1-((1h-pyrazol-4-yl)methyl)-3-(phenyl)-1,3-dihydro-2h-imidazol-2-one derivatives and related compounds as GPR139 antagonists for treatment of depression and the like

Abstract

To provide 1-((1H-pyrazol-4-yl)methyl)-3-(phenyl)-1,3-dihydro-2H-imidazol-2-one derivatives and related compounds as GPR139 antagonists for treatment of depression and the like.SOLUTION: The present invention refers to compounds of formula (I). The present invention also relates to compounds of formula (I) for use as G Protein coupled Receptor 139 (GPR139) antagonists in methods of medical treatment of, e.g., depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. Exemplary compounds are, e.g., 1-((1H-pyrazol-4-yl)methyl)-3-(phenyl)-1,3-dihydro-2H-imidazol-2-one derivatives and related compounds. The present specification discloses the synthesis and characterization of exemplary compounds, pharmacological data thereof, as well as exemplary tablet formulations comprising the compounds of the invention.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority from Japanese Patent Application No. 2020-090110, filed May 22, 2020, the entire contents of which are incorporated herein by reference.

[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 the treatment or prevention of 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 human, mouse, and rat GPR139 protein sequences share over 94% identity at the amino acid level. Furthermore, GPR139 expression is high in the central nervous system, particularly in the striatum, septal area, hypothalamus, and habenula, but low in peripheral tissues. The high sequence homology among different species and its predominant expression in the brain 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). The habenula, one of the brain regions where GPR139 is highly expressed, is known to regulate stress responses and learning; the habenula is thought to be overactivated in patients with depression. In patients who also exhibit treatment-resistant neurological symptoms, intense stimulation of the habenula using deep brain stimulation (DBS) has been reported to improve scores on the HAMD21 scale, which assesses depressive symptoms (Biol Psychiatry 2010 67:e9-e11). Furthermore, in 20 patients with treatment-resistant habenula, DBS was shown to improve scores on the HAMD21 scale, which assesses depressive symptoms (Biol Psychiatry 2010 67:e9-e11). In patients with treatment-resistant depression, positron emission tomography (PET) was used to examine brain regions where neural activity changed after ketamine administration. This revealed that glucose metabolism, which reflects neural activity, was suppressed in brain regions such as the habenula, leading to improvement in depressive symptoms (Biol Psychiatry 2013 73(12): 1213-1221). In animal studies, direct administration of ketamine to the habenula suppressed neural activity in the habenula and improved anhedonic-like behavior (Nature 2018 554(7692):317-322). Taken together, these results suggest that GPR139 activity is involved in the regulation of the habenula's neuronal activity. This suggests that it can affect meridian activity and dramatically alter 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, and attention deficit hyperactivity disorder. Therefore, there is a need for novel compounds that exhibit GPR139 receptor antagonism.

[0006] Certain heterocyclic compounds may be useful as antagonists of the GPR139 receptor. WO 2008 / 094556 describes a compound represented by the formula: [ka] (wherein each symbol is as defined in WO 2008 / 094556) This compound has a TGF3 inhibitory effect and may be useful for treating neuronal demyelination in multiple sclerosis, Alzheimer's disease, cerebrovascular disease, etc. Furthermore, WO 2008 / 089005 discloses compounds represented by the following formula: [ka] (wherein each symbol is as defined in WO 2008 / 089005) The compound exhibits renin inhibitory activity and may be useful in the treatment of cardiovascular disease, hypertension, congestive heart failure, myocardial infarction, renal protection, inflammation, neurological disorders, cancer, etc.

[0007] The following compound is also known in the art under the CAS number 1174845-16-9: [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2008 / 094556 [Patent Document 2] International Publication No. 2008 / 089005 [Non-patent literature]

[0009] [Non-Patent Document 1] Journal of Biomolecular Screen 2009 14:789-797 [Non-patent document 2] Biochemical and Biophysical Research Communications 331 (2005) 363-369 [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 Summary of the Invention [Means for solving the problem]

[0010] Disclosed herein are compounds that exhibit GPR139 receptor antagonism and 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.

[0011] A compound of formula (I) in its salt form (hereinafter also referred to as compound (I)) [ka] is disclosed herein, wherein: R 1teeth, [ka] is a group represented by 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; Z is CR 2 or N, R 2 and R 3 is a hydrogen atom, a halogen atom, or an optionally halogenated C 1-6 are each independently selected from alkyl groups, R 4 and R 5 are each independently selected from a hydrogen atom and a substituent; R 6a and R 6b are each independently selected from the substituents; Ring B is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; provided that the compound or salt is not 1-(3-chlorophenyl)-3-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-dihydro-2H-imidazol-2-one or a salt thereof). DETAILED DESCRIPTION OF THE INVENTION

[0012] In some embodiments, R 1 teeth, [ka] is a group represented by

[0013] In some embodiments, R 1 teeth, [ka] wherein: X is CH or N; Y is CH or N; L is a bond, -O-, -OR 9a - * , -NH- and -N(R 9b )R 9a - * is selected from * represents the point of attachment to ring C, Ring C is a 6- to 8-membered aromatic ring, a 5- to 8-membered monocyclic aromatic heterocycle, C 3-8 selected from cycloalkyl groups and 5- to 8-membered heterocyclic groups; R 9a is C 1-3 alkyl groups, R 9b is a hydrogen atom and C 1-3 alkyl groups, R 10a are halogens, C 1-6 Alkyl and C 1-6 independently selected from alkoxy groups, C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted by 1 to 4 halogen atoms; R 11a are cyano, halogen, and C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 independently selected from alkoxy groups, C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted by 1 to 4 halogen atoms; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3.

[0014] In some embodiments, L is a bond, —O—, —NH—, —NHCH 2 — * and -N(CH3)CH2- * and all other variables are as defined above.

[0015] In some embodiments, L is a bond, and all other variables are as defined above. In some embodiments, L is -O-, and all other variables are as defined above. In some embodiments, L is -NH-, and all other variables are as defined above. In some embodiments, L is -NHCH2- * and all other variables are as defined above. In some embodiments, L is -N(CH3)CH2- * and all other variables are as defined above.

[0016] In some embodiments, X is N, Y is CH, and all other variables are as defined above.

[0017] In some embodiments, X is N, Y is N, and all other variables are as defined above. This is exactly what is being said.

[0018] In some embodiments, X is CH and Y is CH, and all other variables are as defined above.

[0019] In some embodiments, Ring C is selected from benzene, morpholine, oxane, piperidine, and cyclobutane, and all other variables are as defined above.

[0020] In some embodiments, Ring C is benzene, and all other variables are as defined above. In some embodiments, Ring C is morpholine, and all other variables are as defined above. In some embodiments, Ring C is oxane, and all other variables are as defined above. In some embodiments, Ring C is piperidine, and all other variables are as defined above. In some embodiments, Ring C is cyclobutane, and all other variables are as defined above.

[0021] In some embodiments, R 1 teeth, [ka] and X, Y, ring C, R 10a , R 11a , m and n are as defined above.

[0022] In some embodiments, X is N, Y is CH, and all other variables are as defined above.

[0023] In some embodiments, X is N and Y is N, and all other variables are as defined above.

[0024] In some embodiments, X is CH and Y is CH, and all other variables are as defined above.

[0025] In some embodiments, Ring C is selected from benzene, morpholine, oxane, piperidine, and cyclobutane, and all other variables are as defined above.

[0026] In some embodiments, Ring C is benzene, and all other variables are as defined above. In some embodiments, Ring C is morpholine, and all other variables are as defined above. In some embodiments, Ring C is oxane, and all other variables are as defined above. In some embodiments, Ring C is piperidine, and all other variables are as defined above. In some embodiments, Ring C is cyclobutane, and all other variables are as defined above.

[0027] In some embodiments, R 1 teeth, [ka] and R 10a , R 11a , m and n are as defined above.

[0028] In some embodiments, R 1 teeth, [ka] and R 11a and n is as defined above.

[0029] In some embodiments, R 1 teeth, [ka] and X, R are groups represented by 10a , R 11a , m and n are as defined above. In some embodiments, X is CH. In some embodiments, X is N.

[0030] In some embodiments, R 1 teeth, [ka] and X, R are groups represented by 10a , R 11a , m and n are as defined above. In some embodiments, X is CH.

[0031] In some embodiments, R 1 teeth, [ka] and X, Y, and R are groups represented by 10a , R 11a , m and n are as defined above. In some embodiments, X is N and Y is CH.

[0032] In some embodiments, R 1 teeth, [ka] and L, R are groups represented by 10a , R 11a , m and n are as defined above. In some embodiments, L is -NHCH2- * In some embodiments, L is -N(CH3)CH2- * is.

[0033] In some embodiments, R 1 teeth, [ka] and L, R are groups represented by 10a , R 11a , m and n are as defined above. In some embodiments, L is -NHCH2- * In some embodiments, L is -N(CH3)CH2- * is.

[0034] In some embodiments, R 1 teeth, [ka] wherein: R 10a are halogen atoms, C 1-6 Alkyl and C 1-6 independently selected from alkoxy groups, C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted by 1 to 4 halogen atoms; R 11a are cyano, halogen, and C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 independently selected from alkoxy groups, C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted by 1 to 4 halogen atoms; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3.

[0035] In some embodiments, R 10a are halogen atoms and C 1-6 independently selected from alkyl groups, C 1-6 The alkyl group may be substituted with 1 to 4 halogen atoms, and R 11a are cyano, halogen, and C 1-6 Alkyl and C 1-6 independently selected from alkoxy groups, C 1-6 Alkyl and C 1-6 The alkoxy 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.

[0036] In some embodiments, R 1 teeth, [ka] wherein: X is CH or N; R 10a are halogen atoms, C 1-6 Alkyl and C 1-6 independently selected from alkoxy groups, C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted by 1 to 4 halogen atoms; R 11a are halogens, C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 independently selected from alkoxy groups, C 3-6 Cycloalkyl, C 1-6 Alkyl and C 1-6 the alkoxy group is optionally substituted by 1 to 4 halogen atoms; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3.

[0037] In some embodiments, R 1 teeth, [ka] is a group represented by

[0038] In some embodiments, R 4 and R 5 is hydrogen and C 1-3 In some embodiments, R 4 and R 5 are both hydrogen atoms.

[0039] In some embodiments, Ring B is [ka] and R 12a are respectively, C 1-3 alkyl groups; and p is 0, 1, or 2.

[0040] In some embodiments, Ring B is [ka] and R 12a is C 1-3 In some embodiments, R 11a is ethyl.

[0041] In some embodiments, compounds of Formula (I) and pharmaceutically acceptable salts thereof are provided for use in the treatment or prevention of a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. In some embodiments, compounds selected from Examples 1-167 and pharmaceutically acceptable salts thereof are provided for use in the treatment or prevention of a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, 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 compositions comprise 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, there are provided compounds selected from Examples 1-167 and pharmaceutically acceptable salts thereof for use in therapy.

[0044] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof 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 disorders, pain, and attention deficit hyperactivity disorder. In some embodiments, when used simultaneously, the compound or a pharmaceutically acceptable salt and at least one other drug are present in separate pharmaceutical compositions. In some embodiments, when used simultaneously, the compound or a pharmaceutically acceptable salt and at least one other drug are present together in the same pharmaceutical composition. In some embodiments, the compound or a pharmaceutically acceptable salt is selected from Examples 1-167 and pharmaceutically acceptable salts thereof.

[0045] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a combination drug are provided for use in 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. In some embodiments, the compound or a pharmaceutically acceptable salt thereof and the combination drug are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound or a pharmaceutically acceptable salt thereof and the combination drug are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound or a pharmaceutically acceptable salt thereof and the combination drug are prepared for simultaneous administration. In some embodiments, the compound or a pharmaceutically acceptable salt thereof and the combination drug are prepared for sequential administration. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is selected from Examples 1-167 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, there are provided pharmaceutical compositions comprising a compound selected from Examples 1-167 and 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 administering at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] When referring herein to a method of treatment or prevention (e.g., a method of treating or preventing a disease selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder) using one or more compounds (e.g., compounds of Formula (I) and pharmaceutically acceptable salts thereof), the following may be used: For example, one or more compounds for use in a method for treating and / or preventing 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, or attention deficit hyperactivity disorder. It should be understood that the above should be interpreted as referring to Non-limiting example embodiment 1:

[0049] Without limitation, some embodiments of the present disclosure include: 1. A compound of formula (I): [ka] or its salts (In the formula, R 1 teeth, [ka] is a group represented by 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; Z is CR 2 or N, R 2 and R 3 is a hydrogen atom, a halogen atom, or an optionally halogenated C 1- 6 alkyl groups, each independently selected from R 4 and R 5 are each independently selected from a hydrogen atom and a substituent; R 6a and R 6b are each independently selected from the substituents; Ring B is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; provided that the compound or salt is not 1-(3-chlorophenyl)-3-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-dihydro-2H-imidazol-2-one or a salt thereof). 2. A medicament comprising a compound according to embodiment 1 or a pharmaceutically acceptable salt thereof. 3. A medicament according to embodiment 2, which is a GPR139 receptor antagonist. 4. A medicament according to embodiment 2, which is a drug for preventing or treating depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, or attention deficit hyperactivity disorder. Non-limiting example embodiment 2:

[0050] Without limitation, some embodiments / items of the present disclosure include: 1. A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 teeth, [ka] is a group represented by 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; Z is CR 2 or N, R 2 and R 3 is a hydrogen atom, a halogen atom, or an optionally halogenated C 1-6 are each independently selected from alkyl groups, R 4 and R 5 are each independently selected from a hydrogen atom and a substituent; R 6a and R 6b are each independently selected from the substituents; Ring B is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; provided that the compound or pharmaceutically acceptable salt thereof is not 1-(3-chlorophenyl)-3-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-dihydro-2H-imidazol-2-one or a salt thereof. 2. R 1 but, [ka] is a group represented by Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring; R 6a but, (1) optionally substituted C 3-10 cycloalkyl group (2) optionally substituted C 6-14 aryl group (3) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (4) an optionally substituted 5- to 14-membered aromatic heterocyclic group (5) optionally substituted mono- or di-C 1-6 Alkylamino group (6) Optionally substituted NC 1-6 Alkyl-N-3 to 14-membered non-aromatic heterocyclic amino group (7) optionally substituted C 1-6 alkoxy group (8) optionally substituted C 6-14 aryloxy groups, and (9) an optionally substituted 3- to 14-membered non-aromatic heterocyclic oxy group Selected from: A compound according to item 1 or a pharmaceutically acceptable salt thereof. 3. R 1 but, [ka] is a group represented by Ring A 1 But the following: (a) a halogen atom, (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom, and (ii) a hydroxy group. 1-6 alkyl groups, (c) optionally halogenated C 1-6 alkoxy groups, (d) C optionally substituted by 1 to 3 halogen atoms 3-10 cycloalkyl groups, (e)C 2-6 alkenyl groups, and (f) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents independently selected from R 6a but, (1) C optionally substituted by 1 to 3 halogen atoms 3-10 cycloalkyl groups, (2) C optionally substituted by 1 to 3 halogen atoms 6-14 aryl groups, (3) a 3- to 14-membered non-aromatic heterocyclic group, (a) a halogen atom, and (b) optionally halogenated C 1-6 Alkyl group a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents independently selected from (4) 1 to 3 C 1-6 a 5- to 14-membered aromatic heterocyclic group optionally substituted by an alkyl group, (5) 1 to 3 C optionally substituted by 1 to 3 halogen atoms 3-10 Mono- or di-C optionally substituted by cycloalkyl groups 1-6 alkylamino groups, (6)NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino group, (7) C 1-6 an alkoxy group, (a)C 1-6 alkoxy groups, (b)C 3-10 cycloalkyl groups, and (c) a 3- to 14-membered non-aromatic heterocyclic group C optionally substituted by 1 to 3 substituents independently selected from 1-6 alkoxy groups, (8) C optionally substituted by 1 to 3 halogen atoms 6-14 aryloxy groups, and (9) 3- to 14-membered non-aromatic heterocyclic oxy group Selected from: 3. A compound or a pharmaceutically acceptable salt according to item 1 or 2. 4. R 1 but, [ka] is a group represented by Ring A 1 But the following: (1) A benzene ring: (a) a halogen atom, (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom, and (ii) a hydroxy group. 1-6 alkyl groups, (c) optionally halogenated C 1-6 alkoxy groups, (d) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (e)C 2-6 alkenyl groups, and (f) a piperidyl group optionally substituted by 1 to 3 halogen atoms a benzene ring which may be further substituted by 1 to 3 substituents independently selected from (2) a pyridine ring, (a) a halogen atom, (b) optionally halogenated C 1-6 alkyl groups, (c) optionally halogenated C 1-6 an alkoxy group, and (d)C 3-6 cycloalkyl group a pyridine ring optionally further substituted by 1 to 3 substituents independently selected from (3) One or two optionally halogenated C 1-6 A pyrimidine ring optionally further substituted with an alkyl group is selected from R 6a but, (1) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (2) a phenyl group optionally substituted by 1 to 3 halogen atoms, (3) a morpholinyl group, (a) a halogen atom, and (b) optionally halogenated C 1-6 Alkyl group a morpholinyl group optionally substituted by 1 to 3 substituents independently selected from (4) a piperidyl group optionally substituted by 1 to 3 halogen atoms, (5) a pyrrolidinyl group optionally substituted by 1 to 3 halogen atoms, (6) 4-oxa-7-azaspiro[2.5]octyl group, (7) 1 to 3 C 1-6 an imidazolyl group optionally substituted by an alkyl group; (8) 1 to 3 C optionally substituted by 1 to 3 halogen atoms 3-6 Mono- or di-C optionally substituted by cycloalkyl groups 1-6 alkylamino groups, (9)NC 1-6 alkyl-N-tetrahydropyranylamino group, (10)C 1-6 an alkoxy group, (a)C 1-6 alkoxy groups, (b) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (c) an oxetanyl group, and (d) a tetrahydrofuryl group, C optionally substituted by 1 to 3 substituents independently selected from 1-6 alkoxy groups, (11) a phenoxy group optionally substituted by 1 to 3 halogen atoms, and (12) Tetrahydropyranyloxy group Selected from: 3. A compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof. 5. [ka] is a group represented by [ka] is a group represented by R 6a is as defined in item 2, R 7a but, (a) a hydrogen atom, (b) a halogen atom, (c) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom, and (ii) a hydroxy group. 1-6 alkyl groups, (d) optionally halogenated C 1-6 alkoxy groups, (e) C optionally substituted by 1 to 3 halogen atoms 3-10 cycloalkyl groups, (f)C 2-6 alkenyl groups, and (g) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms is selected from R 8a but, (a) a hydrogen atom, (b) a halogen atom, and (c)C 1-6 Alkyl group Selected from: 3. A compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof. 6. [ka] is a group represented by [ka] is a group represented by R 6a is as defined in item 2, R 7a1 but, (a) a halogen atom, (b) C optionally substituted by 1 to 3 substituents independently selected from a halogen atom and a hydroxy group 1-6 alkyl groups, (c) optionally halogenated C 1-6 alkoxy groups, (d) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (e)C 2-6 alkenyl groups, and (f) a piperidyl group optionally substituted by 1 to 3 halogen atoms is selected from R 7a2 but, (a) a hydrogen atom, (b) optionally halogenated C 1-6 alkyl groups, (c) optionally halogenated C 1-6 an alkoxy group, and (d)C 3-6 cycloalkyl group is selected from R7a3 may be halogenated C 1-6 alkyl groups, R 8a1 but, (a) a hydrogen atom, (b) a halogen atom, and (c)C 1-6 Alkyl group is selected from R 8a2 but, (a) a hydrogen atom, (b) a halogen atom, and (c)C 1-6 Alkyl group Selected from: 3. A compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof. 7. [ka] is a group represented by [ka] is a group represented by R 6a is as defined in item 2, R 7a2 But halogenated C 1-6 alkyl groups, R 8a2 is selected from hydrogen atoms and halogen atoms; 3. A compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof. 8. [ka] is a group represented by [ka] is a group represented by R 6a is as defined in item 2, R 7a2 But halogenated C1-6 alkyl groups, R 8a2 is a hydrogen atom, 3. A compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof. 9. R 1 but, [ka] is a group represented by Ring A 1 But the following: (a) a halogen atom, and (b) Halogenated C 1-6 Alkyl group a pyridine ring optionally further substituted by one or two substituents independently selected from R 6a But 1 to 3 C 1-6 a morpholinyl group optionally substituted by an alkyl group; A compound according to item 1 or a pharmaceutically acceptable salt thereof. 10. R 1 but, [ka] is a group represented by Ring A 1 But one halogenated C 1-6 a pyridine ring further substituted with an alkyl group; R 6a But one C 1-6 morpholinyl groups substituted by alkyl groups; A compound according to item 1 or a pharmaceutically acceptable salt thereof. 11. R 1 but, [ka] is a group represented by Ring A 2 is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; R 6b may be substituted C 1-6 alkyl groups, A compound according to item 1 or a pharmaceutically acceptable salt thereof. 12. Ring A 2 and 1 to 3 optionally halogenated C 1-6 a 5-membered monocyclic aromatic heterocycle optionally further substituted by an alkyl group; R 6b But 1 to 3 C 3-10 C optionally substituted by a cycloalkyl group 1-6 alkyl groups, 12. A compound or a pharmaceutically acceptable salt according to item 1 or 11. 13. Ring A 2 and 1 to 3 optionally halogenated C 1-6 a pyrazole ring optionally further substituted with an alkyl group; R 6b But 1 to 3 C 3-6 C optionally substituted by a cycloalkyl group 1-6 alkyl groups, 12. A compound or a pharmaceutically acceptable salt according to item 1 or 11. 14. [ka] is a group represented by [ka] is a group represented by R 6b But 1 to 3 C 3-10 C optionally substituted by a cycloalkyl group 1-6 alkyl groups, R 7b may be halogenated C 1-6 alkyl groups, 12. A compound or a pharmaceutically acceptable salt according to item 1 or 11. 15. Ring B has 1 to 3 C 1-615. A compound or a pharmaceutically acceptable salt according to any one of items 1 to 14, wherein the compound or a pharmaceutically acceptable salt thereof is selected from a 5-membered monocyclic aromatic heterocycle optionally further substituted by an alkyl group. 16. Ring B has 1 to 3 C 1-6 16. A compound or a pharmaceutically acceptable salt according to any one of items 1 to 15, wherein the compound is selected from a pyrazole ring optionally further substituted with an alkyl group. 17. Ring B has one C 1-6 18. A compound or pharmaceutically acceptable salt according to any one of items 1 to 15, wherein Ring B is selected from the group consisting of: [ka] (In the formula, R 1c is a hydrogen atom and C 1-6 alkyl groups, R 2c and R 3c is a hydrogen atom and C 1-6 alkyl groups) 17. The compound or pharmaceutically acceptable salt according to any one of items 1 to 16, wherein 19. Ring B is [ka] (In the formula, R 1c is C 1-6 alkyl groups) 17. The compound or pharmaceutically acceptable salt according to any one of items 1 to 16, wherein 20. Z is CR 2 and R 2 is a hydrogen atom and optionally halogenated C 1-6 alkyl groups, 19. A compound or a pharmaceutically acceptable salt according to any one of items 1 to 19. 21. Z is CR 2 and R 2 However, hydrogen atoms and C1-3 alkyl groups, 21. A compound or a pharmaceutically acceptable salt according to any one of items 1 to 20. 22. Z is CR 2 and R 2 But C 1-3 alkyl groups, 22. A compound or a pharmaceutically acceptable salt according to any one of items 1 to 21. 23. A compound or pharmaceutically acceptable salt according to any one of items 1 to 19, wherein Z is N. 24. R 3 However, hydrogen atoms and C 1-3 24. A compound or a pharmaceutically acceptable salt according to any one of items 1 to 23, wherein the compound or the pharmaceutically acceptable salt is selected from alkyl groups. 25. R 3 But C 1-3 25. A compound or pharmaceutically acceptable salt according to any one of items 1 to 24, wherein the compound or pharmaceutically acceptable salt is selected from an alkyl group. 26. R 4 and R 5 However, hydrogen atoms and C 1-6 26. A compound or pharmaceutically acceptable salt according to any one of items 1 to 25, each independently selected from: alkyl groups. 27. R 4 and R 5 is a hydrogen atom and optionally substituted C 1-6 27. The compound or pharmaceutically acceptable salt according to any one of items 1 to 26, each independently selected from alkyl groups. 28. R 4 However, hydrogen atoms and C 1-6 alkyl groups, R 5 is a hydrogen atom, 28. A compound or a pharmaceutically acceptable salt according to any one of items 1 to 27. 29. R 4 and R 5 and are both hydrogen atoms. 30. A compound selected from Examples 1-167, or a pharmaceutically acceptable salt thereof. 31. At least one compound or pharmaceutically acceptable salt according to any one of items 1 to 30, and at least one pharmaceutically acceptable carrier A pharmaceutical composition comprising: 32. A method for treating or preventing a disease in a mammal in need thereof, comprising administering to the mammal at least one compound according to any one of items 1 to 30. 33. The method according to item 32, wherein the disease is selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. 34. The method according to item 32 or 33, wherein the mammal is a human. 35. Item 3, further comprising the step of administering at least one concomitant drug to the mammal. Any one of methods 2 to 34.

[0051] The definition of each of the substituents used herein is described in detail hereinafter. Unless otherwise specified, each substituent is defined as follows:

[0052] Non-limiting examples of "halogen atoms" herein include fluorine, chlorine, bromine and iodine.

[0053] In this specification, "C 1-6 Non-limiting examples of "alkyl groups" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0054] In the present specification, "optionally halogenated C 1-6 Non-limiting examples of "alkyl group" include C alkyl groups which may have 1 to 7, for example 1 to 5, halogen atoms.1-6 and alkyl groups, additional non-limiting examples of which include 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 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 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0058] In the present specification, "optionally halogenated C 3-10Non-limiting examples of "cycloalkyl groups" include C alkyl groups which may have 1 to 7, for example 1 to 5, halogen atoms. 3-10 Includes cycloalkyl groups, additional non-limiting examples of which include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

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

[0060] In this specification, "C 6-14 Non-limiting examples of "aryl groups" include phenyl, 1-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0061] In this specification, "C 7-16 Non-limiting examples of "aralkyl groups" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0062] In this specification, "C 1-6 Non-limiting examples of "alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0063] In the present specification, "optionally halogenated C 1-6 Non-limiting examples of "alkoxy groups" include C alkyl groups which may have 1 to 7, for example 1 to 5, halogen atoms. 1-6 Alkoxy groups, additional non-limiting examples of which include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy.

[0064] In this specification, "C 3-10 Non-limiting examples of "cycloalkyloxy groups" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0065] In this specification, "C 1-6 Non-limiting examples of "alkylthio groups" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

[0066] In the present specification, "optionally halogenated C 1-6 Non-limiting examples of "alkylthio groups" include C alkylthio groups which may have 1 to 7, for example 1 to 5, halogen atoms. 1-6 and alkylthio groups, further non-limiting examples of which include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0067] In this specification, "C 1-6 Non-limiting examples of "alkyl-carbonyl groups" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl.

[0068] In the present specification, "optionally halogenated C 1-6 Non-limiting examples of "alkyl-carbonyl group" include C alkyl groups optionally having 1 to 7, for example 1 to 5, halogen atoms. 1-6 Includes alkyl-carbonyl groups, additional non-limiting examples of which include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl.

[0069] In this specification, "C1-6 Non-limiting examples of "alkoxy-carbonyl groups" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

[0070] In this specification, "C 6-14 Non-limiting examples of "aryl-carbonyl groups" include benzoyl, Includes 1-naphthoyl and 2-naphthoyl.

[0071] In this specification, "C 7-16 Non-limiting examples of "aralkyl-carbonyl groups" include phenylacetyl and phenylpropionyl.

[0072] As used herein, non-limiting examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0073] As used herein, non-limiting examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0074] As used herein, "mono- or di-C 1-6 Non-limiting examples of "alkyl-carbamoyl groups" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[0075] As used herein, "mono- or di-C 7-16 Non-limiting examples of "aralkyl-carbamoyl groups" include benzylcarbamoyl and phenethylcarbamoyl.

[0076] In this specification, "C 1-6Non-limiting examples of "aralkylsulfonyl groups" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

[0077] In the present specification, "optionally halogenated C 1-6 Non-limiting examples of "alkylsulfonyl group" include C alkylsulfonyl groups which may have 1 to 7, for example, 1 to 5 halogen atoms. 1-6 and alkylsulfonyl groups, additional non-limiting examples of which include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0078] In this specification, "C 6-14 Non-limiting examples of "arylsulfonyl groups" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0079] Non-limiting examples of "substituents" herein include 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.

[0080] Non-limiting examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") herein include C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl groups and C 7-16 Contains aralkyl groups.

[0081] Non-limiting examples of the "optionally substituted hydrocarbon group" herein include hydrocarbon groups which may have substituents independently selected from Substituent Group A.

[0082] 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 or naphthoxy); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), (10) a 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy or piperidinyloxy), (11)C 1-6 alkyl-carbonyloxy groups (e.g., acetoxy or propanoyloxy); (12)C 6-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, or 2-naphthoyloxy); (13)C 1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, or butoxycarbonyloxy), (14) Mono- or di-C 1-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, or diethylcarbamoyloxy); (15)C 6-14 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy or naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy or piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy or trifluoromethylsulfonyloxy), (19)C 1-6 C optionally substituted with an alkyl group 6-14 arylsulfonyloxy groups (e.g., phenylsulfonyloxy or 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, or 2-naphthyloxycarbonyl); (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl or 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) a 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl or thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl group) moyl or piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 alkylsulfonyl groups, (39)C 6-14 arylsulfonyl groups, (40) a 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl or thienylsulfonyl), (41) Optionally halogenated C 1-6 alkylsulfinyl groups, (42)C 6-14 arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, or 2-naphthylsulfinyl); (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl or thienylsulfinyl), (44) amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, or 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 1-6alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, or butanoylamino); (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (52)C 6-14 aryl-carbonylamino groups (e.g., phenylcarbonylamino or naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, or tert-butoxycarbonylamino), (54)C 7-16 aralkyloxy-carbonylamino groups (e.g., benzyloxycarbonylamino), (55)C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino or ethylsulfonylamino), (56)C 1-6 C optionally substituted with an alkyl group 6-14 arylsulfonylamino groups (e.g., phenylsulfonylamino or toluenesulfonylamino); (57) Optionally halogenated C 1-6 alkyl groups, (58)C 2-6 alkenyl groups, (59)C 2-6 alkynyl groups, (60)C 3-10 cycloalkyl groups, (61)C 3-10 cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0083] In some embodiments, the number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, for example, 1 to 3. When the number of substituents is two or more, the individual substituents may be the same or different from each other.

[0084] Non-limiting examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") used herein include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered heterocyclic bridged ring group, each of which contains, as ring-constituting atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to carbon atoms.

[0085] Non-limiting examples of the "aromatic heterocyclic group" (including "5- to 14-membered non-aromatic heterocyclic group") herein include 5- to 14-membered (e.g., 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms, carbon atoms and 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms.

[0086] Non-limiting examples of these "aromatic heterocyclic groups" 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; and benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, fluoropyridinyl, pyrrolopyridinyl, pyrazinyl, pyrazinyl, benzophenone, benzophenone, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, fluoropyridinyl, pyrrolopyridinyl, pyrazinyl, benzophenone ... and 8- to 14-membered fused polycyclic (e.g., bi- or tricyclic) aromatic heterocyclic groups such as pyrrolopyridinyl, 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.

[0087] Non-limiting examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") herein include 3- to 14-membered (e.g., 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms, carbon atoms and 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms.

[0088] Additional non-limiting examples of these "non-aromatic heterocyclic groups" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazonyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl and azocanyl; and dihydro and 9- to 14-membered fused polycyclic (e.g., bi- or tricyclic) non-aromatic heterocyclic groups such as tetrahydrobenzofuranyl, 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, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0089] Non-limiting examples of the "7- to 10-membered heterocyclic bridged ring group" herein include quinuclidinyl and and 7-azabicyclo[2.2.1]heptanyl.

[0090] As used herein, non-limiting examples of the term "nitrogen-containing heterocyclic group" include "heterocyclic groups" that contain at least one nitrogen atom as a ring-constituting atom.

[0091] In this specification, non-limiting examples of the "optionally substituted heterocyclic group" include heterocyclic groups which may have substituents independently selected from Substituent Group A.

[0092] 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 individual substituents may be the same or different from each other.

[0093] Non-limiting examples of "acyl groups" herein include formyl groups, carboxy groups, thiocarbamoyl groups, sulfino groups, sulfo groups, sulfamoyl groups, and phosphono groups, which are 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 Aralkyl groups, 5- to 14-membered aromatic heterocyclic groups and 3- to 14-membered non-aromatic heterocyclic groups (these include halogen atoms, optionally halogenated C 1-6 each of which may have 1 to 3 substituents independently selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group)

[0094] Additional non-limiting examples of acyl groups include hydrocarbyl-sulfonyl, heterocycle-sulfonyl, hydrocarbylsulfinyl, and heterocycle-sulfinyl groups.

[0095] Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto.

[0096] Further non-limiting examples of "acyl groups" include formyl groups, carboxy groups, C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl groups (e.g., crotonoyl), C 3-10 cycloalkyl-carbonyl groups (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, or cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl groups (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl or naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl or phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl groups (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6Alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl or N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl or cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl or phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl), sulfino groups, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl or ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, and mono- or di-C 1-6 It includes alkylphosphono groups (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono or dibutylphosphono).

[0097] Non-limiting examples of the "optionally substituted amino group" herein include 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 non-aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 It includes an amino group which may have one or two substituents independently selected from arylsulfonyl groups.

[0098] Non-limiting examples of optionally substituted amino groups include amino groups, mono- or di-(optionally halogenated C 1-6 alkyl)amino groups (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, or dibutylamino), mono- or di-C 2-6 Alkenylamino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino or dibenzylamino), mono- or di-(optionally halogenated C 1-6 alkyl)-carbonylamino group (e.g., acetylamino or propionylamino), mono- or di-C 6-14 Aryl-carbonyl groups (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 or 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 groups (e.g., methylcarbamoylamino), (mono- or di-C 7-16aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino or ethylsulfonylamino), C 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino) groups.

[0099] Non-limiting examples of the "optionally substituted carbamoyl group" herein include 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-Carbo Nyl 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 non-aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 Aralkyl-carbamoyl groups include carbamoyl groups which may have one or two substituents independently selected from carbamoyl groups.

[0100] Additional 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 groups (e.g., diallylcarbamoyl), mono- or di-C 3-10Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl or cyclohexylcarbamoyl), mono- or di-C 6-14 Arylcarbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl groups (e.g., acetylcarbamoyl or propionylcarbamoyl), mono- or di-C 6-14 It includes aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0101] Non-limiting examples of the "optionally substituted thiocarbamoyl group" herein include 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 non-aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and thiocarbamoyl groups which may have one or two substituents independently selected from aralkyl-carbamoyl groups.

[0102] Additional non-limiting examples of optionally substituted thiocarbamoyl groups include thiocarbamoyl groups, mono- or di-C 1-6Alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, or N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl or cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl or phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl groups (e.g., acetylthiocarbamoyl or propionylthiocarbamoyl), mono- or di-C 6-14 It includes aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0103] Non-limiting examples of the "optionally substituted sulfamoyl group" herein include 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 non-aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Archi Carbamoyl group and mono- or di-C 7-16Aralkyl-carbamoyl groups include sulfamoyl groups which may have one or two substituents independently selected from carbamoyl groups.

[0104] Additional non-limiting examples of optionally substituted sulfamoyl groups include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl groups (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, or N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl groups (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl groups (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl groups (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl groups (e.g., benzylsulfamoyl or phenethylsulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl groups (e.g., acetylsulfamoyl or propionylsulfamoyl), mono- or di-C 6-14 It includes aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0105] Non-limiting examples of the "optionally substituted hydroxy group" herein include 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 7-16Aralkyl-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 non-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 It includes a hydroxy group which may have substituents independently selected from arylsulfonyl groups.

[0106] Non-limiting examples of optionally substituted hydroxy groups include hydroxy groups, C 1-6 Alkoxy group, C 2-6 alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, or 3-hexenyloxy), C 3-10 cycloalkyloxy groups (e.g., cyclohexyloxy), C 6-14 aryloxy groups (e.g., phenoxy or naphthyloxy), C 7-16 aralkyloxy groups (e.g., benzyloxy or phenethyloxy), C 1-6 Alkyl-carbonyloxy groups (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, or pivaloyloxy), C 6-14 Aryl-carbonyloxy groups (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 groups (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy groups (e.g., benzylcarbamoyloxy), C1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy or ethyl sulfonyloxy) and C 6-14 Arylsulfonyloxy groups (eg, phenylsulfonyloxy) are included.

[0107] Non-limiting examples of the "optionally substituted sulfanyl group" herein include 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 It includes a sulfanyl group and a halogenated sulfanyl group which may have a substituent independently selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group.

[0108] Additional 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, or 3-hexenylthio), C 3-10 cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 arylthio groups (e.g., phenylthio or naphthylthio), C 7-16 aralkylthio groups (e.g., benzylthio or phenethylthio), C 1-6 alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butylthio, isobutylthio, or pivaloylthio), C 6-14 These include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0109] Non-limiting examples of the "optionally substituted silyl group" herein include C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and silyl groups which may have 1 to 3 substituents independently selected from aralkyl groups.

[0110] Non-limiting examples of optionally substituted silyl groups include tri-C 1-6 It includes alkylsilyl groups (eg, trimethylsilyl or tert-butyl(dimethyl)silyl).

[0111] Non-limiting examples of "hydrocarbon rings" herein include C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkanes and C 3-10 Contains cycloalkenes.

[0112] In this specification, "C 6-14 Non-limiting examples of "aromatic hydrocarbon groups" include benzene and naphthalene.

[0113] In this specification, "C 3-10 Non-limiting examples of "cycloalkanes" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0114] In this specification, "C 3-10 Non-limiting examples of "cycloalkenes" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

[0115] Non-limiting examples of the "heterocycle" herein include aromatic heterocycles and non-aromatic heterocycles each containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.

[0116] Non-limiting examples of "aromatic heterocycles" herein include 5- to 14-membered (e.g., 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms, carbon atoms and 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Additional non-limiting examples of "aromatic heterocycles" 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; and benzothiophene. Benzofuran, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, fluoropyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, fluoropyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiine, indole, isoindole, 1H-indazole, propranolol, and 8- to 14-membered fused polycyclic (e.g., bicyclic or tricyclic) aromatic heterocycles such as phosphorus, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0117] Non-limiting examples of the "non-aromatic heterocycle" herein include 3- to 14-membered (e.g., 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms, carbon atoms and 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Additional non-limiting examples of these "non-aromatic heterocycles" 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; dihydrobenzofuran, ... 9- to 14-membered fused polycyclic rings (e.g., 2-membered rings) such as benzo[2,3-b]benzoximidazole, 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 octahydroisoquinole. or tricyclic) non-aromatic heterocyclic groups.

[0118] As used herein, non-limiting examples of a "nitrogen-containing heterocycle" include a "heterocycle" that contains at least one nitrogen atom as a ring-constituting atom.

[0119] Non-limiting examples of "6-membered aromatic ring" herein include benzene, pyridine, pyridazine, pyrimidine, pyrazine and triazine.

[0120] Non-limiting examples of "5-membered monocyclic aromatic heterocycle" herein 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 and tetrazole.

[0121] The definition of each of the symbols in formula (I) is described in detail hereinafter.

[0122] In some embodiments, R 1 teeth, [ka] wherein: 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 6a and R 6b are each independently selected from the substituents.

[0123] In some embodiments, R 1 teeth, [ka] is a group represented by

[0124] 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. In some embodiments, ring A 1The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" represented by the formula: is pyridine.

[0125] Ring A 1 Non-limiting examples of optional substituents in the "optionally further substituted 6-membered aromatic ring" represented by the formula: are substituents independently selected from Substituent Group A. In some embodiments, the number of these optional substituents is an integer of 1 to 3. When the number of optional substituents is two or more, the individual substituents may be the same or different from one another.

[0126] In some embodiments, ring A 1 is selected from a 6-membered aromatic ring (e.g., benzene, pyridine, or pyrimidine) optionally further substituted with 1 to 3 substituents independently selected from: (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) A 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atom).

[0127] In some embodiments, ring A 1 is selected from: (1) A benzene ring: (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). a benzene ring which may be further substituted by 1 to 3 substituents independently selected from (2) a pyridine ring, (a) a halogen atom (e.g., a fluorine atom or a chlorine atom), (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl, difluoromethyl, or trifluoromethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-10 cycloalkyl groups (e.g., cyclopropyl) a pyridine ring optionally further substituted by 1 to 3 substituents independently selected from (3) One or two optionally halogenated C 1-6A pyrimidine ring optionally further substituted with an alkyl group (eg, trifluoromethyl).

[0128] In some embodiments, ring A 1 is selected from: (1) A benzene ring: (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) a piperidyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) a benzene ring which may be further substituted by 1 to 3 substituents independently selected from (2) a pyridine ring, (a) a halogen atom (e.g., a fluorine atom or a chlorine atom), (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl, difluoromethyl, or trifluoromethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-6 cycloalkyl groups (e.g., cyclopropyl) a pyridine ring optionally further substituted by 1 to 3 substituents independently selected from (3) One or two optionally halogenated C 1-6 A pyrimidine ring optionally further substituted with an alkyl group (eg, trifluoromethyl).

[0129] In some embodiments, ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom), and (b) Halogenated C 1-6 Alkyl groups (e.g., trifluoromethyl) and wherein the pyridine ring is further substituted with one or two substituents independently selected from:

[0130] In some embodiments, ring A 1 is one halogenated C 1-6 It is selected from pyridine rings further substituted with alkyl groups (eg, trifluoromethyl).

[0131] In some embodiments, ring A 1 is selected from a pyridine ring further substituted with one trifluoromethyl group.

[0132] 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.

[0133] In some embodiments, ring A 1 is selected from optionally further substituted pyridine rings.

[0134] In some embodiments, ring A 1 is selected from further substituted pyridine rings.

[0135] In some embodiments, R 6a is selected from: (1) optionally substituted C 3-10cycloalkyl groups (e.g., cyclohexyl); (2) optionally substituted C 6-14 aryl groups (e.g., phenyl); (3) 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, or pyrrolidinyl) or a 6- to 9-membered non-aromatic spiro heterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl)); (4) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., imidazolyl)), (5)-NR 9 R 10 (In the formula, R 9 teeth, (A) optionally substituted C 1-6 alkyl groups (e.g., methyl), and (B) 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., tetrahydropyranyl)). is selected from R 10 teeth, (A) a hydrogen atom, and (B) optionally substituted C 1-6 Alkyl groups (e.g., methyl) ), and (6)-OR 11 (In the formula, R 11 teeth, (A) optionally substituted C 1-6 alkyl groups (e.g., methyl); (B) optionally substituted C 6-14 aryl groups (e.g., phenyl), and (C) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (e.g., 3- to 8-membered heterocyclic group) a monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) (selected from).

[0136] In some embodiments, the above-mentioned "optionally substituted C 1-6 alkyl group," "optionally substituted C 3-10 "cycloalkyl group," "optionally substituted C 6-14 The optional substituents in the "aryl group," "optionally substituted 3- to 14-membered non-aromatic heterocyclic group," and "5- to 14-membered aromatic ring group" are substituents independently selected from Substituent Group A. In some embodiments, the number of these optional substituents is an integer of 1 to 3. When the number of optional substituents is two or more, the individual optional substituents may be the same or different from each other.

[0137] In some embodiments, the "3- to 14-membered non-aromatic heterocyclic group" of the above-mentioned "optionally substituted 3- to 14-membered non-aromatic heterocyclic group" is selected from 6- to 9-membered non-aromatic spiroheterocyclic groups.

[0138] In some embodiments, R 6a is selected from: (1) optionally substituted C 3-10 cycloalkyl groups (e.g., cyclohexyl); (2) optionally substituted C 6-14 aryl groups (e.g., phenyl); (3) 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, or pyrrolidinyl) or a 6- to 9-membered non-aromatic spiro heterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl)); (4) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., imidazolyl)), (5) optionally substituted mono- or di-C 1-6 alkylamino groups (e.g., methylamino), (6) Optionally substituted NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino groups (e.g., NC 1-6alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amino group (e.g., N-methyl-N-tetrahydropyranylamino); (7) optionally substituted C 1-6 alkoxy groups (e.g., methoxy), (8) optionally substituted C 6-14 aryloxy groups (e.g., phenoxy), and (9) An optionally substituted 3- to 14-membered non-aromatic heterocyclic oxy group (for example, a 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group (for example, tetrahydropyranyloxy)).

[0139] In some embodiments, R 6a is selected from: (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclohexyl); (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-14 aryl groups (e.g., phenyl); (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, or pyrrolidinyl) or a 6- to 9-membered non-aromatic spiroheterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl)), (a) a halogen atom (e.g., a fluorine atom), and (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl or difluoromethyl) a 3- to 14-membered non-aromatic heterocyclic group or a 6- to 9-membered non-aromatic spiroheterocyclic group optionally substituted by 1 to 3 substituents independently selected from (4) 1 to 3 C 1-6 an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., imidazolyl)) optionally substituted by an alkyl group (e.g., methyl); (5) 1 to 3 C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Mono- or di-C optionally substituted by a cycloalkyl group (e.g., cyclobutyl) 1-6 alkylamino groups (e.g., methylamino), (6)NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino groups (e.g., NC 1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amino group (e.g., N-methyl-N-tetrahydropyranylamino); (7) C 1-6 an alkoxy group (e.g., methoxy), (a)C 1-6 alkoxy groups (e.g., methoxy), (b) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl), and (c) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl or tetrahydrofuryl)). C optionally substituted by 1 to 3 substituents independently selected from 1-6 alkoxy groups, (8) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-14 aryloxy groups (e.g., phenoxy), and (9) A 3- to 14-membered non-aromatic heterocyclic oxy group (for example, a 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group (for example, tetrahydropyranyloxy)).

[0140] In some embodiments, R 6a is selected from: (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclohexyl); (2) a phenyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (3) a morpholinyl group, (a) a halogen atom (e.g., a fluorine atom), and (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl or difluoromethyl) a morpholinyl group optionally substituted by 1 to 3 substituents independently selected from (4) a piperidyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (5) a pyrrolidinyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (6) 4-oxa-7-azaspiro[2.5]octyl group, (7) 1 to 3 C 1-6 an imidazolyl group optionally substituted by an alkyl group (e.g., methyl); (8) 1 to 3 C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 Mono- or di-C optionally substituted by a cycloalkyl group (e.g., cyclobutyl) 1-6 alkylamino groups (e.g., methylamino), (9)NC 1-6 alkyl-N-tetrahydropyranylamino groups (e.g., N-methyl-N-tetrahydropyranylamino); (10)C 1-6 an alkoxy group (e.g., methoxy), (a)C 1-6 alkoxy groups (e.g., methoxy), (b) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl); (c) an oxetanyl group, and (d) tetrahydrofuryl group C optionally substituted by 1 to 3 substituents independently selected from1-6 alkoxy groups, (11) a phenoxy group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), and (12) Tetrahydropyranyloxy group.

[0141] In some embodiments, R 6a is 1 to 3 C 1-6 It is a morpholinyl group optionally substituted by an alkyl group (for example, methyl).

[0142] In some embodiments, R 6a is one C 1-6 A morpholinyl group substituted with an alkyl group (eg, methyl).

[0143] In some embodiments, [ka] The group represented by [ka] is a group represented by R 7a and R 8a are each independently selected from a hydrogen atom and a substituent, and the other symbols are as defined above.

[0144] In some embodiments, R 7a is selected from: (a) a hydrogen atom, (b) a halogen atom (e.g., a chlorine atom or a bromine atom); (c) optionally substituted C 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (d) optionally substituted C 1-6 Alkoxy groups (e.g., methoxy or ethoxy) ), (e) optionally substituted C 3-10 cycloalkyl groups (e.g., cyclopropyl); (f) optionally substituted C 2-6 alkenyl groups (e.g., vinyl), and (g) An optionally substituted 3- to 14-membered non-aromatic heterocyclic group (for example, a 3- to 8-membered monocyclic non-aromatic heterocyclic group (for example, piperidyl)).

[0145] In some embodiments, R 7a is: (a) a hydrogen atom, (b) a halogen atom (e.g., a chlorine atom or a bromine atom); (c) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (d) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy); (e) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl); (f)C 2-6 an alkenyl group (e.g., vinyl), or (g) A 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atom).

[0146] In some embodiments, R 7a is selected from: (a) a hydrogen atom, (b) a halogen atom (e.g., a chlorine atom or a bromine atom); (c) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (d) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (e) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclopropyl) (f)C 2-6 alkenyl groups (e.g., vinyl), and (g) A piperidyl group optionally substituted by 1 to 3 halogen atoms (for example, fluorine atoms).

[0147] In some embodiments, R 7a is halogenated C 1-6 alkyl groups (eg, trifluoromethyl).

[0148] In some embodiments, R 7a is a trifluoromethyl group.

[0149] In some embodiments, R 8a teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c) optionally substituted C 1-6 Alkyl groups (e.g., methyl) is selected from.

[0150] In some embodiments, R 8a teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from.

[0151] In some embodiments, R 8a is selected from a hydrogen atom and a halogen atom (eg, a fluorine atom).

[0152] In some embodiments, R 8a is a hydrogen atom or a fluorine atom.

[0153] In some embodiments, R 8a is a hydrogen atom.

[0154] In some embodiments, [ka] The group represented by [ka] is a group represented by In the formula, R 7a1 , R 7a2 , R 7a3 , R 8a1 and R 8a2 are each independently selected from a hydrogen atom and a substituent, and the other symbols are as defined above.

[0155] In some embodiments, R 7a1 is selected from: (a) a halogen atom (e.g., a chlorine atom or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl); (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) A 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atom).

[0156] In some embodiments, R 7a1 is selected from: (a) a halogen atom (e.g., a chlorine atom or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) A piperidyl group optionally substituted by 1 to 3 halogen atoms (for example, fluorine atoms).

[0157] In some embodiments, R 7a2 teeth, (a) a hydrogen atom, (b) optionally halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-10 cycloalkyl groups (e.g., cyclopropyl) is selected from.

[0158] In some embodiments, R 7a2 teeth, (a) a hydrogen atom, (b) optionally halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-6 cycloalkyl groups (e.g., cyclopropyl) is selected from.

[0159] In some embodiments, R 7a2 is halogenated C 1-6 It is an alkyl group (eg, trifluoromethyl).

[0160] In some embodiments, R 7a2 is a trifluoromethyl group.

[0161] In some embodiments, R 7a3 may be halogenated C 1-6 It is an alkyl group (eg, trifluoromethyl).

[0162] In some embodiments, R 8a1 teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from.

[0163] In some embodiments, R 8a2 teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from.

[0164] In some embodiments, R 8a2is selected from a hydrogen atom and a halogen atom (eg, a fluorine atom).

[0165] In some embodiments, R 8a2 is a hydrogen atom or a fluorine atom.

[0166] In some embodiments, R 8a2 is a hydrogen atom.

[0167] In some embodiments, [ka] The group represented by [ka] is a group represented by Each symbol in the formula is as defined above.

[0168] In some embodiments, R 7a2 is halogenated C 1-6 alkyl groups (eg, trifluoromethyl).

[0169] In some embodiments, R 7a2 is a trifluoromethyl group.

[0170] In some embodiments, R 8a2 is selected from a hydrogen atom and a halogen atom (eg, a fluorine atom).

[0171] In some embodiments, R 8a2 is a hydrogen atom or a fluorine atom.

[0172] In some embodiments, R 8a2 is a hydrogen atom.

[0173] In some embodiments, ring A 2The "5-membered monocyclic aromatic heterocyclic group" of the "optionally further substituted 5-membered monocyclic aromatic heterocyclic group" represented by the formula: is pyrazole.

[0174] Ring A 2 Non-limiting examples of optional substituents in the "optionally further substituted 5-membered monocyclic aromatic heterocycle" represented by the formula: are substituents independently selected from Substituent Group A. In some embodiments, the number of these optional substituents is an integer from 1 to 3. When the number of optional substituents is two or more, the individual substituents may be the same or different from one another.

[0175] In some embodiments, ring A 2 is a C group having 1 to 3 optionally halogenated groups; 1-6 and 5-membered monocyclic aromatic heterocycles (eg, pyrazole) optionally further substituted with an alkyl group (eg, trifluoromethyl).

[0176] In some embodiments, ring A 2 is a C group having 1 to 3 optionally halogenated groups; 1-6 It is a pyrazole ring which may be further substituted with an alkyl group (eg, trifluoromethyl).

[0177] In some embodiments, ring A 2 is one halogenated C 1-6 It is a pyrazole ring that is further substituted with an alkyl group (eg, trifluoromethyl).

[0178] In some embodiments, ring A 2 is a pyrazole ring further substituted with one trifluoromethyl group.

[0179] In some embodiments, ring A 2 is an optionally further substituted pyrazole group. 2 is a further substituted pyrazole ring.

[0180] In some embodiments, R 6b may be substituted C 1-6 It is an alkyl group (eg, ethyl).

[0181] The above "Optionally substituted C 1-6 Non-limiting examples of optional substituents in the "alkyl group" are substituents independently selected from Substituent Group A. In some embodiments, the number of these optional substituents is an integer from 1 to 3. When the number of optional substituents is two or more, the individual substituents may be the same or different from one another.

[0182] In some embodiments, R 6b is 1 to 3 C 3-10 C optionally substituted with a cycloalkyl group (e.g., cyclobutyl) 1-6 It is an alkyl group (eg, ethyl).

[0183] In some embodiments, R 6b is 1 to 3 C 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclobutyl) 1-6 It is an alkyl group (eg, ethyl).

[0184] In some embodiments, [ka] The group represented by [ka] and R 7b is selected from a hydrogen atom and a substituent, and all other symbols are as defined above.

[0185] In some embodiments, R 7b may be substituted C 1-6 It is an alkyl group (eg, methyl).

[0186] In some embodiments, R 7b may be halogenated C 1-6 It is an alkyl group (eg, trifluoromethyl).

[0187] In some embodiments, R 7b is halogenated C 1-6 It is an alkyl group (eg, trifluoromethyl).

[0188] In some embodiments, R 7b is a trifluoromethyl group.

[0189] In some embodiments, Z is CR 2 or N. In some embodiments, R 2 is a hydrogen atom, a halogen atom, or an optionally halogenated C 1-6 The alkyl group is selected from the group consisting of:

[0190] In some embodiments, Z is CR 2 In some embodiments, R 2 is a hydrogen atom and optionally halogenated C 1-6 It is selected from alkyl groups (eg, methyl or ethyl).

[0191] In some embodiments, R 2 is a hydrogen atom and C 1-6 It is selected from alkyl groups (eg, methyl or ethyl).

[0192] In some embodiments, R 2 is a hydrogen atom and C 1-3 It is selected from alkyl groups (eg, methyl).

[0193] In some embodiments, R 2 is C 1-3 It is selected from alkyl groups (eg, methyl).

[0194] In some embodiments, Z is N or CR2 and R 2 is a hydrogen atom and optionally halogenated C 1-6 It is selected from alkyl groups (eg, methyl or ethyl).

[0195] In some embodiments, Z is N or CR 2 and R 2 is a hydrogen atom and C 1-6 It is selected from alkyl groups (eg, methyl or ethyl).

[0196] In some embodiments, Z is CR 2 and R 2 is a hydrogen atom and C 1-3 It is selected from alkyl groups (eg, methyl).

[0197] In some embodiments, Z is CR 2 and R 2 is C 1-3 It is selected from alkyl groups (eg, methyl).

[0198] In some embodiments, R 3 is a hydrogen atom, a halogen atom (e.g., a chlorine atom), and optionally halogenated C 1-6 It is selected from alkyl groups (for example, methyl, ethyl or trifluoromethyl).

[0199] In some embodiments, R 3 is a hydrogen atom and C 1-6 It is selected from alkyl groups (eg, methyl).

[0200] In some embodiments, R 3 is a hydrogen atom and C 1-3 It is selected from alkyl groups (eg, methyl).

[0201] In some embodiments, R 3 is C 1-3 It is an alkyl group (eg, methyl).

[0202] In some embodiments, R 4 and R 5 are each independently selected from a hydrogen atom and a substituent.

[0203] In some embodiments, R 4 and R 5 represents a hydrogen atom and optionally substituted C 1-6 are each independently selected from alkyl groups (e.g., methyl).

[0204] The above "Optionally substituted C 1-6 Non-limiting examples of optional substituents in the "alkyl group" are substituents independently selected from Substituent Group A. In some embodiments, the number of these optional substituents is an integer from 1 to 3. When the number of optional substituents is two or more, the individual substituents may be the same or different from one another.

[0205] In some embodiments, R 4 and R 5 is a hydrogen atom and C 1-6 are each independently selected from alkyl groups (e.g., methyl).

[0206] In some embodiments, R 4 is a hydrogen atom and C 1-6 It is selected from alkyl groups (eg, methyl).

[0207] In some embodiments, R 5 is a hydrogen atom.

[0208] In some embodiments, R 4 and R 5 are both hydrogen atoms.

[0209] In some embodiments, Ring B is an optionally further substituted 5-membered monocyclic aromatic heterocycle.

[0210] In some embodiments, the "5-membered monocyclic aromatic heterocyclic group" of the "optionally further substituted 5-membered monocyclic aromatic heterocyclic group" represented by ring B is a pyrazole ring (e.g., 1H-pyrazol-4-yl).

[0211] Non-limiting examples of optional substituents in the "optionally further substituted 5-membered monocyclic aromatic heterocycle" represented by ring B are substituents independently selected from substituent group A. In some embodiments, the number of these optional substituents is an integer of 1 to 3. When the number of optional substituents is two or more, the individual substituents may be the same or different from each other.

[0212] In some embodiments, ring B is selected from the group consisting of 1 to 3 C 1-6 It is a 5-membered monocyclic aromatic heterocycle (eg, pyrazole) which may be further substituted with an alkyl group (eg, methyl, ethyl, or isopropyl).

[0213] In some embodiments, ring B is selected from the group consisting of 1 to 3 C 1-6 It is a pyrazole ring (eg, 1H-pyrazol-4-yl) which may be further substituted with an alkyl group (eg, methyl, ethyl, or isopropyl).

[0214] In some embodiments, ring B contains one C 1-6 It is a pyrazole ring (eg, 1H-pyrazol-4-yl) that is further substituted with an alkyl group (eg, ethyl).

[0215] In some embodiments, Ring B is an optionally further substituted pyrazole group.

[0216] In some embodiments, Ring B is a further substituted pyrazole ring.

[0217] In some embodiments, Ring B is [ka] is a cyclic group represented by the formula: R 1c is a hydrogen atom and C 1-6 alkyl groups (e.g., ethyl or isopropyl); R 2c and R 3c is a hydrogen atom and C 1-6 are each independently selected from alkyl groups (e.g., methyl).

[0218] In some embodiments, R 1c is C 1-6 It is an alkyl group (eg, ethyl or isopropyl, eg, ethyl).

[0219] In some embodiments, R 2c is a hydrogen atom and C 1-6 alkyl groups (e.g., methyl); R 3c is a hydrogen atom. In some embodiments, R 2c and R 3c are both hydrogen atoms.

[0220] In some embodiments, Ring B is [ka] and R is a cyclic group represented by 1c is C 1-6 It is selected from alkyl groups (eg, ethyl).

[0221] Compounds represented by formula (I) do not include 1-(3-chlorophenyl)-3-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-dihydro-2H-imidazol-2-one.

[0222] Non-limiting examples of Compound (I) include the following subformulas:

[0223] Similarly, disclosed herein is a compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof (also referred to herein as Compound A), wherein: R 1 teeth, [ka] is a group represented by Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring (e.g., benzene, pyridine, or pyrimidine); R 6a teeth, (1) optionally substituted C 3-10 cycloalkyl groups (e.g., cyclohexyl); (2) optionally substituted C 6-14 aryl groups (e.g., phenyl); (3) 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, or pyrrolidinyl) or a 6- to 9-membered non-aromatic spiro heterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl)); (4) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., imidazolyl)), (5) optionally substituted mono- or di-C 1-6 alkylamino groups (e.g., methylamino), (6) Optionally substituted NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino groups (e.g., NC 1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amino group (e.g., N-methyl-N-tetrahydropyranylamino); (7) optionally substituted C 1-6 alkoxy groups (e.g., methoxy), (8) optionally substituted C 6-14 aryloxy groups (e.g., phenoxy), and (9) 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)). is selected from Ring A 2 is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles (e.g., pyrazole); R 6b may be substituted C 1-6 alkyl groups (e.g., ethyl); Z is CR 2 or N, R 2 is a hydrogen atom and optionally halogenated C 1-6 alkyl groups (e.g., methyl or ethyl); R 3 is a hydrogen atom, a halogen atom (e.g., a chlorine atom), and optionally halogenated C 1-6 Selected from alkyl groups (e.g., methyl, ethyl, or trifluoromethyl) And, R 4 and R 5 represents a hydrogen atom and optionally substituted C 1-6 are each independently selected from an alkyl group (e.g., methyl); Ring B is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles (eg, pyrazole).

[0224] Similarly, disclosed herein is a compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof (also referred to herein as Compound B), wherein R 1 teeth, [ka] is a group represented by Ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). a 6-membered aromatic ring (e.g., benzene, pyridine, or pyrimidine) optionally further substituted by 1 to 3 substituents independently selected from R 6a teeth, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclohexyl); (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-14 aryl groups (e.g., phenyl); (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, or pyrrolidinyl) or a 6- to 9-membered non-aromatic spiroheterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl)), (a) a halogen atom (e.g., a fluorine atom), and (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl or difluoromethyl) a 3- to 14-membered non-aromatic heterocyclic group or a 6- to 9-membered non-aromatic spiroheterocyclic group optionally substituted by 1 to 3 substituents independently selected from (4) 1 to 3 C 1-6a 5- to 14-membered aromatic heterocyclic group (for example, a 5- or 6-membered monocyclic aromatic heterocyclic group (for example, imidazolyl)) optionally substituted by an alkyl group (for example, methyl); (5) 1 to 3 C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 Mono- or di-C optionally substituted by a cycloalkyl group (e.g., cyclobutyl) 1-6 alkylamino groups (e.g., methylamino), (6)NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino groups (e.g., NC 1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amino group (e.g., N-methyl-N-tetrahydropyranylamino); (7) C 1-6 an alkoxy group (e.g., methoxy), (a)C 1-6 alkoxy groups (e.g., methoxy), (b)C 3-10 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl), and (c) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl or tetrahydrofuryl)). C optionally substituted by 1 to 3 substituents independently selected from 1-6 alkoxy group (8) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-14 aryloxy groups (e.g., phenoxy), and (9) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group (e.g., tetrahydropyranyloxy)) is selected from.

[0225] In some embodiments, [ka] The group represented by [ka] is a group represented by During the ceremony, R 6a is as defined above, R 7a teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a chlorine atom or a bromine atom); (c) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (d) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (e) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl) (f)C 2-6 alkenyl groups (e.g., vinyl), and (g) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). is selected from R 8a teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from Ring A 2 is a C group having 1 to 3 optionally halogenated groups; 1-6 a 5-membered monocyclic aromatic heterocycle (e.g., pyrazole) optionally further substituted with an alkyl group (e.g., trifluoromethyl); R6b is 1 to 3 C 3-10 C optionally substituted with a cycloalkyl group (e.g., cyclobutyl) 1-6 It is selected from alkyl groups (eg, ethyl).

[0226] In some embodiments, [ka] The group represented by [ka] is a group represented by During the ceremony, R 6b is as defined above, R 7b may be halogenated C 1-6 an alkyl group (e.g., trifluoromethyl); Z is CR 2 or N, R 2 is a hydrogen atom and C 1-6 alkyl groups (e.g., methyl or ethyl); R 3 is a hydrogen atom, a halogen atom (e.g., a chlorine atom), and optionally halogenated C 1-6 alkyl groups (e.g., methyl, ethyl, or trifluoromethyl); R 4 and R 5 is a hydrogen atom and C 1-6 are each independently selected from an alkyl group (e.g., methyl); Ring B contains 1 to 3 C 1-6 and 5-membered monocyclic aromatic heterocycles (eg, pyrazole) optionally further substituted with alkyl groups (eg, methyl, ethyl, or isopropyl).

[0227] Similarly, disclosed herein is a compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof (also referred to herein as Compound C), wherein R 1 teeth, [ka] is a group represented by Ring A 1 teeth, (1) A benzene ring: (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl); (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). a benzene ring which may be further substituted by 1 to 3 substituents independently selected from (2) a pyridine ring, (a) a halogen atom (e.g., a fluorine atom or a chlorine atom), (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl, difluoromethyl, or trifluoromethyl); (c) optionally halogenated C 1-6alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-10 cycloalkyl groups (e.g., cyclopropyl) Pyridine optionally further substituted by 1 to 3 substituents independently selected from Ring, (3) One or two optionally halogenated C 1-6 A pyrimidine ring optionally further substituted with an alkyl group (e.g., trifluoromethyl). is selected from R 6a teeth, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclohexyl); (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-14 aryl groups (e.g., phenyl); (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, or pyrrolidinyl) or a 6- to 9-membered non-aromatic spiroheterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl)), (a) a halogen atom (e.g., a fluorine atom), and (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl or difluoromethyl) a 3- to 14-membered non-aromatic heterocyclic group or a 6- to 9-membered non-aromatic spiroheterocyclic group optionally substituted by 1 to 3 substituents independently selected from (4) 1 to 3 C 1-6 a 5- to 14-membered non-aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., imidazolyl)) optionally substituted by an alkyl group (e.g., methyl); (5) 1 to 3 C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10Mono- or di-C optionally substituted by a cycloalkyl group (e.g., cyclobutyl) 1-6 alkylamino groups (e.g., methylamino), (6)NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino groups (e.g., NC 1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amino group (e.g., N-methyl-N-tetrahydropyranylamino); (7) C 1-6 an alkoxy group (e.g., methoxy), (a)C 1-6 alkoxy groups (e.g., methoxy), and (b) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl), and (c) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl or tetrahydrofuryl)). C optionally substituted by 1 to 3 substituents independently selected from 1-6 alkoxy groups, (8) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-14 aryloxy groups (e.g., phenoxy), and (9) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group (e.g., tetrahydropyranyloxy)) is selected from.

[0228] In some embodiments, [ka] The group represented by [ka] is a group represented by During the ceremony, R6a is as defined above, R 7a1 teeth, (a) a halogen atom (e.g., a chlorine atom or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-10 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) a 3- to 14-membered non-aromatic heterocyclic group (e.g., a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., piperidyl)) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). is selected from R 7a2 teeth, (a) a hydrogen atom, (b) optionally halogenated C 1-6 alkyl groups (e.g., trifluoromethyl), (c) optionally halogenated C 1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-10 cycloalkyl groups (e.g., cyclopropyl) is selected from R 7a3 may be halogenated C 1-6 an alkyl group (e.g., trifluoromethyl); R 8a1 teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from R 8a2 teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from Ring A 2 is a C group having 1 to 3 optionally halogenated groups; 1-6 a pyrazole ring optionally further substituted with an alkyl group (e.g., trifluoromethyl); R 6b is 1 to 3 C 3-10 C optionally substituted with a cycloalkyl group (e.g., cyclobutyl) 1-6 It is selected from alkyl groups (eg, ethyl).

[0229] In some embodiments, [ka] The group represented by [ka] wherein each symbol is the same as in compound B, Ring B contains 1 to 3 C 1-6 It is selected from pyrazole rings (eg, 1H-pyrazol-4-yl) which may be further substituted with alkyl groups (eg, methyl, ethyl, or isopropyl).

[0230] In some embodiments, Ring B is [ka] where: R 1c is a hydrogen atom and C1-6 alkyl groups (e.g., ethyl or isopropyl); R 2c and R 3c is a hydrogen atom and C 1-6 are each independently selected from alkyl groups (e.g., methyl).

[0231] Similarly, disclosed herein is a compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof (also referred to herein as Compound D), wherein: R 1 teeth, [ka] is a group represented by Ring A 1 teeth, (1) A benzene ring: (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) a piperidyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) a benzene ring which may be further substituted by 1 to 3 substituents independently selected from (2) a pyridine ring, (a) a halogen atom (e.g., a fluorine atom or a chlorine atom), (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl, difluoromethyl, or trifluoromethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-6 cycloalkyl groups (e.g., cyclopropyl) a pyridine ring optionally further substituted by 1 to 3 substituents independently selected from (3) One or two optionally halogenated C 1-6 A pyrimidine ring optionally further substituted with an alkyl group (e.g., trifluoromethyl). is selected from R 6a teeth, (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclohexyl); (2) a phenyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (3) a morpholinyl group, (a) a halogen atom (e.g., a fluorine atom), and (b) optionally halogenated C 1-6 an alkyl group (e.g., methyl or difluoromethyl) morpholinyl optionally substituted by 1 to 3 substituents independently selected from aryl group, (4) a piperidyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (5) a pyrrolidinyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (6) 4-oxa-7-azaspiro[2.5]octyl group, (7) 1 to 3 C 1-6an imidazolyl group optionally substituted by an alkyl group (e.g., methyl); (8) 1 to 3 C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 Mono- or di-C optionally substituted by a cycloalkyl group (e.g., cyclobutyl) 1-6 alkylamino groups (e.g., methylamino), (9)NC 1-6 alkyl-N-tetrahydropyranylamino groups (e.g., N-methyl-N-tetrahydropyranylamino); (10)C 1-6 an alkoxy group (e.g., methoxy), (a)C 1-6 alkoxy groups (e.g., methoxy), (b) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl) (c) an oxetanyl group, and (d) tetrahydrofuryl group C optionally substituted by 1 to 3 substituents independently selected from 1-6 alkoxy group (11) a phenoxy group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), and (12) Tetrahydropyranyloxy group is selected from.

[0232] In some embodiments, [ka] The group represented by [ka] is a group represented by During the ceremony, R 6a is as defined above, R 7a1 teeth, (a) a halogen atom (e.g., a chlorine atom or a bromine atom), (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom (e.g., a fluorine atom) and (ii) a hydroxy group. 1-6 an alkyl group (e.g., methyl, ethyl, or isopropyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy); (d) C optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) 3-6 cycloalkyl groups (e.g., cyclopropyl) (e)C 2-6 alkenyl groups (e.g., vinyl), and (f) a piperidyl group optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) is selected from R 7a2 teeth, (a) a hydrogen atom, (b) optionally halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); (c) optionally halogenated C 1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy), and (d)C 3-6 cycloalkyl groups (e.g., cyclopropyl) is selected from R 7a3 may be halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); R 8a1 teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from R8a2 teeth, (a) a hydrogen atom, (b) a halogen atom (e.g., a fluorine atom or a chlorine atom), and (c)C 1-6 Alkyl groups (e.g., methyl) is selected from.

[0233] In some embodiments, ring A 2 is a C group having 1 to 3 optionally halogenated groups; 1-6 pyrazole ring optionally further substituted with an alkyl group (e.g., trifluoromethyl); R 6b is 1 to 3 C 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclobutyl) 1-6 It is selected from alkyl groups (eg, ethyl).

[0234] In some embodiments, [ka] The group represented by [ka] wherein: R 6b is as defined above, The other symbols are the same as those in Compound B. R 4 is a hydrogen atom and C 1-6 alkyl groups (e.g., methyl); R 5 is a hydrogen atom, Ring B contains 1 to 3 C 1-6 It is selected from pyrazole rings (eg, 1H-pyrazol-4-yl) which may be further substituted with alkyl groups (eg, methyl, ethyl, or isopropyl).

[0235] In some embodiments, Ring B is [ka] wherein the symbols are the same as those in Compound B.

[0236] Similarly, disclosed herein is a compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof (also referred to herein as Compound E), wherein: R 1 teeth, [ka] is a group represented by Ring A 1 teeth, (a) a halogen atom (e.g., a fluorine atom), and (b) Halogenated C 1-6 Alkyl groups (e.g., trifluoromethyl) a pyridine ring optionally further substituted by one or two substituents independently selected from R 6a is 1 to 3 C 1-6 The morpholinyl group is selected from morpholinyl groups optionally substituted by alkyl groups (eg, methyl).

[0237] In some embodiments, [ka] The group represented by [ka] is a group represented by During the ceremony, R 6a is as defined above, R 7a2 is halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); R 8a2 is selected from a hydrogen atom and a halogen atom (e.g., a fluorine atom), Z is CR 2and R 2 is a hydrogen atom and C 1-3 alkyl groups (e.g., methyl); R 3 is a hydrogen atom and C 1-3 alkyl groups (e.g., methyl); R 4 and R 5 are both hydrogen atoms, Ring B has one C 1-6 Pi is further substituted with an alkyl group (e.g., ethyl). pyrazole ring (e.g., 1H-pyrazol-4-yl).

[0238] In some embodiments, Ring B is [ka] is a group represented by In the formula, R 1c is C 1-6 It is selected from alkyl groups (eg, ethyl).

[0239] Similarly, disclosed herein is a compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof (also referred to herein as Compound F), wherein: R 1 teeth, [ka] is a group represented by Ring A 1 is one halogenated C 1-6 a pyridine ring further substituted with an alkyl group (e.g., trifluoromethyl); R 6a is one C 1-6 morpholinyl groups substituted with alkyl groups (eg, methyl).

[0240] In some embodiments, [ka] The group represented by [ka] is a group represented by During the ceremony, R 6a is as defined above, R 7a2 is halogenated C 1-6 alkyl groups (e.g., trifluoromethyl); R 8a2 is a hydrogen atom, Z is CR 2 and R 2 is C 1-3 alkyl groups (e.g., methyl); R 3 is C 1-3 alkyl groups (e.g., methyl); R 4 and R 5 are both hydrogen atoms, Ring B has one C 1-6 A pyrazole ring (eg, 1H-pyrazol-4-yl) further substituted with an alkyl group (eg, ethyl).

[0241] In some embodiments, Ring B is [ka] wherein R 1c is C 1-6 It is selected from alkyl groups (eg, ethyl).

[0242] Compounds of formula (I) include, but are not limited to, the compounds of Examples 1 to 167, and pharmaceutically acceptable salts thereof (eg, the compounds of Examples 1 to 167).

[0243] When Compound (I) is in the form of a salt, such as a pharmaceutically acceptable salt, non-limiting examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. 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 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., and non-limiting examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. For example, compound (I) may be a pharmaceutically acceptable salt. Similarly, for example, when the compound contains an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.) or alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc. may be used; when the compound contains a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, or phosphoric acid, or salts with organic acids 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.

[0244] When compound (I) contains isomers such as tautomers, enantiomers, stereoisomers, positional isomers, or rotational isomers, any one of these isomers and mixtures thereof are also included in compound (I). Furthermore, when compound (I) contains enantiomers, it is possible to convert the enantiomers from the racemate to the The resolved enantiomers are also included in compound (I).

[0245] In some embodiments, Compound (I) may be crystalline. Thus, Compound (I) includes single crystalline forms and mixtures of crystalline forms.

[0246] 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 comprises two or more distinct solids at room temperature, each of which has different physical characteristics (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). Co-crystals or co-crystal salts can be produced according to known co-crystallization methods.

[0247] In some embodiments, Compound (I) may be a solvate (e.g., a hydrate, etc.) or a solvent-free material, both of which are included within the scope of Compound (I).

[0248] In some embodiments, isotopes (e.g., 2 H, 3 H, 11 C. 14 C. 18 F, 35 S, 125 Compound (I) also includes compounds labeled or substituted with isotopes (e.g., I). For example, in some embodiments, isotope-labeled or substituted compounds can be used as tracers (PET tracers) used in positron emission tomography (PET). In some embodiments, isotope-labeled or substituted compounds can be useful in fields such as medical diagnosis.

[0249] Non-limiting exemplary methods for producing the compounds of the present disclosure are described hereinafter.

[0250] The raw materials or 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 described above.

[0251] If the compound obtained in each step is a free compound, it may be converted into a target salt using a method known per se. Conversely, if the compound obtained in each step is a salt, it may be converted into another type of free form or target salt using a method known per se.

[0252] The compound obtained in each step can be used as a reaction solution directly in the next reaction or as a crude product after isolation. Alternatively, the compound obtained in each step can be isolated and / or purified from the reaction mixture using a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation or chromatography according to conventional techniques.

[0253] When the raw materials or reagents in each step are commercially available, the commercially available products can be used directly.

[0254] In the reaction of each step, the reaction time may vary depending on the reagent or solvent used, but unless otherwise specified, the reaction time is usually 1 minute to 48 hours, for example, 10 minutes to 8 hours.

[0255] In the reaction of each step, the reaction temperature may vary depending on the reagent or solvent used, but unless otherwise specified, the reaction temperature is usually from -78°C to 300°C, for example, from -78°C to 150°C.

[0256] In the reaction of each step, the pressure may vary depending on the reagent or solvent used, but unless otherwise specified, the pressure is usually 1 atm to 20 atm, for example, 1 atm to 3 atm.

[0257] In the reactions of each step, a microwave synthesizer such as a starting device available from Biotage can be used, for example. The reaction temperature may vary depending on the reagents or solvents used, but unless otherwise specified, the reaction temperature is usually room temperature to 300°C, for example, 50°C to 250°C. The reaction time may vary depending on the reagents or solvents used, but unless otherwise specified, the reaction time is usually 1 minute to 48 hours, for example, 1 minute to 8 hours.

[0258] 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 a 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 a reagent also functions as a reaction solvent, the reagent is used in the solvent amount.

[0259] In the reaction of each step, unless otherwise specified, the reaction is carried out without a solvent or after dissolving or suspending in a suitable solvent. Non-limiting examples of the solvent are the solvents described in the Examples or the solvents described below. 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.

[0260] In some embodiments, two or more types of the above solvents may be mixed in an appropriate ratio and used in the described methods.

[0261] In some embodiments, when a base is used in the reaction of each step, the bases listed below or the bases 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 alkoxides: 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.

[0262] In some embodiments, when an acid or acidic catalyst is used in the reaction of each step, the acid or acidic catalysts listed below or 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.

[0263] Unless otherwise specified, the reactions in each step are carried out according to a method known per se, for example, the methods described in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Chemistry 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 (Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (Elsevier Japan KK); Learning from Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989 Edition, or the method described in the Examples can be used.

[0264] In each step, the protection or deprotection reaction of functional groups can be carried out according to a method known per se, for example, Wiley-Interscience 2007 Edition "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts); Thieme 2004 Edition "Protecting Groups 3rd Ed." (PJ Kocienski), or the like, or according to the methods described in the Examples. This is done in accordance with the method described in

[0265] Examples of the protecting group for a hydroxyl group of an alcohol or a phenolic hydroxyl group 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; sulfonic acid ester-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate.

[0266] Non-limiting examples of protecting groups 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.

[0267] Non-limiting examples of protecting groups for the carbonyl group of a ketone 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.

[0268] Non-limiting examples of protecting groups for carboxyl groups include ester-type protecting groups such as methyl esters, and amide-type protecting groups such as N,N-dimethylamides.

[0269] Non-limiting examples of protecting groups for thiols include ether-type protecting groups such as benzylthioether, and and ester-type protecting groups such as thioacetates, thiocarbonates and thiocarbamates.

[0270] Non-limiting examples of protecting groups for amino groups or aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate, amide-type protecting groups such as acetamide, alkylamine-type protecting groups such as N-triphenylmethylamine, and sulfonamide-type protecting groups such as methanesulfonamide and o-nitrobenzenesulfonamide.

[0271] Protecting groups can be removed using methods known per se, such as, for example, acids, bases, thiols, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl hydrides (e.g., trimethylsilyl iodide or trimethylsilyl bromide), reduction methods, and the like.

[0272] When the reduction reaction is carried out in a step, 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, and triethylsilane. When reducing a carbon-carbon double or triple bond, a catalyst such as palladium-carbon or Lindlar's catalyst can be used.

[0273] When an oxidation reaction is carried out in the process, non-limiting examples of oxidizing agents that can be used 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, Highly 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).

[0274] When a radical cyclization reaction is carried out in the process, non-limiting examples of radical initiators that can be used 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, and benzoyl peroxide.Further, non-limiting examples of radical reaction reagents that can be used include tributylstannane, tris-trimethylsilyl-silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium diiodide.

[0275] When a Wittig reaction is carried out in the step, non-limiting examples of Wittig reagents that can be used include alkylidenephosphoranes. For example, alkylidenephosphoranes can be prepared by methods known per se, such as by reacting a phosphonium salt with a strong base.

[0276] If a Horner-Emmons reaction is carried out in the process, non-limiting examples of reagents that can be used include phosphonoacetates such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate, as well as alkali metal hydrides and organolithium compounds. It includes bases such as

[0277] When a Friedal-Crafts reaction is performed in the process, 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 or inorganic acid can be used in place of the Lewis acid, and an acid anhydride, such as acetic anhydride, can also be used in place of the acid chloride.

[0278] When an aromatic nucleophilic substitution reaction is carried out in the process, a nucleophile (eg, amines, 2-pyridone, imidazole, etc.) and a base (eg, organic or inorganic bases, etc.) are used as reagents.

[0279] When a carbanion-mediated nucleophilic addition reaction, a carbanion-mediated nucleophilic 1,4-addition reaction (Michael addition reaction), or a carbanion-mediated nucleophilic substitution reaction is carried out in the process, non-limiting examples of bases that can be used to generate the carbanion include organolithiums, metal alkoxides, organosilicon compounds, inorganic bases, and organic bases.

[0280] When a Grignard reaction is carried out in the 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.

[0281] When the Knoevanegel reaction is used in the process, 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, or inorganic bases) can be used as reagents.

[0282] When a Vilsmeier-Haack reaction is carried out in the process, phosphoryl chloride and amide derivatives (such as N,N'-dimethylformamide) may be used as reagents.

[0283] When azidation of carboxylic acids, alcohols, alkyl halides, and sulfonic acid esters is carried out in the process, usable azidation agents include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide. For example, when azidation of alcohols is carried out, 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 can be used.

[0284] If a Curtius rearrangement reaction is carried out in the process, non-limiting examples of solvents that can be used include toluene and dichloromethane.

[0285] When a reductive amination reaction is carried out in the step, non-limiting examples of reducing agents that can be used include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, hydrogen, and formic acid. When the substrate is an amine compound, non-limiting examples of carbonyl compounds that can be used include aldehydes such as paraformaldehyde and acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, non-limiting examples of amines that can be used include: These include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0286] When the Mitsunobu reaction is carried out in the step, azodicarboxylic acid esters (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine can be used as reagents. Furthermore, cyanomethylenetributylphosphorane (CMBP), cyanomethylenetrimethylphosphorane (CMMP), etc. can also be used as reagents.

[0287] If an esterification or amidation reaction is carried out in the process, non-limiting examples of reagents that can be used include acyl halides such as acid chlorides and acid bromides, acid anhydrides, activated carboxylic acids such as activated esters and sulfates. Non-limiting examples of activating agents for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD), triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM), benzotriazol-1-yloxy-trisdimethylaminophosphonium salts (BOP reagents), 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 a carbodiimide-based condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu) and dimethylaminopyridine (DMAP) may be further added to the reaction.

[0288] When a urea reaction of amines is carried out in the process, non-limiting examples of reagents that can be used include phosgene equivalents such as bis(trichloromethyl)carbonate, trichloromethyl chloroformate, and 1,1'-carbonyldiimidazole. When a urea reaction of carboxylic acids is carried out, non-limiting examples of reagents that can be used include azidation reagents such as diphenylphosphoryl azide (DPPA). Furthermore, in some embodiments, this reaction is carried out in the presence of a base. Non-limiting examples of bases include tertiary amines, aromatic amines, and basic salts.

[0289] When a dehydration condensation reaction is carried out in the process, non-limiting examples of solvents that can be used include alcohols such as ethanol, or aromatic hydrocarbons such as toluene. Additionally, in some embodiments, the reaction can be accelerated by adding an acid such as p-toluenesulfonic acid, or a dehydrating agent such as magnesium sulfate to the reaction.

[0290] When a coupling reaction is carried out in the step, non-limiting examples of metal catalysts that can 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, and platinum compounds. In some embodiments, a base may be further added to the reaction. Non-limiting examples of such bases include inorganic bases. Furthermore, in some embodiments, the reaction can be carried out by heat, light, or radicals such as benzoyl peroxide or azobisisobutyronitrile. The reaction can be accelerated by adding an initiator to the reaction.

[0291] When a thiocarbonylation reaction is carried out in the process, diphosphorus pentasulfide may be used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0292] When the Wohl-Ziegler reaction is used in the process, non-limiting examples of halogenating reagents that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, and sulfuryl chloride. Additionally, in some embodiments, the reaction can be accelerated by adding heat, light, or a radical initiator such as benzoyl peroxide or azobisisobutyronitrile to the reaction.

[0293] When the halogenation reaction of a hydroxy group is carried out in the step, non-limiting examples of halogenating agents that can be used include acid halides of hydrohalic acids and inorganic acids. Specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. can be used, and for bromination, 48% hydrobromic acid, etc. can be used. Furthermore, in some embodiments, a method can be used in which an alkyl halide is obtained from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc. Alternatively, in some embodiments, a method can be used in which an alkyl halide is synthesized by a two-step reaction in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide.

[0294] If an Arbuzov reaction is carried out in the process, non-limiting examples of reagents that can be used include alkyl halides such as ethyl bromoacetate, and phosphites such as triethyl phosphite or tri(isopropyl) phosphite.

[0295] When a sulfonate esterification reaction is carried out in the process, non-limiting examples of sulfonylating agents include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride and p-toluenesulfonic anhydride.

[0296] When a hydrolysis reaction is carried out in the process, an acid or a base may be used as a reagent. Furthermore, in some embodiments, when an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid, triethylsilane, etc. may be added to capture the tert-butyl cation generated as a by-product, respectively.

[0297] If a dehydration reaction is carried out in the process, non-limiting examples of dehydrating agents that can be used include sulfuric acid, diphosphorus pentasulfide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, and polyphosphoric acid.

[0298] Compound (I) can be produced according to the reaction schemes exemplified below or methods based on these schemes. The raw materials for compound (I) may be commercially available products or can be produced using methods known per se. Unless otherwise specified, the abbreviations in each general formula in the reaction schemes are as defined above.

[0299] For example, compound (Ia), in which Z in compound (I) is CH, can be produced from compound (1) or compound (4) using the following method: 101 and R 12 is a substituent, and each of the other symbols is as defined above.

[0300] R 101 and R 12 Non-limiting examples of the "substituents" denoted by include methyl and ethyl groups. [ka]

[0301] Compound (3) can be produced by a urea reaction of compound (1) and compound (2).

[0302] Compound (5) can be produced by azidation of compound (4) followed by a Curtius rearrangement reaction.

[0303] Compound (3) can also be produced by a urea reaction of compound (5) and compound (2).

[0304] Compound (Ia) can be produced by deprotection of the acetal of compound (3) followed by intramolecular cyclization.

[0305] Compound (Ib), in which Z in compound (I) is C—CH, can be produced from compound (1) using the following method, where each symbol is as defined above. [ka]

[0306] Compound (7) can be produced by a urea reaction of compound (1) and compound (6).

[0307] Compound (Ib) can be produced by cyclization of compound (7) by activation of the alkyne, followed by isomerization by acid treatment. When performing the cyclization reaction, non-limiting examples of reagents that can be used include tetrabutylammonium fluoride (TBAF) and gold(I) chloride. Furthermore, when performing the isomerization reaction, non-limiting examples of reagents that can be used include hydrochloric acid and trifluoroacetic acid.

[0308] Z in compound (I) is CR 2 Compound (Ic), which is: can be prepared from compound (1) using the following method: 13 and R 14 is a substituent, and each of the other symbols is as defined above.

[0309] Non-limiting examples of "leaving groups" represented by L include halogen atoms, C 1-6 Alkyl sulfonyloxy groups (e.g., methanesulfonyloxy or ethanesulfonyloxy) and C 1-6C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (eg, benzenesulfonyloxy or toluenesulfonyloxy) are included.

[0310] R 13 and R 14 Non-limiting examples of the "substituents" denoted by include methyl and ethyl groups. [ka]

[0311] Compound (9) can be produced by a urea reaction of compound (1) and compound (8). This can be done.

[0312] Compound (12) can be produced by deprotection of the acetal of compound (9) followed by intramolecular cyclization.

[0313] Compound (11) can be produced by a urea reaction of compound (1) and compound (10).

[0314] Compound 12 can be produced by ureation of compound 11. When an intramolecular cyclization reaction is performed, non-limiting examples of reagents include trifluoroacetic acid.

[0315] Compound (Ic) can be produced by the Mitsunobu reaction of compound (12) and compound (13).

[0316] Compound (Ic) can also be produced by alkylation reaction of compound (12) and compound (14).

[0317] Compound (Id), in which Z in compound (I) is N, can be prepared from compound (15) using the following method: 15 is a substituent, and each of the other symbols is as defined above.

[0318] R 15 Non-limiting examples of the "substituents" denoted by include methyl and ethyl groups. [ka]

[0319] Compound (17) can be produced by a dehydration condensation reaction of compound (15) and compound (16).

[0320] Compound (18) can be produced by hydrolysis of compound (17).

[0321] Compound (19) can be produced by azidation of compound (18).

[0322] Compound (20) can be produced by the Curtius rearrangement of compound (19) followed by a cyclization reaction.

[0323] Compound (Id) can be produced by the Mitsunobu reaction of compound (20) and compound (13).

[0324] Compound (Id) can also be produced by alkylation reaction of compound (20) and compound (14).

[0325] Compound (2) can be produced from compound (21a) or (21b) by the following method, where the symbols are as defined above. [ka]

[0326] Compound (2) can be produced by a reductive amination reaction of compound (21a) and compound (22).

[0327] Compound (23) can be produced by a dehydration condensation reaction of compound (21b) and compound (22).

[0328] Compound (2) can also be produced by carbanion-mediated nucleophilic addition of compound (23). When nucleophilic addition is performed, non-limiting examples of reagents that can be used include methylmagnesium bromide and trifluoromethyltrimethylsilane.

[0329] Compound (6) can be produced from compound (24) using the following method: wherein P is a protecting group for the amino group, and the other symbols are as defined above.

[0330] Non-limiting examples of "protecting groups" denoted by P include acetyl and o-nitrobenzenesulfonyl groups. [ka]

[0331] Compound (25) can be produced by a protection reaction of compound (24).

[0332] Compound (26) can be produced by the Mitsunobu reaction of compound (25) and compound (13).

[0333] Compound (26) can also be produced by alkylation reaction of compound (25) and compound (14).

[0334] Compound (6) can be produced by deprotection reaction of compound (26).

[0335] Compounds (1), (4), (8), (10), (13) to (16), (21a), (21b), (22), and (24) can be obtained as commercially available products or can be produced by known methods, analogous methods, or methods described in the Examples.

[0336] In the compound (I) obtained by this method, the functional groups in the molecule can be converted to the desired functional group by combining known chemical reactions, including, but not limited to, oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0337] In the above-mentioned production method, 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 that is thought to be commonly used in peptide chemistry for these groups may be introduced, and the target compound can be obtained by removing the protecting group after the reaction, as necessary.

[0338] The configurational isomers (E- and Z-isomers) of Compound (I) can be isolated and purified by separation techniques such as extraction, recrystallization, distillation, or chromatography to produce pure compounds upon isomerization. Furthermore, the corresponding pure isomers can be obtained by allowing the isomerization of the double bond to proceed using heating, acid catalysts, transition metal complexes, metal catalysts, radical species catalysts, light irradiation, strong base catalysts, etc., according to the methods described in New Experimental Chemistry Lectures vol. 14 (edited by the Chemical Society of Japan), pp. 251-253, and in Fourth Edition Experimental Chemistry Lectures vol. 19 (edited by the Chemical Society of Japan), pp. 273-274, or methods analogous thereto.

[0339] Stereoisomers may be produced depending on which type of substituents are used in compound (I), in which case compounds without this isomerization and mixtures thereof are also included within the scope of the present disclosure.

[0340] If the target product is to be obtained in the free state by the above reaction, the conventional method In the case where the target product is obtained as a salt, the salt may be converted into a free form or another salt by a conventional method. For example, the compound (I) obtained in this manner can be isolated and purified from the reaction solution by known means, such as elution, concentration, solvent extraction, fractional distillation, crystallization, recrystallization or chromatography.

[0341] When compound (I) exists as a configurational isomer, diastereomer, conformer, or the like, it may be optionally converted into the above-mentioned isomer. Furthermore, when Compound (I) is racemic, it can be separated into d- and l-forms, or S- and R-forms, by conventional optical resolution.

[0342] Compound (I) obtained by this method, as well as other reaction intermediates and starting compounds, can be isolated and purified from the reaction mixture by a method known per se, for example, by using means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, preparative high-performance liquid chromatography (preparative HPLC) or medium-pressure preparative liquid chromatography (medium-pressure preparative LC).

[0343] The salt of compound (I) can be produced in accordance with 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.

[0344] When enantiomers exist in compound (I), these individual enantiomers and mixtures thereof are also included within the scope of the present disclosure. These isomers can also be optically resolved or individually produced, if desired, according to known means.

[0345] 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.

[0346] As described in detail in the test examples below, the GPR139 receptor inverse agonism can be confirmed, for example, by a decrease or inhibition of the production of inositol monophosphate (also abbreviated herein as IP1), which is a metabolic product of inositol triphosphate (also abbreviated herein as IP3), a second messenger downstream of signal transduction in GPR139.

[0347] Compound (I) can be used as a preventive or therapeutic agent or diagnostic agent for various diseases described below in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). Compound (I) can be used, for example, as follows: (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), 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, anhedonia) 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, 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 depression with anhedonia, Treatment-resistant bipolar disorder with anhedonia, Depressive symptoms, Mania, Manic episode, Hypomanic episode, Manic-like episode, Hypomanic-like episode, Delirium, Peri-dementia 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 disorder, post-traumatic stress disorder, schizoaffective disorder, paranoid or depressive schizoaffective disorder, paranoid personality disorder, Tourette's syndrome, autism spectrum disorder, fragile X syndrome, Rett syndrome, adjustment disorder, bipolar disorder (including bipolar disorder type I and bipolar disorder type II), neurosis, substance addiction, schizophrenia (e.g., positive symptoms, negative symptoms, cognitive dysfunction, paranoid schizophrenia, disorganized schizophrenia, catatonic Schizophrenia, undifferentiated schizophrenia, and residual schizophrenia), schizophrenia spectrum disorder, movement disorder, mental retardation, paranoia, schizophreniform disorder, catatonia, neurosis, fatigue, chronic fatigue syndrome, loss of energy, anxiety neurosis, obsessive-compulsive disorder, panic disorder, epilepsy, anxiety symptoms, dysphoric mental state, dysthymia, cyclothymia, irritability, syncope, dependence, decreased libido, attention deficit hyperactivity disorder (ADHD), psychotic major depression, treatment-refractory major depression, treatment-resistant depression, treatment-resistant major depression, cognitive dysfunction in major depression, treatment-resistant bipolar disorder, temper tantrums, weight gain, weight loss , psychomotor agitation, psychomotor retardation, feelings of worthlessness, guilt, impaired thinking or concentration, suicidal ideation, suicide attempt, melancholia, psychotic disorders (e.g., brief psychotic disorder and 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 and Anorexia Nervosa), Psychogenic Anorexia, Atypical Anorexia Nervosa, Bulimia, Bulimia Nervosa (Bulimia Nervosa), Hyperemesis Nervosa, Atypical Bulimia Nervosa, Binge Eating Disorder, Psychogenic Binge Eating, Psychogenic Emesis of Pregnancy and 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 disorders, mild cognitive impairment, learning disabilities (e.g., dyslexia, dyscalculia, and written expression disorders), or age-related cognitive / memory disorders (e.g., age-related memory impairment and senile dementia) (4) Sleep disorders (e.g., endogenous sleep disorders (e.g., psychophysiological insomnia), exogenous sleep disorders, circadian rhythm disorders (e.g., jet lag, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake pattern, etc.), parasomnias (e.g., non-REM sleep arousal disorders (e.g., sleepwalking, sleep startle disorder, etc.), nightmare disorders, REM sleep disorders, and restless legs syndrome, etc.), medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, pulmonary Sleep disorders associated with Parkinson's disease, vascular dementia, schizophrenia, depression and anxiety), stress 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, hypnotic dependence, anxiolytic dependence, psychostimulant (e.g., amphetamine-type substances, cocaine, cathinone, synthetic cations, NMDA, NMDA-related drugs (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) dependence, cannabis (including synthetic cannabinoids) withdrawal, hallucinogen intoxication, hallucinogen persistent perception disorder, inhalant dependence, opioid dependence, opioid withdrawal, analgesic dependence, hypnotic dependence, anxiolytic dependence, analgesic withdrawal, hypnotic withdrawal, anxiolytic withdrawal, psychostimulant intoxication, psychostimulant withdrawal, caffeine withdrawal, tobacco withdrawal, nicotine withdrawal, substances (alcohol, caffeine) Drugs, 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, obsessive-compulsive disorder and related disorders, sleep disorders, sexual dysfunction, delirium, neurocognitive disorders, etc.), acute intoxication, 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 with delirium, psychotic disorders (e.g., toxic psychosis, steroid psychosis, etc.), amnesic syndromes, residual and delayed-onset psychotic disorders (e.g., drug-addicted depressive states, etc.), psychotropic drug side effects, addictive mental disorders, drug-induced mental disorders, drug addiction, drug phobia, drug mania, and drug withdrawal) (6) Respiratory depression caused by anesthetics, trauma, or neurodegenerative diseases (7) Pain (e.g., psychogenic pain (somatoform disorders, pain disorders, somatization disorders, hypochondriasis, conversion disorders, chronic pain with depression, psychogenic glossodynia, psychogenic headache, psychogenic back pain, psychogenic abdominal pain, neurogenic otalgia, somatic pain disorders, psychopathia, and 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, post-thoracotomy pain syndrome, peripheral neuropathic pain, peripheral neuropathic pain, neuropathic pain, central neuropathic pain, central neuropathic pain) pain, central post-stroke pain, etc.), tenderness, generalized pain, dull pain, cutaneous pain, radiating pain, headache (e.g., inflammatory headache, facial pain, occipital pain, odontogenic facial pain, habitual headache, neuralgic headache, frontal pain, temporal pain, head and neck pain, heavy head, vertex pain, paroxysmal headache, buccal pain, traction headache, burning mouth syndrome, primary headache, headache due to psychiatric disorders, migraine, chronic cluster headache, cluster headache, trigeminal / autonomic headache, episodic cluster headache, paroxysmal hemicrania, episodic hemicrania, chronic paroxysmal hemicrania, conjunctival congestion and flow Short-lasting unilateral neuralgiform headache attacks with tearing, 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 unilateral headache, 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, sleep headache, new-onset persistent daily headache, headache due to epileptic seizures, hypertensive headache, nasal / headache due to sinus disease, tension headache, etc.), trigeminal neuropathy (e.g., trigeminal neuralgia, atypical facial pain, trigeminal hypersensitivity, trigeminal neuropathy, etc.), glossopharyngeal neuropathy (e.g., glossopharyngeal neuralgia, etc.), vagal neuropathy (e.g., superior laryngeal neuralgia, vagal pain, etc.), hypoglossal neuropathy, cranial multiple neuropathy, postherpetic neuralgia, postherpetic trigeminal neuralgia, postherpetic polyneuropathy, neuralgic amyotrophy, phantom limb pain, amputation neuralgia, deafferentation pain, lumbar sciatica, mononeuropathy of the upper limb (e.g., median nerve neuralgia, ulnar neuralgia, etc.), mononeuropathy of the lower extremities (e.g., dyssensory femoral 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 somatic symptom 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), and (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 , 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), stress-induced immunodeficiency syndrome, 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, and postoperative ileus It is expected that the compound will be useful as a preventive or therapeutic agent for diseases such as the above.

[0348] Compound (I) may also be used in the form of a prodrug.

[0349] A prodrug of compound (I) refers to a compound that is converted to compound (I) under physiological conditions in the body by a reaction induced by an enzyme, gastric acid, or the like, i.e., a compound that is converted to compound (I) by oxidation, reduction, hydrolysis, or the like induced by an enzyme, or a compound that is converted to compound (I) by inducing hydrolysis, etc., by gastric acid, etc.

[0350] Non-limiting examples of prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosanosylated, alanylated, pentylaminocarbonylated (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated, etc.), compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated, or boronated (e.g., compounds in which the hydroxylation of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, etc.), Compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated, or the like) are included. These compounds can be produced from compound (I) according to methods known per se. A prodrug of compound (I) may be a compound that is converted to compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163-198, Hirokawa Shoten, 1990.

[0351] Compound (I) has excellent pharmacokinetic properties (e.g., blood drug half-life, brain transferability, and metabolic stability) and low toxicity (e.g., excellent as a pharmaceutical in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, carcinogenicity, etc.), and can be used as a pharmaceutical directly or in a mixture with at least one pharmaceutically acceptable carrier. The pharmaceutical composition 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.).

[0352] As used herein, "parenteral administration" includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, and peritumoral administration, and administration directly to a lesion.

[0353] In some embodiments, the dosage of Compound (I) varies depending on the route of administration, symptoms, etc. In some embodiments, when orally administered to a patient with depression (e.g., an adult weighing 40 kg to 80 kg, e.g., 60 kg), the dosage is, for example, 0.001 to 1000 mg per kg of body weight per day, for example, 0.01 to 100 mg per kg of body weight per day, and for example, 0.1 to 10 mg per kg of body weight per day. This amount can be divided into, for example, one to three doses per day.

[0354] The medicament containing compound (I) can be used as compound (I) alone, or as a pharmaceutical composition prepared by mixing compound (I) and at least one pharmaceutically acceptable carrier in accordance with a method known per se as a method for producing pharmaceutical preparations (for example, a method described in the Japanese Pharmacopoeia). The medicament containing compound (I) can be used 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 (for example, immediate-release preparations, sustained-release preparations, or sustained-release microcapsules), aerosols, films (for example, orally disintegrating films or oral mucus). The compositions can be safely administered orally or parenterally (intravenously, intramuscularly, subcutaneously, intraviscerally, intranasally, intradermally, by eye drop, intracerebral, rectal, vaginal, intraperitoneal or intralesional administration, etc.) as a drug, injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection or intraperitoneal injection), drip infusion, transdermal preparation, ointment, lotion, patch, suppository (e.g., rectal suppository or vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop, etc.

[0355] Various organic or inorganic carriers commonly used as starting materials for formulations may be used as the "pharmaceutically acceptable carrier" described above. For example, excipients, lubricants, binders, disintegrants, etc. may be used in solid formulations, while solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. may be used in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, coloring agents, and sweeteners may also be used, if necessary.

[0356] Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.

[0357] Non-limiting examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.

[0358] Non-limiting examples of binders include microcrystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose.

[0359] Non-limiting examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, and L-hydroxypropyl cellulose. Contains cellulose.

[0360] Non-limiting examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.

[0361] Non-limiting examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0362] Non-limiting examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerol monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0363] Non-limiting examples of tonicity agents include glucose, D-sorbitol, sodium chloride, glycerin, and D-mannitol.

[0364] Non-limiting examples of buffering agents include buffer solutions such as phosphate, acetate, carbonate and citrate.

[0365] Non-limiting examples of soothing agents include, for example, benzyl alcohol.

[0366] Non-limiting examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0367] Non-limiting examples of antioxidants include sulfites, ascorbic acid, and alpha-tocopherol.

[0368] The pharmaceutical composition may vary depending on the dosage form, and in some embodiments, the administration method, carrier, etc., but can be produced according to conventional methods by adding Compound (I) in a ratio of, for example, 0.01 to 100% (w / w), e.g., 0.1 to 95% (w / w), relative to the total amount of the pharmaceutical composition.

[0369] Compound (I) may also be used in combination with other active ingredients (herein referred to as concomitant drugs).

[0370] Non-limiting examples of concomitant drugs include acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, and 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, Larin, 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 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin and 6-(3',4'-dimethoxyphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, their optically active forms, salts thereof, hydrates thereof and OM99-2 (WO 01 / 00663)), γ-secretase inhibitors, β-amyloid protein aggregation inhibitors (e.g., PTI-00703, Tramiprosate, PPI-368 (Japanese translation of JP 11-514333), PPI-558 (Japanese translation of JP 2001-500852), SKF-74652 (2-(4-methoxyphenyl)-3-[4-[3-(diethylamino)propoxy]benzoyl]-5-chlorobenzofuran, Biochem. J. (1999), 340(1), 283-289)), β-amyloid vaccines, β-amyloid Neurostimulants such as myloid-degrading enzymes (e.g., aniracetam and nicergoline), other Parkinson's disease medications (e.g., dopamine receptor agonists (e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, and amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline, remacemide, and riluzole), anticholinergics (e.g., thiamin monophosphate, thiamin monophosphate, thiamin monophosphate, thiamin monophosphate), ... drugs for treating abnormal behaviors and wandering associated with the progression of dementia (e.g., sedatives and 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-methoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline 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 their optically active substances, salts and hydrates), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, Rofecoxib, xylitol, aspirin, indomethacin, etc.), steroids (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anticytokine drugs (e.g., TNF inhibitors and MAP kinase inhibitors), urinary incontinence and frequent urination treatment agents (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or derivatives thereof (e.g., progesterone, estradiol, and estradiol benzoate), osteoporosis treatment agents (e.g., alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate dihydrogen nitrite; thorium, alendronate sodium hydrate, and incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, insomnia medications (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, and orexin receptor antagonists), schizophrenia medications (e.g., typical antipsychotics such as haloperidol; typical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; agents acting on metabotropic or ionotropic glutamate receptors; and ho 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, escitalopram hydrobromide, sertraline hydrochloride, paraxetine hydrochloride, escitalopram oxalate, plum, etc.), serotonin and norepinephrine reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT2A antagonists (e.g., pivamanserine tartrate), 5-HT2A inverse agonists, 5-HT3 antagonists (cyamemazine, etc.), non-cardioselective beta-blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), antipsychotics (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, thyroid hormones (T3 and 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 alcohol dependence, drugs for treating autism, drugs for treating chronic fatigue syndrome , anticonvulsants, antifibromyalgia drugs, anti-headache drugs, drugs for smoking cessation, drugs for myasthenia gravis, drugs for stroke, drugs for mania, drugs for hypersomnia, drugs for pain, drugs for dysthymia, drugs for autonomic nervous system disorders, drugs for male and female sexual dysfunction, drugs for migraine, drugs for pathological gambling, drugs for restless legs syndrome, drugs for substance abuse, drugs for alcohol-related disorders, drugs for irritable bowel syndrome, drugs for dyslipidemia such as cholesterol-lowering drugs (statins (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.) and squalene synthesis inhibitors), drugs for treating abnormal behavior or dementia-related wanderlust (sedatives, anti-anxiety drugs, etc.), anti-obesity drugs, anti-diabetics, drugs for treating diabetic complications, anti-hypertensive drugs, anti-hypotensive drugs, diuretics, chemotherapy drugs, immunotherapy drugs, anti-thrombotic drugs, anti-cancer drugs, etc.;

[0371] The above two or more types of concomitant drugs can also be used in combination in an appropriate ratio.

[0372] Furthermore, when the compounds of the present disclosure are used to treat or prevent one or more of the above-mentioned diseases, the compounds or pharmaceutically acceptable salts thereof 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, and vaccine preparations). Furthermore, the compounds or pharmaceutically acceptable salts thereof can also be used in combination with gene therapy or the like, or in combination with non-drug psychiatric treatments.

[0373] Non-limiting examples of antibody drugs and vaccine formulations include vaccine formulations for angiotensin II, vaccine formulations for CETP, CETP antibodies, TNFα antibodies and antibodies against other cytokines, amyloid beta vaccine formulations, type 1 diabetes vaccines (e.g., DIAPEP-277 available from Peptor), anti-HIV antibody or HIV vaccine formulations, and serotonin-releasing hormone (SHR) vaccines. These include antibodies or vaccine preparations against cytokines, renin / angiotensin 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 the blood coagulation and fibrinolysis system, and antibodies or vaccine preparations against proteins involved in carbohydrate metabolism or insulin resistance. Furthermore, compound (I) may also be used in combination with biologics related to growth factors such as GH or IGF.

[0374] Non-limiting examples of gene therapy methods include therapies using genes associated with cytokines, renin-angiotensin enzymes and their products, G-proteins, and G-protein coupled receptors and their phosphorylating enzymes, therapies using DNA decoys such as NFκB decoys, therapies using antisense, therapies using genes associated with enzymes or proteins involved in blood lipid metabolism (e.g., genes associated with the metabolism, excretion, and absorption of cholesterol, triglycerides, HDL cholesterol, or blood phospholipids), therapies using genes associated with enzymes or proteins involved in angiogenesis therapy for peripheral vascular disease, etc. (e.g., growth factors such as HGF and VEGF), therapies using genes associated with proteins involved in carbohydrate metabolism or insulin resistance, antisense to 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.).

[0375] Non-limiting examples of non-drug psychiatric treatments include psychotherapy, including modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and cognitive behavioral therapy.

[0376] Furthermore, the compounds of the present disclosure may 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 genetic modification), cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells and bone marrow stem cells), or artificial organs using tissue engineering (e.g., artificial blood vessels and cardiomyocyte sheets).

[0377] In some embodiments, combining Compound (I) with a concomitant drug may enable one or more of the following outcomes: (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 that of compound (I), the therapeutic effect can be maintained. (5) A synergistic effect can be obtained by using Compound (I) in combination with a concomitant drug.

[0378] The combined use of Compound (I) and a concomitant drug is referred to as the "concomitant drug of the present disclosure."

[0379] When using the combination agent of the present disclosure, the administration period of compound (I) and the combination drug is not limited, and compound (I) or a pharmaceutical composition thereof and the combination drug or a pharmaceutical composition thereof may be administered to a subject simultaneously or at staggered times. The dosage of the combination drug may be in accordance with the dosage used clinically and can be appropriately selected based on the administration subject, administration route, disease, combination, etc.

[0380] The administration form of the combination drug of the present disclosure is not 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: (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 for the same administration route; (3) administration of two preparations obtained by separately formulating compound (I) and the concomitant drug via the same administration route at different times; (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 at different times (for example, administration of compound (I) and then the concomitant drug in that order, or administration in the reverse order).

[0381] In some embodiments, the combination drug of the present disclosure has low toxicity, and the above-mentioned compound (I) and / or combination drug can be mixed with at least one pharmaceutically acceptable carrier in accordance with known methods and safely administered orally or parenterally (for example, by topical, rectal, or intravenous administration) in the form of a pharmaceutical composition, for example, a tablet (e.g., sugar-coated tablet or 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.

[0382] Non-limiting examples of pharmaceutically acceptable carriers that can be used to form the combinations of the present disclosure include those described above.

[0383] The mixing ratio of Compound (I) and the concomitant drug in the combination agent of the present disclosure can be appropriately selected based on the subject of administration, the administration route, the disease, etc.

[0384] For example, the content of Compound (I) in the combination agent of the present disclosure varies depending on the form of the formulation, and in some embodiments, the content 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.

[0385] The content of the concomitant drug in the combination agent of the present disclosure varies depending on the form of the formulation, but the content is usually 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, relative to the total weight of the formulation. [Example]

[0386] The present disclosure will be described in further detail hereinafter using examples, test examples and formulation examples. However, these examples, test examples and formulation examples do not limit the present disclosure and may be modified without departing from the scope of the present disclosure.

[0387] In the following examples, "room temperature" generally refers to a temperature between about 10°C and about 35°C. Unless otherwise specified, the ratios shown for mixed solvents refer to volume ratios. Furthermore, unless otherwise specified, % refers to % by weight.

[0388] Unless otherwise specified, elution by column chromatography in the examples was performed 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 also used for detection. For silica gel column chromatography, when the column is labeled as NH, aminopropylsilane-bonded silica gel was used, and when the column is labeled as Diol, 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel was used. For preparative high-performance liquid chromatography (HPLC), when the column is labeled as C18, In some cases, octadecyl-bonded silica gel was used. Unless otherwise specified, the ratios given for elution solvents refer to volume ratios.

[0389] 1 For H NMR analysis, ADC / SpecManager (trade name) software was used. Peaks with very gradual proton peaks, such as those of hydroxyl groups and amino groups, may not be specified.

[0390] MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shows the actual values ​​(found). Molecular ion peaks are usually observed, but data may also be observed as fragment ions. In the case of salts, molecular ion peaks or fragment ion peaks of the free form are observed.

[0391] Optical rotation ([α] D The unit of sample concentration (c) in ) is g / 100 mL.

[0392] Elemental analysis values ​​(Anal.) are presented as calculated values ​​(Calcd) and found values ​​(Found).

[0393] In the examples, the powder X-ray diffraction peaks refer to peaks measured at room temperature using an ULtima IV (Rigaku Corporation, Japan) with Cu Kα radiation as the radiation source. The measurement conditions were as follows: Electric pressure / Electric current:40 kV / 50 mA Scan speed: 6 degrees / min Scan range of 2 Theta:2-35 degree

[0394] In the examples, the crystallinity determined by powder X-ray diffraction was calculated by the Hermans method.

[0395] 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 1 H NMR: proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: Atmospheric pressure chemical ionization CH3CN:Acetonitrile DIPEA: Diisopropylethylamine NBS: N-bromosuccinimide BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl TFA: Trifluoroacetic acid THF: tetrahydrofuran DMSO: dimethyl sulfoxide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dba)2: bis(dibenzylideneacetone)palladium(0) PdCl2(dppf): Dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium TEA: Triethylamine DPPA: Diphenylphosphoryl azide DEAD: Diethyl azodicarboxylate MeOH: Methanol PPh3: Triphenylphosphine EtOH: ethanol NaBH4: sodium borohydride TBAF: Tetrabutylammonium fluoride NFSI: N-fluorobenzenesulfonimide Example 1 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[4'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-1,3-dihydro-2H-imidazol-2-one A) 4'-Fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-3-amine

[0396] Potassium carbonate (1.73 g) and PdCl2(dppf) (0.457 g) were added to a mixture of (4-fluorophenyl)boronic acid (1.84 g) and 3-bromo-5-(trifluoromethyl)aniline (3.00 g) at room temperature, followed by stirring overnight at 80 °C under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and added to water at room temperature. 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). The resulting solid was washed with diisopropyl ether and dried under reduced pressure to give the title compound (3.45 g).

[0397] 1 H NMR(300 MHz, CDCl3) δ 3.93 (2H, brs), 6.88 (1H, s), 6.97 (1H, s), 7.06-7.18 (3H, m), 7.46-7.56 (2H, m). B) 1-[4'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-1,3-dihydro-2H-imidazol-2-one

[0398] To a solution of 4'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-3-amine (636 mg) in toluene (10 mL) was added bis(trichloromethyl)carbonate (370 mg) and triethanolamine (378 mg) at room temperature. The mixture was stirred overnight. 2,2-Dimethoxyethylamine (0.266 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was diluted with CH3CN (5.0 mL), and water (1.0 mL) and trifluoroacetic acid (1.0 mL) were added at room temperature. The mixture was stirred at 60 °C for 5 hours. The mixture was diluted with ethyl acetate and added to water at room temperature. 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). The resulting solid was washed with diisopropyl ether and dried under reduced pressure to give the title compound (245 mg). MS: [M+H] + 309.2. C) 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[4'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-1,3-dihydro-2H-imidazol-2-one

[0399] A suspension of sodium hydride (60% content, 12.4 mg) in DMF (0.5 mL) was added to 1-[4'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl] To the mixture was added 1,3-dihydro-2H-imidazol-2-one (40 mg) at room temperature. The mixture was stirred at room temperature for 10 minutes. A solution of 4-(chloromethyl)-1-ethyl-1H-pyrazole (26.9 mg) in DMF (0.30 mL) was added dropwise at room temperature. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and added to water at room temperature. 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 (13 mg).

[0400] 1 H NMR (300 MHz, CDCl3) δ 1.48 (3H, t, J= 7.3 Hz), 4.09-4.21 (2H, m), 4.74 (2H, s), 6.38 (1H, d, J = 3.0 Hz), 6.64 (1H, d, J = 3.0 Hz), 7.16 (2H, t, J = 8.7 Hz), 7.49 (2H, d, J = 10.5 Hz), 7.54-7.68 (3H, m), 7.78 (1H, s), 8.07-8.20 (1H, m). Example 2 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 A) (2R)-4-[4-fluoro-3-nitro-5-(trifluoromethyl)phenyl]-2-methylmorpholine

[0401] 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).

[0402] MS: [M+H] + 309.2. B) 2-Fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)aniline

[0403] 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).

[0404] MS: [M+H] + 279.2. C) N-(2,2-dimethoxyethyl)-N'-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}urea

[0405] 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).

[0406] 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

[0407] 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 obtain the title compound (722 mg).

[0408] MS: [M+H] + 346.2. E) Ethyl 1-ethyl-1H-pyrazole-4-carboxylate

[0409] 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).

[0410] 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

[0411] 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 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. Impurities were removed by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (29.9 g).

[0412] 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

[0413] To a mixture of (1-ethyl-1H-pyrazol-4-yl)methanol (2.33 g) and CH3 (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).

[0414] 1H 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

[0415] To a mixture of sodium hydride (60% content, 29.0 mg) and DMF (3 mL), 1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one (100 mg) was added at room temperature. The mixture was stirred at room temperature for 30 minutes, and then added to a mixture of 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (79 mg) and DMF (2 mL) and sodium iodide. Thorium (43.4 mg) was added and the mixture was stirred at room temperature overnight. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (70.0 mg).

[0416] 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). Example 18 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one A) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]prop-2-yn-1-amine

[0417] To a mixture of 1-ethyl-1H-pyrazole-4-carbaldehyde (1.20 g) and toluene (10 mL), prop-2-yn-1-amine (0.928 mL) was added, and the mixture was heated to reflux for 2 hours. After cooling, the mixture was added to a mixture of NaBH (0.366 g) and MeOH (10 mL) at 0 °C and stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.21 g).

[0418] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.3 Hz), 2.09-2.22 (1H, m), 3.06 (1H, t, J = 2.4 Hz), 3.26 (2H, d, J = 2.6 Hz), 3.57 (2H, s), 4.06 (2H, q, J = 7.2 Hz), 7.30 (1H, s), 7.57 (1H, s). B) (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine

[0419] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (140 g), potassium carbonate (224 g), (2R)-2-methylmorpholine hydrochloride (94.0 g), and DMSO (1400 mL) was stirred at 100° C. for 5 hours. After cooling to room temperature, the mixture was diluted with water and stirred at room temperature for 30 minutes. The resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (180 g).

[0420] MS: [M+H] + 281.0. C) 6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine

[0421] A mixture of (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (800 mg), diphenylmethanimine (0.622 mL), Pd(dba)2 (246 mg), BINAP (355 mg), sodium tert-butoxide (411 mg), and toluene (13 mL) was heated at 140 °C under microwave irradiation for 1 hour, and then methanol (10 mL) and 1N hydrochloric acid (10 mL) were added. The mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and then by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (612 mg).

[0422] 1 H NMR (300 MHz, DMSO-d6) δ 1.13 (3H, d, J = 6.0 Hz), 2.42 (1H, dd, J = 12.8, 10.2 Hz), 2.74 (1H, td, J = 12.3, 3.6 Hz), 3.41-3.61 (2H, m), 3.82-3.92 (1H, m), 3.96-4.17 (2H, m), 5.98 (1H, s), 6.08 (1H, s), 6.13 (2H, s). D) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-N-prop-2-yn-1-yl urea

[0423] To a mixture of 6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (200 mg) and THF (3 mL), TEA (0.107 mL) and bis(trichloromethyl)carbonate (114 mg) were added at 0°C and stirred at room temperature for 2 hours. To the mixture, a mixture of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]prop-2-yn-1-amine (214 mg) and THF (2 mL) and TEA (0.107 mL) were added, 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 (ethyl acetate / hexane) to give the title compound (248 mg).

[0424] MS: [M+H] + 451.3. H) 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one

[0425] To a mixture of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-N-prop-2-yn-1-ylurea (100 mg) and THF (1 mL) was added 1M TBAF / THF solution (0.244 mL) at room temperature, and the mixture was stirred at 80 °C for 30 minutes in a sealed tube. After cooling to room temperature, the mixture was poured into 2N hydrogen chloride / ethanol solution (1 mL), and the mixture was stirred at room temperature for 5 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (74.6 g).

[0426] 1 H NMR (300 MHz, DMSO-d6) δ 1.13-1.17 (3H, m), 1.33 (3H, t, J = 7.3 Hz), 2.16 (3H, d, J = 1.1 Hz), 2.54-2.63 (1H, m), 2.90 (1H, td, J = 12.4, 3.4 Hz), 3.47-3.60 (2H, m), 3.90 (1H, dd, J = 11.5, 2.4 Hz), 4.06-4.21 (4H, m), 4.56 (2H, s), 6.44 (1H, d, J = 1.1 Hz), 7.02 (1H, s), 7.29 (1H, s), 7.42 (1H, s), 7.72 (1H, s). Example 30 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one A) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1-dimethoxypropan-2-amine

[0427] To a mixture of 1-ethyl-1H-pyrazole-4-carbaldehyde (300 mg) and toluene (4 mL), 1,1-dimethoxypropan-2-amine (331 mg) was added, and the mixture was heated to reflux at 130 °C for 2 hours. After cooling to room temperature, the mixture was added to a suspension of NaBH (183 mg) and MeOH (4 mL) at 0 °C and stirred at the same temperature for 30 minutes. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (510 mg).

[0428] MS: [M+H] + 228.2 B) (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine

[0429] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (140 g), potassium carbonate (224 g), (2R)-2-methylmorpholine hydrochloride (94.0 g), and DMSO (1400 mL) was stirred at 100° C. for 5 hours. After cooling to room temperature, the mixture was diluted with water and stirred at room temperature for 30 minutes. The resulting solid was collected by filtration and dried under reduced pressure to obtain the title compound (180 g). C) (2R)-4-[6-chloro-5-iodo-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine

[0430] To a mixture of (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (90.0 g) and THF (720 ml), 2M lithium diisopropylazanide solution (240 ml) was added at -60°C under an argon atmosphere and stirred at the same temperature for 30 minutes. To the mixture, a mixture of iodine (122 g) and THF (180 ml) was added at -60°C and stirred at the same temperature for 30 minutes. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with water, 20% aqueous sodium thiosulfate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with diisopropyl ether to give the title compound (101 g).

[0431] MS: [M+H] + 406.9 D) 3-Fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine

[0432] To a mixture of (2R)-4-[6-chloro-5-iodo-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (3.00 g) and THF (15 mL) was added dropwise 1.0 M isopropylmagnesium chloride-lithium chloride / THF solution (9.40 mL) at 0°C under a nitrogen atmosphere and stirred at the same temperature for 40 minutes. The mixture was added dropwise to a mixture of NFSI (3.72 g), THF (12 mL), and heptane (6 mL) at 0°C under a nitrogen atmosphere and stirred at the same temperature for 30 minutes. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with 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). A mixture of the resulting oil, Pd2(dba)3 (353 mg), BINAP (480 mg), diphenylmethanimine (0.84 mL), sodium tert-butoxide (555 mg), and toluene (13 mL) was irradiated with microwaves at 140 °C for 1 hour. MeOH (20 mL) and 2N hydrochloric acid (20 mL) were added to the mixture at room temperature. The mixture was stirred at room temperature for 30 minutes, then water was added 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 (NH, ethyl acetate / hexane) to give the title compound (370 mg).

[0433] MS: [M+H] + 280.1 E) N-(1,1-dimethoxypropan-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}urea

[0434] To a mixture of 3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (167 mg), TEA (0.208 mL), and THF (3 mL) was added bis(trichloromethyl)carbonate (96.0 mg) at 0°C. The mixture was stirred at the same temperature for 30 minutes. A mixture of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1-dimethoxypropan-2-amine (163 mg), TEA (0.125 mL), and THF (2 mL) was added to the mixture at 0°C, and the mixture was warmed to room temperature and stirred at the same temperature for 1 hour. The mixture was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (170 mg).

[0435] MS: [M+H] + 533.2. H) 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-1,3-dihydro-2H-imidazol-2-one

[0436] N-(1,1-dimethoxypropan-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}urea (171 mg), CH3CN (5 mL), and water (1 mL) were added to a mixture of TFA (1.5 mL), and the mixture was stirred at 60 ° C. for 1.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), followed by silica gel column chromatography (ethyl acetate / hexane to ethyl acetate / methanol), and the resulting purified product was crystallized from ethyl acetate / heptane to obtain the title compound (92.3 mg).

[0437] 1H NMR (300 MHz, DMSO-d6) δ 1.15 (3H, d, J = 6.4 Hz), 1.32 (3H, t, J = 7.2 Hz), 2.09 (3H, d, J = 1.1 Hz), 2.52-2.59 (1H, m), 2.78-2.93 (1H, m), 3.46-3.64 (2H, m), 3.84-3.94 (1H, m), 3.97-4.18 (4H, m), 4.61 (2H, s), 6.59 (1H, d, J = 1.1 Hz), 7.11 (1H, d, J = 3.0 Hz), 7.37 (1H, s), 7.70 (1H, s). Example 60 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one A) (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine

[0438] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (3.10 g), (2R)-2-methylmorpholine hydrochloride (1.98 g), DIPEA (7.52 mL), and DMSO (6 mL) was heated at 160 °C for 30 minutes under microwave irradiation. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.63 g).

[0439] MS: [M+H] + 281.0. B) 6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine

[0440] A mixture of (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (800 mg), diphenylmethanimine (0.622 mL), Pd(dba)2 (246 mg), BINAP (355 mg), sodium tert-butoxide (411 mg), and toluene (13 mL) was heated at 140°C for 1 hour under microwave irradiation, and methanol (10 mL) and 1N hydrochloric acid (10 mL) were added. The mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was then washed with magnesium sulfate. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and then by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (612 mg).

[0441] 1 H NMR (300 MHz, DMSO-d6) δ 1.13 (3H, d, J = 6.0 Hz), 2.42 (1H, dd, J = 12.8, 10.2 Hz), 2.74 (1H, td, J = 12.3, 3.6 Hz), 3.41-3.61 (2H, m), 3.82-3.92 (1H, m), 3.96-4.17 (2H, m), 5.98 (1H, s), 6.08 (1H, s), 6.13 (2H, s). C) 2-(but-3-yn-2-yl)-1H-isoindole-1,3(2H)-dione

[0442] To a mixture of but-3-yn-2-ol (6.00 g), phthalimide (15.1 g), PPh3 (26.9 g), and THF (171 mL) was added a 40% DEAD / toluene solution (41.0 g) at 0 °C. The mixture was warmed to room temperature and stirred at the same temperature for 72 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate / hexane (200 mL). Insoluble matter was removed by filtration and washed with ethyl acetate / hexane (200 mL). The filtrate and washings were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) (twice) to give the title compound (7.08 g).

[0443] MS: [M+H] + 200.1. D) But-3-yn-2-amine hydrochloride

[0444] To a mixture of 2-(but-3-yn-2-yl)-1H-isoindole-1,3(2H)-dione (7.00 g) and EtOH (150 mL), hydrazine monohydrate (3.52 g) was added, and the mixture was stirred at 70 °C for 45 minutes. After cooling to room temperature, the insoluble material was removed by filtration and washed with ethanol (150 mL). The filtrate and washings were distilled at 30 °C and 45 mmHg to obtain a but-3-yn-2-amine / ethanol solution. To the mixture, a 2N hydrogen chloride / ethanol solution (35.1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure to obtain the title compound (3.09 g).

[0445] 1 H NMR (300 MHz, DMSO-d6) δ 1.43 (3H, d, J = 6.8 Hz), 3.67 (1H, d, J = 2.3 Hz), 4.03-4.24 (1H, m), 8.68 (3H, br s). E) N-(but-3-yn-2-yl)-2-nitrobenzene-1-sulfonamide

[0446] To a mixture of but-3-yn-2-amine hydrochloride (2.50 g) and pyridine (50 mL), 2-nitrobenzenesulfonyl chloride (5.77 g) and triethanolamine (9.90 mL) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.41 g).

[0447] 1H NMR (300 MHz, DMSO-d6) δ 1.32 (3H, d, J = 6.8 Hz), 3.09 (1H, d, J = 2.3 Hz), 3.33 (1H, s), 4.05-4.25 (1H, m), 7.82-7.90 (1H, m), 7.95-7.98 (1H, m), 8.02-8.10 (1H, m), 8.69 (1H, d, J = 8.3 Hz). F) Ethyl 1-ethyl-1H-pyrazole-4-carboxylate

[0448] 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).

[0449] 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). G) (1-Ethyl-1H-pyrazol-4-yl)methanol

[0450] 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).

[0451] 1H 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) H) N-(but-3-yn-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-nitrobenzene-1-sulfonamide

[0452] A mixture of N-(but-3-yn-2-yl)-2-nitrobenzene-1-sulfonamide (3.09 g), (1-ethyl-1H-pyrazol-4-yl)methanol (1.79 g), cyanomethylenetributylphosphorane (3.43 g), and THF (15 mL) was heated at 100° C. for 12 hours under microwave irradiation. After cooling to room temperature, the mixture was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.56 g).

[0453] MS: [M+H] + 363.1. I) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]but-3-yn-2-amine

[0454] Mercaptoacetic acid (3.25 g) was added to a mixture of N-(but-3-yn-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-nitrobenzene-1-sulfonamide (2.56 g), lithium hydroxide monohydrate (2.96 g), and DMF (30 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and toluene (100 mL), and the insoluble material was removed by filtration and washed with ethyl acetate (50 mL). The filtrate and washings were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.12 g).

[0455] MS: [M+H] + 178.2. J) N-but-3-yn-2-yl-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}urea

[0456] To a mixture of 6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (85.0 mg), TEA (0.095 mL), and THF (3 mL), bis(trichloromethyl)carbonate (43.4 mg) was added at 0°C and stirred at the same temperature for 30 minutes. To the mixture, a mixture of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]but-3-yn-2-amine (69.2 mg), TEA (0.054 mL), and THF (2 mL) was added at 0°C and stirred at room temperature for 1 hour. The mixture was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (120 mg).

[0457] MS: [M+H] + 465.2. K) 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one

[0458] To a mixture of N-but-3-yn-2-yl-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}urea (360 mg) and THF (5 mL) was added 1M TBAF / THF solution (1.0 mL), and the mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, 2N hydrogen chloride / ethanol solution (5.0 mL) was added, and the mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the resulting purified product was crystallized from ethyl acetate / hexane to give the title compound (252 mg).

[0459] 1 H NMR (300 MHz, DMSO-d6) δ 1.15 (3H, d, J = 6.0 Hz), 1.32 (3H, t, J = 7.3 Hz), 2.04 (3H, d, J = 1.1 Hz), 2.11 (3H, s), 2.54-2.65 (1H, m), 2.79-3.01 (1H, m), 3.43-3.64 (2H, m), 3.84-3.97 (1H, m), 4.02-4.22 (4H, m), 4.61 (2H, s), 7.00 (1H, s), 7.25 (1H, s), 7.37 (1H, d, J = 0.8 Hz), 7.69 (1H, s). Example 91 2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one A) (5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazine

[0460] To a degassed solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.71 g) in THF (50 mL) was added di-μ-methoxybis(1,5-cyclooctadiene)diiridium(I) (0.236 g) followed by 4,4'-di-tert-butyl-2,2'-bipyridine (0.191 g) under an argon atmosphere. The mixture was stirred for 10 minutes, and then 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (5.03 g) was added. The mixture was stirred overnight at 40°C under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was dissolved in methanol (50 mL) and di-tert-butyl azodicarboxylate (4.08 g) and copper(II) acetate (3.21 g) were added at room temperature. The mixture was stirred at 45°C under a nitrogen atmosphere for 2.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and saturated aqueous ammonium chloride solution was added at room temperature. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution 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). The resulting solid was washed with diisopropyl ether and dried under reduced pressure. The resulting solid was suspended in methanol (25 mL), and 4 M hydrogen chloride / ethyl acetate solution (25 mL) was added at room temperature. The mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and added to saturated aqueous sodium bicarbonate solution at room temperature. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.42 g).

[0461] 1 H NMR (300 MHz, CDCl3) δ 3.64 (2H, br s), 5.62 (1H, br s), 7.04 (1H, dd, J = 5.7, 2.6 Hz), 7.54 (1H, dd, J = 7.0, 2.4 Hz). B) Ethyl 2-(2-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazinylidene)propanoate

[0462] Ethyl pyruvate (0.635 mL) was added to a solution of (5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazine (1.42 g) in methanol (20 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was suspended in diisopropyl ether. The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (1.45 g).

[0463] MS: [M+H] + 371.0 C) 2-(2-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazinylidene)propanoic acid

[0464] To a solution of ethyl 2-(2-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazinylidene)propanoate (1.93 g) in methanol (20 mL) was added 2 M aqueous sodium hydroxide solution (5.0 mL) at room temperature. The mixture was stirred at 40° C. for 2 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with water (15 mL), and then 1 M hydrochloric acid (10 mL) was added dropwise at room temperature. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (1.48 g).

[0465] 1 H NMR (300 MHz, DMSO-d6) δ1.55 (3H, s), 6.86 (1H, dd, J = 5.7, 2.6 Hz), 7.62 (1H, dd, J = 7.2, 2.3 Hz), 9.04 (1H, br s), 11.87 (1H, br d, J = 2.6 Hz). D) 2-{2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]hydrazinylidene}propanoyl azide

[0466] To a solution of 2-(2-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazinylidene)propanoic acid (1.48 g) in THF (15 mL) were added diphenylphosphoryl azide (1.21 mL) and TEA (0.783 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and added to water. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain the title compound (1.03 g).

[0467] 1 H NMR (300 MHz, CDCl3) δ 2.16 (3H, s), 7.32 (1H, dd, J = 5.7, 2.3 Hz), 7.92 (1H, br d, J = 2.6 Hz), 7.97 (1H, dd, J = 6.6, 2.4 Hz). E) 2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0468] A mixture of 2-{2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]hydrazinylidene}propanoyl azide (1.59 g) and toluene (15 mL) was stirred for 2 hours at 110° C. The mixture was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.09 g).

[0469] 1 H NMR (300 MHz, CDCl3) δ2.32 (3H, s), 7.73 (1H, dd, J = 5.5, 2.4 Hz), 7.92 (1H, dd, J = 6.0, 2.6 Hz), 9.73-10.14 (1H, m). F) 2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0470] 2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl To a mixture of 2,4-dihydro-3H-1,2,4-triazol-3-one (495 mg), [1-(propan-2-yl)-1H-pyrazol-4-yl]methanol (408 mg), and THF (10 mL), cyanomethylenetributylphosphorane (703 mg) was added, and the mixture was stirred at 80° C. for 4 hours. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (463 mg).

[0471] MS: [M+H] + 462.1. G) 2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0472] A mixture of 2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (47.4 mg), (2R)-2-methylmorpholine hydrochloride (21.2 mg), Pd(dba) (9.91 mg), sodium tert-butoxide (52.0 mg), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (10.3 mg), and toluene (2.0 mL) was stirred overnight at 80°C under a nitrogen atmosphere. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and HPLC (C18, mobile phase: water / CH3CN (10 mM ammonium bicarbonate system)), and then concentrated under reduced pressure to obtain the title compound (12.6 mg).

[0473] 1 H NMR (300 MHz, DMSO-d6) δ 1.14 (3H, d, J = 6.0 Hz), 1.38 (6H, d, J = 6.4 Hz), 2.29 (3H, s), 2.37 (1H, dd, J = 11.3, 10.2 Hz), 2.63-2.77 (1H, m),3.49 - 3.75 (4H, m), 3.84-3.97 (1H, m), 4.47 (1H, q, J = 6.7 Hz), 4.71 (2H, s), 7.20-7.27 (1H, m), 7.32 (1H, dd, J = 6.0, 3.0 Hz), 7.44 (1H, s), 7.80 (1H, s). Example 99 1-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one A) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1-dimethoxypropan-2-amine

[0474] To a mixture of 1-ethyl-1H-pyrazole-4-carbaldehyde (300 mg) and toluene (4 mL), 1,1-dimethoxypropan-2-amine (331 mg) was added, and the mixture was refluxed for 2 hours. After cooling, the mixture was added to a mixture of NaBH4 (183 mg) and MeOH (4 mL) at 0 °C and stirred at the same temperature for 30 minutes. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (510 mg).

[0475] MS: [M+H] + 228.1. B) Ethyl 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0476] Methanesulfonyl chloride (1.54 g) and TEA (1.36 g) were added to a mixture of 2-cyclobutylethan-1-ol (900 mg) and THF (20 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was neutralized with saturated aqueous sodium bicarbonate at 0°C 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 crude 2-cyclobutyl methanesulfonate (1.6 g). Ethyl To a mixture of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1.56 g) and DMF (15 mL), crude 2-cyclobutyl methanesulfonate (1.6 g) and potassium carbonate (1.55 g) were added and 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 (ethyl acetate / hexane) to give the title compound (1.99 g).

[0477] MS: [M+H] + 291.1. C) N'-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(1,1-dimethoxypropan-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]urea

[0478] To a mixture of ethyl 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1.99 g), THF (15 mL), and MeOH (5 mL) was added 4 M aqueous lithium hydroxide (5.14 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 6 N hydrochloric acid at 0 °C 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 crude 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid. To a mixture of crude 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (100 mg) and toluene (1 mL), TEA (46.3 mg) and DPPA (126 mg) were added at room temperature. The mixture was stirred at room temperature for 30 minutes, and then N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1-dimethoxypropan-2-amine (87 mg) was added. The mixture was stirred at 100° C. under an argon atmosphere for 2 hours. The residue was purified by HPLC (C18, mobile phase: water / CH3CN (10 mM ammonium bicarbonate system)) to give the title compound (185 mg).

[0479] MS: [M+H] + 487.3. D) 1-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one

[0480] To a mixture of N'-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(1,1-dimethoxypropan-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]urea (185 mg), CH3CN (2 mL), and water (0.4 mL) was added TFA (1 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (104 g).

[0481] 1 H NMR (300 MHz, CDCl3) δ 1.46 (3H, td, J = 7.3, 1.3 Hz), 1.50-1.64 (2H, m), 1.70-2.02 (4H, m), 2.11-2.15 (3H, m), 2.15-2.25 (1H, m), 4.01 (2H, t, J = 7.4 Hz), 4.13 (2H, qd, J = 7.4, 1.0 Hz), 4.71 (2H, s), 6.01 (1H, d, J = 1.4 Hz), 6.42 (1H, s), 7.46 (2H, d, J = 5.1 Hz). Example 103 4-Methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one A) N-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}prop-2-yn-1-amine

[0482] To a mixture of 1-isopropyl-1H-pyrazole-4-carbaldehyde (2.07 g) and toluene (30 mL), prop-2-yn-1-amine (1.07 g) was added, and the mixture was stirred at 80 °C for 3 hours. After cooling, the mixture was concentrated, and MeOH (30 mL) was added to the resulting residue. NaBH (0.851 g) was added to the mixture at 0 °C, and the mixture was stirred at the same temperature for 1 hour. The mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.00 g).

[0483] MS: [M+H] + 178.2. B) N'-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-N-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-N-prop-2-yn-1-yl urea

[0484] To a mixture of 6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (202.0 mg) and THF (15 mL), bis(trichloromethyl)carbonate (115 mg) and TEA (117 mg) were added at 0°C, and the mixture was stirred at room temperature for 30 minutes. After concentrating the mixture, the residue was suspended in THF (15 mL), and a mixture of N-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}prop-2-yn-1-amine (144 mg) and THF (4 mL) with TEA (218 mg) was added. The mixture was stirred at room temperature overnight. The mixture was added to saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, 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 (58.0 mg).

[0485] MS: [M+H] + 465.3. C) 4-methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one

[0486] To a mixture of N'-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-N-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-N-prop-2-yn-1-ylurea (50 mg) and THF (2 mL) was added 1M TBAF / THF solution (0.118 mL), and the mixture was stirred in a sealed tube at 80 °C for 30 min. After cooling, 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 5 min. The reaction mixture was then concentrated. The resulting residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (20 mg).

[0487] 1 H NMR (300 MHz, CDCl3) δ 1.26 (3H, d, J = 6.0 Hz), 1.49 (6H, d, J = 6.8 Hz), 2.20 (3H, d, J = 1.1 Hz), 2.67 (1H, dd, J = 12.8, 10.2 Hz), 2.93-3.10 (1H, m), 3.56-3.76 (2H, m), 3.93-4.10 (3H, m), 4.46 (1H, spt, J = 6.7 Hz), 4.66 (2H, s), 6.01 (1H, d, J = 1.5 Hz), 6.65 (1H, s), 7.42 (1H, s), 7.47 (1H, s), 7.49 (1H, s). Example 110 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[6-{[(1-fluorocyclobutyl)methyl]amino}-4-(trifluoromethyl)pyridin-2-yl]-4-methyl-1,3-dihydro-2H-imidazol-2-one A) 6-chloro-4-(trifluoromethyl)pyridin-2-amine

[0488] 2,6-Dichloro-4-(trifluoromethyl)pyridine (1 g), diphenylmethanimine (1.1 g), Pd2(dba)3 (0.21 g), BINAP (0.29 g), A mixture of sodium tert-butoxide (0.67 g) and toluene (17 mL) was irradiated with microwaves at 140°C for 1 hour. A 2N hydrogen chloride / ethanol solution (10 mL) was added to the mixture at room temperature. After stirring the mixture at room temperature for 1 hour, saturated aqueous sodium bicarbonate solution was added 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 obtain the title compound (277 mg).

[0489] 1 H NMR (300 MHz, CDCl3) δ 6.66 (1H, s), 6.77-6.83 (1H, m), 7.00 (2H, s). B) N'-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N-prop-2-yn-1-yl urea

[0490] To a mixture of 6-chloro-4-(trifluoromethyl)pyridin-2-amine (0.24 g) and THF (8 mL), TEA (0.13 g) and bis(trichloromethyl)carbonate (0.18 g) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, and then a solution of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]prop-2-yn-1-amine (0.20 mg) in THF (1 mL) and TEA (0.5 mL) were added. The mixture was stirred at room temperature for 12 hours, water was added, 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 (0.32 g).

[0491] MS: [M+H] +386.1. C) 3-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one

[0492] To a mixture of N'-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N-prop-2-yn-1-ylurea (320 mg) and THF (3 mL) was added 1M TBAF / THF solution (0.91 mL) and stirred at 80°C for 1 hour. 2N hydrogen chloride / ethanol solution (1 mL) was added to the reaction mixture at room temperature and stirred for 10 minutes. Saturated aqueous sodium bicarbonate 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 (ethyl acetate / hexane) to give the title compound (0.11 g).

[0493] MS: [M+H] + 386.2. D) 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[6-{[(1-fluorocyclobutyl)methyl]amino}-4-(trifluoromethyl)pyridin-2-yl]-4-methyl-1,3-dihydro-2H-imidazol-2-one

[0494] A mixture of 1-(1-fluorocyclobutyl)methanamine hydrochloride (21.7 mg), sodium tert-butoxide (49.8 mg), and DME (1 mL) was stirred at room temperature for 10 minutes. The mixture was then added with a solution of 3-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one (50 mg) in THF (0.5 mL), chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl tert-butyl ether adduct (4.7 mg), and dicyclohexyl(2',6'-diisopropoxy)phenyl. To the resulting mixture was added 2,4-dihydroxybenzophenone (6.1 mg) at room temperature. The mixture was irradiated with microwaves at 110°C for 1 hour, purified by silica gel column chromatography (ethyl acetate / hexane), and then further purified by HPLC (C18, mobile phase: water / CHCN (10 mM TFA system)). The resulting fraction was concentrated under reduced pressure to give the title compound (26 mg).

[0495] 1 H NMR (300 MHz, CDCl3) δ 0.85-0.94 (1H, m), 1.47 (3H, t, J = 7.3 Hz), 1.79-1.94 (1H, m), 2.08-2.19 (1H, m), 2.08-2.09 (1H, m), 2.21 (3H, d, J = 1.3 Hz), 2.24-2.46 (2H, m), 3.62-3.75 (1H, m), 3.66-3.67 (1H, m), 4.09 (1H, s), 4.10-4.18 (2H,m), 4.63-4.70 (1H, m), 4.66 (1H, s), 4.92 (1H, br t, J = 5.6 Hz), 5.99-6.02 (1H, m), 6.51 (1H, s), 7.32-7.36 (1H, m), 7.34 (1H, s), 7.47 (2H, d, J = 8.7 Hz). Example 127 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1,3-dihydro-2H-imidazol-2-one A) (1E)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2,2-dimethoxyethan-1-imine

[0496] Dimethoxyacetaldehyde (1.27 g) was added to a mixture of 1-(1-ethyl-1H-pyrazol-4-yl)methanamine (731 mg) and toluene (10 mL), and the mixture was stirred at 100° C. for 2 hours. After cooling, the mixture was concentrated under reduced pressure to obtain the title compound (1.23 mg).

[0497] 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.2 Hz), 3.30 (6H, s), 4.08 (2H, q, J = 7.3 Hz), 4.44 (2H, d, J = 0.8 Hz), 4.62 (1H, d, J = 4.9 Hz), 7.29 (1H, s), 7.51-7.57 (1H, m), 7.58 (1H, s). B) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1,1-trifluoro-3,3-dimethoxypropan-2-amine

[0498] To a mixture of (1E)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2,2-dimethoxyethan-1-imine (423 mg), potassium bifluoride (117 mg), DMF (439 mg), and CH3CN (4 mL), TFA (228 mg) was added at 0 °C and stirred at the same temperature for 5 minutes. Trimethyl(trifluoromethyl)silane (355 mg) was added to the mixture at 0 °C, and the mixture was stirred at room temperature for 15 minutes. The residue was purified by HPLC (C18, mobile phase: water / CH3CN (10 mM ammonium bicarbonate system)). The resulting fraction was concentrated under reduced pressure to give the title compound (75 mg).

[0499] MS: [M+H] + 282.2. C) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,1,1-trifluoro-3,3-dimethoxypropan-2-yl)urea

[0500] To a mixture of 3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (62 mg), TEA (53.9 mg), and THF (2 mL), bis(trichloromethyl)carbonate (26.4 mg) was added at 0°C, and the mixture was stirred at the same temperature for 30 minutes. N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1,1-trifluoro-3,3-dimethoxypropan-2-amine was added to the mixture. A solution of (73 mg) and TEA (33.7 mg) in THF (1 mL) was added at 0° C. and stirred at room temperature for 30 minutes. The mixture was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (116 mg).

[0501] MS: [M+H] + 587.3. D) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1,3-dihydro-2H-imidazol-2-one

[0502] A mixture of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N'-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,1,1-trifluoro-3,3-dimethoxypropan-2-yl}urea (116 mg), TFA (666 mg), CH3CN (3 mL) and water (0.3 mL) was irradiated with microwaves for 3 hours at 130 ° C. After cooling, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (64 mg).

[0503] 1H NMR (300 MHz, DMSO-d6) δ 1.15 (3H, d, J = 6.0 Hz), 1.31 (3H, t, J = 7.3 Hz), 2.54-2.62 (1H, m), 2.81-2.95 (1H, m), 3.45-3.63 (2H, m), 3.83-3.96 (1H, m), 4.04-4.19 (4H, m), 4.72 (2H, s), 7.26 (1H, d, J = 3.0 Hz), 7.36 (1H, s), 7.70 (1H, s), 7.76-7.81 (1H, m). Example 134 3-[4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]-1-[(1-ethyl-H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one A) 4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-amine

[0504] A mixture of 2,2-dimethylmorpholine (61.2 mg), 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine (70.0 mg), DIPEA (0.186 mL), and n-butyl alcohol (1 mL) was stirred overnight at 120° C. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (90.0 mg).

[0505] MS: [M+H] + 277.2. B) N'-[4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N-propion-2-yn-1-yl urea

[0506] To a mixture of 4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-amine and THF (2 mL) was added bis(trichloromethyl)carbonate (19.3 mg) at 0°C. The mixture was stirred at room temperature for 4 hours. N-[(1-ethyl-1H-pyrazol-4-yl)methyl]prop-2-yn-1-amine (31.9 mg) and triethanolamine (24.7 mg) were added to the mixture, which was then 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 (ethyl acetate / hexane) to give the title compound (73.1 mg).

[0507] MS: [M+H] + 466.3. C) 3-[4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one

[0508] To a mixture of N'-[4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-N-prop-2-yn-1-ylurea (73.1 mg) and THF (2 mL) was added 1M TBAF / THF solution (0.2 mL), and the mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, 2M hydrogen chloride / ethanol solution (0.12 mL) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). The resulting product was purified by HPLC (C18, mobile phase: water / CH3CN (10 mM ammonium bicarbonate system)). The resulting fraction was concentrated under reduced pressure to give the title compound (34.1 mg).

[0509] 1H NMR (300 MHz, DMSO-d6) δ 1.16 (6H, s), 1.34 (3H, t, J = 7.3 Hz), 2.00-2.06 (3H, m), 3.55-3.79 (6H, m), 4.08 (2H, q, J = 7.3 Hz), 4.53 (2H, s),6.38 (1H, d, J = 1.5 Hz), 7.26 (1H, s), 7.40-7.42 (1H, m), 7.72 (1H, s).

[0510] The compounds of the examples are shown in the following table, where MS represents the actual measured value. The compounds in the following table were prepared according to the methods described in the above examples or similar methods. Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 [Table 1-29] Test Example 1: Measurement of the inhibition rate of IP1 amount at 30 μM of the compound of Example 2 in GPR139-expressing CHO cells

[0511] 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 levels 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.

[0512] 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).

[0513] 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 provided with the cis-bio IP-ONE HTRF Assay Kit) prepared in lysis buffer (provided with 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 Envision (PerkinElmer) HTRF setting, and the ratio was calculated as {(signal 665 nm) / (signal 615 nm)} × 10000. The inhibition rate of IP1 at 30 μM of the compound of Example 2 was 84%, with 0% vehicle and 0 IP1 concentration set as 100%.

[0514] The compound of Example 2 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 compound of Example 2 has a GPR139 receptor inverse agonist effect. Test Example 2: Measurement of IP1 level inhibition rate in GPR139-expressing CHO cells (inverse agonist assay)

[0515] The activities of the compounds of Examples 1 and 3 to 167 were measured for IP1 level inhibition rate in the same manner as in Test Example 1, and are shown in Table 2 as relative values, with the IP1 level inhibition rate of Example Compound 2 in Test Example 1 set at 100%. Table 2 [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0516] 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 signal transduction, in CHO cells expressing GPR139. That is, the compounds of the present disclosure have GPR139 receptor antagonistic activity (inverse agonistic activity). Formulation Examples

[0517] In some embodiments, medicaments containing a compound of the present disclosure as an active ingredient can be produced using the following non-limiting example formulations. Table 3 [Table 3]

[0518] The total amount of (1), (2), and (3) and 5 mg of (4) are mixed and granulated, and then the remaining 5 mg of (4) is added, and the whole is enclosed in a gelatin capsule. Table 4 [Table 4]

[0519] The total amount of (1), (2), and (3), 20 mg of (4), and 2.5 mg of (5) are mixed and granulated, and the remaining 10 mg of (4) and 2.5 mg of (5) are added to the granules, which are then 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 (In the formula, R 1 teeth, [ka] is a group represented by 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; Z is CR 2 or N, R 2 and R 3 is a hydrogen atom, a halogen atom, or an optionally halogenated C 1-6 are each independently selected from alkyl groups, R 4 and R 5 are each independently selected from a hydrogen atom and a substituent; R 6a and R 6b are each independently selected from the substituents; Ring B is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; provided that the compound or pharmaceutically acceptable salt thereof is not 1-(3-chlorophenyl)-3-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-dihydro-2H-imidazol-2-one or a salt thereof. (Item 2) R 1 but, [ka] wherein: Ring A 1 is selected from an optionally further substituted 6-membered aromatic ring; R 6a teeth, (1) optionally substituted C 3-10 cycloalkyl groups, (2) optionally substituted C 6-14 aryl groups, (3) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, (4) an optionally substituted 5- to 14-membered aromatic heterocyclic group, (5) optionally substituted mono- or di-C 1-6 alkylamino groups, (6) Optionally substituted NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino group, (7) optionally substituted C 1-6 alkoxy groups, (8) optionally substituted C 6-14 aryloxy groups, and (9) an optionally substituted 3- to 14-membered non-aromatic heterocyclic oxy group Selected from: Item 1. The compound or a pharmaceutically acceptable salt thereof. (Item 3) R 1 but, [ka] wherein: Ring A 1 but, (a) a halogen atom, (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom, and (ii) a hydroxy group. 1-6 alkyl groups, (c) optionally halogenated C 1-6 alkoxy groups, (d) C optionally substituted by 1 to 3 halogen atoms 3-10 cycloalkyl groups, (e)C 2-6 alkenyl groups, and (f) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms a 6-membered aromatic ring optionally further substituted by 1 to 3 substituents independently selected from R 6a but, (1) C optionally substituted by 1 to 3 halogen atoms 3-10 cycloalkyl groups, (2) C optionally substituted by 1 to 3 halogen atoms 6-14 aryl groups, (3) a 3- to 14-membered non-aromatic heterocyclic group, (a) a halogen atom, and (b) optionally halogenated C 1-6 Alkyl group a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents independently selected from (4) 1 to 3 C 1-6 a 5- to 14-membered aromatic heterocyclic group optionally substituted by an alkyl group, (5) 1 to 3 C optionally substituted by 1 to 3 halogen atoms 3-10 Mono- or di-C optionally substituted by cycloalkyl groups 1-6 alkylamino groups, (6)NC 1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino group, (7) C 1-6 an alkoxy group, (a)C 1-6 alkoxy groups, (b)C 3-10 cycloalkyl groups, and (c) a C optionally substituted by 1 to 3 substituents independently selected from 3- to 14-membered non-aromatic heterocyclic groups; 1-6 alkoxy groups, (8) C optionally substituted by 1 to 3 halogen atoms 6-14 an aryloxy group, and (9) 3- to 14-membered non-aromatic heterocyclic oxy group Selected from: Item 1 or 2, a compound or a pharmaceutically acceptable salt thereof. (Item 4) R 1 but, [ka] wherein: Ring A 1 but, (1) A benzene ring: (a) a halogen atom, (b) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom, and (ii) a hydroxy group. 1-6 alkyl groups, (c) optionally halogenated C 1-6 alkoxy groups, (d) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (e)C 2-6 alkenyl groups, and (f) a piperidyl group optionally substituted by 1 to 3 halogen atoms a benzene ring which may be further substituted by 1 to 3 substituents independently selected from (2) a pyridine ring, (a) Halogen atoms (b) optionally halogenated C 1-6 Alkyl group (c) optionally halogenated C 1-6 an alkoxy group, and (d)C 3-6 cycloalkyl group a pyridine ring optionally further substituted by 1 to 3 substituents independently selected from (3) One or two optionally halogenated C 1-6 A pyrimidine ring optionally further substituted with an alkyl group is selected from R 6a but, (1) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (2) a phenyl group optionally substituted by 1 to 3 halogen atoms, (3) a morpholinyl group, (a) a halogen atom, and (b) optionally halogenated C 1-6 Alkyl group a morpholinyl group optionally substituted by 1 to 3 substituents independently selected from (4) a piperidyl group optionally substituted by 1 to 3 halogen atoms, (5) a pyrrolidinyl group optionally substituted by 1 to 3 halogen atoms, (6) 4-oxa-7-azaspiro[2.5]octyl group, (7) 1 to 3 C 1-6 an imidazolyl group optionally substituted by an alkyl group; (8) 1 to 3 C optionally substituted by 1 to 3 halogen atoms 3-6 Mono- or di-C optionally substituted by cycloalkyl groups 1-6 Alkylamine Nomoto, (9)NC 1-6 alkyl-N-tetrahydropyranylamino group, (10)C 1-6 an alkoxy group, (a)C 1-6 alkoxy groups, (b) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (c) an oxetanyl group, and (d) tetrahydrofuryl group C optionally substituted by 1 to 3 substituents independently selected from 1-6 alkoxy groups, (11) a phenoxy group optionally substituted by 1 to 3 halogen atoms, and (12) Tetrahydropyranyloxy group Selected from: Item 1 or 2, a compound or a pharmaceutically acceptable salt thereof. (Item 5) [ka] is a group represented by [ka] is a group represented by During the ceremony, R 6a is as defined in item 2, R 7a but, (a) a hydrogen atom, (b) a halogen atom, (c) C optionally substituted by 1 to 3 substituents independently selected from (i) a halogen atom, and (ii) a hydroxy group. 1-6 alkyl groups, (d) optionally halogenated C 1-6 alkoxy groups, (e) C optionally substituted by 1 to 3 halogen atoms 3-10 cycloalkyl groups, (f)C 2-6 alkenyl groups, and (g) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms is selected from R 8a but, (a) a hydrogen atom, (b) a halogen atom, and (c)C 1-6 Alkyl group Selected from: Item 1 or 2, a compound or a pharmaceutically acceptable salt thereof. (Item 6) [ka] is a group represented by [ka] is a group represented by During the ceremony, R 6a is as defined in item 2, R 7a1 but, (a) a halogen atom, (b) C optionally substituted by 1 to 3 substituents independently selected from a halogen atom and a hydroxy group 1-6 alkyl groups, (c) optionally halogenated C 1-6 alkoxy groups, (d) C optionally substituted by 1 to 3 halogen atoms 3-6 cycloalkyl groups, (e)C 2-6 alkenyl groups, and (f) a piperidyl group optionally substituted by 1 to 3 halogen atoms is selected from R 7a2 but, (a) a hydrogen atom, (b) optionally halogenated C 1-6 alkyl groups, (c) optionally halogenated C 1-6 an alkoxy group, and (d)C 3-6 cycloalkyl group is selected from R 7a3 may be halogenated C 1-6 alkyl groups, R 8a1 but, (a) a hydrogen atom, (b) a halogen atom, and (c)C 1-6 Alkyl group is selected from R 8a2 but, (a) a hydrogen atom, (b) a halogen atom, and (c)C 1-6 Alkyl group Selected from: Item 1 or 2, a compound or a pharmaceutically acceptable salt thereof. (Item 7) [ka] is a group represented by [ka] is a group represented by During the ceremony, R 6a is as defined in item 2, R 7a2 But halogenated C 1-6 alkyl groups, R 8a2 is selected from hydrogen atoms and halogen atoms; Item 1 or 2, a compound or a pharmaceutically acceptable salt thereof. (Item 8) [ka] is a group represented by [ka] is a group represented by During the ceremony, R 6a is as defined in item 2, R 7a2 But halogenated C 1-6 alkyl groups, R 8a2 is a hydrogen atom, Item 1 or 2, a compound or a pharmaceutically acceptable salt thereof. (Item 9) R 1 but, [ka] wherein: Ring A 1 but, (a) a halogen atom, and (b) Halogenated C 1-6 Alkyl group a pyridine ring optionally further substituted by one or two substituents independently selected from R 6a But 1 to 3 C1-6 a morpholinyl group optionally substituted by an alkyl group; Item 1. The compound or a pharmaceutically acceptable salt thereof. (Item 10) R 1 but, [ka] wherein: Ring A 1 But one halogenated C 1-6 a pyridine ring further substituted with an alkyl group; R 6a But one C 1-6 morpholinyl groups substituted by alkyl groups; Item 1. The compound or a pharmaceutically acceptable salt thereof. (Item 11) R 1 but, [ka] wherein: Ring A 2 is selected from optionally further substituted 5-membered monocyclic aromatic heterocycles; R 6b may be substituted C 1-6 alkyl groups, Item 1. The compound or a pharmaceutically acceptable salt thereof. (Item 12) Ring A 2 and 1 to 3 optionally halogenated C 1-6 a 5-membered monocyclic aromatic heterocycle optionally further substituted by an alkyl group; R 6b But 1 to 3 C 3-10 C optionally substituted by a cycloalkyl group 1-6 alkyl groups, 12. The compound or pharmaceutically acceptable salt thereof according to item 1 or 11. (Item 13) Ring A 2 and 1 to 3 optionally halogenated C 1-6 a pyrazole ring optionally further substituted with an alkyl group; R 6b But 1 to 3 C 3-6 C optionally substituted by a cycloalkyl group 1-6 alkyl groups, 12. The compound or pharmaceutically acceptable salt thereof according to item 1 or 11. (Item 14) [ka] is a group represented by [ka] wherein: R 6b But 1 to 3 C 3-10 C optionally substituted by a cycloalkyl group 1-6 alkyl groups, R 7b may be halogenated C 1-6 alkyl groups, 12. The compound according to item 1 or 11, or a pharmaceutically acceptable salt thereof. (Item 15) Ring B is one to three C 1-6 15. The compound according to any one of items 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 5-membered monocyclic aromatic heterocycles optionally further substituted by an alkyl group. (Item 16) Ring B is one to three C 1-6 16. The compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the pyrazole ring is selected from the group consisting of pyrazole rings optionally further substituted with an alkyl group. (Item 17) Ring B has one C 1-6 16. The compound or pharmaceutically acceptable salt according to any one of items 1 to 15, wherein the pyrazole ring is selected from the group consisting of a pyrazole ring further substituted with an alkyl group. (Item 18) Ring B is [ka] where: R 1c However, hydrogen atoms and C 1-6 alkyl groups, R 2c and R 3c However, hydrogen atoms and C 1-6 alkyl groups, 17. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 16. (Item 19) Ring B is [ka] where R 1c But C 1-6 17. The compound or pharmaceutically acceptable salt according to any one of items 1 to 16, wherein the compound or pharmaceutically acceptable salt is selected from alkyl groups. (Item 20) Z is CR 2 and R 2 is a hydrogen atom and optionally halogenated C 1-6 alkyl groups, 20. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 19. (Item 21) Z is CR 2 and R 2 However, hydrogen atoms and C 1-3 alkyl groups, 21. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 20. (Item 22) Z is CR 2 and R 2 But C 1-3 alkyl groups, 22. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 21. (Item 23) 20. The compound or pharmaceutically acceptable salt according to any one of items 1 to 19, wherein Z is N. (Item 24) R 3 However, hydrogen atoms and C 1-3 24. The compound or pharmaceutically acceptable salt according to any one of items 1 to 23, wherein the compound or pharmaceutically acceptable salt is selected from alkyl groups. (Item 25) R 3 But C 1-3 25. The compound or pharmaceutically acceptable salt according to any one of items 1 to 24, wherein the compound or pharmaceutically acceptable salt is selected from alkyl groups. (Item 26) R 4 and R 5 However, hydrogen atoms and C 1-6 26. The compound or pharmaceutically acceptable salt according to any one of items 1 to 25, wherein each independently is selected from the group consisting of alkyl groups. (Item 27) R 4 and R 5 is a hydrogen atom and optionally substituted C 1-6 27. The compound or pharmaceutically acceptable salt according to any one of items 1 to 26, wherein each independently is selected from the group consisting of alkyl groups. (Item 28) R 4 However, hydrogen atoms and C 1-6 alkyl groups, R 5 is a hydrogen atom, 28. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 27. (Item 29) R 4 and R 5 and are both hydrogen atoms, or a pharmaceutically acceptable salt thereof. (Item 30) below: 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[4'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-1,3-dihydro-2H-imidazol-2-one; 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; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[4'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[3-(4-fluorophenoxy)-5-(trifluoromethyl)phenyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[(oxan-4-yl)oxy]-5-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 3-{3-[(3,3-difluorocyclobutyl)methoxy]-5-(trifluoromethyl)phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-methyl-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[1-(1-ethyl-1H-pyrazol-4-yl)ethyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2S)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[5-(2,2-dimethylmorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[(2R)-2-methylmorpholin-4-yl]-5-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-{2-chloro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-{3-[(2R)-2-methylmorpholin-4-yl]-5-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 3-[3-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 3-[3-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-{3-[2-(difluoromethyl)morpholin-4-yl]-5-(trifluoromethyl)phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one; 3-{3-[(2,2-difluorocyclopropyl)methoxy]-5-(trifluoromethyl)phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(trifluoromethyl)phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl yl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-[3-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[(2S)-2-methylmorpholin-4-yl]-5-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 3-[3-(2,2-dimethylmorpholin-4-yl)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-fluoro-3-(trifluoromethyl)phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-{3-chloro-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 3-[3-(4,4-difluorocyclohexyl)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-fluoro-3-(trifluoromethyl)phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[5-(4,4-difluoropiperidin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[5-(3,3-difluoropiperidin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[methyl(oxan-4-yl)amino]-5-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[5-(3,3-difluoropyrrolidin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[5-(2,2-difluoromorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)methyl] fluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 3-[3-(2,2-difluoromorpholin-4-yl)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{3-methyl-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[2-fluoro-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)-3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1-{3-methyl-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 1-{3-(2,2-difluoroethoxy)-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-{3-[(2R)-2-methylmorpholin-4-yl]-5-(2,2,2-trifluoroethoxy)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[3-(methoxymethoxy)-5-(trifluoromethyl)phenyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[(oxetan-2-yl)methoxy]-5-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{3-[(1-fluorocyclobutyl)methoxy]-5-(trifluoromethyl)phenyl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[5-(2,2-difluoromorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(2,2,2-trifluoroethoxy)phenyl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{3-[(1-fluorocyclopropyl)methoxy]-5-(trifluoromethyl)phenyl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{2-chloro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{2-chloro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]- 4-Methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 1-{2-fluoro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1-{2-methyl-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[3-(2,2-difluoromorpholin-4-yl)-5-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-one; 1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 3-{3-bromo-5-[(3,3-difluorocyclobutyl)methoxy]phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-[3-{[(2S)-oxolan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one; 3-{3-cyclopropyl-5-[(3,3-difluorocyclobutyl)methoxy]phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-{3-[(3,3-difluorocyclobutyl)methoxy]-5-(difluoromethyl)phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{2-chloro-5-[(3,3-difluorocyclobutyl)methoxy]-3-(difluoromethyl)phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[5-(2,2-difluoromorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-one; 3-{3-(2,2-difluoroethoxy)-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[(2R)-2-methylmorpholin-4-yl]-5-(2,2,2-trifluoroethoxy)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-{3-[methyl(oxan-4-yl)amino]-5-(2,2,2-trifluoroethoxy)phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-{3-ethenyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3 -dihydro-2H-imidazol-2-one; 1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-{3-(difluoromethyl)-5-[methyl(oxan-4-yl)amino]phenyl}-4,5-dimethyl-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 3-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{3-(2,2-difluorocyclopropyl)-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[3-(difluoromethyl)-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-4-methyl-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-{3-ethyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-{3-ethyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-{2-chloro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{3-chloro-6-[methyl(oxan-4-yl)amino]-4-(trifluoromethyl)pyridin-2-yl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{3-chloro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{3-chloro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[methyl(oxan-4-yl)amino]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 1-{2-fluoro-3-methyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-4-methyl-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[methyl(oxan-4-yl)amino]-5-(2,2,2-trifluoroethoxy)phenyl}-1,3-dihydro-2H-imidazol-2-one; 3-{3-bromo-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 2-{2-fluoro-5-[(2S)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propan-2-yl)-1 H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-{2-fluoro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-[5-(2,2-dimethylmorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-[5-(3,3-difluoropyrrolidin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-{2-fluoro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-[5-(2,2-dimethylmorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-[5-(4,4-difluoropiperidin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-{3-(difluoromethyl)-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-4-methyl-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-[3-{[(2S)-oxolan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one; 4-methyl-3-[3-{[(2S)-oxolan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 4-methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 3-{3-cyclopropyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6 -[(2R)-2-methylmorpholin-4-yl]-4-(2,2,2-trifluoroethoxy)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[(oxolan-2-yl)methoxy]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[2-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-3-(trifluoromethyl)phenyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[6-{[(1-fluorocyclobutyl)methyl]amino}-4-(trifluoromethyl)pyridin-2-yl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-[6-(2,2-difluoromorpholin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[6-(2,2-dimethylmorpholin-4-yl)-3-fluoro-4-(trifluoromethyl)pyridin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-3-(2-hydroxypropan-2-yl)-5-[methyl(oxan-4-yl)amino]phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-[6-{[(2R)-oxolan-2-yl]methoxy}-4-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-[6-{[(2S)-oxolan-2-yl]methoxy}-4-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(oxan-4-yl)oxy]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{2-fluoro-5-[(oxan-4-yl)oxy]-3-(trifluoromethyl)phenyl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[2-fluoro-5-{[(2S)-oxolan-2-yl]methoxy}-3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one; 1-{2-fluoro-5-[(oxan-4-yl)oxy]-3-(trifluoromethyl)phenyl}-4-methyl-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[6-(2,2-dimethylmorpholin-4-yl)-3-methyl-4-(trifluoromethyl)pyridin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[3-fluoro-6-{[(1-fluorocyclobutyl)methyl]amino}-4-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-3-(2-fluoropropan-2-yl)-5-[methyl(oxan-4-yl)amino]phenyl}-1,3-dihydro-2H-imidazol-2-one; 1-[6-(2,2-difluoromorpholin-4-yl)-3-fluoro-4-(trifluoromethyl)pyridin-2-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{4-[(2R)-2-methylmorpholin-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 3-[6-(2,2-dimethylmorpholin-4-yl)-4-(trifluoromethyl)pyridin-2-yl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-{4-cyclopropyl-6-[(2R)-2-methylmorpholin-4-yl]pyridin-2-yl}-4-methyl-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1,3-dihydro-2H-imidazol-2-one; 4-methyl-3-{6-[methyl(oxan-4-yl)amino]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 4-methyl-1-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 3-[4-cyclopropyl-6-(2,2-dimethylmorpholin-4-yl)pyridin-2-yl]-4-methyl-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[5-(2,2-difluorocyclopropyl)-4,4'-difluoro[1,1'-biphenyl]-3-yl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[6-(2,2-dimethylmorpholin-4-yl)-3-fluoro-4-(trifluoromethyl)pyridin-2-yl]-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[3-fluoro-6-{[(1-fluorocyclobutyl)methyl]amino}-4-(trifluoromethyl)pyridin-2-yl]-3-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 3-[4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 3-[4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]-4-methyl-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 2-[5-(2,2-dimethylmorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-5-ethyl-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 3-[3-bromo-5-(2,2-dimethylmorpholin-4-yl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 2-[5-(4,4-difluoropiperidin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-5-ethyl-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-{3-chloro-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-{3-cyclopropyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 2-[6-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-[6-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-{3-(2,2-difluorocyclopropyl)-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-(trifluoromethyl)-1,3-dihydro-2H-imidazol-2-one; 1-[3-bromo-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 3-[3-cyclopropyl-5-(2,2-dimethylmorpholin-4-yl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 4-methyl-3-[6-{[(2S)-oxolan-2-yl]methoxy}-4-(trifluoromethyl)pyridin-2-yl]-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{5-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{5-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-one; 2-{5-[(3,3-difluorocyclobutyl)methoxy]-2-fluoro-3-(trifluoromethyl)phenyl}-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-[3,5-bis(4,4-difluoropiperidin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethoxy)phenyl}-1,3-dihydro-2H-imidazol-2-one; 2-[6-(4,4-difluoropiperidin-1-yl)-5-fluoro-4-(trifluoromethyl)pyridin-2-yl]-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-chloro-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-[3-(2,2-difluorocyclopropyl)-5-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one; 4-ethyl-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethoxy)phenyl}-5-methyl-4-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 3-{3-cyclopropyl-4-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 2-[5-(4,4-difluoropiperidin-1-yl)-2-methyl-3-(trifluoromethyl)phenyl]-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 1-{4-cyclopropyl-6-[(2R)-2-methylmorpholin-4-yl]pyridin-2-yl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-one; 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-{6-[(2R)-2-methylmorpholin-4-yl]pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one; 1-[3-cyclopropyl-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[3-cyclopropyl-5-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; 1-[3-chloro-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one; and 1-[3-chloro-5-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one or a pharmaceutically acceptable salt thereof. (Item 31) At least one compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 30, and at least one pharmaceutically acceptable carrier A pharmaceutical composition comprising: (Item 32) 31. A method for treating or preventing a disease in a mammal in need thereof, comprising administering to said mammal at least one compound according to any one of items 1 to 30. (Item 33) 33. The method of claim 32, wherein the disease is selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. (Item 34) 34. The method of claim 32 or 33, wherein the mammal is a human. (Item 35) 35. The method according to any one of items 32 to 34, further comprising administering to the mammal at least one concomitant drug.

Claims

[Claim 1] The invention described in the specification.

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