound (0.218 g, 0.876 mmol, yield 87%) was obtained as a yellow solid by the same method as in Reference Example 1. 1 H-NMR(CDCl3)δ:8.19(1H,d,J=8.6Hz),8.13(1H,t,J=4.8Hz),7.82-7.79(2H,m),7.72(2H,tt,J= 8.8,2.9Hz),7.66(1H,dd,J=8.2,1.8Hz),7.53-7.49(1H,m),6.96(1H,d,J=8.2Hz),6.05(2H,s). MS(ESI)[M+H] + :250.

[0403] (Example 9) Synthesis of 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline:

[0404] [ka]

[0405] Using 2-(benzo[d][1,3]dioxol-5-yl)-quinoline (60.0 mg, 0.241 mmol) synthesized in Reference Example 5, the title compound (hereinafter referred to as the compound of Example 9) (37.7 mg, 0.149 mmol, yield 62%) was obtained as a colorless, transparent oil by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.00(2H,t,J=7.2Hz),6.90(1H,d,J=1.8Hz),6.84(1H,dd,J=8.4, 1.6Hz),6.77(1H,d,J=7.7Hz),6.64(1H,td,J=7.4,1.1Hz),6.53(1H,d,J=7.2Hz),5 .95(2H,t,J=1.6Hz),4.35(1H,dd,J=9.5,3.2Hz),3.98(1H,s),2.95-2.87(1H,m), 2.73(1H,dt,J=16.3,4.8Hz),2.08(1H,tdd,J=8.4,4.4,2.7Hz),1.99-1.89(1H,m). MS(ESI)[M+H] + :254.

[0406] (Reference Example 6) Synthesis of 2-(2-(trifluoromethyl)phenyl)quinoline:

[0407] [ka]

[0408] 2-chloroquinoline (50.0 mg, 0.306 mmol), (2-(trifluoromethyl)phenyl)boronic acid (87.1 mg, 0.458 mmol), tetrakis(triphenylphosphine)palladium (0) (7.1 mg, 0.0061 mmol), and potassium carbonate (127 mg, 0.917 mmol) were dissolved in 1,4-dioxane / water (5 / 1, v / v, 3 mL), and the mixture was heated and stirred at 100°C for 16 hours. After the reaction mixture cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane-ethyl acetate) to obtain the title compound (81.5 mg, 0.298 mmol, yield 98%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:8.23(1H,d,J=8.2Hz),8.16(1H,d,J=8.7Hz),7.89(1H,d,J=7.8Hz),7 .81(1H,d,J=7.8Hz),7.77(1H,t,J=8.2Hz),7.67(1H,t,J=7.5Hz),7.62-7.54(4H,m). MS(ESI)[M+H] + :274.

[0409] (Example 10) Synthesis of 2-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline:

[0410] [ka]

[0411] Using 2-(2-(trifluoromethyl)phenyl)quinoline (62.0 mg, 0.227 mmol) synthesized in Reference Example 6, the title compound (hereinafter referred to as the compound of Example 10) (52.2 mg, 0.188 mmol, yield 83%) was obtained as a colorless, transparent oil by the same method as in Example 4. 1H-NMR(CDCl3)δ:7.82(1H,d,J=8.2Hz),7.65(1H,d,J=7.8Hz),7.56(1H,t,J=7.5Hz),7.38(1H,t,J=7.5Hz),7.04-7.01(2H,m),6.69(1H,t,J=7. 5Hz),6.55(1H,d,J=7.8Hz),4.82(1H,d,J=9.6Hz),3.97(1H,brs),3.03 -2.94(1H,m),2.81-2.75(1H,m),2.17-2.12(1H,m),1.97-1.91(1H,m). MS(ESI)[M+H] + :278.

[0412] (Reference Example 7) Synthesis of 2-(1H-pyrazole-4-yl)quinoline:

[0413] [ka]

[0414] Using 2-chloroquinoline (100 mg, 0.611 mmol) and (1H-pyrazole-4-yl)boronic acid (137 mg, 1.22 mmol), the title compound (63.7 mg, 0.326 mmol, yield 53%) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.29(2H,s),8.16(1H,d,J=8.7Hz),8.07(1H,d,J=8.7Hz),7.79(1 H,d,J=8.2Hz),7.70(1H,t,J=7.5Hz),7.66(1H,d,J=8.2Hz),7.49(1H,t,J=7.5Hz). MS(ESI)[M+H] + :196.

[0415] (Example 11) Synthesis of 2-(1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline:

[0416] [ka]

[0417] Using 2-(1H-pyrazole-4-yl)quinoline (30.0 mg, 0.154 mmol) synthesized in Reference Example 7, the title compound (hereinafter referred to as the compound of Example 11) (28.8 mg, 0.145 mmol, yield 94%) was obtained as a white solid by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.58(2H,s),7.02-6.98(2H,m),6.66(1H,t,J=7.1Hz),6.52(1H,d,J=7.8Hz),4.50 (1H,dd,J=9.1,3.2Hz),2.96-2.88(1H,m),2.80-2.74(1H,m),2.17-2.11(1H,m),2.04-1.95(1H,m). MS(ESI)[M+H] + :200.

[0418] (Example 12) Synthesis of one optically active compound of 2-(1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline:

[0419] [ka]

[0420] [In the formula, the carbon atom indicated by * represents the carbon atom that acts as a chiral center.] 2-(1H-pyrazole-4-yl)quinoline (50.0 mg, 0.256 mmol) synthesized in Reference Example 7 and hydrogen phosphate (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (3.8 mg, 0.0051 mmol) were suspended in 1,4-dioxane (2 mL), and 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (0.155 g, 0.614 mmol) was added. The mixture was stirred at room temperature under an argon atmosphere for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate), and the resulting solid was recrystallized with hexane / ethyl acetate to obtain the title compound (hereinafter referred to as the compound of Example 12) (9.0 mg, 0.045 mmol, yield 18%, enantiomeric excess 98.1% ee) as a white solid. 1 H-NMR(CDCl3)δ:7.58(2H,s),6.98(2H,d,J=8.8Hz),6.65(1H,t,J=7.2Hz),6.52(1H,d,J=8.2Hz),4.50(1H,dd,J= 9.3,2.9Hz),3.96(1H,s),2.96-2.88(1H,m),2.76(1H,dt,J=16.3,4.8Hz),2.17-2.11(1H,m),2.05-1.95(1H,m). MS(ESI)[M+H] + :200. Rt:17.78 minutes HPLC analysis conditions: Column: Daicel Chiralcel OZ-3 chiral column (Inner diameter: 4.6 mm, length: 150 mm, particle size: 3 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 10:90 Flow rate: 0.6mL / min Detection: UV (254nm)

[0421] (Example 13) Synthesis of the other optically active compound of 2-(1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline:

[0422] [ka]

[0423] [In the formula, the carbon atom indicated by * represents the carbon atom that acts as a chiral center.] Using 2-(1H-pyrazole-4-yl)quinoline (70.0 mg, 0.359 mmol) synthesized in Reference Example 7 and hydrogen(S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (5.40 mg, 7.17 μmol) hydrogen phosphate, the title compound (hereinafter referred to as the compound of Example 13) (30.0 mg, 0.151 mmol, yield 42%, enantiomeric excess 96.9% ee) was obtained as a white solid by the same method as in Example 12. 1 H-NMR(CDCl3)δ:7.58(2H,s),7.01-6.98(2H,m),6.67-6.63(1H,m),6.53-6.50(1H,m),4.49(1H,dd,J=9 .3,2.9Hz),3.97(1H,brs),2.96-2.88(1H,m),2.79-2.73(1H,m),2.17-2.10(1H,m),2.05-1.94(1H,m). MS(ESI)[M+H] + :200. Rt:13.11 minutes HPLC analysis conditions: Column: Daicel Chiralcel OZ-3 chiral column (Inner diameter: 4.6 mm, length: 150 mm, particle size: 3 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 10:90 Flow rate: 0.6mL / min Detection: UV (254nm)

[0424] (Example 14) Synthesis of 2-(1-methyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline (novel compound):

[0425] [ka]

[0426] 2-(1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline (25.0 mg, 0.125 mmol) synthesized in Example 11 was dissolved in DMF (1.2 mL), then potassium carbonate (34.7 mg, 0.251 mmol) and methyl iodide (7.8 μL, 0.125 mmol) were added, and the mixture was stirred at 50°C for 2 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform / methanol) and column chromatography (aminosilica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 14) (4.1 mg, 0.019 mmol, yield 15%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.46(1H,s),7.32(1H,s),7.01-6.97(2H,m),6.64(1H,t,J=7.1Hz),6.50(1H,d,J=8.2Hz),4.43(1H,dd, J=9.4,3.0Hz),3.95(1H,brs),3.88(3H,s),2.94-2.86(1H,m),2.79-2.72(1H,m),2.14-2.08(1H,m),1.99-1.93(1H,m). MS(ESI)[M+H] + :214.

[0427] (Reference Example 8) Synthesis of 2-(6-methoxypyridine-3-yl)quinoline:

[0428] [ka]

[0429] Using 2-chloroquinoline (100 mg, 0.611 mmol) and (6-methoxypyridine-3-yl)boronic acid (140 mg, 0.917 mmol), the title compound (134 mg, 0.568 mmol, yield 93%) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.91(1H,d,J=2.3Hz),8.48(1H,dd,J=8.7,2.3Hz),8.22(1H,d,J=8.2Hz),8.13(1H,d,J=8.7 Hz),7.83(2H,d,J=8.7Hz),7.73(1H,t,J=7.1Hz),7.53(1H,t,J=7.1Hz),6.90(1H,d,J=8.7Hz),4.03(3H,s). MS(ESI)[M+H] + :237.

[0430] (Example 15) Synthesis of 2-(6-methoxypyridine-3-yl)-1,2,3,4-tetrahydroquinoline (novel compound):

[0431] [ka]

[0432] Using 2-(6-methoxypyridine-3-yl)quinoline (50.0 mg, 0.212 mmol) synthesized in Reference Example 8, the title compound (hereinafter referred to as the compound of Example 15) (11.0 mg, 0.0458 mmol, yield 22%) was obtained as a colorless, transparent oil by the same method as in Example 4. 1 H-NMR(CDCl3)δ:8.14(1H,d,J=2.3Hz),7.63(1H,dd,J=8.7,2.3Hz),7.03-6.99(2H,m),6.74(1H,d,J=8.0Hz),6.66(1H,t,J=7.3Hz),6. 53(1H,d,J=8.0Hz),4.40(1H,dd,J=9.6,3.2Hz),3.94(3H,s),3.94(1H,brs),2.99-2.91(1H,m),2.78-2.72(1H,m),2.09-1.93(2H,m). MS(ESI)[M+H] + :241.

[0433] (Reference Example 9) Synthesis of 2-(4-(methylsulfonyl)phenyl)quinoline:

[0434] [ka]

[0435] Using 2-chloroquinoline (200 mg, 1.22 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (489 mg, 2.45 mmol), a mixture of the title compound and impurities (296 mg) was obtained as a white solid in the same manner as in Reference Example 6. MS(ESI)[M+H] + :284.

[0436] (Example 16) Synthesis of 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline (novel compound):

[0437] [ka]

[0438] Using 2-(4-(methylsulfonyl)phenyl)quinoline (100 mg, 0.353 mmol) synthesized in Reference Example 9, the title compound (hereinafter referred to as the compound of Example 16) (65.6 mg, 0.228 mmol, yield 65%) was obtained as a white solid by the same method as in Example 4. 1H-NMR(CDCl3)δ:7.92(2H,dt,J=8.7,1.8Hz),7.60(2H,dt,J=8.7,1.8Hz),7.06-7.00(2H,m),6.69(1H,td,J=7.3,0.9Hz),6.59(1H,dd,J=7.8,0.9H z),4.57(1H,dd,J=8.7,3.2Hz),4.09(1H,brs),3.06(3H,s),2.95-2.87(1 H,m),2.70(1H,td,J=10.9,5.5Hz),2.19-2.12(1H,m),2.01-1.97(1H,m). MS(ESI)[M+H] + :288.

[0439] (Reference Example 10) Synthesis of methyl 4-(quinoline-2-yl)benzoate:

[0440] [ka]

[0441] Using 2-chloroquinoline (1.50 g, 9.17 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (1.98 g, 11.0 mmol), the title compound (1.95 g, 7.40 mmol, yield 81%) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.28-8.24(3H,m),8.21-8.18(3H,m),7.93(1H,d,J=8.7Hz ),7.86(1H,d,J=8.2Hz),7.78-7.74(1H,m),7.59-7.55(1H,m),3.97(3H,s). MS(ESI)[M+H] + :264.

[0442] (Example 17) Synthesis of methyl 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzoate:

[0443] [ka]

[0444] Using methyl 4-(quinoline-2-yl)benzoate (600 mg, 2.28 mmol) synthesized in Reference Example 10, the title compound (hereinafter referred to as the compound of Example 17) (267 mg, 0.998 mmol, yield 44%) was obtained as a colorless, transparent oil by the same method as in Example 4. 1 H-NMR(CDCl3)δ:8.02(2H,dt,J=8.2,1.8Hz),7.46(2H,dt,J=8.2,1.8Hz),7.05-6.99(2H,m),6.67(1H,td,J=7.3,0.9Hz),6.57(1H,dd,J=7.8,0.9H z),4.52(1H,dd,J=9.1,3.2Hz),4.07(1H,brs),3.92(3H,s),2.95-2.87(1 H,m),2.71(1H,td,J=10.7,5.5Hz),2.16-2.12(1H,m),2.03-1.94(1H,m). MS(ESI)[M+H] + :268.

[0445] (Example 18) Synthesis of 2-(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)propan-2-ol (novel compound):

[0446] [ka]

[0447] 50.0 mg, 0.187 mmol of 4-(1,2,3,4-tetrahydroquinoline-2-yl)methyl benzoate (50.0 mg) synthesized in Example 17 was dissolved in 1.9 mL of THF. Then, under ice cooling, 0.56 mL, 0.65 mmol of methyllithium THF solution was added dropwise, and the mixture was stirred under ice cooling for 2 hours. After the reaction was complete, water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 18) (13.1 mg, 0.0490 mmol, yield 26%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.48(2H,d,J=8.2Hz),7.37(2H,d,J=8.2Hz),7.02-7.00(2H,m),6.65(1H,t,J=7.5Hz),6.54(1H,d,J=7.7Hz),4.44(1H,dd,J= 9.5,3.2Hz),4.02(1H,brs),2.97-2.89(1H,m),2.74(1H,dt,J=16.3,4 .5Hz),2.14-2.10(1H,m),2.02-1.96(1H,m),1.73(1H,s),1.59(6H,s). MS(ESI)[M+H] + :268.

[0448] (Reference Example 11) Synthesis of 3-(quinoline-2-yl)benzenesulfonamide:

[0449] [ka]

[0450] 2-chloroquinoline (100 mg, 0.611 mmol), (3-sulfamoylphenyl)boronic acid (184 mg, 0.917 mmol), tetrakis(triphenylphosphine)palladium (0) (21.2 mg, 0.0183 mmol), and potassium carbonate (169 mg, 1.22 mmol) were dissolved in DMF / water (5 / 1, v / v, 3 mL), and the mixture was heated and stirred at 100°C for 17 hours. After the reaction mixture cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (135 mg, 0.474 mmol, yield 78%) as a white solid. 1H-NMR(CDCl3)δ:8.78(1H,t,J=1.6Hz),8.41(1H,d,J=7.8Hz),8.29(1H,d,J=8.5Hz),8.18(1H,d,J=7.8Hz),8.03(1H,d,J=7.8Hz) ,7.92(1H,d,J=8.5Hz),7.87(1H,d,J=7.8Hz),7.77(1H,t,J=7.8Hz),7.70(1H,t,J=7.8Hz),7.58(1H,t,J=7.8Hz),4.87(2H,brs). MS(ESI)[M+H] + :285.

[0451] (Example 19) Synthesis of 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide (novel compound):

[0452] [ka]

[0453] Using 3-(quinoline-2-yl)benzenesulfonamide (131 mg, 0.461 mmol) synthesized in Reference Example 11, the title compound (hereinafter referred to as the compound of Example 19) (118 mg, 0.409 mmol, yield 89%) was obtained as a colorless, transparent oil by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.98(1H,s),7.85(1H,d,J=7.8Hz),7.63(1H,d,J=7.8Hz),7.51(1H,t,J=7.8Hz),7.04-7.01(2H,m),6.69(1H,t,J=7.1Hz),6 .58(1H,d,J=7.8Hz),4.80(2H,brs),4.54(1H,dd,J=9.1,3.2Hz),2.97-2.89(1H,m),2.74-2.69(1H,m),2.16-2.12(1H,m),2.02-1.97(1H,m). MS(ESI)[M+H] + :289.

[0454] (Reference Example 12) Synthesis of 2-(quinoline-2-yl)benzenesulfonamide:

[0455] [ka]

[0456] Using 2-chloroquinoline (100 mg, 0.611 mmol) and (2-sulfamoylphenyl)boronic acid (184 mg, 0.917 mmol), the title compound (153 mg, 0.540 mmol, yield 88%) was obtained as a white solid by the same method as in Reference Example 11. 1 H-NMR(DMSO-d6)δ:8.54(1H,d,J=8.7Hz),8.10-8.06(3H,m),7.86-7.67(6H,m),7.61(2H,brs). MS(ESI)[M+H] + :285.

[0457] (Example 20) Synthesis of 2-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide (novel compound):

[0458] [ka]

[0459] Using 2-(quinoline-2-yl)benzenesulfonamide (150 mg, 0.528 mmol) synthesized in Reference Example 12, the title compound (hereinafter referred to as the compound of Example 20) (28.8 mg, 0.0999 mmol, yield 19%) was obtained as a white solid by the same method as in Example 4. 1H-NMR(CDCl3)δ:8.06(1H,d,J=7.8Hz),7.83(1H,d,J=7.4Hz),7.60(1H,t,J= 7.8Hz),7.41(1H,t,J=7.4Hz),7.05-7.01(2H,m),6.71(1H,t,J=7.4Hz),6.56 (1H,d,J=7.8Hz),5.25(1H,dd,J=9.6,2.3Hz),4.96(2H,brs),4.00(1H,brs) ,3.04-2.96(1H,m),2.82-2.78(1H,m),2.32-2.29(1H,m),2.05-1.95(1H,m). MS(ESI)[M+H] + :289.

[0460] (Reference Example 13) Synthesis of N-(4-(quinoline-2-yl)phenyl)acetamide:

[0461] [ka]

[0462] 2-chloroquinoline (100 mg, 0.611 mmol), potassium carbonate (211 mg, 1.53 mmol), palladium(II) acetate (13.7 mg, 61.1 μmol), tri-tert-butylphosphonium tetrafluoroborate (17.7 mg, 61.1 μmol), and 4-acetoxyphenylboronic acid (164 mg, 0.917 mmol) were suspended in acetonitrile / water (2.3 mL / 0.70 mL) and stirred at 100°C for 1 hour under microwave irradiation. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (48.8 mg, 0.186 mmol, yield 30%) as a white solid. 1H-NMR(CDCl3)δ:8.21(1H,d,J=8.6Hz),8.17-8.13(3H,m),7.86(1H,d,J=8.8Hz),7.8 2(1H,d,J=8.2Hz),7.74-7.67(3H,m),7.54-7.50(1H,m),7.39(1H,brs),2.22(3H,s). MS(ESI)[M+H] + :263.

[0463] (Example 21) Synthesis of N-(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)acetamide:

[0464] [ka]

[0465] Using N-(4-(quinoline-2-yl)phenyl)acetamide (40.0 mg, 0.152 mmol) synthesized in Reference Example 13, the title compound (hereinafter referred to as the compound of Example 21) (6.60 mg, 24.8 μmol, yield 16%) was obtained as a white amorphous material by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.46(2H,d,J=8.6Hz),7.34(2H,d,J=8.6Hz),7.15(1H,brs),7.03-6.99(2H,m),6.65(1H,dd,J=6.8,8.4Hz),6.54(1H,d,J=7 .7Hz),4.41(1H,dd,J=9.5,3.2Hz),4.01(1H,brs),2.95-2.87(1H,m),2.76-2.69(1H,m),2.19(3H,s),2.12-2.06(1H,m),2.01-1.91(1H,m). MS(ESI)[M+H] + :267.

[0466] (Reference Example 14) Synthesis of 2-(1H-pyrazole-3-yl)quinoline:

[0467] [ka]

[0468] Using 2-chloroquinoline (100 mg, 0.611 mmol) and 1H-pyrazole-3-boronic acid (164 mg, 0.917 mmol), the title compound (56.0 mg, 0.287 mmol, yield 47%) was obtained as a white solid by the same method as in Reference Example 11. 1 H-NMR(CDCl3)δ:8.21(1H,d,J=8.6Hz),8.10(1H,d,J=8.6Hz),7.86(1H,d,J=8. 6Hz),7.82(1H,d,J=8.2Hz),7.75-7.71(2H,m),7.56-7.52(1H,m),6.96(1H,s). MS(ESI)[M+H] + :196.

[0469] (Example 22) Synthesis of 2-(1H-pyrazole-3-yl)-1,2,3,4-tetrahydroquinoline:

[0470] [ka]

[0471] Using 2-(1H-pyrazole-3-yl)quinoline (56.0 mg, 0.287 mmol) synthesized in Reference Example 14, the title compound (hereinafter referred to as the compound of Example 22) (33.7 mg, 0.169 mmol, yield 59%) was obtained as a white amorphous material by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.52(1H,s),7.02-6.98(2H,m),6.67(1H,ddd,J=7.6,7.6,1.2Hz),6.56(1H,d,J=7.7Hz),6.27(1H,s), 4.64(1H,dd,J=9.1,3.6Hz),4.23(1H,brs),2.96-2.86(1H,m),2.80-2.72(1H,m),2.24-2.17(1H,m),2.12-2.02(1H,m). MS(ESI)[M+H] + :200.

[0472] (Reference Example 15) Synthesis of 3',4'-dihydro-[2,6'-biquinoline]-2'(1'H)-one:

[0473] [ka]

[0474] Using 2-chloroquinoline (100 mg, 0.611 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-2(1H)-one (250 mg, 0.917 mmol), the title compound (118 mg, 0.431 mmol, yield 71%) was obtained as a white solid by the same method as in Reference Example 11. 1 H-NMR(DMSO-d6)δ:10.31(1H,s),8.41(1H,d,J=8.6Hz),8.15(1H,s),8.12-8.08(2H,m),8.03(1H,d,J=8.2Hz),7.97(1 H,d,J=7.2Hz),7.78-7.74(1H,m),7.59-7.55(1H,m),7.01(1H,d,J=8.2Hz),3.02(2H,t,J=7.5Hz),2.55-2.51(2H,m). MS(ESI)[M+H] + :275.

[0475] (Example 23) Synthesis of 1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one (novel compound):

[0476] [ka]

[0477] Using 3',4'-dihydro-[2,6'-biquinoline]-2'(1'H)-one (118 mg, 0.431 mmol) synthesized in Reference Example 15, the title compound (hereinafter referred to as the compound of Example 23) (80.6 mg, 0.290 mmol, yield 67%) was obtained as a white solid by the same method as in Example 4. 1 H-NMR(CDCl3)δ:8.30(1H,brs),7.21-7.18(2H,m),7.03-6.99(2H,m),6.77-6.74(1H,m),6.66(1H,ddd,J=7.6,7.2,1.2Hz),6.54(1H,d,J=7.2H z),4.38(1H,dd,J=9.5,3.2Hz),3.99(1H,brs),2.99-2.89(3H,m),2.77 -2.71(1H,m),2.66-2.62(2H,m),2.12-2.05(1H,m),2.01-1.91(1H,m). MS(ESI)[M+H] + :279.

[0478] (Reference Example 16) Synthesis of 1'-methyl-3',4'-dihydro-[2,6'-biquinoline]-2'(1'H)-one:

[0479] [ka]

[0480] 2-chloroquinoline (100 mg, 0.611 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-2(1H)-one (263 mg, 0.917 mmol) were mixed with DMF / water (2.4 mL / 0.60 mL) in the same manner as in Reference Example 11 to obtain the title compound (171 mg, 0.593 mmol, yield 97%) as a white solid. 1 H-NMR(CDCl3)δ:8.22(1H,d,J=8.6Hz),8.15(1H,d,J=8.6Hz),8.08-8.07(1H,m),8.03(1H,dd,J=8.6,2.3Hz),7.88-7.82( 2H,m),7.76-7.71(1H,m),7.55-7.51(1H,m),7.13(1H,d,J=8.6Hz),3.43(3H,s),3.06(2H,t,J=7.5Hz),2.74-2.71(2H,m). MS(ESI)[M+H] + :289.

[0481] (Example 24) Synthesis of 1'-methyl-1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one (novel compound):

[0482] [ka]

[0483] Using 1'-methyl-3',4'-dihydro-[2,6'-biquinoline]-2'(1'H)-one (171 mg, 0.593 mmol) synthesized in Reference Example 16, the title compound (hereinafter referred to as the compound of Example 24) (54.3 mg, 0.186 mmol, yield 31%) was obtained as a white solid by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.28-7.25(1H,m),7.21(1H,s),7.03-7.00(2H,m),6.95(1H,d,J=8.6Hz),6.68-6.64(1H,m),6.55(1H,d,J=7.2Hz),4.40(1H, dd,J=9.5,3.2Hz),4.00(1H,brs),3.36(3H,s),3.00-2.88(3H,m),2.78 -2.71(1H,m),2.67-2.63(2H,m),2.13-2.06(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :293.

[0484] (Reference Example 17) Synthesis of 5-(quinoline-2-yl)isoindorin-1one:

[0485] [ka]

[0486] Using 2-chloroquinoline (100 mg, 0.611 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-1-one (104 mg, 0.917 mmol), the title compound (61.6 mg, 0.237 mmol, yield 39%) was obtained as a gray solid by the same method as in Reference Example 11. 1 H-NMR(DMSO-d6)δ:8.69(1H,brs),8.54-8.49(2H,m),8.40(1H,d,J=8.2Hz),8.24(1H,d,J=8.6Hz) ,8.11(1H,d,J=8.6Hz),8.04(1H,d,J=7.2Hz),7.85-7.80(2H,m),7.66-7.62(1H,m),4.51(2H,s). MS(ESI)[M+H] + :261.

[0487] (Example 25) Synthesis of 5-(1,2,3,4-tetrahydroquinoline-2-yl)isoindorin-1-one (novel compound):

[0488] [ka]

[0489] Using 5-(quinoline-2-yl)isoindorin-1-one (61.6 mg, 0.237 mmol) synthesized in Reference Example 17, the title compound (hereinafter referred to as the compound of Example 25) (35.7 mg, 0.135 mmol, yield 57%) was obtained as a white solid by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.85(1H,d,J=7.7Hz),7.53(1H,s),7.49(1H,d,J=7.7Hz),7.06-7.00(2H,m),6.70-6.67(1H,m),6.58(1H,d,J=7.7Hz),6.1 5(1H,brs),4.58(1H,d,J=9.1Hz),4.44(2H,s),4.10(1H,brs),2.95-2.88(1H,m),2.75-2.68(1H,m),2.18-2.14(1H,m),2.06-1.99(1H,m). MS(ESI)[M+H] + :265.

[0490] (Reference Example 18) Synthesis of 2-(4-fluorophenyl)quinoline:

[0491] [ka]

[0492] Using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (4-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol), the title compound (65.3 mg, 0.293 mmol, yield 96%) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.23(1H,d,J=8.7Hz),8.19-8.14(3H,m),7.85-7.82(2H,m),7.74(1H,t,J=7.1Hz),7.54(1H,t,J=7.1Hz),7.24-7.19(2H,m). MS(ESI)[M+H] + :224.

[0493] (Example 26) Synthesis of 2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline:

[0494] [ka]

[0495] 2-(4-fluorophenyl)quinoline (62.0 mg, 0.278 mmol) synthesized in Reference Example 18 was dissolved in dichloromethane (2.8 mL), and then 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (148 mg, 0.583 mmol) and iodine (7.0 mg, 0.028 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 26) (60.2 mg, 0.264 mmol, yield 95%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.37-7.33(2H,m),7.05-6.99(4H,m),6.66(1H,t,J=7.3Hz),6.54(1H,d,J=7.8Hz),4.42(1H, dd,J=9.4,3.0Hz),4.00(1H,brs),2.96-2.88(1H,m),2.76-2.69(1H,m),2.12-2.06(1H,m),2.00-1.90(1H,m). MS(ESI)[M+H] + :228.

[0496] (Reference Example 19) Synthesis of 2-(3-fluorophenyl)quinoline:

[0497] [ka]

[0498] Using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (3-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol), the title compound (68.5 mg, 0.307 mmol, yield quant.) was obtained as a white solid by the same method as in Reference Example 6. 1H-NMR(CDCl3)δ:8.25(1H,d,J=8.2Hz),8.17(1H,d,J=8.2Hz),7.94-7.92(2H,m),7.87-7.85(2H,m ),7.75(1H,td,J=7.5,1.4Hz),7.56(1H,td,J=7.5,1.4Hz),7.52-7.47(1H,m),7.19-7.14(1H,m). MS(ESI)[M+H] + :224.

[0499] (Example 27) Synthesis of 2-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline:

[0500] [ka]

[0501] Using 2-(3-fluorophenyl)quinoline (65.0 mg, 0.291 mmol) synthesized in Reference Example 19, the title compound (hereinafter referred to as the compound of Example 27) (66.3 mg, 0.291 mmol, yield 99%) was obtained as a colorless, transparent oil by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.32-7.28(1H,m),7.16-7.09(2H,m),7.03-6.95(3H,m),6.66(1H,t,J=7.3Hz),6.55(1H,d,J=7.8Hz), 4.44(1H,dd,J=9.1,2.7Hz),4.04(1H,brs),2.94-2.86(1H,m),2.74-2.68(1H,m),2.15-2.08(1H,m),2.01-1.92(1H,m). MS(ESI)[M+H] + :228.

[0502] (Reference Example 20) Synthesis of 2-(2-fluorophenyl)quinoline:

[0503] [ka]

[0504] Using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (2-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol), the title compound (69.9 mg, 0.309 mmol, yield quant.) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.23(1H,d,J=8.7Hz),8.18(1H,d,J=8.2Hz),8.10(1H,td,J=7.8,1.8Hz),7.91-7.85(2H,m),7.75( 1H,td,J=7.8,1.8Hz),7.57(1H,t,J=7.3Hz),7.46-7.42(1H,m),7.33(1H,t,J=7.3Hz),7.21(1H,dd,J=10.5,8.7Hz). MS(ESI)[M+H] + :224.

[0505] (Example 28) Synthesis of 2-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoline:

[0506] [ka]

[0507] Using 2-(3-fluorophenyl)quinoline (65.0 mg, 0.291 mmol) synthesized in Reference Example 20, the title compound (hereinafter referred to as the compound of Example 28) (65.2 mg, 0.287 mmol, yield 99%) was obtained as a colorless, transparent oil by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.47(1H,t,J=7.5Hz),7.27-7.22(1H,m),7.12(1H,t,J=7.5Hz),7.07-6.99(3H,m),6.66(1H,t,J=7.2Hz),6.57(1 H,d,J=7.7Hz),4.85(1H,d,J=6.8Hz),4.00(1H,brs),2.93-2.85(1H,m),2.72-2.66(1H,m),2.20-2.13(1H,m),2.04-1.97(1H,m). MS(ESI)[M+H] + :228.

[0508] (Reference Example 21) Synthesis of 2-(4-(trifluoromethyl)phenyl)quinoline:

[0509] [ka]

[0510] Using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (87.1 mg, 0.458 mmol), the title compound (80.7 mg, 0.295 mmol, yield 97%) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.30-8.28(3H,m),8.19(1H,d,J=8.2Hz),7.90(1H,d,J=8.7Hz),7.87(1H,d,J=8.2Hz),7.79-7.76(3H,m),7.58(1H,t,J=8.2Hz). MS(ESI)[M+H] + :274.

[0511] (Example 29) Synthesis of 2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline:

[0512] [ka]

[0513] Using 2-(4-(trifluoromethyl)phenyl)quinoline (80.0 mg, 0.293 mmol) synthesized in Reference Example 21, the title compound (hereinafter referred to as the compound of Example 29) (77.0 mg, 0.278 mmol, yield 95%) was obtained as a colorless, transparent oil by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.60(2H,d,J=8.2Hz),7.50(2H,d,J=8.2Hz),7.04-7.00(2H,m),6.68(1H,t,J=7.1Hz),6.57(1H,d,J=7.8H z),4.52(1H,dd,J=8.7,1.8Hz),4.05(1H,brs),2.95-2.87(1H,m),2.74-2.67(1H,m),2.17-2.10(1H,m),2.02-1.94(1H,m). MS(ESI)[M+H] + :278.

[0514] (Reference Example 22) Synthesis of 2-(3-(trifluoromethyl)phenyl)quinoline:

[0515] [ka]

[0516] Using 2-chloroquinoline (24.0 mg, 0.147 mmol) and (3-(trifluoromethyl)phenyl)boronic acid (30.6 mg, 0.161 mmol), the title compound (40.1 mg, 0.147 mmol, yield quant.) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.47(1H,brs),8.36(1H,d,J=7.8Hz),8.27(1H,d,J=8.2Hz),8.19(1H,d,J=8.7Hz),7.90(1H,d,J= 8.7Hz),7.86(1H,d,J=8.2Hz),7.78-7.74(1H,m),7.72(1H,d,J=7.8Hz),7.65(1H,t,J=7.8Hz),7.59-7.55(1H,m). MS(ESI)[M+H] + :274.

[0517] (Example 30) Synthesis of 2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline:

[0518] [ka]

[0519] Using 2-(3-(trifluoromethyl)phenyl)quinoline (40.0 mg, 0.146 mmol) synthesized in Reference Example 22, the title compound (hereinafter referred to as the compound of Example 30) (39.1 mg, 0.141 mmol, yield 96%) was obtained as a colorless, transparent oil by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.66(1H,s),7.59(1H,d,J=7.8Hz),7.55(1H,d,J=7.8Hz),7 .46(1H,t,J=7.5Hz),7.05-6.99(2H,m),6.68(1H,td,J=7.4,1.0Hz),6.58(1 H,dd,J=7.8,1.0Hz),4.51(1H,dd,J=9.1,2.3Hz),4.04(1H,brs),2.98-2.90 (1H,m),2.74(1H,dt,J=16.5,4.8Hz),2.16-2.10(1H,m),2.04-1.94(1H,m). MS(ESI)[M+H] + :278.

[0520] (Reference Example 23) Synthesis of 2-(4-(trifluoromethoxy)phenyl)quinoline:

[0521] [ka]

[0522] Using (4-(trifluoromethoxy)phenyl)boronic acid (138 mg, 0.672 mmol), the title compound (158 mg, 0.547 mmol, 90% yield) was obtained as a white solid by the same method as in Reference Example 6. 1H-NMR(CDCl3)δ:8.25(1H,d,J=8.7Hz),8.22-8.20(2H,m),8.16(1H,d,J=8.7Hz),7.86-7.84(2 H,m),7.75(1H,ddd,J=8.7,6.9,1.4Hz),7.56(1H,ddd,J=7.8,6.9,0.9Hz),7.40-7.38(2H,m). MS(ESI)[M+H] + :290.

[0523] (Example 31) Synthesis of 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline (novel compound):

[0524] [ka]

[0525] Using 2-(4-(trifluoromethoxy)phenyl)quinoline (158 mg, 0.547 mmol) synthesized in Reference Example 23, the title compound (hereinafter referred to as the compound of Example 31) (160 mg, 0.544 mmol, yield 99%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.43-7.39(2H,m),7.19(2H,d,J=8.2Hz),7.02-7.01(2H,m),6.67(1H,ddd,J=7.8,7.8,1.4Hz),6.55(1H,d,J=7.8Hz),4.46(1H, dd. MS(ESI)[M+H] + :294.

[0526] (Reference Example 24) Synthesis of 4-(quinoline-2-yl)benzenesulfonamide:

[0527] [ka]

[0528] Using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (4-sulfamoylphenyl)boronic acid (92.1 mg, 0.458 mmol), the title compound (66.1 mg, 0.232 mmol, yield 76%) was obtained as a pale yellow solid by the same method as in Reference Example 11. 1 H-NMR(DMSO-d6)δ:8.54(1H,d,J=8.2Hz),8.48(2H,d,J=8.2Hz),8.25(1H,d,J=8.2Hz),8.12(1H,d,J=8.2Hz ),8.05(1H,d,J=8.2Hz),8.00(2H,d,J=8.2Hz),7.83(1H,t,J=7.2Hz),7.65(1H,t,J=7.2Hz),7.51(2H,brs). MS(ESI)[M+H] + :285.

[0529] (Example 32) Synthesis of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide (novel compound):

[0530] [ka]

[0531] Using 4-(quinoline-2-yl)benzenesulfonamide (70.0 mg, 0.246 mmol) synthesized in Reference Example 24, the title compound (hereinafter referred to as the compound of Example 32) (36.1 mg, 0.125 mmol, yield 51%) was obtained as a white solid by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.91(2H,d,J=8.2Hz),7.55(2H,d,J=8.2Hz),7.06-7.00(2H,m),6.69(1H,t,J=7.1Hz),6.59(1H,d,J=8.2Hz),4.83 (2H,brs),4.55(1H,dd,J=8.7,3.2Hz),4.08(1H,brs),2.92-2.87(1H,m),2.72-2.67(1H,m),2.17-2.11(1H,m),2.01-1.95(1H,m). MS(ESI)[M+H] + :289.

[0532] (Example 33) Synthesis of one optically active form (novel compound) of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide:

[0533] [ka]

[0534] [In the formula, the carbon atom indicated by * represents the carbon atom that acts as a chiral center.] 4-(quinoline-2-yl)benzenesulfonamide (50.0 mg, 0.176 mmol) synthesized in Reference Example 24 and hydrogen phosphate (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (2.6 mg, 0.0035 mmol) were suspended in 1,4-dioxane (1.75 mL), and then 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (106 mg, 0.422 mmol) was added and the mixture was stirred at 60°C for 6 hours. Further addition of 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (106 mg, 0.422 mmol) was added and the mixture was stirred at 60°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (hereinafter referred to as the compound of Example 33) (22.4 mg, 0.0774 mmol, yield 44%, enantiomeric excess 98.1% ee) as a pale yellow solid. 1H-NMR(CDCl3)δ:7.91(2H,d,J=8.2Hz),7.55(2H,d,J=8.2Hz),7.06-7.00(2H,m),6.69(1H,t,J=7.1Hz),6.59(1H,d,J=8.2Hz),4.83 (2H,brs),4.55(1H,dd,J=8.7,3.2Hz),4.08(1H,brs),2.92-2.87(1H,m),2.72-2.67(1H,m),2.17-2.11(1H,m),2.01-1.95(1H,m). MS(ESI)[M+H] + :289. Rt:20.76 minutes HPLC analysis conditions: Column: DaicelChiralcelOD-H chiral column (Inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 60:40 Flow rate: 0.6mL / min Detection: UV (254nm)

[0535] (Example 34) Synthesis of the other optically active compound (novel compound) of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide:

[0536] [ka]

[0537] [In the formula, the carbon atom indicated by * represents the carbon atom that acts as a chiral center.] Using 4-(quinoline-2-yl)benzenesulfonamide (50.0 mg, 0.176 mmol) synthesized in Reference Example 24 and hydrogen phosphate (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (2.6 mg, 0.0035 mmol), the title compound (hereinafter referred to as the compound of Example 34) (37.7 mg, 0.131 mmol, yield 74%, enantiomeric excess 99.0% ee) was obtained as a white solid by the same method as in Example 33. 1 H-NMR(CDCl3)δ:7.91(2H,d,J=8.2Hz),7.55(2H,d,J=8.2Hz),7.06-7.00(2H,m),6.69(1H,t,J=7.1Hz),6.59(1H,d,J=8.2Hz),4.83 (2H,brs),4.55(1H,dd,J=8.7,3.2Hz),4.08(1H,brs),2.92-2.87(1H,m),2.72-2.67(1H,m),2.17-2.11(1H,m),2.01-1.95(1H,m). MS(ESI)[M+H] + :289. Rt:17.40 minutes HPLC analysis conditions: Column: DaicelChiralcelOD-H chiral column (Inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 60:40 Flow rate: 0.6mL / min Detection: UV (254nm)

[0538] (Reference Example 25) Synthesis of 4-(quinoline-2-yl)benzonitrile:

[0539] [ka]

[0540] Using 2-chloroquinoline (150 mg, 0.917 mmol) and (4-cyanophenyl)boronic acid (269 mg, 1.83 mmol), the title compound (100 mg, 0.917 mmol, yield 47%) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.32-8.29(3H,m),8.18(1H,d,J=8.2Hz),7.92-7.86(2H,m),7.84-7.82(2H,m),7.78(1H,t,J=7.1Hz),7.59(1H,t,J=7.1Hz). MS(ESI)[M+H] + :231.

[0541] (Example 35) Synthesis of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzonitrile:

[0542] [ka]

[0543] Using 4-(quinoline-2-yl)benzonitrile (95.0 mg, 0.413 mmol) synthesized in Reference Example 25, the title compound (hereinafter referred to as the compound of Example 35) (94.9 mg, 0.405 mmol, yield 98%) was obtained as a white solid by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.64(2H,d,J=8.2Hz),7.50(2H,d,J=8.2Hz),7.06-7.00(2H,m),6.69(1H,t,J=7.3Hz),6.58(1H,d,J=7. 8Hz),4.53(1H,d,J=7.3Hz),4.07(1H,brs),2.93-2.86(1H,m),2.72-2.64(1H,m),2.17-2.10(1H,m),2.00-1.93(1H,m). MS(ESI)[M+H] + :235.

[0544] (Example 36) Synthesis of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide (novel compound):

[0545] [ka]

[0546] 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzonitrile (32.0 mg, 0.137 mmol) synthesized in Example 35 was dissolved in DMSO / THF (1 / 4, v / v, 1.4 mL), and then 1 mol / L aqueous sodium hydroxide solution (300 μL, 0.300 mmol) and 30% hydrogen peroxide solution (23 μL, 0.300 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 36) (29.9 mg, 0.119 mmol, yield 87%) as a pale yellow solid. 1 H-NMR(CDCl3)δ:7.80(2H,d,J=8.2Hz),7.48(2H,d,J=7.8Hz),7.05-7.00(2H,m),6.68(1H,t,J=7.1Hz),6.58(1H,d,J=8.2Hz),6.08(1H,br s),5.67(1H,brs),4.52(1H,dd,J=8.9,3.4Hz),4.08(1H,brs),2.96-2.87(1H,m),2.72-2.68(1H,m),2.17-2.10(1H,m),2.02-1.95(1H,m). MS(ESI)[M+H] + :253.

[0547] (Reference Example 26) Synthesis of 4-(chloroquinoline-2-yl)-benzamide:

[0548] [ka]

[0549] Using 2-chloroquinoline (400 mg, 2.45 mmol) and (4-carbamoylphenyl)boronic acid (605 mg, 3.67 mmol), the title compound (329.0 mg, 1.32 mmol, yield 54%) was obtained as a pale yellow solid by the same method as in Reference Example 6. 1H-NMR(DMSO-d6)δ:8.51(1H,d,J=8.6Hz),8.37(2H,d,J=8.6Hz),8.24(1H,d,J=8.6 Hz),8.12-8.02(5H,m),7.81(1H,t,J=7.7Hz),7.63(1H,t,J=7.0Hz),7.48(1H,s). MS(ESI)[M+H] + :249.

[0550] (Example 37) Synthesis of one optically active form (novel compound) of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide:

[0551] [ka]

[0552] [In the formula, the carbon atom indicated by * represents the carbon atom that acts as a chiral center.] 4-(quinoline-2-yl)benzamide (50.0 mg, 0.201 mmol) synthesized in Reference Example 26 and hydrogen phosphate (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (3.0 mg, 0.0040 mmol) were suspended in 1,4-dioxane (2 mL), and 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (0.122 g, 0.483 mmol) was added. The mixture was stirred at room temperature under an argon atmosphere for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) and recrystallization (ethyl acetate / methanol) to obtain the title compound (hereinafter referred to as the compound of Example 37) (11.0 mg, 0.0436 mmol, yield 22%, enantiomeric excess 98.2% ee) as a white solid. 1H-NMR(CDCl3)δ:7.80(2H,d,J=8.2Hz),7.49(2H,t,J=11.3Hz),7.02(2H,d,J=6.9Hz),6.67(1H,t,J=7.2Hz),6.58(1H,d,J=7.7Hz),6.05(1H ,s),5.58(1H,s),4.52(1H,d,J=6.8Hz),4.07(1H,s),2.95-2.87(1H,m ),2.71(1H,dt,J=16.6,5.1Hz),2.16-2.11(1H,m),2.05-1.94(1H,m). MS(ESI)[M+H] + :253. Rt:14.28 minutes HPLC analysis conditions: Column: DaicelChiralcelOD-H chiral column (Inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 40:60 Flow rate: 0.6mL / min Detection: UV (254nm)

[0553] (Example 38) Synthesis of the other optically active compound (novel compound) of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide:

[0554] [ka]

[0555] [In the formula, the carbon atom indicated by * represents the carbon atom that acts as a chiral center.] Using 4-(quinoline-2-yl)benzamide (50.0 mg, 0.201 mmol) synthesized in Reference Example 26 and hydrogen phosphate (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (3.0 mg, 0.0040 mmol), the title compound (hereinafter referred to as the compound of Example 38) (13.7 mg, 0.0543 mmol, yield 46%, enantiomeric excess 97.6% ee) was obtained as a white solid by the same method as in Example 37. 1 H-NMR(CDCl3)δ:7.80(2H,d,J=8.2Hz),7.49(2H,t,J=11.3Hz),7.02(2H,d,J=6.9Hz),6.67(1H,t,J=7.2Hz),6.58(1H,d,J=7.7Hz),6.05(1H ,s),5.58(1H,s),4.52(1H,d,J=6.8Hz),4.07(1H,s),2.95-2.87(1H,m ),2.71(1H,dt,J=16.6,5.1Hz),2.16-2.11(1H,m),2.05-1.94(1H,m). MS(ESI)[M+H] + :253. Rt:24.14 minutes HPLC analysis conditions: Column: DaicelChiralcelOD-H chiral column (Inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm) Column temperature: 40℃ Mobile phase:propan-2-ol:hexane = 40:60 Flow rate: 0.6mL / min Detection: UV (254nm)

[0556] (Reference Example 27) Synthesis of 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzoic acid:

[0557] [ka]

[0558] Methyl 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoate (545 mg, 2.04 mmol) synthesized in Example 17 was dissolved in THF / methanol (5.0 mL / 5.0 mL), 8 mol / L aqueous sodium hydroxide solution (0.764 mL, 6.11 mmol) was added, and the mixture was stirred at room temperature for 20 hours under an argon atmosphere. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The obtained crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (497 mg, 1.96 mmol, yield 96%) as a cream-colored solid. 1 1H-NMR (CD3OD) δ: 7.97 (2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.2 Hz), 6.94 - 6.89 (2H, m), 6.61 - 6.52 (2H, m), 4.52 - 4.49 (1H, m), 2.88 - 2.80 (1H, m), 2.65 - 2.58 (1H, m), 2.14 - 2.07 (1H, m), 2.01 - 1.91 (1H, m). MS (ESI) [M+H] + : 254.

[0559] (Example 39) Synthesis of N,N-diethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (novel compound):

[0560]

Chemical formula

[0561] 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzoic acid (37.9 mg, 0.150 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (68.3 mg, 0.180 mmol), diethylamine (17.0 μL, 0.165 mmol), and N,N-diisopropylethylamine (39.1 μL, 0.224 mmol), synthesized in Reference Example 27, were dissolved in DMF (1.2 mL) and stirred at room temperature for 16 hours. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 39) (14.5 mg, 47.0 μmol, yield 31%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.41(2H,d,J=8.4Hz),7.35(2H,d,J=8.4Hz),7.04-6.99(2 H,m),6.68-6.64(1H,m),6.56(1H,d,J=8.4Hz),4.47(1H,dd,J=9.1,3.6Hz) ,4.05(1H,brs),3.60-3.22(2H,m),3.33-3.22(2H,m),2.95-2.87(1H,m),2 .76-2.69(1H,m),2.15-2.09(1H,m),2.03-1.93(1H,m),1.28-1.08(6H,m). MS(ESI)[M+H] + :309.

[0562] (Example 40) Synthesis of N-ethyl-4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide (novel compound):

[0563] [ka]

[0564] 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzoic acid (30.0 mg, 0.118 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (54.0 mg, 0.142 mmol), 2 mol / L ethylamine methanol solution (65.1 μL, 0.130 mmol), and N,N-diisopropylethylamine (30.9 μL, 0.178 mmol) synthesized in Reference Example 27 were dissolved in DMF (1.2 mL) and stirred at room temperature for 16 hours. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 40) (24.5 mg, 47.0 μmol, yield 74%) as a white solid. 1 H-NMR(CDCl3)δ:7.75-7.72(2H,m),7.44(2H,d,J=8.2Hz),7.04-6.99(2H,m ),6.68-6.66(1H,ddd,J=7.6,7.6,0.8Hz),6.57(1H,dd,J=7.7,0.9Hz),6.0 9(1H,brs),4.50(1H,dd,J=9.1,3.6Hz),4.06(1H,brs),3.54-3.47(2H,m), 2.95-2.87(1H,m),2.74-2.67(1H,m),2.16-2.09(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :281.

[0565] (Example 41) Synthesis of piperidine-1-yl(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone (novel compound):

[0566] [ka]

[0567] 4-(1,2,3,4-Tetrahydroquinolin-2-yl)benzoic acid (30.0 mg, 0.118 mmol) synthesized in Reference Example 27, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (54.0 mg, 0.142 mmol) were dissolved in DMF (1.2 mL), piperidine (12.9 μL, 0.130 mmol) and N,N-diisopropylethylamine (30.9 μL, 0.178 mmol) were added, and the mixture was stirred at room temperature for 14 hours under an argon atmosphere. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were washed with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter, the compound of Example 41) (28.6 mg, 89.3 μmol, yield 75%) as a white amorphous solid. 1 1H-NMR (CDCl3) δ: 7.42 - 7.36 (4H, m), 7.04 - 7.00 (2H, m), 6.66 (1H, ddd, J = 7.6, 7.6, 1.2 Hz), 6.56 (1H, d, J = 7.7 Hz), 4.47 (1H, dd, J = 9.1, 3.6 Hz), 4.05 (1H, brs), 3.71 (2H, brs), 3.36 (2H, brs), 2.95 - 2.87 (1H, m), 2.76 - 2.69 (1H, m), 2.16 - 2.09 (1H, m), 2.03 - 1.93 (1H, m), 1.68 (4H, brs), 1.53 (2H, brs). MS (ESI) [M + H] + : 321.

[0568] (Example 42) Synthesis of morpholino(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone (novel compound):

[0569]

Chemical formula

[0570] 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzoic acid (30.0 mg, 0.118 mmol) synthesized in Reference Example 27 and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (54.0 mg, 0.142 mmol) were dissolved in DMF (1.2 mL), morpholine (11.2 μL, 0.130 mmol) and N,N-diisopropylethylamine (30.9 μL, 0.178 mmol) were added, and the mixture was stirred at room temperature under an argon atmosphere for 16 hours. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 42) (33.4 mg, 0.104 mmol, yield 88%) as a white solid. 1 H-NMR(CDCl3)δ:7.45-7.38(4H,m),7.04-6.98(2H,m),6.69-6.64(1H,m),6.56(1H,d,J=7.7Hz),4.48(1H,dd,J=9.1,3 .2Hz),4.05(1H,brs),3.77-3.48(8H,m),2.95-2.87(1H,m),2.75-2.68(1H,m),2.21-2.09(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :323.

[0571] (Example 43) Synthesis of (4-methylpiperazine-1-yl)(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone (novel compound):

[0572] [ka]

[0573] 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzoic acid (30.0 mg, 0.118 mmol) synthesized in Reference Example 27 and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (54.0 mg, 0.142 mmol) were dissolved in DMF (1.2 mL), and 1-methylpiperazine (14.3 μL, 0.130 mmol) and N,N-diisopropylethylamine (30.9 μL, 0.178 mmol) were added. The mixture was stirred at room temperature under an argon atmosphere for 14 hours. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 43) (32.8 mg, 97.8 μmol, yield 83%) as a white amorphous material. 1 H-NMR(CDCl3)δ:7.44-7.37(4H,m),7.04-7.00(2H,m),6.67(1H,ddd,J=7.5,1.1,0.5Hz),6.56(1H,d,J=8.4Hz),4.48(1H,dd,J=8.8,3.4Hz), 4.04(1H,brs),3.80(2H,brs),3.46(2H,brs),2.96-2.87(1H,m),2.75 -2.69(1H,m),2.49-2.33(7H,m),2.16-2.09(1H,m),2.03-1.93(1H,m). MS(ESI)[M+H] + :336.

[0574] (Reference Example 28) Synthesis of N-methyl-3-(quinoline-2-yl)benzamide:

[0575] [ka]

[0576] 2-chloroquinoline (100 mg, 0.611 mmol), (4-(methylcarbamoyl)phenyl)boronic acid (164 mg, 0.917 mmol), tetrakis(triphenylphosphine)palladium (0) (14.1 mg, 0.0122 mmol), and potassium carbonate (253 mg, 1.83 mmol) were suspended in 1,4-dioxane (2 mL) and then heated and stirred at 100°C for 15 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (156 mg, 0.593 mmol, yield 97%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:8.58(1H,s),8.29-8.25(2H,m),8.17(1H,d,J=8.7Hz),7.94-7.84(3 H,m),7.76(1H,t,J=7.3Hz),7.62-7.54(2H,m),6.44(1H,brs),3.07(3H,d,J=5.0Hz). MS(ESI)[M+H] + :263.

[0577] (Example 44) Synthesis of N-methyl-3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide (novel compound):

[0578] [ka]

[0579] Using N-methyl-3-(quinoline-2-yl)benzamide (155 mg, 0.591 mmol) synthesized in Reference Example 28, the title compound (hereinafter referred to as the compound of Example 44) (132 mg, 0.496 mmol, yield 84%) was obtained as a colorless, transparent oil by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.80(1H,s),7.68(1H,d,J=7.8Hz),7.53(1H,d,J=7.3Hz),7.41 (1H,t,J=7.8Hz),7.04-7.00(2H,m),6.67(1H,t,J=7.1Hz),6.57(1H,d,J=7.8Hz ),6.16(1H,brs),4.50(1H,dd,J=9.4,3.0Hz),4.06(1H,brs),3.02(3H,d,J=5.0 Hz),2.97-2.89(1H,m),2.75-2.71(1H,m),2.16-2.09(1H,m),2.04-1.94(1H,m). MS(ESI)[M+H] + :267.

[0580] (Reference Example 29) Synthesis of 3-(quinoline-2-yl)benzonitrile:

[0581] [ka]

[0582] Using 2-chloroquinoline (150 mg, 0.917 mmol) and (3-cyanophenyl)boronic acid (269 mg, 1.83 mmol), the title compound (211 mg, 0.917 mmol, yield quant.) was obtained as a white solid by the same method as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.23(1H,d,J=8.7Hz),8.19-8.14(3H,m),7.85-7.82(2H,m),7.74(1H,t,J=7.1Hz),7.54(1H,t,J=7.1Hz),7.24-7.19(2H,m). MS(ESI)[M+H] + :224.

[0583] (Example 45) Synthesis of 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzonitrile (novel compound):

[0584] [ka]

[0585] Using 3-(quinoline-2-yl)benzonitrile (210 mg, 0.912 mmol) synthesized in Reference Example 29, the title compound (hereinafter referred to as the compound of Example 45) (191 mg, 0.812 mmol, yield 89%) was obtained as a colorless, transparent oil by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.70(1H,s),7.63(1H,d,J=7.8Hz),7.58(1H,d,J=7.8Hz),7.46(1H,t,J=7.8Hz),7.05-7.01(2H,m),6.69(1H,t,J=7.3Hz) ,6.58(1H,d,J=7.8Hz),4.50(1H,d,J=6.9Hz),4.05(1H,brs),2.95-2.87(1H,m),2.73-2.67(1H,m),2.17-2.10(1H,m),2.01-1.94(1H,m). MS(ESI)[M+H] + :235.

[0586] (Example 46) Synthesis of 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide (novel compound):

[0587] [ka]

[0588] 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzonitrile (140 mg, 0.598 mmol) synthesized in Example 45 was dissolved in DMSO / THF (1 / 4, v / v, 6 mL), and then 8 mol / L aqueous sodium hydroxide solution (164 μL, 1.31 mmol) and 30% hydrogen peroxide solution (103 μL, 1.31 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 46) (115 mg, 0.454 mmol, yield 76%) as a white solid. 1 H-NMR(CDCl3)δ:7.86(1H,s),7.73(1H,d,J=7.8Hz),7.57(1H,d,J=7.8Hz),7. 44(1H,t,J=7.5Hz),7.04-6.99(2H,m),6.68(1H,t,J=7.5Hz),6.57(1H,d,J=7. 8Hz),6.11(1H,brs),5.62(1H,brs),4.51(1H,dd,J=9.4,3.0Hz),4.06(1H,brs ),2.98-2.90(1H,m),2.76-2.70(1H,m),2.16-2.10(1H,m),2.05-1.95(1H,m). MS(ESI)[M+H] + :253.

[0589] (Reference Example 30) Synthesis of (2-(quinoline-2-yl)phenyl)methanol:

[0590] [ka]

[0591] Using 2-chloroquinoline (100 mg, 0.611 mmol) and (2-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol), the title compound (139 mg, 0.592 mmol, yield 97%) was obtained as a white solid by the same method as in Reference Example 28. 1 H-NMR(CDCl3)δ:8.33(1H,d,J=8.7Hz),8.12(1H,d,J=7.8Hz),7.89(1H,dd,J=8.0,1.1Hz),7.78-7.76(2H,m),7.72-7.69(1H,m ),7.60(1H,ddd,J=8.2,6.9,0.9Hz),7.57-7.53(1H,m),7.49-7.46(2H,m),6.81(1H,dd,J=6.9,6.9Hz),4.56(2H,d,J=6.9Hz). MS(ESI)[M+H] + :236.

[0592] (Example 47) Synthesis of (2-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol (novel compound):

[0593] [ka]

[0594] Using (2-(quinoline-2-yl)phenyl)methanol (139 mg, 0.592 mmol) synthesized in Reference Example 30, the title compound (hereinafter referred to as the compound of Example 47) (56.6 mg, 0.237 mmol, yield 40%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.57(1H,dd,J=7.3,1.4Hz),7.41-7.27(4H,m),7.04-7.00(2H,m),6.69(1H,ddd,J=7.3,7.3,1.4Hz),6.56(1H,d,J=8.2Hz),4.79 (2H,dd,J=19.7,12.3Hz),4.73(1H,dd,J=9.6,3.2Hz),2.99(1H,ddd,J=16.9,11.4,5.5Hz),2.81(1H,ddd,J=16.5,4.1,4.1Hz),2.19-2.05(2H,m). MS(ESI)[M+H] + :240.

[0595] (Reference Example 31) Synthesis of (3-(quinoline-2-yl)phenyl)methanol:

[0596] [ka]

[0597] Using 2-chloroquinoline (100 mg, 0.611 mmol) and (3-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol), the title compound (143 mg, 0.607 mmol, 99% yield) was obtained as a colorless amorphous material in the same manner as in Reference Example 28. 1 H-NMR(CDCl3)δ:8.24(1H,d,J=8.7Hz),8.18-8.17(2H,m),8.06(1H,ddd,J=7.8,1.4,1.4Hz),7.89(1H,d,J=8.2Hz),7.8 5-7.83(1H,m),7.74(1H,ddd,J=8.2,6.9,1.4Hz),7.56-7.46(3H,m),4.83(2H,d,J=5.9Hz),1.95(1H,dd,J=5.9,5.9Hz). MS(ESI)[M+H] + :236.

[0598] (Example 48) Synthesis of (3-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol (novel compound):

[0599] [ka]

[0600] Using (3-(quinoline-2-yl)phenyl)methanol (143 mg, 0.607 mmol) synthesized in Reference Example 31, the title compound (hereinafter referred to as the compound of Example 48) (133 mg, 0.554 mmol, yield 94%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.37-7.33(4H,m),7.02-7.00(2H,m),6.66(1H,dd,J=7.3,7 .3Hz),6.55(1H,d,J=8.2Hz),4.71(2H,d,J=4.6Hz),4.45(1H,dd,J=9.1,3.2 Hz),4.03(1H,brs),2.93(1H,ddd,J=16.5,11.0,5.9Hz),2.74(1H,ddd,J=16 .0,4.6,4.6Hz),2.14-2.10(1H,m),2.05-1.95(1H,m),1.67(1H,t,J=5.5Hz). MS(ESI)[M+H] + :240.

[0601] (Reference Example 32) Synthesis of (4-(quinoline-2-yl)phenyl)methanol:

[0602] [ka]

[0603] Using 2-chloroquinoline (100 mg, 0.611 mmol) and (4-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol), the title compound (136 mg, 0.576 mmol, yield 94%) was obtained as a white solid by the same method as in Reference Example 28. 1 H-NMR(CDCl3)δ:8.23(1H,d,J=8.7Hz),8.18-8.17(3H,m),7.89(1H,d,J=8.7Hz),7.84(1H,dd,J=8.0,1.1 Hz),7.74(1H,ddd,J=8.2,6.9,12.8Hz),7.56-7.52(3H,m),4.80(2H,d,J=5.9Hz),1.81(1H,t,J=5.9Hz). MS(ESI)[M+H] + :236.

[0604] (Example 49) Synthesis of (4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol (novel compound):

[0605] [ka]

[0606] Using (4-(quinoline-2-yl)phenyl)methanol (136 mg, 0.576 mmol) synthesized in Reference Example 32, the title compound (hereinafter referred to as the compound of Example 49) (77.3 mg, 0.323 mmol, yield 56%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.40(2H,d,J=8.2Hz),7.36(2H,d,J=8.2Hz),7.02-7.00(2H,m),6.6 6(1H,ddd,J=7.2,7.2,1.4Hz),6.55(1H,d,J=7.7Hz),4.70(2H,d,J=5.9Hz),4.45(1H ,dd,J=9.3,3.4Hz),4.03(1H,brs),2.92(1H,ddd,J=16.3,10.4,5.4Hz),2.73(1H,dd d,J=16.3,4.5,4.5Hz),2.15-2.08(1H,m),2.03-1.93(1H,m),1.64(1H,t,J=5.9Hz). MS(ESI)[M+H] + :240.

[0607] (Reference Example 33) Synthesis of 4-(quinoline-2-yl)isothiazole:

[0608] [ka]

[0609] Using 2-chloroquinoline (100 mg, 0.611 mmol) and isothiazole-4-ylboronic acid (118 mg, 0.917 mmol), the title compound (122 mg, 0.574 mmol, yield 94%) was obtained as a yellow solid by the same method as in Reference Example 6. 1H-NMR(CDCl3)δ:9.28(1H,s),9.25(1H,s),8.23(1H,d,J=8.7Hz),8.13(1H,d ,J=8.2Hz),7.83(1H,d,J=8.2Hz),7.78-7.73(2H,m),7.55(1H,t,J=7.5Hz). MS(ESI)[M+H] + :213.

[0610] (Example 50) Synthesis of 4-(1,2,3,4-tetrahydroquinoline-2-yl)isothiazole:

[0611] [ka]

[0612] Using 4-(quinoline-2-yl)isothiazole (110 mg, 0.518 mmol) synthesized in Reference Example 33, the title compound (hereinafter referred to as the compound of Example 50) (77.5 mg, 0.357 mmol, yield 69%) was obtained as a yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:8.51(1H,s),8.50(1H,s),7.04-6.99(2H,m),6.68(1H,t,J=7.1Hz),6.55(1H,d,J=7.8Hz),4.71( 1H,dd,J=8.7,2.7Hz),4.09(1H,brs),2.95-2.87(1H,m),2.75-2.70(1H,m),2.22-2.15(1H,m),2.07-2.01(1H,m). MS(ESI)[M+H] + :217.

[0613] (Reference Example 34) Synthesis of (2-phenylquinoline-5-yl)methanol:

[0614] [ka]

[0615] 60.0 mg, 0.228 mmol of methyl 2-phenylquinoline-5-carboxylate was dissolved in toluene (1 mL) under an argon atmosphere. 0.912 mL, 0.912 mmol of 1.0 mol / L diisobutylaluminum hydride / hexane solution was added at -78°C, and the mixture was stirred at -78°C for 1.5 hours. After the reaction was complete, the reaction mixture was raised to 0°C, saturated potassium sodium tartrate aqueous solution was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The aqueous layer was extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (51.7 mg, 0.220 mmol, yield 96%) as a white solid. 1 H-NMR(CDCl3)δ:8.59(1H,d,J=9.1Hz),8.19-8.14(3H,m),7.94(1H,d,J=8.7Hz),7.69(1H,dd ,J=8.5,7.1Hz),7.57-7.52(3H,m),7.50-7.46(1H,m),5.17(2H,d,J=5.9Hz),5.12(1H,brs). MS(ESI)[M+H] + :236.

[0616] (Example 51) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinoline-5-yl)methanol (novel compound):

[0617] [ka]

[0618] Using (2-phenylquinoline-5-yl)methanol (51.7 mg, 0.220 mmol) synthesized in Reference Example 34, the title compound (hereinafter referred to as the compound of Example 51) (47.2 mg, 0.197 mmol, yield 90%) was obtained as a pale yellow solid by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.39-7.36(5H,m),7.03(1H,dd,J=7.8,7.8Hz),6.74(1H,d,J=7.3Hz),6.54(1H,d,J=7.8Hz),5.09(1H,brs) ,4.65(2H,d,J=5.9Hz),4.42(1H,dd,J=9.8,3.0Hz),4.10(1H,brs),2.93-2.80(2H,m),2.17-2.15(1H,m),2.02-1.99(1H,m). MS(ESI)[M+H] + :240.

[0619] (Example 52) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinoline-7-yl)methanol (novel compound):

[0620] [ka]

[0621] Using (2-phenylquinoline-7-yl)methanol (40.0 mg, 0.170 mol), the title compound (hereinafter referred to as the compound of Example 52) (38.8 mg, 0.162 mmol, yield 95%) was obtained as a colorless amorphous solution in the same manner as in Example 26. 1 H-NMR(CDCl3)δ:7.41-7.28(5H,m),7.00-6.99(1H,m),6.64(1H,d,J=7.8Hz),6.57(1H,s),4.58(2H,d,J=5.9Hz),4.45(1H,dd,J=9.1, 3.2Hz),4.10(1H,brs),2.90(1H,ddd,J=16.0,10.5,5.5Hz),2.73(1H,ddd,J=16.5,5.0,5.0Hz),2.16-2.09(1H,m),2.05-1.93(1H,m). MS(ESI)[M+H] + :240.

[0622] (Example 53) Synthesis of 2-(pyridine-2-yl)-1,2,3,4-tetrahydroquinoline:

[0623] [ka]

[0624] Using 2-(pyridine-2-yl)quinoline (30.0 mg, 0.145 mmol), the title compound (hereinafter referred to as the compound of Example 53) (25.3 mg, 0.120 mmol, yield 83%) was obtained as a pale yellow amorphous material in the same manner as in Example 26. 1 H-NMR(CDCl3)δ:8.59-8.58(1H,m),7.68(1H,ddd,J=7.8,7.8,1.4Hz),7.43(1H,d,J= 8.2Hz),7.20(1H,dd,J=7.5,4.8Hz),7.05-6.99(2H,m),6.67(1H,d,J=7.3Hz),6.64(1 H,d,J=7.8Hz),4.60(1H,dd,J=8.5,3.4Hz),4.52(1H,brs),2.92(1H,ddd,J=15.6,10 .1,5.0Hz),2.70(1H,ddd,J=16.0,4.6,4.6Hz),2.31-2.24(1H,m),2.05-2.02(1H,m). MS(ESI)[M+H] + :211.

[0625] (Reference Example 35) Synthesis of 2-(2-chloroquinoline-6-yl)propan-2-ol:

[0626] [ka]

[0627] 2-chloroquinoline-6-carboxylate methyl (100 mg, 0.451 mmol) was dissolved in THF (2 mL), and 1 mol / L methylmagnesium bromide / THF solution (1.35 mL, 1.35 mmol) was added under an argon atmosphere at -78°C, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, saturated ammonium chloride aqueous solution was added to the reaction mixture until the pH reached 6-7, and the aqueous layer was extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (75.5 mg, 0.341 mmol, yield 75%) as a white solid. 1 H-NMR(CDCl3)δ:8.11(1H,d,J=8.7Hz),8.00(1H,d,J=9.1Hz),7.95(1H,d,J=2.3H z),7.85(1H,dd,J=8.9,2.1Hz),7.39(1H,d,J=8.2Hz),1.88(1H,s),1.68(6H,s). MS(ESI)[M+H] + :222.

[0628] (Reference Example 36) Synthesis of 2-(2-phenylquinoline-6-yl)propan-2-ol:

[0629] [ka]

[0630] Using 2-(2-chloroquinoline-6-yl)propan-2-ol (75.5 mg, 0.341 mmol) and phenylboronic acid (45.7 mg, 0.375 mmol) synthesized in Reference Example 35, the title compound (89.2 mg, 0.339 mmol, 99% yield) was obtained as a white solid by the same method as in Reference Example 28. 1H-NMR(CDCl3)δ:8.22(1H,d,J=8.6Hz),8.16-8.14(3H,m),7.94(1H,d,J=1.8Hz),7.88(1 H,d,J=8.6Hz),7.85(1H,dd,J=9.1,2.3Hz),7.53-7.47(3H,m),1.90(1H,s),1.71(6H,s). MS(ESI)[M+H] + :264.

[0631] (Example 54) Synthesis of 6-isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline (novel compound):

[0632] [ka]

[0633] Using 2-(2-phenylquinoline-6-yl)propan-2-ol (40.0 mg, 0.152 mmol) synthesized in Reference Example 36, the title compound (hereinafter referred to as the compound of Example 54) (21.4 mg, 85.1 μmol, yield 56%) was obtained as a colorless amorphous material by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.40-7.33(4H,m),7.30-7.26(1H,m),6.90-6.88(2H,m),6.50(1H,d,J=7.7Hz),4.40(1H,dd,J=9.5,3.2Hz),3.93 (1H,brs),2.94(1H,ddd,J=16.8,11.3,5.9Hz),2.84-2.70(2H,m),2.12-2.09(1H,m),2.01-1.97(1H,m),1.22(3H,s),1.21(3H,s). MS(ESI)[M+H] + :252.

[0634] (Reference Example 37) Synthesis of 2-phenylquinoline-6-ol:

[0635] [ka]

[0636] Using 2-chloroquinoline-6-ol (50.0 mg, 0.278 mmol), the title compound (47.0 mg, 0.212 mmol, yield 76%) was obtained as a white solid by the same method as in Reference Example 28. 1 H-NMR(CDCl3)δ:8.13-8.11(2H,m),8.08(2H,dd,J=8.8,4.3Hz),7.83(1H,d,J=8.6Hz),7.53-7 .51(2H,m),7.46-7.42(1H,m),7.33(1H,dd,J=9.1,2.7Hz),7.12(1H,d,J=2.7Hz),5.32(1H,s). MS(ESI)[M+H] + :222.

[0637] (Example 55) Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinoline-6-ol:

[0638] [ka]

[0639] Using 2-phenylquinoline-6-ol (20.0 mg, 90.4 μmol) synthesized in Reference Example 37, the title compound (hereinafter referred to as the compound of Example 55) (20.3 mg, 90.1 μmol, yield >99%) was obtained as a colorless amorphous material by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.41-7.24(5H,m),6.57-6.38(3H,m),4.36(1H,dd,J=9.5,2.7Hz),4.20(1H,brs),2.91(1H,ddd ,J=16.8,10.9,5.9Hz),2.70(1H,ddd,J=16.8,4.5,4.5Hz),2.11-2.09(1H,m),2.00-1.96(1H,m),1.79(1H,brs). MS(ESI)[M+H] + :226.

[0640] (Reference Example 38) Synthesis of methyl 2-phenylquinoline-6-carboxylate:

[0641] [ka]

[0642] Using methyl 2-chlorophenylquinoline-6-carboxylate (100 mg, 0.451 mmol), the title compound (91.0 mg, 0.346 mmol, yield 77%) was obtained as a white solid by the same method as in Reference Example 28. 1 H-NMR(CDCl3)δ:8.61(1H,d,J=1.8Hz),8.33-8.31(2H,m),8.21-8.19(3H,m),7.96(1H,d,J=8.6Hz),7.52-7.47(3H,m),4.01(3H,s). MS(ESI)[M+H] + :264.

[0643] (Example 56) Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate methyl (novel compound):

[0644] [ka]

[0645] Using methyl 2-phenylquinoline-6-carboxylate (120 mg, 0.456 mmol) synthesized in Reference Example 38, the title compound (hereinafter referred to as the compound of Example 56) (112 mg, 0.420 mmol, yield 92%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.71-7.70(2H,m),7.39-7.28(5H,m),6.50(1H,d,J=8.6Hz),4.55-4.50(2H,m),3.85(3H,s), 2.89(1H,ddd,J=16.3,10.9,5.4Hz),2.75(1H,ddd,J=16.3,5.0,5.0Hz),2.16-2.13(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :268.

[0646] (Example 57) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)propan-2-ol (novel compound):

[0647] [ka]

[0648] 2-phenyl-1,2,3,4-tetrahydroquinoline-6-methyl carboxylate (25.0 mg, 93.5 μmol) synthesized in Example 56 was dissolved in THF (1 mL), and 1 mol / L methylmagnesium bromide / THF solution (0.374 mL, 0.374 mmol) was added under an argon atmosphere at 0°C, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by thin-layer preparative chromatography (hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 57) (3.70 mg, 13.8 μmol, yield 15%) as a pale yellow amorphous material. 1H-NMR(CDCl3)δ:7.38-7.31(5H,m),7.14-7.13(2H,m),6.53(1H,d,J=8.2Hz),4.43(1H,dd,J=9.5,3.2Hz),4.05(1H,brs),2.94(1 H,ddd,J=16.8,10.9,6.3Hz),2.75(1H,ddd,J=16.8,5.0,5.0Hz),2.18-2.10(1H,m),2.01-1.98(1H,m),1.63(1H,s),1.57(6H,s). MS(ESI)[M+H] + :268.

[0649] (Example 58) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanol (novel compound):

[0650] [ka]

[0651] 38.0 mg, 0.142 mmol of methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (38.0 mg) synthesized in Example 56 was dissolved in toluene (2.0 mL), and then 0.426 mL, 0.426 mmol, of a 1.01 mol / L diisobutylaluminum hydride / toluene solution was slowly added dropwise at -78°C under an argon atmosphere. The reaction mixture was then slowly heated to room temperature and stirred for 6 hours. After the reaction was complete, 8 mL of aqueous potassium sodium tartrate solution was added, and the mixture was stirred overnight at room temperature. The aqueous layer was extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 58) (25.6 mg, 0.107 mmol, yield 75%) as a colorless, transparent oil. 1H-NMR(CDCl3)δ:7.40-7.33(4H,m),7.31-7.25(1H,m),7.05-7.00(2H,m),6.54(1H,dd,J=6.3,2.3Hz),4.54(2H,d,J=4.5Hz),4.45(1H,dd,J= 9.1,3.2Hz),4.12(1H,q,J=7.1Hz),2.95-2.87(1H,m),2.73(1H,td,J=10.6,5.6Hz),2.16-2.10(1H,m),2.05-1.94(1H,m),1.44(1H,t,J=5.4 Hz). MS(ESI)[M+H] + :240.

[0652] (Example 59) Synthesis of 4-((2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methyl)morpholine (novel compound):

[0653] [ka]

[0654] (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanol (30.0 mg, 0.125 mmol) synthesized in Example 58 was dissolved in dichloromethane (1.3 mL), then morpholine (55 μL, 0.63 mmol), triphenylphosphine (39.5 mg, 0.150 mmol), and iodine (38.2 mg, 0.150 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by amino column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 59) (21.0 mg, 0.0675 mmol, yield 54%) as a colorless, transparent oil. 1H-NMR(CDCl3)δ:7.40-7.33(4H,m),7.30-7.27(1H,m),6.95-6.93(2H,m),6.50(1H,d,J=8.7Hz),4.42(1H,dd,J=9.4,3.0Hz),4.03(1H ,brs),3.71(4H,t,J=4.6Hz),3.37(2H,s),2.96-2.88(1H,m),2.76-2.70(1H,m),2.44(4H,brs),2.15-2.08(1H,m),2.03-1.93(1H,m). MS(ESI)[M-morpholine] + :222.

[0655] (Reference Example 39) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetonitrile:

[0656] [ka]

[0657] (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanol (100 mg, 0.418 mmol) synthesized in Example 58 was dissolved in THF (4.2 mL), and then acetone cyanohydrin (114 μL, 1.25 mmol) and tri-n-butylphosphine (207 μL, 0.836 mmol) were added. Under ice cooling, 1,1'-(azodicarbonyl)dipiperidine (211 mg, 0.836 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (64.2 mg, 0.259 mmol, yield 62%) as a colorless, transparent oil. 1H-NMR(CDCl3)δ:7.37-7.27(5H,m),6.96-6.92(2H,m),6.52(1H,d,J=7.8Hz),4.45(1H,ddd,J=9.1,3.2,1.4Hz),4 .12(1H,brs),3.62(2H,s),2.94-2.86(1H,m),2.72(1H,dt,J=16.5,4.8Hz),2.15-2.10(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :249.

[0658] (Example 60) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide (novel compound):

[0659] [ka]

[0660] 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetonitrile (62.0 mg, 0.250 mmol) synthesized in Reference Example 39 was dissolved in DMSO / THF / ethanol (1 / 1 / 2, v / v / v, 5 mL). Then, 8 mol / L aqueous sodium hydroxide solution (69 μL, 0.55 mmol) and 30% hydrogen peroxide solution (43 μL, 0.55 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Further 30% hydrogen peroxide solution (43 μL, 0.55 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 60) (59.0 mg, 0.223 mmol, yield 89%) as a white solid. 11H-NMR (CDCl3) δ: 7.38 - 7.28 (5H, m), 6.91 - 6.89 (2H, m), 6.53 (1H, d, J = 8.7 Hz), 5.48 (1H, brs), 5.41 (1H, brs), 4.44 (1H, dd, J = 9.4, 3.0 Hz), 4.09 (1H, brs), 3.46 (2H, s), 2.94 - 2.86 (1H, m), 2.72 (1H, dt, J = 16.5, 4.8 Hz), 2.14 - 2.10 (1H, m), 2.02 - 1.95 (1H, m). MS (ESI) [M + H] + : 267.

[0661] (Reference Example 40) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid:

[0662]

Chemical Structure

[0663] <​​​​​​​​​

[0664] (Example 61) Synthesis of N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide (novel compound):

[0665] [ka]

[0666] 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetic acid (20.0 mg, 0.0748 mmol) synthesized in Reference Example 40 was dissolved in DMF (0.75 mL), and then N,N-diisopropylethylamine (39 μL, 0.22 mmol), tert-butylamine (79 μL, 0.75 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (42.7 mg, 0.112 mmol) were added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 61) (9.7 mg, 0.030 mmol, yield 40%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.40-7.27(5H,m),6.87-6.84(2H,m),6.51(1H,dd,J=6.2,2.5Hz),5.29(1H,brs),4.44(1H,dd,J=9.1,3.2Hz), 4.05(1H,brs),3.35(2H,s),2.95-2.87(1H,m),2.72(1H,dt,J=16.5,4.8Hz),2.16-2.09(1H,m),2.05-1.94(1H,m),1.29(9H,s). MS(ESI)[M+H] + :323.

[0667] (Example 62) Synthesis of 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one (novel compound):

[0668] [ka]

[0669] 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetic acid (20.0 mg, 0.0748 mmol) synthesized in Reference Example 40 was dissolved in DMF (0.75 mL), and then N,N-diisopropylethylamine (104 μL, 0.599 mmol), azetidine-3-ol (41.0 mg, 0.374 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (42.7 mg, 0.112 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (hereinafter referred to as the compound of Example 62) (9.4 mg, 0.029 mmol, yield 39%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.38-7.28(5H,m),6.90-6.87(2H,m),6.48(1H,d,J=8.2Hz),4.58(1H, brs),4.41(1H,dd,J=9.4,3.0Hz),4.30(1H,t,J=8.2Hz),4.21(1H,dd,J=10.4,7.1Hz), 4.02(1H,brs),3.97(1H,dd,J=9.4,3.9Hz),3.83(1H,dd,J=10.4,4.1Hz),3.33(2H,s), 2.92-2.86(2H,m),2.70(1H,dt,J=16.3,4.7Hz),2.13-2.07(1H,m),2.01-1.92(1H,m). MS(ESI)[M+H] + :323.

[0670] (Reference Example 41) Synthesis of 2-phenylquinoline-6-carboxylic acid:

[0671] [ka]

[0672] 2-phenylquinoline-6-methyl carboxylate (0.279 g, 1.06 mmol) synthesized in Reference Example 38 was dissolved in THF / methanol solution (10 mL), and 1 mol / L sodium hydroxide aqueous solution (2.12 mL, 2.12 mmol) was added. The mixture was stirred at room temperature for 17 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. 1 mol / L hydrochloric acid (4 mL) was added to the crude product, and the precipitated solid was filtered off. The solid was washed with water and dried under vacuum to obtain the title compound (0.246 g, 0.988 mmol, yield 93%) as a white solid. 1 H-NMR(DMSO-d6)δ:8.67(2H,dd,J=10.4,5.0Hz),8.32(2H,td,J=4.2,2.1Hz),8.27-8.22(2H,m),8.13(1H,d,J=9.1Hz),7.61-7.52(3H,m). MS(ESI)[M+H] + :250.

[0673] (Reference Example 42) Synthesis of tert-butyl (2-phenylquinoline-6-yl)carbamate:

[0674] [ka]

[0675] 2-phenylquinoline-6-carboxylic acid (0.224 g, 0.898 mmol) synthesized in Reference Example 41 was dissolved in tert-butanol (4.0 mL), triethylamine (0.189 mL, 1.35 mmol) and diphenyl phosphate azide (0.254 mL, 1.17 mmol) were added, and the mixture was stirred at 80°C for 5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (0.269 g, 0.840 mmol, yield 94%) as a white solid. 1 H-NMR(CDCl3)δ:8.16-8.07(4H,m),7.84(1H,d,J=8.6Hz),7.54-7.35(4H,m),7.27-7.24(1H,m),6.72(1H,s),1.57(9H,s). MS(ESI)[M+H] + :321.

[0676] (Example 63) Synthesis of tert-butyl (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate (novel compound):

[0677] [ka]

[0678] Using tert-butyl (2-phenylquinoline-6-yl)carbamate (72.0 mg, 0.225 mmol) synthesized in Reference Example 42, the title compound (hereinafter referred to as the compound of Example 63) (29.0 mg, 0.0895 mmol, yield 40%) was obtained as a white solid by the same method as in Example 4. 1H-NMR(CDCl3)δ:7.39-7.32(4H,m),7.30-7.20(1H,m),7.10(1H,brs),6.90(1H,dd,J=8.4,2.5Hz),6.48(1H,d,J=8.6Hz),4.40(1H,dd,J=9.1 ,3.2Hz),3.95(1H,s),2.94-2.86(1H,m),2.71(1H,dt,J=16.5,4.8Hz),2.12-2.07(1H,m),1.97(1H,ddt,J=16.8,10.6,3.6Hz),1.50(9H,s). MS(ESI)[M+H] + :325.

[0679] (Example 64) Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinoline-6-amine dihydrochloride (novel compound):

[0680] [ka]

[0681] (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate tert-butyl (25.0 mg, 0.0771 mmol) synthesized in Example 63 was dissolved in ethyl acetate (1.0 mL), and a 4 mol / L hydrogen chloride / ethyl acetate solution (0.50 mL, 1.54 mmol) was added. The mixture was stirred at room temperature under an argon atmosphere for 16 hours. After the reaction was complete, the precipitated solid was filtered and washed with ethyl acetate to obtain the title compound (hereinafter referred to as the compound of Example 64) (20.4 mg, 0.0784 mmol, yield 99%) as a white solid. 1 H-NMR(DMSO-d6)δ:9.69(2H,brs),7.38-7.33(4H,m),7.28(1H,dq,J=11.7,3.1Hz),6.89(2H,dt,J=15.1,5.3Hz),6.66(1H,d,J=8. 2Hz),4.44(1H,dd,J=7.9,3.4Hz),2.82-2.75(1H,m),2.60-2.50(1H,m),1.99(1H,dd,J=9.7,7.0Hz),1.85(1H,dt,J=14.6,5.3Hz). MS(ESI)[M+H] + :225.

[0682] (Reference Example 43) Synthesis of 5-(quinoline-2-yl)oxazole:

[0683] [ka]

[0684] Quinoline-2-carbaldehyde (200 mg, 1.27 mmol) and potassium carbonate (352 mg, 2.55 mmol) were suspended in methanol (6.3 mL), and then toluenesulfonylmethyl isocyanide (273 mg, 1.40 mmol) was added, and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture. The solution was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (205 mg, 1.04 mmol, yield 82%) as an orange solid. 1 H-NMR(CDCl3)δ:8.23(1H,d,J=8.5Hz),8.14(1H,dd,J=8.4,0.9Hz),8.06(1H,s),7.86(1H,s ),7.82(1H,dd,J=8.4,1.4Hz),7.79(1H,d,J=8.5Hz),7.77-7.73(1H,m),7.58-7.54(1H,m). MS(ESI)[M+H] + :197.

[0685] (Example 65) Synthesis of 5-(1,2,3,4-tetrahydroquinoline-2-yl)oxazole:

[0686] [ka]

[0687] Using 5-(quinoline-2-yl)oxazole (70.0 mg, 0.357 mmol) synthesized in Reference Example 43, the title compound (hereinafter referred to as the compound of Example 65) (52.1 mg, 0.261 mmol, yield 73%) was obtained as a colorless, transparent oil by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.83(1H,s),7.04-6.96(3H,m),6.68(1H,t,J=7.1Hz),6.57(1H,d,J=7.8H z),4.63(1H,brs),4.11(1H,brs),2.90-2.84(1H,m),2.77-2.73(1H,m),2.27-2.12(2H,m). MS(ESI)[M+H] + :201.

[0688] (Reference Example 44) Synthesis of 5-fluoro-2-phenylquinoline:

[0689] [ka]

[0690] Acetophenone (0.165 mL, 1.42 mmol) and potassium tert-butoxide (119 mg, 1.06 mmol) were added to a 1,4-dioxane solution (2 mL) of (2-amino-6-fluorophenyl)methanol (100 mg, 0.709 mmol), and the mixture was stirred at 80°C for 1 hour. After the reaction was complete, the reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (74.4 mg, 0.333 mmol, yield 47%) as a pale yellow solid. 1 H-NMR(CDCl3)δ:8.50(1H,d,J=9.1Hz),8.18-8.17(2H,m),7.98(1H,d,J=8.6Hz),7.95(1 H,d,J=9.1Hz),7.66(1H,ddd,J=8.2,8.2,5.9Hz),7.57-7.47(3H,m),7.22-7.18(1H,m). MS(ESI)[M+H]+ :224.

[0691] (Example 66) Synthesis of 5-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (novel compound):

[0692] [ka]

[0693] Using 5-fluoro-2-phenylquinoline (74.4 mg, 0.333 mmol) synthesized in Reference Example 44, the title compound (hereinafter referred to as the compound of Example 66) (69.3 mg, 0.305 mmol, yield 91%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.34-7.32(5H,m),6.99-6.92(1H,m),6.38(1H,dd,J=8.6,8.6Hz),6.32(1H,d,J=8.2Hz ),4.40(1H,dd,J=9.5,2.7Hz),4.17(1H,brs),2.86-2.72(2H,m),2.17-2.11(1H,m),2.00-1.90(1H,m). MS(ESI)[M+H] + :228.

[0694] (Reference Example 45) Synthesis of 5-chloro-2-phenylquinoline:

[0695] [ka]

[0696] Using (2-amino-6-chlorophenyl)methanol (100 mg, 0.635 mmol), the title compound (86.3 mg, 0.360 mmol, yield 57%) was obtained as a pale yellow solid in the same manner as in Reference Example 44. 1H-NMR(CDCl3)δ:8.64(1H,d,J=9.1Hz),8.19-8.17(2H,m),8.10(1H,dd,J=8.2,0.9Hz),7.99(1H,d,J=8.6Hz),7.67-7.47(5H,m). MS(ESI)[M+H] + :240.

[0697] (Example 67) Synthesis of 5-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0698] [ka]

[0699] Using 5-chloro-2-phenylquinoline (86.3 mg, 0.360 mmol) synthesized in Reference Example 45, the title compound (hereinafter referred to as the compound of Example 67) (71.1 mg, 0.292 mmol, yield 81%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.38-7.27(5H,m),6.93(1H,dd,J=8.2,8.2Hz),6.72(1H,dd,J=7.9,1.1Hz),6.45(1H,dd,J=7. 9,1.1Hz),4.39(1H,dd,J=9.1,2.7Hz),4.15(1H,brs),2.93-2.78(2H,m),2.20-2.14(1H,m),2.03-1.94(1H,m). MS(ESI)[M+H] + :244.

[0700] (Reference Example 46) Synthesis of 7-fluoro-2-phenylquinoline:

[0701] [ka]

[0702] Using (2-amino-4-fluorophenyl)methanol (100 mg, 0.709 mmol), the title compound (107 mg, 0.478 mmol, yield 68%) was obtained as a yellow solid in the same manner as in Reference Example 44. 1 H-NMR(CDCl3)δ:8.22(1H,d,J=8.7Hz),8.17-8.14(2H,m),7.86(1H,d,J=8.7Hz),7.83-7.81(1H,m),7.60-7.43(4H,m),7.35-7.30(1H,m). MS(ESI)[M+H] + :224.

[0703] (Example 68) Synthesis of 7-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0704] [ka]

[0705] Using 7-fluoro-2-phenylquinoline (107 mg, 0.478 mmol) synthesized in Reference Example 46, the title compound (hereinafter referred to as the compound of Example 68) (95.6 mg, 0.421 mmol, yield 88%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.38-7.27(5H,m),6.91(1H,dd,J=6.8,6.8Hz),6.33(1H,ddd,J=8.6,8.6,2.7Hz),6.24(1H,dd,J=10.6,2.5Hz),4.44(1H,ddd,J =9.1,3.2,1.4Hz),4.13(1H,brs),2.84(1H,ddd,J=15.9,10.4,5.0Hz),2.68(1H,ddd,J=16.3,5.0,5.0Hz),2.15-2.07(1H,m),2.01-1.92(1H,m). MS(ESI)[M+H] + :228.

[0706] (Reference Example 47) Synthesis of 7-chloro-2-phenylquinoline:

[0707] [ka]

[0708] Using (2-amino-4-chlorophenyl)methanol (100 mg, 0.635 mmol), the title compound (110 mg, 0.457 mmol, yield 72%) was obtained as a yellow solid in the same manner as in Reference Example 44. 1 H-NMR(CDCl3)δ:8.21(1H,d,J=8.7Hz),8.17-8.16(3H,m),7.89(1H,d,J=8.7Hz),7.77(1H,d,J=8.7Hz),7.59-7.45(5H,m). MS(ESI)[M+H] + :240.

[0709] (Example 69) Synthesis of 7-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0710] [ka]

[0711] Using 7-chloro-2-phenylquinoline (110 mg, 0.457 mmol) synthesized in Reference Example 47, the title compound (hereinafter referred to as the compound of Example 69) (107 mg, 0.438 mmol, yield 96%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.35-7.31(5H,m),6.89(1H,d,J=8.2Hz),6.59(1H,dd,J=8.2,1.8Hz),6.52(1H,d,J=2.3Hz),4.44(1H,dd,J=9.1,2. 7Hz),4.11(1H,brs),2.84(1H,ddd,J=15.9,10.4,5.4Hz),2.68(1H,ddd,J=16.3,5.0,5.0Hz),2.15-2.08(1H,m),1.97-1.94(1H,m). MS(ESI)[M+H] + :244.

[0712] (Reference Example 48) Synthesis of (2-amino-5-bromophenyl)methanol:

[0713] [ka]

[0714] (2-aminophenyl)methanol (2.80 g, 22.7 mmol) was dissolved in DMF (11.3 mL), and then N-bromosuccinimide (4.05 g, 22.7 mmol) was added in three portions at 5-minute intervals under ice cooling, and the mixture was stirred under ice cooling for 2 hours. After the reaction was complete, the reaction mixture was poured into ice water (56 mL). The resulting solid was filtered off. The obtained brown solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.52 g, 17.5 mmol, yield 77%) as a brown solid. 1 H-NMR(CDCl3)δ:7.22-7.20(2H,m),6.58(1H,d,J=8.2Hz),4.63(2H,d,J=4.1Hz),4.19(2H,s),1.60(1H,brs). MS(ESI)[M+H] + :202.

[0715] (Reference Example 49) Synthesis of 6-bromo-2-phenylquinoline:

[0716] [ka]

[0717] (2-amino-5-bromophenyl)methanol (2.46 g, 12.2 mmol), synthesized in Reference Example 48, was dissolved in 1,4-dioxane (36 mL). Acetophenone (2.91 mL, 25.0 mmol) and potassium tert-butoxide (2.05 g, 18.3 mmol) were added, and the mixture was stirred at 80°C for 4 hours. Ice and saturated ammonium chloride aqueous solution were added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / chloroform) and slurry washing (hexane) to obtain the title compound (1.49 g, 5.25 mmol, yield 43%) as a white solid. 1 H-NMR(CDCl3)δ:8.17-8.13(3H,m),8.04(1H,d,J=9.1Hz),8.00(1H,d,J=2. 3Hz),7.91(1H,d,J=8.7Hz),7.79(1H,dd,J=9.1,2.3Hz),7.56-7.46(3H,m). MS(ESI)[M+H] + :284.

[0718] (Example 70) Synthesis of 6-bromo-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0719] [ka]

[0720] Using 6-bromo-2-phenylquinoline (50.0 mg, 0.176 mmol) synthesized in Reference Example 49, the title compound (hereinafter referred to as the compound of Example 70) (47.0 mg, 0.163 mmol, yield 93%) was obtained as a yellow oil by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.36-7.27(5H,m),7.11-7.07(2H,m),6.42(1H,d,J=8.4Hz),4.44-4.41(1H,m ),4.07(1H,brs),2.91-2.83(1H,m),2.73-2.66(1H,m),2.14-2.07(1H,m),2.00-1.91(1H,m). MS(ESI)[M+H] + :288.

[0721] (Reference Example 50) Synthesis of 3-(2-phenylquinoline-6-yl)oxetan-3-ol:

[0722] [ka]

[0723] 6-bromo-2-phenylquinoline (100 mg, 0.352 mmol) synthesized in Reference Example 49 was dissolved in THF (unstabilized, 3.5 mL), and then 1.67 mol / L n-butyllithium / hexane solution (0.25 mL, 0.42 mmol) was added dropwise over 3 minutes at -78°C. Oxetane-3-one (26 μL, 0.026 mmol) was added, and the mixture was heated from -78°C to room temperature for 15 minutes, followed by stirring at room temperature for another 15 minutes. Under ice cooling, saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (73.7 mg, 0.268 mmol, yield 76%) as a white solid. 1 H-NMR(CDCl3)δ:8.25-8.23(2H,m),8.18-8.16(2H,m),8.02-8.01(2H,m),7.92(1H,d,J=8.7 Hz),7.55-7.54(2H,m),7.48(1H,t,J=7.1Hz),5.04(2H,d,J=6.9Hz),5.01(2H,d,J=6.9Hz). MS(ESI)[M+H] + :278.

[0724] (Example 71) Synthesis of 3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)oxetan-3-ol (novel compound):

[0725] [ka]

[0726] 3-(2-phenylquinoline-6-yl)oxetan-3-ol (70.0 mg, 0.252 mmol) synthesized in Reference Example 50 was dissolved in THF / ethanol (1 / 1, v / v, 2.5 mL), and then acetic acid (44 μL, 0.76 mmol) and platinum(IV) oxide (7.0 mg, 0.031 mmol) were added. The mixture was vigorously stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 71) (49.2 mg, 0.174 mmol, yield 69%) as a colorless, transparent oil. 1 H-NMR(CDCl3)δ:7.39-7.27(5H,m),7.18-7.16(2H,m),6.58(1H,d,J=8.9Hz),4.94(2H,d,J=7.1Hz),4.87(2H,d,J=7.1Hz),4.46(1H,dd ,J=9.1,3.2Hz),4.16(1H,brs),2.97-2.89(1H,m),2.75(1H,dt,J=16.3,4.9Hz),2.43(1H,brs),2.18-2.11(1H,m),2.04-1.95(1H,m). MS(ESI)[M+H] + :282.

[0727] (Reference Example 51) Synthesis of 2-phenyl-6-(piperidine-1-yl)quinoline:

[0728] [ka]

[0729] 6-bromo-2-phenylquinoline (60.0 mg, 0.211 mmol), cesium carbonate (241 mg, 0.739 mmol), palladium(II) acetate (4.74 mg, 21.1 μmol), and 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (26.3 mg, 42.2 μmol), synthesized in Reference Example 49, were suspended in 1,4-dioxane (2.10 mL), piperidine (69.7 μL, 0.633 mmol) was added, and the mixture was stirred at 100 °C for 15 hours under an argon atmosphere. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layers were dried together over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (27.3 mg, 94.7 μmol, yield 45%) as a yellow solid. 1 H-NMR(CDCl3)δ:8.12-8.10(2H,m),8.03(2H,dd,J=8.8,8.0Hz),7.78(1H,d,J=8.6Hz),7.54-7.48(3H,m ),7.44-7.40(1H,m),7.04(1H,d,J=2.7Hz),3.31(4H,t,J=7.2Hz),1.80-1.75(4H,m),1.67-1.61(2H,m). MS(ESI)[M+H] + :289.

[0730] (Example 72) Synthesis of 2-phenyl-6-(piperidine-1-yl)-1,2,3,4-tetrahydroquinoline (novel compound):

[0731] [ka]

[0732] 2-phenyl-6-(piperidine-1-yl)quinoline (27.3 mg, 94.7 μmol) synthesized in Reference Example 51 was dissolved in dioxane (1.4 mL), iodine (2.40 mg, 9.46 μmol) and 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (50.4 mg, 0.199 mmol) were added, and the mixture was stirred at room temperature under an argon atmosphere for 17 hours. Next, 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (50.4 mg, 0.199 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere for 3 hours. Furthermore, iodine (2.40 mg, 9.46 μmol) and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (50.4 mg, 0.199 mmol) were added, and the mixture was stirred at 40°C for 19 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 72) (6.00 mg, 20.5 μmol, yield 22%) as a brown solid. 1 H-NMR(CDCl3)δ:7.41-7.39(2H,m),7.36-7.32(2H,m),7.30-7.26(1H,m),6.73-6.70(2H,m),6.50(1H,d,J=8.2Hz),4.37(1H,dd ,J=9.5,3.2Hz),2.99-2.89(5H,m),2.72(1H,ddd,J=12.0,4.8,4.4Hz),2.13-1.93(2H,m),1.75-1.69(4H,m),1.56-1.50(2H,m). MS(ESI)[M+H] + :293.

[0733] (Reference Example 52) Synthesis of 1,1-diphenyl-N-(2-phenylquinoline-6-yl)methanymine:

[0734] [ka]

[0735] Cesium carbonate (161 mg, 0.493 mmol), palladium(II) acetate (1.58 mg, 7.04 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.11 mg, 10.6 μmol) were suspended in dioxane (0.50 mL) and stirred at room temperature under an argon atmosphere for 10 minutes. Next, triethylamine (1.47 μL, 10.6 μmol) was added and stirred at room temperature under an argon atmosphere for 10 minutes. Furthermore, a dioxane solution (0.50 mL) of 6-bromo-2-phenyl-1,2,3,4-tetrahydroquinoline (100 mg, 0.352 mmol) and diphenylmethanymine (76.5 mg, 0.422 mmol) synthesized in Reference Example 49 was added and stirred at 100°C for 17 hours under an argon atmosphere. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were dried together over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (108 mg, 0.280 mmol, yield 80%) as a yellow amorphous material. 1 H-NMR(CDCl3)δ:8.12-8.09(2H,m),8.01(1H,d,J=8.6Hz),7.93(1H,d,J=9.1Hz),7.82-7. 77(3H,m),7.53-7.41(6H,m),7.25-7.21(3H,m),7.19-7.14(3H,m),7.11(1H,d,J=2.3Hz). MS(ESI)[M+H] + :365.

[0736] (Reference Example 53) Synthesis of 2-phenylquinoline-6-amine:

[0737] [ka]

[0738] 1,1-diphenyl-N-(2-phenylquinoline-6-yl)methaneimine (108 mg, 0.280 mmol) synthesized in Reference Example 52 was dissolved in THF (1.0 mL), 2 mol / L hydrochloric acid (0.420 mL, 0.840 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (47.3 mg, 0.215 mmol, yield 77%) as a pale orange solid. 1 H-NMR(CDCl3)δ:8.12-8.09(2H,m),7.98(2H,dd,J=8.6,2.7Hz),7.77(1H,d,J=8.8Hz),7.52-7. 48(2H,m),7.44-7.40(1H,m),7.18(1H,dd,J=8.8,2.5Hz),6.93(1H,d,J=2.7Hz),3.96(2H,brs). MS(ESI)[M+H] + :221.

[0739] (Reference Example 54) Synthesis of N-(2-phenylquinoline-6-yl)acetamide:

[0740] [ka]

[0741] 2-phenylquinoline-6-amine (13.5 mg, 61.3 μmol) synthesized in Reference Example 53 was dissolved in pyridine (0.5 mL), acetic anhydride (6.36 μL, 67.4 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the title compound (15.5 mg, 59.1 μmol, 96% yield) as a pale yellow solid. 1H-NMR(CDCl3)δ:8.37(1H,d,J=1.8Hz),8.20(1H,d,J=8.6Hz),8.14-8.12(3H,m),7. 87(1H,d,J=8.6Hz),7.55-7.52(3H,m),7.47-7.45(1H,m),7.36(1H,s),2.27(3H,s). MS(ESI)[M+H] + :263.

[0742] (Example 73) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide (novel compound):

[0743] [ka]

[0744] Using N-(2-phenylquinoline-6-yl)acetamide (15.5 mg, 59.1 μmol) synthesized in Reference Example 54, the title compound (hereinafter referred to as the compound of Example 73) (12.1 mg, 45.4 μmol, yield 77%) was obtained as a colorless amorphous material by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.39-7.28(5H,m),7.16(1H,d,J=2.7Hz),7.02(1H,dd,J=8.7,2.3Hz),6.93(1H,brs),6.50(1H,d,J=8.7Hz),4.42(1H,dd,J=9.1,3 .2Hz),4.02(1H,brs),2.91(1H,ddd,J=16.0,10.5,5.5Hz),2.72(1H,ddd ,J=16.5,4.6,4.6Hz),2.14(3H,s),2.12-2.08(1H,m),2.02-1.92(1H,m). MS(ESI)[M+H] + :267.

[0745] (Reference Example 55) Synthesis of N-(2-phenylquinoline-6-yl)pivalamide:

[0746] [ka]

[0747] 2-phenylquinoline-6-amine (50.0 mg, 0.226 mmol) synthesized in Reference Example 53 was dissolved in THF (1.0 mL), and pivaloyl chloride (30.4 μL, 0.250 mmol) and triethylamine (35.0 μL, 0.250 mmol) were added. The mixture was stirred at room temperature under an argon atmosphere for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (64.8 mg, 0.213 mmol, yield 94%) as a white solid. 1 H-NMR(CDCl3)δ:8.44(1H,d,J=2.3Hz),8.18(1H,d,J=8.7Hz),8.15-8.14(2H,m),8.11(1 H,d,J=9.1Hz),7.87(1H,d,J=8.2Hz),7.57-7.50(4H,m),7.46-7.44(1H,m),1.38(9H,s). MS(ESI)[M+H] + :305.

[0748] (Example 74) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)pivaramide (novel compound):

[0749] [ka]

[0750] Using N-(2-phenylquinoline-6-yl)pivalamide (64.8 mg, 0.213 mmol) synthesized in Reference Example 55, the title compound (hereinafter referred to as the compound of Example 74) (62.6 mg, 0.203 mmol, yield 95%) was obtained as a white solid by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.39-7.32(4H,m),7.30-7.27(1H,m),7.26-7.24(1H,m),7. 12(1H,brs),7.04(1H,dd,J=8.5,2.5Hz),6.50(1H,d,J=8.7Hz),4.41(1H,dd, J=9.1,3.2Hz),4.00(1H,brs),2.90(1H,ddd,J=16.0,10.1,5.5Hz),2.71(1H, ddd,J=16.5,5.0,5.0Hz),2.14-2.08(1H,m),2.02-1.92(1H,m),1.30(9H,s). MS(ESI)[M+H] + :309.

[0751] (Reference Example 56) Synthesis of N-(2-phenylquinoline-6-yl)methanesulfonamide:

[0752] [ka]

[0753] 2-phenylquinoline-6-amine (40.0 mg, 0.182 mmol) synthesized in Reference Example 53 was dissolved in dichloromethane (1.8 mL) and cooled to 0°C. Triethylamine (38.0 μL, 0.272 mmol) and methanesulfonyl chloride (14.1 μL, 0.182 mmol) were added, and the mixture was stirred at 0°C for 2 hours under an argon atmosphere. Next, triethylamine (25.3 μL, 0.182 mmol) and methanesulfonyl chloride (16.9 μL, 0.218 mmol) were added, and the mixture was stirred at room temperature for 18 hours under an argon atmosphere. Furthermore, 8 mol / L aqueous sodium hydroxide solution (230 μL, 1.81 mmol) was added, and the mixture was stirred at room temperature for 7 hours. Finally, 8 mol / L aqueous sodium hydroxide solution (230 μL, 1.81 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (48.7 mg, 0.163 mmol, 90% yield) as a white solid. 1 H-NMR(CDCl3)δ:8.20-8.14(4H,m),7.92(1H,d,J=8.6Hz),7.73(1H,d,J=2.3Hz),7.56-7.46(4H,m),6.59(1H,brs),3.10(3H,s). MS(ESI)[M+H] + :299.

[0754] (Example 75) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanesulfonamide (novel compound):

[0755] [ka]

[0756] Using N-(2-phenylquinoline-6-yl)methanesulfonamide (48.7 mg, 0.163 mmol) synthesized in Reference Example 56, the title compound (hereinafter referred to as the compound of Example 75) (20.2 mg, 66.8 μmol, yield 41%) was obtained as a white solid by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.38-7.27(5H,m),6.93-6.90(2H,m),6.51(1H,d,J=8.6Hz),6.07-6.07(1H,brm),4.46- 4.43(1H,m),4.13(1H,brs),2.96-2.86(4H,m),2.76-2.69(1H,m),2.16-2.09(1H,m),2.02-1.92(1H,m). MS(ESI)[M+H] + :303.

[0757] (Reference Example 57) Synthesis of 1-(tert-butyl)-3-(2-phenylquinoline-6-yl)urea:

[0758] [ka]

[0759] 40.0 mg, 0.182 mmol of 2-phenylquinoline-6-amine synthesized in Reference Example 53 and potassium carbonate (201 mg, 1.45 mmol) were suspended in acetonitrile (1.8 mL), and 0.150 mL, 1.27 mmol of tert-butyl isocyanate was added. The mixture was stirred at 85°C for 2 hours under an argon atmosphere. Further addition of 0.150 mL, 1.27 mL of tert-butyl isocyanate was added, and the mixture was stirred at 85°C for 16 hours under an argon atmosphere. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (58.0 mg, 0.182 mmol, 100% yield) as a white solid. 1H-NMR(CDCl3)δ:8.13-8.10(4H,m),8.04(1H,d,J=9.1Hz),7.81(1H,d,J=8.6Hz),7.51( 2H,dd,J=8.0,10.8Hz),7.46-7.39(2H,m),6.94(1H,brs),4.98(1H,brs),1.41(9H,s). MS(ESI)[M+H] + :320.

[0760] (Example 76) Synthesis of 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea (novel compound):

[0761] [ka]

[0762] Using 1-(tert-butyl)-3-(2-phenylquinoline-6-yl)urea (58.0 mg, 0.182 mmol) synthesized in Reference Example 57, the title compound (hereinafter referred to as the compound of Example 76) (27.2 mg, 84.1 μmol, yield 46%) was obtained as a purple amorphous material by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.40-7.27(5H,m),6.88(1H,d,J=1.8Hz),6.83(1H,dd,J=8.8,2.0Hz),6.50(1H,d,J=8.6Hz),5.77(1H,brs),4.54(1H,br s),4.43(1H,dd,J=9.5,3.2Hz),4.07(1H,brs),2.94-2.86(1H,m),2.75-2.68(1H,m),2.15-2.09(1H,m),2.02-1.93(1H,m),1.34(9H,s). MS(ESI)[M+H] + :324.

[0763] (Reference Example 58) Synthesis of 1-(2-phenylquinoline-6-yl)urea:

[0764] [ka]

[0765] 2-phenylquinoline-6-amine (40.0 mg, 0.182 mmol) synthesized in Reference Example 53 was suspended in THF (2.2 mL), and trichloroacetyl isocyanate (29.6 μL, 0.250 mmol) was added. The mixture was stirred at 0°C for 1 hour under an argon atmosphere. Next, methanol / triethylamine (2.2 mL / 1.1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by slurry washing (hexane / chloroform) to obtain the title compound (49.3 mg, 0.187 mmol, yield 83%) as a reddish-purple solid. 1 H-NMR(DMSO-d6)δ:8.92(1H,brs),8.30(1H,d,J=8.7Hz),8.23(2H,d,J=6.9Hz),8.13(1H,d,J=2.3Hz),8.04(1H,d,J=8. 7Hz),7.94(1H,d,J=9.1Hz),7.67(1H,dd,J=9.1,2.3Hz),7.54(2H,dd,J=7.2,7.2Hz),7.49-7.45(1H,m),6.02(2H,brs). MS(ESI)[M+H] + :264.

[0766] (Example 77) Synthesis of 1-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea (novel compound):

[0767] [ka]

[0768] Using 1-(2-phenylquinoline-6-yl)urea (47.9 mg, 0.182 mmol) synthesized in Reference Example 58, the title compound (hereinafter referred to as the compound of Example 77) (40.6 mg, 0.152 mmol, yield 84%) was obtained as a white amorphous material by the same method as in Example 4. 1H-NMR(CDCl3)δ:7.37-7.28(5H,m),6.91-6.88(2H,m),6.52(1H,d,J=8.0Hz),6.14(1H,brs),4.64(2H,brs ),4.45(1H,dd,J=9.1,3.6Hz),2.93-2.85(1H,m),2.75-2.68(1H,m),2.16-2.09(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :268.

[0769] (Reference Example 59) Synthesis of 3,3-dimethyl-N-(2-phenylquinoline-6-yl)butanamide:

[0770] [ka]

[0771] 2-phenylquinoline-6-amine (40.0 mg, 0.182 mmol) synthesized in Reference Example 53 was dissolved in dichloromethane (0.90 mL), and 3,3-dimethylbutyryl chloride (26.5 μL, 0.191 mmol) was added. The mixture was stirred at room temperature under an argon atmosphere for 2 hours. Further, tert-butyl isocyanate (0.150 mL, 1.27 mL) was added, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layers were dried together over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (53.7 mg, 0.169 mmol, yield 93%) as a white solid. 1 H-NMR(CDCl3)δ:8.41(1H,d,J=2.4Hz),8.20-8.09(4H,m),7.87(1H,d,J=8.6Hz),7.55-7.51(3H,m),7.48-7.44(1H,m),2.31(2H,s),1.16(9H,s). MS(ESI)[M+H] + :319.

[0772] (Example 78) Synthesis of 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)butanamide (novel compound):

[0773] [ka]

[0774] Using 3,3-dimethyl-N-(2-phenylquinoline-6-yl)butanamide (53.7 mg, 0.169 mmol) synthesized in Reference Example 59, the title compound (hereinafter referred to as the compound of Example 78) (18.7 mg, 58.0 μmol, yield 34%) was obtained as a white amorphous material by the same method as in Example 4. 1 H-NMR(CDCl3)δ:7.39-7.27(5H,m),7.22(1H,d,J=2.3Hz),7.02(1H,dd,J=8.8,2.8Hz),6.85(1H,brs),6.49(1H,d,J=8.2Hz),4. 41(1H,dd,J=9.1,3.2Hz),2.94-2.86(1H,m),2.75-2.68(1H,m),2.18(2H,s),2.14-2.97(1H,m),2.01-1.92(1H,m),1.10(9H,s). MS(ESI)[M+H] + :323.

[0775] (Reference Example 60) Synthesis of 8-chloro-2-phenylquinoline:

[0776] [ka]

[0777] 2-Chloroaniline (0.325 mL, 3.91 mmol) and cinnamaldehyde (0.493 mmol, 3.91 mmol) were dissolved in DMSO (2 mL), and palladium(II) acetate (87.9 mg, 0.391 mmol) was added. The mixture was stirred at 130°C for 18 hours under an oxygen atmosphere. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were washed together with water and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (109 mg, 0.456 mmol, yield 12%) as a pale yellow solid. 1 H-NMR(CDCl3)δ:8.31-8.28(2H,m),8.24(1H,d,J=8.6Hz),7.99(1H,d,J=8.6Hz ),7.85(1H,dd,J=7.5,1.1Hz),7.76(1H,dd,J=8.2,1.4Hz),7.57-7.42(4H,m). MS(ESI)[M+H] + :240.

[0778] (Example 79) Synthesis of 8-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline (novel compound):

[0779] [ka]

[0780] Using 8-chloro-2-phenylquinoline (109 mg, 0.456 mmol) synthesized in Reference Example 60, the title compound (hereinafter referred to as the compound of Example 79) (93.8 mg, 0.385 mmol, yield 84%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.41-7.29(4H,m),7.12(1H,d,J=7.3Hz),6.91(1H,d,J=7.3Hz),6.56(1H,dd,J=8.0,7.6Hz),4.67(1H,brs),4.53(1H ,ddd,J=9.2,3.6,1.2),2.91(1H,ddd,J=16.0,10.4,5.2Hz),2.74(1H,ddd,J=16.8,5.2,4.7Hz),2.16-2.12(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :244.

[0781] (Reference Example 61) Synthesis of 8-fluoro-2-phenylquinoline:

[0782] [ka]

[0783] Using 2-fluoroaniline (0.325 mL, 4.50 mmol) and cinnamaldehyde (0.566 mmol, 4.50 mmol), the title compound (68.9 mg, 0.309 mmol, yield 7%) was obtained as a pale yellow solid by the same method as in Reference Example 60. 1 H-NMR(CDCl3)δ:8.25(1H,dd,J=8.7,1.8Hz),8.23-8.20(2H,m),7.96(1H,d,J=8.7Hz),7.62(1H,dd,J=7.1,1.6Hz),7.56-7.39(5H,m). MS(ESI)[M+H] + :224.

[0784] (Example 80) Synthesis of 8-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (novel compound):

[0785] [ka]

[0786] Using 8-fluoro-2-phenylquinoline (68.9 mg, 0.309 mmol) synthesized in Reference Example 61, the title compound (hereinafter referred to as the compound of Example 80) (51.2 mg, 0.225 mmol, yield 73%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.41-7.28(5H,m),6.84(1H,dd,J=11.4,8.2Hz),6.79(1H,d,J=7.3Hz),6.55(1H,ddd,J=8.0,5.2,5.2Hz),4.46(1H,ddd,J=9. 2,3.2,1.2Hz),4.26(1H,brs),2.93(1H,ddd,J=16.0,10.8,5.6Hz),2.76(1H,ddd,J=16.4,5.2,4.4Hz),2.16-2.13(1H,m),2.05-1.96(1H,m). MS(ESI)[M+H] + :228.

[0787] (Reference Example 62) Synthesis of 2-phenyl-6-(trifluoromethoxy)quinoline:

[0788] [ka]

[0789] Using 4-(trifluoromethoxy)aniline (0.325 mL, 2.82 mmol) and cinnamaldehyde (0.355 mmol, 2.82 mmol), the title compound (70.1 mg, 0.242 mmol, yield 9%) was obtained as a pale yellow solid in the same manner as in Reference Example 60. 1 H-NMR(CDCl3)δ:8.23-8.21(2H,m),8.18-8.15(2H,m),7.95(1H,d,J=8.6Hz),7.66(1H,s),7.60-7.47(4H,m). MS(ESI)[M+H] + :290.

[0790] (Example 81) Synthesis of 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline (novel compound):

[0791] [ka]

[0792] Using 2-phenyl-6-(trifluoromethoxy)quinoline (83.1 mg, 0.287 mmol) synthesized in Reference Example 62, the title compound (hereinafter referred to as the compound of Example 81) (83.1 mg, 0.283 mmol, yield 99%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.38-7.28(5H,m),6.89-6.86(2H,m),6.49-6.48(1H,m),4.44(1H,dd,J=9.4,3.4Hz),4.11(1H,br s),2.91(1H,ddd,J=16.5,10.5,5.9Hz),2.73(1H,ddd,J=16.5,4.6,5.0Hz),2.16-2.09(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :294.

[0793] (Reference Example 63) Synthesis of 6-fluoro-2-phenylquinoline:

[0794] [ka]

[0795] Using 4-fluoroaniline (0.431 mL, 4.50 mmol) and cinnamaldehyde (0.566 mmol, 4.50 mmol), the title compound (48.2 mg, 0.216 mmol, yield 5%) was obtained as a pale yellow solid by the same method as in Reference Example 60. 1 H-NMR(CDCl3)δ:8.20-8.13(3H,m),7.91-7.89(2H,m),7.57-7.44(5H,m). MS(ESI)[M+H] + :224.

[0796] (Example 82) Synthesis of 6-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0797] [ka]

[0798] Using 6-fluoro-2-phenylquinoline (48.2 mg, 0.216 mmol) synthesized in Reference Example 63, the title compound (hereinafter referred to as the compound of Example 82) (29.7 mg, 0.131 mmol, yield 61%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.40-7.32(5H,m),6.74-6.71(2H,m),6.47(1H,dd,J=9.1,5.0Hz),4.39(1H,dd,J=9.1,3.2Hz),3.94(1 H,brs),2.92(1H,ddd,J=16.5,10.5,5.5Hz),2.72(1H,ddd,J=16.9,4.6,4.6Hz),2.14-2.08(1H,m),2.02-1.93(1H,m). MS(ESI)[M+H] + :228.

[0799] (Reference Example 64) Synthesis of 6-chloro-2-phenylquinoline:

[0800] [ka]

[0801] Using 4-chloroaniline (100 mg, 0.784 mmol) and (E)-cinnamyl alcohol (105 mg, 0.784 mmol), the title compound (28.0 mg, 0.117 mmol, yield 15%) was obtained as an orange solid in the same manner as in Reference Example 60. 1H-NMR(CDCl3)δ:8.17-8.14(3H,m),8.11(1H,d,J=9.1Hz),7.91(1H,d,J=8. 2Hz),7.82(1H,d,J=2.3Hz),7.67(1H,dd,J=8.9,2.5Hz),7.56-7.46(3H,m). MS(ESI)[M+H] + :240.

[0802] (Example 83) Synthesis of 6-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0803] [ka]

[0804] Using 6-chloro-2-phenylquinoline (28.0 mg, 0.117 mmol) synthesized in Reference Example 64, the title compound (hereinafter referred to as the compound of Example 83) (28.0 mg, 0.114 mmol, yield 98%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.35-7.31(5H,m),6.96-6.95(2H,m),6.46(1H,d,J=8.2Hz),4.43(1H,dd,J=9.1,3.2Hz),4.06(1H, brs),2.88(1H,ddd,J=15.9,10.4,5.4Hz),2.70(1H,ddd,J=16.3,5.0,5.0Hz),2.14-2.08(1H,m),2.01-1.91(1H,m). MS(ESI)[M+H] + :244.

[0805] (Reference Example 65) Synthesis of 2-phenyl-6-(trifluoromethyl)quinoline:

[0806] [ka]

[0807] Using 4-(trifluoromethyl)aniline (76.9 μL, 0.621 mmol) and (E)-cinnamyl alcohol (83.3 mg, 0.621 mmol), the title compound (42.0 mg, 0.154 mmol, yield 25%) was obtained as an orange solid in the same manner as in Reference Example 60. 1 H-NMR(CDCl3)δ:8.32(1H,d,J=8.7Hz),8.28(1H,d,J=8.7Hz),8.19(2H,d,J=7.8Hz) ,8.15(1H,s),7.99(1H,d,J=8.7Hz),7.90(1H,dd,J=8.9,1.6Hz),7.56-7.51(3H,m). MS(ESI)[M+H] + :274.

[0808] (Example 84) Synthesis of 2-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (novel compound):

[0809] [ka]

[0810] Using 2-phenyl-6-(trifluoromethyl)quinoline (42.0 mg, 0.154 mmol) synthesized in Reference Example 65, the title compound (hereinafter referred to as the compound of Example 84) (30.8 mg, 0.111 mmol, yield 72%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.37-7.29(5H,m),7.25-7.23(2H,m),6.54(1H,d,J=9.1Hz),4.51(1H,dd,J=8.7,2.3Hz),4.38(1H, brs),2.90(1H,ddd,J=15.6,10.1,5.0Hz),2.74(1H,ddd,J=16.5,5.0,5.0Hz),2.18-2.12(1H,m),2.06-1.93(1H,m). MS(ESI)[M+H] + :278.

[0811] (Reference example 66) Synthesis of 6,7-difluoro-2-phenylquinoline:

[0812] [ka]

[0813] Using 3,4-difluoroaniline (150 mg, 1.16 mmol) and (E)-cinnamyl alcohol (156 mg, 1.16 mmol), the title compound (57.7 mg, 0.239 mmol, yield 21%) was obtained as an orange solid by the same method as in Reference Example 60. 1 H-NMR(CDCl3)δ:8.16-8.14(3H,m),7.92(1H,dd,J=11.6,7.6Hz),7.89(1H,d,J=8.4Hz),7.56-7.46(4H,m). MS(ESI)[M+H] + :242.

[0814] (Example 85) Synthesis of 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (novel compound):

[0815] [ka]

[0816] Using 6,7-difluoro-2-phenylquinoline (57.7 mg, 0.239 mmol) synthesized in Reference Example 66, the title compound (hereinafter referred to as the compound of Example 85) (41.6 mg, 0.170 mmol, yield 71%) was obtained as a colorless, transparent oil by the same method as in Example 26. 1H-NMR(CDCl3)δ:7.38-7.28(5H,m),6.78(1H,dd,J=10.6,8.8Hz),6.31(1H,dd,J=12.0,7.0Hz),4.39(1H,ddd,J=9.1,3.2,0.9Hz ),3.97(1H,brs),2.83(1H,ddd,J=16.3,10.9,5.4Hz),2.65(1H,ddd,J=16.3,5.0,5.0Hz),2.13-2.07(1H,m),2.00-1.90(1H,m). MS(ESI)[M+H] + :246.

[0817] (Reference example 67) Synthesis of 6,8-difluoro-2-phenylquinoline:

[0818] [ka]

[0819] Using 2,4-difluoroaniline (150 mg, 1.16 mmol) and (E)-cinnamyl alcohol (156 mg, 1.16 mmol), the title compound (13.5 mg, 56.0 μmol, yield 5%) was obtained as a yellow solid in the same manner as in Reference Example 60. 1 H-NMR(CDCl3)δ:8.21-8.17(3H,m),7.98(1H,d,J=8.7Hz),7.93-7.88(1H,m),7.56-7.44(4H,m). MS(ESI)[M+H] + :242.

[0820] (Example 86) Synthesis of 6,8-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (novel compound):

[0821] [ka]

[0822] Using 6,8-difluoro-2-phenylquinoline (13.5 mg, 56.0 μmol) synthesized in Reference Example 67, the title compound (hereinafter referred to as the compound of Example 86) (7.70 mg, 31.4 μmol, yield 56%) was obtained as an orange solid by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.41-7.30(5H,m),6.65(1H,ddd,J=11.3,8.6,3.2Hz),6.57(1H,d,J=9.1Hz),4.41(1H,dd,J=9.5,3.2Hz),4 .07(1H,brs),2.92(1H,ddd,J=16.3,10.4,5.9Hz),2.74(1H,ddd,J=17.2,5.0,5.0Hz),2.16-2.13(1H,m),2.05-1.95(1H,m). MS(ESI)[M+H] + :246.

[0823] (Reference Example 68) Synthesis of 4-(6-nitroquinoline-2-yl)benzonitrile:

[0824] [ka]

[0825] 2-Chloro-6-nitroquinoline (700 mg, 3.36 mmol), 4-cyanophenylboronic acid (641 mg, 4.36 mmol), tetrakis(triphenylphosphine)palladium (0) (77.5 mg, 0.0671 mmol), and potassium carbonate (1.39 g, 10.1 mmol) were dissolved in 1,4-dioxane / water (5 / 1, v / v, 17 mL), and then heated and stirred at 100°C for 16 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting solid was filtered to obtain the title compound (647 mg, 2.35 mmol, yield 70%) as a gray solid. 1H-NMR(DMSO-d6)δ:9.14(1H,d,J=2.7Hz),8.90(1H,d,J=8.7Hz),8.56-8.51(3H ,m),8.49(1H,d,J=8.7Hz),8.31(1H,d,J=9.1Hz),8.09(2H,dt,J=8.2,1.8Hz). MS(ESI)[M+H] + :276.

[0826] (Reference Example 69) Synthesis of 4-(6-aminoquinoline-2-yl)benzonitrile:

[0827] [ka]

[0828] 4-(6-nitroquinoline-2-yl)benzonitrile (100 mg, 0.363 mmol) synthesized in Reference Example 68 was dissolved in acetic acid (3.6 mL), and then iron powder (81.2 mg, 1.45 mmol) was added. The mixture was stirred at 50°C for 14 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH to 12, and then extracted with ethyl acetate. The resulting reddish-brown solid was removed by filtration, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (31.8 mg, 0.131 mmol, yield 36%) as a yellow solid. 1 H-NMR(CDCl3)δ:8.24(2H,dt,J=8.4,1.8Hz),8.01(1H,d,J=8.9Hz),7.97(1H,d,J=8.9Hz ),7.80-7.76(3H,m),7.20(1H,dd,J=8.9,2.6Hz),6.93(1H,d,J=2.6Hz),4.05(2H,brs). MS(ESI)[M+H] + :246.

[0829] (Reference Example 70) Synthesis of 1-(tert-butyl)-3-(2-(4-cyanophenyl)quinoline-6-yl)urea:

[0830] [ka]

[0831] 4-(6-aminoquinoline-2-yl)benzonitrile (30.0 mg, 0.122 mmol) synthesized in Reference Example 69 was dissolved in acetonitrile / THF (2 / 1, v / v, 1.8 mL), then potassium carbonate (33.8 mg, 0.245 mmol) and tert-butyl isocyanate (86.6 μL, 0.733 mmol) were added, and the mixture was heated under reflux for 23 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (aminosilica gel, chloroform / methanol) to obtain the title compound (37.2 mg, 0.107 mmol, yield 88%) as a pale orange solid. 1 H-NMR(CDCl3)δ:8.23(2H,dt,J=8.5,1.7Hz),8.15-8.12(2H,m),8.02(1H,d,J=9.1Hz),7. 80-7.77(3H,m),7.42(1H,dd,J=9.1,2.7Hz),6.72(1H,brs),4.84(1H,brs),1.43(9H,s). MS(ESI)[M+H] + :345.

[0832] (Reference Example 71) Synthesis of 4-(6-(3-(tert-butyl)ureido)quinoline-2-yl)benzamide:

[0833] [ka]

[0834] 1-(tert-butyl)-3-(2-(4-cyanophenyl)quinoline-6-yl)urea (37.0 mg, 0.107 mmol) synthesized in Reference Example 70 was dissolved in THF (1.1 mL), then 1 mol / L aqueous sodium hydroxide solution (60 μL, 0.453 mmol) and 30% hydrogen peroxide solution (37 μL, 0.453 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was slurry-washed (hexane / ethyl acetate) to obtain the title compound (32.4 mg, 0.0888 mmol, yield 83%) as a pale yellow solid. 1 H-NMR(DMSO-d6)δ:8.71(1H,brs),8.32-8.30(3H,m),8.16(1H,d,J=2.3Hz),8.11(1H,d,J=9.1Hz),8.10(1H,brs),8 .02(2H,d,J=8.7Hz),7.95(1H,d,J=9.1Hz),7.59(1H,dd,J=9.1,2.3Hz),7.44(1H,brs),6.21(1H,brs),1.33(9H,s). MS(ESI)[M+H] + :363.

[0835] (Example 87) Synthesis of 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinoline-2-yl)benzamide (novel compound):

[0836] [ka]

[0837] 4-(6-(3-(tert-butyl)ureido)quinoline-2-yl)benzamide (31.0 mg, 0.0855 mmol) synthesized in Reference Example 71 was suspended in THF / methanol (1 / 1, v / v, 0.85 mL), acetic acid (0.015 mL, 0.26 mmol) and platinum(IV) oxide (3.0 mg, 0.13 mmol) were added, and the mixture was stirred at room temperature under atmospheric pressure and hydrogen for 48 hours. After the reaction was complete, the mixture was purged with nitrogen, and the reaction mixture was filtered using Celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (hereinafter referred to as the compound of Example 87) (26.1 mg, 0.0564 mmol, yield 66%) as a white solid. 1 H-NMR(CDCl3)δ:7.92(2H,dt,J=8.7,1.8Hz),7.60(2H,dt,J=8.7,1.8Hz),7.06-7.00(2H,m),6.69(1H,td,J=7.3,0.9Hz),6.59(1H,dd,J=7.8,0.9H z),4.57(1H,dd,J=8.7,3.2Hz),4.09(1H,brs),3.06(3H,s),2.95-2.87(1 H,m),2.70(1H,td,J=10.9,5.5Hz),2.19-2.12(1H,m),2.01-1.97(1H,m). MS(ESI)[M+H] + :288.

[0838] (Example 88) (2R) * ,4R * Synthesis of methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylate (novel compound):

[0839] [ka]

[0840] 2-phenylquinoline-4-carboxylate methyl (300 mg, 1.14 mmol) was dissolved in THF / ethanol (1 / 1, v / v, 5.7 mL), then acetic acid (0.197 mL, 3.42 mmol) and platinum(IV) oxide (30 mg, 0.043 mmol) were added, and the mixture was stirred at room temperature under atmospheric pressure and hydrogen for 23 hours. After the reaction was complete, the mixture was purged with nitrogen, and the reaction mixture was filtered using Celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 88) (274 mg, 1.03 mmol, yield 90%) as a pale yellow oil. 1 H-NMR(CDCl3)δ:7.44-7.42(2H,m),7.39-7.35(2H,m),7.33-7.29(1H,m),7.08-7.02(2H,m),6.70(1H,td,J=7.5,1.1Hz),6.57(1 H,dd,J=8.2,1.1Hz),4.42(1H,dd,J=10.5,3.2Hz),4.11(1H,dd,J=11.2,6.2Hz),4.05(1H,brs),3.71(3H,s),2.40-2.31(2H,m). MS(ESI)[M+H] + :268.

[0841] (Example 89) ((2R * ,4R * Synthesis of )-2-phenyl-1,2,3,4-tetrahydroquinoline-4-yl)methanol (novel compound):

[0842] [ka]

[0843] (2R) synthesized in Example 88 * ,4R *)-2-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylate methyl (70.0 mg, 0.262 mmol) was dissolved in THF (2.6 mL), and then 2 mol / L lithium borohydride / THF solution (0.656 mL, 1.31 mmol) was added dropwise, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, saturated potassium sodium tartrate aqueous solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was extracted with ethyl acetate. The organic layers were dried together over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 89) (32.3 mg, 0.135 mmol, yield 52%) as a white solid. 1 H-NMR(CDCl3)δ:7.45-7.42(2H,m),7.39-7.35(2H,m),7.33-7.28(1H,m),7.23( 1H,d,J=7.4Hz),7.05(1H,t,J=7.4Hz),6.73(1H,td,J=7.4,1.2Hz),6.58(1H,dd, J=8.0,1.2Hz),4.44(1H,dd,J=11.0,2.7Hz),4.01-3.93(3H,m),3.28-3.25(1H,m ),2.26-2.23(1H,m),2.04(1H,dt,J=12.8,11.0Hz),1.41(1H,dd,J=7.3,4.6Hz). MS(ESI)[M+H] + :240.

[0844] (Reference Example 72) Synthesis of 4-methyl-2-phenylquinoline:

[0845] [ka]

[0846] Using 2-chloro-4-methylquinoline (300 mg, 1.69 mmol) and phenylboronic acid (227 mg, 1.86 mmol), the title compound (360 mg, 1.64 mmol, 97%) was obtained as a colorless oil in the same manner as in Reference Example 6. 1 H-NMR(CDCl3)δ:8.18-8.15(3H,m),8.01(1H,d,J=8.2Hz),7.74-7.71(2H,m),7.56-7.53(3H,m),7.47-7.45(1H,m),2.78(3H,s). MS(ESI)[M+H] + :220.

[0847] (Example 90) (2R) * ,4R * Synthesis of )-4-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0848] [ka]

[0849] Using 4-methyl-2-phenylquinoline (100 mg, 0.456 mmol) synthesized in Reference Example 72, the title compound (hereinafter referred to as the compound of Example 90) (46.1 mg, 0.206 mmol, 45%) was obtained as a pale yellow oily substance by the same method as in Example 26. 1 H-NMR(CDCl3)δ:7.43-7.42(2H,m),7.38-7.34(2H,m),7.30-7.28(1H,m),7.19(1H,d,J=7.7H z),7.01(1H,ddd,J=7.2,7.2,0.9Hz),6.71(1H,ddd,J=7.2,7.2,0.9Hz),6.53(1H,dd,J=8.2, 0.9Hz),4.47(1H,dd,J=11.3,2.7Hz),3.97(1H,brs),3.13(1H,ddd,J=6.3,12.2,6.3Hz),2.1 1(1H,ddd,J=12.7,5.0,2.7Hz),1.76(1H,ddd,J=11.8,11.8,11.8Hz),1.35(3H,d,J=6.8Hz). MS(ESI)[M+H] + :224.

[0850] (Reference Example 73) Synthesis of 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate tert-butyl:

[0851] [ka]

[0852] 2-phenyl-1,2,3,4-tetrahydroquinoline (30.0 mg, 0.143 mmol) was dissolved in tetrahydrofuran (1 mL), and a 1.64 mol / L n-butyllithium / hexane solution (0.140 mL, 0.229 mmol) was added under an argon atmosphere at -78°C and the mixture was stirred for 0.5 hours. Subsequently, a tetrahydrofuran solution (1 mL) of di-tert-butyl dicarbonate (93.9 mg, 0.430 mmol) was added and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the organic layer was separated. The resulting aqueous layer was extracted with diethyl ether. The organic layers were washed together with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (aminosilica gel, hexane / ethyl acetate) to obtain the title compound (44.3 mg, 0.143 mmol, yield 99%) as a colorless amorphous material. 1 H-NMR(CDCl3)δ:7.80(1H,d,J=8.2Hz),7.28-7.16(6H,m),7.08(1H,d,J=5.9Hz),7.01(1H,ddd,J=7.3,7.3, 1.4Hz),5.35(1H,dd,J=8.5,7.1Hz),2.70-2.58(2H,m),2.45-2.41(1H,m),1.84-1.81(1H,m),1.34(9H,s).

[0853] (Reference Example 74) Synthesis of 2-methyl-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate tert-butyl:

[0854] [ka]

[0855] 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate tert-butyl (22.2 mg, 71.1 μmol) synthesized in Reference Example 73 was dissolved in tetrahydrofuran (1.0 mL), and 1.64 mol / L n-butyllithium / hex...

Claims

1. A tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacoposly acceptable salt thereof. 【Chemistry 1】 [In the formula, R １ｘ This represents a hydrogen atom, a phenyl group, or a 5 or 6-membered heteroaryl ring selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, and pyridyl group. R １ｙ R represents a hydrogen atom, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl group (however, R １ｘ When R is a hydrogen atom １ｙ R is a substituent other than a hydrogen atom, １ｘ When R is a substituent other than a hydrogen atom １ｙ (This is a hydrogen atom.) R ２ 、 R ４ and R ５ combination is, R ２ 、 R ４ and R ５ are all hydrogen atoms, or R ２ and R ４ is, one is a fluorine atom, a chlorine atom, a methoxy group or a methyl group in which one hydrogen atom may be substituted by a hydroxy group, and the other and R ５ are hydrogen atoms, or R ２ and R ４ are both hydrogen atoms, and R ５ is a fluorine atom or a chlorine atom, R ３ This includes hydrogen atoms, halogen atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may each be independently substituted with hydroxyl groups or fluorine atoms, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, C1-C3 alkoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, -NR ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ This represents, R ｖ This represents a hydrogen atom, R ｗ This represents a hydrogen atom, Here, R １ｘ However, a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, a C1-C3 alkyl group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, a C1-C3 alkoxy group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, a cyano group, a methoxycarbonyl group, and -NHCOR ８ It may be substituted with one substituent selected from the group consisting of, except for the m-cyanophenyl group and the p-trifluoromethoxyphenyl group), or when representing a 5 or 6-membered ring heteroaryl group (any one hydrogen atom of the 5 or 6-membered ring heteroaryl group may be substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group, except for the 1-methyl-1H-pyrazole-4-yl group and the 6-methoxypyridine-3-yl group), R ３ This includes C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms, C1-C3 alkyl groups in which 1 arbitrary hydrogen atom is substituted with a hydroxyl group, ethyl groups, propyl groups, isopropyl groups, 3-hydroxyoxetane-3-yl groups, methoxy groups, methoxycarbonyl groups, and -NR groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms. ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ (However, R ２ and R ４ Both are hydrogen atoms, and R ５ If R is a fluorine atom or a chlorine atom, ３ R may be a hydrogen atom or a fluorine atom, ２ and R ５ Both are hydrogen atoms, and R ４ If R is a fluorine atom or a chlorine atom, ３ R may be a fluorine atom, ２ However, a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and R ４ and R ５ If all of them are hydrogen atoms, then R ３ (This may also represent a hydrogen atom) R ８ This represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R ９ This represents a hydrogen atom, R １０ is a hydrogen atom, -COR １５ Or it represents an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ (CH ２ ) ｎ - represents, n represents 4 or 5, R １１ and R １２ They become one—(CH ２ ) ｍ - represents, m represents 4 or 5, where any one methylene group may be substituted with an oxygen atom. R １３ This represents a hydrogen atom or a methyl group. R １４ This represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a C3 or C4 cycloalkyl group in which any one carbon atom may be substituted with an oxygen atom, or a methyl group substituted with a C3 or C4 cycloalkyl group in which any one carbon atom may be substituted with a nitrogen atom or an oxygen atom, or R １３ and R １４ Together with the nitrogen atoms bonded to them, they may form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a piperazinone ring, or an azetidine ring in which two arbitrary hydrogen atoms are substituted with methyl groups or fluorine atoms, or one arbitrary hydrogen atom is substituted with a hydroxyl group or a methoxy group. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ This represents, R １６ This represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Or, R １ｘ However, hydrogen atoms, phenyl groups (any one hydrogen atom of the phenyl group is a C1-C3 alkyl group in which any one hydrogen atom is substituted with a hydroxyl group, -CONR ６ R ７ , substituted with an aminosulfonyl group, a methylsulfonylamino group, an aminosulfonylamino group, or a C1-C3 alkylsulfonyl group, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group), representing a 1-methyl-1H-pyrazole-4-yl group or a 6-methoxypyridine-3-yl group, or, R １ｘ However, when representing a fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (where any one hydrogen atom of the fused ring group may be substituted with a methyl group), R ３ This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, -NR ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ This represents, R ６ and R ７ Each of these independently represents either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R ６ and R ７ These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atoms bonded to them. R ９ This represents a hydrogen atom, R １０ represents a hydrogen atom, -COR １５ or an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ (CH ２ ) ｎ - represents, n represents 4 or 5, R １１ and R １２ are combined to represent -(CH ２ ) ｍ - and m represents 4 or 5, where any one methylene group may be substituted with an oxygen atom. R １３ This represents a hydrogen atom or a methyl group. R １４ This represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a C3 or C4 cycloalkyl group in which any one carbon atom may be substituted with an oxygen atom, or a methyl group substituted with a C3 or C4 cycloalkyl group in which any one carbon atom may be substituted with a nitrogen atom or an oxygen atom, or R １３ and R １４ Together with the nitrogen atoms bonded to them, they may form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a piperazinone ring, or an azetidine ring in which two arbitrary hydrogen atoms are substituted with methyl groups or fluorine atoms, or one arbitrary hydrogen atom is substituted with a hydroxyl group or a methoxy group. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ This represents, R １６ This represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms (excluding 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-methyl carboxylate and 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline).

2. R １ｘ This is a phenyl group, or a 5 or 6-membered heteroaryl group selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, and pyridyl group. R １ｙ It is a hydrogen atom, R ２ , R ４ and R ５ The combination is R ２ , R ４ and R ５ Are they all hydrogen atoms, or R ２ and R ４ One of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other and R ５ Is it a hydrogen atom, or R ２ and R ４ Both are hydrogen atoms, and R ５ is a fluorine atom or a chlorine atom, R ｖ It is a hydrogen atom, R ｗ It is a hydrogen atom, Here, R １ｘ However, a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, a C1-C3 alkyl group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, a C1-C3 alkoxy group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, a cyano group, a methoxycarbonyl group, and -NHCOR ８ It may be substituted with one substituent selected from the group consisting of, except for the m-cyanophenyl group and the p-trifluoromethoxyphenyl group), or a 5 or 6-membered ring heteroaryl group (any one hydrogen atom of the 5 or 6-membered ring heteroaryl group may be substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group, except for the 1-methyl-1H-pyrazole-4-yl group and the 6-methoxypyridine-3-yl group), R ３ This includes C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms, C1-C3 alkyl groups in which 1 arbitrary hydrogen atom is substituted with a hydroxyl group, ethyl groups, propyl groups, isopropyl groups, 3-hydroxyoxetane-3-yl groups, methoxy groups, methoxycarbonyl groups, and -NR groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms. ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ (However, R ２ and R ４ Both are hydrogen atoms, and R ５ If R is a fluorine atom or a chlorine atom, ３ R may be a hydrogen atom or a fluorine atom, ２ and R ５ Both are hydrogen atoms, and R ４ If R is a fluorine atom or a chlorine atom, ３ R may be a fluorine atom, ２ However, a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and R ４ and R ５ If all of them are hydrogen atoms, then R ３ (This may be a hydrogen atom) R ８ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R ９ It is a hydrogen atom, R １０ is a hydrogen atom, -COR １５ Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ (CH ２ ) ｎ - and n is either 4 or 5. R １１ and R １２ They become one—(CH ２ ) ｍ - and m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R １３ It is a hydrogen atom, R １４ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R １３ and R １４ These may form an azetidine ring with the nitrogen atom bonded to them, in which one arbitrary hydrogen atom may be substituted with a hydroxyl group. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ And, R １６ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Or, R １ｘ However, a phenyl group (where any one hydrogen atom of the phenyl group is replaced by a C1-C3 alkyl group, -CONR ６ R ７ (substituted with an aminosulfonyl group or a C1-C3 alkylsulfonyl group, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group), a 1-methyl-1H-pyrazole-4-yl group or a 6-methoxypyridine-3-yl group, or R １ｘ However, if it is a fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (where any one hydrogen atom of the fused ring group may be substituted with a methyl group), R ３ This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, -NR ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ And, R ６ and R ７ Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ６ and R ７ These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atoms bonded to them. R ９ It is a hydrogen atom, R １０ is a hydrogen atom, -COR １５ Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ (CH ２ ) ｎ - and n is either 4 or 5. R １１ and R １２ They become one—(CH ２ ) ｍ - and m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R １３ It is a hydrogen atom, R １４ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R １３ and R １４ These may form an azetidine ring with the nitrogen atom bonded to them, in which one arbitrary hydrogen atom may be substituted with a hydroxyl group. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ And, R １６ [wherein is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms (excluding 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate methyl and 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline), the tetrahydroquinoline derivative according to claim 1 or a pharmaceutically acceptable salt thereof.]

3. A tetrahydroquinoline derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the following group: (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanol, (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate tert-butyl, 2-phenyl-1,2,3,4-tetrahydroquinoline-6-amine, 2-(benzo[d][1,3]dioxol-5-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline, (2-phenyl-1,2,3,4-tetrahydroquinoline-7-yl)methanol, 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline, 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline, (2-phenyl-1,2,3,4-tetrahydroquinoline-5-yl)methanol, (2-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, (3-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, (4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, N-methyl-3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzonitrile, 6-Isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline, 2-(1-methyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline, 2-(6-methoxypyridine-3-yl)-1,2,3,4-tetrahydroquinoline, 4-((2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)propan-2-ol, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)oxetan-3-ol, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, 2-phenyl-6-(piperidine-1-yl)-1,2,3,4-tetrahydroquinoline, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanesulfonamide, 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, 2-(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)propan-2-ol, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 2-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl) pivalamide, 1-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, 1,2,3,3',4,4'-Hexahydro-[2,6'-Biquinoline]-2'(1'H)-one, 1'-methyl-1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one, N,N-diethyl-4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, N-ethyl-4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 5-(1,2,3,4-tetrahydroquinoline-2-yl)isoindorin-1-one, (4-methylpiperazine-1-yl)(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, Piperidine-1-yl(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, and Morphorino(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, or a pharmacokinetically acceptable salt thereof.

4. A tetrahydroquinoline derivative according to any one of claims 1 to 3, selected from the following group, or a pharmaceutically acceptable salt thereof: (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate tert-butyl, (4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-((2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanesulfonamide, 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl) pivalamide, 1-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, and 5-(1,2,3,4-tetrahydroquinoline-2-yl)isoindorin-1-one, or a pharmacopositically acceptable salt thereof.

5. R １ｘ It is a phenyl group, R １ｙ It is a hydrogen atom, R ２ , R ４ and R ５ The combination is R ２ , R ４ and R ５ Are they all hydrogen atoms, or R ２ and R ４ One is a fluorine atom, a chlorine atom, or a methyl group, and the other is R ５ That is a hydrogen atom, R ｖ is a hydrogen atom. R ｗ It is a hydrogen atom, Here, R １ｘ However, if it is a phenyl group (the hydrogen atom at the para position of the phenyl group may be substituted with one substituent selected from the group consisting of a fluorine atom, a trifluoromethyl group, a cyano group, and an acetamide group), R ３ This refers to a trifluoromethoxy group, a hydroxymethyl group, or -CH ２ CONR １３ R １４ (However, R ２ is a methyl group, and R ４ and R ５ If all of them are hydrogen atoms, then R ３ (This may be a hydrogen atom) R １３ is a hydrogen atom or a methyl group, R １４ is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, or an oxetan-3-yl group, or R １３ and R １４ These may form a piperazine ring, a piperazine-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, a 3-hydroxyazetidine ring, or a 3-methoxyazetidine ring together with the nitrogen atom bonded to them. Or, R １ｘ However, if it is a phenyl group (where the para hydrogen atom of the phenyl group is substituted with a trifluoromethoxy group, an aminocarbonyl group, an aminosulfonyl group, a methylsulfonylamino group, or a methylsulfonyl group), R ３ This includes hydrogen atoms, fluorine atoms, chlorine atoms, methyl groups, hydroxymethyl groups, trifluoromethoxy groups, or -CH ２ CONR １３ R １４ And, R １３ is a hydrogen atom or a methyl group, R １４ is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, or an oxetan-3-yl group, or R １３ and R １４ The tetrahydroquinoline derivative or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the nitrogen atoms bonded thereto may form a piperazine ring, a piperazine-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, a 3-hydroxyazetidine ring, or a 3-methoxyazetidine ring, together with the nitrogen atoms to which they are bonded.

6. A tetrahydroquinoline derivative according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following group: 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, 4-(6-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(5-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(5-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 1-(3-methoxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3,3-difluoroazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(2-hydroxyethyl)-N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(azetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-1-(piperazine-1-yl)ethane-1-one, and 4-(1,2,3,4-tetrahydroquinoline-3-yl)benzenesulfonamide, or a pharmacopositically acceptable salt thereof.

7. A pharmaceutical product containing a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacoposly acceptable salt thereof as an active ingredient. 【Chemistry 2】 [In the formula, R １ｘ This refers to a five- or six-membered ring heteroaryl group containing one or two heteroatoms selected from a hydrogen atom, an aryl group, or a nitrogen atom, an oxygen atom, and a sulfur atom (the aryl group and one or two of the five- or six-membered ring heteroaryl group may each be independently substituted with a halogen atom, a C1-C3 alkyl group in which one to three of the hydrogen atoms may each be independently substituted with a hydroxyl group or a fluorine atom, a C1-C3 alkoxy group in which one to three of the hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, or -CONR ６ R ７ ,-NHCOR ８ (which may be substituted with an aminosulfonyl group, a C1-C3 alkylsulfonylamino group, an aminosulfonylamino group, or a C1-C3 alkylsulfonyl group), or R １ｘ In this case, if the aryl group is a phenyl group, the phenyl group may be fused with a ring selected from the group consisting of a 5- and 6-membered lactam ring and a 5- and 6-membered saturated heterocycle containing one or two oxygen atoms as constituent atoms of the ring, forming a fused ring group (one of the hydrogen atoms of the fused ring group may be substituted with a methyl group). R １ｙ R represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group (however, R １ｘ and R １ｙ (Except that both are hydrogen atoms), R ２ , R ４ and R ５ The combination is R ２ , R ４ and R ５ Are they all hydrogen atoms? Or, R ２ , R ４ and R ５ One of them is a halogen atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other two are hydrogen atoms. R ３ This includes hydrogen atoms, halogen atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may each be independently substituted with hydroxyl groups or fluorine atoms, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, C1-C3 alkoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, -NR ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ This represents, R ６ and R ７ Each of these independently represents either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R ６ and R ７ They become one—(CH ２ ) ｈ - represents, h represents an integer between 3 and 5, where any one methylene group is an oxygen atom, -NH- or -N(CH) ３ ) - may also be substituted, R ８ This represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R ９ and R １０ These are, independently, hydrogen atoms and -COR １５ Or it represents an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ They become one—(CH ２ ) ｎ - represents, n represents an integer between 3 and 6. R １１ and R １２ They become one—(CH ２ ) ｍ - represents, m represents an integer between 3 and 5, where any one methylene group may be substituted with an oxygen atom. R １３ and R １４ Each of these independently represents a hydrogen atom, a C1-C5 alkyl group, a 2-hydroxyethyl group, a C3 or C4 cycloalkyl group in which one of the carbon atoms may be substituted with an oxygen atom, or a methyl group in which one of the carbon atoms may be substituted with a C3 or C4 cycloalkyl group in which one of the carbon atoms may be substituted with a nitrogen atom or an oxygen atom, or R １３ and R １４ This is formed by one or two arbitrary hydrogen atoms being a fluorine atom, a methyl group, a hydroxyl group, or a methoxy group, or by one arbitrary CH ２ The group may be substituted with an oxygen atom, a nitrogen atom, or -CONH- - (CH ２ ) ｋ - represents, k represents an integer between 3 and 5. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ This represents, R １６ This represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R ｖ This represents a hydrogen atom, a methyl group in which any one hydrogen atom may be substituted with a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group. R ｗ This represents a hydrogen atom, a methyl group, a hydroxymethyl group, or a methoxycarbonyl group (excluding 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydroquinoline).

8. R １ｘ This includes a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom, or one arbitrary hydrogen atom may be substituted with a hydroxyl group, a C1 to C3 alkoxy group where one to three arbitrary hydrogen atoms may be substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, and -CONR ６ R ７ ,-NHCOR ８ (which may be substituted with an aminosulfonyl group or a C1-C3 alkylsulfonyl group), or a 5 or 6-membered ring heteroaryl group selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group and pyridyl group (any one hydrogen atom of the 5 or 6-membered ring heteroaryl group may be substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group), or R １ｘ This may form a fused ring group in which a phenyl group is fused with one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (any one hydrogen atom of the fused ring group may be substituted with a methyl group), R １ｙ It is a hydrogen atom, R ２ , R ４ and R ５ The combination is R ２ , R ４ and R ５ Are they all hydrogen atoms, or R ２ and R ４ One of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other and R ５ Is it a hydrogen atom, or R ２ and R ４ Both are hydrogen atoms, and R ５ is a fluorine atom or a chlorine atom, R ３ This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, -NR ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ And, R ６ and R ７ Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ６ and R ７ These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atom bonded to them. R ８ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R ９ It is a hydrogen atom, R １０ is a hydrogen atom, -COR １５ Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ They become one—(CH ２ ) ｎ - and n is either 4 or 5. R １１ and R １２ They become one—(CH ２ ) ｍ - and m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R １３ It is a hydrogen atom, R １４ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R １３ and R １４ These may form an azetidine ring with the nitrogen atom bonded to them, in which one arbitrary hydrogen atom may be substituted with a hydroxyl group. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ And, R １６ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. R ｖ It is a hydrogen atom, R ｗ A pharmaceutical product containing, as an active ingredient, a tetrahydroquinoline derivative according to claim 7 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom (except for 2-phenyl-1,2,3,4-tetrahydroquinoline).

9. R １ｘ This is a phenyl group, or a 5 or 6-membered heteroaryl group selected from the group consisting of a furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, and pyridyl group. R １ｙ It is a hydrogen atom, R ２ , R ４ and R ５ The combination is R ２ , R ４ and R ５ Are they all hydrogen atoms, or R ２ and R ４ One of them is a fluorine atom, a chlorine atom, a methoxy group, or a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and the other and R ５ Is it a hydrogen atom, or R ２ and R ４ Both are hydrogen atoms, and R ５ is a fluorine atom or a chlorine atom, R ｖ It is a hydrogen atom, R ｗ It is a hydrogen atom, Here, R １ｘ However, a phenyl group (where any one hydrogen atom of the phenyl group may be a halogen atom, a C1-C3 alkyl group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, a C1-C3 alkoxy group in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, a cyano group, a methoxycarbonyl group, and -NHCOR ８ It may be substituted with one substituent selected from the group consisting of, except for the m-cyanophenyl group and the p-trifluoromethoxyphenyl group), or a 5 or 6-membered ring heteroaryl group (any one hydrogen atom of the 5 or 6-membered ring heteroaryl group may be substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group, except for the 1-methyl-1H-pyrazole-4-yl group and the 6-methoxypyridine-3-yl group), R ３ This includes C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms, C1-C3 alkyl groups in which 1 arbitrary hydrogen atom is substituted with a hydroxyl group, ethyl groups, propyl groups, isopropyl groups, 3-hydroxyoxetane-3-yl groups, methoxy groups, methoxycarbonyl groups, and -NR groups in which 1-3 arbitrary hydrogen atoms are substituted with fluorine atoms. ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ (However, R ２ and R ４ Both are hydrogen atoms, and R ５ If R is a fluorine atom or a chlorine atom, ３ R may be a hydrogen atom or a fluorine atom, ２ and R ５ Both are hydrogen atoms, and R ４ If R is a fluorine atom or a chlorine atom, ３ R may be a fluorine atom, ２ However, a methyl group in which one hydrogen atom may be substituted with a hydroxyl group, and R ４ and R ５ If all of them are hydrogen atoms, then R ３ (This may be a hydrogen atom) R ８ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R ９ It is a hydrogen atom, R １０ is a hydrogen atom, -COR １５ Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ (CH ２ ) ｎ - and n is either 4 or 5. R １１ and R １２ They become one—(CH ２ ) ｍ - and m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R １３ It is a hydrogen atom, R １４ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R １３ and R １４ These may form an azetidine ring with the nitrogen atom bonded to them, in which one arbitrary hydrogen atom may be substituted with a hydroxyl group. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ And, R １６ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Or, R １ｘ However, a phenyl group (where any one hydrogen atom of the phenyl group is replaced by a C1-C3 alkyl group, -CONR ６ R ７ (substituted with an aminosulfonyl group or a C1-C3 alkylsulfonyl group, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group), a 1-methyl-1H-pyrazole-4-yl group or a 6-methoxypyridine-3-yl group, or R １ｘ However, if it is a fused ring group formed by the fusion of a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one, and 1,3-dioxolane (where any one hydrogen atom of the fused ring group may be substituted with a methyl group), R ３ This includes hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C1-C3 alkyl groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms or 1 arbitrary hydrogen atom may be substituted with a hydroxyl group, 3-hydroxyoxetane-3-yl groups, hydroxyl groups, methoxy groups in which 1-3 arbitrary hydrogen atoms may be substituted with fluorine atoms, methoxycarbonyl groups, -NR ９ R １０ ien-CH ２ NR １１ R １２ or -CH ２ CONR １３ R １４ And, R ６ and R ７ Each of these is independently either a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ６ and R ７ These may form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring together with the nitrogen atoms bonded to them. R ９ It is a hydrogen atom, R １０ is a hydrogen atom, -COR １５ Or it is an alkylsulfonyl group having 1 to 3 carbon atoms, or R ９ and R １０ (CH ２ ) ｎ - and n is either 4 or 5. R １１ and R １２ They become one—(CH ２ ) ｍ - and m is 4 or 5, where any one methylene group may be substituted with an oxygen atom. R １３ It is a hydrogen atom, R １４ is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a tert-butyl group, or R １３ and R １４ These may form an azetidine ring with the nitrogen atom bonded to them, in which one arbitrary hydrogen atom may be substituted with a hydroxyl group. R １５ This is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR １６ And, R １６ A pharmaceutical product comprising, as an active ingredient, a tetrahydroquinoline derivative according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, which is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

10. The pharmacopoeia according to any one of claims 7 to 9, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the following group: (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanol, (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate tert-butyl, 2-phenyl-1,2,3,4-tetrahydroquinoline-6-amine, 2-(benzo[d][1,3]dioxol-5-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline, (2-phenyl-1,2,3,4-tetrahydroquinoline-7-yl)methanol, 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline, 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline, (2-phenyl-1,2,3,4-tetrahydroquinoline-5-yl)methanol, (2-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, (3-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, (4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, N-methyl-3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzonitrile, 6-Isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline, 2-(1-methyl-1H-pyrazole-4-yl)-1,2,3,4-tetrahydroquinoline, 2-(6-methoxypyridine-3-yl)-1,2,3,4-tetrahydroquinoline, 4-((2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)propan-2-ol, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)oxetan-3-ol, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, 2-phenyl-6-(piperidine-1-yl)-1,2,3,4-tetrahydroquinoline, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanesulfonamide, 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, 2-(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)propan-2-ol, 3-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 2-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl) pivalamide, 1-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, 1,2,3,3',4,4'-Hexahydro-[2,6'-Biquinoline]-2'(1'H)-one, 1'-methyl-1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one, N,N-diethyl-4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, N-ethyl-4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 5-(1,2,3,4-tetrahydroquinoline-2-yl)isoindorin-1-one, (4-methylpiperazine-1-yl)(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, Piperidine-1-yl(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, and Morphorino(4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanone, or a pharmacokinetically acceptable salt thereof.

11. The pharmacopoeia according to any one of claims 7 to 10, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the following group: (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)carbamate tert-butyl, (4-(1,2,3,4-tetrahydroquinoline-2-yl)phenyl)methanol, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-((2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)methanesulfonamide, 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, N-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl) pivalamide, 1-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)urea, and 5-(1,2,3,4-tetrahydroquinoline-2-yl)isoindorin-1-one, or a pharmacopositically acceptable salt thereof.

12. R １ｘ This is a phenyl group (the hydrogen atom at the para position of the phenyl group may be substituted with a fluorine atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetamide group, an aminosulfonyl group, a methylsulfonylamino group, or a methylsulfonyl group), R １ｙ It is a hydrogen atom, R ２ , R ４ and R ５ The combination is R ２ , R ４ and R ５ Are they all hydrogen atoms, or R ２ and R ４ One is a fluorine atom, a chlorine atom, or a methyl group, and the other is R ５ That is a hydrogen atom, R ３ This includes hydrogen atoms, fluorine atoms, chlorine atoms, methyl groups, hydroxymethyl groups, trifluoromethoxy groups, or -CH ２ CONR １３ R １４ And, R １３ is a hydrogen atom or a methyl group, R １４ is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group, or an oxetan-3-yl group, or R １３ and R １４ These may form a piperazine ring, a piperazine-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, a 3-hydroxyazetidine ring, or a 3-methoxyazetidine ring together with the nitrogen atom bonded to them. R ｖ It is a hydrogen atom, R ｗ A pharmaceutical product containing, as an active ingredient, a tetrahydroquinoline derivative according to any one of claims 7 to 9 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom (except for 2-phenyl-1,2,3,4-tetrahydroquinoline).

13. The pharmacopoeia according to claim 7 or 8, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the following group: 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 1-(3-hydroxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, 4-(6-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(5-methyl-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(7-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzenesulfonamide, 4-(5-fluoro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinoline-2-yl)benzamide, 1-(3-methoxyazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(3,3-difluoroazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-(2-hydroxyethyl)-N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 1-(azetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)ethane-1-one, N-cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, N-cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)acetamide, 2-(2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl)-1-(piperazine-1-yl)ethane-1-one, and 4-(1,2,3,4-tetrahydroquinoline-3-yl)benzenesulfonamide, or a pharmacopositically acceptable salt thereof.

14. A pharmaceutical agent according to any one of claims 7 to 13, for treating or preventing a disease, disorder, or syndrome related to ferroptosis inhibition.

15. The pharmaceutical product according to claim 14, wherein the disease, disorder, or syndrome is multiple sclerosis.

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