RU2850795C1 - Tetrahydroquinoline derivative and its medical application - Google Patents

Abstract

FIELD: organic and pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to the field of organic and pharmaceutical chemistry, namely to a tetrahydroquinoline derivative of formula (I), its pharmaceutically acceptable salts, the use of the tetrahydroquinoline derivative, individual tetrahydroquinoline derivatives represented in the invention formula, and their use. In formula (I), R^ly represents hydrogen; for the combination of R^{2 ,}R⁴ and R^5,all of R^{2 ,}R⁴ and R⁵ are hydrogen; otherwise, one of R² and R⁴ is fluorine, chlorine or methyl and both the other and R⁵ are hydrogen; R^v is hydrogen; R^w is hydrogen; in cases where R^1x is phenyl, R³ is trifluoromethyl, hydroxymethyl, 2-hydroxypropan-2-yl, isopropyl, 3-hydroxyoxetan-3-yl, trifluoromethoxy, -NR⁹ R¹⁰, morpholinomethyl or -CH₂CONR¹³R¹⁴; or in cases where R^1x is phenyl (the hydrogen atom in the para- or meta-position of the phenyl group is substituted by aminocarbonyl, aminosulphonyl, methylsulphonylamino, aminosulphonylamino or methylsulphonyl; otherwise, the hydrogen atom in the meta position of the phenyl group is substituted with a cyano group; otherwise, the hydrogen atom in the para position of the phenyl group is substituted with a trifluoromethoxy group), 2-oxoindolin-5-yl or 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl, R³ is hydrogen, fluorine, chlorine or methyl; R⁹ is hydrogen; R¹⁰ is hydrogen, -COR¹⁵ or methylsulfonyl; or R⁹ and R¹⁰ together represent -(CH(₂)₅ ; R¹³ is hydrogen or methyl; R¹⁴ is hydrogen, methyl, tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, oxetan-3-yl, cyclopropylmethyl or oxetan-3-ylmethyl; or R¹³ and R¹⁴ together with the nitrogen atom to which R¹³ and R14 ^,optionally form a pyrrolidine ring, a piperazine ring, a morpholine ring, a piperazine-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, 3-hydroxyazetidine or 3-methoxyazetidine; R¹⁵ is methyl, tert-butyl, neopentyl, tert-butoxy or -NHR¹⁶; and R¹⁶ is hydrogen or tert-butyl

EFFECT: tetrahydroquinoline derivatives exhibiting inhibitory activity against ferroptosis.

13 cl, 6 dwg, 15 tbl, 180 ex

Description

AREA OF TECHNOLOGY

[0001]

The present invention relates to tetrahydroquinoline derivatives and their pharmaceutical use.

LEVEL OF TECHNOLOGY

[0002]

Recently, various forms of regulated cell death have been discovered, and ferroptosis has been described as one of the new forms of cell death, which is a form of regulated cell death that is dependent on ferrous iron (Non-Patent Document 1). Ferroptosis is a reaction in which antioxidant function is reduced by various stimuli, such as a decrease in intracellular glutathione or a decrease in glutathione peroxidase 4 (GPX4) levels, and the ferrous iron-dependent reaction progresses, increasing intracellular lipid peroxides to lethal levels, thereby causing cell death.

[0003]

The relationship between the inhibitory effect against ferroptosis and the therapeutic effect in kidney diseases, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, Friedreich's ataxia, cardiomyopathy, and multiple sclerosis has been reported (Non-patent documents 2-6).

[0004]

For example, multiple sclerosis, which is reported to have decreased GPX4 levels in the brains of patients and is thought to have some connection with ferroptosis, is characterized by demyelination, which damages the myelin sheath surrounding nerve fibers in the brain, spinal cord, optic nerve, and other organs. It is a disease in which impairments occur through repeated cycles of relapse and remission. Multiple sclerosis is known to manifest various pathologies depending on the affected sites, including various neurological symptoms such as visual impairment, quadriplegia, sensory disturbances, and gait disturbances (Non-patent documents 7 and 8).

[0005]

Aniline derivatives such as ferrostatin-1 are known as compounds exhibiting an inhibitory effect against ferroptosis (Non-patent Documents 1 and 9). Tetrahydroquinoxaline derivatives and 3,4-dihydro-2H-benzo-[1,4]oxazine derivatives are also known to have an inhibitory effect against ferroptosis (Patent Documents 1 and 2).

[0006]

It is reported that the free radical scavenging action is important for exerting the inhibitory effect against ferroptosis (Non-Patent Document 10). Furthermore, it is described that the tetrahydroquinoxaline derivatives described in Patent Document 1 have a strong free radical scavenging action and thus exert the inhibitory effect against ferroptosis (Non-Patent Documents 11 and 12).

[0007]

Moreover, tetrahydroquinoline derivatives with antiviral, antitumor, analgesic or immunomodulatory effects are described in patent documents 3-7.

PRIOR ART DOCUMENTS

Patent documents

[0008]

Patent Document 1: CN 110372614 A

Patent Document 2: CN110464727 A

Patent Document 3: JP S56-051456 A

Patent Document 4: WO 2007/054138

Patent Document 5: JP H5-125052 A

Patent Document 6: WO 2005/063735

Patent Document 7: DE 10236910 A

Non-patent documents

[0009]

Non-patent document 1: Dixon et al ., Cell, 2012, vol. 149, pp. 1060–1072

Non-patent document 2: Friedmann et al ., Nature Cell Biology, 2014, vol. 16, pp. 1180–1191

Non-patent document 3: Masaldan et al ., Free Radical Biology and Medicine, 2019, vol. 133, pp. 221–233

Non-patent document 4: Tsurusaki et al ., Cell Death and Disease, 2019, vol. 10, 449

Non-patent document 5: Yoshida et al ., Nature Communications, 2019, vol. 10

Non-Patent Document 6: Xuexian et al ., Proceedings of the National Academy of Sciences of the United States of America, 2019, vol. 116, p. 2672-2680

Non-patent document 7: Madeline et al ., International Journal of Molecular Sciences, 2020, vol. 21, 4312

Non-patent document 8: Che-Lin et al ., Journal of Neurochemistry, 2019, vol. 148, pp. 426–439

Non-patent document 9: Lars et al ., Journal of Medicinal Chemistry, 2018, vol. 61, pp. 10126–10140

Non-Patent Document 10: Jennifer Yinus Cao et al ., Cellular and Molecular Life Science, 2016, vol. 73, pp. 2195–2209

Non-patent document 11: Yu-Zhen Li et al ., Frontiers in Chemistry, 2019, vol. 7, 850

Non-patent document 12: Hong-Xu Lei et al ., Journal of Molecular Structure, 2021, vol. 1228, 129485

ESSENCE OF THE INVENTION

PROBLEM SOLVED BY THE INVENTION

[0010]

However, Patent Documents 1-7 and Non-Patent Documents 1-12 do not describe the ferroptosis inhibitory effect of tetrahydroquinoline derivatives and do not suggest its possibility.

[0011]

Thus, the aim of the present invention is to provide compounds that have an inhibitory effect on ferroptosis and have a therapeutic or prophylactic effect on diseases, disorders or syndromes associated with the inhibition of ferroptosis, such as multiple sclerosis.

SOLUTIONS TO THE PROBLEM

[0012]

The present inventors have intensively studied a solution to the above problem and therefore found that compounds having a tetrahydroquinoline skeleton have an inhibitory effect against ferroptosis and a pharmacological action based on the inhibitory effect, thereby completing the present invention.

[0013]

That is, the present invention includes the following.

[1] A tetrahydroquinoline derivative represented by the general formula (I) below or a pharmaceutically acceptable salt thereof,

[0014]

[0015]

[Where

R ^1x is hydrogen, phenyl (optionally, the phenyl group is substituted with a substituent as described below or forms a fused ring group as described below), or a 5- or 6-membered heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyridyl (the heteroaryl is optionally substituted with a substituent as described below);

R ^1y is hydrogen, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl (provided that R ^1y is a substituent other than hydrogen in cases where R ^1x is hydrogen, or that R ^1y is hydrogen in cases where R ^1x is a substituent other than hydrogen);

for a combination of ^R2 , ^R4 and ^R5 , all of ^R2 , ^R4 and ^R5 are hydrogen; in another case, one of ^R2 and ^R4 is fluorine, chlorine, methoxy or methyl in which one hydrogen atom is optionally substituted by hydroxy and both the other and ^R5 are hydrogen; in another case, both ^R2 and ^R4 are hydrogen and ^R5 is fluorine or chlorine;

R ³ is hydrogen, halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), 3-hydroxyoxetan-3-yl, hydroxy, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ^v is hydrogen; and

R ^w is hydrogen;

wherein, in cases where R ^1x is phenyl (any one hydrogen atom of the phenyl group is optionally substituted with one substituent selected from the group consisting of halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), cyano, methoxycarbonyl and -NHCOR ⁸ , provided that m- cyanophenyl and p- (trifluoromethoxy)phenyl are excluded) or 5- or 6-membered heteroaryl (any one hydrogen atom of the 5- or 6-membered heteroaryl is optionally substituted with C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy, provided that 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl excluded),

R ³ is C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are replaced by fluorine atom(s), C ₁ -C ₃ alkyl in which any one hydrogen atom is replaced by hydroxy, ethyl, propyl, isopropyl, 3-hydroxyoxetan-3-yl, methoxy in which any one to three hydrogen atoms are replaced by fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ (wherein, in cases where both R ² and R ⁴ are hydrogen and R ⁵ is fluorine or chlorine, R ³ is optionally hydrogen or fluorine, or in cases where both R ² and R ⁵ are hydrogen and R ⁴ is fluorine or chlorine, R ³ is optionally fluorine, or in cases where R ² is is methyl in which one hydrogen atom is optionally replaced by a hydroxy group and both R ⁴ and R ⁵ are hydrogen, R ³ is optionally hydrogen);

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen, -COR ¹⁵ , or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ represents hydrogen or methyl;

R ¹⁴ is hydrogen, methyl, ethyl, isopropyl, tert- butyl, 2-hydroxyethyl, C ₃ or C ₄ cycloalkyl in which any one carbon atom is optionally substituted by an oxygen atom, or methyl which is substituted by a C ₃ or C ₄ cycloalkyl group in which any one carbon atom is optionally substituted by a nitrogen or oxygen atom, or

R ¹³ and R ¹⁴ , together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ , optionally form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a piperazinone ring or an azetidine ring, in which any two hydrogen atoms are optionally substituted by methyl group(s) and/or fluorine atom(s) or in which any one hydrogen atom is optionally substituted by hydroxy or methoxy group;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or -NHR ¹⁶ ; and

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl; or

in cases where R ^1x is hydrogen, phenyl (any one hydrogen atom of the phenyl group is substituted by a C ₁ -C ₃ alkyl group in which any one hydrogen atom is substituted by a hydroxy group, -CONR ⁶ R ⁷ , aminosulfonyl, methylsulfonylamino, aminosulfonylamino or C ₁ -C ₃ alkylsulfonyl; in another case, the hydrogen atom at the meta position of the phenyl group is substituted by a cyano group; in another case, 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

in cases where R ^1x is a fused ring group formed by condensation between a phenyl group and one ring selected from the group consisting of pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane (wherein any one hydrogen atom in the fused group is optionally substituted with a methyl group),

R ³ is hydrogen, fluorine, chlorine, bromine, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s) or any one hydrogen atom is optionally substituted by a hydroxy group, 3-hydroxyoxetan-3-yl, hydroxy, methoxy in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or

R ⁶ and R ⁷ , together with the nitrogen atom that is bonded to R ⁶ and R ⁷ , optionally form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ represents hydrogen or methyl;

R ¹⁴ is hydrogen, methyl, ethyl, isopropyl, tert- butyl, 2-hydroxyethyl, C ₃ or C ₄ cycloalkyl in which any one carbon atom is optionally substituted by an oxygen atom, or methyl which is substituted by a C ₃ or C ₄ cycloalkyl group in which any one carbon atom is optionally substituted by a nitrogen or oxygen atom, or

R ¹³ and R ¹⁴ , together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ , optionally form a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a piperazinone ring or an azetidine ring, in which any two hydrogen atoms are optionally substituted by methyl group(s) and/or fluorine atom(s), or in which any one hydrogen atom is optionally substituted by hydroxy or methoxy group;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or -NHR ¹⁶ ; and

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl (provided that methyl 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate and 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline are excluded)].

[0016]

[2] A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to [1], wherein

R ^1x is phenyl (optionally, the phenyl group is substituted with a substituent as described below or forms a fused ring group as described below) or a 5- or 6-membered heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyridyl (the heteroaryl is optionally substituted with a substituent as described below);

for a combination of ^R2 , ^R4 and ^R5 , all of ^R2 , ^R4 and ^R5 are hydrogen; in another case, one of ^R2 and ^R4 is fluorine, chlorine, methoxy, or methyl in which one hydrogen atom is optionally substituted with hydroxy, and both of the other and ^R5 are hydrogen; in another case, both ^R2 and ^R4 are hydrogen and ^R5 is fluorine or chlorine;

R ^v is hydrogen; and

R ^w is hydrogen;

wherein, in cases where R ^1x is phenyl (any one hydrogen atom of the phenyl group is optionally substituted with one substituent selected from the group consisting of halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), cyano, methoxycarbonyl and -NHCOR ⁸ , provided that m- cyanophenyl and p- (trifluoromethoxy)phenyl are excluded) or 5- or 6-membered heteroaryl (any one hydrogen atom of the 5- or 6-membered heteroaryl is optionally substituted with C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy, provided that 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl excluded),

R ³ is C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are replaced by fluorine atom(s), C ₁ -C ₃ alkyl in which any one hydrogen atom is replaced by hydroxy, ethyl, propyl, isopropyl, 3-hydroxyoxetan-3-yl, methoxy in which any one to three hydrogen atoms are replaced by fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ (wherein, in cases where both R ² and R ⁴ are hydrogen and R ⁵ is fluorine or chlorine, R ³ is optionally hydrogen or fluorine, or in cases where both R ² and R ⁵ are hydrogen and R ⁴ is fluorine or chlorine, R ³ is optionally fluorine, or in cases where R ² is methyl in which one hydrogen atom is optionally replaced by a hydroxy group and both R ⁴ and R ⁵ are hydrogen, R ³ is optionally hydrogen);

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen, -COR ¹⁵ , or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen, methyl, ethyl, isopropyl, or tert -butyl, or

R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , optionally form an azetidine ring in which any one hydrogen atom is optionally replaced by a hydroxy group;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or -NHR ¹⁶ ; and

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl; or

in cases where R ^1x is phenyl (any one hydrogen atom of the phenyl group is substituted by C ₁ -C ₃ alkyl in which any one hydrogen atom is substituted by hydroxy, -CONR ⁶ R ⁷ , aminosulfonyl, or C ₁ -C ₃ alkylsulfonyl; in another case, the hydrogen atom at the meta position of the phenyl group is substituted by cyano; in another case, the hydrogen atom at the para position of the phenyl group is substituted by trifluoromethoxy), 1-methyl-1H-pyrazol-4-yl or 6-methoxypyridin-3-yl, or

in cases where R ^1x is a fused ring group formed by condensation between a phenyl group and one ring selected from the group consisting of pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane (wherein any one hydrogen atom in the fused group is optionally substituted with a methyl group),

R ³ is hydrogen, fluorine, chlorine, bromine, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s) or any one hydrogen atom is optionally substituted by a hydroxy group, 3-hydroxyoxetan-3-yl, hydroxy, methoxy in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or

R ⁶ and R ⁷ , together with the nitrogen atom that is bonded to R ⁶ and R ⁷ , optionally form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen, methyl, ethyl, isopropyl or tert -butyl, or

R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , optionally form an azetidine ring in which any one hydrogen atom is optionally replaced by a hydroxy group;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or -NHR ¹⁶ ; and

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl (provided that methyl 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate and 2-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydroquinoline are excluded).

[0017]

[3] A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol,

tert -butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate,

2-phenyl-1,2,3,4-tetrahydroquinolin-6-amine,

2-(benzo[d][1,3]dioxol-5-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline,

(2-phenyl-1,2,3,4-tetrahydroquinolin-7-yl)methanol,

2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline,

2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline,

(2-phenyl-1,2,3,4-tetrahydroquinolin-5-yl)methanol,

(2-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol,

(3-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol,

(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol,

6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline,

N-methyl-3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

3-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile,

6-isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline,

2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline,

2-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydroquinoline,

4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine,

2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)propan-2-ol,

2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

N-( tert -butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)oxetan-3-ol,

N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

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

2-phenyl-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline,

N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide,

4-(6-(3-( tert -butyl)ureido)-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline,

3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide,

1-( tert -butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea,

2-(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)propan-2-ol,

3-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

2-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide,

1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea,

1,2,3,3’,4,4’-hexahydro-[2,6’-biquinoline]-2’(1’H)-one,

1’-methyl-1,2,3,3’,4,4’-hexahydro-[2,6’-biquinolin]-2’(1’H)-one,

N,N-diethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

N-ethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

5-(1,2,3,4-tetrahydroquinolin-2-yl)isoindolin-1-one,

(4-methylpiperazin-1-yl)(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone,

piperidin-1-yl(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone, and

morpholino(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone and their pharmaceutically acceptable salts.

[0018]

[4] A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

tert -butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate,

(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol,

4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide,

4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine,

2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

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

N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide,

4-(6-(3-( tert -butyl)ureido)-1,2,3,4-tetrahydroquinolin-2-yl)benzamide,

3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide,

1-( tert -butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea,

N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide,

1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, and

5-(1,2,3,4-tetrahydroquinolin-2-yl)isoindolin-1-one and their pharmaceutically acceptable salts.

[0019]

[5] A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein

R ^1x is phenyl (the phenyl group is optionally substituted with a substituent as described below);

R ^1y is hydrogen;

for a combination of R ² , R ⁴ and R ⁵ , all of R ² , R ⁴ and R ⁵ are hydrogen; otherwise, one of R ² and R ⁴ is fluorine, chlorine, or methyl and both of the others and R ⁵ are hydrogen;

R ^v is hydrogen; and

R ^w is hydrogen;

where, in cases where R ^1x is phenyl (the hydrogen atom at the para -position of the phenyl group is optionally substituted with one substituent selected from the group consisting of fluoro, trifluoromethyl, cyano and acetamide),

R ³ is trifluoromethoxy, hydroxymethyl, or -CH ₂ CONR ¹³ R ¹⁴ (wherein, in cases where R ² is methyl and both R ⁴ and R ⁵ are hydrogen, R ³ is optionally hydrogen);

R ¹³ represents hydrogen or methyl;

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

R ¹³ and R ¹⁴ , together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ , optionally 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; or

in cases where R ^1x is phenyl (the hydrogen atom at the para -position of the phenyl group is substituted by trifluoromethoxy, aminocarbonyl, aminosulfonyl, methylsulfonylamino or methylsulfonyl group),

R ³ is hydrogen, fluorine, chlorine, methyl, hydroxymethyl, trifluoromethoxy or -CH ₂ CONR ¹³ R ¹⁴ ;

R ¹³ represents hydrogen or methyl;

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

R ¹³ and R ¹⁴ , together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ , optionally 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.

[0020]

[6] A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to [1], wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

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-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide,

1-(3,3-difluoroazetidin-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 and their pharmaceutically acceptable salts.

[0021]

[7] A medicinal product containing a tetrahydroquinoline derivative represented by the general formula (I) below (hereinafter also referred to as “tetrahydroquinoline derivative (I)”) or a pharmaceutically acceptable salt thereof as an active ingredient,

[0022]

[0023]

[Where

R ^1x is hydrogen, aryl, or a 5- or 6-membered heteroaryl having one or two heteroatoms selected from nitrogen, oxygen, and sulfur (any one or two hydrogen atoms in an aryl or 5- or 6-membered heteroaryl are each independently optionally substituted with halogen atom(s), C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), cyano, methoxycarbonyl, -CONR ⁶ R ⁷ , -NHCOR ⁸ , aminosulfonyl, C ₁ -C ₃ alkylsulfonylamino, aminosulfonylamino, or C ₁ -C ₃ alkylsulfonyl group(s)), or

in cases where the aryl group is phenyl (phenyl optionally forms a fused ring group as described below), R ^1x optionally represents a fused ring group formed by condensing a phenyl group with one ring selected from the group consisting of 5- or 6-membered lactam rings and 5- or 6-membered saturated heterocycles, each containing one or two oxygen atoms as a ring constituent atom (any one hydrogen atom in the fused group is optionally substituted with a methyl group);

R ^1y is hydrogen, phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl, or 3-pyridyl (except when both R ^1x and R ^1y are hydrogen);

for a combination of R ² , R ⁴ , and R ⁵ , all of R ² , R ⁴ , and R ⁵ are hydrogen, or

one of R ² , R ⁴ and R ⁵ is halogen, methoxy, or methyl in which one hydrogen atom is optionally replaced by a hydroxy group and the other two are hydrogen;

R ³ is hydrogen, halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), 3-hydroxyoxetan-3-yl, hydroxy, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or

R ⁶ and R ⁷ together represent -(CH ₂ ) _h -;

h is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom, -NH- or -N(CH ₃ )-;

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ and R ¹⁰ each independently represent hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is an integer from 3 to 6;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ and R ¹⁴ each independently represent hydrogen, a C ₁ -C ₅ alkyl group, 2-hydroxyethyl, C ₃ or C ₄ cycloalkyl in which any one carbon atom is optionally substituted by an oxygen atom, or methyl which is substituted by a C ₃ or C ₄ cycloalkyl group in which any one carbon atom is optionally substituted by a nitrogen or oxygen atom, or

R ¹³ and R ¹⁴ together represent -(CH ₂ ) _k -, in which any one or two hydrogen atoms are optionally substituted by a fluorine atom(s), a methyl group(s), a hydroxy group(s) or a methoxy group(s), or in which any one CH ₂ group is optionally substituted by an oxygen atom, a nitrogen atom or -CONH-;

k is an integer from 3 to 5;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or -NHR ¹⁶ ;

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl;

R ^v represents hydrogen, methyl in which any one hydrogen atom is optionally replaced by a hydroxy or methoxycarbonyl group, or methoxycarbonyl; and

R ^w is hydrogen, methyl, hydroxymethyl, or methoxycarbonyl (provided that 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydroquinoline are excluded).

[0024]

[8] A medicinal product according to [7], containing a tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient, where

R ^1x is phenyl (any one hydrogen atom of the phenyl group is optionally substituted by a halogen atom or C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s) or any one hydrogen atom is optionally substituted by a hydroxy group, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s), cyano, methoxycarbonyl, -CONR ⁶ R ⁷ , -NHCOR ⁸ , aminosulfonyl or a C ₁ -C ₃ alkylsulfonyl group) or a 5- or 6-membered heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyridyl (any one hydrogen atom of the 5- or 6-membered heteroaryl is optionally substituted with C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy group), or

R ^1x optionally represents a fused ring formed by condensing a phenyl group with one ring selected from the group consisting of pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane (wherein any one hydrogen atom in the fused group is optionally substituted with a methyl group);

R ^1y is hydrogen;

for a combination of ^R2 , ^R4 and ^R5 , all of ^R2 , ^R4 and ^R5 are hydrogen; in another case, one of ^R2 and ^R4 is fluorine, chlorine, methoxy or methyl in which one hydrogen atom is optionally substituted by hydroxy and both the other and ^R5 are hydrogen; in another case, both ^R2 and ^R4 are hydrogen and ^R5 is fluorine or chlorine;

R ³ is hydrogen, fluorine, chlorine, bromine, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted with a fluorine atom(s) or any one hydrogen atom is optionally substituted with a hydroxy group, 3-hydroxyoxetan-3-yl, hydroxy, methoxy in which any one to three hydrogen atoms are optionally substituted with a fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or

R ⁶ and R ⁷ , together with the nitrogen atom that is bonded to R ⁶ and R ⁷ , optionally form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring;

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen, methyl, ethyl, isopropyl or tert -butyl, or

R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , optionally form an azetidine ring in which any one hydrogen atom is optionally replaced by a hydroxy group;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or -NHR ¹⁶ ;

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl;

R ^v is hydrogen; and

R ^w is hydrogen (assuming 2-phenyl-1,2,3,4-tetrahydroquinoline is excluded).

[0025]

[9] A medicinal product according to [7] or [8], containing a tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient, where

R ^1x is phenyl (optionally, the phenyl group has a substituent as described below or forms a fused ring group as described below) or a 5- or 6-membered heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and pyridyl (the heteroaryl is optionally substituted with a substituent as described below);

R ^1y is hydrogen;

for a combination of ^R2 , ^R4 and ^R5 , all of ^R2 , ^R4 and ^R5 are hydrogen; in another case, one of ^R2 and ^R4 is fluorine, chlorine, methoxy, or methyl in which one hydrogen atom is optionally substituted with hydroxy and both the other and ^R5 are hydrogen; in another case, both ^R2 and ^R4 are hydrogen and ^R5 is fluorine or chlorine;

R ^v is hydrogen; and

R ^w is hydrogen;

wherein, in cases where R ^1x is phenyl (any one hydrogen atom of the phenyl group is optionally substituted with one substituent selected from the group consisting of halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), cyano, methoxycarbonyl and -NHCOR ⁸ , provided that m- cyanophenyl and p- (trifluoromethoxy)phenyl are excluded) or 5- or 6-membered heteroaryl (any one hydrogen atom of the 5- or 6-membered heteroaryl is optionally substituted with C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy, provided that 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl excluded),

R ³ is C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are replaced by fluorine atom(s), C ₁ -C ₃ alkyl in which any one hydrogen atom is replaced by hydroxy, ethyl, propyl, isopropyl, 3-hydroxyoxetan-3-yl, methoxy in which any one to three hydrogen atoms are replaced by fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ (wherein, in cases where both R ² and R ⁴ are hydrogen and R ⁵ is fluorine or chlorine, R ³ is optionally hydrogen or fluorine, or in cases where both R ² and R ⁵ are hydrogen and R ⁴ is fluorine or chlorine, R ³ is optionally fluorine, or in cases where R ² is is methyl in which one hydrogen atom is optionally replaced by a hydroxy group, and both R ⁴ and R ⁵ are hydrogen, R ³ is optionally hydrogen);

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen, methyl, ethyl, isopropyl or tert -butyl, or

R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , optionally form an azetidine ring in which any one hydrogen atom is optionally replaced by a hydroxy group;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or -NHR ¹⁶ ; and

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl; or

in cases where R ^1x is phenyl (any one hydrogen atom of the phenyl group is substituted by C ₁ -C ₃ alkyl in which any one hydrogen atom is substituted by hydroxy, -CONR ⁶ R ⁷ , aminosulfonyl, or C ₁ -C ₃ alkylsulfonyl; in another case, the hydrogen atom at the meta position of the phenyl group is substituted by cyano; in another case, the hydrogen atom at the para position of the phenyl group is substituted by trifluoromethoxy), 1-methyl-1H-pyrazol-4-yl or 6-methoxypyridin-3-yl, or

in cases where R ^1x is a fused ring group formed by the condensation of a phenyl group with one ring selected from the group consisting of pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane (wherein any one hydrogen atom in the fused group is optionally substituted with a methyl group),

R ³ is hydrogen, fluorine, chlorine, bromine, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s) or any one hydrogen atom is optionally substituted by a hydroxy group, 3-hydroxyoxetan-3-yl, hydroxy, methoxy in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or

R ⁶ and R ⁷ , together with the nitrogen atom that is bonded to R ⁶ and R ⁷ , optionally form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring;

R ⁹ is hydrogen;

R ¹⁰ is hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen, methyl, ethyl, isopropyl or tert -butyl, or

R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , optionally form an azetidine ring in which any one hydrogen atom is optionally replaced by a hydroxy group;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, or -NHR ¹⁶ ; and

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl.

[0026]

[10] The medicinal product according to any one of [7] to [9], wherein the tetrahydroquinoline derivative or pharmaceutically acceptable salt thereof is selected from the group consisting of those described in [3].

[0027]

[11] The medicinal product according to any one of [7] to [10], wherein the tetrahydroquinoline derivative or pharmaceutically acceptable salt thereof is selected from the group consisting of those described in [4].

[0028]

[12] A medicinal product according to any one of [7] to [9], containing a tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient, wherein

R ^1x represents phenyl (the hydrogen atom at the para -position of the phenyl group is optionally substituted by a fluorine atom or a trifluoromethyl, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylamino or methylsulfonyl group);

R ^1y is hydrogen;

for a combination of R ² , R ⁴ and R ⁵ , all of R ² , R ⁴ and R ⁵ are hydrogen; otherwise, one of R ² and R ⁴ is fluorine, chlorine or methyl, and both of the others and R ⁵ are hydrogen;

R ³ is hydrogen, fluorine, chlorine, methyl, hydroxymethyl, trifluoromethoxy or -CH ₂ CONR ¹³ R ¹⁴ ;

R ¹³ represents hydrogen or methyl;

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

R ¹³ and R ¹⁴ , together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ , optionally 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 hydrogen; and

R ^w is hydrogen (assuming 2-phenyl-1,2,3,4-tetrahydroquinoline is excluded).

[0029]

[13] The medicinal product according to [7] or [8], wherein the tetrahydroquinoline derivative or its pharmaceutically acceptable salt is selected from the group consisting of those described in [6].

[0030]

[14] A medicinal product according to any of [7] to [13], for the treatment or prevention of a disease, disorder or syndrome associated with inhibition of ferroptosis.

[0031]

[15] The medicinal product according to [14], wherein the disease, disorder or syndrome is multiple sclerosis.

[0032]

In another aspect, the present invention includes a ferroptosis inhibitor comprising a tetrahydroquinoline derivative represented by the general formula (I) below or a pharmaceutically acceptable salt thereof as an active ingredient,

[0033]

[0034]

[Where

R ^1x is hydrogen, aryl, or a 5- or 6-membered heteroaryl having one or two heteroatoms selected from nitrogen, oxygen, and sulfur (any one or two hydrogen atoms in an aryl or 5- or 6-membered heteroaryl are each independently optionally substituted with halogen atom(s), C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), cyano, methoxycarbonyl, -CONR ⁶ R ⁷ , -NHCOR ⁸ , aminosulfonyl, C ₁ -C ₃ alkylsulfonylamino, aminosulfonylamino, or C ₁ -C ₃ alkylsulfonyl group(s)), or

in cases where the aryl group is phenyl (phenyl optionally forms a fused ring group as described below), R ^1x optionally represents a fused ring group formed by condensing a phenyl group with one ring selected from the group consisting of 5- or 6-membered lactam rings and 5- or 6-membered saturated heterocycles, each containing one or two oxygen atoms as a ring constituent atom (any one hydrogen atom in the fused group is optionally substituted with a methyl group);

R ^1y is hydrogen, phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl, or 3-pyridyl (except when both R ^1x and R ^1y are hydrogen);

for a combination of R ² , R ⁴ , and R ⁵ , all of R ² , R ⁴ , and R ⁵ are hydrogen, or

one of R ² , R ⁴ and R ⁵ is halogen, methoxy, or methyl, in which one hydrogen atom is optionally replaced by a hydroxy group and the other two are hydrogen;

R ³ is hydrogen, halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), 3-hydroxyoxetan-3-yl, hydroxy, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or

R ⁶ and R ⁷ together represent -(CH ₂ ) _h -;

h is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom, -NH- or -N(CH ₃ )-;

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ and R ¹⁰ each independently represent hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is an integer from 3 to 6;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ and R ¹⁴ each independently represent hydrogen, a C ₁ -C ₅ alkyl group, 2-hydroxyethyl, C ₃ or C ₄ cycloalkyl in which any one carbon atom is optionally substituted by an oxygen atom, or methyl which is substituted by a C ₃ or C ₄ cycloalkyl group in which any one carbon atom is optionally substituted by a nitrogen or oxygen atom, or

R ¹³ and R ¹⁴ together represent -(CH ₂ ) _k -, in which any one or two hydrogen atoms are optionally substituted by a fluorine atom(s), a methyl group(s), a hydroxy group(s) or a methoxy group(s), or in which any one CH ₂ group is optionally substituted by an oxygen atom, a nitrogen atom or -CONH-;

k is an integer from 3 to 5;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or -NHR ¹⁶ ;

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl;

R ^v represents hydrogen, methyl in which any one hydrogen atom is optionally replaced by a hydroxy or methoxycarbonyl group, or methoxycarbonyl; and

R ^w is hydrogen, methyl, hydroxymethyl, or methoxycarbonyl].

[0035]

In another aspect, the present invention includes the use of a tetrahydroquinoline derivative (I) as described above, or a pharmaceutically acceptable salt thereof, in the manufacture of a ferroptosis inhibitor.

[0036]

In another aspect, the present invention includes the use of a tetrahydroquinoline derivative (I) as described above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament, preferably the use of a tetrahydroquinoline derivative (I) as described above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a disease, disorder or syndrome associated with inhibition of ferroptosis, more preferably the use of a tetrahydroquinoline derivative (I) as described above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of multiple sclerosis.

[0037]

In another aspect, the present invention includes a tetrahydroquinoline (I) derivative as described above or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease, disorder or syndrome associated with inhibition of ferroptosis, preferably a tetrahydroquinoline (I) derivative as described above or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of multiple sclerosis.

[0038]

In another aspect, the present invention includes a method for the treatment or prevention of a disease, disorder or syndrome associated with inhibition of ferroptosis, wherein the method comprises administering an effective amount of a tetrahydroquinoline (I) derivative as described above, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, preferably a method for the treatment or prevention of multiple sclerosis, wherein the method comprises administering an effective amount of a tetrahydroquinoline (I) derivative as described above, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

EFFECT OF INVENTION

[0039]

Tetrahydroquinoline derivatives or their pharmaceutically acceptable salts, each of which is the active ingredient of the medicinal product of the invention, exhibit an inhibitory effect against ferroptosis and a pharmacological action based on this inhibitory effect. Therefore, the medicinal product of the present invention has a therapeutic or prophylactic effect on diseases, disorders, or syndromes associated with ferroptosis inhibition, such as multiple sclerosis.

BRIEF DESCRIPTION OF DRAWINGS

[0040]

FIG. 1 shows the inhibitory effect of the compound of Example 1 on increasing the neurological score in a mouse model of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein.

FIG. 2 shows the inhibitory effect of the compounds of Examples 11, 32 and 36 on increasing the neurological score in the myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis model in mice.

FIG. 3 shows the inhibitory effect of the compounds of Examples 144, 171 and 172 on increasing the neurological score in a mouse model of experimental autoimmune encephalomyelitis caused by myelin oligodendrocyte glycoprotein.

FIG. 4 shows the inhibitory effect of the compounds of Examples 38 and 119 on increasing neurological score in a mouse model of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein.

FIG. 5 shows the inhibitory effect of the compound of Example 33 on increasing the neurological score in a mouse model of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein.

FIG. 6 shows the inhibitory effect of the compounds of Examples 108 and 117 on increasing neurological score in a mouse model of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein.

METHOD FOR CARRYING OUT THE INVENTION

[0041]

A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof, which is an active ingredient of the drug of the present invention, is characterized by the following general formula (I):

[0042]

[0043]

[Where

R ^1x is hydrogen, aryl, or a 5- or 6-membered heteroaryl having one or two heteroatoms selected from nitrogen, oxygen, and sulfur (any one or two hydrogen atoms in an aryl or 5- or 6-membered heteroaryl are each independently optionally substituted with halogen atom(s), C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), cyano, methoxycarbonyl, -CONR ⁶ R ⁷ , -NHCOR ⁸ , aminosulfonyl, C ₁ -C ₃ alkylsulfonylamino, aminosulfonylamino, or C ₁ -C ₃ alkylsulfonyl group(s)), or

in cases where the aryl group is phenyl (phenyl optionally forms a fused ring group as described below), R ^1x optionally represents a fused ring group formed by condensing a phenyl group with one ring selected from the group consisting of 5- or 6-membered lactam rings and 5- or 6-membered saturated heterocycles, each containing one or two oxygen atoms as a ring constituent atom (any one hydrogen atom in the fused group is optionally substituted with a methyl group);

R ^1y is hydrogen, phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl, or 3-pyridyl (except when both R ^1x and R ^1y are hydrogen);

for a combination of R ² , R ⁴ , and R ⁵ , all of R ² , R ⁴ , and R ⁵ are hydrogen, or

one of R ² , R ⁴ and R ⁵ is halogen, methoxy or methyl, in which one hydrogen atom is optionally replaced by a hydroxy group and the other two are hydrogen;

R ³ is hydrogen, halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), 3-hydroxyoxetan-3-yl, hydroxy, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), methoxycarbonyl, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or

R ⁶ and R ⁷ together represent -(CH ₂ ) _h -;

h is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom, -NH- or -N(CH ₃ )-;

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ and R ¹⁰ each independently represent hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or

R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -;

n is an integer from 3 to 6;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is an integer from 3 to 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ and R ¹⁴ each independently represent hydrogen, C ₁ -C ₅ alkyl, 2-hydroxyethyl, C ₃ or C ₄ cycloalkyl in which any one carbon atom is optionally substituted by an oxygen atom, or methyl which is substituted by a C ₃ or C ₄ cycloalkyl group in which any one carbon atom is optionally substituted by a nitrogen or oxygen atom, or

R ¹³ and R ¹⁴ together represent -(CH ₂ ) _k - in which any one or two hydrogen atoms are optionally substituted by a fluorine atom(s), a methyl group(s), a hydroxy group(s) or a methoxy group(s), or in which any one CH ₂ group is optionally substituted by an oxygen atom, a nitrogen atom or -CONH-;

k is an integer from 3 to 5;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or -NHR ¹⁶ ;

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl;

R ^v represents hydrogen, methyl in which any one hydrogen atom is optionally replaced by a hydroxy or methoxycarbonyl group, or methoxycarbonyl; and

R ^w is hydrogen, methyl, hydroxymethyl, or methoxycarbonyl (provided that 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydroquinoline are excluded).

[0044]

Among the tetrahydroquinoline (I) derivatives or their pharmaceutically acceptable salts, each of which is an active ingredient of the medicament of the present invention, the tetrahydroquinoline derivatives or their pharmaceutically acceptable salts according to [1] as described above are novel compounds. The tetrahydroquinoline derivatives or their pharmaceutically acceptable salts according to [1] are included in the tetrahydroquinoline (I) derivatives as described above or their pharmaceutically acceptable salts.

[0045]

Unless otherwise specified, the following terms used in this description have the following definitions.

[0046]

The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0047]

The term "C ₁ -C ₃ alkyl" means methyl, ethyl, propyl or isopropyl.

[0048]

The term "C₁-WITH₅"alkyl" means a linear or branched hydrocarbon group containing from one to five carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,twelfth-butyl,rubs-butyl, pentyl, isopentyl,twelfth-pentyl,rubs-pentyl or neopentyl.

[0049]

The expression "C ₁ -C ₃ alkyl in which each of one to three hydrogen atoms is independently optionally substituted with hydroxyl group(s) or fluorine atom(s)" means "C ₁ -C ₃ alkyl" as described above in which any one to three hydrogen atoms are each independently optionally substituted with hydroxy group(s) or fluorine atom(s), for example, methyl, hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, propyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,2-dihydroxypropyl, 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.

[0050]

The expression "C ₁ -C ₃ alkyl in which one to three hydrogen atoms are optionally substituted by fluorine atom(s)" means "C ₁ -C ₃ alkyl" as described above, in which any one to three hydrogen atoms are optionally substituted by fluorine atom(s), for example, 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 or 1,1,1-trifluoropropan-2-yl.

[0051]

The expression "C ₁ -C ₃ alkyl in which one to three hydrogen atoms are replaced by fluorine atom(s)" means "C ₁ -C ₃ alkyl" as described above in which one to three hydrogen atoms are replaced by fluorine atom(s), for example, 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.

[0052]

The expression "C ₁ -C ₃ alkyl in which any one hydrogen atom is optionally substituted with a hydroxyl group" means "C ₁ -C ₃ alkyl" as described above, in which any one hydrogen atom is optionally substituted with a hydroxyl group, for example, methyl, hydroxymethyl, ethyl, 1-hydroxyethyl, 2-hydroxyethyl, propyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, isopropyl, 2-hydroxypropan-2-yl or 1-hydroxypropan-2-yl.

[0053]

The expression "C ₁ -C ₃ alkyl in which any one hydrogen atom is replaced by a hydroxyl group" means "C ₁ -C ₃ alkyl" as described above in which any one hydrogen atom is replaced by a hydroxyl group, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl or 1-hydroxypropan-2-yl.

[0054]

The expression "C ₁ -C ₃ alkyl in which one to three hydrogen atoms are optionally substituted by fluorine atom(s) or any one hydrogen atom is optionally substituted by hydroxyl group" means "C ₁ -C ₃ alkyl in which one to three hydrogen atoms are optionally substituted by fluorine atom(s)" as described above, or "C ₁ -C ₃ alkyl in which any one hydrogen atom is optionally substituted by hydroxyl group" as described above.

[0055]

The expression "Methyl in which one hydrogen atom is optionally replaced by a hydroxyl group" means methyl or hydroxymethyl.

[0056]

"C ₁ -C ₃ alkoxy" means methoxy, ethoxy, propoxy or isopropoxy.

[0057]

The expression "C ₁ -C ₅ alkoxy" means a monovalent substituent in which a linear or branched C ₁ -C ₅ hydrocarbon group is bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -butoxy, tert -butoxy, pentyloxy, isopentyloxy, sec -pentyloxy, tert -pentyloxy or neopentyloxy.

[0058]

The expression "C ₁ -C ₃ alkoxy in which one to three hydrogen atoms are optionally substituted by fluorine atom(s)" means "C ₁ -C ₃ alkoxy" as described above, in which any one to three hydrogen atoms are optionally substituted by fluorine atom(s), for example, 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 or (1,1,1-trifluoropropan-2-yl)oxy.

[0059]

The expression "methoxy in which one to three hydrogen atoms are replaced by fluorine atom(s)" means fluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0060]

The expression "methoxy in which one to three hydrogen atoms are optionally replaced by fluorine atom(s)" means "methoxy in which any one to three hydrogen atoms are replaced by fluorine atom(s)" as described above, or methoxy.

[0061]

The term "C ₁ -C ₃ alkylsulfonyl" means methylsulfonyl, ethylsulfonyl, propylsulfonyl or isopropylsulfonyl.

[0062]

The term "aryl" means a monocyclic or bicyclic aromatic hydrocarbon group, such as phenyl or naphthyl (1-naphthyl or 2-naphthyl).

[0063]

The expression "5- or 6-membered heteroaryl having one or two heteroatoms selected from nitrogen, oxygen and sulfur atoms" means a 5- or 6-membered monocyclic aromatic heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen and sulfur atoms, other than carbon atoms, as a ring constituent atom, for example, 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 or 4-pyrazolyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl or 5-thiazolyl), isothiazolyl (for example, 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl), oxazolyl (for example, 2-oxazolyl, 4-oxazolyl or 5-oxazolyl) or isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl), pyridazinyl (eg 3-pyridazinyl or 4-pyridazinyl) or pyrazinyl (eg 2-pyridazinyl).

[0064]

The term "5- or 6-membered lactam rings" refers to pyrrolidin-2-one and piperidin-2-one rings.

[0065]

The expression "5- or 6-membered saturated heterocycles, each of which contains one or two oxygen atoms as a ring constituent atom" means 5- or 6-membered monocyclic saturated heterocycles, each of which contains one or two oxygen atoms, other than carbon atoms, as a ring constituent atom, and includes, for example, 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.

[0066]

The expression "a fused ring group formed by the condensation of a phenyl group with one ring selected from the group consisting of 5- or 6-membered lactam rings and 5- or 6-membered saturated heterocycles, each of which contains one or two oxygen atoms as a ring constituent atom" means a bicyclic fused ring group formed by the condensation between a phenyl group and one ring selected from the group consisting of "5- or 6-membered lactam rings" as described above and "5- or 6-membered saturated heterocycles, each of which contains one or two oxygen atoms as a ring constituent atom" as described above. Examples of the bicyclic fused ring group 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, 2,3-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-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[c][1,2]dioxin-6-yl, 3,4-dihydrobenzo[c][1,2]dioxin-7-yl, 3,4-dihydrobenzo[c][1,2]dioxin-8-yl, 1,4-dihydrobenzo[d][1,2]dioxin-5-yl and 1,4-dihydrobenzo[d][1,2]dioxin-6-yl.

[0067]

The expression "fused ring group formed by condensing a phenyl group with one ring selected from the group consisting of pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane" refers to a bicyclic fused ring group such as 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, 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-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.

[0068]

The expression "one of R ² , R ⁴ and R ⁵ is halogen, methoxy, or methyl, in which one hydrogen atom is optionally substituted by a hydroxy group and the other two are hydrogen" means that R ² is halogen, methoxy or methyl, in which one hydrogen atom is optionally substituted by a hydroxy group and both R ⁴ and R ⁵ are hydrogen, or that R ⁴ is halogen, methoxy, or methyl, in which one hydrogen atom is optionally substituted by a hydroxy group and both R ² and R ⁵ are hydrogen, or that R ⁵ is halogen, methoxy, or methyl, in which one hydrogen atom is optionally substituted by a hydroxy group and both R ² and R ⁴ are hydrogen.

[0069]

The expression "one of R ² and R ⁴ is fluorine, chlorine, methoxy, or methyl, in which one hydrogen atom is optionally substituted by a hydroxy group and both the others and R ⁵ are hydrogen" means that R ² is fluorine, chlorine, methoxy, or methyl, in which one hydrogen atom is optionally substituted by a hydroxy group and both R ⁴ and R ⁵ are hydrogen, or that R ⁴ is fluorine, chlorine, methoxy, or methyl, in which one hydrogen atom is optionally substituted by a hydroxy group and both R ² and R ⁵ are hydrogen.

[0070]

The expression "R ⁶ and R ⁷ together represent -(CH ₂ ) _h -; h is an integer from 3 to 5, wherein any one of the methylene groups is optionally substituted with an oxygen atom, -NH-, or -N(CH ₃ )-" means that R ⁶ and R ⁷ , together with the nitrogen atom which is bonded to R ⁶ and R ⁷ , form an azetidine ring (h=3), a pyrrolidine ring (h=4) or a piperidine ring (h=5), in which any one of the methylene groups is optionally substituted with an oxygen atom, -NH-, or -N(CH ₃ )-, and examples of the rings include azetidine ring (h=3), pyrrolidine ring (h=4), piperidine ring (h=5), morpholine ring (h=5), piperazine ring (h=5) and 1-methylpiperazine ring (h=5).

[0071]

The expression "R ⁹ and R ¹⁰ together represent -(CH ₂ ) _n -; n is an integer from 3 to 6" means that R ⁹ and R ¹⁰ , together with the nitrogen atom that is bonded to R ⁹ and R ¹⁰ , form an azetidine ring (n=3), a pyrrolidine ring (n=4), a piperidine ring (n=5), or an azepane ring (n=6).

[0072]

The expression "R ¹¹ and R ¹² together represent -(CH ₂ ) _m -; m is an integer from 3 to 5, wherein any one of the methylene groups is optionally substituted with an oxygen atom" means that R ¹¹ and R ¹² , together with the nitrogen atom which is bonded to R ¹¹ and R ¹² , form an azetidine ring (m=3), a pyrrolidine ring (m=4), or a piperidine ring (m=5), in which any one of the methylene groups is optionally substituted with an oxygen atom, and examples of the rings include azetidine ring (m=3), pyrrolidine ring (m=4), piperidine ring (m=5), morpholine ring (m=5), piperazine ring (m=5) and 1-methylpiperazine ring (m=5).

[0073]

The expression "R ¹³ and R ¹⁴ together represent -(CH ₂ ) _k - in which any one hydrogen atom is optionally substituted with a hydroxy group; k is 3 or 4" means that R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , form an azetidine ring (k=3) or a pyrrolidine ring (k=4), in which any one hydrogen atom is optionally substituted with a hydroxy group, and examples of the rings include azetidine ring (k=3), 3-hydroxyazetidine ring (k=3), pyrrolidine ring (k=4) and 3-hydroxypyrrolidine ring (k=4).

[0074]

The expression "R ¹³ and R ¹⁴ together represent -(CH ₂ ) _k - in which any one or two hydrogen atoms are optionally substituted by fluorine atom(s), methyl group(s), hydroxy group(s), or methoxy group(s), or in which any one CH ₂ group is optionally substituted by an oxygen atom, a nitrogen atom, or -CONH-; k is an integer from 3 to 5" means that R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , form an azetidine ring (k=3), a pyrrolidine ring (k=4), or a piperidine ring (k=5), in which any one or two hydrogen atoms are optionally substituted by a fluorine atom(s), methyl group(s), hydroxy group(s) or methoxy group(s), or in which any one CH ₂ group is optionally substituted by an oxygen atom, a nitrogen atom or -CONH-, and examples of the rings include azetidine ring (k=3), 3-fluoroazetidine ring (k=3), 3,3-difluoroazetidine ring (k=3), 2-methylazetidine ring (k=3), 3-methylazetidine ring (k=3), 4-methylazetidine ring (k=3), 2,2-dimethylazetidine ring (k=3), 2,3-dimethylazetidine ring (k=3), 2,4-dimethylazetidine ring (k=3), 3,3-dimethylazetidine ring (k=3), 3-hydroxyazetidine ring (k=3), 3-methoxyazetidine ring (k=3), pyrrolidine ring (k=4), 3-fluoropyrrolidine ring (k=4), 3,3-difluoropyrrolidine ring (k=4), 3,4-difluoropyrrolidine ring (k=4), 2-methylpyrrolidine ring (k=4), 3-methylpyrrolidine ring (k=4), 2,2-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), 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-diazepan-2-one ring (k=5), 1,4-diazepan-2-one ring (k=5) and 1,4-diazepan-5-one ring (k=5).

[0075]

The expression "R ¹³ and R ¹⁴ , together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ , form an azetidine ring in which any one hydrogen atom is optionally replaced by a hydroxy group" refers to, for example, an azetidine ring or a 3-hydroxyazetidine ring.

[0076]

The expression "azetidine ring in which any two hydrogen atoms are optionally substituted by methyl group(s) and/or fluorine atom(s) or in which any one hydrogen atom is optionally substituted by hydroxy or methoxy group" refers to 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 or a 3-methoxyazetidine ring.

[0077]

The expression " _C3 or _C4 cycloalkyl in which any one carbon atom is optionally replaced by an oxygen atom" refers to, for example, cyclopropyl, cyclobutyl, oxiran-2-yl or oxetan-3-yl.

[0078]

The expression "methyl which is substituted by a _C3 or _C4 cycloalkyl group in which any one carbon atom is optionally substituted by a nitrogen or oxygen atom" refers to, for example, cyclopropylmethyl, cyclobutylmethyl, oxiran-2-ylmethyl, oxetan-2-ylmethyl, oxetan-3-ylmethyl, aziridin-2-ylmethyl, azetidin-2-ylmethyl or azetidin-3-ylmethyl.

[0079]

The expression "methyl in which any one hydrogen atom is optionally substituted by a hydroxy or methoxycarbonyl group" refers to, for example, methyl, hydroxymethyl or methoxycarbonylmethyl.

[0080]

Preferably, R ^1x is phenyl (any one hydrogen atom of the phenyl group is optionally substituted by a fluorine or chlorine atom, or C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s) or any one hydrogen atom is optionally substituted by a hydroxy group, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted by a fluorine atom(s), cyano, methoxycarbonyl, -CONR ⁶ R ⁷ , -NHCOR ⁸ , aminosulfonyl, C ₁ -C ₃ alkylsulfonylamino, aminosulfonylamino or C ₁ -C ₃ alkylsulfonyl group), 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 (any one hydrogen atom of the phenyl group is optionally substituted by a fluorine atom or by a trifluoromethyl, hydroxymethyl, 2-hydroxypropan-2-yl, methoxy, trifluoromethoxy, cyano, methoxycarbonyl, -CONR ⁶ R ⁷ , -NHCOR ⁸ , aminosulfonyl, methylsulfonylamino, aminosulfonylamino or methylsulfonyl group), pyrazolyl, 1-oxoisoindolin-5-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or benzo[d][1,3]dioxol-5-yl, even more preferably phenyl (any one hydrogen atom of the phenyl group is optionally substituted by a fluorine atom or by a hydroxymethyl, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylamino or methylsulfonyl group).

[0081]

In cases where R ^1x is a substituted phenyl group, substitution of the hydrogen atom in the para position is preferred.

[0082]

In the tetrahydroquinoline derivatives or pharmaceutically acceptable salts thereof according to [1] as described above, which are novel compounds, R ^1x is preferably phenyl (any one hydrogen atom in the phenyl group is optionally substituted with one substituent selected from the group consisting of halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), cyano, methoxycarbonyl and -NHCOR ⁸ , provided that m- cyanophenyl and p- (trifluoromethoxy)phenyl are excluded) or 5- or 6-membered heteroaryl (any one hydrogen atom in the 5- or 6-membered heteroaryl is optionally substituted with C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy, provided that 1-methyl-1H-pyrazol-4-yl and 6-methoxypyridin-3-yl are excluded).

[0083]

Moreover, in the tetrahydroquinoline derivatives or pharmaceutically acceptable salts thereof according to [1] as described above, which are novel compounds, R ^1x is preferably hydrogen, phenyl (any one hydrogen atom of the phenyl group is substituted by C ₁ -C ₃ alkyl in which any one hydrogen atom is substituted by hydroxy, -CONR ⁶ R ⁷ , aminosulfonyl, methylsulfonylamino, aminosulfonylamino or C ₁ -C ₃ alkylsulfonyl group; in another case, the hydrogen atom at the meta position of the phenyl group is substituted by a cyano group; in another case, 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 condensed ring formed by condensing a phenyl group with one ring selected from the group consisting of pyrrolidin-2-one, piperidin-2-one and 1,3-dioxolane (where any one hydrogen atom in the fused group is optionally replaced by a methyl group).

[0084]

Preferably, R ^1y is hydrogen, phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl, more preferably 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl, even more preferably 4-aminocarbonylphenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl.

[0085]

However, the case where both R ^1x and R ^1y are hydrogen is excluded.

[0086]

For the combination of R ^1x and R ^1y , it is preferred that R ^1x is hydrogen and R ^1y is a substituent other than hydrogen, or that R ^1x is a substituent other than hydrogen and R ^1y is hydrogen; more preferably, R ^1x is a substituent other than hydrogen and R ^1y is hydrogen.

[0087]

Preferably, R ² is hydrogen, fluorine, chlorine, hydroxymethyl or methyl, more preferably hydrogen.

[0088]

Preferably, R ³ is hydrogen, fluorine, chlorine, C ₁ -C ₃ alkyl, in which any one hydrogen atom is optionally substituted by hydroxy, trifluoromethoxy, -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ , more preferably, hydrogen, fluorine, chlorine, methyl, hydroxymethyl, trifluoromethoxy or -CH ₂ CONR ¹³ R ¹⁴ , even more preferably, hydrogen, fluorine, chlorine or methyl.

[0089]

Preferably, R ⁴ is hydrogen, fluorine, chlorine or methyl, more preferably hydrogen.

[0090]

Preferably, R ⁵ is hydrogen.

[0091]

Preferably, R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or R ⁶ and R ⁷ , together with the nitrogen atom that is bonded to R ⁶ and R ⁷ , form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring; more preferably, both R ⁶ and R ⁷ represent hydrogen.

[0092]

Preferably, R ⁸ is hydrogen or C ₁ -C ₃ alkyl, more preferably methyl.

[0093]

Preferably, R ⁹ is hydrogen and R ¹⁰ is hydrogen, -COR ¹⁵ , or C ₁ -C ₃ alkylsulfonyl, or R ⁹ and R ¹⁰ together are -(CH ₂ ) _n - and n is 4 or 5; more preferably, R ⁹ is hydrogen and R ¹⁰ is -COR ¹⁵ .

[0094]

Preferably, R ¹¹ and R ¹² together represent -(CH ₂ ) _m - and m is 4 or 5 (wherein any one of the methylene groups is optionally substituted with an oxygen atom).

[0095]

It is preferred that R ¹³ is hydrogen or methyl and R ¹⁴ is hydrogen, methyl, ethyl, isopropyl, tert -butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, oxetan-3-yl, cyclopropylmethyl, cyclobutylmethyl or oxetan-3-ylmethyl, or that R ¹³ and R ¹⁴ , together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ , 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.

[0096]

Preferably, R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or -NHR ¹⁶ .

[0097]

Preferably, R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl.

[0098]

Preferably, R ^v is hydrogen.

[0099]

Preferably, R ^w is hydrogen.

[0100]

The tetrahydroquinoline derivatives (I) as described above, or pharmaceutically acceptable salts thereof, include not only the individual stereoisomers, but also all of the mixtures of stereoisomers, such as racemates or diastereomeric mixtures (e.g., mixtures of enantiomers).

[0101]

The term "stereoisomer" refers to compounds that have identical chemical structures but different three-dimensional configurations, and includes, for example, conformer, rotamer, tautomer, enantiomer, and diastereomer.

[0102]

Derivatives of tetrahydroquinoline (I) can be represented by the following general formulas (I-1) - (I-8).

[0103]

[0104]

[In the formulas, R ^1x , R ^1y , R ² , R ³ , R ⁴ , R ⁵ , R ^v and R ^w have the same definitions as described above.]

[0105]

In the tetrahydroquinoline derivatives (I), any aspect of the preferred R ^1x , R ^1y , R ² - R ¹⁶ , R ^v and R ^w described above and the preferred h, k, m and n described above may be selected and combined together. The following combinations are shown as examples, but the present invention is not limited to these examples.

[0106]

For example, in the tetrahydroquinoline derivative (I) as described above, R ^1x is phenyl (any hydrogen atom in the phenyl group is optionally substituted with a fluorine or chlorine atom, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are optionally substituted with a fluorine atom(s) or any one hydrogen atom is optionally substituted with a hydroxy group, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with a fluorine atom(s), cyano, methoxycarbonyl, -CONR ⁶ R ⁷ , -NHCOR ⁸ , aminosulfonyl, C ₁ -C ₃ alkylsulfonylamino, aminosulfonylamino or C ₁ -C ₃ alkylsulfonyl group), pyrazolyl, 1-oxoisoindolin-5-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or benzo[d][1,3]dioxol-5-yl;

R ^1y is hydrogen;

R ² is hydrogen;

R ³ is hydrogen, fluorine, chlorine, C ₁ -C ₃ alkyl in which any one hydrogen atom is optionally substituted by hydroxy, methoxy, -NR ⁹ R ¹⁰ , -CH ₂ NR ¹¹ R ¹² or -CH ₂ CONR ¹³ R ¹⁴ ;

R ⁴ represents hydrogen or methoxy;

R ⁵ is hydrogen;

R ⁶ and R ⁷ each independently represent hydrogen or C ₁ -C ₃ alkyl, or R ⁶ and R ⁷ , together with the nitrogen atom that is bonded to R ⁶ and R ⁷ , optionally form a piperidine ring, a morpholine ring, a piperazine ring, or an N-methylpiperazine ring;

R ⁸ is hydrogen or C ₁ -C ₃ alkyl;

R ⁹ is hydrogen and R ¹⁰ is hydrogen, -COR ¹⁵ , or C ₁ -C ₃ alkylsulfonyl, or R ⁹ and R ¹⁰ together are -(CH ₂ ) _n -;

n is 4 or 5;

R ¹¹ and R ¹² together represent -(CH ₂ ) _m -;

m is 4 or 5, where any one of the methylene groups is optionally substituted by an oxygen atom;

R ¹³ is hydrogen or methyl and R ¹⁴ is hydrogen, methyl, ethyl, isopropyl, tert -butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, oxetan-3-yl, cyclopropylmethyl, cyclobutylmethyl or oxetan-3-ylmethyl, or R ¹³ and R ¹⁴ , together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ , optionally 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;

R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or -NHR ¹⁶ ;

R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl;

R ^v is hydrogen; and

R ^w is hydrogen (assuming 2-phenyl-1,2,3,4-tetrahydroquinoline is excluded).

[0107]

In one embodiment, the tetrahydroquinoline derivatives (I) are, for example, the tetrahydroquinoline derivatives represented by the general formula (II-a) below or pharmaceutically acceptable salts thereof,

[0108]

[0109]

[where A is hydrogen or -CONH ₂ and R ⁹ and R ¹⁰ each independently are hydrogen, -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl, or R ⁹ and R ¹⁰ together are -(CH ₂ ) _n - and n is an integer from 3 to 6 and R ¹⁵ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or -NHR ¹⁶ , and R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl].

[0110]

Preferably, in the tetrahydroquinoline derivatives represented by the general formula (II-a) (hereinafter also referred to as tetrahydroquinoline derivatives (II-a)), R ⁹ is hydrogen and R ¹⁰ is -COR ¹⁵ and R ¹⁵ is C ₁ -C ₅ alkoxy; more preferably, A is hydrogen and R ⁹ is hydrogen and R ¹⁰ is -COR ¹⁵ and R ¹⁵ is C ₁ -C ₅ alkoxy; even more preferably, A is hydrogen and R ⁹ is hydrogen and R ¹⁰ is -COR ¹⁵ and R ¹⁵ is tert -butoxy.

[0111]

For pharmaceutically acceptable salts of tetrahydroquinoline derivatives (II-a), reference may be made to the following description of pharmaceutically acceptable salts of tetrahydroquinoline derivatives (I).

[0112]

In addition, each of the tetrahydroquinoline (II-a) derivatives or pharmaceutically acceptable salts thereof can be used as a medicine that contains the tetrahydroquinoline (II-a) derivative or pharmaceutically acceptable salt thereof as an active ingredient, and is more preferably used as a medicine for the treatment or prevention of a disease, disorder or syndrome associated with inhibition of ferroptosis.

[0113]

The disease, disorder or syndrome associated with inhibition of ferroptosis will be described below.

[0114]

In addition, each of the tetrahydroquinoline (II-a) derivatives or pharmaceutically acceptable salts thereof can be used as a ferroptosis inhibitor, which contains the tetrahydroquinoline (II-a) derivative or pharmaceutically acceptable salt thereof as an active ingredient.

[0115]

Ferroptosis inhibitor will be described below.

[0116]

In one embodiment, the tetrahydroquinoline derivatives (I) are, for example, the tetrahydroquinoline derivatives represented by the general formula (II-b) below or pharmaceutically acceptable salts thereof,

[0117]

[0118]

[where R ^1y is phenyl, 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl or 3-pyridyl, and R ³ is hydrogen or halogen, and R ⁴ is hydrogen or halogen (provided that 3-phenyl-1,2,3,4-tetrahydroquinoline is excluded)].

[0119]

Preferably, in the tetrahydroquinoline derivatives represented by the general formula (II-b) (hereinafter also referred to as tetrahydroquinoline derivatives (II-b)), R ^1y is 4-hydroxymethylphenyl, 4-aminocarbonylphenyl, 4-acetamidophenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl, and R ³ is hydrogen, fluorine or chlorine, and R ⁴ is hydrogen, fluorine or chlorine; more preferably, R ^1y is 4-aminocarbonylphenyl, 4-aminosulfonylphenyl or 4-methylsulfonylphenyl, and R ³ is hydrogen, and R ⁴ is hydrogen.

[0120]

For pharmaceutically acceptable salts of tetrahydroquinoline derivatives (II-b), reference may be made to the following description of pharmaceutically acceptable salts of tetrahydroquinoline derivatives (I).

[0121]

In addition, each of the tetrahydroquinoline (II-b) derivatives or pharmaceutically acceptable salts thereof can be used as a medicine that contains the tetrahydroquinoline (II-b) derivative or pharmaceutically acceptable salt thereof as an active ingredient, and is more preferably used as a medicine for the treatment or prevention of a disease, disorder or syndrome associated with inhibition of ferroptosis.

[0122]

The disease, disorder or syndrome associated with inhibition of ferroptosis will be described below.

[0123]

In addition, each of the tetrahydroquinoline (II-b) derivatives or pharmaceutically acceptable salts thereof can be used as a ferroptosis inhibitor, which contains the tetrahydroquinoline (II-b) derivative or pharmaceutically acceptable salt thereof as an active ingredient.

[0124]

Ferroptosis inhibitor will be described below.

[0125]

Specific examples of tetrahydroquinoline derivatives (I) are shown in Tables 1-1 to 1-7, but the present invention is not limited to these compounds.

[0126]

[Table 1-1]

[0127]

[Table 1-2]

[0128]

[Table 1-3]

[0129]

[Table 1-4]

[0130]

[Table 1-5]

[0131]

[Table 1-6]

[0132]

[Table 1-7]

[0133]

The compounds shown in Tables 1-1 through 1-7 include stereoisomers, solvates, and pharmaceutically acceptable salts of these compounds and mixtures thereof.

[0134]

Furthermore, the present invention includes prodrugs of tetrahydroquinoline (I) derivatives. A prodrug of a tetrahydroquinoline (I) derivative, as described above, is a compound that is enzymatically or chemically converted into a tetrahydroquinoline (I) derivative in the body. The active substance of the prodrug of a tetrahydroquinoline (I) derivative is a tetrahydroquinoline (I) derivative, but the prodrug of a tetrahydroquinoline (I) derivative itself may also have activity.

[0135]

The groups used to prepare the prodrug of the tetrahydroquinoline derivative (I) as described above include those described in the published literature (e.g., “Development of Pharmaceutical Products,” Hirokawa Shoten Co., 1990, vol. 7, pp. 163-198 and Progress in Medicine, vol. 5, 1985, pp. 2157-2161).

[0136]

Examples of "pharmaceutically acceptable salts" of tetrahydroquinoline (I) derivatives include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and 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, and cinnamate.

[0137]

Tetrahydroquinoline (I) derivatives may be crystals, and these crystals are included in the tetrahydroquinoline (I) derivatives, regardless of whether these crystals are a single crystal form or a mixture of crystalline forms.

[0138]

Tetrahydroquinoline (I) derivatives may be pharmaceutically acceptable cocrystals or cocrystal salts thereof. As used herein, the term "cocrystal" or "cocrystal salt" refers to a crystalline material consisting of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Cocrystals or cocrystal salts can be prepared using known cocrystallization methods.

[0139]

Tetrahydroquinoline derivatives (I) or their pharmaceutically acceptable salts may be anhydrates or may form solvates such as hydrates.

[0140]

Tetrahydroquinoline (I) derivatives or their pharmaceutically acceptable salts can be converted into solvates, such as hydrates, by known methods. For example, in a known method, a tetrahydroquinoline (I) derivative as described above or a pharmaceutically acceptable salt thereof is treated with water or another solvent (e.g., an alcoholic solvent such as methanol, ethanol, or n -propanol, N,N-dimethylformamide (hereinafter referred to as DMF), dimethyl sulfoxide (hereinafter referred to as DMSO), or any combination thereof.

[0141]

Tetrahydroquinoline (I) derivatives may be labeled with one or more isotopes, and examples of isotopes for labeling include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O and/or ¹²⁵ I.

[0142]

Tetrahydroquinoline (I) derivatives can be prepared by a suitable method based on the features derived from their basic skeleton and the types of substituents. The starting materials and reagents used to prepare these compounds are commercially available or can be prepared by known methods.

[0143]

Tetrahydroquinoline (I) derivatives, as well as intermediates and starting materials for use in the production of derivatives, can be isolated and purified using known methods. Examples of known isolation and purification methods include solvent extraction, recrystallization, and chromatography.

[0144]

In cases where tetrahydroquinoline (I) derivatives include optical isomers or stereoisomers, each isomer can be obtained as a separate compound by known or similar methods. Examples of known methods include crystallization, enzymatic separation, and chiral chromatography.

[0145]

Examples of general methods for preparing tetrahydroquinoline (I) derivatives are shown below. Some of the compounds included in the following schemes are in the form of salts, and salts similar to, for example, salts of tetrahydroquinoline (I) derivatives are used. The preparation methods used in the present invention are not limited to the following examples.

[0146]

Method of obtaining 1

Among the tetrahydroquinoline derivatives (I), the tetrahydroquinoline derivatives (Ia) can be prepared by the method shown in, for example, Scheme 1, in which all of R ^1y , R ^v and R ^w are hydrogen and R ³ is hydrogen, halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), hydroxy, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), or methoxycarbonyl.

[0147]

Scheme 1

[0148]

[In the scheme, X is halogen and R ^3a is hydrogen, halogen, C ₁ -C ₃ alkyl in which any one to three hydrogen atoms are each independently substituted with hydroxy group(s) or fluorine atom(s), hydroxy, C ₁ -C ₃ alkoxy in which any one to three hydrogen atoms are optionally substituted with fluorine atom(s), or methoxycarbonyl and the symbols in the scheme have the same definitions as above.]

[0149]

(Stage 1-1)

Quinoline derivatives (IX) can be obtained by coupling 2-haloquinoline derivatives (III) and boronic acid derivatives (IV) in the presence of a metal catalyst and a base.

[0150]

The boronic acid derivatives (IV) used for the coupling reaction are preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 0.8 to 4 equivalents relative to the 2-haloquinoline derivatives (III).

[0151]

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

[0152]

The metal catalyst used for the coupling reaction is preferably used in an amount of 0.01 to 5 equivalents, more preferably in an amount of 0.025 to 1 equivalent with respect to the 2-haloquinoline derivatives (III).

[0153]

The ligand can be further used for the coupling reaction. Examples of useful ligands include triphenylphosphine, tert -butylphosphine, and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0154]

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 and cesium carbonate, lithium amides such as lithium hexamethyldisilazide and lithium diisopropylamide; metal alkoxides such as sodium tert -butoxide and potassium tert -butoxide and mixtures thereof; and an inorganic base such as sodium carbonate, potassium carbonate or cesium carbonate is preferred.

[0155]

The base used for the coupling reaction is preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 1 to 4 equivalents with respect to the 2-haloquinoline derivatives (III).

[0156]

The reaction solvent used in the coupling reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited to a specific solvent as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane and 1,2-dimethoxyethane (hereinafter referred to as DME); nitrile solvents such as acetonitrile and propionitrile; aromatic hydrocarbon solvents such as benzene and toluene; a polar aprotic solvent such as DMF, N,N-dimethylacetamide (hereinafter referred to as DMA) and DMSO; water and a mixture thereof; and an ether solvent such as THF, 1,4-dioxane or DME are preferred; a polar aprotic solvent such as DMF, DMA, or DMSO, or a mixture of water with any of the solvents.

[0157]

The reaction temperature for the coupling reaction is preferably from 0°C to 200°C, more preferably from 50°C to 150°C.

[0158]

The reaction time for the coupling reaction is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 hour to 30 hours.

[0159]

The 2-haloquinoline derivatives (III) and boronic acid derivatives (IV) used in the coupling reaction can be purchased or prepared according to known methods or methods similar thereto.

[0160]

(Stage 1-2)

Quinoline derivatives (IX) can be prepared by cycloaddition reaction of 2-aminobenzyl alcohol derivatives (V) and ketone derivatives (VI) in the presence of a base, for example, according to the method described in Tetrahedron Letters, 2008, 6893-6895, or by methods similar thereto.

[0161]

The ketone derivatives (VI) used for the cycloaddition reaction are preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 0.8 to 5 equivalents relative to the 2-aminobenzyl alcohol derivatives (V).

[0162]

Examples of the base used in the cycloaddition reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, and cesium hydroxide; metal alkoxides such as sodium ethoxide, sodium tert -butoxide, and potassium tert -butoxide; metal hydride compounds such as sodium hydride, potassium hydride, and calcium hydride, and mixtures thereof; and a metal alkoxide such as sodium ethoxide, sodium tert -butoxide, or potassium tert -butoxide is preferred.

[0163]

The base used for the cycloaddition reaction is preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 1 to 3 equivalents with respect to the 2-aminobenzyl alcohol derivatives (V).

[0164]

The reaction solvent used in the cycloaddition reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane, and DME; aromatic hydrocarbon solvents such as benzene and toluene; polar aprotic solvents such as DMF, DMA, and DMSO; and mixtures thereof; and an ether solvent such as THF, 1,4-dioxane, or DME is preferred.

[0165]

The reaction temperature for the cycloaddition reaction is preferably from 0°C to 200°C, more preferably from 50°C to 150°C.

[0166]

The reaction time for the cycloaddition reaction is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 hour to 24 hours.

[0167]

The 2-aminobenzyl alcohol derivatives (V) and ketone derivatives (VI) used in the cycloaddition reaction can be purchased or prepared according to known methods or methods similar thereto.

[0168]

(Stage 1-3)

Quinoline derivatives (IX) can be obtained by the oxidative cyclization reaction of aniline derivatives (VII) and allyl alcohol derivatives (VIII-a) or α,β-unsaturated aldehyde derivatives (VIII-b) in the presence of a metal catalyst in an oxygen atmosphere, for example, according to the method described in RSC Advances, 2017, 36242-36245, or similar methods.

[0169]

The allyl alcohol derivatives (VIII-a) or the α,β-unsaturated aldehyde derivatives (VIII-b) used for the oxidative cyclization reaction are preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 0.8 to 2 equivalents, relative to the aniline derivatives (VII).

[0170]

Examples of the metal catalyst used in the oxidative cyclization reaction include palladium(II) acetate, trifluoropalladium(II) acetate, palladium(II) chloride, and dichlorobis(acetonitrile)palladium(II); and palladium(II) acetate is preferred.

[0171]

The metal catalyst used for the oxidative cyclization reaction is preferably used in an amount of 0.01 to 5 equivalents, more preferably in an amount of 0.025 to 1 equivalent with respect to the aniline (VII) derivatives.

[0172]

The oxygen atmosphere used in the oxidative cyclization reaction preferably has a pressure of about 1 to about 20 atmospheres, more preferably a pressure of about 1 to about 5 atmospheres.

[0173]

The reaction solvent used for the oxidative cyclization reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane, and DME; aromatic hydrocarbon solvents such as benzene and toluene; polar aprotic solvents such as DMF, DMA, and DMSO; and mixtures thereof; and a polar aprotic solvent such as DMF, DMA, or DMSO is preferred.

[0174]

The reaction temperature for the oxidative cyclization reaction is preferably from 0 to 300°C, more preferably from 70 to 200°C.

[0175]

The reaction time for the oxidative cyclization reaction is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 24 hours.

[0176]

The aniline derivatives (VII), allyl alcohol derivatives (VIII-a) and α,β-unsaturated aldehyde derivatives (VIII-b) used for the oxidative cyclization reaction can be purchased or prepared according to known methods or methods similar thereto.

[0177]

(Stage 1-4)

Tetrahydroquinoline derivatives (Ia) can be obtained by the hydrogenation reaction of quinoline derivatives (IX) in the presence of a metal catalyst in a hydrogen atmosphere or by the transfer hydrogenation reaction between 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate derivatives and quinoline derivatives (IX).

[0178]

Examples of the metal catalyst used in the hydrogenation reaction include palladium compounds such as palladium on carbon, palladium(II) hydroxide on carbon, and palladium(II) oxide; nickel compounds such as a nickel sponge catalyst; platinum compounds such as platinum(IV) oxide and platinum on carbon; rhodium compounds such as rhodium on carbon, and the like; and platinum(IV) oxide is preferred.

[0179]

The metal catalyst used for the hydrogenation reaction is preferably used in an amount of 0.001 to 1 equivalent, more preferably in an amount of 0.01 to 0.5 equivalent with respect to the quinoline derivatives (IX).

[0180]

The hydrogen atmosphere used for the hydrogenation reaction preferably has a pressure of about 1 to about 30 atmospheres, more preferably a pressure of about 1 to about 10 atmospheres.

[0181]

The reaction solvent used in the hydrogenation reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert -butyl alcohol; aromatic hydrocarbon solvents such as toluene and xylene; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; ether solvents such as diethyl ether, THF, DME and 1,4-dioxane; ester solvents such as ethyl acetate and propyl acetate; polar aprotic solvents such as DMF, DMA and DMSO; carboxylic acid solvents such as formic acid and acetic acid; water and mixtures thereof; and a mixture of an alcohol solvent such as methanol, ethanol, isopropyl alcohol or tert -butyl alcohol and a carboxylic acid solvent such as formic acid or acetic acid is preferred.

[0182]

The reaction temperature for the hydrogenation reaction is preferably from 0 to 200°C, more preferably from 10 to 100°C.

[0183]

The hydrogenation reaction time is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 0.5 to 40 hours.

[0184]

Examples of the 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative used for the transfer hydrogenation 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, didodecyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and the like; and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate is preferred.

[0185]

The 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative used for the transfer hydrogenation reaction is preferably used in an amount of 1 to 10 equivalents, more preferably in an amount of 1.7 to 3 equivalents, relative to the quinoline derivatives (IX).

[0186]

The reaction solvent used in the transfer hydrogenation reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert -butyl alcohol; aromatic hydrocarbon solvents such as toluene and xylene; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; ether solvents such as diethyl ether, THF, DME and 1,4-dioxane; ester solvents such as ethyl acetate and propyl acetate; polar aprotic solvents such as DMF, DMA and DMSO; and mixtures thereof; and a chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or an ethereal solvent such as diethyl ether, THF, DME or 1,4-dioxane is preferred.

[0187]

The reaction temperature for the transfer hydrogenation reaction is preferably from 0 to 100°C, more preferably from 10 to 50°C.

[0188]

The reaction time for the transfer hydrogenation reaction is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 24 hours.

[0189]

Method of obtaining 2

Among the tetrahydroquinoline derivatives (I), the tetrahydroquinoline derivatives (Ib) can be prepared by the method shown in, for example, Scheme 2, in which all of R ^1y , R ^v and R ^w are hydrogen and R ³ is -NR ⁹ R ¹⁰ and R ⁹ and R ¹⁰ together are -(CH ₂ ) _n -.

[0190]

Scheme 2

[0191]

[In the diagram, each symbol has a definition as given above.]

[0192]

(Stage 2-1)

Aminoquinoline derivatives (XI) can be prepared by coupling 6-haloquinoline derivatives (IX-a) and secondary amine derivatives (X) in the presence of a metal catalyst and a base.

[0193]

The secondary amine derivatives (X) used for the coupling reaction are preferably used in an amount of 0.5 to 20 equivalents, more preferably in an amount of 0.8 to 10 equivalents relative to the 6-haloquinoline derivatives (IX-a).

[0194]

Examples of the metal catalyst used in the coupling reaction include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(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); and palladium(II) acetate is preferred.

[0195]

The metal catalyst used for the coupling reaction is preferably used in an amount of 0.001 to 5 equivalents, more preferably in an amount of 0.02 to 0.5 equivalents with respect to the 6-haloquinoline derivatives (IX-a).

[0196]

A ligand can be further used for the coupling reaction. Examples of the used 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.

[0197]

In cases where a ligand is used for the coupling reaction, the amount of the ligand is preferably from 0.001 to 5 equivalents, more preferably from 0.02 to 1 equivalent, relative to the 6-haloquinoline derivatives (IX-a).

[0198]

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, and cesium carbonate; lithium amides such as lithium hexamethyldisilazide and lithium diisopropylamide; metal alkoxides such as sodium tert -butoxide and potassium tert -butoxide; and mixtures thereof; and an inorganic base such as sodium carbonate, potassium carbonate, or cesium carbonate is preferred.

[0199]

The base used for the coupling reaction is preferably used in an amount of 0.8 to 10 equivalents, more preferably in an amount of 1 to 5 equivalents with respect to the 6-haloquinoline derivatives (IX-a).

[0200]

The reaction solvent used for the coupling reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert -butyl alcohol; ether solvents such as THF, 1,4-dioxane and DME; aromatic hydrocarbon solvents such as benzene and toluene, nitrile solvents such as acetonitrile and propionitrile; polar aprotic solvents such as DMF, DMA and DMSO; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; and mixtures thereof; and an ether solvent such as THF, 1,4-dioxane or DME is preferable.

[0201]

The reaction temperature for the coupling reaction is preferably from 0 to 200°C, more preferably from 50 to 150°C.

[0202]

The reaction time for the coupling reaction is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 30 hours.

[0203]

The 6-haloquinoline derivatives (IX-a) used in the coupling reaction can be purchased or prepared by the methods described in steps 1-1-1-3, known methods or methods similar thereto.

[0204]

The secondary amine derivatives (X) used in the coupling reaction can be purchased or prepared according to known methods or methods similar thereto.

[0205]

(Stage 2-2)

Tetrahydroquinoline derivatives (Ib) can be prepared by hydrogenation or transfer hydrogenation of aminoquinoline derivatives (XI). The conditions selected for this step, including reagents, catalyst, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in steps 1–4.

[0206]

Method of obtaining 3

Among the tetrahydroquinoline derivatives (I), the tetrahydroquinoline derivatives (Ic) can be prepared by the method shown in, for example, Scheme 3, in which all of R ^1y , R ^v and R ^w are hydrogen and R ³ is NR ⁹ R ¹⁰ , and R ⁹ is hydrogen, and R ¹⁰ is -COR ¹⁵ and R ¹⁵ is C ₁ -C ₅ alkoxy.

[0207]

Scheme 3

[0208]

[In the diagram, Y represents C ₁ -C ₅ alkyl and other symbols have the same definitions as above.]

[0209]

(Stage 3-1)

Derivatives of quinoline-6-carboxylic acid (XII) can be obtained by hydrolysis of derivatives of quinoline-6-carboxylic acid ester (IX-b) in the presence of a base.

[0210]

Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide and sodium tert -butoxide, and potassium hydroxide or sodium hydroxide is preferred.

[0211]

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

[0212]

The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the types of the reactants, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane and DME; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbon solvents such as benzene and toluene; polar aprotic solvents such as DMF, DMA and DMSO; ketone solvents such as acetone and methyl ethyl ketone; alcohol solvents such as methanol, ethanol and 2-propanol; water and mixtures thereof; and a mixture of an alcohol solvent such as methanol, ethanol or 2-propanol and water is preferred.

[0213]

The reaction temperature in the hydrolysis reaction is preferably from -50°C to 150°C, more preferably from -20°C to 100°C.

[0214]

The reaction time for the hydrolysis reaction is appropriately selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 30 hours.

[0215]

The quinoline-6-carboxylic acid ester derivatives (IX-b) used in the hydrolysis reaction can be purchased or prepared by the methods described in steps 1-1-1-3, known methods, or equivalent methods.

[0216]

(Stage 3-2)

Derivatives of quinoline-6-carbamic acid ester (XIV) can be prepared by reacting quinoline-6-carboxylic acid derivatives (XII) with diphenylphosphoryl azide to give acyl azides, followed by subjecting the isocyanate derivatives, which are obtained by the acyl azide rearrangement reaction, to a transesterification reaction.

[0217]

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

[0218]

Examples of bases used in the rearrangement reaction include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide; and organic bases such as triethylamine and N,N-diisopropylethylamine; and an organic base such as triethylamine or N,N-diisopropylethylamine is preferred.

[0219]

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

[0220]

The reaction solvent used for the rearrangement reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane, and DME; ester solvents such as ethyl acetate and propyl acetate; chlorinated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; aromatic hydrocarbon solvents such as benzene and toluene; nitrile solvents such as acetonitrile and propionitrile; polar aprotic solvents such as DMF, DMA, and DMSO; and mixtures thereof.

[0221]

Examples of alcohols (XIII) used for the transesterification reaction include methanol, ethanol, isopropyl alcohol, and tert -butyl alcohol.

[0222]

The alcohols (XIII) used for the transesterification reaction are used in an amount of 1 to 20 equivalents relative to the quinoline-6-carboxylic acid derivatives (XII) and can be used as a reaction solvent instead of the reaction solvent used in the rearrangement reaction.

[0223]

The reaction temperature for the rearrangement reaction and the transesterification reaction is preferably from 30 to 200°C, more preferably from 50 to 150°C.

[0224]

The reaction time for the rearrangement reaction and the transesterification reaction is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 30 hours.

[0225]

Moreover, quinoline-6-carbamic acid ester derivatives (XIV) can also be prepared similarly using acyl azides, which are obtained by converting the carboxyl group in quinoline-6-carboxylic acid derivatives (XII) into a reactive functional group and reacting the resulting derivatives with a metal azide (e.g., sodium azide).

[0226]

Examples of compounds with a reactive functional group include acid chlorides, mixed acid anhydrides with chlorocarbonate esters (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, or isobutyl chlorocarbonate), symmetrical acid anhydrides, and activated amides with imidazole.

[0227]

(Stage 3-3)

Tetrahydroquinoline derivatives (I-c) can be prepared by hydrogenation or transfer hydrogenation of quinoline-6-carbamic acid ester derivatives (XIV). The conditions selected for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in steps 1-4.

[0228]

Method of obtaining 4

Among the tetrahydroquinoline derivatives (I), the tetrahydroquinoline derivatives (Id) - (If) can be prepared by the method shown in, for example, Scheme 4, in which all of R ^1y , R ^v and R ^w are hydrogen and R ³ is -NR ⁹ R ¹⁰ and R ⁹ is hydrogen and R ¹⁰ is -COR ¹⁵ or C ₁ -C ₃ alkylsulfonyl and R ¹⁵ is C ₁ -C ₅ alkyl or -NHR ¹⁶ and R ¹⁶ is hydrogen or C ₁ -C ₅ alkyl.

[0229]

Scheme 4

[0230]

[In the diagram, each L independently represents a leaving group and Z represents C ₁ -C ₃ alkyl and other symbols have the same definitions as above.]

[0231]

Examples of the leaving group represented by L include halogen such as fluorine, chlorine, bromine or iodine; _C1 - _C12 alkylthio such as methylthio, ethylthio or dodecylthio; aryloxy such as phenoxy; methanesulfonyloxy, ethanesulfonyloxy or alkylsulfonyloxy in which the hydrogen atom(s) is(are) optionally substituted by halogen atom(s), such as trifluoromethanesulfonyloxy; alkylsulfonylamino such as trifluoromethanesulfonylamino; and azolyl such as imidazol-1-yl or pyrazol-1-yl.

[0232]

(Stage 4-1)

Diphenylmethanimine derivatives (XV) can be prepared by coupling 6-haloquinoline derivatives (IX-a) and diphenylmethanimine in the presence of a metal catalyst and a base. The conditions chosen for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in Step 2-1.

[0233]

The 6-haloquinoline derivatives (IX-a) used in the coupling reaction can be purchased or prepared by the methods described in steps 1-1-1-3, known methods, or methods similar thereto.

[0234]

(Stage 4-2)

Aminoquinoline derivatives (XVI) can be obtained by deprotection of diphenylmethanimine derivatives (XV).

[0235]

Examples of the acid used in the deprotection reaction include hydrochloric acid, 10% by mass hydrogen chloride-methanol solution, 4 mol/L hydrochloride-ethyl acetate solution, trifluoroacetic acid, and hydrochloric acid; and hydrochloric acid is preferred.

[0236]

The acid used for the deprotection reaction is preferably used in an amount of 0.5 to 100 equivalents, more preferably in an amount of 1 to 10 equivalents relative to the diphenylmethanimine derivatives (XV).

[0237]

The reaction solvent used for the deprotection reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as diethyl ether, THF, DME and 1,4-dioxane; ester solvents such as ethyl acetate and propyl acetate; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; alcohol solvents such as methanol and ethanol; and mixtures thereof; and ester solvents such as ethyl acetate or propyl acetate and chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.

[0238]

The reaction temperature for the deprotection reaction is preferably from 0 to 200°C, more preferably from 0 to 100°C.

[0239]

The reaction time for the deprotection reaction varies depending on the reaction conditions, and the preferred reaction time is 1 to 48 hours.

[0240]

(Stage 4-3)

Amidoquinoline derivatives (XVIII) can be obtained by the acylation reaction of aminoquinoline derivatives (XVI) with an acylating agent (XVII).

[0241]

The acylating agent (XVII) used for the acylation reaction is preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 1 to 3 equivalents, relative to the aminoquinoline derivatives (XVI).

[0242]

A base may optionally be used for the acylation reaction. Examples of the base used include organic bases such as triethylamine, N,N-diisopropylethylamine and pyridine; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; and mixtures thereof; and an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide is preferred.

[0243]

The reaction solvent used for the acylation reaction is suitably selected depending on the types of reagents used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include nitrile solvents such as acetonitrile and propionitrile; polar aprotic 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 mixtures thereof; and a mixture of an ether solvent such as diethyl ether, THF, DME, or 1,4-dioxane and water is preferred.

[0244]

The reaction temperature for the acylation reaction is preferably from -78°C to 100°C, more preferably from -20°C to 50°C.

[0245]

The reaction time for the acylation reaction varies depending on the reaction conditions, and the preferred reaction time is 1 to 30 hours.

[0246]

The acylating agent (XVII) used for the acylation reaction can be purchased or prepared according to a known method or similar methods.

[0247]

(Stage 4-4)

Tetrahydroquinoline derivatives (I-d) can be prepared by hydrogenation or transfer hydrogenation of amidoquinoline derivatives (XVIII). The conditions chosen for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in steps 1-4.

[0248]

(Stage 4-5)

Urea-quinoline derivatives (XX) can be prepared by the urea formation reaction between aminoquinoline derivatives (XVI) and a urea forming agent (XIX).

[0249]

The urea forming agent (XIX) used for the urea forming reaction is preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 1 to 3 equivalents, relative to the aminoquinoline derivatives (XVI).

[0250]

A base may optionally be used for the urea formation reaction. Examples of the base used include organic bases such as triethylamine, N,N-diisopropylethylamine, and pyridine; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; and mixtures thereof; and an organic base such as triethylamine, N,N-diisopropylethylamine, or pyridine is preferred.

[0251]

The reaction solvent used for the urea formation reaction is suitably selected depending on the types of reagents used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include nitrile solvents such as acetonitrile and propionitrile, polar aprotic 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 mixtures thereof; and an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane is preferred.

[0252]

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

[0253]

The reaction time for the urea formation reaction varies depending on the reaction conditions, and the preferred reaction time is 1 to 30 hours.

[0254]

The urea forming agent (XIX) used for the urea forming reaction can be purchased or prepared according to a known method or similar methods.

[0255]

(Stage 4-6)

Tetrahydroquinoline derivatives (I-e) can be prepared by hydrogenation or transfer hydrogenation of urea-quinoline derivatives (XX). The conditions selected for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in steps 1-4.

[0256]

(Stage 4-7)

Sulfonylamidoquinoline derivatives (XXII) can be obtained by sulfonylation reaction of aminoquinoline derivatives (XVI) with a sulfonylating agent (XXI).

[0257]

The sulfonylating agent (XXI) used for the sulfonylation reaction is preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 1 to 3 equivalents, relative to the aminoquinoline derivatives (XVI).

[0258]

A base may optionally be used for the sulfonylation reaction. Examples of the base used include organic bases such as triethylamine, N,N-diisopropylethylamine, and pyridine; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkali metal hydrocarboxylate such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; and mixtures thereof; and an organic base such as triethylamine, N,N-diisopropylethylamine, or pyridine is preferred.

[0259]

The reaction solvent used for the sulfonylation reaction is suitably selected depending on the types of reagents used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include nitrile solvents such as acetonitrile and propionitrile; polar aprotic 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 mixtures thereof; and an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane are preferred.

[0260]

The reaction temperature for the sulfonylation reaction is preferably from -78°C to 100°C, more preferably from -20°C to 50°C.

[0261]

The reaction time in the sulfonylation reaction varies depending on the reaction conditions, and the preferred reaction time is from 1 to 30 hours.

[0262]

The sulfonylating agent (XXI) used in the sulfonylation reaction can be purchased or prepared according to a known method or similar methods.

[0263]

(Stage 4-8)

Tetrahydroquinoline derivatives (I-f) can be prepared by hydrogenation or transfer hydrogenation of sulfonylamidoquinoline derivatives (XXII). The conditions chosen for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in steps 1-4.

[0264]

Method of obtaining 5

Among the tetrahydroquinoline (I) derivatives, tetrahydroquinoline (Ig) derivatives can be prepared by the method shown in, for example, Scheme 5, in which all of R ^1y , R ^v , and R ^w are hydrogen and R ³ is -CH ₂ NR ¹¹ R ¹² .

[0265]

Scheme 5

[0266]

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

[0267]

(Stage 5-1)

(Methoxycarbonyl)tetrahydroquinoline derivatives (XXIII) can be prepared by hydrogenation or transfer hydrogenation of quinoline-6-carboxylic acid ester derivatives (IX-b). The conditions selected for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in steps 1-4.

[0268]

The quinoline-6-carboxylic acid ester derivatives (IX-b) used in the hydrogenation reaction or the transfer hydrogenation reaction can be purchased or prepared by the methods described in steps 1-1-1-3, known methods, or methods similar thereto.

[0269]

(Stage 5-2)

Derivatives of (hydroxymethyl)tetrahydroquinoline (XXIV) can be obtained by the reduction reaction of derivatives of (methoxycarbonyl)tetrahydroquinoline (XXIII).

[0270]

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; and an aluminum-based reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride is preferred.

[0271]

The reducing agent used in the reduction reaction is preferably used in an amount of 0.3 to 100 equivalents, more preferably in an amount of 0.5 to 20 equivalents, relative to the (methoxycarbonyl)tetrahydroquinoline derivatives (XXIII).

[0272]

The reaction solvent used for the reduction reaction is suitably selected depending on the types of reagents used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert -butyl alcohol; polar aprotic solvents such as DMF, DMA and DMSO; ether solvents such as diethyl ether, THF, DME and 1,4-dioxane; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbon solvents such as toluene and xylene; and mixtures thereof; and an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane, or an aromatic hydrocarbon solvent such as toluene or xylene is preferred.

[0273]

The reaction temperature for the reduction reaction is preferably from -100°C to 200°C, more preferably from -50°C to 50°C.

[0274]

The reaction time for the reduction reaction varies depending on the reaction conditions, and the preferred reaction time is 1 to 30 hours.

[0275]

(Stage 5-3)

Tetrahydroquinoline derivatives (I-g) can be obtained by the substitution reaction between (hydroxymethyl)tetrahydroquinoline derivatives (XXIV) and secondary amine derivatives (XXV) in the presence of a phosphine derivative and iodine.

[0276]

The secondary amine derivatives (XXV) used for the substitution reaction are preferably used in an amount of 0.5 to 100 equivalents, more preferably in an amount of 1 to 20 equivalents, relative to the (hydroxymethyl)tetrahydroquinoline derivatives (XXIV).

[0277]

Examples of the phosphine derivative used in the substitution reaction include triphenylphosphine, trimethylphosphine and tri- n -butylphosphine; and triphenylphosphine is preferred.

[0278]

The phosphine derivatives used for the substitution reaction are preferably used in an amount of 0.5 to 20 equivalents, more preferably in an amount of 1 to 5 equivalents, relative to the (hydroxymethyl)tetrahydroquinoline derivatives (XXIV).

[0279]

Iodine used for the substitution reaction is preferably used in an amount of 0.5 to 20 equivalents, more preferably in an amount of 1 to 5 equivalents, relative to the (hydroxymethyl)tetrahydroquinoline derivatives (XXIV).

[0280]

The reaction solvent used for the substitution reaction is not particularly limited as long as the reaction is not inhibited by the reaction solvent. Examples of the reaction solvent include polar aprotic solvents such as DMF, DMA and DMSO; ketone solvents such as acetone and methyl ethyl ketone; ester solvents such as ethyl acetate and propyl acetate; ether solvents such as diethyl ether, THF, DME and 1,4-dioxane; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbon solvents such as toluene and xylene; and mixtures thereof; and chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.

[0281]

The reaction temperature for the substitution reaction is preferably from 0 to 150°C, more preferably from 10 to 70°C.

[0282]

The reaction time for the substitution reaction varies depending on the reaction conditions, and the preferred reaction time is 1 to 24 hours.

[0283]

Method of obtaining 6

Among the tetrahydroquinoline derivatives (I), tetrahydroquinoline derivatives (Ih) and (Ii) can be prepared by the method shown in, for example, Scheme 6, in which all of R ^1y , R ^v and R ^w are hydrogen and R ³ is -CH ₂ CONR ¹³ R ¹⁴ .

[0284]

Scheme 6

[0285]

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

[0286]

(Stage 6-1)

Nitrile derivatives (XXVI) can be prepared by the Mitsunobu reaction between (hydroxymethyl)tetrahydroquinoline derivatives (XXIV) and acetone cyanohydrin using an azodicarboxylic acid ester derivative in the presence of a phosphine derivative.

[0287]

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

[0288]

The azodicarboxylic acid ester derivative used for the Mitsunobu reaction is preferably used in an amount of 0.5 to 30 equivalents, more preferably in an amount of 1 to 10 equivalents, relative to the (hydroxymethyl)tetrahydroquinoline derivatives (XXIV).

[0289]

Examples of the phosphine derivative used in the Mitsunobu reaction include triphenylphosphine, trimethylphosphine and tri- n -butylphosphine; and tri- n -butylphosphine is preferred.

[0290]

The phosphine derivative used in the Mitsunobu reaction is preferably used in an amount of 0.5 to 30 equivalents, more preferably in an amount of 1 to 10 equivalents, relative to the (hydroxymethyl)tetrahydroquinoline derivatives (XXIV).

[0291]

Acetone cyanohydrin is preferably used in the Mitsunobu reaction in an amount of 0.5 to 50 equivalents, more preferably in an amount of 1 to 20 equivalents, relative to the (hydroxymethyl)tetrahydroquinoline derivatives (XXIV).

[0292]

The reaction solvent used for the Mitsunobu reaction is not particularly limited as long as the reaction is not inhibited by the reaction solvent. Examples of the reaction solvent include polar aprotic solvents such as DMF, DMA, and DMSO; ketone solvents such as acetone and methyl ethyl ketone; ester solvents such as ethyl acetate and propyl acetate; ether solvents such as diethyl ether, THF, DME, and 1,4-dioxane; chlorinated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; aromatic hydrocarbon solvents such as toluene and xylene; and mixtures thereof; and an ether solvent such as diethyl ether, THF, DME, or 1,4-dioxane is preferred.

[0293]

The reaction temperature for the Mitsunobu reaction is preferably from -20°C to 200°C, more preferably from -10°C to 100°C.

[0294]

The reaction time for the Mitsunobu reaction varies depending on the reaction conditions, and the preferred reaction time is 1 to 12 hours.

[0295]

(Stage 6-2)

Tetrahydroquinoline derivatives (I-h) can be obtained by hydrolysis of nitrile derivatives (XXVI) in the presence of an aqueous solution of hydrogen peroxide and a base.

[0296]

The aqueous hydrogen peroxide solution used for the hydrolysis reaction is preferably used in an amount of 0.5 to 100 equivalents, more preferably in an amount of 1 to 30 equivalents, relative to the nitrile derivatives (XXVI).

[0297]

Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide and sodium tert -butoxide; and potassium hydroxide or sodium hydroxide are preferred.

[0298]

The base used in the hydrolysis reaction is preferably used in an amount of 0.5 to 100 equivalents, more preferably in an amount of 0.8 to 20 equivalents, relative to the nitrile derivatives (XXVI).

[0299]

The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the types of the reactants, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane and DME; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbon solvents such as benzene and toluene; polar aprotic solvents such as DMF, DMA and DMSO, ketone solvents such as acetone and methyl ethyl ketone, alcohol solvents such as methanol, ethanol and 2-propanol and mixtures thereof, and a mixture of a polar aprotic solvent such as DMF, DMA or DMSO; and an ether solvent such as THF, 1,4-dioxane or DME is preferred.

[0300]

The reaction temperature in the hydrolysis reaction is preferably from -50°C to 150°C, more preferably from -20°C to 100°C.

[0301]

The reaction time for the hydrolysis reaction is appropriately selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 30 hours.

[0302]

(Stage 6-3)

Carboxylic acid derivatives (XXVII) can be obtained by hydrolysis of tetrahydroquinoline derivatives (I-h) in the presence of a base.

[0303]

Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide and sodium tert -butoxide; and potassium hydroxide or sodium hydroxide are preferred.

[0304]

The base used in the hydrolysis reaction is preferably used in an amount of 0.5 to 100 equivalents, more preferably in an amount of 0.8 to 30 equivalents, relative to the tetrahydroquinoline derivatives (I-h).

[0305]

The reaction solvent used in the hydrolysis reaction is appropriately selected depending on the types of the reactants, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane and DME; chlorinated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbon solvents such as benzene and toluene; polar aprotic solvents such as DMF, DMA and DMSO; ketone solvents such as acetone and methyl ethyl ketone; alcohol solvents such as methanol, ethanol and 2-propanol; water and mixtures thereof; and a mixture of an alcohol solvent such as methanol, ethanol or 2-propanol and water is preferred.

[0306]

The reaction temperature in the hydrolysis reaction is preferably from 0 to 200°C, more preferably from 20°C to 100°C.

[0307]

The reaction time for the hydrolysis reaction is appropriately selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 30 hours.

[0308]

(Stage 6-4)

The tetrahydroquinoline derivative (I-i) can be obtained by the condensation reaction between carboxylic acid derivatives (XXVII) and amine derivatives (XXVIII) in the presence of a condensing agent.

[0309]

The amine derivatives (XXVIII) used for the condensation reaction are preferably used in an amount of 0.1 to 10 equivalents, more preferably in an amount of 0.5 to 5 equivalents, relative to the carboxylic acid derivatives (XXVII).

[0310]

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; and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is preferred.

[0311]

The condensing agent used for the condensation reaction is preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 1 to 3 equivalents, relative to the carboxylic acid derivatives (XXVII).

[0312]

Examples of the base used in the condensation reaction include organic bases such as triethylamine and diisopropylethylamine; inorganic bases such as sodium hydrogencarbonate and potassium carbonate; metal hydride compounds such as sodium hydride, potassium hydride and calcium hydride; alkyl lithium compounds such as methyllithium and butyllithium; lithium amides such as lithium hexamethyldisilazide and lithium diisopropylamide; and mixtures thereof; and an organic base such as triethylamine or diisopropylethylamine is preferred.

[0313]

The base used for the condensation reaction is preferably used in an amount of 0.5 to 10 equivalents, more preferably in an amount of 1 to 5 equivalents, relative to the carboxylic acid derivatives (XXVII).

[0314]

Each amine derivative (XXVIII) can be used as a base for use in the condensation reaction. In cases where amine derivative (XXVIII) is used as a base for use in the condensation reaction, amine derivative (XXVIII) is preferably used in an amount of 0.6 to 20 equivalents, more preferably in an amount of 1 to 10 equivalents, relative to carboxylic acid derivatives (XXVII).

[0315]

The reaction solvent used for the condensation reaction is appropriately selected depending on the types of reagents and the like used, and the reaction solvent is not limited as long as the reaction is not inhibited by the solvent. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane, and DME; chlorinated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; polar aprotic solvents such as DMF and DMSO; and nitrile solvents such as acetonitrile and propionitrile; and chlorinated solvents such as dichloromethane, chloroform, or 1,2-dichloroethane; and a polar aprotic solvent such as DMF or DMSO is preferred.

[0316]

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

[0317]

The reaction time for the condensation reaction is suitably selected depending on conditions such as the reaction temperature, and the preferred reaction time is from 1 to 30 hours.

[0318]

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

[0319]

The amine derivatives (XXVIII) used in the condensation reaction can be purchased or prepared according to known methods or methods analogous thereto.

[0320]

Method of obtaining 7

Among the tetrahydroquinoline derivatives (I), optical isomers of the tetrahydroquinoline derivatives (I-j') and (Ij") can be prepared by the method shown in, for example, Scheme 7, in which all of R ^1y , R ^v and R ^w are hydrogen.

[0321]

Stage 7

[0322]

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

[0323]

(Stage 7-1)

Optical isomers (I-j’) and (I-j”) of tetrahydroquinoline derivatives (I) can be obtained by asymmetric transfer hydrogenation of quinoline derivatives (XXIX) with a 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative in the presence of a chiral phosphate catalyst, for example, according to the method described in Tetrahedron: Asymmetry, 2015, p. 1174-1179 or by methods similar thereto.

[0324]

The quinoline derivatives (XXIX) used in the asymmetric transfer hydrogenation reaction can be purchased or prepared by the methods described in steps 1-1-1-3, 2-1, 3-1, 3-2, 4-1-4-3, 4-5 and 4-7, known methods or methods similar to them.

[0325]

Examples of the chiral phosphate catalyst used in the asymmetric transfer hydrogenation reaction include ( S )-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, ( R )-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, ( S )-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, ( R )-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, ( S )-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, ( R )-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate ( S )-3,3'-bis(9-phenanthryl)-1,1'-binaphthalene-2,2'-diyl, hydrogen phosphate ( R )-3,3'-bis(9-phenanthryl)-1,1'-binaphthalene-2,2'-diyl, hydrogen phosphate ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl; and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate and ( 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 are preferred.

[0326]

Method of obtaining 8

Among the tetrahydroquinoline (I) derivatives, tetrahydroquinoline (Ik) derivatives can be prepared by the method shown in, for example, Scheme 8, in which all of R ^1x , R ^v and R ^w are hydrogen.

[0327]

Stage 8

[0328]

[In the diagram, X represents halogen and other symbols have the same definitions as above.]

[0329]

(Stage 8-1)

Quinoline derivatives (XXXII) can be prepared by coupling 3-haloquinoline derivatives (XXX) and boronic acid derivatives (XXXI) in the presence of a metal catalyst and a base. The conditions chosen for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in Step 1-1.

[0330]

The 3-haloquinoline derivatives (XXX) and boronic acid derivatives (XXXI) used in the coupling reaction can be purchased or prepared according to known methods or methods similar thereto.

[0331]

(Stage 8-2)

Tetrahydroquinoline derivatives (I-k) can be prepared by hydrogenation or transfer hydrogenation of quinoline derivatives (XXXII). The conditions selected for this step, including reagents, hydrogen pressure, reaction solvent, and reaction temperature, are similar to those in steps 1-4.

[0332]

Method of obtaining 9

Among the tetrahydroquinoline (I) derivatives, the optical isomers (I-k') and (Ik") of the tetrahydroquinoline (Ik) derivatives can be prepared by the method shown in, for example, Scheme 9, in which all of R ^1x , R ^v and R ^w are hydrogen.

[0333]

Stage 9

[0334]

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

[0335]

(Stage 9-1)

Optical isomers (I-k’) and (I-k”) of tetrahydroquinoline derivatives (I-k) can be obtained by preparative HPLC using a chiral column.

[0336]

In one embodiment, each medicament of the present invention can be used as a medicament for the treatment or prevention of a disease, disorder or syndrome associated with inhibition of ferroptosis.

[0337]

The term "ferroptosis inhibition" refers to the inhibition of ferroptosis (ferrous iron-dependent, controlled cell death). The ferroptosis inhibitors of the present invention can be used against diseases, disorders, or syndromes in which improvement of clinical conditions or remission of symptoms can be expected through the inhibition of ferroptosis.

[0338]

The phrase "diseases, disorders, or syndromes associated with ferroptosis inhibition" means diseases, disorders, or syndromes in which improvement of the clinical condition or remission of symptoms can be expected through the inhibition of ferroptosis described above. Examples of diseases, disorders, or syndromes associated with ferroptosis inhibition include kidney disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, nonalcoholic steatohepatitis, chronic obstructive pulmonary disease, Friedreich's ataxia, and multiple sclerosis; multiple sclerosis is preferred.

[0339]

Multiple sclerosis is characterized by demyelination, which damages the myelin sheath surrounding nerve fibers in the brain, spinal cord, optic nerve, and other areas. It is a progressive disease characterized by recurring relapses and remissions. Multiple sclerosis presents with varying pathologies depending on the location of the lesion, including various neurological symptoms such as visual impairment, quadriplegia, sensory impairment, and gait disturbances. Types of multiple sclerosis include relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis.

[0340]

Each of the tetrahydroquinoline (I) derivatives, their pharmaceutically acceptable salts, or the medicinal product of the present invention can be used as a ferroptosis inhibitor that contains a tetrahydroquinoline (I) derivative or a pharmaceutically acceptable salt thereof as an active ingredient. In this regard, a tetrahydroquinoline (I) derivative or a pharmaceutically acceptable salt thereof, or 2-phenyl-1,2,3,4-tetrahydroquinoline or a pharmaceutically acceptable salt thereof can be used as a ferroptosis inhibitor.

[0341]

The term "ferroptosis inhibitor" means a compound that inhibits ferroptosis, thereby increasing cell survival and enhancing and maintaining cellular functions, or a composition containing the compound as an active ingredient.

[0342]

It is reported that the presence of free radical scavenging activity is important for exhibiting the inhibitory effect against ferroptosis, as described in Non-Patent Document 10. Furthermore, Patent Document 1 and Non-Patent Document 11 disclose that tetrahydroquinoxaline derivatives have a strong free radical scavenging activity. In contrast, Non-Patent Document 11 discloses tetrahydroquinoline derivatives with a very low free radical scavenging activity. However, each tetrahydroquinoline derivative (I) of the present invention or a pharmaceutically acceptable salt thereof has an inhibitory effect on ferroptosis and, therefore, can be used as a new drug for the treatment or prevention of diseases, disorders, or syndromes associated with the inhibition of ferroptosis.

[0343]

The inhibitory effect of a tetrahydroquinoline (I) derivative or its pharmaceutically acceptable salt on ferroptosis can be assessed using an in vitro assay. For example, the inhibitory effect can be assessed using the inhibitory effect on cell death induced by treatment of established cells, such as human fibrosarcoma cells (HT-1080 cells), primary cultured cells, iPS cells, or similar cells, with a ferroptosis inducer such as erastin, RSL3, FIN56, or buthionine sulfoximine.

[0344]

The free radical scavenging activity of the test compound can be assessed usingin in vitrotest and, for example, by a method (Antioxidants, 2019, vol. 258) using a stable radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH).

[0345]

The efficacy of a tetrahydroquinoline (I) derivative or a pharmaceutically acceptable salt thereof in the treatment or prevention of a disease, disorder, or syndrome associated with ferroptosis inhibition can be evaluated using a pathological model. Examples of the pathological model include the experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, vol. 84, pp. 1225-1234; International Immunology, 1997, vol. 9, pp. 1243-1251). The experimental autoimmune encephalomyelitis model is an animal model obtained by immunizing laboratory animals with myelin oligodendrocyte glycoprotein (hereinafter referred to as MOG) or proteolipid protein or its partial peptide to induce neurological disorders such as hind limb paralysis due to demyelination in the central nervous system. The pathological model is widely used to evaluate the efficacy of therapeutic or prophylactic agents against multiple sclerosis because the conditions and pathological findings in the pathological model are similar to those in patients with multiple sclerosis. The efficacy of treatment or prevention of multiple sclerosis can be assessed using a model of experimental autoimmune encephalomyelitis and, for example, can be assessed using a decline in neurological score, a characteristic marker of multiple sclerosis.

[0346]

Each of the tetrahydroquinoline derivatives (I) or a pharmaceutically acceptable salt thereof has an inhibitory effect on ferroptosis and can therefore be used as a useful drug (in particular, for the treatment or prevention of a disease, disorder, or syndrome associated with ferroptosis inhibition, such as multiple sclerosis) for mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and human).

[0347]

In cases where the tetrahydroquinoline (I) derivative or its pharmaceutically acceptable salt is used as a medicine in clinical settings, the tetrahydroquinoline (I) derivative or its pharmaceutically acceptable salt can be administered orally, parenterally or topically, directly or in combination with a pharmaceutically acceptable carrier(s). In the medicine, additives such as an excipient, a binder, a lubricant, a disintegrating agent, a sweetener, a stabilizer, a taste-masking agent, a flavoring agent, a coloring agent, a diluent, a preservative, a buffering agent, a solubilizing agent, an emulsifying agent, a surfactant, a suspending agent, a diluent, and a tonicity adjusting agent can be suitably mixed if necessary. Examples of pharmaceutically acceptable carriers include these additives. In addition, the above-described medicine can be prepared by a conventional method using appropriate pharmaceutically acceptable carriers. Dosage forms of the drug include, for example, oral forms such as tablets, pills, capsules, granules, powders, syrups, emulsions, and suspensions; parenteral forms such as inhalants, injections, suppositories, and liquids; and topical forms such as ointments, creams, and patches. In addition, a suitable base (e.g., polybutyric acid, polyglycolic acid, poly(butyric acid-co-glycolic acid), a mixture of polybutyric acid and polyglycolic acid, or a polyglycerol fatty acid ester) is effectively combined to provide a drug with prolonged release.

[0348]

A preparation containing a tetrahydroquinoline derivative (I) as described above or a pharmaceutically acceptable salt thereof can be prepared according to a production method commonly used and known in the pharmaceutical field. Tablets can be prepared in admixture with, for example, an excipient, a binder, a disintegrating agent, a lubricant and the like; pills and granules can be prepared in admixture with, for example, an excipient, a binder, a disintegrating agent and the like; capsules and powders can be prepared in admixture with, for example, an excipient and the like; syrups can be prepared in admixture with, for example, a sweetener and the like; and emulsions and suspensions can be prepared in admixture with, for example, a surfactant, a suspending agent, an emulsifying agent and the like.

[0349]

Examples of fillers include lactose, dextrose, starch, sucrose, microcrystalline cellulose, powdered licorice, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

[0350]

Examples of the binding agent include starch paste solution, acacia solution, gelatin solution, gum tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, and glycerin.

[0351]

Examples of leavening agents include starch and calcium carbonate.

[0352]

Examples of a lubricant include magnesium stearate, calcium stearate, polyethylene glycol, purified talc, and silicon dioxide.

[0353]

Examples of sweetener include dextrose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.

[0354]

Examples of surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid esters, and polyoxyl stearate 40.

[0355]

Examples of the suspending agent include gum acacia, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.

[0356]

Examples of emulsifiers include gum acacia, gum tragacanth, gelatin, and polysorbate 80.

[0357]

In addition, in cases where a drug containing a tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof is formulated into any of the above-described dosage forms, agents commonly used in the pharmaceutical field such as a coloring agent, a preservative, a flavoring agent, a taste-masking agent, a stabilizing agent, and a thickening agent may be suitably added thereto.

[0358]

The drug preferably contains from 0.00001 to 90% by weight, more preferably from 0.01 to 70% by weight, of a tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof. The daily dose of the drug is appropriately selected depending on the patient's condition, body weight, and age, route of administration, and the like. The amount of the active ingredient administered, for example, to adults (with a body weight of approximately 60 kg) is preferably from 1 mg to 1000 mg for oral agents and from 0.01 mg to 100 mg for injections, and can be administered as a single dose or in divided doses.

[0359]

The drug may be mixed or used with an appropriate amount of another drug to complement or enhance the therapeutic or prophylactic effects or to reduce the dosage. The drug and the other drug may be administered simultaneously or sequentially in any order. The drug may be used in combination with other agents, such as, but not limited to, the following therapeutic agents for the treatment of multiple sclerosis and agents for the treatment of symptoms in patients with multiple sclerosis, such as spasms and rigidity.

[0360]

Other therapeutic agents for the treatment of multiple sclerosis include, for example, adrenocorticosteroids (e.g., prednisolone and methylprednisolone), interferon preparations (e.g., interferon-α, interferon-β-1b, interferon-β-1a, and peg-interferon-β-1a), glatiramer acetate, fumarate compounds (dimethyl fumarate, diroximel fumarate, monomethyl fumarate), teriflunomide, S1P receptor agonists (fingorimod, siponimod, ozanimod, ponesimod), anti-integrin α4 antibodies (natalizumab), anti-CD20 antibodies (ocrelizumab, ofatumumab), anti-CD52 antibodies (alemtuzumab), cladribine, mitoxantrone, Bruton's tyrosine kinase inhibitor, immunomodulators (e.g., methotrexate, azathioprine, cyclophosphamide, cyclosporine A, tacrolimus, mizoribine, and leflunomide), copolymer I, immunoglobulin, T-cell receptor vaccine, adhesion inhibitor, analgesics (e.g., indomethacin and diclofenac), and muscle relaxants (e.g., tizanidine, eperisone, afloqualone, baclofen, diazepam, and dantrolene sodium).

[0361]

Examples of medications used to treat symptoms in patients with multiple sclerosis, such as spasms and rigidity, include anticonvulsants (eg, carbamazepine, phenytoin, clonazepam, and amitriptyline).

EXAMPLES

[0362]

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

[0363]

For any compounds used in the synthesis of reference examples and examples, but for which the synthetic methods are not described, commercially available compounds were used. "Room temperature" as used in the examples and reference examples below generally refers to a temperature from approximately 10°C to approximately 35°C. The solvent names listed in the NMR data represent the solvents used for the measurements. Additionally, the 400 MHz NMR spectrum was measured using a JNM-ECS400 nuclear magnetic resonance spectrometer or a JNM-ECZ400S nuclear magnetic resonance spectrometer (JEOL Ltd.). Chemical shifts are expressed in δ (unit: ppm) relative to tetramethylsilane, and the multiplicity of each signal is expressed as s (singlet), d (doublet), t (triplet), qv (quartet), quint (quintet), sept (septet), m (multiplet), sh (broad), dd (double doublet), dt (double triplet), ddd (double double doublet), dqv (double quartet), td (triple doublet), or tt (triple triplet). In ^1H NMR, protons such as hydroxyl groups, amino groups, and carboxyl groups, which give very broad peaks, are not listed. ESI-MS spectra were measured using an Agilent Technologies 1200 Series, G6130A (Agilent Technologies, Inc.). Silica gel 60 (Merck Co.) is used as the silica gel, amino silica gel from Fuji Silysia Chemical Ltd. is used as the amino silica gel, and YFLCW-prep2XY (Yamazen Co.) is used for flash chromatography. Silica gel 60 (Merck Co.) is used for preparative thin-layer chromatography (hereinafter referred to as "preparative TLC").

[0364]

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

[0365]

[0366]

2-Phenyl-1,2,3,4-tetrahydroquinoline (7.48 g, 35.7 mmol) was dissolved in ethyl acetate (100 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (17.8 mL, 71.5 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 16 hours under an argon atmosphere. After completion of the reaction, the resulting precipitated solid was filtered and washed with ethyl acetate to give the title compound (hereinafter referred to as “the compound of Example 1”) as a white solid (8.07 g, 32.9 mmol, yield: 92%).

¹ H-NMR (DMSO-d ₆ ) δ: 7.40-7.34 (4H, m), 7.28 (1H, t, J=6.8 Hz), 6.94 (2H, t, J=7.9 Hz), 6.67 (1H, d, J=6.8 Hz), 6.56 (1H, s), 4.44 (1H, dd, J=8.6, 3.2 Hz), 2.81 (1H, dt, J=17.8, 6.1 Hz), 2.55 (1H, ddd, J=25.0, 12.3, 8.7 Hz), 2.03-1.99 (1H, m), 1.91 (1H, s).

MS(IER) [M+H] ⁺ : 210.

[0367]

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

[0368]

[0369]

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), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (0.296 g, 1.17 mmol) was added to the suspension, and the resulting mixture was stirred at -10°C for 24 hours under 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 give the title compound (hereinafter referred to as “the compound of Example 2”) as a colorless transparent oily substance (95.0 mg, 0.457 mmol, yield: 95%, enantiomeric excess: 98.5% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.37 (4H, ddt, J=16.0, 8.9, 2.8 Hz), 7.28 (1H, tt, J=7.0, 2.2 Hz), 7.01 (2H, td, J=7.2 Hz), 6.65 (1H, td, J=7.4, 1.1 Hz), 6.54 (1H, dd, J=8.4, 1.1 Hz), 4.44 (1H, dd, J=9.3, 3.4 Hz), 4.04 (1H, s), 2.97-2.89 (1H, m), 2.74 (1H, dt, J=16.3, 4.8 Hz), 2.16-2.09 (1H, m), 2.05-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 210.

Retention time (hereinafter referred to as Rt): 18.40 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=5:95

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0370]

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

[0371]

[0372]

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) were used according to the procedure of Example 2 to obtain the title compound (hereinafter referred to as "the compound of Example 3") as a colorless transparent oily substance (49.0 mg, 0.236 mmol, yield: 97%, enantiomeric excess: 97.2% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.32 (4H, m), 7.31-7.25 (1H, m), 7.01 (2H, t, J=7.2 Hz), 6.65 (1H, td, J=7.4, 1.2 Hz), 6.55 (1H, dd, J=7.2, 1.4 Hz), 4.44 (1H, dd, J=9.3, 3.4 Hz), 4.04 (1H, s), 2.97-2.89 (1H, m), 2.74 (1H, dt, J=16.5, 4.9 Hz), 2.16-2.09 (1H, m), 2.04-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 210.

Rt: 14.28 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=5:95

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0373]

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

[0374]

[0375]

2-(4-Methoxyphenyl)quinoline (40.0 mg, 0.170 mmol) was dissolved in THF/methanol (1/1, v/v, 3.0 ml), and acetic acid (0.029 ml, 0.51 mmol) and platinum(IV) oxide (3.8 mg, 0.017 mmol) were added to the resulting solution, and the resulting mixture was stirred at room temperature and normal pressure for 6 hours under a hydrogen atmosphere. After completion of the reaction, hydrogen was exchanged for nitrogen, and the reaction mixture was filtered using celite. The residue was washed with chloroform, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 4 compound”) as a white solid (26.9 mg, 0.113 mmol, yield: 66%).

¹ H-NMR (CDCl ₃ ) δ: 7.31 (2H, dt, J=9.2, 2.5 Hz), 7.00 (2H, dt, J=7.2, 6.3 Hz), 6.89 (2H, td, J=5.8, 3.5 Hz), 6.64 (1H, td, J=7.4, 1.2 Hz), 6.54-6.51 (1H, m), 4.38 (1H, dd, J=9.5, 3.2 Hz), 3.99 (1H, s), 3.81 (3H, s), 2.97-2.89 (1H, m), 2.74 (1H, dt, J=16.3, 4.5 Hz), 2.11-2.05 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 240.

[0376]

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

[0377]

[0378]

2-Chloroquinoline (0.120 g, 0.734 mmol) and 3-methoxyphenylboronic acid (0.111 g, 0.734 mmol) were dissolved in DME (4.0 mL), 1 mol/L aqueous sodium carbonate solution (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0073 mmol) were added to the resulting solution, and the resulting mixture was stirred at 100°C for 4 hours under argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with hexane/ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (0.165 g, 0.702 mmol, yield: 95%).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.6 Hz), 8.18 (1H, t, J=4.8 Hz), 7.85 (2H, dt, J=12.5, 5.5 Hz), 7.77-7.69 (3H, m), 7.56-7.51 (1H, m), 7.44 (1H, t, J=7.9 Hz), 7.02 (1H, tt, J=5.4, 2.4 Hz), 3.94 (3H, s).

MS(IER) [M+H] ⁺ : 236.

[0379]

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

[0380]

[0381]

2-(3-methoxyphenyl)quinoline synthesized in Reference Example 1 (60.0 mg, 0.255 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 5”) as a white solid (23.7 mg, 0.0991 mmol, yield: 39%).

¹ H-NMR (CDCl ₃ ) δ: 7.27 (1H, dd, J=8.8, 7.0 Hz), 7.03-6.96 (4H, m), 6.83 (1H, dq, J=8.2, 1.2 Hz), 6.65 (1H, td, J=7.4, 1.1 Hz), 6.54 (1H, d, J=7.7 Hz), 4.42 (1H, dd, J=9.3, 3.4 Hz), 4.01 (1H, brs), 3.81 (3H, s), 2.97-2.88 (1H, m), 2.74 (1H, dt, J=16.3, 4.8 Hz), 2.15-2.09 (1H, m), 2.05-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 240.

[0382]

(Reference Example 2) Synthesis of 2-(2-methoxyphenyl)quinoline:

[0383]

[0384]

2-Chloroquinoline (0.100 g, 0.611 mmol) and 2-methoxyphenylboronic acid (92.8 mg, 0.611 mmol) were used in a similar manner to Reference Example 1 to give the title compound as a white solid (0.157 g, 0.668 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 8.16 (2H, t, J=8.8 Hz), 7.89 (1H, d, J=8.2 Hz), 7.84 (2H, dq, J=7.7, 1.8 Hz), 7.73-7.69 (1H, m), 7.55-7.51 (1H, m), 7.43 (1H, td, J=7.9, 1.5 Hz), 7.13 (1H, td, J=7.5, 1.1 Hz), 7.04 (1H, t, J=4.3 Hz), 3.87 (3H, s).

MS(IER) [M+H] ⁺ : 236

[0385]

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

[0386]

[0387]

2-(2-methoxyphenyl)quinoline synthesized in Reference Example 2 (60.0 mg, 0.255 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 6”) as a white solid (35.5 mg, 0.148 mmol, yield: 58%).

¹ H-NMR (CDCl ₃ ) δ: 7.43 (1H, dd, J=7.7, 1.8 Hz), 7.28-7.22 (1H, m), 7.05-6.85 (4H, m), 6.63 (1H, td, J=7.4, 1.2 Hz), 6.56 (1H, d, J=7.7 Hz), 4.87 (1H, dd, J=8.2, 3.6 Hz), 4.04 (1H, s), 3.85 (3H, s), 2.92-2.84 (1H, m), 2.69 (1H, td, J=10.8, 5.4 Hz), 2.14 (1H, dtd, J=13.4, 5.0, 2.9 Hz), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 240.

[0388]

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

[0389]

[0390]

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) were used in a similar manner to Reference Example 1 to give the title compound as a pale yellow solid (0.128 g, 0.459 mmol, yield: 68%).

¹ H-NMR (CDCl ₃ ) δ: 8.08 (1H, d, J=8.6 Hz), 8.02 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=8.6 Hz), 7.70 (1H, d, J=1.8 Hz), 7.62 (1H, dd, J=8.2, 1.8 Hz), 7.37 (1H, dd, J=9.1, 2.7 Hz), 7.08 (1H, d, J=2.7 Hz), 6.94 (1H, d, J=4.1 Hz), 6.04 (2H, d, J=5.0 Hz), 3.95 (3H, s).

MS(IER) [M+H] ⁺ : 280.

[0391]

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

[0392]

[0393]

2-(benzo[d][1,3]dioxol-5-yl)-6-methoxyquinoline synthesized in Reference Example 3 (60.0 mg, 0.215 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 7”) as a white solid (24.3 mg, 0.0859 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 6.91 (1H, d, J=1.8 Hz), 6.84 (1H, dd, J=8.2, 1.8 Hz), 6.77 (1H, d, J=7.7 Hz), 6.62 (2H, td, J=7.4, 2.7 Hz), 6.49 (1H, d, J=8.6 Hz), 5.95 (2H, s), 4.28 (1H, dd, J=9.7, 2.9 Hz), 3.74 (3H, s), 2.97-2.88 (1H, m), 2.72 (1H, dt, J=16.5, 4.5 Hz), 2.09-2.03 (1H, m), 1.98-1.88 (1H, m).

MS(IER) [M+H] ⁺ : 284.

[0394]

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

[0395]

[0396]

2-Chloro-7-methoxyquinoline (0.130 g, 0.671 mmol) and 4-methoxyphenylboronic acid (0.102 g, 0.671 mmol) were used in a similar manner to Reference Example 1 to give the title compound as a white solid (0.155 g, 0.585 mmol, yield: 87%).

¹ H-NMR (CDCl ₃ ) δ: 8.13-8.09 (3H, m), 7.69 (2H, dd, J=8.6, 5.0 Hz), 7.47 (1H, d, J=2.7 Hz), 7.16 (1H, dd, J=8.8, 2.5 Hz), 7.04 (2H, td, J=6.0, 3.5 Hz), 3.98 (3H, s), 3.89 (3H, s).

MS(IER) [M+H] ⁺ : 266.

[0397]

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

[0398]

[0399]

7-Methoxy-2-(4-methoxyphenyl)quinoline synthesized in Reference Example 4 (62.0 mg, 0.234 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 8”) as a white solid (62.3 mg, 0.234 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 7.30 (2H, td, J=5.8, 3.5 Hz), 6.91-6.87 (3H, m), 6.24 (1H, dd, J=8.4, 2.5 Hz), 6.10 (1H, d, J=2.3 Hz), 4.36 (1H, dd, J=9.5, 3.2 Hz), 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, 4.6 Hz), 2.10-2.03 (1H, m), 1.99-1.89 (1H, m).

MS(IER) [M+H] ⁺ : 270.

[0400]

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

[0401]

[0402]

2-Chloroquinoline (0.150 g, 0.917 mmol) and benzo[d][1,3]dioxol-5-ylphenylboronic acid (0.167 g, 1.01 mmol) were used in a similar manner to Reference Example 1 to give the title compound as a yellow solid (0.218 g, 0.876 mmol, yield: 87%).

¹ H-NMR (CDCl ₃ ) δ: 8.19 (1H, d, J=8.6 Hz), 8.13 (1H, t, J=4.8 Hz), 7.82-7.79 (2H, m), 7.72 (2H, tt, J=8.8, 2.9 Hz), 7.66 (1H, dd, J=8.2, 1.8 Hz), 7.53-7.49 (1H, m), 6.96 (1H, d, J=8.2 Hz), 6.05 (2H, s).

MS(IER) [M+H] ⁺ : 250.

[0403]

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

[0404]

[0405]

2-(Benzo[d][1,3]dioxol-5-yl)-quinoline synthesized in Reference Example 5 (60.0 mg, 0.241 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 9”) as a colorless transparent oily substance (37.7 mg, 0.149 mmol, yield: 62%).

^1H -NMR (CDCl ₃ ) δ: 7.00 (2H, t, J=7.2 Hz), 6.90 (1H, d, J=1.8 Hz), 6.84 (1H, dd, J=8.4, 1.6 Hz), 6.77 (1H, d, J=7.7 Hz), 6.64 (1H, td, J=7.4, 1.1 Hz), 6.53 (1H, d, J=7.2 Hz), 5.95 (2H, t, J=1.6 Hz), 4.35 (1H, dd, J=9.5, 3.2 Hz), 3.98 (1H, s), 2.95-2.87 (1H, m), 2.73 (1H, dt, J=16.3, 4.8 Hz), 2.08 (1H, tdd, J=8.4, 4.4, 2.7 Hz), 1.99-1.89 (1H, m).

MS(IER) [M+H] ⁺ : 254.

[0406]

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

[0407]

[0408]

2-Chloroquinoline (50.0 mg, 0.306 mmol), (2-(trifluoromethyl)phenyl)boronic acid (87.1 mg, 0.458 mmol), tetrakis(triphenylphosphine)palladium(0) (7.1 mg, 0.0061 mmol), and potassium carbonate (127 mg, 0.917 mmol) were dissolved in 1,4-dioxane/water (5/1, v/v, 3 mL), and the resulting solution was then stirred under heating at 100°C for 16 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane-ethyl acetate) to give the title compound as a colorless transparent oily substance (81.5 mg, 0.298 mmol, yield: 98%).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.2 Hz), 8.16 (1H, d, J=8.7 Hz), 7.89 (1H, d, J=7.8 Hz), 7.81 (1H, d, J=7.8 Hz), 7.77 (1H, t, J=8.2 Hz), 7.67 (1H, t, J=7.5 Hz), 7.62-7.54 (4H, m).

MS(IER) [M+H] ⁺ : 274.

[0409]

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

[0410]

[0411]

2-(2-(Trifluoromethyl)phenyl)quinoline synthesized in Reference Example 6 (62.0 mg, 0.227 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 10”) as a colorless transparent oily substance (52.2 mg, 0.188 mmol, yield: 83%).

¹ H-NMR (CDCl ₃ ) δ: 7.82 (1H, d, J=8.2 Hz), 7.65 (1H, d, J=7.8 Hz), 7.56 (1H, t, J=7.5 Hz), 7.38 (1H, t, J=7.5 Hz), 7.04-7.01 (2H, m), 6.69 (1H, t, J=7.5 Hz), 6.55 (1H, d, J=7.8 Hz), 4.82 (1H, d, J=9.6 Hz), 3.97 (1H, shs), 3.03-2.94 (1H, m), 2.81-2.75 (1H, m), 2.17-2.12 (1H, m), 1.97-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 278.

[0412]

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

[0413]

[0414]

2-Chloroquinoline (100 mg, 0.611 mmol) and (1H-pyrazol-4-yl)boronic acid (137 mg, 1.22 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (63.7 mg, 0.326 mmol, yield: 53%).

¹ H-NMR (CDCl ₃ ) δ: 8.29 (2H, s), 8.16 (1H, d, J=8.7 Hz), 8.07 (1H, d, J=8.7 Hz), 7.79 (1H, d, J=8.2 Hz), 7.70 (1H, t, J=7.5 Hz), 7.66 (1H, d, J=8.2 Hz), 7.49 (1H, t, J=7.5 Hz).

MS(IER) [M+H] ⁺ : 196.

[0415]

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

[0416]

[0417]

2-(1H-pyrazol-4-yl)quinoline synthesized in Reference Example 7 (30.0 mg, 0.154 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 11”) as a white solid (28.8 mg, 0.145 mmol, yield: 94%).

¹ H-NMR (CDCl ₃ ) δ: 7.58 (2H, s), 7.02-6.98 (2H, m), 6.66 (1H, t, J=7.1 Hz), 6.52 (1H, d, J=7.8 Hz), 4.50 (1H, dd, J=9.1, 3.2 Hz), 2.96-2.88 (1H, m), 2.80-2.74 (1H, m), 2.17-2.11 (1H, m), 2.04-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 200.

[0418]

(Example 12) Synthesis of one of the optical isomers of 2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline:

[0419]

[0420]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

2-(1H-pyrazol-4-yl)quinoline synthesized in Reference Example 7 (50.0 mg, 0.256 mmol) 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), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (0.155 g, 0.614 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature 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), and the resulting solid was recrystallized with hexane/ethyl acetate to give 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).

¹ H-NMR (CDCl ₃ ) δ: 7.58 (2H, s), 6.98 (2H, d, J=8.8 Hz), 6.65 (1H, t, J=7.2 Hz), 6.52 (1H, d, J=8.2 Hz), 4.50 (1H, dd, J=9.3, 2.9 Hz), 3.96 (1H, s), 2.96-2.88 (1H, m), 2.76 (1H, dt, J=16.3, 4.8 Hz), 2.17-2.11 (1H, m), 2.05-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 200.

Rt: 17.78 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 3 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=10:90

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0421]

(Example 13) Synthesis of another optical isomer of 2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline:

[0422]

[0423]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

2-(1H-pyrazol-4-yl)quinoline synthesized in Reference Example 7 (70.0 mg, 0.359 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (5.40 mg, 7.17 μmol) were used according to the procedure of Example 12 to give the title compound (hereinafter referred to as "the compound of Example 13") as a white solid (30.0 mg, 0.151 mmol, yield: 42%, enantiomeric excess: 96.9% ee).

¹ H-NMR (CDCl ₃ ) 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, 2.9 Hz), 3.97 (1H, shs), 2.96-2.88 (1H, m), 2.79-2.73 (1H, m), 2.17-2.10 (1H, m), 2.05-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 200.

Rt: 13.11 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 3 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=10:90

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0424]

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

[0425]

[0426]

2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline synthesized in Example 11 (25.0 mg, 0.125 mmol) was dissolved in DMF (1.2 mL), and potassium carbonate (34.7 mg, 0.251 mmol) and methyl iodide (7.8 μL, 0.125 mmol) were added to the resulting solution, and the resulting 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 the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) and column chromatography (amino silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “the compound of Example 14”) as a colorless transparent oily substance (4.1 mg, 0.019 mmol, yield: 15%).

¹ H-NMR (CDCl ₃ ) δ: 7.46 (1H, s), 7.32 (1H, s), 7.01-6.97 (2H, m), 6.64 (1H, t, J=7.1 Hz), 6.50 (1H, d, J=8.2 Hz), 4.43 (1H, dd, J=9.4, 3.0 Hz), 3.95 (1H, ws), 3.88 (3H, s), 2.94-2.86 (1H, m), 2.79-2.72 (1H, m), 2.14-2.08 (1H, m), 1.99-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 214.

[0427]

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

[0428]

[0429]

2-Chloroquinoline (100 mg, 0.611 mmol) and (6-methoxypyridin-3-yl)boronic acid (140 mg, 0.917 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (134 mg, 0.568 mmol, yield: 93%).

^1H -NMR (CDCl ₃ ) δ: 8.91 (1H, d, J=2.3 Hz), 8.48 (1H, dd, J=8.7, 2.3 Hz), 8.22 (1H, d, J=8.2 Hz), 8.13 (1H, d, J=8.7 Hz), 7.83 (2H, d, J=8.7 Hz), 7.73 (1H, t, J=7.1 Hz), 7.53 (1H, t, J=7.1 Hz), 6.90 (1H, d, J=8.7 Hz), 4.03 (3H, s).

MS(IER) [M+H] ⁺ : 237.

[0430]

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

[0431]

[0432]

2-(6-Methoxypyridin-3-yl)quinoline synthesized in Reference Example 8 (50.0 mg, 0.212 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 15”) as a colorless transparent oily substance (11.0 mg, 0.0458 mmol, yield: 22%).

¹ H-NMR (CDCl ₃ ) δ: 8.14 (1H, d, J=2.3 Hz), 7.63 (1H, dd, J=8.7, 2.3 Hz), 7.03-6.99 (2H, m), 6.74 (1H, d, J=8.0 Hz), 6.66 (1H, t, J=7.3 Hz), 6.53 (1H, d, J=8.0 Hz), 4.40 (1H, dd, J=9.6, 3.2 Hz), 3.94 (3H, s), 3.94 (1H, shs), 2.99-2.91 (1H, m), 2.78-2.72 (1H, m), 2.09-1.93 (2H, m).

MS(IER) [M+H] ⁺ : 241.

[0433]

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

[0434]

[0435]

2-Chloroquinoline (200 mg, 1.22 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (489 mg, 2.45 mmol) were used in a similar manner to Reference Example 6 to give a mixture of the title compound and impurities as a white solid (296 mg).

MS(IER) [M+H] ⁺ : 284.

[0436]

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

[0437]

[0438]

2-(4-(Methylsulfonyl)phenyl)quinoline synthesized in Reference Example 9 (100 mg, 0.353 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 16”) as a white solid (65.6 mg, 0.228 mmol, yield: 65%).

¹ H-NMR (CDCl ₃ ) δ: 7.92 (2H, dt, J=8.7, 1.8 Hz), 7.60 (2H, dt, J=8.7, 1.8 Hz), 7.06-7.00 (2H, m), 6.69 (1H, td, J=7.3, 0.9 Hz), 6.59 (1H, dd, J=7.8, 0.9 Hz), 4.57 (1H, dd, J=8.7, 3.2 Hz), 4.09 (1H, shs), 3.06 (3H, s), 2.95-2.87 (1H, m), 2.70 (1H, td, J=10.9, 5.5 Hz), 2.19-2.12 (1H, m), 2.01-1.97 (1H, m).

MS(IER) [M+H] ⁺ : 288.

[0439]

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

[0440]

[0441]

2-Chloroquinoline (1.50 g, 9.17 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (1.98 g, 11.0 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (1.95 g, 7.40 mmol, yield: 81%).

¹ H-NMR (CDCl ₃ ) δ: 8.28-8.24 (3H, m), 8.21-8.18 (3H, m), 7.93 (1H, d, J=8.7 Hz), 7.86 (1H, d, J=8.2 Hz), 7.78-7.74 (1H, m), 7.59-7.55 (1H, m), 3.97 (3H, s).

MS(IER) [M+H] ⁺ : 264.

[0442]

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

[0443]

[0444]

Methyl 4-(quinolin-2-yl)benzoate synthesized in Reference Example 10 (600 mg, 2.28 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 17”) as a colorless transparent oily substance (267 mg, 0.998 mmol, yield: 44%).

¹ H-NMR (CDCl ₃ ) δ: 8.02 (2H, dt, J=8.2, 1.8 Hz), 7.46 (2H, dt, J=8.2, 1.8 Hz), 7.05-6.99 (2H, m), 6.67 (1H, td, J=7.3, 0.9 Hz), 6.57 (1H, dd, J=7.8, 0.9 Hz), 4.52 (1H, dd, J=9.1, 3.2 Hz), 4.07 (1H, shs), 3.92 (3H, s), 2.95-2.87 (1H, m), 2.71 (1H, td, J=10.7, 5.5 Hz), 2.16-2.12 (1H, m), 2.03-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 268.

[0445]

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

[0446]

[0447]

Methyl 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoate synthesized in Example 17 (50.0 mg, 0.187 mmol) was dissolved in THF (1.9 ml), and a THF solution of methyl lithium (0.56 ml, 0.65 mmol) was then added dropwise to the resulting solution under ice cooling, and the resulting mixture was stirred for 2 hours under ice cooling. After completion of the reaction, 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 then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 18 compound”) as a colorless transparent oily substance (13.1 mg, 0.0490 mmol, yield: 26%).

¹ H-NMR (CDCl ₃ ) δ: 7.48 (2H, d, J=8.2 Hz), 7.37 (2H, d, J=8.2 Hz), 7.02-7.00 (2H, m), 6.65 (1H, t, J=7.5 Hz), 6.54 (1H, d, J=7.7 Hz), 4.44 (1H, dd, J=9.5, 3.2 Hz), 4.02 (1H, shs), 2.97-2.89 (1H, m), 2.74 (1H, dt, J=16.3, 4.5 Hz), 2.14-2.10 (1H, m), 2.02-1.96 (1H, m), 1.73 (1H, s), 1.59 (6H, s).

MS(IER) [M+H] ⁺ : 268.

[0448]

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

[0449]

[0450]

2-Chloroquinoline (100 mg, 0.611 mmol), (3-sulfamoylphenyl)boronic acid (184 mg, 0.917 mmol), tetrakis(triphenylphosphine)palladium(0) (21.2 mg, 0.0183 mmol), and potassium carbonate (169 mg, 1.22 mmol) were dissolved in DMF/water (5/1, v/v, 3 mL), and the resulting solution was then stirred under heating at 100°C for 17 hours. After the reaction mixture was cooled to room temperature, water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (135 mg, 0.474 mmol, yield: 78%).

¹ H-NMR (CDCl ₃ ) δ: 8.78 (1H, t, J=1.6 Hz), 8.41 (1H, d, J=7.8 Hz), 8.29 (1H, d, J=8.5 Hz), 8.18 (1H, d, J=7.8 Hz), 8.03 (1H, d, J=7.8 Hz), 7.92 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=7.8 Hz), 7.77 (1H, t, J=7.8 Hz), 7.70 (1H, t, J=7.8 Hz), 7.58 (1H, t, J=7.8 Hz), 4.87 (2H, shs).

MS(IER) [M+H] ⁺ : 285.

[0451]

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

[0452]

[0453]

3-(Quinolin-2-yl)benzenesulfonamide synthesized in Reference Example 11 (131 mg, 0.461 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 19”) as a colorless transparent oily substance (118 mg, 0.409 mmol, yield: 89%).

¹ H-NMR (CDCl ₃ ) δ: 7.98 (1H, s), 7.85 (1H, d, J=7.8 Hz), 7.63 (1H, d, J=7.8 Hz), 7.51 (1H, t, J=7.8 Hz), 7.04-7.01 (2H, m), 6.69 (1H, t, J=7.1 Hz), 6.58 (1H, d, J=7.8 Hz), 4.80 (2H, ws), 4.54 (1H, dd, J=9.1, 3.2 Hz), 2.97-2.89 (1H, m), 2.74-2.69 (1H, m), 2.16-2.12 (1H, m), 2.02-1.97 (1H, m).

MS(IER) [M+H] ⁺ : 289.

[0454]

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

[0455]

[0456]

2-Chloroquinoline (100 mg, 0.611 mmol) and (2-sulfamoylphenyl)boronic acid (184 mg, 0.917 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (153 mg, 0.540 mmol, yield: 88%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.54 (1H, d, J=8.7 Hz), 8.10-8.06 (3H, m), 7.86-7.67 (6H, m), 7.61 (2H, br s).

MS(IER) [M+H] ⁺ : 285.

[0457]

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

[0458]

[0459]

2-(Quinolin-2-yl)benzenesulfonamide synthesized in Reference Example 12 (150 mg, 0.528 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 20”) as a white solid (28.8 mg, 0.0999 mmol, yield: 19%).

¹ H-NMR (CDCl ₃ ) δ: 8.06 (1H, d, J=7.8 Hz), 7.83 (1H, d, J=7.4 Hz), 7.60 (1H, t, J=7.8 Hz), 7.41 (1H, t, J=7.4 Hz), 7.05-7.01 (2H, m), 6.71 (1H, t, J=7.4 Hz), 6.56 (1H, d, J=7.8 Hz), 5.25 (1H, dd, J=9.6, 2.3 Hz), 4.96 (2H, shs), 4.00 (1H, shs), 3.04-2.96 (1H, m), 2.82-2.78 (1H, m), 2.32-2.29 (1H, m), 2.05-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 289.

[0460]

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

[0461]

[0462]

2-Chloroquinoline (100 mg, 0.611 mmol), potassium carbonate (211 mg, 1.53 mmol), palladium(II) acetate (13.7 mg, 61.1 μmol), tri- tert -butylphosphonium tetrafluoroborate (17.7 mg, 61.1 μmol), and 4-acetoxyphenylboronic acid (164 mg, 0.917 mmol) were suspended in acetonitrile/water (2.3 mL/0.70 mL), and the resulting suspension was stirred at 100°C for 1 hour under microwave irradiation. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (48.8 mg, 0.186 mmol, yield: 30%).

¹ H-NMR (CDCl ₃ ) δ: 8.21 (1H, d, J=8.6 Hz), 8.17-8.13 (3H, m), 7.86 (1H, d, J=8.8 Hz), 7.82 (1H, d, J=8.2 Hz), 7.74-7.67 (3H, m), 7.54-7.50 (1H, m), 7.39 (1H, shs), 2.22 (3H, s).

MS(IER) [M+H] ⁺ : 263.

[0463]

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

[0464]

[0465]

N-(4-(quinolin-2-yl)phenyl)acetamide synthesized in Reference Example 13 (40.0 mg, 0.152 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 21”) as a white amorphous substance (6.60 mg, 24.8 μmol, yield: 16%).

¹ H-NMR (CDCl ₃ ) δ: 7.46 (2H, d, J=8.6 Hz), 7.34 (2H, d, J=8.6 Hz), 7.15 (1H, ws), 7.03-6.99 (2H, m), 6.65 (1H, dd, J=6.8, 8.4 Hz), 6.54 (1H, d, J=7.7 Hz), 4.41 (1H, dd, J=9.5, 3.2 Hz), 4.01 (1H, shs), 2.95-2.87 (1H, m), 2.76-2.69 (1H, m), 2.19 (3H, s), 2.12-2.06 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 267.

[0466]

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

[0467]

[0468]

2-Chloroquinoline (100 mg, 0.611 mmol) and 1H-pyrazole-3-boronic acid (164 mg, 0.917 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (56.0 mg, 0.287 mmol, yield: 47%).

¹ H-NMR (CDCl ₃ ) δ: 8.21 (1H, d, J=8.6 Hz), 8.10 (1H, d, J=8.6 Hz), 7.86 (1H, d, J=8.6 Hz), 7.82 (1H, d, J=8.2 Hz), 7.75-7.71 (2H, m), 7.56-7.52 (1H, m), 6.96 (1H, s).

MS(IER) [M+H] ⁺ : 196.

[0469]

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

[0470]

[0471]

2-(1H-pyrazol-3-yl)quinoline synthesized in Reference Example 14 (56.0 mg, 0.287 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 22”) as a white amorphous substance (33.7 mg, 0.169 mmol, yield: 59%).

¹ H-NMR (CDCl ₃ ) δ: 7.52 (1H, s), 7.02-6.98 (2H, m), 6.67 (1H, ddd, J=7.6, 7.6, 1.2 Hz), 6.56 (1H, d, J=7.7 Hz), 6.27 (1H, s), 4.64 (1H, dd, J=9.1, 3.6 Hz), 4.23 (1H, shs), 2.96-2.86 (1H, m), 2.80-2.72 (1H, m), 2.24-2.17 (1H, m), 2.12-2.02 (1H, m).

MS(IER) [M+H] ⁺ : 200.

[0472]

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

[0473]

[0474]

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) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (118 mg, 0.431 mmol, yield: 71%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.31 (1H, s), 8.41 (1H, d, J=8.6 Hz), 8.15 (1H, s), 8.12-8.08 (2H, m), 8.03 (1H, d, J=8.2 Hz), 7.97 (1H, d, J=7.2 Hz), 7.78-7.74 (1H, m), 7.59-7.55 (1H, m), 7.01 (1H, d, J=8.2 Hz), 3.02 (2H, t, J=7.5 Hz), 2.55-2.51 (2H, m).

MS(IER) [M+H] ⁺ : 275.

[0475]

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

[0476]

[0477]

3',4'-Dihydro-[2,6'-biquinolin]-2'(1'H)-one synthesized in Reference Example 15 (118 mg, 0.431 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as "the compound of Example 23") as a white solid (80.6 mg, 0.290 mmol, yield: 67%).

¹ H-NMR (CDCl ₃ ) δ: 8.30 (1H, shs), 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, 1.2 Hz), 6.54 (1H, d, J=7.2 Hz), 4.38 (1H, dd, J=9.5, 3.2 Hz), 3.99 (1H, shs), 2.99-2.89 (3H, m), 2.77-2.71 (1H, m), 2.66-2.62 (2H, m), 2.12-2.05 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 279.

[0478]

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

[0479]

[0480]

2-Chloroquinoline (100 mg, 0.611 mmol), 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) and DMF/water (2.4 ml/0.60 ml) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (171 mg, 0.593 mmol, yield: 97%).

¹ H-NMR (CDCl ₃ ) δ: 8.22 (1H, d, J=8.6 Hz), 8.15 (1H, d, J=8.6 Hz), 8.08-8.07 (1H, m), 8.03 (1H, dd, J=8.6, 2.3 Hz), 7.88-7.82 (2H, m), 7.76-7.71 (1H, m), 7.55-7.51 (1H, m), 7.13 (1H, d, J=8.6 Hz), 3.43 (3H, s), 3.06 (2H, t, J=7.5 Hz), 2.74-2.71 (2H, m).

MS(IER) [M+H] ⁺ : 289.

[0481]

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

[0482]

[0483]

1'-Methyl-3',4'-dihydro-[2,6'-biquinolin]-2'(1'H)-one synthesized in Reference Example 16 (171 mg, 0.593 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as "the compound of Example 24") as a white solid (54.3 mg, 0.186 mmol, yield: 31%).

¹ H-NMR (CDCl ₃ ) δ: 7.28-7.25 (1H, m), 7.21 (1H, s), 7.03-7.00 (2H, m), 6.95 (1H, d, J=8.6 Hz), 6.68-6.64 (1H, m), 6.55 (1H, d, J=7.2 Hz), 4.40 (1H, dd, J=9.5, 3.2 Hz), 4.00 (1H, shs), 3.36 (3H, s), 3.00-2.88 (3H, m), 2.78-2.71 (1H, m), 2.67-2.63 (2H, m), 2.13-2.06 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 293.

[0484]

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

[0485]

[0486]

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) were used in a similar manner to Reference Example 11 to give the title compound as a gray solid (61.6 mg, 0.237 mmol, yield: 39%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.69 (1H, br s), 8.54-8.49 (2H, m), 8.40 (1H, d, J=8.2 Hz), 8.24 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=8.6 Hz), 8.04 (1H, d, J=7.2 Hz), 7.85-7.80 (2H, m), 7.66-7.62 (1H, m), 4.51 (2H, s).

MS(IER) [M+H] ⁺ : 261.

[0487]

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

[0488]

[0489]

5-(Quinolin-2-yl)isoindolin-1-one synthesized in Reference Example 17 (61.6 mg, 0.237 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 25”) as a white solid (35.7 mg, 0.135 mmol, yield: 57%).

¹ H-NMR (CDCl ₃ ) δ: 7.85 (1H, d, J=7.7 Hz), 7.53 (1H, s), 7.49 (1H, d, J=7.7 Hz), 7.06-7.00 (2H, m), 6.70-6.67 (1H, m), 6.58 (1H, d, J=7.7 Hz), 6.15 (1H, shs), 4.58 (1H, d, J=9.1 Hz), 4.44 (2H, s), 4.10 (1H, shs), 2.95-2.88 (1H, m), 2.75-2.68 (1H, m), 2.18-2.14 (1H, m), 2.06-1.99 (1H, m).

MS(IER) [M+H] ⁺ : 265.

[0490]

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

[0491]

[0492]

2-Chloroquinoline (50.0 mg, 0.306 mmol) and (4-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (65.3 mg, 0.293 mmol, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.7 Hz), 8.19-8.14 (3H, m), 7.85-7.82 (2H, m), 7.74 (1H, t, J=7.1 Hz), 7.54 (1H, t, J=7.1 Hz), 7.24-7.19 (2H, m).

MS(IER) [M+H] ⁺ : 224.

[0493]

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

[0494]

[0495]

2-(4-Fluorophenyl)quinoline synthesized in Reference Example 18 (62.0 mg, 0.278 mmol) was dissolved in dichloromethane (2.8 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (148 mg, 0.583 mmol) and iodine (7.0 mg, 0.028 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 3 hours. 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 give the title compound (hereinafter referred to as the compound of Example 26) as a colorless transparent oily substance (60.2 mg, 0.264 mmol, yield: 95%).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.33 (2H, m), 7.05-6.99 (4H, m), 6.66 (1H, t, J=7.3 Hz), 6.54 (1H, d, J=7.8 Hz), 4.42 (1H, dd, J=9.4, 3.0 Hz), 4.00 (1H, shs), 2.96-2.88 (1H, m), 2.76-2.69 (1H, m), 2.12-2.06 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 228.

[0496]

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

[0497]

[0498]

2-Chloroquinoline (50.0 mg, 0.306 mmol) and (3-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (68.5 mg, 0.307 mmol, yield: quant. ).

¹ H-NMR (CDCl ₃ ) δ: 8.25 (1H, d, J=8.2 Hz), 8.17 (1H, d, J=8.2 Hz), 7.94-7.92 (2H, m), 7.87-7.85 (2H, m), 7.75 (1H, td, J=7.5, 1.4 Hz), 7.56 (1H, td, J=7.5, 1.4 Hz), 7.52-7.47 (1H, m), 7.19-7.14 (1H, m).

MS(IER) [M+H] ⁺ : 224.

[0499]

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

[0500]

[0501]

2-(3-Fluorophenyl)quinoline synthesized in Reference Example 19 (65.0 mg, 0.291 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 27”) as a colorless transparent oily substance (66.3 mg, 0.291 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 7.32-7.28 (1H, m), 7.16-7.09 (2H, m), 7.03-6.95 (3H, m), 6.66 (1H, t, J=7.3 Hz), 6.55 (1H, d, J=7.8 Hz), 4.44 (1H, dd, J=9.1, 2.7 Hz), 4.04 (1H, shs), 2.94-2.86 (1H, m), 2.74-2.68 (1H, m), 2.15-2.08 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 228.

[0502]

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

[0503]

[0504]

2-Chloroquinoline (50.0 mg, 0.306 mmol) and (2-fluorophenyl)boronic acid (64.1 mg, 0.458 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (69.9 mg, 0.309 mmol, yield: quant. ).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.7 Hz), 8.18 (1H, d, J=8.2 Hz), 8.10 (1H, td, J=7.8, 1.8 Hz), 7.91-7.85 (2H, m), 7.75 (1H, td, J=7.8, 1.8 Hz), 7.57 (1H, t, J=7.3 Hz), 7.46-7.42 (1H, m), 7.33 (1H, t, J=7.3 Hz), 7.21 (1H, dd, J=10.5, 8.7 Hz).

MS(IER) [M+H] ⁺ : 224.

[0505]

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

[0506]

[0507]

2-(3-Fluorophenyl)quinoline synthesized in Reference Example 20 (65.0 mg, 0.291 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 28”) as a colorless transparent oily substance (65.2 mg, 0.287 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 7.47 (1H, t, J=7.5 Hz), 7.27-7.22 (1H, m), 7.12 (1H, t, J=7.5 Hz), 7.07-6.99 (3H, m), 6.66 (1H, t, J=7.2 Hz), 6.57 (1H, d, J=7.7 Hz), 4.85 (1H, d, J=6.8 Hz), 4.00 (1H, shs), 2.93-2.85 (1H, m), 2.72-2.66 (1H, m), 2.20-2.13 (1H, m), 2.04-1.97 (1H, m).

MS(IER) [M+H] ⁺ : 228.

[0508]

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

[0509]

[0510]

2-Chloroquinoline (50.0 mg, 0.306 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (87.1 mg, 0.458 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (80.7 mg, 0.295 mmol, yield: 97%).

¹ H-NMR (CDCl ₃ ) δ: 8.30-8.28 (3H, m), 8.19 (1H, d, J=8.2 Hz), 7.90 (1H, d, J=8.7 Hz), 7.87 (1H, d, J=8.2 Hz), 7.79-7.76 (3H, m), 7.58 (1H, t, J=8.2Hz).

MS(IER) [M+H] ⁺ : 274.

[0511]

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

[0512]

[0513]

2-(4-(Trifluoromethyl)phenyl)quinoline synthesized in Reference Example 21 (80.0 mg, 0.293 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 29”) as a colorless transparent oily substance (77.0 mg, 0.278 mmol, yield: 95%).

¹ H-NMR (CDCl ₃ ) δ: 7.60 (2H, d, J=8.2 Hz), 7.50 (2H, d, J=8.2 Hz), 7.04-7.00 (2H, m), 6.68 (1H, t, J=7.1 Hz), 6.57 (1H, d, J=7.8 Hz), 4.52 (1H, dd, J=8.7, 1.8 Hz), 4.05 (1H, brs), 2.95-2.87 (1H, m), 2.74-2.67 (1H, m), 2.17-2.10 (1H, m), 2.02-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 278.

[0514]

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

[0515]

[0516]

2-Chloroquinoline (24.0 mg, 0.147 mmol) and (3-(trifluoromethyl)phenyl)boronic acid (30.6 mg, 0.161 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (40.1 mg, 0.147 mmol, yield: quant. ).

¹ H-NMR (CDCl ₃ ) δ: 8.47 (1H, shs), 8.36 (1H, d, J=7.8 Hz), 8.27 (1H, d, J=8.2 Hz), 8.19 (1H, d, J=8.7 Hz), 7.90 (1H, d, J=8.7 Hz), 7.86 (1H, d, J=8.2 Hz), 7.78-7.74 (1H, m), 7.72 (1H, d, J=7.8 Hz), 7.65 (1H, t, J=7.8 Hz), 7.59-7.55 (1H, m).

MS(IER) [M+H] ⁺ : 274.

[0517]

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

[0518]

[0519]

2-(3-(Trifluoromethyl)phenyl)quinoline synthesized in Reference Example 22 (40.0 mg, 0.146 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 30”) as a colorless transparent oily substance (39.1 mg, 0.141 mmol, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 7.66 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=7.8 Hz), 7.46 (1H, t, J=7.5 Hz), 7.05-6.99 (2H, m), 6.68 (1H, td, J=7.4, 1.0 Hz), 6.58 (1H, dd, J=7.8, 1.0 Hz), 4.51 (1H, dd, J=9.1, 2.3 Hz), 4.04 (1H, brs), 2.98-2.90 (1H, m), 2.74 (1H, dt, J=16.5, 4.8 Hz), 2.16-2.10 (1H, m), 2.04-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 278.

[0520]

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

[0521]

[0522]

(4-(Trifluoromethoxy)phenyl)boronic acid (138 mg, 0.672 mmol) was used in a similar manner to Reference Example 6 to give the title compound as a white solid (158 mg, 0.547 mmol, yield: 90%).

¹ H-NMR (CDCl ₃ ) δ: 8.25 (1H, d, J=8.7 Hz), 8.22-8.20 (2H, m), 8.16 (1H, d, J=8.7 Hz), 7.86-7.84 (2H, m), 7.75 (1H, ddd, J=8.7, 6.9, 1.4 Hz), 7.56 (1H, ddd, J=7.8, 6.9, 0.9 Hz), 7.40-7.38 (2H, m).

MS(IER) [M+H] ⁺ : 290.

[0523]

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

[0524]

[0525]

2-(4-(Trifluoromethoxy)phenyl)quinoline synthesized in Reference Example 23 (158 mg, 0.547 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 31”) as a pale yellow oily substance (160 mg, 0.544 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 7.43-7.39 (2H, m), 7.19 (2H, d, J=8.2 Hz), 7.02-7.01 (2H, m), 6.67 (1H, ddd, J=7.8, 7.8, 1.4 Hz), 6.55 (1H, d, J=7.8 Hz), 4.46 (1H, dd, J=9.1, 3.2 Hz), 4.03 (1H, shs), 2.92 (1H, ddd, J=16.5, 10.5, 5.5 Hz), 2.72 (1H, ddd, J=16.5, 5.0, 5.0 Hz), 2.15-2.08 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 294.

[0526]

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

[0527]

[0528]

2-Chloroquinoline (50.0 mg, 0.306 mmol) and (4-sulfamoylphenyl)boronic acid (92.1 mg, 0.458 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a pale yellow solid (66.1 mg, 0.232 mmol, yield: 76%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.54 (1H, d, J=8.2 Hz), 8.48 (2H, d, J=8.2 Hz), 8.25 (1H, d, J=8.2 Hz), 8.12 (1H, d, J=8.2 Hz), 8.05 (1H, d, J=8.2 Hz), 8.00 (2H, d, J=8.2 Hz), 7.83 (1H, t, J=7.2 Hz), 7.65 (1H, t, J=7.2 Hz), 7.51 (2H, brs).

MS(IER) [M+H] ⁺ : 285.

[0529]

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

[0530]

[0531]

4-(Quinolin-2-yl)benzenesulfonamide synthesized in Reference Example 24 (70.0 mg, 0.246 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 32”) as a white solid (36.1 mg, 0.125 mmol, yield: 51%).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=8.2 Hz), 7.55 (2H, d, J=8.2 Hz), 7.06-7.00 (2H, m), 6.69 (1H, t, J=7.1 Hz), 6.59 (1H, d, J=8.2 Hz), 4.83 (2H, brs), 4.55 (1H, dd, J=8.7, 3.2 Hz), 4.08 (1H, brs), 2.92-2.87 (1H, m), 2.72-2.67 (1H, m), 2.17-2.11 (1H, m), 2.01-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 289.

[0532]

(Example 33) Synthesis of one of the optical isomers of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0533]

[0534]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(Quinolin-2-yl)benzenesulfonamide synthesized in Reference Example 24 (50.0 mg, 0.176 mmol) 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 diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (106 mg, 0.422 mmol) was then added to the resulting suspension, and the resulting mixture was stirred at 60°C for 6 hours. Further, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (106 mg, 0.422 mmol) was added, and the resulting mixture was stirred at 60°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound (hereinafter referred to as “the compound of Example 33”) as a pale yellow solid (22.4 mg, 0.0774 mmol, yield: 44%, enantiomeric excess: 98.1% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=8.2 Hz), 7.55 (2H, d, J=8.2 Hz), 7.06-7.00 (2H, m), 6.69 (1H, t, J=7.1 Hz), 6.59 (1H, d, J=8.2 Hz), 4.83 (2H, brs), 4.55 (1H, dd, J=8.7, 3.2 Hz), 4.08 (1H, brs), 2.92-2.87 (1H, m), 2.72-2.67 (1H, m), 2.17-2.11 (1H, m), 2.01-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 289.

Rt: 20.76 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=60:40

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0535]

(Example 34) Synthesis of another optical isomer of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0536]

[0537]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(Quinolin-2-yl)benzenesulfonamide synthesized in Reference Example 24 (50.0 mg, 0.176 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (2.6 mg, 0.0035 mmol) were used according to the procedure of Example 33 to give the title compound (hereinafter referred to as "the compound of Example 34") as a white solid (37.7 mg, 0.131 mmol, yield: 74%, enantiomeric excess: 99.0% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=8.2 Hz), 7.55 (2H, d, J=8.2 Hz), 7.06-7.00 (2H, m), 6.69 (1H, t, J=7.1 Hz), 6.59 (1H, d, J=8.2 Hz), 4.83 (2H, brs), 4.55 (1H, dd, J=8.7, 3.2 Hz), 4.08 (1H, brs), 2.92-2.87 (1H, m), 2.72-2.67 (1H, m), 2.17-2.11 (1H, m), 2.01-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 289.

Rt: 17.40 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=60:40

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0538]

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

[0539]

[0540]

2-Chloroquinoline (150 mg, 0.917 mmol) and (4-cyanophenyl)boronic acid (269 mg, 1.83 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (100 mg, 0.917 mmol, yield: 47%).

¹ H-NMR (CDCl ₃ ) δ: 8.32-8.29 (3H, m), 8.18 (1H, d, J=8.2 Hz), 7.92-7.86 (2H, m), 7.84-7.82 (2H, m), 7.78 (1H, t, J=7.1 Hz), 7.59 (1H, t, J=7.1Hz).

MS(IER) [M+H] ⁺ : 231.

[0541]

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

[0542]

[0543]

4-(Quinolin-2-yl)benzonitrile synthesized in Reference Example 25 (95.0 mg, 0.413 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 35”) as a white solid (94.9 mg, 0.405 mmol, yield: 98%).

¹ H-NMR (CDCl ₃ ) δ: 7.64 (2H, d, J=8.2 Hz), 7.50 (2H, d, J=8.2 Hz), 7.06-7.00 (2H, m), 6.69 (1H, t, J=7.3 Hz), 6.58 (1H, d, J=7.8 Hz), 4.53 (1H, d, J=7.3 Hz), 4.07 (1H, brs), 2.93-2.86 (1H, m), 2.72-2.64 (1H, m), 2.17-2.10 (1H, m), 2.00-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 235.

[0544]

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

[0545]

[0546]

4-(1,2,3,4-Tetrahydroquinolin-2-yl)benzonitrile synthesized in Example 35 (32.0 mg, 0.137 mmol) was dissolved in DMSO/THF (1/4, v/v, 1.4 mL), and 1 mol/L aqueous sodium hydroxide solution (300 μL, 0.300 mmol) and 30% aqueous hydrogen peroxide solution (23 μL, 0.300 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 36 compound”) as a pale yellow solid (29.9 mg, 0.119 mmol, yield: 87%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, d, J=8.2 Hz), 7.48 (2H, d, J=7.8 Hz), 7.05-7.00 (2H, m), 6.68 (1H, t, J=7.1 Hz), 6.58 (1H, d, J=8.2 Hz), 6.08 (1H, shs), 5.67 (1H, shs), 4.52 (1H, dd, J=8.9, 3.4 Hz), 4.08 (1H, shs), 2.96-2.87 (1H, m), 2.72-2.68 (1H, m), 2.17-2.10 (1H, m), 2.02-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 253.

[0547]

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

[0548]

[0549]

2-Chloroquinoline (400 mg, 2.45 mmol) and (4-carbamoylphenyl)boronic acid (605 mg, 3.67 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a pale yellow solid (329.0 mg, 1.32 mmol, yield: 54%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.51 (1H, d, J=8.6 Hz), 8.37 (2H, d, J=8.6 Hz), 8.24 (1H, d, J=8.6 Hz), 8.12-8.02 (5H, m), 7.81 (1H, t, J=7.7 Hz), 7.63 (1H, t, J=7.0 Hz), 7.48 (1H, s).

MS(IER) [M+H] ⁺ : 249.

[0550]

(Example 37) Synthesis of one of the optical isomers of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0551]

[0552]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(Quinolin-2-yl)benzamide synthesized in Reference Example 26 (50.0 mg, 0.201 mmol) 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), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (0.122 g, 0.483 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 24 hours under 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) and recrystallization (ethyl acetate/methanol) to give the title compound (hereinafter referred to as “Example 37 compound”) as a white solid (11.0 mg, 0.0436 mmol, yield: 22%, enantiomeric excess: 98.2% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, d, J=8.2 Hz), 7.49 (2H, t, J=11.3 Hz), 7.02 (2H, d, J=6.9 Hz), 6.67 (1H, t, J=7.2 Hz), 6.58 (1H, d, J=7.7 Hz), 6.05 (1H, s), 5.58 (1H, s), 4.52 (1H, d, J=6.8 Hz), 4.07 (1H, s), 2.95-2.87 (1H, m), 2.71 (1H, dt, J=16.6, 5.1 Hz), 2.16-2.11 (1H, m), 2.05-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 253.

Rt: 14.28 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0553]

(Example 38) Synthesis of another optical isomer of 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0554]

[0555]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(Quinolin-2-yl)benzamide synthesized in Reference Example 26 (50.0 mg, 0.201 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (3.0 mg, 0.0040 mmol) were used according to the procedure of Example 37 to give the title compound (hereinafter referred to as "the compound of Example 38") as a white solid (13.7 mg, 0.0543 mmol, yield: 46%, enantiomeric excess: 97.6% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, d, J=8.2 Hz), 7.49 (2H, t, J=11.3 Hz), 7.02 (2H, d, J=6.9 Hz), 6.67 (1H, t, J=7.2 Hz), 6.58 (1H, d, J=7.7 Hz), 6.05 (1H, s), 5.58 (1H, s), 4.52 (1H, d, J=6.8 Hz), 4.07 (1H, s), 2.95-2.87 (1H, m), 2.71 (1H, dt, J=16.6, 5.1 Hz), 2.16-2.11 (1H, m), 2.05-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 253.

Rt: 24.14 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[0556]

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

[0557]

[0558]

Methyl 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzoate synthesized in Example 17 (545 mg, 2.04 mmol) was dissolved in THF/methanol (5.0 mL/5.0 mL), and 8 mol/L aqueous sodium hydroxide solution (0.764 mL, 6.11 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 20 hours under an argon atmosphere. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a cream-colored solid (497 mg, 1.96 mmol, yield: 96%).

¹ H-NMR (CD ₃ OD) δ: 7.97 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.2 Hz), 6.94-6.89 (2H, m), 6.61-6.52 (2H, m), 4.52-4.49 (1H, m), 2.88-2.80 (1H, m), 2.65-2.58 (1H, m), 2.14-2.07 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 254.

[0559]

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

[0560]

[0561]

4-(1,2,3,4-Tetrahydroquinolin-2-yl)benzoic acid synthesized in Reference Example 27 (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) were dissolved in DMF (1.2 mL), and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound (hereinafter referred to as "Example 39 compound") as a colorless, transparent oil (14.5 mg, 47.0 μmol, yield: 31%).

¹ H-NMR (CDCl ₃ ) δ: 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.04-6.99 (2H, m), 6.68-6.64 (1H, m), 6.56 (1H, d, J=8.4 Hz), 4.47 (1H, dd, J=9.1, 3.6 Hz), 4.05 (1H, shs), 3.60-3.22 (2H, m), 3.33-3.22 (2H, m), 2.95-2.87 (1H, m), 2.76-2.69 (1H, m), 2.15-2.09 (1H, m), 2.03-1.93 (1H, m), 1.28-1.08 (6H, m).

MS(IER) [M+H] ⁺ : 309.

[0562]

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

[0563]

[0564]

4-(1,2,3,4-Tetrahydroquinolin-2-yl)benzoic acid synthesized in Reference Example 27 (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 in methanol (65.1 μL, 0.130 mmol) and N,N-diisopropylethylamine (30.9 μL, 0.178 mmol) were dissolved in DMF (1.2 mL), and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound (hereinafter referred to as "Example 40 compound") as a white solid (24.5 mg, 47.0 μmol, yield: 74%).

¹ H-NMR (CDCl ₃ ) δ: 7.75-7.72 (2H, m), 7.44 (2H, d, J=8.2 Hz), 7.04-6.99 (2H, m), 6.68-6.66 (1H, ddd, J=7.6, 7.6, 0.8 Hz), 6.57 (1H, dd, J=7.7, 0.9 Hz), 6.09 (1H, br s), 4.50 (1H, dd, J=9.1, 3.6 Hz), 4.06 (1H, br s), 3.54-3.47 (2H, m), 2.95-2.87 (1H, m), 2.74-2.67 (1H, m), 2.16-2.09 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 281.

[0565]

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

[0566]

[0567]

4-(1,2,3,4-Tetrahydroquinolin-2-yl)benzoic acid synthesized in Reference Example 27 (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) 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 to the resulting solution, and the resulting mixture was stirred at room temperature for 14 hours under argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound (hereinafter referred to as "Example 41 compound") as a white amorphous solid (28.6 mg, 89.3 μmol, yield: 75%).

¹ H-NMR (CDCl ₃ ) δ: 7.42-7.36 (4H, m), 7.04-7.00 (2H, m), 6.66 (1H, ddd, J=7.6, 7.6, 1.2 Hz), 6.56 (1H, d, J=7.7 Hz), 4.47 (1H, dd, J=9.1, 3.6 Hz), 4.05 (1H, shs), 3.71 (2H, shs), 3.36 (2H, shs), 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, shs), 1.53 (2H, shs).

MS(IER) [M+H] ⁺ : 321.

[0568]

(Example 42) Synthesis of morpholino(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone (new compound):

[0569]

[0570]

4-(1,2,3,4-Tetrahydroquinolin-2-yl)benzoic acid synthesized in Reference Example 27 (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) 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 to the resulting solution, and the resulting mixture was stirred at room temperature for 16 hours under argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound (hereinafter referred to as "Example 42 compound") as a white solid (33.4 mg, 0.104 mmol, yield: 88%).

¹ H-NMR (CDCl ₃ ) δ: 7.45-7.38 (4H, m), 7.04-6.98 (2H, m), 6.69-6.64 (1H, m), 6.56 (1H, d, J=7.7 Hz), 4.48 (1H, dd, J=9.1, 3.2 Hz), 4.05 (1H, shs), 3.77-3.48 (8H, m), 2.95-2.87 (1H, m), 2.75-2.68 (1H, m), 2.21-2.09 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 323.

[0571]

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

[0572]

[0573]

4-(1,2,3,4-Tetrahydroquinolin-2-yl)benzoic acid synthesized in Reference Example 27 (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) were dissolved in DMF (1.2 ml), and 1-methylpiperazine (14.3 μl, 0.130 mmol) and N,N-diisopropylethylamine (30.9 μl, 0.178 mmol) were added to the resulting solution, and the resulting mixture was stirred at room temperature for 14 hours under an argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound (hereinafter referred to as "Example 43 compound") as a white amorphous solid (32.8 mg, 97.8 μmol, yield: 83%).

¹ H-NMR (CDCl ₃ ) δ: 7.44-7.37 (4H, m), 7.04-7.00 (2H, m), 6.67 (1H, ddd, J=7.5, 1.1, 0.5 Hz), 6.56 (1H, d, J=8.4 Hz), 4.48 (1H, dd, J=8.8, 3.4 Hz), 4.04 (1H, brs), 3.80 (2H, brs), 3.46 (2H, brs), 2.96-2.87 (1H, m), 2.75-2.69 (1H, m), 2.49-2.33 (7H, m), 2.16-2.09 (1H, m), 2.03-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 336.

[0574]

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

[0575]

[0576]

2-Chloroquinoline (100 mg, 0.611 mmol), (4-(methylcarbamoyl)phenyl)boronic acid (164 mg, 0.917 mmol), tetrakis(triphenylphosphine)palladium(0) (14.1 mg, 0.0122 mmol) and potassium carbonate (253 mg, 1.83 mmol) were suspended in 1,4-dioxane (2 ml), and the resulting suspension was stirred under heating at 100°C for 15 hours. After cooling the reaction mixture to room temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a colorless transparent oil (156 mg, 0.593 mmol, yield: 97%).

¹ H-NMR (CDCl ₃ ) δ: 8.58 (1H, s), 8.29-8.25 (2H, m), 8.17 (1H, d, J=8.7 Hz), 7.94-7.84 (3H, m), 7.76 (1H, t, J=7.3 Hz), 7.62-7.54 (2H, m), 6.44 (1H, brs), 3.07 (3H, d, J=5.0 Hz).

MS(IER) [M+H] ⁺ : 263.

[0577]

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

[0578]

[0579]

N-methyl-3-(quinolin-2-yl)benzamide synthesized in Reference Example 28 (155 mg, 0.591 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 44”) as a colorless transparent oily substance (132 mg, 0.496 mmol, yield: 84%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (1H, s), 7.68 (1H, d, J=7.8 Hz), 7.53 (1H, d, J=7.3 Hz), 7.41 (1H, t, J=7.8 Hz), 7.04-7.00 (2H, m), 6.67 (1H, t, J=7.1 Hz), 6.57 (1H, d, J=7.8 Hz), 6.16 (1H, shs), 4.50 (1H, dd, J=9.4, 3.0 Hz), 4.06 (1H, shs), 3.02 (3H, d, J=5.0 Hz), 2.97-2.89 (1H, m), 2.75-2.71 (1H, m), 2.16-2.09 (1H, m), 2.04-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 267.

[0580]

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

[0581]

[0582]

2-Chloroquinoline (150 mg, 0.917 mmol) and (3-cyanophenyl)boronic acid (269 mg, 1.83 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (211 mg, 0.917 mmol, yield: quant. ).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.7 Hz), 8.19-8.14 (3H, m), 7.85-7.82 (2H, m), 7.74 (1H, t, J=7.1 Hz), 7.54 (1H, t, J=7.1 Hz), 7.24-7.19 (2H, m).

MS(IER) [M+H] ⁺ : 224.

[0583]

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

[0584]

[0585]

3-(Quinolin-2-yl)benzonitrile synthesized in Reference Example 29 (210 mg, 0.912 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 45”) as a colorless transparent oily substance (191 mg, 0.812 mmol, yield: 89%).

¹ H-NMR (CDCl ₃ ) δ: 7.70 (1H, s), 7.63 (1H, d, J=7.8 Hz), 7.58 (1H, d, J=7.8 Hz), 7.46 (1H, t, J=7.8 Hz), 7.05-7.01 (2H, m), 6.69 (1H, t, J=7.3 Hz), 6.58 (1H, d, J=7.8 Hz), 4.50 (1H, d, J=6.9 Hz), 4.05 (1H, shs), 2.95-2.87 (1H, m), 2.73-2.67 (1H, m), 2.17-2.10 (1H, m), 2.01-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 235.

[0586]

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

[0587]

[0588]

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

¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, s), 7.73 (1H, d, J=7.8 Hz), 7.57 (1H, d, J=7.8 Hz), 7.44 (1H, t, J=7.5 Hz), 7.04-6.99 (2H, m), 6.68 (1H, t, J=7.5 Hz), 6.57 (1H, d, J=7.8 Hz), 6.11 (1H, shs), 5.62 (1H, shs), 4.51 (1H, dd, J=9.4, 3.0 Hz), 4.06 (1H, shs), 2.98-2.90 (1H, m), 2.76-2.70 (1H, m), 2.16-2.10 (1H, m), 2.05-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 253.

[0589]

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

[0590]

[0591]

2-Chloroquinoline (100 mg, 0.611 mmol) and (2-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol) were used in a similar manner to Reference Example 28 to give the title compound as a white solid (139 mg, 0.592 mmol, yield: 97%).

¹ H-NMR (CDCl ₃ ) δ: 8.33 (1H, d, J=8.7 Hz), 8.12 (1H, d, J=7.8 Hz), 7.89 (1H, dd, J=8.0, 1.1 Hz), 7.78-7.76 (2H, m), 7.72-7.69 (1H, m), 7.60 (1H, ddd, J=8.2, 6.9, 0.9 Hz), 7.57-7.53 (1H, m), 7.49-7.46 (2H, m), 6.81 (1H, dd, J=6.9, 6.9 Hz), 4.56 (2H, d, J=6.9 Hz).

MS(IER) [M+H] ⁺ : 236.

[0592]

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

[0593]

[0594]

(2-(Quinolin-2-yl)phenyl)methanol synthesized in Reference Example 30 (139 mg, 0.592 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 47”) as a pale yellow oily substance (56.6 mg, 0.237 mmol, yield: 40%).

¹ H-NMR (CDCl ₃ ) δ: 7.57 (1H, dd, J=7.3, 1.4 Hz), 7.41-7.27 (4H, m), 7.04-7.00 (2H, m), 6.69 (1H, dd, J=7.3, 7.3, 1.4 Hz), 6.56 (1H, d, J=8.2 Hz), 4.79 (2H, dd, J=19.7, 12.3 Hz), 4.73 (1H, dd, J=9.6, 3.2 Hz), 2.99 (1H, ddd, J=16.9, 11.4, 5.5 Hz), 2.81 (1H, dd, J=16.5, 4.1, 4.1 Hz), 2.19-2.05 (2H, m).

MS(IER) [M+H] ⁺ : 240.

[0595]

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

[0596]

[0597]

2-Chloroquinoline (100 mg, 0.611 mmol) and (3-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol) were used in a similar manner to Reference Example 28 to give the title compound as a colorless amorphous substance (143 mg, 0.607 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 8.24 (1H, d, J=8.7 Hz), 8.18-8.17 (2H, m), 8.06 (1H, ddd, J=7.8, 1.4, 1.4 Hz), 7.89 (1H, d, J=8.2 Hz), 7.85-7.83 (1H, m), 7.74 (1H, ddd, J=8.2, 6.9, 1.4 Hz), 7.56-7.46 (3H, m), 4.83 (2H, d, J=5.9 Hz), 1.95 (1H, dd, J=5.9, 5.9 Hz).

MS(IER) [M+H] ⁺ : 236.

[0598]

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

[0599]

[0600]

(3-(Quinolin-2-yl)phenyl)methanol synthesized in Reference Example 31 (143 mg, 0.607 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 48”) as a pale yellow oily substance (133 mg, 0.554 mmol, yield: 94%).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.33 (4H, m), 7.02-7.00 (2H, m), 6.66 (1H, dd, J=7.3, 7.3 Hz), 6.55 (1H, d, J=8.2 Hz), 4.71 (2H, d, J=4.6 Hz), 4.45 (1H, dd, J=9.1, 3.2 Hz), 4.03 (1H, shs), 2.93 (1H, ddd, J=16.5, 11.0, 5.9 Hz), 2.74 (1H, ddd, J=16.0, 4.6, 4.6 Hz), 2.14-2.10 (1H, m), 2.05-1.95 (1H, m), 1.67 (1H, t, J=5.5Hz).

MS(IER) [M+H] ⁺ : 240.

[0601]

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

[0602]

[0603]

2-Chloroquinoline (100 mg, 0.611 mmol) and (4-(hydroxymethyl)phenyl)boronic acid (102 mg, 0.672 mmol) were used in a similar manner to Reference Example 28 to give the title compound as a white solid (136 mg, 0.576 mmol, yield: 94%).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.7 Hz), 8.18-8.17 (3H, m), 7.89 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=8.0, 1.1 Hz), 7.74 (1H, ddd, J=8.2, 6.9, 12.8 Hz), 7.56-7.52 (3H, m), 4.80 (2H, d, J=5.9 Hz), 1.81 (1H, t, J=5.9 Hz).

MS(IER) [M+H] ⁺ : 236.

[0604]

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

[0605]

[0606]

(4-(Quinolin-2-yl)phenyl)methanol synthesized in Reference Example 32 (136 mg, 0.576 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 49”) as a pale yellow oily substance (77.3 mg, 0.323 mmol, yield: 56%).

¹ H-NMR (CDCl ₃ ) δ: 7.40 (2H, d, J=8.2 Hz), 7.36 (2H, d, J=8.2 Hz), 7.02-7.00 (2H, m), 6.66 (1H, ddd, J=7.2, 7.2, 1.4 Hz), 6.55 (1H, d, J=7.7 Hz), 4.70 (2H, d, J=5.9 Hz), 4.45 (1H, dd, J=9.3, 3.4 Hz), 4.03 (1H, brs), 2.92 (1H, ddd, J=16.3, 10.4, 5.4 Hz), 2.73 (1H, ddd, J=16.3, 4.5, 4.5 Hz), 2.15-2.08 (1H, m), 2.03-1.93 (1H, m), 1.64 (1H, t, J=5.9Hz).

MS(IER) [M+H] ⁺ : 240.

[0607]

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

[0608]

[0609]

2-Chloroquinoline (100 mg, 0.611 mmol) and isothiazol-4-ylboronic acid (118 mg, 0.917 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a yellow solid (122 mg, 0.574 mmol, yield: 94%).

¹ H-NMR (CDCl ₃ ) δ: 9.28 (1H, s), 9.25 (1H, s), 8.23 (1H, d, J=8.7 Hz), 8.13 (1H, d, J=8.2 Hz), 7.83 (1H, d, J=8.2 Hz), 7.78-7.73 (2H, m), 7.55 (1H, t, J=7.5 Hz).

MS(IER) [M+H] ⁺ : 213.

[0610]

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

[0611]

[0612]

4-(Quinolin-2-yl)isothiazole synthesized in Reference Example 33 (110 mg, 0.518 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 50”) as a yellow oily substance (77.5 mg, 0.357 mmol, yield: 69%).

¹ H-NMR (CDCl ₃ ) δ: 8.51 (1H, s), 8.50 (1H, s), 7.04-6.99 (2H, m), 6.68 (1H, t, J=7.1 Hz), 6.55 (1H, d, J=7.8 Hz), 4.71 (1H, dd, J=8.7, 2.7 Hz), 4.09 (1H, shs), 2.95-2.87 (1H, m), 2.75-2.70 (1H, m), 2.22-2.15 (1H, m), 2.07-2.01 (1H, m).

MS(IER) [M+H] ⁺ : 217.

[0613]

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

[0614]

[0615]

Methyl 2-phenylquinoline-5-carboxylate (60.0 mg, 0.228 mmol) was dissolved in toluene (1 mL) under argon atmosphere, and a 1.0 mol/L solution of diisobutylaluminum hydride in hexane (0.912 mL, 0.912 mmol) was added to the resulting solution at -78°C, and the resulting mixture was stirred at -78°C for 1.5 hours. After completion of the reaction, the reaction mixture was allowed to warm to 0°C, and a saturated aqueous solution of potassium sodium tartrate was added to the reaction mixture, and the resulting mixture was 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 and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (51.7 mg, 0.220 mmol, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 8.59 (1H, d, J=9.1 Hz), 8.19-8.14 (3H, m), 7.94 (1H, d, J=8.7 Hz), 7.69 (1H, dd, J=8.5, 7.1 Hz), 7.57-7.52 (3H, m), 7.50-7.46 (1H, m), 5.17 (2H, d, J=5.9 Hz), 5.12 (1H, brs).

MS(IER) [M+H] ⁺ : 236.

[0616]

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

[0617]

[0618]

(2-Phenylquinolin-5-yl)methanol synthesized in Reference Example 34 (51.7 mg, 0.220 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 51”) as a pale yellow solid (47.2 mg, 0.197 mmol, yield: 90%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.36 (5H, m), 7.03 (1H, dd, J=7.8, 7.8 Hz), 6.74 (1H, d, J=7.3 Hz), 6.54 (1H, d, J=7.8 Hz), 5.09 (1H, shs), 4.65 (2H, d, J=5.9 Hz), 4.42 (1H, dd, J=9.8, 3.0 Hz), 4.10 (1H, shs), 2.93-2.80 (2H, m), 2.17-2.15 (1H, m), 2.02-1.99 (1H, m).

MS(IER) [M+H] ⁺ : 240.

[0619]

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

[0620]

[0621]

(2-Phenylquinolin-7-yl)methanol (40.0 mg, 0.170 mol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 52”) as a colorless amorphous solid (38.8 mg, 0.162 mmol, yield: 95%).

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.28 (5H, m), 7.00-6.99 (1H, m), 6.64 (1H, d, J=7.8 Hz), 6.57 (1H, s), 4.58 (2H, d, J=5.9 Hz), 4.45 (1H, dd, J=9.1, 3.2 Hz), 4.10 (1H, shs), 2.90 (1H, ddd, J=16.0, 10.5, 5.5 Hz), 2.73 (1H, ddd, J=16.5, 5.0, 5.0 Hz), 2.16-2.09 (1H, m), 2.05-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 240.

[0622]

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

[0623]

[0624]

2-(Pyridin-2-yl)quinoline (30.0 mg, 0.145 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 53”) as a pale yellow amorphous solid (25.3 mg, 0.120 mmol, yield: 83%).

¹ H-NMR (CDCl ₃ ) δ: 8.59-8.58 (1H, m), 7.68 (1H, ddd, J=7.8, 7.8, 1.4 Hz), 7.43 (1H, d, J=8.2 Hz), 7.20 (1H, dd, J=7.5, 4.8 Hz), 7.05-6.99 (2H, m), 6.67 (1H, d, J=7.3 Hz), 6.64 (1H, d, J=7.8 Hz), 4.60 (1H, dd, J=8.5, 3.4 Hz), 4.52 (1H, shs), 2.92 (1H, ddd, J=15.6, 10.1, 5.0 Hz), 2.70 (1H, ddd, J=16.0, 4.6, 4.6 Hz), 2.31-2.24 (1H, m), 2.05-2.02 (1H, m).

MS(IER) [M+H] ⁺ : 211.

[0625]

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

[0626]

[0627]

Methyl 2-chloroquinoline-6-carboxylate (100 mg, 0.451 mmol) was dissolved in THF (2 ml) and a 1 mol/L solution of methylmagnesium bromide in THF (1.35 ml, 1.35 mmol) was added to the resulting solution at -78°C under an argon atmosphere, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture until the reaction mixture reached pH 6-7, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (75.5 mg, 0.341 mmol, yield: 75%).

¹ H-NMR (CDCl ₃ ) δ: 8.11 (1H, d, J=8.7 Hz), 8.00 (1H, d, J=9.1 Hz), 7.95 (1H, d, J=2.3 Hz), 7.85 (1H, dd, J=8.9, 2.1 Hz), 7.39 (1H, d, J=8.2 Hz), 1.88 (1H, s), 1.68 (6H, s).

MS(IER) [M+H] ⁺ : 222.

[0628]

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

[0629]

[0630]

2-(2-Chloroquinolin-6-yl)propan-2-ol synthesized in Reference Example 35 (75.5 mg, 0.341 mmol) and phenylboronic acid (45.7 mg, 0.375 mmol) were used in a similar manner to Reference Example 28 to give the title compound as a white solid (89.2 mg, 0.339 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 8.22 (1H, d, J=8.6 Hz), 8.16-8.14 (3H, m), 7.94 (1H, d, J=1.8 Hz), 7.88 (1H, d, J=8.6 Hz), 7.85 (1H, dd, J=9.1, 2.3 Hz), 7.53-7.47 (3H, m), 1.90 (1H, s), 1.71 (6H, s).

MS(IER) [M+H] ⁺ : 264.

[0631]

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

[0632]

[0633]

2-(2-Phenylquinolin-6-yl)propan-2-ol synthesized in Reference Example 36 (40.0 mg, 0.152 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 54”) as a colorless amorphous substance (21.4 mg, 85.1 μmol, yield: 56%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (4H, m), 7.30-7.26 (1H, m), 6.90-6.88 (2H, m), 6.50 (1H, d, J=7.7 Hz), 4.40 (1H, dd, J=9.5, 3.2 Hz), 3.93 (1H, shs), 2.94 (1H, ddd, J=16.8, 11.3, 5.9 Hz), 2.84-2.70 (2H, m), 2.12-2.09 (1H, m), 2.01-1.97 (1H, m), 1.22 (3H, s), 1.21 (3H, s).

MS(IER) [M+H] ⁺ : 252.

[0634]

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

[0635]

[0636]

2-Chloroquinolin-6-ol (50.0 mg, 0.278 mmol) was used in a similar manner to Reference Example 28 to give the title compound as a white solid (47.0 mg, 0.212 mmol, yield: 76%).

¹ H-NMR (CDCl ₃ ) δ: 8.13-8.11 (2H, m), 8.08 (2H, dd, J=8.8, 4.3 Hz), 7.83 (1H, d, J=8.6 Hz), 7.53-7.51 (2H, m), 7.46-7.42 (1H, m), 7.33 (1H, dd, J=9.1, 2.7 Hz), 7.12 (1H, d, J=2.7 Hz), 5.32 (1H, s).

MS(IER) [M+H] ⁺ : 222.

[0637]

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

[0638]

[0639]

2-Phenylquinolin-6-ol synthesized in Reference Example 37 (20.0 mg, 90.4 μmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 55”) as a colorless amorphous substance (20.3 mg, 90.1 μmol, yield: >99%).

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.24 (5H, m), 6.57-6.38 (3H, m), 4.36 (1H, dd, J=9.5, 2.7 Hz), 4.20 (1H, shs), 2.91 (1H, dd, J=16.8, 10.9, 5.9 Hz), 2.70 (1H, ddd, J=16.8, 4.5, 4.5 Hz), 2.11-2.09 (1H, m), 2.00-1.96 (1H, m), 1.79 (1H, shs).

MS(IER) [M+H] ⁺ : 226.

[0640]

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

[0641]

[0642]

Methyl 2-chlorophenylquinoline-6-carboxylate (100 mg, 0.451 mmol) was used in a similar manner to Reference Example 28 to give the title compound as a white solid (91.0 mg, 0.346 mmol, yield: 77%).

¹ H-NMR (CDCl ₃ ) δ: 8.61 (1H, d, J=1.8 Hz), 8.33-8.31 (2H, m), 8.21-8.19 (3H, m), 7.96 (1H, d, J=8.6 Hz), 7.52-7.47 (3H, m), 4.01 (3H, s).

MS(IER) [M+H] ⁺ : 264.

[0643]

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

[0644]

[0645]

Methyl 2-phenylquinoline-6-carboxylate synthesized in Reference Example 38 (120 mg, 0.456 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 56”) as a pale yellow oily substance (112 mg, 0.420 mmol, yield: 92%).

¹ H-NMR (CDCl ₃ ) δ: 7.71-7.70 (2H, m), 7.39-7.28 (5H, m), 6.50 (1H, d, J=8.6 Hz), 4.55-4.50 (2H, m), 3.85 (3H, s), 2.89 (1H, ddd, J=16.3, 10.9, 5.4 Hz), 2.75 (1H, ddd, J=16.3, 5.0, 5.0 Hz), 2.16-2.13 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 268.

[0646]

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

[0647]

[0648]

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

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.31 (5H, m), 7.14-7.13 (2H, m), 6.53 (1H, d, J=8.2 Hz), 4.43 (1H, dd, J=9.5, 3.2 Hz), 4.05 (1H, shs), 2.94 (1H, ddd, J=16.8, 10.9, 6.3 Hz), 2.75 (1H, ddd, J=16.8, 5.0, 5.0 Hz), 2.18-2.10 (1H, m), 2.01-1.98 (1H, m), 1.63 (1H, s), 1.57 (6H, s).

MS(IER) [M+H] ⁺ : 268.

[0649]

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

[0650]

[0651]

Methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate synthesized in Example 56 (38.0 mg, 0.142 mmol) was dissolved in toluene (2.0 mL), and a 1.01 mol/L solution of diisobutylaluminum hydride in toluene (0.426 mL, 0.426 mmol) was then slowly added dropwise to the resulting solution at -78°C under an argon atmosphere. Then, the reaction mixture was allowed to slowly warm to room temperature and stirred for 6 hours. After completion of the reaction, an aqueous solution of sodium potassium tartrate (8 mL) was added to the reaction mixture, and the resulting mixture was stirred overnight at room temperature. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 58 compound”) as a colorless transparent oily substance (25.6 mg, 0.107 mmol, yield: 75%).

¹ H-NMR (CDCl ₃ ) 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, 2.3 Hz), 4.54 (2H, d, J=4.5 Hz), 4.45 (1H, dd, J=9.1, 3.2 Hz), 4.12 (1H, q, J=7.1 Hz), 2.95-2.87 (1H, m), 2.73 (1H, td, J=10.6, 5.6 Hz), 2.16-2.10 (1H, m), 2.05-1.94 (1H, m), 1.44 (1H, t, J=5.4 Hz).

MS(IER) [M+H] ⁺ : 240.

[0652]

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

[0653]

[0654]

(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol synthesized in Example 58 (30.0 mg, 0.125 mmol) was dissolved in dichloromethane (1.3 mL), and morpholine (55 μL, 0.63 mmol), triphenylphosphine (39.5 mg, 0.150 mmol), and iodine (38.2 mg, 0.150 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by amino column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “the compound of Example 59”) as a colorless transparent oily substance (21.0 mg, 0.0675 mmol, yield: 54%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (4H, m), 7.30-7.27 (1H, m), 6.95-6.93 (2H, m), 6.50 (1H, d, J=8.7 Hz), 4.42 (1H, dd, J=9.4, 3.0 Hz), 4.03 (1H, shs), 3.71 (4H, t, J=4.6 Hz), 3.37 (2H, s), 2.96-2.88 (1H, m), 2.76-2.70 (1H, m), 2.44 (4H, shs), 2.15-2.08 (1H, m), 2.03-1.93 (1H, m).

MS(ESI)[M-morpholine] ⁺ : 222.

[0655]

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

[0656]

[0657]

(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol synthesized in Example 58 (100 mg, 0.418 mmol) was dissolved in THF (4.2 ml), and acetone cyanohydrin (114 μl, 1.25 mmol) and tri -n -butylphosphine (207 μl, 0.836 mmol) were added to the resulting solution. 1,1'-(azodicarbonyl)dipiperidine (211 mg, 0.836 mmol) was added to the solution under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a colorless transparent oil (64.2 mg, 0.259 mmol, yield: 62%).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 6.96-6.92 (2H, m), 6.52 (1H, d, J=7.8 Hz), 4.45 (1H, ddd, J=9.1, 3.2, 1.4 Hz), 4.12 (1H, shs), 3.62 (2H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.15-2.10 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 249.

[0658]

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

[0659]

[0660]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetonitrile synthesized in Reference Example 39 (62.0 mg, 0.250 mmol) was dissolved in DMSO/THF/ethanol (1/1/2, v/v/v, 5 mL), and 8 mol/L aqueous sodium hydroxide solution (69 μL, 0.55 mmol) and 30% aqueous hydrogen peroxide solution (43 μL, 0.55 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 1 hour. 30% aqueous hydrogen peroxide solution (43 μL, 0.55 mmol) was further added to the solution, and the resulting mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound (hereinafter referred to as "Example 60 compound") as a white solid (59.0 mg, 0.223 mmol, yield: 89%).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 6.91-6.89 (2H, m), 6.53 (1H, d, J=8.7 Hz), 5.48 (1H, shs), 5.41 (1H, shs), 4.44 (1H, dd, J=9.4, 3.0 Hz), 4.09 (1H, ws), 3.46 (2H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.14-2.10 (1H, m), 2.02-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 267.

[0661]

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

[0662]

[0663]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide synthesized in Example 60 (57.0 mg, 0.214 mmol) was suspended in ethanol (1.05 mL)/water (1.05 mL), and potassium hydroxide (240 mg, 4.28 mmol) was then added to the resulting suspension, and the resulting mixture was heated to reflux for 4 hours. After cooling the reaction mixture to room temperature, the reaction mixture was concentrated under reduced pressure. After adjusting pH to 5 by adding 6 mol/L hydrochloric acid to the resulting crude product, the crude product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound as a pale yellow oily substance (40.9 mg, 0.152 mmol, yield: 71%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.29 (5H, m), 6.94-6.91 (2H, m), 6.51 (1H, d, J=8.7 Hz), 4.43 (1H, dd, J=9.1, 3.2 Hz), 3.52 (2H, s), 2.95-2.87 (1H, m), 2.72 (1H, dt, J=16.3, 4.7 Hz), 2.14-2.07 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 268.

[0664]

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

[0665]

[0666]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.0 mg, 0.0748 mmol) 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 then added to the resulting solution, and the resulting mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound (hereinafter referred to as "Example 61 compound") as a colorless, transparent oil (9.7 mg, 0.030 mmol, yield: 40%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.27 (5H, m), 6.87-6.84 (2H, m), 6.51 (1H, dd, J=6.2, 2.5 Hz), 5.29 (1H, ws), 4.44 (1H, dd, J=9.1, 3.2 Hz), 4.05 (1H, ws), 3.35 (2H, s), 2.95-2.87 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.16-2.09 (1H, m), 2.05-1.94 (1H, m), 1.29 (9H, s).

MS(IER) [M+H] ⁺ : 323.

[0667]

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

[0668]

[0669]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.0 mg, 0.0748 mmol) 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 then added to the resulting solution, and the resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to afford the title compound (hereinafter referred to as "Example 62 compound") as a colorless, transparent oil (9.4 mg, 0.029 mmol, yield: 39%).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 6.90-6.87 (2H, m), 6.48 (1H, d, J=8.2 Hz), 4.58 (1H, shs), 4.41 (1H, dd, J=9.4, 3.0 Hz), 4.30 (1H, t, J=8.2 Hz), 4.21 (1H, dd, J=10.4, 7.1 Hz), 4.02 (1H, shs), 3.97 (1H, dd, J=9.4, 3.9 Hz), 3.83 (1H, dd, J=10.4, 4.1 Hz), 3.33 (2H, s), 2.92-2.86 (2H, m), 2.70 (1H, dt, J=16.3, 4.7 Hz), 2.13-2.07 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 323.

[0670]

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

[0671]

[0672]

Methyl 2-phenylquinoline-6-carboxylate synthesized in Reference Example 38 (0.279 g, 1.06 mmol) was dissolved in a THF/methanol solution (10 ml), and 1 mol/L aqueous sodium hydroxide solution (2.12 ml, 2.12 mmol) was added to the resulting solution, and the resulting mixture was 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 resulting crude product, and the resulting precipitated solid was filtered. The solid was washed with water and dried under vacuum to give the title compound as a white solid (0.246 g, 0.988 mmol, yield: 93%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.67 (2H, dd, J=10.4, 5.0 Hz), 8.32 (2H, td, J=4.2, 2.1 Hz), 8.27-8.22 (2H, m), 8.13 (1H, d, J=9.1 Hz), 7.61-7.52 (3H, m).

MS(IER) [M+H] ⁺ : 250.

[0673]

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

[0674]

[0675]

2-Phenylquinoline-6-carboxylic acid synthesized in Reference Example 41 (0.224 g, 0.898 mmol) 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) was added to the resulting solution, and the resulting mixture was stirred at 80°C for 5 hours. 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 give the title compound as a white solid (0.269 g, 0.840 mmol, yield: 94%).

¹ H-NMR (CDCl ₃ ) δ: 8.16-8.07 (4H, m), 7.84 (1H, d, J=8.6 Hz), 7.54-7.35 (4H, m), 7.27-7.24 (1H, m), 6.72 (1H, s), 1.57 (9H, s).

MS(IER) [M+H] ⁺ : 321.

[0676]

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

[0677]

[0678]

Tert- butyl (2-phenylquinolin-6-yl)carbamate synthesized in Reference Example 42 (72.0 mg, 0.225 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 63”) as a white solid (29.0 mg, 0.0895 mmol, yield: 40%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.32 (4H, m), 7.30-7.20 (1H, m), 7.10 (1H, shs), 6.90 (1H, dd, J=8.4, 2.5 Hz), 6.48 (1H, d, J=8.6 Hz), 4.40 (1H, dd, J=9.1, 3.2 Hz), 3.95 (1H, s), 2.94-2.86 (1H, m), 2.71 (1H, dt, J=16.5, 4.8 Hz), 2.12-2.07 (1H, m), 1.97 (1H, ddt, J=16.8, 10.6, 3.6 Hz), 1.50 (9H, s).

MS(IER) [M+H] ⁺ : 325.

[0679]

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

[0680]

[0681]

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

¹ H-NMR (DMSO-d ₆ ) δ: 9.69 (2H, brs), 7.38-7.33 (4H, m), 7.28 (1H, dq, J=11.7, 3.1 Hz), 6.89 (2H, dt, J=15.1, 5.3 Hz), 6.66 (1H, d, J=8.2 Hz), 4.44 (1H, dd, J=7.9, 3.4 Hz), 2.82-2.75 (1H, m), 2.60-2.50 (1H, m), 1.99 (1H, dd, J=9.7, 7.0 Hz), 1.85 (1H, dt, J=14.6, 5.3 Hz).

MS(IER) [M+H] ⁺ : 225.

[0682]

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

[0683]

[0684]

Quinoline-2-carbaldehyde (200 mg, 1.27 mmol) and potassium carbonate (352 mg, 2.55 mmol) were suspended in methanol (6.3 mL), and toluenesulfonylmethyl isoicanide (273 mg, 1.40 mmol) was then added to the resulting suspension, and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as an orange solid (205 mg, 1.04 mmol, yield: 82%).

^1H -NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.5 Hz), 8.14 (1H, dd, J=8.4, 0.9 Hz), 8.06 (1H, s), 7.86 (1H, s), 7.82 (1H, dd, J=8.4, 1.4 Hz), 7.79 (1H, d, J=8.5 Hz), 7.77-7.73 (1H, m), 7.58-7.54 (1H, m).

MS(IER) [M+H] ⁺ : 197.

[0685]

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

[0686]

[0687]

5-(Quinolin-2-yl)oxazole synthesized in Reference Example 43 (70.0 mg, 0.357 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 65”) as a colorless transparent oily substance (52.1 mg, 0.261 mmol, yield: 73%).

¹ H-NMR (CDCl ₃ ) δ: 7.83 (1H, s), 7.04-6.96 (3H, m), 6.68 (1H, t, J=7.1 Hz), 6.57 (1H, d, J=7.8 Hz), 4.63 (1H, shs), 4.11 (1H, shs), 2.90-2.84 (1H, m), 2.77-2.73 (1H, m), 2.27-2.12 (2H, m).

MS(IER) [M+H] ⁺ : 201.

[0688]

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

[0689]

[0690]

Acetophenone (0.165 ml, 1.42 mmol) and potassium tert -butoxide (119 mg, 1.06 mmol) were added to a solution of (2-amino-6-fluorophenyl)methanol (100 mg, 0.709 mmol) in 1,4-dioxane (2 ml), and the resulting mixture was stirred at 80°C for 1 hour. After completion of the reaction, the reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a pale yellow solid (74.4 mg, 0.333 mmol, yield: 47%).

¹ H-NMR (CDCl ₃ ) δ: 8.50 (1H, d, J=9.1 Hz), 8.18-8.17 (2H, m), 7.98 (1H, d, J=8.6 Hz), 7.95 (1H, d, J=9.1 Hz), 7.66 (1H, ddd, J=8.2, 8.2, 5.9 Hz), 7.57-7.47 (3H, m), 7.22-7.18 (1H, m).

MS(IER) [M+H] ⁺ : 224.

[0691]

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

[0692]

[0693]

5-Fluoro-2-phenylquinoline synthesized in Reference Example 44 (74.4 mg, 0.333 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 66”) as a pale yellow oily substance (69.3 mg, 0.305 mmol, yield: 91%).

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.32 (5H, m), 6.99-6.92 (1H, m), 6.38 (1H, dd, J=8.6, 8.6 Hz), 6.32 (1H, d, J=8.2 Hz), 4.40 (1H, dd, J=9.5, 2.7 Hz), 4.17 (1H, shs), 2.86-2.72 (2H, m), 2.17-2.11 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 228.

[0694]

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

[0695]

[0696]

(2-Amino-6-chlorophenyl)methanol (100 mg, 0.635 mmol) was used in a similar manner to Reference Example 44 to give the title compound as a pale yellow solid (86.3 mg, 0.360 mmol, yield: 57%).

¹ H-NMR (CDCl ₃ ) δ: 8.64 (1H, d, J=9.1 Hz), 8.19-8.17 (2H, m), 8.10 (1H, dd, J=8.2, 0.9 Hz), 7.99 (1H, d, J=8.6 Hz), 7.67-7.47 (5H, m).

MS(IER) [M+H] ⁺ : 240.

[0697]

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

[0698]

[0699]

5-Chloro-2-phenylquinoline synthesized in Reference Example 45 (86.3 mg, 0.360 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 67”) as a pale yellow oily substance (71.1 mg, 0.292 mmol, yield: 81%).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.27 (5H, m), 6.93 (1H, dd, J=8.2, 8.2 Hz), 6.72 (1H, dd, J=7.9, 1.1 Hz), 6.45 (1H, dd, J=7.9, 1.1 Hz), 4.39 (1H, dd, J=9.1, 2.7 Hz), 4.15 (1H, shs), 2.93-2.78 (2H, m), 2.20-2.14 (1H, m), 2.03-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 244.

[0700]

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

[0701]

[0702]

(2-Amino-4-fluorophenyl)methanol (100 mg, 0.709 mmol) was used in a similar manner to Reference Example 44 to give the title compound as a yellow solid (107 mg, 0.478 mmol, yield: 68%).

¹ H-NMR (CDCl ₃ ) δ: 8.22 (1H, d, J=8.7 Hz), 8.17-8.14 (2H, m), 7.86 (1H, d, J=8.7 Hz), 7.83-7.81 (1H, m), 7.60-7.43 (4H, m), 7.35-7.30 (1H, m).

MS(IER) [M+H] ⁺ : 224.

[0703]

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

[0704]

[0705]

7-Fluoro-2-phenylquinoline synthesized in Reference Example 46 (107 mg, 0.478 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 68”) as a pale yellow oily substance (95.6 mg, 0.421 mmol, yield: 88%).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.27 (5H, m), 6.91 (1H, dd, J=6.8, 6.8 Hz), 6.33 (1H, ddd, J=8.6, 8.6, 2.7 Hz), 6.24 (1H, dd, J=10.6, 2.5 Hz), 4.44 (1H, ddd, J=9.1, 3.2, 1.4 Hz), 4.13 (1H, shs), 2.84 (1H, ddd, J=15.9, 10.4, 5.0 Hz), 2.68 (1H, ddd, J=16.3, 5.0, 5.0 Hz), 2.15-2.07 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 228.

[0706]

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

[0707]

[0708]

(2-Amino-4-chlorophenyl)methanol (100 mg, 0.635 mmol) was used in a similar manner to Reference Example 44 to give the title compound as a yellow solid (110 mg, 0.457 mmol, yield: 72%).

¹ H-NMR (CDCl ₃ ) δ: 8.21 (1H, d, J=8.7 Hz), 8.17-8.16 (3H, m), 7.89 (1H, d, J=8.7 Hz), 7.77 (1H, d, J=8.7 Hz), 7.59-7.45 (5H, m).

MS(IER) [M+H] ⁺ : 240.

[0709]

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

[0710]

[0711]

7-Chloro-2-phenylquinoline synthesized in Reference Example 47 (110 mg, 0.457 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 69”) as a pale yellow oily substance (107 mg, 0.438 mmol, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.31 (5H, m), 6.89 (1H, d, J=8.2 Hz), 6.59 (1H, dd, J=8.2, 1.8 Hz), 6.52 (1H, d, J=2.3 Hz), 4.44 (1H, dd, J=9.1, 2.7 Hz), 4.11 (1H, shs), 2.84 (1H, ddd, J=15.9, 10.4, 5.4 Hz), 2.68 (1H, ddd, J=16.3, 5.0, 5.0 Hz), 2.15-2.08 (1H, m), 1.97-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 244.

[0712]

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

[0713]

[0714]

(2-Aminophenyl)methanol (2.80 g, 22.7 mmol) was dissolved in DMF (11.3 ml), and N-bromosuccinimide (4.05 g, 22.7 mmol) was then added to the resulting solution in three portions every 5 minutes under ice-cooling, and the resulting 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 resulting solid was filtered. The resulting brown solid was dissolved in ethyl acetate, and the resulting solution was dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure to give the title compound as a brown solid (3.52 g, 17.5 mmol, yield: 77%).

¹ H-NMR (CDCl ₃ ) δ: 7.22-7.20 (2H, m), 6.58 (1H, d, J=8.2 Hz), 4.63 (2H, d, J=4.1 Hz), 4.19 (2H, s), 1.60 (1H, shs).

MS(IER) [M+H] ⁺ : 202.

[0715]

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

[0716]

[0717]

(2-Amino-5-bromophenyl)methanol synthesized in Reference Example 48 (2.46 g, 12.2 mmol) was dissolved in 1,4-dioxane (36 ml), and acetophenone (2.91 ml, 25.0 mmol) and potassium tert -butoxide (2.05 g, 18.3 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 80°C for 4 hours. Ice and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/chloroform) and washing the suspension (hexane) to give the title compound as a white solid (1.49 g, 5.25 mmol, yield: 43%).

¹ H-NMR (CDCl ₃ ) δ: 8.17-8.13 (3H, m), 8.04 (1H, d, J=9.1 Hz), 8.00 (1H, d, J=2.3 Hz), 7.91 (1H, d, J=8.7 Hz), 7.79 (1H, dd, J=9.1, 2.3 Hz), 7.56-7.46 (3H, m).

MS(IER) [M+H] ⁺ : 284.

[0718]

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

[0719]

[0720]

6-Bromo-2-phenylquinoline synthesized in Reference Example 49 (50.0 mg, 0.176 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 70”) as a yellow oil (47.0 mg, 0.163 mmol, yield: 93%).

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.27 (5H, m), 7.11-7.07 (2H, m), 6.42 (1H, d, J=8.4 Hz), 4.44-4.41 (1H, m), 4.07 (1H, shs), 2.91-2.83 (1H, m), 2.73-2.66 (1H, m), 2.14-2.07 (1H, m), 2.00-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 288.

[0721]

(Reference Example 50) Synthesis of 3-(2-phenylquinolin-6-yl)oxetan-3-ol:

[0722]

[0723]

6-Bromo-2-phenylquinoline synthesized in Reference Example 49 (100 mg, 0.352 mmol) was dissolved in THF (without adding a stabilizing agent, 3.5 ml), and a 1.67 mol/L solution of n -butyl lithium in hexane (0.25 ml, 0.42 mmol) was then added dropwise at -78°C to the resulting solution over 3 minutes. Oxetan-3-one (26 μl, 0.026 mmol) was added to the solution, and the resulting mixture was heated from -78°C to room temperature over 15 minutes and then stirred at room temperature for 15 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound as a white solid (73.7 mg, 0.268 mmol, yield: 76%).

¹ H-NMR (CDCl ₃ ) 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=7.1 Hz), 5.04 (2H, d, J=6.9 Hz), 5.01 (2H, d, J=6.9 Hz).

MS(IER) [M+H] ⁺ : 278.

[0724]

(Example 71) Synthesis of 3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)oxetan-3-ol (new compound):

[0725]

[0726]

3-(2-Phenylquinolin-6-yl)oxetan-3-ol synthesized in Reference Example 50 (70.0 mg, 0.252 mmol) 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 to the resulting solution. The resulting mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 71 compound”) as a colorless transparent oily substance (49.2 mg, 0.174 mmol, yield: 69%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 7.18-7.16 (2H, m), 6.58 (1H, d, J=8.9 Hz), 4.94 (2H, d, J=7.1 Hz), 4.87 (2H, d, J=7.1 Hz), 4.46 (1H, dd, J=9.1, 3.2 Hz), 4.16 (1H, shs), 2.97-2.89 (1H, m), 2.75 (1H, dt, J=16.3, 4.9 Hz), 2.43 (1H, shs), 2.18-2.11 (1H, m), 2.04-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 282.

[0727]

(Reference Example 51) Synthesis of 2-phenyl-6-(piperidin-1-yl)quinoline:

[0728]

[0729]

6-Bromo-2-phenylquinoline synthesized in Reference Example 49 (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) were suspended in 1,4-dioxane (2.10 ml), and piperidine (69.7 μl, 0.633 mmol) was added to the resulting suspension, and the resulting mixture was stirred at 100°C for 15 hours under argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound as a yellow solid (27.3 mg, 94.7 μmol, yield: 45%).

¹ H-NMR (CDCl ₃ ) δ: 8.12-8.10 (2H, m), 8.03 (2H, dd, J=8.8, 8.0 Hz), 7.78 (1H, d, J=8.6 Hz), 7.54-7.48 (3H, m), 7.44-7.40 (1H, m), 7.04 (1H, d, J=2.7 Hz), 3.31 (4H, t, J=7.2 Hz), 1.80-1.75 (4H, m), 1.67-1.61 (2H, m).

MS(IER) [M+H] ⁺ : 289.

[0730]

(Example 72) Synthesis of 2-phenyl-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[0731]

[0732]

2-Phenyl-6-(piperidin-1-yl)quinoline synthesized in Reference Example 51 (27.3 mg, 94.7 μmol) 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 to the resulting solution, and the resulting mixture was stirred at room temperature for 17 hours under an argon atmosphere. Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (50.4 mg, 0.199 mmol) was then added to the mixture, and the resulting mixture was stirred at room temperature for 3 hours under an argon atmosphere. 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 then added to the mixture, and the resulting mixture was stirred at 40°C for 19 hours. 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 give the title compound (hereinafter referred to as “the compound of Example 72”) as a brown solid (6.00 mg, 20.5 μmol, yield: 22%).

¹ H-NMR (CDCl ₃ ) 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=8.2 Hz), 4.37 (1H, dd, J=9.5, 3.2 Hz), 2.99-2.89 (5H, m), 2.72 (1H, ddd, J=12.0, 4.8, 4.4 Hz), 2.13-1.93 (2H, m), 1.75-1.69 (4H, m), 1.56-1.50 (2H, m).

MS(IER) [M+H] ⁺ : 293.

[0733]

(Reference Example 52) Synthesis of 1,1-diphenyl-N-(2-phenylquinolin-6-yl)methanimine:

[0734]

[0735]

Cesium carbonate (161 mg, 0.493 mmol), palladium(II) acetate (1.58 mg, 7.04 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.11 mg, 10.6 μmol) were suspended in dioxane (0.50 mL), and the resulting suspension was stirred at room temperature for 10 minutes under argon atmosphere. Triethylamine (1.47 μL, 10.6 μmol) was then added to the mixture, and the resulting mixture was stirred at room temperature for 10 minutes under argon atmosphere. 6-Bromo-2-phenyl-1,2,3,4-tetrahydroquinoline synthesized in Reference Example 49 (100 mg, 0.352 mmol) and a solution of diphenylmethanimine (76.5 mg, 0.422 mmol) in dioxane (0.50 ml) were then added to the mixture, and the resulting mixture was stirred at 100°C for 17 hours under an argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a yellow amorphous substance (108 mg, 0.280 mmol, yield: 80%).

¹ H-NMR (CDCl ₃ ) δ: 8.12-8.09 (2H, m), 8.01 (1H, d, J=8.6 Hz), 7.93 (1H, d, J=9.1 Hz), 7.82-7.77 (3H, m), 7.53-7.41 (6H, m), 7.25-7.21 (3H, m), 7.19-7.14 (3H, m), 7.11 (1H, d, J=2.3Hz).

MS(IER) [M+H] ⁺ : 365.

[0736]

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

[0737]

[0738]

1,1-Diphenyl-N-(2-phenylquinolin-6-yl)methanimine synthesized in Reference Example 52 (108 mg, 0.280 mmol) was dissolved in THF (1.0 mL), and 2 mol/L hydrochloric acid (0.420 mL, 0.840 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a pale orange solid (47.3 mg, 0.215 mmol, yield: 77%).

¹ H-NMR (CDCl ₃ ) δ: 8.12-8.09 (2H, m), 7.98 (2H, dd, J=8.6, 2.7 Hz), 7.77 (1H, d, J=8.8 Hz), 7.52-7.48 (2H, m), 7.44-7.40 (1H, m), 7.18 (1H, dd, J=8.8, 2.5 Hz), 6.93 (1H, d, J=2.7 Hz), 3.96 (2H, shs).

MS(IER) [M+H] ⁺ : 221.

[0739]

(Reference Example 54) Synthesis of N-(2-phenylquinolin-6-yl)acetamide:

[0740]

[0741]

2-Phenylquinolin-6-amine synthesized in Reference Example 53 (13.5 mg, 61.3 μmol) was dissolved in pyridine (0.5 mL), and acetic anhydride (6.36 μL, 67.4 μmol) was added to the resulting solution, and the resulting 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 as a pale yellow solid (15.5 mg, 59.1 μmol, yield: 96%).

¹ H-NMR (CDCl ₃ ) δ: 8.37 (1H, d, J=1.8 Hz), 8.20 (1H, d, J=8.6 Hz), 8.14-8.12 (3H, m), 7.87 (1H, d, J=8.6 Hz), 7.55-7.52 (3H, m), 7.47-7.45 (1H, m), 7.36 (1H, s), 2.27 (3H, s).

MS(IER) [M+H] ⁺ : 263.

[0742]

(Example 73) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[0743]

[0744]

N-(2-phenylquinolin-6-yl)acetamide synthesized in Reference Example 54 (15.5 mg, 59.1 μmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 73”) as a colorless amorphous substance (12.1 mg, 45.4 μmol, yield: 77%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.28 (5H, m), 7.16 (1H, d, J=2.7 Hz), 7.02 (1H, dd, J=8.7, 2.3 Hz), 6.93 (1H, shs), 6.50 (1H, d, J=8.7 Hz), 4.42 (1H, dd, J=9.1, 3.2 Hz), 4.02 (1H, shs), 2.91 (1H, ddd, J=16.0, 10.5, 5.5 Hz), 2.72 (1H, ddd, J=16.5, 4.6, 4.6 Hz), 2.14 (3H, s), 2.12-2.08 (1H, m), 2.02-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 267.

[0745]

(Reference Example 55) Synthesis of N-(2-phenylquinolin-6-yl)pivalamide:

[0746]

[0747]

2-Phenylquinolin-6-amine synthesized in Reference Example 53 (50.0 mg, 0.226 mmol) 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 to the resulting solution, and the resulting mixture was stirred at room temperature for 2 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 give the title compound as a white solid (64.8 mg, 0.213 mmol, yield: 94%).

¹ H-NMR (CDCl ₃ ) δ: 8.44 (1H, d, J=2.3 Hz), 8.18 (1H, d, J=8.7 Hz), 8.15-8.14 (2H, m), 8.11 (1H, d, J=9.1 Hz), 7.87 (1H, d, J=8.2 Hz), 7.57-7.50 (4H, m), 7.46-7.44 (1H, m), 1.38 (9H, s).

MS(IER) [M+H] ⁺ : 305.

[0748]

(Example 74) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide (new compound):

[0749]

[0750]

N-(2-phenylquinolin-6-yl)pivalamide synthesized in Reference Example 55 (64.8 mg, 0.213 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 74”) as a white solid (62.6 mg, 0.203 mmol, yield: 95%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.32 (4H, m), 7.30-7.27 (1H, m), 7.26-7.24 (1H, m), 7.12 (1H, shs), 7.04 (1H, dd, J=8.5, 2.5 Hz), 6.50 (1H, d, J=8.7 Hz), 4.41 (1H, dd, J=9.1, 3.2 Hz), 4.00 (1H, shs), 2.90 (1H, ddd, J=16.0, 10.1, 5.5 Hz), 2.71 (1H, ddd, J=16.5, 5.0, 5.0 Hz), 2.14-2.08 (1H, m), 2.02-1.92 (1H, m), 1.30 (9H, s).

MS(IER) [M+H] ⁺ : 309.

[0751]

(Reference Example 56) Synthesis of N-(2-phenylquinolin-6-yl)methanesulfonamide:

[0752]

[0753]

2-Phenylquinolin-6-amine synthesized in Reference Example 53 (40.0 mg, 0.182 mmol) was dissolved in dichloromethane (1.8 ml), and the resulting solution was cooled to 0°C, and triethylamine (38.0 μl, 0.272 mmol) and methanesulfonyl chloride (14.1 μl, 0.182 mmol) were added to the solution, and the resulting mixture was stirred at 0°C for 2 hours under an argon atmosphere. Triethylamine (25.3 μl, 0.182 mmol) and methanesulfonyl chloride (16.9 μl, 0.218 mmol) were then added to the mixture, and the resulting mixture was stirred at room temperature for 18 hours under an argon atmosphere. 8 mol/L aqueous sodium hydroxide solution (230 μL, 1.81 mmol) was further added to the mixture, and the resulting mixture was stirred at room temperature for 7 hours. 8 mol/L aqueous sodium hydroxide solution (230 μL, 1.81 mmol) was finally added to the mixture, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (48.7 mg, 0.163 mmol, yield: 90%).

¹ H-NMR (CDCl ₃ ) δ: 8.20-8.14 (4H, m), 7.92 (1H, d, J=8.6 Hz), 7.73 (1H, d, J=2.3 Hz), 7.56-7.46 (4H, m), 6.59 (1H, br s), 3.10 (3H, s).

MS(IER) [M+H] ⁺ : 299.

[0754]

(Example 75) Synthesis of N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide (new compound):

[0755]

[0756]

N-(2-phenylquinolin-6-yl)methanesulfonamide synthesized in Reference Example 56 (48.7 mg, 0.163 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 75”) as a white solid (20.2 mg, 66.8 μmol, yield: 41%).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.27 (5H, m), 6.93-6.90 (2H, m), 6.51 (1H, d, J=8.6 Hz), 6.07-6.07 (1H, shm), 4.46-4.43 (1H, m), 4.13 (1H, shs), 2.96-2.86 (4H, m), 2.76-2.69 (1H, m), 2.16-2.09 (1H, m), 2.02-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 303.

[0757]

(Reference Example 57) Synthesis of 1-( tert- butyl)-3-(2-phenylquinolin-6-yl)urea:

[0758]

[0759]

2-Phenylquinolin-6-amine synthesized in Reference Example 53 (40.0 mg, 0.182 mmol) and potassium carbonate (201 mg, 1.45 mmol) were suspended in acetonitrile (1.8 ml), and tert -butyl isocyanate (0.150 ml, 1.27 mmol) was added to the resulting suspension, and the resulting mixture was stirred at 85°C for 2 hours under an argon atmosphere. In addition, tert -butyl isocyanate (0.150 ml, 1.27 ml) was added to the mixture, and the resulting mixture was stirred at 85°C for 16 hours under an argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound as a white solid (58.0 mg, 0.182 mmol, yield: 100%).

¹ H-NMR (CDCl ₃ ) δ: 8.13-8.10 (4H, m), 8.04 (1H, d, J=9.1 Hz), 7.81 (1H, d, J=8.6 Hz), 7.51 (2H, dd, J=8.0, 10.8 Hz), 7.46-7.39 (2H, m), 6.94 (1H, shs), 4.98 (1H, shs), 1.41 (9H, s).

MS(IER) [M+H] ⁺ : 320.

[0760]

(Example 76) Synthesis of 1-( tert -butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea (new compound):

[0761]

[0762]

1-( Tert- butyl)-3-(2-phenylquinolin-6-yl)urea synthesized in Reference Example 57 (58.0 mg, 0.182 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 76”) as a violet amorphous substance (27.2 mg, 84.1 μmol, yield: 46%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.27 (5H, m), 6.88 (1H, d, J=1.8 Hz), 6.83 (1H, dd, J=8.8, 2.0 Hz), 6.50 (1H, d, J=8.6 Hz), 5.77 (1H, shs), 4.54 (1H, shs), 4.43 (1H, dd, J=9.5, 3.2 Hz), 4.07 (1H, shs), 2.94-2.86 (1H, m), 2.75-2.68 (1H, m), 2.15-2.09 (1H, m), 2.02-1.93 (1H, m), 1.34 (9H, s).

MS(IER) [M+H] ⁺ : 324.

[0763]

(Reference Example 58) Synthesis of 1-(2-phenylquinolin-6-yl)urea:

[0764]

[0765]

2-Phenylquinolin-6-amine synthesized in Reference Example 53 (40.0 mg, 0.182 mmol) was suspended in THF (2.2 mL), and trichloroacetyl isocyanate (29.6 μL, 0.250 mmol) was added to the resulting suspension, and the resulting mixture was stirred at 0°C for 1 hour under an argon atmosphere. Methanol/triethylamine (2.2 mL/1.1 mL) was then added to the mixture, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by washing the suspension (hexane/chloroform) to give the title compound as a reddish-violet solid (49.3 mg, 0.187 mmol, yield: 83%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.92 (1H, br s), 8.30 (1H, d, J=8.7 Hz), 8.23 (2H, d, J=6.9 Hz), 8.13 (1H, d, J=2.3 Hz), 8.04 (1H, d, J=8.7 Hz), 7.94 (1H, d, J=9.1 Hz), 7.67 (1H, dd, J=9.1, 2.3 Hz), 7.54 (2H, dd, J=7.2, 7.2 Hz), 7.49-7.45 (1H, m), 6.02 (2H, br s).

MS(IER) [M+H] ⁺ : 264.

[0766]

(Example 77) Synthesis of 1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea (new compound):

[0767]

[0768]

1-(2-Phenylquinolin-6-yl)urea synthesized in Reference Example 58 (47.9 mg, 0.182 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 77”) as a white amorphous substance (40.6 mg, 0.152 mmol, yield: 84%).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 6.91-6.88 (2H, m), 6.52 (1H, d, J=8.0 Hz), 6.14 (1H, shs), 4.64 (2H, shs), 4.45 (1H, dd, J=9.1, 3.6 Hz), 2.93-2.85 (1H, m), 2.75-2.68 (1H, m), 2.16-2.09 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 268.

[0769]

(Reference Example 59) Synthesis of 3,3-dimethyl-N-(2-phenylquinolin-6-yl)butanamide:

[0770]

[0771]

2-Phenylquinolin-6-amine synthesized in Reference Example 53 (40.0 mg, 0.182 mmol) was dissolved in dichloromethane (0.90 mL), and 3,3-dimethylbutyryl chloride (26.5 μL, 0.191 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. In addition, tert -butyl isocyanate (0.150 mL, 1.27 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (53.7 mg, 0.169 mmol, yield: 93%).

¹ H-NMR (CDCl ₃ ) δ: 8.41 (1H, d, J=2.4 Hz), 8.20-8.09 (4H, m), 7.87 (1H, d, J=8.6 Hz), 7.55-7.51 (3H, m), 7.48-7.44 (1H, m), 2.31 (2H, s), 1.16 (9H, s).

MS(IER) [M+H] ⁺ : 319.

[0772]

(Example 78) Synthesis of 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide (new compound):

[0773]

[0774]

3,3-Dimethyl-N-(2-phenylquinolin-6-yl)butanamide synthesized in Reference Example 59 (53.7 mg, 0.169 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 78”) as a white amorphous substance (18.7 mg, 58.0 μmol, yield: 34%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 7.22 (1H, d, J=2.3 Hz), 7.02 (1H, dd, J=8.8, 2.8 Hz), 6.85 (1H, shs), 6.49 (1H, d, J=8.2 Hz), 4.41 (1H, dd, J=9.1, 3.2 Hz), 2.94-2.86 (1H, m), 2.75-2.68 (1H, m), 2.18 (2H, s), 2.14-2.97 (1H, m), 2.01-1.92 (1H, m), 1.10 (9H, s).

MS(IER) [M+H] ⁺ : 323.

[0775]

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

[0776]

[0777]

2-Chloroaniline (0.325 mL, 3.91 mmol) and cinnamaldehyde (0.493 mmol, 3.91 mmol) were dissolved in DMSO (2 mL), and palladium(II) acetate (87.9 mg, 0.391 mmol) was added to the resulting solution, and the resulting mixture was stirred at 130°C for 18 hours under an oxygen atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a pale yellow solid (109 mg, 0.456 mmol, yield: 12%).

¹ H-NMR (CDCl ₃ ) δ: 8.31-8.28 (2H, m), 8.24 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=8.6 Hz), 7.85 (1H, dd, J=7.5, 1.1 Hz), 7.76 (1H, dd, J=8.2, 1.4 Hz), 7.57-7.42 (4H, m).

MS(IER) [M+H] ⁺ : 240.

[0778]

(Example 79) Synthesis of 8-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[0779]

[0780]

8-Chloro-2-phenylquinoline synthesized in Reference Example 60 (109 mg, 0.456 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 79”) as a pale yellow oily substance (93.8 mg, 0.385 mmol, yield: 84%).

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.29 (4H, m), 7.12 (1H, d, J=7.3 Hz), 6.91 (1H, d, J=7.3 Hz), 6.56 (1H, dd, J=8.0, 7.6 Hz), 4.67 (1H, shs), 4.53 (1H, ddd, J=9.2, 3.6,1.2), 2.91 (1H, ddd, J=16.0, 10.4, 5.2 Hz), 2.74 (1H, ddd, J=16.8, 5.2, 4.7 Hz), 2.16-2.12 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 244.

[0781]

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

[0782]

[0783]

2-Fluoroaniline (0.325 ml, 4.50 mmol) and cinnamaldehyde (0.566 mmol, 4.50 mmol) were used in a similar manner to Reference Example 60 to give the title compound as a pale yellow solid (68.9 mg, 0.309 mmol, yield: 7%).

¹ H-NMR (CDCl ₃ ) δ: 8.25 (1H, dd, J=8.7, 1.8 Hz), 8.23-8.20 (2H, m), 7.96 (1H, d, J=8.7 Hz), 7.62 (1H, dd, J=7.1, 1.6 Hz), 7.56-7.39 (5H, m).

MS(IER) [M+H] ⁺ : 224.

[0784]

(Example 80) Synthesis of 8-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[0785]

[0786]

8-Fluoro-2-phenylquinoline synthesized in Reference Example 61 (68.9 mg, 0.309 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 80”) as a pale yellow oily substance (51.2 mg, 0.225 mmol, yield: 73%).

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.28 (5H, m), 6.84 (1H, dd, J=11.4, 8.2 Hz), 6.79 (1H, d, J=7.3 Hz), 6.55 (1H, dd, J=8.0, 5.2, 5.2 Hz), 4.46 (1H, ddd, J=9.2, 3.2, 1.2 Hz), 4.26 (1H, shs), 2.93 (1H, ddd, J=16.0, 10.8, 5.6 Hz), 2.76 (1H, ddd, J=16.4, 5.2, 4.4 Hz), 2.16-2.13 (1H, m), 2.05-1.96 (1H, m).

MS(IER) [M+H] ⁺ : 228.

[0787]

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

[0788]

[0789]

4-(Trifluoromethoxy)aniline (0.325 ml, 2.82 mmol) and cinnamaldehyde (0.355 mmol, 2.82 mmol) were used in a similar manner to Reference Example 60 to give the title compound as a pale yellow solid (70.1 mg, 0.242 mmol, yield: 9%).

¹ H-NMR (CDCl ₃ ) δ: 8.23-8.21 (2H, m), 8.18-8.15 (2H, m), 7.95 (1H, d, J=8.6 Hz), 7.66 (1H, s), 7.60-7.47 (4H, m).

MS(IER) [M+H] ⁺ : 290.

[0790]

(Example 81) Synthesis of 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline (new compound):

[0791]

[0792]

2-Phenyl-6-(trifluoromethoxy)quinoline synthesized in Reference Example 62 (83.1 mg, 0.287 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 81”) as a pale yellow oily substance (83.1 mg, 0.283 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) 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, 3.4 Hz), 4.11 (1H, shs), 2.91 (1H, ddd, J=16.5, 10.5, 5.9 Hz), 2.73 (1H, ddd, J=16.5, 4.6, 5.0 Hz), 2.16-2.09 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 294.

[0793]

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

[0794]

[0795]

4-Fluoroaniline (0.431 ml, 4.50 mmol) and cinnamaldehyde (0.566 mmol, 4.50 mmol) were used in a similar manner to Reference Example 60 to give the title compound as a pale yellow solid (48.2 mg, 0.216 mmol, yield: 5%).

¹ H-NMR (CDCl ₃ ) δ: 8.20-8.13 (3H, m), 7.91-7.89 (2H, m), 7.57-7.44 (5H, m).

MS(IER) [M+H] ⁺ : 224.

[0796]

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

[0797]

[0798]

6-Fluoro-2-phenylquinoline synthesized in Reference Example 63 (48.2 mg, 0.216 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 82”) as a pale yellow oily substance (29.7 mg, 0.131 mmol, yield: 61%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.32 (5H, m), 6.74-6.71 (2H, m), 6.47 (1H, dd, J=9.1, 5.0 Hz), 4.39 (1H, dd, J=9.1, 3.2 Hz), 3.94 (1H, shs), 2.92 (1H, ddd, J=16.5, 10.5, 5.5 Hz), 2.72 (1H, ddd, J=16.9, 4.6, 4.6 Hz), 2.14-2.08 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 228.

[0799]

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

[0800]

[0801]

4-Chloroaniline (100 mg, 0.784 mmol) and ( E )-cinnamic alcohol (105 mg, 0.784 mmol) were used in a similar manner to Reference Example 60 to give the title compound as an orange solid (28.0 mg, 0.117 mmol, yield: 15%).

¹ H-NMR (CDCl ₃ ) δ: 8.17-8.14 (3H, m), 8.11 (1H, d, J=9.1 Hz), 7.91 (1H, d, J=8.2 Hz), 7.82 (1H, d, J=2.3 Hz), 7.67 (1H, dd, J=8.9, 2.5 Hz), 7.56-7.46 (3H, m).

MS(IER) [M+H] ⁺ : 240.

[0802]

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

[0803]

[0804]

6-Chloro-2-phenylquinoline synthesized in Reference Example 64 (28.0 mg, 0.117 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 83”) as a pale yellow oily substance (28.0 mg, 0.114 mmol, yield: 98%).

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.31 (5H, m), 6.96-6.95 (2H, m), 6.46 (1H, d, J=8.2 Hz), 4.43 (1H, dd, J=9.1, 3.2 Hz), 4.06 (1H, shs), 2.88 (1H, ddd, J=15.9, 10.4, 5.4 Hz), 2.70 (1H, ddd, J=16.3, 5.0, 5.0 Hz), 2.14-2.08 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 244.

[0805]

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

[0806]

[0807]

4-(Trifluoromethyl)aniline (76.9 µL, 0.621 mmol) and ( E )-cinnamic alcohol (83.3 mg, 0.621 mmol) were used in a similar manner to Reference Example 60 to give the title compound as an orange solid (42.0 mg, 0.154 mmol, yield: 25%).

¹ H-NMR (CDCl ₃ ) δ: 8.32 (1H, d, J=8.7 Hz), 8.28 (1H, d, J=8.7 Hz), 8.19 (2H, d, J=7.8 Hz), 8.15 (1H, s), 7.99 (1H, d, J=8.7 Hz), 7.90 (1H, dd, J=8.9, 1.6 Hz), 7.56-7.51 (3H, m).

MS(IER) [M+H] ⁺ : 274.

[0808]

(Example 84) Synthesis of 2-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (new compound):

[0809]

[0810]

2-Phenyl-6-(trifluoromethyl)quinoline synthesized in Reference Example 65 (42.0 mg, 0.154 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 84”) as a pale yellow oily substance (30.8 mg, 0.111 mmol, yield: 72%).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.29 (5H, m), 7.25-7.23 (2H, m), 6.54 (1H, d, J=9.1 Hz), 4.51 (1H, dd, J=8.7, 2.3 Hz), 4.38 (1H, shs), 2.90 (1H, ddd, J=15.6, 10.1, 5.0 Hz), 2.74 (1H, ddd, J=16.5, 5.0, 5.0 Hz), 2.18-2.12 (1H, m), 2.06-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 278.

[0811]

(Reference Example 66) Synthesis of 6,7-difluoro-2-phenylquinoline:

[0812]

[0813]

3,4-Difluoroaniline (150 mg, 1.16 mmol) and ( E )-cinnamic alcohol (156 mg, 1.16 mmol) were used in a similar manner to Reference Example 60 to give the title compound as an orange solid (57.7 mg, 0.239 mmol, yield: 21%).

¹ H-NMR (CDCl ₃ ) δ: 8.16–8.14 (3H, m), 7.92 (1H, dd, J=11.6, 7.6 Hz), 7.89 (1H, d, J=8.4 Hz), 7.56–7.46 (4H, m).

MS(IER) [M+H] ⁺ : 242.

[0814]

(Example 85) Synthesis of 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[0815]

[0816]

6,7-Difluoro-2-phenylquinoline synthesized in Reference Example 66 (57.7 mg, 0.239 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 85”) as a colorless transparent oily substance (41.6 mg, 0.170 mmol, yield: 71%).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 6.78 (1H, dd, J=10.6, 8.8 Hz), 6.31 (1H, dd, J=12.0, 7.0 Hz), 4.39 (1H, dd, J=9.1, 3.2, 0.9 Hz), 3.97 (1H, shs), 2.83 (1H, ddd, J=16.3, 10.9, 5.4 Hz), 2.65 (1H, ddd, J=16.3, 5.0, 5.0 Hz), 2.13-2.07 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 246.

[0817]

(Reference Example 67) Synthesis of 6,8-difluoro-2-phenylquinoline:

[0818]

[0819]

2,4-Difluoroaniline (150 mg, 1.16 mmol) and ( E )-cinnamic alcohol (156 mg, 1.16 mmol) were used in a similar manner to Reference Example 60 to give the title compound as a yellow solid (13.5 mg, 56.0 μmol, yield: 5%).

¹ H-NMR (CDCl ₃ ) δ: 8.21-8.17 (3H, m), 7.98 (1H, d, J=8.7 Hz), 7.93-7.88 (1H, m), 7.56-7.44 (4H, m).

MS(IER) [M+H] ⁺ : 242.

[0820]

(Example 86) Synthesis of 6,8-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline (new compound):

[0821]

[0822]

6,8-Difluoro-2-phenylquinoline synthesized in Reference Example 67 (13.5 mg, 56.0 μmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 86”) as an orange solid (7.70 mg, 31.4 μmol, yield: 56%).

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.30 (5H, m), 6.65 (1H, ddd, J=11.3, 8.6, 3.2 Hz), 6.57 (1H, d, J=9.1 Hz), 4.41 (1H, dd, J=9.5, 3.2 Hz), 4.07 (1H, shs), 2.92 (1H, ddd, J=16.3, 10.4, 5.9 Hz), 2.74 (1H, ddd, J=17.2, 5.0, 5.0 Hz), 2.16-2.13 (1H, m), 2.05-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 246.

[0823]

(Reference Example 68) Synthesis of 4-(6-nitroquinolin-2-yl)benzonitrile:

[0824]

[0825]

2-Chloro-6-nitroquinoline (700 mg, 3.36 mmol), 4-cyanophenylboronic acid (641 mg, 4.36 mmol), tetrakis(triphenylphosphine)palladium(0) (77.5 mg, 0.0671 mmol) and potassium carbonate (1.39 g, 10.1 mmol) were dissolved in 1,4-dioxane/water (5/1, v/v, 17 mL), and the resulting mixture was then stirred under heating at 100°C for 16 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture, and the resulting solid was filtered to give the title compound as a gray solid (647 mg, 2.35 mmol, yield: 70%).

¹ H-NMR (DMSO-d ₆ ) δ: 9.14 (1H, d, J=2.7 Hz), 8.90 (1H, d, J=8.7 Hz), 8.56-8.51 (3H, m), 8.49 (1H, d, J=8.7 Hz), 8.31 (1H, d, J=9.1 Hz), 8.09 (2H, dt, J=8.2, 1.8 Hz).

MS(IER) [M+H] ⁺ : 276.

[0826]

(Reference Example 69) Synthesis of 4-(6-aminoquinolin-2-yl)benzonitrile:

[0827]

[0828]

4-(6-Nitroquinolin-2-yl)benzonitrile synthesized in Reference Example 68 (100 mg, 0.363 mmol) was dissolved in acetic acid (3.6 mL), and iron powder (81.2 mg, 1.45 mmol) was then added to the resulting solution, and the resulting mixture was stirred at 50°C for 14 hours. After cooling the reaction mixture to room temperature, the reaction mixture was concentrated under reduced pressure, adjusted to pH 12 by adding 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. After removing the resulting reddish-brown solid by filtration, the filtrate was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound as a yellow solid (31.8 mg, 0.131 mmol, yield: 36%).

¹ H-NMR (CDCl ₃ ) δ: 8.24 (2H, dt, J=8.4, 1.8 Hz), 8.01 (1H, d, J=8.9 Hz), 7.97 (1H, d, J=8.9 Hz), 7.80-7.76 (3H, m), 7.20 (1H, dd, J=8.9, 2.6 Hz), 6.93 (1H, d, J=2.6 Hz), 4.05 (2H, shs).

MS(IER) [M+H] ⁺ : 246.

[0829]

(Reference Example 70) Synthesis of 1-( tert -butyl)-3-(2-(4-cyanophenyl)quinolin-6-yl)urea:

[0830]

[0831]

4-(6-Aminoquinolin-2-yl)benzonitrile synthesized in Reference Example 69 (30.0 mg, 0.122 mmol) 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 then added to the resulting solution, and the resulting mixture was heated to reflux for 23 hours. After cooling the reaction mixture to room temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (amino silica gel, chloroform/methanol) to give the title compound as a pale orange solid (37.2 mg, 0.107 mmol, yield: 88%).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (2H, dt, J=8.5, 1.7 Hz), 8.15-8.12 (2H, m), 8.02 (1H, d, J=9.1 Hz), 7.80-7.77 (3H, m), 7.42 (1H, dd, J=9.1, 2.7 Hz), 6.72 (1H, shs), 4.84 (1H, shs), 1.43 (9H, s).

MS(IER) [M+H] ⁺ : 345.

[0832]

(Reference Example 71) Synthesis of 4-(6-(3-( tert -butyl)ureido)quinolin-2-yl)benzamide:

[0833]

[0834]

1-( Tert- butyl)-3-(2-(4-cyanophenyl)quinolin-6-yl)urea synthesized in Reference Example 70 (37.0 mg, 0.107 mmol) 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 solution (37 μL, 0.453 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 3 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was subjected to suspension washing (hexane/ethyl acetate) to give the title compound as a pale yellow solid (32.4 mg, 0.0888 mmol, yield: 83%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.71 (1H, shs), 8.32-8.30 (3H, m), 8.16 (1H, d, J=2.3 Hz), 8.11 (1H, d, J=9.1 Hz), 8.10 (1H, shs), 8.02 (2H, d, J=8.7 Hz), 7.95 (1H, d, J=9.1 Hz), 7.59 (1H, dd, J=9.1, 2.3 Hz), 7.44 (1H, shs), 6.21 (1H, shs), 1.33 (9H, s).

MS(IER) [M+H] ⁺ : 363.

[0835]

(Example 87) Synthesis of 4-(6-(3-( tert -butyl)ureido)-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0836]

[0837]

4-(6-(3-( Tert- butyl)ureido)quinolin-2-yl)benzamide synthesized in Reference Example 71 (31.0 mg, 0.0855 mmol) was suspended in THF/methanol (1/1, v/v, 0.85 mL) and acetic acid (0.015 mL, 0.26 mmol), and platinum(IV) oxide (3.0 mg, 0.13 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature and normal pressure for 48 hours under a hydrogen atmosphere. After completion of the reaction, hydrogen was exchanged for nitrogen, and the reaction mixture was filtered using celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound (hereinafter referred to as “Example 87 compound”) as a white solid (26.1 mg, 0.0564 mmol, yield: 66%).

¹ H-NMR (CDCl ₃ ) δ: 7.92 (2H, dt, J=8.7, 1.8 Hz), 7.60 (2H, dt, J=8.7, 1.8 Hz), 7.06-7.00 (2H, m), 6.69 (1H, td, J=7.3, 0.9 Hz), 6.59 (1H, dd, J=7.8, 0.9 Hz), 4.57 (1H, dd, J=8.7, 3.2 Hz), 4.09 (1H, shs), 3.06 (3H, s), 2.95-2.87 (1H, m), 2.70 (1H, td, J=10.9, 5.5 Hz), 2.19-2.12 (1H, m), 2.01-1.97 (1H, m).

MS(IER) [M+H] ⁺ : 288.

[0838]

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

[0839]

[0840]

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) was then added to the resulting solution, and the resulting mixture was stirred at room temperature and normal pressure for 23 hours under a hydrogen atmosphere. After completion of the reaction, hydrogen was exchanged for nitrogen, and the reaction mixture was filtered using celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 88 compound”) as a pale yellow oily substance (274 mg, 1.03 mmol, yield: 90%).

¹ H-NMR (CDCl ₃ ) 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, 1.1 Hz), 6.57 (1H, dd, J=8.2, 1.1 Hz), 4.42 (1H, dd, J=10.5, 3.2 Hz), 4.11 (1H, dd, J=11.2, 6.2 Hz), 4.05 (1H, brs), 3.71 (3H, s), 2.40-2.31 (2H, m).

MS(IER) [M+H] ⁺ : 268.

[0841]

(Example 89) Synthesis of ((2 R *,4 R *)-2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl)methanol (new compound):

[0842]

[0843]

Methyl (2 R *,4 R *)-2-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylate synthesized in Example 88 (70.0 mg, 0.262 mmol) was dissolved in THF (2.6 mL) and a 2 mol/L solution of lithium borohydride in THF (0.656 mL, 1.31 mmol) was then added dropwise to the resulting solution, and the resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, a saturated aqueous solution of sodium potassium tartrate was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 89 compound”) as a white solid (32.3 mg, 0.135 mmol, yield: 52%).

¹ H-NMR (CDCl ₃ ) δ: 7.45-7.42 (2H, m), 7.39-7.35 (2H, m), 7.33-7.28 (1H, m), 7.23 (1H, d, J=7.4 Hz), 7.05 (1H, t, J=7.4 Hz), 6.73 (1H, td, J=7.4, 1.2 Hz), 6.58 (1H, dd, J=8.0, 1.2 Hz), 4.44 (1H, dd, J=11.0, 2.7 Hz), 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, 11.0 Hz), 1.41 (1H, dd, J=7.3, 4.6 Hz).

MS(IER) [M+H] ⁺ : 240.

[0844]

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

[0845]

[0846]

2-Chloro-4-methylquinoline (300 mg, 1.69 mmol) and phenylboronic acid (227 mg, 1.86 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a colorless oily substance (360 mg, 1.64 mmol, 97%).

¹ H-NMR (CDCl ₃ ) δ: 8.18-8.15 (3H, m), 8.01 (1H, d, J=8.2 Hz), 7.74-7.71 (2H, m), 7.56-7.53 (3H, m), 7.47-7.45 (1H, m), 2.78 (3H, s).

MS(IER) [M+H] ⁺ : 220.

[0847]

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

[0848]

[0849]

4-Methyl-2-phenylquinoline synthesized in Reference Example 72 (100 mg, 0.456 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 90”) as a pale yellow oily substance (46.1 mg, 0.206 mmol, 45%).

¹ H-NMR (CDCl ₃ ) δ: 7.43-7.42 (2H, m), 7.38-7.34 (2H, m), 7.30-7.28 (1H, m), 7.19 (1H, d, J=7.7 Hz), 7.01 (1H, ddd, J=7.2, 7.2, 0.9 Hz), 6.71 (1H, dd, J=7.2, 7.2, 0.9 Hz), 6.53 (1H, dd, J=8.2, 0.9 Hz), 4.47 (1H, dd, J=11.3, 2.7 Hz), 3.97 (1H, ws), 3.13 (1H, ddd, J=6.3, 12.2, 6.3 Hz), 2.11 (1H, ddd, J=12.7, 5.0, 2.7 Hz), 1.76 (1H, ddd, J=11.8, 11.8, 11.8 Hz), 1.35 (3H, d, J=6.8 Hz).

MS(IER) [M+H] ⁺ : 224.

[0850]

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

[0851]

[0852]

2-Phenyl-1,2,3,4-tetrahydroquinoline (30.0 mg, 0.143 mmol) was dissolved in tetrahydrofuran (1 ml), and a 1.64 mol/L solution of n -butyl lithium in hexane (0.140 ml, 0.229 mmol) was added to the resulting solution at -78°C under an argon atmosphere, and the resulting mixture was stirred for 0.5 hour. Then, a solution of di- tert- butyl dicarbonate (93.9 mg, 0.430 mmol) in tetrahydrofuran (1 ml) was added to the mixture, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. The resulting aqueous phase was extracted with diethyl ether. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (amino silica gel, hexane/ethyl acetate) to afford the title compound as a colorless amorphous solid (44.3 mg, 0.143 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (1H, d, J=8.2 Hz), 7.28-7.16 (6H, m), 7.08 (1H, d, J=5.9 Hz), 7.01 (1H, ddd, J=7.3, 7.3, 1.4 Hz), 5.35 (1H, dd, J=8.5, 7.1 Hz), 2.70-2.58 (2H, m), 2.45-2.41 (1H, m), 1.84-1.81 (1H, m), 1.34 (9H, s).

[0853]

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

[0854]

[0855]

Tert- butyl 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate synthesized in Reference Example 73 (22.2 mg, 71.1 μmol) was dissolved in tetrahydrofuran (1.0 mL), and a 1.64 mol/L solution of n -butyl lithium in hexane (73.9 μL, 0.121 mmol) was added to the resulting solution at -78°C under an argon atmosphere, and the resulting mixture was stirred for 10 hours. Then, iodomethane (13.4 μL, 0.215 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, methanol was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (silica gel, hexane/ethyl acetate) to afford the title compound as a colorless amorphous solid (16.5 mg, 51.0 μmol, yield: 71%).

¹ H-NMR (CDCl ₃ ) δ: 7.67 (1H, d, J=8.2 Hz), 7.36-7.29 (4H, m), 7.23-7.18 (2H, m), 7.07 (1H, d, J=7.3 Hz), 6.97 (1H, dd, J=7.8, 7.8 Hz), 2.71 (1H, ddd, J=14.2, 9.1, 4.6 Hz), 2.48 (1H, ddd, J=14.6, 5.9, 2.7 Hz), 2.01 (3H, s), 1.95-1.91 (2H, m), 1.17 (9H, s).

[0856]

(Example 91) Synthesis of 2-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline:

[0857]

[0858]

Tert- butyl 2-methyl-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate synthesized in Reference Example 74 (16.5 mg, 51.0 μmol) was dissolved in dichloromethane (1 ml), and trifluoroacetic acid (37.9 μl, 0.510 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (amino silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as the "compound of Example 91") as a colorless amorphous substance (8.10 mg, 36.3 μmol, yield: 71%).

¹ H-NMR (CDCl ₃ ) 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=7.3 Hz), 6.61-6.59 (2H, m), 2.60 (1H, ddd, J=16.5, 4.6, 4.6 Hz), 2.32 (1H, ddd, J=16.5, 11.4, 5.5 Hz), 2.21 (1H, ddd, J=12.8, 5.0, 5.0 Hz), 1.91 (1H, ddd, J=12.8, 11.0, 5.0 Hz), 1.58 (3H, s).

MS(IER) [M+H] ⁺ : 224.

[0859]

(Reference Example 75) Synthesis of 1-( tert- butyl) 2-methyl 2-phenyl-3,4-dihydroquinoline-1,2(2H)-dicarboxylate:

[0860]

[0861]

Tert- butyl 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate synthesized in Reference Example 73 (300 mg, 0.970 mmol) was dissolved in tetrahydrofuran (6 ml) under an argon atmosphere, and a 1.64 mol/L solution of n -butyl lithium in hexane (0.887 ml, 1.45 mmol) was added dropwise at -78°C to the resulting solution, and the resulting mixture was stirred at -78°C for 10 minutes. Then, methyl chloroformate (0.261 ml, 3.39 mmol) was added at -78°C to the mixture, and the resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, methanol (1 ml) was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a colorless transparent oil (250 mg, 0.681 mmol, yield: 70%).

¹ H-NMR (CDCl ₃ ) δ: 7.87 (1H, d, J=8.2 Hz), 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, 3.1 Hz), 2.57-2.43 (2H, m), 2.18-2.11 (1H, m), 1.29 (9H, s).

[0862]

(Reference Example 76) Synthesis of tert -butyl 2-(hydroxymethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate:

[0863]

[0864]

1-( Tert- butyl)2-methyl 2-phenyl-3,4-dihydroquinoline-1,2(2H)-dicarboxylate synthesized in Reference Example 75 (141 mg, 0.383 mmol) was dissolved in dichloromethane (4.0 mL) under an argon atmosphere, and a 1 mol/L solution of diisobutylaluminum hydride in hexane (1.53 mL, 1.53 mmol) was added to the resulting solution at -78°C, and the resulting mixture was stirred at -78°C for 4 hours. After completion of the reaction, the reaction mixture was allowed to warm to 0°C, and a saturated aqueous solution of potassium sodium tartrate was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 hours. The organic layer was separated from the resulting mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound as a colorless, transparent oil (95.9 mg, 0.283 mmol, yield: 74%).

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.33 (5H, m), 7.25-7.23 (1H, m), 7.17-7.15 (1H, m), 7.05 (1H, d, J=6.9 Hz), 6.99 (1H, ddd, J=7.8, 7.8, 1.4 Hz), 4.42 (1H, dd, J=11.4, 7.3 Hz), 4.29 (1H, dd, J=7.1, 4.3 Hz), 4.12-4.08 (2H, m), 2.82-2.74 (1H, m), 2.40 (1H, dd, J=15.1, 3.7, 3.7 Hz), 2.00-1.96 (1H, m), 1.33 (9H, s).

[0865]

(Example 92) Synthesis of (2-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)methanol (new compound):

[0866]

[0867]

Tert- butyl 2-(hydroxymethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate synthesized in Reference Example 76 (95.9 mg, 0.283 mmol) was dissolved in dichloromethane (2 ml), and trifluoroacetic acid (0.104 ml, 1.41 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 92 compound”) as a colorless transparent oily substance (37.0 mg, 0.154 mmol, yield: 55%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.31 (4H, m), 7.25-7.20 (1H, m), 7.07-7.01 (1H, m), 6.89 (1H, d, J=7.3 Hz), 6.70 (1H, dd, J=8.2, 0.9 Hz), 6.61 (1H, ddd, J=7.3, 7.3, 1.4 Hz), 4.70 (1H, shs), 4.42 (1H, s), 3.95 (1H, dd, J=10.7, 3.0 Hz), 3.77 (1H, t, J=10.5 Hz), 2.58 (1H, ddd, J=16.0, 4.6, 3.2 Hz), 2.31 (1H, ddd, J=16.5, 12.8, 5.0 Hz), 2.15 (1H, ddd, J=12.8, 5.0, 2.7 Hz), 2.01 (1H, ddd, J=12.8, 12.8,5.0 Hz).

MS(IER) [M+H] ⁺ : 240.

[0868]

(Example 93) Synthesis of methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (new compound):

[0869]

[0870]

1-( Tert- butyl) 2-methyl 2-phenyl-3,4-dihydroquinoline-1,2(2H)-dicarboxylate synthesized in Reference Example 75 (100 mg, 0.272 mmol) was used in a similar manner to Example 92 to give the title compound (hereinafter referred to as “the compound of Example 93”) as a colorless transparent oily substance (70.0 mg, 0.262 mmol, yield: 96%).

¹ H-NMR (CDCl ₃ ) 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, 1.1 Hz), 6.71 (1H, dd, J=7.8, 0.9 Hz), 6.65 (1H, ddd, J=7.3, 7.3, 0.9 Hz), 3.75 (3H, s), 2.72 (1H, ddd, J=16.0, 5.9, 5.9 Hz), 2.52-2.36 (3H, m).

MS(IER) [M+H] ⁺ : 268.

[0871]

(Reference Example 77) Synthesis of tert -butyl 2-(2-methoxy-2-oxoethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate:

[0872]

[0873]

Tert- butyl 2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate (600 mg, 1.94 mmol) and methyl bromoacetate (0.625 ml, 6.79 mmol) were used in a similar manner to Reference Example 75 to give the title compound as a colorless transparent oily substance (275 mg, 0.722 mmol, yield: 37%).

¹ H-NMR (CDCl ₃ ) δ: 7.55 (1H, d, J=8.2 Hz), 7.36-7.27 (4H, m), 7.25-7.23 (1H, m), 7.16 (1H, ddd, J=8.2, 8.2, 1.8 Hz), 7.04 (1H, d, J=6.9 Hz), 6.95 (1H, ddd, J=7.3, 7.3, 0.9 Hz), 3.83 (1H, d, J=12.3 Hz), 3.54 (3H, s), 3.20 (1H, d, J=12.3 Hz), 2.77-2.73 (1H, m), 2.58 (1H, ddd, J=13.3, 13.3, 2.7 Hz), 2.29 (1H, ddd, J=14.6, 2.7, 2.7 Hz), 1.97 (1H, ddd, J=13.3, 3.2, 3.2 Hz), 1.19 (9H, s).

[0874]

(Example 94) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)methyl acetate:

[0875]

[0876]

Tert- butyl 2-(2-methoxy-2-oxoethyl)-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate synthesized in Reference Example 77 (57.4 mg, 0.150 mmol) was used in a similar manner to Example 93 to give the title compound (hereinafter referred to as “the compound of Example 94”) as a colorless oily substance (34.4 mg, 0.262 mmol, yield: 81%).

¹ H-NMR (CDCl ₃ ) 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=7.3 Hz), 6.70 (1H, dd, J=8.2, 0.9 Hz), 6.60 (1H, ddd, J=7.3, 7.3, 0.9 Hz), 5.58 (1H, shs), 3.49 (3H, s), 3.09 (1H, d, J=15.6 Hz), 2.86 (1H, d, J=15.6 Hz), 2.57 (1H, ddd, J=16.0, 4.1, 4.1 Hz), 2.31 (1H, ddd, J=16.0, 11.4, 5.0 Hz), 2.22-2.17 (1H, m), 2.02 (1H, ddd, J=12.3, 11.4,4.6 Hz).

MS(IER) [M+H] ⁺ : 282.

[0877]

(Reference Example 78) Synthesis of 5-(6-chloroquinolin-2-yl)indolin-2-one:

[0878]

[0879]

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 the resulting solution was then stirred under heating at 100°C for 4 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture, and the resulting mixture was filtered. The resulting solid was washed with water, acetone and chloroform/hexane (9/1) to give the title compound as a colorless transparent oily substance (243.4 mg, 0.828 mmol, yield: 82%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.63 (1H, s), 8.39 (1H, d, J=8.2 Hz), 8.19-8.14 (3H, m), 8.11 (1H, d, J=2.3 Hz), 8.03 (1H, d, J=9.1 Hz), 7.76 (1H, dd, J=9.1, 2.3 Hz), 6.97 (1H, d, J=8.2 Hz), 3.62 (2H, s).

MS(IER) [M+H] ⁺ : 295.

[0880]

(Example 95) Synthesis of 5-(6-chloro-2,3,4,4-tetrahydroquinolin-2-yl)indolin-2-one (new compound):

[0881]

[0882]

5-(6-Chloroquinolin-2-yl)indolin-2-one synthesized in Reference Example 78 (243.0 mg, 0.824 mmol) was dissolved in THF (8 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (501 mg, 1.98 mmol) and iodine (20.9 mg, 0.082 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was subjected to column chromatography (silica gel, chloroform/methanol) and suspended and washed with chloroform (6.0 ml) to give the title compound (hereinafter referred to as “the compound of Example 95”) as a pale red solid (157 mg, 0.526 mmol, yield: 64%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.35 (1H, s), 7.18 (1H, s), 7.13 (1H, d, J=7.8 Hz), 6.90-6.89 (2H, m), 6.77 (1H, d, J=7.8 Hz), 6.57 (1H, dd, J=6.6, 2.5 Hz), 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).

MS(IER) [M+H] ⁺ : 299.

[0883]

(Reference Example 79) Synthesis of 6-chloro-2-(1H-pyrazol-4-yl)quinoline:

[0884]

[0885]

2,6-Dichloroquinoline (200.0 mg, 1.010 mmol), (1H-pyrazol-4-yl)boronic 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 the resulting solution was then stirred under heating at 100°C for 18 hours. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound as a pale yellow solid (49.7 mg, 0.214 mmol, yield: 21%).

¹ H-NMR (CDCl ₃ ) δ: 8.27 (2H, s), 8.07 (1H, d, J=8.7 Hz), 7.99 (1H, d, J=9.1 Hz), 7.77 (1H, d, J=2.7 Hz), 7.67 (1H, d, J=8.7 Hz), 7.63 (1H, dd, J=9.1, 2.3 Hz).

MS(IER) [M+H] ⁺ : 230.

[0886]

(Example 96) Synthesis of 6-chloro-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[0887]

[0888]

6-Chloro-2-(1H-pyrazol-4-yl)quinoline synthesized in Reference Example 79 (49.7 mg, 0.216 mmol) was dissolved in THF (2.16 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (131.6 mg, 0.519 mmol) and iodine (5.5 mg, 0.022 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound (hereinafter referred to as “Example 96 compound”) as a pale yellow amorphous substance (37.4 mg, 0.160 mmol, yield: 74%).

¹ H-NMR (CDCl ₃ ) δ: 7.57 (2H, s), 7.00-6.93 (2H, m), 6.44 (1H, d, J=8.2 Hz), 4.48 (1H, dd, J=9.4, 3.0 Hz), 3.98 (1H, shs), 2.92-2.84 (1H, m), 2.73 (1H, dt, J=16.8, 4.9 Hz), 2.16-2.09 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 234.

[0889]

(Reference Example 80) Synthesis of 6-methyl-2-(1H-pyrazol-4-yl)quinoline:

[0890]

[0891]

2-Chloro-6-methylquinoline (200.0 mg, 1.126 mmol), (1H-pyrazol-4-yl)boronic 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 the resulting solution was then stirred under heating at 100°C for 18 hours. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound as a pale yellow solid (49.9 mg, 0.236 mmol, yield: 21%).

¹ H-NMR (CDCl ₃ ) δ: 8.26 (1H, s), 8.26 (1H, s), 8.06 (1H, d, J=8.7 Hz), 7.95 (1H, d, J=8.7 Hz), 7.62-7.52 (3H, m), 2.53 (3H, s).

MS(IER) [M+H] ⁺ : 210.

[0892]

(Example 97) Synthesis of 6-methyl-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[0893]

[0894]

6-Methyl-2-(1H-pyrazol-4-yl)quinoline synthesized in Reference Example 80 (49.9 mg, 0.238 mmol) was dissolved in THF (2.38 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (145.0 mg, 0.572 mmol) and iodine (6.1 mg, 0.024 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound (hereinafter referred to as “Example 97 compound”) as a pale yellow solid (37.2 mg, 0.174 mmol, yield: 73%).

¹ H-NMR (CDCl ₃ ) δ: 7.58 (2H, s), 6.82-6.81 (2H, m), 6.45 (1H, d, J=8.7 Hz), 4.46 (1H, dd, J=9.4, 3.0 Hz), 2.94-2.85 (1H, m), 2.73 (1H, dt, J=16.5, 4.8 Hz), 2.22 (3H, s), 2.16-2.09 (1H, m), 2.03-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 214.

[0895]

(Reference Example 81) Synthesis of 6-fluoro-2-(1H-pyrazol-4-yl)quinoline:

[0896]

[0897]

2-Chloro-6-fluoroquinoline (200.0 mg, 1.101 mmol), (1H-pyrazol-4-yl)boronic 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 the resulting solution was then stirred under heating at 100°C for 18 hours. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound as a pale yellow solid (69.9 mg, 0.330 mmol, yield: 30%).

¹ H-NMR (CDCl ₃ ) δ: 8.27 (2H, s), 8.10 (1H, d, J=8.7 Hz), 8.05 (1H, dd, J=9.1, 5.5 Hz), 7.66 (1H, d, J=8.7 Hz), 7.47 (1H, td, J=8.7, 3.0 Hz), 7.40 (1H, dd, J=8.7, 3.0 Hz).

MS(IER) [M+H] ⁺ : 214.

[0898]

(Example 98) Synthesis of 6-fluoro-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[0899]

[0900]

6-Fluoro-2-(1H-pyrazol-4-yl)quinoline synthesized in Reference Example 81 (69.9 mg, 0.328 mmol) was dissolved in THF (3.28 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (199.3 mg, 0.787 mmol) and iodine (8.3 mg, 0.033 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 3.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound (hereinafter referred to as “Example 98 compound”) as a pale yellow amorphous substance (49.9 mg, 0.230 mmol, yield: 70%).

¹ H-NMR (CDCl ₃ ) 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, 4.8 Hz), 2.16-2.10 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 218.

[0901]

(Reference Example 82) Synthesis of 4-(6-methylquinolin-2-yl)benzamide:

[0902]

[0903]

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 the resulting solution was then stirred under heating at 100°C for 3 hours. Water was added to the reaction mixture at room temperature, and the precipitated solid was filtered. The resulting solid was washed with chloroform/hexane and filtered to give the title compound as a pale brown solid (283 mg, 1.08 mmol, yield: 77%).

¹ H-NMR (CDCl ₃ ) δ: 8.26 (2H, d, J=8.2 Hz), 8.18 (1H, d, J=8.2 Hz), 8.07 (1H, d, J=8.2 Hz), 7.97 (2H, d, J=8.2 Hz), 7.88 (1H, d, J=8.2 Hz), 7.62 (1H, d, J=2.0 Hz), 7.59 (1H, dd, J=8.2, 2.0 Hz), 6.15 (1H, br s), 5.62 (1H, br s), 2.57 (3H, s).

MS(IER) [M+H] ⁺ : 262.

[0904]

(Example 99) Synthesis of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0905]

[0906]

4-(6-Methylquinolin-2-yl)benzamide synthesized in Reference Example 82 (280 mg, 1.07 mmol) was dissolved in tetrahydrofuran (8.0 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (649 mg, 2.56 mmol) and iodine (27.1 mg, 0.107 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 50°C for 17 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give the title compound (hereinafter referred to as “Example 99 compound”) as a white solid (188 mg, 0.706 mmol, yield: 66%).

¹ H-NMR (CDCl ₃ ) δ: 7.79 (2H, d, J=8.2 Hz), 7.48 (2H, d, J=8.2 Hz), 6.86-6.83 (2H, m), 6.51 (1H, d, J=8.2 Hz), 6.06 (1H, shs), 5.56 (1H, shs), 4.48 (1H, dd, J=8.8, 3.4 Hz), 4.02 (1H, shs), 2.93-2.85 (1H, m), 2.68 (1H, td, J=10.8, 5.6 Hz), 2.24 (3H, s), 2.15-2.09 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 267.

[0907]

(Reference Example 83) Synthesis of 4-(6-methylquinolin-2-yl)benzenesulfonamide:

[0908]

[0909]

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, 3.52 mmol) were dissolved in DMF/water (5/1, v/v, 12 mL), and the resulting solution was then stirred under heating at 100°C for 3 hours. Water was added to the reaction mixture at room temperature, and the precipitated solid was filtered and washed with hexane/chloroform to give the title compound as a pale brown solid (320 mg, 1.07 mmol, yield: 76%).

¹ H-NMR (CDCl ₃ ) δ: 8.32 (2H, d, J=8.6 Hz), 8.20 (1H, d, J=8.6 Hz), 8.07 (3H, d, J=8.6 Hz), 7.87 (1H, d, J=8.6 Hz), 7.63-7.59 (2H, m), 4.82 (2H, brs), 2.57 (3H, s).

MS(IER) [M+H] ⁺ : 299.

[0910]

(Example 100) Synthesis of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0911]

[0912]

4-(6-Methylquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 83 (310 mg, 1.04 mmol) was dissolved in tetrahydrofuran (10 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (631 mg, 2.49 mmol) and iodine (26.4 mg, 0.104 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 50°C for 18 hours. 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 give the title compound (hereinafter referred to as “Example 100 compound”) as a white solid (186 mg, 0.615 mmol, yield: 59%).

¹ H-NMR (CDCl ₃ ) δ: 7.90 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 6.87-6.84 (2H, m), 6.51 (1H, d, J=7.7 Hz), 4.77 (2H, s), 4.51 (1H, dd, J=8.8, 3.4 Hz), 3.96 (1H, s), 2.92-2.84 (1H, m), 2.66 (1H, td, J=10.8, 5.6 Hz), 2.15-2.09 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 303.

[0913]

(Reference Example 84) Synthesis of 6-methyl-3’,4’-dihydro-[2,6’-biquinolin]-2’(1’H)-one:

[0914]

[0915]

2-Chloro-6-methylquinoline (250 mg, 1.41 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (576 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 the resulting solution was then stirred under heating at 100°C for 3 hours. Water was added to the reaction mixture at room temperature, and the precipitated solid was filtered and washed with chloroform/hexane to give the title compound (357 mg, 1.24 mmol, yield: 88%) as a pale brown solid.

¹ H-NMR (CDCl ₃ ) δ: 8.12 (1H, d, J=8.6 Hz), 8.06-8.02 (2H, m), 7.94 (1H, dd, J=8.2, 1.8 Hz), 7.80 (1H, d, J=8.6 Hz), 7.72 (1H, shs), 7.59 (1H, s), 7.56 (1H, dd, J=8.6, 1.8 Hz), 6.87 (1H, d, J=8.2 Hz), 3.11 (2H, t, J=7.5 Hz), 2.71 (2H, t, J=7.5 Hz), 2.55 (3H, s).

MS(IER) [M+H] ⁺ : 289.

[0916]

(Example 101) Synthesis of 6-methyl-1,2,3,3’,4,4’-hexahydro-[2,6’-biquinolin]-2’(1’H)-one (new compound):

[0917]

[0918]

6-Methyl-3',4'-dihydro-[2,6'-biquinolin]-2'(1'H)-one synthesized in Reference Example 84 (240 mg, 0.832 mmol) was dissolved in tetrahydrofuran (8 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (506 mg, 2.00 mmol) and iodine (21.1 mg, 0.0832 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 50°C for 26 hours. 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 give the title compound (hereinafter referred to as “Example 101 compound”) as a white solid (200 mg, 0.684 mmol, yield: 82%).

¹ H-NMR (CDCl ₃ ) δ: 7.49 (1H, br s), 7.22-7.17 (2H, m), 6.84-6.83 (2H, m), 6.70 (1H, d, J=8.2 Hz), 6.50-6.47 (1H, m), 4.34 (1H, dd, J=9.5, 3.2 Hz), 3.88 (1H, br s), 2.98-2.87 (3H, m), 2.75-2.68 (1H, m), 2.63 (2H, dd, J=8.4, 6.6 Hz), 2.23 (3H, s), 2.11-1.93 (2H, m).

MS(IER) [M+H] ⁺ : 293.

[0919]

(Reference Example 85) Synthesis of 2-(furan-3-yl)-6-methylquinoline:

[0920]

[0921]

2-Chloro-6-methylquinoline (100 mg, 0.563 mmol), 3-furylboronic acid (94.5 mg, 0.844 mmol), tetrakis(triphenylphosphine)palladium(0) (19.5 mg, 0.0169 mmol), and potassium carbonate (195 mg, 1.41 mmol) were dissolved in DMF/water (5/1, v/v, 3.6 mL), and the resulting solution was then stirred under heating at 100°C for 4 hours. After the reaction mixture was cooled to room temperature, water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (118 mg, 0.563 mmol, yield: 100%).

¹ H-NMR (CDCl ₃ ) δ: 8.12 (1H, dd, J=1.8, 0.9 Hz), 8.03 (1H, d, J=9.1 Hz), 7.97 (1H, d, J=9.1 Hz), 7.56-7.51 (4H, m), 7.09 (1H, dd, J=1.8, 0.9 Hz), 2.52 (3H, s).

MS(IER) [M+H] ⁺ : 210.

[0922]

(Example 102) Synthesis of 2-(furan-3-yl)-6-methyl-1,2,3,4-tetrahydroquinoline (new compound):

[0923]

[0924]

2-(Furan-3-yl)-6-methylquinoline synthesized in Reference Example 85 (115 mg, 0.550 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 102”) as a white solid (113 mg, 0.531 mmol, yield: 97%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.38 (2H, m), 6.82-6.80 (2H, m), 6.45 (1H, d, J=8.6 Hz), 6.41 (1H, dd, J=1.6, 1.1 Hz), 4.37 (1H, dd, J=9.1, 3.2 Hz), 2.92-2.83 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.22 (3H, s), 2.13-2.06 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 214.

[0925]

(Reference Example 86) Synthesis of 4-(6-methylquinolin-2-yl)thiazole:

[0926]

[0927]

2-Chloro-6-methylquinoline (70.0 mg, 0.394 mmol), thiazol-4-ylboronic acid (76.2 mg, 0.591 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (32.2 mg, 0.0394 mmol) and potassium carbonate (109 mg, 0.788 mmol) were dissolved in 1,2-dimethoxyethane/water (8/1, v/v, 2.25 ml), and the resulting solution was then stirred under heating at 90°C for 5 hours. After cooling the reaction mixture to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (5.00 mg, 0.0221 mmol, yield: 5.6%).

¹ H-NMR (CDCl ₃ ) δ: 8.94 (1H, d, J=1.8 Hz), 8.34 (1H, s), 8.27 (1H, d, J=8.6 Hz), 8.17 (1H, d, J=8.6 Hz), 8.04 (1H, d, J=8.6 Hz), 7.60 (1H, s), 7.56 (1H, dd, J=8.6, 1.8 Hz), 2.55 (3H, s).

MS(IER) [M+H] ⁺ : 227.

[0928]

(Example 103) Synthesis of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)thiazole (new compound):

[0929]

[0930]

4-(6-methylquinolin-2-yl)thiazole synthesized in Reference Example 86 (5.00 mg, 0.0221 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 103”) as a pale yellow oily substance (2.00 mg, 0.00869 mmol, yield: 39%).

¹ H-NMR (CDCl ₃ ) δ: 8.80 (1H, d, J=2.0 Hz), 7.22 (1H, dd, J=2.0, 1.1 Hz), 6.85-6.82 (2H, m), 6.54 (1H, d, J=7.7 Hz), 4.73 (1H, dd, J=8.2, 3.6 Hz), 2.91-2.83 (1H, m), 2.66 (1H, td, J=11.1, 5.4 Hz), 2.34-2.26 (1H, m), 2.23 (3H, s), 2.19-2.10 (1H, m).

MS(IER) [M+H] ⁺ : 231.

[0931]

(Reference Example 87) Synthesis of 4-(6-methylquinolin-2-yl)isoxazole:

[0932]

[0933]

2-Chloro-6-methylquinoline (70.0 mg, 0.394 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl isoxazole (115 mg, 0.591 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (32.2 mg, 0.0394 mmol) and potassium carbonate (109 mg, 0.788 mmol) were dissolved in DMF/water (5/1, v/v, 3.6 mL), and the resulting solution was then stirred under heating at 90°C for 5 hours. After cooling the reaction mixture to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (17.0 mg, 0.0808 mmol, yield: 21%).

¹ H-NMR (CDCl ₃ ) δ: 9.05 (1H, shs), 8.97 (1H, s), 8.12 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=8.6 Hz), 7.59-7.55 (3H, m), 2.55 (3H, s).

MS(IER) [M+H] ⁺ : 211.

[0934]

(Example 104) Synthesis of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)isoxazole (new compound):

[0935]

[0936]

4-(6-Methylquinolin-2-yl)isoxazole synthesized in Reference Example 87 (17.0 mg, 0.0808 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 104”) as a white solid (12.0 mg, 0.0560 mmol, yield: 69%).

¹ H-NMR (CDCl ₃ ) δ: 8.38 (1H, s), 8.30 (1H, s), 6.85-6.83 (2H, m), 6.47 (1H, d, J=8.6 Hz), 4.47 (1H, dd, J=9.1, 3.2 Hz), 2.93-2.84 (1H, m), 2.71 (1H, td, J=10.9, 5.7 Hz), 2.23 (3H, s), 2.17-2.10 (1H, m), 2.03-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 215.

[0937]

(Reference Example 88) Synthesis of 4-(7-methylquinolin-2-yl)benzenesulfonamide:

[0938]

[0939]

2-Chloro-7-methylquinoline (110 mg, 0.619 mmol) and (4-sulfamoylphenyl)boronic acid (187 mg, 0.929 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (185 mg, 0.619 mmol, yield: 100%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.46 (1H, d, J=8.7 Hz), 8.44-8.40 (2H, m), 8.15 (1H, d, J=8.7 Hz), 7.99-7.95 (2H, m), 7.94-7.90 (2H, m), 7.48 (1H, dd, J=8.2, 1.8 Hz), 2.56 (3H, s).

MS(IER) [M+H] ⁺ : 299.

[0940]

(Example 105) Synthesis of 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0941]

[0942]

4-(7-Methylquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 88 (185 mg, 0.619 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 105”) as a white solid (135 mg, 0.447 mmol, yield: 72%).

¹ H-NMR (CDCl ₃ ) δ: 7.92-7.88 (2H, m), 7.56-7.52 (4H, m), 6.90 (1H, d, J=7.8 Hz), 6.52 (1H, dd, J=7.8, 0.9 Hz), 6.42-6.41 (1H, m), 4.81 (2H, s), 4.53 (1H, dd, J=8.7, 3.7 Hz), 4.01 (1H, shs), 2.90-2.81 (1H, m), 2.69-2.61 (1H, m), 2.26 (3H, s), 2.16-2.08 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 303.

[0943]

(Reference Example 89) Synthesis of 4-(7-methylquinolin-2-yl)benzamide:

[0944]

[0945]

2-Chloro-7-methylquinoline (126 mg, 0.709 mmol) and (4-carbamoylphenyl)boronic acid (176 mg, 1.06 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (173 mg, 0.658 mmol, yield: 93%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.44 (1H, d, J=8.5 Hz), 8.36-8.33 (2H, m), 8.15 (1H, d, J=8.5 Hz), 8.12-8.09 (1H, m), 8.06-8.03 (2H, m), 7.93-7.90 (2H, m), 7.49-7.46 (2H, m), 2.56 (3H, s).

MS(IER) [M+H] ⁺ : 263.

[0946]

(Example 106) Synthesis of 4-(7-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0947]

[0948]

4-(7-Methylquinolin-2-yl)benzamide synthesized in Reference Example 89 (170 mg, 0.648 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 106”) as a white solid (170 mg, 0.638 mmol, yield: 98%).

¹ H-NMR (CDCl ₃ ) δ: 7.81-7.77 (2H, m), 7.48-7.45 (2H, m), 6.90 (1H, d, J=7.8 Hz), 6.52-6.49 (1H, m), 6.42-6.40 (1H, m), 6.07 (1H, shs), 5.64 (1H, shs), 4.50 (1H, dd, J=8.7, 3.2 Hz), 4.01 (1H, shs), 2.91-2.82 (1H, m), 2.70-2.63 (1H, m), 2.25 (3H, s), 2.15-2.08 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 367.

[0949]

(Reference Example 90) Synthesis of 4-(6-fluoroquinolin-2-yl)benzenesulfonamide:

[0950]

[0951]

2-Chloro-6-fluoroquinoline (300 mg, 1.65 mmol) and (4-sulfamoylphenyl)boronic acid (498 mg, 2.48 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (267 mg, 0.883 mmol, yield: 54%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.53 (1H, d, J=8.9 Hz), 8.47-8.43 (2H, m), 8.29 (1H, d, J=8.9 Hz), 8.21-8.16 (1H, m), 8.01-7.98 (2H, m), 7.88-7.85 (1H, m), 7.77-7.71 (1H, m), 7.40 (2H, shs).

MS(IER) [M+H] ⁺ : 267.

[0952]

(Example 107) Synthesis of 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0953]

[0954]

4-(6-Fluoroquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 90 (265 mg, 0.877 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 107”) as a white solid (211 mg, 0.689 mmol, yield: 70%).

¹ H-NMR (CDCl ₃ ) δ: 7.93-7.89 (2H, m), 7.56-7.52 (2H, m), 6.78-6.72 (2H, m), 6.53-6.49 (1H, m), 4.84-4.81 (2H, m), 4.50 (1H, dd, J=9.1, 3.2 Hz), 3.97 (1H, brs), 2.95-2.86 (1H, m), 2.72-2.65 (1H, m), 2.16-2.09 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 307.

[0955]

(Example 108) Preparation of one of the optical isomers of 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0956]

[0957]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide synthesized in Example 107 (58.0 mg, 0.189 mmol) was dissolved in propan-2-ol (5.8 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as “the compound of Example 108”) as a white solid (24.0 mg, 0.0783 mmol, yield: 41%, enantiomeric excess: 99.8% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.93-7.89 (2H, m), 7.56-7.52 (2H, m), 6.78-6.72 (2H, m), 6.53-6.49 (1H, m), 4.84-4.81 (2H, m), 4.50 (1H, dd, J=9.1, 3.2 Hz), 3.97 (1H, brs), 2.95-2.86 (1H, m), 2.72-2.65 (1H, m), 2.16-2.09 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 307.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OZ-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=70:30

Total injection volume: 6.8 ml (0.80-1.0 ml/injection)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 11.34 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 3 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 9.26 min

[0958]

(Example 109) Preparation of another of the optical isomers of 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0959]

[0960]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide synthesized in Example 107 (58.0 mg, 0.189 mmol) was dissolved in propan-2-ol (5.8 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as “the compound of Example 109”) as a white solid (23.2 mg, 0.0757 mmol, yield: 39%, enantiomeric excess: 99.9% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.93-7.89 (2H, m), 7.56-7.52 (2H, m), 6.78-6.72 (2H, m), 6.53-6.49 (1H, m), 4.84-4.81 (2H, m), 4.50 (1H, dd, J=9.1, 3.2 Hz), 3.97 (1H, brs), 2.95-2.86 (1H, m), 2.72-2.65 (1H, m), 2.16-2.09 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 307.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OZ-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=70:30

Total injection volume: 6.8 ml (0.80-1.0 ml/injection)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 16.55 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 3 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 15.96 min

[0961]

(Example 110) Preparation of one of the optical isomers of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0962]

[0963]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide synthesized in Example 99 (60.0 mg, 0.225 mmol) was dissolved in propan-2-ol (30 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as “the compound of Example 110”) as a white solid (21.0 mg, 0.0788 mmol, yield: 35%, enantiomeric excess: 100% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.79 (2H, d, J=8.2 Hz), 7.48 (2H, d, J=8.2 Hz), 6.86-6.83 (2H, m), 6.51 (1H, d, J=8.2 Hz), 6.06 (1H, shs), 5.56 (1H, shs), 4.48 (1H, dd, J=8.8, 3.4 Hz), 4.02 (1H, shs), 2.93-2.85 (1H, m), 2.68 (1H, td, J=10.8, 5.6 Hz), 2.24 (3H, s), 2.15-2.09 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 267.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=70:30

Total injection volume: 30 ml (1.0-5.0 ml/injection)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 12.51 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 11.30 min

[0964]

(Example 111) Preparation of another of the optical isomers of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[0965]

[0966]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide synthesized in Example 99 (60.0 mg, 0.225 mmol) was dissolved in propan-2-ol (30 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as “the compound of Example 111”) as a white solid (25.5 mg, 0.0957 mmol, yield: 43%, enantiomeric excess: 99.9% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.79 (2H, d, J=8.2 Hz), 7.48 (2H, d, J=8.2 Hz), 6.86-6.83 (2H, m), 6.51 (1H, d, J=8.2 Hz), 6.06 (1H, shs), 5.56 (1H, shs), 4.48 (1H, dd, J=8.8, 3.4 Hz), 4.02 (1H, shs), 2.93-2.85 (1H, m), 2.68 (1H, td, J=10.8, 5.6 Hz), 2.24 (3H, s), 2.15-2.09 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 267.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=70:30

Total injection volume: 30 ml (1.0-5.0 ml/injection)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 15.51 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 15.51 min

[0967]

(Reference Example 91) Synthesis of 4-(5-methylquinolin-2-yl)benzenesulfonamide:

[0968]

[0969]

2-Chloro-5-methylquinoline (30.0 mg, 0.169 mmol) and (4-sulfamoylphenyl)boronic acid (37.3 mg, 0.186 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (46.3 mg, 0.155 mmol, yield: 92%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.61 (1H, d, J=8.7 Hz), 8.50-8.46 (2H, m), 8.25 (1H, d, J=8.7 Hz), 8.02-7.98 (2H, m), 7.97-7.94 (1H, m), 7.72-7.68 (2H, m), 7.49-7.47 (3H, m), 2.71 (3H, s).

MS(IER) [M+H] ⁺ : 299.

[0970]

(Example 112) Synthesis of 4-(5-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0971]

[0972]

4-(5-methylquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 91 (44.0 mg, 0.147 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 112”) as a white solid (23.3 mg, 0.0771 mmol, yield: 52%).

¹ H-NMR (CDCl ₃ ) δ: 7.92-7.89 (2H, m), 7.57-7.53 (2H, m), 6.95 (1H, dd, J=7.6, 7.6 Hz), 6.59 (1H, d, J=7.6 Hz), 6.47 (1H, d, J=7.6 Hz), 4.81 (2H, s), 4.50-4.46 (1H, m), 4.04 (1H, shs), 2.79-2.71 (1H, m), 2.67-2.60 (1H, m), 2.20 (3H, s), 2.19-2.13 (1H, m), 2.04-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 303.

[0973]

(Reference Example 92) Synthesis of 2-fluoro-4-(6-methylquinolin-2-yl)benzenesulfonamide:

[0974]

[0975]

2-Chloro-6-methylquinoline (30.0 mg, 0.169 mmol) and (3-fluoro-4-sulfamoylphenyl)boronic acid (40.7 mg, 0.186 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (30.4 mg, 0.0961 mmol, yield: 92%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.46-8.42 (1H, m), 8.31-8.20 (2H, m), 8.05-8.00 (1H, m), 7.98-7.93 (1H, m), 7.84-7.76 (3H, m), 7.70-7.65 (1H, m), 2.54 (3H, s).

MS(IER) [M+H] ⁺ : 317.

[0976]

(Example 113) Synthesis of 2-fluoro-4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0977]

[0978]

2-Fluoro-4-(6-methylquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 92 (38.0 mg, 0.120 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 113”) as a white solid (21.0 mg, 0.0655 mmol, yield: 55%).

¹ H-NMR (CDCl ₃ ) δ: 7.88-7.83 (1H, m), 7.31-7.27 (2H, m), 6.87-6.82 (2H, m), 6.52 (1H, d, J=8.2 Hz), 5.07 (2H, s), 4.52-4.48 (1H, m), 3.97 (1H, ws), 2.90-2.81 (1H, m), 2.68-2.60 (1H, m), 2.23 (3H, s), 2.16-2.07 (1H, m), 1.99-1.89 (1H, m).

MS(IER) [M+H] ⁺ : 321.

[0979]

(Reference Example 93) Synthesis of N-(4-(6-methylquinolin-2-yl)phenyl)sulfamoylamine:

[0980]

[0981]

Chlorosulfonyl isocyanate (36.2 mg, 0.256 mmol) was added to a solution of 2-methylpropan-2-ol (21.5 mg, 0.290 mmol) in dichloromethane (0.70 ml) at 0 °C, and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to a solution of 4-(6-methylquinolin-2-yl)aniline (40.0 mg, 0.171 mmol) and triethylamine (0.0432 ml, 0.307 mmol) in dichloromethane (1.0 ml), and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was dissolved in dichloromethane (1 ml), and trifluoroacetic acid (0.0916 ml) was then added to the resulting solution, and the resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to afford the title compound as a yellow solid (37.8 mg, 0.121 mmol, yield: 71%).

¹ H-NMR (CD ₃ OD) δ: 8.25 (1H, d, J=8.7 Hz), 8.06-8.02 (2H, m), 7.98 (1H, d, J=8.7 Hz), 7.88 (1H, d, J=8.7 Hz), 7.68-7.66 (1H, m), 7.60 (1H, dd, J=8.7, 1.8 Hz), 7.39-7.35 (2H, m), 2.55 (3H, s).

MS(IER) [M+H] ⁺ : 314.

[0982]

(Example 114) Synthesis of N-(4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)sulfamoylamine (new compound):

[0983]

[0984]

N-(4-(6-methylquinolin-2-yl)phenyl)sulfamoylamine synthesized in Reference Example 93 (37.8 mg, 0.121 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 114”) as a white solid (17.3 mg, 0.0545 mmol, yield: 45%).

¹ H-NMR (DMSO-d ₆ ) δ: 9.40 (1H, s), 7.26-7.22 (2H, m), 7.13-7.10 (2H, m), 7.04 (2H, s), 6.70-6.67 (2H, m), 6.48 (1H, d, J=8.2 Hz), 5.70 (1H, s), 4.30-4.26 (1H, m), 2.79-2.70 (1H, m), 2.54-2.47 (1H, m), 2.12 (3H, s), 1.96-1.89 (1H, m), 1.83-1.73 (1H, m).

MS(IER) [M+H] ⁺ : 318.

[0985]

(Reference Example 94) Synthesis of 4-(6-chloroquinolin-2-yl)benzenesulfonamide:

[0986]

[0987]

2,6-Dichloroquinoline (1.00 g, 5.05 mmol) and (4-sulfamoylphenyl)boronic acid (964 mg, 4.80 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a pale pink solid (1.38 g, 4.34 mmol, yield: 86%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.52 (1H, d, J=8.7 Hz), 8.47 (2H, d, J=8.7 Hz), 8.30 (1H, d, J=8.7 Hz), 8.20 (1H, d, J=2.3 Hz), 8.13 (1H, d, J=9.1 Hz), 8.00 (2H, d, J=8.2 Hz), 7.83 (1H, dd, J=9.1, 2.3 Hz), 7.50 (2H, s).

MS(IER) [M+H] ⁺ : 319.

[0988]

(Example 115) Synthesis of 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0989]

[0990]

4-(6-Chloroquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 94 (200 mg, 0.627 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 115”) as a pale pink solid (127 mg, 0.394 mmol, yield: 63%).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.2 Hz), 6.99-6.98 (2H, m), 6.51 (1H, d, J=9.1 Hz), 4.79 (2H, brs), 4.54 (1H, ddd, J=8.7, 3.2, 1.8 Hz), 4.09 (1H, brs), 2.86 (1H, ddd, J=15.6, 9.6, 5.5 Hz), 2.66 (1H, ddd, J=16.5, 5.5, 5.5 Hz), 2.15-2.11 (1H, m), 2.00-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 323.

[0991]

(Example 116) Synthesis of one of the optical isomers of 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0992]

[0993]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Chloroquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 94 (600 mg, 1.88 mmol) and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (28.3 mg, 0.0376 mmol) were used according to the procedure of Example 37 to give the title compound (hereinafter referred to as "the compound of Example 116") as a pale pink solid (431 mg, 1.34 mmol, yield: 71%, enantiomeric excess: 94.8% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.2 Hz), 6.99-6.98 (2H, m), 6.51 (1H, dd, J=5.9, 3.2 Hz), 4.79 (2H, s), 4.54 (1H, dd, J=11.0, 3.7 Hz), 4.09 (1H, shs), 2.86 (1H, ddd, J=15.6, 9.6, 5.0 Hz), 2.66 (1H, ddd, J=16.5, 5.0, 5.9 Hz), 2.16-2.09 (1H, m), 1.97-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 323.

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 0.46 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 15.47 min

[0994]

(Example 117) Synthesis of another optical isomer of 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[0995]

[0996]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Chloroquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 94 (600 mg, 1.88 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (28.3 mg, 0.0376 mmol) were used according to the procedure of Example 37 to give the title compound (hereinafter referred to as "the compound of Example 117") as a pale pink solid (380 mg, 1.18 mmol, yield: 63%, enantiomeric excess: 99.1% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.2 Hz), 7.00-6.96 (2H, m), 6.51 (1H, dd, J=5.9, 3.2 Hz), 4.79 (2H, s), 4.56-4.52 (1H, m), 4.09 (1H, brs), 2.86 (1H, ddd, J=15.6, 9.6, 4.6 Hz), 2.66 (1H, ddd, J=16.5, 5.0, 5.0 Hz), 2.16-2.09 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 323.

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 0.46 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 18.58 min

[0997]

(Reference Example 95) Synthesis of 4-(7-fluoroquinolin-2-yl)benzenesulfonamide:

[0998]

[0999]

2-Chloro-7-fluoroquinoline (200 mg, 1.10 mmol) and (4-sulfamoylphenyl)boronic acid (266 mg, 1.32 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a yellowish-brown solid (297 mg, 0.982 mmol, yield: 89%).

¹ H-NMR (CDCl ₃ ) δ: 8.33 (2H, d, J=8.6 Hz), 8.29 (1H, d, J=8.6 Hz), 8.09 (2H, d, J=8.6 Hz), 7.89-7.86 (2H, m), 7.81 (1H, dd, J=10.0, 2.7 Hz), 7.38 (1H, ddd, J=8.2, 8.2, 2.3 Hz), 4.84 (2H, brs).

MS(IER) [M+H] ⁺ : 303.

[1000]

(Example 118) Synthesis of 4-(7-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[1001]

[1002]

4-(7-Fluoroquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 95 was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 118”) as a white solid (182 mg, 0.595 mmol, yield: 90%).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=7.8 Hz), 7.52 (2H, d, J=8.2 Hz), 6.92 (1H, dd, J=6.9, 7.3 Hz), 6.37 (1H, ddd, J=8.2, 8.2, 2.3 Hz), 6.28 (1H, dd, J=10.5, 2.3 Hz), 4.80 (2H, shs), 4.55 (1H, d, J=8.2 Hz), 4.17 (1H, shs), 2.83 (1H, ddd, J=15.1, 9.6, 5.0 Hz), 2.63 (1H, ddd, J=16.0, 5.5, 5.5 Hz), 2.17-2.10 (1H, m), 1.97-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 307.

[1003]

(Example 119) Synthesis of one of the optical isomers of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[1004]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Methylquinolin-2-yl)benzenesulfonamide synthesized in Reference Example 83 (600 mg, 2.01 mmol) and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate ((R)-TRIP, 30.3 mg, 0.0402 mmol) were suspended in 1,4-dioxane (6.7 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1.53 g, 6.03 mmol) was added to the resulting suspension, and the resulting mixture was stirred at 60°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 give the title compound (hereinafter referred to as “Example 119 compound”) as a white solid (443 mg, 1.47 mmol, yield: 73%, enantiomeric excess: 99.4% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.90 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 6.87-6.84 (2H, m), 6.51 (1H, d, J=7.7 Hz), 4.77 (2H, s), 4.51 (1H, dd, J=8.8, 3.4 Hz), 3.96 (1H, s), 2.92-2.84 (1H, m), 2.66 (1H, td, J=10.8, 5.6 Hz), 2.15-2.09 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 303.

Rt: 6.92 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1005]

(Example 120) Synthesis of another optical isomer of 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[1006]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide synthesized in Example 100 (40.5 mg, 0.134 mmol) was dissolved in propan-2-ol (4.2 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as the “compound of Example 120”) as a white solid (14.9 mg, 49.3 μmol, yield: 37%, enantiomeric excess: 99.9%).

¹ H-NMR (CDCl ₃ ) δ: 7.90 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 6.87-6.84 (2H, m), 6.51 (1H, d, J=7.7 Hz), 4.77 (2H, s), 4.51 (1H, dd, J=8.8, 3.4 Hz), 3.96 (1H, s), 2.92-2.84 (1H, m), 2.66 (1H, td, J=10.8, 5.6 Hz), 2.15-2.09 (1H, m), 2.01-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 303.

MS(IER) [M+H] ⁺ : 303.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OZ-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=70:30

Total injection volume: 4.0 ml (1.0 ml x 4)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 17:00 to 22:00 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 0.46 mm, length: 150 mm, particle size: 3 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 12.17 min

[1007]

(Example 121) Synthesis of one of the optical isomers of 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1008]

[1009]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide synthesized in Example 131 (40.8 mg, 0.125 mmol) was dissolved in propan-2-ol (13 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as "the compound of Example 121") as a white solid (17.1 mg, 50.2 μmol, yield: 42%, enantiomeric excess: 99.9%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, d, J=8.2 Hz), 7.45 (2H, d, J=8.2 Hz), 6.97 (2H, d, J=5.9 Hz), 6.50 (1H, d, J=4.5 Hz), 4.51 (1H, d, J=6.8 Hz), 4.11 (1H, brs), 2.91-2.83 (1H, m), 2.72-2.63 (1H, m), 2.16-2.08 (1H, m), 2.11-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 287.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=70:30

Total injection volume: 12.0 ml (5.0 ml x 2, 1.0 ml x 2)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 9:00 to 13:50 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 0.46 mm, length: 150 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 11.26 min

[1010]

(Example 122) Synthesis of another optical isomer of 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1011]

[1012]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(6-Chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide synthesized in Example 131 (40.8 mg, 0.125 mmol) was dissolved in propan-2-ol (13 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as “the compound of Example 122”) as a white solid (17.0 mg, 44.0 μmol, yield: 42%, enantiomeric excess: 99.9%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, d, J=8.2 Hz), 7.45 (2H, d, J=8.2 Hz), 6.97 (2H, d, J=5.9 Hz), 6.50 (1H, d, J=4.5 Hz), 4.51 (1H, d, J=6.8 Hz), 4.11 (1H, brs), 2.91-2.83 (1H, m), 2.72-2.63 (1H, m), 2.16-2.08 (1H, m), 2.11-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 287.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=70:30

Total injection volume: 12.0 ml (5.0 ml x 2, 1.0 ml x 2)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 14.00 to 18.00 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 0.46 mm, length: 150 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 18.55 min

[1013]

(Example 123) Synthesis of one of the optical isomers of 5-(1,2,3,4-tetrahydroquinolin-2-yl)isoindolin-1-one (new compound):

[1014]

[1015]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

5-(Quinolin-2-yl)isoindolin-1-one synthesized in Reference Example 17 (100 mg, 0.384 mmol) and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (5.79 mg, 0.00768 mmol) were suspended in 1,4-dioxane (4 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (234 mg, 0.922 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 24 hours and at 60°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 give the title compound (hereinafter referred to as “Example 123 compound”) as a white solid (49.3 mg, 0.187 mmol, yield: 49%, enantiomeric excess: 97.0% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.85 (1H, d, J=7.7 Hz), 7.53 (1H, s), 7.49 (1H, d, J=8.8 Hz), 7.04 (2H, dd, J=12.9, 7.0 Hz), 6.69 (1H, dd, J=7.2, 7.2 Hz), 6.59 (1H, d, J=7.7 Hz), 6.49 (1H, s), 4.62-4.55 (1H, m), 4.44 (2H, s), 4.12 (1H, s), 2.96-2.88 (1H, m), 2.72 (1H, dd, J=10.6, 5.4, 5.4 Hz), 2.21-2.11 (1H, m), 2.06-1.96 (1H, m).

MS(IER) [M+H] ⁺ : 265.

Rt: 22.04 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1016]

(Example 124) Synthesis of another optical isomer of 5-(1,2,3,4-tetrahydroquinolin-2-yl)isoindolin-1-one (new compound):

[1017]

[1018]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

5-(Quinolin-2-yl)isoindolin-1-one synthesized in Reference Example 17 (50.0 mg, 0.192 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (2.89 mg, 0.00384 mmol) were suspended in 1,4-dioxane (2 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (117 mg, 0.461 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 hours and at 60°C for 4 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 give the title compound (hereinafter referred to as “Example 124 compound”) as a white amorphous substance (32.9 mg, 0.187 mmol, yield: 65%, enantiomeric excess: 97.0% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.85 (1H, d, J=7.7 Hz), 7.53 (1H, s), 7.49 (1H, d, J=8.8 Hz), 7.04 (2H, dd, J=12.9, 7.0 Hz), 6.69 (1H, dd, J=7.2, 7.2 Hz), 6.59 (1H, d, J=7.7 Hz), 6.49 (1H, s), 4.62-4.55 (1H, m), 4.44 (2H, s), 4.12 (1H, s), 2.96-2.88 (1H, m), 2.72 (1H, dd, J=10.6, 5.4, 5.4 Hz), 2.21-2.11 (1H, m), 2.06-1.96 (1H, m).

MS(IER) [M+H] ⁺ : 265.

Rt: 26.97 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=40:60

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1019]

(Example 125) Synthesis of one of the optical isomers of 1,2,3,3’,4,4’-hexahydro-[2,6’-biquinoline]-2’(1’H)-one (new compound):

[1020]

[1021]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

3',4'-Dihydro-[2,6'-biquinolin]-2'(1'H)-one synthesized in Reference Example 15 (100 mg, 0.364 mmol) and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (5.49 mg, 0.00729 mmol) were suspended in 1,4-dioxane (4 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (222 mg, 0.875 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 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 give the title compound (hereinafter referred to as “Example 125 compound”) as a white solid (74.0 mg, 0.266 mmol, yield: 73%, enantiomeric excess: 99.1% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.24-7.17 (2H, m), 7.04-7.68 (2H, m), 6.72-6.64 (2H, m), 6.54 (1H, d, J=7.7 Hz), 4.38 (1H, dd, J=9.3, 2.9 Hz), 3.98 (1H, s), 2.99-2.89 (3H, m), 2.79-2.70 (1H, m), 2.68-2.60 (2H, m), 2.11-2.07 (1H, m), 2.02-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 279.

Rt: 27.76 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=10:90

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1022]

(Example 126) Synthesis of another optical isomer of 1,2,3,3’,4,4’-hexahydro-[2,6’-biquinoline]-2’(1’H)-one (new compound):

[1023]

[1024]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

3',4'-Dihydro-[2,6'-biquinolin]-2'(1'H)-one synthesized in Reference Example 15 (90.0 mg, 0.328 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (4.94 mg, 0.00656 mmol) were suspended in 1,4-dioxane (2 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (199 mg, 0.787 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 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 give the title compound (hereinafter referred to as “Example 126 compound”) as a white solid (41.0 mg, 0.147 mmol, yield: 45%, enantiomeric excess: 99.0% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, s), 7.24-7.17 (2H, m), 7.04-7.68 (2H, m), 6.72-6.64 (2H, m), 6.54 (1H, d, J=7.7 Hz), 4.38 (1H, dd, J=9.3, 2.9 Hz), 3.98 (1H, s), 2.99-2.89 (3H, m), 2.79-2.70 (1H, m), 2.68-2.60 (2H, m), 2.11-2.07 (1H, m), 2.02-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 279.

Rt: 21.04 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=10:90

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1025]

(Example 127) Synthesis of one of the optical isomers of 1-( tert -butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea (new compound):

[1026]

[1027]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

1-( Tert- butyl)-3-(2-phenylquinolin-6-yl)urea synthesized in Reference Example 57 (75.0 mg, 0.235 mmol) and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (3.54 mg, 0.00470 mmol) were suspended in 1,4-dioxane (3 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (143 mg, 0.564 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 hours and at 60°C for 8 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 (amine-silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 127 compound”) as a white amorphous substance (73.0 mg, 0.226 mmol, yield: 96%, enantiomeric excess: 97.3% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.25 (5H, m), 6.88-6.82 (2H, m), 6.50 (1H, d, J=8.6 Hz), 5.69 (1H, s), 4.50 (1H, s), 4.43 (1H, dd, J=9.5, 3.2 Hz), 4.09 (1H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.15-2.10 (1H, m), 2.05-1.93 (1H, m), 1.34 (9H, s).

MS(IER) [M+H] ⁺ : 324.

Rt: 8.64 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1028]

(Example 128) Synthesis of another optical isomer of 1-( tert -butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea (new compound):

[1029]

[1030]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

1-( Tert- butyl)-3-(2-phenylquinolin-6-yl)urea synthesized in Reference Example 57 (52.0 mg, 0.163 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (2.45 mg, 0.00326 mmol) were suspended in 1,4-dioxane (2 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (99.0 mg, 0.391 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 hours and at 60°C for 8 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 (amine-silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as “Example 128 compound”) as a white amorphous substance (50.0 mg, 0.155 mmol, yield: 95%, enantiomeric excess: 97.1% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.25 (5H, m), 6.88-6.82 (2H, m), 6.50 (1H, d, J=8.6 Hz), 5.69 (1H, s), 4.50 (1H, s), 4.43 (1H, dd, J=9.5, 3.2 Hz), 4.09 (1H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.15-2.10 (1H, m), 2.05-1.93 (1H, m), 1.34 (9H, s).

MS(IER) [M+H] ⁺ : 324.

Rt: 24.37 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1031]

(Example 129) Synthesis of one of the optical isomers of 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide (new compound):

[1032]

[1033]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

3,3-Dimethyl-N-(2-phenylquinolin-6-yl)butanamide synthesized in Reference Example 59 (100 mg, 0.314 mmol) and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (4.73 mg, 0.00628 mmol) were suspended in 1,4-dioxane (3 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (191 mg, 0.736 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 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 give the title compound (hereinafter referred to as “Example 129 compound”) as a white solid (57.7 mg, 0.179 mmol, yield: 57%, enantiomeric excess: 99.3% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.32 (3H, m), 7.30-7.25 (2H, m), 7.23-7.20 (1H, m), 7.04-7.00 (1H, m), 6.85 (1H, s), 6.49 (1H, d, J=8.2 Hz), 4.42 (1H, dd, J=9.1, 3.2 Hz), 4.01 (1H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.20 (2H, s), 2.14-2.07 (1H, m), 2.02-1.92 (1H, m), 1.12 (9H, s).

MS(IER) [M+H] ⁺ : 323.

Rt: 10.36 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1034]

(Example 130) Synthesis of another optical isomer of 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide (new compound):

[1035]

[1036]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

3,3-Dimethyl-N-(2-phenylquinolin-6-yl)butanamide synthesized in Reference Example 59 (100 mg, 0.314 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (4.73 mg, 0.00628 mmol) were suspended in 1,4-dioxane (3 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (191 mg, 0.736 mmol) was added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 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 give the title compound (hereinafter referred to as “Example 130 compound”) as a white amorphous substance (41.2 mg, 0.128 mmol, yield: 40%, enantiomeric excess: 99.0% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.32 (3H, m), 7.30-7.25 (2H, m), 7.23-7.20 (1H, m), 7.04-7.00 (1H, m), 6.85 (1H, s), 6.49 (1H, d, J=8.2 Hz), 4.42 (1H, dd, J=9.1, 3.2 Hz), 4.01 (1H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.20 (2H, s), 2.14-2.07 (1H, m), 2.02-1.92 (1H, m), 1.12 (9H, s).

MS(IER) [M+H] ⁺ : 323.

Rt: 12.89 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

[1037]

(Reference Example 96) Synthesis of 4-(6-chloroquinolin-2-yl)benzamide:

[1038]

[1039]

2,6-Dichloroquinoline (300 mg, 1.51 mmol), (4-carbamoylphenyl)boronic acid (325 mg, 1.97 mmol), tetrakis(triphenylphosphine)palladium(0) (17.5 mg, 0.0151 mmol) and potassium carbonate (419 mg, 3.03 mmol) were dissolved in 1,4-dioxane/water (5/1, v/v, 7 mL), and the resulting solution was then stirred under heating at 100°C for 3 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture, and the precipitated solid was filtered. The resulting crude product was washed with water, acetone, and hexane/chloroform to give the title compound as a brown solid (338 mg, 1.20 mmol, yield: 79%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.50 (1H, d, J=8.6 Hz), 8.36 (2H, d, J=8.2 Hz), 8.30 (1H, d, J=9.1 Hz), 8.19 (1H, d, J=5.2 Hz), 8.12 (2H, d, J=9.1 Hz), 8.06 (2H, d, J=8.6 Hz), 7.82 (1H, dd, J=8.8, 2.5 Hz), 7.50 (1H, brs).

MS(IER) [M+H] ⁺ : 283.

[1040]

(Example 131) Synthesis of 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1041]

[1042]

4-(6-Chloroquinolin-2-yl)benzamide synthesized in Reference Example 96 (280 mg, 0.990 mmol) was dissolved in THF (10.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (602 mg, 2.38 mmol) and iodine (25.1 mg, 0.0990 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 18 hours. 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 give the title compound (hereinafter referred to as “Example 131 compound”) as a pale pink solid (230 mg, 0.909 mmol, yield: 81%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, d, J=8.2 Hz), 7.45 (2H, d, J=8.2 Hz), 6.97 (2H, d, J=5.9 Hz), 6.50 (1H, d, J=4.5 Hz), 4.51 (1H, d, J=6.8 Hz), 4.11 (1H, brs), 2.91-2.83 (1H, m), 2.72-2.63 (1H, m), 2.16-2.08 (1H, m), 2.11-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 287.

[1043]

(Reference Example 97) Synthesis of 4-(6-fluoroquinolin-2-yl)benzamide:

[1044]

[1045]

2-Chloro-6-fluoroquinoline (250 mg, 1.38 mmol), (4-carbamoylphenyl)boronic acid (295 mg, 1.79 mmol), tetrakis(triphenylphosphine)palladium(0) (31.3 mg, 0.0275 mmol) and potassium carbonate (381 mg, 2.75 mmol) were dissolved in 1,4-dioxane/water (5/1, v/v, 7 mL), and the resulting solution was then stirred under heating at 100°C for 5 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone, and hexane/chloroform to give the title compound as a gray solid (280 mg, 1.05 mmol, yield: 77%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.50 (1H, d, J=8.6 Hz), 8.36-8.34 (2H, m), 8.28 (1H, d, J=8.6 Hz), 8.17 (1H, dd, J=9.1, 5.4 Hz), 8.12 (1H, brs), 8.07-8.04 (2H, m), 7.85 (1H, dd, J=9.3, 2.9 Hz), 7.73 (1H, dd, J=8.9, 3.0 Hz), 7.49 (1H, s).

MS(IER) [M+H] ⁺ : 267.

[1046]

(Example 132) Synthesis of 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1047]

[1048]

4-(6-Fluoroquinolin-2-yl)benzamide synthesized in Reference Example 97 (180 mg, 0.676 mmol) was dissolved in THF (7.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (620 mg, 2.45 mmol) and iodine (34.2 mg, 0.135 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 24 hours. 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 give the title compound (hereinafter referred to as “Example 132 compound”) as a pale pink solid (141 mg, 0.522 mmol, yield: 77%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, dd, J=8.2, 1.8 Hz), 7.47 (2H, d, J=8.2 Hz), 6.75 (2H, dd, J=13.4, 5.7 Hz), 6.54-6.46 (1H, m), 4.47 (1H, d, J=6.8 Hz), 3.97 (1H, brs), 2.95-2.86 (1H, m), 2.74-2.65 (1H, m), 2.15-2.09 (1H, m), 2.02-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 271.

[1049]

(Reference Example 98) Synthesis of 6-fluoro-3’,4’-dihydro-[2,6’-biquinoline]-2’(1’H)-one:

[1050]

[1051]

2-Chloro-6-fluoroquinoline (200 mg, 1.10 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (325 mg, 1.65 mmol), tetrakis(triphenylphosphine)palladium(0) (40.5 mg, 0.0350 mmol) and potassium carbonate (304 mg, 2.21 mmol) were dissolved in 1,4-dioxane/water (5/1, v/v, 7 mL), and the resulting solution was then stirred under heating at 100°C for 18 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone, and hexane/chloroform to give the title compound as a brown solid (234 mg, 0.801 mmol, yield: 73%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.31 (1H, s), 8.40 (1H, d, J=8.6 Hz), 8.16-8.06 (4H, m), 7.78 (1H, dd, J=9.3, 2.9 Hz), 7.67 (1H, dd, J=8.9, 3.0 Hz), 7.00 (1H, d, J=8.2 Hz), 3.05-2.97 (2H, m), 2.55-2.45 (2H, m).

MS(IER) [M+H] ⁺ : 293.

[1052]

(Example 133) Synthesis of 6-fluoro-1,2,3,3’,4,4’-hexahydro-[2,6’-biquinoline]-2’(1’H)-one (new compound):

[1053]

[1054]

6-Fluoro-3',4'-dihydro-[2,6'-biquinolin]-2'(1'H)-one synthesized in Reference Example 98 (200 mg, 0.684 mmol) was dissolved in THF (7 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (516 mg, 2.04 mmol) and iodine (17.4 mg, 0.0684 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 48 hours. 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 give the title compound (hereinafter referred to as “Example 133 compound”) as a pale pink solid (144 mg, 0.486 mmol, yield: 71%).

¹ H-NMR (CDCl ₃ ) δ: 7.54-7.68 (1H, m), 7.22-7.15 (2H, m), 6.76-6.70 (3H, m), 6.47 (1H, dd, J=9.5, 5.0 Hz), 4.33 (1H, dd, J=9.7, 2.9 Hz), 3.87 (1H, shs), 3.00-2.89 (3H, m), 2.77-2.68 (1H, m), 2.66-2.62 (2H, m), 2.10-2.03 (1H, m), 2.00-1.89 (1H, m).

MS(IER) [M+H] ⁺ : 297.

[1055]

(Reference Example 99) Synthesis of 4-(5-chloroquinolin-2-yl)benzenesulfonamide:

[1056]

[1057]

2,5-Dichloroquinoline (180 mg, 0.909 mmol), (4-sulfamoylphenyl)boronic acid (274 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium(0) (31.5 mg, 0.0273 mmol) and potassium carbonate (251 mg, 1.82 mmol) were dissolved in DMF/water (5/1, v/v, 7 mL), and the resulting solution was then stirred under heating at 100°C for 4 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone and hexane/chloroform to give the title compound as a gray solid (160 mg, 0.503 mmol, yield: 55%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.71 (1H, d, J=4.5 Hz), 8.48 (3H, dd, J=10.4, 3.6 Hz), 8.40 (1H, d, J=9.1 Hz), 8.14-8.11 (1H, m), 8.02 (2H, d, J=8.6 Hz), 7.85-7.80 (3H, m).

MS(IER) [M+H] ⁺ : 319.

[1058]

(Example 134) Synthesis of 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[1059]

[1060]

4-(5-Chloroquinolin-2-yl)benzamide synthesized in Reference Example 99 (160 mg, 0.502 mmol) was dissolved in THF (5.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (305 mg, 1.20 mmol) and iodine (12.7 mg, 0.0502 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 18 hours. 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 give the title compound (hereinafter referred to as “Example 134 compound”) as a pale yellow solid (105 mg, 0.326 mmol, yield: 65%).

¹ H-NMR (CDCl ₃ ) δ: 7.93-7.90 (2H, m), 7.55-7.50 (2H, m), 6.97 (1H, dd, J=14.7, 6.6 Hz), 6.76 (1H, dd, J=7.9, 1.1 Hz), 6.49 (1H, dd, J=3.9, 3.9 Hz), 4.77 (2H, br s), 4.50 (1H, d, J=7.7 Hz), 4.18 (1H, br s), 2.86-2.80 (2H, m), 2.20-2.14 (1H, m), 2.05-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 323.

[1061]

(Reference Example 100) Synthesis of 4-(5-fluoroquinolin-2-yl)benzenesulfonamide:

[1062]

[1063]

2-Chloro-5-fluoroquinoline (160 mg, 0.881 mmol), (4-sulfamoylphenyl)boronic acid (266 mg, 1.32 mmol), tetrakis(triphenylphosphine)palladium(0) (30.5 mg, 0.0264 mmol) and potassium carbonate (243 mg, 1.76 mmol) were dissolved in DMF/water (5/1, v/v, 6 mL), and the resulting solution was then stirred under heating at 100°C for 4 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone, and hexane/chloroform to give the title compound as a gray solid (215 mg, 0.712 mmol, yield: 81%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.65 (1H, d, J=9.1 Hz), 8.48 (2H, dd, J=6.8, 1.8 Hz), 8.34 (1H, dd, J=7.5, 7.5 Hz), 8.05-7.90 (4H, m), 7.86-7.79 (1H, m), 7.55-7.45 (2H, m).

MS(IER) [M+H] ⁺ : 303.

[1064]

(Example 135) Synthesis of 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[1065]

[1066]

4-(5-Fluoroquinolin-2-yl)benzamide synthesized in Reference Example 100 (210 mg, 0.660 mmol) was dissolved in THF (12.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (401 mg, 1.58 mmol) and iodine (16.7 mg, 0.0660 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 18 hours. 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 give the title compound (hereinafter referred to as “Example 135 compound”) as a pale yellow solid (155 mg, 0.507 mmol, yield: 77%).

¹ H-NMR (CDCl ₃ ) δ: 7.93-7.90 (2H, m), 7.56-7.50 (2H, m), 7.00-6.95 (1H, m), 6.44-6.36 (2H, m), 4.79 (2H, shs), 4.52 (1H, d, J=8.6 Hz), 4.19 (1H, shs), 2.85-2.70 (2H, m), 2.20-2.10 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 307.

[1067]

(Reference Example 101) Synthesis of N-(4-(quinolin-2-yl)phenyl)methanesulfonamide:

[1068]

[1069]

2-Chloroquinoline (140 mg, 0.859 mmol), (4-(methylsulfonamide)phenyl)boronic acid (256 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium(0) (27.5 mg, 0.0238 mmol) and potassium carbonate (275 mg, 1.99 mmol) were dissolved in DMF/water (5/1, v/v, 5 mL), and the resulting solution was then stirred under heating at 100°C for 4 hours. After the reaction mixture was cooled to room temperature, water was poured into the reaction mixture, and the resulting mixture was extracted with hexane/ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (267 mg, 0.896 mmol, yield: quantitative).

¹ H-NMR (CDCl ₃ ) δ: 8.23 (1H, d, J=8.6 Hz), 8.20-8.14 (2H, m), 7.86-7.83 (2H, m), 7.76-7.65 (2H, m), 7.57-7.52 (1H, m), 7.50-7.47 (1H, m), 7.40-7.35 (1H, m), 6.69 (1H, s), 3.06 (3H, s).

MS(IER) [M+H] ⁺ : 299.

[1070]

(Example 136) Synthesis of N-(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanesulfonamide (new compound):

[1071]

[1072]

N-(4-(quinolin-2-yl)phenyl)methanesulfonamide synthesized in Reference Example 101 (180 mg, 0.573 mmol) was dissolved in THF (6.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (348 mg, 1.38 mmol) and iodine (14.5 mg, 0.0573 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 24 hours. 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 give the title compound (hereinafter referred to as “Example 136 compound”) as a pale yellow solid (113 mg, 0.374 mmol, yield: 65%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.37 (2H, m), 7.21-7.18 (2H, m), 7.05-7.68 (2H, m), 6.66 (1H, dd, J=7.5, 1.1 Hz), 6.55 (1H, d, J=8.2 Hz), 6.39 (1H, s), 4.46-4.40 (1H, m), 4.00 (1H, s), 3.02 (3H, s), 2.96-2.88 (1H, m), 2.77-2.68 (1H, m), 2.13-2.07 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 303.

[1073]

(Reference Example 102) Synthesis of 4-(5-fluoroquinolin-2-yl)benzamide:

[1074]

[1075]

2-Chloro-5-fluoroquinoline (150 mg, 0.826 mmol), (4-carbamoylphenyl)boronic acid (204 mg, 1.24 mmol), tetrakis(triphenylphosphine)palladium(0) (28.6 mg, 0.0248 mmol) and potassium carbonate (228 mg, 1.65 mmol) were dissolved in DMF/water (5/1, v/v, 6 mL), and the resulting solution was then stirred under heating at 100°C for 4 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone and hexane/chloroform to give the title compound as a gray solid (206 mg, 0.774 mmol, yield: 94%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.61 (1H, d, J=8.6 Hz), 8.38 (2H, dd, J=4.3, 4.3 Hz), 8.33 (1H, d, J=8.6 Hz), 8.15-8.05 (3H, m), 7.98 (2H, dd, J=8.4, 2.9 Hz), 7.85-7.78 (1H, m), 7.50-7.43 (1H, m).

MS(IER) [M+H] ⁺ : 267.

[1076]

(Example 137) Synthesis of 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1077]

[1078]

4-(5-Fluoroquinolin-2-yl)benzamide synthesized in Reference Example 102 (180 mg, 0.642 mmol) was dissolved in THF (6.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (390 mg, 1.54 mmol) and iodine (16.3 mg, 0.0642 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 18 hours. 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 give the title compound (hereinafter referred to as “Example 137 compound”) as a white solid (131 mg, 0.485 mmol, yield: 76%).

¹ H-NMR (CDCl ₃ ) δ: 7.80 (2H, dd, J=8.5, 1.9 Hz), 7.48-7.45 (2H, m), 6.99-6.93 (1H, m), 6.43-6.35 (2H, m), 4.51-4.45 (1H, m), 4.20 (1H, shs), 2.80-2.75 (2H, m), 2.18-2.11 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 271.

[1079]

(Reference Example 103) Synthesis of 4-(5-chloroquinolin-2-yl)benzamide:

[1080]

[1081]

2,5-Dichloroquinoline (150 mg, 0.757 mmol), (4-carbamoylphenyl)boronic acid (149 mg, 0.903 mmol), tetrakis(triphenylphosphine)palladium(0) (26.2 mg, 0.0227 mmol) and potassium carbonate (209 mg, 1.51 mmol) were dissolved in DMF/water (5/1, v/v, 7 mL), and the resulting solution was then stirred under heating at 100°C for 4 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone and hexane/chloroform to give the title compound as a gray solid (209 mg, 0.741 mmol, yield: 98%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.68 (1H, d, J=4.5 Hz), 8.40-8.36 (3H, m), 8.15-8.05 (4H, m), 7.81 (2H, dd, J=11.2, 4.1 Hz), 7.48 (1H, brs).

MS(IER) [M+H] ⁺ : 283.

[1082]

(Example 138) Synthesis of 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide (new compound):

[1083]

[1084]

4-(5-Chloroquinolin-2-yl)benzamide synthesized in Reference Example 103 (180 mg, 0.605 mmol) was dissolved in THF (6.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (547 mg, 2.16 mmol) and iodine (15.3 mg, 0.0605 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 48 hours. 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 give the title compound (hereinafter referred to as “Example 138 compound”) as a white solid (155 mg, 0.542 mmol, yield: 89%).

¹ H-NMR (CDCl ₃ ) δ: 7.82-7.79 (2H, m), 7.48-7.42 (2H, m), 6.95 (1H, dd, J=8.0, 8.0 Hz), 6.75 (1H, dd, J=8.0, 1.1 Hz), 6.48 (1H, dd, J=8.2, 0.9 Hz), 4.50-4.45 (1H, m), 4.17 (1H, ws), 2.84 (2H, dd, J=7.5, 5.3 Hz), 2.21-2.15 (1H, m), 2.05-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 287.

[1085]

(Reference Example 104) Synthesis of 7-fluoro-3’,4’-dihydro-[2,6’-biquinoline]-2’(1’H)-one:

[1086]

[1087]

2-Chloro-7-fluoroquinoline (60.0 mg, 0.330 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (135 mg, 0.496 mmol), tetrakis(triphenylphosphine)palladium(0) (11.4 mg, 0.00991 mmol) and potassium carbonate (91.3 mg, 0.660 mmol) were dissolved in 1,4-dioxane/water (5/1, v/v, 3 mL), and the resulting solution was then stirred under heating at 100°C for 4 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone and hexane/chloroform to give the title compound as a gray solid (96.7 mg, 0.331 mmol, yield: 100%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.32 (1H, s), 8.46 (1H, d, J=8.6 Hz), 8.14-8.05 (4H, m), 7.75 (1H, dd, J=10.4, 2.7 Hz), 7.50 (1H, dd, J=8.8, 2.4 Hz), 7.01 (1H, d, J=8.6 Hz), 3.05-2.99 (2H, m), 2.55-2.45 (2H, m).

MS(IER) [M+H] ⁺ : 293.

[1088]

(Example 139) Synthesis of 7-fluoro-1,2,3,3’,4,4’-hexahydro-[2,6’-biquinoline]-2’(1’H)-one (new compound):

[1089]

[1090]

7-Fluoro-3',4'-dihydro-[2,6'-biquinolin]-2'(1'H)-one synthesized in Reference Example 104 (71.0 mg, 0.231 mmol) was dissolved in THF (3.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (140 mg, 0.554 mmol) and iodine (5.8 mg, 0.023 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 18 hours. 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 give the title compound (hereinafter referred to as “Example 139 compound”) as a white solid (35.7 mg, 0.121 mmol, yield: 52%).

¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, ws), 7.20-7.12 (2H, m), 6.91 (1H, dd, J=7.2, 7.2 Hz), 6.72 (1H, d, J=7.7 Hz), 6.34 (1H, dd, J=8.5, 2.6 Hz), 6.24 (1H, dd, J=10.9, 2.7 Hz), 4.40-4.35 (1H, m), 4.07 (1H, s), 3.00-2.93 (2H, m), 2.89-2.81 (1H, m), 2.73-2.62 (3H, m), 2.11-2.05 (1H, m), 1.98-1.88 (1H, m).

MS(IER) [M+H] ⁺ : 297.

[1091]

(Reference Example 105) Synthesis of 7-fluoro-2-(1H-pyrazol-4-yl)quinoline:

[1092]

[1093]

2-Chloro-7-fluoroquinoline (70.0 mg, 0.385 mmol), (1H-pyrazol-4-yl)boronic acid (64.0 mg, 0.576 mmol), tetrakis(triphenylphosphine)palladium(0) (13.3 mg, 0.0115 mmol) and potassium carbonate (106 mg, 0.768 mmol) were dissolved in DMF/water (5/1, v/v, 2 mL), and the resulting solution was then stirred under heating at 100°C for 6 hours. After cooling the reaction mixture to room temperature, water was poured into the reaction mixture and the precipitated solid was filtered. The resulting crude product was washed with water, acetone, and hexane/chloroform to give the title compound as a gray solid (20.0 mg, 0.0938 mmol, yield: 24%).

¹ H-NMR (CDCl ₃ ) δ: 8.28 (2H, s), 8.14 (1H, d, J=8.6 Hz), 7.77 (1H, dd, J=9.1, 5.9 Hz), 7.69 (1H, dd, J=10.4, 2.3 Hz), 7.62 (1H, d, J=8.6 Hz), 7.30-7.25 (1H, m).

MS(IER) [M+H] ⁺ : 214.

[1094]

(Example 140) Synthesis of 7-fluoro-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (new compound):

[1095]

[1096]

7-Fluoro-2-(1H-pyrazol-4-yl)quinoline synthesized in Reference Example 105 (20.0 mg, 0.0891 mmol) was dissolved in THF (2.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (54.2 mg, 0.214 mmol) and iodine (2.26 mg, 0.00891 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 18 hours. 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 give the title compound (hereinafter referred to as “Example 140 compound”) as a yellow oily substance (14.1 mg, 0.0650 mmol, yield: 73%).

¹ H-NMR (CDCl ₃ ) δ: 7.57 (2H, s), 6.92-6.89 (1H, m), 6.34 (1H, dd, J=8.5, 2.4 Hz), 6.21 (1H, dd, J=10.6, 2.5 Hz), 4.50 (1H, dd, J=9.1, 3.2 Hz), 2.89-2.80 (1H, m), 2.75-2.67 (1H, m), 2.16-2.10 (1H, m), 2.02-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 218.

[1097]

(Reference Example 106) Synthesis of 2-fluoro-4-(quinolin-2-yl)benzonitrile:

[1098]

[1099]

2-Chloroquinoline (70.0 mg, 0.428 mmol), (4-cyano-3-fluorophenyl)boronic acid (106 mg, 0.642 mmol), tetrakis(triphenylphosphine)palladium(0) (14.8 mg, 0.0128 mmol) and potassium carbonate (118 mg, 0.856 mmol) were dissolved in 1,4-dioxane/water (5/1, v/v, 3 mL), and the resulting solution was then stirred under heating at 100°C for 3 hours. After the reaction mixture was cooled to room temperature, water was poured into the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a white solid (92.0 mg, 0.371 mmol, yield: 86%).

¹ H-NMR (CDCl ₃ ) δ: 8.31 (1H, d, J=8.6 Hz), 8.19-8.07 (3H, m), 7.88 (2H, d, J=8.6 Hz), 7.81-7.76 (2H, m), 7.63-7.59 (1H, m).

MS(IER) [M+H] ⁺ : 249.

[1100]

(Example 141) Synthesis of 4-fluoro-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile (new compound):

[1101]

[1102]

2-Fluoro-4-(quinolin-2-yl)benzonitrile synthesized in Reference Example 106 (50.0 mg, 0.201 mmol) was dissolved in THF (2.0 mL), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (122 mg, 0.483 mmol) and iodine (5.11 mg, 0.0201 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 18 hours. 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 give the title compound (hereinafter referred to as “Example 141 compound”) as a yellow oily substance (36.6 mg, 0.145 mmol, yield: 72%).

¹ H-NMR (CDCl ₃ ) δ: 7.61-7.58 (1H, m), 7.31-7.25 (2H, dd, J=7.7, 5.4 Hz), 7.08-7.68 (2H, m), 6.72-6.66 (1H, m), 6.61-6.57 (1H, m), 4.57-4.50 (1H, m), 4.10 (1H, shs), 2.93-2.83 (1H, m), 2.70-2.62 (1H, m), 2.18-2.10 (1H, m), 2.00-1.90 (1H, m).

MS(IER) [M+H] ⁺ : 253.

[1103]

(Reference Example 107) Synthesis of 4-(6-(trifluoromethyl)quinolin-2-yl)benzenesulfonamide:

[1104]

[1105]

2-Chloro-6-(trifluoromethyl)quinoline (200 mg, 0.864 mmol), (4-sulfamoylphenyl)boronic acid (260 mg, 1.30 mmol), tetrakis(triphenylphosphine)palladium(0) (29.9 mg, 0.0259 mmol), and potassium carbonate (239 mg, 1.73 mmol) were dissolved in DMF/water (5/1, v/v, 4.3 mL), and the resulting solution was then stirred under heating at 100°C for 17 hours. After the reaction mixture was cooled to room temperature, water was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by recrystallization (hexane/chloroform) to give the title compound as a pale yellow solid (220 mg, 0.624 mmol, yield: 72%).

¹ H-NMR (DMSO-d ₆ ) δ: 8.75 (1H, d, J=8.7 Hz), 8.59 (1H, s), 8.52 (2H, dt, J=8.7, 1.8 Hz), 8.41 (1H, d, J=8.7 Hz), 8.31 (1H, d, J=8.7 Hz), 8.07 (1H, dd, J=8.9, 2.1 Hz), 8.02 (2H, d, J=8.7 Hz), 7.52 (2H, s).

MS(IER) [M+H] ⁺ : 353.

[1106]

(Example 142) Synthesis of 4-(6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide (new compound):

[1107]

[1108]

4-(6-(Trifluoromethyl)quinolin-2-yl)benzenesulfonamide synthesized in Reference Example 107 (218 mg, 0.619 mmol) was dissolved in THF (6.2 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (376 mg, 1.49 mmol) and iodine (15.7 mg, 0.0619 mmol) were then added to the resulting solution, and the resulting mixture was stirred at 60°C for 16 hours. 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 give the title compound (hereinafter referred to as “Example 142 compound”) as a white solid (166 mg, 0.466 mmol, yield: 75%).

¹ H-NMR (CDCl ₃ ) δ: 7.92 (2H, ddd, J=8.5, 8.5, 1.8 Hz), 7.51 (2H, d, J=8.5 Hz), 7.28-7.24 (2H, m), 6.60 (1H, d, J=8.2 Hz), 4.79 (2H, s), 4.63 (1H, d, J=7.8 Hz), 4.41 (1H, brs), 2.93-2.85 (1H, m), 2.73-2.68 (1H, m), 2.20-2.15 (1H, m), 2.02-1.96 (1H, m).

MS(IER) [M+H] ⁺ : 357.

[1109]

(Reference Example 108) Synthesis of ethyl 2-(2-phenylquinolin-6-yl) acetate:

[1110]

[1111]

Ethyl 2-(4-aminophenyl)acetate (10.0 g, 55.8 mmol) was dissolved in acetonitrile (56 mL), and benzaldehyde (6.2 mL, 61 mmol) was then added to the resulting solution, and the resulting mixture was stirred at 50°C for 19 hours with a flow of nitrogen gas in the open air. After confirming complete dissolution of the starting material, the solution was allowed to cool to room temperature. Acetonitrile/dichloromethane (1/1, v/v, 56 mL) was added to the solution, and ethyl vinyl ether (0.75 mL, 67 mmol) and ytterbium(III) triflate hydrate (769 mg, 1.12 mmol) were added to the resulting mixture under ice-cooling, and the resulting mixture was stirred for 1 hour. Then, the reaction mixture was distilled under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give a mixture as a white solid (14.9 g, crude yield: 79%), which contained ethyl 2-(4-ethoxy-2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetate as the main component.

The resulting mixture (14.9 g) was dissolved in acetic acid/toluene (1/2, v/v, 220 ml), and the resulting solution was then stirred at 60°C for 20 hours in open air. Then, the reaction mixture was distilled under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a pale yellow solid (6.31 g, 21.7 mmol, yield over 2 steps: 39%).

¹ H-NMR (CDCl ₃ ) δ: 8.19-8.13 (4H, m), 7.87 (1H, d, J=8.7 Hz), 7.73 (1H, d, J=1.6 Hz), 7.66 (1H, dd, J=8.7, 1.6 Hz), 7.55-7.50 (2H, m), 7.46 (1H, tt, J=7.3, 1.8 Hz), 4.19 (2H, q, J=7.2 Hz), 3.81 (2H, s), 1.27 (3H, t, J=7.2 Hz).

MS(IER) [M+H] ⁺ : 292.

[1112]

(Reference Example 109) Synthesis of 2-(2-phenylquinolin-6-yl)acetic acid:

[1113]

[1114]

Ethyl 2-(2-phenylquinolin-6-yl)acetate synthesized in Reference Example 108 (6.31 g, 21.7 mmol) was dissolved in ethanol/tetrahydrofuran (1/1, v/v, 86 mL), and 1 mol/L aqueous sodium hydroxide solution (45.5 mL, 45.5 mmol) was then added to the resulting solution, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 6 by adding 1 mol/L hydrochloric acid (about 30 mL) and then diluted with ethyl acetate (86 mL). After separating the organic layer, the aqueous phase was extracted three times with ethyl acetate (170 mL). The organic layers were combined, washed with water (170 ml) and saturated brine (85 ml), dried over anhydrous sodium sulfate, and then distilled under reduced pressure to give the title compound as a yellow solid (6.31 g, 21.7 mmol, yield: 39%).

¹ H-NMR (CDCl ₃ ) δ: 8.19-8.12 (4H, m), 7.87 (1H, d, J=8.5 Hz), 7.74 (1H, d, J=1.8 Hz), 7.66 (1H, dd, J=8.5, 1.8 Hz), 7.54-7.50 (2H, m), 7.48-7.44 (1H, m), 3.85 (2H, s).

MS(IER) [M+H] ⁺ : 264.

[1115]

(Reference Example 110) Synthesis of 1-(3-hydroxyazetidin-1-yl)-2-(2-phenylquinolin-6-yl)ethan-1-one:

[1116]

[1117]

2-(2-Phenylquinolin-6-yl)acetic acid synthesized in Reference Example 109 (4.90 g, 18.6 mmol) was dissolved in DMF (93 ml), and N,N-diisopropylethylamine (11.3 ml, 65.1 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 10.6 g, 27.9 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 20 minutes. Then, 3-hydroxyazetidine hydrochloride (2.65 g, 24.2 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for another 15 hours. Water (280 ml) was added to the reaction mixture, and the resulting mixture was stirred for 30 minutes, and the resulting suspension was then filtered. The filtrate was extracted three times with ethyl acetate (180 ml) and then extracted four times with ethyl acetate (90 ml). The organic layer was washed twice with saturated brine (180 ml), dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) and column chromatography (silica gel, ethyl acetate/methanol) to give the title compound as a pale yellow solid (1.43 g, 4.50 mmol, yield: 24%).

¹ H-NMR (CDCl ₃ ) δ: 8.19-8.11 (4H, m), 7.87 (1H, d, J=8.2 Hz), 7.72 (1H, s), 7.63 (1H, dd, J=8.5, 2.1 Hz), 7.55-7.47 (3H, m), 4.62 (1H, shs), 4.34 (1H, dd, J=8.0, 6.6 Hz), 4.27 (1H, dd, J=10.3, 6.6 Hz), 4.01 (1H, dd, J=9.6, 3.8 Hz), 3.89 (1H, dd, J=10.7, 3.8 Hz), 3.65 (2H, s), 2.60 (1H, shs).

MS(IER) [M+H] ⁺ : 319.

[1118]

(Example 143) Synthesis of one of the optical isomers of 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one hydrochloride (new compound):

[1119]

[1120]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

1-(3-hydroxyazetidin-1-yl)-2-(2-phenylquinolin-6-yl)ethan-1-one synthesized in Reference Example 110 (50.0 mg, 0.157 mmol) and ( S )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (( S )-TRIP, 2.4 mg, 0.0031 mmol) were suspended in 1,4-dioxane (0.8 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (87.5 mg, 0.346 mmol) was then added to the resulting suspension, and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was distilled under reduced pressure and the resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) to give one of the optical isomers of 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one as a pale yellow amorphous substance (44.7 mg).

The obtained optical isomer 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (44.7 mg), which is one of the optical isomers, was dissolved in ethyl acetate (2 ml), and 4 mol/L hydrogen chloride-ethyl acetate solution (0.136 ml) was then added to the resulting solution under stirring. The resulting mixture was then stirred at room temperature for 30 minutes, and the resulting solid was then filtered, to give the title compound (hereinafter referred to as the “compound of Example 143”) as a white solid (40.5 mg, 0.113 mmol, yield: 72%, enantiomeric excess: 95.6% ee).

¹ H-NMR (DMSO-d ₆ ) δ: 7.49-7.47 (2H, m), 7.41-7.39 (2H, m), 7.34-7.31 (1H, m), 6.93 (2H, br s), 6.83 (1H, br s), 4.51-4.49 (1H, br m), 4.44-4.43 (1H, m), 4.34 (1H, dd, J=8.5, 6.8 Hz), 4.01 (1H, dd, J=10.3, 6.8 Hz), 3.88 (1H, dd, J=8.5, 4.4 Hz), 3.56 (1H, dd, J=10.3, 4.4 Hz), 3.29 (2H, s), 2.88-2.85 (1H, bmm), 2.71-2.67 (1H, bmm), 2.09-2.03 (2H, m).

MS(IER) [M+H] ⁺ : 323.

Rt: 12.27 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=60:40

Flow rate: 0.6 ml/min

Injection volume: 10 µl

Detection: UV (254 nm)

[1121]

(Example 144) Synthesis of another optical isomer of 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one hydrochloride (new compound):

[1122]

[1123]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

1-(3-Hydroxyazetidin-1-yl)-2-(2-phenylquinolin-6-yl)ethan-1-one synthesized in Reference Example 110 (1.43 g, 4.49 mmol) and ( R )-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl (( R )-triP, 67.6 mg, 0.0898 mmol) hydrogen phosphate were suspended in 1,4-dioxane (22 ml), and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (2.50 g, 9.88 mmol) was then added to the resulting suspension, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was distilled under reduced pressure and the resulting crude product was purified by column chromatography (amino silica gel, chloroform/methanol) and column chromatography (silica gel, ethyl acetate/methanol) to give another of the optical isomers 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one as a pale yellow amorphous substance (1.13 g).

The obtained optical isomer 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (1.13 g), which is another of the optical isomers, was dissolved in ethyl acetate (45 ml), and 4 mol/L hydrogen chloride-ethyl acetate solution (3.5 ml) was then added to the resulting solution under stirring. The resulting mixture was then stirred at room temperature for 30 minutes, and the resulting solid was then filtered to give the title compound (hereinafter referred to as the “compound of Example 144”) as a white solid (1.13 g, 3.15 mmol, yield: 70%, enantiomeric excess: 95.4% ee).

¹ H-NMR (DMSO-d ₆ ) δ: 7.49-7.47 (2H, m), 7.41-7.39 (2H, m), 7.34-7.31 (1H, m), 6.93 (2H, br s), 6.83 (1H, br s), 4.51-4.49 (1H, br m), 4.44-4.43 (1H, m), 4.34 (1H, dd, J=8.5, 6.8 Hz), 4.01 (1H, dd, J=10.3, 6.8 Hz), 3.88 (1H, dd, J=8.5, 4.4 Hz), 3.56 (1H, dd, J=10.3, 4.4 Hz), 3.29 (2H, s), 2.88-2.85 (1H, bmm), 2.71-2.67 (1H, bmm), 2.09-2.03 (2H, m).

MS(IER) [M+H] ⁺ : 323.

Rt: 9.30 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=60:40

Flow rate: 0.6 ml/min

Injection volume: 10 µl

Detection: UV (254 nm)

[1124]

(Example 145) Synthesis of 1-morpholino-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (new compound):

[1125]

[1126]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (92.0 mg, 0.344 mmol) was dissolved in DMF (0.75 mL), and N,N-diisopropylethylamine (89.8 μL, 0.516 mmol), morpholine (24.8 μL, 0.413 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 157 mg, 0.413 mmol) were then added to the resulting solution, and the resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, chloroform/methanol) and column chromatography (amino silica gel, hexane/ethyl acetate) to give the title compound (hereinafter referred to as "Example 145 compound") as a colorless transparent oily substance (83.3 mg, 0.248 mmol, yield: 72%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.33 (4H, m), 7.31-7.27 (1H, m), 6.89-6.84 (2H, m), 6.50 (1H, d, J=8.2 Hz), 4.42 (1H, dd, J=9.1, 3.2 Hz), 4.02 (1H, brs), 3.65 (4H, s), 3.60 (2H, s), 3.54-3.52 (2H, m), 3.48-3.46 (2H, m), 2.94-2.86 (1H, m), 2.71 (1H, dt, J=16.5, 4.8 Hz), 2.14-2.08 (1H, m), 2.02-1.93 (1H, m).

MS(IER) [M+H] ⁺ : 337.

[1127]

(Example 146) Synthesis of 1-(3,3-dimethylazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (new compound):

[1128]

[1129]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.0 mg, 0.0748 mmol), N,N-diisopropylethylamine (39.0 μL, 0.224 mmol), 3,3-dimethylazetidine (10.9 mg, 0.0898 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 34.1 mg, 0.0898 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as the “compound of Example 146”) as a colorless transparent oily substance (20.0 mg, 0.0598 mmol, yield: 80%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.32 (4H, m), 7.30-7.27 (1H, m), 6.92 (1H, d, J=2.3 Hz), 6.89 (1H, dd, J=8.2, 2.3 Hz), 6.49 (1H, d, J=8.2 Hz), 4.42 (1H, dd, J=9.5, 3.2 Hz), 4.01 (1H, ws), 3.78 (2H, s), 3.69 (2H, s), 3.33 (2H, s), 2.96-2.86 (1H, m), 2.72 (1H, dt, J=16.3, 4.8 Hz), 2.14-2.07 (1H, m), 2.02-1.93 (1H, m), 1.25 (6H, s).

MS(IER) [M+H] ⁺ : 335.

[1130]

(Example 147) Synthesis of 1-(3-methoxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (new compound):

[1131]

[1132]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.0 mg, 0.0748 mmol), N,N-diisopropylethylamine (19.5 μL, 0.112 mmol), 3-methoxyazetidine (7.82 mg, 0.0898 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 34.1 mg, 0.0898 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as the “compound of Example 147”) as a colorless transparent oily substance (8.00 mg, 0.0238 mmol, yield: 32%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.33 (4H, m), 7.30-7.27 (1H, m), 6.91 (1H, d, J=2.0 Hz), 6.88 (1H, dd, J=8.2, 2.0 Hz), 6.49 (1H, d, J=8.2 Hz), 4.42 (1H, dd, J=8.8, 3.4 Hz), 4.26-4.22 (1H, m), 4.18-4.13 (2H, m), 3.98 (1H, dd, J=8.8, 2.9 Hz), 3.91-3.86 (1H, m), 3.35 (2H, s), 3.28 (3H, s), 2.94-2.86 (1H, m), 2.71 (1H, dt, J=16.6, 4.8 Hz), 2.14-2.07 (1H, m), 2.02-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 337.

[1133]

(Example 148) Synthesis of N-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1134]

[1135]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.0 mg, 0.0748 mmol), N,N-diisopropylethylamine (19.5 μL, 0.112 mmol), oxetan-3-amine (6.56 mg, 0.0898 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 34.1 mg, 0.0898 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as “the compound of Example 148”) as a white solid (2.50 mg, 0.00775 mmol, yield: 10%).

¹ H-NMR (DMSO-d ₆ ) δ: 7.37-7.31 (4H, m), 7.27-7.23 (1H, m), 6.73-6.70 (2H, m), 6.52 (1H, dd, J=8.2, 3.6 Hz), 5.95 (1H, shs), 4.98-4.87 (1H, m), 4.48-4.36 (2H, m), 3.99-3.86 (1H, m), 3.71-3.64 (1H, m), 3.49-3.34 (4H, m), 2.80-2.69 (1H, m), 2.02-1.94 (1H, m), 1.86-1.77 (1H, m).

MS(IER) [M+H] ⁺ : 323.

[1136]

(Example 149) Synthesis of 1-(3,3-difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (new compound):

[1137]

[1138]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (19.1 mg, 0.0715 mmol), N,N-diisopropylethylamine (37 μL, 0.21 mmol), 3,3-difluoroazetidine hydrochloride (18.5 mg, 0.143 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 32.6 mg, 0.0857 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as “the compound of Example 149”) as a colorless transparent oily substance (15.4 mg, 0.0715 mmol, yield: 63%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (4H, m), 7.31-7.27 (1H, m), 6.89-6.86 (2H, m), 6.50 (1H, d, J=8.2 Hz), 4.43 (1H, dd, J=9.1, 3.2 Hz), 4.34 (4H, q, J=11.4 Hz), 4.06 (1H, brs), 3.43 (2H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.6, 4.7 Hz), 2.15-2.09 (1H, m), 2.01-1.96 (1H, m).

MS(IER) [M+H] ⁺ : 343.

[1139]

(Example 150) Synthesis of N-(2-hydroxyethyl)-N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1140]

[1141]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (18.0 mg, 0.0673 mmol), N,N-diisopropylethylamine (35 μL, 0.20 mmol), 2-(methylamino)ethanol (10.1 mg, 0.135 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 30.7 mg, 0.0808 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as “the compound of Example 150”) as a white solid (20.1 mg, 0.0620 mmol, yield: 92%).

¹ H-NMR is used to observe a mixture of two rotamers.

Main rotamer:

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (4H, m), 7.30-7.28 (1H, m), 6.92-6.87 (2H, m), 6.51 (1H, d, J=7.9 Hz), 4.42 (1H, dd, J=9.4, 3.0 Hz), 4.02 (1H, ws), 3.79 (2H, kv, J=5.0 Hz), 3.61 (2H, s), 3.57 (2H, t, J=5.0 Hz), 3.19 (1H, t, J=5.0 Hz), 3.08 (3H, s), 2.95-2.87 (1H, m), 2.75-2.70 (1H, m), 2.13-2.09 (1H, m), 2.00-1.95 (1H, m).

Minor rotamer:

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (4H, m), 7.30-7.28 (1H, m), 6.92-6.87 (2H, m), 6.50 (1H, d, J=7.9 Hz), 4.42 (1H, dd, J=9.4, 3.0 Hz), 4.02 (1H, shs), 3.72 (2H, kv, J=5.6 Hz), 3.67 (2H, s), 3.50 (2H, t, J=5.6 Hz), 3.19 (1H, t, J=5.0 Hz), 2.98 (3H, s), 2.95-2.87 (1H, m), 2.75-2.70 (1H, m), 2.13-2.09 (1H, m), 2.00-1.95 (1H, m).

MS(IER) [M+H] ⁺ : 325.

[1142]

(Example 151) Synthesis of 1-(azetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (new compound):

[1143]

[1144]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (18.5 mg, 0.0692 mmol), N,N-diisopropylethylamine (36 μL, 0.21 mmol), azetidine hydrochloride (12.9 mg, 0.138 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 31.6 mg, 0.0830 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as the “compound of Example 151”) as a colorless transparent oily substance (21.0 mg, 0.0685 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.33 (4H, m), 7.30-7.27 (1H, m), 6.93 (1H, s), 6.90 (1H, dd, J=7.9, 2.1 Hz), 6.49 (1H, d, J=7.9 Hz), 4.42 (1H, dd, J=9.1, 3.2 Hz), 4.14 (2H, t, J=7.5 Hz), 4.03 (2H, t, J=7.8 Hz), 4.02 (1H, shs), 3.32 (2H, s), 2.94-2.88 (1H, m), 2.72 (1H, dt, J=16.3, 4.7 Hz), 2.26-2.18 (2H, m), 2.14-2.08 (1H, m), 2.02-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 307.

[1145]

(Example 152) Synthesis of N-cyclopropyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1146]

[1147]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.7 mg, 0.0774 mmol), N,N-diisopropylethylamine (20.2 μL, 0.116 mmol), cyclopropylamine (6.5 μL, 0.093 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 35.3 mg, 0.0929 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as the “compound of Example 152”) as a white amorphous substance (20.2 mg, 0.0658 mmol, yield: 85%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.30 (5H, m), 6.84-6.83 (2H, m), 6.51 (1H, d, J=8.7 Hz), 5.55 (1H, ws), 4.44 (1H, dd, J=9.1, 3.2 Hz), 4.08 (1H, shs), 3.42 (2H, s), 2.91-2.88 (1H, m), 2.73-2.65 (2H, m), 2.16-2.11 (1H, m), 2.04-1.97 (1H, m), 0.73 (2H, td, J=7.0, 5.3 Hz), 0.43-0.39 (2H, m).

MS(IER) [M+H] ⁺ : 307.

[1148]

(Example 153) Synthesis of N-(cyclopropylmethyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1149]

[1150]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.9 mg, 0.0782 mmol), N,N-diisopropylethylamine (20.4 μL, 0.117 mmol), cyclopropylmethylamine (8.0 μL, 0.094 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 35.7 mg, 0.0938 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as “the compound of Example 153”) as a pale yellow amorphous substance (13.0 mg, 0.0407 mmol, yield: 52%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.28 (5H, m), 6.89-6.88 (2H, m), 6.53 (1H, d, J=8.7 Hz), 5.58 (1H, shs), 4.45 (1H, dd, J=9.1, 2.7 Hz), 4.08 (1H, shs), 3.45 (2H, s), 3.09 (2H, dd, J=6.9, 5.9 Hz), 2.96-2.88 (1H, m), 2.73 (1H, dt, J=16.9, 5.0 Hz), 2.16-2.10 (1H, m), 2.04-1.98 (1H, m), 0.91-0.87 (1H, m), 0.47-0.43 (2H, m), 0.16-0.12 (2H, m).

MS(IER) [M+H] ⁺ : 321.

[1151]

(Example 154) Synthesis of N-(oxetan-3-ylmethyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1152]

[1153]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.9 mg, 0.0782 mmol), N,N-diisopropylethylamine (20.4 μL, 0.117 mmol), 3-(aminomethyl)oxetane (8.1 μL, 0.094 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 35.7 mg, 0.0938 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as the “compound of Example 154”) as a pale yellow amorphous substance (19.1 mg, 0.0571 mmol, yield: 73%).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.26 (5H, m), 6.87-6.85 (2H, m), 6.53 (1H, d, J=8.7 Hz), 5.68 (1H, ws), 4.73 (2H, dd, J=7.8, 6.4 Hz), 4.45 (1H, dd, J=9.1, 3.2 Hz), 4.34 (2H, dd, J=5.9, 6.4 Hz), 4.09 (1H, shs), 3.46 (2H, s), 3.19-3.12 (1H, m), 2.96-2.86 (1H, m), 2.80 (2H, s), 2.72 (1H, dt, J=16.5, 4.8 Hz), 2.17-2.10 (1H, m), 2.03-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 337.

[1154]

(Example 155) Synthesis of N-cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1155]

[1156]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (18.0 mg, 0.0673 mmol), N,N-diisopropylethylamine (17.5 μL, 0.101 mmol), cyclobutylamine (23.9 μL, 0.336 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 33.2 mg, 0.0875 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as the “compound of Example 155”) as a white amorphous substance (11.4 mg, 0.0356 mmol, yield: 53%).

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.34 (4H, m), 7.30 (1H, tt, J=6.8, 2.0 Hz), 6.86 (2H, d, J=5.9 Hz), 6.53 (1H, dd, J=5.7, 2.9 Hz), 5.57 (1H, d, J=5.4 Hz), 4.41 (2H, ddd, J=25.5, 13.0, 5.8 Hz), 4.08 (1H, shs), 3.40 (2H, s), 2.97-2.88 (1H, m), 2.74 (1H, dt, J=16.5, 4.6 Hz), 2.29 (2H, ddt, J=14.2, 7.7, 2.5 Hz), 2.15 (1H, td, J=8.8, 4.2 Hz), 2.05-1.95 (1H, m), 1.80-1.61 (4H, m).

MS(IER) [M+H] ⁺ : 321.

[1157]

(Example 156) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(pyrrolidin-1-yl)ethan-1-one (new compound):

[1158]

[1159]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.0 mg, 0.0748 mmol), N,N-diisopropylethylamine (65.1 μL, 0.374 mmol), pyrrolidine (12.2 μL, 0.150 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 56.9 mg, 0.150 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as the “compound of Example 156”) as a colorless transparent oily substance (24.0 mg, 0.0748 mmol, yield: 100%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.31 (4H, m), 7.30-7.27 (1H, m), 6.94-6.89 (2H, m), 6.49 (1H, d, J=7.8 Hz), 4.43-4.39 (1H, m), 4.01 (1H, shs), 3.52-3.42 (6H, m), 2.96-2.85 (1H, m), 2.75-2.67 (1H, m), 2.13-2.06 (1H, m), 2.02-1.88 (3H, m), 1.86-1.79 (2H, m).

MS(IER) [M+H] ⁺ : 321.

[1160]

(Example 157) Synthesis of 2-(2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetyl)piperazin-2-one (new compound):

[1161]

[1162]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (20.0 mg, 0.0748 mmol), N,N-diisopropylethylamine (65.1 μL, 0.374 mmol), piperazin-2-one (15.0 mg, 0.150 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 56.9 mg, 0.150 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as “the compound of Example 157”) as a colorless transparent oily substance (22.8 mg, 0.0652 mmol, yield: 87%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.32 (4H, m), 7.31-7.27 (1H, m), 6.98 (0H, s), 6.89-6.83 (2H, m), 6.77 (1H, ws), 6.49 (1H, d, J=8.2 Hz), 4.44-4.40 (1H, m), 4.26 (1H, s), 4.14 (1H, s), 4.06 (1H, shs), 3.83-3.80 (1H, m), 3.67-3.58 (3H, m), 3.38-3.34 (1H, m), 3.22-3.18 (1H, m), 2.93-2.84 (1H, m), 2.74-2.66 (1H, m), 2.14-2.07 (1H, m), 2.01-1.91 (1H, m).

MS(IER) [M+H] ⁺ : 350.

[1163]

(Example 158) Synthesis of 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(piperazin-1-yl)ethan-1-one (new compound):

[1164]

[1165]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (18.0 mg, 0.0673 mmol), N,N-diisopropylethylamine (35 μL, 0.20 mmol), piperazine (116.0 mg, 1.35 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 30.7 mg, 0.0808 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as “the compound of Example 158”) as a colorless transparent oily substance (17.7 mg, 0.0528 mmol, yield: 78%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.33 (4H, m), 7.30-7.28 (1H, m), 6.89-6.85 (2H, m), 6.49 (1H, d, J=7.8 Hz), 4.42 (1H, dd, J=9.6, 3.2 Hz), 4.00 (1H, brs), 3.63-3.60 (2H, m), 3.60 (2H, s), 3.44 (2H, t, J=5.0 Hz), 2.94-2.86 (1H, m), 2.82 (2H, t, J=5.3 Hz), 2.73-2.68 (3H, m), 2.14-2.07 (1H, m), 2.02-1.92 (1H, m).

MS(IER) [M+H] ⁺ : 336.

[1166]

(Example 159) Synthesis of N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (new compound):

[1167]

[1168]

2-(2-Phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid synthesized in Reference Example 40 (25.0 mg, 0.0935 mmol), N,N-diisopropylethylamine (97.6 μL, 0.561 mmol), methylamine hydrochloride (31.6 mg, 0.468 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (GATU, 42.7 mg, 0.112 mmol) were used according to the procedure of Example 145 to give the title compound (hereinafter referred to as “the compound of Example 159”) as a colorless transparent oily substance (24.9 mg, 0.0888 mmol, yield: 95%).

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.35 (4H, m), 7.31-7.28 (1H, m), 6.87-6.86 (2H, m), 6.53 (1H, d, J=8.7 Hz), 5.47 (1H, br s), 4.44 (1H, dd, J=9.6, 3.2 Hz), 4.09 (1H, br s), 3.45 (2H, s), 2.95-2.87 (1H, m), 2.77-2.69 (2H, m), 2.76 (2H, d, J=5.0 Hz), 2.16-2.12 (1H, m), 2.03-1.94 (1H, m).

MS(IER) [M+H] ⁺ : 281.

[1169]

(Example 160) Obtaining one of the optical isomers (new compound) of 1-(3,3-difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one:

[1170]

[1171]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

1-(3,3-Difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one synthesized in Example 149 (91.2 mg, 0.266 mmol) was dissolved in propan-2-ol (4.8 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as “the compound of Example 160”) as a white solid (33.4 mg, 0.0975 mmol, yield: 37%, enantiomeric excess: 100% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (4H, m), 7.31-7.27 (1H, m), 6.89-6.86 (2H, m), 6.50 (1H, d, J=8.2 Hz), 4.43 (1H, dd, J=9.1, 3.2 Hz), 4.34 (4H, q, J=11.4 Hz), 4.06 (1H, brs), 3.43 (2H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.6, 4.7 Hz), 2.15-2.09 (1H, m), 2.01-1.96 (1H, m).

MS(IER) [M+H] ⁺ : 343.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=90:10

Total injection volume: 4.8 ml (0.8-1.0 ml/injection)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 15.45 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 14.54 min

[1172]

(Example 161) Preparation of another of the optical isomers of 1-(3,3-difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one (new compound):

[1173]

[1174]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

1-(3,3-Difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one synthesized in Example 149 (91.2 mg, 0.266 mmol) was dissolved in propan-2-ol (4.8 ml) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as “the compound of Example 161”) as a white solid (31.0 mg, 0.0905 mmol, yield: 34%, enantiomeric excess: 99.6% ee).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.33 (4H, m), 7.31-7.27 (1H, m), 6.89-6.86 (2H, m), 6.50 (1H, d, J=8.2 Hz), 4.43 (1H, dd, J=9.1, 3.2 Hz), 4.34 (4H, q, J=11.4 Hz), 4.06 (1H, brs), 3.43 (2H, s), 2.94-2.86 (1H, m), 2.72 (1H, dt, J=16.6, 4.7 Hz), 2.15-2.09 (1H, m), 2.01-1.96 (1H, m).

MS(IER) [M+H] ⁺ : 343.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=90:10

Total injection volume: 4.8 ml (0.8-1.0 ml/injection)

Flow rate: 10 ml/min

Detection: UV (254 nm)

Rt: 21.67 min

HPLC analysis conditions:

Column: Daicel Chiralcel OD-H chiral column

(inner diameter: 4.6 mm, length: 150 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 21.44 min

[1175]

(Example 162) Preparation and synthesis of 3-phenyl-1,2,3,4-tetrahydroquinoline:

[1176]

[1177]

For 3-phenyl-1,2,3,4-tetrahydroquinoline (hereinafter referred to as the "compound of Example 162"), a commercial product from, for example, Enamine Ltd. can be used, or the compound can be synthesized according to a known method or equivalent methods.

[1178]

(Reference Example 111) Synthesis of 6-chloro-3-phenylquinoline:

[1179]

[1180]

4-Chloroaniline (0.202 ml, 1.57 mmol) was dissolved in DMSO (4 ml), and 2-phenylacetaldehyde (0.264 ml, 2.35 mmol), copper(I) bromide (22.5 mg, 0.157 mmol), and trifluoromethanesulfonic acid (13.9 μl, 0.157 mmol) were added to the resulting solution, and the resulting mixture was stirred at 110°C for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting reaction mixture was washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) and preparative thin layer chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a pale yellow solid (41.8 mg, 0.174 mmol, yield: 11%).

¹ H-NMR (CDCl ₃ ) δ: 9.17 (1H, d, J=2.3 Hz), 8.22 (1H, d, J=2.3 Hz), 8.08 (1H, d, J=9.1 Hz), 7.88 (1H, d, J=2.3 Hz), 7.72-7.69 (2H, m), 7.66 (1H, dd, J=8.8, 2.5 Hz), 7.55-7.54 (2H, m), 7.47-7.46 (1H, m).

MS(IER) [M+H] ⁺ : 240.

[1181]

(Example 163) Synthesis of 6-chloro-3-phenyl-1,2,3,4-tetrahydroquinoline:

[1182]

[1183]

6-Chloro-3-phenylquinoline synthesized in Reference Example 111 (20.0 mg, 83.4 μmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 163”) as a pale yellow solid (18.9 mg, 77.5 μmol, yield: 93%).

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.33 (2H, m), 7.28-7.27 (1H, m), 7.24-7.22 (2H, m), 7.00-6.94 (2H, m), 6.47 (1H, d, J=8.2 Hz), 4.04 (1H, shs), 3.46 (1H, ddd, J=11.0, 3.2, 1.4 Hz), 3.32 (1H, dd, J=11.4, 11.0 Hz), 3.15-3.07 (1H, m), 3.02-2.90 (2H, m).

MS(IER) [M+H] ⁺ : 244.

[1184]

(Reference Example 112) Synthesis of 7-chloro-3-phenylquinoline:

[1185]

[1186]

(2-Amino-4-chlorophenyl)methanol (100 mg, 0.635 mmol) was dissolved in 1,4-dioxane (3 ml), and 2-phenylacetaldehyde (0.141 ml, 1.27 mmol) and potassium tert -butoxide (107 mg, 0.952 mmol) were added to the resulting solution, and the resulting mixture was stirred at 80°C for 4 hours. After completion of the reaction, the reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give the title compound as a pale yellow solid (7.20 mg, 30.0 μmol, yield: 5%).

¹ H-NMR (CDCl ₃ ) δ: 9.19 (1H, d, J=2.3 Hz), 8.29 (1H, d, J=2.3 Hz), 8.14 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=8.7 Hz), 7.72-7.69 (2H, m), 7.56-7.52 (3H, m), 7.47-7.45 (1H, m).

MS(IER) [M+H] ⁺ : 240.

[1187]

(Example 164) Synthesis of 7-chloro-3-phenyl-1,2,3,4-tetrahydroquinoline:

[1188]

[1189]

7-Chloro-3-phenylquinoline synthesized in Reference Example 112 (7.20 mg, 30.0 μmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as “the compound of Example 164”) as a pale yellow solid (6.20 mg, 25.4 μmol, yield: 85%).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.33 (2H, m), 7.26-7.24 (3H, m), 6.90 (1H, d, J=7.8 Hz), 6.59 (1H, dd, J=8.0, 2.1 Hz), 6.52 (1H, d, J=1.8 Hz), 4.10 (1H, ws), 3.46 (1H, dd, J=11.0, 3.2 Hz), 3.32 (1H, dd, J=11.0, 11.0 Hz), 3.12-3.09 (1H, m), 2.95-2.93 (2H, m).

MS(IER) [M+H] ⁺ : 244.

[1190]

(Reference Example 113) Synthesis of (4-(quinolin-3-yl)phenyl)methanol:

[1191]

[1192]

3-Chloroquinoline (200 mg, 1.22 mmol) and (4-(hydroxymethyl)phenyl)boronic acid (186 mg, 1.22 mmol) were dissolved in toluene (5 ml), and palladium(II) acetate (5.49 mg, 24.5 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 22.8 mg, 48.9 μmol), potassium carbonate (507 mg, 3.67 mmol), and water (0.5 ml) were added to the resulting solution, and the resulting mixture was stirred at 80°C for 17 hours under argon atmosphere. After completion of the reaction, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate, and the filtrate was then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, hexane/ethyl acetate) to afford the title compound as a white solid (111 mg, 0.471 mol, yield: 39%).

¹ H-NMR (CDCl ₃ ) δ: 9.15 (1H, d, J=2.3 Hz), 8.31 (1H, d, J=2.3 Hz), 8.14 (1H, d, J=8.2 Hz), 7.89 (1H, dd, J=8.2, 1.4 Hz), 7.76-7.71 (3H, m), 7.59 (1H, ddd, J=8.2, 6.9, 0.9 Hz), 7.55-7.52 (2H, m), 4.80 (2H, d, J=5.5 Hz), 1.91 (1H, t, J=5.5 Hz).

MS(IER) [M+H] ⁺ : 236.

[1193]

(Example 165) Synthesis of (4-(1,2,3,4-tetrahydroquinolin-3-yl)phenyl)methanol (new compound):

[1194]

[1195]

(4-(Quinolin-3-yl)phenyl)methanol synthesized in Reference Example 113 (30.0 mg, 0.128 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 165”) as a white solid (16.2 mg, 67.7 μmol, yield: 53%).

¹ H-NMR (CDCl ₃ ) δ: 7.35 (2H, d, J=8.2 Hz), 7.25-7.23 (2H, m), 7.03-7.01 (2H, m), 6.65 (1H, ddd, J=7.3, 7.3, 0.9 Hz), 6.56-6.55 (1H, m), 4.69 (2H, s), 4.03 (1H, brs), 3.45 (1H, ddd, J=11.4, 3.7, 1.8 Hz), 3.33 (1H, dd, J=11.4, 11.4 Hz), 3.20-3.12 (1H, m), 3.06-2.94 (2H, m), 1.63 (1H, brs).

MS(IER) [M+H] ⁺ : 240.

[1196]

(Reference Example 114) Synthesis of 4-(quinolin-3-yl)benzamide:

[1197]

[1198]

3-Bromoquinoline (150 mg, 0.721 mmol) and (4-carbamoylphenyl)boronic acid (178 mg, 1.08 mmol) were used in a similar manner to Reference Example 6 to give the title compound as a white solid (32.7 mg, 0.132 mol, yield: 18%).

¹ H-NMR (CDCl ₃ ) δ: 9.20 (1H, d, J=2.3 Hz), 8.37 (1H, d, J=2.3 Hz), 8.17-8.15 (1H, m), 8.00-7.98 (2H, m), 7.92 (1H, dd, J=8.2, 1.4 Hz), 7.84-7.81 (2H, m), 7.77 (1H, ddd, J=8.7, 6.9, 1.8 Hz), 7.62 (1H, ddd, J=7.8, 6.9, 0.9 Hz).

MS(IER) [M+H] ⁺ : 249.

[1199]

(Example 166) Synthesis of 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzamide (new compound):

[1200]

[1201]

4-(Quinolin-3-yl)benzamide synthesized in Reference Example 114 (32.7 mg, 0.132 mol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 166”) as a white solid (11.1 mg, 44.0 μmol, yield: 33%).

¹ H-NMR (CDCl ₃ ) δ: 7.81-7.77 (2H, m), 7.34-7.32 (2H, m), 7.04-7.02 (2H, m), 6.66 (1H, ddd, J=7.3, 7.3, 0.9 Hz), 6.56 (1H, d, J=7.8 Hz), 5.59-5.56 (2H, shm), 4.74 (1H, shs), 3.49-3.47 (1H, m), 3.36 (1H, dd, J=10.5, 11.0 Hz), 3.24-3.20 (1H, m), 3.07-2.98 (2H, m).

MS(IER) [M+H] ⁺ : 253.

[1202]

(Reference Example 115) Synthesis of 4-(quinolin-3-yl)benzenesulfonamide:

[1203]

[1204]

3-Bromoquinoline (5.00 g, 24.0 mmol) and (4-sulfamoylphenyl)boronic acid (6.76 g, 33.6 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a pale brown solid (6.10 g, 21.5 mmol, yield: 89%).

¹ H-NMR (DMSO-d ₆ ) δ: 9.29 (1H, d, J=2.3 Hz), 8.74 (1H, d, J=2.3 Hz), 8.09-8.06 (4H, m), 7.97-7.95 (2H, m), 7.80 (1H, ddd, J=8.2, 6.9, 1.4 Hz), 7.67-7.65 (1H, m).

MS(IER) [M+H] ⁺ : 285.

[1205]

(Example 167) Synthesis of 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide (new compound):

[1206]

[1207]

4-(Quinolin-3-yl)benzenesulfonamide synthesized in Reference Example 115 (500 mg, 1.75 mmol) was used in a similar manner to Example 72 to give the title compound (hereinafter referred to as “the compound of Example 167”) as a white solid (363 mg, 1.26 mmol, yield: 72%).

¹ H-NMR (CDCl ₃ ) δ: 7.89 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.2 Hz), 7.05-7.00 (2H, m), 6.68-6.66 (1H, m), 6.56 (1H, d, J=9.1 Hz), 4.75 (2H, s), 3.49 (1H, dd, J=10.7, 3.4 Hz), 3.36 (1H, dd, J=11.0, 12.8 Hz), 3.27-3.25 (1H, m), 3.03-3.01 (2H, m).

MS(IER) [M+H] ⁺ : 289.

[1208]

(Reference Example 116) Synthesis of N-(4-(quinolin-3-yl)phenyl)acetamide:

[1209]

[1210]

3-Bromoquinoline (150 mg, 0.721 mmol) and (4-acetamidophenyl)boronic acid (194 mg, 1.08 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (178 mg, 0.680 mmol, yield: 94%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.13 (1H, s), 9.25 (1H, d, J=2.3 Hz), 8.61 (1H, d, J=2.3 Hz), 8.04 (2H, d, J=9.1 Hz), 7.85 (2H, d, J=8.7 Hz), 7.76 (3H, dd, J=12.1, 4.8 Hz), 7.64 (1H, dd, J=7.8, 7.8 Hz), 2.09 (3H, s).

MS(IER) [M+H] ⁺ : 263.

[1211]

(Example 168) Synthesis of N-(4-(1,2,3,4-tetrahydroquinolin-3-yl)phenyl)acetamide (new compound):

[1212]

[1213]

N-(4-(quinolin-3-yl)phenyl)acetamide synthesized in Reference Example 116 (50.0 mg, 0.191 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 168”) as a white solid (17.5 mg, 65.7 μmol, yield: 34%).

¹ H-NMR (CDCl ₃ ) δ: 7.45 (2H, d, J=8.7 Hz), 7.20 (2H, d, J=8.2 Hz), 7.11 (1H, brs), 7.02-7.00 (2H, m), 6.65 (1H, ddd, J=7.3, 7.3, 1.4 Hz), 6.55 (1H, d, J=7.8 Hz), 3.44 (1H, ddd, J=11.0, 3.2, 1.4 Hz), 3.30 (1H, dd, J=11.0, 10.5 Hz), 3.13-3.12 (1H, m), 2.99-2.97 (2H, m), 2.18 (3H, s).

MS(IER) [M+H] ⁺ : 267.

[1214]

(Reference Example 117) Synthesis of 3-(4-(methylsulfonyl)phenyl)quinoline:

[1215]

[1216]

3-Bromoquinoline (90.8 mg, 0.437 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (131 mg, 0.655 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (124 mg, 0.437 mmol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 9.19 (1H, d, J=2.3 Hz), 8.38 (1H, d, J=2.3 Hz), 8.18 (1H, d, J=8.7 Hz), 8.11 (2H, d, J=8.7 Hz), 7.94-7.92 (3H, m), 7.80 (1H, ddd, J=8.2, 6.9, 1.4 Hz), 7.64 (1H, ddd, J=8.2, 6.9, 1.4 Hz), 3.13 (3H, s).

MS(IER) [M+H] ⁺ : 284.

[1217]

(Example 169) Synthesis of 3-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline (new compound):

[1218]

[1219]

3-(4-(Methylsulfonyl)phenyl)quinoline synthesized in Reference Example 117 (124 mg, 0.437 mmol) was used in a similar manner to Example 26 to give the title compound (hereinafter referred to as the compound of Example 169) as a white solid (94.1 mg, 0.327 mmol, yield: 75%).

¹ H-NMR (CDCl ₃ ) δ: 7.91 (2H, d, J=8.2 Hz), 7.45 (2H, d, J=8.2 Hz), 7.05-7.01 (2H, m), 6.67 (1H, ddd, J=7.3, 7.3, 0.5 Hz), 6.57 (1H, dd, J=7.8, 0.9 Hz), 4.05 (1H, brs), 3.49-3.47 (1H, m), 3.37 (1H, dd, J=10.5, 10.5 Hz), 3.28-3.25 (1H, m), 3.06 (3H, s), 3.03 (2H, d, J=7.8 Hz).

MS(IER) [M+H] ⁺ : 288.

[1220]

(Reference Example 118) Synthesis of 3-(pyridin-3-yl)quinoline:

[1221]

[1222]

3-Bromoquinoline (200 mg, 0.961 mmol) and pyridin-3-ylboronic acid (177 mg, 1.44 mmol) were used in a similar manner to Reference Example 11 to give the title compound as a white solid (196 mg, 0.949 mol, yield: 99%).

¹ H-NMR (CDCl ₃ ) δ: 9.17 (1H, d, J=2.3 Hz), 8.99 (1H, d, J=1.8 Hz), 8.70 (1H, dd, J=5.0, 1.4 Hz), 8.35 (1H, d, J=1.8 Hz), 8.17 (1H, d, J=8.2 Hz), 8.04-8.02 (1H, m), 7.92 (1H, d, J=8.2 Hz), 7.78 (1H, ddd, J=8.7, 6.9, 1.8 Hz), 7.63 (1H, ddd, J=8.2, 6.9, 0.9 Hz), 7.48-7.47 (2H, m).

MS(IER) [M+H] ⁺ : 207.

[1223]

(Example 170) Synthesis of 3-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline:

[1224]

[1225]

3-(Pyridin-3-yl)quinoline synthesized in Reference Example 118 (100 mg, 0.484 mmol) was used in a similar manner to Example 4 to give the title compound (hereinafter referred to as “the compound of Example 170”) as a pale yellow solid (52.3 mg, 0.249 mol, yield: 52%).

¹ H-NMR (CDCl ₃ ) δ: 8.54 (1H, d, J=2.3 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz), 7.55 (1H, ddd, J=7.8, 1.8, 1.8 Hz), 7.30-7.26 (1H, m), 7.04-7.02 (2H, m), 6.67 (1H, dd, J=7.3, 7.3, 0.9 Hz), 6.56 (1H, dd, J=8.2, 0.9 Hz), 3.51-3.48 (1H, m), 3.35 (1H, dd, J=11.2, 9.8 Hz), 3.24-3.17 (1H, m), 3.02-2.99 (2H, m), 2.10 (1H, s).

MS(IER) [M+H] ⁺ : 211.

[1226]

(Example 171) Synthesis of one of the optical isomers of 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide (new compound):

[1227]

[1228]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(1,2,3,4-Tetrahydroquinolin-3-yl)benzenesulfonamide synthesized in Example 167 (1.00 g, 3.47 mmol) was dissolved in propan-2-ol (1.0 L) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as the "compound of Example 171") as a white solid (394.9 mg, 1.37 mmol, yield: 39%, enantiomeric excess: 97.9%).

¹ H-NMR (CDCl ₃ ) δ: 7.89 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.2 Hz), 7.05-7.00 (2H, m), 6.68-6.66 (1H, m), 6.56 (1H, d, J=9.1 Hz), 4.75 (2H, s), 3.49 (1H, dd, J=10.7, 3.4 Hz), 3.36 (1H, dd, J=11.0, 12.8 Hz), 3.27-3.25 (1H, m), 3.03-3.01 (2H, m).

MS(IER) [M+H] ⁺ : 289.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OZ-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=90:10

Total injection volume: 975 ml (5.0 ml/injection)

Flow rate: 5 ml/min

Detection: UV (254 nm)

Rt: 23.00 to 26.00 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 0.46 mm, length: 150 mm, particle size: 3 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 18.83 min

[1229]

(Example 172) Synthesis of another optical isomer of 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide (new compound):

[1230]

[1231]

In the formula, the carbon atom marked with an asterisk (*) represents the asymmetric center.

4-(1,2,3,4-Tetrahydroquinolin-3-yl)benzenesulfonamide synthesized in Reference Example 167 (1.00 g, 3.47 mmol) was dissolved in propan-2-ol (1.0 L) and optically separated using HPLC under the following conditions to give the title compound (hereinafter referred to as the “compound of Example 172”) as a white solid (378.6 mg, 1.31 mmol, yield: 38%, enantiomeric excess: 94.0%).

¹ H-NMR (CDCl ₃ ) δ: 7.89 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.2 Hz), 7.05-7.00 (2H, m), 6.68-6.66 (1H, m), 6.56 (1H, d, J=9.1 Hz), 4.75 (2H, s), 3.49 (1H, dd, J=10.7, 3.4 Hz), 3.36 (1H, dd, J=11.0, 12.8 Hz), 3.27-3.25 (1H, m), 3.03-3.01 (2H, m).

MS(IER) [M+H] ⁺ : 289.

Conditions for optical separation using HPLC:

Column: Daicel Chiralcel OZ-H chiral column

(inner diameter: 20 mm, length: 250 mm, particle size: 5 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=90:10

Total injection volume: 975 ml (5.0 ml/injection)

Flow rate: 5 ml/min

Detection: UV (254 nm)

Rt: 26.50 to 31.50 min

HPLC analysis conditions:

Column: Daicel Chiralcel OZ-3 chiral column

(inner diameter: 0.46 mm, length: 150 mm, particle size: 3 μm)

Column temperature: 40°C

Mobile phase: propan-2-ol:hexane=50:50

Flow rate: 0.6 ml/min

Detection: UV (254 nm)

Rt: 22.46 min

[1232]

(Comparative Example 1) Preparation and synthesis of 2-phenyl-1,2,3,4-tetrahydroquinoxaline:

[1233]

[1234]

For 2-phenyl-1,2,3,4-tetrahydroquinoxaline (hereinafter referred to as the “compound of Comparative Example 1”), a commercial product from, for example, Enamine Ltd. can be used, or the compound can be synthesized according to a known method or equivalent methods.

[1235]

(Example 173) In vitro inhibitory effect on ferroptosis:

The inhibitory effect on ferroptosis of a tetrahydroquinoline (I) derivative or its pharmaceutically acceptable salt is assessed on human fibrosarcoma cells (HT-1080 cells) using the inhibitory effect on cell death caused by treatment with the ferroptosis inducer, Erastin, as an indicator.

[1236]

HT-1080 cells (ATCC) were cultured in a mixture (hereinafter referred to as the vehicle) consisting of DMEM/F12 (Thermo Fisher Scientific, Inc.), a final concentration of 10% fetal bovine serum (Thermo Fisher Scientific, Inc.), and a final concentration of 1% penicillin-streptomycin solution (Nacalai Tesque, Inc.). Cells were seeded in 96-well plates (Corning Inc.) at ^5x104 cells/well and cultured overnight.

[1237]

The test compound is dissolved in DMSO, and the resulting solution is diluted with vehicle to a final concentration of 1% DMSO before use. The day after cell seeding, the test compound, diluted in vehicle, is added to the wells to a final test concentration of 25, 30, or 50 μmol/L. Thirty minutes after adding the test compound, Erastin (Cayman Chemical Co.), diluted in vehicle to a final concentration of 3 μmol/L, is added to the wells. Wells with the added test compound and Erastin are grouped as "test compound," wells without the addition of the test compound and without Erastin are grouped as "background," and wells without the addition of the test compound but with Erastin are grouped as "control." Twenty-four hours after adding Erastin, 5 μl of the Cell Counting Kit-8 (Dojindo Laboratories) was added to each well and incubated for 4 hours. The absorbance at 450 nm was then measured for each well (N=2). The average absorbance at 450 nm was calculated from the absorbance values of the wells, and the inhibition rate of ferroptosis by the test compound (hereinafter referred to as the ferroptosis inhibition rate, %) was then calculated using Equation 1 below.

[1238]

Ferroptosis inhibition rate (%) = [1 - {(Mean absorbance value at 450 nm measured with the addition of the test compound) - (Mean absorbance value at 450 nm measured in the background)} / {(Mean absorbance value at 450 nm measured in the control) - (Mean absorbance value at 450 nm measured in the background)}] x 100

Equation 1

[1239]

Ferroptosis inhibition rates (%) for treatment with the test compounds are shown in Tables 2-1 to 2-6.

[1240]

Table 2-1 Tested connection Ferroptosis inhibition rate (%) Estimated concentration Compound from Example 1 110.5 30 μmol/L Compound from Example 2 117.4 30 μmol/L Compound from Example 3 110.2 30 μmol/L Compound from Example 4 99.10 50 μmol/L Compound from Example 5 99.69 50 μmol/L Compound from Example 6 90.22 50 μmol/L Compound from Example 7 93.95 50 μmol/L Compound from Example 8 100.6 50 μmol/L Compound from Example 9 88.84 50 μmol/L Compound from Example 10 103.9 50 μmol/L Compound from Example 11 106.0 50 μmol/L Compound from Example 12 110.9 30 μmol/L Compound from Example 13 119.6 30 μmol/L Compound from Example 14 97.39 50 μmol/L Compound from Example 15 89.22 30 μmol/L Compound from Example 16 90.31 50 μmol/L Compound from Example 17 98.12 50 μmol/L Compound from Example 18 66.52 30 μmol/L Compound from Example 19 100.5 30 μmol/L Compound from Example 20 95.88 30 μmol/L Compound from Example 21 88.33 30 μmol/L Compound from Example 22 103.2 30 μmol/L Compound from Example 23 68.45 30 μmol/L Compound from Example 24 59.67 30 μmol/L Compound from Example 25 105.3 30 μmol/L Compound from Example 26 107.7 50 μmol/L Compound from Example 27 113.1 50 μmol/L Compound from Example 28 109.4 50 μmol/L Compound from Example 29 95.38 50 μmol/L Compound from Example 30 83.09 50 μmol/L Compound from Example 31 98.99 50 μmol/L Compound from Example 32 100.5 30 μmol/L Compound from Example 33 84.88 30 μmol/L Compound from Example 34 86.96 30 μmol/L Compound from Example 35 106.5 30 μmol/L Compound from Example 36 98.76 30 μmol/L Compound from Example 37 98.69 30 μmol/L Compound from Example 38 104.0 30 μmol/L Compound from Example 39 101.5 30 μmol/L Compound from Example 40 111.1 30 μmol/L

[1241]

Table 2-2 Tested connection Ferroptosis inhibition rate (%) Estimated concentration Compound from Example 41 102.2 30 μmol/L Compound from Example 42 98.89 30 μmol/L Compound from Example 43 107.1 30 μmol/L Compound from Example 44 114.3 50 μmol/L Compound from Example 45 109.1 30 μmol/L Compound from Example 46 109.0 30 μmol/L Compound from Example 47 85.21 30 μmol/L Compound from Example 48 81.80 30 μmol/L Compound from Example 49 99.20 30 μmol/L Compound from Example 50 103.2 30 μmol/L Compound from Example 51 84.55 50 μmol/L Compound from Example 52 74.96 50 μmol/L Compound from Example 53 111.3 50 μmol/L Compound from Example 54 109.9 30 μmol/L Compound from Example 55 93.72 30 μmol/L Compound from Example 56 100.1 50 μmol/L Compound from Example 57 89.18 30 μmol/L Compound from Example 58 91.37 30 μmol/L Compound from Example 59 76.73 30 μmol/L Compound from Example 60 98.74 30 μmol/L Compound from Example 61 103.9 30 μmol/L Compound from Example 62 103.2 30 μmol/L Compound from Example 63 68.73 50 μmol/L Compound from Example 64 82.89 25 μmol/L Compound from Example 65 89.25 30 μmol/L Compound from Example 66 101.5 30 μmol/L Compound from Example 67 102.4 30 μmol/L Compound from Example 68 101.9 30 μmol/L Compound from Example 69 106.4 30 μmol/L Compound from Example 70 97.10 30 μmol/L Compound from Example 71 108.9 30 μmol/L Compound from Example 72 110.6 30 μmol/L Compound from Example 73 88.18 50 μmol/L Compound from Example 74 85.08 30 μmol/L Compound from Example 75 110.6 30 μmol/L Compound from Example 76 85.43 50 μmol/L Compound from Example 77 101.6 30 μmol/L Compound from Example 78 88.56 25 μmol/L Compound from Example 79 104.4 30 μmol/L Compound from Example 80 103.9 30 μmol/L

[1242]

Table 2-3 Tested connection Ferroptosis inhibition rate (%) Estimated concentration Compound from Example 81 103.9 50 μmol/L Compound from Example 82 112.6 30 μmol/L Compound from Example 83 103.8 50 μmol/L Compound from Example 84 107.1 50 μmol/L Compound from Example 85 94.94 50 μmol/L Compound from Example 86 98.80 50 μmol/L Compound from Example 87 95.20 50 μmol/L

[1243]

Table 2-4 Tested connection Ferroptosis inhibition rate (%) Estimated concentration Compound from Example 88 97.70 30 μmol/L Compound from Example 89 99.12 30 μmol/L Compound from Example 90 102.4 30 μmol/L Compound from Example 91 105.2 30 μmol/L Compound from Example 92 66.40 30 μmol/L Compound from Example 93 89.78 30 μmol/L Compound from Example 94 93.68 30 μmol/L Compound from Example 95 68.84 30 μmol/L Compound from Example 96 98.01 30 μmol/L Compound from Example 97 83.94 30 μmol/L Compound from Example 98 98.95 30 μmol/L Compound from Example 99 98.85 30 μmol/L Compound from Example 100 103.5 30 μmol/L Compound from Example 101 109.6 30 μmol/L Compound from Example 102 77.96 30 μmol/L Compound from Example 103 76.76 30 μmol/L Compound from Example 104 64.65 30 μmol/L Compound from Example 105 99.03 30 μmol/L Compound from Example 106 111.7 30 μmol/L Compound from Example 107 100.8 30 μmol/L Compound from Example 108 83.78 10 μmol/L Compound from Example 109 83.63 10 μmol/L Compound from Example 110 103.0 10 μmol/L Compound from Example 111 98.91 10 μmol/L Compound from Example 112 105.5 30 μmol/L Compound from Example 113 97.54 30 μmol/L Compound from Example 114 87.04 30 μmol/L Compound from Example 115 105.8 30 μmol/L Compound from Example 116 80.69 10 μmol/L Compound from Example 117 76.27 10 μmol/L Compound from Example 118 95.28 30 μmol/L Compound from Example 119 89.67 10 μmol/L Compound from Example 120 87.34 10 μmol/L

[1244]

Table 2-5 Tested connection Ferroptosis inhibition rate (%) Estimated concentration Compound from Example 121 92.10 10 μmol/L Compound from Example 122 97.59 10 μmol/L Compound from Example 123 113.4 30 μmol/L Compound from Example 124 106.3 30 μmol/L Compound from Example 125 102.6 30 μmol/L Compound from Example 126 97.29 30 μmol/L Compound from Example 127 87.93 30 μmol/L Compound from Example 128 91.83 30 μmol/L Compound from Example 129 88.31 30 μmol/L Compound from Example 130 104.2 30 μmol/L Compound from Example 131 102.5 30 μmol/L Compound from Example 132 105.6 30 μmol/L Compound from Example 133 98.54 30 μmol/L Compound from Example 134 77.77 30 μmol/L Compound from Example 135 62.32 30 μmol/L Compound from Example 136 75.50 30 μmol/L Compound from Example 137 93.06 30 μmol/L Compound from Example 138 65.15 30 μmol/L Compound from Example 139 60.63 30 μmol/L Compound from Example 140 72.81 30 μmol/L Compound from Example 141 59.10 30 μmol/L Compound from Example 142 64.86 30 μmol/L Compound from Example 143 93.97 30 μmol/L Compound from Example 144 96.14 30 μmol/L Compound from Example 145 102.0 30 μmol/L Compound from Example 146 112.8 30 μmol/L Compound from Example 147 93.00 30 μmol/L Compound from Example 148 86.55 30 μmol/L Compound from Example 149 99.36 30 μmol/L Compound from Example 150 106.9 30 μmol/L Compound from Example 151 108.2 30 μmol/L Compound from Example 152 108.1 30 μmol/L Compound from Example 153 110.1 30 μmol/L Compound from Example 154 114.6 30 μmol/L Compound from Example 155 106.1 30 μmol/L Compound from Example 156 57.76 30 μmol/L Compound from Example 157 69.89 30 μmol/L Compound from Example 158 55.98 30 μmol/L Compound from Example 159 76.27 30 μmol/L Compound from Example 160 99.11 10 μmol/L

[1245]

Table 2-6 Tested connection Ferroptosis inhibition rate (%) Estimated concentration Compound from Example 161 94.01 10 μmol/L Compound from Example 162 108.4 50 μmol/L Compound from Example 163 89.32 30 μmol/L Compound from Example 164 72.33 30 μmol/L Compound from Example 165 96.77 30 μmol/L Compound from Example 166 96.52 30 μmol/L Compound from Example 167 76.82 30 μmol/L Compound from Example 168 86.46 30 μmol/L Compound from Example 169 85.58 30 μmol/L Compound from Example 170 93.41 30 μmol/L Compound from Example 171 90.71 30 μmol/L Compound from Example 172 92.87 30 μmol/L

[1246]

These results indicate that the tetrahydroquinoline (I) derivatives of the present invention or pharmaceutically acceptable salts thereof have an inhibitory effect against ferroptosis.

[1247]

(Example 174) In vitro free radical scavenging activity:

The free radical scavenging activity was assessed using the DPPH method on the compound of Comparative Example 1, which is a tetrahydroquinoxaline derivative, and on tetrahydroquinoline derivatives (I) or their pharmaceutically acceptable salts. The DPPH method was conducted using an antioxidant capacity measurement kit (Dojindo Laboratories).

[1248]

The test compound is dissolved in DMSO, and the resulting solution is then mixed with the assay buffer and DPPH solution provided in the kit to a total volume of 200 μL to obtain a final concentration of 10% DMSO, and the reaction is allowed to proceed. Wells to which 100 μmol/L ferrostatin-1, a radical scavenger, is added are grouped as "control", and wells to which the test compound is not added are grouped as "background". The test compound is serially diluted 3-fold, starting with a maximum concentration of 100 μmol/L, the diluted test compound (1.2, 3.7, 11.1, 33.3, or 100 μmol/L) is added, and the reaction is allowed to proceed at room temperature. Thirty minutes after the reaction, the absorbance is measured at 517 nm, and the mean absorbance value is calculated (N = 2). The free radical scavenging activity of the test compound (hereinafter referred to as the free radical scavenging rate, %) is calculated based on the following equation 2. The EC ₅₀ value of the test compound is calculated from the free radical scavenging rate.

[1249]

Free radical scavenging rate (%) = [1 - {(Mean absorbance at 517 nm measured with test compound added) - (Mean absorbance at 517 nm measured in background)} / {(Mean absorbance at 517 nm measured in control) - (Mean absorbance at 517 nm measured in background)}] x 100

Equation 2

[1250]

The free radical scavenging activity (%) for the tested compounds is shown in Tables 3-1 and 3-2. The designation "no free radical scavenging activity (ND)" is given for compounds with an EC ₅₀ >100 μmol/L.

[1251]

Table 3-1 Tested connection Free radical scavenging activity, EC ₅₀ (μmol/L) Compound from Comparative Example 1 8.54 Compound from Example 1 N.D. Compound from Example 2 N.D. Compound from Example 3 N.D. Compound from Example 16 N.D. Compound from Example 21 N.D. Compound from Example 26 N.D. Compound from Example 29 N.D. Compound from Example 31 N.D. Compound from Example 32 N.D. Compound from Example 33 N.D. Compound from Example 34 N.D. Compound from Example 35 N.D. Compound from Example 36 N.D. Compound from Example 37 N.D. Compound from Example 38 N.D. Compound from Example 58 N.D. Compound from Example 60 N.D. Compound from Example 61 N.D. Compound from Example 62 N.D. Compound from Example 66 N.D. Compound from Example 67 N.D. Compound from Example 68 N.D. Compound from Example 69 N.D. Compound from Example 81 N.D. Compound from Example 82 N.D. Compound from Example 83 N.D. Compound from Example 85 N.D. Compound from Example 99 N.D. Compound from Example 105 N.D. Compound from Example 106 N.D. Compound from Example 107 N.D. Compound from Example 108 N.D. Compound from Example 109 N.D. Compound from Example 112 N.D. Compound from Example 115 N.D.

[1252]

Table 3-2 Tested connection Free radical scavenging activity, EC ₅₀ (μmol/L) Compound from Example 116 N.D. Compound from Example 117 N.D. Compound from Example 118 N.D. Compound from Example 119 N.D. Compound from Example 120 N.D. Compound from Example 121 N.D. Compound from Example 122 N.D. Compound from Example 131 N.D. Compound from Example 132 N.D. Compound from Example 134 N.D. Compound from Example 135 N.D. Compound from Example 136 N.D. Compound from Example 137 N.D. Compound from Example 138 N.D. Compound from Example 143 N.D. Compound from Example 144 N.D. Compound from Example 145 N.D. Compound from Example 146 N.D. Compound from Example 147 N.D. Compound from Example 148 N.D. Compound from Example 149 N.D. Compound from Example 150 N.D. Compound from Example 151 N.D. Compound from Example 152 N.D. Compound from Example 155 N.D. Compound from Example 157 N.D. Compound from Example 158 N.D. Compound from Example 160 N.D. Compound from Example 161 N.D.

[1253]

These results demonstrate that the compound of Comparative Example 1, a tetrahydroquinoxaline derivative, exhibits free radical scavenging activity. In contrast, the tetrahydroquinoline derivatives (I) of the present invention or their pharmaceutically acceptable salts do not exhibit free radical scavenging activity.

[1254]

(Example 175) Evaluation of the activity of 1 in a mouse model of experimental autoimmune encephalomyelitis induced by MOG:

The effect of the compound of Example 1 on increasing the neurological score was evaluated in a mouse model of experimental autoimmune encephalomyelitis induced by MOG. The model of experimental autoimmune encephalomyelitis induced by MOG was prepared according to the method of Jianfeng et al. (The Journal of Immunology, 2009, vol. 182, pp. 4036-4045) with partial modification.

[1255]

A PBS solution containing the synthetic partial MOG peptide (MOG35-55; CSBio) at a concentration of 4 mg/mL was mixed with an equal volume of Freund's complete adjuvant, and a total of 0.1 mL (0.05 mL per flank) of the resulting MOG35-55 dosing solution was inoculated intradermally into the bilateral flanks of C57BL/6J mice (male, 10 weeks old, Charles River Laboratories Japan, Inc.). On the day of inoculation of the MOG35-55 dosing solution and on the second day after inoculation, the mice were additionally injected intraperitoneally with 200 μL of pertussis toxin (Sigma Co. LLC) prepared at a concentration of 1 μg/mL.

[1256]

The test compound is administered orally at a dose of 30 mg/kg twice daily for 15 days, beginning on day 55 after inoculation with the MOG35-55 dosing solution. The test compound is suspended in a 0.5% methylcellulose solution (hereinafter referred to as the vehicle), and the resulting suspension is used. The group of mice administered with the compound of Example 1 is referred to as the compound dosing group from Example 1. Additionally, the group of mice administered with the vehicle is referred to as the vehicle dosing group. The vehicle is administered to the vehicle dosing group in the same volume, amount, and route of administration as the test compound dosing group.

[1257]

The neurological score determination (0: normal, 1: tail relaxation or hind limb weakness, 2: tail relaxation and hind limb weakness, 3: partial hind limb paralysis, 4: complete hind limb paralysis, 5: moribund) was started 15 days after the inoculation of MOG35-55 dosing solution to evaluate the paralytic symptoms in mice. The score determination was carried out according to the method of Jianfeng et al. (The Journal of Immunology, 2009, vol. 182, p. 4036-4045) with partial modification.

[1258]

FIG. 1 shows the neurological score determined the day after the last administration of the test compound. The vertical axis represents the neurological score (mean ± standard error, n=7). On the horizontal axis, "Vehicle" represents the vehicle dosing group, and "Example 1 Compound" represents the Example 1 compound dosing group.

[1259]

Administration of the MOG35-55 dosing solution increased the mean neurological score to 2.43 in the vehicle dosing group. In contrast, the neurological score in the Example 1 dosing group was 1.29, indicating a decrease in the neurological score compared to the neurological score in the vehicle dosing group. The rate of neurological score decline was 46.9%.

[1260]

This result indicates that the compound of Example 1 has an ameliorating effect on the neurological symptoms of multiple sclerosis.

[1261]

(Example 176) Evaluation of the activity of 2 in a mouse model of experimental autoimmune encephalomyelitis induced by MOG:

The compound of Example 11, the compound of Example 32, and the compound of Example 36 were used as test compounds to evaluate the effect of the test compounds on increasing the neurological score in a mouse model of MOG-induced experimental autoimmune encephalomyelitis. The test was conducted in the same manner as in Example 175, except that the day of starting administration of the test compound, the evaluation method, and the time of determining the neurological score were changed compared with those in Example 175. Each test compound was administered orally at a dose of 30 mg/kg twice a day for 15 days, starting from the 50th day after inoculation of the MOG35-55 dosing solution. In addition, the score was determined by the following criteria: 0, normal; 0.5, partially drooping tail; 1, complete drooping tail or weakness of the hind limbs; 2, complete drooping tail and weakness of the hind limbs; 3, partial paralysis of the hind limbs; 4, complete paralysis of the hind limbs; 5, complete paralysis of the front and hind limbs.

[1262]

FIG. 2 shows the neurological score determined the day after the last administration of the test compound. The vertical axis represents the neurological score (mean ± standard error, n=7 or 8). On the horizontal axis, "Vehicle" represents the vehicle dosing group, "Compound of Example 11" represents the dosing group of the compound of Example 11, "Compound of Example 32" represents the dosing group of the compound of Example 32, and "Compound of Example 36" represents the dosing group of the compound of Example 36.

[1263]

Administration of the MOG35-55 dosing solution increased the mean neurological score to 1.93 in the vehicle-treated group. In contrast, the neurological score was reduced in the group receiving the compound of Example 11, in the group receiving the compound of Example 32, and in the group receiving the compound of Example 36. The rate of reduction in neurological score under the influence of the test compounds was 54.4% for the compound of Example 11, 55.4% for the compound of Example 32, and 45.1% for the compound of Example 36.

[1264]

This result shows that the compound of Example 11, the compound of Example 32 and the compound of Example 36 have an ameliorating effect on the neurological symptoms of multiple sclerosis.

[1265]

(Example 177) Evaluation of the activity of 3 in a mouse model of experimental autoimmune encephalomyelitis induced by MOG:

The compound from Example 144, the compound from Example 171, and the compound from Example 172 are used as test compounds to evaluate the effect of the test compounds on increasing the neurological score in a mouse model of experimental autoimmune encephalomyelitis induced by MOG. The study is conducted in the same manner as in Example 176, except for the day of the start of test compound administration, the administered dose of the test compound, and the number of days of test compound administration. Each test compound is administered orally at a dose of 10 mg/kg twice daily for 10 days, beginning on day 53 after inoculation with the MOG35-55 dosing solution. The group of mice administered with the compound of Example 144 is called the dosing group of the compound of Example 144, and the group of mice administered with the compound of Example 171 is called the dosing group of the compound of Example 171, and the group of mice administered with the compound of Example 172 is called the dosing group of the compound of Example 172. In addition, the group of mice administered with the vehicle is called the vehicle dosing group.

FIG. 3 shows the neurological score determined the day after the last administration of the test compound. The vertical axis represents the neurological score (mean ± standard error, n=8). On the horizontal axis, "Vehicle" represents the vehicle dosing group, "Compound of Example 144" represents the dosing group of the compound of Example 144, "Compound of Example 171" represents the dosing group of the compound of Example 171, and "Compound of Example 172" represents the dosing group of the compound of Example 172.

Administration of the MOG35-55 dosing solution increased the mean neurological score to 2.25 in the vehicle dosing group. In contrast, the neurological score was reduced in the dosing group of the compound of Example 144, in the dosing group of the compound of Example 171, and in the dosing group of the compound of Example 172. The rate of reduction in neurological score under the influence of the test compounds was 25.0% for the compound of Example 144, 47.2% for the compound of Example 171, and 27.8% for the compound of Example 172.

This result showed that the compound of Example 144, the compound of Example 171 and the compound of Example 172 have an ameliorating effect on the neurological symptoms of multiple sclerosis.

[1266]

(Example 178) Evaluation of the activity of 4 in a mouse model of experimental autoimmune encephalomyelitis induced by MOG:

The compound from Example 38 and the compound from Example 119 are used as test compounds to evaluate the effect of the test compounds on increasing neurological scores in a mouse model of experimental autoimmune encephalomyelitis induced by MOG. The study is conducted in the same manner as in Example 176, except for the day of initiation of test compound administration, the dose of test compound administered, and the number of days of test compound administration.

Each test compound was administered orally at a dose of 10 mg/kg twice daily for 16 days, starting from day 52 after inoculation with the MOG35-55 dosing solution. The group of mice administered with the compound of Example 38 was referred to as the dosing group for the compound of Example 38, and the group of mice administered with the compound of Example 119 was referred to as the dosing group for the compound of Example 119. In addition, the group of mice administered with the vehicle was referred to as the vehicle dosing group.

FIG. 4 shows the neurological score determined the day after the last administration of the test compound. The vertical axis represents the neurological score (mean ± standard error, n=8). On the horizontal axis, "Vehicle" represents the vehicle dosing group, "Compound of Example 38" represents the dosing group of the compound of Example 38, and "Compound of Example 119" represents the dosing group of the compound of Example 119.

Administration of the MOG35-55 dosing solution increased the mean neurological score to 2.25 in the vehicle-treated group. In contrast, the neurological score was reduced in the compound-treated group of Example 38 and in the compound-treated group of Example 119. The rate of neurological score reduction by the test compounds was 27.8% for the compound of Example 38 and 33.3% for the compound of Example 119.

This result indicates that the compound of Example 38 and the compound of Example 119 have an ameliorating effect on the neurological symptoms of multiple sclerosis.

[1267]

(Example 179) Evaluation of the activity of 5 in a mouse model of experimental autoimmune encephalomyelitis induced by MOG:

The compound from Example 33 is used as a test compound to evaluate the effect of the test compound on increasing neurological scores in a mouse model of experimental autoimmune encephalomyelitis induced by MOG. The study is conducted in the same manner as in Example 176, except for the day of initiation of test compound administration, the dose of test compound administered, and the number of days of test compound administration.

The test compound is administered orally at a dose of 10 mg/kg twice daily for 15 days, starting on day 52 after inoculation with the MOG35-55 dosing solution. The group of mice administered with the compound from Example 33 is referred to as the dosing group for the compound from Example 33. In addition, the group of mice administered with the vehicle is referred to as the vehicle dosing group.

FIG. 5 shows the neurological score determined the day after the last administration of the test compound. The vertical axis represents the neurological score (mean ± standard error, n=8). On the horizontal axis, "Vehicle" represents the vehicle dosing group, and "Compound from Example 33" represents the compound from Example 33 dosing group.

Administration of the MOG35-55 dosing solution increased the mean neurological score to 2.13 in the vehicle dosing group. In contrast, the neurological score was reduced in the dosing group receiving the compound from Example 33. The rate of neurological score reduction for the compound from Example 33 was 38.2%.

This result indicates that the compound of Example 33 has an ameliorating effect on the neurological symptoms of multiple sclerosis.

[1268]

(Example 180) Evaluation of the activity of 6 in a mouse model of experimental autoimmune encephalomyelitis induced by MOG:

The compound from Example 108 and the compound from Example 117 are used as test compounds to evaluate the effect of the test compounds on increasing neurological scores in a mouse model of experimental autoimmune encephalomyelitis induced by MOG. The study is conducted in the same manner as in Example 176, except for the day of initiation of test compound administration, the dose of test compound administered, and the number of days for test compound administration.

Each test compound was administered orally at a dose of 10 mg/kg twice a day for 12 days, starting from day 52 after inoculation with the MOG35-55 dosing solution. The group of mice administered with the compound of Example 108 was referred to as the dosing group for the compound of Example 108, and the group of mice administered with the compound of Example 117 was referred to as the dosing group for the compound of Example 117. In addition, the group of mice administered with the vehicle was referred to as the vehicle dosing group.

FIG. 6 shows the neurological score determined the day after the last administration of the test compound. The vertical axis represents the neurological score (mean ± standard error, n=8). On the horizontal axis, "Vehicle" represents the vehicle dosing group, "Compound of Example 108" represents the dosing group of the compound of Example 108, and "Compound of Example 117" represents the dosing group of the compound of Example 117.

Administration of the MOG35-55 dosing solution increased the mean neurological score to 2.13 in the vehicle dosing group. In contrast, the neurological score was reduced in the dosing group of the compound from Example 108 and in the dosing group of the compound from Example 117. The rate of reduction in neurological score under the influence of the test compounds was 29.4% for the compound from Example 108 and 32.4% for the compound from Example 117.

This result indicates that the compound of Example 108 and the compound of Example 117 have an ameliorating effect on the neurological symptoms of multiple sclerosis.

[1269]

Based on the above results, it was shown that the tetrahydroquinoline (I) derivatives of the present invention or their pharmaceutically acceptable salts have an inhibitory effect on ferroptosis and have a therapeutic or prophylactic effect on diseases, disorders or syndromes associated with the inhibition of ferroptosis.

INDUSTRIAL APPLICABILITY

[1270]

The tetrahydroquinoline (I) derivatives of the present invention or their pharmaceutically acceptable salts have an inhibitory effect on ferroptosis and can therefore be used as therapeutic or prophylactic agents for diseases, disorders or syndromes associated with inhibition of ferroptosis, such as multiple sclerosis.

Claims (316)

1. A tetrahydroquinoline derivative represented by the general formula (I) below or a pharmaceutically acceptable salt thereof, , where R ^ly represents hydrogen; for a combination of R ² , R ⁴ and R ⁵ , all of R ² , R ⁴ and R ⁵ are hydrogen; in another case, one of R ² and R ⁴ is fluorine, chlorine or methyl and both the other and R ⁵ are hydrogen; R ^v is hydrogen; R ^w is hydrogen; in cases where R ^1x is phenyl, R ³ is trifluoromethyl, hydroxymethyl, 2-hydroxypropan-2-yl, isopropyl, 3-hydroxyoxetan-3-yl, trifluoromethoxy, -NR ⁹ R ¹⁰ , morpholinomethyl or -CH ₂ CONR ¹³ R ¹⁴ ; or in cases where R ^1x is phenyl (the hydrogen atom at the para- or meta-position of the phenyl group is substituted by aminocarbonyl, aminosulfonyl, methylsulfonylamino, aminosulfonylamino or methylsulfonyl; in another case, the hydrogen atom at the meta-position of the phenyl group is substituted by a cyano group; in another case, the hydrogen atom at the para-position of the phenyl group is substituted by a trifluoromethoxy group), 2-oxoindolin-5-yl or 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl, R ³ represents hydrogen, fluorine, chlorine or methyl; R ⁹ is hydrogen; R ¹⁰ is hydrogen, -COR ¹⁵ or methylsulfonyl; or R ⁹ and R ¹⁰ together represent -(CH ₂ ) ₅ -; R ¹³ represents hydrogen or methyl; R ¹⁴ is hydrogen, methyl, tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, oxetan-3-yl, cyclopropylmethyl or oxetan-3-ylmethyl; or R ¹³ and R ¹⁴ together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ optionally form a pyrrolidine ring, a piperazine ring, a morpholine ring, a piperazin-2-one ring, an azetidine ring, a 3,3-difluoroazetidine ring, a 3,3-dimethylazetidine ring, 3-hydroxyazetidine or 3-methoxyazetidine; R ¹⁵ is methyl, tert-butyl, neopentyl, tert-butoxy or - NHR ¹⁶ ; and R ¹⁶ is hydrogen or tert-butyl. 2. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol, tert-butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate, 2-phenyl-1,2,3,4-tetrahydroquinolin-6-amine, 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline, 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile, 6-isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline, 4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)propan-2-ol, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)oxetan-3-ol, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, 2-phenyl-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide, 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide, 1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, 1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one, and their pharmaceutically acceptable salts. 3. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of: tert-butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide, 1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, and their pharmaceutically acceptable salts. 4. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^1y is hydrogen; for a combination of R ² , R ⁴ and R ⁵ , all of R ² , R ⁴ and R ⁵ are hydrogen; in another case, one of R ² and R ⁴ is fluorine, chlorine or methyl and both the other and R ⁵ are hydrogen; R ^v is hydrogen; R ^w is hydrogen; in cases where R ^lx is phenyl, R ³ is trifluoromethoxy, hydroxymethyl, or -CH ₂ CONR ¹³ R ¹⁴ ; or in cases where R ^lx is phenyl (the hydrogen atom in the para-position of the phenyl group is substituted by trifluoromethoxy, aminocarbonyl, aminosulfonyl, methylsulfonylamino or methylsulfonyl group), R ³ represents hydrogen, fluorine, chlorine or methyl; R ¹³ represents hydrogen or methyl; R ¹⁴ is tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl or oxetan-3-yl; or R ¹³ and R ¹⁴ together with the nitrogen atom that is bonded to R ¹³ and R ¹⁴ optionally 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. 5. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 4, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 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-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3,3-difluoroazetidin-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 and 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(piperazin-1-yl)ethan-1-one, and their pharmaceutically acceptable salts. 6. The use of a tetrahydroquinoline derivative represented by the general formula (I) below or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a medicament for the treatment of a disease, disorder or syndrome associated with inhibition of ferroptosis, [where R ^ly represents hydrogen; for a combination of R ² , R ⁴ and R ⁵ , all of R ² , R ⁴ and R ⁵ are hydrogen, otherwise one of R ² and R ⁴ is fluorine, chlorine or methyl and both the other and R ⁵ are hydrogen; R ^v is hydrogen; and R ^w is hydrogen; in the case where R ^lx is phenyl, R ³ is hydrogen, fluoro, chlorine, trifluoromethyl, hydroxymethyl, 2-hydroxypropan-2-yl, isopropyl, 3-hydroxyoxetan-3-yl, hydroxy, trifluoromethoxy, -NR ⁹ R ¹⁰ , morpholinomethyl or -CH ₂ CONR ¹³ R ¹⁴ ; in the case where R ^1x is phenyl (the hydrogen atom at the para- or meta-position of the phenyl group is substituted by a fluorine atom, trifluoromethyl, methoxy, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylamino, aminosulfonylamino or methylsulfonyl group), 3-furyl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 1H-pyrazol-3-yl, thiazol-4-yl, isothiazol-4-yl, oxazol-5-yl, isoxazol-4-yl, 2-oxoindolin-5-yl or 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl, R ³ represents hydrogen, fluorine, chlorine or methyl; R ⁹ is hydrogen; R ¹⁰ is hydrogen, -COR ¹⁵ or methylsulfonyl; or R ⁹ and R ¹⁰ together represent -(CH ₂ ) ₅ -; R ¹³ represents hydrogen or methyl; R ¹⁴ is hydrogen, methyl, tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, oxetan-3-yl, cyclopropylmethyl or oxetan-3-ylmethyl; or R ¹³ and R ¹⁴ together with the nitrogen atom which is bonded to R ¹³ and R ¹⁴ optionally form a pyrrolidine ring, a piperazine ring, a morpholine 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 ¹⁵ is methyl, tert-butyl, neopentyl, tert-butoxy or -NHR ¹⁶ ; and R ¹⁶ represents hydrogen or tert-butyl, provided that 2-phenyl-1,2,3,4-tetrahydroquinoline is excluded]. 7. The use according to claim 6, wherein the tetrahydroquinoline derivative or its pharmaceutically acceptable salt is selected from the group consisting of: (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol, tert-butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate, 2-phenyl-1,2,3,4-tetrahydroquinolin-6-amine, 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline, 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline, 6,7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile, 6-isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline, 2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, 4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)propan-2-ol, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)oxetan-3-ol, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, 2-phenyl-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide, 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide, 1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, 1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2' (1'H)-one, and their pharmaceutically acceptable salts. 8. The use according to claim 6 or 7, wherein the tetrahydroquinoline derivative or its pharmaceutically acceptable salt is selected from the group consisting of: tert-butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide and 1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea. 9. Application according to paragraph 6, where R ^ly represents hydrogen; for a combination of R ² , R ⁴ and R ⁵ , all of R ² , R ⁴ and R ⁵ are hydrogen; in another case, one of R ² and R ⁴ is fluorine, chlorine or methyl and both the other and R ⁵ are hydrogen; R ^v is hydrogen; R ^w is hydrogen; in the case where R ^lx is phenyl, R ³ is -CH ₂ CONR ¹³ R ¹⁴ ; when R ^lx is phenyl (the hydrogen atom at the para-position of the phenyl group is substituted by fluorine, trifluoromethyl, trifluoromethoxy, cyano, aminocarbonyl, acetamide, aminosulfonyl, methylsulfonylamino or methylsulfonyl group), R ³ is hydrogen, fluorine, chlorine or methyl; R ¹³ is hydrogen or methyl; and R ¹⁴ is tert-butyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl or oxetan-3-yl; or R ¹³ and R ¹⁴ together with the nitrogen atom that links R ¹³ and R ¹⁴ optionally 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. 10. The use according to claim 6 or 9, wherein the tetrahydroquinoline derivative or its pharmaceutically acceptable salt is selected from the group consisting of: 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-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3,3-difluoroazetidin-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 their pharmaceutically acceptable salts. 11. The use according to any one of claims 6 to 10, wherein the disease, disorder or syndrome is multiple sclerosis. 12. A tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof, wherein the tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 2-(benzo[d][1,3]dioxol-5-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline, 2-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, 2-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline, 2-(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)propan-2-ol, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 2-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one, 1'-methyl-1,2,3,3',4,4'-hexahydro-[2,6'-biquinolin]-2'(1'H)-one, 5-(1,2,3,4-tetrahydroquinolin-2-yl)isoindolin-1-one, 2-(4-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, N,N-diethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, N-ethyl-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, piperidin-1-yl(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone, morpholino(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone, (4-methylpiperazin-1-yl)(4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanone, N-methyl-3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile, 3-(1,2,3,4-tetrahydroquinolin-2-yl)benzamide, (2-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol, (3-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol, (4-(1,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanol, (2-phenyl-1,2,3,4-tetrahydroquinolin-5-yl)methanol, (2-phenyl-1,2,3,4-tetrahydroquinolin-7-yl)methanol, 6-isopropyl-2-phenyl-1,2,3,4-tetrahydroquinoline, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)propan-2-ol, (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanol, 4-((2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)morpholine, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-(tert-butyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) acetamide, 1-(3-hydroxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, tert-butyl (2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate, 2-phenyl-1,2,3,4-tetrahydroquinolin-6-amine, 5-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, 3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)oxetan-3-ol, 2-phenyl-6-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)pivalamide, N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide, 1-(tert-butyl)-3-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, 1-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)urea, 3,3-dimethyl-N-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)butanamide, 8-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline, 8-fluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, 2-phenyl-6-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoline, 2-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline, 6.7-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, 6.8-difluoro-2-phenyl-1,2,3,4-tetrahydroquinoline, 4-(6-(3-(tert-butyl)ureido)-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, methyl (2R*,4R*)-2-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylate, ((2R*,4R*)-2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl)methanol, (2-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)methanol, methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxylate, 5-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)indolin-2-one, 6-chloro-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, 6-methyl-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, 6-fluoro-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 6-methyl-1,2,3,3',4,4'-hexahydro-[2,6'-biquinolin]-2'(1'H)-one, 2-(furan-3-yl)-6-methyl-1,2,3,4-tetrahydroquinoline, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)thiazole, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)isoxazole, 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-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(5-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 2-fluoro-4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, N-(4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)sulfamoylamine, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-chloro-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-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-methyl-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 5-(1,2,3,4-tetrahydroquinolin-2-yl)isoindolin-1-one, 4-(6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(6-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 6-fluoro-1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one, 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, N-(4-(l,2,3,4-tetrahydroquinolin-2-yl)phenyl)methanesulfonamide, 4-(5-fluoro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 4-(5-chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzamide, 7-fluoro-1,2,3,3',4,4'-hexahydro-[2,6'-biquinoline]-2'(1'H)-one, 7-fluoro-2-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, 2-fluoro-4-(1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile, 4-(6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)benzenesulfonamide, 1-morpholino-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, 1-(3,3-dimethylazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, 1-(3-methoxyazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, N-(oxetan-3-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3,3-difluoroazetidin-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-(cyclopropylmethyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, N-(oxetan-3-ylmethyl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) cetamide, N-cyclobutyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(pyrrolidin-1-yl)ethan-1-one, 4-(2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetyl)piperazin-2-one, 2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(piperazin-1-yl)ethan-1-one, N-methyl-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide, 1-(3,3-difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, 1-(3,3-difluoroazetidin-1-yl)-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-one, (4-(1,2,3,4-tetrahydroquinolin-3-yl)phenyl)methanol, 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzamide, 4-(1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide, N-(4-(l,2,3,4-tetrahydroquinolin-3-yl)phenyl)acetamide and 3-(4-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline, and their pharmaceutically acceptable salts. 13. The use of a tetrahydroquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 12 as an active ingredient for the manufacture of a medicinal product for the treatment of diseases, disorders or syndromes associated with ferroptosis.