Therapeutic or prophylactic agent for amyotrophic lateral sclerosis

Abstract

The purpose of the present invention is to provide a therapeutic or prophylactic agent for amyotrophic lateral sclerosis, said therapeutic or prophylactic agent having a ferroptosis-inhibiting effect. The present invention provides a therapeutic or prophylactic agent for amyotrophic lateral sclerosis, which contains, as an active ingredient, a tetrahydroquinoline derivative represented by the following compound or a pharmacologically acceptable salt thereof. [Chemical Formula 1] # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a therapeutic or preventive agent for amyotrophic lateral sclerosis. Background Art

[0002] Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by the selective degeneration and loss of motor neurons, which leads to systemic neurogenic muscle atrophy, movement disorders, and ultimately respiratory muscle paralysis.

[0003] Approximately 10% of cases of amyotrophic lateral sclerosis are familial, with mutations in genes such as the superoxide dismutase 1 (SOD1), 43kDa TAR DNA-binding protein (TDP-43), and Fusedin Sarcoma (FUS) genes known to be causative genes. The remaining 90% are sporadic with no family history, some of which have genetic mutations.

[0004] Excitotoxicity, oxidative stress, and accumulation of abnormal proteins are known to be the pathological mechanisms of amyotrophic lateral sclerosis. However, the only therapeutic agents currently marketed as ALS treatments are riluzole, which inhibits excitotoxicity, and edaravone, which has an antioxidant effect (Patent Document 1).

[0005] In recent years, various forms of controlled cell death have been identified, and ferroptosis has been reported as a new form of controlled cell death that is ferrous iron-dependent (Non-Patent Document 1). Ferroptosis is a reaction in which various stimuli cause a decrease in intracellular glutathione levels and glutathione peroxidase 4 (GPX4)-induced antioxidant function, leading to an ferrous iron-dependent reaction that increases intracellular lipid peroxides to lethal levels and causes cell death.

[0006] It has been reported that iron accumulates in the spinal cord of patients with amyotrophic lateral sclerosis, causing lipid peroxidation (Non-Patent Document 2). Furthermore, iron accumulation in the spinal cord of superoxide dismutase 1 (SOD1) gene mutant mice, a model animal for amyotrophic lateral sclerosis, has been reported to result in a lifespan extension effect achieved by iron chelators (Non-Patent Document 3).

[0007] As compounds that exhibit ferroptosis-inhibiting effects, aniline derivatives such as ferrostatin-1 are known (Non-Patent Documents 1 and 4). Furthermore, tetrahydroquinoxaline derivatives and 3,4-dihydro-2H-benzo-[1,4]oxazine derivatives have also been disclosed to exhibit ferroptosis-inhibiting effects (Patent Documents 2 and 3).

[0008] It is reported that free radical scavenging is important for the expression of ferroptosis inhibitory effect (Non-Patent Document 5). In addition, it is disclosed that the tetrahydroquinoxaline derivatives described in Patent Document 2 have a strong free radical scavenging effect, which results in the expression of ferroptosis inhibitory effect (Non-Patent Documents 6 and 7).

[0009] On the other hand, Patent Documents 4 to 8 disclose tetrahydroquinoline derivatives having antiviral action, antitumor action, pain therapeutic action, or immune response-modifying action.

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1: International Publication No. 2013 / 035712

[0013] Patent Document 2: Chinese Patent Application Publication No. 110372614

[0014] Patent Document 3: Chinese Patent Application Publication No. 110464727

[0015] Patent Document 4: Japanese Patent Application Laid-Open No. 56-051456

[0016] Patent Document 5: International Publication No. 2007 / 054138

[0017] Patent Document 6: Japanese Patent Application Laid-Open No. 5-125052

[0018] Patent Document 7: International Publication No. 2005 / 063735

[0019] Patent Document 8: German Patent Application Publication No. 10236910

[0020] Non-patent literature

[0021] Non-patent document 1: Dixon et al., Cell, 2012, Vol. 149, p. 1060-1072 Non-patent document 2: Liddell et al., bioRxiv, 2022, qianbrush

[0022] Non-patent document 3: Jeong et al., Journal of Neuroscience, 2009, Vol. 29, No. 3, pp. 610-619

[0023] Non-patent document 4: Lars et al., Journal of Medicinal Chemistry, 2018, Vol. 61, pp. 10126-10140

[0024] Non-patent document 5: Jennifer Yinus Cao et al., Cellular and Molecular Life Science, 2016, Vol. 73, p2195-2209

[0025] Non-patent literature 6: Yu-Zhen Li et al., Frontiers in Chemistry, 2019, Vol. 7, 850

[0026] Non-patent document 7: Hong-Xu Lei et al., Journal of Molecular Structure, 2021, Vol. 1228, 129485 Summary of the Invention

[0027] Problems to be solved by the invention

[0028] However, Patent Documents 2 to 8 and Non-Patent Documents 1 to 7 do not disclose the ferroptosis-inhibiting effect of tetrahydroquinoline derivatives and the treatment or prevention of amyotrophic lateral sclerosis, nor do they suggest its possibility. In addition, although various studies have been conducted on therapeutic agents for amyotrophic lateral sclerosis, the currently marketed amyotrophic lateral sclerosis therapeutic agents are therapeutic agents that act on cell death caused by excitotoxicity or cell death caused by oxidative stress as a mechanism, and do not treat amyotrophic lateral sclerosis by protecting cells through ferroptosis inhibition. The marketed therapeutic agents only delay the progression of movement disorders and other pathological conditions by a few months, and the therapeutic effect cannot be said to be sufficient.

[0029] Therefore, an object of the present invention is to provide a therapeutic or preventive agent for amyotrophic lateral sclerosis having ferroptosis inhibitory activity.

[0030] Solutions to Problems

[0031] The present inventors have conducted intensive studies to solve the above-mentioned problems and have found that novel compounds having a tetrahydroquinoline skeleton and having ferroptosis inhibitory activity are effective for the treatment or prevention of amyotrophic lateral sclerosis, thereby completing the present invention.

[0032] That is, the present invention provides a therapeutic or preventive agent for amyotrophic lateral sclerosis comprising a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[0033] That is, the present invention includes the following contents.

[0034] [1] A therapeutic or preventive agent for amyotrophic lateral sclerosis, comprising as an active ingredient a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof,

[0035] [Chemical Formula 1]

[0036]

[0037] [Where R 1x represents a hydrogen atom, an aryl group, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (one or two arbitrary hydrogen atoms of the aryl group and the 5- or 6-membered heteroaryl group are each independently optionally substituted with a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are each independently optionally substituted with a hydroxyl group or a fluorine atom, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, -CONR 6 R 7 、-NHCOR 8 , aminosulfonyl, alkylsulfonylamino having 1 to 3 carbon atoms, aminosulfonylamino or alkylsulfonyl having 1 to 3 carbon atoms), or

[0038] In R 1x In the case where the aryl group is a phenyl group, the phenyl group may be fused with one ring selected from a 5- and 6-membered lactam ring and a 5- and 6-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms as ring constituent atoms to form a fused ring group (one arbitrary hydrogen atom of the fused ring group may be substituted with a methyl group),

[0039] R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetylaminophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group (wherein R 1x and R 1y Except for the case where all are hydrogen atoms),

[0040] For R 2 、R 4 and R 5 Combination of R 2 、R 4 and R 5 All hydrogen atoms,

[0041] 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 is optionally substituted by a hydroxyl group, and the other two are hydrogen atoms,

[0042] R 3represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are independently optionally substituted with a hydroxyl group or a fluorine atom, a 3-hydroxyoxetan-3-yl group, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, a methoxycarbonyl group, a -NR 9 R 10 、-CH2NR 11 R 12 or -CH2CONR 13 R 14 ,

[0043] R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or

[0044] R 6 and R 7 Become one and express -(CH2) h -,

[0045] h represents an integer of 3 to 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom, -NH- or -N(CH3)-,

[0046] R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

[0047] R 9 and R 10 Each independently represents a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or

[0048] R 9 and R 10 Become one and express -(CH2) n -,

[0049] n represents an integer from 3 to 6,

[0050] R 11 and R 12 Become one and express -(CH2) m -,

[0051] m represents an integer of 3 to 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom.

[0052] R 13 and R 14each independently represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 2-hydroxyethyl group, a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by an oxygen atom, or a methyl group substituted with a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by a nitrogen atom or an oxygen atom, or

[0053] R 13 and R 14 Taken together, it represents -(CH2) in which one or two hydrogen atoms are optionally replaced by a fluorine atom, a methyl group, a hydroxyl group or a methoxy group, or one CH2 group is optionally replaced by an oxygen atom, a nitrogen atom or -CONH-. k -,

[0054] k represents an integer from 3 to 5,

[0055] R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 ,

[0056] R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,

[0057] R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom is optionally substituted by a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group,

[0058] R w represents a hydrogen atom, a methyl group, a hydroxymethyl group or a methoxycarbonyl group. ].

[0059] [2] A therapeutic or preventive agent for amyotrophic lateral sclerosis, comprising the tetrahydroquinoline derivative according to [1] or a pharmacologically acceptable salt thereof as an active ingredient, wherein:

[0060] R 1x is a hydrogen atom, a phenyl group (the hydrogen atom at the para position of the phenyl group may be substituted by a fluorine atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetylamino group, an aminosulfonyl group, a methylsulfonylamino group or a methylsulfonyl group),

[0061] R 1y is a hydrogen atom or a 4-aminosulfonylphenyl group (wherein R 1x When R is a hydrogen atom, 1y is 4-aminosulfonylphenyl, or R 1x In the case of a phenyl group (the hydrogen atom at the para position of the phenyl group may be substituted by a fluorine atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetylamino group, an aminosulfonyl group, a methylsulfonylamino group or a methylsulfonyl group), R 1y is a hydrogen atom),

[0062] For R 2 、R 4 and R 5 Combination of R 2 、R 4 and R 5 All hydrogen atoms, or R 2 and R 4 One of them is a fluorine atom, a chlorine atom or a methyl group, and the other and R 5 is a hydrogen atom,

[0063] R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a trifluoromethoxy group or -CH2CONR 13 R 14 ,

[0064] R 13 is a hydrogen atom or a methyl group,

[0065] R 14 is tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl or oxetan-3-yl, or

[0066] R 13 and R 14 optionally forming together with the nitrogen atom to which they are bound a piperazine ring, a piperazin-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,

[0067] R v is a hydrogen atom,

[0068] R w A hydrogen atom.

[0069] [3] The therapeutic or preventive agent for amyotrophic lateral sclerosis according to [1] or [2], wherein the tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof is selected from the following group:

[0070] 2-phenyl-1,2,3,4-tetrahydroquinoline,

[0071] 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0072] 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

[0073] 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one,

[0074] 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

[0075] 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0076] 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0077] 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

[0078] 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0079] 4-(5-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0080] 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0081] 4-(7-Fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0082] 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

[0083] 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

[0084] 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

[0085] 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

[0086] 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

[0087] 1-(3-methoxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one,

[0088] N-(oxetane-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

[0089] 1-(3,3-difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one,

[0090] N-(2-hydroxyethyl)-N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

[0091] 1-(azetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one,

[0092] N-cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

[0093] N-cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

[0094] 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(piperazin-1-yl)ethan-1-one, and

[0095] 4-(1,2,3,4-Tetrahydroquinolin-3-yl)benzenesulfonamide, or a pharmacologically acceptable salt thereof.

[0096] [4] The therapeutic or preventive agent for amyotrophic lateral sclerosis according to any one of [1] to [3], wherein the tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof is 2-phenyl-1,2,3,4-tetrahydroquinoline.

[0097] [5] The therapeutic or preventive agent for amyotrophic lateral sclerosis according to any one of [1] to [4], which is a ferroptosis inhibitor.

[0098] In another embodiment, the present invention includes a ferroptosis inhibitor comprising a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient:

[0099] [Chemical Formula 2]

[0100]

[0101] [Where R 1x represents a hydrogen atom, an aryl group, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (one or two arbitrary hydrogen atoms of the aryl group and the 5- or 6-membered heteroaryl group are each independently optionally substituted with a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are each independently optionally substituted with a hydroxyl group or a fluorine atom, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, -CONR 6 R 7 、-NHCOR 8 , aminosulfonyl, alkylsulfonylamino having 1 to 3 carbon atoms, aminosulfonylamino or alkylsulfonyl having 1 to 3 carbon atoms), or

[0102] In R 1xIn the case where 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 5- and 6-membered lactam rings and 5- and 6-membered saturated heterocyclic rings containing 1 or 2 oxygen atoms as ring constituent atoms to form a fused ring group (one arbitrary hydrogen atom of the fused ring group may be substituted with a methyl group),

[0103] R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetylaminophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group (wherein R 1x and R 1y Except for the case where all are hydrogen atoms),

[0104] For R 2 、R 4 and R 5 Combination of R 2 、R 4 and R 5 All hydrogen atoms,

[0105] 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 is optionally substituted by a hydroxyl group, and the other two are hydrogen atoms,

[0106] R 3 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are independently optionally substituted with a hydroxyl group or a fluorine atom, a 3-hydroxyoxetan-3-yl group, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, a methoxycarbonyl group, a -NR 9 R 10 、-CH2NR 11 R 12 or -CH2CONR 13 R 14 ,

[0107] R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or

[0108] R 6 and R 7 Become one and express -(CH2) h -,

[0109] h represents an integer of 3 to 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom, -NH- or -N(CH3)-,

[0110] R8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

[0111] R 9 and R 10 Each independently represents a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or

[0112] R 9 and R 10 Become one and express -(CH2) n -,

[0113] n represents an integer from 3 to 6,

[0114] R 11 and R 12 Become one and express -(CH2) m -,

[0115] m represents an integer of 3 to 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom.

[0116] R 13 and R 14 each independently represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 2-hydroxyethyl group, a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by an oxygen atom, or a methyl group substituted with a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by a nitrogen atom or an oxygen atom, or

[0117] R 13 and R 14 Taken together, it represents -(CH2) in which one or two hydrogen atoms are optionally replaced by a fluorine atom, a methyl group, a hydroxyl group or a methoxy group, or one CH2 group is optionally replaced by an oxygen atom, a nitrogen atom or -CONH-. k -,

[0118] k represents an integer from 3 to 5,

[0119] R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 ,

[0120] R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,

[0121] R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom is optionally substituted by a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group,

[0122] R wrepresents a hydrogen atom, a methyl group, a hydroxymethyl group or a methoxycarbonyl group. ].

[0123] In another embodiment, the present invention includes use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof in the production of a ferroptosis inhibitor.

[0124] In still another embodiment, the present invention includes use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof for the manufacture of a therapeutic or preventive agent for amyotrophic lateral sclerosis.

[0125] In still another embodiment, the present invention comprises the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof for use in the treatment or prevention of amyotrophic lateral sclerosis.

[0126] In still another embodiment, the present invention includes a method for treating or preventing amyotrophic lateral sclerosis, comprising administering an effective amount of the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof to a subject in need thereof.

[0127] Effects of the Invention

[0128] The tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof of the present invention has the effect of treating or preventing amyotrophic lateral sclerosis through ferroptosis inhibitory action and pharmacological action based thereon.

[0129] Brief description of the accompanying drawings

[0130] Figure 1 This figure shows the method for evaluating the motor function of amyotrophic lateral sclerosis model mice.

[0131] Figure 2 This is a graph showing the effect of the compound of Example 1 on the age of onset of movement disorders in amyotrophic lateral sclerosis model mice. DETAILED DESCRIPTION

[0132] The tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof according to one embodiment of the present invention is characterized by being represented by the following general formula (I).

[0133] [Chemical Formula 3]

[0134]

[0135] [Where R 1xrepresents a hydrogen atom, an aryl group, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (one or two arbitrary hydrogen atoms of the aryl group and the 5- or 6-membered heteroaryl group are each independently optionally substituted with a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are each independently optionally substituted with a hydroxyl group or a fluorine atom, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, a cyano group, a methoxycarbonyl group, -CONR 6 R 7 、-NHCOR 8 , aminosulfonyl, alkylsulfonylamino having 1 to 3 carbon atoms, aminosulfonylamino or alkylsulfonyl having 1 to 3 carbon atoms), or

[0136] In R 1x In the case where 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 5- and 6-membered lactam rings and 5- and 6-membered saturated heterocyclic rings containing 1 or 2 oxygen atoms as ring constituent atoms to form a fused ring group (one arbitrary hydrogen atom of the fused ring group may be substituted with a methyl group),

[0137] R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetylaminophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group, or a 3-pyridyl group (wherein R 1x and R 1y Except for the case where all are hydrogen atoms),

[0138] For R 2 、R 4 and R 5 Combination of R 2 、R 4 and R 5 All hydrogen atoms,

[0139] 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 is optionally substituted by a hydroxyl group, and the other two are hydrogen atoms,

[0140] R 3 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are independently optionally substituted with a hydroxyl group or a fluorine atom, a 3-hydroxyoxetan-3-yl group, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, a methoxycarbonyl group, a -NR 9 R 10 、-CH2NR 11 R12 or -CH2CONR 13 R 14 ,

[0141] R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or

[0142] R 6 and R 7 Become one and express -(CH2) h -,

[0143] h represents an integer of 3 to 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom, -NH- or -N(CH3)-,

[0144] R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

[0145] R 9 and R 10 Each independently represents a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or

[0146] R 9 and R 10 Become one and express -(CH2) n -,

[0147] n represents an integer from 3 to 6,

[0148] R 11 and R 12 Become one and express -(CH2) m -,

[0149] m represents an integer of 3 to 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom.

[0150] R 13 and R 14 each independently represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 2-hydroxyethyl group, a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by an oxygen atom, or a methyl group substituted with a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by a nitrogen atom or an oxygen atom, or

[0151] R 13 and R 14 Taken together, it represents -(CH2) in which one or two hydrogen atoms are optionally replaced by a fluorine atom, a methyl group, a hydroxyl group or a methoxy group, or one CH2 group is optionally replaced by an oxygen atom, a nitrogen atom or -CONH-. k -,

[0152] k represents an integer from 3 to 5,

[0153] R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 ,

[0154] R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,

[0155] R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom is optionally substituted by a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group,

[0156] R w represents a hydrogen atom, a methyl group, a hydroxymethyl group or a methoxycarbonyl group. ].

[0157] The following terms used in this specification are defined as follows unless otherwise specified.

[0158] The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0159] The "alkyl group having 1 to 3 carbon atoms" refers to a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0160] The "alkyl group having 1 to 5 carbon atoms" refers to a linear or branched hydrocarbon group having 1 to 5 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, and neopentyl.

[0161] The term "alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are independently optionally substituted by hydroxyl or fluorine atoms" refers to a group in which 1 to 3 arbitrary hydrogen atoms of the aforementioned "alkyl group having 1 to 3 carbon atoms" are independently optionally substituted by hydroxyl or fluorine atoms, and examples thereof include methyl, hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, propyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, Hydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl, isopropyl, 2-hydroxypropan-2-yl, 1-hydroxypropan-2-yl, 1,2-dihydroxy-1-methylethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2-fluoropropan-2-yl or 1,1,1-trifluoropropan-2-yl.

[0162] The “alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted by fluorine atoms” means a group in which 1 to 3 arbitrary hydrogen atoms of the above-mentioned “alkyl group having 1 to 3 carbon atoms” are optionally substituted by fluorine atoms, and examples thereof include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, propyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, 2-fluoropropan-2-yl, and 1,1,1-trifluoropropan-2-yl.

[0163] The “alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are substituted by fluorine atoms” refers to a group in which 1 to 3 arbitrary hydrogen atoms of the above-mentioned “alkyl group having 1 to 3 carbon atoms” are substituted by fluorine atoms, and examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2-fluoropropan-2-yl, and 1,1,1-trifluoropropan-2-yl.

[0164] The “alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted by a hydroxy group” means a group in which one arbitrary hydrogen atom of the above-mentioned “alkyl group having 1 to 3 carbon atoms” is optionally substituted by a hydroxy group, and examples thereof include methyl, hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, propyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, isopropyl, 2-hydroxypropan-2-yl, and 1-hydroxypropan-2-yl.

[0165] The “alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is replaced by a hydroxy group” means a group in which one arbitrary hydrogen atom of the above-mentioned “alkyl group having 1 to 3 carbon atoms” is replaced by a hydroxy group, and examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, and 1-hydroxypropan-2-yl.

[0166] The “alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted by fluorine atoms or 1 arbitrary hydrogen atom is optionally substituted by a hydroxyl group” refers to the above-mentioned “alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted by fluorine atoms” or the above-mentioned “alkyl group having 1 to 3 carbon atoms in which 1 arbitrary hydrogen atom is optionally substituted by a hydroxyl group”.

[0167] The "methyl group in which one hydrogen atom is optionally substituted by a hydroxy group" refers to a methyl group or a hydroxymethyl group.

[0168] The "alkoxy group having 1 to 3 carbon atoms" refers to a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.

[0169] The "alkoxy group having 1 to 5 carbon atoms" refers to a monovalent substituent formed by bonding a linear or branched hydrocarbon group having 1 to 5 carbon atoms to an oxygen atom, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, sec-pentyloxy, tert-pentyloxy, and neopentyloxy.

[0170] The “alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted by fluorine atoms” refers to a group in which 1 to 3 arbitrary hydrogen atoms of the above-mentioned “alkoxy group having 1 to 3 carbon atoms” are optionally substituted by fluorine atoms, and examples thereof include methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 1,1-difluoroethoxy, 2,2,2-trifluoroethoxy, propoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy, 3,3,3-trifluoropropoxy, isopropoxy, (2-fluoropropan-2-yl)oxy, and (1,1,1-trifluoropropan-2-yl)oxy.

[0171] The "methoxy group in which 1 to 3 arbitrary hydrogen atoms are substituted by fluorine atoms" refers to a fluoromethoxy group, a difluoromethoxy group or a trifluoromethoxy group.

[0172] The "methoxy group in which 1 to 3 arbitrary hydrogen atoms are optionally substituted by fluorine atoms" refers to the above-mentioned "methoxy group in which 1 to 3 arbitrary hydrogen atoms are substituted by fluorine atoms" or a methoxy group.

[0173] The "alkylsulfonyl group having 1 to 3 carbon atoms" refers to a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group or an isopropylsulfonyl group.

[0174] The "aryl group" refers to a monocyclic or bicyclic aromatic hydrocarbon group, and examples thereof include a phenyl group and a naphthyl group (1-naphthyl or 2-naphthyl).

[0175] A “5- or 6-membered heteroaryl ring containing 1 or 2 hetero atoms selected from nitrogen, oxygen and sulfur atoms” refers to a 5- or 6-membered monocyclic aromatic heterocyclic group containing, as ring constituent atoms, 1 or 2 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, and examples thereof include furyl (e.g., 2-furyl or 3-furyl), thienyl (e.g., 2-thienyl or 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl or 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl or 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl, 4-pyridazinyl, or 6-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl or 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl).

[0176] The "5- and 6-membered lactam rings" refer to pyrrolidin-2-one rings and piperidin-2-one rings.

[0177] The “5- and 6-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms as ring constituent atoms” refers to a 5- and 6-membered monocyclic saturated heterocyclic ring containing 1 or 2 oxygen atoms as ring constituent atoms in addition to carbon atoms, and examples thereof include a tetrahydrofuran ring, a 1,3-dioxolane ring, a tetrahydro-2H-pyran ring, a 1,2-dioxane ring, a 1,3-dioxane ring, and a 1,4-dioxane ring.

[0178] The “fused ring group in which a phenyl group is fused with one ring selected from a 5- or 6-membered lactam ring and a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms as a ring constituent atom” refers to a bicyclic fused ring group in which a phenyl group is fused with one ring selected from the above “5- or 6-membered lactam ring” and the above “5- or 6-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms as a ring constituent atom”, and examples thereof include 3-oxoisoindolin-4-yl, 3-oxoisoindolin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 2-oxoindolin-4-yl, 2-oxoindolin-5-yl, 2-oxoindolin-6-yl, 2-oxoindolin-7-yl, 2-oxoindolin-8-yl, 2-oxoindolin-9-yl, 2-oxoindolin-10-yl, 2-oxoindolin-11-yl, 2-oxoindolin-12-yl, 2-oxoindolin-13-yl, 2-oxoindolin-14-yl, 2-oxoindolin-15-yl, 2-oxoindolin-16-yl, 2-oxoindolin-17-yl, 2-oxoindolin-18-yl, 2-oxoindolin-19-yl, 2-oxoindolin-20-yl, 2-oxoindolin-21-yl, 2-oxoindolin-22-yl, 2-oxoindolin-23-yl, 2-oxoindolin-24-yl, 2-oxoindolin-25-yl, 2-oxoindolin-26 ,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-1 oxo-6-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl, 3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl, 3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl, 3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, chroman-8-yl, isochroman-5-yl, isochroman-6-yl, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl , 4H-benzo[d][1,3]dioxin-5-yl, 4H-benzo[d][1,3]dioxin-6-yl, 4H-benzo[d][1,3]dioxin-7-yl, 4H-benzo[d][1,3]dioxin-8-yl, 3,4-dihydrobenzo[c][1,2]dioxin-5-yl, 3,4-dihydrobenzo[ a bicyclic fused ring group such as a 1,4-dihydrobenzo[d][1,2]dioxin-6-yl group, a 3,4-dihydrobenzo[c][1,2]dioxin-7-yl group, a 3,4-dihydrobenzo[c][1,2]dioxin-8-yl group, a 1,4-dihydrobenzo[d][1,2]dioxin-5-yl group or a 1,4-dihydrobenzo[d][1,2]dioxin-6-yl group.

[0179] Examples of the “fused ring group in which a phenyl group is fused with one ring selected from pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane” include 3-oxoisoindolin-4-yl, 3-oxoisoindolin-5-yl, 1-oxoisoindolin-5-yl, 1-oxoisoindolin-4-yl, 2-oxoindolin-4-yl, 2-oxoindolin-5-yl, 2-oxoindolin-6-yl, 2-oxoindolin-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, and 1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl. 1,2,3,4-tetrahydroisoquinolin-7-yl, 1-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl, 3-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl, 3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl, 3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl or 3-oxo-1,2,3,4-tetrahydroisoquinolin-8-yl.

[0180] “R 2 、R 4 and R 5 wherein one of the two is a halogen atom, a methoxy group or a methyl group in which one hydrogen atom is optionally substituted by a hydroxyl group, and the other two are hydrogen atoms” means R 2 is a halogen atom, a methoxy group or a methyl group in which one hydrogen atom is optionally substituted by a hydroxyl group, and R 4 and R 5 are all hydrogen atoms, or R 4 is a halogen atom, a methoxy group or a methyl group in which one hydrogen atom is optionally substituted by a hydroxyl group, and R 2 and R 5 are all hydrogen atoms, or R 5 is a halogen atom, a methoxy group or a methyl group in which one hydrogen atom is optionally substituted by a hydroxyl group, and R 2 and R 4 All are hydrogen atoms.

[0181] “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 is optionally substituted with a hydroxyl group, and the other and R 5 "is a hydrogen atom" means R 2 is a fluorine atom, a chlorine atom, a methoxy group or a methyl group in which one hydrogen atom is optionally substituted by a hydroxyl group, and R 4 and R5 are all hydrogen atoms, or R 4 is a fluorine atom, a chlorine atom, a methoxy group or a methyl group in which one hydrogen atom is optionally substituted by a hydroxy group, and R 2 and R 5 All are hydrogen atoms.

[0182] “R 6 and R 7 Become one and express -(CH2) h -, h represents an integer of 3 to 5, and herein, one arbitrary methylene group is optionally replaced by an oxygen atom, -NH- or -N(CH3)-" means R 6 and R 7 Together with the nitrogen atom to which they are bonded, they form an azetidine (h=3), pyrrolidine (h=4) or piperidine ring (h=5) ring in which any methylene group is optionally replaced by an oxygen atom, -NH- or -N(CH3)-, for example, azetidine (h=3), pyrrolidine (h=4), piperidine (h=5), morpholine (h=5), piperazine (h=5) or 1-methylpiperazine (h=5).

[0183] “R 9 and R 10 Become one and express -(CH2) n -, n represents an integer from 3 to 6" means R 9 and R 10 Together with the nitrogen atom to which they are bonded, they form an azetidine ring (n=3), a pyrrolidine ring (n=4), a piperidine ring (n=5), or an azepane ring (n=6).

[0184] “R 11 and R 12 Become one and express -(CH2) m -, m represents an integer of 3 to 5, and herein, one arbitrary methylene group is optionally replaced by an oxygen atom" means R 11 and R 12 Together with the nitrogen atom to which they are bonded, they form an azetidine (m=3), pyrrolidine (m=4) or piperidine (m=5) ring in which any methylene group is optionally replaced by 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).

[0185] “R 13 and R 14 Taken together, it represents -(CH2) in which one hydrogen atom is optionally replaced by a hydroxyl group. k -, k means 3 or 4" means R 13 and R 14Together with the nitrogen atom to which they are bonded, they form an azetidine ring (k=3) or a pyrrolidine ring (k=4) in which one arbitrary hydrogen atom is optionally substituted by a hydroxy 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).

[0186] “R 13 and R 14 Taken together, it represents -(CH2) in which one or two arbitrary hydrogen atoms are optionally replaced by a fluorine atom, a methyl group, a hydroxyl group or a methoxy group, or one arbitrary CH2 group is optionally replaced by an oxygen atom, a nitrogen atom or -CONH- k -, k represents an integer from 3 to 5" means R 13 and R 14Together with the nitrogen atom to which they are bonded, they form an azetidine ring (k=3), a pyrrolidine ring (k=4) or a piperidine ring (k=5), in which one or two arbitrary hydrogen atoms are optionally substituted by a fluorine atom, a methyl group, a hydroxyl group or a methoxy group, or one arbitrary CH2 group is optionally replaced by an oxygen atom, a nitrogen atom or -CONH-, 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), a 4-methylazetidine ring (k=3), a 2,2-dimethylazetidine ring (k=3), a 2,3-dimethylazetidine ring (k=3), a 2,4-dimethylazetidine ring azetidine 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-dimethylpyrrolidine 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), Methylpyrrolidine 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), tetrahydropyrimidin-2(1H)-one ring (k=4), piperazin-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), 2,3-dimethylpiperidine ring (k=5), 2,4-dimethylpiperidine ring (k=5), 2,5-dimethylpiperidine ring (k=5), 3,3-dimethylpiperidine ring (k=5), 3,4-dimethylpiperidine ring (k=5), 3,5-dimethylpiperidine ring (k=5), 3-hydroxypiperidine ring (k=5), 4-hydroxypiperidine ring (k=5), 3,4-dihydroxypiperidine ring (k=5), 3,5-dihydroxypiperidine ring (k=5), morpholine ring (k=5), piperazine ring (k=5), 1,3-diazacycloheptan-2-one ring (k=5), 1,4-diazacycloheptan-2-one ring (k=5) or 1,4-diazepan-5-one ring (k=5).

[0187] “R 13 and R 14 The term "azetidine ring" that forms, together with the nitrogen atom to which they are bonded, one arbitrary hydrogen atom of which is optionally substituted by a hydroxyl group includes, for example, an azetidine ring or a 3-hydroxyazetidine ring.

[0188] Examples of the “azetidine ring in which two arbitrary hydrogen atoms are optionally substituted by methyl or fluorine atoms or one arbitrary hydrogen atom is optionally substituted by a hydroxyl or methoxy group” include an azetidine ring, a 2,2-dimethylazetidine ring, a 2,3-dimethylazetidine ring, a 2,4-dimethylazetidine ring, a 3,3-dimethylazetidine ring, a 3,3-difluoroazetidine ring, a 3-hydroxyazetidine ring, and a 3-methoxyazetidine ring.

[0189] Examples of the “cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by an oxygen atom” include cyclopropyl, cyclobutyl, oxiran-2-yl and oxetane-3-yl.

[0190] Examples of the “methyl group substituted by a cycloalkyl group having 3 or 4 carbon atoms in which any carbon atom is optionally replaced by a nitrogen atom or an oxygen atom” include cyclopropylmethyl, cyclobutylmethyl, oxiran-2-ylmethyl, oxetane-2-ylmethyl, oxetane-3-ylmethyl, aziridin-2-ylmethyl, azetidin-2-ylmethyl and azetidin-3-ylmethyl.

[0191] Examples of the “methyl group in which one arbitrary hydrogen atom is optionally substituted by a hydroxy group or a methoxycarbonyl group” include a methyl group, a hydroxymethyl group, and a methoxycarbonylmethyl group.

[0192] R 1x Preferably, it is a phenyl group (an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted by a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted by a fluorine atom, or one arbitrary hydrogen atom is optionally substituted by a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted by a fluorine atom, a cyano group, a methoxycarbonyl group, a -CONR 6 R 7 、-NHCOR 8, aminosulfonyl, alkylsulfonylamino having 1 to 3 carbon atoms, aminosulfonylamino or alkylsulfonyl having 1 to 3 carbon atoms), pyrazolyl, 1-oxoisoindolin-5-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or benzo[d][1,3]dioxol-5-yl, more preferably phenyl (one arbitrary hydrogen atom of the phenyl group is optionally replaced by a fluorine atom, trifluoromethyl, hydroxymethyl, 2-hydroxypropane-2-yl, methoxy, trifluoromethoxy, cyano, methoxycarbonyl, -CONR 6 R 7 、-NHCOR 8 , aminosulfonyl, methylsulfonylamino, aminosulfonylamino or methylsulfonyl substituted), pyrazolyl, 1-oxoisoindolin-5-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or benzo[d][1,3]dioxol-5-yl, further preferably phenyl (one arbitrary hydrogen atom of the phenyl group is optionally substituted by a fluorine atom, hydroxymethyl, trifluoromethoxy, cyano, aminocarbonyl, acetylamino, aminosulfonyl, methylsulfonylamino or methylsulfonyl).

[0193] R 1x In the case of a substituted phenyl group, the hydrogen atom at the para position is preferably substituted.

[0194] In the case of the tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof as described in [1] above as a new compound, R 1x Preferably, it is a phenyl group (one arbitrary hydrogen atom of the phenyl group is optionally substituted by a halogen atom, an alkyl group having 1 to 3 carbon atoms in which one to three arbitrary hydrogen atoms are optionally substituted by a fluorine atom, an alkoxy group having 1 to 3 carbon atoms in which one to three arbitrary hydrogen atoms are optionally substituted by a fluorine atom, a cyano group, a methoxycarbonyl group and -NHCOR 8 substituted with one substituent in (excluding m-cyanophenyl and p-trifluoromethoxyphenyl), or a 5- or 6-membered heteroaryl group (one arbitrary hydrogen atom of the 5- or 6-membered heteroaryl group is optionally substituted with an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, excluding 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl).

[0195] In the case of the tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof as described in [1] above as a new compound, it is preferred that R 1x represents a hydrogen atom, a phenyl group (an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom of the phenyl group is replaced by one arbitrary hydrogen atom of a hydroxyl group), -CONR 6 R 7, aminosulfonyl, methylsulfonylamino, aminosulfonylamino or alkylsulfonyl having 1 to 3 carbon atoms, or one hydrogen atom at the meta-position of the phenyl group is substituted by a cyano group, or the hydrogen atom at the para-position of the phenyl group is substituted by a trifluoromethoxy group), 1-methyl-1H-pyrazol-4-yl or 6-methoxypyridin-3-yl, or a fused ring group obtained by condensing a phenyl group with one ring selected from pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane (one arbitrary hydrogen atom of the fused ring group is optionally substituted by a methyl group).

[0196] R 1y Preferred are hydrogen atom, phenyl group, 4-hydroxymethylphenyl group, 4-aminocarbonylphenyl group, 4-acetylaminophenyl group, 4-aminosulfonylphenyl group, or 4-methylsulfonylphenyl group; more preferred are 4-hydroxymethylphenyl group, 4-aminocarbonylphenyl group, 4-acetylaminophenyl group, 4-aminosulfonylphenyl group, or 4-methylsulfonylphenyl group; further preferred are 4-aminocarbonylphenyl group, 4-aminosulfonylphenyl group, or 4-methylsulfonylphenyl group.

[0197] Among them, R 1x and R 1y Not all are hydrogen atoms.

[0198] About R 1x and R 1y Combination, preferably R 1x is a hydrogen atom, R 1y is a substituent other than a hydrogen atom, or R 1x is a substituent other than a hydrogen atom, R 1y is a hydrogen atom, more preferably R 1x is a substituent other than a hydrogen atom, R 1y A hydrogen atom.

[0199] 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.

[0200] R 3 Preferred are hydrogen atom, fluorine atom, chlorine atom, alkyl group with 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted with a hydroxyl group, trifluoromethoxy group, -CH2NR 11 R 12 or -CH2CONR 13 R 14 , more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a trifluoromethoxy group or -CH2CONR 13 R 14 , more preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group.

[0201] R 4It is preferably a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and more preferably a hydrogen atom.

[0202] R 5 Preferred is a hydrogen atom.

[0203] Preferred R 6 and R 7 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 They can form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring together with the nitrogen atom to which they are bonded, and more preferably R 6 and R 7 All are hydrogen atoms.

[0204] R 8 It is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group.

[0205] Preferred R 9 is a hydrogen atom, R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 Become one as -(CH2) n -, n is 4 or 5, more preferably R 9 is a hydrogen atom, R 10 COR 15 .

[0206] Preferred R 11 and R 12 Become one as -(CH2) m -, m is 4 or 5 (herein, one arbitrary methylene group is optionally replaced by an oxygen atom).

[0207] Preferred R 13 is a hydrogen atom or a methyl group, R 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 oxetan-3-yl group, a cyclopropylmethyl group, a cyclobutylmethyl group or an oxetan-3-ylmethyl group, or R 13 and R 14 Together with the nitrogen atom to which they are bonded, they form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, an azetidine ring, a 3,3-dimethylazetidine ring, a 3,3-difluoroazetidine ring, a 3-hydroxyazetidine ring or a 3-methoxyazetidine ring.

[0208] Preferred R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 .

[0209] Preferred R 16 It is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0210] Preferred R v A hydrogen atom.

[0211] Preferred R w A hydrogen atom.

[0212] The aforementioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof includes not only a single stereoisomer but also mixtures of stereoisomers such as racemates and diastereomeric mixtures (for example, mixtures of mirror image isomers).

[0213] "Stereoisomers" refer to compounds that have the same chemical structure but differ in their arrangement in three-dimensional space, and examples thereof include conformers, rotational isomers, tautomers, mirror image isomers, and diastereomers.

[0214] The tetrahydroquinoline derivative (I) may be represented by the following general formulas (I-1) to (I-8).

[0215] [Chemical Formula 4]

[0216]

[0217] [Where R 1x 、R 1y 、R 2 、R 3 、R 4 、R 5 、R v and R w Same definition as above.]

[0218] Among the above tetrahydroquinoline derivatives (I), the preferred R 1x 、R 1y 、R 2 ~R 16 、R v 、R w The preferred embodiments of h, k, m, and n can be combined with each other. For example, the following combinations can be mentioned, but are not limited to these.

[0219] For example, among the above tetrahydroquinoline derivatives (I), R 1x Phenyl (an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom of the phenyl group is optionally substituted by a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted by a fluorine atom, or one arbitrary hydrogen atom is optionally substituted by a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted by a fluorine atom, a cyano group, a methoxycarbonyl group, -CONR 6 R7 、-NHCOR 8 , aminosulfonyl, alkylsulfonylamino having 1 to 3 carbon atoms, aminosulfonylamino or alkylsulfonyl substituted with 1 to 3 carbon atoms), pyrazolyl, 1-oxoisoindolin-5-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or benzo[d][1,3]dioxol-5-yl,

[0220] R 1y is a hydrogen atom,

[0221] R 2 is a hydrogen atom,

[0222] R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is optionally substituted with a hydroxyl group, a methoxy group, -NR 9 R 10 、-CH2NR 11 R 12 or -CH2CONR 13 R 14 ,

[0223] R 4 is a hydrogen atom or a methoxy group,

[0224] R 5 is a hydrogen atom,

[0225] R 6 and R 7 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 Together with the nitrogen atom to which they are bonded, they can form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring,

[0226] R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

[0227] R 9 is a hydrogen atom, R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 Become one as -(CH2) n -,

[0228] n is 4 or 5,

[0229] R 11 and R 12 Become one as -(CH2) m -,

[0230] m is 4 or 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom,

[0231] R 13 is a hydrogen atom or a methyl group, R 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 oxetan-3-yl group, a cyclopropylmethyl group, a cyclobutylmethyl group or an oxetan-3-ylmethyl group, or R 13 and R 14 can form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, an azetidine ring, a 3,3-dimethylazetidine ring, a 3,3-difluoroazetidine ring, a 3-hydroxyazetidine ring or a 3-methoxyazetidine ring together with the nitrogen atom to which they are bonded,

[0232] R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 ,

[0233] R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,

[0234] R v is a hydrogen atom,

[0235] R w A hydrogen atom.

[0236] Among the above-mentioned tetrahydroquinoline derivatives (I), one embodiment includes, for example, a tetrahydroquinoline derivative represented by the following general formula (II-a) or a pharmacologically acceptable salt thereof.

[0237] [Chemical Formula 5]

[0238]

[0239] [wherein, A is a hydrogen atom or -CONH2, R 9 and R 10 are each independently a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 Become one as -(CH2) n -, n is an integer from 3 to 6, R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 , R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. ].

[0240] Among the tetrahydroquinoline derivatives represented by the above-mentioned general formula (II-a) (hereinafter also referred to as tetrahydroquinoline derivatives (II-a)), R 9 is a hydrogen atom, R 10 COR 15 , R 15 is an alkoxy group having 1 to 5 carbon atoms, more preferably A is a hydrogen atom, and R 9 is a hydrogen atom, R 10 COR 15 , R 15 is an alkoxy group having 1 to 5 carbon atoms, more preferably A is a hydrogen atom, R 9 is a hydrogen atom, R 10 COR 15 , R 15 It is tert-butoxy.

[0241] As the pharmacologically acceptable salt of the tetrahydroquinoline derivative (II-a), the description of the pharmacologically acceptable salt of the tetrahydroquinoline derivative (I) described later can be cited.

[0242] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof can be used as a therapeutic or preventive agent for amyotrophic lateral sclerosis containing the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof as an active ingredient.

[0243] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof can be used as a ferroptosis inhibitor containing the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof as an active ingredient.

[0244] The above-mentioned ferroptosis inhibitors are described below.

[0245] Among the above-mentioned tetrahydroquinoline derivatives (I), one embodiment includes, for example, a tetrahydroquinoline derivative represented by the following general formula (II-b) or a pharmacologically acceptable salt thereof.

[0246] [Chemical Formula 6]

[0247]

[0248] [Where R 1y is phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetylaminophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl or 3-pyridyl, R 3 is a hydrogen atom or a halogen atom, R 4 is a hydrogen atom or a halogen atom (except 3-phenyl-1,2,3,4-tetrahydroquinoline)].

[0249] Among the tetrahydroquinoline derivatives represented by the above-mentioned general formula (II-b) (hereinafter also referred to as tetrahydroquinoline derivatives (II-b)), R 1y is 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetylaminophenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl, R 3 is a hydrogen atom, a fluorine atom or a chlorine atom, R 4 is a hydrogen atom, a fluorine atom or a chlorine atom, more preferably R 1y is 4-aminocarbonylphenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl, R 3 is a hydrogen atom, R 4 A hydrogen atom.

[0250] As the pharmacologically acceptable salt of the tetrahydroquinoline derivative (II-b), the description of the pharmacologically acceptable salt of the tetrahydroquinoline derivative (I) described later can be cited.

[0251] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof can be used as a therapeutic or preventive agent for amyotrophic lateral sclerosis containing the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof as an active ingredient.

[0252] Furthermore, the aforementioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof can be used as a ferroptosis inhibitor containing the aforementioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof as an active ingredient.

[0253] The above-mentioned ferroptosis inhibitors are described below.

[0254] Among the above-mentioned tetrahydroquinoline derivatives (I), one embodiment includes, for example, a tetrahydroquinoline derivative represented by the following general formula (II-c) or a pharmacologically acceptable salt thereof.

[0255] [Chemical Formula 7]

[0256]

[0257] [Where R 1x is a hydrogen atom, a phenyl group, a 4-carbamoylphenyl group, a 4-aminosulfonylphenyl group or a pyrazolyl group, R 1y is a hydrogen atom or a 4-aminosulfonylphenyl group, R 3 is a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom, wherein R 1x When R is a hydrogen atom, 1y is 4-aminosulfonylphenyl, R 3 is a hydrogen atom, or R 1x When R is phenyl, 4-carbamoylphenyl, 4-aminosulfonylphenyl or pyrazolyl,1y is a hydrogen atom, R 3 is a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom. ].

[0258] Among the tetrahydroquinoline derivatives represented by the above-mentioned general formula (II-c) (hereinafter also referred to as tetrahydroquinoline derivatives (II-c)), R 1x is a hydrogen atom, a phenyl group, a 4-carbamoylphenyl group, a 4-aminosulfonylphenyl group or a pyrazolyl group, R 1y is a hydrogen atom or a 4-aminosulfonylphenyl group, R 3 is a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom, wherein R 1x When R is a hydrogen atom, 1y is 4-aminosulfonylphenyl, R 3 is a hydrogen atom, or R 1x When R is phenyl, 4-carbamoylphenyl, 4-aminosulfonylphenyl or pyrazolyl, 1y is a hydrogen atom, R 3 is a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom, and more preferably R 1x is a hydrogen atom, a phenyl group, a 4-carbamoylphenyl group or a 4-aminosulfonylphenyl group, R 1y is a hydrogen atom or a 4-aminosulfonylphenyl group, R 3 is a hydrogen atom or a methyl group, in which case R 1x When R is a hydrogen atom, 1y is 4-aminosulfonylphenyl, R 3 is a hydrogen atom, or R 1x When R is phenyl, 4-carbamoylphenyl or 4-aminosulfonylphenyl, 1y is a hydrogen atom, R 3 is a hydrogen atom or a methyl group.

[0259] As the pharmacologically acceptable salt of the tetrahydroquinoline derivative (II-c), the description of the pharmacologically acceptable salt of the tetrahydroquinoline derivative (I) described later can be cited.

[0260] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof can be used as a therapeutic or preventive agent for amyotrophic lateral sclerosis containing the above-mentioned tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof as an active ingredient.

[0261] Furthermore, the above-mentioned tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof can be used as a ferroptosis inhibitor containing the above-mentioned tetrahydroquinoline derivative (II-c) or a pharmacologically acceptable salt thereof as an active ingredient.

[0262] The above-mentioned ferroptosis inhibitors are described below.

[0263] Specific examples of preferred compounds of the tetrahydroquinoline derivative (I) are shown in Tables 1-1 to 1-7, but the present invention is not limited thereto.

[0264] [Table 1-1]

[0265]

[0266] [Table 1-2]

[0267]

[0268] [Table 1-3]

[0269]

[0270] [Table 1-4]

[0271]

[0272] [Table 1-5]

[0273]

[0274] [Table 1-6]

[0275]

[0276] [Table 1-7]

[0277]

[0278] The compounds described in Table 1-1 to Table 1-7 also include stereoisomers, solvates thereof, pharmacologically acceptable salts thereof, and mixtures thereof.

[0279] The present invention also includes prodrugs of the aforementioned tetrahydroquinoline derivatives (I). The prodrugs of the aforementioned tetrahydroquinoline derivatives (I) are compounds that are enzymatically or chemically converted into the aforementioned tetrahydroquinoline derivatives (I) in vivo. The active substance of the prodrugs of the aforementioned tetrahydroquinoline derivatives (I) is the aforementioned tetrahydroquinoline derivative (I), but the prodrugs of the aforementioned tetrahydroquinoline derivatives (I) may also be active themselves.

[0280] Examples of the group that forms a prodrug of the tetrahydroquinoline derivative (I) include groups described in known documents (e.g., "Pharmaceutical Development", Hirokawa Shoten, 1990, Vol. 7, pp. 163-198 and Progress in Medicine, Vol. 5, 1985, pp. 2157-2161).

[0281] Examples of the "pharmacologically acceptable salt" of the tetrahydroquinoline derivative (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, and organic acid 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.

[0282] The above-mentioned tetrahydroquinoline derivative (I) may be crystalline, and whether it is a single crystal form or a mixture of crystal forms, it is included in the above-mentioned tetrahydroquinoline derivative (I).

[0283] The tetrahydroquinoline derivative (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more distinct solids having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, or stability) at room temperature. Cocrystals or cocrystal salts can be produced using a known cocrystal method.

[0284] The aforementioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof may be an anhydrate or a solvate such as a hydrate.

[0285] The above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be converted into a solvate such as a hydrate by a known method. Examples of known methods include treating the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof with water, other solvents (e.g., alcoholic solvents such as methanol, ethanol, or n-propanol, N,N-dimethylformamide (hereinafter referred to as DMF), dimethyl sulfoxide (hereinafter referred to as DMSO)), or a mixed solvent thereof.

[0286] The above-mentioned tetrahydroquinoline derivative (I) may be labeled with one or more isotopes. Examples of the labeled isotopes include 2 H. 3 H. 13 C. 14 C. 15 N. 15 O. 17 O. 18 O and / or 125 I.

[0287] The above-mentioned tetrahydroquinoline derivatives (I) can be prepared by appropriate methods according to the characteristics of their basic skeletons and the types of substituents. It should be noted that the starting materials and reagents used to prepare these compounds can usually be purchased or prepared by known methods.

[0288] The aforementioned tetrahydroquinoline derivative (I) and the intermediates and starting materials used in its production can be isolated and purified by known methods. Examples of known methods for isolation and purification include solvent extraction, recrystallization, and chromatography.

[0289] When the tetrahydroquinoline derivative (I) contains optical isomers or stereoisomers, each isomer can be obtained as a single compound by a known method or a method based thereon. Examples of known methods include crystallization, enzymatic resolution, and chiral chromatography.

[0290] The following examples illustrate a typical method for producing the aforementioned tetrahydroquinoline derivative (I). It should be noted that the compounds in the following synthetic routes also include cases where salts are formed. As such salts, for example, the same salts as those in the aforementioned tetrahydroquinoline derivative (I) can be used. The production method of the present invention is not limited to the examples shown below.

[0291] Manufacturing method 1

[0292] In the above tetrahydroquinoline derivative (I), R 1y 、R v and R w All hydrogen atoms, R 3 The tetrahydroquinoline derivative (Ia) which is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are independently optionally substituted with a hydroxyl group or a fluorine atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, or a methoxycarbonyl group can be obtained, for example, by the method described in Synthesis Scheme 1.

[0293] [Chemical Formula 8]

[0294]

[0295] [wherein, X represents a halogen atom, R 3a represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are independently optionally substituted with a hydroxyl group or a fluorine atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are optionally substituted with a fluorine atom, or a methoxycarbonyl group, wherein each symbol in the formula has the same meaning as defined above.].

[0296] (Process 1-1)

[0297] The quinoline derivative (IX) can be obtained by coupling a 2-halogenoquinoline derivative (III) with a boronic acid derivative (IV) in the presence of a metal catalyst and a base.

[0298] The amount of the boronic acid derivative (IV) used in the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 4 equivalents, relative to the 2-halogenoquinoline derivative (III).

[0299] Examples of the metal catalyst used in the coupling reaction include 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane adduct, palladium(II) chloride, palladium(II) acetate, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), and dichlorobis(triphenylphosphine)palladium(0), preferably tetrakis(triphenylphosphine)palladium(0).

[0300] The amount of the metal catalyst used in the coupling reaction is preferably 0.01 to 5 equivalents, more preferably 0.025 to 1 equivalent, relative to the 2-halogenoquinoline derivative (III).

[0301] A ligand may also be used in the coupling reaction. Examples of the ligand include triphenylphosphine, tert-butylphosphine, and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0302] Examples of the base used in the coupling reaction include organic bases such as triethylamine and 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, and inorganic bases such as sodium carbonate, potassium carbonate, or cesium carbonate are preferred.

[0303] The amount of the base used in the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 4 equivalents, relative to the 2-halogenoquinoline derivative (III).

[0304] The reaction solvent used in the coupling reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether solvents such as tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane, or 1,2-dimethoxyethane (hereinafter referred to as DME), nitrile solvents such as acetonitrile or propionitrile, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF, N,N-dimethylacetamide (hereinafter referred to as DMA), or DMSO, water, or a mixed solvent thereof. Preferably, it is an ether solvent such as THF, 1,4-dioxane, or DME, an aprotic polar solvent such as DMF, DMA, or DMSO, or water, and a mixed solvent thereof.

[0305] The reaction temperature of the coupling reaction is preferably 0 to 200°C, more preferably 50 to 150°C.

[0306] The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 30 hours.

[0307] The 2-halogenoquinoline derivative (III) and the boronic acid derivative (IV) used in the coupling reaction can be purchased or prepared by a known method or a method based thereon.

[0308] (Process 1-2)

[0309] Quinoline derivative (IX) can be obtained by cycloaddition reaction of 2-aminobenzyl alcohol derivative (V) with ketone derivative (VI) in the presence of a base, for example, according to the method described in (Tetrahedron Letters, 2008, pp. 6893-6895) or a method based thereon.

[0310] The amount of the ketone derivative (VI) used in the cycloaddition reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, relative to the 2-aminobenzyl alcohol derivative (V).

[0311] Examples of the base 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, preferably metal alkoxides such as sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide.

[0312] The amount of the base used in the cycloaddition reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the 2-aminobenzyl alcohol derivative (V).

[0313] The reaction solvent used in the cycloaddition reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof 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, and mixed solvents thereof. Ether solvents such as THF, 1,4-dioxane, or DME are preferred.

[0314] The reaction temperature of the cycloaddition reaction is preferably 0 to 200°C, more preferably 50 to 150°C.

[0315] The reaction time of the cycloaddition reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 24 hours.

[0316] The 2-aminobenzyl alcohol derivative (V) and ketone derivative (VI) used in the cycloaddition reaction can be purchased or prepared by a known method or a method based thereon.

[0317] (Process 1-3)

[0318] Quinoline derivatives (IX) can be obtained by oxidative cyclization of aniline derivatives (VII) with allyl alcohol derivatives (VIII-a) or α,β-unsaturated aldehyde derivatives (VIII-b) in the presence of a metal catalyst under an oxygen atmosphere. For example, this can be carried out according to the method described in (RSC Advances, 2017, pp. 36242-36245) or a method based thereon.

[0319] The amount of the allyl alcohol derivative (VIII-a) or the α,β-unsaturated aldehyde derivative (VIII-b) used in the oxidative cyclization reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 2 equivalents, relative to the aniline derivative (VII).

[0320] Examples of the metal catalyst used in the oxidative cyclization reaction include palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II) chloride, and dichlorobis(acetonitrile)palladium (II), with palladium (II) acetate being preferred.

[0321] The amount of the metal catalyst used in the oxidative cyclization reaction is preferably 0.01 to 5 equivalents, more preferably 0.025 to 1 equivalent, relative to the aniline derivative (VII).

[0322] The pressure of oxygen used in the oxidative cyclization reaction is preferably about 1 to about 20 atmospheres, more preferably about 1 to about 5 atmospheres.

[0323] The reaction solvent used in the oxidative cyclization reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether solvents such as THF, 1,4-dioxane, and DME, aromatic hydrocarbon solvents such as benzene and toluene, aprotic polar solvents such as DMF, DMA, and DMSO, and mixed solvents thereof. Aprotic polar solvents such as DMF, DMA, and DMSO are preferred.

[0324] The reaction temperature of the oxidative cyclization reaction is preferably 0 to 300°C, more preferably 70 to 200°C.

[0325] The reaction time of the oxidative cyclization reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 24 hours.

[0326] 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 prepared by a known method or a method based thereon.

[0327] (Process 1-4)

[0328] Tetrahydroquinoline derivatives (Ia) can be obtained by hydrogenation of quinoline derivatives (IX) in the presence of a metal catalyst under a hydrogen atmosphere, or by hydrogen transfer reduction of 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate derivatives with quinoline derivatives (IX).

[0329] Examples of the metal catalyst used in the hydrogenation reaction include palladium-based catalysts such as palladium carbon, palladium (II) hydroxide carbon, or palladium (II) oxide; nickel-based catalysts such as expanded nickel catalysts; platinum-based catalysts such as platinum (IV) oxide or platinum carbon; and rhodium-based catalysts such as rhodium carbon. Platinum (IV) oxide is preferred.

[0330] The amount of the metal catalyst used in the hydrogenation reaction is preferably 0.001 to 1 equivalent, more preferably 0.01 to 0.5 equivalent, relative to the quinoline derivative (IX).

[0331] The pressure of hydrogen used in the hydrogenation reaction is preferably about 1 to about 30 atmospheres, more preferably about 1 to about 10 atmospheres.

[0332] The reaction solvent used in the hydrogenation reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include alcoholic solvents such as methanol, ethanol, isopropanol, or tert-butanol; aromatic hydrocarbon solvents such as toluene or xylene; chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane; ester solvents such as ethyl acetate or propyl acetate; aprotic polar solvents such as DMF, DMA, or DMSO; carboxylic acid solvents such as formic acid or acetic acid; water, or mixed solvents thereof. Preferred are mixed solvents of alcoholic solvents such as methanol, ethanol, isopropanol, or tert-butanol and carboxylic acid solvents such as formic acid or acetic acid.

[0333] The reaction temperature of the hydrogenation reaction is preferably 0 to 200°C, more preferably 10 to 100°C.

[0334] The reaction time of the hydrogenation reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 0.5 to 40 hours.

[0335] Examples of the 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate derivative used in the hydrogen transfer reduction reaction include dimethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, and didodecyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate is preferred.

[0336] The amount of the 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate derivative used in the hydrogen transfer reduction reaction is preferably 1 to 10 equivalents, more preferably 1.7 to 3 equivalents, relative to the quinoline derivative (IX).

[0337] The reaction solvent used in the hydrogen transfer reduction reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include alcoholic solvents such as methanol, ethanol, isopropanol, or tert-butanol; 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; and mixed solvents thereof. Chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; and ether-based solvents such as diethyl ether, THF, DME, or 1,4-dioxane are preferred.

[0338] The reaction temperature of the hydrogen transfer reduction reaction is preferably 0 to 100°C, more preferably 10 to 50°C.

[0339] The reaction time of the hydrogen transfer reduction reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 24 hours.

[0340] Manufacturing method 2

[0341] In the above tetrahydroquinoline derivative (I), R 1y 、R v and R w All hydrogen atoms, R 3 -NR 9 R 10 , R 9 and R 10 Become one-(CH2) n -tetrahydroquinoline derivative (Ib) can be obtained by the method described in Synthesis Scheme 2, for example.

[0342] [Chemical Formula 9]

[0343]

[0344] [In the formula, the symbols have the same definitions as above.]

[0345] (Process 2-1)

[0346] The aminoquinoline derivative (XI) can be obtained by coupling a 6-halogenoquinoline derivative (IX-a) with a secondary amine derivative (X) in the presence of a metal catalyst and a base.

[0347] The amount of the secondary amine derivative (X) used in the coupling reaction is preferably 0.5 to 20 equivalents, more preferably 0.8 to 10 equivalents, relative to the 6-halogenoquinoline derivative (IX-a).

[0348] Examples of the metal catalyst used in the coupling reaction include 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane adduct, palladium(II) chloride, palladium(II) acetate, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), and dichlorobis(triphenylphosphine)palladium(0), preferably palladium(II) acetate.

[0349] The amount of the metal catalyst used in the coupling reaction is preferably 0.001 to 5 equivalents, more preferably 0.02 to 0.5 equivalents, relative to the 6-halogenoquinoline derivative (IX-a).

[0350] The coupling reaction may further use a ligand. Examples of the ligand include triphenylphosphine, tert-butylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0351] When a ligand is used in the coupling reaction, the amount of the ligand is preferably 0.001 to 5 equivalents, more preferably 0.02 to 1 equivalent, relative to the 6-halogenoquinoline derivative (IX-a).

[0352] Examples of the base used in the coupling reaction include organic bases such as triethylamine and 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, and inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate are preferred.

[0353] The amount of the base used in the coupling reaction is preferably 0.8 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the 6-halogenoquinoline derivative (IX-a).

[0354] The reaction solvent used in the coupling reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include alcoholic solvents such as methanol, ethanol, isopropanol, or tert-butanol; ether 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; chlorinated solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; and mixed solvents thereof. Preferably, the solvent is an ether solvent such as THF, 1,4-dioxane, or DME.

[0355] The reaction temperature of the coupling reaction is preferably 0 to 200°C, more preferably 50 to 150°C.

[0356] The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 30 hours.

[0357] The 6-halogenoquinoline derivative (IX-a) used in the coupling reaction can be purchased or produced according to the methods described in Steps 1-1 to 1-3, a known method, or a method based thereon.

[0358] The secondary amine derivative (X) used in the coupling reaction can be purchased or prepared by a known method or a method based thereon.

[0359] (Process 2-2)

[0360] The tetrahydroquinoline derivative (Ib) can be obtained by hydrogenation or hydrogen transfer reduction of the aminoquinoline derivative (XI). The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-4.

[0361] Manufacturing method 3

[0362] In the above tetrahydroquinoline derivative (I), R 1y 、R v and R w All hydrogen atoms, R 3 NR 9 R 10 , R 9 is a hydrogen atom, R 10 COR 15 , R 15 The tetrahydroquinoline derivative (Ic) which is an alkoxy group having 1 to 5 carbon atoms can be obtained by the method described in Synthesis Scheme 3, for example.

[0363] [Chemical Formula 10]

[0364]

[0365] [In the formula, Y represents an alkyl group having 1 to 5 carbon atoms, and the other symbols have the same meanings as above.]

[0366] (Process 3-1)

[0367] The quinoline-6-carboxylic acid derivative (XII) can be obtained by hydrolysis of the quinoline-6-carboxylate derivative (IX-b) in the presence of a base.

[0368] Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium tert-butoxide, with potassium hydroxide and sodium hydroxide being preferred.

[0369] The amount of the base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 30 equivalents, relative to the quinoline-6-carboxylate derivative (IX-b).

[0370] The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether solvents such as THF, 1,4-dioxane, or DME, chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF, DMA, or DMSO, ketone solvents such as acetone or methyl ethyl ketone, alcoholic solvents such as methanol, ethanol, or 2-propanol, water, or mixed solvents thereof, preferably a mixed solvent of an alcoholic solvent such as methanol, ethanol, or 2-propanol and water.

[0371] The reaction temperature of the hydrolysis reaction is preferably -50°C to 150°C, more preferably -20°C to 100°C.

[0372] The reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 30 hours.

[0373] The quinoline-6-carboxylate derivative (IX-b) used in the hydrolysis reaction can be purchased or produced by the methods described in Steps 1-1 to 1-3, a known method, or a method based thereon.

[0374] (Process 3-2)

[0375] The quinoline-6-carbamate derivative (XIV) can be obtained by alcoholysis of an isocyanate derivative produced by rearrangement of an acid azide produced by treating a quinoline-6-carboxylic acid derivative (XII) with diphenylphosphoryl azide.

[0376] The amount of diphenylphosphoryl azide used in the rearrangement reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the quinoline-6-carboxylic acid derivative (XII).

[0377] Examples of the base used in the rearrangement reaction include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide; and organic bases such as triethylamine and N,N-diisopropylethylamine. Organic bases such as triethylamine and N,N-diisopropylethylamine are preferred.

[0378] The amount of the base used in the rearrangement reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the quinoline-6-carboxylic acid derivative (XII).

[0379] The reaction solvent used in the rearrangement reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether solvents such as THF, 1,4-dioxane, and DME, ester solvents such as ethyl acetate and propyl acetate, chlorine solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene and toluene, nitrile solvents such as acetonitrile and propionitrile, aprotic polar solvents such as DMF, DMA, and DMSO, and mixed solvents thereof.

[0380] Examples of the alcohol (XIII) used in the alcoholysis reaction include methanol, ethanol, isopropanol and tert-butyl alcohol.

[0381] The alcohol (XIII) used in the alcoholysis reaction may be used in an amount of 1 to 20 equivalents relative to the quinoline-6-carboxylic acid derivative (XII), or may be used as a reaction solvent in place of the reaction solvent used in the rearrangement reaction.

[0382] The reaction temperature of the rearrangement reaction and the alcoholysis reaction is preferably 30 to 200°C, more preferably 50 to 150°C.

[0383] The reaction time of the rearrangement reaction and the alcoholysis reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 30 hours.

[0384] It should be noted that even when an acid azide produced by converting the carboxyl group of a quinoline-6-carboxylic acid derivative (XII) into a reactive functional group and reacting it with a metal azide (e.g., sodium azide) is used, a quinoline-6-carbamate derivative (XIV) can be obtained in the same manner.

[0385] Examples of the reactive functional group include mixed anhydrides with acid chlorides and chlorocarbonates (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate), and activated amides with symmetrical acid anhydrides and imidazoles.

[0386] (Process 3-3)

[0387] The tetrahydroquinoline derivative (Ic) can be obtained by hydrogenation or hydrogen transfer reduction of a quinoline-6-carbamate derivative (XIV). The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-4.

[0388] Manufacturing Method 4

[0389] In the above tetrahydroquinoline derivative (I), R 1y 、R v and R w All hydrogen atoms, R 3 -NR 9 R 10 , R9 is a hydrogen atom, R 10 COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, R 15 Alkyl with 1 to 5 carbon atoms or -NHR 16 , R 16 Tetrahydroquinoline derivatives (Id) to (If) which are hydrogen atoms or alkyl groups having 1 to 5 carbon atoms can be obtained by the method described in Synthesis Scheme 4, for example.

[0390] [Chemical Formula 11]

[0391]

[0392] [In the formula, L each independently represents a leaving group, Z represents an alkyl group having 1 to 3 carbon atoms, and the other symbols have the same meanings as above.]

[0393] Examples of the leaving group represented by L include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group or a dodecylthio group; an aryloxy group such as a phenoxy group; an alkylsulfonyloxy group in which a hydrogen atom is optionally substituted with a halogen atom such as a methanesulfonyloxy group, an ethylsulfonyloxy group or a trifluoromethanesulfonyloxy group; an alkylsulfonylamino group such as a trifluoromethanesulfonylamino group; and an oxazolyl group such as an imidazol-1-yl group or a pyrazol-1-yl group.

[0394] (Process 4-1)

[0395] Benzophenone imine derivative (XV) can be obtained by coupling reaction of 6-halogenoquinoline derivative (IX-a) with benzophenone imine in the presence of a metal catalyst and a base. The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 2-1.

[0396] The 6-halogenoquinoline derivative (IX-a) used in the coupling reaction can be purchased or produced by the methods described in Steps 1-1 to 1-3, a known method, or a method based thereon.

[0397] (Process 4-2)

[0398] The aminoquinoline derivative (XVI) can be obtained by deprotection reaction of the benzophenone imine derivative (XV).

[0399] Examples of the acid used in the deprotection reaction include hydrochloric acid, a 10 wt% hydrogen chloride / methanol solution, a 4 mol / L hydrogen chloride / ethyl acetate solution, trifluoroacetic acid, and hydrofluoric acid, and hydrochloric acid is preferred.

[0400] The amount of the acid used in the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 10 equivalents, relative to the benzophenone imine derivative (XV).

[0401] The reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, alcohol solvents such as methanol or ethanol, and mixed solvents thereof. Preferably, it is an ester solvent such as ethyl acetate or propyl acetate, or a chlorine solvent such as dichloromethane, chloroform, or 1,2-dichloroethane.

[0402] The reaction temperature of the deprotection reaction is preferably 0 to 200°C, more preferably 0 to 100°C.

[0403] The reaction time of the deprotection reaction varies depending on the reaction conditions, but is preferably 1 to 48 hours.

[0404] (Process 4-3)

[0405] The amidoquinoline derivative (XVIII) can be obtained by acylation reaction of an aminoquinoline derivative (XVI) with an acylating agent (XVII).

[0406] The amount of the acylating agent (XVII) used in the acylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).

[0407] A base may be used in the acylation reaction as needed. Examples of the base 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. Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or lithium hydroxide are preferred.

[0408] The reaction solvent used in the acylation reaction is appropriately selected depending on the type of reagent used and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include nitrile solvents such as acetonitrile and 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 mixed solvents thereof. A mixed solvent of an ether solvent such as diethyl ether, THF, DME, or 1,4-dioxane and water is preferred.

[0409] The reaction temperature of the acylation reaction is preferably -78°C to 100°C, more preferably -20°C to 50°C.

[0410] The reaction time of the acylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

[0411] The acylating agent (XVII) used in the acylation reaction can be purchased or prepared by a known method or a method based thereon.

[0412] (Process 4-4)

[0413] The tetrahydroquinoline derivative (Id) can be obtained by hydrogenation or hydrogen transfer reduction of an amide quinoline derivative (XVIII). The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-4.

[0414] (Process 4-5)

[0415] The ureaquinoline derivative (XX) can be obtained by ureidation reaction of an aminoquinoline derivative (XVI) with a ureidating agent (XIX).

[0416] The amount of the ureidating agent (XIX) used in the ureidation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).

[0417] The ureidation reaction may be carried out using a base as needed. Examples of the base 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 and potassium carbonate; or mixtures thereof. Organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine are preferred.

[0418] The reaction solvent used in the ureidation reaction is appropriately selected depending on the type of reagent used and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include nitrile solvents such as acetonitrile and propionitrile, aprotic polar solvents such as DMF, DMA, and DMSO, ether solvents such as diethyl ether, THF, DME, and 1,4-dioxane, ester solvents such as ethyl acetate and propyl acetate, ketone solvents such as acetone and methyl ethyl ketone, water, and mixed solvents thereof. Preferably, the solvent is an ether solvent such as a diethyl ether, THF, DME, or 1,4-dioxane.

[0419] The reaction temperature of the ureidation reaction is preferably -78°C to 100°C, more preferably -20°C to 50°C.

[0420] The reaction time of the ureidation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

[0421] The urea-forming agent (XIX) used in the urea-forming reaction can be purchased or prepared by a known method or a method based thereon.

[0422] (Steps 4-6)

[0423] The tetrahydroquinoline derivative (Ie) can be obtained by hydrogenation or hydrogen transfer reduction of the ureaquinoline derivative (XX). The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-4.

[0424] (Process 4-7)

[0425] The sulfonylamide quinoline derivative (XXII) can be obtained by sulfonylation of an aminoquinoline derivative (XVI) with a sulfonylating agent (XXI).

[0426] The amount of the sulfonylating agent (XXI) used in the sulfonylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, based on the aminoquinoline derivative (XVI).

[0427] The sulfonylation reaction may be carried out using a base as needed. Examples of the base 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. Organic bases such as triethylamine, N,N-diisopropylethylamine, or pyridine are preferred.

[0428] The reaction solvent used in the sulfonylation reaction is appropriately selected depending on the type of reagent used and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include nitrile solvents such as acetonitrile and 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 mixed solvent thereof. Preferably, the ether solvent is diethyl ether, THF, DME, or 1,4-dioxane.

[0429] The reaction temperature of the sulfonylation reaction is preferably -78°C to 100°C, more preferably -20°C to 50°C.

[0430] The reaction time of the sulfonylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

[0431] The sulfonylating agent (XXI) used in the sulfonylation reaction can be purchased or prepared by a known method or a method based thereon.

[0432] (Steps 4-8)

[0433] The tetrahydroquinoline derivative (If) can be obtained by hydrogenation or hydrogen transfer reduction of the sulfonylamide quinoline derivative (XXII). The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-4.

[0434] Manufacturing method 5

[0435] In the above tetrahydroquinoline derivative (I), R 1y 、R v and R w All hydrogen atoms, R 3 -CH2NR 11 R 12 The tetrahydroquinoline derivative (Ig) can be obtained, for example, by the method described in Synthesis Scheme 5.

[0436] [Chemical Formula 12]

[0437]

[0438] [In the formula, each symbol has the same meaning as above. ]

[0439] (Process 5-1)

[0440] The methoxycarbonyltetrahydroquinoline derivative (XXIII) can be obtained by hydrogenation or hydrogen transfer reduction of a quinoline-6-carboxylate derivative (IX-b). The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-4.

[0441] The quinoline-6-carboxylate 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, a known method, or a method based thereon.

[0442] (Process 5-2)

[0443] The hydroxymethyltetrahydroquinoline derivative (XXIV) can be obtained by reducing a methoxycarbonyltetrahydroquinoline derivative (XXIII).

[0444] Examples of the reducing agent used in the reduction reaction include aluminum-based reducing agents such as lithium aluminum hydride and diisobutylaluminum hydride, and boron-based reducing agents such as sodium borohydride and lithium borohydride. An aluminum-based reducing agent such as lithium aluminum hydride and diisobutylaluminum hydride is preferred.

[0445] The amount of the reducing agent used in the reduction reaction is preferably 0.3 to 100 equivalents, more preferably 0.5 to 20 equivalents, based on the methoxycarbonyltetrahydroquinoline derivative (XXIII).

[0446] The reaction solvent used in the reduction reaction is appropriately selected depending on the type of reagent used and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include alcoholic solvents such as methanol, ethanol, isopropanol, or tert-butanol; aprotic polar solvents such as DMF, DMA, or DMSO; 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; and mixed solvents thereof. Preferably, diethyl ether, THF, DME, or 1,4-dioxane; or aromatic hydrocarbon solvents such as toluene or xylene are used.

[0447] The reaction temperature of the reduction reaction is preferably -100°C to 200°C, more preferably -50°C to 50°C.

[0448] The reaction time of the reduction reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.

[0449] (Process 5-3)

[0450] A tetrahydroquinoline derivative (Ig) can be obtained by a substitution reaction of a hydroxymethyltetrahydroquinoline derivative (XXIV) with a secondary amine derivative (XXV) in the presence of a phosphine derivative and iodine.

[0451] The amount of the secondary amine derivative (XXV) used in the substitution reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 20 equivalents, based on the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0452] Examples of the phosphine derivative used in the substitution reaction include triphenylphosphine, trimethylphosphine, and tri-n-butylphosphine, with triphenylphosphine being preferred.

[0453] The amount of the phosphine derivative used in the substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, based on the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0454] The amount of iodine used in the substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, based on the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0455] The reaction solvent used in the substitution reaction is not particularly limited as long as it does not inhibit the reaction. Examples thereof 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-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, aromatic hydrocarbon solvents such as toluene or xylene, and mixed solvents thereof. Chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane are preferred.

[0456] The reaction temperature of the substitution reaction is preferably 0 to 150°C, more preferably 10 to 70°C.

[0457] The reaction time of the substitution reaction varies depending on the reaction conditions, but is preferably 1 to 24 hours.

[0458] Manufacturing Method 6

[0459] In the above tetrahydroquinoline derivative (I), R 1y 、R v and R w All hydrogen atoms, R 3 -CH2CONR 13 R 14 The tetrahydroquinoline derivatives (Ih) and (Ii) can be obtained, for example, by the method described in Synthesis Scheme 6.

[0460] [Chemical Formula 13]

[0461]

[0462] [In the formula, each symbol has the same meaning as above. ]

[0463] (Process 6-1)

[0464] The nitrile derivative (XXVI) can be obtained by Mitsunobu reacting a hydroxymethyltetrahydroquinoline derivative (XXIV) with acetone cyanohydrin using an azodicarboxylate derivative in the presence of a phosphine derivative.

[0465] Examples of the azodicarboxylic acid ester derivative used in the Mitsunobu reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and 1,1'-(azodicarbonyl)dipiperidine, and 1,1'-(azodicarbonyl)dipiperidine is preferred.

[0466] The amount of the azodicarboxylic acid ester derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, more preferably 1 to 10 equivalents, based on the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0467] Examples of the phosphine derivative used in the Mitsunobu reaction include triphenylphosphine, trimethylphosphine, and tri-n-butylphosphine, with tri-n-butylphosphine being preferred.

[0468] The amount of the phosphine derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, more preferably 1 to 10 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0469] The amount of acetone cyanohydrin used in the Mitsunobu reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 20 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).

[0470] The reaction solvent used in the Mitsunobu reaction is not particularly limited as long as it does not inhibit the reaction. Examples thereof 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; and mixed solvents thereof. Ether solvents such as diethyl ether, THF, DME, or 1,4-dioxane are preferred.

[0471] The reaction temperature of the Mitsunobu reaction is preferably -20°C to 200°C, more preferably -10°C to 100°C.

[0472] The reaction time of the Mitsunobu reaction varies depending on the reaction conditions, but is preferably 1 to 12 hours.

[0473] (Process 6-2)

[0474] A tetrahydroquinoline derivative (Ih) can be obtained by hydrolysis reaction with a nitrile derivative (XXVI) in the presence of aqueous hydrogen peroxide and a base.

[0475] The amount of aqueous hydrogen peroxide used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the nitrile derivative (XXVI).

[0476] Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium tert-butoxide, with potassium hydroxide and sodium hydroxide being preferred.

[0477] The amount of the base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 20 equivalents, based on the nitrile derivative (XXVI).

[0478] The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether solvents such as THF, 1,4-dioxane, or DME, chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF, DMA, or DMSO, ketone solvents such as acetone or methyl ethyl ketone, alcohol solvents such as methanol, ethanol, or 2-propanol, or mixed solvents thereof. Preferred is a mixed solvent of an aprotic polar solvent such as DMF, DMA, or DMSO and an ether solvent such as THF, 1,4-dioxane, or DME.

[0479] The reaction temperature of the hydrolysis reaction is preferably -50°C to 150°C, more preferably -20°C to 100°C.

[0480] The reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 30 hours.

[0481] (Process 6-3)

[0482] The carboxylic acid derivative (XXVII) can be obtained by hydrolysis of a tetrahydroquinoline derivative (Ih) in the presence of a base.

[0483] Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium tert-butoxide, with potassium hydroxide and sodium hydroxide being preferred.

[0484] The amount of the base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 30 equivalents, relative to the tetrahydroquinoline derivative (Ih).

[0485] The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the type of reagent used and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether solvents such as THF, 1,4-dioxane, or DME, chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF, DMA, or DMSO, ketone solvents such as acetone or methyl ethyl ketone, alcoholic solvents such as methanol, ethanol, or 2-propanol, water, or mixed solvents thereof. Mixed solvents of alcoholic solvents such as methanol, ethanol, or 2-propanol and water are preferred.

[0486] The reaction temperature of the hydrolysis reaction is preferably 0 to 200°C, more preferably 20 to 100°C.

[0487] The reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 30 hours.

[0488] (Process 6-4)

[0489] The tetrahydroquinoline derivative (Ii) can be obtained by condensing a carboxylic acid derivative (XXVII) with an amine derivative (XXVIII) in the presence of a condensing agent.

[0490] The amount of the amine derivative (XXVIII) used in the condensation reaction is preferably 0.1 to 10 equivalents, more preferably 0.5 to 5 equivalents, relative to the carboxylic acid derivative (XXVII).

[0491] Examples of the condensing agent used in the condensation reaction include N,N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride, N,N'-carbodiimidazole, {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is preferred.

[0492] The amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, based on the carboxylic acid derivative (XXVII).

[0493] Examples of the base 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, alkyl lithiums such as methyl lithium or butyl lithium, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, preferably organic bases such as triethylamine or diisopropylethylamine.

[0494] The amount of the base used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XXVII).

[0495] It should be noted that the amine derivative (XXVIII) can be used as a base for the condensation reaction. When the amine derivative (XXVIII) is used as a base for the condensation reaction, the amount of the amine derivative (XXVIII) is preferably 0.6 to 20 equivalents, more preferably 1 to 10 equivalents, relative to the carboxylic acid derivative (XXVII).

[0496] The reaction solvent used in the condensation reaction is appropriately selected depending on the type of reagent used, and is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ether 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, and nitrile solvents such as acetonitrile or propionitrile. Chlorine-based solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, and aprotic polar solvents such as DMF or DMSO are preferred.

[0497] The reaction temperature of the condensation reaction is preferably 0 to 200°C, more preferably 20 to 100°C.

[0498] The reaction time of the condensation reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably 1 to 30 hours.

[0499] The amine derivative (XXVIII) used in the condensation reaction may be in the form of a free form or a salt such as hydrochloride.

[0500] The amine derivative (XXVIII) used in the condensation reaction can be purchased or produced by a known method or a method based thereon.

[0501] Manufacturing Method 7

[0502] In the above tetrahydroquinoline derivative (I), R 1y 、R v and R w Optically active tetrahydroquinoline derivatives (I-j') and (Ij") containing hydrogen atoms can be obtained, for example, by the method described in Synthesis Scheme 7.

[0503] [Chemical Formula 14]

[0504]

[0505] [In the formula, each symbol has the same meaning as above. ]

[0506] (Process 7-1)

[0507] Optically active forms (I-j') and (Ij") of tetrahydroquinoline derivatives (I) can be obtained by asymmetric hydrogen transfer reduction of 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate derivatives with quinoline derivatives (XXIX) in the presence of a chiral phosphoric acid catalyst. For example, the reaction can be carried out according to the method described in (Tetrahedron: Asymmetry, 2015, pp. 1174-1179) or a method based thereon.

[0508] The quinoline derivative (XXIX) used in the asymmetric hydrogen transfer reduction reaction can be purchased or produced according to the methods described in steps 1-1 to 1-3, step 2-1, step 3-1, step 3-2, step 4-1 to step 4-3, step 4-5 and step 4-7, a known method or a method based thereon.

[0509] Examples of the chiral phosphoric acid catalyst used in the asymmetric hydrogen transfer reduction reaction include (S)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-1,1'-binaphthyl-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, and (R)-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate. (S)-3,3'-bis(9-phenanthrenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (R)-3,3'-bis(9-phenanthrenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, or (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, preferably (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate and (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate.

[0510] Manufacturing method 8

[0511] In the above tetrahydroquinoline derivative (I), R 1x 、R v and R w The tetrahydroquinoline derivative (Ik) in which all hydrogen atoms are present can be obtained, for example, by the method described in Synthesis Scheme 8.

[0512] [Chemical Formula 15]

[0513]

[0514] [In the formula, X represents a halogen atom, and the symbols in the formula have the same meanings as above.]

[0515] (Process 8-1)

[0516] Quinoline derivative (XXXII) can be obtained by coupling reaction of 3-halogenoquinoline derivative (XXX) with boronic acid derivative (XXXI) in the presence of a metal catalyst and a base. The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-1.

[0517] The 3-halogenoquinoline derivative (XXX) and the boronic acid derivative (XXXI) used in the coupling reaction can be purchased or prepared by a known method or a method based thereon.

[0518] (Process 8-2)

[0519] The tetrahydroquinoline derivative (Ik) can be obtained by hydrogenation or hydrogen transfer reduction of the quinoline derivative (XXXII). The reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as those in step 1-4.

[0520] Manufacturing method 9

[0521] In the above tetrahydroquinoline derivative (I), R 1x 、R v and R w Optically active forms (I-k') and (Ik") of the tetrahydroquinoline derivative (Ik) containing only hydrogen atoms can be obtained, for example, by the method described in Synthesis Scheme 9.

[0522] [Chemical Formula 16]

[0523]

[0524] [In the formula, each symbol has the same meaning as above. ]

[0525] (Process 9-1)

[0526] Optically active forms (I-k') and (Ik") of the tetrahydroquinoline derivative (Ik) can be prepared by HPLC using a chiral column.

[0527] As one embodiment of the present invention, the invention has the effect of inhibiting ferroptosis and can be used to treat or prevent amyotrophic lateral sclerosis.

[0528] "Ferroptosis inhibition" refers to the inhibition of ferroptosis (cell death controlled by divalent iron). The ferroptosis inhibitor of the present invention can be expected to prevent, delay, improve, or alleviate symptoms of a disease by inhibiting ferroptosis.

[0529] The so-called "amyotrophic lateral sclerosis" refers to a progressive, fatal neurodegenerative disease characterized by selective degeneration / loss of motor neurons, which leads to movement disorders and respiratory muscle paralysis in the end stage due to the resulting systemic muscle atrophy. The age of onset and the progression of the disease are diverse. The amyotrophic lateral sclerosis that is the subject of treatment or prevention of the present invention includes both familial and sporadic forms, and includes both conditions accompanied by and without causative gene mutations. There is no particular limitation on the mutated gene, and examples include superoxide dismutase 1 (SOD1), TDP-43, C9orf72, alsin, SETX, FUS / TLS, VAPB, ANG, FIG4, OPTN, ATXN2, DAO, UBQLN2, PFN1, DCTN1, CHPM2B, VCP, etc.

[0530] It should be noted that the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof of the present invention can also be used as a ferroptosis inhibitor containing the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient, that is, a therapeutic or preventive agent for amyotrophic lateral sclerosis. Here, as the above-mentioned ferroptosis inhibitor, a tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof, 2-phenyl-1,2,3,4-tetrahydroquinoline or a pharmacologically acceptable salt thereof can be used.

[0531] The term "ferroptosis inhibitor" refers to a compound that inhibits ferroptosis, thereby improving cell survival rate, and improving and maintaining cell function, or a composition containing the compound as an active ingredient.

[0532] However, in order to show the ferroptosis inhibitory effect, as described in Non-Patent Document 5, it is reported that it is important to have a free radical scavenging effect. In addition, Patent Document 2 and Non-Patent Document 6 disclose that tetrahydroquinoxaline derivatives have a strong free radical scavenging effect. On the other hand, Non-Patent Document 11 reports that the free radical scavenging effect of tetrahydroquinoxaline derivatives is extremely weak. Nevertheless, the tetrahydroquinoline derivative (I) of the present invention or its pharmacologically acceptable salt shows a ferroptosis inhibitory effect and can be used as a new drug for treating or preventing amyotrophic lateral sclerosis.

[0533] The ferroptosis inhibitory effect of a tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be evaluated using an invitro assay. For example, the evaluation can be performed using the inhibitory effect on cell death caused by treatment of ferroptosis inducers such as erastin, RSL3, FIN56, or buthionine-sulfoximine on cultured cells, primary cultured cells, iPS cells, and the like, such as human fibrosarcoma cells (HT-1080 cells).

[0534] The free radical scavenging activity of a test compound can be evaluated using in vitro assays. For example, the method using 1,1-diphenyl-2-picrylhydrazyl (DPPH) as a stable free radical can be used (Antioxidants, 2019, Vol. 258).

[0535] Tetrahydroquinoline derivatives (I) or pharmacologically acceptable salts thereof are effective for the treatment or prevention of amyotrophic lateral sclerosis, which can be evaluated using a pathological model. As pathological models, for example, superoxide dismutase 1 (SOD1) gene mutant mice (Science, 1994, Vol. 264 p. 1772-1775), TDP-43 gene mutant mice, motor neurons derived from iPS cells of patients with amyotrophic lateral sclerosis, etc. can be cited. Among them, SOD1 gene mutant mice are mice in which the human mutant SOD1 gene, which is the most common causative gene for familial amyotrophic lateral sclerosis, is overexpressed. It is an animal model in which motor neurons degenerate / necrosis with age. The above-mentioned animal model can be used for the efficacy study of therapeutic agents or preventive agents for amyotrophic lateral sclerosis due to the similarity of its symptoms and pathological observation results with those of human patients. The effectiveness of the treatment or prevention of amyotrophic lateral sclerosis can be evaluated using the above-mentioned SOD1 gene mutant mice, for example, using motor dysfunction, a characteristic symptom of amyotrophic lateral sclerosis, such as hind limb extension disorder, as an indicator.

[0536] Since the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof has a ferroptosis inhibitory effect, it can be used for the treatment or prevention of amyotrophic lateral sclerosis in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys or humans).

[0537] When a tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof is used clinically as a therapeutic or preventive agent for amyotrophic lateral sclerosis, the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be administered orally, parenterally or topically, directly or in combination with a pharmacologically acceptable carrier. The therapeutic or preventive agent for amyotrophic lateral sclerosis can be appropriately mixed with additives such as excipients, binders, lubricants, disintegrants, sweeteners, stabilizers, flavorings, fragrances, colorants, fluidizers, preservatives, buffers, dissolution aids, emulsifiers, surfactants, suspending agents, diluents or isotonic agents as needed. These additives can be cited as pharmacologically acceptable carriers. In addition, the therapeutic or preventive agent for amyotrophic lateral sclerosis can be manufactured by conventional methods using these pharmacologically acceptable carriers as appropriate. Examples of administration methods for the therapeutic or preventive agent for amyotrophic lateral sclerosis include oral preparations such as tablets, pills, capsules, granules, powders, syrups, emulsions, or suspensions, parenteral preparations such as inhalants, injections, suppositories, or liquids, and ointments, creams, or patches for topical administration. Furthermore, it is also effective to combine the agent with an appropriate matrix (e.g., a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid and glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester) to form a sustained-release preparation.

[0538] The preparation of the above-mentioned preparation containing the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be carried out according to a known manufacturing method commonly used in the field of pharmaceutical preparations. For example, tablets can be prepared by containing excipients, binders, disintegrants, lubricants, etc., pills and granules can be prepared by containing excipients, binders, disintegrants, etc., capsules and dispersants can be prepared by containing excipients, etc., syrups can be prepared by containing sweeteners, etc., and emulsions and suspensions can be prepared by containing surfactants, suspending agents, emulsifiers, etc.

[0539] Examples of the excipient include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

[0540] Examples of the binder include starch slurry, gum arabic solution, gelatin solution, tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, and glycerin.

[0541] Examples of the disintegrant include starch and calcium carbonate.

[0542] Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, purified talc, and silicon dioxide.

[0543] Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and monosaccharide syrup.

[0544] Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl (40) stearate.

[0545] Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.

[0546] Examples of the emulsifier include gum arabic, gum tragacanth, gelatin, and polysorbate 80.

[0547] Furthermore, when the therapeutic or preventive agent for amyotrophic lateral sclerosis containing the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof is prepared in the above-mentioned dosage form, colorants, preservatives, fragrances, flavoring agents, stabilizers, thickeners, etc. commonly used in the pharmaceutical field can be appropriately added.

[0548] The therapeutic or preventive agent for amyotrophic lateral sclerosis preferably contains 0.00001 to 90% by weight of a tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof, and more preferably 0.01 to 70% by weight. The daily dosage can be appropriately selected depending on the patient's condition, weight, age, administration route, etc. For example, as the amount of the active ingredient per adult (weighing approximately 60 kg), an oral dosage form is preferably administered in a range of 1 mg to 1000 mg, and an injection form is preferably administered in a range of 0.01 to 100 mg. Each can be administered in a single dose or in divided doses.

[0549] The above-mentioned therapeutic or preventive agents for amyotrophic lateral sclerosis may be mixed or used in combination with other agents in appropriate amounts to supplement or enhance their therapeutic or preventive effects or to reduce the dosage. These agents may be administered simultaneously with other agents or sequentially in any order. Examples of these other agents include, but are not limited to, other agents for treating amyotrophic lateral sclerosis listed below, agents for treating symptoms such as movement disorders and paralysis in patients with amyotrophic lateral sclerosis, or treatments based on stem cell transplantation.

[0550] Examples of other drugs for treating amyotrophic lateral sclerosis include riloquinolone and edaravone.

[0551] Example

[0552] The present invention will be described in detail below using reference examples and examples, but the present invention is not limited thereto.

[0553] For compounds used in the synthesis of the compounds in the reference examples and examples, for which the synthesis method is not described, commercially available compounds were used. "Room temperature" in the following examples and reference examples generally means about 10 to about 35°C. The solvent name shown in the NMR data indicates the solvent used for the measurement. In addition, a JNM-ECS400 nuclear magnetic resonance apparatus or a JNM-ECZ400S nuclear magnetic resonance apparatus (JEOL Ltd.) was used to measure the 400 MHz NMR spectrum. The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are represented by s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets), ddd (double of doublets), dq (double of quartets), td (triplet of triplet), and tt (triplet of triplets). In 1 In H-NMR, there is no description when protons such as hydroxyl, amino, and carboxyl groups are very gentle peaks. ESI-MS spectra were measured using Agilent Technologies 1200 Series and G6130A (Agilent Technologies). Silica gel 60 (Merck) was used for silica gel, amino silica gel (Fuji Silysia Chemical Co., Ltd.) was used for amino silica gel, and YFLCW-prep2XY (Yamayama) was used for flash preparative chromatography. Silica gel 60 (Merck) was used for preparative thin layer chromatography (hereinafter referred to as preparative TLC).

[0554] (Example 1) Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinoline hydrochloride:

[0555] [Chemical Formula 17]

[0556]

[0557] 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 completion of the reaction, the precipitated solid was collected by filtration and washed with ethyl acetate to obtain the title compound (hereinafter referred to as the compound of Example 1) as a white solid (8.07 g, 32.9 mmol, 92% yield).

[0558] 1H-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).

[0559] MS (ESI) [M+H] + :210.

[0560] (Example 2) Synthesis of (R)-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0561] [Chemical Formula 18]

[0562]

[0563] 2-Phenylquinoline (0.100 g, 0.487 mmol) and (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). Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (0.296 g, 1.17 mmol) was added, and the mixture was stirred at -10°C for 24 hours under an argon atmosphere. After completion of the reaction, 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 Example 2) as a colorless, transparent oil (95.0 mg, 0.457 mmol, 95% yield, 98.5% enantiomeric excess ee).

[0564] 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).

[0565] MS (ESI) [M+H] + :210.

[0566] Retention time (hereinafter referred to as Rt): 18.40 minutes

[0567] HPLC analysis conditions:

[0568] Column: DaicelChiralcelOD-H chiral column

[0569] (Inner diameter: 4.6mm, length: 250mm, particle size: 5μm)

[0570] Column temperature: 40℃

[0571] Mobile phase: propane-2-ol: hexane = 5:95

[0572] Flow rate: 0.6mL / min

[0573] Detection: UV (254nm)

[0574] (Example 3) Synthesis of (S)-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0575] [Chemical Formula 19]

[0576]

[0577] Using 2-phenylquinoline (50.0 mg, 0.243 mmol) and (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (3.7 mg, 0.0048 mmol), the title compound (hereinafter referred to as the compound of Example 3) was obtained as a colorless transparent oil (49.0 mg, 0.236 mmol, yield 97%, enantiomeric excess 97.2% ee) by the same method as in Example 2.

[0578] 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).

[0579] MS (ESI) [M+H]+ :210.

[0580] Rt: 14.28 minutes

[0581] HPLC analysis conditions:

[0582] Column: DaicelChiralcelOD-H chiral column

[0583] (Inner diameter: 4.6mm, length: 250mm, particle size: 5μm)

[0584] Column temperature: 40℃

[0585] Mobile phase: propane-2-ol: hexane = 5:95

[0586] Flow rate: 0.6mL / min

[0587] Detection: UV (254nm)

[0588] (Example 4) Synthesis of 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0589] [Chemical Formula 20]

[0590]

[0591] 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 for 6 hours under a hydrogen atmosphere at normal pressure. After completion of the reaction, nitrogen substitution was performed 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.

[0592] 1H-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).

[0593] MS (ESI) [M+H] + :240.

[0594] (Reference Example 1) Synthesis of 2-(3-methoxyphenyl)quinoline:

[0595] [Chemical Formula 21]

[0596]

[0597] 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 mol / L sodium carbonate aqueous solution (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0073 mmol) were added, and stirred at 100 ° C for 4 hours under an argon atmosphere. After the reaction was completed, water was added to the reaction mixture and extracted with hexane / ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, 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 (0.165 g, 0.702 mmol, yield 95%) as a white solid.

[0598] 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).

[0599] MS (ESI) [M+H] + :236.

[0600] (Example 5) Synthesis of 2-(3-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0601] [Chemical Formula 22]

[0602]

[0603] 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) was obtained as a white solid (23.7 mg, 0.0991 mmol, yield 39%) by the same method as in Example 4.

[0604] 1 H-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).

[0605] MS (ESI) [M+H] + :240.

[0606] (Reference Example 2) Synthesis of 2-(2-methoxyphenyl)quinoline:

[0607] [Chemical Formula 23]

[0608]

[0609] The title compound (0.157 g, 0.668 mmol, yield 99%) was obtained as a white solid by the same method as Reference Example 1 using 2-chloroquinoline (0.100 g, 0.611 mmol) and 2-methoxyphenylboronic acid (92.8 mg, 0.611 mmol).

[0610] 1H-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).

[0611] MS (ESI) [M+H] + :236

[0612] (Example 6) Synthesis of 2-(2-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0613] [Chemical Formula 24]

[0614]

[0615] 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) was obtained as a white solid (35.5 mg, 0.148 mmol, yield 58%) by the same method as in Example 4.

[0616] 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).

[0617] MS (ESI) [M+H] + :240.

[0618] (Reference Example 3) Synthesis of 2-(Benzo[d][1,3]dioxol-5-yl)-6-methoxyquinoline:

[0619] [Chemical Formula 25]

[0620]

[0621] 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 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).

[0622] 1 H-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).

[0623] MS (ESI) [M+H] + :280.

[0624] (Example 7) Synthesis of 2-(Benzo[d][1,3]dioxol-5-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline (new compound):

[0625] [Chemical Formula 26]

[0626]

[0627] 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 Example 4.

[0628] 1H-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).

[0629] MS (ESI) [M+H] + :284.

[0630] (Reference Example 4) Synthesis of 7-methoxy-2-(4-methoxyphenyl)quinoline:

[0631] [Chemical Formula 27]

[0632]

[0633] The title compound (0.155 g, 0.585 mmol, yield 87%) was obtained as a white solid by the same method as Reference Example 1 using 2-chloro-7-methoxyquinoline (0.130 g, 0.671 mmol) and 4-methoxyphenylboronic acid (0.102 g, 0.671 mmol).

[0634] 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).

[0635] MS (ESI) [M+H] + :266.

[0636] (Example 8) Synthesis of 7-methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline:

[0637] [Chemical Formula 28]

[0638]

[0639] 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.

[0640] 1 H-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).

[0641] MS (ESI) [M+H] + :270.

[0642] (Reference Example 5) Synthesis of 2-(Benzo[d][1,3]dioxol-5-yl)quinoline:

[0643] [Chemical Formula 29]

[0644]

[0645] The title compound (0.218 g, 0.876 mmol, yield 87%) was obtained as a yellow solid by the same method as Reference Example 1 using 2-chloroquinoline (0.150 g, 0.917 mmol) and benzo[d][1,3]dioxol-5-ylphenylboronic acid (0.167 g, 1.01 mmol).

[0646] 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).

[0647] MS (ESI) [M+H] + :250.

[0648] (Example 9) Synthesis of 2-(Benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline:

[0649] [Chemical formula 30]

[0650]

[0651] 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 Example 4.

[0652] 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).

[0653] MS (ESI) [M+H] + :254.

[0654] (Reference Example 6) Synthesis of 2-(2-(trifluoromethyl)phenyl)quinoline:

[0655] [Chemical Formula 31]

[0656]

[0657] 2-Chloroquinoline (50.0 mg, 0.306 mmol), (2-(trifluoromethyl)phenyl)boric 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 heated with stirring at 100°C for 16 hours. After cooling the reaction mixture to room temperature, water was injected and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The 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.

[0658] 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).

[0659] MS (ESI) [M+H] + :274.

[0660] (Example 10) Synthesis of 2-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline:

[0661] [Chemical Formula 32]

[0662]

[0663] 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 Example 4.

[0664] 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).

[0665] MS (ESI) [M+H] + :278.

[0666] (Reference Example 7) Synthesis of 2-(1H-pyrazol-4-yl)quinoline:

[0667] [Chemical Formula 33]

[0668]

[0669] The title compound (63.7 mg, 0.326 mmol, yield 53%) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (100 mg, 0.611 mmol) and (1H-pyrazol-4-yl)boronic acid (137 mg, 1.22 mmol).

[0670] 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).

[0671] MS (ESI) [M+H] + :196.

[0672] (Example 11) Synthesis of 2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline:

[0673] [Chemical Formula 34]

[0674]

[0675] Using 2-(1H-pyrazol-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 Example 4.

[0676] 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).

[0677] MS (ESI) [M+H] + :200.

[0678] (Example 12) Synthesis of an optically active form of 2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline:

[0679] [Chemical Formula 35]

[0680]

[0681] [In the formula, the carbon atom marked with * represents the carbon atom that serves as an asymmetric center.]

[0682] 2-(1H-pyrazol-4-yl)quinoline (50.0 mg, 0.256 mmol) synthesized in Reference Example 7 and (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (3.8 mg, 0.0051 mmol) were suspended in 1,4-dioxane (2 mL). Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (0.155 g, 0.614 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate), and the solid was recrystallized from hexane / ethyl acetate to obtain the title compound (hereinafter referred to as the compound of Example 12) as a white solid (9.0 mg, 0.045 mmol, yield 18%, enantiomeric excess 98.1% ee).

[0683] 1H-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).

[0684] MS (ESI) [M+H] + :200.

[0685] Rt: 17.78 minutes

[0686] HPLC analysis conditions:

[0687] Column: DaicelChiralcelOZ-3 chiral column

[0688] (Inner diameter: 4.6mm, length: 150mm, particle size: 3μm)

[0689] Column temperature: 40℃

[0690] Mobile phase: propan-2-ol: hexane = 10:90

[0691] Flow rate: 0.6mL / min

[0692] Detection: UV (254nm)

[0693] (Example 13) Synthesis of other optically active forms of 2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline:

[0694] [Chemical Formula 36]

[0695]

[0696] [In the formula, the carbon atom marked with * represents the carbon atom that serves as an asymmetric center.]

[0697] Using 2-(1H-pyrazol-4-yl)quinoline (70.0 mg, 0.359 mmol) synthesized in Reference Example 7 and (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (5.40 mg, 7.17 μmol), the title compound (hereinafter referred to as the compound of Example 13) was obtained as a white solid (30.0 mg, 0.151 mmol, yield 42%, enantiomeric excess 96.9% ee) by the same method as in Example 12.

[0698] 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).

[0699] MS (ESI) [M+H] + :200.

[0700] Rt: 13.11 minutes

[0701] HPLC analysis conditions:

[0702] Column: DaicelChiralcelOZ-3 chiral column

[0703] (Inner diameter: 4.6mm, length: 150mm, particle size: 3μm)

[0704] Column temperature: 40℃

[0705] Mobile phase: propan-2-ol: hexane = 10:90

[0706] Flow rate: 0.6mL / min

[0707] Detection: UV (254nm)

[0708] (Example 14) Synthesis of 2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[0709] [Chemical Formula 37]

[0710]

[0711] After dissolving 2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (25.0 mg, 0.125 mmol) synthesized in Example 11 in DMF (1.2 mL), potassium carbonate (34.7 mg, 0.251 mmol) and iodomethane (7.8 μL, 0.125 mmol) were added, and the mixture was stirred at 50°C for 2 hours. After cooling the reaction mixture to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) and column chromatography (amino silica 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.

[0712] 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).

[0713] MS (ESI) [M+H] + :214.

[0714] (Reference Example 8) Synthesis of 2-(6-methoxypyridin-3-yl)quinoline:

[0715] [Chemical Formula 38]

[0716]

[0717] The title compound (134 mg, 0.568 mmol, 93% yield) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (100 mg, 0.611 mmol) and (6-methoxypyridin-3-yl)boronic acid (140 mg, 0.917 mmol).

[0718] 1H-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).

[0719] MS (ESI) [M+H] + :237.

[0720] (Example 15) Synthesis of 2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[0721] [Chemical Formula 39]

[0722]

[0723] Using 2-(6-methoxypyridin-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 Example 4.

[0724] 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).

[0725] MS (ESI) [M+H] + :241.

[0726] (Reference Example 9) Synthesis of 2-(4-(methylsulfonyl)phenyl)quinoline:

[0727] [Chemical Formula 40]

[0728]

[0729] Using 2-chloroquinoline (200 mg, 1.22 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (489 mg, 2.45 mmol), the same method as Reference Example 6 was used to obtain a mixture of the title compound and impurities (296 mg) as a white solid.

[0730] MS (ESI) [M+H] + :284.

[0731] (Example 16) Synthesis of 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline (new compound):

[0732] [Chemical Formula 41]

[0733]

[0734] 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.

[0735] 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).

[0736] MS (ESI) [M+H] + :288.

[0737] (Reference Example 10) Synthesis of methyl 4-(quinolin-2-yl)benzoate:

[0738] [Chemical Formula 42]

[0739]

[0740] The title compound (1.95 g, 7.40 mmol, yield 81%) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (1.50 g, 9.17 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (1.98 g, 11.0 mmol).

[0741] 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).

[0742] MS (ESI) [M+H] + :264.

[0743] (Example 17) Synthesis of methyl 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoate:

[0744] [Chemical Formula 43]

[0745]

[0746] Using methyl 4-(quinolin-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.

[0747] 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).

[0748] MS (ESI) [M+H] + :268.

[0749] (Example 18) Synthesis of 2-(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)propan-2-ol (new compound):

[0750] [Chemical Formula 44]

[0751]

[0752] After dissolving methyl 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoate (50.0 mg, 0.187 mmol) synthesized in Example 17 in THF (1.9 mL), methyllithium THF solution (0.56 mL, 0.65 mmol) was added dropwise under ice cooling, and stirred for 2 hours under ice cooling. After the reaction was completed, 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 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.

[0753] 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).

[0754] MS (ESI) [M+H] + :268.

[0755] (Reference Example 11) Synthesis of 3-(quinolin-2-yl)benzenesulfonamide:

[0756] [Chemical Formula 45]

[0757]

[0758] 2-Chloroquinoline (100 mg, 0.611 mmol), (3-sulfamoylphenyl)boric 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 heated at 100°C with stirring for 17 hours. The reaction mixture was cooled to room temperature, injected with water and 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 crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (135 mg, 0.474 mmol, yield 78%) as a white solid.

[0759] 1 H-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).

[0760] MS (ESI) [M+H] + :285.

[0761] (Example 19) Synthesis of 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0762] [Chemical Formula 46]

[0763]

[0764] Using 3-(quinolin-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.

[0765] 1H-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).

[0766] MS (ESI) [M+H] + :289.

[0767] (Reference Example 12) Synthesis of 2-(quinolin-2-yl)benzenesulfonamide:

[0768] [Chemical Formula 47]

[0769]

[0770] The title compound (153 mg, 0.540 mmol, yield 88%) was obtained as a white solid by the same method as Reference Example 11 using 2-chloroquinoline (100 mg, 0.611 mmol) and (2-sulfamoylphenyl)boronic acid (184 mg, 0.917 mmol).

[0771] 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).

[0772] MS (ESI) [M+H] + :285.

[0773] (Example 20) Synthesis of 2-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0774] [Chemical Formula 48]

[0775]

[0776] Using 2-(quinolin-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.

[0777] 1 H-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).

[0778] MS (ESI) [M+H] + :289.

[0779] (Reference Example 13) Synthesis of N-(4-(quinolin-2-yl)phenyl)acetamide:

[0780] [Chemical Formula 49]

[0781]

[0782] 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 completed, water was added to the reaction mixture and extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, 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 (48.8 mg, 0.186 mmol, yield 30%) as a white solid.

[0783] 1 H-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).

[0784] MS (ESI) [M+H] + :263.

[0785] (Example 21) Synthesis of N-(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)acetamide:

[0786] [Chemical Formula 50]

[0787]

[0788] Using N-(4-(Quinolin-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 substance by the same method as Example 4.

[0789] 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).

[0790] MS (ESI) [M+H] + :267.

[0791] (Reference Example 14) Synthesis of 2-(1H-pyrazol-3-yl)quinoline:

[0792] [Chemical Formula 51]

[0793]

[0794] The title compound (56.0 mg, 0.287 mmol, yield 47%) was obtained as a white solid by the same method as Reference Example 11 using 2-chloroquinoline (100 mg, 0.611 mmol) and 1H-pyrazole-3-boronic acid (164 mg, 0.917 mmol).

[0795] 1H-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).

[0796] MS (ESI) [M+H] + :196.

[0797] (Example 22) Synthesis of 2-(1H-pyrazol-3-yl)-1,2,3,4-tetrahydroquinoline:

[0798] [Chemical Formula 52]

[0799]

[0800] Using 2-(1H-pyrazol-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 substance by the same method as in Example 4.

[0801] 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).

[0802] MS (ESI) [M+H] + :200.

[0803] (Reference Example 15) Synthesis of 3',4'-dihydro-[2,6'-biquinolinyl]-2'(1'H)-one:

[0804] [Chemical Formula 53]

[0805]

[0806] Using 2-chloroquinoline (100 mg, 0.611 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-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 Reference Example 11.

[0807] 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).

[0808] MS (ESI) [M+H] + :275.

[0809] (Example 23) Synthesis of 1,2,3,3',4,4'-hexahydro-[2,6'-biquinolin]-2'(1'H)-one (new compound):

[0810] [Chemical Formula 54]

[0811]

[0812] Using 3',4'-dihydro-[2,6'-biquinolin]-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.

[0813] 1H-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).

[0814] MS (ESI) [M+H] + :279.

[0815] (Reference Example 16) Synthesis of 1'-methyl-3',4'-dihydro-[2,6'-biquinolinyl]-2'(1'H)-one:

[0816] [Chemical Formula 55]

[0817]

[0818] 2-Chloroquinoline (100 mg, 0.611 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (263 mg, 0.917 mmol) were dissolved in DMF / water (2.4 mL / 0.60 mL) and the title compound (171 mg, 0.593 mmol, 97% yield) was obtained as a white solid by the same method as in Reference Example 11.

[0819] 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).

[0820] MS (ESI) [M+H] + :289.

[0821] (Example 24) Synthesis of 1'-methyl-1,2,3,3',4,4'-hexahydro-[2,6'-biquinolin]-2'(1'H)-one (new compound):

[0822] [Chemical Formula 56]

[0823]

[0824] Using 1'-methyl-3',4'-dihydro-[2,6'-biquinolin]-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.

[0825] 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).

[0826] MS (ESI) [M+H] + :293.

[0827] (Reference Example 17) Synthesis of 5-(quinolin-2-yl)isoindolin-1-one:

[0828] [Chemical Formula 57]

[0829]

[0830] Using 2-chloroquinoline (100 mg, 0.611 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-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 Reference Example 11.

[0831] 1H-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).

[0832] MS (ESI) [M+H] + :261.

[0833] (Example 25) Synthesis of 5-(1,2,3,4-tetrahydroquinolin-2-yl)isoindolin-1-one (new compound):

[0834] [Chemical Formula 58]

[0835]

[0836] Using 5-(quinolin-2-yl)isoindolin-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.

[0837] 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).

[0838] MS (ESI) [M+H] + :265.

[0839] (Reference Example 18) Synthesis of 2-(4-fluorophenyl)quinoline:

[0840] [Chemical Formula 59]

[0841]

[0842] The title compound (65.3 mg, 0.293 mmol, yield 96%) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (4-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol).

[0843] 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).

[0844] MS (ESI) [M+H] + :224.

[0845] (Example 26) Synthesis of 2-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline:

[0846] [Chemical Formula 60]

[0847]

[0848] After dissolving 2-(4-fluorophenyl)quinoline (62.0 mg, 0.278 mmol) synthesized in Reference Example 18 in dichloromethane (2.8 mL), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester (148 mg, 0.583 mmol) and iodine (7.0 mg, 0.028 mmol) were added and stirred at room temperature for 3 hours. After completion of the reaction, 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.

[0849] 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).

[0850] MS (ESI) [M+H] + :228.

[0851] (Reference Example 19) Synthesis of 2-(3-fluorophenyl)quinoline:

[0852] [Chemical Formula 61]

[0853]

[0854] The title compound (68.5 mg, 0.307 mmol, quant. yield) was obtained as a white solid by the same method as in Reference Example 6 using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (3-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol).

[0855] 1 H-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).

[0856] MS (ESI) [M+H] + :224.

[0857] (Example 27) Synthesis of 2-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoline:

[0858] [Chemical Formula 62]

[0859]

[0860] 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.

[0861] 1H-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).

[0862] MS (ESI) [M+H] + :228.

[0863] (Reference Example 20) Synthesis of 2-(2-fluorophenyl)quinoline:

[0864] [Chemical Formula 63]

[0865]

[0866] The title compound (69.9 mg, 0.309 mmol, quant. yield) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (2-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol).

[0867] 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).

[0868] MS (ESI) [M+H] + :224.

[0869] (Example 28) Synthesis of 2-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoline:

[0870] [Chemical Formula 64]

[0871]

[0872] 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.

[0873] 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).

[0874] MS (ESI) [M+H] + :228.

[0875] (Reference Example 21) Synthesis of 2-(4-(trifluoromethyl)phenyl)quinoline:

[0876] [Chemical Formula 65]

[0877]

[0878] The title compound (80.7 mg, 0.295 mmol, yield 97%) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (87.1 mg, 0.458 mmol).

[0879] 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).

[0880] MS (ESI) [M+H] + :274.

[0881] (Example 29) Synthesis of 2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline:

[0882] [Chemical Formula 66]

[0883]

[0884] 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 Example 26.

[0885] 1 H-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).

[0886] MS (ESI) [M+H] + :278.

[0887] (Reference Example 22) Synthesis of 2-(3-(trifluoromethyl)phenyl)quinoline:

[0888] [Chemical Formula 67]

[0889]

[0890] The title compound (40.1 mg, 0.147 mmol, quant. yield) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (24.0 mg, 0.147 mmol) and (3-(trifluoromethyl)phenyl)boronic acid (30.6 mg, 0.161 mmol).

[0891] 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).

[0892] MS (ESI) [M+H] + :274.

[0893] (Example 30) Synthesis of 2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline:

[0894] [Chemical Formula 68]

[0895]

[0896] 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 Example 26.

[0897] 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).

[0898] MS (ESI) [M+H] + :278.

[0899] (Reference Example 23) Synthesis of 2-(4-(trifluoromethoxy)phenyl)quinoline:

[0900] [Chemical Formula 69]

[0901]

[0902] 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 using (4-(trifluoromethoxy)phenyl)boronic acid (138 mg, 0.672 mmol).

[0903] 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).

[0904] MS (ESI) [M+H] + :290.

[0905] (Example 31) Synthesis of 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline (new compound):

[0906] [Chemical Formula 70]

[0907]

[0908] 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 light yellow oil by the same method as Example 26.

[0909] 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, J=9.1, 3.2Hz), 4.03 (1H, brs), 2.92 (1H, ddd, J=16.5, 10.5, 5.5Hz), 2.72 (1H, ddd, J=16.5, 5.0, 5.0Hz), 2.15-2.08 (1H, m), 2.01-1.92 (1H, m).

[0910] MS (ESI) [M+H] + :294.

[0911] (Reference Example 24) Synthesis of 4-(quinolin-2-yl)benzenesulfonamide:

[0912] [Chemical Formula 71]

[0913]

[0914] The title compound (66.1 mg, 0.232 mmol, yield 76%) was obtained as a pale yellow solid by the same method as Reference Example 11 using 2-chloroquinoline (50.0 mg, 0.306 mmol) and (4-sulfamoylphenyl)boronic acid (92.1 mg, 0.458 mmol).

[0915] 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).

[0916] MS (ESI) [M+H] + :285.

[0917] (Example 32) Synthesis of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0918] [Chemical Formula 72]

[0919]

[0920] Using 4-(quinolin-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.

[0921] 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).

[0922] MS (ESI) [M+H] + :289.

[0923] (Example 33) Synthesis of an optically active form (new compound) of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide:

[0924] [Chemical Formula 73]

[0925]

[0926] [In the formula, the carbon atom marked with * represents the carbon atom that serves as an asymmetric center.]

[0927] 4-(Quinolin-2-yl)benzenesulfonamide (50.0 mg, 0.176 mmol) synthesized in Reference Example 24 and (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (2.6 mg, 0.0035 mmol) were suspended in 1,4-dioxane (1.75 mL), and then diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (106 mg, 0.422 mmol) was added, and the mixture was stirred at 60°C for 6 hours. Furthermore, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (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 obtained 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.

[0928] 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).

[0929] MS (ESI) [M+H] + :289.

[0930] Rt: 20.76 minutes

[0931] HPLC analysis conditions:

[0932] Column: DaicelChiralcelOD-H chiral column

[0933] (Inner diameter: 4.6mm, length: 250mm, particle size: 5μm)

[0934] Column temperature: 40℃

[0935] Mobile phase: propan-2-ol: hexane = 60:40

[0936] Flow rate: 0.6mL / min

[0937] Detection: UV (254nm)

[0938] (Example 34) Synthesis of other optically active substances (new compounds) of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide:

[0939] [Chemical Formula 74]

[0940]

[0941] [In the formula, the carbon atom marked with * represents the carbon atom that serves as an asymmetric center.]

[0942] Using 4-(quinolin-2-yl)benzenesulfonamide (50.0 mg, 0.176 mmol) synthesized in Reference Example 24 and (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (2.6 mg, 0.0035 mmol), the title compound (hereinafter referred to as the compound of Example 34) was obtained as a white solid (37.7 mg, 0.131 mmol, yield 74%, enantiomeric excess 99.0% ee) by the same method as Example 33.

[0943] 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).

[0944] MS (ESI) [M+H] + :289.

[0945] Rt: 17.40 minutes

[0946] HPLC analysis conditions:

[0947] Column: DaicelChiralcelOD-H chiral column

[0948] (Inner diameter: 4.6mm, length: 250mm, particle size: 5μm)

[0949] Column temperature: 40℃

[0950] Mobile phase: propan-2-ol: hexane = 60:40

[0951] Flow rate: 0.6mL / min

[0952] Detection: UV (254nm)

[0953] (Reference Example 25) Synthesis of 4-(quinolin-2-yl)benzonitrile:

[0954] [Chemical Formula 75]

[0955]

[0956] The title compound (100 mg, 0.917 mmol, yield 47%) was obtained as a white solid by the same method as Reference Example 6 using 2-chloroquinoline (150 mg, 0.917 mmol) and (4-cyanophenyl)boronic acid (269 mg, 1.83 mmol).

[0957] 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).

[0958] MS (ESI) [M+H] + :231.

[0959] (Example 35) Synthesis of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile:

[0960] [Chemical Formula 76]

[0961]

[0962] Using 4-(quinolin-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.

[0963] 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).

[0964] MS (ESI) [M+H] + :235.

[0965] (Example 36) Synthesis of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0966] [Chemical Formula 77]

[0967]

[0968] After dissolving 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile (32.0 mg, 0.137 mmol) synthesized in Example 35 in DMSO / THF (1 / 4, v / v, 1.4 mL), 1 mol / L sodium hydroxide aqueous 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. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (hereinafter referred to as the compound of Example 36) (29.9 mg, 0.119 mmol, yield 87%) as a light yellow solid.

[0969] 1H-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).

[0970] MS (ESI) [M+H] + :253.

[0971] (Reference Example 26) Synthesis of 4-(chloroquinolin-2-yl)-benzamide:

[0972] [Chemical Formula 78]

[0973]

[0974] The title compound (329.0 mg, 1.32 mmol, yield 54%) was obtained as a pale yellow solid by the same method as Reference Example 6 using 2-chloroquinoline (400 mg, 2.45 mmol) and (4-carbamoylphenyl)boronic acid (605 mg, 3.67 mmol).

[0975] 1 H-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).

[0976] MS (ESI) [M+H] + :249.

[0977] (Example 37) Synthesis of an optically active form (new compound) of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide:

[0978] [Chemical Formula 79]

[0979]

[0980] [In the formula, the carbon atom marked with * represents the carbon atom that serves as an asymmetric center.]

[0981] 4-(Quinolin-2-yl)benzamide (50.0 mg, 0.201 mmol) synthesized in Reference Example 26 and (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (3.0 mg, 0.0040 mmol) were suspended in 1,4-dioxane (2 mL). Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (0.122 g, 0.483 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained crude product 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.

[0982] 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).

[0983] MS (ESI) [M+H] + :253.

[0984] Rt: 14.28 minutes

[0985] HPLC analysis conditions:

[0986] Column: DaicelChiralcelOD-H chiral column

[0987] (Inner diameter: 4.6mm, length: 250mm, particle size: 5μm)

[0988] Column temperature: 40℃

[0989] Mobile phase: propane-2-ol: hexane = 40:60

[0990] Flow rate: 0.6mL / min

[0991] Detection: UV (254nm)

[0992] (Example 38) Synthesis of other optically active forms (new compounds) of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide:

[0993] [Chemical formula 80]

[0994]

[0995] [In the formula, the carbon atom marked with * represents the carbon atom that serves as an asymmetric center.]

[0996] Using 4-(quinolin-2-yl)benzamide (50.0 mg, 0.201 mmol) synthesized in Reference Example 26 and (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (3.0 mg, 0.0040 mmol), the title compound (hereinafter referred to as the compound of Example 38) was obtained as a white solid (13.7 mg, 0.0543 mmol, yield 46%, enantiomeric excess 97.6% ee) by the same method as Example 37.

[0997] 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).

[0998] MS (ESI) [M+H] + :253.

[0999] Rt: 24.14 minutes

[1000] HPLC analysis conditions:

[1001] Column: DaicelChiralcelOD-H chiral column

[1002] (Inner diameter: 4.6mm, length: 250mm, particle size: 5μm)

[1003] Column temperature: 40℃

[1004] Mobile phase: propane-2-ol: hexane = 40:60

[1005] Flow rate: 0.6mL / min

[1006] Detection: UV (254nm)

[1007] (Reference Example 27) Synthesis of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid:

[1008] [Chemical Formula 81]

[1009]

[1010] 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), and an 8 mol / L aqueous sodium hydroxide solution (0.764 mL, 6.11 mmol) was added. The mixture was stirred at room temperature under an argon atmosphere for 20 hours. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture, which was concentrated under reduced pressure and extracted with ethyl acetate. The resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (497 mg, 1.96 mmol, 96% yield) as a cream-colored solid.

[1011] 1 H-NMR (CD3OD) δ: 7.97 (2H, d, J = 8.4Hz), 7.46 (2H, d, J = 8.2Hz), 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).

[1012] MS (ESI) [M+H] + :254.

[1013] (Example 39) Synthesis of N,N-diethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1014] [Chemical Formula 82]

[1015]

[1016] 4-(1,2,3,4-tetrahydroquinolin-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 completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed 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 39) (14.5 mg, 47.0 μmol, yield 31%) as a colorless transparent oil.

[1017] 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).

[1018] MS (ESI) [M+H] + :309.

[1019] (Example 40) Synthesis of N-ethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1020] [Chemical Formula 83]

[1021]

[1022] 4-(1,2,3,4-tetrahydroquinolin-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 completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed 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 40) (24.5 mg, 47.0 μmol, yield 74%) as a white solid.

[1023] 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).

[1024] MS (ESI) [M+H] + :281.

[1025] (Example 41) Synthesis of piperidin-1-yl(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone (new compound):

[1026] [Chemical formula 84]

[1027]

[1028] 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (30.0 mg, 0.118 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (54.0 mg, 0.142 mmol) synthesized in Reference Example 27 were dissolved in DMF (1.2 mL), and piperidine (12.9 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 completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with aqueous sodium bicarbonate solution 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 (hereinafter referred to as the compound of Example 41) (28.6 mg, 89.3 μmol, yield 75%) as a white amorphous substance.

[1029] 1 H-NMR (CDCl3) δ: 7.42-7.36 (4H, m), 7.04-7.00 (2H, m), 6.66 (1H, ddd, J=7.6, 7.6, 1.2Hz), 6.56 (1H, d, J=7.7Hz), 4.47 (1H, dd, J=9.1, 3.6Hz), 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).

[1030] MS (ESI) [M+H] + :321.

[1031] (Example 42) Synthesis of Morpholino(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone (new compound):

[1032] [Chemical Formula 85]

[1033]

[1034] 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (30.0 mg, 0.118 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (54.0 mg, 0.142 mmol) synthesized in Reference Example 27 were dissolved in DMF (1.2 mL), and morpholine (11.2 μL, 0.130 mmol) and N,N-diisopropylethylamine (30.9 μL, 0.178 mmol) were added. The mixture was stirred at room temperature for 16 hours under an argon atmosphere. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with aqueous sodium bicarbonate solution 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 (hereinafter referred to as the compound of Example 42) (33.4 mg, 0.104 mmol, yield 88%) as a white solid.

[1035] 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).

[1036] MS (ESI) [M+H] + :323.

[1037] (Example 43) Synthesis of (4-methylpiperazin-1-yl)(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone (new compound):

[1038] [Chemical Formula 86]

[1039]

[1040] 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (30.0 mg, 0.118 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (54.0 mg, 0.142 mmol) synthesized in Reference Example 27 were dissolved in DMF (1.2 mL), 1-methylpiperazine (14.3 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 14 hours. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with aqueous sodium bicarbonate solution 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 (hereinafter referred to as the compound of Example 43) (32.8 mg, 97.8 μmol, yield 83%) as a white amorphous substance.

[1041] 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).

[1042] MS (ESI) [M+H] + :336.

[1043] (Reference Example 28) Synthesis of N-methyl-3-(quinolin-2-yl)benzamide:

[1044] [Chemical Formula 87]

[1045]

[1046] 2-Chloroquinoline (100 mg, 0.611 mmol), (4-(methylcarbamoyl)phenyl)boric 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 heated with stirring at 100 ° C for 15 hours. After cooling the reaction mixture 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 crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (156 mg, 0.593 mmol, yield 97%) as a colorless transparent oil.

[1047] 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).

[1048] MS (ESI) [M+H] + :263.

[1049] (Example 44) Synthesis of N-methyl-3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1050] [Chemical Formula 88]

[1051]

[1052] Using N-methyl-3-(quinolin-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 Example 26.

[1053] 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).

[1054] MS (ESI) [M+H] + :267.

[1055] (Reference Example 29) Synthesis of 3-(quinolin-2-yl)benzonitrile:

[1056] [Chemical Formula 89]

[1057]

[1058] The title compound (211 mg, 0.917 mmol, quant. yield) was obtained as a white solid by the same method as in Reference Example 6 using 2-chloroquinoline (150 mg, 0.917 mmol) and (3-cyanophenyl)boronic acid (269 mg, 1.83 mmol).

[1059] 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).

[1060] MS (ESI) [M+H] + :224.

[1061] (Example 45) Synthesis of 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile (new compound):

[1062] [Chemical Formula 90]

[1063]

[1064] Using 3-(quinolin-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.

[1065] 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).

[1066] MS (ESI) [M+H] + :235.

[1067] (Example 46) Synthesis of 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1068] [Chemical Formula 91]

[1069]

[1070] After dissolving 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile (140 mg, 0.598 mmol) synthesized in Example 45 in DMSO / THF (1 / 4, v / v, 6 mL), 8 mol / L aqueous sodium hydroxide solution (164 μL, 1.31 mmol) and 30% aqueous hydrogen peroxide (103 μL, 1.31 mmol) were added, and the mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (hereinafter referred to as the compound of Example 46) (115 mg, 0.454 mmol, yield 76%) as a white solid.

[1071] 1H-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).

[1072] MS (ESI) [M+H] + :253.

[1073] (Reference Example 30) Synthesis of (2-(quinolin-2-yl)phenyl)methanol:

[1074] [Chemical Formula 92]

[1075]

[1076] The title compound (139 mg, 0.592 mmol, yield 97%) was obtained as a white solid by the same method as Reference Example 28 using 2-chloroquinoline (100 mg, 0.611 mmol) and (2-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol).

[1077] 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).

[1078] MS (ESI) [M+H] + :236.

[1079] (Example 47) Synthesis of (2-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol (new compound):

[1080] [Chemical Formula 93]

[1081]

[1082] Using (2-(Quinolin-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 light yellow oil by the same method as Example 26.

[1083] 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).

[1084] MS (ESI) [M+H] + :240.

[1085] (Reference Example 31) Synthesis of (3-(quinolin-2-yl)phenyl)methanol:

[1086] [Chemical Formula 94]

[1087]

[1088] The title compound (143 mg, 0.607 mmol, yield 99%) was obtained as a colorless amorphous substance by the same method as in Reference Example 28 using 2-chloroquinoline (100 mg, 0.611 mmol) and (3-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol).

[1089] 1H-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).

[1090] MS (ESI) [M+H] + :236.

[1091] (Example 48) Synthesis of (3-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol (new compound):

[1092] [Chemical Formula 95]

[1093]

[1094] Using (3-(Quinolin-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 light yellow oil by the same method as Example 26.

[1095] 1 H-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).

[1096] MS (ESI) [M+H] + :240.

[1097] (Reference Example 32) Synthesis of (4-(quinolin-2-yl)phenyl)methanol:

[1098] [Chemical Formula 96]

[1099]

[1100] The title compound (136 mg, 0.576 mmol, 94% yield) was obtained as a white solid by the same method as in Reference Example 28 using 2-chloroquinoline (100 mg, 0.611 mmol) and (4-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol).

[1101] 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).

[1102] MS (ESI) [M+H] + :236.

[1103] (Example 49) Synthesis of (4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol (new compound):

[1104] [Chemical Formula 97]

[1105]

[1106] Using (4-(Quinolin-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 light yellow oil by the same method as Example 26.

[1107] 1H-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).

[1108] MS (ESI) [M+H] + :240.

[1109] (Reference Example 33) Synthesis of 4-(quinolin-2-yl)isothiazole:

[1110] [Chemical Formula 98]

[1111]

[1112] The title compound (122 mg, 0.574 mmol, yield 94%) was obtained as a yellow solid by the same method as Reference Example 6 using 2-chloroquinoline (100 mg, 0.611 mmol) and isothiazol-4-ylboronic acid (118 mg, 0.917 mmol).

[1113] 1 H-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).

[1114] MS (ESI) [M+H] + :213.

[1115] (Example 50) Synthesis of 4-(1,2,3,4-tetrahydroquinolin-2-yl)isothiazole:

[1116] [Chemical Formula 99]

[1117]

[1118] Using 4-(quinolin-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 oil by the same method as in Example 26.

[1119] 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).

[1120] MS (ESI) [M+H] + :217.

[1121] (Reference Example 34) Synthesis of (2-phenylquinolin-5-yl)methanol:

[1122] [Chemical Formula 100]

[1123]

[1124] Methyl 2-phenylquinoline-5-carboxylate (60.0 mg, 0.228 mmol) was dissolved in toluene (1 mL) under an argon atmosphere, and a 1.0 mol / L diisobutylaluminum hydride / hexane solution (0.912 mL, 0.912 mmol) was added at -78°C, and stirred at -78°C for 1.5 hours. After the reaction was completed, the reaction mixture was warmed to 0°C, and a saturated aqueous solution of potassium sodium tartrate was added to the reaction mixture, stirred at room temperature for 16 hours, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, 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 (51.7 mg, 0.220 mmol, yield 96%) as a white solid.

[1125] 1H-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).

[1126] MS (ESI) [M+H] + :236.

[1127] (Example 51) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinolin-5-yl)methanol (new compound):

[1128] [Chemical Formula 101]

[1129]

[1130] Using (2-phenylquinolin-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 light yellow solid by the same method as Example 26.

[1131] 1 H-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).

[1132] MS (ESI) [M+H] + :240.

[1133] (Example 52) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinolin-7-yl)methanol (new compound):

[1134] [Chemical Formula 102]

[1135]

[1136] Using (2-phenylquinolin-7-yl)methanol (40.0 mg, 0.170 mol), the title compound (hereinafter referred to as the compound of Example 52) was obtained as a colorless amorphous substance (38.8 mg, 0.162 mmol, yield 95%) by the same method as in Example 26.

[1137] 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).

[1138] MS (ESI) [M+H] + :240.

[1139] (Example 53) Synthesis of 2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline:

[1140] [Chemical Formula 103]

[1141]

[1142] Using 2-(pyridin-2-yl)quinoline (30.0 mg, 0.145 mmol), the title compound (hereinafter referred to as the compound of Example 53) was obtained as a pale yellow amorphous substance (25.3 mg, 0.120 mmol, yield 83%) by the same method as in Example 26.

[1143] 1H-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).

[1144] MS (ESI) [M+H] + :211.

[1145] (Reference Example 35) Synthesis of 2-(2-chloroquinolin-6-yl)propan-2-ol:

[1146] [Chemical Formula 104]

[1147]

[1148] 2-Chloroquinoline-6-carboxylic acid methyl ester (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 at -78 ° C under an argon atmosphere and stirred at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride 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 combined, washed with saturated brine, dried over anhydrous sodium sulfate, 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 (75.5 mg, 0.341 mmol, yield 75%) as a white solid.

[1149] 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).

[1150] MS (ESI) [M+H] + :222.

[1151] (Reference Example 36) Synthesis of 2-(2-phenylquinolin-6-yl)propan-2-ol:

[1152] [Chemical Formula 105]

[1153]

[1154] Using 2-(2-chloroquinolin-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, yield 99%) was obtained as a white solid by the same method as Reference Example 28.

[1155] 1 H-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).

[1156] MS (ESI) [M+H] + :264.

[1157] (Example 54) Synthesis of 6-isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[1158] [Chemical Formula 106]

[1159]

[1160] Using 2-(2-phenylquinolin-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 substance by the same method as Example 4.

[1161] 1H-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).

[1162] MS (ESI) [M+H] + :252.

[1163] (Reference Example 37) Synthesis of 2-phenylquinolin-6-ol:

[1164] [Chemical Formula 107]

[1165]

[1166] The title compound (47.0 mg, 0.212 mmol, yield 76%) was obtained as a white solid by the same method as Reference Example 28 using 2-chloroquinolin-6-ol (50.0 mg, 0.278 mmol).

[1167] 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).

[1168] MS (ESI) [M+H] + :222.

[1169] (Example 55) Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinolin-6-ol:

[1170] [Chemical Formula 108]

[1171]

[1172] Using 2-phenylquinolin-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) was obtained as a colorless amorphous substance (20.3 mg, 90.1 μmol, yield >99%) by the same method as in Example 4.

[1173] 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).

[1174] MS (ESI) [M+H] + :226.

[1175] (Reference Example 38) Synthesis of methyl 2-phenylquinoline-6-carboxylate:

[1176] [Chemical Formula 109]

[1177]

[1178] The title compound (91.0 mg, 0.346 mmol, yield 77%) was obtained as a white solid by the same method as Reference Example 28 using methyl 2-chlorophenylquinoline-6-carboxylate (100 mg, 0.451 mmol).

[1179] 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).

[1180] MS (ESI) [M+H] + :264.

[1181] (Example 56) Synthesis of methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (new compound):

[1182] [Chemical Formula 110]

[1183]

[1184] 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 oil by the same method as in Example 26.

[1185] 1 H-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).

[1186] MS (ESI) [M+H] + :268.

[1187] (Example 57) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)propan-2-ol (new compound):

[1188] [Chemical Formula 111]

[1189]

[1190] The methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (25.0 mg, 93.5 μmol) synthesized in Example 56 was dissolved in THF (1 mL), and a 1 mol / L methylmagnesium bromide / THF solution (0.374 mL, 0.374 mmol) was added at 0°C under an argon atmosphere, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer preparative chromatography (hexane / ethyl acetate) to give the title compound (hereinafter referred to as the compound of Example 57) (3.70 mg, 13.8 μmol, yield 15%) as a light yellow amorphous form.

[1191] 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).

[1192] MS (ESI) [M+H] + :268.

[1193] (Example 58) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol (new compound):

[1194] [Chemical Formula 112]

[1195]

[1196] After dissolving methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (38.0 mg, 0.142 mmol) synthesized in Example 56 in toluene (2.0 mL), 1.01 mol / L diisobutylaluminum hydride / toluene solution (0.426 mL, 0.426 mmol) was slowly added dropwise at -78°C under an argon atmosphere. The reaction mixture was then slowly warmed to room temperature and stirred for 6 hours. After the reaction was completed, an aqueous solution of potassium sodium tartrate (8 mL) was added and stirred at room temperature overnight. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, 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 58) (25.6 mg, 0.107 mmol, yield 75%) as a colorless transparent oil.

[1197] 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=5.4Hz).

[1198] MS (ESI) [M+H] + :240.

[1199] (Example 59) Synthesis of 4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine (new compound):

[1200] [Chemical Formula 113]

[1201]

[1202] (2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol (30.0 mg, 0.125 mmol) synthesized in Example 58 was dissolved in dichloromethane (1.3 mL), and then morpholine (55 μL, 0.63 mmol), triphenylphosphine (39.5 mg, 0.150 mmol), and iodine (38.2 mg, 0.150 mmol) were added, followed by stirring 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, 54% yield) as a colorless, transparent oil.

[1203] 1 H-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).

[1204] MS (ESI) [M-morpholine] + :222.

[1205] (Reference Example 39) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetonitrile:

[1206] [Chemical formula 114]

[1207]

[1208] After dissolving (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol (100 mg, 0.418 mmol) synthesized in Example 58 in THF (4.2 mL), 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 the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (64.2 mg, 0.259 mmol, 62% yield) as a colorless transparent oil.

[1209] 1 H-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).

[1210] MS (ESI) [M+H] + :249.

[1211] (Example 60) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1212] [Chemical Formula 115]

[1213]

[1214] 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-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), and 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. 30% hydrogen peroxide solution (43 μL, 0.55 mmol) was further added, and the mixture was stirred at room temperature for 1 hour. 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (hereinafter referred to as the compound of Example 60) (59.0 mg, 0.223 mmol, yield 89%) as a white solid.

[1215] 1 H-NMR (CDCl3) δ: 7.38-7.28 (5H, m), 6.91-6.89 (2H, m), 6.53 (1H, d, J = 8.7Hz), 5.48 (1H, brs), 5.41 (1H, brs), 4.44 (1H, dd, J = 9. 4, 3.0Hz), 4.09 (1H, brs), 3.46 (2H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.5, 4.8Hz), 2.14-2.10 (1H, m), 2.02-1.95 (1H, m).

[1216] MS (ESI) [M+H] + :267.

[1217] (Reference Example 40) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid:

[1218] [Chemical Formula 116]

[1219]

[1220] 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (57.0 mg, 0.214 mmol) synthesized in Example 60 was suspended in ethanol (1.05 mL) / water (1.05 mL), and potassium hydroxide (240 mg, 4.28 mmol) was added, followed by heating under reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 6 mol / L hydrochloric acid was added to the crude product to adjust the pH to 5, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (40.9 mg, 0.152 mmol, 71% yield) as a light yellow oil.

[1221] 1 H-NMR (CDCl3) δ: 7.39-7.29 (5H, m), 6.94-6.91 (2H, m), 6.51 (1H, d, J = 8.7Hz), 4.43 (1H, dd, J = 9.1, 3.2H z), 3.52 (2H, s), 2.95-2.87 (1H, m), 2.72 (1H, dt, J=16.3, 4.7Hz), 2.14-2.07 (1H, m), 2.02-1.93 (1H, m).

[1222] MS (ESI) [M+H] + :268.

[1223] (Example 61) Synthesis of N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1224] [Chemical Formula 117]

[1225]

[1226] 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid (20.0 mg, 0.0748 mmol) synthesized in Reference Example 40 was dissolved in DMF (0.75 mL), and 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-oxide hexafluorophosphate (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 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 obtained 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 61) (9.7 mg, 0.030 mmol, yield 40%) as a colorless transparent oil.

[1227] 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).

[1228] MS (ESI) [M+H] + :323.

[1229] (Example 62) Synthesis of 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (new compound):

[1230] [Chemical Formula 118]

[1231]

[1232] 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid (20.0 mg, 0.0748 mmol) synthesized in Reference Example 40 was dissolved in DMF (0.75 mL), and N,N-diisopropylethylamine (104 μL, 0.599 mmol), azetidin-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 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 obtained crude product 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.

[1233] 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).

[1234] MS (ESI) [M+H] + :323.

[1235] (Reference Example 41) Synthesis of 2-phenylquinoline-6-carboxylic acid:

[1236] [Chemical Formula 119]

[1237]

[1238] The methyl 2-phenylquinoline-6-carboxylate (0.279 g, 1.06 mmol) synthesized in Reference Example 38 was dissolved in a THF / methanol solution (10 mL), and a 1 mol / L aqueous sodium hydroxide solution (2.12 mL, 2.12 mmol) was added and stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. 1 mol / L hydrochloric acid (4 mL) was added to the obtained 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, 93% yield) as a white solid.

[1239] 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).

[1240] MS (ESI) [M+H] + :250.

[1241] (Reference Example 42) Synthesis of tert-butyl (2-phenylquinolin-6-yl)carbamate:

[1242] [Chemical Formula 120]

[1243]

[1244] 2-Phenylquinoline-6-carboxylic acid (0.224 g, 0.898 mmol) synthesized in Reference Example 41 was dissolved in tert-butanol (4.0 mL), and triethylamine (0.189 mL, 1.35 mmol) and diphenylphosphoryl azide (0.254 mL, 1.17 mmol) were added. The mixture was stirred at 80°C for 5 hours. After completion of the reaction, 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 (0.269 g, 0.840 mmol, 94% yield) as a white solid.

[1245] 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).

[1246] MS (ESI) [M+H] + :321.

[1247] (Example 63) Synthesis of tert-butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate (new compound):

[1248] [Chemical Formula 121]

[1249]

[1250] Using tert-butyl (2-phenylquinolin-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.

[1251] 1 H-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).

[1252] MS (ESI) [M+H] + :325.

[1253] (Example 64) Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinolin-6-amine dihydrochloride (new compound):

[1254] [Chemical Formula 122]

[1255]

[1256] tert-Butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate (25.0 mg, 0.0771 mmol) synthesized in Example 63 was dissolved in ethyl acetate (1.0 mL). A 4 mol / L hydrogen chloride / ethyl acetate solution (0.50 mL, 1.54 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere for 16 hours. After completion of the reaction, the precipitated solid was collected by filtration and washed with ethyl acetate to obtain the title compound (hereinafter referred to as the compound of Example 64) as a white solid (20.4 mg, 0.0784 mmol, 99% yield).

[1257] 1H-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).

[1258] MS (ESI) [M+H] + :225.

[1259] (Reference Example 43) Synthesis of 5-(quinolin-2-yl)oxazole:

[1260] [Chemical formula 123]

[1261]

[1262] After suspending quinoline-2-carboxaldehyde (200 mg, 1.27 mmol) and potassium carbonate (352 mg, 2.55 mmol) in methanol (6.3 mL), tosylmethyl isocyanide (273 mg, 1.40 mmol) was added and heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and water was added to the reaction mixture. The solution obtained by concentration under reduced pressure was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and 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.

[1263] 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).

[1264] MS (ESI) [M+H] + :197.

[1265] (Example 65) Synthesis of 5-(1,2,3,4-tetrahydroquinolin-2-yl)oxazole:

[1266] [Chemical Formula 124]

[1267]

[1268] Using 5-(quinolin-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 Example 26.

[1269] 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).

[1270] MS (ESI) [M+H] + :201.

[1271] (Reference Example 44) Synthesis of 5-fluoro-2-phenylquinoline:

[1272] [Chemical Formula 125]

[1273]

[1274] To a solution of (2-amino-6-fluorophenyl)methanol (100 mg, 0.709 mmol) in 1,4-dioxane (2 mL) were added acetophenone (0.165 mL, 1.42 mmol) and potassium tert-butoxide (119 mg, 1.06 mmol), and the mixture was stirred at 80°C for 1 hour. After completion of the reaction, the reaction mixture was filtered through 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, 47% yield) as a pale yellow solid.

[1275] 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).

[1276] MS (ESI) [M+H] + :224.

[1277] (Example 66) Synthesis of 5-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[1278] [Chemical Formula 126]

[1279]

[1280] 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 oil by the same method as in Example 26.

[1281] 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).

[1282] MS (ESI) [M+H] + :228.

[1283] (Reference Example 45) Synthesis of 5-chloro-2-phenylquinoline:

[1284] [Chemical Formula 127]

[1285]

[1286] 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 by the same method as Reference Example 44.

[1287] 1 H-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).

[1288] MS (ESI) [M+H] + :240.

[1289] (Example 67) Synthesis of 5-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1290] [Chemical Formula 128]

[1291]

[1292] 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) was obtained as a pale yellow oil (71.1 mg, 0.292 mmol, yield 81%) by the same method as in Example 26.

[1293] 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).

[1294] MS (ESI) [M+H] + :244.

[1295] (Reference Example 46) Synthesis of 7-fluoro-2-phenylquinoline:

[1296] [Chemical Formula 129]

[1297]

[1298] 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 by the same method as Reference Example 44.

[1299] 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).

[1300] MS (ESI) [M+H] + :224.

[1301] (Example 68) Synthesis of 7-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1302] [Chemical Formula 130]

[1303]

[1304] 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 oil by the same method as in Example 26.

[1305] 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 = 10.6, 2.5Hz) =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).

[1306] MS (ESI) [M+H] + :228.

[1307] (Reference Example 47) Synthesis of 7-chloro-2-phenylquinoline:

[1308] [Chemical Formula 131]

[1309]

[1310] 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 by the same method as Reference Example 44.

[1311] 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).

[1312] MS (ESI) [M+H] +:240.

[1313] (Example 69) Synthesis of 7-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1314] [Chemical Formula 132]

[1315]

[1316] 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 oil by the same method as in Example 26.

[1317] 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).

[1318] MS (ESI) [M+H] + :244.

[1319] (Reference Example 48) Synthesis of (2-amino-5-bromophenyl)methanol:

[1320] [Chemical Formula 133]

[1321]

[1322] After dissolving (2-aminophenyl)methanol (2.80 g, 22.7 mmol) in DMF (11.3 mL), N-bromosuccinimide (4.05 g, 22.7 mmol) was added three times at 5-minute intervals under ice cooling, and the mixture was stirred for 2 hours under ice cooling. After completion of the reaction, the reaction mixture was poured into ice water (56 mL). The generated solid was filtered. 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.

[1323] 1H-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).

[1324] MS (ESI) [M+H] + :202.

[1325] (Reference Example 49) Synthesis of 6-bromo-2-phenylquinoline:

[1326] [Chemical Formula 134]

[1327]

[1328] After dissolving (2-amino-5-bromophenyl)methanol (2.46 g, 12.2 mmol) synthesized in Reference Example 48 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 stirred at 80 ° C for 4 hours. Ice and saturated aqueous ammonium chloride solution were 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 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.

[1329] 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).

[1330] MS (ESI) [M+H] + :284.

[1331] (Example 70) Synthesis of 6-bromo-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1332] [Chemical Formula 135]

[1333]

[1334] 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.

[1335] 1 H-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).

[1336] MS (ESI) [M+H] + :288.

[1337] (Reference Example 50) Synthesis of 3-(2-phenylquinolin-6-yl)oxetane-3-ol:

[1338] [Chemical Formula 136]

[1339]

[1340] 6-Bromo-2-phenylquinoline (100 mg, 0.352 mmol) synthesized in Reference Example 49 was dissolved in THF (no stabilizer added, 3.5 mL), and 1.67 mol / L n-butyllithium / hexane solution (0.25 mL, 0.42 mmol) was added dropwise at -78 ° C for 3 minutes. Oxetane-3-one (26 μL, 0.026 mmol) was added thereto, and the temperature was raised from -78 ° C to room temperature over 15 minutes, and further stirred at room temperature for 15 minutes. Under ice cooling, saturated aqueous ammonium chloride 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 obtained 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.

[1341] 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).

[1342] MS (ESI) [M+H] + :278.

[1343] (Example 71) Synthesis of 3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)oxetane-3-ol (new compound):

[1344] [Chemical Formula 137]

[1345]

[1346] 3-(2-phenylquinolin-6-yl)oxetane-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 acetic acid (44 μL, 0.76 mmol) and platinum (IV) oxide (7.0 mg, 0.031 mmol) were added. Under a hydrogen atmosphere, the mixture was vigorously stirred at room temperature for 16 hours. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give 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.

[1347] 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).

[1348] MS (ESI) [M+H] + :282.

[1349] (Reference Example 51) Synthesis of 2-phenyl-6-(piperidin-1-yl)quinoline:

[1350] [Chemical Formula 138]

[1351]

[1352] 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(diphenylphosphino)-1,1'-binaphthyl (26.3 mg, 42.2 μmol) synthesized in Reference Example 49 were suspended in 1,4-dioxane (2.10 mL), and piperidine (69.7 μL, 0.633 mmol) was added and stirred at 100 ° C. for 15 hours under an argon atmosphere. After completion of the reaction, water was added to the reaction mixture and extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, 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 (27.3 mg, 94.7 μmol, yield 45%) as a yellow solid.

[1353] 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).

[1354] MS (ESI) [M+H] + :289.

[1355] (Example 72) Synthesis of 2-phenyl-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[1356] [Chemical Formula 139]

[1357]

[1358] 2-Phenyl-6-(piperidin-1-yl)quinoline (27.3 mg, 94.7 μmol) synthesized in Reference Example 51 was dissolved in dioxane (1.4 mL), and 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 room temperature under an argon atmosphere for 17 hours. Subsequently, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (50.4 mg, 0.199 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere for 3 hours. Further, 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 completion of the reaction, the reaction mixture 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 72) (6.00 mg, 20.5 μmol, yield 22%) as a brown solid.

[1359] 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).

[1360] MS (ESI) [M+H] + :293.

[1361] (Reference Example 52) Synthesis of 1,1-diphenyl-N-(2-phenylquinolin-6-yl)formanimine:

[1362] [Chemical Formula 140]

[1363]

[1364] 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 for 10 minutes under an argon atmosphere. Triethylamine (1.47 μL, 10.6 μmol) was then added, and the mixture was stirred at room temperature for 10 minutes under an argon atmosphere. Furthermore, a dioxane solution (0.50 mL) of 6-bromo-2-phenyl-1,2,3,4-tetrahydroquinoline (100 mg, 0.352 mmol) and benzophenone imine (76.5 mg, 0.422 mmol) synthesized in Reference Example 49 was added, and the mixture was stirred at 100°C under an argon atmosphere for 17 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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 (108 mg, 0.280 mmol, 80% yield) as a yellow amorphous substance.

[1365] 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).

[1366] MS (ESI) [M+H] + :365.

[1367] (Reference Example 53) Synthesis of 2-phenylquinolin-6-amine:

[1368] [Chemical Formula 141]

[1369]

[1370] 1,1-diphenyl-N-(2-phenylquinolin-6-yl)methanimine (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 completed, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, 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 (47.3 mg, 0.215 mmol, yield 77%) as a light orange solid.

[1371] 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).

[1372] MS (ESI) [M+H] + :221.

[1373] (Reference Example 54) Synthesis of N-(2-phenylquinolin-6-yl)acetamide:

[1374] [Chemical Formula 142]

[1375]

[1376] 2-Phenylquinolin-6-amine (13.5 mg, 61.3 μmol) synthesized in Reference Example 53 was dissolved in pyridine (0.5 mL), and acetic anhydride (6.36 μL, 67.4 μmol) was added. The mixture was stirred at room temperature for 30 minutes. After completion of the reaction, 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.

[1377] 1 H-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).

[1378] MS (ESI) [M+H]+ :263.

[1379] (Example 73) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1380] [Chemical Formula 143]

[1381]

[1382] Using N-(2-phenylquinolin-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 form by the same method as Example 4.

[1383] 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).

[1384] MS (ESI) [M+H] + :267.

[1385] (Reference Example 55) Synthesis of N-(2-phenylquinolin-6-yl)trimethylacetamide:

[1386] [Chemical formula 144]

[1387]

[1388] 2-Phenylquinolin-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 completion of the reaction, 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, 94% yield) as a white solid.

[1389] 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).

[1390] MS (ESI) [M+H] + :305.

[1391] (Example 74) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)trimethylacetamide (new compound):

[1392] [Chemical Formula 145]

[1393]

[1394] Using N-(2-phenylquinolin-6-yl)trimethylacetamide (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 Example 26.

[1395] 1 H-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).

[1396] MS (ESI) [M+H] + :309.

[1397] (Reference Example 56) Synthesis of N-(2-phenylquinolin-6-yl)methanesulfonamide:

[1398] [Chemical Formula 146]

[1399]

[1400] 2-Phenylquinolin-6-amine (40.0 mg, 0.182 mmol) synthesized in Reference Example 53 was dissolved in dichloromethane (1.8 mL), cooled to 0°C, and triethylamine (38.0 μL, 0.272 mmol) and methanesulfonyl chloride (14.1 μL, 0.182 mmol) were added. The mixture was stirred at 0°C for 2 hours under an argon atmosphere. Subsequently, 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 under an argon atmosphere for 18 hours. 8 mol / L aqueous sodium hydroxide solution (230 μL, 1.81 mmol) was then 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 completed, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed 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.

[1401] 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).

[1402] MS (ESI) [M+H] + :299.

[1403] (Example 75) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide (new compound):

[1404] [Chemical Formula 147]

[1405]

[1406] Using N-(2-phenylquinolin-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.

[1407] 1H-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).

[1408] MS (ESI) [M+H] + :303.

[1409] (Reference Example 57) Synthesis of 1-(tert-butyl)-3-(2-phenylquinolin-6-yl)urea:

[1410] [Chemical Formula 148]

[1411]

[1412] 2-Phenylquinolin-6-amine (40.0 mg, 0.182 mmol) and potassium carbonate (201 mg, 1.45 mmol) synthesized in Reference Example 53 were suspended in acetonitrile (1.8 mL), tert-butyl isocyanate (0.150 mL, 1.27 mmol) was added, and the mixture was stirred at 85 ° C for 2 hours under an argon atmosphere. Tert-butyl isocyanate (0.150 mL, 1.27 mL) was further added, and the mixture was stirred at 85 ° C for 16 hours under an argon atmosphere. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, 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 (58.0 mg, 0.182 mmol, yield 100%) as a white solid.

[1413] 1 H-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).

[1414] MS (ESI) [M+H] + :320.

[1415] (Example 76) Synthesis of 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea (new compound):

[1416] [Chemical Formula 149]

[1417]

[1418] Using 1-(tert-butyl)-3-(2-phenylquinolin-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 in a purple amorphous form by the same method as in Example 4.

[1419] 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).

[1420] MS (ESI) [M+H] + :324.

[1421] (Reference Example 58) Synthesis of 1-(2-phenylquinolin-6-yl)urea:

[1422] [Chemical Formula 150]

[1423]

[1424] 2-Phenylquinolin-6-amine (40.0 mg, 0.182 mmol) synthesized in Reference Example 53 was suspended in THF (2.2 mL), trichloroacetyl isocyanate (29.6 μL, 0.250 mmol) was added, and the mixture was stirred at 0°C for 1 hour under an argon atmosphere. Subsequently, methanol / triethylamine (2.2 mL / 1.1 mL) was added and stirred at room temperature for 2 hours. After completion of the reaction, the filtrate was concentrated under reduced pressure. The obtained 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.

[1425] 1H-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).

[1426] MS (ESI) [M+H] + :264.

[1427] (Example 77) Synthesis of 1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea (new compound):

[1428] [Chemical Formula 151]

[1429]

[1430] Using 1-(2-phenylquinolin-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 substance by the same method as Example 4.

[1431] 1 H-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).

[1432] MS (ESI) [M+H] + :268.

[1433] (Reference Example 59) Synthesis of 3,3-dimethyl-N-(2-phenylquinolin-6-yl)butanamide:

[1434] [Chemical formula 152]

[1435]

[1436] 2-Phenylquinolin-6-amine (40.0 mg, 0.182 mmol) synthesized in Reference Example 53 was dissolved in dichloromethane (0.90 mL), 3,3-dimethylbutyryl chloride (26.5 μL, 0.191 mmol) was added, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Tert-butyl isocyanate (0.150 mL, 1.27 mL) was further added, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. After the reaction was completed, water was added to the reaction mixture and extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, 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 (53.7 mg, 0.169 mmol, yield 93%) as a white solid.

[1437] 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).

[1438] MS (ESI) [M+H] + :319.

[1439] (Example 78) Synthesis of 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide (new compound):

[1440] [Chemical Formula 153]

[1441]

[1442] Using 3,3-dimethyl-N-(2-phenylquinolin-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 substance by the same method as Example 4.

[1443] 1H-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).

[1444] MS (ESI) [M+H] + :323.

[1445] (Reference Example 60) Synthesis of 8-chloro-2-phenylquinoline:

[1446] [Chemical formula 154]

[1447]

[1448] 2-Chloroaniline (0.325 mL, 3.91 mmol) and cinnamaldehyde (0.493 mmol, 3.91 mmol) were dissolved in DMSO (2 mL), palladium (II) acetate (87.9 mg, 0.391 mmol) was added, and the mixture was stirred at 130 ° C for 18 hours under an oxygen atmosphere. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, 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 (109 mg, 0.456 mmol, yield 12%) as a light yellow solid.

[1449] 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).

[1450] MS (ESI) [M+H] + :240.

[1451] (Example 79) Synthesis of 8-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[1452] [Chemical Formula 155]

[1453]

[1454] 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 oil by the same method as in Example 26.

[1455] 1 H-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).

[1456] MS (ESI) [M+H] + :244.

[1457] (Reference Example 61) Synthesis of 8-fluoro-2-phenylquinoline:

[1458] [Chemical formula 156]

[1459]

[1460] The title compound (68.9 mg, 0.309 mmol, yield 7%) was obtained as a pale yellow solid by the same method as Reference Example 60 using 2-fluoroaniline (0.325 mL, 4.50 mmol) and cinnamaldehyde (0.566 mmol, 4.50 mmol).

[1461] 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).

[1462] MS (ESI) [M+H] + :224.

[1463] (Example 80) Synthesis of 8-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[1464] [Chemical Formula 157]

[1465]

[1466] 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 oil by the same method as in Example 26.

[1467] 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).

[1468] MS (ESI) [M+H] + :228.

[1469] (Reference Example 62) Synthesis of 2-phenyl-6-(trifluoromethoxy)quinoline:

[1470] [Chemical formula 158]

[1471]

[1472] The title compound (70.1 mg, 0.242 mmol, yield 9%) was obtained as a pale yellow solid by the same method as Reference Example 60 using 4-(trifluoromethoxy)aniline (0.325 mL, 2.82 mmol) and cinnamaldehyde (0.355 mmol, 2.82 mmol).

[1473] 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).

[1474] MS (ESI) [M+H] + :290.

[1475] (Example 81) Synthesis of 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline (new compound):

[1476] [Chemical Formula 159]

[1477]

[1478] 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 light yellow oil by the same method as Example 26.

[1479] 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).

[1480] MS (ESI) [M+H] + :294.

[1481] (Reference Example 63) Synthesis of 6-fluoro-2-phenylquinoline:

[1482] [Chemical formula 160]

[1483]

[1484] The title compound (48.2 mg, 0.216 mmol, yield 5%) was obtained as a pale yellow solid by the same method as Reference Example 60 using 4-fluoroaniline (0.431 mL, 4.50 mmol) and cinnamaldehyde (0.566 mmol, 4.50 mmol).

[1485] 1 H-NMR (CDCl3) δ: 8.20-8.13 (3H, m), 7.91-7.89 (2H, m), 7.57-7.44 (5H, m).

[1486] MS (ESI) [M+H] + :224.

[1487] (Example 82) Synthesis of 6-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1488] [Chemical Formula 161]

[1489]

[1490] 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 oil by the same method as in Example 26.

[1491] 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).

[1492] MS (ESI) [M+H] + :228.

[1493] (Reference Example 64) Synthesis of 6-chloro-2-phenylquinoline:

[1494] [Chemical formula 162]

[1495]

[1496] The title compound (28.0 mg, 0.117 mmol, yield 15%) was obtained as an orange solid by the same method as in Reference Example 60 using 4-chloroaniline (100 mg, 0.784 mmol) and (E)-cinnamyl alcohol (105 mg, 0.784 mmol).

[1497] 1 H-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).

[1498] MS (ESI) [M+H] +:240.

[1499] (Example 83) Synthesis of 6-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1500] [Chemical formula 163]

[1501]

[1502] 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) was obtained as a pale yellow oil (28.0 mg, 0.114 mmol, yield 98%) by the same method as in Example 26.

[1503] 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).

[1504] MS (ESI) [M+H] + :244.

[1505] (Reference Example 65) Synthesis of 2-phenyl-6-(trifluoromethyl)quinoline:

[1506] [Chemical formula 164]

[1507]

[1508] The title compound (42.0 mg, 0.154 mmol, yield 25%) was obtained as an orange solid by the same method as Reference Example 60 using 4-(trifluoromethyl)aniline (76.9 μL, 0.621 mmol) and (E)-cinnamyl alcohol (83.3 mg, 0.621 mmol).

[1509] 1H-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).

[1510] MS (ESI) [M+H] + :274.

[1511] (Example 84) Synthesis of 2-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (new compound):

[1512] [Chemical Formula 165]

[1513]

[1514] 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 oil by the same method as in Example 26.

[1515] 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).

[1516] MS (ESI) [M+H] + :278.

[1517] (Reference Example 66) Synthesis of 6,7-difluoro-2-phenylquinoline:

[1518] [Chemical Formula 166]

[1519]

[1520] 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 using 3,4-difluoroaniline (150 mg, 1.16 mmol) and (E)-cinnamyl alcohol (156 mg, 1.16 mmol).

[1521] 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).

[1522] MS (ESI) [M+H] + :242.

[1523] (Example 85) Synthesis of 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[1524] [Chemical Formula 167]

[1525]

[1526] 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.

[1527] 1 H-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).

[1528] MS (ESI) [M+H] + :246.

[1529] (Reference Example 67) Synthesis of 6,8-difluoro-2-phenylquinoline:

[1530] [Chemical Formula 168]

[1531]

[1532] The title compound (13.5 mg, 56.0 μmol, yield 5%) was obtained as a yellow solid by the same method as in Reference Example 60 using 2,4-difluoroaniline (150 mg, 1.16 mmol) and (E)-cinnamyl alcohol (156 mg, 1.16 mmol).

[1533] 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).

[1534] MS (ESI) [M+H] + :242.

[1535] (Example 86) Synthesis of 6,8-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[1536] [Chemical Formula 169]

[1537]

[1538] 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) was obtained as an orange solid (7.70 mg, 31.4 μmol, yield 56%) by the same method as in Example 26.

[1539] 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).

[1540] MS (ESI) [M+H] + :246.

[1541] (Reference Example 68) Synthesis of 4-(6-nitroquinolin-2-yl)benzonitrile:

[1542] [Chemical Formula 170]

[1543]

[1544] 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 heated with stirring at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water, and the resulting solid was filtered to obtain the title compound (647 mg, 2.35 mmol, 70% yield) as a gray solid.

[1545] 1 H-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).

[1546] MS (ESI) [M+H] + :276.

[1547] (Reference Example 69) Synthesis of 4-(6-aminoquinolin-2-yl)benzonitrile:

[1548] [Chemical Formula 171]

[1549]

[1550] After dissolving 4-(6-nitroquinolin-2-yl)benzonitrile (100 mg, 0.363 mmol) synthesized in Reference Example 68 in acetic acid (3.6 mL), iron powder (81.2 mg, 1.45 mmol) was added and stirred at 50°C for 14 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture to reach pH 12, and then extracted with ethyl acetate. After the generated reddish-brown solid was removed by filtration, the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product 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.

[1551] 1H-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).

[1552] MS (ESI) [M+H] + :246.

[1553] (Reference Example 70) Synthesis of 1-(tert-butyl)-3-(2-(4-cyanophenyl)quinolin-6-yl)urea:

[1554] [Chemical formula 172]

[1555]

[1556] 4-(6-aminoquinolin-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), and 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 extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (amino silica gel, chloroform / methanol) to give the title compound (37.2 mg, 0.107 mmol, yield 88%) as a light orange solid.

[1557] 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).

[1558] MS (ESI) [M+H] + :345.

[1559] (Reference Example 71) Synthesis of 4-(6-(3-(tert-butyl)ureido)quinolin-2-yl)benzamide:

[1560] [Chemical formula 173]

[1561]

[1562] 1-(tert-Butyl)-3-(2-(4-cyanophenyl)quinolin-6-yl)urea (37.0 mg, 0.107 mmol) synthesized in Reference Example 70 was dissolved in THF (1.1 mL), and 1 mol / L aqueous sodium hydroxide solution (60 μL, 0.453 mmol) and 30% aqueous hydrogen peroxide (37 μL, 0.453 mmol) were added, and the mixture was stirred at room temperature for 3 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was slurry washed (hexane / ethyl acetate) to give the title compound (32.4 mg, 0.0888 mmol, yield 83%) as a light yellow solid.

[1563] 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).

[1564] MS (ESI) [M+H] + :363.

[1565] (Example 87) Synthesis of 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1566] [Chemical formula 174]

[1567]

[1568] 4-(6-(3-(tert-butyl)ureido)quinolin-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 for 48 hours under a normal pressure hydrogen atmosphere. After completion of the reaction, nitrogen substitution was performed, and the reaction mixture was filtered using celite. The filtrate was concentrated under reduced pressure, and the obtained 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.

[1569] 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).

[1570] MS (ESI) [M+H] + :288.

[1571] (Example 88) (2R * ,4R * Synthesis of methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylate (new compound):

[1572] [Chemical Formula 175]

[1573]

[1574] Methyl 2-phenylquinoline-4-carboxylate (300 mg, 1.14 mmol) was dissolved in THF / ethanol (1 / 1, v / v, 5.7 mL), and 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 for 23 hours under a normal pressure hydrogen atmosphere. After completion of the reaction, nitrogen was purged and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (hereinafter referred to as the compound of Example 88) (274 mg, 1.03 mmol, 90% yield) as a light yellow oil.

[1575] 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).

[1576] MS (ESI) [M+H] + :268.

[1577] (Example 89) ((2R ＊ , 4R ＊ Synthesis of 2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl)methanol (new compound):

[1578] [Chemical Formula 176]

[1579]

[1580] The (2R * ,4R *)-2-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylic acid methyl ester (70.0 mg, 0.262 mmol) was dissolved in THF (2.6 mL), and 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 completed, a saturated sodium potassium tartrate aqueous solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The obtained reaction mixture was extracted with ethyl acetate. The organic layers were combined, 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 give the title compound (hereinafter referred to as the compound of Example 89) (32.3 mg, 0.135 mmol, yield 52%) as a white solid.

[1581] 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).

[1582] MS (ESI) [M+H] + :240.

[1583] (Reference Example 72) Synthesis of 4-methyl-2-phenylquinoline:

[1584] [Chemical Formula 177]

[1585]

[1586] The title compound (360 mg, 1.64 mmol, 97%) was obtained as a colorless oil by the same method as in Reference Example 6 using 2-chloro-4-methylquinoline (300 mg, 1.69 mmol) and phenylboronic acid (227 mg, 1.86 mmol).

[1587] 1H-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).

[1588] MS (ESI) [M+H] + :220.

[1589] (Example 90) (2R ＊ , 4R ＊ Synthesis of 4-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1590] [Chemical Formula 178]

[1591]

[1592] 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 light yellow oil by the same method as Example 26.

[1593] 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).

[1594] MS (ESI) [M+H] + :224.

[1595] (Reference Example 73) Synthesis of tert-butyl 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate:

[1596] [Chemical Formula 179]

[1597]

[1598] 2-Phenyl-1,2,3,4-tetrahydroquinoline (30.0 mg, 0.143 mmol) was dissolved in tetrahydrofuran (1 mL), and 1.64 mol / L n-butyllithium / hexane solution (0.140 mL, 0.229 mmol) was added at -78 ° C under an argon atmosphere and stirred for 0.5 hours. Then, a tetrahydrofuran solution (1 mL) of di-tert-butyl dicarbonate (93.9 mg, 0.430 mmol) was added and stirred at room temperature for 16 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture and the organic layer was separated. The obtained aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (amino silica gel, hexane / ethyl acetate) to obtain the title compound (44.3 mg, 0.143 mmol, yield 99%) as a colorless amorphous substance.

[1599] 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).

[1600] (Reference Example 74) Synthesis of tert-butyl 2-methyl-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate:

[1601] [Chemical formula 180]

[1602]

[1603] The tert-butyl 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (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 / hexane solution (73.9 μL, 0.121 mmol) was added at -78 ° C under an argon atmosphere and stirred for 10 minutes. Then, iodomethane (13.4 μL, 0.215 mmol) was added and stirred at room temperature for 16 hours. After the reaction was completed, methanol was added and the reaction mixture was concentrated under reduced pressure. The crude product was purified by thin layer preparative chromatography (silica gel, hexane / ethyl acetate) to obtain the title compound (16.5 mg, 51.0 μmol, yield 71%) as a colorless amorphous substance.

[1604] 1 H-NMR (CDCl3) δ: 7.67 (1H, d, J=8.2Hz), 7.36-7.29 (4H, m), 7.23-7.18 (2H, m), 7.07 (1H, d, J=7.3Hz), 6.97 (1H, dd, J=7.8, 7. 8Hz), 2.71 (1H, ddd, J=14.2, 9.1, 4.6Hz), 2.48 (1H, ddd, J=14.6, 5.9, 2.7Hz), 2.01 (3H, s), 1.95-1.91 (2H, m), 1.17 (9H, s).

[1605] (Example 91) Synthesis of 2-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline:

[1606] [Chemical Formula 181]

[1607]

[1608] The tert-butyl 2-methyl-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (16.5 mg, 51.0 μmol) synthesized in Reference Example 74 was dissolved in dichloromethane (1 mL), trifluoroacetic acid (37.9 μL, 0.510 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (amino silica gel, hexane / ethyl acetate) to obtain the title compound (hereinafter referred to as the compound of Example 91) (8.10 mg, 36.3 μmol, yield 71%) as a colorless amorphous substance.

[1609] 1 H-NMR (CDCl3) δ: 7.40-7.38 (2H, m), 7.31-7.27 (2H, m), 7.21-7.19 (1H, m) , 7.03-7.01 (1H, m), 6.90 (1H, d, J = 7.3Hz), 6.61-6.59 (2H, m), 2.60 (1H, dd d, J=16.5, 4.6, 4.6Hz), 2.32 (1H, ddd, J=16.5, 11.4, 5.5Hz), 2.21 (1H, dd d, J=12.8, 5.0, 5.0Hz), 1.91 (1H, ddd, J=12.8, 11.0, 5.0Hz), 1.58 (3H, s).

[1610] MS (ESI) [M+H] + :224.

[1611] (Reference Example 75) Synthesis of 2-(tert-butyl)-2-methyl 2-phenyl-3,4-dihydroquinoline-1,2(2H)-dicarboxylate:

[1612] [Chemical formula 182]

[1613]

[1614] Under an argon atmosphere, tert-butyl 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (300 mg, 0.970 mmol) synthesized in Reference Example 73 was dissolved in tetrahydrofuran (6 mL), and 1.64 mol / L n-butyllithium / hexane solution (0.887 mL, 1.45 mmol) was added dropwise at -78 ° C. and stirred at -78 ° C for 10 minutes. Then, methyl chloroformate (0.261 mL, 3.39 mmol) was added at -78 ° C. and stirred at room temperature for 18 hours. After completion of the reaction, methanol (1 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (250 mg, 0.681 mmol, 70% yield) as a colorless transparent oil.

[1615] 1 H-NMR (CDCl3) δ: 7.87 (1H, d, J=8.2Hz), 7.61-7.59 (2H, m), 7.32-7.28 (2H, m), 7.23-7.21 (2H, m), 7.03-6.99 (2H, m), 3.78 (3H, s), 2.81 (1H, ddd, J=14.5, 9.9, 3.1Hz), 2.57-2.43 (2H, m), 2.18-2.11 (1H, m), 1.29 (9H, s).

[1616] (Reference Example 76) Synthesis of tert-butyl 2-(hydroxymethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate:

[1617] [Chemical formula 183]

[1618]

[1619] Under an argon atmosphere, 2-phenyl-3,4-dihydroquinoline-1,2(2H)-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (141 mg, 0.383 mmol) synthesized in Reference Example 75 was dissolved in dichloromethane (4.0 mL), and 1 mol / L diisobutylaluminum hydride / hexane solution (1.53 mL, 1.53 mmol) was added at -78 ° C. and stirred at -78 ° C for 4 hours. After the reaction was completed, the reaction mixture was warmed to 0 ° C, saturated potassium sodium tartrate aqueous solution was added, and stirred at room temperature for 16 hours. The organic layer of the obtained mixture was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (95.9 mg, 0.283 mmol, yield 74%) as a colorless transparent oil.

[1620] 1 H-NMR (CDCl3) δ: 7.36-7.33 (5H, m), 7.25-7.23 (1H, m), 7.17-7.15 (1H, m), 7.05 (1H, d, J = 6.9Hz), 6.99 (1H, ddd, J = 7.8, 7.8, 1.4Hz), 4.42 (1H, dd, J = 1 1.4, 7.3Hz), 4.29 (1H, dd, J = 7.1, 4.3Hz), 4.12-4.08 (2H, m), 2.82-2.74 (1 H, m), 2.40 (1H, ddd, J=15.1, 3.7, 3.7Hz), 2.00-1.96 (1H, m), 1.33 (9H, s).

[1621] (Example 92) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)methanol (new compound):

[1622] [Chemical formula 184]

[1623]

[1624] The tert-butyl 2-(hydroxymethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (95.9 mg, 0.283 mmol) synthesized in Reference Example 76 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.104 mL, 1.41 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to give the title compound (hereinafter referred to as the compound of Example 92) (37.0 mg, 0.154 mmol, yield 55%) as a colorless transparent oil.

[1625] 1 H-NMR (CDCl3) δ: 7.39-7.31 (4H, m), 7.25-7.20 (1H, m), 7.07-7.01 (1H, m), 6.89 (1H, d, J = 7.3Hz), 6.70 (1H, dd, J = 8.2, 0.9Hz), 6.61 (1H, ddd, J = 7.3, 7.3, 1.4Hz), 4.70 (1H, brs), 4.42 (1H, s), 3.95 (1H, dd, J = 10.7, 3.0Hz), 3.77 (1H, t, J = 10.5Hz), 2.58 (1H, ddd, J = 16.0, 4.6, 3.2Hz), 2.31 (1H, dd d, J=16.5, 12.8, 5.0Hz), 2.15 (1H, ddd, J=12.8, 5.0, 2.7Hz), 2.01 (1H, ddd, J=12.8, 12.8, 5.0Hz).

[1626] MS (ESI) [M+H] + :240.

[1627] (Example 93) Synthesis of methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (new compound):

[1628] [Chemical formula 185]

[1629]

[1630] Using 2-phenyl-3,4-dihydroquinoline-1,2(2H)-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (100 mg, 0.272 mmol) synthesized in Reference Example 75, the title compound (hereinafter referred to as the compound of Example 93) (70.0 mg, 0.262 mmol, yield 96%) was obtained as a colorless transparent oil by the same method as Example 92.

[1631] 1 H-NMR (CDCl3) δ: 7.51-7.49 (2H, m), 7.36-7.27 (3H, m), 7.06-7.04 (1H, m), 6.93 (1H, dd, J=7.5, 1.1Hz), 6.71 (1H, dd, J =7.8, 0.9Hz), 6.65 (1H, ddd, J = 7.3, 7.3, 0.9Hz), 3.75 (3H, s), 2.72 (1H, ddd, J = 16.0, 5.9, 5.9Hz), 2.52-2.36 (3H, m).

[1632] MS (ESI) [M+H] + :268.

[1633] (Reference Example 77) Synthesis of tert-butyl 2-(2-methoxy-2-oxoethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate:

[1634] [Chemical formula 186]

[1635]

[1636] Using tert-butyl 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (600 mg, 1.94 mmol) and methyl bromoacetate (0.625 mL, 6.79 mmol), the title compound (275 mg, 0.722 mmol, yield 37%) was obtained as a colorless transparent oil by the same method as Reference Example 75.

[1637] 1 H-NMR (CDCl3) δ: 7.55 (1H, d, J=8.2Hz), 7.36-7.27 (4H, m), 7.25-7.23 (1H, m), 7.16 (1H, ddd, J=8.2, 8.2, 1.8Hz), 7.04 (1H, d, J=6.9Hz), 6.95 (1H, ddd, J=7.3, 7.3, 0.9Hz), 3.83 (1H, d, J=1 2.3Hz), 3.54 (3H, s), 3.20 (1H, d, J = 12.3Hz), 2.77-2.73 (1H, m), 2.58 (1H, ddd, J = 13.3, 13.3, 2.7Hz), 2.29 (1H, ddd, J=14.6, 2.7, 2.7Hz), 1.97 (1H, ddd, J=13.3, 3.2, 3.2Hz), 1.19 (9H, s).

[1638] (Example 94) Synthesis of methyl 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)acetate:

[1639] [Chemical Formula 187]

[1640]

[1641] Using tert-butyl 2-(2-methoxy-2-oxoethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (57.4 mg, 0.150 mmol) synthesized in Reference Example 77, the title compound (hereinafter referred to as the compound of Example 94) (34.4 mg, 0.262 mmol, yield 81%) was obtained as a colorless oil by the same method as Example 93.

[1642] 1 H-NMR (CDCl3) δ: 7.37-7.34 (2H, m), 7.30-7.28 (2H, m), 7.20-7.19 (1H, m), 7.05-7.03 (1H, m), 6. 88 (1H, d, J = 7.3Hz), 6.70 (1H, dd, J = 8.2, 0.9Hz), 6.60 (1H, ddd, J = 7.3, 7.3, 0.9Hz), 5.58 (1H, brs ), 3.49 (3H, s), 3.09 (1H, d, J = 15.6Hz), 2.86 (1H, d, J = 15.6Hz), 2.57 (1H, ddd, J = 16.0, 4.1, 4.1H z), 2.31 (1H, ddd, J=16.0, 11.4, 5.0Hz), 2.22-2.17 (1H, m), 2.02 (1H, ddd, J=12.3, 11.4, 4.6Hz).

[1643] MS (ESI) [M+H] + :282.

[1644] (Reference Example 78) Synthesis of 5-(6-chloroquinolin-2-yl)indolin-2-one:

[1645] [Chemical formula 188]

[1646]

[1647] 2,6-Dichloroquinoline (200.0 mg, 1.010 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (287.8 mg, 1.111 mmol), tetrakis(triphenylphosphine)palladium(0) (35.0 mg, 0.030 mmol), and potassium carbonate (348.9 mg, 2.525 mmol) were dissolved in DMF / water (4 / 1, v / v, 10 mL) and heated with stirring at 100°C for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and filtered. The resulting solid was washed with water, acetone, and chloroform / hexane (9 / 1) to obtain the title compound (243.4 mg, 0.828 mmol, yield 82%) as a colorless, transparent oil.

[1648] 1 H-NMR (DMSO-d6) δ: 10.63 (1H, s), 8.39 (1H, d, J = 8.2Hz), 8.19-8.14 (3H, m), 8.11 (1H, d, J = 2. 3Hz), 8.03 (1H, d, J = 9.1Hz), 7.76 (1H, dd, J = 9.1, 2.3Hz), 6.97 (1H, d, J = 8.2Hz), 3.62 (2H, s).

[1649] MS (ESI) [M+H] + :295.

[1650] (Example 95) Synthesis of 5-(6-chloro-2,3,4,4-tetrahydroquinolin-2-yl)indolin-2-one (new compound):

[1651] [Chemical formula 189]

[1652]

[1653] After dissolving 5-(6-chloroquinolin-2-yl)indolin-2-one (243.0 mg, 0.824 mmol) synthesized in Reference Example 78 in THF (8 mL), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester (501 mg, 1.98 mmol) and iodine (20.9 mg, 0.082 mmol) were added and stirred at 60 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was washed with column chromatography (silica gel, chloroform / methanol) and suspended in chloroform (6.0 mL) to give the title compound (hereinafter referred to as the compound of Example 95) (157 mg, 0.526 mmol, yield 64%) as a light red solid.

[1654] 1H-NMR (DMSO-d6) δ: 10.35 (1H, s), 7.18 (1H, s), 7.13 (1H, d, J = 7.8Hz), 6.90-6.89 (2H, m), 6.77 (1H, d, J = 7.8Hz), 6.57 (1H, dd, J = 6.6 , 2.5Hz), 6.18 (1H, s), 4.35-4.33 (1H, m), 3.45 (2H, s), 2.79-2.58 (1H, m), 2.58-2.52 (1H, m), 1.95-1.91 (1H, m), 1.82-1.73 (1H, m).

[1655] MS (ESI) [M+H] + :299.

[1656] (Reference Example 79) Synthesis of 6-chloro-2-(1H-pyrazol-4-yl)quinoline:

[1657] [Chemical formula 190]

[1658]

[1659] 2,6-Dichloroquinoline (200.0 mg, 1.010 mmol), (1H-pyrazol-4-yl)boric acid (212.0 mg, 1.616 mmol), tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.060 mmol), and potassium carbonate (348.9 mg, 2.525 mmol) were dissolved in DMF / water (5 / 1, v / v, 10 mL) and heated with stirring at 100°C for 18 hours. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) to give the title compound (49.7 mg, 0.214 mmol, yield 21%) as a light yellow solid.

[1660] 1 H-NMR (CDCl3) δ: 8.27 (2H, s), 8.07 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 9.1Hz), 7.77 (1H, d, J = 2.7Hz), 7.67 (1H, d, J = 8.7Hz), 7.63 (1H, dd, J = 9.1, 2.3Hz).

[1661] MS (ESI) [M+H] + :230.

[1662] (Example 96) Synthesis of 6-chloro-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[1663] [Chemical formula 191]

[1664]

[1665] After dissolving 6-chloro-2-(1H-pyrazol-4-yl)quinoline (49.7 mg, 0.216 mmol) synthesized in Reference Example 79 in THF (2.16 mL), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester (131.6 mg, 0.519 mmol) and iodine (5.5 mg, 0.022 mmol) were added and stirred at 60 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (hereinafter referred to as the compound of Example 96) (37.4 mg, 0.160 mmol, yield 74%) as a light yellow amorphous substance.

[1666] 1 H-NMR (CDCl3) δ: 7.57 (2H, s), 7.00-6.93 (2H, m), 6.44 (1H, d, J=8.2Hz), 4.48 (1H, dd, J=9.4, 3.0Hz), 3 .98 (1H, brs), 2.92-2.84 (1H, m), 2.73 (1H, dt, J=16.8, 4.9Hz), 2.16-2.09 (1H, m), 2.01-1.92 (1H, m).

[1667] MS (ESI) [M+H] + :234.

[1668] (Reference Example 80) Synthesis of 6-methyl-2-(1H-pyrazol-4-yl)quinoline:

[1669] [Chemical formula 192]

[1670]

[1671] 2-Chloro-6-methylquinoline (200.0 mg, 1.126 mmol), (1H-pyrazol-4-yl)boric acid (278.0 mg, 2.484 mmol), tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.060 mmol) and potassium carbonate (348.9 mg, 2.525 mmol) were dissolved in DMF / water (5 / 1, v / v, 10 mL) and heated with stirring at 100°C for 18 hours. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (49.9 mg, 0.236 mmol, yield 21%) as a light yellow solid.

[1672] 1 H-NMR (CDCl3) δ: 8.26 (1H, s), 8.26 (1H, s), 8.06 (1H, d, J = 8.7Hz), 7.95 (1H, d, J = 8.7Hz), 7.62-7.52 (3H, m), 2.53 (3H, s).

[1673] MS (ESI) [M+H] + :210.

[1674] (Example 97) Synthesis of 6-methyl-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[1675] [Chemical formula 193]

[1676]

[1677] After dissolving 6-methyl-2-(1H-pyrazol-4-yl)quinoline (49.9 mg, 0.238 mmol) synthesized in Reference Example 80 in THF (2.38 mL), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester (145.0 mg, 0.572 mmol) and iodine (6.1 mg, 0.024 mmol) were added and stirred at 60 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (hereinafter referred to as the compound of Example 97) (37.2 mg, 0.174 mmol, yield 73%) as a light yellow solid.

[1678] 1H-NMR (CDCl3) δ: 7.58 (2H, s), 6.82-6.81 (2H, m), 6.45 (1H, d, J = 8.7Hz), 4.46 (1H, dd, J = 9.4, 3.0Hz), 2.94-2.85(1H,m), 2.73(1H,dt,J=16.5,4.8Hz), 2.22(3H,s), 2.16-2.09(1H,m), 2.03-1.93(1H,m).

[1679] MS (ESI) [M+H] + :214.

[1680] (Reference Example 81) Synthesis of 6-fluoro-2-(1H-pyrazol-4-yl)quinoline:

[1681] [Chemical formula 194]

[1682]

[1683] 2-Chloro-6-fluoroquinoline (200.0 mg, 1.101 mmol), (1H-pyrazol-4-yl)boric acid (272.0 mg, 2.431 mmol), tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.060 mmol) and potassium carbonate (348.9 mg, 2.525 mmol) were dissolved in DMF / water (5 / 1, v / v, 10 mL) and heated with stirring at 100°C for 18 hours. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (69.9 mg, 0.330 mmol, yield 30%) as a light yellow solid.

[1684] 1 H-NMR (CDCl3) δ: 8.27 (2H, s), 8.10 (1H, d, J = 8.7Hz), 8.05 (1H, dd, J = 9.1, 5.5Hz) , 7.66 (1H, d, J = 8.7Hz), 7.47 (1H, td, J = 8.7, 3.0Hz), 7.40 (1H, dd, J = 8.7, 3.0Hz).

[1685] MS (ESI) [M+H] + :214.

[1686] (Example 98) Synthesis of 6-fluoro-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[1687] [Chemical formula 195]

[1688]

[1689] After dissolving 6-fluoro-2-(1H-pyrazol-4-yl)quinoline (69.9 mg, 0.328 mmol) synthesized in Reference Example 81 in THF (3.28 mL), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester (199.3 mg, 0.787 mmol) and iodine (8.3 mg, 0.033 mmol) were added and stirred at 60 ° C for 3.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) to obtain the title compound (hereinafter referred to as the compound of Example 98) (49.9 mg, 0.230 mmol, yield 70%) as a light yellow amorphous substance.

[1690] 1 H-NMR (CDCl3) δ: 7.58 (2H, s), 6.74-6.69 (2H, m), 6.47-6.43 (1H, m), 4.45 (1H, dd, J=9.4, 3.0 Hz), 2.95-2.87 (1H, m), 2.74 (1H, dt, J=16.8, 4.8Hz), 2.16-2.10 (1H, m), 2.02-1.93 (1H, m).

[1691] MS (ESI) [M+H] + :218.

[1692] (Reference Example 82) Synthesis of 4-(6-methylquinolin-2-yl)benzamide:

[1693] [Chemical Formula 196]

[1694]

[1695] 2-Chloro-6-methylquinoline (250 mg, 1.41 mmol), 4-aminocarbonylphenylboronic acid (348 mg, 2.11 mmol), tetrakis(triphenylphosphine)palladium(0) (48.8 mg, 0.0422 mmol), and potassium carbonate (486 mg, 3.52 mmol) were dissolved in DMF / water (5 / 1, v / v, 12 mL) and heated with stirring at 100°C for 3 hours. Water was poured into the reaction mixture at room temperature, and the precipitated solid was filtered out. The resulting solid was washed with chloroform / hexane and filtered out to obtain the title compound (283 mg, 1.08 mmol, 77% yield) as a light brown solid.

[1696] 1H-NMR (CDCl3) δ: 8.26 (2H, d, J = 8.2Hz), 8.18 (1H, d, J = 8.2Hz), 8.07 (1H, d, J = 8.2Hz), 7.97 (2H, d, J = 8.2Hz), 7.88 (1H, d, J = 8.2Hz), 7.62 (1H, d, J = 2.0Hz), 7.59 (1H, dd, J = 8.2, 2.0Hz), 6.15 (1H, brs), 5.62 (1H, brs), 2.57 (3H, s).

[1697] MS (ESI) [M+H] + :262.

[1698] (Example 99) Synthesis of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1699] [Chemical Formula 197]

[1700]

[1701] After dissolving 4-(6-methylquinolin-2-yl)benzamide (280 mg, 1.07 mmol) synthesized in Reference Example 82 in tetrahydrofuran (8.0 mL), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester (649 mg, 2.56 mmol) and iodine (27.1 mg, 0.107 mmol) were added and stirred at 50 ° C for 17 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, chloroform / methanol) to give the title compound (hereinafter referred to as the compound of Example 99) (188 mg, 0.706 mmol, yield 66%) as a white solid.

[1702] 1 H-NMR (CDCl3) δ: 7.79 (2H, d, J = 8.2Hz), 7.48 (2H, d, J = 8.2Hz), 6.86-6.83 (2H, m), 6.51 (1H, d, J = 8.2Hz), 6.06 (1H, brs), 5.56 (1H, brs), 4.48 (1H, dd, J = 8.8, 3.4Hz), 4.02 (1H, brs), 2.93-2.85 (1H, m), 2.68 (1H, td, J = 10.8, 5.6Hz), 2.24 (3H, s), 2.15-2.09 (1H, m), 2.02-1.93 (1H, m).

[1703] MS (ESI) [M+H] + :267.

[1704] (Reference Example 83) Synthesis of 4-(6-methylquinolin-2-yl)benzenesulfonamide:

[1705] [Chemical formula 198]

[1706]

[1707] 2-Chloro-6-methylquinoline (250 mg, 1.41 mmol), 4-aminosulfonylphenylboronic acid (424 mg, 2.11 mmol), tetrakis(triphenylphosphine)palladium(0) (48.8 mg, 0.0422 mmol), and potassium carbonate (486 mg,...

Claims

1. A therapeutic or preventive agent for amyotrophic lateral sclerosis, comprising a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, [Chemical formula 1] In the formula, R 1x represents a hydrogen atom, an aryl group, or a 5- or 6-membered heteroaryl group containing 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (the aryl group and the 5- or 6-membered heteroaryl group wherein 1 or 2 arbitrary hydrogen atoms are each independently optionally replaced by a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are each independently optionally replaced by a hydroxyl group or a fluorine atom, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are each independently optionally replaced by a fluorine atom, a cyano group, a methoxycarbonyl group, -CONR 6 R 7 、-NHCOR 8 , aminosulfonyl, alkylsulfonylamino having 1 to 3 carbon atoms, aminosulfonylamino or alkylsulfonyl having 1 to 3 carbon atoms), or In R 1x In the case where the aryl group is a phenyl group, the phenyl group may be fused with one ring selected from a 5- and 6-membered lactam ring and a 5- and 6-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms as the constituent atoms of the ring to form a fused ring group (one arbitrary hydrogen atom of the fused ring group may be substituted with a methyl group), R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetylaminophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group or a 3-pyridyl group (wherein, R 1x and R 1y Except for the case where all are hydrogen atoms), For R 2 , R 4 and R 5 The combination of R 2 , R 4 and R 5 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 is optionally substituted by a hydroxyl group, and the other two are hydrogen atoms, R 3 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are each independently optionally substituted with a hydroxyl group or a fluorine atom, a 3-hydroxyoxetan-3-yl group, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are each independently optionally substituted with a fluorine atom, a methoxycarbonyl group, a -NR 9 R 10 、-CH2NR 11 R 12 or -CH2CONR 13 R 14 , R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 Become one and express -(CH2) h -, h represents an integer of 3 to 5, wherein one arbitrary methylene group is optionally replaced by an oxygen atom, -NH- or -N(CH3)-, R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 9 and R 10 Each independently represents a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 Become one and express -(CH2) n -, n represents an integer from 3 to 6, R 11 and R 12 Become one and express -(CH2) m -, m represents an integer of 3 to 5, wherein one arbitrary methylene group may be optionally replaced by an oxygen atom. R 13 and R 14 each independently represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 2-hydroxyethyl group, a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by an oxygen atom, or a methyl group substituted with a cycloalkyl group having 3 or 4 carbon atoms in which one arbitrary carbon atom is optionally replaced by a nitrogen atom or an oxygen atom, or, R 13 and R 14 Taken together, it represents -(CH2) in which one or two hydrogen atoms are optionally replaced by a fluorine atom, a methyl group, a hydroxyl group or a methoxy group, or one CH2 group is optionally replaced by an oxygen atom, a nitrogen atom or -CONH-. k -, k represents an integer from 3 to 5, R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or -NHR 16 , R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom is optionally substituted by a hydroxyl group or a methoxycarbonyl group, or a methoxycarbonyl group, R w It represents a hydrogen atom, a methyl group, a hydroxymethyl group or a methoxycarbonyl group.

2. The therapeutic or preventive agent for amyotrophic lateral sclerosis according to claim 1, comprising the tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof as an active ingredient, wherein: R 1x is a hydrogen atom, a phenyl group (the hydrogen atom at the para position of the phenyl group is optionally substituted by a fluorine atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetylamino group, an aminosulfonyl group, a methylsulfonylamino group or a methylsulfonyl group), R 1y is a hydrogen atom or a 4-aminosulfonylphenyl group (wherein R 1x In the case of a hydrogen atom, R 1y is 4-aminosulfonylphenyl, or R 1x In the case of 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 acetylamino group, an aminosulfonyl group, a methylsulfonylamino group or a methylsulfonyl group), R 1y is a hydrogen atom), For R 2 , R 4 and R 5 The combination of R 2 , R 4 and R 5 All hydrogen atoms, or R 2 and R 4 One of them is a fluorine atom, a chlorine atom or a methyl group, and the other and R 5 is a hydrogen atom, R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a trifluoromethoxy group or -CH2CONR 13 R 14 , R 13 is a hydrogen atom or a methyl group, R 14 is tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl or oxetan-3-yl, or R 13 and R 14 optionally together with the nitrogen atom to which they are bound, form a piperazine ring, a piperazin-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, R v is a hydrogen atom, R w A hydrogen atom.

3. The therapeutic or preventive agent for amyotrophic lateral sclerosis according to claim 2, wherein The tetrahydroquinoline derivative or its pharmacologically acceptable salt is selected from the following group: 2-phenyl-1,2,3,4-tetrahydroquinoline, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-Fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(5-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(7-Fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-Fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 1-(3-methoxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-(3-oxetane-2-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3,3-difluoroazetidine-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-(2-hydroxyethyl)-N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(azetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(piperazin-1-yl)ethan-1-one, and 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide, or pharmacologically acceptable salts thereof.

4. The therapeutic or preventive agent for amyotrophic lateral sclerosis according to claim 3, wherein The tetrahydroquinoline derivative or a pharmacologically acceptable salt thereof is 2-phenyl-1,2,3,4-tetrahydroquinoline. 5 . The therapeutic or preventive agent for amyotrophic lateral sclerosis according to any one of claims 1 to 4 , which is a ferroptosis inhibitor.

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