Cyclic organic compound as prophylactic and / or therapeutic agent for diseases associated with immune function abnormalities

Abstract

To provide a cyclic organic compound and the like that are useful as prophylactic and / or therapeutic agents for diseases associated with immune function abnormalities.SOLUTION: According to one embodiment of the present invention, there is provided a compound represented by formula (I), or a salt thereof. (In the formula, the symbols have the meanings as defined in the specification).SELECTED DRAWING: None

Description

[Technical field]

[0001] In one embodiment, the present invention provides a cyclic organic compound that is useful as an agent for preventing and / or treating diseases accompanied by abnormalities in immune function, and is useful, for example, in the field of medicine. [Background technology]

[0002] One in two people in Japan suffers from some kind of immune dysfunction disorder, such as allergies, but no effective cure has been developed. In recent years, highly effective drugs, such as biological agents, have been developed for intractable allergic diseases, but these drugs are very expensive and can only be administered by injection, placing a heavy burden on the medical economy and on patients. Therefore, there is a need for the development of an orally administrable anti-allergy drug. In the immune response of the living body, cytokines produced by various immunocompetent cells control the direction of the immune response. Helper T cells play a central role in controlling this immune response, and are classified into subsets such as Th1, Th2, and Th17 depending on the type of cytokines they produce. Among them, Th2 type cells mainly produce interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13), etc., and are known to be involved in humoral immunity such as defense against parasite infection and antibody production from B cells. On the other hand, excessive activation of Th2 cells induces the onset of allergic diseases. Among the cytokines produced by Th2 cells, inhibition of the production of IL-5 has traditionally been attracting attention as a drug discovery target for anti-allergic drugs, and for example, Patent Documents 1 and 2 describe compounds that inhibit the production of IL-5. However, anti-allergy drugs that are fully satisfactory in terms of efficacy and safety have not yet been provided. Furthermore, the creation of a new type of anti-allergy drug that has actions other than the IL-5 production inhibitory action and exerts an anti-allergy action through a comprehensive action has been awaited. In particular, Th2 cells express IL-33 receptors on the cell surface, and in the presence of IL-33, they are activated in an allergen (antigen)-independent manner, producing cytokines such as IL-5 and IL-13, which causes chronic allergies, so the creation of a low molecular weight compound that inhibits the action of IL-33 has been anticipated. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2002-249473 A [Patent Document 2] JP 2004-018465 A Summary of the Invention [Problem to be solved by the invention]

[0004] In order to solve the above problems, the present invention aims to provide a cyclic organic compound that is useful as a preventive and / or therapeutic agent for diseases accompanied by abnormalities in immune function not only by virtue of its inhibitory effect on IL-5 production but also by virtue of its comprehensive effect together with other effects. [Means for solving the problem]

[0005] The present inventors have found for the first time that a cyclic organic compound represented by the following formula (I) has an excellent effect of suppressing IL-5 production as well as an effect of suppressing the expression of IL-33 receptor in Th2 cells, and have completed the present invention as a result of intensive research. Specifically, the present invention can be embodied in the following manner. However, the present invention is not limited thereto.

[0006] [1] Formula (I):

[0007] [ka]

[0008] [In the formula, ring A is a nitrogen-containing 5- to 7-membered non-aromatic heterocycle or a pyrrole ring; Ring B is a benzene ring or a pyridine ring; X is a halogen atom; R1 is a hydrogen atom or an acyl group; m R a are present at any substitutable position of ring A, and each independently represents 1-6 ) an alkyl group or an oxo group; m is an integer from 0 to 3; n R b are present at any substitutable position of ring B, and each independently represents 1-6 ) an alkyl group or a halogen atom; n is an integer from 0 to 3; and M is a group represented by the formula: -(M1)o-R2 (In the formula, M1 represents a methylene group which may be substituted with an oxo group; o is an integer from 0 to 3, and R2 is optionally substituted (C 1-12 ) alkyl group, optionally substituted (C 2-12 ) alkenyl group, optionally substituted (C 3-12 ) a cycloalkyl group, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted saturated heterocyclic group; (representing the (wherein M is not a carbamate group); are shown respectively.] 2. Compound (I) represented by the formula: [2] Ring A is dihydropyridine, tetrahydropyridine, pyrroline, tetrahydroazepine, dihydro-1,4-oxazine or pyrrole; The compound or a salt thereof according to the above [1]. [3] In formula (I), the following formula (II):

[0009] [ka]

[0010] (In the formula, * indicates the bonding position with N, and other symbols are the same as those in [1] above.) The partial structure (II) represented by the following formulae (IIIa) to (IIIl):

[0011] [ka]

[0012] [ka]

[0013] [ka]

[0014] (wherein each symbol has the same meaning as above) A partial structure represented by The compound or salt thereof according to the above [2]. [4] The partial structure (II) has the following formula (IIa):

[0015] [ka]

[0016] (In the formula, ring A' represents a nitrogen-containing 5- to 7-membered non-aromatic heterocycle or a pyrrole ring. Y represents CH or N; * indicates the position of bond to N, and Other symbols are as defined above in [1].) The compound or salt thereof according to the above [1], wherein the compound has a partial structure (IIa) represented by the following formula: [5] Ring A' is tetrahydropyridine, pyrroline, tetrahydroazepine, dihydro-1,4-oxazine or pyrrole. The compound or salt thereof according to the above [4]. [6] The partial structure (IIa) is represented by the following formulae (IIIa) to (IIIg):

[0017] [ka]

[0018] [ka]

[0019] (In the formula, each symbol has the same meaning as in [4] above.) A partial structure represented by The compound or salt thereof according to the above [5]. [7] R1 is a hydrogen atom or (C 1-6 ) an alkyl-carbonyl group (preferably a hydrogen atom); The compound or a salt thereof according to any one of the above [1] to [6]. [8] R2 is optionally substituted (C 1-12 ) alkyl group, optionally substituted (C 2-12 ) alkenyl group, optionally substituted (C 3-12 ) cycloalkyl group, optionally substituted (C 6-14 ) an aryl group, an optionally substituted nitrogen-containing 5- or 6-membered aromatic heterocyclic group, or an optionally substituted 5- to 7-membered saturated heterocyclic group; The compound or a salt thereof according to any one of the above [1] to [7]. [9] R2, Optionally substituted (C 1-12 ) alkyl group, optionally substituted (C 1-12 ) alkoxy group, optionally substituted (C 2-12) each of which is optionally substituted with 1 to 5 (preferably 1 to 3) substituents which may be the same or different and are selected from an alkynyloxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, and a halogen atom; (C 1-12 ) alkyl group, (C 2-12 ) alkenyl group, (C 3-12 ) cycloalkyl group, (C 6-14 ) an aryl group, a nitrogen-containing 5- or 6-membered aromatic heterocyclic group, or an optionally substituted 5- to 7-membered saturated heterocyclic group; The compound or salt thereof according to the above [8].

[10] R2, (1)(C 1-12 ) an alkyl group (preferably (C 1-6 ) alkyl group), (2)(C 2-12 ) an alkenyl group (preferably, (C 2-6 ) alkenyl group), (3) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) an aryloxy group, and (vi) a halogen atom (C 3-12 ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (C 6-14 ) an aryl group, (5) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (6)(i) a nitrogen-containing 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to 5 (preferably 1 to 3) substituents, which may be the same or different, selected from 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms is a 5- to 7-membered saturated heterocyclic group optionally substituted with 1 to 5 (preferably 1 to 3) substituents which may be the same or different and are selected from The compound or salt thereof according to the above [8].

[11] R2, (1)(C 1-12 ) an alkyl group (preferably (C 1-6 ) alkyl group), (2)(C 2-12 ) an alkenyl group (preferably, (C 2-6 ) alkenyl group), (3) 1 to 5 (preferably 1 to 3) (C 1-6 ) may be substituted by an alkyl group (C 3-12 ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (C 6-14 ) an aryl group, (5) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl groups, and (ii) Halogen atom or (6) a nitrogen-containing 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to 5 (preferably 1 to 3) substituents, which may be the same or different, selected from 1-6 ) a 5- to 7-membered saturated heterocyclic group optionally substituted by an alkyl group; The compound or salt thereof according to the above [8].

[12] R2, (i) optionally substituted with 1 to 3 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted by 1 to 3 substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) an aryloxy group, and (vi) a halogen atom (C 6-14 ) an aryl group, That is, The compound or salt thereof according to the above [8].

[13] The partial structure (II) in the formula (I) is represented by the following formula (IIIa):

[0020] [ka]

[0021] (In the formula, * indicates the bonding position with N, and other symbols are the same as those in [1] above.) The compound or salt thereof according to any one of the above [1] to

[12] , wherein the compound has a partial structure represented by the following formula:

[14] R1 is a hydrogen atom; m is 0, Rb is a halogen atom; n is 0 or 1; o is 1, R2 may be substituted with (i) 1 to 3 halogen atoms (C 1-6 ) alkyl groups, and (ii) Halogen atom A phenyl group which may be substituted by 1 to 3 substituents which may be the same or different and are selected from The compound or a salt thereof according to the above

[13] .

[15] 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide, 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide, and 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide, The compound or salt thereof according to the above-mentioned

[14] , which is a compound or salt thereof selected from the group consisting of:

[16] A pharmaceutical composition comprising the compound or a salt thereof according to any one of [1] to

[15] above as an active ingredient.

[17] The pharmaceutical agent described in

[16] above, which is an IL-5 production inhibitor.

[18] The pharmaceutical agent according to any one of the above

[16] to

[17] , which is an IL-33 receptor expression inhibitor.

[19] The pharmaceutical agent according to any one of

[16] to

[18] above, which is an IL-13 production inhibitor.

[20] The pharmaceutical agent according to any one of the above

[16] to

[19] , which is a preventive and / or therapeutic agent for a disease accompanied by immune dysfunction.

[21] The pharmaceutical agent according to

[20] above, which is a preventive and / or therapeutic agent for allergic diseases and autoimmune diseases.

[22] Diseases include urticaria, food allergies, anaphylactic shock, hypereosinophilic syndrome, asthma, allergic rhinitis, allergic conjunctivitis, allergic bronchitis, atopic dermatitis, rheumatoid arthritis, type I diabetes mellitus, Hashimoto's thyroiditis, myasthenia gravis, multiple sclerosis, organ transplant rejection; atopic asthma, nonallergic rhinitis, severe asthma, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, celiac disease, Churg-Strauss syndrome, eosinophilic myalgia syndrome, hypereosinophilic syndrome, edematous reactions including episodic angioedema, helminth infections, onchocercal dermatitis, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastrointestinal disorders, and helminth infections. inflammatory bowel disease, eosinophilic enteritis, eosinophilic colitis, nasal micropolyposis, nasal polyposis, aspirin intolerant asthma, obstructive sleep apnea, chronic asthma, Crohn's disease, scleroderma and endomyocardial fibrosis; hay fever, sinusitis (including eosinophilic sinusitis), ulcerative colitis, arthritis, systemic lupus erythematosus, pemphigus, pemphigoid, scleroderma, ankylosing spondylitis, hepatic fibrosis (including primary biliary cirrhosis), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute kidney injury, vasculitis, cancer, pulmonary hypertension, Sjogren's syndrome, muscular dystrophy, autoimmune hepatitis, and bronchiectasis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present invention is described in detail below. Unless otherwise specified in the text, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications and patents mentioned herein are incorporated by reference for the purpose of describing and disclosing, for example, the constructs and methodologies described in the publications that can be used in connection with the described invention.

[0023] [Regarding compound (I) of the present invention] According to one embodiment of the present invention, "The following formula (I):

[0024] [ka]

[0025] [In the formula, ring A is a nitrogen-containing 5- to 7-membered non-aromatic heterocycle or a pyrrole ring; Ring B is a benzene ring or a pyridine ring; X is a halogen atom; R1 is a hydrogen atom or an acyl group; m R a are present at any substitutable position of ring A, and each independently represents 1-6 ) an alkyl group or an oxo group; m is an integer from 0 to 3; n R b are present at any substitutable position of ring B, and each independently represents 1-6 ) an alkyl group or a halogen atom; n is an integer from 0 to 3; and M is a group represented by the formula: -(M1)o-R2 (In the formula, M1 represents a methylene group which may be substituted with an oxo group; o is an integer from 0 to 3, and R2 is optionally substituted (C 1-12) alkyl group, optionally substituted (C 2-12 ) alkenyl group, optionally substituted (C 3-12 ) a cycloalkyl group, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted saturated heterocyclic group; (representing the (wherein M is not a carbamate group); are shown respectively.] Compound (I) represented by the formula: or a salt thereof." is provided.

[0026] In this specification, "C a-b " (For example, C 1-6 ) or "C a -C b " (e.g., C1-C6) indicates that the group has a to b carbon atoms (e.g., 1 to 6).

[0027] In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0028] In this specification, "(C 1-12 Examples of the "alkyl (group)" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. "(C 1-6 Examples of the "alkyl (group)" include those having 1 to 6 carbon atoms among the above.

[0029] In this specification, "(C 2-12Examples of the "alkenyl (group)" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 2-heptenyl, 3-octenyl, 4-nonenyl, 5-decenyl, 6-undecenyl, and 7-dodecenyl. "(C 2-6 Examples of the "alkenyl (group)" include those having 2 to 6 carbon atoms among the above.

[0030] In this specification, "(C 2-12 Examples of the "alkynyl (group)" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, and dodecynyl. "(C 2-6 Examples of the "alkynyl (group)" include those having 2 to 6 carbon atoms among the above.

[0031] In this specification, "(C 1-12 Examples of the alkoxy (group) include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, and dodecyloxy. "(C 1-6 Examples of the "alkoxy (group)" include those having 1 to 6 carbon atoms among the above.

[0032] In this specification, "(C 3-12Examples of the "cycloalkyl (group)" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0033] In the present specification, the term "aryl (group)" refers to "(C 6-14 Preferred examples include aryl (groups) such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

[0034] In the present specification, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms.

[0035] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as benzene, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0036] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered, more preferably 5- to 7-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, dihydro-1,4-oxazine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, diazepane, azepine, tetrahydroazepine, azocane, diazocane, and oxepane; Examples of the heterocyclic ring include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.

[0037] In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") include: (i) an aromatic heterocyclic group each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group.

[0038] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0039] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl Examples of such 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups include tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl. In the present specification, the term "saturated heterocyclic group" refers to a "heterocyclic group" that does not contain any unsaturated bond, preferably a 5- to 7-membered saturated heterocyclic group.

[0040] In the present specification, preferable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes "heterocyclic groups" which contain at least one nitrogen atom as a ring-constituting atom.

[0041] In the present specification, preferred examples of the "acyl group" include a formyl group, a carboxy group, 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl groups (e.g., crotonoyl), C 3-10 Cycloalkyl-carbonyl groups (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl groups (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl groups (e.g., diallylcarbamoyl), mono- or di-C 2-6 Alkynyl-carbamoyl group, mono- or di-C 3-10 Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C2-6 Alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl), sulfino groups, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, mono- or di-C 1-6 Examples of the alkylphosphono group include dimethylphosphono, diethylphosphono, diisopropylphosphono, and dibutylphosphono groups.

[0042] In the present specification, "optionally substituted (C 1-12 ) alkyl group," "optionally substituted (C 2-12 Examples of the "substituent" in the "optionally substituted group or ring" in the definition of compound (I), such as "(1) alkenyl group", include substituents selected from the following [Substituent group A]. The "substituent" may be present in 1 to 5 (preferably 1 to 3) substitutable positions, and when the number of substituents is 2 or more, the respective substituents may be the same or different. In addition, when a special explanation is given about the "substituents" of each group, each ring, etc., the explanation should be followed.

[0043] [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C1-C6 alkoxy group (e.g., methoxy, chloromethoxy, trifluoroethoxy); (7) C6-C 14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C7-C 16 aralkyloxy groups (e.g., benzyloxy); (9) C1-C6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (10) C6-C 14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (11) C1-C6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (12) 5- to 14-membered aromatic heterocyclic groups (e.g., thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl), in which 5- to 6-membered monocyclic aromatic heterocyclic groups are preferred, and 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic groups are more preferred. (13) 3- to 14-membered non-aromatic heterocyclic groups (e.g., aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropi lysinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl), wherein a 3- to 8-membered monocyclic non-aromatic heterocyclic group is preferred, and a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group or a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group is more preferred. (14) a formyl group, (15) a carboxy group, (16) An optionally halogenated C1-C6 alkyl-carbonyl group (e.g., acetyl, chloroacetyl, trifluoroacetyl), (17) C6-C 14 Aryl-carbonyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl), (18) C1-C6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (19) a carbamoyl group, (20) an amino group, (21) mono- or di-C1-C6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (22) mono- or di-C6-C 14 (23) an arylamino group (e.g., phenylamino); (24) a formylamino group; (24) C1-C6 alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (25) C1-C6 alkoxy-carbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (26) optionally halogenated C1-C6 alkyl groups (e.g., methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl); (27) C2-C6 alkenyl groups (e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl), (28) C2-C6 alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl), (29) C3-C 10 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl); (30) C3-C 10 cycloalkenyl groups (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl); (31)C6-C 14 Aryl groups (e.g., phenyl, naphthyl); (32) (mono- or di-C1-C6 alkylamino)carbonyl groups (e.g., methylamino-carbonyl groups), and (33) A C1-C6 alkyl-sulfonyl group (e.g., a methylsulfonyl group).

[0044] Preferred embodiments of the groups represented by each symbol in compound (I) are described below.

[0045] X is as defined above, but is preferably chlorine or bromine.

[0046] R1 is as defined above, but is a hydrogen atom or (C 1-6 ) An alkyl-carbonyl group is preferable, and a hydrogen atom is more preferable.

[0047] Ring A is as defined above, but is preferably dihydropyridine, tetrahydropyridine, pyrroline, tetrahydroazepine, dihydro-1,4-oxazine or pyrrole.

[0048] Ring B is as defined above.

[0049] In formula (I), the following formula (II):

[0050] [ka]

[0051] (In the formula, * indicates the bonding position to N, and the other symbols are as defined above for formula (I).) Regarding the partial structure (II) represented by (1) One preferred embodiment is the following formula (IIIa) to (IIIl):

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] (In the formula, * indicates the bonding position to N, and the other symbols are as defined above for formula (I).) The partial structure is selected from the partial structures represented by (2) Another preferred embodiment of the partial structure (II) is represented by the following formula (IIa):

[0056] [ka]

[0057] (wherein ring A' represents a nitrogen-containing 5- to 7-membered non-aromatic heterocycle or a pyrrole ring, and preferably represents tetrahydropyridine, pyrroline, tetrahydroazepine, dihydro-1,4-oxazine or pyrrole; Y represents CH or N; * indicates the position of bond to N, and The other symbols are as defined above for formula (I). and more preferably, the partial structure (IIa) represented by the following formulae (IIIa) to (IIIg):

[0058] [ka]

[0059] [ka]

[0060] (In the formula, each symbol has the same meaning as in the partial structure (IIa) above.) and more preferably, the partial structure represented by the following formula (IIIa):

[0061] [ka]

[0062] (In the formula, each symbol has the same meaning as in the partial structure (IIa) above.) It is a partial structure represented by:

[0063] R a is as defined above, but is preferably a methyl or oxo group.

[0064] m is as defined above.

[0065] R b is as defined above, but is preferably a halogen atom.

[0066] n is as defined above.

[0067] M1 is as defined above.

[0068] o is as defined above.

[0069] R2 is as defined above, Optionally substituted (C 1-12 ) alkyl group, optionally substituted (C 2-12 ) alkenyl group, optionally substituted (C 3-12 ) cycloalkyl group, optionally substituted (C 6-14 ) an aryl group, an optionally substituted nitrogen-containing 5- or 6-membered aromatic heterocyclic group, or an optionally substituted 5- to 7-membered saturated heterocyclic group; Optionally substituted (C 1-12 ) alkyl group, optionally substituted (C 1-12 ) alkoxy group, optionally substituted (C 2-12 ) each of which is optionally substituted by 1 to 5 (preferably 1 to 3) substituents which may be the same or different and are selected from an alkynyloxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, and a halogen atom; (C 1-12 ) alkyl group, (C 2-12 ) alkenyl group, (C 3-12 ) cycloalkyl group, (C 6-14) an aryl group, a nitrogen-containing 5- or 6-membered aromatic heterocyclic group, or an optionally substituted 5- to 7-membered saturated heterocyclic group is more preferred; (1)(C 1-12 ) an alkyl group (preferably (C 1-6 ) alkyl group), (2)(C 2-12 ) an alkenyl group (preferably, (C 2-6 ) alkenyl group), (3) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) an aryloxy group (preferably a phenoxy group), (C 6-14 )Aryloxy(C 1-6 ) an alkoxy group (preferably phenoxy (C 1-6 ) alkoxy groups), and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group (preferably a phenyl group); (v)(C 6-14 ) an aryloxy group (preferably a phenoxy group), and (vi) Halogen atoms (C 3-12 ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) an aryloxy group (preferably a phenoxy group), (C 6-14 )Aryloxy(C 1-6 ) an alkoxy group (preferably phenoxy (C 1-6 ) alkoxy groups), and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group (preferably a phenyl group); (v)(C 6-14 ) an aryloxy group (preferably a phenoxy group), and (vi) Halogen atoms (C 6-14 ) an aryl group (preferably a phenyl group); (5) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) an aryloxy group (preferably a phenoxy group), (C 6-14 )Aryloxy(C 1-6 ) an alkoxy group (preferably phenoxy (C 1-6 ) alkoxy groups), and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group (preferably a phenyl group); (v)(C 6-14 ) an aryloxy group (preferably a phenoxy group), and (vi) Halogen atoms or a nitrogen-containing 5- or 6-membered aromatic heterocyclic group (preferably a pyridyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents which may be the same or different and are selected from (6) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) an aryloxy group (preferably a phenoxy group), (C 6-14 )Aryloxy(C 1-6 ) an alkoxy group (preferably phenoxy (C 1-6 ) alkoxy groups), and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group (preferably a phenyl group); (v)(C 6-14 ) an aryloxy group (preferably a phenoxy group), and (vi) Halogen atoms and more preferably a 5- to 7-membered saturated heterocyclic group (preferably a piperidinyl group, a morpholinyl group, or a tetrahydropyranyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents which may be the same or different and are selected from (1)(C 1-12 ) an alkyl group (preferably (C 1-6 ) alkyl group), (2)(C 2-12 ) an alkenyl group (preferably, (C 2-6 ) alkenyl group), (3) 1 to 5 (preferably 1 to 3) (C 1-6 ) may be substituted by an alkyl group (C 3-12 ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) an aryloxy group (preferably a phenoxy group), (C 6-14 )Aryloxy(C 1-6 ) an alkoxy group (preferably phenoxy (C 1-6 ) alkoxy groups), and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group (preferably a phenyl group); (v)(C 6-14 ) an aryloxy group (preferably a phenoxy group), and (vi) Halogen atoms (C 6-14 ) an aryl group (preferably a phenyl group); (5) (i) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (C 1-6 ) alkyl groups, and (ii) Halogen atom or a nitrogen-containing 5- or 6-membered aromatic heterocyclic group (preferably a pyridyl group) optionally substituted by 1 to 5 (preferably 1 to 3) substituents which may be the same or different and are selected from (6) (i) 1 to 5 (preferably 1 to 3) (C 1-6 ) a 5- to 7-membered saturated heterocyclic group optionally substituted by an alkyl group (preferably a piperidinyl group, a morpholinyl group, or a tetrahydropyranyl group); (i) optionally substituted with 1 to 3 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) an aryloxy group (preferably a phenoxy group), (C 6-14 )Aryloxy(C 1-6 ) an alkoxy group (preferably phenoxy (C 1-6 ) alkoxy groups), and acyl (C 1-6 ) an alkoxy group (preferably, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy group or (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group), which may be the same or different and may be substituted by 1 to 3 substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group (preferably a phenyl group); (v)(C 6-14 ) an aryloxy group (preferably a phenoxy group), and (vi) Halogen atoms (C 6-14 ) an aryl group (preferably a phenyl group); It is most preferable if:

[0070] Particularly preferred specific examples of compound (I) include the following.

[0071] [Compound A-1] X is a halogen atom; R1 is a hydrogen atom or (C 1-6 ) an alkyl-carbonyl group, The partial structure (II) has the following formula (IIa):

[0072] [ka]

[0073] (wherein ring A' is a nitrogen-containing 5- to 7-membered non-aromatic heterocycle or a pyrrole ring (preferably tetrahydropyridine, pyrroline, tetrahydroazepine, dihydro-1,4-oxazine or pyrrole), Y is CH or N; m R a are present at any substitutable position of ring A, and each independently represents 1-6 ) an alkyl group or an oxo group; m is an integer from 0 to 3; n R b are present at any substitutable position of ring B', and each independently represents 1-6 ) an alkyl group or a halogen atom; n is an integer from 0 to 3; and M is a group represented by the formula: -(M1)o-R2 (In the formula, M1 represents a methylene group which may be substituted with an oxo group; o is an integer from 0 to 3, and R2 is (1)(C 1-12 ) alkyl group, (2)(C 2-12 ) an alkenyl group, (3) (i) optionally substituted with 1 to 5 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different and may be substituted with 1 to 5 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (C 3-12 ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different and may be substituted with 1 to 5 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (C 6-14) an aryl group, (5) (i) optionally substituted with 1 to 5 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different, and may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms or a nitrogen-containing 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to 5 substituents, which may be the same or different, selected from (6) (i) optionally substituted with 1 to 5 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different and may be substituted with 1 to 5 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms is a 5- to 7-membered saturated heterocyclic group optionally substituted with 1 to 5 substituents, which may be the same or different, selected from (wherein M is not a carbamate group), The partial structure (IIa) is represented by the following formula: Compound (I) or a salt thereof.

[0074] [Compound A-2] The partial structure (IIa) is represented by the following formulae (IIIa) to (IIIg):

[0075] [ka]

[0076] [ka]

[0077] (In the formula, each symbol has the same meaning as in [Compound A-1] above.) A partial structure represented by The above [Compound A-1] or a salt thereof.

[0078] [Compound A-3] The partial structure (II) has the following formula (IIIa):

[0079] [ka]

[0080] (In the formula, each symbol has the same meaning as in [Compound A-1] above.) A partial structure represented by The above [Compound A-1] or a salt thereof.

[0081] [Compound A-4] R1 is a hydrogen atom, R2, (1)(C 1-12 ) alkyl group, (2)(C 2-12 ) an alkenyl group, (3) (i) optionally substituted with 1 to 5 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different and may be substituted with 1 to 5 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (C 3-12 ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different and may be substituted with 1 to 5 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (C 6-14 ) an aryl group, (5) (i) optionally substituted with 1 to 5 halogen atoms (C1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different and may be substituted with 1 to 5 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms or a nitrogen-containing 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group) optionally substituted by 1 to 5 substituents, which may be the same or different, selected from (6) (i) optionally substituted with 1 to 5 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups, and acyl (C 1-6 ) alkoxy groups, which may be the same or different and may be substituted with 1 to 5 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms a 5- to 7-membered saturated heterocyclic group (e.g., a piperidinyl group, a morpholinyl group, or a tetrahydropyranyl group) optionally substituted by 1 to 5 substituents, which may be the same or different, selected from The above [Compound A-1] to [Compound A-3] or salts thereof.

[0082] [Compound A-5] R2, (1)(C 1-6 ) alkyl group, (2)(C 2-6 ) an alkenyl group, (3) 1 to 3 (C 1-6 ) may be substituted by an alkyl group (C 3-12 ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 3 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy group, (C 6-14 )Aryloxy(C 1-6 ) alkoxy group, (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy groups, and (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group, which may be the same or different and may be substituted with 1 to 3 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group, (v)(C 6-14 ) aryloxy groups, and (vi) Halogen atoms (C 6-14 ) an aryl group, (5) (i) optionally substituted with 1 to 3 halogen atoms (C 1-6 ) alkyl groups, and (ii) Halogen atom a nitrogen-containing 5- or 6-membered aromatic heterocyclic group (e.g., a pyridyl group) optionally substituted by 1 to 3 substituents, which may be the same or different, selected from (6) 1 to 3 (C 1-6) a 5- to 7-membered saturated heterocyclic group optionally substituted by an alkyl group (e.g., a piperidinyl group, a morpholinyl group, or a tetrahydropyranyl group); The above [Compound A-1] to [Compound A-4] or salts thereof.

[0083] [Compound A-6] R2, (i) optionally substituted with 1 to 3 halogen atoms (C 1-6 ) alkyl group, (ii)(C 6-14 ) aryloxy groups (e.g., phenoxy groups), (C 6-14 )Aryloxy(C 1-6 ) alkoxy groups (e.g., phenoxy (C 1-6 ) alkoxy group), (C 1-6 ) Alkylamino-carbonyl (C 1-6 ) alkoxy groups, and (C 2-6 ) Alkynylamino-carbonyl (C 1-6 ) an alkoxy group, which may be the same or different and may be substituted with 1 to 3 substituents (C 1-6 ) an alkoxy group, (iii)(C 2-6 ) an alkynyloxy group, (iv)(C 6-14 ) an aryl group (e.g., a phenyl group); (v)(C 6-14 ) aryloxy groups (e.g., phenoxy groups), and (vi) Halogen atoms (C 6-14 ) an aryl group (e.g., a phenyl group); That is, The above [Compound A-1] to [Compound A-5] or salts thereof.

[0084] [Compound A-7] R1 is a hydrogen atom, m is 0, Rb is a halogen atom; n is 0 or 1; o is 1, R2 may be substituted with (i) 1 to 3 halogen atoms (C 1-6 ) alkyl groups, and (ii) Halogen atom A phenyl group which may be substituted by 1 to 3 substituents which may be the same or different and are selected from The above [Compound A-1] to [Compound A-6] or salts thereof.

[0085] [Compound A-8] 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide, 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide, and 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide, or a salt thereof.

[0086] In carrying out the present invention, compound (I) can be used in either the free form or the form of its salt (preferably, its medicamentously acceptable salt). A person skilled in the art can carry out the present invention by appropriately selecting either form based on the characteristics of each compound (I) used. Examples of pharma- ceutically acceptable salts include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts with organic acids such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, maleate, etc.; salts with bases such as alkali metal salts such as sodium salt, potassium salt, etc., and alkaline earth metal salts such as calcium salt; salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate, etc.

[0087] [Regarding the method for producing compound (I) or a salt thereof of the present invention] The following are embodiments of the method for producing compound (I) or a salt thereof. However, the method for producing compound (I) or a salt thereof is not limited to these, and a person skilled in the art can produce compound (I) or a salt thereof by appropriately selecting and carrying out a synthesis scheme according to the target compound.

[0088] Manufacturing method 1 Among the compounds (I), the compound (Ia) in which R1 is a hydrogen atom can be produced, for example, according to the following synthesis scheme. Compound (B) can be produced by subjecting compound (A) to an alkylation reaction with an alkyl halide or to an aromatic nucleophilic substitution reaction with an aromatic halide. The base used in these reactions can be sodium hydride, potassium carbonate, cesium carbonate, or the like. Compound (C) can be produced by subjecting compound (B) to a reduction reaction. When iron or zinc is used as the reducing agent, compound (C) can be produced by using hydrochloric acid, acetic acid, or ammonium chloride as the acid. Alternatively, compound (C) can be produced by catalytic reduction using a palladium catalyst. Compound (Ia) can be produced by subjecting compound (C) and compound (D) or a reactive derivative thereof (e.g., an acid chloride) to a condensation reaction, or by using a condensation agent (e.g., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride).

[0089] [ka]

[0090] (In the formula, R 1a is a hydrogen atom, and the other symbols are the same as those in the compound represented by formula (I). Those skilled in the art can appropriately carry out the above series of synthetic reactions according to the methods described in detail in the Examples below or methods modified as appropriate thereto.

[0091] Manufacturing method 2 Among the compounds (I), the compound (Ia) in which R1 is a hydrogen atom can also be produced according to, for example, the following synthesis scheme. Compound (B) can be synthesized by subjecting compound (A) to a condensation reaction using a carboxylic acid or a reactive derivative thereof (eg, acid chloride, acid anhydride). Compound (C) can be produced by subjecting compound (B) to a reduction reaction. In the synthesis scheme below, compound (Ia) containing a methylene chain substituted with an oxo group in M ​​can be produced by subjecting compound (B) to a reduction reaction. When iron or zinc is used as a reducing agent, compound (Ia) can be produced by using hydrochloric acid, acetic acid, or ammonium chloride as an acid. Alternatively, compound (C) can be produced by catalytic reduction using a palladium catalyst. In the synthesis scheme below, when compound (Ia) in which M does not contain a methylene chain substituted with an oxo group is produced, it can be produced by the following two-step reduction reaction. In the first step, a reduction reaction of a boron-tetrahydrofuran complex, a boron-dimethylsulfide complex, or the like is carried out, and in the second step, compound (C) can be produced by catalytic reduction using an iron, zinc, or palladium catalyst. Compound (Ia) can be produced from compound (C) by the same method as in Production Method 1.

[0092] [ka]

[0093] (wherein each symbol has the same meaning as above) Those skilled in the art can appropriately carry out the above series of synthetic reactions according to the methods described in detail in the Examples below or methods modified as appropriate thereto.

[0094] Manufacturing method 3 Among the compounds (I), compound (Ia) in which R1 is a hydrogen atom can also be produced, for example, according to the following synthesis scheme: X in compound (A) is also a halogen atom. Compound (B) can be produced by subjecting compound (A) to an alkylation reaction with an alkyl halide, or to an aromatic nucleophilic substitution reaction with an aromatic halide. Compound (C) can be produced by aminating compound (B) with benzophenone imine by Buchwald-Hartwig coupling reaction. Compound (Ia) can be produced from compound (C) by the same method as in Production Method 1.

[0095] [ka]

[0096] (wherein each symbol has the same meaning as above) Those skilled in the art can appropriately carry out the above series of synthetic reactions according to the methods described in detail in the Examples below or methods modified as appropriate thereto.

[0097] Manufacturing method 4 Among compounds (I), compound (Ib) in which R1 is an acyl group can be produced, for example, by subjecting compound (Ia) or a salt thereof to an acylation reaction according to the following synthesis scheme.

[0098] [ka]

[0099] (In the formula, R 1b is an acyl group, and the other symbols are as defined above. The above acylation reaction can be suitably carried out by those skilled in the art according to the methods described in detail in the Examples below or methods modified as appropriate thereto. Suitable salts of compound (Ib) may refer to those mentioned as suitable salts of compound (I).

[0100] [Use of compound (I) of the present invention or a salt thereof] Compound (I) or a salt thereof has the effect of suppressing differentiation into Th2 cells which produce IL-5, and based on this effect, can suppress IL-5 production caused by antigen-dependent stimulation. In addition, compound (I) or a salt thereof has an effect of suppressing the expression of IL-33 receptor in Th2 cells. In general, the expression of IL-33 receptor is maintained at a low level in Th2 cells, but when the expression of IL-33 receptor is high, Th2 cells produce IL-5 not only by antigen stimulation but also by IL-33 stimulation. Compound (I) or a salt thereof can suppress the expression of IL-33 receptor in Th2 cells, which makes Th2 cells less susceptible to IL-33 stimulation, and thus can suppress IL-5 and IL-13 produced by Th2 cells in response to IL-33 stimulation. Therefore, compound (I) or a salt thereof can suppress the occurrence of chronic allergic reactions that occur even without antigen stimulation. Furthermore, compound (I) or a salt thereof can also suppress the production of IL-5 and IL-13 induced by stimulation with IL-33 in Th2 cells expressing IL-33 receptors. As described above, compound (I) or a salt thereof has the above-mentioned excellent actions, and therefore exhibits its effects synergistically and comprehensively, making it extremely useful for preventing or treating diseases accompanied by immune dysfunction.

[0101] Examples of such diseases include urticaria, food allergies, anaphylactic shock, hypereosinophilic syndrome, asthma, allergic rhinitis, allergic conjunctivitis, allergic bronchitis, atopic dermatitis, rheumatoid arthritis, type I diabetes, Hashimoto's thyroiditis, myasthenia gravis, multiple sclerosis, rejection reactions following organ transplantation; atopic asthma, non-allergic rhinitis, severe asthma, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, abdominal diseases, Churg-Strauss syndrome, eosinophilic myalgia syndrome, hypereosinophilic syndrome, edematous reactions including episodic angioedema, helminth infections, onchocerca dermatitis, eosinophilic esophagitis, eosinophilic stomach The present invention relates to a method for treating chronic myocardial infarction and / or pulmonary edema, including, but not limited to, one or more of the following diseases: eosinophilic gastroenteritis, eosinophilic enteritis, eosinophilic colitis, nasal micropolyposis, nasal polyposis, aspirin intolerant asthma, obstructive sleep apnea, chronic asthma, Crohn's disease, scleroderma, and endomyocardial fibrosis; hay fever, sinusitis (including eosinophilic sinusitis), ulcerative colitis, arthritis, systemic lupus erythematosus, pemphigus, pemphigoid, scleroderma, ankylosing spondylitis, hepatic fibrosis (including primary biliary cirrhosis), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute kidney injury, vasculitis, cancer, pulmonary hypertension, Sjogren's syndrome, muscular dystrophy, autoimmune hepatitis, and bronchiectasis.

[0102] As used herein, "prevention" includes preventing the onset of a disease (either an entire pathology or one or more pathologies) and delaying the onset of the disease. A "prophylactically effective amount" refers to a dose of Compound (I) sufficient to achieve this purpose. As used herein, "treatment" includes curing a disease (all or one or more pathological conditions), improving the disease, and inhibiting the progression of the severity of the disease. "Therapeutically effective amount" refers to a dose of Compound (I) sufficient to achieve such a purpose.

[0103] In carrying out the present invention, compound (I) or a salt thereof (the compound of the present invention) can be used in either a single form or a pharmaceutical composition containing the compound of the present invention as an active ingredient together with a pharma- ceutical acceptable carrier.

[0104] Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosa patch films), injections (e.g., subcutaneous injections, intravenous injections (e.g., bolus), intramuscular injections, intraperitoneal injections), infusions, transdermal preparations, ointments, lotions, patches, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops.

[0105] As used herein, the term "pharmaceutical acceptable carrier" refers to various carriers commonly used in the field of pharmaceutical formulation technology.

[0106] Specific examples of "pharmaceutical acceptable carriers" that can be used in solid preparations include excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., magnesium stearate, talc, colloidal silica, etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), and disintegrants (e.g., starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylstarch, L-hydroxypropylcellulose, etc.).

[0107] In the liquid preparation, solvents (e.g., water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizing agents (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (e.g., surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffering agents (e.g., buffer solutions such as phosphates and citrates, etc.), and soothing agents (e.g., benzyl alcohol, etc.), etc. may be used.

[0108] If necessary, formulation additives such as preservatives (e.g., paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, α-tocopherol, etc.), colorants, sweeteners, etc. may be further added.

[0109] The pharmaceutical composition of the present invention may be prepared by adding the compound of the present invention in an amount of usually 0.01-99% (w / w), preferably 0.1-85% (w / w) based on the total amount of the preparation, depending on the dosage form, administration method, carrier, etc. The pharmaceutical composition may be prepared by a method commonly used in the field of formulation technology depending on the form. The pharmaceutical composition of the present invention may be formed into a sustained release preparation containing an active ingredient.

[0110] (Regarding subjects of administration) The compound of the present invention is expected to have low toxicity and few side effects, and has excellent properties as a pharmaceutical. Therefore, the compound of the present invention can be safely administered to mammals (e.g., humans, dogs, or cats, especially humans). (Regarding administration route) In practicing the present invention, the compounds of the present invention may be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intraorgan, intranasally, intradermally, ophthalmically, intracerebrally, intrarectally, intravaginally, intraperitoneally, and into a lesion) either alone or as a pharmaceutical composition. (Dosage) The dosage of the compound of the present invention varies depending on the subject, route of administration, and age and symptoms of the subject, but is not particularly limited. For example, the dosage of the compound of the present invention is 1 to 250 mg per dose when administered orally, and 0.1 to 1000 mg per dose when administered parenterally.

[0111] (Use as a prodrug) Compound (I) can also be used in the form of a prodrug, and such prodrugs are encompassed in compound (I). A prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in the body, i.e., a compound that is enzymatically oxidized, reduced, hydrolyzed, or the like to be converted to compound (I), or a compound that is hydrolyzed by gastric acid or the like to be converted to compound (I). Examples of prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated [e.g., Compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated, etc.; compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, Examples of such compounds include borated compounds (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); and compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated, etc.). These compounds can be prepared from compound (I) by a method known per se. It can be manufactured. In addition, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Publishing in 1990.

[0112] Compound (I) may be any of a hydrate, a non-hydrate, a solvate, and a non-solvate. Compound (I) may also contain isotopes (e.g., 2 H, 3 H, 11 C. 14 C. 18 F, 35 S, 125 The compound may be a compound labeled or substituted with an isotope, such as I, and a compound labeled or substituted with an isotope may be used, for example, as a tracer used in positron emission tomography (PET) (PET tracer), and may be useful in fields such as medical diagnosis. 1 H 2 Deuterium converted to H(D) is also encompassed in compound (I). Compound (I) also encompasses tautomers. Compound (I) may be a pharma- ceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance that is composed of two or more unique solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared according to a cocrystallization method known per se.

[0113] (Concomitant use with other drugs) The compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs). The concomitant drug may be a compound or a salt thereof that has a preventive and / or therapeutic effect depending on the disease to be prevented or treated, such as an anti-IL-4 receptor α antibody preparation, a JAK inhibitor, a histamine H1 receptor antagonist, a leukotriene receptor antagonist, an anti-thromboxane A2 drug, an anti-IL-31 receptor α antibody preparation, an anti-TSLP antibody preparation, an anti-IgE antibody preparation, an anti-OX40 antibody, a steroid preparation, a long-acting beta 2 agonist (LABA), a short-acting beta 2 agonist (SABA), a long-acting anticholinergic agent (LAMA), a short-acting anticholinergic agent (SAMA), a CRTH2 receptor antagonist, a phosphodiesterase 4 inhibitor, an aryl hydrocarbon receptor (AHR) modulator, etc. By combining the compound of the present invention with a concomitant drug, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to the case where the compound is administered alone. (2) Drugs to be used in combination with the compound of the present invention can be selected depending on the symptoms of the patient (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a concomitant drug having a different mechanism of action from that of the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0114] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as "the combined drug of the present invention." When using the combination drug of the present invention, the administration time of the compound of the present invention and the combination drug is not limited, and the compound of the present invention or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the subject at the same time or at a time lag. The dosage of the combination drug may be in accordance with the dosage used in clinical practice, and may be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the combination drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes with a time lag (for example, administration in the order of the compound of the present invention; the combination drug, or administration in the reverse order). The mixing ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the subject of administration, the administration route, the disease, etc. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total preparation. The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total preparation. In addition, when the compound of the present invention and the concomitant drug are separately formulated, the contents may be similar. EXAMPLES

[0115] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention.

[0116] Example 1 Synthesis of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 1,2,3,4-tetrahydro-6-nitroquinoline 500 mg in dimethylformamide 10 mL was mixed with sodium hydride (60%, dispersed in liquid paraffin) 123 mg, stirred at room temperature for 30 minutes, 3-chloro-4-fluorobenzotrifluoride 0.462 mL was added, and stirred at room temperature for 12 hours. Then, water and a mixed solution of ethyl acetate:hexane = 1:1 were added and separated, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate = 9:1) to obtain 1-[2-chloro-4-(trifluoromethyl)phenyl]-6-nitro-1,2,3,4-tetrahydroquinoline 540 mg. (2) 117 mg of reduced iron and 90 mg of ammonium chloride were added to 3 mL of a mixed solution of 150 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-6-nitro-1,2,3,4-tetrahydroquinoline in ethanol:water=2:1, and the mixture was stirred for 2 hours at 90° C. The reaction solution was filtered using silica gel to obtain 132 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-amine. (3) 176 μL of triethylamine was added to a solution of 132 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-amine in 3 mL of dichloromethane, and a solution of 102 mg of 2-chloro-5-nitrobenzoyl chloride in 2 mL of dichloromethane was slowly added dropwise and stirred at room temperature for 30 minutes. Then, water was added to the reaction solution, and the mixture was separated using dichloromethane. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by recrystallization using ethyl acetate and hexane to obtain 150 mg of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.60 (d, J = 2.7 Hz, 1H), 8.25 (dd, J = 8.7, 2.7 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.66-7.63 (m, 2H), 7.55 (dd, J = 8.4, 1.5 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 8.7, 2.5 Hz, 1H), 6.26 (d, J = 8.7 Hz, 1H), 3.59-3.57 (m, 2H), 2.94 (t, J = 6.4 Hz, 2H), 2.12-2.06 (m, 2H)

[0117] Example 2 Synthesis of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-5-yl}-5-nitrobenzamide (1) 195 mg of sodium hydride (60%, dispersed in liquid paraffin) was added to 10 mL of a solution of 500 mg of 5-nitroindoline in dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. 0.63 mL of 3-chloro-4-fluorobenzotrifluoride was then added dropwise, and the mixture was stirred at room temperature for 1 hour. The mixture was then separated using water and a mixed solution of hexane:ethyl acetate=1:1. The organic layer obtained was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate=4:1), and the solvent was removed under reduced pressure to obtain 734 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-5-nitro-2,3-dihydro-1H-indol. (2) 10 mg of palladium activated carbon (Pd 5%) was added with 10 mL of toluene and 200 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-5-nitro-2,3-dihydro-1H-indol, and stirred at room temperature under a hydrogen atmosphere for 15 hours. The reaction solution was filtered through silica gel, and the solvent was distilled off under reduced pressure to obtain 201 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-5-amine as a crude product. (3) 1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-5-amine (145 mg) was added to a dichloromethane (10 mL) solution of triethylamine (0.14 mL) and 2-chloro-5-nitrobenzoyl chloride (205 mg), and the mixture was stirred at room temperature for 2.5 hours. Then, water and dichloromethane were added to separate the mixture. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified using silica gel chromatography (hexane:ethyl acetate=4:1), and the solvent was removed under reduced pressure to obtain 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-5-yl}-5-nitrobenzamide (48 mg). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58 (d, J = 2.8 Hz, 1H), 8.23 ​​(dd, J = 8.8, 2.8 Hz, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.50 (s, 2H), 7.15 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.01 (t, J = 8.4 Hz, 2H), 3.22 (t, J = 8.4 Hz, 2H)

[0118] Example 3 Synthesis of 2-chloro-N-{4-[2-chloro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-5-nitrobenzamide (1) 300 mg of 7-nitro-3,4-dihydro-2H-1,4-benzoxazine was dissolved in 3 mL of dimethylformamide, and 80 mg of sodium hydride (60%, dispersed in liquid paraffin) and 297 μL of 3-chloro-4-fluorobenzotrifluoride were added and stirred at room temperature for 22 hours. The reaction solution was separated by adding a mixture of water and ethyl acetate:hexane = 1:1, and the obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain 524 mg of 4-[2-chloro-4-(trifluoromethyl)phenyl]-7-nitro-3,4-dihydro-2H-1,4-benzoxazine. (2) 312 mg of ammonium chloride and 408 mg of reduced iron were added to a mixture of 524 mg of 4-[2-chloro-4-(trifluoromethyl)phenyl]-7-nitro-3,4-dihydro-2H-1,4-benzoxazine in 4 mL of ethanol and 2 mL of water, and the mixture was heated under reflux for 1.5 hours. The reaction solution was then filtered using silica gel, and the filtrate was distilled under reduced pressure to obtain 488 mg of 4-[2-chloro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-7-amine. (3) 610 μL of triethylamine was added to a solution of 488 mg of 4-[2-chloro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazin-7-amine in 30 mL of dichloromethane, and a solution of 353 mg of 2-chloro-5-nitrobenzoyl chloride in 5 mL of dichloromethane was added dropwise. The reaction solution was stirred at room temperature for 45 minutes, and water and dichloromethane were added to separate the layers. The organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), and further recrystallized using ethyl acetate and hexane to obtain 503 mg of 2-chloro-N-{4-[2-chloro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.7 Hz, 1H), 8.24 (dd, J = 8.7, 2.7 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.5, 1.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 6.96 (dd, J = 8.7, 2.3 Hz, 1H), 6.50 (d, J = 8.7 Hz, 1H), 4.32 (dd, J = 5.0, 3.2 Hz, 2H), 3.69 (t, J = 4.2 Hz, 2H)

[0119] Example 4 Synthesis of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-4-yl}-4-nitrobenzamide (1) 148 mg of sodium hydride (60%, dispersed in liquid paraffin) was added to a 10 mL solution of 4-nitroindole (500 mg), and the mixture was stirred at room temperature for 30 minutes. Then, 735 mg of 3-chloro-4-fluorobenzotrifluoride was added and stirred at room temperature for 7 hours. After cooling, water and a mixed solution of hexane:ethyl acetate = 1:1 were added and the mixture was separated. The obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 10:1), and the solvent was distilled off under reduced pressure to obtain 898 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-nitro-1H-indole. (2) 123 mg of reduced iron and 94 mg of ammonium chloride were added to 10 mL of a mixed solution of 150 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-nitro-1H-indole in ethanol:water=2:1, and the mixture was stirred for 2 hours at 90° C. The reaction solution was filtered using silica gel to obtain 112 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indole-4-amine. (3) 49 μL of triethylamine was added to a solution of 100 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-4-amine in 3 mL of dichloromethane, and a solution of 77 mg of 2-chloro-5-nitrobenzoyl chloride in 2 mL of dichloromethane was slowly added dropwise and stirred at room temperature for 2 hours. Then, water was added to the reaction solution, and the mixture was separated using dichloromethane. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by recrystallization using ethyl acetate and hexane to obtain 72 mg of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-4-yl}-4-nitrobenzamide. 1H-NMR (400 MHz, ACETONE-D6) δ 9.80 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.36 (dd, J = 8.8, 2.4 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 7.6, 3.6 Hz, 1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.86 (t, J = 7.6 Hz, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 3.6 Hz, 1H)

[0120] Example 5 Synthesis of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-4-yl}-5-nitrobenzamide (1) 1-[2-chloro-4-(trifluoromethyl)phenyl]-4-nitro-1H-indole 121 mg in trifluoroacetic acid 3 mL solution was added with sodium borohydride 40 mg under ice cooling, and stirred at room temperature for 2 hours. Then, saturated aqueous sodium bicarbonate solution was added to neutralize, and ethyl acetate was added to separate the layers. The organic layer obtained was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate=6:1), and the solvent was distilled off under reduced pressure to obtain 1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indole-4-amine 56 mg. (2) 24 μL of triethylamine and 39 mg of 2-chloro-5-nitrobenzoyl chloride were added to a 3 mL solution of 50 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-4-amine, and the mixture was stirred at room temperature for 3.5 hours. Then, water and dichloromethane were added to separate the layers. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was recrystallized using ethyl acetate and hexane, filtered, and dried to obtain 40 mg of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-4-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, ACETN) δ 9.48 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.35 (dd, J = 8.8, 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.4, 2.0 Hz, 1H), 7.33 (dd, J = 8.0, 4.8 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 4.07 (t, J = 8.4 Hz, 2H), 3.28 (t, J = 8.4Hz, 2H)

[0121] Example 6 2-Chloro-N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,2,3,4-tetrahydrofuran Synthesis of 4-hydroxyquinoline-6-yl}-5-nitrobenzamide (1) 1,2,3,4-tetrahydro-6-nitroquinoline (500 mg) was dissolved in 3 mL of dimethylformamide, and 135 mg of sodium hydride (60%, dispersed in liquid paraffin) was added and stirred at room temperature for 5 minutes. Then, 507 μL of 2,3-dichloro-5-(trifluoromethyl)pyridine was added and stirred at room temperature for 19 hours. The reaction solution was separated by adding a mixture of water and ethyl acetate:hexane = 1:1. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 19:1) to obtain 571 mg of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 340 mg of ammonium chloride and 444 mg of reduced iron were added to a mixture of 571 mg of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-6-nitro-1,2,3,4-tetrahydroquinoline in 4 mL of ethanol, 2 mL of tetrahydrofuran, and 2 mL of water, and the mixture was stirred at 90° C. for 1 hour. The reaction solution was filtered using silica gel, and the filtrate was evaporated under reduced pressure to obtain 525 mg of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,2,3,4-tetrahydroquinolin-6-amine. 1 mL of triethylamine was added to a solution of 525 mg of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,2,3,4-tetrahydroquinolin-6-amine in 40 mL of dichloromethane, and a solution of 384 mg of 2-chloro-5-nitrobenzoyl chloride in 5 mL of dichloromethane was slowly added dropwise and stirred at room temperature for 1 hour. The reaction solution was distilled under reduced pressure, and 40 mL of acetone and 50 mL of water were added to the obtained solid, and the solid was stirred at room temperature for 10 minutes, and then filtered. The obtained solid was washed with water and air-dried to obtain 768 mg of 2-chloro-N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.61 (d, J = 2.5 Hz, 1H), 8.54 (s, 1H), 8.25 (dd, J = 8.9, 2.7 Hz, 1H), 7.87 (s, 1H), 7.68-7.64 (m, 2H), 7.57 (s, 1H), 7.17 (dd, J = 8.4, 2.6 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 3.84 (t, J = 6.0 Hz, 2H), 2.91 (t, J = 6.5 Hz, 2H), 2.09 (t, J = 6.2Hz, 2H)

[0122] Example 7 2-Chloro-N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydro-1H- Synthesis of indol-5-yl}-5-nitrobenzamide (1) 5-nitroindoline 1.50 g in dimethylformamide 10 mL solution was added with sodium hydride (60%, dispersed in liquid paraffin) 512 mg, stirred at room temperature for 30 minutes, then 2,3-dichloro-5-(trifluoromethyl)pyridine 1.65 mL was added dropwise, and stirred at room temperature for 26 hours. Then, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 4:1), and the solvent was distilled off under reduced pressure to obtain 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-5-nitro-2,3-dihydro-1H-indole 2.53 g. (2) 2.43 g of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-5-nitro-2,3-dihydro-1H-indole in 10 mL of a mixture of ethanol and water (3:2) was added to 1.97 g of reduced iron and salt. 1.51 g of ammonium chloride was added, and the mixture was stirred for 2 hours at 90° C. The reaction solution was filtered using Celite, and the solvent was distilled off under reduced pressure to obtain 3.11 g of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydro-1H-indol-5-amine as a crude product. (3) 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydro-1H-indol-5-amine 150 mg in dichloromethane 10 mL solution was added with triethylamine 146 μL and 2-chloro-5-nitrobenzoyl chloride 210 mg, stirred at room temperature for 3.5 hours, and then 2 mL of ammonia water (25%) was added and stirred at room temperature for 30 minutes. After that, hydrochloric acid was added to neutralize, and water and dichloromethane were added to separate the liquid. The obtained organic layer was separated, washed with saturated saline, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was recrystallized using ethyl acetate and hexane, filtered and dried to obtain 2-chloro-N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydro-1H-indol-5-yl}-5-nitrobenzamide 8 mg. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.63 (d, J = 2.8 Hz, 1H), 8.45 (s, 1H), 8.27 (dd, J = 8.8, 2.8 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.73 (s, 2H), 7.66 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.32 (t, J = 8.4 Hz, 2H), 3.23 (t, J = 8.4 Hz, 2H)

[0123] Example 8 Synthesis of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-5-yl}-5-nitrobenzamide (1) 345 mg of sodium hydride (60%, dispersed in liquid paraffin) was added to a 10 mL solution of 1.00 g of 5-nitroindole in dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. 1.10 mL of 3-chloro-4-fluorobenzotrifluoride was then added dropwise, and the mixture was stirred at room temperature for 26 hours. The mixture was then separated using water and a mixed solution of hexane:ethyl acetate=1:1. The organic layer obtained was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate=4:1), and the solvent was removed under reduced pressure to obtain 1.96 g of 1-[2-chloro-4-(trifluoromethyl)phenyl]-5-nitro-1H-indole. (2) 1.56 g of reduced iron and 1.19 g of ammonium chloride were added to 10 mL of a mixed solution of 1.90 g of 1-[2-chloro-4-(trifluoromethyl)phenyl]-5-nitro-1H-indole in ethanol:water=3:2, and the mixture was stirred at 90° C. for 2 hours. The reaction solution was filtered using Celite, and the solvent was distilled off under reduced pressure to obtain 1.34 g of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indole-5-amine as a crude product. (3) 1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-5-amine (150 mg) in dichloromethane (10 mL) was added with triethylamine (147 μL) and 2-chloro-5-nitrobenzoyl chloride (212 mg), and stirred at room temperature for 3.5 hours. Then, 2 mL of aqueous ammonia (25%) was added and stirred at room temperature for 30 minutes. After neutralization with hydrochloric acid, water and dichloromethane were added to separate the layers. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was recrystallized using ethanol and hexane, filtered and dried to obtain 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-5-yl}-5-nitrobenzamide (80 mg). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.65 (d, J = 2.4 Hz, 1H), 8.26 (dd, J = 8.8, 2.8 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.90-7.88 (m, 2H), 7.70 (dd, J = 8.6, 1.6 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.30 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H)

[0124] Example 9 Synthesis of 2-bromo-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-5-yl}-5-nitrobenzamide In a solution of 150 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-5-amine in 10 mL of dichloromethane, 147 μL of triethylamine and 238 mg of 2-bromo-5-nitrobenzoic acid were added to 10 mL of dichloromethane, 104 μL of oxalyl chloride, and 1 drop of dimethylformamide, and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. After stirring at room temperature for 3.5 hours, 3 mL of aqueous ammonia (25%) was added and stirred at room temperature for 30 minutes. After neutralizing with hydrochloric acid, water and dichloromethane were added and the mixture was separated. The obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was recrystallized using ethanol and hexane, filtered and dried to obtain 51 mg of 2-bromo-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1H-indol-5-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.53 (d, J = 2.8 Hz, 1H), 8.16 (dd, J = 8.4, 2.8 Hz, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.69 (s, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.29 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H)

[0125] Example 10 Synthesis of 2-chloro-N-[1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) 1,2,3,4-tetrahydro-6-nitroquinoline (500 mg) was dissolved in 5 mL of dimethylformamide, and 135 mg of sodium hydride (60%, dispersed in liquid paraffin) was added and stirred at room temperature for 10 minutes. Then, 666 mg of 2,3,5-trichloropyridine was added and stirred at 90 °C for 7 hours. Water and a mixture of ethyl acetate and hexane (1:1) were added to the reaction solution and the mixture was separated. The organic layer obtained was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 424 mg of 1-(3,5-dichloropyridin-2-yl)-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 200 mg of 1-(3,5-dichloropyridin-2-yl)-6-nitro-1,2,3,4-tetrahydroquinoline was added to a mixture of 4 mL of ethanol, 2 mL of tetrahydrofuran, and 2 mL of water, and ammonia chloride was added. 132 mg of ammonium and 172 mg of reduced iron were added, and the mixture was stirred for 1 hour at 90° C. The reaction solution was filtered through silica gel, and the filtrate was evaporated under reduced pressure to obtain 197 mg of 1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-amine. (3) To a solution of 197 mg of 1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-amine in 30 mL of dichloromethane, add 258 μL of triethylamine. A solution of 149 mg of nitrobenzoyl chloride in 5 mL of dichloromethane was slowly added dropwise and stirred at room temperature for 1 hour. The reaction solution was distilled under reduced pressure, and 40 mL of acetone and 50 mL of water were added to the resulting residue and stirred at room temperature for 10 minutes. The precipitated solid was collected by filtration, washed with water, and air-dried to obtain 267 mg of 2-chloro-N-[1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.56-8.64 (1H), 8.30 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 8.9, 2.7 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.65-7.62 (m, 2H), 7.50 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.7, 2.5 Hz, 1H), 6.40 (d, J = 8.7 Hz, 1H), 3.72 (t, J = 5.7 Hz, 2H), 2.91 (t, J = 6.5 Hz, 2H), 2.11-2.05 (m, 2H)

[0126] Example 11 Synthesis of 2-chloro-N-[1-(5-chloro-3-methylpyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) 500 mg of 1,2,3,4-tetrahydro-6-nitroquinoline, 695 mg of 2-bromo-5-chloro-3-methylpyridine, 539 mg of sodium tert-butoxide, 64 mg of tris(dibenzylideneacetone)dipalladium(0) and 122 mg of Xantphos were dissolved in 6 mL of 1,4-dioxane and stirred at 90 ° C for 30 minutes. Insoluble components were removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) and further purified by preparative thin layer chromatography (chloroform:hexane = 9:1) to obtain 28 mg of 1-(5-chloro-3-methylpyridin-2-yl)-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 20 mg of ammonium chloride and 26 mg of reduced iron were added to a mixed solution of 28 mg of 1-(5-chloro-3-methylpyridin-2-yl)-6-nitro-1,2,3,4-tetrahydroquinoline in 1 mL of ethanol and 0.5 mL of water, and the mixture was stirred at 90°C for 1 hour. The reaction solution was filtered using silica gel, and the filtrate was distilled under reduced pressure to obtain 25 mg of 1-(5-chloro-3-methylpyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-amine. The obtained 25 mg of 1-(5-chloro-3-methylpyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-amine was dissolved in 2 mL of dichloromethane, and triethyl ether was added. 39 μL of 2-chloro-5-nitrobenzoyl chloride was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was then distilled under reduced pressure, and the mixture was recrystallized using acetone and hexane to obtain 22 mg of 2-chloro-N-[1-(5-chloro-3-methylpyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.60 (d, J = 2.7 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.24 (dd, J = 8.7, 2.7 Hz, 1H), 7.64-7.61 (m, 2H), 7.54 (d, J = 2.5 Hz, 1H), 7.44 (s, 1H), 7.08 (dd, J = 8.8, 1.9 Hz, 1H), 6.17 (d, J = 8.9 Hz, 1H), 3.66 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 6.5 Hz, 2H), 2.12-2.08 (m, 5H)

[0127] Example 12 Synthesis of 2-bromo-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide To a solution of 166 mg of 2-bromo-5-nitrobenzoic acid in 5 mL of dichloromethane, 131 μL of oxalyl chloride and 1 drop of dimethylformamide were added and stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure to obtain 2-bromo-5-nitrobenzoyl chloride. To a solution of 200 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-amine in 10 mL of dichloromethane, 256 μL of triethylamine was added, and the resulting solution of 2-bromo-5-nitrobenzoyl chloride in 3 mL of dichloromethane was added dropwise, and the mixture was stirred at room temperature for 40 minutes. Water was then added to the reaction solution, and the mixture was separated using dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), and further recrystallized using ethyl acetate and hexane to obtain 218 mg of 2-bromo-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.46 (d, J = 2.5 Hz, 1H), 8.14 (dd, J = 8.8, 2.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.76 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.47-7.47 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.04 (dd, J = 8.7, 2.1 Hz, 1H), 6.25 (d, J = 8.7 Hz, 1H), 3.58 (t, J = 5.4 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H), 2.12-2.06 (m, 2H)

[0128] Example 13 Synthesis of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl}-5-nitrobenzamide (1) A solution of 2.00 g of 5-nitroquinoline in 30 mL of methanol was cooled on ice and diluted with nickel(II) chloride. 16.4 g of hexahydrate was added, and 9.12 g of sodium borohydride powder was added little by little, and the mixture was stirred for 30 minutes under ice cooling. Water was then slowly added to the reaction solution, and the mixture was separated using dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain 1.10 g of 1,2,3,4-tetrahydroquinolin-5-amine. (2) 633 μL of acetonylacetone and 172 μL of trifluoroacetic acid were added to a solution of 940 mg of 1,2,3,4-tetrahydroquinolin-5-amine in 1 mL of dichloromethane, and the mixture was stirred at room temperature for 48 hours. After that, dichloromethane and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution, and the mixture was separated. The organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product obtained was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 710 mg of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1,2,3,4-tetrahydroquinoline. (3) 8 mg of tris(dibenzylideneacetone)dipalladium(0) and 17 mg of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl were dissolved in 3 mL of toluene, substituted with nitrogen, and stirred at 90 °C for 15 minutes. Then, 120 mg of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1,2,3,4-tetrahydroquinoline, 98 μL of 3-chloro-4-iodobenzotrifluoride, and 56 mg of sodium tert-butoxide were added to the reaction solution, and the mixture was further stirred at 90 °C for 15 hours. Then, the reaction solution was filtered through Celite, and the filtrate was distilled under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to obtain 82 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1,2,3,4-tetrahydroquinoline. (4) 1-[2-chloro-4-(trifluoromethyl)phenyl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1,2,3,4-tetrahydroquinoline 44 mg in ethanol 2 mL and water 1 mL was mixed with hydroxylamine hydrochloride 113 mg and triethylamine 61 μL, and heated under reflux for 19 hours. Then, water and ethyl acetate were added and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain 1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline-5-amine 11 mg. (5) 14 μL of triethylamine was added to a solution of 11 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-5-amine in 2.5 mL of dichloromethane, and a solution of 8 mg of 2-chloro-5-nitrobenzoyl chloride in 1 mL of dichloromethane was added dropwise and stirred at room temperature for 50 minutes. Then, water and dichloromethane were added to the reaction solution and the mixture was separated. The organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), and then recrystallized using chloroform and hexane to obtain 9 mg of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-5-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, DMSO-D6) δ 10.08 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 8.34 (dd, J = 8.8, 2.6 Hz, 1H), 8.00 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 6.94-6.92 (m, 2H), 6.04 (d, J = 7.3 Hz, 1H), 3.53 (t, J = 4.9 Hz, 2H), 2.84 (t, J = 6.3 Hz, 2H), 2.05-1.98 (m, 2H)

[0129] Example 14 Synthesis of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide (1) 1.37 g of triphenylphosphine, 1.33 g of iodine, and 128 mg of 4-dimethylaminopyridine were added to a solution of 1.00 g of 2-chloro-4-(trifluoromethyl)benzyl alcohol in 10 mL of dichloromethane, and the mixture was stirred at room temperature for 19 hours. Then, water and dichloromethane were added and the mixture was separated. The organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19) to obtain 1.21 g of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene. (2) 54 mg of sodium hydride (60%, dispersed in liquid paraffin) and 432 mg of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene were added to a solution of 200 mg of 1,2,3,4-tetrahydro-6-nitroquinoline in 3 mL of dimethylformamide, and the mixture was stirred at room temperature for 13 hours. After that, water and a mixed solution of ethyl acetate:hexane = 1:1 were added to the reaction solution and the liquids were separated. The obtained organic layer was washed with water and saturated saline, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4) to obtain 271 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-6-nitro-1,2,3,4-tetrahydroquinoline. (3) 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-6-nitro-1,2,3,4-tetrafluoroethane To a mixture of 271 mg of tetrahydroquinoline in 4 mL of ethanol, 4 mL of tetrahydrofuran, and 2 mL of water, 156 mg of ammonium chloride and 204 mg of reduced iron were added and stirred at 100 ° C for 2 hours. The reaction solution was filtered using silica gel to obtain 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-amine. The obtained 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-amine was dissolved in 3 mL of dichloromethane, 305 μL of triethylamine was added, and a solution of 193 mg of 2-chloro-5-nitrobenzoyl chloride in 2 mL of dichloromethane was added dropwise and stirred at room temperature for 25 minutes. Then, water and dichloromethane were added to the reaction solution to separate the liquids. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 302 mg of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.56 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 8.9, 2.7 Hz, 1H), 7.67-7.60 (m, 3H), 7.45 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.24 (d, J = 8.7 Hz, 1H), 4.55 (s, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H), 2.11-2.05 (m, 2H)

[0130] Example 15 Synthesis of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-6-yl}-5-nitrobenzamide (1) 342 mg of sodium hydride (60%, dispersed in liquid paraffin) was added to a 10 mL solution of 701 mg of 6-nitroindole in dimethylformamide, and the mixture was stirred at room temperature for 30 minutes, after which 0.7 mL of 3-chloro-4-fluorobenzotrifluoride was added and stirred at 50 °C for 7 hours. After cooling, water and a mixed solution of hexane:ethyl acetate = 1:1 were added and the mixture was separated. The obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 9:1), and the solvent was distilled off under reduced pressure to obtain 917 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-6-nitro-1H-indole. (2) 50 mg of sodium borohydride was added to 3 mL of a solution of 150 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-6-nitro-1H-indole in trifluoroacetic acid under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After that, a saturated aqueous solution of sodium bicarbonate was added to neutralize the mixture, and then ethyl acetate was added to separate the mixture. The organic layer obtained was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate=4:1), and the solvent was distilled off under reduced pressure to obtain 232 mg of 1-[2-chloro-4-(trifluoromethyl)phenyl]-6-nitro-2,3-dihydro-1H-indole. (3) 1-[2-chloro-4-(trifluoromethyl)phenyl]-6-nitro-2,3-dihydro-1H-indole (200 mg) in a 7.5 mL mixed solvent of ethanol:water=1.5:1 was added with reduced iron (163 mg) and ammonium chloride (125 mg), and the mixture was stirred at 90°C for 2 hours. After cooling, the mixture was filtered through Celite, and water and ethyl acetate were added to separate the mixture. The obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Then, 60 μL of triethylamine and 93 mg of 2-chloro-5-nitrobenzoyl chloride were added to a 5 mL solution of the obtained 130 mg in dichloromethane, and the mixture was stirred at room temperature for 1 hour. Then, water and dichloromethane were added to separate the mixture. The obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was recrystallized using ethyl acetate and hexane, filtered and dried to obtain 81 mg of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indol-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CDCL3) δ 8.49 (s, 1H), 8.19 (dd, J = 8.8, 2.8 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.96 (dd, J = 8.0, 2.0 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 4.01 (t, J = 8.0 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H)

[0131] Example 16 Synthesis of N-acetyl-2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide 18 mg of sodium hydride (60%, dispersed in liquid paraffin) was added to a 5 mL solution of 120 mg of 2-chloro-5-nitro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl-1,2,3,4-tetrahydroquinolin-6-yl}benzamide in tetrahydrofuran. After stirring at room temperature for 10 minutes, 65 μL of acetic anhydride was added and stirred at room temperature for 18 hours. Then, the mixture was separated into water and ethyl acetate. The organic layer obtained was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate=9:1), and the solvent was distilled off under reduced pressure to obtain 74 mg of N-acetyl-2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.4 Hz, 1H), 8.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.68 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 2.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.24 (d, J = 8.8 Hz, 1H), 4.55 (s, 2H), 3.44 (t, J = 6.4 Hz, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H), 2.11-2.07 (m, 2H)

[0132] Example 17 Synthesis of N-acetyl-2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide 16 mg of sodium hydride (60%, dispersed in liquid paraffin) was added to a 5 mL solution of 2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 10 minutes. 60 μL of acetic anhydride was added and the mixture was stirred at room temperature for 18 hours. The mixture was then separated with water and ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified using silica gel chromatography (hexane:ethyl acetate=9:1), and the solvent was removed under reduced pressure to obtain 82 mg of N-acetyl-2-chloro-N-{1-[2-chloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.7 Hz, 1H), 8.15 (dd, J = 8.7, 2.5 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.2, 2.1 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 8.5, 2.5 Hz, 1H), 6.20 (d, J = 8.7 Hz, 1H), 3.57 (d, J = 2.3 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H), 2.23 (s, 3H), 2.13-2.07 (m, 2H)

[0133] Example 18 Synthesis of N-(1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-chloro-5-nitrobenzamide (1) 102 mg of sodium hydride (60%, dispersed in liquid paraffin) was added to a 5 mL solution of 300 mg of 1,2,3,4-tetrahydro-6-nitroquinoline in dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. 0.24 mL of benzyl bromide was then added and stirred at room temperature for 30 minutes. The mixture was then separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer obtained was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate = 4:1), and the solvent was distilled off under reduced pressure to obtain 356 mg of 1-benzyl-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 312 mg of reduced iron and 239 mg of ammonium chloride were added to 7.5 mL of a mixed solution of 326 mg of 1-benzyl-6-nitro-1,2,3,4-tetrahydroquinoline in ethanol:water=3:2, and the mixture was stirred at 90°C for 1 hour. After cooling, the mixture was filtered through Celite, and water and ethyl acetate were added for liquid separation. The resulting organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 284 mg of 1-benzyl-1,2,3,4-tetrahydroquinolin-6-amine as a crude product. (3) 1-benzyl-1,2,3,4-tetrahydroquinolin-6-amine (270 mg) in 2 mL of dichloromethane solution was added with 170 μL of triethylamine and 249 mg of 2-chloro-5-nitrobenzoyl chloride, and stirred at room temperature for 10 minutes. Then, 2 mL of ammonia water (25%) was added and stirred at room temperature for 10 minutes. After that, hydrochloric acid was added to neutralize, and water and dichloromethane were added to separate the layers. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was recrystallized using chloroform and hexane, filtered, and dried to obtain 270 mg of N-(1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-chloro-5-nitrobenzamide. 1H-NMR (400 MHz, ACETONE-D6) δ 9.38 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.31 (dd, J = 8.8, 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.35-7.23 (m, 6H), 6.51 (d, J = 8.8 Hz, 1H), 4.53 (s, 2H), 3.42 (t, J = 5.6 Hz, 2H), 2.84 (s, 2H), 2.81 (d, J = 5.6 Hz, 3H)

[0134] Example 19 Synthesis of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide hydrochloride A solution of 100 mg of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide in 2 mL of ethyl acetate was cooled on ice, and then 100 μL of 4M hydrogen chloride / ethyl acetate was added and stirred for 30 minutes under ice cooling, and the mixture was further warmed to room temperature and stirred for 20 minutes. The solvent was then removed under reduced pressure, and the mixture was powdered with diethyl ether, filtered, and dried to obtain 65 mg of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide hydrochloride. 1H-NMR (500 MHz, CHLOROFORM-D) δ 9.07 (s, 1H), 8.55 (d, J = 2.9 Hz, 1H), 8.25 (dd, J = 8.9, 2.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.68 (s, 2H), 3.45 (t, J = 5.4 Hz, 2H), 2.98 (t, J = 6.3 Hz, 2H), 2.21 (t, J = 5.4 Hz, 2H)

[0135] Example 20 Synthesis of 2-chloro-5-nitro-N-{1-[2-(2,4-dichlorophenyl)ethyl]-1,2,3,4-tetrahydroquinolin-6-yl}benzamide (1) To a solution of 100 mg of 1,2,3,4-tetrahydro-6-nitroquinoline in 3 mL of dimethylformamide, 34 mg of sodium hydride (60%, dispersed in liquid paraffin) was added and stirred at room temperature for 20 minutes. Then, 0.1 mL of 2,4-dichlorophenethyl bromide was added dropwise and the mixture was stirred at room temperature for 2 hours. Then, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 9:1), and then the solvent was distilled off under reduced pressure to obtain 72 mg of 1-[2-(2,4-dichlorophenyl)ethyl]-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 159 mg of reduced iron and 122 mg of ammonium chloride were added to 1.5 mL of a mixed solution of 200 mg of 1-[2-(2,4-dichlorophenyl)ethyl]-6-nitro-1,2,3,4-tetrahydroquinoline in ethanol:water=3:2, and the mixture was stirred at 90° C. for 2.5 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 163 mg of 1-[2-(2,4-dichlorophenyl)ethyl]-1,2,3,4-tetrahydroquinolin-6-amine as a crude product. (3) 219 mg of 2-chloro-5-nitrobenzoyl chloride was added to a pyridine 5 mL solution of 160 mg of 1-[2-(2,4-dichlorophenyl)ethyl]-1,2,3,4-tetrahydroquinolin-6-amine, and the mixture was stirred at room temperature for 1.5 hours, and then 2 mL of ammonia water (25%) was added under ice cooling and stirred for 30 minutes. After that, hydrochloric acid was added to neutralize the mixture, and then ethyl acetate was added to separate the mixture. The organic layer obtained was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate=4:1), and the solvent was distilled off under reduced pressure to obtain 158 mg of 2-chloro-5-nitro-N-{1-[2-(2,4-dichlorophenyl)ethyl]-1,2,3,4-tetrahydroquinolin-6-yl}benzamide.

[0136] Example 21 Synthesis of 2-chloro-N-{1-[(2,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 413.5 mg of 6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 4 mL of dimethylformamide, 64.7 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 25 minutes. Then, 65.7 mg of 2,4-dichlorobenzyl bromide was added, and the mixture was stirred at 60° C. for 2 hours, and water was added to stop the reaction. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate=1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=9:1), and the solvent was distilled off under reduced pressure to obtain 544.6 mg of 1-[(2,4-dichlorophenyl)methyl]-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 304.1 mg of 1-[(2,4-dichlorobenzyl-6-nitro-1,2,3,4-tetrahydroquinoline] was dissolved in 4 mL of tetrahydrofuran, and then 248.4 mg of reduced iron and 190.4 mg of ammonium chloride were added to 6 mL of a mixed solution of ethanol:water = 2:1, and the mixture was heated and refluxed at 100 °C and stirred for 2 hours. After cooling, the mixture was filtered through silica gel and concentrated. Then, 3 mL of dichloromethane, 0.37 mL of triethylamine, 235 mL of 2-chloro-5-nitrobenzoyl chloride, and 1 mL of ethyl acetate were added. mg was added and stirred at room temperature for 20 minutes. After the reaction, water and dichloromethane were added and the mixture was separated, and the obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=3:1), and then the solvent was distilled off under reduced pressure to obtain 253.7 mg of 2-chloro-N-{1-[(2,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.7 Hz, 1H), 8.24 (dd, J = 8.7, 2.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.17 (dd, J = 8.1, 1.5 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.08 (dd, J = 8.7, 2.3 Hz, 1H), 6.26 (d, J = 8.7 Hz, 1H), 4.48 (s, 2H), 3.41 (t, J = 5.5 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H), 2.10-2.04 (m, 2H)

[0137] Example 22 Synthesis of 2-chloro-N-{1-[(2,4-difluorophenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 54 mg of sodium hydride (60% liquid paraffin dispersion) and 279 mg of 2,4-difluorobenzyl bromide were added to a solution of 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 5 mL of dimethyl sulfoxide, and the mixture was stirred at room temperature for 2 hours. Water was then added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate:hexane (1:1). The resulting organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 401 mg of 1-{(2,4-difluorophenyl)methyl]-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 311 mg of reduced iron and 239 mg of ammonium chloride were added to a mixture of 339 mg of 1-{(2,4-difluorophenyl)methyl]-6-nitro-1,2,3,4-tetrahydroquinoline, 4 mL of tetrahydrofuran, 4 mL of methanol, and 1 mL of water, and the mixture was stirred at 65 °C for 2 hours. The reaction mixture was then filtered through silica gel. The resulting residue was dissolved in 20 mL of dichloromethane and 1 mL of triethylamine, and 294 mg of 2-chloro-5-nitrobenzoyl chloride was added and stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 362 mg of 2-chloro-N-{1-[(2,4-difluorophenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.7 Hz, 1H), 8.24 (dd, J = 8.9, 2.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.17-7.11 (m, 2H), 6.86-6.79 (m, 2H), 6.43 (d, J = 8.7 Hz, 1H), 4.49 (s, 2H), 3.39 (t, J = 5.6 Hz, 2H), 2.85 (t, J = 6.3 Hz, 2H), 2.07-2.01 (m, 2H)

[0138] Example 23 Synthesis of 2-chloro-N-[1-(cyclohexylmethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) 54 mg of sodium hydride (dispersed in 60% liquid paraffin) and 239 mg of (bromomethyl)cyclohexane were added to a solution of 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 5 mL of dimethyl sulfoxide, and the mixture was stirred at room temperature for 26 hours. Water was then added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate:hexane (1:1). The organic layer obtained was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain 137 mg of 1-(cyclohexylmethyl)-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 139 mg of reduced iron and 107 mg of ammonium chloride were added to a mixture of 137 mg of 1-(cyclohexylmethyl)-6-nitro-1,2,3,4-tetrahydroquinoline, 2 mL of tetrahydrofuran, 2 mL of methanol, and 1 mL of water, and the mixture was stirred at 65 °C for 2 hours. The reaction mixture was then filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 10 mL of dichloromethane and 208 μL of triethylamine, and 132 mg of 2-chloro-5-nitrobenzoyl chloride was added and stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain 159 mg of 2-chloro-N-[1-(cyclohexylmethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58 (d, J = 2.7 Hz, 1H), 8.22 (dd, J = 8.7, 2.7 Hz, 1H), 7.63-7.61 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.7, 2.7 Hz, 1H), 6.49 (d, J = 8.7 Hz, 1H), 3.32 (t, J = 5.6 Hz, 2H), 3.04 (d, J = 6.9 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 1.96-1.90 (m, 2H), 1.78-1.67 (m, 7H), 1.21-1.18 (m, 2H), 0.96-0.93 (m, 2H)

[0139] Example 24 Synthesis of 2-chloro-5-nitro-N-(1-hexyl-1,2,3,4-tetrahydroquinolin-6-yl)benzamide (1) 54 mg of sodium hydride (dispersed in 60% liquid paraffin) and 222 mg of 1-bromohexane were added to a solution of 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 5 mL of dimethyl sulfoxide, and the mixture was stirred at room temperature for 26 hours. Water was then added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate:hexane (1:1). The organic layer obtained was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4) to obtain 197 mg of 1-hexyl-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 210 mg of reduced iron and 161 mg of ammonium chloride were added to a mixture of 197 mg of 1-hexyl-6-nitro-1,2,3,4-tetrahydroquinoline, 2 mL of tetrahydrofuran, 2 mL of methanol, and 1 mL of water, and the mixture was stirred at 65 °C for 2 hours. The reaction mixture was then filtered using silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 10 mL of dichloromethane and 314 μL of triethylamine, and 198 mg of 2-chloro-5-nitrobenzoyl chloride was added and stirred for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4) to obtain 246 mg of 2-chloro-5-nitro-N-(1-hexyl-1,2,3,4-tetrahydroquinolin-6-yl)benzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.5 Hz, 1H), 8.23 ​​(dd, J = 8.9, 2.7 Hz, 1H), 7.64-7.62 (m, 2H), 7.23-7.20 (m, 2H), 6.54 (d, J = 8.7 Hz, 1H), 3.30-3.22 (m, 4H), 2.77 (t, J = 6.3 Hz, 2H), 1.95 (dd, J = 6.3, 5.1 Hz, 2H), 1.56 (t, J = 7.5 Hz, 2H), 1.35-1.32 (m, 6H), 0.90 (t, J = 6.9Hz, 3H)

[0140] Example 25 Synthesis of N-{5-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl}-2-chloro-5-nitrobenzamide (1) A solution of 11.2 g of 2-amino-6-bromopyridine in 50 mL of concentrated sulfuric acid was cooled to 0°C, and 6.04 g of potassium nitrate was slowly added in small portions. The temperature was slowly raised to room temperature and the mixture was stirred for 2 hours. The reaction solution was added to ice water, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (ethyl acetate:hexane = 2:3 to 19:1) to obtain 7.01 g of 6-bromo-5-nitropyridin-2-amine. (2) 6-bromo-5-nitropyridin-2-amine (11.5 g) in toluene (150 mL) was added with acetonylacetone (6.81 mL) and p-toluenesulfonic acid monohydrate (91 mg) and heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-nitropyridine (14.1 g). (3) 2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-nitropyridine 1.9 g, (E)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborane-2-yl)-acrylic acid ester 2.14 g, 1,4-dioxane 72 mL, water 18 mL, sodium carbonate 3.53 g, bis(triphenylphosphine)palladium(II) dichloride 0.47 g were added and stirred at 80 °C for 22 hours under nitrogen atmosphere. Insoluble components of the reaction solution were removed by filtration and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:9 to 2:3) to obtain ethyl-3-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-nitropyridin-2-yl]prop-2-enoate 405 mg. (4) 304.7 mg of ethyl-3-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-nitropyridin-2-yl]prop-2-enoate and 102.8 mg of 10% palladium on carbon were added to 3 mL of methanol and 3 mL of ethyl acetate, and the mixture was stirred under a hydrogen atmosphere for 1 hour. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 3 mL of methanol, and 1.62 g of potassium hydroxide and 3 mL of water were added, followed by stirring at room temperature for 20 minutes under a nitrogen atmosphere. 6 mL of 6M hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was neutralized by adding an aqueous solution of sodium bicarbonate, and the mixture was separated using ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 183.9 mg of 6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one. (5) 6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one (183.9 mg) in dimethylformamide (3 mL) was added with 36.7 mg of sodium hydride (dispersed in 60% liquid paraffin) under ice cooling, and stirred at 0°C for 10 minutes under nitrogen atmosphere. 2-Chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene (293 mg) in dimethylformamide (3 mL) was slowly added dropwise to the reaction solution, and stirred at 0°C for 25 minutes. Water was added to the reaction solution, and the mixture was separated with a mixed solvent of ethyl acetate:hexane (1:1). The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 208.8 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one. (6) 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one (189.0 mg) in tetrahydrofuran (3 mL) was added with borane dimethylsulfide complex (206 μL) and stirred at 60 °C for 30 minutes under nitrogen atmosphere. While cooling the reaction solution with ice, 3 mL of methanol was slowly added dropwise. After that, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4) to obtain 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-6-(2,5-dimethyl-1H-pyrrol-1-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin (143.5 mg). (7) 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-6-(2,5-dimethyl-1H-pyrrol-1-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine 143.5 mg in ethanol 4 mL and water 2.0 mL was mixed with hydroxylamine hydrochloride 356.2 mg and stirred at 100 °C for 21 hours under nitrogen atmosphere. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction solution and the mixture was separated. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol:chloroform = 1:19) to obtain 5-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,6,7,8-tetrahydro-1,5-naphthyridine-2-amine 130.0 mg. (8) 5-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,6,7,8-tetrahydro-1,5-naphthyridin-2-amine 121.0 mg of pyridine 3 mL of solution was slowly added dropwise to 2-chloro-5-nitrobenzoyl chloride 171.4 mg of dichloromethane 3 mL under ice cooling. After stirring the reaction solution at 0 °C for 40 minutes, 2 mL of 28% ammonia water was added and stirred at 0 °C for 20 minutes. Then, a saturated aqueous ammonium chloride solution and ethyl acetate were added and the mixture was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 155.9 mg of N-{5-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl}-2-chloro-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.56 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H), 8.25 (dd, J = 8.9, 2.7 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 1.1 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.47 (dd, J = 8.0, 0.9 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.55 (s, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H), 2.19-2.13 (m, 2H)

[0141] Example 26 Synthesis of 2-chloro-N-[(1-adamantane)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 7.5 mL of aqueous hydrogen bromide (47%) was added to 516.1 mg of 1-adamantanemethanol, and the mixture was heated to reflux at 100° C. and stirred for 4 hours. The mixture was then neutralized with a saturated aqueous sodium bicarbonate solution, and dichloromethane was added to separate the layers. The resulting organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 684.5 mg of 1-bromomethyladamantane. (2) 300 mg of 6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 10 mL of dimethylformamide, 80.5 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 25 minutes. Then, 510.3 mg of 1-bromomethyladamantane was added, and the mixture was stirred at 100°C for 52 hours, and water was added to stop the reaction. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 4:1), and the solvent was distilled off under reduced pressure to obtain 108.3 mg of 1-[(adamantan-1-yl)]methyl]-6-nitro-1,2,3,4-tetrahydroquinoline. (3) 100 mg of 1-[(adamantan-1-yl)]methyl]-6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 2 mL of tetrahydrofuran, and then 119.7 mg of reduced iron and 79.8 mg of ammonium chloride were added to 3 mL of a mixed solution of ethanol:water = 2:1, and the mixture was heated and refluxed at 100 °C for 2 hours. After cooling, the mixture was filtered through silica gel and concentrated. Then, 3 mL of dichloromethane, 0.13 mL of triethylamine, and 81 mg of 2-chloro-5-nitrobenzoyl chloride were added, and the mixture was stirred at room temperature for 20 minutes. After the reaction, water and dichloromethane were added and the mixture was separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. Ethyl acetate and hexane were added to the crude product obtained, and the product was recrystallized. The crystals were collected on a membrane filter to obtain 20.0 mg of 2-chloro-N-[(1-adamantane)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.61 (d, J = 2.7 Hz, 1H), 8.25 (dd, J = 8.8,2.6 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7.19 (dd, J = 8.8, 2.6 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 3.30 (t, J = 5.5 Hz, 2H), 2.92 (s, 2H), 2.83 (t, J = 6.3 Hz, 2H), 1.99-1.93 (m, 5H), 1.74-1.62 (m, 12H)

[0142] Example 27 Synthesis of 2-chloro-N-(8-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-5-nitrobenzamide (1) 810 mg of 6-bromo-3,4,dihydro-1H-[1,8]naphthyridin-2-one was dissolved in 15 mL of dimethylformamide, 111.2 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 1.38 g of 2-chloro-4-(trifluoromethyl)benzyl iodide was added, and the mixture was stirred at room temperature for 17 hours, and water was added to stop the reaction. After stopping the reaction, the mixture was separated using water and a mixed solution of hexane:ethyl acetate=1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=4:1), and the solvent was distilled off under reduced pressure to obtain 1.164 g of 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3.4-dihydro-1,8-naphthyridin-2(1H)-one. (2) 100 mg of 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3.4-dihydro-1,8-naphthyridin-2(1H)-one, 52 mg of benzophenone imine, 32 mg of sodium tert-butoxide, 7.19 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 4.4 mg of tris(dibenzylideneacetone)dipalladium(0), and 3 mL of toluene were mixed and stirred at 100 °C for 4.5 hours under nitrogen. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=4:1), and the solvent was then distilled off under reduced pressure to obtain 60.2 mg of 6-[(diphenylmethylidyne)amino]-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one. (3) 60 mg of 6-[(diphenylmethylidyne)amino]-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one and 1.5 mL of tetrahydrofuran were mixed, 0.2 mL of 2N hydrochloric acid was added, and the mixture was stirred at room temperature under nitrogen for 2.5 hours. After the reaction was stopped, the mixture was separated using a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (methanol:chloroform = 1:20), and the solvent was distilled off under reduced pressure to obtain 29.6 mg of 6-amino-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one. (4) 6-Amino-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one was dissolved in 3 mL of tetrahydrofuran, and 0.460 mL of tetrahydrofuran borane (8.5% solution in tetrahydrofuran, 0.9 mol / L) was added under 0° C. conditions. The mixture was then stirred under nitrogen at 60° C. for 2 hours. Methanol was added to stop the reaction, and the solvent was distilled off to obtain a crude product. The crude product was purified using preparative thin-layer chromatography, and the solvent was distilled off under reduced pressure to obtain 10.2 mg of 8-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-amine. (5) 10 mg of 8-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-amine was dissolved in 3 mL of pyridine, and 32 mg of 2-chloro-5-nitrobenzyl chloride was added and stirred for 20 minutes. After stirring, the mixture was cooled to 0°C, 2 mL of aqueous ammonia was added, and stirred for 60 minutes. Then, 2 mL of aqueous ammonia chloride was added. After the reaction, the reaction was stopped and the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified by thin layer chromatography to obtain 20 mg of 2-chloro-N-(8-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.7 Hz, 1H), 8.25 (dd, J = 8.9, 2.7 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 2.5 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 4.96 (s, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H)

[0143] Example 28 Synthesis of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl)-5-nitrobenzamide (1) 0.233 mL of oxalyl chloride was added to a mixed solution of 500 mg of 2-chloro-5-nitroisonicotinic acid and 10 mL of dichloromethane, and 3 drops of dimethylformamide were slowly added. The mixture was stirred for 1 hour while warming to room temperature. The reaction solution was concentrated under reduced pressure. 10 mL of dichloromethane and 365.9 mg of N,O-dimethylhydroxylamine hydrochloride were added to the resulting residue and cooled on ice, and 1.03 mL of triethylamine was added under ice cooling and stirred for 2 hours while warming to room temperature. Water and dichloromethane were added to the reaction solution to separate the layers, and the resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:3) to obtain 545.4 mg of 2-chloro-N-methoxy-N-methyl-5-nitropyridine-4-carboxamide. (2) 2-chloro-N-methoxy-N-methyl-5-nitropyridine-4-carboxamide (545.0 mg) in dimethyl sulfoxide (20 mL) was mixed with triethylamine (0.688 mL) and 4-methoxybenzylamine (0.345 mL) and stirred at room temperature for 5 hours under nitrogen atmosphere. The reaction solution was separated by adding water and a mixed solvent of ethyl acetate:hexane (1:1), and the obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by recrystallization using ethyl acetate and hexane to obtain N-methoxy-2-{[(4-methoxyphenyl)methyl]amino}-N-methyl-5-nitropyridine-4-carboxamide (677.8 mg). (3) To a solution of 193 mg of N-methoxy-2-{[(4-methoxyphenyl)methyl]amino}-N-methyl-5-nitropyridine-4-carboxamide in 20 mL of tetrahydrofuran, 2.78 mL of diisobutylaluminum hydride (19% hexane solution, about 1.0 mol / L) was slowly added dropwise under ice cooling, and the mixture was stirred at 0 °C for 20 minutes under a nitrogen atmosphere. 300 mg of ammonium chloride was added to the reaction solution, which was then filtered using silica gel and washed with a mixed solution of ethyl acetate:methanol = 20:1. The obtained filtrate was concentrated under reduced pressure. 10 mL of tetrahydrofuran, 10 mL of dichloromethane, and 232 mg of (triphenylphosphoranylidene)ethyl acetate were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:5) to obtain 85.4 mg of ethyl 3-(2-{[(4-methoxyphenyl)methyl]amino}-5-nitropyridin-4-yl)prop-2-enoate (E:Z = 2:1). (4) A mixture of 120 mg of ethyl 3-(2-{[(4-methoxyphenyl)methyl]amino}-5-nitropyridin-4-yl)prop-2-enoate, 35.7 mg of 10% palladium on carbon, 1.5 mL of methanol, and 1.5 mL of ethyl acetate was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 1 mL of methanol, and 565.3 mg of potassium hydroxide and 1 mL of water were added, and the mixture was stirred at room temperature for 20 minutes under a nitrogen atmosphere. 4 mL of 6M hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized by adding a saturated aqueous solution of sodium bicarbonate, and the mixture was separated using ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 95.5 mg of 6-{[(4-methoxyphenyl)methyl]amino}-3,4-dihydro-1,7-naphthyridin-2(1H)-one. (5) 6-{[(4-methoxyphenyl)methyl]amino}-3,4-dihydro-1,7-naphthyridin-2(1H)-one 95.5 mg in dimethylformamide 5 mL was added with sodium hydride (dispersed in 60% liquid paraffin) 14.8 mg, and stirred at room temperature for 15 minutes under nitrogen atmosphere. 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene 118.8 mg in dimethylformamide 2 mL was slowly added dropwise to the reaction solution, and stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was separated with a mixed solvent of ethyl acetate:hexane (1:1). The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4 to 1:1) to obtain 134.8 mg of 6-(4-methoxybenzylamino)-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,7-naphthyridin-2(1H)-one. (6) 6-(4-methoxybenzylamino)-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,7-naphthyridin-2(1H)-one (100 mg) in tetrahydrofuran (3 mL) was added with borane dimethylsulfide complex (1.05 mL) and stirred at 60° C. for 1.5 hours under nitrogen atmosphere. While cooling the reaction solution with ice, methanol (5 mL) was slowly added dropwise. The reaction solution was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 76.6 mg of N-(4-methoxybenzyl)-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-1,7-naphthyridin-6-amine. (7) N-(4-methoxybenzyl)-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-1,7-naphthyridin-6-amine (76.6 mg) in dichloromethane (5 mL) was added with trifluoroacetic acid (1.50 mL) while cooling with ice, and stirred at 0 °C under nitrogen atmosphere for 40 minutes. The reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, and dichloromethane was added to separate the solution. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4 to 1:1) and purified by preparative thin layer chromatography (ethyl acetate:hexane = 2:3) to obtain 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-1,7-naphthyridin-6-amine (23.1 mg). (8) To a solution of 15 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-1,7-naphthyridin-6-amine in 1 mL of pyridine, a solution of 21.2 mg of 2-chloro-5-nitrobenzoyl chloride in 1 mL of dichloromethane was slowly added dropwise under ice cooling. The reaction solution was stirred at room temperature for 1 hour, and then 1 mL of 28% aqueous ammonia was added and stirred at 0°C for 30 minutes. Thereafter, a saturated aqueous solution of ammonium chloride and ethyl acetate were added to separate the mixture. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (ethyl acetate:hexane = 1:4) to obtain 8.7 mg of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl)-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.61 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.23 ​​(dd, J = 8.7, 2.7 Hz, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 4.55 (s, 2H), 3.45 (t, J = 5.6 Hz, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.11-2.08 (m, 2H)

[0144] Example 29 Synthesis of 2-chloro-N-[1-(cyclopropylmethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) 80.8 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 300 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 5 mL of dimethylformamide, and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. 272.7 mg of (bromomethyl)cyclopropane was further added, and the mixture was stirred at room temperature for 21 hours. Water was then added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate:hexane (1:1). The organic layer obtained was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate:hexane = 1:4) to obtain 328.2 mg of 1-(cyclopropylmethyl)-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 1-(cyclopropylmethyl)-6-nitro-1,2,3,4-tetrahydroquinoline (152.7 mg) in tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL) were mixed with reduced iron (183.6 mg) and ammonium chloride (140.7 mg) and stirred under nitrogen atmosphere at 60°C for 2 hours. Reduced iron (140 mg) and ammonium chloride (120 mg) were further added and stirred under nitrogen atmosphere at 60°C for 1 hour. The reaction solution was filtered using silica gel, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (15 mL), and triethylamine (0.275 mL) was added. A solution of 2-chloro-5-nitrobenzoyl chloride (173.6 mg) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. Saturated ammonium chloride water and chloroform were added to the reaction solution, and the mixture was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4 to 1:0) to obtain 198.8 mg of 2-chloro-N-[1-(cyclopropylmethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.60 (d, J = 2.5 Hz, 1H), 8.24 (dd, J = 8.9, 2.7 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.58 (s, 1H), 7.25-7.21 (m, 2H), 6.68 (d, J = 8.7 Hz, 1H), 3.36 (t, J = 5.6 Hz, 2H), 3.18 (d, J = 6.2 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 1.99-1.96 (m, 2H), 1.09-1.01 (m, 1H), 0.54-0.50 (m, 2H), 0.22 (q, J = 5.1 Hz, 2H)

[0145] Example 30 Synthesis of 2-chloro-5-nitro-N-[1-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroquinolin-6-yl]benzamide (1) 101.0 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 300 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 5 mL of dimethylformamide, and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. 0.511 mL of pivalic anhydride was further added, and the mixture was stirred at room temperature for 20 hours. Then, water and ethyl acetate were added to the reaction solution and the mixture was separated. The organic layer obtained was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate:hexane = 3:17 to 3:2) to obtain 433.8 mg of 2,2-dimethyl-1-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-one. (2) To a solution of 300 mg of 2,2-dimethyl-1-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-one in 10 mL of tetrahydrofuran, 6.35 mL of borane dimethylsulfide complex was slowly added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After further stirring the reaction solution at 60 °C for 2 hours, 5 mL of methanol was slowly added dropwise while cooling the reaction solution on ice. The reaction solution was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 3:17 to 1:1) to obtain 226.8 mg of 1-(2,2-dimethylpropyl)-6-nitro-1,2,3,4-tetrahydroquinoline. (3) 1-(2,2-dimethylpropyl)-6-nitro-1,2,3,4-tetrahydroquinoline (227.8 mg) in tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL) were mixed with reduced iron (191.7 mg) and ammonium chloride (146.9 mg), and the mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (15 mL), and triethylamine (0.287 mL) was added. A solution of 2-chloro-5-nitrobenzoyl chloride (181.2 mg) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Water and dichloromethane were added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9 to 1:1) to obtain 97.9 mg of 2-chloro-5-nitro-N-[1-(2,2-dimethylpropyl)-1,2,3,4-tetrahydroquinolin-6-yl]benzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.3 Hz, 1H), 8.23 ​​(dd, J = 8.7, 2.7 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.59 (s, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 8.9, 2.5 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 3.32 (t, J = 5.4 Hz, 2H), 3.04 (s, 2H), 2.82 (t, J = 6.4 Hz, 2H), 1.97-1.91 (m, 2H), 1.00 (s, 9H)

[0146] Example 31 Synthesis of 2-chloro-N-[1-(3-methylbut-2-en-1-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 4 mL of dimethylformamide, 53.9 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 200 mg of 1-bromo-3-methyl-butene was added, and the mixture was stirred at room temperature for 18 hours, and water was added to stop the reaction. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (gradient extraction from hexane:ethyl acetate = 9:1 to hexane:ethyl acetate = 4:1), and the solvent was distilled off under reduced pressure to obtain 267.8 mg of 1-(3-methylbut-2-en-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 200 mg of 1-(3-methylbut-2-en-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 3 mL of ethanol and 1.5 mL of water, and then 313 mg of reduced iron and 240 mg of ammonium chloride were added and stirred at 100 °C for 1 hour under reflux. After cooling, the mixture was filtered through silica gel and concentrated. Then, 5 mL of dichloromethane, 0.47 mL of triethylamine, and 300 mg of 2-chloro-5-nitrobenzoyl chloride were added and stirred at room temperature for 1 hour. After the reaction, water and dichloromethane were added and the mixture was separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. Then, 8 mL of pyridine and 2 mL of ammonia were added to the crude product and stirred at 0 °C for 15 minutes. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=7:3), and the solvent was then distilled off under reduced pressure to obtain 134 mg of 2-chloro-N-[1-(3-methylbut-2-en-1-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, DMSO-D6) δ 10.25 (s, 1H), 8.31 (d, J = 2.7 Hz, 1H), 8.27 (dd, J = 8.7, 2.7 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.23-7.19 (m, 2H), 6.51 (d, J = 8.7 Hz, 1H), 5.12 (t, J = 6.4 Hz, 1H), 3.79 (d, J = 6.4 Hz, 2H), 3.13 (t, J = 5.6 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H), 1.86-1.80 (m, 2H), 1.66 (d, J = 6.6 Hz, 6H)

[0147] Example 32 Synthesis of 2-chloro-N-{1-[(oxan-4-yl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 200 mg of tetrahydropyran-4-methanol was dissolved in 10 mL of dichloromethane, and then 546 mg of triphenylphosphine, 536.5 mg of iodine, and 142 mg of imidazole were added and stirred at room temperature for 30 minutes. Water was then added and the mixture was separated with dichloromethane. The organic layer was separated, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=9:1), and the solvent was distilled off under reduced pressure to obtain 305.2 mg of 4-(iodomethyl)oxane. (2) 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 5 mL of dimethylformamide, 53.9 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 304 mg of 4-(iodomethyl)oxane was added, and the mixture was stirred at room temperature for 18 hours, and water was added to stop the reaction. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 1:1), and the solvent was distilled off under reduced pressure to obtain 40.2 mg of 1-[(oxan-4-yl)methyl]-6-nitro-1,2,3,4-tetrahydroquinoline. (3) 40.2 mg of 1-[(oxan-4-yl)methyl]-6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 3 mL of ethanol and 1.5 mL of water, and then 37.4 mg of reduced iron and 28.7 mg of ammonium chloride were added and the mixture was heated to reflux at 100 °C and stirred for 2 hours. After cooling, the mixture was filtered through silica gel and concentrated. Then, 5 mL of dichloromethane, 0.4 mL of triethylamine, and 35 mg of 2-chloro-5-nitrobenzoyl chloride were added and stirred at room temperature for 15 minutes. After the reaction, water and dichloromethane were added and the mixture was separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. After purification using silica gel chromatography (hexane:ethyl acetate=1:1), the solvent was distilled off under reduced pressure to obtain 24.1 mg of 2-chloro-N-{1-[(oxan-4-yl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.54 (d, J = 2.1 Hz, 1H), 8.21 (dd, J = 8.7, 1.6 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.27-7.20 (m, 2H), 6.49 (d, J = 8.5 Hz, 1H), 3.98 (dd, J = 11.3, 4.0 Hz, 2H), 3.39-3.31 (m, 4H), 3.12 (d, J = 7.1 Hz, 2H), 2.77 (t, J = 6.2 Hz, 2H), 2.04-1.91 (m, 4H), 1.66 (d, J = 12.3 Hz, 2H), 1.39-1.19 (m, 3H)

[0148] Example 33 Synthesis of 2-chloro-N-[1-(cycloheptylmethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) 282 mg of cycloheptane carboxylic acid was dissolved in 10 mL of dichloromethane, and 0.5 mL of oxalyl chloride was added. Then, one drop of dimethylformamide was added, and the mixture was stirred for 45 minutes. After the reaction, toluene was added, and the solvent was distilled off under reduced pressure to remove the oxalyl chloride, and cycloheptane carbonyl chloride was obtained. 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 10 mL of dimethylformamide, and 72 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 10 minutes. Then, the adjusted cycloheptane carbonyl chloride was added, and the mixture was stirred for 2 hours. After stirring, water was added to stop the reaction, and the mixture was separated using a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=7:3), and the solvent was distilled off under reduced pressure to obtain 264.8 mg of cycloheptyl(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methanone. (2) 100 mg of cycloheptyl(6-nitro-3,4-dihydroquinoline 1(2H)-yl)methanone was dissolved in 10 mL of tetrahydrofuran and cooled to 0°C. After cooling, 1.9 mL of borane-tetrahydrofuran complex solution (0.9M) was added and heated and stirred at 50°C. After the reaction, the mixture was cooled to 0°C, methanol was added to terminate the reaction, and the solvent was distilled off under reduced pressure to obtain a crude product. After purification using silica gel chromatography (hexane:ethyl acetate=4:1), the solvent was distilled off under reduced pressure to obtain 69.4 mg of 1-(cycloheptylmethyl)-6-nitro-1,2,3,4-tetrahydroquinoline. (3) 69.4 mg of 1-(cycloheptylmethyl)-6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 5 mL of ethanol and 1 mL of water, and then 134 mg of reduced iron and 103 mg of ammonium chloride were added and stirred at 100 °C for 1 hour and 30 minutes under reflux. After cooling, the mixture was filtered through silica gel and concentrated. Then, 5 mL of dichloromethane, 0.1 mL of triethylamine, and 73 mg of 2-chloro-5-nitrobenzoyl chloride were added and stirred at room temperature for 30 minutes. After the reaction, water and dichloromethane were added and the mixture was separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. After purification using silica gel chromatography (gradient extraction from hexane:ethyl acetate 9:1 to 1:1), the solvent was distilled off under reduced pressure to obtain 78.2 mg of 2-chloro-N-[1-(cycloheptylmethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58 (d, J = 2.5 Hz, 1H), 8.22 (dd, J = 8.7, 2.7 Hz, 1H), 7.62 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.19 (dd, J = 8.6, 2.6 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 3.30 (t, J = 5.5 Hz, 2H), 3.02 (d, J = 7.3 Hz, 2H), 2.77 (t, J = 6.3 Hz, 2H), 1.97-1.91 (m, 3H), 1.79-1.62 (m, 5H), 1.54-1.38 (m, 4H), 1.31-1.09 (m, 3H)

[0149] Example 34 Synthesis of 2-chloro-N-[1-(cycloheptanecarbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide Cycloheptyl(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methanone (160 mg) was dissolved in 3 mL ethanol and 1 mL water, and then reduced iron (148 mg) and ammonium chloride (113 mg) were added and stirred at 100°C for 2 hours under reflux. After cooling, the mixture was filtered through silica gel and concentrated. Then, dichloromethane (5 mL), triethylamine (0.2 mL), and 2-chloro-5-nitrobenzoyl chloride (140 mg) were added and stirred at room temperature for 30 minutes. After the reaction, water and dichloromethane were added to separate the liquids, and the resulting organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. After purification using silica gel chromatography (hexane:ethyl acetate 1:1), the solvent was distilled off under reduced pressure to obtain 78.2 mg of 2-chloro-N-[1-(cycloheptanecarbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.55 (d, J = 34.1 Hz, 2H), 8.22 (d, J = 8.0 Hz, 1H), 7.64-7.60 (m, 2H), 7.26 (d, J = 107.9 Hz, 2H), 3.70 (t, J = 5.8 Hz, 2H), 2.92 (s, 1H), 2.72 (t, 2H), 1.96-1.35 (m, 14H)

[0150] Example 35 Synthesis of 2-chloro-N-[8-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]-5-nitrobenzamide (1) 500 mg of 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one, 262 mg of benzophenone imine, 160 mg of sodium tert-butoxide, 179 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 109 mg of tris(dibenzylideneacetone)dipalladium(0), and 15 mL of toluene were mixed and stirred at 100 °C under nitrogen for 4.5 hours. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was dissolved in 10 mL of tetrahydrofuran, 2 mL of 2N hydrochloric acid was added, and the mixture was stirred at room temperature under nitrogen for 2 hours. After the reaction, diethyl ether and water were added, and the aqueous layer was separated under acidic conditions. The aqueous layer was neutralized by adding an aqueous sodium bicarbonate solution, and the mixture was separated using a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel column chromatography (hexane:ethyl acetate = 1:1), and then the solvent was distilled off under reduced pressure to obtain 263.3 mg of 6-amino-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one. (2) 50 mg of 6-amino-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-3,4-dihydro-1,8-naphthyridin-2(1H)-one was dissolved in 6 mL of pyridine, and 97 mg of 2-chloro-5-nitrobenzyl chloride was added and stirred for 20 minutes. After stirring, the mixture was cooled to 0°C, 1.5 mL of aqueous ammonia was added, and the mixture was stirred for 60 minutes. Then, 2 mL of aqueous ammonia chloride was added. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was removed from the organic layer under reduced pressure to obtain a crude product. The crude product was purified using column chromatography (hexane:ethyl acetate=1:1) to obtain 26.1 mg of 2-chloro-N-[8-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.56 (d, J = 11.9 Hz, 1H), 8.26-8.21 (m, 2H), 8.14 (s, 1H), 7.67-7.63 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.42 (s, 2H), 3.05 (t, 2H), 2.83 (t, J = 6.9 Hz, 2H)

[0151] Example 36 Synthesis of 2-chloro-5-nitro-N-[1-{(4-tert-butylcyclohexyl)methyl}-1,2,3,4-tetrahydroquinolin-6-yl]benzamide (1) 0.433 mL of oxalyl chloride was added to a mixed solution of 465.4 mg of 4-tert-butylcyclohexanecarboxylic acid and 5 mL of dichloromethane, and 3 drops of dimethylformamide were slowly added thereto, and the mixture was stirred for 1 hour while warming to room temperature. The reaction solution was concentrated under reduced pressure to obtain an acid chloride. Next, 74.1 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 300 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 10 mL of dimethylformamide, and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Furthermore, 3 mL of the prepared acid chloride solution in THF was slowly added dropwise, and the mixture was stirred at room temperature for 17 hours. Then, water and ethyl acetate were added to the reaction solution to separate the layers. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 2:3) to obtain 434 mg of (4-tert-butylcyclohexyl) (6-nitro-3,4-dihydroquinolin-1(2H)-yl)methanone. (2) (4-tert-butylcyclohexyl) (6-nitro-3,4-dihydroquinolin-1(2H)-yl)methanone 434.0 mg in tetrahydrofuran 7.0 mL was slowly added dropwise to borane dimethylsulfide complex 7.0 mL under ice cooling, and the mixture was stirred at 70 ° C for 1 hour under nitrogen atmosphere, and then 5 mL of methanol was slowly added dropwise while cooling the reaction solution on ice. The reaction solution was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:49 to 1:4) to obtain 1-[(4-tert-butylcyclohexyl)methyl]-6-nitro-1,2,3,4-tetrahydroquinoline 295.6 mg. (3) 249.8 mg of reduced iron and 191.4 mg of ammonium chloride were added to a mixture of 295.6 mg of 1-[(4-tert-butylcyclohexyl)methyl]-6-nitro-1,2,3,4-tetrahydroquinoline in 2 mL of tetrahydrofuran, 2 mL of methanol, and 1 mL of water, and the mixture was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 15 mL of dichloromethane, and 0.374 mL of triethylamine was added. A solution of 236.2 mg of 2-chloro-5-nitrobenzoyl chloride in 5 mL of dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Water and dichloromethane were added to the reaction solution, and the mixture was separated. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9 to 1:1) to obtain 273.5 mg of 2-chloro-5-nitro-N-[1-{(4-tert-butylcyclohexyl)methyl}-1,2,3,4-tetrahydroquinolin-6-yl]benzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58 (d, J = 2.7 Hz, 1H), 8.22 (dd, J = 8.7, 2.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.56 (s, 1H), 7.23-7.18 (m, 2H), 6.48 (d, J = 8.7 Hz, 1H), 3.32 (t, J = 5.6 Hz, 2H), 3.23 (d, J = 7.5 Hz, 2H), 2.77 (t, J = 6.3 Hz, 2H), 2.07-2.21 (m, 1H), 1.95-1.92 (m, 2H), 1.75-1.88 (m, 1H), 1.73-1.60 (m, 3H), 1.48-1.46 (m, 1H), 1.16-1.12 (m, 1H), 1.03-0.81 (m, 12H)

[0152] Example 37 Synthesis of 2-chloro-N-[1-{(2-chloro-4-(trifluoromethyl)phenyl)methyl}-2,2-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) A solution of 2.00 g of 4-nitroaniline, 1.49 g of 3-chloro-3-methyl-1-butyne, and 1.43 g of copper chloride in 30 mL of toluene was heated under reflux for 24 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, the insoluble components were removed by filtration, and the filtrate was extracted with water and dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 201.5 mg of 2,2-dimethyl-6-nitro-1,2-dihydroquinoline. (2) 2,2-dimethyl-6-nitro-1,2-dihydroquinoline 204.0 mg in dimethylformamide 5 mL was mixed with sodium hydride (60%, dispersed in liquid paraffin) 47.9 mg and stirred at room temperature for 2 hours. Then, 2 mL of dimethylformamide solution containing 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene 384.1 mg was slowly added dropwise, stirred at room temperature for 1 hour, and further stirred at 80 °C for 5 hours. Then, water and a mixed solution of ethyl acetate:hexane = 1:1 were added to the reaction solution and separated. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (ethyl acetate:hexane = 1:19) to obtain 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-2,2-dimethyl-6-nitro-1,2-dihydroquinoline 24.4 mg. (3) 24.4 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-2,2-dimethyl-6-nitro-1,2-dihydroquinoline and 6.5 mg of 10% palladium on carbon in 1 mL of methanol 1 mL of ethyl acetate was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. Thereafter, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 5 mL of dichloromethane, and 26 μL of triethylamine was added. Furthermore, a solution of 16.2 mg of 2-chloro-5-nitrobenzoyl chloride in 2 mL of dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water and dichloromethane were added to the reaction solution and the mixture was separated. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:19 to 1:4) to obtain 9.1 mg of 2-chloro-N-[1-{(2-chloro-4-(trifluoromethyl)phenyl)methyl}-2,2-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58 (d, J = 2.7 Hz, 1H), 8.24 (dd, J = 8.9, 2.7 Hz, 1H), 7.67-7.60 (m, 3H), 7.45-7.42 (m, 3H), 7.04 (dd, J = 8.9, 2.5 Hz, 1H), 6.09 (d, J = 8.7 Hz, 1H), 4.50 (s, 2H), 2.93 (t, J = 6.5 Hz, 2H), 1.97 (t, J = 6.5 Hz, 2H), 1.27 (s, 6H)

[0153] Example 38 Synthesis of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)-5-nitrobenzamide (1) 2.40 mL of acetonylacetone and 32 mg of p-toluenesulfonic acid monohydrate were added to a solution of 3.00 g of 6-amino-1-tetralone in 40 mL of toluene, and a Dean-Stark tube was attached to remove water derived from the reaction, and the mixture was heated under reflux for 2 hours under a nitrogen atmosphere. Insoluble matter in the reaction solution was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by recrystallization using ethyl acetate and hexane to obtain 3.89 g of 6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydronaphthalen-1(2H)-one. (2) 290.4 mg of hydroxylamine hydrochloride was added to a solution of 500 mg of 6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydronaphthalen-1(2H)-one in 7 mL of pyridine, and the mixture was stirred for 4 hours at room temperature under a nitrogen atmosphere. Then, a mixture of water and ethyl acetate:hexane = 1:1 was added to the reaction solution and the mixture was separated. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 453.9 mg of [6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydronaphthalen-1(2H)-ylidene]hydroxylamine. (3) [6-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydronaphthalene-1(2H)-ylidene]hydroxylamine 454.0 mg in dichloromethane 10 mL was slowly added dropwise with diisobutylaluminum hydride (19% hexane solution, about 1.0 mol / L) 10.7 mL, and stirred at room temperature for 2 hours. Then, saturated potassium sodium tartrate solution was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. Then, the mixture was separated using dichloromethane, and the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:hexane = 1:1 to 1:0) to obtain 7-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepine 256.7 mg. (4) To a solution of 388.1 mg of 2-chloro-4-(trifluoromethyl)benzoic acid in 5 mL of dichloromethane, 0.222 mL of oxalyl chloride was added, and 3 drops of dimethylformamide were slowly added. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the acid chloride. Next, 482 μL of triethylamine was added to a solution of 207.7 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 10 mL of dichloromethane, and then 5 mL of the prepared acid chloride in dichloromethane was slowly added dropwise and stirred at room temperature for 10 hours. Then, water and dichloromethane were added to the reaction solution to separate the liquid, and the resulting organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (ethyl acetate:hexane = 3:7) to obtain 119.5 mg of [7-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl][2-chloro-4-(trifluoromethyl)phenyl]methanone. Next, the obtained [7-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl][2-chloro-4-(trifluoromethyl)phenyl]methanone was dissolved in 3.0 mL of tetrahydrofuran, and 1.29 mL of borane dimethylsulfide complex was slowly added dropwise under ice cooling, and the mixture was stirred at 60 ° C for 2 hours under a nitrogen atmosphere, and then 5 mL of methanol was slowly added dropwise while cooling the reaction solution with ice. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19 to 2:3), and 66.5 mg of 1-[{2-chloro-4-(trifluoromethyl)phenyl}methyl]-7-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin was obtained. (5) 1-[{2-chloro-4-(trifluoromethyl)phenyl}methyl]-7-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepine 66.5 mg, ethanol 2 mL, water 1.0 mL mixed solution, added hydroxylamine hydrochloride 480.3 mg, stirred at 100 ° C for 24 hours under nitrogen atmosphere. Then, saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution and separated, the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:19 to 1:4) to obtain 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-7-amine 27.6 mg. (6) 33μL of triethylamine was added to a solution of 27.6mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepine-7-amine in 3mL of dichloromethane. Next, 20.5mg of 2-chloro-5-nitrobenzoyl chloride in 2mL of dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. 3mL of pyridine and 1mL of ammonia water (25%) were added to the reaction solution under ice cooling, and the mixture was stirred for 30 minutes under ice cooling, neutralized by adding saturated ammonium chloride water, and separated by adding water and dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:4) to obtain 27.4 mg of 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.5 Hz, 1H), 8.25 (dd, J = 8.9, 2.7 Hz, 1H), 7.71 (s, 1H), 7.66-7.63 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.6, 2.6 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 4.50 (s, 2H), 3.03-3.01 (m, 2H), 2.93-2.90 (m, 2H), 1.71-1.70 (m, 4H)

[0154] Example 39 Synthesis of 2-chloro-N-[2-{(2-chloro-4-(trifluoromethyl)phenyl)methyl}-2,3-dihydro-1H-isoindol-5-yl]-5-nitrobenzamide (1) 62.5 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 250 mg of 4-nitrophthalimide in 5 mL of dimethylformamide, and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Furthermore, a solution of 384.1 mg of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene in 2 mL of dimethylformamide was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. After that, water was added to the reaction solution, and the precipitated solid was collected to obtain 710.7 mg of 2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-nitro-1H-isoindole-1,3(2H)-dione. (2) 5.0 mL of borane dimethylsulfide complex was slowly added dropwise to a solution of 342 mg of 2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-nitro-1H-isoindole-1,3(2H)-dione in 5 mL of tetrahydrofuran, and the mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. Then, 5 mL of methanol was slowly added dropwise while cooling the reaction solution with ice. The reaction solution was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19 to 2:3) to obtain 106.9 mg of 2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-nitro-2,3-dihydro-1H-isoindole. (3) 106.9 mg of 2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-nitro-2,3-dihydro-1H-isoindole and 31.9 mg of 10% palladium on carbon were added with 1 mL of methanol and 1 mL of ethyl acetate, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 3 mL of pyridine, and a solution of 79.1 mg of 2-chloro-5-nitrobenzoyl chloride in 2 mL of dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction solution was cooled on ice, and ammonia water (25%) was added, and the mixture was stirred for 30 minutes under ice cooling, and saturated ammonium chloride water was added to neutralize the mixture, and water and ethyl acetate were added to separate the mixture. The resulting organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 12.3 mg of 2-chloro-N-[2-{(2-chloro-4-(trifluoromethyl)phenyl)methyl}-2,3-dihydro-1H-isoindol-5-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.61 (d, J = 2.5 Hz, 1H), 8.27 (dd, J = 8.8, 2.6 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.67-7.65 (m, 3H), 7.54 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.09 (s, 2H), 4.06 (s, 2H), 4.03 (s, 2H)

[0155] Example 40 Synthesis of 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-nitrobenzamide (1) 73.1 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 300 mg of 5-bromo-1H-pyrrolo[2,3-b]pyridine in 5 mL of dimethylformamide, and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Furthermore, a solution of 585.6 mg of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene in 3 mL of dimethylformamide was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. Then, a mixture of water and ethyl acetate:hexane = 1:1 was added to the reaction solution, and the mixture was separated. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 585.8 mg of 5-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridine. (2) 5-Bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridine 585.8 mg in toluene 8 mL solution was added with benzophenone imine 329.7 mg, sodium tert-butoxide 200.9 mg, (±)-BINAP 187.3 mg, and tris(dibenzylideneacetone)dipalladium(0) 137.7 mg, and stirred at 90 °C for 17 hours under nitrogen atmosphere. Then, the reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran 5 mL, 6M hydrochloric acid 3 mL was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and a mixed solvent of ethyl acetate:hexane = 1:1 was added to the residue. The precipitated solid was washed with hexane to obtain 624 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridin-5-amine. (3) 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridin-5-amine 150 mg of pyridine 5 mL of solution was slowly added dropwise with 253.3 mg of 2-chloro-5-nitrobenzoyl chloride in 2 mL of dichloromethane, and stirred at room temperature for 30 minutes under nitrogen atmosphere. The reaction solution was ice-cooled, and ammonia water (25%) was added and stirred for 30 minutes under ice cooling, and saturated ammonium chloride water was added to neutralize, and water and ethyl acetate were added to separate the layers. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 72.1 mg of 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.67 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.30 (dd, J = 8.5, 2.3 Hz, 1H), 7.94 (s, 1H), 7.70-7.68 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 3.4 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 5.65 (s, 2H)

[0156] Example 41 Synthesis of 2-chloro-N-[1-{(2-chloro-4-(trifluoromethyl)phenyl)methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-nitrobenzamide (1) 73.1 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 300 mg of 4-bromo-1H-pyrrolo[2,3-b]pyridine in 5 mL of dimethylformamide, and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Furthermore, a solution of 585.6 mg of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene in 3 mL of dimethylformamide was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was separated by adding a mixture of water and ethyl acetate:hexane = 1:1. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 586.9 mg of 4-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridine. (2) 586.9 mg of 4-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridine was dissolved in 8 mL of toluene, and 330.34 mg of benzophenone imine, 201.2 mg of sodium tert-butoxide, 187.6 mg of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and 137.9 mg of tris(dibenzylideneacetone)dipalladium(0) were added and stirred at 90 °C for 23 hours under a nitrogen atmosphere. The reaction solution was then filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 5 mL of tetrahydrofuran, and 4 mL of 6M hydrochloric acid was added and stirred at room temperature for 1 hour. Water, ethyl acetate, and hexane were added to the reaction solution, and the precipitated solid was collected by filtration to obtain 673 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine. (3) 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (66 mg) in dichloromethane (5 mL) was slowly added dropwise to a solution of 2-chloro-5-nitrobenzoyl chloride (193.5 mg) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was cooled on ice, and 2 mL of pyridine and 1 mL of ammonia water (25%) were added, and the mixture was stirred for 30 minutes under ice cooling, and then neutralized by adding saturated ammonium chloride water, and water and ethyl acetate were added to separate the mixture. The resulting organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 71.4 mg of 2-chloro-N-[1-{(2-chloro-4-(trifluoromethyl)phenyl)methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, ACETONE-D6) δ 10.16 (s, 1H), 8.60 (d, J = 2.7 Hz, 1H), 8.39 (dd, J = 8.9, 2.7 Hz, 1H), 8.29 (d, J = 5.5 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 7.59 (dd, J = 8.2, 1.1 Hz, 1H), 7.52 (d, J = 3.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 3.7 Hz, 1H), 5.73 (s, 2H)

[0157] Example 42 Synthesis of 2-chloro-N-(2-hexyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-nitrobenzamide (1) 450 mg of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one was dissolved in 10 mL of dimethylformamide, 85 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 438 mg of n-bromohexane was added, and the mixture was stirred at room temperature for 17 hours, and water was added to stop the reaction. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 1:1), and the solvent was distilled off under reduced pressure to obtain 564.9 mg of 6-bromo-2-hexyl-3,4-dihydroisoquinolin-1(2H)-one. (2) 500 mg of 6-bromo-2-hexylisoquinolin-1(2H)-one, 356 mg of benzophenone imine, 217 mg of sodium tert-butoxide, 245 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 149 mg of tris(dibenzylideneacetone)dipalladium(0), and 7.5 mL of toluene were mixed and stirred under nitrogen at 100 °C for 4.5 hours. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure, and the mixture was purified using silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain 6-[(diphenylmethylidyne)amino]-2-hexylisoquinolin-1(2H)-one. 6-[(diphenylmethylidyne)amino]-2-hexylisoquinolin-1(2H)-one was dissolved in 8 mL of tetrahydrofuran, 1 mL of 2M hydrochloric acid was added, and the mixture was stirred at room temperature under nitrogen for 5 minutes. After the reaction, the solvent was distilled off under reduced pressure, and diethyl ether was added to recover the resulting crystals, yielding 558.2 mg of 6-bromo-2-hexylisoquinolin-1(2H)-one hydrochloride (solvent included). (3) 100 mg of 6-bromo-2-hexylisoquinolin-1(2H)-one hydrochloride was dissolved in 3 mL of dichloromethane, 94 mg of 2-chloro-5-nitrobenzoyl chloride, and 0.15 mL of triethylamine were added and stirred for 30 minutes. After the reaction, water and dichloromethane were added and the mixture was separated. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. After purification using silica gel chromatography (hexane:ethyl acetate=3:2), the solvent was removed under reduced pressure to obtain 83.9 mg of 2-chloro-N-(2-hexyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 9.43 (s, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.26-8.24 (m, 2H), 8.05 (s, 1H), 7.48 (dd, J = 6.4, 2.3 Hz, 2H), 7.07-7.01 (m, 1H), 6.52 (d, J = 7.3 Hz, 1H), 3.96-3.92 (m, 2H), 1.74-0.85 (m, 11H)

[0158] Example 43 Synthesis of 2-chloro-N-(2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-nitrobenzamide (1) 209 mg of 6-bromo-1,2,3,4-tetrahydroisoquinoline was dissolved in 2 mL of dichloromethane, 0.4 mL of triethylamine and 453 mg of 2-chloro-4-(trifluoromethyl)benzyl iodide were added, and the mixture was stirred under nitrogen for 2 hours. After the reaction, water was added to stop the reaction, and the mixture was separated using a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 7:3), and then the solvent was distilled off under reduced pressure to obtain 346.3 mg of 6-bromo-2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroisoquinoline. (2) 300 mg of 6-bromo-2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroisoquinoline, 163 mg of benzophenone imine, 99 mg of sodium tert-butoxide, 112 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 68 mg of tris(dibenzylideneacetone)dipalladium(0), and 7.5 mL of toluene were mixed and stirred under nitrogen at 100°C for 15.5 hours. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was removed from the organic layer under reduced pressure, and the mixture was purified using silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain N-({[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,1-diphenylmethanimine. The mixture was then dissolved in 8 mL of tetrahydrofuran, 1 mL of 2M hydrochloric acid was added, and the mixture was stirred for 5 minutes at room temperature under nitrogen. After the reaction, the solvent was removed under reduced pressure, and hexane was added to recover the resulting crystals. A mixed solution of hexane:ethyl acetate=1:1 was then added, and the mixture was neutralized with sodium bicarbonate. The organic layer was separated by a separation operation, and the solvent was removed under reduced pressure to obtain 190.6 mg of 6-amino-2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroisoquinoline. (3) 190 mg of 6-amino-2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroisoquinoline was dissolved in 5 mL of dichloromethane, 245 mg of 2-chloro-5-nitrobenzoyl chloride and 0.2 mL of triethylamine were added, and the mixture was stirred for 30 minutes. After the reaction, water and dichloromethane were added and the mixture was separated, and the organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. After purification using silica gel chromatography (hexane:ethyl acetate=7:3), the solvent was removed under reduced pressure to obtain 142 mg of 2-chloro-N-(2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.61 (d, J = 2.7 Hz, 1H), 8.27 (dd, J = 8.7, 2.7 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.52 (dd, J = 8.5, 1.1 Hz, 2H), 7.32 (dd, J = 8.3, 2.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 3.85 (s, 2H), 3.72 (s, 2H), 2.97 (t, J = 5.7 Hz, 2H), 2.83 (t, J = 5.8 Hz, 2H)

[0159] Example 44 Synthesis of 2-chloro-N-{1-[(2-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 0.289 mL of oxalyl chloride was added to a mixed solution of 360.6 mg of 2-phenoxybenzoic acid and 5 mL of dichloromethane, and 3 drops of dimethylformamide were slowly added. The mixture was stirred for 30 minutes while warming to room temperature. The reaction solution was concentrated under reduced pressure to obtain an acid chloride. Next, 49.4 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 10 mL of dimethylformamide, and the mixture was stirred for 5 minutes at room temperature under a nitrogen atmosphere. Further, a solution of the prepared acid chloride in 3 mL of THF was slowly added dropwise, and the mixture was stirred at room temperature for 17 hours. After that, water and a mixed solution of ethyl acetate:hexane = 1:1 were added to the reaction solution, and the mixture was separated. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 2:3) to obtain (6-nitro-3,4-dihydroquinolin-1(2H)-yl)(2-phenoxyphenyl)methanone. Next, the obtained (6-nitro-3,4-dihydroquinolin-1(2H)-yl)(2-phenoxyphenyl)methanone was dissolved in 15 mL of tetrahydrofuran, and 4.93 mL of borane dimethylsulfide complex was slowly added dropwise. After stirring for 3 hours at 60 °C under a nitrogen atmosphere, 5 mL of methanol was slowly added dropwise while cooling the reaction solution with ice. Thereafter, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19 to 3:2) to obtain 108.7 mg of 6-nitro-1-[(2-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinoline. (2) 84.2 mg of reduced iron and 64.5 mg of ammonium chloride were added to a mixed solution of 108.7 mg of 6-nitro-1-[(2-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinoline in 2 mL of tetrahydrofuran, 2 mL of ethanol, and 1 mL of water, and the mixture was stirred at 90 °C for 3 hours under a nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 15 mL of dichloromethane, and 0.126 mL of triethylamine was added. A solution of 79.6 mg of 2-chloro-5-nitrobenzoyl chloride in 5 mL of dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water and dichloromethane were added to the reaction solution, and the mixture was separated. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9 to 1:0) to obtain 58.3 mg of 2-chloro-N-{1-[(2-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.59 (d, J = 2.7 Hz, 1H), 8.23 ​​(dd, J = 8.9, 2.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (s, 1H), 7.37-7.31 (m, 3H), 7.25-7.21 (m, 2H), 7.11-7.08 (m, 3H), 7.00-6.98 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.7 Hz, 1H), 4.51 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 2.84 (t, J = 6.2 Hz, 2H), 2.05-2.01 (m, 2H)

[0160] Example 45 Synthesis of 2-chloro-N-{1-[(4-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 0.289 mL of oxalyl chloride was added to a mixed solution of 360.7 mg of 4-phenoxybenzoic acid and 5 mL of dichloromethane, and 3 drops of dimethylformamide were slowly added thereto. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the acid chloride. Next, 49.4 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 10 mL of dimethylformamide, and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. Furthermore, 3 mL of the prepared acid chloride solution in tetrahydrofuran was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. Then, water and a mixed solution of ethyl acetate:hexane = 1:1 were added to the reaction solution to separate the liquid. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 2:3) to obtain (6-nitro-3,4-dihydroquinolin-1(2H)-yl)(4-phenoxyphenyl)methanone. Next, the obtained (6-nitro-3,4-dihydroquinolin-1(2H)-yl)(4-phenoxyphenyl)methanone was dissolved in 15 mL of tetrahydrofuran, and 4.93 mL of borane dimethylsulfide complex was slowly added dropwise. After stirring at 60° C. for 3 hours under a nitrogen atmosphere, 5 mL of methanol was slowly added dropwise while cooling the reaction solution on ice. Thereafter, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19 to 3:2) to obtain 160.2 mg of 6-nitro-1-[(4-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinoline. (2) 124.1 mg of reduced iron and 95.1 mg of ammonium chloride were added to a mixture of 160.2 mg of 6-nitro-1-[(4-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinoline in 2 mL of tetrahydrofuran, 2 mL of ethanol, and 1 mL of water, and the mixture was stirred at 90 °C for 3 hours under a nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 15 mL of dichloromethane, and 0.186 mL of triethylamine was added. A solution of 117.4 mg of 2-chloro-5-nitrobenzoyl chloride in 5 mL of dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water and dichloromethane were added to the reaction solution, and the mixture was separated. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9 to 1:0) to obtain 191.5 mg of 2-chloro-N-{1-[(4-phenoxyphenyl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58-8.58 (m, 1H), 8.23 ​​(dd, J = 8.7, 2.7 Hz, 1H), 7.63-7.61 (m, 2H), 7.35-7.31 (m, 3H), 7.21 (d, J = 8.5 Hz, 2H), 7.14 (dd, J = 8.7, 2.5 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.01-6.98 (m, 2H), 6.98-6.96 (m, 2H), 6.50 (d, J = 8.7 Hz, 1H), 4.47 (s, 2H), 3.39 (t, J = 5.7 Hz, 2H), 2.84 (t, J = 6.3 Hz, 2H), 2.06-2.01 (m, 2H)

[0161] Example 46 Synthesis of 2-chloro-N-(1-{[2-(-2-phenoxyethoxy)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide (1) 369 mg of 2-(hydroxymethyl)phenol was dissolved in 20 mL of dimethylformamide, and then 970 mg of cesium carbonate was added. A mixture of 10 mL of dimethylformamide and 500 mg of (2-bromoethoxy)benzene was added, and the mixture was heated and stirred at 80° C. under nitrogen. After the reaction, the mixture was separated using a mixture of water and hexane:ethyl acetate=1:1. The organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=1:1), and the solvent was distilled off under reduced pressure to obtain 430 mg of [2-(2-phenoxyethoxy)phenyl]methanol. (2) 318 mg of [2-(2-phenoxyethoxy)phenyl]methanol was dissolved in 5 mL of dichloromethane, and then 410 mg of triphenylphosphine, 397 mg of iodine, and 106 mg of imidazole were added and stirred at room temperature for 30 minutes. Water was then added and the mixture was separated with dichloromethane. The organic layer was separated, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=7:3), and then the solvent was distilled off under reduced pressure to obtain 406 mg of 1-(iodomethyl)-2-(2-phenoxyethoxy)benzene. (3) 103 mg of 6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 3 mL of dimethylformamide, 21 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 241 mg of 1-(iodomethyl)-2-(2-phenoxyethoxy)benzene was added, and the mixture was stirred at room temperature for 30 minutes, and water was added to stop the reaction. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was recrystallized and collected to obtain 133 mg of 1-{[2-(-2-phenoxyethoxy)phenyl]methyl}-6-nitro-1,2,3,4-tetrahydroquinoline. (4) 1-{[2-(-2-phenoxyethoxy)phenyl]methyl}-6-nitro-1,2,3,4-tetrahydroquinoline (110 mg) was dissolved in ethyl acetate (5 mL), palladium-activated carbon (10% Pd) (48 mg) was added, and the mixture was stirred under hydrogen gas conditions for 8 hours. After the reaction, the mixture was filtered through Celite, and the solvent was removed under reduced pressure to obtain an aniline intermediate. The aniline intermediate was added with dichloromethane (5 mL), triethylamine (0.09 mL), and 2-chloro-5-nitrobenzoyl chloride (59 mg), and the mixture was stirred at room temperature for 10 minutes. After the reaction, water and dichloromethane were added to separate the mixture, and the obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate=3:2), and the solvent was then distilled off under reduced pressure to obtain 33.4 mg of 2-chloro-N-(1-{[2-(-2-phenoxyethoxy)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.57 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 8.8, 2.6 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.53 (s, 1H), 7.31-7.27 (m, 3H), 7.21 (dd, J = 7.7, 1.3 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.00-6.90 (m, 6H), 6.40 (d, J = 8.7 Hz, 1H), 4.45 (s, 2H), 4.39-4.33 (m, 4H), 3.36 (t, J = 5.6 Hz, 2H), 2.83 (t, J = 6.3 Hz, 2H), 2.02-1.97 (m, 2H)

[0162] Example 47 Synthesis of 2-chloro-N-{1-(2-{[2-(-2-phenoxyethoxy)ethoxy]phenyl}methyl)-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 1 g of phenol and 4.15 g of cesium carbonate were dissolved in 30 mL of dimethylformamide, and then 5.04 g of 1-bromo-2-(2-bromoethoxy)ethane dissolved in 30 mL of dimethylformamide was added, and the mixture was heated and stirred at 80 °C for 3 hours under nitrogen conditions. After the reaction, the mixture was separated using a mixed solution of water and hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 9:1), and the solvent was distilled off under reduced pressure to obtain 2.06 g of [2-(2-bromoethoxy)ethoxy]benzene. (2) 633 mg of 2-(hydroxymethyl)phenol was dissolved in 20 mL of dimethylformamide, and then 798 mg of cesium carbonate was added. A mixture of 10 mL of dimethylformamide and 500 mg of [2-(2-bromoethoxy)ethoxy]benzene was added, and the mixture was heated and stirred at 70 °C for 6 hours under nitrogen conditions. After the reaction, the mixture was separated using a mixture of water and hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was purified using silica gel chromatography (hexane:ethyl acetate = 1:1), and the solvent was distilled off under reduced pressure to obtain 376 mg of {2-[2-(2-phenoxyethoxy)ethoxy]phenyl}methanol. (3) 200 mg of {2-[2-(2-phenoxyethoxy)ethoxy]phenyl}methanol was dissolved in 3.5 mL of dichloromethane, and then 218 mg of triphenylphosphine, 264 mg of iodine, and 56.7 mg of imidazole were added and stirred at room temperature for 10 minutes. Water was then added and the mixture was separated with dichloromethane. The organic layer was separated, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The crude product obtained was purified using silica gel chromatography (hexane:ethyl acetate=7:3), and the solvent was distilled off under reduced pressure to obtain 150 mg of 1-(iodomethyl)-2-[2-(2-phenoxyethoxy)ethoxy]benzene. (4) 103 mg of 6-nitro-1,2,3,4-tetrahydroquinoline was dissolved in 5 mL of dimethylformamide, 21 mg of sodium hydride (60%, dispersed in liquid paraffin) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 149 mg of 1-(iodomethyl)-2-[2-(2-phenoxyethoxy)ethoxy]benzene was added, and the mixture was stirred for 8 hours under nitrogen conditions, and water was added to stop the reaction. After the reaction was stopped, the mixture was separated using water and a mixed solution of hexane:ethyl acetate = 1:1. The organic layer was separated, washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off from the organic layer under reduced pressure to obtain a crude product. The obtained crude product was recrystallized and collected to obtain 122 mg of 1-{2-[2-(2-phenoxyethoxy)ethoxy}phenyl]methyl}-6-nitro-1,2,3,4-tetrahydroquinoline. (5) 1-{2-[2-(2-phenoxyethoxy)ethoxy}phenyl]methyl}-6-nitro-1,2,3,4-tetrahydroquinoline (120 mg) was dissolved in ethyl acetate (3 mL), palladium-activated carbon (10% Pd) (28 mg) was added, and the mixture was stirred for 1 hour under hydrogen gas conditions. After the reaction, the mixture was filtered through Celite, and the solvent was removed under reduced pressure to obtain an aniline intermediate. The aniline intermediate was added with dichloromethane (3 mL), triethylamine (0.11 mL), and 2-chloro-5-nitrobenzoyl chloride (71 mg), and stirred at room temperature for 10 minutes. After the reaction, the solvent was removed under reduced pressure, and the mixture was dissolved in pyridine (4 mL), and 1.5 mL of aqueous ammonia was added and stirred. After the reaction, water and dichloromethane were added and the mixture was separated, and the obtained organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The obtained crude product was purified by thin layer chromatography to obtain 26.8 mg of 2-chloro-N-{1-(2-{[2-(-2-phenoxyethoxy)ethoxy]phenyl}methyl)-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.57 (d, J = 2.7 Hz, 1H), 8.22 (dd, J = 8.9, 2.7 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.27-7.19 (m, 3H), 7.11 (dd, J = 7.3, 1.1 Hz, 1H), 7.03 (dd, J = 8.8, 2.6 Hz, 1H), 6.93-6.87 (m, 5H), 6.41 (d, J = 8.7 Hz, 1H), 4.48 (s, 2H), 4.22 (t, J = 4.8 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H), 3.98-3.94 (m, 4H), 3.37 (t, J = 5.7 Hz, 2H), 2.85 (t, J = 6.2 Hz, 2H), 2.03 (q, J = 5.2 Hz, 2H)

[0163] Example 48 Synthesis of 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 5.26 mL of pyridine was added to a solution of 2.90 g of 3-fluoroaniline in 100 mL of acetone, and 3.01 mL of 3-chloropropionyl chloride was slowly added dropwise at room temperature. The mixture was then stirred at room temperature for 4 hours. Saturated saline and ethyl acetate were added to the reaction solution to separate the layers. The resulting organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by recrystallization using ethyl acetate and hexane to obtain 3.56 g of 3-chloro-N-(3-fluorophenyl)propanamide. (2) 1.0 mL of N,N-dimethylacetamide was slowly added dropwise to a mixture of 2.47 g of 3-chloro-N-(3-fluorophenyl)propanamide and 5.72 g of aluminum chloride under ice cooling, and the mixture was stirred at 130 °C for 6 hours under a nitrogen atmosphere. The reaction solution was ice-cooled, diluted with ethyl acetate, and ice water was slowly added dropwise. The mixture was then separated with ethyl acetate, and the resulting organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by recrystallization using ethyl acetate and hexane to obtain 1.19 g of 7-fluoro-3,4-dihydroquinolin-2(1H)-one. Also, 477.0 mg of a mixture of 5-fluoro-3,4-dihydroquinolin-2(1H)-one was obtained from the residue in the purification operation. a) 7-Fluoro-3,4-dihydroquinolin-2(1H)-one: 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.45 (brs, 1H), 7.10 (dd, J = 8.1, 6.1 Hz, 1H), 6.69 (td, J = 8.5, 2.5 Hz, 1H), 6.54 (dd, J = 9.3, 2.6 Hz, 1H), 2.94 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H) b) 5-Fluoro-3,4-dihydroquinolin-2(1H)-one: 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.97 (brs, 1H), 7.16-7.14 (m, 1H), 6.77-6.73 (m, 1H), 6.55 (d, J = 8.0 Hz, 1H), 3.01 (t, J = 7.7 Hz, 2H), 2.67-2.65 (m, 2H) (3) 1.00 g of 7-fluoro-3,4-dihydroquinolin-2(1H)-one was dissolved in 12 mL of dimethylformamide, and 1.19 g of N-bromosuccinimide was added under a nitrogen atmosphere while cooling with ice, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water, and air-dried to obtain 1.40 g of 6-bromo-7-fluoro-3,4-dihydroquinolin-2(1H)-one. (4) 59.0 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 300 mg of 6-bromo-7-fluoro-3,4-dihydroquinolin-2(1H)-one in 5 mL of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. Furthermore, a solution of 472.7 mg of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene in 3 mL of dimethylformamide was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. After that, a mixture of water and ethyl acetate:hexane = 1:1 was added to the reaction solution to separate the liquids. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:19 to 3:2) to obtain 490.4 mg of 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-fluoro-3,4-dihydroquinolin-2(1H)-one. (5) 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-fluoro-3,4-dihydroquinolin-2(1H)-one 300 mg in tetrahydrofuran 15 mL solution was slowly added dropwise with borane dimethylsulfide complex 5.91 mL, stirred at 60 ° C for 30 minutes under nitrogen atmosphere, and then cooled with ice while slowly adding methanol 5 mL. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19 to 3:2) to obtain 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-fluoro-1,2,3,4-tetrahydroquinoline 411.1 mg. (6) 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-fluoro-1,2,3,4-tetrahydroquinoline 411.1 mg in toluene 8 mL solution was added with benzophenone imine 213.3 mg, sodium tert-butoxide 129.9 mg, (±)-BINAP 121.1 mg, tris(dibenzylideneacetone)dipalladium(0) 89.1 mg, and stirred at 90 °C for 17 hours under nitrogen atmosphere. Then, the reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran 5 mL, 6M hydrochloric acid 2 mL was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized by adding saturated sodium bicarbonate water, and separated with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4 to 7:13) to obtain 270.1 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-fluoro-1,2,3,4-tetrahydroquinolin-6-amine. (7) 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-7-fluoro-1,2,3,4-tetrahydroquinolin-6-amine 270.1 mg in dichloromethane 5 mL was added with triethylamine 0.315 mL, and then 2-chloro-5-nitrobenzoyl chloride 193.5 mg in dichloromethane 2 mL was slowly added dropwise and stirred at room temperature for 30 minutes under nitrogen atmosphere. Water and dichloromethane were added to the reaction solution and the mixture was separated. The organic layer obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by recrystallization using ethyl acetate and hexane to obtain 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide 180.7 mg. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.64 (d, J = 2.7 Hz, 1H), 8.26 (dd, J = 8.7, 2.7 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.29-7.29 (m, 1H), 6.04 (d, J = 13.7 Hz, 1H), 4.53 (s, 2H), 3.42 (t, J = 5.7 Hz, 2H), 2.88 (t, J = 6.2 Hz, 2H), 2.11-2.07 (m, 2H)

[0164] Example 49 Synthesis of 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 5-fluoro-3,4-dihydroquinolin-2(1H)-one mixture (see Example 48) 477.0 mg of N-bromosuccinimide was added to 6 mL of dimethylformamide under a nitrogen atmosphere while cooling with ice, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dissolved in 5 mL of dimethylformamide, and 116.6 mg of sodium hydride (60% liquid paraffin dispersion) was added, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. Furthermore, a solution of 934.6 mg of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene in 3 mL of dimethylformamide was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After that, a mixture of water and ethyl acetate:hexane=1:1 was added to the reaction solution, and the mixture was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:19-3:2) to give 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-fluoro-3,4-dihydroquinolin-2(1H)-one (352.4 mg). (2) 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-fluoro-3,4-dihydroquinolin-2(1H)-one 352.4 mg in tetrahydrofuran 5 mL solution was slowly added with borane dimethyl sulfide complex 4.43 mL, stirred at 60 ° C for 1 hour under nitrogen atmosphere, and then cooled with ice while slowly adding methanol 5 mL. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-fluoro-1,2,3,4-tetrahydroquinoline 286.8 mg. (3) 148.8 mg of benzophenone imine, 90.7 mg of sodium tert-butoxide, 62.1 mg of (±)-BINAP, and 62.1 mg of tris(dibenzylideneacetone)dipalladium(0) were added to a solution of 286.8 mg of 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-fluoro-1,2,3,4-tetrahydroquinoline in 10 mL of toluene, and the mixture was stirred at 95 °C for 16 hours under a nitrogen atmosphere. The reaction solution was then filtered through silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 5 mL of tetrahydrofuran, and 2 mL of 6M hydrochloric acid was added and stirred at room temperature for 30 minutes. The reaction solution was neutralized by adding saturated aqueous sodium bicarbonate, and separated with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:23 to 3:2) to obtain 174.9 mg of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-fluoro-1,2,3,4-tetrahydroquinolin-6-amine. (4) 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5-fluoro-1,2,3,4-tetrahydroquinolin-6-amine 174.9 mg of pyridine 5 mL of a solution of 2-chloro-5-nitrobenzoyl chloride 236.0 mg of dichloromethane 3 mL was slowly added dropwise and stirred at room temperature for 30 minutes. Then, while cooling the reaction solution with ice, 1 mL of ammonia water (25%) was added and stirred for 30 minutes under ice cooling, and then saturated ammonium chloride water was added to neutralize, and water and ethyl acetate were added to separate the layers. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 118.5 mg of 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.64 (d, J = 2.7 Hz, 1H), 8.25 (dd, J = 8.9, 2.7 Hz, 1H), 7.86 (brs, 1H), 7.80 (t, J = 8.9 Hz, 1H), 7.68 (d, J = 0.9 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.10 (dd, J = 9.0, 1.0 Hz, 1H), 4.58 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 2.86 (t, J = 6.3 Hz, 2H), 2.10-2.06 (m, 2H)

[0165] Example 50 Synthesis of 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5,7-difluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 5.24 mL of pyridine was added to a solution of 3.36 g of 3,5-difluoroaniline in 100 mL of acetone, and 3.00 mL of 3-chloropropionyl chloride was slowly added dropwise at room temperature. The mixture was then stirred at room temperature for 4 hours. Saturated saline and ethyl acetate were added to the reaction solution and the mixture was separated. The resulting organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by recrystallization using ethyl acetate and hexane to obtain 3.16 g of 3-chloro-N-(3,5-difluorophenyl)propanamide. (2) 1.2 mL of N,N-dimethylacetamide was slowly added dropwise to a mixture of 3.07 g of 3-chloro-N-(3,5-difluorophenyl)propanamide and 6.52 g of aluminum chloride under ice cooling, and the mixture was stirred at 130 °C for 6 hours under a nitrogen atmosphere, and then stirred at 145 °C for 4 hours. The reaction solution was ice-cooled, diluted with ethyl acetate, and ice water was slowly added dropwise. Then, the mixture was separated with ethyl acetate, and the obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by recrystallization using ethyl acetate and hexane to obtain 1.74 g of 5,7-difluoro-3,4-dihydroquinolin-2(1H)-one. (3) 1.07 g of N-bromosuccinimide was added to a solution of 1.00 g of 5,7-difluoro-3,4-dihydroquinolin-2(1H)-one in 12 mL of dimethylformamide under a nitrogen atmosphere while cooling with ice, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water to obtain 1.07 g of 6-bromo-5,7-difluoro-3,4-dihydroquinolin-2(1H)-one. (4) 55.0 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 300.0 mg of 6-bromo-5,7-difluoro-3,4-dihydroquinolin-2(1H)-one in 5 mL of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. Furthermore, a solution of 440.3 mg of 2-chloro-1-(iodomethyl)-4-(trifluoromethyl)benzene in 3 mL of dimethylformamide was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. After that, a mixture of water and ethyl acetate:hexane = 1:1 was added to the reaction solution to separate the liquids. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:19 to 3:2) to obtain 437.2 mg of 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,7-difluoro-3,4-dihydroquinolin-2(1H)-one. (5) 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,7-difluoro-3,4-dihydroquinolin-2(1H)-one 420.0 mg in tetrahydrofuran 15 mL solution was slowly added dropwise with borane dimethyl sulfide complex 5.08 mL, stirred at 60 ° C for 30 minutes under nitrogen atmosphere, and then cooled with ice while slowly adding methanol 5 mL. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19 to 3:2) to obtain 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,7-difluoro-1,2,3,4-tetrahydroquinoline 342.8 mg. (6) 6-bromo-1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,7-difluoro-1,2,3,4-tetrahydroquinoline 342.8 mg in toluene 8 mL solution, benzophenone imine 170.6 mg, sodium tert-butoxide 1103.9 mg, (±)-BINAP 96.9 mg, tris(dibenzylideneacetone)dipalladium(0) 71.2 mg were added and stirred at 90 ° C for 17 hours under nitrogen atmosphere. Then, the reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran 5 mL, 6M hydrochloric acid 2 mL was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized by adding saturated sodium bicarbonate water, and separated with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4 to 7:13) to obtain a mixture of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,7-difluoro-1,2,3,4-tetrahydroquinolin-6-amine. A mixture of 1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-5,7-difluoro-1,2,3,4-tetrahydroquinolin-6-amine was dissolved in 5 mL of dichloromethane, and 0.050 mL of triethylamine was added. Then, a solution of 107.5 mg of 2-chloro-5-nitrobenzoyl chloride in 2 mL of dichloromethane was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Then, while cooling the reaction solution with ice, 2 mL of pyridine and 1 mL of ammonia water (25%) were added, and the mixture was stirred for 20 minutes under ice cooling. The reaction solution was neutralized by adding saturated ammonium chloride water, and water and ethyl acetate were added to separate the mixture. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:1) and further purified by preparative thin layer chromatography (ethyl acetate:hexane = 1:4) to obtain 25.9 mg of 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5,7-difluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, ACETONE-D6) δ 9.14 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.35 (dd, J = 8.9, 2.7 Hz, 1H), 7.87-7.83 (m, 2H), 7.68 (dd, J = 8.1, 1.0 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 6.11 (dd, J = 12.9, 1.7 Hz, 1H), 4.72 (s, 2H), 3.56 (t, J = 5.6 Hz, 2H), 2.81 (t, J = 6.3 Hz, 2H), 2.13-2.09 (m, 2H)

[0166] Example 51 Synthesis of 2-chloro-N-{1-[2-([1,1'-biphenyl]-4-yl)ethyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide (1) 0.289 mL of oxalyl chloride was added to a mixed solution of 357.3 mg of 4-biphenylacetic acid and 5 mL of dichloromethane, and 3 drops of dimethylformamide were slowly added. The mixture was stirred for 30 minutes while warming to room temperature. The reaction solution was concentrated under reduced pressure to obtain the acid chloride. Next, the acid chloride prepared was added to a solution of 200 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 5 mL of toluene, and the mixture was stirred at 115 °C for 1 hour. Then, water and ethyl acetate were added to the reaction solution to separate the liquids. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 2:3) to obtain 2-([1,1'-biphenyl]-4-yl)-1-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one. Next, the obtained 2-([1,1'-biphenyl]-4-yl)-1-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one was dissolved in 10 mL of tetrahydrofuran, and 6.17 mL of borane dimethylsulfide complex was slowly added dropwise. After stirring for 2 hours at 60 °C under a nitrogen atmosphere, 5 mL of methanol was slowly added dropwise while cooling the reaction solution with ice. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:9 to 1:1) to obtain 201.0 mg of 1-[2-([1,1'-biphenyl]-4-yl)ethyl]-6-nitro-1,2,3,4-tetrahydroquinoline. (2) 1-[2-([1,1'-biphenyl]-4-yl)ethyl]-6-nitro-1,2,3,4-tetrahydroquinoline 201.0 mg in tetrahydrofuran 2 mL, ethanol 2 mL, water 1 mL, reduced iron 156.6 mg, and ammonium chloride 120.0 mg were added and stirred at 90 °C for 3 hours under nitrogen atmosphere. The reaction solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane 15 mL, 2-chloro-5-nitrobenzoic acid 147.0 mg, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 311.0 mg, and 4-dimethylaminopyridine 96.0 mg were added, and the mixture was stirred at room temperature for 3 hours. Water and dichloromethane were added to the reaction solution, and the mixture was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 3:17 to 1:0) to obtain 188.4 mg of 2-chloro-N-{1-[2-([1,1'-biphenyl]-4-yl)ethyl]-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.62 (d, J = 2.5 Hz, 1H), 8.25 (dd, J = 8.7, 2.7 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.61-7.54 (m, 5H), 7.44 (t, J = 7.7 Hz, 2H), 7.36-7.28 (m, 5H), 6.67 (d, J = 9.6 Hz, 1H), 3.55 (t, J = 7.5 Hz, 2H), 3.24 (t, J = 5.6 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 1.95-1.89 (m, 2H)

[0167] Example 52 Synthesis of N-butyl-[2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetamide (1) A solution of 3.00 g of 2-hydroxybenzyl alcohol in 10 mL of dimethylformamide was cooled on ice, and 1.06 g of sodium hydride (60% liquid paraffin dispersion) was added and stirred at 0 °C for 30 minutes under a nitrogen atmosphere. Furthermore, 1.06 mL of chloromethyl methyl ether was slowly added dropwise, and the mixture was stirred at 0 °C for 2 hours. Then, water and a mixed solution of ethyl acetate:hexane = 1:1 were added to the reaction solution and the liquids were separated. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:1 to 4:1) to obtain 2.32 g of [2-(methoxymethoxy)phenyl]methanol. (2) [2-(methoxymethoxy)phenyl]methanol 1.10 g in dichloromethane 50 mL solution was added with triphenylphosphine 2.23 g and iodine 2.16 g under ice cooling, then imidazole 0.579 g was added little by little, and stirred at 0 ° C for 2 hours. While cooling the reaction solution with ice, hexane 50 mL was added, precipitated insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:9 to 1:4) to obtain 1-(iodomethyl)-2-(methoxymethoxy)benzene 1.26 g. (3) 175 mg of sodium hydride (60% liquid paraffin dispersion) was added to a solution of 650 mg of 6-nitro-1,2,3,4-tetrahydroquinoline in 10 mL of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. Furthermore, a solution of 1.22 g of 1-(iodomethyl)-2-(methoxymethoxy)benzene in 5 mL of dimethylformamide was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. After that, water was added to the reaction solution, and the precipitated solid was collected. The obtained solid was washed with water and dried under reduced pressure to obtain 1.17 g of 1-{[2-(methoxymethoxy)phenyl]methyl}-6-nitro-1,2,3,4-tetrahydroquinoline. (4) 1-{[2-(methoxymethoxy)phenyl]methyl}-6-nitro-1,2,3,4-tetrahydroquinoline 1.05 g in a mixed solution of 30 mL of tetrahydrofuran and 10 mL of methanol was added with 20 mL of 6M hydrochloric acid and stirred at 70 °C for 2 hours. Water and ethyl acetate were added to the reaction solution and the mixture was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (methanol:chloroform = 1:0 to 1:49) to obtain 787 mg of 2-[(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methyl]phenol. (5) 100.0 mg of 2-[(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methyl]phenol was dissolved in 5 mL of dimethylformamide, and 103.1 mg of ethylene carbonate and 145.8 mg of potassium carbonate were added and stirred at 110 °C for 3 hours. Then, water and a mixture of ethyl acetate and hexane (1:1) were added to the reaction solution to separate the liquid. The organic layer obtained was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (ethyl acetate:hexane (2:3 to 4:1) to obtain 111.1 mg of 2-{2-[(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methyl]phenoxy}ethan-1-ol. (6) 2-{2-[(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methyl]phenoxy}ethan-1-ol 231.0 mg in dimethylformamide 5 mL was added with 33.8 mg of sodium hydride (60% liquid paraffin dispersion) under ice cooling, and stirred at 0 °C for 20 minutes under nitrogen atmosphere. Further, a solution of 0.154 mL of tert-butyl bromoacetate in 3 mL of dimethylformamide was slowly added dropwise under ice cooling, and stirred at room temperature for 2 hours. Then, water and a mixed solution of ethyl acetate:hexane = 1:1 were added to the reaction solution to separate the liquids. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4 to 3:2) to obtain 101.7 mg of tert-butyl (2-{2-[(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methyl]phenoxy}ethoxy)acetate. (7) tert-butyl (2-{2-[(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methyl]phenoxy}ethoxy)acetate (117.3 mg) and 10% palladium-on-carbon (14.9 mg) were added to methanol (1 mL) and ethyl acetate (2 mL), and the mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4 to 3:2) to give tert-butyl (2-{2-[(6-amino-3,4-dihydroquinolin-1(2H)-yl)methyl]phenoxy}ethoxy)acetate (64.9 mg). (8) To a solution of 60.3 mg of tert-butyl (2-{2-[(6-amino-3,4-dihydroquinolin-1(2H)-yl)methyl]phenoxy}ethoxy)acetate in 5 mL of dichloromethane, 41.3 mg of 2-chloro-5-nitrobenzoic acid, 81.3 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 25.0 mg of 4-dimethylaminopyridine were added and stirred at room temperature for 5 hours. Water and dichloromethane were added to the reaction solution, and the mixture was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:99 to 3:2) to obtain 69.2 mg of tert-butyl [2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetate. (9) tert-Butyl [2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetate (69.0 mg) in dichloromethane (1 mL) was slowly added dropwise with ice cooling, and the mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. Then, the reaction solution was diluted with toluene (2 mL) and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and water was added to separate the layers. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetic acid (61.6 mg). (10) To a solution of 9.1 mg of [2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetic acid in 0.2 mL of dimethylformamide, 0.95 mg of butylamine, 1.8 mg of 1-hydroxybenzotriazole monohydrate, 2.9 μL of N,N-diisopropylethylamine, 0.16 mg of 4-dimethylaminopyridine, and 3.2 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added under ice cooling, and the mixture was stirred at room temperature for 24 hours. Water, a mixed solution of saturated ammonium chloride water and ethyl acetate:hexane=1:1 were added to the reaction solution, and the mixture was separated. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (ethyl acetate:hexane = 7:3) to obtain 4.8 mg of N-butyl-[2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58 (d, J = 2.7 Hz, 1H), 8.23 ​​(dd, J = 8.7, 2.7 Hz, 1H), 7.64-7.61 (m, 2H), 7.33 (d, J = 2.5 Hz, 1H), 7.25-7.21 (m, 1H), 7.15 (dd, J = 7.5, 1.1 Hz, 1H), 7.07 (dd, J = 8.8, 2.6 Hz, 1H), 6.94-6.90 (m, 2H), 6.59 (s, 1H), 6.39 (d, J = 8.7 Hz, 1H), 4.49 (s, 2H), 4.24-4.22 (m, 2H), 4.06 (s, 2H), 3.93-3.91 (m, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.25 (q, J = 6.9 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.07-2.01 (m, 2H), 1.48-1.40 (m, 2H), 1.34-1.28 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H)

[0168] Example 53 Synthesis of 2-chloro-N-[1-({2-[(prop-2-yn-1-yl)oxy]phenyl}methyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide (1) 275.0 mg of cesium carbonate was added to a solution of 200.0 mg of 2-[(6-nitro-3,4-dihydroquinolin-1(2H)-yl)methyl]phenol in 3 mL of dimethylformamide, and the mixture was stirred under a nitrogen atmosphere for 15 minutes. Then, 0.099 mL of propargyl bromide (80% toluene solution, about 9.2 mol / L) was added to the reaction solution, and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. Then, water and a mixed solution of ethyl acetate:hexane = 1:1 were added to the reaction solution, and the mixture was separated. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 3:17 to 3:2) to obtain 215.9 mg of 6-nitro-1-({2-[(prop-2-yn-1-yl)oxy]phenyl}methyl)-1,2,3,4-tetrahydroquinoline. (2) 6-nitro-1-({2-[(prop-2-yn-1-yl)oxy]phenyl}methyl)-1,2,3,4-tetrahydroquinoline 100.0 mg in a mixed solution of ethanol 2 mL and water 1 mL was added with reduced iron (346.5 mg) and ammonium chloride (265.5 mg), and the mixture was stirred at 90 ° C for 2 hours. The reaction mixture was then filtered through silica gel, and the filtrate was concentrated under reduced pressure to obtain an intermediate. Next, N,N-diisopropylethylamine 59.4 μL was added to a solution of 2-chloro-5-nitrobenzoic acid 75.0 mg, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate 139.5 mg in dimethylformamide 2 mL under ice cooling, and the mixture was stirred at 0 ° C for 10 minutes. Next, the obtained intermediate was dissolved in 2 mL of dimethylformamide, slowly added dropwise to the reaction solution, and stirred at room temperature for 17 hours under a nitrogen atmosphere. Then, a mixed solution of water and ethyl acetate:hexane = 1:1 was added to the reaction solution and the liquids were separated. The obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:4 to 3:2) to obtain 113.0 mg of 2-chloro-N-[1-({2-[(prop-2-yn-1-yl)oxy]phenyl}methyl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.58 (d, J = 2.3 Hz, 1H), 8.23 (dd, J = 8.7, 2.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 6.4 Hz, 1H), 7.07 (dd, J = 8.7, 2.7 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.40 (d, J = 8.7 Hz, 1H), 4.77 (d, J = 2.3 Hz, 2H), 4.50 (s, 2H), 3.42 (t, J = 5.7 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.55 (t, J = 2.3 Hz, 1H), 2.08 - 2.02 (m, 2H)

[0169] Example 54 N-(but-3-yn-1-yl)-[2-(2-{[6-(2-chloro-5-nitrobenzamide)-3,4-dihydroxy Synthesis of 1(2H)-yl]methyl}phenoxy)ethoxy]acetamide To a solution of 76.4 mg of [2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetic acid in 4 mL of dimethylformamide, 24.9 mg of 1-hydroxybenzotriazole monohydrate and 35.3 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added under ice cooling, and the mixture was stirred at 0 ° C. for 15 minutes. Next, a solution of 19.4 mg of 3-butyn-1-amine hydrochloride in 1.5 mL of dimethylformamide was slowly added dropwise, and 29.6 μL of triethylamine was added, and the mixture was stirred at room temperature for 25 hours under a nitrogen atmosphere. After that, a mixture of water and ethyl acetate:hexane = 1:1 was added to the reaction solution and the mixture was separated. The obtained organic layer was washed with saturated sodium bicarbonate water, water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (ethyl acetate:hexane = 2:3 to 99:1) and further purified by preparative thin layer chromatography (methanol:chloroform = 1:19) to obtain 39.7 mg of N-(but-3-yn-1-yl)-[2-(2-{[6-(2-chloro-5-nitrobenzamido)-3,4-dihydroquinolin-1(2H)-yl]methyl}phenoxy)ethoxy]acetamide. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.57 (d, J = 2.7 Hz, 1H), 8.22 (dd, J = 9.1, 2.7 Hz, 1H), 7.63-7.61 (m, 2H), 7.32 (d, J = 2.7 Hz, 1H), 7.23-7.21 (m, 1H), 7.14 (d, J = 7.3 Hz, 1H), 7.08 (dd, J = 8.7, 2.3 Hz, 1H), 6.94-6.90 (m, 3H), 6.39 (d, J = 8.7 Hz, 1H), 4.49 (s, 2H), 4.24-4.22 (m, 2H), 4.08 (s, 2H), 3.95-3.93 (m, 2H), 3.42 (q, J = 6.3 Hz, 4H), 2.86 (t, J = 6.2 Hz, 2H), 2.38 (td, J = 6.5, 2.6 Hz, 2H), 2.07-2.01 (m, 2H), 1.90 (t, J = 2.7 Hz, 1H)

[0170] The following compounds (Examples 55 to 64) were synthesized starting from known compounds by the synthesis methods disclosed in the above Examples or methods analogous thereto. Example 55: 2-Chloro-N-{4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-5-nitrobenzamide Example 56: 2-Chloro-N-[1-(3-chloropyridin-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide Example 57: 2-Chloro-5-nitro-N-{1-[(pyridin-2-yl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}benzamide Example 58: 2-Chloro-5-nitro-N-{1-[(pyridin-3-yl)methyl]-1,2,3,4-tetrahydroquinolin-6-yl}benzamide Example 59: N-{1-[2-(morpholin-4-yl)ethyl]-1,2,3,4-tetrahydroquinolin-6-yl}-2-chloro-5-nitrobenzamide Example 60: 2-Chloro-5-nitro-N-{1-[2-(piperidin-1-yl)ethyl]-1,2,3,4-tetrahydroquinolin-6-yl}benzamide Example 61: 2-chloro-N-[1-{(1-methylpiperidin-4-yl)methyl}-1,2,3,4-tetrahydroquinolin-6-yl]-5-nitrobenzamide Example 62: 2-Chloro-N-(2-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-nitrobenzamide Example 63: 2-Chloro-N-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-nitrobenzamide Example 64: 2-Chloro-N-(2-hexyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-nitrobenzamide

[0171] The above-described example compounds are shown in the following Tables 1-1 to 1-13.

[0172] [Table 1-1]

[0173] [Table 1-2]

[0174] [Table 1-3]

[0175] [Table 1-4]

[0176] [Table 1-5]

[0177] [Table 1-6]

[0178] [Table 1-7]

[0179] [Table 1-8]

[0180] [Table 1-9]

[0181] [Table 1-10]

[0182] [Table 1-11]

[0183] [Table 1-12]

[0184] [Table 1-13]

[0185] Test Example 1: Evaluation test of IL-5 production inhibitory effect (1) CD4 positive T cells purified from mouse spleen cells were treated with anti-mouse TCRβ antibody, IL-2, IL-4, anti-mouse CD28 antibody, and anti-mouse IFNγ antibody to induce differentiation into Th2 cells. Test compounds were added to the culture system of these Th2 cells to evaluate their inhibitory effect on differentiation into Th2 cells that produce interleukin 5 (IL-5). Specifically, anti-mouse TCRβ antibody (Clone: ​​H57-597) adjusted to 10 μg / mL in phosphate buffered saline (pH 7.2) was dispensed into 48-well cell culture plates at 180 μL per well and left at room temperature for 1 hour. After removing unreacted liquid and washing with RPMI1640 medium (Fujifilm wako, Code No. 183-02165) containing 2% fetal calf serum (FCS), the cells were incubated with 10 ng / mL mouse recombinant IL-2 (PEPROTECH, Code No. 212-12, or BioLegend, Code No. 57240), 3 ng / mL mouse recombinant IL-4 (PEPROTECH, Code No. 214-14), 1 μg / mL anti-mouse CD28 antibody (Clone: ​​37.51, 750μL / well of RPMI1640 complete medium (hereinafter, containing 10% FCS, 10mM HEPES, 1% non-essential amino acids, 4mM L-glutamine, 1mM sodium pyruvate, 55μM 2-mercaptoethanol, 1% penicillin-streptomycin) containing 2.5μg / mL of anti-mouse IFNγ antibody (Clone:XMG1.2, BioLegend, CodeNo.505802) was dispensed. Next, 1μL / well of test compound dilution (concentration 10μM, 100μM) was dispensed, and 3×10 CD4+ T cells purified from spleen cells of C57BL6 mice were added to the wells. 6 A cell suspension of 250 μL / well was dispensed at 1 μL / well of the negative control group, in place of the diluted solution of the test compound. (2) After 42 to 48 hours of culture in an incubator (37°C, 5% carbon dioxide), the following subculture was performed. The cells were dispensed into another 48-well cell culture plate at 300μL / well, and RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 and 3ng / mL mouse recombinant IL-4 was dispensed into 700μL / well. Next, test compound dilution (concentration 10μM, 100μM) or DMSO was dispensed into 1μL / well, and the cells were cultured in an incubator (37°C, 5% carbon dioxide) for 24 hours, and the following subculture was performed. The cells were dispensed into another 48-well cell culture plate at 500μL / well, and RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 and 3ng / mL mouse recombinant IL-4 was dispensed into 500μL / well. Then, 1 μL of a test compound dilution (concentration 10 μM, 100 μM) or DMSO was dispensed into each well, and the cells were cultured in an incubator (37° C., 5% carbon dioxide) for 24 hours. This subculture procedure was repeated once more. Five days after the cells were seeded, cytokine production of the Th2 cell line was induced. Specifically, anti-mouse TCRβ antibody adjusted to 3 μg / mL in phosphate buffered saline (pH 7.2) was dispensed at 180 μL per well into a 48-well cell culture plate and left at room temperature for 1 hour. Unreacted liquid was removed, and the plate was washed twice with RPMI solution containing 2% FCS, after which 750 μL of RPMI1640 complete medium was dispensed per well. Subsequently, the cell suspension cultured under the Th2 cell differentiation conditions was added to the plate at 1 × 10 6 After 16 hours of culture in an incubator (37°C, 5% carbon dioxide), the supernatant was collected and the amount of cytokines produced was measured by ELISA. (3) Detection of IL-5 as a cytokine was performed by the ELISA method shown below. First, rat anti-mouse IL-5 antibody (Clone:TRFK4, BD Pharmigen, Code No. 554393 or BioLegend, Code No. 504302) was diluted to 1 μg / mL with 0.1 M carbonate solution as the primary antibody, and 50 μL / well was spread on a 96-well plate (Thermo Scientific, Code No. 442404) and coated overnight (16 to 24 hours) at 4°C. The plate was washed three times with PBS containing 0.05% Tween 20 (washing buffer) and blocked with 3% FCS-containing phosphate buffered saline pH 7.2 (blocking buffer) for 2 hours at room temperature (300 μL / well). The plate was washed three times with washing buffer, and 50 μL / well of the diluted culture supernatant was spread and incubated overnight (16 to 24 hours) at 4°C. Recombinant mouse IL-5 (BioLegend, Code No. 576709) was used to create a standard curve. The plate was washed five times with washing buffer, and a biotin-labeled rat anti-mouse IL-5 antibody (Clone:TRFK4, BD Pharmigen, Code No. 554397 or BioLegend, Code No. 504401) was added as a secondary antibody (50 μL / well) diluted to 1 μg / mL with blocking buffer, and incubated at room temperature for 45 minutes. After washing the plate five times with washing buffer, streptavidin-labeled peroxidase (BD Pharmigen, Code No. 554066 or Thermo Scientific, Code No. N100) diluted 4000-fold with blocking buffer was added (50 μL / well) and incubated at room temperature for 30 minutes. The plate was washed seven times with washing buffer, and TMB substrate solution (Bio-Rad, Code No. 1721067) was added at 50 μL / well to develop color for 10 to 20 minutes. The reaction was stopped by adding 50 μL / well of 1 M sulfuric acid solution, and the absorbance was measured (wavelength 450 nm) using a microplate reader (Bio-Rad, iMark). The experiment was performed in triplicate, and the average cytokine production amount was calculated and the inhibition rate (%) was calculated using the following formula. Inhibition rate (%)=(1-T / N)×100 Here, T represents the mean value of the test compound-treated group, and N represents the mean value of the negative control group.

[0186] The inhibition rates (%) of each test compound in the above tests are shown in Tables 2-1 to 2-3.

[0187] [Table 2-1]

[0188] [Table 2-2]

[0189] [Table 2-3]

[0190] From the above test results, it was revealed that compound (I) of the present invention can effectively inhibit IL-5 production induced by Th2 cells.

[0191] Test Example 2: Inhibition test of IL-33 receptor expression and inhibition test of IL-33-dependent cytokine production (1) CD4 positive T cells purified from mouse spleen cells were treated with anti-mouse TCRβ antibody, IL-2, IL-4, anti-mouse CD28 antibody, and anti-mouse IFNγ antibody to induce differentiation into Th2 cells. Specifically, anti-mouse TCRβ antibody (Clone: ​​H57-597) adjusted to 10 μg / mL in phosphate buffered saline (pH 7.2) was dispensed at 180 μL per well into a 48-well cell culture plate and left at room temperature for 1 hour. After removing the unreacted liquid and washing twice with RPMI solution containing 2% fetal calf serum (FCS), 750μL of RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 (PEPROTECH, CodeNo.212-12, or BioLegend, CodeNo.57240), 3ng / mL mouse recombinant IL-4 (PEPROTECH, CodeNo.214-14), 1μg / mL anti-mouse CD28 antibody (Clone:37.51, BIOLEGEND, CodeNo.102102), and 2.5μg / mL anti-mouse IFNγ antibody (Clone:XMG1.2, BioLegend, CodeNo.505802) was dispensed into each well. Then, 3×10 CD4+ T cells purified from spleen cells of C57BL6 mice were added to the medium. 6 A cell suspension at 30 cells / mL was dispensed at 250 μL per well. (2) After 42 to 48 hours of culture in an incubator (37°C, 5% carbon dioxide), the following subculture was performed. The cells were dispensed into another 48-well cell culture plate at 300μL / well, and RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 and 3ng / mL mouse recombinant IL-4 was dispensed into 700μL / well. Next, test compound dilution (concentration 10μM, 100μM) or DMSO was dispensed into 1μL / well and cultured in an incubator (37°C, 5% carbon dioxide) for 24 hours. The cells that were subcultured as shown below were dispensed into another 48-well cell culture plate at 500μL / well, and RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 and 3ng / mL mouse recombinant IL-4 was dispensed into 500μL / well. Next, 1 μL of the test compound dilution (concentration 10 μM, 100 μM) or DMSO was dispensed into each well and cultured in an incubator (37°C, 5% carbon dioxide) for 24 hours. This subculture procedure was repeated once more. IL-33 receptor expression and cytokine production tests were performed on the cells cultured in the Th2 cell differentiation induction system. (3) That is, the cells were washed with RPMI 1640 complete medium, and 4.5 × 10 cells suspended in RPMI 1640 complete medium were placed in a 96-well plate. 5 A cell suspension of 300 μL / well was dispensed at 10 μL / well and cultured in an incubator (37°C, 5% carbon dioxide) for 12 hours. Then, a test compound dilution (concentration 3 μM, DMSO concentration 3%) was dispensed at 10 μL / well and cultured in an incubator (37°C, 5% carbon dioxide). In the negative control group, 3% DMSO was dispensed at 10 μL / well instead of the test compound dilution. Then, 1 mg / mL mouse recombinant IL-7 (PEPROTECH, Code No. 217-17) and 1 mg / mL mouse recombinant IL-33 (BioLegend, Code No. 580506) were dispensed at 3 μL / well and cultured in an incubator (37°C, 5% carbon dioxide) for 36 hours. After the culture, the culture supernatant and cells were separated by centrifugation, and cytokines in the collected culture supernatant were detected by ELISA, and the cells were used to measure the expression level of IL-33 receptor by flow cytometry. The expression level of IL-33 receptor was measured by flow cytometry analysis according to the following procedure. The collected cells were washed with phosphate buffered saline, pH 7.2, and stained with a 30-fold dilution of phycoerythrin rat anti-mouse IL-33 receptor α antibody (Clone: ​​DIH4, BioLegend, Code No. 146608). After staining, the cells were washed with phosphate buffered saline, pH 7.2, containing 1% FCS. The number of IL-33 receptor α-positive cells was analyzed using a flow cytometer cell analyzer, Galios (Beckman Coulter). The inhibition rate (%) was calculated from the percentage of IL-33 receptor α-positive cells using the following formula. Inhibition rate (%)=(1-T / N)×100 Here, T represents the percentage of IL-33 receptor α positive cells in the test compound treatment group, and N represents the percentage of IL-33 receptor α positive cells in the negative control group. (4)(i) Detection of cytokine IL-5 was performed by the following ELISA method. First, rat anti-mouse IL-5 antibody (Clone: ​​TRFK4, BioLegend, Code No. 504302) was diluted to 1 μg / mL with 0.1 M carbonate solution as the primary antibody, and 50 μL / well was spread on a 96-well plate (Thermo Scientific, Code No. 442404) and coated overnight (16 to 24 hours) at 4°C. The plate was washed three times with PBS containing 0.05% Tween 20 (washing buffer), and blocked with 3% FCS-containing phosphate buffered saline pH 7.2 (blocking buffer) for 2 hours at room temperature (300 μL / well). The plate was washed three times with washing buffer, and 50 μL / well of the diluted culture supernatant was spread, and incubated overnight (16 to 24 hours) at 4°C. Recombinant mouse IL-5 (BioLegend, Code No. 576709) was used to create a standard curve. The plate was washed five times with washing buffer, and a biotin-labeled rat anti-mouse IL-5 antibody (Clone: ​​TRFK4, BioLegend, Code No. 504401) was added as a secondary antibody (50 μL / well) diluted to 1 μg / mL with blocking buffer, and incubated at room temperature for 45 minutes. After washing the plate five times with washing buffer, streptavidin-labeled peroxidase (Thermo Scientific, Code No. N100) diluted 4000-fold with blocking buffer was added (50 μL / well) and reacted at room temperature for 30 minutes. The plate was washed seven times with washing buffer, and TMB substrate solution (Bio-Rad, Code No. 1721067) was added at 50 μL / well to develop color for 10 to 20 minutes. The reaction was stopped by adding 50 μL / well of 1 M sulfuric acid solution, and the absorbance was measured (wavelength 450 nm) using a microplate reader (Bio-Rad, iMark). The experiment was performed in triplicate, and the average cytokine production amount was calculated and the inhibition rate (%) was calculated using the following formula. Inhibition rate (%)=(1-T / N)×100 Here, T represents the mean value of the test compound-treated group, and N represents the mean value of the negative control group. (ii) Mouse IL-13 DuoSet ELISA (R&D system, Code No. DIY413) and Duoset ELISA Ancillary Reagent Kit2 (R&D system, Code No. DIY008B) were used to detect the cytokine IL-13. For detection, absorbance (wavelength 450 nm) was measured using a microplate reader (Bio-Rad, iMark). The experiment was performed in triplicate, and the average amount of cytokine production was calculated, and the inhibition rate (%) was calculated using the following formula. Inhibition rate (%)=(1-T / N)×100 Here, T represents the mean value of the test compound-treated group, and N represents the mean value of the negative control group.

[0192] The inhibition rates (%) of each test compound in the above tests are shown in Tables 3-1 to 3-3.

[0193] [Table 3-1]

[0194] [Table 3-2]

[0195] [Table 3-3]

[0196] From the above test results, it was revealed that compound (I) of the present invention can effectively inhibit the expression of IL-33 receptor, and as a result, can inhibit the production of IL-5 and IL-13 induced by IL-33 stimulation.

[0197] Test Example 3: Inhibition test of IL-33-dependent cytokine production (1) CD4 positive T cells purified from mouse spleen cells were treated with anti-mouse TCRβ antibody, IL-2, IL-4, anti-mouse CD28 antibody, and anti-mouse IFNγ antibody to induce differentiation into Th2 cells. Specifically, anti-mouse TCRβ antibody (Clone: ​​H57-597) adjusted to 10 μg / mL in phosphate buffered saline (pH 7.2) was dispensed at 180 μL per well into a 48-well cell culture plate and left at room temperature for 1 hour. After removing the unreacted liquid and washing twice with RPMI solution containing 2% fetal calf serum (FCS), 750μL of RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 (PEPROTECH, CodeNo.212-12, or BioLegend, CodeNo.57240), 3ng / mL mouse recombinant IL-4 (PEPROTECH, CodeNo.214-14), 1μg / mL anti-mouse CD28 antibody (Clone:37.51, BIOLEGEND, CodeNo.102102), and 2.5μg / mL anti-mouse IFNγ antibody (Clone:XMG1.2, BioLegend, CodeNo.505802) was dispensed into each well. Then, 3×10 CD4+ T cells purified from spleen cells of C57BL6 mice were added to the medium. 6 A cell suspension at 30 cells / mL was dispensed at 250 μL per well. (2) After 42 to 48 hours of culture in an incubator (37°C, 5% carbon dioxide), the following subculture was performed. The cells were dispensed into another 48-well cell culture plate at 300μL / well, and RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 and 3ng / mL mouse recombinant IL-4 was dispensed into 700μL / well. Next, test compound dilution (concentration 10μM, 100μM) or DMSO was dispensed into 1μL / well and cultured in an incubator (37°C, 5% carbon dioxide) for 24 hours. The cells that were subcultured as shown below were dispensed into another 48-well cell culture plate at 500μL / well, and RPMI1640 complete medium containing 10ng / mL mouse recombinant IL-2 and 3ng / mL mouse recombinant IL-4 was dispensed into 500μL / well. Then, 1 μL of a test compound dilution (concentration 10 μM, 100 μM) or DMSO was dispensed into each well, and the cells were cultured in an incubator (37° C., 5% carbon dioxide) for 24 hours. This subculture procedure was repeated once more. (3) An IL-33-dependent cytokine production test was performed on cells cultured in the Th2 cell differentiation induction system. Specifically, cells were washed with RPMI1640 complete medium and suspended in RPMI1640 complete medium in a 48-well plate. 5 A cell suspension of 10 cells / mL was dispensed at 1 mL per well and cultured in an incubator (37°C, 5% carbon dioxide) for 12 hours. Next, 1 mg / mL mouse recombinant IL-7 (PEPROTECH, Code No. 217-17) was dispensed at 10 μL per well and cultured in an incubator (37°C, 5% carbon dioxide) for 24 hours. Next, the cultured cells were washed with RPMI1640 complete medium and 4.5 × 10 cells suspended in RPMI1640 complete medium were placed in a 96-well plate. 5A cell suspension of 300 μL / well was dispensed at 10 μL / well of a test compound dilution (concentration 3uM, DMSO concentration 3%) and cultured in an incubator (37℃, 5% carbon dioxide) for 1 hour. In the negative control group, 3% DMSO was dispensed at 10 μL / well instead of the test compound dilution. Next, 1 mg / mL mouse recombinant IL-33 (BioLegend, Code No. 580506) was dispensed at 3 μL / well and cultured in an incubator (37℃, 5% carbon dioxide) for 24 hours. After culture, cytokines in the collected culture supernatant were detected by ELISA. (i) Detection of IL-5 as a cytokine was performed by the ELISA method shown below. First, rat anti-mouse IL-5 antibody (Clone: ​​TRFK4, BioLegend, Code No. 504302) was diluted to 1 μg / mL with 0.1 M carbonate solution as the primary antibody, and 50 μL / well was spread on a 96-well plate (Thermo Scientific, Code No. 442404) and coated overnight (16 to 24 hours) at 4 ° C. The plate was washed three times with PBS containing 0.05% Tween 20 (washing buffer), and blocked with 3% FCS-containing phosphate buffered saline pH 7.2 (blocking buffer) for 2 hours at room temperature (300 μL / well). The plate was washed three times with washing buffer, and 50 μL / well of the diluted culture supernatant was spread, and incubated overnight (16 to 24 hours) at 4 ° C. Recombinant mouse IL-5 (BioLegend, Code No. 576709) was used to create a standard curve. The plate was washed five times with washing buffer, and a biotin-labeled rat anti-mouse IL-5 antibody (Clone: ​​TRFK4, BioLegend, Code No. 504401) was added as a secondary antibody (50 μL / well) diluted to 1 μg / mL with blocking buffer, and incubated at room temperature for 45 minutes. After washing the plate five times with washing buffer, streptavidin-labeled peroxidase (Thermo Scientific, Code No. N100) diluted 4000-fold with blocking buffer was added (50 μL / well) and reacted at room temperature for 30 minutes. The plate was washed seven times with washing buffer, and TMB substrate solution (Bio-Rad, Code No. 1721067) was added at 50 μL / well to develop color for 10 to 20 minutes. The reaction was stopped by adding 50 μL / well of 1 M sulfuric acid solution, and the absorbance was measured (wavelength 450 nm) using a microplate reader (Bio-Rad, iMark). The experiment was performed in triplicate, and the average cytokine production amount was calculated and the inhibition rate (%) was calculated using the following formula. Inhibition rate (%)=(1-T / N)×100 Here, T represents the mean value of the test compound-treated group, and N represents the mean value of the negative control group. (ii) Mouse IL-13 DuoSet ELISA (R&D system, Code No. DIY413) and Duoset ELISA Ancillary Reagent Kit2 (R&D system, Code No. DIY008B) were used to detect the cytokine IL-13. For detection, absorbance (wavelength 450 nm) was measured using a microplate reader (Bio-Rad, iMark). The experiment was performed in triplicate, and the average amount of cytokine production was calculated, and the inhibition rate (%) was calculated using the following formula. Inhibition rate (%)=(1-T / N)×100 Here, T represents the mean value of the test compound-treated group, and N represents the mean value of the negative control group.

[0198] The inhibition rates (%) of each test compound in the above tests are shown in Table 4.

[0199] [Table 4]

[0200] From the above test results, it was revealed that compound (I) of the present invention can effectively inhibit the expression of IL-33 receptor even in Th2 cells expressing the IL-33 receptor, and as a result, can inhibit the IL-33-dependent production of IL-5 and IL-13.

[0201] The following describes formulations of the compound of the present invention, with reference to formulation examples containing the compound of Example 1. However, the form of the formulation of the compound of the present invention is not limited to these.

[0202] Formulation Example 1 (Capsule Production) 1) 30 mg of the compound of Example 1 2) Fine powdered cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0203] Formulation Example 2 (Tablet Production) 1) 30 g of the compound of Example 1 2) Lactose 50g 3) 15 g corn starch 4) Calcium carboxymethylcellulose 44 g 5) Magnesium stearate 1 g 1000 tablets total 140 g The total amount of 1), 2), 3) and 30g of 4) are mixed with water, vacuum dried, and then granulated. 14g of 4) and 1g of 5) are mixed with the granulated powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets containing 30mg of compound 1 per tablet are obtained. [Industrial Applicability]

[0204] In one embodiment, the present invention provides a cyclic organic compound that is useful as an agent for preventing and / or treating diseases accompanied by abnormalities in immune function, and is useful, for example, in the field of medicine.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, ring A is a nitrogen-containing 5- to 7-membered non-aromatic heterocycle or a pyrrole ring; Ring B is a benzene ring or a pyridine ring; X is a halogen atom; R １ is a hydrogen atom or an acyl group; m R ａ are present at any substitutable position of ring A, and each independently represents １－６ ) an alkyl group or an oxo group; m is an integer from 0 to 3; n R ｂ are present at any substitutable position of ring B, and each independently represents １－６ ) an alkyl group or a halogen atom; n is an integer from 0 to 3; and M is represented by the formula: -(M １ )o-R ２ (In the formula, M １ represents a methylene group optionally substituted with an oxo group, o is an integer from 0 to 3, and R ２ may be substituted (C １－１２ ) alkyl group, optionally substituted (C ２－１２ ) alkenyl group, optionally substituted (C ３－１２ ) a cycloalkyl group, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted saturated heterocyclic group; (representing the (wherein M is not a carbamate group); ] 2. Compound (I) represented by the formula:

2. Ring A is dihydropyridine, tetrahydropyridine, pyrroline, tetrahydroazepine, dihydro-1,4-oxazine or pyrrole; 2. The compound according to claim 1 or a salt thereof.

3. In formula (I), the following formula (II): 【Chemistry 2】 (In the formula, * indicates the bonding position with N, and other symbols are the same as those in claim 1.) The partial structure (II) represented by the following formulae (IIIa) to (IIIl): 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 (wherein each symbol has the same meaning as above) A partial structure represented by The compound according to claim 2 or a salt thereof.

4. The partial structure (II) has the following formula (IIa): 【Chemistry 6】 (wherein ring A' represents a nitrogen-containing 5- to 7-membered non-aromatic heterocycle or a pyrrole ring; Y represents CH or N; * indicates the position of bond to N, and The other symbols are the same as those in claim 1. The partial structure (IIa) is represented by the following formula:

2. The compound according to claim 1 or a salt thereof.

5. Ring A' is tetrahydropyridine, pyrroline, tetrahydroazepine, dihydro-1,4-oxazine or pyrrole; The compound according to claim 4 or a salt thereof.

6. The partial structure (IIa) is represented by the following formulae (IIIa) to (IIIg): 【Chemistry 7】 【Chemistry 8】 (wherein each symbol has the same meaning as in claim 4) A partial structure represented by The compound according to claim 5 or a salt thereof.

7. R １ is a hydrogen atom or (C １－６ ) an alkyl-carbonyl group; The compound according to any one of claims 1 to 6, or a salt thereof.

8. R ２ may be substituted (C １－１２ ) alkyl group, optionally substituted (C ２－１２ ) alkenyl group, optionally substituted (C ３－１２ ) cycloalkyl group, optionally substituted (C ６－１４ ) an aryl group, an optionally substituted nitrogen-containing 5- to 6-membered aromatic heterocyclic group, or an optionally substituted 5- to 7-membered saturated heterocyclic group; The compound according to any one of claims 1 to 6, or a salt thereof.

9. R ２ but, (1) a hydrogen atom, (2) Optionally substituted (C １－１２ ) alkyl group, optionally substituted (C １－１２ ) an alkoxy group, optionally substituted (C ２－１２ ) each of which is optionally substituted by 1 to 5 substituents, which may be the same or different, selected from an alkynyloxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, and a halogen atom; (C １－１２ ) alkyl group, (C ２－１２ ) an alkenyl group, (C ３－１２ ) a cycloalkyl group, (C ６－１４ ) an aryl group, a nitrogen-containing 5- or 6-membered aromatic heterocyclic group, or an optionally substituted 5- to 7-membered saturated heterocyclic group; The compound according to claim 8 or a salt thereof.

10. R ２ but, (1) (C １－１２ ) alkyl group, (2) (C ２－１２ ) an alkenyl group, (3) (i) optionally substituted with 1 to 5 halogen atoms (C １－６ ) alkyl group, (ii) (C ６－１４ ) an aryloxy group, (C ６－１４ ) aryloxy (C １－６ ) alkoxy groups, and acyl (C １－６ ) alkoxy groups, which may be the same or different and may be substituted by 1 to 5 substituents selected from １－６ ) an alkoxy group, (iii) (C ２－６ ) an alkynyloxy group, (iv) (C ６－１４ ) an aryl group, (v) (C ６－１４ ) an aryloxy group, and (vi) a halogen atom (C ３－１２ ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 halogen atoms (C １－６ ) alkyl group, (ii) (C ６－１４ ) an aryloxy group, (C ６－１４ ) aryloxy (C １－６ ) alkoxy groups, and acyl (C １－６ ) alkoxy groups, which may be the same or different and may be substituted by 1 to 5 substituents selected from １－６ ) an alkoxy group, (iii) (C ２－６ ) an alkynyloxy group, (iv) (C ６－１４ ) an aryl group, (v) (C ６－１４ ) an aryloxy group, and (vi) a halogen atom (C ６－１４ ) an aryl group, (5) (i) optionally substituted with 1 to 5 halogen atoms (C １－６ ) alkyl group, (ii) (C ６－１４ ) an aryloxy group, (C ６－１４ ) aryloxy (C １－６ ) alkoxy groups, and acyl (C １－６ ) alkoxy groups, which may be the same or different and may be substituted by 1 to 5 substituents selected from １－６ ) an alkoxy group, (iii) (C ２－６ ) an alkynyloxy group, (iv) (C ６－１４ ) an aryl group, (v) (C ６－１４ ) an aryloxy group, and (vi) a halogen atom or a nitrogen-containing 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to 5 substituents, which may be the same or different, selected from (6) (i) optionally substituted with 1 to 5 halogen atoms (C １－６ ) alkyl group, (ii) (C ６－１４ ) an aryloxy group, (C ６－１４ ) aryloxy (C １－６ ) alkoxy groups, and acyl (C １－６ ) alkoxy groups, which may be the same or different and may be substituted by 1 to 5 substituents selected from １－６ ) an alkoxy group, (iii) (C ２－６ ) an alkynyloxy group, (iv) (C ６－１４ ) an aryl group, (v) (C ６－１４ ) an aryloxy group, and (vi) a halogen atom is a 5- to 7-membered saturated heterocyclic group optionally substituted by 1 to 5 substituents, which may be the same or different, selected from The compound according to claim 8 or a salt thereof.

11. R ２ but, (1) (C １－１２ ) alkyl group, (2) (C ２－１２ ) an alkenyl group, (3) 1 to 5 (C １－６ ) optionally substituted with an alkyl group (C ３－１２ ) a cycloalkyl group, (4) (i) optionally substituted with 1 to 5 halogen atoms (C １－６ ) alkyl group, (ii) (C ６－１４ ) an aryloxy group, (C ６－１４ ) aryloxy (C １－６ ) alkoxy groups, and acyl (C １－６ ) alkoxy groups, which may be the same or different and may be substituted by 1 to 5 substituents selected from １－６ ) an alkoxy group, (iii) (C ２－６ ) an alkynyloxy group, (iv) (C ６－１４ ) an aryl group, (v) (C ６－１４ ) an aryloxy group, and (vi) a halogen atom (C ６－１４ ) an aryl group, (5) (i) optionally substituted with 1 to 5 halogen atoms (C １－６ ) alkyl groups, and (ii) a halogen atom or a nitrogen-containing 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to 5 substituents, which may be the same or different, selected from (6) 1 to 5 (C １－６ ) a 5- to 7-membered saturated heterocyclic group optionally substituted by an alkyl group; The compound according to claim 8 or a salt thereof.

12. R ２ but, (i) optionally substituted with 1 to 3 halogen atoms (C １－６ ) alkyl group, (ii) (C ６－１４ ) an aryloxy group, (C ６－１４ ) aryloxy (C １－６ ) alkoxy groups, and acyl (C １－６ ) alkoxy groups, which may be the same or different and may be substituted by 1 to 3 substituents selected from １－６ ) an alkoxy group, (iii) (C ２－６ ) an alkynyloxy group, (iv) (C ６－１４ ) an aryl group, (v) (C ６－１４ ) an aryloxy group, and (vi) a halogen atom (C ６－１４ ) an aryl group, That is, The compound according to claim 8 or a salt thereof.

13. The partial structure (II) in formula (I) is represented by the following formula (IIIa): 【Chemistry 9】 (In the formula, * indicates the bonding position with N, and other symbols are the same as those in claim 1.) A partial structure represented by The compound (I) according to claim 1 or a salt thereof.

14. R １ is a hydrogen atom, m is 0, R ｂ is a halogen atom, n is 0 or 1; o is 1, R ２ (i) optionally substituted with 1 to 3 halogen atoms (C １－６ ) alkyl groups, and (ii) a halogen atom A phenyl group optionally substituted by 1 to 3 substituents, which may be the same or different, selected from 14. The compound according to claim 13 or a salt thereof.

15. 2-chloro-N-(1-{[2-chloro-4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydroquinolin-6-yl)-5-nitrobenzamide, 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide, and 2-chloro-N-{1-[(2-chloro-4-(trifluoromethyl)phenyl)methyl]-5-fluoro-1,2,3,4-tetrahydroquinolin-6-yl}-5-nitrobenzamide, or a salt thereof, 15. The compound according to claim 14 or a salt thereof.

16. A pharmaceutical composition comprising the compound or salt thereof according to claim 1 as an active ingredient.

17. The pharmaceutical agent according to claim 16, which is an IL-5 production inhibitor.

18. The pharmaceutical agent according to claim 16, which is an IL-33 receptor expression inhibitor.

19. The pharmaceutical agent according to claim 16, which is an IL-13 production inhibitor.

20. The pharmaceutical agent according to any one of claims 16 to 19, which is an agent for preventing and / or treating a disease accompanied by immune dysfunction.

21. The pharmaceutical agent according to claim 20, which is a preventive and / or therapeutic agent for allergic diseases and autoimmune diseases.

22. Diseases include urticaria, food allergies, anaphylactic shock, hypereosinophilic syndrome, asthma, allergic rhinitis, allergic conjunctivitis, allergic bronchitis, atopic dermatitis, rheumatoid arthritis, type I diabetes, Hashimoto's thyroiditis, myasthenia gravis, multiple sclerosis, rejection reactions following organ transplants; atopic asthma, non-allergic rhinitis, severe asthma, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, abdominal diseases, Churg-Strauss syndrome, eosinophilic myalgia syndrome, hypereosinophilic syndrome, edematous reactions including episodic angioedema, helminth infections, onchocerca dermatitis, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, The pharmaceutical composition according to claim 21, wherein the disease is one or more selected from the group consisting of acidophilic enteritis, acidophilic colitis, nasal micropolyposis, nasal polyposis, aspirin-intolerant asthma, obstructive sleep apnea, chronic asthma, Crohn's disease, scleroderma, and endomyocardial fibrosis; hay fever, sinusitis (including eosinophilic sinusitis), ulcerative colitis, arthritis, systemic lupus erythematosus, pemphigus, pemphigoid, scleroderma, ankylosing spondylitis, hepatic fibrosis (including primary biliary cirrhosis), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute kidney injury, vasculitis, cancer, pulmonary hypertension, Sjogren's syndrome, muscular dystrophy, autoimmune hepatitis, and bronchiectasis.

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