3-((1h-pyrazole-4-yl)methyl)-6'-(phenyl)-2h-(1,2'-bipyridine)-2-on derivative as GPR139 antagonist used for treatment method of depression for example, and related compound

Abstract

To provide a 3-((1H-pyrazole-4-yl)methyl)-6'-(phenyl)-2H-(1,2'-bipyridine)-2-on derivative as a GPR139 antagonist used for a treatment method of depression for example, and a related compound.SOLUTION: The present invention refers to a compound of the formula (I). The present invention relates to a compound of the formula (I) used as a G protein conjugate receptor 139 (GPR139) antagonist in a medical treatment method of depression, Alzheimer disease, schizophrenia, drug dependence, dysgryphia, pain, attention defect hyperactivity disorder, and the like. An exemplary compound is a 3-((1H-pyrazole-4-yl)methyl)-6'-(phenyl)-2H-(1,2'-bipyridine)-2-on derivative, and a related compound. The present specification discloses synthesis and characterization of the exemplary compound, pharmacological data thereof, and an exemplary tablet formulation including the compound of the present invention.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority from Japanese Patent Application No. 2020-090111, filed May 22, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to heterocyclic compounds that exhibit G protein-coupled receptor (GPR) 139 receptor antagonism and are expected to be useful in treating or preventing GPR139-mediated diseases, such as depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. [Background technology]

[0003] GPR139 is an orphan G protein-coupled receptor that couples with Gs and Gq proteins (Journal of Biomolecular Screen 2009 14:789-797, Biochemical and Biophysical Research Communications 331 (2005) 363-369). The protein sequence of GPR139 is highly conserved among different species. For example, the protein sequences of human, mouse, and rat GPR139 share more than 94% identity at the amino acid level. In addition, the expression of GPR139 is high in the central nervous system, especially in the striatum, septum, hypothalamus, and habenula, and low in peripheral tissues. The high sequence homology and predominant expression in the brain across different species suggest that GPR139 plays an important role in physiology.

[0004] Mutations in the GPR139 gene have been reported in psychiatric disorders such as schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder (Twin Research and Human Genetics 2014 Apr;17(2):108-120, Nature Genetics 2011 Jun;43(6):585-589, Twin Research and Human Genetics 2013 Apr;16(2):560-574). Furthermore, GPR139 is highly expressed in brain regions. The habenula, one of the brain regions, is known to regulate stress responses and learning, and is thought to be overactive in patients with depression. In a study of patients with treatment-resistant depression and psychiatric symptoms, it was reported that intense stimulation of the habenula using deep brain stimulation (DBS) improved the HAMD21 score, which assesses depressive symptoms (Biol Psychiatry 2010 67:e9-e11). Furthermore, in 20 patients with treatment-resistant depression, positron emission tomography (PET) imaging of brain regions where neural activity changed after ketamine administration revealed that glucose metabolism, which reflects neural activity, was suppressed in brain regions such as the habenula, and depressive symptoms improved (Biol Psychiatry 2013 73(12:1213-1221)). In animal studies, direct administration of ketamine into the habenula suppressed neural activity in the habenula and improved anhedonic-like behavior (Nature 2018 554(7692):317-322). Collectively, these results suggest that GPR139 activity can affect neural activity in the habenula, dramatically altering central nervous system function or neuropsychiatric status.

[0005] Antagonists (including inverse agonists) of the GPR139 receptor may be useful for treating CNS disorders such as depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, attention deficit hyperactivity disorder, etc. Therefore, there is a need for novel compounds that exhibit GPR139 receptor antagonism (including inverse agonism). Certain heterocyclic compounds may be useful as antagonists of the GPR139 receptor. Methods for synthesizing derivatives of one class of heterocyclic compounds, 6-(4H-1,2,4-triazol-4-yl)-2(1H)-pyridinone, have been previously described (Synthetic Communication 43:9, 1250-1262, 2013). [ka] [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Journal of Biomolecular Screen 2009 14:789-797 [Non-patent document 2] Biochemical and Biophysical Research Communications 331 (2005) [Non-patent document 3] Twin Research and Human Genetics 2014 Apr;17(2):108-120 [Non-patent document 4] Nature Genetics 2011 Jun;43(6):585-589 [Non-Patent Document 5] Twin Research and Human Genetics 2013 Apr;16(2):560-574 [Non-patent document 6] Biol Psychiatry 2010 67:e9-e11 [Non-Patent Document 7] Biol Psychiatry 2013 73(12):1213-1221 [Non-patent document 8] Nature 2018 554(7692):317-322 [Non-Patent Document 9] Synthetic Communication 43:9, 1250-1262, 2013 Summary of the Invention [Means for solving the problem]

[0007] Disclosed herein are compounds that exhibit GPR139 receptor antagonism, which may be useful for the treatment or prevention of depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, attention deficit hyperactivity disorder, and the like.

[0008] In the present specification, the compound of formula (I) (hereinafter also referred to as compound (I)) [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] and Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring; Ring A 2 is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; Ring B is a halogen atom and an optionally substituted C 1-6 a pyridone ring optionally further substituted by 1 to 3 substituents selected from the group consisting of R 2 and R 3 are each independently selected from a hydrogen atom and a substituent; R 4a and R 4b are each independently selected from the substituents, Ring C is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles.

[0009] In some embodiments, R 1 teeth, [ka] is.

[0010] In some embodiments, R 1 teeth, [ka] wherein X is CH or N; Y is CH or N; Z is a bond, -O-, or -OR 9a - * , -NH-, and -N(R 9b )R 9a - * Selected from, here * indicates the point of attachment to ring D, Ring D is a 6- to 8-membered aromatic ring, a 5- to 8-membered monocyclic aromatic heterocycle, C 3-8 selected from a cycloalkyl group and a 5- to 8-membered heterocyclic group; Each R 7a are independently cyano, halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; Each R 8a are independently halogen, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; R 9a is C 1-3 selected from alkyl groups, R 9b is a hydrogen atom and C 1-3 selected from alkyl groups, m is 0, 1, 2, or 3; n is 0, 1, 2, or 3.]

[0011] In some embodiments, Z is a bond, —O—, —NH—, —NHCH 2 — * , and -N(CH3)CH2- * and all other variables are as defined above.

[0012] In some embodiments, Z is a bond, and all other variables are as defined above. In some embodiments, Z is -O-, and all other variables are as defined above. In some embodiments, Z is -NH-, and all other variables are as defined above. In some embodiments, Z is -NHCH2- * and all other variables are as defined above. In some embodiments, Z is -N(CH3)CH2- * and all other variables are as defined above.

[0013] In some embodiments, X is N, Y is CH, and all other variables are as defined above.

[0014] In some embodiments, X is N and Y is N, and all other variables are as defined above.

[0015] In some embodiments, X is CH and Y is CH, and all other variables are as defined above.

[0016] In some embodiments, Ring D is selected from benzene, morpholine, oxane, piperidine, and cyclobutane, and all other variables are as defined above.

[0017] In some embodiments, Ring D is benzene, and all other variables are as defined above. In some embodiments, Ring D is morpholine, and all other variables are as defined above. In some embodiments, Ring D is oxane, and all other variables are as defined above. In some embodiments, Ring D is piperidine, and all other variables are as defined above. In some embodiments, Ring D is cyclobutane, and all other variables are as defined above.

[0018] In some embodiments, R 1 teeth, [ka] (In the formula, X, Y, ring D, R 7a , R 8a , m, and n are as defined above.

[0019] In some embodiments, X is N, Y is CH, and all other variables are as defined above.

[0020] In some embodiments, X is N and Y is N, and all other variables are as defined above.

[0021] In some embodiments, X is CH and Y is CH, and all other variables are as defined above.

[0022] In some embodiments, Ring D is selected from benzene, morpholine, oxane, piperidine, and cyclobutane, and all other variables are as defined above.

[0023] In some embodiments, Ring D is benzene, and all other variables are as defined above. In some embodiments, Ring D is morpholine, and all other variables are as defined above. In some embodiments, Ring D is oxane, and all other variables are as defined above. In some embodiments, Ring D is piperidine, and all other variables are as defined above. In some embodiments, Ring D is cyclobutane, and all other variables are as defined above.

[0024] In some embodiments, R 1 teeth, [ka] (In the formula, R 7a , R 8a , m, and n are as defined above.

[0025] In some embodiments, R 1 teeth, [ka] (In the formula, R 7a and n has the same meaning as above.

[0026] In some embodiments, R 1 teeth, [ka] (In the formula, X, R 7a , R 8a , m, and n are as defined above. In some embodiments, X is CH. In some embodiments, X is N.

[0027] In some embodiments, R 1 teeth, [ka] (In the formula, X, R 7a , R 8a, m, and n are as defined above. In some embodiments, X is CH.

[0028] In some embodiments, R 1 teeth, [ka] (In the formula, X, Y, R 7a , R 8a , m, and n are as defined above. In some embodiments, X is N and Y is CH.

[0029] In some embodiments, R 1 teeth, [ka] (In the formula, Z, R 7a , R 8a , m, and n are as defined above. In some embodiments, Z is -NHCH2- * In some embodiments, Z is -N(CH3)CH2- * is.

[0030] In some embodiments, R 1 teeth, [ka] (In the formula, Each R 7a are independently cyano, halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; Each R 8a are independently a halogen atom, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 1-6 Alkyl and C1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3. is.

[0031] In some embodiments, each R 7a are independently cyano, halogen, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 1-6 Alkyl and C 1-6 The alkoxy group may be substituted with 1 to 4 halogen atoms, and each R 8a are independently a halogen atom and C 1-6 alkyl groups, wherein C 1-6 The alkyl group may be substituted with 1 to 4 halogen atoms; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.

[0032] In some embodiments, R 1 teeth, [ka] (In the formula, X is CH or N; Y is CH or N; Each R 7a are independently halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 The alkoxy group may be substituted with 1 to 4 halogen atoms, and each R 8a are independently a halogen atom, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 1-6 Alkyl and C 1-6the alkoxy group is optionally substituted with 1 to 4 halogen atoms; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3. is.

[0033] In some embodiments, R 1 teeth, [ka] is.

[0034] In some embodiments, ring B is [ka] (In the formula, Each R 10a are independently a halogen atom and C 1-3 selected from alkyl groups, o is 0, 1, or 2.) is.

[0035] In some embodiments, o is 0.

[0036] In some embodiments, o is 1 and R 10a is a fluorine atom or methyl.

[0037] In some embodiments, o is 2 and each R 10a is independently selected from a fluorine atom and methyl.

[0038] In some embodiments, R 2 and R 3 are each independently hydrogen and C 1-3 In some embodiments, R 2 and R 3 are both hydrogen atoms.

[0039] In some embodiments, ring C is [ka] (In the formula, each R 11a independently, C 1-3 alkyl groups, and p is 0, 1, or 2.

[0040] In some embodiments, ring C is [ka] (In the formula, R 11a is C 1-3 In some embodiments, R 11a is ethyl.

[0041] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment or prevention of a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain, and attention deficit hyperactivity disorder. In some embodiments, a compound selected from Examples 1-33 or a pharmaceutically acceptable salt thereof is provided for use in the treatment or prevention of a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain, and attention deficit hyperactivity disorder.

[0042] Also disclosed herein are pharmaceutical compositions comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0043] Also disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in therapy. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof for use in therapy are In accordance with the present invention, a compound selected from Examples 1 to 33 or a pharmaceutically acceptable salt thereof is provided.

[0044] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is combined with at least one other drug for simultaneous, separate, or sequential use in the treatment or prevention of a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain, and attention deficit hyperactivity disorder.In some embodiments, when used simultaneously, the compound and at least one other drug are in separate pharmaceutical compositions.In some embodiments, when used simultaneously, the compound and at least one other drug are combined in the same pharmaceutical composition.In some embodiments, the compound is selected from Examples 1-33 and pharmaceutically acceptable salts thereof.

[0045] In some embodiments, a combination of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a co-medication is provided for use in a method for treating or preventing a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain, and attention deficit hyperactivity disorder. In some embodiments, the compound and the co-medication are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the co-medication are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the co-medication are prepared for simultaneous administration. In some embodiments, the compound and the co-medication are prepared for sequential administration. In some embodiments, the compound is selected from Examples 1-33 and pharmaceutically acceptable salts thereof.

[0046] Also disclosed herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. In some embodiments, provided are pharmaceutical compositions comprising a compound selected from Examples 1-33 or a pharmaceutically acceptable salt thereof for use in therapy.

[0047] Also disclosed herein is a method for treating or preventing a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder, comprising the step of administering at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] References herein to methods of treatment or prevention using one or more compounds (e.g., compounds of Formula (I) and pharmaceutically acceptable salts thereof) (e.g., methods of treating or preventing a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, attention deficit hyperactivity disorder) are intended to include: one or more compounds for use in a method for treating and / or preventing, for example, depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, or attention deficit hyperactivity disorder; and / or Use of one or more compounds in the manufacture of a medicament for treating and / or preventing, for example, depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, attention deficit hyperactivity disorder. It should be understood that this should be interpreted as referring to DETAILED DESCRIPTION OF THE INVENTION

[0049] Non-limiting exemplary embodiment 1 Some embodiments of the present disclosure include, but are not limited to, the following. 1. Compounds represented by formula (I) [ka] or a salt thereof (wherein R 1 teeth, [ka] is a group represented by Ring A 1 is an optionally further substituted 6-membered aromatic ring, Ring A 2is an optionally further substituted 5-membered monocyclic aromatic heterocycle, Ring B is (1) a halogen atom, and (2) optionally substituted C 1-6 base is a pyridone ring optionally further substituted by 1 to 3 substituents selected from R 2 and R 3 are each independently a hydrogen atom or a substituent, R 4a and R 6b are each independently a substituent, Ring C is an optionally further substituted 5-membered monocyclic aromatic heterocycle. 2. A medicament comprising a compound or salt according to embodiment 1. 3. A medicament according to embodiment 2, which is a GPR139 receptor antagonist. 4. The medicament according to embodiment 2, which is a GPR139 receptor inverse agonist. 5. The medicament according to embodiment 2, which is a drug for preventing or treating depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain, or attention deficit hyperactivity disorder. Non-limiting exemplary embodiment 2

[0050] Some embodiments / provisions of the present disclosure include, but are not limited to: 1. Compounds of formula (I) [ka] or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] and Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring; Ring A 2 is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; Ring B is a halogen atom and an optionally substituted C 1-6 a pyridone ring optionally further substituted by 1 to 3 substituents selected from the group consisting of R 2 and R 3 are each independently selected from a hydrogen atom and a substituent; R 4a and R 4b are each independently selected from the substituents, Ring C is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles. 2. The compound is a compound of formula (I') [ka] and a pharmaceutically acceptable salt thereof, wherein: X is CH or N; Y is CH or N; Z is a bond, -O-, or -OR 9a - * , -NH-, and -N(R 9b )R 9a - * Selected from, here * indicates the point of attachment to ring D, Ring C is selected from 5-membered monocyclic aromatic heterocycles; Ring D is a 6- to 8-membered aromatic ring, a 5- to 8-membered monocyclic aromatic heterocycle, C 3-8 selected from a cycloalkyl group and a 5- to 8-membered heterocyclic group; Each R 7a are independently cyano, halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; Each R 8a are independently halogen, C 1-6 Alkyl, and C1-6 alkoxy groups, wherein C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; R 9a is C 1-3 selected from alkyl groups, R 9b is a hydrogen atom and C 1-3 selected from alkyl groups, Each R 10a are independently a halogen atom and C 1-3 selected from alkyl groups, Each R 11a independently, C 1-3 selected from alkyl groups, m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, or 2; p is 0, 1, or 2.] 3. [ka] but, [ka] (In the formula, Z, R 7a , R 8a , m, and n are as defined in clause 2. A compound or a pharmaceutically acceptable salt according to clause 2, wherein: 4.Z is a bond, -O-, -NH-, -NHCH2- * , and -N(CH3)CH2- * 4. A compound or a pharmaceutically acceptable salt according to clause 2 or 3 selected from: 5. A compound or pharmaceutically acceptable salt according to any one of clauses 2 to 4, wherein Z is a bond. 6. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 4, wherein Z is -O-. 7.Z is -NHCH2- * 5. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 4, wherein 8.Z is -N(CH3)CH2- * 5. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 4, wherein 9. [ka] but, [ka] (In the formula, X, Y, ring D, R 7a , R 8a , m, and n are as defined in clause 2. A compound or a pharmaceutically acceptable salt according to clause 2, wherein: 10. Ring D can be formed from benzene, morpholine, oxane, piperidine, and cyclobutane. A compound or a pharmaceutically acceptable salt thereof selected from any one of clauses 2 to 9. 11. [ka] but, [ka] (In the formula, X, Y, R 7a , R 8a , m, and n are as defined in clause 2. A compound or a pharmaceutically acceptable salt according to clause 2, wherein: 12. A compound or pharmaceutically acceptable salt according to any one of clauses 2 to 11, wherein X is CH. 13. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 11, wherein X is N. 14. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 13, wherein Y is CH. 15. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 13, wherein Y is N. 16. [ka] but, [ka] (In the formula, X, R 7a , R 8a , m, and n are as defined in clause 2. A compound or a pharmaceutically acceptable salt according to clause 2, wherein: 17. [ka] but, [ka] (In the formula, X, R 7a , R 8a , m, and n are as defined in clause 2. A compound or a pharmaceutically acceptable salt according to clause 2, wherein: 18. A compound or a pharmaceutically acceptable salt according to clause 16 or 17, wherein X is CH. 19. A compound or a pharmaceutically acceptable salt according to clause 16 or 17, wherein X is N. 20.R 2 and R 3 13. A compound or pharmaceutically acceptable salt according to any one of clauses 2 to 12, wherein are both hydrogen atoms. 21. Ring C is [ka] 21. A compound or pharmaceutically acceptable salt according to any one of clauses 2 to 20, wherein 22. Ring C is [ka] 22. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 21, wherein 23.Each R 7a are independently halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-623. A compound or a pharmaceutically acceptable salt according to any one of clauses 2 to 22, wherein the alkoxy group is optionally substituted with 1 to 4 halogen atoms. 24.o is 1 and R 10a 24. A compound or pharmaceutically acceptable salt according to any one of clauses 2 to 23, wherein is methyl. 25.o is 1 and R 10a 24. A compound or pharmaceutically acceptable salt according to any one of clauses 2 to 23, wherein is a fluorine atom. 26. A compound or pharmaceutically acceptable salt according to any one of clauses 2 to 23, wherein o is 0. 27. 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluoro Phenyl)-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-4'-(trifluoromethyl)-2H-[1,2'-bipyridine]-3'-carbonitrile; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-4'-(2,2,2-trifluoroethoxy)-2H-[1,2'-bipyridine]-3'-carbonitrile; 4'-(2,2-difluoroethoxy)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-6-methyl-2-oxo-4'-(trifluoromethyl)-2H-[1,2'-bipyridine]-3'-carbonitrile; 4'-(Difluoromethyl)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5'-methyl-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}pyridin-2(1H)-one; 6'-[2-(difluoromethyl)morpholin-4-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-4-methyl-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-5-methyl-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-6'-[(oxan-4-yl)oxy]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[4-{[(1-fluorocyclobutyl)methyl]amino}-6-(trifluoromethyl)pyrimidin-2-yl]pyridin-2(1H)-one; 1-[4-{[(3,3-difluorocyclobutyl)methyl]amino}-6-(trifluoromethyl)pyrimidin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-[4-{[(3,3-difluorocyclobutyl)methyl](methyl)amino}-6-(trifluoromethyl)pyrimidin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[4-{[(1-fluorocyclobutyl)methyl](methyl)amino}-6-(trifluoromethyl)pyrimidin-2-yl]pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-[3-cyclopropyl-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-{3-bromo-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethoxy)phenyl}pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-fluoropyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(propan-2-yl)phenyl}pyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(2,2,2-trifluoroethyl)phenyl}pyridin-2(1H)-one; 1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-methylpyridin-2(1H)-one; 1-[3-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methylpyridin-2(1H)-one; and 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methylpyridin-2(1H)-one or a pharmaceutically acceptable salt of any of the foregoing compounds. 28. At least one compound or a pharmaceutically acceptable salt according to any one of clauses 1 to 27, and at least one pharmaceutically acceptable carrier A pharmaceutical composition comprising: 29. A method for treating or preventing a disease in a mammal in need thereof, comprising administering to the mammal at least one compound or pharmaceutically acceptable salt according to any one of clauses 1 to 27. 30. The method according to clause 29, wherein the disease is selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain, and attention deficit hyperactivity disorder. 31. The method according to clause 28 or 29, wherein the mammal is a human. 32. The method according to any one of clauses 29 to 31, further comprising the step of administering to the mammal at least one concomitant drug.

[0051] The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition.

[0052] As used herein, non-limiting examples of "halogen atom" include fluorine, chlorine, bromine and iodine.

[0053] In this specification, "C 1-6 Non-limiting examples of "alkyl groups" include, for example, 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, and 2-ethylbutyl.

[0054] As used herein, "optionally halogenated C 1-6 Non-limiting examples of the "alkyl group" include, for example, C 11 optionally having 1 to 7, for example, 1 to 5, halogen atoms. 1-6Further non-limiting examples thereof include alkyl groups, such as methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl.

[0055] In this specification, "C 2-6 Non-limiting examples of "alkenyl groups" include, for example, 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, and 5-hexenyl.

[0056] In this specification, "C 2-6 Non-limiting examples of "alkynyl groups" include, for example, 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, and 4-methyl-2-pentynyl.

[0057] In this specification, "C 3-10 Non-limiting examples of "cycloalkyl groups" include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0058] As used herein, "optionally halogenated C 3-10Non-limiting examples of the "cycloalkyl group" include, for example, C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 3-10 Specific examples thereof include cycloalkyl groups, such as cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cyclooctyl include cyclooctyl and cyclooctyl.

[0059] In this specification, "C 3-10 Non-limiting examples of "cycloalkenyl groups" include, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0060] In this specification, "C 6-14 Non-limiting examples of "aryl group" include, for example, phenyl, 1-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. 7-16 Non-limiting examples of "aralkyl groups" include, for example, benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0061] In this specification, "C 1-6 Non-limiting examples of "alkoxy groups" include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0062] As used herein, "optionally halogenated C 1-6 Non-limiting examples of the "alkoxy group" include C alkoxy groups optionally having 1 to 7, for example, 1 to 5, halogen atoms. 1-6Further non-limiting examples of alkoxy groups include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy.

[0063] In this specification, "C 3-10 Non-limiting examples of "cycloalkyloxy groups" include, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0064] In this specification, "C 1-6 Non-limiting examples of "alkylthio groups" include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

[0065] As used herein, "optionally halogenated C 1-6 Non-limiting examples of the "alkylthio group" include, for example, C alkylthio groups which may have 1 to 7, for example, 1 to 5, halogen atoms. 1-6 Specific examples of alkylthio groups include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0066] In this specification, "C 1-6 Non-limiting examples of "alkyl-carbonyl groups" include, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.

[0067] As used herein, "optionally halogenated C 1-6Non-limiting examples of the "alkyl-carbonyl group" include, for example, C alkyl-carbonyl groups which may have 1 to 7, for example, 1 to 5, halogen atoms. 1-6 Further non-limiting examples of alkyl-carbonyl groups include, for example, acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl.

[0068] In this specification, "C 1-6 Non-limiting examples of "alkoxy-carbonyl groups" include, for example, , methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0069] In this specification, "C 6-14 Non-limiting examples of "aryl-carbonyl groups" include, for example, benzoyl, 1-naphthoyl, and 2-naphthoyl.

[0070] In this specification, "C 7-16 Non-limiting examples of "aralkyl-carbonyl groups" include, for example, phenylacetyl and phenylpropionyl.

[0071] As used herein, non-limiting examples of the "5- to 14-membered aromatic heterocyclylcarbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0072]

[0037] As used herein, non-limiting examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0073] As used herein, "mono- or di-C 1-6Non-limiting examples of the "alkyl-carbamoyl group" include, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0074] As used herein, "mono- or di-C 7-16 Non-limiting examples of "aralkyl-carbamoyl groups" include, for example, benzylcarbamoyl and phenethylcarbamoyl.

[0075] In this specification, "C 1-6 Non-limiting examples of "alkylsulfonyl groups" include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.

[0076] As used herein, "optionally halogenated C 1-6 Non-limiting examples of the "alkylsulfonyl group" include C alkylsulfonyl groups which may have 1 to 7, for example, 1 to 5, halogen atoms. 1-6 Further non-limiting examples of alkylsulfonyl groups include, for example, methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0077] In this specification, "C 6-14 Non-limiting examples of the "arylsulfonyl group" include, for example, phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0078] In the present specification, non-limiting examples of "substituents" include, for example, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group.

[0079] In the present specification, non-limiting examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, C 1-6 Alkyl group, C 2-6 Arke Nyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples include aralkyl groups.

[0080] In the present specification, non-limiting examples of the "optionally substituted hydrocarbon group" include hydrocarbon groups which may have a substituent selected from the substituent A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6 alkoxy groups, (7) C 6-14 aryloxy groups (e.g., phenoxy, naphthoxy); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy), (11)C1-6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy); (12)C 6-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (13)C 1-6 Alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) mono- or di-C 1-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15)C 6-14 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy); (19)C 1-6 C optionally substituted with alkyl group 6-14 arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy); (20) Optionally halogenated C 1-6 alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 alkyl-carbonyl groups, (26)C 6-14 aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 alkoxy-carbonyl groups, (30)C 6-14 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 alkyl-carbamoyl groups, (35)C 6-14 aryl-carbamoyl groups (e.g., phenylcarbamoyl); (36) 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 alkylsulfonyl groups, (39)C 6-14 arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 alkylsulfinyl groups, (42)C 6-14 arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl); (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) amino group, (45) Mono- or di-C 1-6alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 arylamino groups (e.g., phenylamino); (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) formylamino group, (50)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino); (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (52)C 6-14 arylcarbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with alkyl group 6-14 arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino); (57) Optionally halogenated C 1-6 alkyl groups, (58)C 2-6 alkenyl groups, (59)C2-6 alkynyl groups, (60)C 3-10 cycloalkyl groups, (61)C 3-10 cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0081] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, such as 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0082]

[0033] In the present specification, non-limiting examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") include, for example, (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom as ring-constituting atoms.

[0083] As used herein, non-limiting examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (e.g., 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.

[0084] Non-limiting examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic 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, fluoropyridinyl, pyrrolopyridinyl, and pyrazolopyridinyl. and 8- to 14-membered fused polycyclic (e.g., bi- or tricyclic) aromatic heterocyclic groups such as thienyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, fluoropyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, 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.

[0085]

[0039] In the present specification, non-limiting examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (e.g., 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.

[0086] Non-limiting 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, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazonyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thio 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as morpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and the like; dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazinyl, and 9- to 14-membered fused polycyclic (e.g., bicyclic or tricyclic) non-aromatic heterocyclic groups such as zolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0087] As used herein, non-limiting examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

[0088] In the present specification, non-limiting examples of the "nitrogen-containing heterocyclic group" include, for example, "heterocyclic groups" that contain at least one nitrogen atom as a ring-constituting atom.

[0089] In the present specification, non-limiting examples of the "optionally substituted heterocyclic group" include, for example, a heterocyclic group which may have a substituent selected from Substituent Group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0090] As used herein, non-limiting examples of the "acyl group" include, for example, a halogen atom, an optionally halogenated C 1-6 C, each of which may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of the acyl group include a formyl group, a carboxy group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has one or two substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group. Further non-limiting examples of the acyl group include a hydrocarbon-sulfonyl group, a heterocycle-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group.

[0091] As used herein, a hydrocarbon-sulfonyl group refers to a sulfonyl group having a hydrocarbon group bonded thereto, a heterocycle-sulfonyl group refers to a sulfonyl group having a heterocycle group bonded thereto, a hydrocarbon-sulfinyl group refers to a sulfinyl group having a hydrocarbon group bonded thereto, and a heterocycle-sulfinyl group refers to a sulfinyl group having a heterocycle group bonded thereto.

[0092] In addition, non-limiting examples of "acyl groups" further include formyl groups, carboxy groups, C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C 3-10 Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (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 group (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 group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (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 group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl groups) Bamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, 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 include alkylphosphono groups (eg, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0093] As used herein, non-limiting examples of the "optionally substituted amino group" include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, 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, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and an amino group which may have one or two substituents selected from an arylsulfonyl group.

[0094] Non-limiting examples of optionally substituted amino groups include amino groups, mono- or di-(optionally halogenated C 1-6alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino group (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino group (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonyl group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 Aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methyl sulfonyl amino, ethyl sulfonyl amino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (C 1-6 Alkyl)(C 6-14and N-aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0095] As used herein, non-limiting examples of the "optionally substituted carbamoyl group" include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, 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, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 Examples include a carbamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group.

[0096] Illustrative, non-limiting examples of optionally substituted carbamoyl groups include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14Examples thereof include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0097] As used herein, non-limiting examples of the "optionally substituted thiocarbamoyl group" include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, 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, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and a thiocarbamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group.

[0098] Illustrative, non-limiting examples of optionally substituted thiocarbamoyl groups include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0099] As used herein, non-limiting examples of the "optionally substituted sulfamoyl group" include, for example, sulfamoyl groups each optionally having 1 to 3 substituents selected from Substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, 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, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 Aralkyl-carbamoyl and a sulfamoyl group which may have one or two substituents selected from the group consisting of aryl, ...

[0100] Illustrative, non-limiting examples of optionally substituted sulfamoyl groups include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include an aryl-carbonyl-sulfamoyl group (eg, benzoylsulfamoyl) and a 5- to 14-membered aromatic heterocyclic sulfamoyl group (eg, pyridylsulfamoyl).

[0101] In the present specification, non-limiting examples of the "optionally substituted hydroxy group" include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, 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, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and a hydroxy group which may have a substituent selected from an arylsulfonyl group.

[0102] Illustrative, non-limiting examples of optionally substituted hydroxy groups include hydroxy groups, C 1-6 Alkoxy group, C 2-6Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy groups (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), C 6-14 Examples include arylsulfonyloxy groups (eg, phenylsulfonyloxy).

[0103] As used herein, non-limiting examples of the "optionally substituted sulfanyl group" include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl -carbonyl group and a sulfanyl group which may have a substituent selected from a 5- to 14-membered aromatic heterocyclic group, and a halogenated sulfanyl group.

[0104] Illustrative, non-limiting examples of optionally substituted sulfanyl groups include sulfanyl (—SH) groups, C 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butylthio, isobutylthio, pivaloylthio), C 6-14 Examples thereof include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0105] In the present specification, non-limiting examples of the "optionally substituted silyl group" include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 Examples include a silyl group which may have 1 to 3 substituents selected from an aralkyl group.

[0106] Illustrative, non-limiting examples of optionally substituted silyl groups include, for example, tri-C 1-6 Examples include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0107] As used herein, non-limiting examples of the "hydrocarbon ring" include, for example, C 6-14Aromatic hydrocarbon ring, C 3-10 Cycloalkane, C 3-10 Cycloalkenes are examples.

[0108] In this specification, "C 6-14 Non-limiting examples of the "aromatic hydrocarbon group" include benzene and naphthalene.

[0109] In this specification, "C 3-10 Non-limiting examples of "cycloalkanes" include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0110] In this specification, "C 3-10 Non-limiting examples of "cycloalkenes" include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

[0111] As used herein, non-limiting examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom as ring-constituting atoms.

[0112] In the present specification, non-limiting examples of the "aromatic heterocycle" include 5- to 14-membered (e.g., 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. Illustratively, non-limiting 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-oxadiazolyl, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; benzothiophene, benzofuran, benzimidazole, benzoxazole, benzo Isoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, fluoropyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, fluoropyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolotriazine, Examples of aromatic heterocycles include 8- to 14-membered fused polycyclic (e.g., bicyclic or tricyclic) aromatic heterocycles such as 1H-indazole, 1H-isoquinoline ...

[0113] As used herein, non-limiting examples of the "non-aromatic heterocycle" include 3- to 14-membered (e.g., 4- to 10-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. Illustratively, non-limiting 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, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, and oxepane; Examples of the heterocyclic group include 9- to 14-membered fused polycyclic (e.g., bi- or tricyclic) non-aromatic heterocyclic groups such as dibenzoimidazole, 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.

[0114] In the present specification, non-limiting examples of "nitrogen-containing heterocycles" include "heterocycles" that contain at least one nitrogen atom as a ring-constituting atom.

[0115] As used herein, non-limiting examples of a "six-membered aromatic ring" include benzene, pyridine, pyridazine, pyrimidine, pyrazine and triazine.

[0116] As used herein, non-limiting examples of the "5-membered monocyclic aromatic heterocycle" include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazolyl, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and the like.

[0117] The definition of each symbol in formula (I) is explained in more detail below.

[0118] In some embodiments, R 1 teeth, [ka] (In the formula, Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring; Ring A 2 is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; R 4a and R 4b are each independently selected from the substituents. is.

[0119] In some embodiments, R 1 teeth, [ka] is.

[0120] In some embodiments, ring A 1 The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" represented by the formula: is benzene, pyridine, or pyrimidine. 1The "six-membered aromatic ring" of the "optionally further substituted six-membered aromatic ring" represented by the formula (I) is benzene.

[0121] Ring A 1 Non-limiting examples of optional substituents in the "optionally further substituted 6-membered aromatic ring" represented by the formula (I) include substituents selected from Substituent Group A. In some embodiments, the number of these optional substituents is 1, 2, or 3. When the number of optional substituents is 2 or more, the optional substituents may be the same or different.

[0122] In some embodiments, ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom, a bromine atom), (b) a cyano group, (c) optionally halogenated C 1-6 alkyl groups (e.g., methyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl); (d) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy), and (e) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Cycloalkyl groups (e.g., cyclopropyl) and a 6-membered aromatic ring (eg, benzene, pyridine, pyrimidine) optionally further substituted with 1 to 3 substituents selected from the group consisting of:

[0123] In some embodiments, ring A 1 teeth, (1) (a) a halogen atom (e.g., a fluorine atom, a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6alkoxy groups (e.g., trifluoromethoxy), and (d) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Cycloalkyl groups (e.g., cyclopropyl) a benzene ring optionally further substituted by 1 to 3 substituents selected from (2) (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, (c) optionally halogenated C 1-6 alkyl groups (e.g., methyl, difluoromethyl, trifluoromethyl), and (d) optionally halogenated C 1-6 Alkoxy groups (e.g., 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) and (3) a pyridine ring optionally further substituted by 1 to 3 substituents selected from the group consisting of: 1-6 a pyrimidine ring optionally further substituted with an alkyl group (e.g., trifluoromethyl); Selected from.

[0124] In some embodiments, ring A 1 teeth, (1) (a) a halogen atom (e.g., a fluorine atom, a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy), and (d) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 Cycloalkyl groups (e.g., cyclopropyl) a benzene ring optionally further substituted by 1 to 3 substituents selected from (2) (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, (c) optionally halogenated C 1-6 alkyl groups (e.g., methyl, difluoromethyl, trifluoromethyl), and (d) optionally halogenated C 1-6 Alkoxy groups (e.g., 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) and (3) a pyridine ring optionally further substituted by 1 to 3 substituents selected from the group consisting of: 1-6 a pyrimidine ring optionally further substituted with an alkyl group (e.g., trifluoromethyl); Selected from.

[0125] In some embodiments, ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom), (b)C 1-6 alkyl groups (e.g., isopropyl), and (c)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) The pyridine ring is further substituted with one or two substituents selected from:

[0126] In some embodiments, ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom), and (b)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) is selected from a benzene ring further substituted with one or two substituents selected from:

[0127] In some embodiments, ring A 1 is selected from an optionally further substituted benzene ring, an optionally further substituted pyridine ring, and an optionally further substituted pyrimidine ring. 1 is selected from an optionally further substituted benzene ring. 1is selected from further substituted benzene rings.

[0128] In some embodiments, R 4a teeth, (1) optionally substituted C 6-14 aryl groups (e.g., phenyl); (2) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidyl)), (3)-NR 9 R 10 (In the formula, R 9 may be substituted C 1-6 alkyl groups (e.g., methyl); R 10 represents a hydrogen atom and optionally substituted C 1-6 alkyl groups (e.g., methyl); and (4)-OR 11 (In the formula, R 11 is selected from optionally substituted 3- to 14-membered non-aromatic heterocyclic groups (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyl)). Selected from.

[0129] In some embodiments, "optionally substituted C 6-14 "aryl group," "optionally substituted C 1-6 The substituents in the "alkyl group" and the "optionally substituted 3- to 14-membered non-aromatic heterocyclic group" are substituents selected from Substituent Group A. In some embodiments, the number of these optional substituents is 1, 2, or 3. When the number of optional substituents is 2 or more, the optional substituents may be the same or different.

[0130] In some embodiments, the "3- to 14-membered non-aromatic heterocyclic group" in the above-mentioned "optionally substituted 3- to 14-membered non-aromatic heterocyclic group" includes a 6- to 9-membered non-aromatic spiro heterocyclic group.

[0131] In some embodiments, R 4a teeth, (1) optionally substituted C 6-14 aryl groups (e.g., phenyl); (2) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidyl)), (3) optionally substituted mono- or di-C 1-6 Alkylamino groups (e.g., methylamino, dimethylamino), and (4) an optionally substituted 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group (e.g., tetrahydropyranyloxy)); Selected from.

[0132] In some embodiments, R 4a teeth, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-14 aryl groups (e.g., phenyl); (2) (a) a halogen atom (e.g., a fluorine atom), and (b) optionally halogenated C 1-6 Alkyl groups (e.g., methyl, difluoromethyl) (3) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidyl)) optionally substituted by 1 to 3 substituents selected from 3-10 Mono- or di-C optionally substituted with a cycloalkyl group (e.g., cyclobutyl) 1-6 Alkylamino groups (e.g., methylamino, dimethylamino), and (4) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic oxy groups (e.g., tetrahydropyranyloxy)). Selected from.

[0133] In some embodiments, R 4a teeth, (1) a phenyl group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), (2) 1 to 3 optionally halogenated C 1-6 a morpholinyl group optionally substituted by an alkyl group (e.g., methyl, difluoromethyl); (3) a piperidyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (4) 1 to 3 C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 Mono- or di-C optionally substituted with a cycloalkyl group (e.g., cyclobutyl) 1-6 Alkylamino groups (e.g., methylamino, dimethylamino), and (5) Tetrahydropyranyloxy group Selected from.

[0134] In some embodiments, R 4a is 1 to 3 C 1-6 It is selected from morpholinyl groups optionally substituted with an alkyl group (eg, methyl).

[0135] In some embodiments, R 4a is one C 1-6 It is selected from morpholinyl groups substituted with alkyl groups (e.g., methyl).

[0136] In some embodiments, [ka] The group represented by [ka] (In the formula, R 5a and R 6a are independently selected from a hydrogen atom and a substituent, and the other symbols have the same meanings as defined above.

[0137] In some embodiments, R 5a teeth, (a) a halogen atom (e.g., a bromine atom), (b) optionally substituted C 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (c) optionally substituted C 1-6 Alkoxy groups (e.g., methoxy, ethoxy), and (d) optionally substituted C 3-10 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0138] In some embodiments, R 5a teeth, (a) a halogen atom (e.g., a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 Alkoxy groups (e.g., trifluoromethoxy 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy), and (d) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0139] In some embodiments, R 5a teeth, (a) a halogen atom (e.g., a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 Alkoxy groups (e.g., trifluoromethoxy 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy), and (d) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0140] In some embodiments, R 5a teeth, (a)C 1-6 alkyl groups (e.g., isopropyl), and (b)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0141] In some embodiments, R 5a is C 3-6 It is selected from cycloalkyl groups (eg, cyclopropyl).

[0142] In some embodiments, R 5a is a cyclopropyl group.

[0143] In some embodiments, R 6a teeth, (a) a hydrogen atom, (b) a cyano group, (c) a halogen atom (e.g., a fluorine atom), and (d) optionally substituted C 1-6 Alkyl groups (e.g., methyl) Selected from.

[0144] In some embodiments, R 6a teeth, (a) a hydrogen atom, (b) a cyano group, (a) a halogen atom (e.g., a fluorine atom), and (d)C 1-6 Alkyl groups (e.g., methyl) Selected from.

[0145] In some embodiments, R 6a is selected from halogen atoms (e.g., fluorine atoms). 6a is a fluorine atom.

[0146] In some embodiments, [ka] The group represented by [ka] (In the formula, R 5a1 , R 5a2 , R 5a3 , R 6a1 , and R 6a2 are each independently selected from a hydrogen atom and a substituent, and the other symbols have the same meanings as defined above.

[0147] In some embodiments, R 5a1 teeth, (a) a halogen atom (e.g., a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy), and (d) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0148] In some embodiments, R 5a1 teeth, (a) a halogen atom (e.g., a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy), and (d) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0149] In some embodiments, R5a1 teeth, (a)C 1-6 alkyl groups (e.g., isopropyl), and (b)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0150] In some embodiments, R 5a1 is C 3-6 In some embodiments, R 5a1 is a cyclopropyl group.

[0151] In some embodiments, R 5a2 teeth, (a) optionally halogenated C 1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), and (b) optionally halogenated C 1-6 Alkoxy groups (e.g., 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) Selected from.

[0152] In some embodiments, R 5a3 may be halogenated C 1-6 It is selected from alkyl groups (e.g., trifluoromethyl).

[0153] In some embodiments, R 6a1 is selected from a hydrogen atom and a halogen atom (eg, a fluorine atom).

[0154] In some embodiments, R 6a1 is selected from halogen atoms (e.g., fluorine atoms). 6a1 is a fluorine atom.

[0155] In some embodiments, R 6a2 teeth, (a) a hydrogen atom, (b) a cyano group, (c) a halogen atom (e.g., a fluorine atom), and (d)C 1-6 Alkyl groups (e.g., methyl) Selected from.

[0156] In some embodiments, [ka] The group represented by [ka] (The symbols in the formulae are as defined above.)

[0157] In some embodiments, R 5a1 teeth, (a)C 1-6 alkyl groups (e.g., isopropyl), and (b)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) Selected from.

[0158] In some embodiments, R 5a1 is C 3-6 In some embodiments, R 5a1 is a cyclopropyl group.

[0159] In some embodiments, R 6a1 is selected from halogen atoms (e.g., fluorine atoms). 6a1 is a fluorine atom.

[0160] Ring A 2 Non-limiting examples of the substituents in the "optionally further substituted 5-membered monocyclic aromatic heterocycle" represented by the formula (I) include substituents selected from Substituent Group A. In some embodiments, the number of these optional substituents is 1 to 3. When the number of optional substituents is 2 or more, the optional substituents may be the same or different.

[0161] In some embodiments, ring B is (1) a halogen atom (e.g., a fluorine atom), and (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl) The pyridone ring is selected from the group consisting of a pyridone ring optionally further substituted with 1 to 3 substituents selected from the group consisting of:

[0162] The above "Optionally substituted C 1-6 Non-limiting examples of substituents on the "alkyl group" include substituents selected from Substituent Group A. In some embodiments, the number of these optional substituents is 1 to 3. When the number of optional substituents is 2 or more, each optional substituent may be the same or different.

[0163] In some embodiments, ring B is (1) a halogen atom (e.g., a fluorine atom), and (2) C 1-6 Alkyl groups (e.g., methyl) The pyridone ring is selected from the group consisting of a pyridone ring optionally further substituted with 1 to 3 substituents selected from the group consisting of:

[0164] In some embodiments, ring B is (1) a halogen atom (e.g., a fluorine atom), and (2) C 1-6 Alkyl groups (e.g., methyl) The pyridone ring is selected from the group consisting of a pyridone ring optionally further substituted with one substituent selected from the group consisting of

[0165] In some embodiments, Ring B is a pyridone ring with no further substitutions.

[0166] In some embodiments, R 2 and R 3 are each independently selected from a hydrogen atom and a substituent.

[0167] In some embodiments, R 2 and R 3 are both hydrogen atoms.

[0168] In some embodiments, Ring C is selected from an optionally further substituted 5-membered monocyclic aromatic heterocycle.

[0169] In some embodiments, the "5-membered monocyclic aromatic heterocyclic group" of the "optionally further substituted 5-membered monocyclic aromatic heterocyclic group" represented by ring C is pyrazole (e.g., 1H-pyrazol-4-yl).

[0170] Non-limiting examples of optional substituents in the "optionally further substituted 5-membered monocyclic aromatic heterocycle" represented by ring C include substituents selected from Substituent Group A. In some embodiments, the number of these optional substituents is 1 to 3. When the number of optional substituents is 2 or more, each optional substituent is selected from the same They may be the same or different.

[0171] In some embodiments, ring C is selected from 1 to 3 C 1-6 In some embodiments, ring C is selected from 5-membered monocyclic aromatic heterocycles (e.g., pyrazole) optionally further substituted with an alkyl group (e.g., ethyl, isopropyl). In some embodiments, ring C is selected from 1 to 3 (e.g., 1) C 1-6 In some embodiments, ring C is selected from a pyrazole ring (e.g., 1H-pyrazol-4-yl) optionally further substituted with an alkyl group (e.g., ethyl, isopropyl). 1-6 It is selected from pyrazole rings (eg, 1H-pyrazol-4-yl) further substituted with an alkyl group (eg, ethyl).

[0172] In some embodiments, Ring C is selected from an optionally further substituted pyrazole group.

[0173] In some embodiments, Ring C is selected from a further substituted pyrazole ring.

[0174] In some embodiments, Ring C is a cyclic group represented by the formula: [ka] (In the formula, R 1c is a hydrogen atom and C 1-6 alkyl groups (e.g., ethyl, isopropyl, e.g., ethyl).

[0175] In some embodiments, R 1c is C 1-6 It is selected from alkyl groups (eg, ethyl, isopropyl, e.g., ethyl).

[0176] Further, in the present specification, a compound selected from compounds of formula (IA) (also referred to as compound A in the present specification) [ka] and pharmaceutically acceptable salts thereof, wherein: Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring (e.g., benzene, pyridine, pyrimidine), R 4a may be substituted C 6-14 Aryl group (e.g., phenyl), optionally substituted 3- to 14-membered non-aromatic heterocyclic group (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidyl)), optionally substituted mono- or di-C 1-6 and ring B is selected from alkylamino groups (e.g., methylamino, dimethylamino) and optionally substituted 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic oxy groups (e.g., tetrahydropyranyloxy)), and ring B is selected from halogen. Atoms (e.g., fluorine atoms) and optionally substituted C 1-6 pyridone groups optionally further substituted with 1 to 3 substituents selected from alkyl groups (e.g., methyl); R 2 and R 3 are each independently a hydrogen atom or an optionally substituted C 1-6and ring C is selected from an optionally further substituted 5-membered monocyclic aromatic heterocycle (eg, pyrazole).

[0177] In some embodiments, ring A 1 is selected from optionally further substituted benzene, optionally further substituted pyridine, and optionally further substituted pyrimidine. 1 is selected from benzene, pyridine, and pyrimidine.

[0178] In some embodiments, R 4a is optionally substituted phenyl. In some embodiments, R 4a is phenyl.

[0179] In some embodiments, R 4a is selected from morpholinyl and piperidyl.

[0180] In some embodiments, R 4a is selected from methylamino and dimethylamino.

[0181] In some embodiments, R 4a is selected from 3- to 8-membered monocyclic non-aromatic heterocyclic oxy groups. 4a is tetrahydropyranyloxy.

[0182] In some embodiments, Ring B is selected from a pyridone group optionally further substituted with 1 to 3 substituents independently selected from fluorine and methyl.

[0183] In some embodiments, R 2 and R 3 are each independently selected from a hydrogen atom and methyl.

[0184] In some embodiments, Ring C is selected from an optionally further substituted pyrazole group. In some embodiments, Ring C is pyrazole.

[0185] Further, in the present specification, a compound selected from the compounds of formula (IB) (also referred to as compound B in the present specification) [ka] and pharmaceutically acceptable salts thereof, wherein: Ring A 1 represents a halogen atom (e.g., a fluorine atom, a bromine atom), a cyano group, an optionally halogenated C 1-6 Alkyl groups (e.g., methyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl), optionally halogenated C 1-6 C optionally substituted with an alkoxy group (e.g., trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) and 1 to 3 halogen atoms (e.g., fluorine atoms). 3-10 independently selected from cycloalkyl groups (e.g., cyclopropyl) a benzene ring further substituted with one or two substituents selected from the group consisting of: R 4a represents a halogen atom (e.g., a fluorine atom), a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidyl)) optionally substituted by 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms), an optionally halogenated C 1-6 C optionally substituted by 1 to 3 substituents independently selected from alkyl groups (e.g., methyl, difluoromethyl) and halogen atoms (e.g., fluorine atoms); 3-10 Mono- or di-C optionally substituted by 1 to 3 substituents independently selected from cycloalkyl groups (e.g., cyclobutyl) 1-6C optionally substituted by 1 to 3 substituents independently selected from alkylamino groups (e.g., methylamino, dimethylamino) and 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic oxy groups (e.g., tetrahydropyranyloxy)). 6-14 aryl groups (e.g., phenyl); All other symbols are as defined above.]

[0186] In some embodiments, ring A 1 is selected from a benzene ring further substituted with 1 or 2 substituents independently selected from fluorine, bromine, methyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, and cyclopropyl optionally substituted with 1 to 3 fluorine atoms.

[0187] In some embodiments, R 4a is selected from phenyl optionally substituted with 1 to 3 fluorine atoms.

[0188] In some embodiments, R 4a is selected from phenyl optionally substituted with 1 to 3 fluorine atoms.

[0189] In some embodiments, R 4a is selected from morpholinyl and piperidyl.

[0190] In some embodiments, [ka] teeth, [ka] [In the formula, R 4a is the same as the above embodiment, R 5ais a halogen atom (e.g., bromine atom), optionally halogenated C 1-6 Alkyl groups (e.g., isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl), optionally halogenated C 1-6 C optionally substituted by 1 to 3 substituents independently selected from alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) and halogen atoms (e.g., fluorine atoms); 3-10 cycloalkyl groups (e.g., cyclopropyl); R 6a represents a hydrogen atom, a cyano group, a halogen atom (e.g., a fluorine atom), and C 1-6 alkyl groups (e.g., methyl); Ring B is a halogen atom (e.g., a fluorine atom) and C 1-6 pyridone groups optionally further substituted by 1 to 3 substituents independently selected from alkyl groups (e.g., methyl); R 2 and R 3 are both hydrogen atoms, Ring C is C 1-6 and 5-membered monocyclic aromatic heterocycles (e.g., pyrazole) optionally further substituted by 1 to 3 substituents independently selected from alkyl groups (e.g., ethyl, isopropyl). Selected from.

[0191] Further, in the present specification, a compound selected from compounds of formula (IC) (also referred to as compound C in the present specification) [ka] and pharmaceutically acceptable salts thereof, wherein: Ring A 1 teeth, (1) (a) halogen atoms (e.g., fluorine atoms, bromine atoms), and (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy), and (d) C optionally substituted by 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms), 3-10 Cycloalkyl groups (e.g., cyclopropyl) a benzene ring optionally further substituted by 1 to 3 substituents independent of (2) (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, (c) optionally halogenated C 1-6 alkyl groups (e.g., methyl, difluoromethyl, trifluoromethyl), and (d) optionally halogenated C 1-6 Alkoxy groups (e.g., 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) a pyridine ring optionally further substituted with 1 to 3 substituents independently selected from (3) Optionally halogenated C 1-6 a pyrimidine ring optionally further substituted with 1 or 2 substituents independently selected from alkyl groups (e.g., trifluoromethyl); a benzene ring further substituted with one or two substituents independently selected from R 4a teeth, (1) C optionally substituted with 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms) 6-14 aryl groups (e.g., phenyl); (2) (a) a halogen atom (e.g., a fluorine atom), and (b) optionally halogenated C 1-6 Alkyl groups (e.g., methyl, difluoromethyl) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidyl)) optionally substituted by 1 to 3 substituents independently selected from (3) C optionally substituted with 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms) 3-10 Mono- or di-C optionally substituted by 1 to 3 substituents independently selected from cycloalkyl groups (e.g., cyclobutyl) 1-6 Alkylamino groups (e.g., methylamino, dimethylamino), and (4) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group (e.g., tetrahydropyranyloxy)) Selected from.]

[0192] In some embodiments, [ka] teeth, [ka] [In the formula, R 4a is as defined above, R 5a1 teeth, (a) a halogen atom (e.g., a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy), and (d) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Cycloalkyl groups (e.g., cyclopropyl) Selected from R 5a2 teeth, (a) optionally halogenated C 1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), and (b) optionally halogenated C 1-6 Alkoxy groups (e.g., 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) Selected from R 5a3 may be halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); R 6a1 is selected from a hydrogen atom and a halogen atom (e.g., a fluorine atom), R 6a2 teeth, (a) a hydrogen atom, (b) a cyano group, (c) a halogen atom (e.g., a fluorine atom), and (d)C 1-6 Alkyl groups (e.g., methyl) Selected from Ring B is (1) a halogen atom (e.g., a fluorine atom), and (2) C 1-6 Alkyl groups (e.g., methyl) a pyridone ring optionally further substituted with 1 to 3 substituents independently selected from R 2 and R 3 are both hydrogen atoms, Ring C is C 1-6 and a pyrazole ring (e.g., 1H-pyrazol-4-yl) optionally further substituted with 1 to 3 (e.g., 1) substituents independently selected from alkyl groups (e.g., ethyl, isopropyl). Selected from.

[0193] In some embodiments, ring C is [ka] (In the formula, R 1c is a hydrogen atom and C 1-6 It is selected from alkyl groups (e.g., ethyl, isopropyl).

[0194] Further, in the present specification, a compound selected from compounds of formula (ID) (also referred to as compound D in the present specification) [ka] and pharmaceutically acceptable salts thereof, wherein: Ring A 1 teeth, (1) (a) a halogen atom (e.g., a fluorine atom, a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy), and (d) C optionally substituted by 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms), 3-6 Cycloalkyl groups (e.g., cyclopropyl) a benzene ring optionally further substituted by 1 to 3 substituents independent of (2) (a) a halogen atom (e.g., a fluorine atom), (b) a cyano group, (c) optionally halogenated C 1-6 alkyl groups (e.g., methyl, difluoromethyl, trifluoromethyl), and (d) optionally halogenated C 1-6 Alkoxy groups (e.g., 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) a pyridine ring optionally further substituted with 1 to 3 substituents independently selected from (3) Optionally halogenated C 1-6 a pyrimidine ring optionally further substituted with 1 or 2 substituents independently selected from alkyl groups (e.g., trifluoromethyl); and R is a benzene ring further substituted with one or two substituents independently selected from 4a teeth, (1) a phenyl group optionally substituted by 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms), (2) Optionally halogenated C 1-6(3) a morpholinyl group optionally substituted by 1 to 3 substituents independently selected from alkyl groups (e.g., methyl, difluoromethyl); (4) a piperidyl group optionally substituted by 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms); (4) C optionally substituted with 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms) 3-6 Mono- or di-C optionally substituted by 1 to 3 substituents independently selected from cycloalkyl groups (e.g., cyclobutyl) 1-6 Alkylamino groups (e.g., methylamino, dimethylamino), and (5) Tetrahydropyranyloxy group Selected from.]

[0195] In some embodiments, [ka] teeth, [ka] #1 and [In the formula, R 4a is as defined above, R 5a1 teeth, (a) a halogen atom (e.g., a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl); (c) optionally halogenated C 1-6 Alkoxy groups (e.g., trifluoromethoxy) , and (d) C optionally substituted by 1 to 3 substituents independently selected from halogen atoms (e.g., fluorine atoms), 3-10 Cycloalkyl groups (e.g., cyclopropyl) Selected from R 5a2 teeth, (a) optionally halogenated C1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), and (b) optionally halogenated C 1-6 Alkoxy groups (e.g., 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy) Selected from R 5a3 may be halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); R 6a1 is selected from a hydrogen atom and a halogen atom (e.g., a fluorine atom), R 6a2 teeth, (a) a hydrogen atom, (b) a cyano group, (c) a halogen atom (e.g., a fluorine atom), and (d)C 1-6 Alkyl groups (e.g., methyl) Selected from Ring B is (1) a halogen atom (e.g., a fluorine atom), and (2) C 1-6 Alkyl groups (e.g., methyl) a pyridone group optionally further substituted by 1 to 3 substituents independently selected from R 2 and R 3 are both hydrogen atoms, Ring C is C 1-6 and a pyrazole ring (e.g., 1H-pyrazol-4-yl) optionally further substituted by 1 to 3 (e.g., 1) substituents selected from alkyl groups (e.g., ethyl, isopropyl). Selected from.

[0196] In some embodiments, ring C is [ka] (In the formula, R 1c is a hydrogen atom and C 1-6 It is selected from alkyl groups (e.g., ethyl, isopropyl).

[0197] Further, in the present specification, a compound selected from compounds of formula (IE) (also referred to as compound E in the present specification) [ka] and pharmaceutically acceptable salts thereof, wherein: Ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom), (b)C 1-6 alkyl groups (e.g., isopropyl), and (c)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) a benzene ring further substituted with one or two substituents independently selected from R 4a is C 1-6 morpholinyl groups optionally substituted by 1 to 3 substituents independently selected from alkyl groups (e.g., methyl); Ring B is a pyridone ring having no further substituents, R 2 and R 3 are both hydrogen atoms, Ring C is a single C 1-6 and a pyrazole ring (eg, 1H-pyrazol-4-yl) further substituted with an alkyl group (eg, ethyl).

[0198] In some embodiments, [ka] is the expression: [ka] A group represented by (In the formula, R 4a is as defined above, R 5a1 teeth, (a)C 1-6 alkyl groups (e.g., isopropyl), and (b)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) Selected from R 6a1 is a halogen atom (e.g., a fluorine atom). is.

[0199] In some embodiments, ring C is [ka] (In the formula, R 1c is C 1-6 It is selected from alkyl groups (e.g., ethyl).

[0200] Further, in the present specification, a compound selected from compounds of formula (IF) (also referred to as compound F in the present specification) [ka] and pharmaceutically acceptable salts thereof, wherein: Ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom), and (b)C 3-6 Cycloalkyl groups (e.g., cyclopropyl) a benzene ring further substituted with one or two substituents independently selected from R 4a is one C 1-6 morpholinyl groups substituted with alkyl groups (e.g., methyl); Ring B is a pyridone ring having no further substituents, R 2 and R 3 are both hydrogen atoms, Ring C is a single C 1-6 and a pyrazole ring (eg, 1H-pyrazol-4-yl) further substituted with an alkyl group (eg, ethyl).

[0201] In some embodiments, ring C is [ka] (In the formula, R 1c is C 1-6 It is selected from alkyl groups (e.g., ethyl).

[0202] In some embodiments, [ka] is the expression: [ka] A group represented by (In the formula, R 4a is as defined above, R 5a1 is C 3-6 cycloalkyl groups (e.g., cyclopropyl); R 6a1 is selected from halogen atoms (e.g., fluorine atoms). is.

[0203] Compounds of formula (I) include, but are not limited to, the compounds of Examples 1-33.

[0204] When Compound (I) is a salt such as a pharmaceutically acceptable salt, non-limiting examples of such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Illustratively, non-limiting examples of metal salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; and aluminum salts. Non-limiting examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Non-limiting examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, etc. Non-limiting examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Non-limiting examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Non-limiting examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. For example, when the compound of the present disclosure contains an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), ammonium salts, etc. may be used. In addition, when the compound has a basic functional group, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, or phosphoric acid, or a salt with an organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, or p-toluenesulfonic acid may be used.

[0205] When compound (I) contains isomers such as tautomers, enantiomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers or a mixture thereof is also included in compound (I). Furthermore, when compound (I) has enantiomers, enantiomers resolved from the racemate are also included in compound (I).

[0206] In some embodiments, Compound (I) may be crystalline, and therefore, Compound (I) encompasses both a single crystalline form and a mixture of crystalline forms.

[0207] In some embodiments, Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. As used herein, a co-crystal or co-crystal salt refers to a crystalline substance that contains two or more distinct solids at room temperature, each with different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). Co-crystals or co-crystal salts can be prepared according to known co-crystallization methods.

[0208] In some embodiments, compound (I) may be a solvate (for example, a hydrate) or a non-solvate, both of which are encompassed by compound (I).

[0209] In some embodiments, isotopes (e.g., 2 H, 3 H, 11 C. 14 C. 18 F, 35 S, 125 Compound (I) also encompasses compounds labeled or substituted with isotopes (e.g., I). For example, in some embodiments, compounds labeled or substituted with isotopes can be used as tracers for positron emission tomography (PET) (PET tracers). In some embodiments, compounds labeled or substituted with isotopes can be useful in fields such as medical diagnosis.

[0210] Methods for preparing the compounds of the present disclosure are described below.

[0211] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compounds of the present disclosure.

[0212] When the compound obtained in each step is in a free form, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into the free form or another desired type of salt by a method known per se.

[0213] The compound obtained in each step can be used in the next reaction either as a reaction solution or after isolation as a crude product. Alternatively, the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc., according to a conventional method.

[0214] When the raw materials and reagents for each step are commercially available, the commercially available products can be used as they are.

[0215] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, the reaction time is usually 1 minute to 48 hours, for example, 10 minutes to 8 hours.

[0216] In the reaction of each step, the reaction temperature may vary depending on the reagents and solvent used, but is usually −78° C. to 300° C., for example, −78° C. to 150° C., unless otherwise specified.

[0217] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, for example, 1 atm to 3 atm.

[0218] In the reactions of each step, a microwave synthesis apparatus such as Biotage's Initiator may be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300°C, for example, 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, for example, 1 minute to 8 hours.

[0219] In the reaction of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, for example, 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, for example, 0.01 to 0.2 equivalents, relative to the substrate. When the reagent also serves as a reaction solvent, the reagent is used in the amount of the solvent.

[0220] Unless otherwise specified, the reactions in each step are carried out without solvent or after dissolving or suspending in a suitable solvent. Non-limiting examples of solvents include those described in the Examples and the following: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc. Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc. Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc. Saturated hydrocarbons: cyclohexane, hexane, etc. Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc. Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc. Nitriles: acetonitrile, etc. Sulfoxides: dimethyl sulfoxide, etc. Aromatic organic bases: pyridine, etc. Acid anhydrides: acetic anhydride, etc. Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc. Inorganic acids: hydrochloric acid, sulfuric acid, etc. Esters: ethyl acetate, etc. Ketones: acetone, methyl ethyl ketone, etc. water.

[0221] In some embodiments, two or more of the above solvents may be mixed in an appropriate ratio and used in the described method.

[0222] In some embodiments, when a base is used in the reaction of each step, the base shown below or the base described in the Examples may be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc. Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc. Metal oxides: sodium ethoxide, potassium tert-butoxide, etc. Alkali metal hydrides: sodium hydride, etc. Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. Organolithium compounds: n-butyllithium, etc.

[0223] In some embodiments, when an acid or an acid catalyst is used in the reaction of each step, Alternatively, the acids and acid catalysts shown in the above or those described in the Examples may be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc. Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0224] Unless otherwise specified, the reactions in each step are carried out according to a method known per se, for example, as described in Experimental Chemistry Lectures, 5th Edition, Vol. 13 to 19 (edited by the Chemical Society of Japan), New Experimental Chemistry Lectures, Vol. 14 to 15 (edited by the Chemical Society of Japan), Precision Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo Co., Ltd.), Revised Methods described in "Organic Named Reactions: Their Mechanisms and Key Points" (by Hideo Togo, Kodansha), "ORGANIC SYNTHESES Collective Volume I-VII" (John Willey & Sons Inc.), "Modern Organic Synthesis in the Laboratory, A Collection of Standard Experimental Procedures" (by Jie Jack Li, published by OXFORD UNIVERSITY), "Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14" (Elsevier Japan KK), "Strategies for Organic Synthesis Learned from Named Reactions" (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); "Comprehensive Organic Transformations" (VCH Publishers Inc.) 1989, etc. Alternatively, it can be carried out in accordance with the method described in the Examples.

[0225] In each step, protection or deprotection of functional groups is carried out according to a method known per se, for example, a method described in Wiley-Interscience 2007 Edition "Protective Groups in Organic Synthesis, 4th Ed." (by Theodora W. Greene and Peter G.M.Wuts), Thieme 2004 Edition "Protecting Groups 3rd Ed." (by P.J. Kocienski), or a method described in the Examples.

[0226] Non-limiting examples of protecting groups for hydroxyl groups of alcohols and the like and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as tert-butyl carbonate.

[0227] Non-limiting examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as 1,3-dioxane.

[0228] Non-limiting examples of protecting groups for the carbonyl group of ketones include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone.

[0229] Non-limiting examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide.

[0230] Non-limiting examples of thiol-protecting groups include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate.

[0231] Non-limiting examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; and alkylamine-type protecting groups such as N-triphenylmethylamine. protecting groups, sulfonamide-type protecting groups such as methanesulfonamide, and the like.

[0232] The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl hydride (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0233] In the step of carrying out a reduction reaction, non-limiting examples of reducing agents that can be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When reducing a carbon-carbon double bond or triple bond, a method using a catalyst such as palladium-carbon or Lindlar's catalyst can be used. Examples of oxidizing agents used in oxidation reactions in each step include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; and high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0234] When a radical cyclization reaction is carried out in the step, non-limiting examples of usable radical initiators include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Non-limiting examples of usable radical reactants include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium diiodide, etc.

[0235] When a Wittig reaction is carried out in the step, non-limiting examples of Wittig reagents that can be used include alkylidenephosphoranes, etc. Alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0236] In the step of carrying out the Horner-Emmons reaction, non-limiting examples of reagents that can be used include phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0237] In the step of carrying out the Friedel-Crafts reaction, non-limiting examples of reagents that can be used include a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0238] When an aromatic nucleophilic substitution reaction is carried out in the step, a nucleophile (eg, amines, 2-pyridone, imidazole, etc.) and a base (eg, organic or inorganic bases, etc.) may be used as the reagent.

[0239] In the step of carrying out a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion, non-limiting examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, organic bases, etc.

[0240] When a Grignard reaction is carried out in this step, non-limiting examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0241] When a Knoevenagel reaction is carried out in the step, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal oxides, inorganic bases) may be used as reagents.

[0242] When the Vilsmeier-Haack reaction is carried out in this step, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) may be used as reagents.

[0243] In the step of azidation of alcohols, alkyl halides, and sulfonate esters, non-limiting examples of the azidation agent include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidation of alcohols is performed, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a method using trimethylsilyl azide and a Lewis acid may be used.

[0244] When a reductive amination reaction is carried out in the step, non-limiting examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, non-limiting examples of the carbonyl compound to be used include paraformaldehyde, as well as aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, non-limiting examples of the amines to be used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0245] When the Mitsunobu reaction is carried out in the step, azodicarboxylic acid esters (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents. Other reagents that may be used include (cyanomethylene)tributylphosphorane (CMBP) and (cyanomethylene)trimethylphosphorane (CMMP).

[0246] In the step of esterification, amidation, or urea formation, non-limiting examples of reagents to be used include acyl halides such as acid chlorides and acid bromides; and activated carboxylic acids such as acid anhydrides, activated esters, and sulfates. Non-limiting examples of activators for carboxylic acids include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholino; Examples of suitable condensing agents include triazine-based condensing agents such as ammonium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. When using carbodiimide-based condensing agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may also be added to the reaction.

[0247] When a coupling reaction is carried out in the step, non-limiting examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; platinum compounds; and the like. A base may also be added to the reaction, and non-limiting examples of such bases include inorganic bases.

[0248] When a thiocarbonylation reaction is carried out in the step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. However, in addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0249] When the Wohl-Ziegler reaction is used in the process, non-limiting examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0250] In the halogenation reaction of a hydroxy group in the step (2), non-limiting examples of the halogenating agent used include hydrohalic acid and an acid halide of an inorganic acid; specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. are used for chlorination, and 48% hydrobromic acid, etc., may be used for bromination. Alternatively, a method may be used in which an alkyl halide is obtained from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. Alternatively, a method may be used in which an alkyl halide is synthesized via a two-step reaction, in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or lithium iodide.

[0251] In the step of carrying out the Arbuzov reaction, non-limiting examples of reagents that can be used include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0252] In the step of carrying out a sulfonate esterification reaction, non-limiting examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0253] When a hydrolysis reaction is carried out in this step, an acid or a base may be used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid, triethylsilane, or the like may be added to reductively trap the by-product tert-butyl cation.

[0254] When a dehydration reaction is carried out in the step, non-limiting examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0255] Compound (I) can be produced according to the reaction scheme shown below or a method similar thereto. The starting materials may be commercially available products or may be produced using methods known per se. The abbreviations in the general formulae in the reaction scheme have the same meanings as above unless otherwise specified.

[0256] For example, R 1 but, [ka] Compounds of formula (Ia), wherein L 1 and L 2 are each independently a leaving group, and R 101 , R 12 and R 13 are each independently a hydrogen atom or a substituent, and the other symbols are as defined above.

[0257] L 1 or L 2 Non-limiting examples of the "leaving group" represented by the formula (I) include, for example, a halogen atom, a nitro group, an optionally halogenated C 1-6 Alkyl sulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C optionally substituted with alkyl group 6-14 Examples thereof include arylsulfonyloxy groups (eg, benzenesulfonyloxy, toluenesulfonyloxy), and the like.

[0258] R 101 Non-limiting examples of the "substituent" represented by R include, for example, a halogen atom, an optionally substituted alkyl group, etc.12 or R 13 Examples of "substituents" represented by C 1-6 alkyl group, and R 12 and R 13 may form, together with the adjacent boron atom, a ring which may be further substituted (e.g., BOR 12 OR 13 is dimethoxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). [ka]

[0259] Compound (3) can be produced by Suzuki-Miyaura coupling reaction of compound (1) and compound (2).

[0260] Compound (4) can be produced by demethylating compound (3). Non-limiting examples of demethylating reagents include pyridine hydrochloride, a combination of trimethylsilyl chloride and sodium iodide, and the like. Non-limiting examples of demethylating reagents include those described above in the "Removal of Protecting Groups" section.

[0261] Compound (6) can be produced by various coupling reactions such as aromatic nucleophilic substitution reaction of compound (4) and compound (5), Ullmann coupling reaction, Buchwald-Hartwig coupling reaction, etc.

[0262] Compound (Ia) can be produced by various coupling reactions such as aromatic nucleophilic substitution reaction of compound (6), Suzuki-Miyaura coupling reaction, Buchwald-Hartwig coupling reaction, etc.

[0263] Compound (Ia) can also be further converted according to a method known per se.

[0264] Compound (Ia) can also be produced from compound (5) using the following method: Each symbol has the same meaning as defined above. [ka]

[0265] Compound (7) can be produced from compound (5) by various coupling reactions such as aromatic nucleophilic substitution reaction, Suzuki-Miyaura coupling reaction, Buchwald-Hartwig coupling reaction, and the like.

[0266] Compound (Ia) can be produced by subjecting compound (7) and compound (4) to various coupling reactions such as aromatic nucleophilic substitution reaction, Ullmann coupling reaction, Buchwald-Hartwig coupling reaction, etc.

[0267] Ring A in compound (Ia) 1 is the substituent R 14 and R 15 Compound (Ib), which is a benzene ring having the formula: 14 , R 15 , R 16 and R 17 are each independently a hydrogen atom or a substituent, and other symbols have the same meanings as defined above.

[0268] R 14 or R 15 Non-limiting examples of substituents include, for example, ring A 1 Examples of the "substituents" of R include those exemplified above. 16 or R 17 Examples of "substituents" represented by C 1-6 alkyl group, and R 16 and R 17 may form, together with the adjacent boron atom, a ring which may be further substituted (e.g., BOR 16 OR 17 is dimethoxyboranyl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). [ka]

[0269] In some embodiments, compound (8), compound (8a), and compound (8b) can be produced from compound (9) using the following method, where each symbol is as defined above. [ka]

[0270] Compound (8a) can be prepared by the Hartwig-Miyaura C-H boronation reaction of compound (9). Non-limiting examples of the metal catalyst used include di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I).

[0271] Compound (10) can be prepared by nucleophilic fluorination of compound (8a). A non-limiting example of a reagent used for the nucleophilic fluorination reaction is potassium bifluoride.

[0272] Compound (8b) can be produced by hydrolysis of compound (10). Non-limiting examples of reagents used for the hydrolysis reaction include trimethylsilyl chloride, lithium hydroxide, etc.

[0273] Compound (9) can be produced from compound (11), compound (14), compound (15), or compound (16) using the following method. 3 is a leaving group, and the other symbols have the same meanings as above.

[0274] L 3 Non-limiting examples of the "leaving group" represented by the formula: 1 or L 2 Examples of the "leaving group" include those exemplified above. [ka]

[0275] Compound (12) can be produced from compound (11) by various coupling reactions such as aromatic nucleophilic substitution reaction, Suzuki-Miyaura coupling reaction, Buchwald-Hartwig coupling reaction, and the like.

[0276] Compound (13) can be produced by triflation of compound (12) (wherein L 3 is a trifluoromethanesulfonyloxy group).

[0277] Compound (13) can also be produced from compound (14) by various coupling reactions such as aromatic nucleophilic substitution reaction, Suzuki-Miyaura coupling reaction, and Buchwald-Hartwig coupling reaction.

[0278] Compound (9) can be produced by Suzuki-Miyaura coupling reaction using compound (13). Compound (9) can also be produced by etherification reaction of compound (15). Compound (9) can also be produced by various coupling reactions such as aromatic nucleophilic substitution reaction, Suzuki-Miyaura coupling reaction, Buchwald-Hartwig coupling reaction, etc. using compound (16).

[0279] Compound (9) can also be further converted according to a method known per se.

[0280] Ring A in compound (5) 1 is a substituent OR 16 Compound (5a), which is a pyridine ring having the formula: 16 It can be prepared by aromatic nucleophilic substitution using OH, where R 16 is a substituent, and the other symbols have the same meanings as defined above. 16 A non-limiting example of the "substituent" represented by the formula: is a benzyl group. [ka]

[0281] Compounds (1), (4), (5), (11), and (14) to (17) are commercially available. They are available or can be produced by known methods or methods similar thereto, or by the methods described in the Examples.

[0282] In the compound (I) thus obtained, the functional groups in the molecule can be converted to the desired functional groups by combining known chemical reactions, such as oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0283] In the above-mentioned production methods, when the starting compound contains an amino group, a carboxyl group, a hydroxy group, a carbonyl group, or a mercapto group as a substituent, a protecting group commonly used in peptide chemistry or the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

[0284] The configurational isomer (E,Z isomer) of compound (I) can be isolated and purified by separation means such as extraction, recrystallization, distillation, chromatography, etc., at the time of isomerization, and thus a pure compound can be produced. Also, New Experimental Chemistry Vol. 14 (edited by Chemical Society of Japan), pp. 251-253 and 4th Edition of The corresponding pure isomers can also be obtained by proceeding with isomerization of the double bond using heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation, a strong base catalyst, or the like, according to the method described on pages 273-274 of Experimental Chemistry Vol. 19 (edited by Chemical Society of Japan) or a method equivalent thereto.

[0285] Compound (I) may have stereoisomers depending on the type of substituents, and both compounds containing these isomers alone and mixtures thereof are included within the scope of the present disclosure.

[0286] If the target compound is obtained in a free form by the above reaction, it may be converted into a salt by a conventional method, and if it is obtained as a salt, it may be converted into a free form or another salt by a conventional method. For example, compound (I) thus obtained can be isolated and purified from the reaction solution by known means, such as transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.

[0287] When compound (I) exists as configurational isomers, diastereomers, conformers, etc., they can be isolated by the above-mentioned separation and purification means, if desired. When compound (I) is a racemate, it can be separated into d- and l-isomers, or S- and R-isomers, by conventional optical resolution means.

[0288] Compound (I), other reaction intermediates and starting compounds thus obtained can be isolated and purified from the reaction mixture by a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, preparative high-performance liquid chromatography (preparative HPLC), medium-pressure preparative liquid chromatography (medium-pressure preparative LC), or the like.

[0289] The salt of compound (I) can be produced by known means, for example, by adding an inorganic acid or an organic acid when compound (I) is a basic compound, or by adding an organic base or an inorganic base when compound (I) is an acidic compound.

[0290] When compound (I) has enantiomers, both the individual enantiomers and mixtures thereof are included within the scope of the present disclosure. If desired, these isomers can be optically resolved or individually prepared according to known methods.

[0291] As used herein, GPR139 receptor antagonism includes GPR139 receptor inverse agonism. In some embodiments, the compound having GPR139 receptor antagonism is a compound having GPR139 receptor inverse agonism.

[0292] The GPR139 receptor inverse agonism can also be confirmed, for example, by a decrease or inhibition of the production of inositol monophosphate (sometimes abbreviated as IP1 herein) (a metabolic product of inositol triphosphate (sometimes abbreviated as IP3 herein), which is a second messenger downstream of signal transduction in GPR139), as described in detail in the test examples below.

[0293] Compound (I) can be used as a preventive, therapeutic or diagnostic agent for various diseases described below in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). For example, compound (I) can be used as a preventive, therapeutic or diagnostic agent for various diseases described below in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). (1) Psychiatric disorders (e.g., depression, major depression, depressive episode, minor depressive disorder, bipolar depression, dysthymic disorder, persistent depressive disorder, affective disorders (e.g., seasonal affective disorder, etc.), recurrent depression, postpartum depression, stress disorder, major depressive disorder comorbid with psychosis (including delusional disorder and schizophrenia), manic or mixed mood episode, hypomanic mood episode, depressive episode with atypical features, depressive episode with melancholic features, depressive episode with catatonic features, depressive episode after stroke, depression with anhedonia) , major depression with anhedonia, minor depressive disorder with anhedonia, bipolar depression with anhedonia, dysthymic disorder with anhedonia, persistent depressive disorder with anhedonia, affective disorder with anhedonia, recurrent depression with anhedonia, postpartum depression with anhedonia, stress disorder with anhedonia, bipolar disorder with anhedonia, schizophrenia with anhedonia, anxiety disorder with anhedonia, mood disorder with anhedonia, Alzheimer's disease with anhedonia, dementia with Lewy bodies, Parkinson's disease with anhedonia, Huntington's disease with anhedonia, treatment-resistant major aphthous ulcers with anhedonia Depression, treatment-resistant bipolar disorder with anhedonia, depressive symptoms, mania, manic episode, hypomanic episode, manic-like episode, hypomanic-like episode, delirium, dementia-related symptoms (psychiatric symptoms or behavioral abnormalities), anxiety, generalized anxiety disorder, anxiety syndrome, mood disorder, cyclothymic disorder, premenstrual dysphoric disorder, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, schizoaffective disorder, paranoid or depressive schizoaffective disorder, paranoid personality disorder, Tourette syndrome group, autism spectrum disorder, fragile X syndrome, Rett syndrome, adjustment disorder, bipolar disorder (including bipolar disorder type I and bipolar disorder type II), neurosis, drug addiction, schizophrenia (e.g., positive symptoms, negative symptoms, cognitive dysfunction, paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia), schizophrenia spectrum disorder, movement disorder, mental retardation, paranoid tendency, schizophreniform disorder, catatonia, neurosis, fatigue, chronic fatigue syndrome, loss of energy, anxiety neurosis, obsessive-compulsive disorder, panic disorder, epilepsy, anxiety symptoms, unpleasant mental state, emotional abnormalities, Cyclothymic temperament, irritability, blackouts, addiction, decreased libido, attention deficit hyperactivity disorder (ADHD), psychotic major depression, treatment-resistant major depression, treatment-resistant major depression, cognitive impairment in major depression, treatment-resistant bipolar disorder, temper tantrums, weight gain, weight loss, psychomotor agitation, psychomotor retardation, feelings of worthlessness, guilt, impaired thinking and concentration, suicidal ideation, suicide attempt, melancholia, psychotic disorders (e.g., brief psychotic disorder, shared psychotic disorder), obesity-induced psychosis, delusional disorder, Noonan syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedimann syndrome, Silver-Russell syndrome, tuberous sclerosis complex, Williams syndrome, Kallmann syndrome, Rubinstein-Taybi syndrome, eating disorders and eating disorders, eating disorders, pica, rumination, avoidant-controlled food intake disorder, anorexia, anorexia nervosa (anorexia nervosa, anorexia nervosa), psychogenic anorexia, atypical anorexia nervosa, bulimia, bulimia nervosa (bulimia nervosa), hyperphagia nervosa, atypical bulimia nervosa, binge eating disorder, psychogenic binge eating, psychogenic, pregnancy vomiting, psychogenic vomiting], (2) Neurodegenerative diseases [e.g., Alzheimer's disease, Alzheimer's-type senile dementia, Parkinson's disease, Huntington's disease, dementia associated with Huntington's disease, multi-infarct dementia, frontotemporal dementia, Parkinson's-type dementia, Parkinson's-type frontotemporal dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, neurodegeneration associated with brain trauma, neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction, neurodegeneration associated with hypoglycemia, neurodegeneration associated with epileptic seizures, neurodegeneration associated with neurotoxicity, multiple system atrophy] atrophy, spinal cord injury, AIDS-related dementia, progressive supranuclear palsy, Pick's syndrome, Niemann-Pick syndrome, corticobasal degeneration, Down's syndrome, vascular dementia (VaD) (e.g., multi-infarct dementia, strategic single-lesion VaD, small vessel dementia, hypoperfusion VaD, cerebral hemorrhagic VaD, chronic subdural hematoma, etc.), postencephalitic parkinsonism, dementia with Lewy bodies, HIV-associated dementia, amyotrophic lateral sclerosis (ALS), motor neurogenic disease (MND), Creutzfeldt-Jakob disease, prion disease, cerebral palsy, multiple sclerosis, neuromyopathy]. (3) Amnesic disorder, mild cognitive impairment, learning disability [e.g., dyslexia, dyscalculia, written expression disorder], or age-related cognitive or memory disorder [e.g., age-related memory disorder, senile dementia], (4) Sleep disorders [e.g., endogenous sleep disorders (e.g., psychophysiological insomnia, etc.), exogenous sleep disorders, circadian rhythm disorders (e.g., time-zone shift syndrome (jet lag), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake, etc.)], parasomnias (e.g., disorders of awakening from non-REM sleep (e.g., sleepwalking, sleep startle, etc.), nightmare disorders, REM sleep disorders, restless legs syndrome, etc.] ), sleep disorders associated with medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, anxiety neurosis), stress-related insomnia, insomnia, insomnia neurosis, sleep apnea syndrome (e.g., obstructive sleep apnea, central sleep apnea, etc.), sleep-related hypoventilation (e.g., primary alveolar hypoventilation syndrome, congenital central hypoventilation syndrome, etc.), narcolepsy, cataplexy, hypersomnia], (5) Drug dependence (substance-related disorders, substance dependence) [e.g., substance use disorders (e.g., alcohol dependence, cannabis (including synthetic cannabinoids) dependence, hallucinogen (e.g., ketamine, phencyclidine, etc.) dependence), inhalant dependence, opioid dependence, analgesic dependence, sleeping pill dependence, anti-anxiety drug dependence, psychostimulant (e.g., amphetamine-type substances, cocaine, cathinone, synthetic cathinone, NMDA, NMDA-related drug (e.g., MDA, etc.) dependence, caffeine dependence, tobacco dependence, nicotine dependence, alcohol use disorder, cannabis (including synthetic cannabinoids) use disorder, hallucinogen use disorder, inhalant use disorder, opioid use disorder, analgesic use disorder, hypnotic use disorder, anxiolytic use disorder, psychostimulant use disorder, caffeine use disorder, tobacco use disorder, nicotine use disorder, etc.), substance-induced disorders (e.g., alcohol intoxication, alcohol withdrawal, caffeine intoxication, caffeine withdrawal, cannabis (including synthetic cannabinoids) intoxication, cannabis (including synthetic cannabinoids) withdrawal, hallucinogen intoxication, hallucinogen persistent perception disorder, inhalant intoxication, opioid intoxication, opioid withdrawal, analgesic intoxication, hypnotic intoxication, anxiolytic intoxication, analgesic withdrawal, hypnotic withdrawal, anxiolytic withdrawal, psychostimulant intoxication, psychostimulant withdrawal, caffeine withdrawal, tobacco withdrawal, Nicotine withdrawal, substance (e.g., alcohol, caffeine, cannabis (including synthetic cannabinoids), hallucinogens, inhalants, opioids, analgesics, hypnotics, anxiolytics, psychostimulants, caffeine, tobacco, nicotine, etc.)-induced psychiatric disorders (e.g., psychotic disorders, bipolar disorder and related disorders, depressive disorders, anxiety disorders, obsessive-compulsive disorders and related disorders, sleep disorders, sexual dysfunction, delirium, neurocognitive disorders, etc.), acute poisoning, harmful use (e.g., antidepressant abuse, substance abuse, etc.), dependence syndromes (e.g., drug dependence, non-narcotic analgesic dependence, etc.), withdrawal states (e.g., drug withdrawal syndrome, etc.), withdrawal states accompanied by delirium, psychotic disorders (e.g., toxic psychosis, steroid psychosis, etc.), amnesic syndromes, residual and delayed-onset psychotic disorders (e.g., drug-dependent depressive states, etc.), psychotropic drug side effects, toxic mental disorders, drug-induced mental disorders, drug addiction, drug phobia, drug mania, drug withdrawal]. (6) Respiratory depression caused by anesthetics, trauma, neurodegenerative diseases, etc. (7) Pain [e.g., psychogenic pain (somatoform disorder, pain disorder, somatization disorder, hypochondriasis, conversion disorder)] Sexual disorders, chronic pain associated with depression, psychogenic glossalgia, psychogenic headaches, psychogenic back pain, psychogenic abdominal pain, neurogenic otalgia, somatic pain disorders, psychopathic pain, psychogenic dyspareunia), inflammatory pain, acute pain, persistent cancer pain, breakthrough cancer pain, cancer pain, persistent pain, body pain, breakthrough pain, chronic pain (e.g., intractable pain, pain after thoracotomy) pain syndrome, peripheral neuropathic pain, peripheral neuropathic pain, neuropathic pain, central neuropathic pain, central neuropathic pain, central post-stroke pain, etc.), tenderness, general pain, dull pain, skin pain syndrome, radiating pain, headache (e.g., inflammatory headache, facial pain, occipital pain, odontofacial pain, habitual headache, neuralgic headache) , frontal headache, temporal headache, head and neck pain, heavy head sensation, vertex pain, paroxysmal headache, cheek pain, traction headache, burning mouth syndrome, primary headache, headache due to psychiatric disorders, migraine, chronic cluster headache, cluster headache, trigeminal and autonomic headache, episodic cluster headache, paroxysmal hemicrania, episodic hemicrania, chronic paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, vascular headache, muscle contraction headache, tension-type headache, episodic tension-type headache, chronic tension-type headache, traumatic headache, chronic post-traumatic headache, medication overuse headache, Sluder neuralgia, Tolosa-Hunt syndrome, ocular headache, mixed headache, persistent hemicrania, primary cough headache, primary exercise headache, primary headache associated with sexual activity, headache due to cold stimulation, primary thunderclap headache, primary stabbing headache, nummular headache, headache during sleep, new-onset persistent daily headache, headache due to epileptic seizure, hypertensive headache, headache due to nasal / sinus disease, tension headache, etc.), trigeminal nerve disorders (e.g., trigeminal neuralgia, atypical facial pain, trigeminal hypersensitivity, trigeminal neuropathy, etc.), glossopharyngeal nerve disorders (e.g., glossopharyngeal neuralgia, etc.), vagus nerve disorders (e.g., superior laryngeal neuralgia, vagal neuralgia, etc.), hypoglossal nerve disorder, multiple cranial nerve disorders, postherpetic neuralgia, postherpetic trigeminal neuralgia, postherpetic polyneuropathy neuropathy, neuralgic amyotrophy, phantom limb pain, stump neuralgia, deafferentation pain, lumbar sciatica, mononeuropathy of the upper limbs (e.g., median nerve neuralgia, ulnar neuralgia, etc.), mononeuropathy of the lower limbs (e.g., dyssensory thigh pain, etc.), rib neuropathy (e.g., intercostal neuralgia, etc.), neuropathic pain, diabetic neuropathy pain, diabetic neuralgia (e.g., type 1 diabetic neuralgia, type 2 diabetic neuralgia, etc.), cardiac neuralgia, persistent somatoform pain disorder, epidemic pleuritic pain, autonomic reflex pain, spinal pain, post-lumbar puncture headache, eye pain, ear pain, thalamic pain, sore throat, nasal pain, tooth pain, jaw pain, glossodynia, rectal pain, joint pain, lower back pain,spinal pain, muscle pain, neuralgia], (8) Traumatic brain injury and its associated disorders or complications, post-concussion syndrome, shaken baby syndrome, stroke, age-related macular degeneration (ARMD), oculopalatal tremor, convulsions, cerebral infarction, cerebral hemorrhage, hearing loss, radiation lethargy syndrome, anorexia nervosa, eating disorders, anorexia nervosa, bulimia, other eating disorders, gambling addiction, gaming addiction, obesity, diabetes, muscle spasms, Meniere's disease, autonomic nervous system imbalance, alopecia, glaucoma, high blood pressure, heart disease, tachycardia, heart failure, hyperventilation, bronchial asthma Breathing, apnea, sudden infant death syndrome, inflammatory diseases, allergic diseases, impotence, menopausal disorders, infertility, cancer, immunodeficiency syndrome due to HIV infection, autoimmune encephalitis (e.g., autoimmune limbic encephalitis), immunodeficiency syndrome due to stress, cerebrospinal meningitis, acromegaly, incontinence, metabolic syndrome, osteoporosis, peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress-related gastrointestinal disorders, vomiting, peptic ulcer, diarrhea, constipation, postoperative ileus It is expected that the compound will be useful as a preventive or therapeutic agent for the above diseases.

[0294] Compound (I) may be used in the form of a prodrug. 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 a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, etc., with gastric acid, or the like.

[0295] Examples of prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (for example, compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (for example, Compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated; compounds in which the carboxyl group of compound (I) is esterified or amidated (for example, 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-dioxol-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidized). These compounds can be produced from compound (I) by methods known per se. The prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions as described in "Development of Pharmaceutical Products," vol. 7, Molecule Design, pp. 163-198, Hirokawa Shoten (1990).

[0296] The compound of formula (I) can exhibit favorable pharmacokinetic properties (e.g., blood drug half-life, brain transferability, metabolic stability) and low toxicity (e.g., superior as a pharmaceutical in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, carcinogenicity, etc.), and can be safely administered orally or parenterally to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) as a pharmaceutical directly or as a pharmaceutical composition mixed with at least one pharmaceutically acceptable carrier, etc.

[0297] As used herein, "parenteral administration" includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ocular, intracerebral, rectal, intravaginal, intraperitoneal, intratumor, administration proximal to a tumor, etc., and administration directly to a lesion.

[0298] In some embodiments, the dosage of Compound (I) varies depending on the administration route, symptoms, etc. In some embodiments, when orally administered to a patient with depression (e.g., an adult weighing 40 to 80 kg, e.g., 60 kg), the dosage is, for example, 0.001 to 1000 mg / kg body weight per day, for example, 0.01 to 100 mg / kg body weight per day, for example, 0.1 to 10 mg / kg body weight per day. This amount can be administered, for example, once to three times a day.

[0299] A medicament containing Compound (I) can be prepared according to a method known per se as a method for producing a pharmaceutical preparation (e.g., a method described in the Japanese Pharmacopoeia, etc.), either using Compound (I) alone or as a pharmaceutical composition obtained by mixing Compound (I) with at least one pharmaceutically acceptable carrier. Medicaments containing Compound (I) can be prepared in the form of, for example, 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), troches, 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, orally disintegrating films, etc.), or the like. They can be administered orally or parenterally (intravenously, intramuscularly, subcutaneously, intraviscerally, intranasally, intradermally, by eye drop, intracerebral, rectally, vaginally, intraperitoneally, or into a lesion, etc.) as a drug solution (e.g., intravenous mucosal patch film), injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip infusion, transdermal preparation, ointment, lotion, patch, suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop, etc.

[0300] As the "pharmaceutically acceptable carrier" mentioned above, various organic or inorganic carriers commonly used as starting materials for preparation can be used. For example, in solid preparations, excipients, lubricants, binders, disintegrants, etc. can be used, and in liquid preparations, solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. can be used. Furthermore, if necessary, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners, etc. can be used. can also be used.

[0301] Non-limiting examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like.

[0302] Non-limiting examples of lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, and the like.

[0303] Non-limiting examples of binders include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose, and the like.

[0304] Non-limiting examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose, and the like.

[0305] Non-limiting examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

[0306] Non-limiting examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

[0307] Non-limiting examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0308] Non-limiting examples of isotonicity agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

[0309] Non-limiting examples of buffering agents include, for example, phosphate, acetate, carbonate, citrate, and the like buffer solutions.

[0310] Non-limiting examples of soothing agents include benzyl alcohol, etc. Non-limiting examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, etc.

[0311] Non-limiting examples of antioxidants include, for example, sulfites, ascorbic acid, α-tocopherol, and the like.

[0312] In some embodiments, the pharmaceutical composition can be prepared according to a conventional method by adding Compound (I) in a proportion of, for example, 0.01% to 100% (w / w), for example, 0.1% to 95% (w / w), based on the total amount of the pharmaceutical composition, although this varies depending on the dosage form, administration method, carrier, etc.

[0313] Compound (I) may be used in combination with other active ingredients, referred to herein as concomitant drugs.

[0314] Non-limiting examples of concomitant drugs include the following: acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil), β-amyloid protein production, secretion, accumulation, aggregation, and / or deposition inhibitors, β-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'- methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, optically active forms thereof, salts thereof and hydrates thereof, OM99-2 (WO 01 / 00663)), gamma secretase inhibitors, beta amyloid protein aggregation inhibitors (e.g., PTI -00703, Tramiprosate, PPI-368 (Patent Document 11-514333), PPI-558 (Patent Document 2001-500852), SKF-74652 (2-(4-methoxyphenyl)-3-[4-[3-(diethylamino)propoxy]benzoyl]-5-chlorobenzofuran, Biochem. J. (1999), 340(1), 283-289)), β-amyloid vaccine, beta-amyloid degrading enzymes, encephalogenic agents (e.g., aniracetam, nicergoline), other Parkinson's disease medications (e.g., dopamine receptor agonists (e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, sergiline (selegiline), remacemide, riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone) ], drugs for treating amyotrophic lateral sclerosis (e.g., riluzole, neurotrophic factors), drugs for treating abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, emricasan, CEP-1347), neuronal differentiation and regeneration promoters (e.g., leteprinim, xaliproden (SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-di 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active substances, salts, hydrates), non-sulfonic acid Steroid anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroid drugs (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anticytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), drugs for treating urinary incontinence and frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors ( (e.g., sildenafil citrate), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), osteoporosis treatment agents (e.g., alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavo), iprivlavone, pamidronate disodium, alendronate sodium hydrate, iprivlavone ancadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, drugs for treating insomnia (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, orexin receptor antagonists), drugs for treating schizophrenia (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; drugs acting on metabotropic glutamate receptors or ionotropic glutamate receptors; phosphodiesterase inhibitors), benzodiazepines (chlordiazepoxide, diazepam, clorazepate potassium, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective Serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paraxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (methicone reboxetine hydrochloride, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT2A antagonists (e.g., pimavanserin tartrate), 5-HT2A inverse agonists, 5-HT3 antagonists (cyamemazine, etc.), non-cardioselective beta-blockers (propranolol hydrochloride, oxiprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxybenzoates, etc.) azine, etc.), antipsychotic drugs (chlorpromazine, haloperidol, sulpride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate, risperidone, aripiprazole, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (aprepitant, saredutant, etc.), drugs acting on metabotropic glutamate receptors, drugs acting on GABA receptors, drugs acting on acetylcholine receptors, CCK antagonists, β3-adrenergic antagonists (amibegron, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel blockers, type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists, NMDA antagonists (ketamine, S-ketamine, R-ketamine, ketamine metabolites (e.g., (2S, 6S;(2R,6R)-hydroxynorketamine, (2R,6R)-hydroxynorketamine, memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid agonists agonists), thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), drugs for treating bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), drugs for treating alcoholism, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia, drugs for treating headaches, drugs for smoking cessation, drugs for treating myasthenia gravis, drugs for treating cerebral infarction, drugs for treating mania, drugs for treating hypersomnia, pain treatment drugs for treating dysthymia, drugs for treating autonomic nervous system disorders, drugs for treating male and female sexual dysfunction, drugs for treating migraines, drugs for treating pathological gambling, drugs for treating restless legs syndrome, drugs for treating substance dependence, drugs for treating alcohol-related disorders, drugs for treating irritable bowel syndrome, drugs for treating dyslipidemia such as cholesterol-lowering drugs (statins (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for treating abnormal behavior or dementia-related wanderlust (sedatives, anti-anxiety drugs, etc.), anti-obesity drugs, drugs for treating diabetes, drugs for treating diabetic complications, drugs for treating hypertension, drugs for treating hypotension, diuretics, chemotherapy drugs, immunotherapy drugs, antithrombotic drugs, anti-cancer drugs, etc.;

[0315] The above concomitant drugs may be used in combination of two or more kinds in an appropriate ratio.

[0316] Furthermore, when the compounds of the present disclosure are used to treat or prevent one or more of the above-mentioned diseases, the compounds can also be used in combination with biologics (e.g., antibody drugs, nucleic acids (e.g., antisense oligonucleotides, siRNA, decoys, etc.) or nucleic acid derivatives, aptamer drugs, peptide drugs, vaccine preparations). In addition, the compounds can be used in combination with gene therapy, etc., or in combination with drug-free therapies used in the field of psychiatry.

[0317] Non-limiting examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFα antibodies and other cytokines, amyloid-β vaccine preparations, type 1 diabetes vaccines (e.g., DIAPEP-277 manufactured by Peptor), anti-HIV antibodies or HIV vaccine preparations, antibodies or vaccine preparations against cytokines, renin-angiotensin system enzymes or their products, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes or proteins involved in blood coagulation and fibrinolysis, antibodies or vaccine preparations against proteins involved in glucose metabolism or insulin resistance, etc. Compound (I) can also be used in combination with biological preparations related to growth factors such as GH or IGF.

[0318] Non-limiting examples of gene therapy methods include therapies using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylating enzymes, therapies using DNA decoys such as NFκB decoys, therapies using antisense, therapies using genes related to enzymes or proteins involved in blood lipid metabolism (e.g., genes related to the metabolism, excretion, and absorption of blood cholesterol, triglycerides, HDL-cholesterol, or phospholipids), therapies using genes related to enzymes or proteins involved in angiogenesis therapy for peripheral vascular occlusive disease and the like (e.g., growth factors such as HGF and VEGF), therapies using genes related to proteins involved in glucose metabolism or insulin resistance, antisense against cytokines such as TNF, and gene therapy using viral vectors (e.g., adenovirus, lentivirus, adeno-associated virus, retrovirus, vaccinia virus, herpes virus, human papillomavirus, Sendai virus, etc.) or non-viral vectors (e.g., plasmids, lipid particles, etc.).

[0319] Non-limiting examples of non-drug psychiatric treatments include, for example, modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy, including cognitive behavioral therapy.

[0320] Furthermore, the compounds of the present disclosure can be used in combination with various organ regeneration methods, such as cardiac regeneration, renal regeneration, pancreatic regeneration, and vascular regeneration, each using autologous or allogeneic cells (including genetically modified cells), cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs using tissue engineering (e.g., artificial blood vessels, cardiomyocyte sheets).

[0321] In some embodiments, the combination of Compound (I) with a concomitant drug can achieve one or more of the following results: (1) The dose of compound (I) or a concomitant drug can be reduced compared to when the compound (I) or a concomitant drug is administered alone. (2) The drug to be used in combination with Compound (I) can be selected depending on the patient's symptoms (mild, severe, etc.). (3) By selecting a concomitant drug with a different mechanism of action from that of Compound (I), the treatment period can be extended. (4) By selecting a concomitant drug with a different mechanism of action from Compound (I), the therapeutic effect can be sustained. It is possible to achieve (5) A synergistic effect can be achieved by using Compound (I) in combination with a concomitant drug.

[0322] Hereinafter, the combined use of Compound (I) and a concomitant drug will be referred to as the "concomitant drug of the present disclosure."

[0323] When using the combination agent of the present disclosure, the timing of administration of compound (I) and the concomitant drug is not limited, and compound (I) or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof may be administered to the subject simultaneously or at staggered times. The dose of the concomitant drug may be in accordance with the dose used clinically and may be appropriately selected depending on the subject, administration route, disease, combination, etc.

[0324] The administration form of the combination drug of the present disclosure is not particularly limited, as long as compound (I) and the concomitant drug are combined at the time of administration. Non-limiting examples of such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating compound (I) and the concomitant drug, (2) simultaneous administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via the same administration route, (3) administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via different administration routes, and (5) administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via different administration routes with a time lag (for example, administration of compound (I) followed by the concomitant drug, or administration in the reverse order).

[0325] In some embodiments, the combination drug of the present disclosure has low toxicity, and Compound (I) and / or the combination drug described above can be mixed with at least one pharmaceutically acceptable carrier according to known methods and safely administered orally or parenterally (for example, topically, rectally, or intravenously) as a pharmaceutical composition, such as a tablet (e.g., sugar-coated tablet, film-coated tablet), powder, granule, capsule (e.g., soft capsule), liquid, injection, suppository, sustained-release agent, etc. Injection can be administered intravenously, intramuscularly, subcutaneously, or intraorganly, or directly into the lesion.

[0326] Non-limiting examples of pharmaceutically acceptable carriers that may be used in the manufacture of the combination agent of the present disclosure include those similar to those described above.

[0327] The blending ratio of Compound (I) and the concomitant drug in the combination agent of the present disclosure can be appropriately selected depending on the subject of administration, the administration route, the disease, etc.

[0328] For example, the content of Compound (I) in the combination agent of the present disclosure varies depending on the form of the formulation, but in some embodiments, it is about 0.01 to 100% by weight, for example, about 0.1 to 50% by weight, for example, about 0.5 to 20% by weight, based on the total weight of the formulation.

[0329] The content of the concomitant drug in the combination agent of the present disclosure varies depending on the form of the formulation, but in some embodiments, it is about 0.01 to 100% by weight, for example, about 0.1 to 50% by weight, for example, about 0.5 to 20% by weight, based on the total weight of the formulation. [Example]

[0330] The present disclosure will be described in more detail using the following examples, test examples and formulation examples. However, these examples, test examples and formulation examples do not limit the present disclosure, and may be changed within the scope of the present disclosure.

[0331] In the following examples, "room temperature" generally refers to a temperature between about 10°C and about 35°C. Ratios shown in mixed solvents are by volume unless otherwise specified. Additionally, % refers to % by weight unless otherwise specified.

[0332] Unless otherwise specified, elution in column chromatography in the examples was carried out under observation by thin layer chromatography (TLC). 254 The TLC plate was used, and the solvent used as the elution solvent in column chromatography was used as the developing solvent. A UV detector was used for detection. In silica gel column chromatography, NH indicates aminopropylsilane-bonded silica gel, and Diol indicates 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative high-performance liquid chromatography (HPLC), C18 indicates octadecyl-bonded silica gel. The ratios of elution solvents are by volume unless otherwise specified.

[0333] 1 H NMR analysis was performed using ACD / SpecManager software. Gentle proton peaks such as those of hydroxyl and amino groups may not be recorded.

[0334] MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shown are actual measurements (found values). Molecular ion peaks are usually observed, but fragment ions may also be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0335] Optical rotation ([α] D The unit of sample concentration (c) in (a) is g / 100 mL.

[0336] Elemental analysis values ​​(Anal.) are shown as calculated values ​​(Calcd) and found values ​​(Found).

[0337] In the examples, the powder X-ray diffraction peaks are measured at room temperature using an Ultima IV (Rigaku Corporation, Japan) with Cu Kα radiation as the radiation source. The measurement conditions are as follows: Electric pressure / Electric current:40 kV / 50 mA Scan speed: 6 degrees / min Scan range of 2 Theta:2-35 degree

[0338] In the examples, the crystallinity measured by powder X-ray diffraction was calculated by the Hermans method.

[0339] The following abbreviations are used in the following examples: mp: melting point MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide DMSO: dimethyl sulfoxide 1 H NMR: proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: Atmospheric pressure chemical ionization Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) TFA: Trifluoroacetic acid DIPEA: N-ethyl-N-isopropylpropan-2-amine PdCl2: Palladium(II) chloride PdCl2(dppf): Dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium PdCl2(dppf)·CH2Cl2: Dichloro(1,1'-bis(diphenylphosphino)ferrocene)para dichloromethane adduct n-BuLi: butyl lithium DMF: N,N-dimethylformamide THF: tetrahydrofuran DME: 1,2-dimethoxyethane EtOH: ethanol AcOH: acetic acid HMPA: hexamethylphosphoric triamide NBS: 1-bromopyrrolidine-2,5-dione XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene RuPhos: Dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl dbbpy: 4,4'-di-tert-butyl-2,2'-bipyridine IPE: Diisopropyl ether BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Example 1 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one A) Ethyl 1-ethyl-1H-pyrazole-4-carboxylate

[0340] A mixture of potassium carbonate (197 g), ethyl 1H-pyrazole-4-carboxylate (100 g), ethyl iodide (122 g), and DMF (200 mL) was stirred at room temperature overnight. Water was added to the mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (121 g).

[0341] 1 H NMR (300 MHz, DMSO-d6) δ 1.26 (3H, t, J = 7.2 Hz), 1.37 (3H, t, J = 7.2 Hz), 4.12-4.27 (4H, dq, J = 11.5, 7.2 Hz), 7.84 (1H, s), 8.33 (1H, s). B) (1-ethyl-1H-pyrazol-4-yl)methanol

[0342] A mixture of ethyl 1-ethyl-1H-pyrazole-4-carboxylate (48.0 g) and THF (100 mL) was added dropwise to a mixture of lithium aluminum hydride (16.3 g) and THF (400 mL) at 0-10°C, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with THF (150 mL) and cooled to 0°C. Sodium sulfate decahydrate (110 g) was added at 0-10°C, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (29.9 g).

[0343] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.3 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.32 (2H, d, J = 5.3 Hz), 4.77 (1H, t, J = 5.5 Hz), 7.32 (1H, s), 7.59 (1H, s) C) 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride

[0344] To a mixture of (1-ethyl-1H-pyrazol-4-yl)methanol (2.33 g) and acetonitrile (20 mL), thionyl chloride (4.39 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. The mixture was concentrated to give the title compound (3.23 g).

[0345] 1 H NMR (300 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.2 Hz), 4.10 (2H, q, J = 7.4 Hz), 4.69 (2H, s), 7.50 (1H, s), 7.85 (1H, s), 12.32 (1H, m). D) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methoxypyridine

[0346] A mixture of 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (2.87 g), cesium carbonate (20.7 g), PdCl(dppf) (2.32 g), (2-methoxypyridin-3-yl)boronic acid (3.15 g), DME (25 mL), and water (2.5 mL) was heated at 110°C under an argon atmosphere. The mixture was stirred at °C for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (2.88 g).

[0347] MS: [M+H] + 218.0. E) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one

[0348] To a solution of 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methoxypyridine (302 mg) in DMF (3 mL) was added pyridine hydrochloride (1.61 g). The mixture was stirred at °C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (C18, mobile phase: water / acetonitrile (10 mM ammonium bicarbonate system)). The obtained fraction was concentrated under reduced pressure to give the title compound (194 mg).

[0349] MS: [M+H] + 204.0. F) 2-chloro-6-(4-fluorophenyl)-4-(trifluoromethyl)pyridine

[0350] To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (10 g) in DMF (150 mL) were added 4-(fluorophenyl)boronic acid (6.8 g), potassium carbonate (19.2 g), water (50 mL), bis(triphenylphosphine)palladium(II) chloride (3.25 g), and tri-o-tolylphosphine (1.41 g). The mixture was stirred overnight at room temperature under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound (10.6 g).

[0351] MS: [M+H] + 276.3. G) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluoromethyl)- (4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one

[0352] A mixture of 2-chloro-6-(4-fluorophenyl)-4-(trifluoromethyl)pyridine (27.1 mg), 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one (20 mg), cesium carbonate (96 mg), Xantphos (11.4 mg), Pd2(dba)3 (9.01 mg), and toluene (0.5 mL) was stirred at 100 °C for 3 hours under an argon atmosphere. After concentrating the mixture, the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (11.1 mg).

[0353] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.3 Hz), 3.57-3.66 (2H, m), 4.02-4.12 (2H, m), 6.40 (1H, t, J = 7.0 Hz), 7.30-7.43 (4H, m), 7.57 (1H, s), 8.02 (1H, dd, J = 7.0, 2.1 Hz), 8.18 (1H, s), 8.27-8.34 (2H, m), 8.42 (1H, s). Example 3 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-4'-(2,2,2-trifluoroethoxy)-2H-[1,2'-bipyridine]-3'-carbonitrile A) 4-(benzyloxy)-2,6-dichloropyridine-3-carbonitrile

[0354] Benzyl alcohol (79 mg) was added to a solution of sodium hydride (60% content, 31.7 mg) in DMF (1 mL) at 0°C. The mixture was stirred at 0°C for 10 minutes. A solution of 2,4,6-trichloropyridine-3-carbonitrile (137 mg) in DMF (1 mL) was added to the mixture at 0°C. The mixture was stirred at 0°C for 4 hours. Water was added to the mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (62.4 mg).

[0355] 1 H NMR (300 MHz, CDCl3) δ 5.29 (2H, s), 6.95 (1H, s), 7.37-7.46 (5H, m). B) 4-(benzyloxy)-2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile

[0356] A mixture of 4-(benzyloxy)-2,6-dichloropyridine-3-carbonitrile (1.56 g), (4-fluorophenyl)boronic acid (0.938 g), PdCl2 (dppf) (0.204 g), cesium carbonate (3.28 g), THF (20 mL), and water (20 mL) was stirred at 80 °C under a nitrogen atmosphere for 3 hours, and then the reaction mixture was concentrated. Water was added to the resulting residue at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.70 g).

[0357] MS:[M+H]+339.0. C) 4'-(benzyloxy)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(fluorophenyl)-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile

[0358] 4-(benzyloxy)-2-chloro-6-(4-fluorophenyl)pyridine-3- A mixture of carbonitrile (60.8 mg), 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one (36.5 mg), Pd2(dba)3 (16.4 mg), Xantphos (20.8 mg), cesium carbonate (175 mg), and toluene (1.5 mL) was stirred in a sealed tube at 100 °C for 1 hour under an argon atmosphere. The mixture was then irradiated with microwaves at 100 °C for 1 hour. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (34.3 mg).

[0359] MS: [M+H] + 506.2. D) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-4'-hydroxy-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile

[0360] A mixture of 4'-(benzyloxy)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(fluorophenyl)-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile (34.3 mg), 10% palladium-carbon (2.89 mg), THF (1 mL), and methanol (0.5 mL) was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (26.4 g).

[0361] MS: [M+H] + 416.1. E) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-4'-(2,2,2-trifluoroethoxy)-2H-[1,2'-bipyridine]-3'-carbonitrile

[0362] To a mixture of 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-4'-(trifluoromethyl)-4'-hydroxy-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile (26.4 mg), potassium carbonate (17.6 mg), and DMF (1 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (27.4 mg) at room temperature. The mixture was stirred at 80°C for 1 hour. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (C18, mobile phase: water / acetonitrile (10 mM ammonium bicarbonate system)). The resulting fraction was concentrated under reduced pressure to give the title compound (9.3 mg).

[0363] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.3 Hz), 3.60 (2H, s), 4.05 (2H, q, J = 7.3 Hz), 5.37 (2H, q, J = 8.7 Hz), 6.39 (1H, t, J = 6.8 Hz), 7.29-7.32 (1H, m), 7.36-7.47 (3H, m), 7.55-7.58 (1H, m), 7.75 (1H, dd, J = 6.9, 2.0 Hz), 8.09-8.13 (1H, m), 8.24-8.32 (2H, m). Example 7 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one A) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3',6'-difluoro-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one

[0364] To a solution of 2,3,6-trifluoro-4-(trifluoromethyl)pyridine (500 mg) in N,N-dimethylacetamide (5 mL) was added 3-((1-ethyl-1H-pyrazol-4-yl)methyl)pyridin-2(1H)-one (657 mg). Sodium hydride (60% content, 90 mg) was added to the mixture at -20°C. The mixture was added portionwise while maintaining the temperature below 0°C, and the temperature was raised to 0°C and stirred at 0°C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture, which was then diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (373 mg).

[0365] MS: [M+H] + 385.1. B) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one

[0366] A mixture of 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3',6'-difluoro-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one (100 mg), (2R)-2-methylmorpholine hydrochloride (39.4 mg), cesium carbonate (93 mg), and DMSO (1 mL) was dissolved in 100 mL of water. The mixture was stirred at °C for 1 hour. The mixture was added to water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then further purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (119 mg).

[0367] 1 H NMR (300 MHz, CDCl3) δ 1.24-1.28 (3H, m), 1.47 (3H, t, J = 7.3 Hz), 2.64 (1H, dd, J = 12.4, 10.5 Hz), 3.00 (1H, td, J = 12.3, 3.6 Hz), 3.56-3.79 (4H, m), 3.88-4.07 (3H, m), 4.09-4.17 (2H, m), 6.22 (1H, t, J = 7.0 Hz), 6.82 (1H, d, J = 3.0 Hz), 7.17-7.24 (1H, m), 7.27-7.41 (3H, m). Example 9 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}pyridin-2(1H)-one A) 5-bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene

[0368] A mixture of 2-fluoro-1-nitro-3-(trifluoromethyl)benzene (4.90 g), NBS (5.01 g), TFA (20 mL), and concentrated sulfuric acid (30 mL) was stirred at 60 °C overnight. The mixture was poured into ice water, followed by water and extraction with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.50 g).

[0369] 1 H NMR (300 MHz, DMSO-d6) δ 8.46 (1H, dd, J = 5.3, 2.3 Hz), 8.70 (1H, dd, J = 6.4, 2.3 Hz). B) (2R)-4-[4-fluoro-3-nitro-5-(trifluoromethyl)phenyl]-2-methylmorpholine

[0370] 5-Bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene (1.00 g), (2R)-2-methylmorpholine hydrochloride (0.717 g), Pd2(dba) A mixture of 3 (0.318 g), sodium tert-butoxide (1.67 g), XPhos (0.331 g), and toluene (13 mL) was stirred at 110 °C for 2 h under microwave irradiation. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (530 mg).

[0371] MS: [M+H] + 309.1. C) 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)aniline

[0372] A mixture of (2R)-4-[4-fluoro-3-nitro-5-(trifluoromethyl)phenyl]-2-methylmorpholine (1.85 g), 10% palladium-carbon (0.319 g), and EtOH (60 mL) was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.67 g).

[0373] MS: [M+H] + 279.2. D) (2R)-4-[4-fluoro-3-nitro-5-(trifluoromethyl)phenyl]-2-methylmorpholine

[0374] To a mixture of 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)aniline (3.1 g) and water (50 mL) were added concentrated sulfuric acid (15 mL) and water (15 mL). A solution of sodium nitrite (1.32 g) in water (10 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour, and then a solution of potassium iodide (6.36 g) in water (10 mL) was added dropwise at 0°C.

[0375] The mixture was warmed to room temperature and stirred overnight at room temperature. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium sulfite, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.37 g).

[0376] MS: [M+H] + 390.0. E) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}pyridin-2(1H)-one

[0377] A mixture of 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one (102 mg), (2R)-4-[4-fluoro-3-iodo-4-(trifluoromethyl)phenyl]-2-methylmorpholine (292 mg), copper(I) iodide (28.6 mg), quinolin-8-ol (21.8 mg), cesium carbonate (326 mg), and DMSO (4 mL) was heated at 120 °C for 3 hours under microwave irradiation. Ethyl acetate and water were added to the mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (4.5 mg).

[0378]

[0379] 1 H NMR (300 MHz, CDCl3) δ 1.25 (3H, d, J = 6.0 Hz), 1.47 (3H, t, J = 7.3 Hz), 2.53 (1H, dd, J = 11.5, 10.4 Hz), 2.88 (1H, td, J = 11.7, 3.8 Hz), 3.31-3.44 (2H, m), 3.67-3.82 (4H, m), 3.97-4.06 (1H, m), 4.13 (2H, q, J = 7.2 Hz), 6.20 (1H, t, J = 7.0 Hz), 7.01 (1H, dd, J = 5.7, 3.0 Hz), 7.09-7.17 (2H, m), 7.21 (1H, dt, J = 6.8, 0.9 Hz), 7.34 (1H, s), 7.39 (1H, s). Example 20 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one A) Ethyl 1-ethyl-1H-pyrazole-4-carboxylate

[0380] A mixture of potassium carbonate (197 g), ethyl 1H-pyrazole-4-carboxylate (100 g), ethyl iodide (122 g), and DMF (200 mL) was stirred at room temperature overnight. The mixture was added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (121 g).

[0381] 1 H NMR (300 MHz, DMSO-d6) δ 1.26 (3H, t, J = 7.2 Hz), 1.37 (3H, t, J = 7.2 Hz), 4.12-4.27 (4H, m), 7.84 (1H, s), 8.33 (1H, s). B) (1-ethyl-1H-pyrazol-4-yl)methanol

[0382] A mixture of ethyl 1-ethyl-1H-pyrazole-4-carboxylate (48.0 g) and THF (100 mL) was added dropwise to a mixture of lithium aluminum hydride (16.3 g) and THF (400 mL) at 0-10°C, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with THF (150 mL) and cooled to 0°C. Sodium sulfate decahydrate (110 g) was added at 0-10°C, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (29.9 g).

[0383] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.3 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.32 (2H, d, J = 5.3 Hz), 4.77 (1H, t, J = 5.5 Hz), 7.32 (1H, s), 7.59 (1H, s) C) 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride

[0384] To a mixture of (1-ethyl-1H-pyrazol-4-yl)methanol (2.33 g) and acetonitrile (20 mL), thionyl chloride (4.39 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. The mixture was concentrated to give the title compound (3.23 g).

[0385] 1 H NMR (300 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.2 Hz), 4.10 (2H, q, J = 7.4 Hz), 4.69 (2H, s), 7.50 (1H, s), 7.85 (1H, s), 12.32 (1H, m). D) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methoxypyridine

[0386] A mixture of 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (2.87 g), cesium carbonate (20.7 g), PdCl(dppf) (2.32 g), (2-methoxypyridin-3-yl)boronic acid (3.15 g), DME (25 ml), and water (2.5 mL) was dissolved in 110 ml of water. The mixture was stirred at ℃ under argon atmosphere for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate The mixture was purified using a solvent (hexane) to give the title compound (2.88 g).

[0387] MS: [M+H] + 218.0. E) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one

[0388] To a solution of 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methoxypyridine in DMF (3 mL) was added pyridine hydrochloride (1.61 g). The mixture was stirred at °C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (C18, mobile phase: water / acetonitrile (10 mM ammonium bicarbonate system)). The obtained fraction was concentrated under reduced pressure to give the title compound (194 mg).

[0389] MS: [M+H] + 204.0. F) 2-Bromo-1-fluoro-4-iodobenzene

[0390] A mixture of 3-bromo-4-fluoroaniline (5 g) and concentrated hydrochloric acid (16.5 mL) was added to a solution of sodium nitrite (2.00 g) in water (20 mL) for 0.5 min. The mixture was added slowly at 0°C. After stirring at 0°C for 30 minutes, a solution of potassium iodide (13.1 g) in water (20 mL) was added at 0°C and stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (6.90 g).

[0391] 1 H NMR (300 MHz, DMSO-d6) δ 7.21 (1H, t, J = 8.8 Hz), 7.77 (1H, ddd, J = 8.7, 4.7, 2.1 Hz), 8.02-8.13 (1H, m). G) (2R)-4-(3-bromo-4-fluorophenyl)-2-methylmorpholine

[0392] A mixture of 2-bromo-1-fluoro-4-iodobenzene (1 g), (2R)-2-methylmorpholine hydrochloride (0.457 g), palladium(II) acetate (0.0750 g), BINAP (0.207 g), cesium carbonate (3.25 g), and toluene (30 mL) was stirred at 120 °C for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.56 g).

[0393] MS: [M+H] + 274.1. H) (2R)-4-(3-cyclopropyl-4-fluorophenyl)-2-methylmorpholine

[0394] To a mixture of (2R)-4-(3-bromo-4-fluorophenyl)-2-methylmorpholine (250 mg), cyclopropylboronic acid (157 mg), SPhos (74.9 mg), sodium carbonate (193 mg), and DME (1 mL) was added Pd2(dba)3 (84 mg) at room temperature under an argon atmosphere. The mixture was stirred in a sealed tube at 120 °C under an argon atmosphere for 1 hour. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (177 mg).

[0395] MS: [M+H] + 236.2. I) (2R)-4-[3-cyclopropyl-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylmorpholine

[0396] A mixture of (2R)-4-(3-cyclopropyl-4-fluorophenyl)-2-methylmorpholine (343 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-dioxaborolane (407 mg), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (19.3 mg), dbbpy (15.7 mg), and 2-methoxy-2-methylpropane (3 mL) was heated at 80°C for 1 hour under microwave irradiation. The mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure to give the title compound (527 mg).

[0397] MS: [M+H] + 362.3. J) 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one

[0398] A mixture of (2R)-4-[3-cyclopropyl-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylmorpholine (711 mg), 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one (200 mg), copper(II) acetate (357 mg), pyridine (311 mg), and acetonitrile (10 ml) was stirred at 40 ° C. for 12 hours and at 60 ° C. for 10 hours. (2R)-4-[3-cyclopropyl-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylmorpholine (527 mg) was added to the mixture, and the mixture was stirred at 60 ° C. for 13 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). The obtained fraction was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate / hexane to give the title compound (131 mg).

[0399] 1 H NMR (300 MHz, DMSO-d6) δ 0.75-0.88 (2H, m), 0.92-1.03 (2H, m), 1.12 (3H, d, J = 6.0 Hz), 1.33 (3H, t, J = 7.3 Hz), 1.98-2.07 (1H, m), 2.26 (1H, t, J = 11.3 Hz), 2.53-2.64 (1H, m), 3.47 (1H, br d, J = 11.3 Hz), 3.52-3.63 (5H, m), 3.87 (1H, dd, J = 11.3, 2.3 Hz), 4.06 (2H, q, J = 7.4 Hz), 6.24 (1H, t, J = 6.8 Hz), 6.54 (1H, dd, J = 5.8, 2.8 Hz), 6.74 (1H, dd, J = 6.0, 3.0 Hz), 7.22-7.29 (2H, m), 7.47 (1H, dd, J = 6.8, 1.9 Hz), 7.54 (1H, s). Example 23 1-{3-bromo-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one A) 4-(3-bromo-4-fluorophenoxy)tetrahydro-2H-pyran

[0400] To a mixture of tetrahydro-2H-pyran-4-ol (1.07 g), 4-fluoro-3-(trifluoromethyl)phenol (2 g), triphenylphosphine (3.30 g), and THF (20 mL) was added ethyl azodicarboxylate (5.74 mL) at room temperature, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.3 g).

[0401] 1 H NMR (300 MHz, DMSO-d6) δ 1.55 (2H, dtd, J = 13.3, 9.0, 4.1 Hz), 1.89-1.97 (2H, m), 3.46 (2H, ddd, J = 11.9, 9.4, 2.8 Hz), 3.83 (2H, dt, J = 11.7, 4.5 Hz), 4.57 (1H, tt, J = 8.6, 4.2 Hz), 6.99-7.06 (1H, m), 7.23-7.38 (2H, m). B) 1-{3-bromo-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one

[0402] Di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (185 mg) was added to a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.64 mg) in degassed THF (2 mL) under an argon atmosphere at room temperature. To the mixture was added dbbpy (7.8 mg) under an argon atmosphere at room temperature. To the mixture was added a mixture of 4-(3-bromo-4-fluorophenoxy)tetrahydro-2H-pyran (200 mg) and THF (1 mL) under an argon atmosphere at room temperature. The mixture was then stirred for 40 minutes under an argon atmosphere. The mixture was stirred at 80°C for 3 hours. The mixture was concentrated under reduced pressure. A mixture of the obtained residue (292 mg), 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one (59.2 mg), copper(II) acetate (79 mg), pyridine (0.047 ml), and acetonitrile (3 mL) was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (5.60 mg).

[0403] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.3 Hz), 1.50-1.62 (2H, m), 1.89-1.98 (2H, m), 3.38-3.56 (4H, m), 3.84 (2H, dt, J = 11.6, 4.2 Hz), 4.02-4.10 (2H, m), 4.64 (1H, dt, J = 8.8, 4.6 Hz), 6.28 (1H, t, J = 6.8 Hz), 7.15-7.32 (3H, m), 7.46 (1H, dd, J = 5.3, 3.0 Hz), 7.52-7.56 (2H, m). Example 27 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(propan-2-yl)phenyl}pyridin-2(1H)-one A) 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenol

[0404] A mixture of 5-bromo-2-fluorophenol (5.00 g), (2R)-2-methylmorpholine hydrochloride (5.40 g), palladium(II) acetate (0.588 g), BINAP (1.63 g), sodium tert-butoxide (10.1 g), and toluene (250 mL) was stirred at 120 °C for 4 hours under a nitrogen atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.10 g).

[0405] MS: [M+H] + 212.1 B) 2-Fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl trifluoromethanesulfonate

[0406] To a mixture of 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenol (1.08 g) and pyridine (8 mL), a solution of trifluoromethanesulfonic anhydride (1.12 mL) in toluene (4 mL) was added dropwise at 0°C over 5 minutes. The mixture was warmed to room temperature, stirred at the same temperature overnight, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. (ethyl acetate / hexane) to give the title compound (1.30 g).

[0407] MS: [M+H] + 344.0 C) (2R)-4-[4-fluoro-3-(prop-1-en-2-yl)phenyl]-2-methylmorpholine

[0408] A mixture of 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl trifluoromethanesulfonate (1.00 g), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.979 g), PdCl2 (dppf)·CHCl2 (0.238 g), sodium carbonate (0.617 g), DME (10 mL), and water (3 mL) was stirred at 120 °C for 12 hours under a nitrogen atmosphere. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.145 g).

[0409] MS: [M+H] + 236.1 D) (2R)-4-[4-fluoro-3-(propan-2-yl)phenyl]-2-methylmorpholine

[0410] A mixture of (2R)-4-[4-fluoro-3-(prop-1-en-2-yl)phenyl]-2-methylmorpholine (145 mg), 10% palladium-carbon (30 mg), and EtOH (8 mL) was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (144 mg).

[0411] MS: [M+H] + 238.2 E) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(propan-2-yl)phenyl}pyridin-2(1H)-one

[0412] A mixture of (2R)-4-[4-fluoro-3-(propan-2-yl)phenyl]-2-methylmorpholine (144 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (169 mg), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (8.04 mg), dbbpy (6.51 mg), and 2-methoxy-2-methylpropane (2 mL) was irradiated with microwaves at 80 °C for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Acetonitrile (2 mL) was added to the resulting residue (Solution A). A mixture of Solution A (1 mL), 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one (62.0 mg), copper(II) acetate (111 mg), and pyridine (97.0 mg) was stirred at 60° C. for 12 hours. Solution A (1 mL) was further added to the mixture, and the mixture was stirred at 60° C. for an additional 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and then further purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (19.0 mg).

[0413] 1 H NMR (400 MHz, CDCl3) δ 1.22-1.25 (3H, m), 1.28 (6H, d, J = 7.0 Hz), 1.47 (3H, t, J = 7.3 Hz), 2.48 (1H, t, J = 10.9 Hz), 2.78-2.86 (1H, m), 3.21-3.39, (3H, m), 3.69-3.81 (4H, m), 3.95-4.03 (1H, m), 4.13 (2H, q, J = 7.3 Hz), 6.16 (1H, t, J = 6.8 Hz), 6.66 (1H, dd, J = 5.6, 2.9 Hz), 6.85 (1H, dd, J = 5.3, 2.9 Hz), 7.17 (2H, br t, J = 8.1 Hz), 7.35 (1H, s), 7.40 (1H, s). Example 31 1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one A) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoro-2-methoxypyridine

[0414] To a mixture of 2,6-difluoro-3-iodopyridine (4.0 g) and methanol (40 mL), a 28% sodium methoxide / methanol solution (3.2 g) was added at 0 °C. The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a mixture of 6-fluoro-3-iodo-2-methoxypyridine and 2-fluoro-3-iodo-6-methoxypyridine (4.0 g). A mixture of the resulting mixture (4.0 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (6.0 g), PdCl2(dppf)·CHCl2 (0.65 g), potassium acetate (4.65 g), and DME (80 mL) was stirred at 100 °C for 36 hours under a nitrogen atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a mixture of 6-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 2-fluoro-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. A mixture of the resulting mixture, 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (4.3 g), PdCl(dppf) CHCl (1.3 g), cesium carbonate (25.7 g), DME (70 mL), and water (15 mL) was stirred at 90 °C for 4 hours under a nitrogen atmosphere. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give a mixture (2.3 g) of the title compound and 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-fluoro-6-methoxypyridine.

[0415] MS: [M+H] + 236.1 B) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one

[0416] A mixture of 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoro-2-methoxypyridine (1.0 g) obtained in Step A) and 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-fluoro-6-methoxypyridine, trimethylsilyl chloride (2.31 g), sodium iodide (0.64 g), and acetonitrile (15 mL) was irradiated with microwaves at 180 °C for 4 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a mixture of the title compound and 5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one (0.25 g).

[0417] MS: [M+H] + 222.1 C) (2R)-4-(3-chlorophenyl)-2-methylmorpholine

[0418] 1-Chloro-3-iodobenzene (5 g), (2R)-2-methylmorpholine hydrochloride (3.2 g), palladium(II) acetate (0.47 g), BINAP (1.3 g), sodium A mixture of ammonium tert-butoxide (8.1 g) and toluene (250 mL) was stirred at 120° C. for 4 hours under a nitrogen atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.8 g).

[0419] MS: [M+H] + 212.1 D) (2R)-4-(3-cyclopropylphenyl)-2-methylmorpholine

[0420] A mixture of (2R)-4-(3-chlorophenyl)-2-methylmorpholine (1.80 g), cyclopropylboronic acid (2.19 g), palladium(II) acetate (0.19 g), tricyclohexylphosphine / toluene solution (20% content, 2.98 g), tripotassium phosphate (8.1 g), toluene (75 mL), and water (15 mL) was stirred at 120 °C for 12 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then further purified by HPLC (C18, mobile phase: water / acetonitrile (10 mM ammonium bicarbonate system)). The resulting fraction was concentrated under reduced pressure to give the title compound (0.83 g).

[0421] MS: [M+H] + 218.2 E) 1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one

[0422] A mixture of (2R)-4-(3-cyclopropylphenyl)-2-methylmorpholine (0.83 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-dioxaborolane (1.07 g), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (50.6 mg), dbbpy (41.0 mg), and 2-methoxy-2-methylpropane (12 mL) was heated under microwave irradiation at 80°C for 1 hour. To the mixture were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (0.5 g), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (50.6 mg), and dbbpy (41.0 mg), and the mixture was stirred under a nitrogen atmosphere at 40° C. for 12 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the resulting residue, 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one obtained in Step B) and 5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one (0.21 g), pyridine (0.31 mL), and acetonitrile (2 mL) was added copper(II) acetate (0.52 g) at room temperature. The mixture was stirred at 40°C for 48 hours and then at room temperature for 72 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)). The resulting fraction was concentrated under reduced pressure to give the title compound (4.8 mg).

[0423] 1 H NMR (300 MHz, CDCl3) δ 0.70-0.73 (2H, m), 0.92-0.98 (2H, m), 1.23 (3H, d, J = 6.24 Hz), 1.47 (3H, t, J = 7.2 Hz), 1.84-1.93 (1H, m), 2.52 (1H, t, J = 10.9 Hz), 2.86 (1H, td, J = 11.9, 3.4 Hz), 3.42 (2H, br t, J = 12.8 Hz), 3.66 (2H, s), 3.68-3.80 (2H, m), 3.93-4.03 (1H, m), 4.08-4.18 (2H, m), 5.82 (1H, dd, J = 7.7, 4.3 Hz), 6.42-6.45 (1H, m), 6.53 (1H, t, J = 2.1 Hz), 6.70-6.73 (1H, m), 7.18 (1H, dd, J = 8.5, 7.7 Hz), 7.35 (1H, s), 7.39 (1H, s).

[0424] The compounds of the examples are shown in Table 1. MS in Table 1 indicates the measured value. The compounds in Table 1 were prepared according to the methods shown in the above examples or similar methods. Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Reference example 1 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one [ka] A) (2R)-4-[4-fluoro-3-nitro-5-(trifluoromethyl)phenyl]-2-methylmorpholine

[0425] A mixture of 5-bromo-2-fluoro-1-nitro-3-(trifluoromethyl)benzene (5.00 g), (2R)-2-methylmorpholine hydrochloride (2.39 g), BINAP (1.08 g), palladium(II) acetate (0.390 g), cesium carbonate (17.0 g), and toluene (40 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. Insoluble matter was removed by filtration through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.85 g).

[0426] MS: [M+H] + 309.2. B) 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)aniline

[0427] A mixture of (2R)-4-[4-fluoro-3-nitro-5-(trifluoromethyl)phenyl]-2-methylmorpholine (1.85 g), 10% palladium-carbon (0.319 g), and EtOH (60 mL) was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.67 g).

[0428] MS: [M+H] + 279.2. C) N-(2,2-dimethoxyethyl)-N'-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}urea

[0429] To a mixture of 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)aniline (1.07 g) and THF (30 mL), bis(trichloromethyl)carbonate (0.571 g) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. 2,2-Dimethoxyethanamine (0.404 g) and triethanolamine (0.389 g) were added to the mixture, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.25 g).

[0430] MS: [M+H] + 410.1. D) 1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one

[0431] To a mixture of N-(2,2-dimethoxyethyl)-N'-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}urea (1.25 g), CH3CN (20 mL), and water (mL) was added TFA (15.4 g). The mixture was stirred at 60°C for 3 hours, and then the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (722 mg).

[0432] MS: [M+H] + 346.2. E) Ethyl 1-ethyl-1H-pyrazole-4-carboxylate

[0433] A mixture of potassium carbonate (197 g), ethyl 1H-pyrazole-4-carboxylate (100 g), ethyl iodide (122 g), and DMF (250 mL) was stirred at room temperature overnight. The mixture was added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (121 g).

[0434] 1 H NMR (300 MHz, DMSO-d6) δ 1.26 (3H, t, J = 7.2 Hz), 1.37 (3H, t, J = 7.2 Hz), 4.19 (4H, m), 7.84 (1H, s), 8.33 (1H, s). F) (1-ethyl-1H-pyrazol-4-yl)methanol

[0435] A mixture of ethyl 1-ethyl-1H-pyrazole-4-carboxylate (48.0 g) and THF (100 mL) was added to a mixture of lithium aluminum hydride (16.3 g) and THF (400 mL) at 0-10°C, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with THF (150 mL) and cooled to 0°C. Sodium sulfate decahydrate (110 g) was added at 0-10°C, and the mixture was stirred at room temperature for 1 hour. Impurities were removed by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (29.9 g).

[0436] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.3 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.32 (2H, d, J = 5.3 Hz), 4.77 (1H, t, J = 5.5 Hz), 7.32 (1H, s), 7.59 (1H, s) G) 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride

[0437] To a mixture of (1-ethyl-1H-pyrazol-4-yl)methanol (2.33 g) and CH3CN (20 mL), thionyl chloride (4.39 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. The mixture was concentrated to give the title compound (3.23 g).

[0438] 1 H NMR (300 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.2 Hz), 4.10 (2H, q, J = 7.4 Hz), 4.69 (2H, s), 7.50 (1H, s), 7.85 (1H, s), 12.32 (1H, bs). H) 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one

[0439] To a mixture of sodium hydride (60% content, 29.0 mg) and DMF (3 mL) was added 1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one (100 mg) at room temperature. After stirring the mixture at room temperature for 30 minutes, a mixture of 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (79 mg) and DMF (2 mL) and sodium iodide (43.4 mg) was added and stirred overnight at room temperature. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (70.0 mg).

[0440] 1 H NMR (300 MHz, DMSO-d6) δ 1.14 (3H, d, J = 6.0 Hz), 1.34 (3H, t, J = 7.2 Hz), 2.27-2.47 (1H, m), 2.63-2.74 (1H, m), 3.52-3.73 (4H, m), 3.86-3.95 (1H, m), 4.09 (2H, q, J = 7.3 Hz), 4.61 (2H, s), 6.74-6.79 (2H, m), 7.19 (1H, dd, J = 4.9, 3.4 Hz), 7.34 (1H, dd, J = 6.0, 3.0 Hz), 7.43 (1H, s), 7.73 (1H, s). Test Example 1 Measurement of the inhibition rate of IP1 amount at 30 μM of the compound of Reference Example 1 in GPR139-expressing CHO cells

[0441] To evaluate the activity of compounds via GPR139, we measured changes in IP1 levels in GPR139-expressing CHO cells. GPR139 is a Gq-coupled receptor that modulates intracellular calcium (Liu C et al., Mol Pharmacol. 2015 Nov;88(5):911-25). Modulation of GPR139 activity alters the production of IP1, a stable metabolite of the second messenger IP3. Because GPR139 is considered constitutively active when recombinantly expressed in mammalian cells, compounds with GPR139 receptor inverse agonism are expected to reduce IP1 production.

[0442] IP1 measurements were performed using the IP-ONE HTRF Assay Kit (cis-bio) and stably GPR139-transfected CHO-TREx (Life Technologies) cells. CHO-TREx cells expressed human GPR139 via a tetracycline-inducible element. Cells were cultured in F12K medium containing 10% tetracycline-free FBS. Human GPR139 expression was induced for 17 hours at 37°C and 5% CO2 in the presence of 2 μg / mL doxycycline (Clontech, 631311) in growth medium the day before the assay. On the day of the assay, cells were washed with 10 mL of PBS, detached with TrypLE Express (Life Technologies), pelleted by centrifugation at 1,000 rpm, and resuspended in stimulation buffer (cis-bio, provided with the IP-ONE HTRF Assay Kit).

[0443] Compounds were diluted with stimulation buffer and added at 4 μL to a 384-well white assay plate (greiner). Cell suspension was added to each well at 2000 cells per well, and the assay plate was incubated at 37°C for 40 minutes. Equal volumes of IP1-d2 and Ab-Cryp solutions (both included in the cis-bio IP-ONE HTRF Assay Kit) prepared with lysis buffer (included in the cis-bio IP-ONE HTRF Assay Kit) were mixed, and 4 μL was added to the assay plate and incubated at room temperature for 1 hour. Fluorescence intensities at two wavelengths were measured using the HTRF setting on an Envision (PerkinElmer) instrument, and the ratio was calculated as {(signal 665 nm) / (signal 615 nm)} × 10000. When the vehicle concentration of 0% and the IP1 concentration of 0 were set to 100%, the inhibition rate of IP1 at 30 μM of the compound in Reference Example 1 was 84%.

[0444] The compound of Reference Example 1 inhibited the amount of IP1, a stable metabolite of IP3, a second messenger downstream of GPR139 signal transduction, in GPR139-expressing CHO cells. That is, the compound of Reference Example 1 has a GPR139 receptor inverse agonist effect. Test Example 2 Measurement of IP1 inhibition rate in GPR139-expressing CHO cells (inverse agonist assay)

[0445] The activity of the compounds of Examples 20 to 33 was measured by measuring the IP1 amount inhibition rate in the same manner as in Test Example 1. The IP1 amount inhibition rate of the compound of Reference Example 1 in Test Example 1 was set as 100%, and the results are shown in Table 2 as relative values. Table 2 [Table 2]

[0446] As shown in Table 2, the compounds of the present disclosure inhibited the amount of IP1, a stable metabolite of IP3, a second messenger downstream of GPR139 signaling, in GPR139-expressing CHO cells. That is, the compounds of the present disclosure have GPR139 receptor antagonistic activity (inverse agonistic activity). Formulation example

[0447] In some embodiments, medicaments containing the compounds of the present disclosure as active ingredients can be prepared using the following non-limiting formulation examples. Table 3 [Table 3]

[0448] The total amount of (1), (2), and (3) is mixed with 5 mg of (4) and granulated, and then the remaining 5 mg of (4) is added thereto, and the entire mixture is encapsulated in a gelatin capsule. Table 4 [Table 4]

[0449] The total amount of (1), (2), and (3) is mixed with 20 mg of (4) and 2.5 mg of (5), and granulated. The remaining 10 mg of (4) and 2.5 mg of (5) are then added to the granules, and the mixture is compressed to form tablets. The present invention provides, for example, the following items. (Item 1) Compounds of formula (I) [ka] or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] and Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring; Ring A 2 is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; Ring B is a halogen atom and an optionally substituted C 1-6 a pyridone ring optionally further substituted by 1 to 3 substituents selected from the group consisting of R 2 and R 3 are each independently selected from a hydrogen atom and a substituent; R 4a and R 4b are each independently selected from the substituents, Ring C is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles. (Item 2) The compound is a compound of formula (I') [ka] and pharmaceutically acceptable salts thereof, wherein: X is CH or N; Y is CH or N; Z is a bond, -O-, or -OR 9a - * , -NH-, and -N(R 9b )R 9a - * Selected from, here * indicates the point of attachment to ring D, Ring C is selected from 5-membered monocyclic aromatic heterocycles; Ring D is a 6- to 8-membered aromatic ring, a 5- to 8-membered monocyclic aromatic heterocycle, C 3-8 selected from a cycloalkyl group and a 5- to 8-membered heterocyclic group; Each R 7a are independently cyano, halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein the C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; Each R 8a are independently halogen, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein the C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted with 1 to 4 halogen atoms; R 9a is C 1-3 selected from alkyl groups, R 9b is a hydrogen atom and C 1-3 selected from alkyl groups, Each R 10a are independently a halogen atom and C 1-3 selected from alkyl groups, Each R 11a independently, C 1-3 selected from alkyl groups, m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, or 2; p is 0, 1, or 2.] (Item 3) [ka] but, [ka] (In the formula, Z, R 7a , R 8a , m, and n are as defined in item 2. 3. The compound according to item 2, or a pharmaceutically acceptable salt thereof, (Item 4) Z is a bond, -O-, -NH-, -NHCH2- * , and -N(CH3)CH2- * 4. The compound according to item 2 or 3, or a pharmaceutically acceptable salt thereof, selected from: (Item 5) 5. The compound or pharmaceutically acceptable salt according to any one of items 2 to 4, wherein Z is a bond. (Item 6) 5. The compound or pharmaceutically acceptable salt according to any one of items 2 to 4, wherein Z is —O—. (Item 7) Z is -NHCH2- * 5. The compound or pharmaceutically acceptable salt thereof according to any one of items 2 to 4, wherein: (Item 8) Z is -N(CH3)CH2- * 5. The compound or pharmaceutically acceptable salt thereof according to any one of items 2 to 4, wherein: (Item 9) [ka] but, [ka] (In the formula, X, Y, ring D, R 7a , R 8a , m, and n are as defined in item 2. 3. The compound according to item 2, or a pharmaceutically acceptable salt thereof, (Item 10) 10. The compound or pharmaceutically acceptable salt thereof according to any one of items 2 to 9, wherein ring D is selected from benzene, morpholine, oxane, piperidine, and cyclobutane. (Item 11) [ka] but, [ka] (In the formula, X, Y, R 7a , R 8a , m, and n are as defined in item 2. The compound according to item 2, or a pharmaceutically acceptable salt thereof, wherein: (Item 12) 12. The compound or pharmaceutically acceptable salt according to any one of items 2 to 11, wherein X is CH. (Item 13) 12. The compound according to any one of items 2 to 11, wherein X is N, or a pharmaceutically acceptable salt thereof. salt. (Item 14) 14. The compound or pharmaceutically acceptable salt according to any one of items 2 to 13, wherein Y is CH. (Item 15) 14. The compound or pharmaceutically acceptable salt according to any one of items 2 to 13, wherein Y is N. (Item 16) [ka] but, [ka] (In the formula, X, R 7a , R 8a , m, and n are as defined in item 2. 3. The compound according to item 2, or a pharmaceutically acceptable salt thereof, (Item 17) [ka] but, [ka] (In the formula, X, R 7a , R 8a , m, and n are as defined in item 2. 3. The compound according to item 2, or a pharmaceutically acceptable salt thereof, (Item 18) 18. The compound or pharmaceutically acceptable salt according to item 16 or 17, wherein X is CH. (Item 19) 18. The compound or pharmaceutically acceptable salt according to item 16 or 17, wherein X is N. (Item 20) R 2 and R 3 and are both hydrogen atoms, or a pharmaceutically acceptable salt thereof. (Item 21) Ring C is [ka] 21. The compound or pharmaceutically acceptable salt according to any one of items 2 to 20, wherein (Item 22) Ring C is [ka] 22. The compound or pharmaceutically acceptable salt according to any one of items 2 to 21, wherein: (Item 23) Each R 7a are independently halogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 alkoxy groups, wherein the C 3-6 Cycloalkyl, C 1-6 Alkyl, and C 1-6 23. The compound or pharmaceutically acceptable salt according to any one of items 2 to 22, wherein the alkoxy group is optionally substituted with 1 to 4 halogen atoms. (Item 24) o is 1 and R 10a24. The compound or pharmaceutically acceptable salt according to any one of items 2 to 23, wherein is methyl. (Item 25) o is 1 and R 10a 24. The compound or pharmaceutically acceptable salt according to any one of items 2 to 23, wherein is a fluorine atom. (Item 26) 24. The compound or pharmaceutically acceptable salt according to any one of items 2 to 23, wherein o is 0. (Item 27) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-4'-(trifluoromethyl)-2H-[1,2'-bipyridine]-3'-carbonitrile; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-4'-(2,2,2-trifluoroethoxy)-2H-[1,2'-bipyridine]-3'-carbonitrile; 4'-(2,2-difluoroethoxy)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6'-(4-fluorophenyl)-6-methyl-2-oxo-4'-(trifluoromethyl)-2H-[1,2'-bipyridine]-3'-carbonitrile; 4'-(Difluoromethyl)-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]methyl ethyl]-6'-(4-fluorophenyl)-2-oxo-2H-[1,2'-bipyridine]-3'-carbonitrile; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5'-methyl-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}pyridin-2(1H)-one; 6'-[2-(difluoromethyl)morpholin-4-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-4-methyl-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-5-methyl-6'-[(2R)-2-methylmorpholin-4-yl]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3'-fluoro-6'-[(oxan-4-yl)oxy]-4'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[4-{[(1-fluorocyclobutyl)methyl]amino}-6-(trifluoromethyl)pyrimidin-2-yl]pyridin-2(1H)-one; 1-[4-{[(3,3-difluorocyclobutyl)methyl]amino}-6-(trifluoromethyl)pyrimidin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-[4-{[(3,3-difluorocyclobutyl)methyl](methyl)amino}-6-(trifluoromethyl)pyrimidin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-[4-{[(1-fluorocyclobutyl)methyl](methyl)amino}-6-(trifluoromethyl)pyrimidin-2-yl]pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-[3-cyclopropyl-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-{3-bromo-2-fluoro-5-[(oxan-4-yl)oxy]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethoxy)phenyl}pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}pyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-fluoropyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(propan-2-yl)phenyl}pyridin-2(1H)-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(2,2,2-trifluoroethyl)phenyl}pyridin-2(1H)-one; 1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-methylpyridin-2(1H)-one; 1-[3-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]pyridin-2(1H)-one; 1-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-fluoropyridin-2(1H)-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methylpyridin-2(1H)-one; and 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methylpyridin-2(1H)-one or a pharmaceutically acceptable salt of any of said compounds. (Item 28) At least one compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 27, and at least one pharmaceutically acceptable carrier A pharmaceutical composition comprising: (Item 29) 28. A method for treating or preventing a disease in a mammal in need thereof, comprising administering to said mammal at least one compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 27. (Item 30) 30. The method according to item 29, wherein the disease is selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. (Item 31) 30. The method of item 28 or 29, wherein the mammal is a human. (Item 32) 32. The method according to any one of items 29 to 31, further comprising the step of administering at least one concomitant drug to the mammal.

Claims

[Claim 1] The invention described in the specification.

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