Heterocyclic compounds

Abstract

This invention relates to compounds exhibiting GPR139 receptor antagonist activity, such as compounds of formula (I) and their pharmaceutically acceptable salts, pharmaceutical compositions comprising the same, and methods of using the same to treat or prevent GPR139 receptor-mediated diseases, such as depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder.

Description

Technical Field

[0001] This disclosure relates to heterocyclic compounds that exhibit G protein-coupled receptor (GPR) 139 receptor antagonist activity and are expected to be used to treat or prevent GPR139-mediated diseases such as depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. Prior Technology

[0002] 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 across species. For example, the human, mouse, and rat GPR139 protein sequences share more than 94% identity at the amino acid level. Furthermore, GPR139 is expressed at higher levels in the central nervous system, specifically in the striatum, septum, hypothalamus, and habenula, and at lower levels in peripheral tissues. The high sequence homology across species and the dominant expression in the brain suggest that GPR139 plays an important physiological role.

[0003] GPR139 gene alterations have been reported in cases of mental disorders (e.g., schizophrenia) and in patients with symptoms of autism spectrum disorder or attention deficit hyperactivity disorder (Twin Research and Human Genetics, April 2014; 17(2):108-120; Nature Genetics, June 2011; 43(6):585-589; Twin Research and Human Genetics, April 2013; 16(2):560-574). Furthermore, the habenula is a region of the brain highly expressed by GPR139 and is known to regulate stress response and learning; it is believed that the habenula is overactive in patients with depression. In patients also exhibiting treatment-resistant mental symptoms, strong deep brain stimulation (DBS) of the habenula has been reported to improve HAMD21 scores for assessing depressive symptoms (Biol Psychiatry 2010 67:e9-e11). Furthermore, when positron emission tomography (PET) was used to study brain regions where neural activity changed after ketamine administration in 20 patients with treatment-resistant depression, glucose metabolism, which reflects neural activity, was suppressed in brain regions (e.g., the habenula), and depressive symptoms were improved (Biol Psychiatry 2013 73(12):1213-1221). In animal studies, neural activity in the habenula was suppressed by direct administration of ketamine to the habenula, and improvements in alexithymia-like behaviors were observed (Nature 2018 554(7692):317-322). These results collectively indicate that GPR139 activity affects neural activity in the habenula and can significantly alter central nervous system function or neuropsychiatric state.

[0004] GPR139 receptor antagonists (including inverse agonists) can be used to treat CNS disorders such as depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. Therefore, there is a need in the industry for novel compounds demonstrating the effects of GPR139 receptor antagonists.

[0005] Some heterocyclic compounds can be used as antagonists of the GPR139 receptor.

[0006] PCT International Publication No. WO 2008 / 094556 describes a compound represented by the following formula: , Each symbol is defined as in WO 2008 / 094556. This compound has TGF3 inhibitory activity and can be used to treat multiple sclerosis, Alzheimer's disease, cerebrovascular diseases, and neuronal demyelination in these conditions.

[0007] In addition, PCT International Publication No. WO 2008 / 089005 discloses a compound represented by the following formula: , Each symbol is as defined in WO 2008 / 089005. This compound exhibits renin inhibition and can be used to treat cardiovascular diseases, hypertension, congestive heart failure, myocardial infarction, kidney protection, inflammation, neurological disorders, cancer, and the like.

[0008] The following compound is also referred to in this technique as CAS number 1174845-16-9. Summary of the Invention

[0009] []

[0010] This article reveals compounds exhibiting GPR139 receptor antagonist activity that can be used to treat or prevent depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, attention deficit hyperactivity disorder, and the like.

[0011] This article reveals compound (I) (hereinafter also referred to as compound (I)): (I), or its salt, wherein: R1 is represented by the following groups: or ; Ring A1 is selected from six aromatic rings that have been further replaced, as appropriate; Cyclic A2 is selected from, as appropriate, 5-member monocyclic aromatic heterocycles that have undergone further substitution; Z-series C-R2 or N; R2 and R3 are each independently selected from hydrogen atoms, halogen atoms, and, where appropriate, halogenated C1-6 alkyl groups; R4 and R5 are each independently selected from hydrogen atoms and substituents; R6a and R6b are each independently selected from substituents; and Cyclo-B series is selected from, depending on the circumstances, five-member monocyclic aromatic heterocycles that have undergone further substitution. The condition is 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.

[0012] In some embodiments, R1 is composed of The group that represents it.

[0013] In some embodiments, R1 is composed of The group to be represented, wherein: X series CH or N; Y series CH or N; The L series is selected from bond, -O-, -OR9a-*, -NH- and -N(R9b)R9a-*, where * indicates the connection point with ring C; The C-rings are selected from 6- to 8-membered aromatic rings, 5- to 8-membered monocyclic aromatic heterocycles, C3-8 cycloalkyl groups, and 5- to 8-membered heterocyclic groups; R9a is selected from C1-3 alkyl groups; R9b is selected from hydrogen atoms and C1-3 alkyl groups; Each R10a group is independently selected from halogens, C1-6 alkyl groups, and C1-6 alkoxy groups, wherein the C1-6 alkyl groups and C1-6 alkoxy groups are substituted with 1 to 4 halogen atoms as appropriate; Each R11a is independently selected from cyano, halogen, C3-6 cycloalkyl, C1-6 alkyl, and C1-6 alkoxy, wherein the C3-6 cycloalkyl, C1-6 alkyl, and C1-6 alkoxy are substituted with 1 to 4 halogen atoms as appropriate; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.

[0014] In some embodiments, L is selected from bond, -O-, -NH-, -NHCH2-* and -N(CH3)CH2-*, and all other variables are as defined above.

[0015] In some embodiments, the L-series bond is used, and all other variables are as defined above. In some embodiments, the L-series bond is used as ...

[0016] In some embodiments, X refers to N, Y refers to 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.

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

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

[0020] In some embodiments, cyclic C-type benzene and all other variables are as defined above. In some embodiments, cyclic C-type morpholine and all other variables are as defined above. In some embodiments, cyclic C-type oxane and all other variables are as defined above. In some embodiments, cyclic C-type hexahydropyridine and all other variables are as defined above. In some embodiments, cyclic C-type cyclobutane and all other variables are as defined above.

[0021] In some embodiments, R1 is composed of The groups represented are X, Y, cyclic C, R10a, R11a, m and n as defined above.

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

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

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

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

[0026] In some embodiments, cyclic C-type benzene and all other variables are as defined above. In some embodiments, cyclic C-type morpholine and all other variables are as defined above. In some embodiments, cyclic C-type oxane and all other variables are as defined above. In some embodiments, cyclic C-type hexahydropyridine and all other variables are as defined above. In some embodiments, cyclic C-type cyclobutane and all other variables are as defined above.

[0027] In some embodiments, R1 is composed of The groups represented are R10a, R11a, m and n as defined above.

[0028] In some embodiments, R1 is composed of The group to be represented, wherein R11a and n are as defined above.

[0029] In some embodiments, R1 is composed of The groups represented, wherein X, R10a, R11a, m, and n are as defined above. In some embodiments, X is CH. In some embodiments, X is N.

[0030] In some embodiments, R1 is composed of The groups represented are X, R10a, R11a, m, and n as defined above. In some embodiments, X is CH.

[0031] In some embodiments, R1 is composed of The groups represented are X, Y, R10a, R11a, m, and n as defined above. In some embodiments, X is N and Y is CH.

[0032] In some embodiments, R1 is composed of The groups represented are L, R10a, R11a, m, and n series as defined above. In some embodiments, L series -NHCH2-*. In some embodiments, L series -N(CH3)CH2-*.

[0033] In some embodiments, R1 is composed of The groups represented are L, R10a, R11a, m, and n series as defined above. In some embodiments, L series -NHCH2-*. In some embodiments, L series -N(CH3)CH2-*.

[0034] In some embodiments, R1 is composed of The group to be represented, wherein: Each R10a is independently selected from halogen atoms, C1-6 alkyl groups, and C1-6 alkoxy groups, wherein the C1-6 alkyl groups and C1-6 alkoxy groups are substituted with 1 to 4 halogen atoms as appropriate; Each R11a is independently selected from cyano, halogen, C3-6 cycloalkyl, C1-6 alkyl, and C1-6 alkoxy, wherein the C3-6 cycloalkyl, C1-6 alkyl, and C1-6 alkoxy are substituted with 1 to 4 halogen atoms as appropriate; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.

[0035] In some embodiments, each R10a is independently selected from halogen atoms and C1-6 alkyl groups, wherein the C1-6 alkyl groups are substituted with 1 to 4 halogen atoms as appropriate; each R11a is independently selected from cyano, halogen, C1-6 alkyl, and C1-6 alkoxy groups, wherein the C1-6 alkyl and C1-6 alkoxy groups are substituted with 1 to 4 halogen atoms as appropriate; m refers to 0, 1, 2, or 3; and n refers to 0, 1, 2, or 3.

[0036] In some embodiments, R1 is composed of The group to be represented, wherein: X series CH or N; Each R10a is independently selected from halogen atoms, C1-6 alkyl groups, and C1-6 alkoxy groups, wherein the C1-6 alkyl groups and C1-6 alkoxy groups are substituted with 1 to 4 halogen atoms as appropriate; Each R11a is independently selected from halogens, C3-6 cycloalkyl, C1-6 alkyl, and C1-6 alkoxy groups, wherein the C3-6 cycloalkyl, C1-6 alkyl, and C1-6 alkoxy groups are substituted with 1 to 4 halogen atoms as appropriate; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3.

[0037] In some embodiments, R1 is composed of The group that represents it.

[0038] In some embodiments, R4 and R5 are each independently selected from hydrogen and C1-3 alkyl groups. In some embodiments, both R4 and R5 are hydrogen atoms.

[0039] In some embodiments, ring B is composed of The group represented by R12a, wherein each R12a is independently selected from C1-3 alkyl groups and p is 0, 1 or 2.

[0040] In some embodiments, ring B is composed of The indicated group, wherein R12a is selected from C1-3 alkyl groups. In some embodiments, R11a is an ethyl group.

[0041] In some embodiments, compounds of formula (I) and their pharmaceutically acceptable salts are provided for the treatment or prevention of diseases selected from: depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder (ADHD). In some embodiments, compounds selected from Examples 1-167 and their pharmaceutically acceptable salts are provided for the treatment or prevention of diseases selected from: depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder (ADHD).

[0042] This document also discloses pharmaceutical compositions comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises: at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.

[0043] This document also discloses the use of compounds of formula (I) or their pharmaceutically acceptable salts in therapeutic applications. In some embodiments, compounds selected from Examples 1-167 and their pharmaceutically acceptable salts are provided for use in therapeutic applications.

[0044] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with at least one combination drug for simultaneous, solitary, or sequential use to treat or prevent diseases selected from: depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder. In some embodiments, when used concurrently, the compound or pharmaceutically acceptable salt and at least one combination drug are in a single pharmaceutical composition. In some embodiments, when used concurrently, the compound or pharmaceutically acceptable salt and at least one combination drug are in the same pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt is selected from Examples 1-167 and their pharmaceutically acceptable salts.

[0045] In some embodiments, a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a combination of pharmaceutically acceptable substances is provided for 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, the compound or pharmaceutically acceptable salt and combination of pharmaceutically acceptable substances are prepared for administration with the same pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt and combination of pharmaceutically acceptable substances are prepared for administration with a single pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt and combination of pharmaceutically acceptable substances are prepared for simultaneous administration. In some embodiments, the compound or pharmaceutically acceptable salt and combination of pharmaceutically acceptable substances are prepared for sequential administration. In some embodiments, the compound or pharmaceutically acceptable salt is selected from Examples 1-167 and their pharmaceutically acceptable salts.

[0046] This document also discloses pharmaceutical compositions comprising compounds of formula (I) or their pharmaceutically acceptable salts for use in therapy. In some embodiments, pharmaceutical compositions comprising compounds selected from Examples 1-167 and their pharmaceutically acceptable salts are provided for use in therapy.

[0047] This article also reveals methods for treating or preventing diseases selected from: depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder, which involve administering at least one compound of formula (I) or a medically acceptable salt thereof. Implementation

[0048] []

[0049] This application claims priority to Japanese Patent Application No. 2020-090110, filed on May 22, 2020, the entire contents of which are incorporated herein by reference.

[0050] It should be understood that any mention herein of methods of treating or preventing diseases using one or more compounds (e.g., compounds of formula (I) and their pharmaceutically acceptable salts) (e.g., methods of treating or preventing diseases selected from: depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, and attention deficit hyperactivity disorder) should be interpreted as mentioning: One or more compounds are used in methods of treating and / or preventing conditions such as depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, or attention deficit hyperactivity disorder; and / or Using one or more compounds to manufacture drugs for the treatment and / or prevention of conditions such as depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, or attention deficit hyperactivity disorder. [Non-limiting examples and embodiments] [1] [:] []

[0051] Some embodiments of this disclosure include (but are not limited to): 1. A compound of formula (I), (I), or its salt, in: R1 is represented by the following groups: or ; Ring A1 is selected from six aromatic rings that have been further replaced, as appropriate; Cyclic A2 is selected from, as appropriate, 5-member monocyclic aromatic heterocycles that have undergone further substitution; Z-series C-R2 or N; R2 and R3 are each independently selected from hydrogen atoms, halogen atoms, and, where appropriate, halogenated C1-6 alkyl groups; R4 and R5 are each independently selected from hydrogen atoms and substituents; R6a and R6b are each independently selected from substituents; and Cyclo-B series is selected from, depending on the circumstances, five-member monocyclic aromatic heterocycles that have undergone further substitution. The condition is 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 pharmaceutical preparation comprising a compound as described in Example 1 or a pharmaceutically acceptable salt. 3. The pharmaceutical preparation as described in Example 2 is a GPR139 receptor antagonist. 4. The pharmaceutical preparation as described in Example 2 is a medicine for the prevention or treatment of depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorders, pain, or attention deficit hyperactivity disorder. [Non-limiting examples and embodiments] [2] [:] []

[0052] Some embodiments / terms of this disclosure include (but are not limited to): 1. A compound of formula (I), (I), or a medically acceptable salt thereof. in: R1 is represented by the following groups: or ; Ring A1 is selected from six aromatic rings that have been further replaced, as appropriate; Cyclic A2 is selected from, as appropriate, 5-member monocyclic aromatic heterocycles that have undergone further substitution; Z-series C-R2 or N; R2 and R3 are each independently selected from hydrogen atoms, halogen atoms, and, where appropriate, halogenated C1-6 alkyl groups; R4 and R5 are each independently selected from hydrogen atoms and substituents; R6a and R6b are each independently selected from substituents; and Cyclo-B series is selected from, depending on the circumstances, five-member monocyclic aromatic heterocycles that have undergone further substitution. The condition is that the compound or its pharmaceutically acceptable 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 compound or a pharmaceutically acceptable salt as described in Clause 1, wherein R1 is a group represented by the following: ,in: Ring A1 is selected from six member aromatic rings that have been further replaced, as appropriate; and R6a series is selected from: (1) C3-10 cycloalkyl groups, substituted as appropriate; (2) Substituted C6-14 aryl groups, as appropriate; (3) Substituted 3 to 14 non-aromatic heterocyclic groups, depending on the situation; (4) Replaced 5 to 14 aromatic heterocyclic groups, depending on the situation; (5) A substituted mono- or di-C1-6 alkylamine group, as appropriate; (6) As appropriate, substituted N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amines; (7) C1-6 alkoxy groups, as appropriate; (8) A substituted C6-14 aryloxy group, as appropriate; and (9) Substituted 3 to 14 non-aromatic heterocyclic groups, depending on the situation. 3. Compounds or pharmaceutically acceptable salts as described in Clause 1 or 2, wherein R1 is a group represented by the following: ,in: Ring A1 is selected from 6-membered aromatic rings, which may be further substituted by 1 to 3 independent substituents selected from the following: (a) Halogen atom; (b) C1-6 alkyl groups, substituted as appropriate, with one to three independently selected substituents: (i) a halogen atom; and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups, as appropriate; (d) C3-10 cycloalkyl groups substituted with 1 to 3 halogen atoms, as appropriate; (e) C2-6 alkenyl; and (f) a 3- to 14-member non-aromatic heterocyclic group, substituted with 1 to 3 halogen atoms, as appropriate; and R6a series is selected from: (1) C3-10 cycloalkyl groups substituted with 1 to 3 halogen atoms, as appropriate; (2) C6-14 aryl groups substituted with 1 to 3 halogen atoms, depending on the case; (3) Depending on the circumstances, a 3 to 14-member non-aromatic heterocyclic group substituted by 1 to 3 independently selected substituents from the following: (a) Halogen atom; and (b) Halogenated C1-6 alkyl groups, as appropriate; (4) A 5- to 14-membered aromatic heterocyclic group, substituted with 1 to 3 C1-6 alkyl groups, as appropriate; (5) A mono- or di-C1-6 alkylamine group substituted with one to three halogen atoms, depending on the case; (6) N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amines; (7) C1-6 alkoxy groups, substituted with one to three independently selected substituents, as appropriate: (a) C1-6 alkoxy group; (b) C3-10 cycloalkyl groups; and (c) 3 to 14 non-aromatic heterocyclic groups; (8) C6-14 aryloxy groups substituted with 1 to 3 halogen atoms, as appropriate; and (9) 3 to 14 non-aromatic heterocyclic groups. 4. Compounds or pharmaceutically acceptable salts as described in Clause 1 or 2, wherein R1 is a group represented by the following: ,in: The A1 series is selected from: (1) Further, as appropriate, the benzene ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atom; (b) C1-6 alkyl groups, substituted as appropriate, with one to three independently selected substituents: (i) a halogen atom; and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups, as appropriate; (d) C3-6 cycloalkyl groups substituted with 1 to 3 halogen atoms, as appropriate; (e) C2-6 alkenyl; and (f) A hexahydropyridyl group, substituted with 1 to 3 halogen atoms, as appropriate; (2) Further, as appropriate, the pyridine ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atom; (b) Halogenated C1-6 alkyl groups, as appropriate; (c) Halogenated C1-6 alkoxy groups, as appropriate; and (d) C3-6 cycloalkyl groups; and (3) Further, as appropriate, via one or two halogenated C1-6 alkyl-substituted pyrimidine rings; and R6a series is selected from: (1) C3-6 cycloalkyl groups substituted with 1 to 3 halogen atoms, depending on the case; (2) Phenyl groups substituted with 1 to 3 halogen atoms, depending on the case; (3) Morpholino group substituted with 1 to 3 independently selected substituents from the following, depending on the case: (a) Halogen atom; and (b) Halogenated C1-6 alkyl groups, as appropriate; (4) A hexahydropyridyl group, substituted with 1 to 3 halogen atoms, depending on the case; (5) A pyrrolidone group substituted with 1 to 3 halogen atoms, depending on the case; (6) 4-oxa-7-azaspiro[2.5]octyl; (7) An imidazolyl group substituted with one to three C1-6 alkyl groups, as appropriate; (8) A mono- or di-C1-6 alkylamine group substituted with one to three halogen atoms, depending on the case; (9) N-C1-6 alkyl-N-tetrahydropyranylamino; (10) A C1-6 alkoxy group, substituted with one to three independently selected substituents, as appropriate: (a) C1-6 alkoxy group; (b) C3-6 cycloalkyl groups substituted with 1 to 3 halogen atoms, as appropriate; (c) Oxycyclic butyl; and (d) Tetrahydrofuranyl; (11) A phenoxy group, substituted with one to three halogens, as appropriate; and (12) Tetrahydropyranyloxy. 5. Compounds or pharmaceutically acceptable salts as described in Clause 1 or 2, wherein the following groups are represented: It consists of the following groups: , in: R6a is as defined in Clause 2; R7a series is selected from: (a) Hydrogen atom; (b) Halogen atoms; (c) A C1-6 alkyl group, as appropriate, substituted with one to three independently selected substituents: (i) a halogen atom; and (ii) a hydroxyl group; (d) Halogenated C1-6 alkoxy groups, as appropriate; (e) C3-10 cycloalkyl groups substituted with 1 to 3 halogen atoms, as appropriate; (f) C2-6 alkenyl; and (g) a 3- to 14-member non-aromatic heterocyclic group, substituted with 1 to 3 halogen atoms, as appropriate; and R8a series is selected from: (a) Hydrogen atom; (b) Halogen atoms; and (c) C1-6 alkyl. 6. Compounds or pharmaceutically acceptable salts as described in Clause 1 or 2, wherein the following groups are represented: It consists of the following groups: , in: R6a is as defined in Clause 2; R7a1 is selected from: (a) Halogen atom; (b) C1-6 alkyl groups, as appropriate, substituted with one to three independently selected substituents chosen from halogen atoms and hydroxyl groups; (c) Halogenated C1-6 alkoxy groups, as appropriate; (d) C3-6 cycloalkyl groups substituted with 1 to 3 halogen atoms, as appropriate; (e) C2-6 alkenyl; and (f) A hexahydropyridyl group, substituted with 1 to 3 halogen atoms, as appropriate; R7a2 is selected from: (a) Hydrogen atom; (b) Halogenated C1-6 alkyl groups, as appropriate; (c) Halogenated C1-6 alkoxy groups, as appropriate; and (d) C3-6 cycloalkyl; R7a3 is selected from C1-6 alkyl groups that are halogenated as appropriate; R8a1 is selected from: (a) Hydrogen atom; (b) Halogen atoms; and (c) C1-6 alkyl; and R8a2 is selected from: (a) Hydrogen atom; (b) Halogen atoms; and (c) C1-6 alkyl. 7. Compounds or pharmaceutically acceptable salts as described in Clause 1 or 2, wherein the following groups are represented: It consists of the following groups: , in: R6a is as defined in Clause 2; R7a2 is selected from C1-6 alkyl halogenates; and R8a2 is selected from hydrogen atoms and halogen atoms. 8. Compounds or pharmaceutically acceptable salts as described in Clause 1 or 2, wherein the following groups are represented: It consists of the following groups: , in: R6a is as defined in Clause 2; R7a2 is selected from C1-6 alkyl halogenates; and R8a2 is a hydrogen atom. 9. A compound or a pharmaceutically acceptable salt as described in Clause 1, wherein R1 is a group represented by the following: ,in: Ring A1 is selected from pyridine rings that are further substituted, as appropriate, by one or two independent substituents selected from the following: (a) Halogen atom; and (b) Halogenated C1-6 alkyl groups; and R6a is selected from morpholino groups substituted with 1 to 3 C1-6 alkyl groups, as appropriate. 10. A compound or a pharmaceutically acceptable salt as described in Clause 1, wherein R1 is a group represented by the following: ,in: Cycle A1 is selected from pyridine rings further substituted with a halogenated C1-6 alkyl group; and R6a is selected from morpholino groups substituted with a C1-6 alkyl group. 11. A compound or a pharmaceutically acceptable salt as described in Clause 1, wherein R1 is a group represented by: ,in: Cyclic A2 is selected from, as appropriate, further substituted 5-member monocyclic aromatic heterocycles; and R6b is selected from C1-6 alkyl groups that are substituted as appropriate. 12. Compounds or pharmaceutically acceptable salts as specified in Clause 1 or 11, wherein: Cyclone A2 is selected from 5-membered monocyclic aromatic heterocycles that are optionally further substituted with 1 to 3 C1-6 alkyl groups, and... R6b is selected from C1-6 alkyl groups that are substituted with 1 to 3 C3-10 cycloalkyl groups, as appropriate. 13. Compounds or pharmaceutically acceptable salts as specified in Clause 1 or 11, wherein: Cycle A2 is selected from pyrazole rings that are optionally further substituted with 1 to 3 C1-6 alkyl groups, depending on the case; and R6b is selected from C1-6 alkyl groups that are substituted with 1 to 3 C3-6 cycloalkyl groups, as appropriate. 14. Compounds or pharmaceutically acceptable salts as described in Clause 1 or 11, wherein the following groups are represented: It consists of the following groups: ,in: R6b is selected from C1-6 alkyl groups substituted with 1 to 3 C3-10 cycloalkyl groups, as appropriate; and R7b is selected from C1-6 alkyl groups that are halogenated as appropriate. 15. A compound or a pharmaceutically acceptable salt of any of the provisions 1 to 14, wherein ring B is selected from a 5-membered monocyclic aromatic heterocycle further substituted with 1 to 3 C1-6 alkyl groups, as appropriate. 16. A compound or a pharmaceutically acceptable salt of any of the provisions 1 to 15, wherein ring B is selected from a pyrazole ring further substituted with one to three C1-6 alkyl groups, as appropriate. 17. A compound or a pharmaceutically acceptable salt of any of the provisions 1 to 15, wherein ring B is selected from a pyrazole ring further substituted with a C1-6 alkyl group. 18. Compounds or pharmaceutically acceptable salts of any of the terms 1 to 16, wherein the cyclic B group is: ,in: R1c is selected from hydrogen atoms and C1-6 alkyl groups; and R2c and R3c are each independently selected from hydrogen atoms and C1-6 alkyl groups. 19. Compounds or pharmaceutically acceptable salts of any of the terms 1 to 16, wherein the cyclic B group is: R1c is selected from C1-6 alkyl groups. 20. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 19, wherein: Z-series C-R2; and R2 is selected from hydrogen atoms and, where appropriate, C1-6 alkyl groups that are halogenated. 21. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 20, wherein: Z-series C-R2; and R2 is selected from hydrogen atoms and C1-3 alkyl groups. 22. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 21, wherein: Z-series C-R2; and R2 is selected from C1-3 alkyl groups. 23. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 19, wherein Z is N. 24. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 23, wherein R3 is selected from hydrogen atoms and C1-3 alkyl groups. 25. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 24, wherein R3 is selected from C1-3 alkyl groups. 26. A compound or a pharmaceutically acceptable salt of any of the provisions 1 to 25, wherein R4 and R5 are each independently selected from hydrogen atoms and C1-6 alkyl groups. 27. A compound or a pharmaceutically acceptable salt of any of the provisions 1 to 26, wherein R4 and R5 are each independently selected from hydrogen atoms and, where appropriate, substituted C1-6 alkyl groups. 28. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 27, wherein: R4 is selected from hydrogen atoms and C1-6 alkyl groups; and R5 series hydrogen atoms. 29. A compound or a pharmaceutically acceptable salt of any of the terms 1 to 28, wherein R4 and R5 are both hydrogen atoms. 30. A compound selected from Examples 1-167 or a pharmaceutically acceptable salt thereof. 31. A pharmaceutical composition comprising: At least one compound or a pharmaceutically acceptable salt as described in any of clauses 1 to 30; and At least one medically acceptable carrier. 32. A method for treating or preventing a disease in a mammal in need, the method comprising administering to the mammal at least one compound as described in any one of clauses 1 to 30. 33. The method as described in Clause 32, wherein the disease is selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain and attention deficit hyperactivity disorder. 34. The method as described in Clause 32 or 33, wherein the mammal is a human being. 35. The method of any of clauses 32 to 34, further comprising administering at least one combination drug to a mammal.

[0053] The definition of each substituent used in this specification will be explained in detail below. Unless otherwise stated, each substituent is defined as follows.

[0054] Non-limiting examples of "halogen atom" in this specification include fluorine, chlorine, bromine, and iodine.

[0055] Non-limiting examples of "C1-6 alkyl" in this specification include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dibutyl, tributyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0056] Non-limiting examples of "halogenated C1-6 alkyl groups as appropriate" in this specification include C1-6 alkyl groups having 1 to 7, for example, 1 to 5 halogen atoms. Other non-limiting examples 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, dibutyl, tributyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl.

[0057] Non-limiting examples of "C2-6 alkenyl" in this specification include vinyl, 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.

[0058] Non-limiting examples of "C2-6 ynyl" in this specification 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.

[0059] Non-limiting examples of "C3-10 cycloalkyl" in this specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0060] Non-limiting examples of "halogenated C3-10 cycloalkyl groups as appropriate" in this specification include C3-10 cycloalkyl groups having 1 to 7, for example 1 to 5, halogen atoms. Other non-limiting examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0061] Non-limiting examples of "C3-10 cycloalkenyl" in this specification include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0062] Non-limiting examples of "C6-14 aryl" in this specification include phenyl, 1-naphthyl, 1-anthrayl, 2-anthrayl and 9-anthrayl.

[0063] Non-limiting examples of "C7-16 aralkyl" in this specification include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0064] Non-limiting examples of "C1-6 alkoxy" in this specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, dibutoxy, terbutoxy, pentoxy, and hexyloxy.

[0065] Non-limiting examples of "halogenated C1-6 alkoxy groups as appropriate" in this specification include C1-6 alkoxy groups that may have 1 to 7, for example, 1 to 5 halogen atoms. Other non-limiting examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, dibutoxy, pentyloxy, and hexyloxy.

[0066] Non-limiting examples of "C3-10 cycloalkyloxy" in this specification include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0067] Non-limiting examples of "C1-6 alkyl thio" in this specification include methyl thio, ethyl thio, propyl thio, isopropyl thio, butyl thio, dibutyl thio, terbutyl thio, pentyl thio, and hexyl thio.

[0068] Non-limiting examples of "halogenated C1-6 alkyl thio groups" in this specification include C1-6 alkyl thio groups having 1 to 7, for example 1 to 5 halogen atoms. Other non-limiting examples include methyl thio, difluoromethyl thio, trifluoromethyl thio, ethyl thio, propyl thio, isopropyl thio, butyl thio, 4,4,4-trifluorobutyl thio, pentyl thio, and hexyl thio.

[0069] Non-limiting examples of "C1-6 alkyl-carbonyl" in this specification include acetyl, propionic, butyryl, 2-methylpropionic, pentapropyl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionic, hexyl, and heptyl.

[0070] Non-limiting examples of "halogenated C1-6 alkyl-carbonyl groups, as appropriate" in this specification include C1-6 alkyl-carbonyl groups having 1 to 7, for example 1 to 5, halogen atoms. Other non-limiting examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propionic, butyryl, pentyl, and hexyl.

[0071] Non-limiting examples of "C1-6 alkoxy-carbonyl" in this specification include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, dibutoxycarbonyl, terbutoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0072] Non-limiting examples of "C6-14 aryl-carbonyl" in this specification include benzoyl, 1-naphthyl and 2-naphthyl.

[0073] Non-limiting examples of "C7-16 aralkyl-carbonyl" in this specification include phenylacetyl and phenylpropionic acid.

[0074] Non-limiting examples of "5 to 14-membered aromatic heterocyclic carbonyl groups" in this specification include nicotinyl, isonicotinyl, thiophenoxyyl, and furanoxyyl.

[0075] Non-limiting examples of "3 to 14 non-aromatic heterocyclic carbonyl groups" in this specification include morpholinocarbonyl, hexahydropyridinylcarbonyl, and pyrrolidinylcarbonyl.

[0076] Non-limiting examples of "mono- or di-C1-6 alkyl-aminomethyl" in this specification include methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, and N-ethyl-N-methylaminomethyl.

[0077] Non-limiting examples of "mono- or di-C7-16 aralkyl-aminomethyl" in this specification include benzylaminomethyl and phenethylaminomethyl.

[0078] Non-limiting examples of "C1-6 aralkylsulfonyl" in this specification include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, dibutylsulfonyl, and tert-butylsulfonyl.

[0079] Non-limiting examples of "halogenated C1-6 alkylsulfonyl groups" in this specification include C1-6 alkylsulfonyl groups having 1 to 7, for example 1 to 5, halogen atoms. Other non-limiting examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0080] Non-limiting examples of "C6-14 arylsulfonyl" in this specification include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0081] Non-limiting examples of "substituents" in this specification include halogen atoms, cyano groups, nitro groups, optionally substituted hydrocarbon groups, optionally substituted heterocyclic groups, acetyl groups, optionally substituted amino groups, optionally substituted aminomethyl groups, optionally substituted thioaminomethyl groups, optionally substituted aminosulfonyl groups, optionally substituted hydroxyl groups, optionally substituted hydrogen sulfide groups (SH groups), and optionally substituted silica groups.

[0082] Non-limiting examples of "hydrocarbon group" (including "hydrocarbon group" as "substituted as appropriate") in this specification include C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl and C7-16 aralkyl.

[0083] Non-limiting examples of "substituted hydrocarbon groups as appropriate" in this specification include hydrocarbon groups that may have substituents independently selected from substituent A.

[0084] Substituent A: (1) Halogen atom; (2) Nitro; (3) Cyano group; (4) Side oxygen group; (5) Hydroxyl group; (6) Halogenated C1-6 alkoxy groups, as appropriate; (7) C6-14 aryloxy group (e.g., phenoxy or naphthoxy); (8) C7-16 arylalkyloxy groups (e.g., benzyloxy groups); (9) 5 to 14 aromatic heterocyclic groups (e.g., pyridinyloxy groups); (10) 3 to 14 non-aromatic heterocyclic groups (e.g., morpholinyloxy or hexahydropyridinyloxy); (11) C1-6 alkyl-carbonyloxy group (e.g., acetoxy or propionic acid); (12) C6-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthyloxy, or 2-naphthyloxy); (13) C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, or butoxycarbonyloxy); (14) Mono- or di-C1-6 alkyl-aminomethoxy (e.g., methylaminomethoxy, ethylaminomethoxy, dimethylaminomethoxy, or diethylaminomethoxy); (15) C6-14 aryl-aminomethoxy (e.g., phenylaminomethoxy or naphthylaminomethoxy); (16) 5 to 14-membered aromatic heterocyclic carbonyloxy groups (e.g., nicotinyloxy groups); (17) 3 to 14 non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinocarbonyloxy or hexahydropyridylcarbonyloxy); (18) Halogenated C1-6 alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy or trifluoromethyl sulfonyloxy groups), as appropriate; (19) C6-14 arylsulfonyloxy group substituted with a C1-6 alkyl group (e.g., phenylsulfonyloxy or toluenesulfonyloxy); (20) Halogenated C1-6 alkyl thio groups, as appropriate; (21) 5 to 14 members of the aromatic heterocyclic group; (22) 3 to 14 non-aromatic heterocyclic groups; (23) Metabolite; (24) Carboxyl group; (25) Halogenated C1-6 alkyl-carbonyl groups, as appropriate; (26) C6-14 aryl-carbonyl; (27) 5 to 14-membered aromatic heterocyclic carbonyl groups; (28) 3 to 14 non-aromatic heterocyclic carbonyl groups; (29) C1-6 alkoxy-carbonyl; (30) C6-14 aryloxy-carbonyl (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl or 2-naphthyloxycarbonyl); (31) C7-16 Arylalkyloxy-carbonyl (e.g., benzyloxycarbonyl or phenethyloxycarbonyl); (32) Aminomethoxy; (33) Thioaminomethyl; (34) Mono- or di-C1-6 alkyl-aminomethyl; (35) C6-14 aryl-aminomethoxy (e.g., phenylaminomethoxy); (36) 5 to 14-membered aromatic heterocyclic amine methoxyl (e.g., pyridylamine methoxyl or thienylamine methoxyl); (37) 3 to 14 non-aromatic heterocyclic aminomethyl groups (e.g., morpholinoaminomethyl or hexahydropyridylaminomethyl); (38) Halogenated C1-6 alkylsulfonyl groups, as appropriate; (39) C6-14 arylsulfonyl; (40) 5 to 14 aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl or thienylsulfonyl); (41) Halogenated C1-6 alkylsulfinyl groups, as appropriate; (42) C6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl or 2-naphthylsulfinyl); (43) 5 to 14 aromatic heterocyclic sulfinyl groups (e.g., pyridylsulfinyl or thienylsulfinyl); (44) Amine group; (45) Mono- or di-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, or N-ethyl-N-methylamino); (46) Mono- or di-C6-14 arylamino group (e.g., phenylamino group); (47) 5 to 14 aromatic heterocyclic amines (e.g., pyridylamines); (48) C7-16 Arylalkylamine (e.g., benzylamine); (49) methylamino group; (50) C1-6 alkyl-carbonylamino (e.g., acetylamino, propionic amino, or butylamino); (51) (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino (e.g., N-acetylated-N-methylamino); (52) C6-14 Aryl-carbonylamine (e.g., phenylcarbonylamine or naphthylcarbonylamine); (53) C1-6 alkoxy-carbonylamine (e.g., methoxycarbonylamine, ethoxycarbonylamine, propoxycarbonylamine, butoxycarbonylamine, or tert-butoxycarbonylamine); (54) C7-16 Arylalkyloxy-carbonylamine (e.g., benzyloxycarbonylamine); (55) C1-6 alkylsulfonylamino (e.g., methanesulfonylamino or ethylsulfonylamino); (56) C6-14 arylsulfonylamino groups substituted with C1-6 alkyl groups (e.g., phenylsulfonylamino or toluenesulfonylamino); (57) Halogenated C1-6 alkyl groups, as appropriate; (58) C2-6 alkenyl; (59) C2-6 alkynyl group; (60) C3-10 cycloalkyl; (61) C3-10 cycloalkenyl; and (62) C6-14 Aryl.

[0085] In some embodiments, the number of substituents mentioned above in "substituted hydrocarbon groups as appropriate" is, for example, 1 to 5, or 1 to 3. When the number of substituents is 2 or greater, the individual substituents may be the same as or different from each other.

[0086] Non-limiting examples of "heterocyclic group" (including "heterocyclic group" in "substituted heterocyclic group as appropriate") in this specification include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered heterocyclic bridging cyclic groups, each containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms as ring atoms in addition to carbon atoms.

[0087] Non-limiting examples of "aromatic heterocyclic group" (including "5 to 14-member aromatic heterocyclic group") in this specification include 5 to 14-member (e.g., 5 to 10-member) aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms as ring atoms in addition to carbon atoms.

[0088] Non-limiting examples of such "aromatic heterocyclic groups" include 5- or 6-membered monocyclic aromatic heterocyclic groups, such as thienyl, furanyl, pyrroloyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazidinecycloyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; and 8 to 14-membered fused polycyclic (e.g., 2- or 3-cyclic) aromatic heterocyclic groups, such as benzo[a]phenylthio, benzo[a]furanyl, benzimidazolyl, benzo[a]oxazolyl, benzo[a]isooxazolyl, benzo[a]thiazolyl, and benzo[a]isothiazolyl. Benzotriazolyl, imidazopyridyl, thiophene-pyridyl, fluoropyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazopyridyl, imidazopyrazinyl, imidazopyrimidine, thiophene-pyrimidine, fluoropyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazopyrimidine, pyrazolotriazinyl, naphtho[2,3-b]thiophene-oxazinyl, indoleyl, isoindoleyl, 1H-inzolyl, purineyl, isoquinolinyl, quinolinyl, terazinyl, naphridinyl, quinoxolinyl, quinazolinyl, phenolinyl, carbazoyl, β-carolinyl, phenanthinyl, acridineyl, phenazinyl, phenothiazinyl, and phenothiazinyl.

[0089] Non-limiting examples of "non-aromatic heterocyclic groups" (including "3 to 14-member non-aromatic heterocyclic groups") in this specification include 3 to 14-member (e.g., 4 to 10-member) non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms as ring atoms in addition to carbon atoms.

[0090] Other non-limiting examples of such "non-aromatic heterocyclic groups" include 3 to 8-membered monocyclic non-aromatic heterocyclic groups, such as aziridinyl, oxacyclopropyl, cyclothioethane, aziridinyl, oxacyclobutyl, thiohexacyclobutyl, tetrahydrothiopheneyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazodinyl, oxazolinyl, oxazolinyl, pyrazolinyl, pyrazolinyl, thiazolinyl, thiazodinyl, tetrahydroisothiazolinyl, tetrahydrooxazolinyl, tetrahydroisooxazolinyl, hexahydropyridinyl, hexahydropyrazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyrazinoneyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, aziridinylheptyl, diaziridinylheptyl, aziridinyl, oxazolinyl, oxazolinyl, oxazolinyl, oxazolinyl, oxazolinyl, thiazolinyl, oxazolinyl, tetrahydroisothiazolinyl, tetrahydropyranyl, oxazolinyl, oxazolinyl, oxazolinyl, oxazolinyl, oxazolinyl, tetrahydroisothiazolinyl, tetrahydropyran ... Heterocyclic heptyl, azaheterocyclic octyl, and azaheterocyclic octyl; and 9 to 14 fused polycyclic (e.g., 2- or 3-cyclic) non-aromatic heterocyclic groups, such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thiophenyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 4H-quinolinidyl, indololinyl, isoindolyl Dolinyl, tetrahydrothieno[2,3-c]pyridyl, tetrahydrobenzopyridyl, tetrahydroquinoxalinyl, tetrahydrophenanthridine, hexahydrophenthiazinyl, hexahydrophenoxazinyl, tetrahydrophenazinyl, tetrahydronaphridinyl, tetrahydroquinazolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbazolyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthryl, and octahydroisoquinolinyl.

[0091] Non-limiting examples of "7 to 10-member heterocyclic bridging cyclogroups" in this specification include quinine cyclogroups and 7-azabicyclo[2.2.1]heptyl.

[0092] Non-limiting examples of "nitrogen-containing heterocyclic groups" in this specification include "heterocyclic groups" containing at least one nitrogen atom as a ring atom.

[0093] Non-limiting examples of "substituted heterocyclic groups as appropriate" in this specification include heterocyclic groups that may have substituents independently selected from substituent A.

[0094] The number of substituents in "substituted heterocyclic groups, as appropriate" 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.

[0095] Non-limiting examples of "acetylation" in this specification include methyl, carboxyl, thioaminomethyl, sulfinyl, sulfonyl, aminesulfonylated, and phosphonyl, each of which may have one or two independent substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-16 aralkyl, 5 to 14-membered aromatic heterocyclic groups, and 3 to 14-membered non-aromatic heterocyclic groups. Each of these substituents may have one to three independent substituents selected from halogen atoms, halogenated C1-6 alkoxy, hydroxyl, nitro, cyano, amino, and aminemethyl groups, where applicable.

[0096] Other non-limiting examples of acetyl groups include hydrocarbon-sulfonyl, heterocyclic-sulfonyl, hydrocarbon-sulfinyl, and heterocyclic-sulfinyl.

[0097] In this paper, alkyl-sulfonyl refers to a sulfonyl group bonded by an alkyl group; heterocyclic-sulfonyl refers to a sulfonyl group bonded by a heterocyclic group; alkyl-sulfinyl refers to a sulfinyl group bonded by an alkyl group; and heterocyclic-sulfinyl refers to a sulfinyl group bonded by a heterocyclic group.

[0098] Other non-limiting examples of "acetyl" include methyl, carboxyl, C1-6 alkyl-carbonyl, C2-6 alkenyl-carbonyl (e.g., crotonyl), C3-10 cycloalkyl-carbonyl (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, or cycloheptanecarbonyl), C3-10 cycloalkenyl-carbonyl (e.g., 2-cyclohexenecarbonyl), C6-14 aryl-carbonyl, C7-16 arylalkyl-carbonyl, 5 to 14 members of aromatic heterocyclic carbonyl, 3 to 14 members of non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryloxy-carbonyl (e.g., phenyloxycarbonyl or naphthyloxycarbonyl), C7-16 arylalkyloxy-carbonyl (e.g., benzyloxycarbonyl or phenethyloxycarbonyl), aminomethyl, mono- or di-C1-6 Alkyl-aminomethyl, mono- or di-C2-6 alkenyl-aminomethyl (e.g., diallylaminomethyl), mono- or di-C3-10 cycloalkyl-aminomethyl (e.g., cyclopropylaminomethyl), mono- or di-C6-14 aryl-aminomethyl (e.g., phenylaminomethyl), mono- or di-C7-16 aralkyl-aminomethyl, 5 to 14-membered aromatic heterocyclic aminomethyl (e.g., pyridylaminomethyl), thioaminomethyl, mono- or di-C1-6 alkyl-thioaminomethyl (e.g., methylthioaminomethyl or N-ethyl-N-methylthioaminomethyl), mono- or di-C2-6 Alkenyl-thioamine methyl (e.g., diallyl thioamine methyl), mono- or di-C3-10 cycloalkyl-thioamine methyl (e.g., cyclopropyl thioamine methyl or cyclohexyl thioamine methyl), mono- or di-C6-14 aryl-thioamine methyl (e.g., phenyl thioamine methyl), mono- or di-C7-16 aralkyl-thioamine methyl (e.g., benzyl thioamine methyl or phenethyl thioamine methyl), 5 to 14-membered aromatic heterocyclic thioamine methyl (e.g., pyridyl thioamine methyl), sulfinyl, C1-6 alkylsulfinyl (e.g., methyl sulfinyl or ethyl sulfinyl), sulfonyl, C1-6 alkylsulfinyl, C6-14 Arylsulfonyl, phosphatyl, and mono- or di-C1-6 alkylphosphatyl (e.g., dimethylphosphatyl, diethylphosphatyl, diisopropylphosphatyl, or dibutylphosphatyl).

[0099] Non-limiting examples of "substituted amino groups as appropriate" in this specification include amino groups that may have one or two independently selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-16 aralkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, 5 to 14-membered aromatic heterocyclic carbonyl, 3 to 14-membered non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, 5 to 14-membered aromatic heterocyclic, aminomethyl, mono- or di-C1-6 alkyl-aminomethyl, mono- or di-C7-16 aralkyl-aminomethyl, C1-6 alkylsulfonyl, and C6-14 Substituents of arylsulfonyl group, each of which may have 1 to 3 independent substituents selected from substituent A.

[0100] Non-limiting examples of substituted amino groups include amino, mono- or di-(halogenated C1-6 alkyl)amino (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, or dibutylamino), mono- or di-C2-6 alkenylamino (e.g., diallylamino), mono- or di-C3-10 cycloalkylamino (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C6-14 arylamino (e.g., phenylamino), mono- or di-C7-16 arylalkylamino (e.g., benzylamino or dibenzylamino), mono- or di-(halogenated C1-6 alkyl)-carbonylamino (e.g., acetylamino or propylamino), mono- or di-C6-14 Aryl-carbonyl (e.g., benzoylamino), mono- or di-C7-16 aralkyl-carbonylamino (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino (e.g., nicotinylamino or isonicylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino (e.g., hexahydropyridylcarbonylamino), mono- or di-C1-6 alkoxy-carbonylamino (e.g., terbutoxycarbonylamino), 5 to 14-membered aromatic heterocyclic amino (e.g., pyridylamino), aminomethylamino, (mono- or di-C1-6 alkyl-aminomethyl)amino (e.g., methylaminomethylamino), (mono- or di-C7-16 aralkyl-aminomethyl)amino (e.g., benzylaminomethylamino), C1-6 Alkylsulfonylamino (e.g., methylsulfonylamino or ethylsulfonylamino), C6-14 arylsulfonylamino (e.g., phenylsulfonylamino), (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino (e.g., N-acetylated-N-methylamino) and (C1-6 alkyl)(C6-14 aryl-carbonyl)amino (e.g., N-benzoyl-N-methylamino).

[0101] Non-limiting examples of "substituted aminomethyl groups as appropriate" in this specification include aminomethyl groups that may have one or two independent substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-16 aralkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, 5 to 14-membered aromatic heterocyclic carbonyl, 3 to 14-membered non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, 5 to 14-membered aromatic heterocyclic, aminomethyl, mono- or di-C1-6 alkyl-aminomethyl, and mono- or di-C7-16 aralkyl-aminomethyl, each of which may have one to three independent substituents selected from substituent A.

[0102] Other non-limiting examples of substituted aminomethyl groups, as appropriate, include aminomethyl, mono- or di-C1-6 alkyl-aminomethyl, mono- or di-C2-6 alkenyl-aminomethyl (e.g., diallylaminomethyl), mono- or di-C3-10 cycloalkyl-aminomethyl (e.g., cyclopropylaminomethyl or cyclohexylaminomethyl), mono- or di-C6-14 aryl-aminomethyl (e.g., phenylaminomethyl), mono- or di-C7-16 aralkyl-aminomethyl, mono- or di-C1-6 alkyl-carbonyl-aminomethyl (e.g., acetylammonomethyl or propylaminomethyl), mono- or di-C6-14 Aryl-carbonyl-aminomethyl (e.g., benzoylaminomethyl) and 5 to 14-membered aromatic heterocyclic aminomethyl (e.g., pyridylaminomethyl).

[0103] Non-limiting examples of "substituted thioaminomethyl" in this specification include thioaminomethyl, which may have one or two independent substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-16 aralkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, 5 to 14-membered aromatic heterocyclic carbonyl, 3 to 14-membered non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, 5 to 14-membered aromatic heterocyclic, aminomethyl, mono- or di-C1-6 alkyl-aminomethyl and mono- or di-C7-16 aralkyl-aminomethyl, each of which may have one to three independent substituents selected from substituent A.

[0104] Other non-limiting examples of substituted thioamine methoxyl groups, as appropriate, include thioamine methoxyl, mono- or di-C1-6 alkyl-thioamine methoxyl (e.g., methylthioamine methoxyl, ethylthioamine methoxyl, dimethylthioamine methoxyl, diethylthioamine methoxyl, or N-ethyl-N-methylthioamine methoxyl), mono- or di-C2-6 alkenyl-thioamine methoxyl (e.g., diallylthioamine methoxyl), mono- or di-C3-10 cycloalkyl-thioamine methoxyl (e.g., cyclopropylthioamine methoxyl or cyclohexylthioamine methoxyl), mono- or di-C6-14 aryl-thioamine methoxyl (e.g., phenylthioamine methoxyl), mono- or di-C7-16 Aryl-thioamine methyl (e.g., benzylthioamine methyl or phenethylthioamine methyl), mono- or di-C1-6 alkyl-carbonyl-thioamine methyl (e.g., acetylated thioamine methyl or propylated thioamine methyl), mono- or di-C6-14 aryl-carbonyl-thioamine methyl (e.g., benzoylthioamine methyl), and 5 to 14-membered aromatic heterocyclic thioamine methyl (e.g., pyridylthioamine methyl).

[0105] Non-limiting examples of "substituted aminesulfonyl" in this specification include aminesulfonyl groups that may have one or two independent substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-16 aralkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, 5 to 14-membered aromatic heterocyclic carbonyl, 3 to 14-membered non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, 5 to 14-membered aromatic heterocyclic, aminemethyl, mono- or di-C1-6 alkyl-aminemethyl, and mono- or di-C7-16 aralkyl-aminemethyl, each of which may have one to three independent substituents selected from substituent A.

[0106] Other non-limiting examples of substituted aminesulfonyl groups, as appropriate, include aminesulfonyl, mono- or di-C1-6 alkyl-aminesulfonyl (e.g., methylaminesulfonyl, ethylaminesulfonyl, dimethylaminesulfonyl, diethylaminesulfonyl, or N-ethyl-N-methylaminesulfonyl), mono- or di-C2-6 alkenyl-aminesulfonyl (e.g., diallylaminesulfonyl), mono- or di-C3-10 cycloalkyl-aminesulfonyl (e.g., cyclopropylaminesulfonyl, cyclohexylaminesulfonyl), mono- or di-C6-14 aryl-aminesulfonyl (e.g., phenylaminesulfonyl), mono- or di-C7-16 Aryl-amine sulfonyl (e.g., benzylamine sulfonyl or phenethylamine sulfonyl), mono- or di-C1-6 alkyl-carbonyl-amine sulfonyl (e.g., acetylamine sulfonyl or propytylamine sulfonyl), mono- or di-C6-14 aryl-carbonyl-amine sulfonyl (e.g., benzoylamine sulfonyl), and 5 to 14-membered aromatic heterocyclic amine sulfonyl (e.g., pyridylamine sulfonyl).

[0107] Non-limiting examples of "substituted hydroxyl groups as appropriate" in this specification include hydroxyl groups that may have substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-16 aralkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, 5 to 14-membered aromatic heterocyclic carbonyl, 3 to 14-membered non-aromatic heterocyclic carbonyl, C1-6 alkoxy-carbonyl, 5 to 14-membered aromatic heterocyclic, aminomethyl, mono- or di-C1-6 alkyl-aminomethyl, mono- or di-C7-16 aralkyl-aminomethyl, C1-6 alkylsulfonyl, and C6-14 arylsulfonyl, each of which may have 1 to 3 substituents independently selected from substituent A.

[0108] Non-limiting examples of substituted hydroxyl groups, as appropriate, include hydroxyl, C1-6 alkoxy, C2-6 alkenyloxy (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, or 3-hexenyloxy), C3-10 cycloalkyloxy (e.g., cyclohexyloxy), C6-14 aryloxy (e.g., phenoxy or naphthyloxy), C7-16 arylalkyloxy (e.g., benzyloxy or phenethyloxy), C1-6 alkyl-carbonyloxy (e.g., acetylatedloxy, propionicloxy, butylatedloxy, isobutylatedloxy, or pentylatedloxy), C6-14 aryl-carbonyloxy (e.g., benzoyloxy), C7-16 Arylalkyl-carbonyloxy (e.g., benzylcarbonyloxy), 5 to 14-membered aromatic heterocyclic carbonyloxy (e.g., nicotinyloxy), 3 to 14-membered non-aromatic heterocyclic carbonyloxy (e.g., hexahydropyridylcarbonyloxy), C1-6 alkoxy-carbonyloxy (e.g., terbutoxycarbonyloxy), 5 to 14-membered aromatic heterocyclic carbonyloxy (e.g., pyridyloxy), aminomethyloxy, C1-6 alkyl-aminomethyloxy (e.g., methylaminomethyloxy), C7-16 arylalkyl-aminomethyloxy (e.g., benzylaminomethyloxy), C1-6 alkylsulfonyloxy (e.g., methylsulfonyloxy or ethylsulfonyloxy), and C6-14 arylsulfonyloxy (e.g., phenylsulfonyloxy).

[0109] Non-limiting examples of "substituted hydrogen sulfide" in this specification include hydrogen sulfide and halohydrogen sulfide, which may have substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl, C7-16 aralkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl and 5 to 14 aromatic heterocyclic groups, each of which may have 1 to 3 substituents independently selected from substituent A.

[0110] Other non-limiting examples of substituted hydrogen sulfide groups, as appropriate, include hydrogen sulfide (-SH), C1-6 alkyl sulfide, C2-6 alkenyl sulfide (e.g., allyl sulfide, 2-butenyl sulfide, 2-pentenyl sulfide, or 3-hexenyl sulfide), C3-10 cycloalkyl sulfide (e.g., cyclohexyl sulfide), C6-14 aryl sulfide (e.g., phenyl sulfide or naphthyl sulfide), C7-16 arylalkyl sulfide (e.g., benzyl sulfide or phenethyl sulfide), C1-6 alkyl-carbonyl sulfide (e.g., acetylsulyl sulfide, propionic sulfide, butyl sulfide, isobutyl sulfide, or pentylsulyl sulfide), C6-14 aryl-carbonyl sulfide (e.g., benzoyl sulfide), 5 to 14-membered aromatic heterocyclic sulfide (e.g., pyridyl sulfide), and halogenated sulfide (e.g., pentafluorosulfide).

[0111] Non-limiting examples of "substituted silicone" in this specification include silicone that may have one to three independent substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C6-14 aryl and C7-16 aralkyl, each of which may have one to three independent substituents selected from substituent A.

[0112] Non-limiting examples of substituted silica groups include tri-C1-6 alkyl silica (e.g., trimethylsilyl or tributyl(dimethyl)silyl).

[0113] Non-limiting examples of "hydrocarbon ring" in this specification include C6-14 aromatic hydrocarbon rings, C3-10 cycloalkanes, and C3-10 cycloalkenes.

[0114] Non-limiting examples of "C6-14 aromatic hydrocarbon group" in this specification include benzene and naphthalene.

[0115] Non-limiting examples of "C3-10 cycloalkanes" in this specification include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0116] Non-limiting examples of "C3-10 cycloolefins" in this specification include cyclopropylene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

[0117] Non-limiting examples of "heterocycle" in this specification include aromatic heterocycles and non-aromatic heterocycles, which contain 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms as ring atoms in addition to carbon atoms.

[0118] Non-limiting examples of "aromatic heterocycles" in this specification include 5- to 14-membered (e.g., 5- to 10-membered) aromatic heterocycles containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring atoms in addition to a carbon atom. Other non-limiting examples of such "aromatic heterocycles" include 5- or 6-membered monocyclic aromatic heterocycles, such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, darazine, 1,2,4-oxadiazole, 1,3,4-oxadiazolyl, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetraazole, and triazine; and 8- to 14-membered fused polycyclic (e.g., 2- or 3-ringed) aromatic heterocycles, such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzyl... The following are listed: isothiazazole, benzotriazole, imidazopyridine, thiophenepyridine, flupyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazopyridine, imidazopyrazine, imidazopyrimidine, thiophenepyrimidine, flupyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenanthrenethiazoline, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, terazine, naphthidine, quinoxaline, quinazoline, phenoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenothiazine.

[0119] Non-limiting examples of "non-aromatic heterocycles" in this specification include non-aromatic heterocycles with 3 to 14 members (e.g., 4 to 10 members) of a ring atom, which contain 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. Other non-limiting examples of such "non-aromatic heterocycles" include 3 to 8-membered monocyclic non-aromatic heterocycles, such as aziridine, ethylene oxide, cyclothioethane, aziridine, oxazoline, oxazoline, thiocyclobutane, tetrahydrothiophene, tetrahydrofuran, pyrrolidine, pyrrolidine, imidazoline, imidazoline, oxazoline, oxazoline, pyrrolidine, thiazoline, thiazoline, tetrahydroisothiazolium, tetrahydrooxazole, tetrahydroisoxazole, hexahydropyridine, hexahydropyrazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydrodarazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, aziridine-heptane, diaziridine-heptane, aziridine, aziridine-octane. , diazacyclooctane and oxacycloheptane; and 9 to 14 fused polycyclic (e.g., 2- or 3-cyclic) non-aromatic heterocyclic groups, such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinazine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzopyrazine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenothiazine, tetrahydrophenoxazine, tetrahydrophenazine, tetrahydronaphthidine, tetrahydroquinazolinoline, tetrahydrocarbazole, tetrahydro-β-carbline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthone and octahydroisoquinoline.

[0120] Non-limiting examples of "nitrogen-containing heterocycles" in this specification include "heterocycles" containing at least one nitrogen atom as a ring atom.

[0121] Non-limiting examples of "6-membered aromatic rings" in this specification include benzene, pyridine, pyrazine, pyrimidine, pyrazine, and triazine.

[0122] Non-limiting examples of "5-membered monocyclic aromatic heterocycles" in this specification 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 tetraazole.

[0123] The definition of each symbol in equation (I) will be explained in detail below.

[0124] In some embodiments, R1 is represented by the following groups: or ,in: Ring A1 is selected from six aromatic rings that have been further replaced, as appropriate; Cyclic A2 is selected from, as appropriate, further substituted 5-member monocyclic aromatic heterocycles; and R6a and R6b are each independently selected from substituents.

[0125] In some embodiments, R1 is represented by the following groups: .

[0126] In some embodiments, the "6-membered aromatic ring" represented by ring A1, which is "a 6-membered aromatic ring that is further substituted as appropriate," is benzene, pyridine, or pyrimidine. In some embodiments, the "6-membered aromatic ring" represented by ring A1, which is "a 6-membered aromatic ring that is further substituted as appropriate," is pyridine.

[0127] Non-limiting examples of substituents present in the "6-membered aromatic ring further substituted as appropriate" represented by ring A1 are independently selected from the substituents of substituent A. In some embodiments, the number of such substituents present as appropriate is an integer from 1 to 3. When the number of substituents present as appropriate is 2 or greater, the individual substituents may be the same as or different from each other.

[0128] In some embodiments, ring A1 is selected from a 6-membered aromatic ring (e.g., benzene, pyridine, or pyrimidine) that may be further substituted with 1 to 3 independent substituents selected from the following: (a) Halogen atoms (e.g., fluorine, chlorine, or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate.

[0129] In some embodiments, ring A1 is selected from: (1) Further, as appropriate, the benzene ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine, chlorine, or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (2) Further, as appropriate, the pyridine ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine or chlorine atoms); (b) Halogenated C1-6 alkyl groups (e.g., methyl, difluoromethyl, or trifluoromethyl), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-10 cycloalkyl groups (e.g., cyclopropyl); and (3) The pyrimidine ring may be further substituted with one or two halogenated C1-6 alkyl groups (e.g., trifluoromethyl) as appropriate.

[0130] In some embodiments, ring A1 is selected from: (1) Further, as appropriate, the benzene ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine, chlorine, or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-6 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) A hexahydropyridyl group, substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; (2) Further, as appropriate, the pyridine ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine or chlorine atoms); (b) Halogenated C1-6 alkyl groups (e.g., methyl, difluoromethyl, or trifluoromethyl), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-6 cycloalkyl (e.g., cyclopropyl); or (3) The pyrimidine ring may be further substituted with one or two halogenated C1-6 alkyl groups (e.g., trifluoromethyl) as appropriate.

[0131] In some embodiments, ring A1 is selected from pyridine rings, which are further substituted by one or two independent substituents selected from: (a) Halogen atoms (e.g., fluorine atoms); and (b) Halogenated C1-6 alkyl groups (e.g., trifluoromethyl).

[0132] In some embodiments, the ring A1 is selected from a pyridine ring further substituted with a halogenated C1-6 alkyl group (e.g., trifluoromethyl).

[0133] In some embodiments, ring A1 is selected from a pyridine ring further substituted with a trifluoromethyl group.

[0134] In some embodiments, ring A1 is selected from a benzene ring that is further substituted, a pyridine ring that is further substituted, and a pyrimidine ring that is further substituted.

[0135] In some embodiments, ring A1 is selected from pyridine rings that are further substituted as appropriate.

[0136] In some embodiments, ring A1 is selected from a further substituted pyridine ring.

[0137] In some embodiments, R6a is selected from: (1) C3-10 cycloalkyl groups, substituted as appropriate (e.g., cyclohexyl); (2) Substituted C6-14 aryl groups (e.g., phenyl groups), depending on the case; (3) Substituted 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., morpholino, hexahydropyridyl, or pyrrolidinyl) or 6 to 9-membered non-aromatic spiroheterocyclic groups (e.g., 4-oxa-7-azaspiro[2.5]octyl)); (4) Depending on the circumstances, a 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., an imidazole group)); (5) -NR9 R10, where: R9 series is selected from: (A) C1-6 alkyl groups substituted as appropriate (e.g., methyl); and (B) Substituted 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyl); and The R10 series is selected from: (A) Hydrogen atom; and (B) C1-6 alkyl groups substituted as appropriate (e.g., methyl)); and (6) -OR11, where R11 is selected from: (A) C1-6 alkyl groups, substituted as appropriate (e.g., methyl); (B) Substituted C6-14 aryl groups (e.g., phenyl); and (C) Substituted 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyl)).

[0138] In some embodiments, the substituents present as appropriate among "substituently substituted C1-6 alkyl", "substituently substituted C3-10 cycloalkyl", "substituently substituted C6-14 aryl", "substituently substituted 3 to 14 non-aromatic heterocyclic", and "5 to 14 aromatic cycloalkyl" described above are independently selected from the substituents of substituent A. In some embodiments, the number of such substituents present as appropriate is an integer from 1 to 3. When the number of substituents present as appropriate is 2 or more, the individual substituents present as appropriate may be the same as or different from each other.

[0139] In some embodiments, the “3 to 14 non-aromatic heterocyclic group” mentioned above, which is “substituted 3 to 14 non-aromatic heterocyclic group as appropriate”, is selected from 6 to 9 non-aromatic spirocyclic groups.

[0140] In some embodiments, R6a is selected from: (1) C3-10 cycloalkyl groups, substituted as appropriate (e.g., cyclohexyl); (2) Substituted C6-14 aryl groups (e.g., phenyl groups), depending on the case; (3) Substituted 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., morpholino, hexahydropyridyl or pyrrolidinyl) or 6 to 9-membered non-aromatic spiroheterocyclic groups (e.g., 4-oxa-7-azaspiro[2.5]octyl)); (4) Depending on the circumstances, a 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., an imidazole group)); (5) A substituted mono- or di-C1-6 alkylamine group (e.g., methylamine group), depending on the case; (6) N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amines, as appropriate (e.g., N-C1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amines (e.g., N-methyl-N-tetrahydropyranylamine)); (7) Substituted C1-6 alkoxy groups (e.g., methoxy groups), as appropriate; (8) As appropriate, a substituted C6-14 aryloxy group (e.g., phenoxy group); and (9) Substituted 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyloxy)).

[0141] In some embodiments, R6a is selected from: (1) C3-10 cycloalkyl groups (e.g., cyclohexyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (2) C6-14 aryl groups (e.g., phenyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), depending on the case; (3) As appropriate, a 3 to 14-membered non-aromatic heterocyclic group (e.g., a 3 to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholino, hexahydropyridinyl, or pyrrolidinyl) or a 6 to 9-membered non-aromatic spiroheterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl) substituted with 1 to 3 independently selected substituents: (a) Halogen atoms (e.g., fluorine atoms); and (b) Halogenated C1-6 alkyl groups (e.g., methyl or difluoromethyl), as appropriate; (4) A substituted 5 to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., an imidazolyl group)) which, as appropriate, is substituted with 1 to 3 C1-6 alkyl groups (e.g., methyl groups); (5) A mono- or di-C1-6 alkylamino group (e.g., methylamino group) substituted with one to three C3-10 cycloalkyl groups (e.g., cyclobutyl, which is substituted with one to three halogen atoms (e.g., fluorine atoms) as appropriate); (6) N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amines (e.g., N-C1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amines (e.g., N-methyl-N-tetrahydropyranylamine)); (7) A C1-6 alkoxy group (e.g., methoxy) substituted with one to three independently selected substituents: (a) C1-6 alkoxy groups (e.g., methoxy groups); (b) C3-10 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; and (c) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., oxo-heterobutyl or tetrahydrofuranyl)); (8) C6-14 aryloxy groups (e.g., phenoxy groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; and (9) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyloxy group)).

[0142] In some embodiments, R6a is selected from: (1) C3-6 cycloalkyl groups (e.g., cyclohexyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), depending on the case; (2) A phenyl group, substituted with one to three halogen atoms (e.g., fluorine atoms), depending on the case; (3) Morpholino group substituted with 1 to 3 independently selected substituents from the following, depending on the case: (a) Halogen atoms (e.g., fluorine atoms); and (b) Halogenated C1-6 alkyl groups (e.g., methyl or difluoromethyl), as appropriate; (4) A hexahydropyridyl group, substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), depending on the case; (5) A pyrrolidin group, substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (6) 4-oxa-7-azaspiro[2.5]octyl; (7) An imidazolyl group substituted with one to three C1-6 alkyl groups (e.g., methyl), as appropriate; (8) A mono- or di-C1-6 alkylamino group (e.g., methylamino group) substituted with one to three C3-6 cycloalkyl groups (e.g., cyclobutyl, which is substituted with one to three halogen atoms (e.g., fluorine atoms) as appropriate); (9) N-C1-6 alkyl-N-tetrahydropyranylamino (e.g., N-methyl-N-tetrahydropyranylamino); (10) A C1-6 alkoxy group (e.g., methoxy) substituted with one to three independently selected substituents: (a) C1-6 alkoxy groups (e.g., methoxy groups); (b) C3-6 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (c) Oxycyclic butyl; and (d) Tetrahydrofuranyl; (11) A phenoxy group, substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; and (12) Tetrahydropyranyloxy.

[0143] In some embodiments, R6a is a morpholino group substituted with one to three C1-6 alkyl groups (e.g., methyl groups), as appropriate.

[0144] In some embodiments, R6a is a morpholino group substituted with a C1-6 alkyl group (e.g., methyl).

[0145] In some embodiments, the following groups are used: It consists of the following groups: , R7a and R8a are each independently selected from hydrogen atoms and substituents, and the other symbols are as defined above.

[0146] In some embodiments, R7a is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., chlorine or bromine atoms); (c) C1-6 alkyl groups, substituted as appropriate (e.g., methyl, ethyl, or isopropyl); (d) C1-6 alkoxy groups, as appropriate (e.g., methoxy or ethoxy); (e) C3-10 cycloalkyl groups, substituted as appropriate (e.g., cyclopropyl); (f) C2-6 alkenyl groups (e.g., vinyl groups), as appropriate; and (g) Substituted 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)).

[0147] In some embodiments, the R7a series: (a) Hydrogen atom; (b) Halogen atoms (e.g., chlorine or bromine atoms); (c) A C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (d) Halogenated C1-6 alkoxy groups, as appropriate (e.g., trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy); (e) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; (f) C2-6 alkenyl (e.g., vinyl); or (g) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate.

[0148] In some embodiments, R7a is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., chlorine or bromine atoms); (c) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (d) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (e) C3-6 cycloalkyl groups (e.g., cyclopropyl groups) substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; (f) C2-6 alkenyl (e.g., vinyl); and (g) A hexahydropyridyl group, which may be substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) as appropriate.

[0149] In some embodiments, R7a is selected from halogenated C1-6 alkyl groups (e.g., trifluoromethyl).

[0150] In some embodiments, R7a is a trifluoromethyl group.

[0151] In some embodiments, R8a is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl groups (e.g., methyl) that are substituted, as appropriate.

[0152] In some embodiments, R8a is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl (e.g., methyl).

[0153] In some embodiments, R8a is selected from hydrogen atoms and halogen atoms (e.g., fluorine atoms).

[0154] In some embodiments, R8a consists of hydrogen or fluorine atoms.

[0155] In some embodiments, R8a is a hydrogen atom.

[0156] In some embodiments, the following groups are used: It consists of the following groups: , R7a1, R7a2, R7a3, R8a1 and R8a2 are each independently selected from hydrogen atoms and substituents, and the other symbols are as defined above.

[0157] In some embodiments, R7a1 is selected from: (a) Halogen atoms (e.g., chlorine or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate.

[0158] In some embodiments, R7a1 is selected from: (a) Halogen atoms (e.g., chlorine or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-6 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) Hexahydropyridyl group substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate.

[0159] In some embodiments, R7a2 is selected from: (a) Hydrogen atom; (b) Halogenated C1-6 alkyl groups (e.g., trifluoromethyl groups), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-10 cycloalkyl (e.g., cyclopropyl).

[0160] In some embodiments, R7a2 is selected from: (a) Hydrogen atom; (b) Halogenated C1-6 alkyl groups (e.g., trifluoromethyl groups), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-6 cycloalkyl (e.g., cyclopropyl).

[0161] In some embodiments, R7a2 is a halogenated C1-6 alkyl group (e.g., trifluoromethyl).

[0162] In some embodiments, R7a2 is a trifluoromethyl group.

[0163] In some embodiments, R7a3 is a C1-6 alkyl group (e.g., trifluoromethyl) that is halogenated as appropriate.

[0164] In some embodiments, R8a1 is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl (e.g., methyl).

[0165] In some embodiments, R8a2 is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl (e.g., methyl).

[0166] In some embodiments, R8a2 is selected from hydrogen atoms and halogen atoms (e.g., fluorine atoms).

[0167] In some embodiments, R8a2 consists of hydrogen or fluorine atoms.

[0168] In some embodiments, R8a2 is a hydrogen atom.

[0169] In some embodiments, the following groups are used: It consists of the following groups: , The symbols in the formula are defined as above.

[0170] In some embodiments, R7a2 is selected from halogenated C1-6 alkyl groups (e.g., trifluoromethyl).

[0171] In some embodiments, R7a2 is a trifluoromethyl group.

[0172] In some embodiments, R8a2 is selected from hydrogen atoms and halogen atoms (e.g., fluorine atoms).

[0173] In some embodiments, R8a2 consists of hydrogen or fluorine atoms.

[0174] In some embodiments, R8a2 is a hydrogen atom.

[0175] In some embodiments, the "5-membered monocyclic aromatic heterocyclic group" represented by ring A2, which is "further substituted 5-membered monocyclic aromatic heterocyclic group as appropriate," is a pyrazole.

[0176] Non-limiting examples of substituents present in the "5-membered monocyclic aromatic heterocycle, which may be further substituted as appropriate" represented by ring A2 are independently selected from substituents of substituent A. In some embodiments, the number of such substituents present as appropriate is an integer from 1 to 3. When the number of substituents present as appropriate is 2 or greater, the individual substituents may be the same as or different from each other.

[0177] In some embodiments, ring A2 is selected from a 5-membered monocyclic aromatic heterocycle (e.g., pyrazole) that is optionally further substituted with 1 to 3 optionally halogenated C1-6 alkyl groups (e.g., trifluoromethyl).

[0178] In some embodiments, the ring A2 is further substituted with one to three pyrazole rings that are, as appropriate, halogenated C1-6 alkyl (e.g., trifluoromethyl) substituted rings.

[0179] In some embodiments, the cycloA2 system is further substituted with a pyrazole ring by a halogenated C1-6 alkyl group (e.g., trifluoromethyl).

[0180] In some embodiments, ring A2 is further substituted with a trifluoromethyl-substituted pyrazole ring.

[0181] In some embodiments, ring A2 is a further substituted pyrazol group, as appropriate. In some embodiments, ring A2 is a further substituted pyrazol ring.

[0182] In some embodiments, R6b is a substituted C1-6 alkyl group (e.g., ethyl group), which may be used as appropriate.

[0183] Non-limiting examples of substituents present as appropriate in the "C1-6 alkyl groups substituted as appropriate" described above are independently selected from substituents of substituent A. In some embodiments, the number of such substituents present as appropriate is an integer from 1 to 3. When the number of substituents present as appropriate is 2 or more, the individual substituents may be the same as or different from each other.

[0184] In some embodiments, R6b is a C1-6 alkyl group (e.g., ethyl) substituted with one to three C3-10 cycloalkyl groups (e.g., cyclobutyl).

[0185] In some embodiments, R6b is a C1-6 alkyl group (e.g., ethyl) substituted with one to three C3-6 cycloalkyl groups (e.g., cyclobutyl).

[0186] In some embodiments, the following groups are used: It consists of the following groups: , R7b is selected from hydrogen atoms and substituents, and all other symbols are as defined above.

[0187] In some embodiments, R7b is a substituted C1-6 alkyl group (e.g., methyl) as appropriate.

[0188] In some embodiments, R7b is a C1-6 alkyl group (e.g., trifluoromethyl) that is halogenated as appropriate.

[0189] In some embodiments, R7b is a halogenated C1-6 alkyl group (e.g., trifluoromethyl).

[0190] In some embodiments, R7b is a trifluoromethyl group.

[0191] In some embodiments, Z is C-R2 or N. In some embodiments, R2 is selected from hydrogen atoms, halogen atoms, and, where appropriate, halogenated C1-6 alkyl groups.

[0192] In some embodiments, Z-based C-R2. In some embodiments, R2 is selected from hydrogen atoms and, where appropriate, halogenated C1-6 alkyl groups (e.g., methyl or ethyl).

[0193] In some embodiments, R2 is selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl or ethyl).

[0194] In some embodiments, R2 is selected from hydrogen atoms and C1-3 alkyl groups (e.g., methyl).

[0195] In some embodiments, R2 is selected from C1-3 alkyl groups (e.g., methyl).

[0196] In some embodiments, Z-series N or C-R2, wherein R2 is selected from hydrogen atoms and, where appropriate, halogenated C1-6 alkyl groups (e.g., methyl or ethyl).

[0197] In some embodiments, Z-series N or C-R2, wherein R2 is selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl or ethyl).

[0198] In some embodiments, Z-series C-R2, wherein R2 is selected from hydrogen atoms and C1-3 alkyl groups (e.g., methyl).

[0199] In some embodiments, Z-series C-R2, wherein R2 is selected from C1-3 alkyl groups (e.g., methyl).

[0200] In some embodiments, R3 is selected from hydrogen atoms, halogen atoms (e.g., chlorine atoms), and, where appropriate, halogenated C1-6 alkyl groups (e.g., methyl, ethyl, or trifluoromethyl).

[0201] In some embodiments, R3 is selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl).

[0202] In some embodiments, R3 is selected from hydrogen atoms and C1-3 alkyl groups (e.g., methyl).

[0203] In some embodiments, R3 is a C1-3 alkyl group (e.g., methyl).

[0204] In some embodiments, R4 and R5 are each independently selected from hydrogen atoms and substituents.

[0205] In some embodiments, R4 and R5 are each independently selected from hydrogen atoms and, where appropriate, substituted C1-6 alkyl groups (e.g., methyl).

[0206] Non-limiting examples of substituents present as appropriate in the "C1-6 alkyl groups substituted as appropriate" described above are independently selected from substituents of substituent A. In some embodiments, the number of such substituents present as appropriate is an integer from 1 to 3. When the number of substituents present as appropriate is 2 or more, the individual substituents may be the same as or different from each other.

[0207] In some embodiments, R4 and R5 are each independently selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl).

[0208] In some embodiments, R4 is selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl).

[0209] In some embodiments, R5-series hydrogen atoms.

[0210] In some embodiments, both R4 and R5 are hydrogen atoms.

[0211] In some embodiments, ring B is further replaced by a 5-member monocyclic aromatic heterocycle, as appropriate.

[0212] In some embodiments, the "5-membered monocyclic aromatic heterocyclic group" represented by ring B as "further substituted 5-membered monocyclic aromatic heterocyclic group, as appropriate" is a pyrazole ring (e.g., 1H-pyrazole-4-yl).

[0213] Non-limiting examples of substituents present in the "5-membered monocyclic aromatic heterocycle, which may be further substituted as appropriate" represented by ring B are independently selected from substituents of substituent A. In some embodiments, the number of such substituents present as appropriate is an integer from 1 to 3. When the number of substituents present as appropriate is 2 or greater, the individual substituents may be the same as or different from each other.

[0214] In some embodiments, the cyclic B system may be further substituted with a 5-membered monocyclic aromatic heterocycle (e.g., pyrazole) by 1 to 3 C1-6 alkyl groups (e.g., methyl, ethyl, or isopropyl).

[0215] In some embodiments, the cyclic B group may be further substituted with a pyrazole ring (e.g., 1H-pyrazole-4-yl) by one to three C1-6 alkyl groups (e.g., methyl, ethyl, or isopropyl).

[0216] In some embodiments, the cyclic B system is further substituted with a pyrazole ring (e.g., 1H-pyrazole-4-yl) of a C1-6 alkyl group (e.g., ethyl group).

[0217] In some embodiments, the cyclic B group is further substituted with a pyrazolyl group, as appropriate.

[0218] In some embodiments, ring B is further substituted with a pyrazole ring.

[0219] In some embodiments, ring B is represented by the following ring base: ,in: R1c is selected from hydrogen atoms and C1-6 alkyl groups (e.g., ethyl or isopropyl); and R2c and R3c are each independently selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl).

[0220] In some embodiments, R1c is a C1-6 alkyl group (e.g., ethyl or isopropyl, e.g., ethyl).

[0221] In some embodiments, R2c is selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl groups), and R3c is a hydrogen atom. In some embodiments, both R2c and R3c are hydrogen atoms.

[0222] In some embodiments, ring B is represented by the following ring base: , where R1c is selected from C1-6 alkyl groups (e.g., ethyl groups).

[0223] 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.

[0224] Non-limiting examples of compound (I) include the following sub-formulas.

[0225] This article also discloses compounds (also referred to herein as compound A), selected from compounds of formula (I) and their pharmaceutically acceptable salts, wherein: R1 is represented by the following groups: or ; Ring A1 is selected from a 6-membered aromatic ring (e.g., benzene, pyridine, or pyrimidine) that may be further substituted, as appropriate. R6a series is selected from: (1) C3-10 cycloalkyl groups, substituted as appropriate (e.g., cyclohexyl); (2) Substituted C6-14 aryl groups (e.g., phenyl groups), depending on the case; (3) Substituted 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., morpholino, hexahydropyridyl or pyrrolidinyl) or 6 to 9-membered non-aromatic spiroheterocyclic groups (e.g., 4-oxa-7-azaspiro[2.5]octyl)); (4) Depending on the circumstances, a 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., an imidazole group)); (5) A substituted mono- or di-C1-6 alkylamine group (e.g., methylamine group), depending on the case; (6) N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amines, as appropriate (e.g., N-C1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amines (e.g., N-methyl-N-tetrahydropyranylamine)); (7) Substituted C1-6 alkoxy groups (e.g., methoxy groups), as appropriate; (8) As appropriate, a substituted C6-14 aryloxy group (e.g., phenoxy group); and (9) Substituted 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyloxy groups)); Cycle A2 is selected from, as appropriate, a 5-membered monocyclic aromatic heterocycle (e.g., pyrazole); R6b is selected from C1-6 alkyl groups that are substituted as appropriate (e.g., ethyl); Z-series C-R2 or N; R2 is selected from hydrogen atoms and, where appropriate, halogenated C1-6 alkyl groups (e.g., methyl or ethyl); R3 is selected from hydrogen atoms, halogen atoms (e.g., chlorine atoms), and, where appropriate, halogenated C1-6 alkyl groups (e.g., methyl, ethyl, or trifluoromethyl); R4 and R5 are each independently selected from hydrogen atoms and, where appropriate, substituted C1-6 alkyl groups (e.g., methyl); and Cycle B is selected from, as appropriate, a 5-membered monocyclic aromatic heterocycle (e.g., pyrazole) that has been further substituted.

[0226] This article also discloses compounds (also referred to herein as compound B), selected from compounds of formula (I) and their pharmaceutically acceptable salts, wherein: R1 is represented by the following groups: or ; Ring A1 is selected from a 6-membered aromatic ring (e.g., benzene, pyridine, or pyrimidine) further substituted with 1 to 3 independent substituents selected from the following: (a) Halogen atoms (e.g., fluorine, chlorine, or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, ...) as appropriate 2,2-Difluoroethoxy or 2,2,2-trifluoroethoxy); (d) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; R6a series is selected from: (1) C3-10 cycloalkyl groups (e.g., cyclohexyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (2) C6-14 aryl groups (e.g., phenyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), depending on the case; (3) As appropriate, a 3 to 14-membered non-aromatic heterocyclic group (e.g., a 3 to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholino, hexahydropyridinyl, or pyrrolidinyl) or a 6 to 9-membered non-aromatic spiroheterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl) substituted with 1 to 3 independently selected substituents: (a) Halogen atoms (e.g., fluorine atoms); and (b) Halogenated C1-6 alkyl groups (e.g., methyl or difluoromethyl), as appropriate; (4) A 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., an imidazolyl group) substituted with 1 to 3 C1-6 alkyl groups (e.g., methyl groups), depending on the case; (5) A mono- or di-C1-6 alkylamino group (e.g., methylamino group) substituted with one to three C3-10 cycloalkyl groups (e.g., cyclobutyl, which is substituted with one to three halogen atoms (e.g., fluorine atoms) as appropriate); (6) N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amines (e.g., N-C1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amines (e.g., N-methyl-N-tetrahydropyranylamine)); (7) A C1-6 alkoxy group (e.g., methoxy) substituted with one to three independently selected substituents: (a) C1-6 alkoxy groups (e.g., methoxy groups); (b) C3-10 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl); and (c) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., oxo-heterobutyl or tetrahydrofuranyl)); (8) C6-14 aryloxy groups (e.g., phenoxy groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; and (9) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyloxy group)).

[0227] In some embodiments, the following groups are used: It consists of the following groups: , in: R6a is as defined above; R7a series is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., chlorine or bromine atoms); (c) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (d) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, ...) as appropriate 2,2-Difluoroethoxy or 2,2,2-trifluoroethoxy); (e) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; (f) C2-6 alkenyl (e.g., vinyl); and (g) a 3- to 14-membered nonaromatic heterocyclic group substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) as appropriate (e.g., a 3- to 8-membered monocyclic nonaromatic heterocyclic group (e.g., a hexahydropyridyl group)); and R8a series is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl groups (e.g., methyl), Cyclone A2 is selected from a 5-membered monocyclic aromatic heterocycle (e.g., pyrazole) that is optionally further substituted with 1 to 3 optionally halogenated C1-6 alkyl groups (e.g., trifluoromethyl); and R6b is selected from C1-6 alkyl groups (e.g., ethyl groups) that are substituted with one to three C3-10 cycloalkyl groups (e.g., cyclobutyl groups), as appropriate.

[0228] In some embodiments, the following groups are used: It consists of the following groups: , in: R6b is as defined above; and R7b is selected from C1-6 alkyl groups (e.g., trifluoromethyl) that are halogenated as appropriate. Z-series C-R2 or N; R2 is selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl or ethyl); R3 is selected from hydrogen atoms, halogen atoms (e.g., chlorine atoms), and, where appropriate, halogenated C1-6 alkyl groups (e.g., methyl, ethyl, or trifluoromethyl); R4 and R5 are each independently selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl); and Cyclo B is selected from 5-membered monocyclic aromatic heterocycles (e.g., pyrazole) that are further substituted with 1 to 3 C1-6 alkyl groups (e.g., methyl, ethyl, or isopropyl), as appropriate.

[0229] This article also discloses compounds (also referred to herein as compound C), selected from compounds of formula (I) and their pharmaceutically acceptable salts, wherein: R1 is represented by the following groups: or ; The A1 series is selected from: (1) Further, as appropriate, the benzene ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine, chlorine, or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (2) Further, as appropriate, the pyridine ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine or chlorine atoms); (b) Halogenated C1-6 alkyl groups (e.g., methyl, difluoromethyl, or trifluoromethyl), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-10 cycloalkyl groups (e.g., cyclopropyl); and (3) Further, as appropriate, a pyrimidine ring substituted with one or two, as appropriate, halogenated C1-6 alkyl groups (e.g., trifluoromethyl); R6a series is selected from: (1) C3-10 cycloalkyl groups (e.g., cyclohexyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (2) C6-14 aryl groups (e.g., phenyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), depending on the case; (3) As appropriate, a 3 to 14-membered non-aromatic heterocyclic group (e.g., a 3 to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholino, hexahydropyridinyl, or pyrrolidinyl) or a 6 to 9-membered non-aromatic spiroheterocyclic group (e.g., 4-oxa-7-azaspiro[2.5]octyl) substituted with 1 to 3 independently selected substituents: (a) Halogen atoms (e.g., fluorine atoms); and (b) Halogenated C1-6 alkyl groups (e.g., methyl or difluoromethyl), as appropriate; (4) A 5- to 14-membered aromatic heterocyclic group (e.g., a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., an imidazolyl group) substituted with 1 to 3 C1-6 alkyl groups (e.g., methyl groups), depending on the case; (5) A mono- or di-C1-6 alkylamino group (e.g., methylamino group) substituted with one to three C3-10 cycloalkyl groups (e.g., cyclobutyl, which is substituted with one to three halogen atoms (e.g., fluorine atoms) as appropriate); (6) N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amines (e.g., N-C1-6 alkyl-N-3 to 8-membered monocyclic aromatic heterocyclic amines (e.g., N-methyl-N-tetrahydropyranylamine)); (7) A C1-6 alkoxy group (e.g., methoxy) substituted with one to three independently selected substituents: (a) C1-6 alkoxy groups (e.g., methoxy groups); and (b) C3-10 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; and (c) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., oxo-heterobutyl or tetrahydrofuranyl)); (8) C6-14 aryloxy groups (e.g., phenoxy groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; and (9) 3 to 14 non-aromatic heterocyclic groups (e.g., 3 to 8 monocyclic non-aromatic heterocyclic groups (e.g., tetrahydropyranyloxy group)).

[0230] In some embodiments, the following groups are used: It consists of the following groups: , in: R6a is as defined above; R7a1 is selected from: (a) Halogen atoms (e.g., chlorine or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, ...) as appropriate 2,2-Difluoroethoxy or 2,2,2-trifluoroethoxy); (d) C3-10 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) 3 to 14-membered non-aromatic heterocyclic groups (e.g., 3 to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., hexahydropyridyl)) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; R7a2 is selected from: (a) Hydrogen atom; (b) Halogenated C1-6 alkyl groups (e.g., trifluoromethyl groups), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-10 cycloalkyl groups (e.g., cyclopropyl); R7a3 is selected from C1-6 alkyl groups that are halogenated as appropriate (e.g., trifluoromethyl); R8a1 is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl groups (e.g., methyl); and R8a2 is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl groups (e.g., methyl); Cycle A2 is selected from pyrazole rings that are optionally further substituted with 1 to 3 C1-6 alkyl groups (e.g., trifluoromethyl); and R6b is selected from C1-6 alkyl groups (e.g., ethyl groups) that are substituted with one to three C3-10 cycloalkyl groups (e.g., cyclobutyl groups), as appropriate.

[0231] In some embodiments, the following groups are used: It consists of the following groups: , where the individual symbol systems are as in compound B; and The cyclic B group is selected from pyrazole rings (e.g., 1H-pyrazole-4-yl) that are further substituted with 1 to 3 C1-6 alkyl groups (e.g., methyl, ethyl or isopropyl) as appropriate.

[0232] In some embodiments, the ring B system: ,in: R1c is selected from hydrogen atoms and C1-6 alkyl groups (e.g., ethyl or isopropyl); and R2c and R3c are each independently selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl).

[0233] This article also discloses compounds (also referred to herein as compound D), selected from compounds of formula (I) and their pharmaceutically acceptable salts, wherein: R1 is represented by the following groups: or ; The A1 series is selected from: (1) Further, as appropriate, the benzene ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine, chlorine, or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-6 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) A hexahydropyridyl group, substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; (2) Further, as appropriate, the pyridine ring may be substituted with one to three independently selected substituents from the following: (a) Halogen atoms (e.g., fluorine or chlorine atoms); (b) Halogenated C1-6 alkyl groups (e.g., methyl, difluoromethyl, or trifluoromethyl), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-6 cycloalkyl groups (e.g., cyclopropyl); and (3) Further, as appropriate, a pyrimidine ring substituted with one or two, as appropriate, halogenated C1-6 alkyl groups (e.g., trifluoromethyl); R6a series is selected from: (1) C3-6 cycloalkyl groups (e.g., cyclohexyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), depending on the case; (2) A phenyl group, substituted with one to three halogen atoms (e.g., fluorine atoms), depending on the case; (3) Morpholino group substituted with 1 to 3 independently selected substituents from the following, depending on the case: (a) Halogen atoms (e.g., fluorine atoms); and (b) Halogenated C1-6 alkyl groups (e.g., methyl or difluoromethyl), as appropriate; (4) A hexahydropyridyl group, substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), depending on the case; (5) A pyrrolidin group, substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (6) 4-oxa-7-azaspiro[2.5]octyl; (7) An imidazolyl group substituted with one to three C1-6 alkyl groups (e.g., methyl), as appropriate; (8) A mono- or di-C1-6 alkylamino group (e.g., methylamino group) substituted with one to three C3-6 cycloalkyl groups (e.g., cyclobutyl, which is substituted with one to three halogen atoms (e.g., fluorine atoms) as appropriate); (9) N-C1-6 alkyl-N-tetrahydropyranylamino (e.g., N-methyl-N-tetrahydropyranylamino); (10) A C1-6 alkoxy group (e.g., methoxy) substituted with one to three independently selected substituents: (a) C1-6 alkoxy groups (e.g., methoxy groups); (b) C3-6 cycloalkyl groups (e.g., cyclopropyl or cyclobutyl) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (c) Oxycyclic butyl; and (d) Tetrahydrofuranyl; (11) A phenoxy group, substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; and (12) Tetrahydropyranyloxy.

[0234] In some embodiments, the following groups are used: It consists of the following groups: , in: R6a is as defined above; R7a1 is selected from: (a) Halogen atoms (e.g., chlorine or bromine atoms); (b) A C1-6 alkyl group (e.g., methyl, ethyl, or isopropyl) substituted, as appropriate, with one to three independently selected substituents: (i) a halogen atom (e.g., a fluorine atom); and (ii) a hydroxyl group; (c) Halogenated C1-6 alkoxy groups (e.g., trifluoromethoxy, 2,2-difluoroethoxy, or 2,2,2-trifluoroethoxy) as appropriate; (d) C3-6 cycloalkyl groups (e.g., cyclopropyl groups) substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), as appropriate; (e) C2-6 alkenyl (e.g., vinyl); and (f) A hexahydropyridyl group, substituted with one to three halogen atoms (e.g., fluorine atoms), as appropriate; R7a2 is selected from: (a) Hydrogen atom; (b) Halogenated C1-6 alkyl groups (e.g., trifluoromethyl groups), as appropriate; (c) Halogenated C1-6 alkoxy groups (e.g., 2,2,2-trifluoroethoxy groups), as appropriate; and (d) C3-6 cycloalkyl groups (e.g., cyclopropyl); R7a3 is selected from C1-6 alkyl groups that are halogenated as appropriate (e.g., trifluoromethyl); R8a1 is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl groups (e.g., methyl); and R8a2 is selected from: (a) Hydrogen atom; (b) Halogen atoms (e.g., fluorine or chlorine atoms); and (c) C1-6 alkyl (e.g., methyl).

[0235] In some embodiments, ring A2 is selected from pyrazole rings that are further substituted with one to three halogenated C1-6 alkyl groups (e.g., trifluoromethyl); and R6b is selected from C1-6 alkyl groups (e.g., ethyl groups) that are substituted with one to three C3-6 cycloalkyl groups (e.g., cyclobutyl groups).

[0236] In some embodiments, the following groups are used: It consists of the following groups: ,in: R6b is as defined above; and Other notation systems, such as those in compound B; R4 is selected from hydrogen atoms and C1-6 alkyl groups (e.g., methyl); R5 series hydrogen atoms; and The cyclic B group is selected from pyrazole rings (e.g., 1H-pyrazole-4-yl) that are further substituted with 1 to 3 C1-6 alkyl groups (e.g., methyl, ethyl or isopropyl) as appropriate.

[0237] In some embodiments, ring B is represented by the following groups: The symbol system is as shown in compound B.

[0238] This article also discloses compounds (also referred to herein as compound E), selected from compounds of formula (I) and their pharmaceutically acceptable salts, wherein: R1 is represented by the following groups: ; Ring A1 is selected from pyridine rings that are further substituted, as appropriate, by one or two independent substituents selected from the following: (a) Halogen atoms (e.g., fluorine atoms); and (b) Halogenated C1-6 alkyl groups (e.g., trifluoromethyl); R6a is selected from morpholino groups substituted with 1 to 3 C1-6 alkyl groups (e.g., methyl), as appropriate.

[0239] In some embodiments, the following groups are used: It consists of the following groups: , in: R6a is as defined above; R7a2 is selected from halogenated C1-6 alkyl groups (e.g., trifluoromethyl); and R8a2 is selected from hydrogen atoms and halogen atoms (e.g., fluorine atoms); Z-series C-R2; R2 is selected from hydrogen atoms and C1-3 alkyl groups (e.g., methyl); R3 is selected from hydrogen atoms and C1-3 alkyl groups (e.g., methyl); R4 and R5 are both hydrogen atoms; and The cyclic B group is selected from pyrazole rings further substituted with a C1-6 alkyl group (e.g., ethyl) (e.g., 1H-pyrazole-4-yl).

[0240] In some embodiments, ring B is represented by the following groups: , R1c is selected from C1-6 alkyl groups (e.g., ethyl).

[0241] This article also discloses compounds (also referred to herein as compound F), selected from compounds of formula (I) and their pharmaceutically acceptable salts, wherein: R1 is represented by the following groups: ,in: Cycle A1 is selected from pyridine rings further substituted with a halogenated C1-6 alkyl group (e.g., trifluoromethyl); and R6a is selected from morpholino groups substituted with a C1-6 alkyl group (e.g., methyl).

[0242] In some embodiments, the following groups are used: It consists of the following groups: , in: R6a is as defined above; R7a2 is selected from halogenated C1-6 alkyl groups (e.g., trifluoromethyl); and R8a2 series hydrogen atoms; Z-series C-R2; R2 is selected from C1-3 alkyl groups (e.g., methyl); R3 is selected from C1-3 alkyl groups (e.g., methyl); R4 and R5 are both hydrogen atoms; and The cyclic B group is selected from pyrazole rings further substituted with a C1-6 alkyl group (e.g., ethyl) (e.g., 1H-pyrazole-4-yl).

[0243] In some embodiments, ring B is represented by the following groups: R1c is selected from C1-6 alkyl groups (e.g., ethyl).

[0244] Compounds of formula (I) include (but are not limited to) the compounds of Examples 1 to 167 and their pharmaceutically acceptable salts (e.g., the compounds of Examples 1 to 167).

[0245] When compound (I) is a salt (e.g., a pharmaceutically acceptable salt), non-limiting examples of such a salt include metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, and salts formed with basic or acidic amino acids. Non-limiting examples of metal salts include alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium, magnesium, and barium salts; and aluminum salts. Non-limiting examples of salts formed with organic bases include salts with trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and salts like these. Non-limiting examples of salts formed with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, and salts like these. Non-limiting examples of salts formed 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, and the like. Non-limiting examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like, and non-limiting examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like. For example, compound (I) may be a pharmaceutically acceptable salt. For example, when a compound contains an acidic functional group, an inorganic salt, such as an alkali metal salt (e.g., sodium, potassium, or the like) or an alkaline earth metal salt (e.g., calcium, magnesium, barium, or the like), an ammonium salt, or the like, can be used. And when a compound contains a basic functional group, a salt with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, or phosphoric acid) or a salt with an organic acid (e.g., acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, or p-toluenesulfonic acid) can be used.

[0246] When compound (I) contains isomers (e.g., tautomers, mirror-image isomers, stereoisomers, regioisomers, or rotational isomers), any isomer and mixtures thereof are also included in compound (I). Additionally, when mirror-image isomers are present in compound (I), mirror-image isomers separated from the racemic mixture are also included in compound (I).

[0247] In some embodiments, compound (I) may be a crystal; therefore, both single crystalline and mixed crystalline forms are included in compound (I).

[0248] In some embodiments, compound (I) may be a pharmaceutically acceptable eutectic or eutectic salt. As used herein, a eutectic or eutectic salt refers to a crystalline substance comprising 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, and the like). Eutectic or eutectic salts may be produced according to known co-crystallization methods.

[0249] In some embodiments, compound (I) may be a solvate (e.g., a hydrate or the like) or a solvent-free substance, and such substances are all included within the scope of compound (I).

[0250] In some embodiments, isotopically labeled or substituted compounds (e.g., 2H, 3H, 11C, 14C, 18F, 35S, 125I, or the like) are also included in compound (I). For example, in some embodiments, the isotopically labeled or substituted compounds can be used as tracers for use in positron emission tomography (PET) (PET tracers). In some embodiments, the isotopically labeled or substituted compounds can be used in fields such as medical diagnostics.

[0251] The following describes non-limiting examples of methods for manufacturing the compounds disclosed herein.

[0252] The starting materials or reagents used in each step of the following manufacturing methods and the resulting compounds may respectively form salts. Examples of such salts include salts identical to the salts of the compounds disclosed above.

[0253] When the compound obtained in each step is a free compound, it can be converted into the target salt using methods known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into a free form or another type of target salt using methods known per se.

[0254] The compounds obtained in each step may be used directly as reaction solutions in the next reaction or, after being separated into crude products, in the next reaction. Alternatively, the compounds obtained in each step may be separated and / or purified from the reaction mixture using conventional techniques such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, or chromatography.

[0255] When the starting materials or reagents in each step are commercially available, commercially available products can be used directly.

[0256] In each step of the reaction, the reaction time may vary depending on the reagents or solvents used. However, unless otherwise specified, the reaction time is typically from 1 minute to 48 hours, for example, from 10 minutes to 8 hours.

[0257] In each step of the reaction, the reaction temperature may vary depending on the reagents or solvents used, but unless otherwise specified, the reaction temperature is generally between -78°C and 300°C, for example, between -78°C and 150°C.

[0258] In each step of the reaction, the pressure may vary depending on the reagent or solvent used, but unless otherwise specified, the pressure is usually from 1 atm to 20 atm, for example from 1 atm to 3 atm.

[0259] In each step of the reaction, a microwave synthesizer, such as an initiator available from Biotage, may be used. The reaction temperature may vary depending on the reagents or solvents used, but unless otherwise specified, it is typically from room temperature to 300°C, for example, from 50°C to 250°C. The reaction time may vary depending on the reagents or solvents used, but unless otherwise specified, it is typically from 1 minute to 48 hours, for example, from 1 minute to 8 hours.

[0260] In each reaction 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 acceptor. When the reagent is used as a catalyst, it is used in an amount of 0.001 to 1 equivalent, for example, 0.01 to 0.2 equivalents, relative to the acceptor. When the reagent is also used as a reaction solvent, it is used in solvent quantities.

[0261] In each step of the reaction, unless otherwise stated, the reaction is carried out in the absence of solvent or after dissolution or suspension in a suitable solvent. Non-limiting examples of solvents are those described in [Examples] or those described below. Alcohols: methanol, ethanol, terbutanol, 2-methoxyethanol, and the like; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, and the like; Saturated hydrocarbons: cyclohexane, hexane, and the like; Acrylamines: N,N-dimethylmethoxymethylamine, N-methylpyrrolidone, and the like; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, and the like; Nitriles: Acetonitriles and the like; Sulfoxide: dimethyl sulfoxide and the like; Aromatic organic bases: pyridine and the like; Acid anhydrides: acetic anhydrides and the like; Organic acids: formic acid, acetic acid, trifluoroacetic acid, and the like; Inorganic acids: hydrochloric acid, sulfuric acid, and the like; Esters: ethyl acetate and the like; Ketones: acetone, methyl ethyl ketone, and the like; water.

[0262] In some embodiments, two or more of the above-mentioned solvents may be mixed in appropriate ratios and used in the method.

[0263] In some embodiments, when a base is used in each step of the reaction, the bases listed below or those described in [Examples] may be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, and the like; 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, hexahydropyridine and the like; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, and the like; Alkali metal hydrides: sodium hydride and the like; Metallic amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilamide, and the like; Organic lithium: n-Butyllithium and the like.

[0264] In some embodiments, when an acid or acidic catalyst is used in each step of the reaction, the acid or acidic catalyst listed below or described in [Examples] may be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and the like; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like; Lewis acids: boron trifluoride diethyl ether complex; zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, and the like.

[0265] Unless otherwise stated, each reaction step can be performed according to methods known in themselves (e.g., Experimental Chemistry, 5th edition, Volumes 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry, Volumes 14-15 (edited by the Chemical Society of Japan); Fine Organic Chemistry, revised 2nd edition (LF Tietze, Th. Eicher, Nankodo Co., Ltd.); Revised Organic Named Reactions: Reaction Mechanism and Essence (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective, Volumes I-VII (John Willey & Sons Inc.); Modern Organic Synthesis in the Laboratory, A Collection of Standard Experimental Procedures (edited by Jie Jack Li, published by Oxford University); Comprehensive Heterocyclic Chemistry III, Volumes 1-14 (Elsevier Japan KK)); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi) Tomioka supervised, published by Kagaku-Dojin Publishing); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989 edition or similar methods) or implemented according to the methods described in [Examples].

[0266] In each step, the protection or deprotection reaction of the functional group is carried out according to methods known in themselves (e.g., Wiley-Interscience 2007 "Protective Groups in Organic Synthesis, 4th Edition" (edited by Theodora W. Greene and Peter GM Wuts); Thieme 2004 "Protecting Groups, 3rd Edition" (edited by PJ Kocienski) or the like) or according to the methods described in [Examples].

[0267] Examples of protecting groups for hydroxyl or phenolic hydroxyl groups (e.g., alcohols) include ether-type protecting groups, such as methoxymethyl ether, benzyl ether, tributyldimethylsilyl ether and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups, such as acetate; sulfonate-type protecting groups, such as methanesulfonate; and carbonate-type protecting groups, such as tributyl carbonate.

[0268] Non-limiting examples of protecting groups for aldehyde carbonyl groups include acetal-type protecting groups, such as dimethyl acetal; and cyclic acetal-type protecting groups, such as 1,3-dioxane.

[0269] Non-limiting examples of protecting groups for ketone carbonyl groups include ketal protecting groups, such as dimethyl ketal; cyclic ketal protecting groups, such as 1,3-dioxane; oxime protecting groups, such as O-methyl oxime; and hydrazone protecting groups, such as N,N-dimethylhydrazone.

[0270] Non-limiting examples of carboxyl protecting groups include ester-type protecting groups, such as methyl esters; and amide-type protecting groups, such as N,N-dimethylamide.

[0271] Non-limiting examples of protecting groups for thiols include ether-type protecting groups, such as benzyl thioether; and ester-type protecting groups, such as thioacetates, thiocarbonates and thiocarbamates.

[0272] Non-limiting examples of protecting groups for amines or aromatic heterocycles (e.g., imidazoles, pyrroles, and indoles) include carbamate-type protecting groups, such as benzyl carbamate; acetylamine-type protecting groups, such as acetylamine; alkylamine-type protecting groups, such as N-triphenylmethylamine; and sulfonylmethane-type protecting groups, such as methanesulfonamide and o-nitrobenzenesulfonamide.

[0273] Protecting groups can be removed using methods known per se (e.g., using 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, or the like).

[0274] Non-limiting examples of reducing agents that can be used when carrying out the reduction reaction in the step include metal hydrides, such as lithium aluminum hydride, sodium triethoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethyltriethoxyborohydride; boranes, such as boranetetrahydrofuran complexes; Raney nickel; Raney cobalt; hydrogen; formic acid; and triethylsilane. Methods using catalysts (e.g., palladium-carbon or Lindlar catalysts) exist for reducing carbon-carbon double or triple bonds.

[0275] When the oxidation reaction is carried out in the step, non-limiting examples of oxidants that can be used include peracids, such as m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, and tert-butylhydrogen peroxide; perchlorates, such as tetrabutylammonium perchlorate; chlorites, such as sodium chlorite; periodates, such as sodium periodate, hypervalent iodine reagents (e.g., iodophenyl); manganese-containing reagents, such as manganese dioxide and potassium permanganate; lead, 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 complexes; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0276] When performing the free radical cyclization reaction in the step, non-limiting examples of free radical initiators include azo compounds, such as azobisisobutyronitrile (AIBN); water-soluble free radical initiators, such as 4-4'-azobis-4-cyanopentanoic acid (ACPA); triethylboron in the presence of air or oxygen; and benzoyl peroxide. Additionally, non-limiting examples of free radical reaction reagents include tributyltinane, trimethylsilyl-silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium diiodide.

[0277] When the Wittig reaction is carried out in the step, non-limiting examples of Wittig reagents include alkylphosphines. For example, alkylphosphines can be prepared by methods known per se, such as by reacting a phosphonium salt with a strong base.

[0278] When the Horner-Emmons reaction is carried out in the step, non-limiting examples of reagents that can be used include phosphonoacetic esters, such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases, such as alkali metal hydrides and organolithium compounds.

[0279] When performing a Friedel-Crafts reaction in the step, non-limiting examples of reagents that can be used include combinations of Lewis acids and acetic acid, or combinations of Lewis acids and alkylating agents (e.g., alkyl halides, alcohols, alkenes, and the like). Alternatively, organic or inorganic acids may be used instead of Lewis acids, and acid anhydrides (e.g., acetic anhydride) may be used instead of acetic acid.

[0280] When an aromatic nucleophilic substitution reaction is carried out in the step, a nucleophile (e.g., an amine, 2-pyridone, imidazole, or the like) and a base (e.g., an organic or inorganic base or the like) are used as reagents.

[0281] Non-limiting examples of bases that can be used to generate carbanions 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 step include organolithium compounds, metal alkoxides, organosilicon compounds, inorganic bases and organic bases.

[0282] When the Grignard reaction is carried out in the step, non-limiting examples of Grignard reagents include aryl magnesium halides, such as phenyl magnesium bromide; and alkyl magnesium halides, such as methyl magnesium bromide. Grignard reagents can be prepared by methods known per se, for example by reacting alkyl halides or aryl halides with metallic magnesium using ethers or tetrahydrofurans as solvents.

[0283] When performing the Knoevanegel reaction in the step, an active methylene compound (such as malonic acid, diethyl malonate, malononitrile, or the like) sandwiched between two electron-withdrawing groups and a base (such as an organic base, metal oxide, or inorganic base) can be used as a reagent.

[0284] When performing the Vilsmeier-Haack reaction in the steps, phosphochloride and acetamide derivatives (such as N,N'-dimethylmethoxymethylamine or similar) can be used as reagents.

[0285] When performing the azidation reaction of carboxylic acids, alcohols, alkyl halides, and sulfonates in the steps, non-limiting examples of azidating agents include diphenylphosphinohydride (DPPA), trimethylsilylhydride, and sodium azide. For example, when azidating alcohols, a method using diphenylphosphinohydride and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a method using trimethylsilylhydride and a Lewis acid can be used.

[0286] Non-limiting examples of solvents that can be used when carrying out the Curtius rearrangement reaction in the step include toluene and dichloromethane.

[0287] When a reductive amination reaction is carried out in the step, non-limiting examples of reducing agents include sodium triethoxyborohydride, sodium cyanoborohydride, sodium borohydride, hydrogen, and formic acid. When the acceptor is an amine compound, non-limiting examples of carbonyl compounds include paraformaldehyde, aldehydes (e.g., acetaldehyde), and ketones (e.g., cyclohexanone). When the acceptor is a carbonyl compound, non-limiting examples of amines include ammonia, primary amines (e.g., methylamine), and secondary amines (e.g., dimethylamine).

[0288] When performing the Mitsunobu reaction in the step, azodicarbonate esters (such as diethyl azodicarbonate (DEAD), diisopropyl azodicarbonate (DIAD), and the like) and triphenylphosphine can be used as reagents. Alternatively, cyanomethylenetributylphosphine (CMBP), cyanomethylenetrimethylphosphine (CMMP), or the like can also be used as reagents.

[0289] When esterification or amination is performed in the step, non-limiting examples of reagents that can be used include amide halides, such as amide chloride and amide bromide; and activated carboxylic acids, such as acid anhydrides, active esters and sulfate esters. Non-limiting examples of activators of carboxylic acids include condensing agents based on carbodiimides, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); condensing agents based on triazines, such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); benzotriazol-1-yloxy-triazinium dimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent); thionyl chloride; low-carbon alkyl esters of haloformic acids, such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. When using carbodiimide-based condensing agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) can be further added to the reaction.

[0290] Non-limiting examples of reagents that can be used when carrying out the urea formation reaction of amines in the step include phosgene equivalents, such as bis(trichloromethyl) carbonate, trichloromethyl chloroformate, and 1,1'-carbonyldiimidazole. Non-limiting examples of reagents that can be used when carrying out the urea formation reaction of carboxylic acids include azide reagents, such as diphenylphosphohydrazine (DPPA). Additionally, 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.

[0291] When the dehydration condensation reaction is carried out in the step, non-limiting examples of solvents that can be used include alcohols (e.g., ethanol) or aromatic hydrocarbons (e.g., toluene). Additionally, in some embodiments, the reaction can be accelerated by adding an acid (e.g., p-toluenesulfonic acid) or a dehydrating agent (e.g., magnesium sulfate) to the reaction.

[0292] When the coupling reaction is carried out in the step, non-limiting examples of metal catalysts used include palladium compounds, such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (O), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), triphenylacetone (dibenzylacetone)palladium (O), and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (II); nickel compounds, such as tetrakis(triphenylphosphine)nickel (O); rhodium compounds, such as triphenylphosphine rhodium chloride (III); cobalt compounds; copper compounds, such as copper oxide and copper iodide (I); and platinum compounds. In some embodiments, a base may be further added to the reaction; non-limiting examples of such bases include inorganic bases. Additionally, in some embodiments, the reaction may be accelerated by adding a thermal, light, or free radical initiator (e.g., benzoyl peroxide or azobisisobutyronitrile) to the reaction.

[0293] When performing the thiocarbonylation reaction in the step, phosphorus pentasulfide can be used as the thiocarbonylating agent; alternatively, a phosphorus pentasulfide reagent (Lawesson reagent) having a 1,3,2,4-dithiaphosphonium heterocyclic butane-2,4-disulfide structure (e.g., 2,4-bis(methoxyphenyl)-1,3,2,4-dithiaphosphonium heterocyclic butane-2,4-disulfide) can also be used.

[0294] When the Wohl-Ziegler reaction is used in the step, non-limiting examples of halogenating agents include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromosuccinimide, and thiosuccinimide. Additionally, in some embodiments, the reaction can be accelerated by adding a thermal, light, or free radical initiator (e.g., benzoyl peroxide or azobisisobutyronitrile) to the reaction.

[0295] When the halogenation reaction of the hydroxyl group is carried out in the step, non-limiting examples of halogenating agents include hydrohalic acids and acetic halides of inorganic acids; specifically, in the case of chlorination, hydrochloric acid, thionyl chloride, phosphochloride, or the like can be used, and in the case of bromination, 48% hydrobromic acid or the like can be used. Additionally, in some embodiments, a method for obtaining alkyl halides from alcohols by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide can be used. Alternatively, in some embodiments, a method for synthesizing alkyl halides via a two-step reaction can be employed, wherein the alcohol is converted to a sulfonate ester and then reacted with lithium bromide, lithium chloride, or sodium iodide.

[0296] When the Arbuzov reaction is carried out in the step, 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.

[0297] When the sulfonation reaction is carried out in the step, non-limiting examples of sulfonating agents include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and p-toluenesulfonic anhydride.

[0298] When performing the hydrolysis reaction in the steps, an acid or base may be used as a reagent. Additionally, in some embodiments, when performing the acid hydrolysis reaction of the third butyl ester, formic acid, triethylsilane, or similar third butyl cations generated as by-products through reducing capture may be added.

[0299] When the dehydration reaction is carried out in the step, non-limiting examples of dehydrating agents include sulfuric acid, phosphorus pentasulfide, phosphatidyl chloride, N,N'-dicyclohexylcarbodiimide, alumina, and polyphosphoric acid.

[0300] Compound (I) can be produced according to the reaction formula illustrated below or by a method conforming to that equation. The starting material of compound (I) can be a commercially available product or can be produced using methods known per se. Unless otherwise stated, the abbreviations for each general formula in the reaction formula are as defined above.

[0301] For example, compound (Ia) (where Z is CH in compound (I)) can be generated from compound (1) or compound (4) by the following method. In the formula, R101 and R12 are substituents, and the other symbols are as defined above.

[0302] Non-limiting examples of "substituents" indicated by R101 and R12 include methyl and ethyl.

[0303] Compound (3) can be produced by the urea formation reaction of compounds (1) and (2).

[0304] Compound (5) can be produced by the azidation reaction of compound (4) followed by the Curtiss rearrangement reaction.

[0305] Compound (3) can also be produced by the urea formation reaction of compounds (5) and (2).

[0306] Compound (Ia) can be produced by the deprotection reaction of acetal of compound (3) followed by intramolecular cyclization.

[0307] Compound (Ib) (where Z is C-CH3 in compound (I)) can be generated from compound (1) by the following method. The symbols are as defined above.

[0308] Compound (7) can be produced by the urea formation reaction of compounds (1) and (6).

[0309] Compound (Ib) can be generated by cyclization of the alkyne activating compound (7), followed by isomerization by acid treatment. Non-limiting examples of reagents that can be used when performing the cyclization reaction include tetrabutylammonium fluoride (TBAF) and gold chloride (I). In addition, non-limiting examples of reagents that can be used when performing the isomerization reaction include hydrochloric acid and trifluoroacetic acid.

[0310] Compound (Ic) (where Z is C-R2 in compound (I)) can be generated from compound (1) by the following method. In the formula, L is the leaving group, R13 and R14 are substituents, and the other symbols are as defined above.

[0311] Non-limiting examples of the "leaving group" indicated by L include halogen atoms, C1-6 alkyl sulfonyloxy groups (e.g., methanesulfonyloxy or ethanesulfonyloxy), and, where applicable, C6-14 aryl sulfonyloxy groups substituted with C1-6 alkyl groups (e.g., benzenesulfonyloxy or toluenesulfonyloxy).

[0312] Non-limiting examples of "substituents" indicated by R13 and R14 include methyl and ethyl.

[0313] Compound (9) can be produced by the urea formation reaction of compounds (1) and (8).

[0314] Compound (12) can be produced by the deprotection reaction of acetal of compound (9) followed by intramolecular cyclization.

[0315] Compound (11) can be produced by the urea formation reaction of compounds (1) and (10).

[0316] Compound (12) can be produced by the urea formation reaction of compound (11). Non-limiting examples of reagents for intramolecular cyclization reactions include trifluoroacetic acid.

[0317] Compound (Ic) can be generated by the photoelongation reaction of compounds (12) and (13).

[0318] Compound (Ic) can also be produced by alkylation of compounds (12) and (14).

[0319] Compound (Id) (where Z is N in compound (I)) can be generated from compound (15) by the following method. In the formula, R15 is a substituent, and the other symbols are each as defined above.

[0320] Non-limiting examples of "substituents" indicated by R15 include methyl and ethyl.

[0321] Compound (17) can be produced by the dehydration condensation reaction of compounds (15) and (16).

[0322] Compound (18) can be produced by the hydrolysis of compound (17).

[0323] Compound (19) can be produced by azidation of compound (18).

[0324] Compound (20) can be produced by the Curtiss rearrangement of compound (19) followed by a cyclization reaction.

[0325] Compound (Id) can be produced by photoelongation reaction of compounds (20) and (13).

[0326] Compound (Id) can also be produced by alkylation of compounds (20) and (14).

[0327] Compound (2) can be produced from compound (21a) or (21b) by the following methods. The symbols are as defined above.

[0328] Compound (2) can be produced by the reductive amination reaction of compounds (21a) and (22).

[0329] Compound (23) can be produced by the dehydration condensation reaction of compounds (21b) and (22).

[0330] Compound (2) can also be generated by a carboanion-mediated nucleophilic addition reaction of compound (23). Non-limiting examples of reagents that can be used when carrying out a nucleophilic addition reaction include magnesium methyl bromide and trifluoromethyltrimethylsilane.

[0331] Compound (6) can be generated from compound (24) by the following method. In the formula, P is the protecting group of the amino group, and the other symbols are as defined above.

[0332] Non-limiting examples of a "protecting group" indicated by P include acetyl and o-nitrobenzenesulfonyl.

[0333] Compound (25) can be produced by the protective reaction of compound (24).

[0334] Compound (26) can be produced by the photoelongation reaction of compounds (25) and (13).

[0335] Compound (26) can also be produced by alkylation of compounds (25) and (14).

[0336] Compound (6) can be produced by the deprotection reaction of compound (26).

[0337] Compounds (1), (4), (8), (10), (13) to (16), (21a), (21b), (22) and (24) can be obtained as commercially available products or produced by methods known by themselves, similar methods or methods described in [Examples].

[0338] In the compound (I) obtained in this manner, the functional groups in the molecule can be transformed into the target functional group by combining known chemical reactions. Non-limiting examples of chemical reactions include oxidation, reduction, alkylation, amide formation, hydrolysis, amination, esterification, aryl coupling, and deprotection reactions.

[0339] In the manufacturing method described above, when the starting material compound includes amino, carboxyl, hydroxyl, carbonyl or mercapto groups as substituents, a protecting group that is typically used in peptide chemistry or the like can be introduced, and the target compound can be obtained by removing the protecting group as needed after the reaction.

[0340] Configurational isomers (E-isomers and Z-isomers) of compound (I) can be separated and purified at the point of isomerization by separation methods such as extraction, recrystallization, distillation, or chromatography, thereby yielding pure compounds. Alternatively, pure isomers can be obtained by methods described in New Experimental Chemistry, Vol. 14, pp. 251-253 (edited by the Chemical Society of Japan), and Experimental Chemistry, 4th Edition, Vol. 19, pp. 273-274 (edited by the Chemical Society of Japan), or methods conforming to these methods, by advancing double bond isomerization through heating, acid catalysts, transition metal complexes, metal catalysts, free radical catalysts, light irradiation, strong basic catalysts, or the like.

[0341] Although stereoisomers may be generated depending on the type of substituents used in compound (I), compounds and mixtures thereof in which such isomers are not occupied are also included within the scope of this disclosure.

[0342] When the target product is to be obtained in its free state via the reaction described above, it can be converted into a salt by conventional methods, and when it is to be obtained as a salt, it can be converted into a free form or another salt by conventional methods. By way of illustration, the compound (I) obtained in this manner can be separated and purified from the reaction solution by known methods (e.g., dissolution, concentration, solvent extraction, fractionation, crystallization, recrystallization, or chromatography).

[0343] When compound (I) exists as a configurational isomer, a non-mirror image isomer, a conformer, or something similar, it can be separated as needed using the separation and purification methods mentioned above. Additionally, when compound (I) is racemic, it can be separated into d- and l-forms or S- and R-forms using conventional optical resolution methods.

[0344] The compound (I) obtained in this manner, along with other reaction intermediates and their starting material compounds, can be separated and purified from the reaction mixture by methods known to them, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin film chromatography, preparative high-performance liquid chromatography (preparative HPLC) or medium-pressure preparative liquid chromatography (medium-pressure preparative LC).

[0345] The salt compound (I) can be produced by known methods, for example by adding an inorganic or organic acid (when compound (I) is a basic compound) or by adding an organic or inorganic base (when compound (I) is an acidic compound).

[0346] When mirror-image isomers are present in compound (I), such individual mirror-image isomers and mixtures thereof are also included within the scope of this disclosure. Such isomers may also be individually optically separated or generated as needed using known methods.

[0347] In this specification, the GPR139 receptor antagonist effect includes the GPR139 receptor inverse agonist effect. In some embodiments, the compound having the GPR139 receptor antagonist effect is a compound having the GPR139 receptor inverse agonist effect.

[0348] As detailed in the test examples below, the GPR139 receptor inverse agonist effect can be confirmed, for example, by a reduction or inhibition of the production of inositol monophosphate (also abbreviated as IP1 in this specification), which is a metabolite of inositol triphosphate, a second messenger downstream of GPR139 signaling (also abbreviated as IP3 in this specification).

[0349] Compound (I) can be used as a medicine for the prevention, treatment, or diagnosis of a variety of diseases described below in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, and the like). For example, compound (I) is expected to be used as a medicine for the prevention or treatment of diseases such as: (1) Mental disorders (e.g., depression, major depressive disorder, depressive episode, mild depression, bipolar depression, mild depressive disorder, persistent depression, mood disturbance (e.g., seasonal affective disorder or similar), recurrent depression, postpartum depression, stress disorders, major depressive disorder with mental illness (including paranoia and schizophrenia), manic disorder or mixed mood episode, hypomanic mood episode, depressive episode with atypical features, depressive episode with depressive features, depressive episode with catatonic features, post-stroke depressive episode, depression with aphasia, major depressive disorder with aphasia, mild depression with aphasia, bipolar depression with aphasia, mild depressive disorder with aphasia, persistent depression with aphasia, mood disturbance with aphasia, recurrent depression with aphasia, postpartum depression with aphasia, stress disorder with aphasia, bipolar disorder with aphasia, schizophrenia with aphasia, anxiety disorder with aphasia, mood disorder with aphasia, Alzheimer's disease with aphasia, dementia with Lewy body syndrome). (body), Parkinson's disease with aphasia, Huntington's disease with aphasia, treatment-resistant major depressive disorder with aphasia, treatment-resistant bipolar disorder with aphasia, depressive symptoms, manic disorders, manic episodes, hypomanic episodes, maniform episodes, hypomaniform episodes, delirium, peripheral symptoms of dementia (psychiatric symptoms or behavioral disorders), anxiety, generalized anxiety disorder, anxiety syndrome, mood disorders, cyclothymic affective disorder, premenstrual depression, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, post-traumatic stress disorder, schizophrenia, paranoid or depressive schizophrenia, paranoid personality disorder, Tourette syndrome syndromes, autism spectrum disorder, X schizophrenia, Rett syndrome, disorders, bipolar disorder (including type I)Bipolar disorder and type II bipolar disorder), neurosis, drug addiction, schizophrenia (e.g., positive symptoms, negative symptoms, cognitive impairment, paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, nonsocial schizophrenia, and residual schizophrenia), schizophrenia spectrum disorders, motor difficulties, intellectual disability, delusional tendencies, schizophrenia-like disorders, catatonia, neurosis, fatigue, chronic fatigue syndrome, lack of energy, anxiety neurosis, obsessive-compulsive neurosis, panic disorder, epilepsy, anxiety symptoms, unpleasant mental states, mood abnormalities, emotional disturbances. Cyclic temperament, neuroticism, syncope, addiction, hypoactive sexual function, attention deficit hyperactivity disorder (ADHD), psychotic major depressive disorder, refractory major depressive disorder, treatment-resistant major depressive disorder, treatment-resistant major depressive disorder, cognitive impairment with major depressive disorder, treatment-resistant bipolar disorder, irritability, weight gain, weight loss, psychomotor agitation, psychomotor slowing, feelings of worthlessness, feelings of guilt, impaired thinking or concentration, suicidal ideation, suicide attempt, depression, mental disorders (e.g., short-term psychotic disorder and co-occurring psychotic disorder), obesity-induced mental illness, paranoia, Noonan's syndrome. Syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Silver-Russell syndrome, tuberous sclerosis, Williams' syndrome, Kallmann syndrome, Rubinstein-Taybi syndrome, eating behavior disorders and eating disorder groups, pica, rumination, avoidant / restrictive eating disorder, anorexia, anorexia nervosa (psychogenic anorexia and anorexia nervosa), psychogenic loss of appetite, atypical psychogenic loss of appetite, bulimia, bulimia nervosa (neurogenic bulimia, bulimia nervosa), hyperoxia nervosa, atypical bulimia nervosa, bulimia nervosa, psychogenic overeating, psychogenic morning sickness and psychogenic vomiting); (2) Neurodegenerative diseases (e.g., Alzheimer's disease, Alzheimer's-type dementia, Parkinson's disease, Huntington's disease, dementia with Huntington's disease, multiple infarction dementia, frontotemporal dementia, Parkinson's-type dementia, Parkinson's-type frontotemporal dementia, alcohol-related dementia or other drug-related dementia, dementia with intracranial tumors or brain trauma, neurodegeneration with brain trauma, neurodegeneration with stroke, neurodegeneration with cerebral infarction, neurodegeneration with hypoglycemia, neurodegeneration with seizures, neurodegeneration with neurotoxin poisoning, multiple system atrophy, spinal cord injury, AIDS-related dementia, progressive supranuclear palsy, Pick's syndrome, Niemann-Pick syndrome, corticobasal ganglia degeneration, Down's syndrome, vascular dementia (VaD)). (e.g., multiple infarct dementia, strategic single infarct VaD, small vessel lesion dementia, hypoperfusion VaD, cerebral hemorrhage VaD, chronic subdural hematoma and the like), post-encephalitis Parkinson's disease, Lewy body disease-related dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), Creutzfeldt-Jakob disease, Prion disease, cerebral palsy, multiple sclerosis and neuromyopathy); (3) Amnesia, mild cognitive impairment, learning disabilities (e.g., dyslexia, arithmetic and writing disorders) or age-related cognitive / memory impairment (e.g., age-related memory impairment and Alzheimer's disease); (4) Sleep disorders (e.g., intrinsic sleep disorders (e.g., psychophysiological insomnia and the like), extrinsic sleep disorders, circadian rhythm disorders (e.g., time zone change syndrome (jet lag), shift work sleep disorders, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake syndrome and the like), parasomnias (e.g., arousal disorders arising from non-REM sleep (e.g., sleepwalking, sleep panic disorder and the like), nightmare disorders, REM sleep disorders, and restless legs syndrome). Sleep disorders with medical or mental health conditions (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, and anxiety), stress-related insomnia, insomnia, insomnia neuropathy, sleep apnea syndrome (e.g., obstructive sleep apnea, central sleep apnea, and the like), sleep-related hypoventilation (e.g., primary alveolar hypoventilation syndrome, congenital central hypoventilation syndrome, and the like), narcolepsy, cataplexy, and hypersomnia); (5) Drug addiction (substance-related disorders and substance addiction) (e.g., substance use disorders such as alcohol dependence, cannabis (including synthetic cannabinoids) dependence, hallucinogen (e.g., ketamine, phencyclidine and the like) dependence, inhalant dependence, opioid dependence, analgesic addiction, hypnotics addiction, anxiolytics dependence, psychostimulant (e.g., amphetamine-type substances, cocaine, cathinone, synthetic cartetinone, NMDA, NMDA-related drugs (e.g., MDA and the like) dependence, caffeine addiction, tobacco dependence, nicotine dependence, alcohol use disorders, cannabis (including synthetic cannabinoids) use disorders, hallucinogen use disorders, inhalant use disorders, opioid use disorders, analgesic use disorders, hypnotics use disorders, anxiolytics use disorders, psychostimulant use disorders, caffeine use disorders, tobacco use disorders, nicotine use disorders, etc.) Cod use disorder, substance-induced disorders (e.g., alcohol addiction, alcohol withdrawal, caffeine addiction, caffeine withdrawal, cannabis (including synthetic cannabinoids) addiction, cannabis (including synthetic cannabinoids) withdrawal, hallucinogen addiction, hallucinogen persistent perception disorder, inhalant addiction, opioid addiction, opioid withdrawal, painkiller addiction, sleeping pill addiction, anti-anxiety drug addiction, painkiller withdrawal, sleeping pill withdrawal, anti-anxiety drug withdrawal, psychostimulant addiction, psychostimulant withdrawal, caffeine withdrawal, tobacco withdrawal, nicotine addiction, etc.) Withdrawal, substance-induced mental illnesses (e.g., mental disorders, bipolar disorder and related disorders, depressive disorders, anxiety, obsessive-compulsive disorder and related disorders, sleep disorders, sexual dysfunction, delirium, neurocognitive disorders and the like) induced by substances (including alcohol, caffeine, cannabis (including synthetic cannabinoids), hallucinogens, inhalants, opioids, analgesics, sleeping pills, anti-anxiety drugs, psychotropic agents, tobacco, nicotine and the like), acute poisoning, harmful use (e.g., antidepressant abuse, drug abuse and the like), dependence syndromes (e.g., drug dependence, non-narcotic analgesic addiction and the like), withdrawal states (e.g., withdrawal syndrome and the like), withdrawal states with delirium, mental disorders (e.g., addictive psychosis, steroid psychosis and the like), amnesia syndrome, residual and delayed mental disorders (e.g., drug-induced depression and the like), psychotic side effects, addictive mental disorders, drug-induced mental disorders, drug preference, drug phobia, drug addiction and withdrawal); (6) Anesthetic-induced respiratory depression, traumatic illness, neurodegenerative disease, or similar conditions; (7) Pain (e.g., psychogenic pain (somatic disorders, pain disorders, somatization disorders, hypochondria, conversion disorder, chronic pain with depression, psychogenic glossitis, psychogenic headache, psychogenic back pain, psychogenic stomach pain, neurogenic earache, bodily pain disorders, psychological pain, and psychogenic dyspareunia), inflammatory pain, acute pain, cancer-related persistent pain, cancer-related penetrating pain, cancer-related pain, persistent pain, somatic pain, penetrating pain, chronic pain (e.g., intractable pain, post-thoracotomy pain syndrome, peripheral neuropathy, peripheral neuropathy, neuropathic pain, central nervous system disorder pain, central neuropathy, central post-stroke pain, and the like), tenderness, generalized pain, dull pain, cutaneous pain, radiating pain, headache (e.g.) Examples of headache types include inflammatory headaches, facial pain, occipital pain, dental pain, chronic daily headaches, neuralgia, frontal headaches, temporal headaches, neck pain, neck heaviness, vertex headaches, paroxysmal headaches, cheek pain, traction headaches, oral burning headaches, primary headaches, headaches caused by mental illness, migraines, chronic cluster headaches, cluster headaches, trigeminal / autonomic headaches, recurrent cluster headaches, paroxysmal migraines, recurrent paroxysmal migraines, chronic paroxysmal migraines, transient unilateral neuralgia with conjunctival infection and tearing, vascular headaches, muscle contraction headaches, tension headaches, recurrent tension headaches, chronic tension headaches, traumatic headaches, chronic post-traumatic headaches, medication overuse headaches, Sluder neuralgia, and Tolosa-Hunt syndrome.Trigeminal nerve disorders (e.g., trigeminal neuralgia, atypical facial pain, trigeminal hypersensitivity, trigeminal neuropathy, etc.), glossopharyngeal nerve disorders (e.g., glossopharyngeal neuralgia, etc.), vagus nerve disorders (e.g., superior laryngeal neuralgia, vagus nerve neuralgia, etc.), hypoglossal nerve disorders, multiple cranial nerve disorders, postherpetic neuralgia, postherpetic trigeminal neuralgia, etc. Dysmenorrhea, postherpetic polyneuropathy, neuropathic amyotrophic lateral sclerosis, phantom pain, stump neuralgia, deafferent pain, lumbar sciatica, upper extremity mononeuropathy (e.g., median neuralgia, ulnar neuralgia, etc.), lower extremity mononeuropathy (e.g., paresthetic femoral pain, etc.), costal neuropathy (e.g., intercostal neuralgia, etc.), neuropathic pain, diabetic neuropathy, diabetic neuropathy (e.g., type 1 diabetic neuropathy, type 2 diabetic neuropathy, etc.), cardiac neuralgia, persistent somatic symptom disorder, epidemic pleuropneumonia, autonomic reflex pain, spinal cord pain, lumbar puncture headache, eye pain, ear pain, thalamic pain, sore throat, nasal pain, toothache, jaw pain, glossitis, rectal pain, joint pain, back pain, spinal pain, myalgia, and neuralgia); and (8) Traumatic brain injury and related disorders or complications, post-concussion syndrome, shaken infant syndrome, stroke, age-related macular degeneration (ARMD), tremor of the eye and palate, seizures, cerebral infarction, cerebral hemorrhage, hearing loss, radiation-induced narcolepsy, anorexia nervosa, eating disorders, psychogenic anorexia, overeating, other eating disorders, gambling addiction, video game addiction, obesity, diabetes, muscle spasms, Ménière's disease. Diseases, autonomic nervous system disorders, hair loss, glaucoma, hypertension, heart disease, tachycardia, heart failure, hyperventilation, bronchial asthma, sleep apnea, sudden infant death syndrome, inflammatory diseases, allergic diseases, impotence, menopausal disorders, infertility, cancer, HIV-induced immunodeficiency syndrome, autoimmune encephalitis (e.g., autoimmune limbic encephalitis), stress-induced immunodeficiency syndrome, 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 bowel obstruction.

[0350] Compound (I) can also be used in the form of a prodrug.

[0351] Compound (I) prodrug refers to a compound that is converted into compound (I) under physiological conditions in vivo by enzymes, gastric acid or such induced reactions; that is, a compound that is converted into compound (I) by enzyme-induced oxidation, reduction, hydrolysis or such induced reactions, or a compound that is converted into compound (I) by the use of gastric acid or such induced hydrolysis or such induced reactions.

[0352] Non-limiting examples of the prodrug 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 eicosylated, alanineized, pentylaminocarbonylated, (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methoxycarbonylated, tetrahydrofuranized, pyrrolidinylmethylated, pentyloxymethylated, or tert-butylated, and such compounds); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of compound (I) is acetylated). Compounds that are palmitized, propionicized, pentatylated, succinified, fumarated, alaninated, or dimethylaminomethylcarbonylated, and the like); and compounds in which the carboxyl group of compound (I) is esterified or amylated (e.g., compounds in which the carboxyl group of compound (I) is ethylated, phenylated, carboxymethylated, dimethylaminomethylated, pentatylated, ethoxycarbonyloxyethylated, phthaloylated, (5-methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl)methylated, cyclohexyloxycarbonylethylated, or methylamylated, and the like). These compounds may be produced from compound (I) by methods known per se. The precursor of compound (I) may be a compound that is transformed into compound (I) under physiological conditions (e.g., conditions described in "Development of Pharmaceutical Products", Vol. 7, Molecule Design, pp. 163-198, Hirokawa Shoten (1990)).

[0353] Compound (I) exhibits favorable pharmacokinetic properties (e.g., drug half-life in blood, translocation to the brain, and metabolic stability) and low toxicity (e.g., excellent as a pharmaceutical agent in terms of acute toxicity, chronic toxicity, genotoxicity, replication toxicity, cardiotoxicity, drug interactions, carcinogenicity, and the like), thereby allowing safe oral or non-oral administration to mammals (e.g., humans, monkeys, cattle, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, and the like) directly as a pharmaceutical agent or in a pharmaceutical composition mixed with at least one pharmaceutically acceptable carrier or the like.

[0354] As used in this article, "non-oral administration" includes intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, intravenous drip, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, administration near the tumor, and direct administration to the lesion.

[0355] In some embodiments, the dosage of compound (I) varies depending on the route of administration, symptoms, and such. In some embodiments, when administered orally to a patient with depression (e.g., an adult weighing between 40 kg and 80 kg, such as a 60 kg adult), the dosage is, for example, 0.001 to 1000 mg / kg body weight / day, for example, 0.01 to 100 mg / kg body weight / day, and for example, 0.1 to 10 mg / kg body weight / day. This amount may be spread out, for example, 1 to 3 doses per day.

[0356] Pharmaceutical preparations containing compound (I) can be used as a single compound (I) or as a pharmaceutical composition prepared by mixing compound (I) and at least one pharmaceutically acceptable carrier according to methods known in themselves as methods of manufacturing pharmaceutical preparations (e.g., methods described in the Japanese Pharmacopoeia). Pharmaceutical preparations containing compound (I) can be safely administered orally or non-orally (intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, intravenous drip, intracerebral, rectal, vaginal, intraperitoneal, or lesion administration or the like), for example in the form of tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets and the like), pills, powdered drugs, granules, capsules (including soft capsules and microcapsules), lozenges, syrups, liquid preparations, emulsions Liquids, suspensions, controlled-release formulations (e.g., rapid-release formulations, sustained-release formulations, or sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films or oral mucosal films), injections (e.g., subcutaneous, intravenous, intramuscular, or intraperitoneal injections), intravenous infusions, transdermal formulations, ointments, lotions, patches, suppositories (e.g., rectal or vaginal suppositories), pellets, nasal transdermal formulations, inhaled formulations, ophthalmic solutions, or similar forms.

[0357] A variety of organic or inorganic carriers commonly used as starting materials for formulations can be used as the "pharmaceutically acceptable carriers" mentioned above. For example, in solid dosage forms, excipients, lubricants, binders, disintegrants, and the like can be used, and in liquid dosage forms, solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, and the like can be used. Additionally, additives to the formulation, such as preservatives, antioxidants, colorants, and sweeteners, may be used as needed.

[0358] Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and silicic anhydride.

[0359] Non-limiting examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silicon dioxide.

[0360] Non-limiting examples of adhesives include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethyl cellulose.

[0361] Non-limiting examples of disintegrants include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, and L-hydroxypropyl cellulose.

[0362] Non-limiting examples of solvents include water for injection, alcohols, propylene glycol, polyethylene glycol, sesame oil, corn oil, and olive oil.

[0363] Non-limiting examples of solvent aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0364] Non-limiting examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzyl chloride, and glyceryl monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

[0365] Non-limiting examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerol, and D-mannitol.

[0366] Non-limiting examples of buffers include buffer solutions, such as phosphates, acetates, carbonates, and citrates.

[0367] Non-limiting examples of analgesics include benzyl alcohol and the like.

[0368] Non-limiting examples of preservatives include parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0369] Non-limiting examples of antioxidants include sulfites, ascorbic acid, and α-tocopherol.

[0370] Although the dosage form, administration method, carrier and such vary in some embodiments, the pharmaceutical composition can be manufactured by adding compound (I) in a ratio of, for example, 0.01% to 100% (w / w) or, for example, 0.1% to 95% (w / w) relative to the total amount of the pharmaceutical composition, according to conventional methods.

[0371] Compound (I) may also be used in combination with other active ingredients (referred to as combination drugs in this document).

[0372] Non-limiting examples of combination drugs include acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galanthamine, and zanapezil), inhibitors of β-amyloid protein production, secretion, accumulation, aggregation, and / or deposition, and β-secretase inhibitors (e.g., 6-(4-biphenyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-(N,N-dimethylamino)methyltetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-(N,N-dipropylamino)methyltetrahydronaphthalene, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-(4-biphenyl) )Methoxy-2-[2-(N,N-diethylamino)ethyl]tetrahydronaphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetrahydronaphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2 -(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-[4-(1,3-benzodioxane-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene and 6-(3',4'-dimethoxyphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, their optically active substances, their salts, their hydrates and OM99-2 (WO 01 / 00663)), γ-selectase inhibitors, β-amyloid protein aggregation inhibitors (e.g., PTI-00703, high taurine, PPI-368 (Japanese translation of PCT application No. H11-514333), PPI-558 (Japanese translation of PCT application No. 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 degrading enzymes and the like, brain function enhancers (e.g., aniracetam and nicergoline), other Parkinson's disease drugs (e.g., dopamine receptor agonists (e.g., levodopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, and amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprednisolone)). [nyl), selegiline, remacemide, and riluzole; anti-parasympathetic agents (e.g., trihexyphenidyl and biperiden) and COMT inhibitors (e.g., entacapone); amyotrophic lateral sclerosis (ALS) treatments (e.g., riluzole and neurotrophic factors); drugs used for abnormal behavior, wandering, or similar conditions associated with dementia progression (e.g., sedatives and anxiolytics); apoptosis inhibitors (e.g., CPI-1189, Emricasan, CEP-1347); neurons Differentiation / 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, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl ...6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl [-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxanepenten[4,5-f]isoindole and its optically active substances, salts and hydrates), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin and the like), steroids (dexamethasone, hexestrol, cortisone)Acetate and similar drugs), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors and MAP kinase inhibitors), drugs for urinary frequency and incontinence (e.g., flavonoid hydrochloride, oxybutynn hydrochloride, and propiverine hydrochloride), dioxin diesterase inhibitors (e.g., sildenafil citrate), dopaminergic drugs (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, and estradiol benzoate), osteoporosis drugs (e.g., alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, iprivlavone, pamidronate disodium, alendronate sodium hydrate, and icardronate disodium), parathyroid hormone (PTH), and calcium receptor antagonists. Insomnia medications (e.g., benzodiazepine-based drugs, non-benzodiazepine-based drugs, melatonin agonists, and orexin receptor antagonists), schizophrenia medications (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; drugs affecting metabolotropic glutamate receptors or ion channel-binding glutamate receptors; and dioxindiesterase inhibitors), benzodiazepine-based drugs (clodiazepine, diazapine, potassium loratadine). Clorazepate, lorazepam, clonazepam, alprazolam and similar drugs, L-type calcium channel inhibitors (pregabalin and similar drugs), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride and similar drugs), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride)Hydrochlorides, paroxetine hydrochloride, escitalopram oxalate and the like, serotonin and norepinephrine reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride and the like), norepinephrine reuptake inhibitors (reboxetine mesylate and the like), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT2A antagonists (e.g., pimavanserin tartrate) 5-HT2A inverse agonists, 5-HT3 antagonists (cyamemazine and the like), non-cardiac selective beta inhibitors (propranolol hydrochloride, oxiprenolol hydrochloride and the like), histamine H1 antagonists (hydroxyzine hydrochloride and the like), schizophrenia medications (chlorpromazine, fluphenazine, sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate) Fumarate, risperidone, aripiprazole and similar drugs, CRF antagonists, other anxiolytics (meprobamate and similar drugs), tachykinin antagonists (aprepitant, saredutant and similar drugs), drugs affecting prometabolic glutamate receptors, drugs affecting GABA receptors, drugs affecting acetylcholine receptors, CCK antagonists, β3-adrenergic antagonists (amibegron and similar drugs), GAT-1 inhibitors (tiagabine hydrochloride)Hydrochlorides and similar substances, N-type calcium channel inhibitors, type 2 carbonic acid dehydratase inhibitors, NMDA glycine site agonists, NMDA antagonists (ketamine, S-ketamine, R-ketamine, ketamine metabolites (e.g., (2S,6S;2R,6R)-hydroxychloramine, (2R,6R)-hydroxychloramine and similar substances), memantine and similar substances), peripheral benzodiazepine receptor agonists, antidiuretic hormone antagonists, antidiuretic hormone V1b antagonists, antidiuretic hormone V1a antagonists, dioxophosphatase inhibitors, opioid inhibitors, opioid agonists Activators, uridine, nicotinic acid agonists, thyroid hormones (T3 and T4), TSH, TRH, MAO inhibitors (phenylhydrazine sulfate, transphenylcyclopropane sulfate, moclobemide, and the like), bipolar disorder drugs (lithium carbonate, sodium valproate, lamotrigine, liluthiazole, felbamate, and the like), cannabinoid CB1 antagonists (rimonabant, and the like), FAAH inhibitors, sodium channel inhibitors, anti-ADHD drugs (methylphenidate hydrochloride), etc. Hydrochloride, methamphetamine hydrochloride and similar drugs, alcohol dependence drugs, autism drugs, chronic fatigue syndrome drugs, epilepsy drugs, fibromyalgia drugs, headache drugs, smoking cessation drugs, myasthenia gravis drugs, stroke drugs, mania drugs, excessive sleep drugs, pain drugs, dysphoric drugs, autonomic nervous system dysfunction drugs, male and female sexual dysfunction drugs, migraine drugs, pathological gambling drugs, restless legs syndrome drugs, substance dependence drugs, alcohol-related disease drugs, irritable bowel syndrome drugs, dyslipidemia drugs (e.g., hypocholesterol drugs, statin series, pravastatin sodium). Sodium, atorvastatin, simvastatin, rosuvastatin and the like, fibrates (clofibrate and the like) and squalene synthesis inhibitors), drugs for abnormal behavior or drugs used to inhibit wandering induced by dementia (sedatives, anxiolytics and the like), anti-obesity drugs, antidiabetic drugs, drugs for diabetic complications, antihypertensive drugs, antihypertensive drugs, diuretics, chemotherapeutic agents, immune modifiers, antithrombotic agents, anticancer agents and the like.

[0373] Two or more types of the combination drugs described above may also be used in appropriate ratios.

[0374] Furthermore, when using the compounds disclosed herein to treat or prevent one or more of the diseases described above, the compounds or pharmaceutically acceptable salts may also be used in combination with biological agents (e.g., antibody drugs, nucleic acids (e.g., antisense oligonucleotides, siRNA, decoys, and the like) or nucleic acid derivatives, aptamer drugs, peptide drugs, and vaccine formulations). Additionally, the compounds or pharmaceutically acceptable salts may also be used in combination with gene therapy or similar treatments, or in combination with treatments used in psychotic cases where no medication is used.

[0375] Non-limiting examples of antibody drugs and vaccine formulations include angiotensin II vaccines, CETP vaccines, CETP antibodies, TNFα antibodies and antibodies against other intercytokines, amyloid-β vaccines, type 1 diabetes vaccines (e.g., DIAPEP-277 from Peptor), anti-HIV antibodies or HIV vaccines, antibodies or vaccines against intercytokines, renin / angiotensinase or their products, antibodies or vaccines against enzymes or proteins involved in lipid metabolism in the blood, antibodies or vaccines related to enzymes or proteins involved in the fibrinogenolysis system, and antibodies or vaccines against proteins involved in carbohydrate metabolism or insulin resistance. Additionally, compound (I) may also be used in combination with growth factor (e.g., GH or IGF)-related biologics.

[0376] Non-limiting examples of gene therapy include therapies using genes associated with interferons, renin / angiotensinase and their products, G proteins and G protein-coupled receptors and their phosphatases; therapies using DNA decoys (e.g., NFκB decoys); therapies using antisense genes; therapies using genes associated with enzymes or proteins involved in lipid metabolism in the blood (e.g., genes associated with the metabolism, excretion and absorption of cholesterol, triglycerides, HDL cholesterol or phospholipids in the blood); therapies using genes associated with enzymes or proteins involved in peripheral vascular disease or angiogenesis therapies such as growth factors (e.g., HGF and VEGF); therapies using genes associated with proteins involved in carbohydrate metabolism or insulin resistance; and antisense gene therapies using interferons (e.g., TNF), viral vectors (e.g., adenovirus, lentivirus, adeno-associated virus, retrovirus, vaccinia virus, herpesvirus, human papillomavirus, Sendai virus and the like), or non-viral vectors (e.g., plastids, lipid particles and the like).

[0377] Non-limiting examples of treatments used in non-pharmacological psychiatric cases include psychotherapy, including transcranial electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and cognitive behavioral therapy.

[0378] In addition, the compounds disclosed herein can be used in combination with various organ regeneration methods (such as heart regeneration, kidney regeneration, pancreatic regeneration and angiogenesis), cell transplantation therapy using bone marrow cells (bone marrow mononuclear globules and bone marrow stem cells) or artificial organs using tissue-modified materials (such as artificial blood vessels and cardiomyocyte slices), each of which uses internal or external cells (including genetically modified ones).

[0379] In some embodiments, the combination compound (I) and the combination drug may achieve one or more of the following results: (1) The dosage can be reduced compared to cases in which compound (I) or combination drugs are administered alone; (2) The medication to be used in combination with compound (I) may be selected based on the patient's symptoms (mild symptoms, severe symptoms, or the like); (3) Long-term treatment can be established by selecting combination drugs with mechanisms of action different from those of compound (I); (4) The therapeutic effect can be maintained by selecting combination drugs with mechanisms of action different from those of compound (I); and (5) Synergistic effects can be achieved by using a combination of compound (I) and combination drugs.

[0380] The combined use of compound (I) and combination drugs will be referred to as "the combination of the present disclosure".

[0381] When using the combination formulations disclosed herein, there are no restrictions on the timing of administration of compound (I) and the combination drug, and compound (I) or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to individuals simultaneously or at different times. The dosage of the combination drug must not only conform to the dosage used clinically, but may also be appropriately selected based on the individual, route of administration, disease, combination, or the like.

[0382] The administration of the combination formulation disclosed herein is not limited, as long as the compound (I) and the combination drug are combined at the time of administration. Non-limiting examples of such administration include: (1) administration of a single formulation obtained by simultaneously dispensing the compound (I) and the combination drug; (2) simultaneous administration of two types of formulations obtained by separately dispensing the compound (I) and the combination drug for the same administration route; (3) administration of two types of formulations obtained by separately dispensing the compound (I) and the combination drug for the same administration route at different times; (4) simultaneous administration of two types of formulations obtained by separately dispensing the compound (I) and the combination drug for different administration routes; and (5) administration of two types of formulations obtained by separately dispensing the compound (I) and the combination drug for different administration routes at different times (e.g., administration in the order of compound (I) followed by the combination drug or in the reverse order).

[0383] In some embodiments, the combination formulations disclosed herein are of low toxicity, and the compounds (I) and / or combination drugs described above can be mixed with at least one pharmaceutically acceptable carrier according to known methods and safely administered orally or non-orally (e.g., via local, rectal, or intravenous administration) as pharmaceutical compositions, such as tablets (e.g., sugar-coated tablets and film-coated tablets), powdered drugs, granules, capsules (e.g., soft capsules), liquid formulations, injections, suppositories, sustained-release formulations, or the like. Injection can be administered intravenously, intramuscularly, subcutaneously, or intra-organically, or directly to the lesion.

[0384] Non-limiting examples of pharmaceutically acceptable carriers that can be used to produce the combinations disclosed herein include the carriers described above.

[0385] The blending ratio of compound (I) and combination drugs in the combination formulation disclosed herein may be appropriately selected based on the individual, administration route, disease, and such.

[0386] For example, although the content of compound (I) in the combination of the present disclosure varies depending on the form of the formulation, in some embodiments, the content is from about 0.01 wt.% to 100 wt.% relative to the whole formulation, for example from about 0.1 wt.% to 50 wt.%, for example from about 0.5 wt.% to 20 wt.%.

[0387] Although the content of the combination drugs in the combination formulation of this disclosure varies based on the form of the formulation, the content is generally from about 0.01 wt.% to 100 wt.% relative to the whole formulation, for example from about 0.1 wt.% to 50 wt.%, for example from about 0.5 wt.% to 20 wt.%. [Example]

[0388] The present disclosure will be further elaborated below 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.

[0389] "Room temperature" in the examples below generally refers to a temperature between about 10°C and about 35°C. Unless otherwise stated, ratios indicated in mixed solvents are by volume. Also, unless otherwise stated, % refers to wt.%.

[0390] Unless otherwise specified, the dissolution in the column chromatography examples was performed under observation by thin-layer chromatography (TLC). For TLC observation, 60 F254 plates, available from Merck, were used as the TLC plates, and the solvent used as the dissolution solvent in the column chromatography was used as the developing solvent. A UV detector was also used for detection. In silicone column chromatography, aminopropylsilane-bonded silicone was used when indicated as NH, and 3-(2,3-dihydroxypropoxy)propylsilane-bonded silicone was used when indicated as diol. In preparative high-performance liquid chromatography (HPLC), octadecyl-bonded silicone was used when indicated as C18. Unless otherwise specified, the ratios indicated in the dissolution solvent are volume ratios.

[0391] Perform 1H NMR analysis using ADC / SpecManager software or similar tools. Fine proton peaks for hydroxyl, amino, or similar groups may go unnoticed.

[0392] MS is measured by LC / MS. ESI or APCI is used as the ionization method. Data indicates actual measured values ​​(experimental values). Molecular ion peaks are usually observed, but data as fragment ions can also be observed. In the case of salts, peaks of free molecular ions or fragment ions are observed.

[0393] The unit of sample concentration (c) in optical rotation ([α]D) is g / 100 mL.

[0394] Elemental analysis values ​​(Anal.) indicate both calculated values ​​(Calcd) and actual measured values ​​(experimental values).

[0395] In this example, the peak measured by powder X-ray diffraction refers to the peak measured at room temperature using CuKα rays as the radiation source with Ultima IV (Rigaku Corporation, Japan). The measurement conditions are as follows. Voltage / Current: 40 kV / 50 mA Scanning speed: 6 degrees / min 2θ scan range: 2-35 degrees

[0396] The Hermans method was used to calculate the crystallinity of the powder based on X-ray diffraction in the example.

[0397] The following abbreviations will be used in the examples below. mp: melting point MS: Mass Spectrometry M: molar concentration N: Normal CDCl3: Dichloroform DMSO-d6: Dimethyl sulfoxide 1H NMR: Proton Nuclear Magnetic Resonance LC / MS: Liquid Chromatography-Mass Spectrometry ESI: Electrospray Ionization APCI: Atmospheric Pressure Chemical Ionization CH3 CN: 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:Dibenzylacetone)dipalladium(0) Pd(dba)2 :bis(dibenzylacetone)palladium(0) PdCl2 (dppf): dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium TEA: Triethylamine DPPA: Diphenylphosphine azide DEAD: Diethyl azodicarbonate MeOH: Methanol PPh3: Triphenylphosphine EtOH: Ethanol NaBH4: Sodium borohydride TBAF: Tetrabutylammonium fluoride NFSI: N-Fluorobenzenesulfonamide [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

[0398] 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 and stirred overnight under a nitrogen atmosphere at 80 °C. The mixture was diluted with ethyl acetate at room temperature 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 purified by silica gel column chromatography (NH₃, ethyl acetate / hexane). The solid was washed with diisopropyl ether and dried under reduced pressure to obtain the title compound (3.45 g).

[0399] 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

[0400] At room temperature, bis(trichloromethyl) carbonate (370 mg) and TEA (378 mg) were added to a toluene solution (10 mL) of 4'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-3-amine (636 mg). The mixture was stirred overnight. Then, 2,2-dimethoxyethylamine (0.266 mL) was added to the mixture at room temperature. After stirring the mixture at room temperature for 1 hour, it was 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 at room temperature and added to water. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane). The solid was washed with diisopropyl ether and dried under reduced pressure to obtain the target 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

[0401] First, 1-[4'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-1,3-dihydro-2H-imidazol-2-one (40 mg) was added to a DMF (0.5 mL) suspension of sodium hydride (60% concentration, 12.4 mg) at room temperature. The mixture was stirred at room temperature for 10 minutes. Then, a DMF (0.30 mL) solution of 4-(chloromethyl)-1-ethyl-1H-pyrazole (26.9 mg) was added dropwise to the mixture at room temperature. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate at room temperature 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 purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (13 mg).

[0402] 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

[0403] 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 under a nitrogen atmosphere for 16 hours. Insoluble substances were filtered off using Celite®, and the filtrate was distilled off under reduced pressure. The residue was purified by silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (1.85 g).

[0404] MS: [M+H]+ 309.2. B) 2-Fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)aniline

[0405] A mixture of (2R)-4-[4-fluoro-3-nitro-5-(trifluoromethyl)phenyl]-2-methylmorpholine (1.85 g), 10% palladium-carbon (0.319 g), and EtOH (60 mL) was stirred at room temperature under a hydrogen atmosphere and normal pressure for 2 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (1.67 g).

[0406] MS: [M+H]+ 279.2. C) N-(2,2-Dimethoxyethyl)-N'-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}urea

[0407] Bis(trichloromethyl) carbonate (0.571 g) was added to a mixture of 2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)aniline (1.07 g) and THF (30 mL) at 0 °C, and the mixture was stirred at room temperature for 4 hours. Then, 2,2-dimethoxyethaneamine (0.404 g) and TEA (0.389 g) were added to the mixture, and the mixture was stirred overnight at room temperature. 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 silicone column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (1.25 g).

[0408] 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

[0409] TFA (15.4 g) was added 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). The mixture was stirred at 60 °C for 3 hours, and the reaction mixture was concentrated. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (722 mg).

[0410] MS: [M+H]+ 346.2. E) ethyl 1-ethyl-1H-pyrazole-4-carboxylate

[0411] A mixture of potassium carbonate (197 g), ethyl 1H-pyrazole-4-carboxylate (100 g), iodoethane (122 g), and DMF (250 mL) was stirred overnight at room temperature. The mixture was then added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated brine solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (121 g).

[0412] 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-pyrazole-4-yl)methanol

[0413] 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, and then sodium sulfate decahydrate (110 g) was added at 0–10 °C, and the mixture was stirred at room temperature for 1 hour. Impurities were filtered off, and the filtrate was distilled off under reduced pressure to obtain the title compound (29.9 g).

[0414] 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

[0415] Thionium chloride (4.39 g) was added to a mixture of (1-ethyl-1H-pyrazole-4-yl)methanol (2.33 g) and CH3 (20 mL) at room temperature, and the mixture was stirred overnight at the same temperature. The mixture was concentrated to obtain the title compound (3.23 g).

[0416] 1 H NMR (300 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.2 Hz), 4.10 (2H, q, J = 7.4 Hz), 4.69 (2H, s), 7.50 (1H, s), 7.85 (1H, s), 12.32 (1H, bs). H) 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one

[0417] First, 1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one (100 mg) was added to a mixture of sodium hydride (60% content, 29.0 mg) and DMF (3 mL) at room temperature. After stirring the mixture at room temperature for 30 minutes, a mixture of 4-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (79 mg), DMF (2 mL), and sodium iodide (43.4 mg) was added and stirred overnight at room temperature. Water was added to the mixture, and the mixture was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (70.0 mg).

[0418] 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

[0419] Proprynne-1-amine (0.928 mL) was added to a mixture of 1-ethyl-1H-pyrazole-4-carboxaldehyde (1.20 g) and toluene (10 mL), and the mixture was refluxed for 2 hours. After cooling, the mixture was added to a mixture of NaBH4 (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 silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (1.21 g).

[0420] 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

[0421] 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 the mixture to room temperature, it was diluted with water and stirred at room temperature for 30 minutes. The resulting solid was filtered off and dried under reduced pressure to obtain the title compound (180 g).

[0422] MS: [M+H]+ 281.0. C) 6-[(2R)-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridine-2-amine

[0423] A mixture of (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (800 mg), diphenylmethaneimine (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 1 N hydrochloric acid (10 mL) were added. The mixture was stirred at room temperature for 30 minutes, and water was added and 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 obtain the title compound (612 mg).

[0424] 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-ylurea

[0425] TEA (0.107 mL) and bis(trichloromethyl) carbonate (114 mg) were added to a mixture of 6-[(2R)-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (200 mg) and THF (3 mL) at 0 °C and stirred at room temperature for 2 hours. A mixture of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]prop-2-yn-1-amine (214 mg), THF (2 mL), and TEA (0.107 mL) was added to the mixture and stirred at room temperature overnight. Water was added to the mixture, and the mixture 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 silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (248 mg).

[0426] 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

[0427] At room temperature, 0.244 mL of 1 M TBAF / THF solution was added 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), and the mixture was stirred in a sealed tube at 80 °C for 30 min. After cooling the mixture to room temperature, it was poured into 1 mL of 2N hydrogen chloride / ethanol solution, and the mixture was stirred at room temperature for 5 min. After concentrating the mixture under reduced pressure, the residue was purified by silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (74.6 g).

[0428] 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-dimethoxypropane-2-amine

[0429] First, 1,1-dimethoxypropane-2-amine (331 mg) was added to a mixture of 1-ethyl-1H-pyrazole-4-carboxaldehyde (300 mg) and toluene (4 mL), and the mixture was refluxed at 130 °C for 2 hours. After cooling the mixture to room temperature, it was added to a suspension 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 silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (510 mg).

[0430] MS: [M+H]+ 228.2. B) (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine

[0431] 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 the mixture to room temperature, it was diluted with water and stirred at room temperature for 30 minutes. The resulting solid was filtered off 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

[0432] A 2 M solution of diisopropylaminolithium (240 mL) was added to a mixture of (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (90.0 g) and THF (720 mL) at -60 °C under an argon atmosphere, and stirred for 30 min at the same temperature. A mixture of iodine (122 g) and THF (180 mL) was added to the mixture at -60 °C, and stirred for 30 min at the same temperature. The mixture was neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated and washed with water, 20% sodium thiosulfate aqueous solution, and saturated salt solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to obtain the title compound (101 g).

[0433] MS: [M+H]+ 406.9. D) 3-Fluoro-6-[(2R)-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridine-2-amine

[0434] Under a nitrogen atmosphere at 0 °C, a 1.0 M magnesium isopropyl chloride-lithium chloride / THF solution (9.40 mL) was added dropwise to a mixture of (2R)-4-[6-chloro-5-iodo-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (3.00 g) and THF (15 mL), and stirred at the same temperature for 40 min. Under a nitrogen atmosphere at 0 °C, the mixture was added dropwise to a mixture of NFSI (3.72 g), THF (12 mL), and heptane (6 mL), and stirred at the same temperature for 30 min. The mixture was neutralized with 2 N 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 (NH4, ethyl acetate / hexane). The resulting oily substance, a mixture of Pd2(dba)3 (353 mg), BINAP (480 mg), diphenylmethaneimine (0.84 mL), sodium tert-butoxide (555 mg), and toluene (13 mL) was irradiated with a microwave at 140 °C for 1 hour. Then, MeOH (20 mL) and 2 N hydrochloric acid (20 mL) were added to the mixture at room temperature. After stirring the mixture at room temperature for 30 minutes, 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 (NH4, ethyl acetate / hexane) to obtain the title compound (370 mg).

[0435] MS: [M+H]+ 280.1 E) N-(1,1-Dimethoxypropane-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

[0436] Bis(trichloromethyl) carbonate (96.0 mg) was added to a mixture of 3-fluoro-6-[(2R)-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridine-2-amine (167 mg), TEA (0.208 mL), and THF (3 mL) at 0 °C, and stirred for 30 min at the same temperature. A mixture of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1-dimethoxypropane-2-amine (163 mg), TEA (0.125 mL), and THF (2 mL) was added to the mixture at 0 °C, and the mixture was heated to room temperature and stirred for 1 h at the same temperature. The mixture was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (170 mg).

[0437] 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

[0438] TFA (1.5 mL) was added to a mixture of N-(1,1-dimethoxypropane-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), and the mixture was stirred at 60 °C for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silicone column chromatography (NH, ethyl acetate / hexane), followed by silicone column chromatography (from ethyl acetate / hexane to ethyl acetate / methanol), and the purified product was crystallized from ethyl acetate / heptane to obtain the title compound (92.3 mg).

[0439] 1 H 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

[0440] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (3.10 g), (2R)-methylmorpholine hydrochloride (1.98 g), DIPEA (7.52 mL), and DMSO (6 mL) was heated at 160 °C for 30 min 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 silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (3.63 g).

[0441] MS: [M+H]+ 281.0. B) 6-[(2R)-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridine-2-amine

[0442] A mixture of (2R)-4-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-2-methylmorpholine (800 mg), diphenylmethaneimine (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 1 N 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 obtain the title compound (612 mg).

[0443] 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

[0444] A DEAD / toluene solution (40% concentration, 41.0 g) was added at 0 °C to a mixture of butyryl-3-yn-2-ol (6.00 g), phthalimide (15.1 g), PPh3 (26.9 g), and THF (171 mL). The mixture was heated to room temperature and stirred at the same temperature for 72 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate / hexane (200 mL). Insoluble substances were filtered off and washed with ethyl acetate / hexane (200 mL). The filtrate and washing solution were concentrated under reduced pressure, and the residue was purified twice by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (7.08 g).

[0445] MS: [M+H]+ 200.1. D) But-3-yne-2-amine hydrochloride

[0446] Hydrazine monohydrate (3.52 g) was added to a mixture of 2-(but-3-yn-2-yl)-1H-isoindole-1,3(2H)-dione (7.00 g) and EtOH (150 mL), and the mixture was stirred at 70 °C for 45 min. After cooling the mixture to room temperature, the insoluble matter was filtered off and washed with ethanol (150 mL). The filtrate and washings were distilled off at 30 °C and 45 mmHg to obtain a but-3-yn-2-amine / ethanol solution. A 2 N hydrogen chloride / ethanol solution (35.1 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 min, then concentrated under reduced pressure to obtain the title compound (3.09 g).

[0447] 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

[0448] 2-Nitrobenzenesulfonyl chloride (5.77 g) and TEA (9.90 mL) were added to a mixture of but-3-yn-2-amine hydrochloride (2.50 g) and pyridine (50 mL) 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 silicone column chromatography (NH, ethyl acetate / hexane) and silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (2.41 g).

[0449] 1 H 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

[0450] A mixture of potassium carbonate (197 g), ethyl 1H-pyrazole-4-carboxylate (100 g), iodoethane (122 g), and DMF (250 mL) was stirred overnight at room temperature. The mixture was then added to water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated brine solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (121 g).

[0451] 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-pyrazole-4-yl)methanol

[0452] 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, and sodium sulfate decahydrate (110 g) was added at 0–10 °C, and the mixture was stirred at room temperature for 1 hour. Insoluble substances were filtered off, and the filtrate was distilled off under reduced pressure to obtain the title compound (29.9 g).

[0453] 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). H) N-(But-3-yn-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-nitrobenzene-1-sulfonamide

[0454] 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), cyanomethylenetributylphosphine (3.43 g), and THF (15 mL) was heated at 100 °C for 12 hours under microwave irradiation. After cooling the mixture to room temperature, it was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (2.56 g).

[0455] MS: [M+H]+ 363.1. I) N-[(1-ethyl-1H-pyrazol-4-yl)methyl]but-3-yn-2-amine

[0456] At 0 °C, thioglycolic 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), 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 matter was filtered off and washed with ethyl acetate (50 mL). The filtrate and washing solution were concentrated under reduced pressure, and the residue was purified by silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (1.12 g).

[0457] 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

[0458] At 0 °C, bis(trichloromethyl) carbonate (43.4 mg) was added to a mixture of 6-[(2R)-methylmorpholino-4-yl]-4-(trifluoromethyl)pyridin-2-amine (85.0 mg), TEA (0.095 mL), and THF (3 mL), and the mixture was stirred at the same temperature for 30 minutes. At 0 °C, 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 to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (120 mg).

[0459] 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

[0460] 1 M TBAF / THF solution (1.0 mL) was added 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), and the mixture was stirred at 60 °C for 2 hours. After cooling the mixture to room temperature, 2 N 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 silicone column chromatography (NH, ethyl acetate / hexane), and the purified product was crystallized with ethyl acetate / hexane to obtain the title compound (252 mg).

[0461] 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-(propane-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

[0462] Di-μ-methoxybis(1,5-cyclooctadiene)diiridium(I) (0.236 g) and then 4,4'-di-tert-butyl-2,2'-bipyridine (0.191 g) were added to a degassed THF (50 mL) solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborane (2.71 g). After stirring the mixture for 10 minutes, 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 azodicarbonate (4.08 g) and copper acetate(II) (3.21 g) were added. 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 a saturated aqueous solution of ammonium chloride was added at room temperature. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and a saturated salt solution, then 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 a 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 at room temperature and added to a saturated aqueous solution of sodium bicarbonate. The organic layer was separated and washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.42 g).

[0463] 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)hydrazine)propionate

[0464] Ethyl pyruvate (0.635 mL) was added to a methanol (20 mL) solution of 1.42 g of 5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazine at 0 °C. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was suspended in diisopropyl ether. The precipitate was filtered off and dried under reduced pressure to obtain the title compound (1.45 g).

[0465] MS: [M+H]+ 371.0. C) 2-(2-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazine)propionic acid

[0466] At room temperature, 5.0 mL of 2 M sodium hydroxide aqueous solution was added to 20 mL of methanol solution of 1.93 g of ethyl 2-(2-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazine)propionate. The mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure, and after diluting the residue with water (15 mL), 1 M hydrochloric acid (10 mL) was added dropwise to the mixture. The precipitate was filtered off, washed with water, and dried under reduced pressure to obtain the title compound (1.48 g).

[0467] 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]hydrazine}propionic acid azide

[0468] At room temperature, 1.21 mL of diphenylphosphine azide and 0.783 mL of TEA were added to a 15 mL solution of 1.48 g of 2-(2-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)hydrazine)propionic acid in THF. The mixture was stirred overnight at room temperature. 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 filtered off, washed with diisopropyl ether, and dried under reduced pressure to obtain the title compound (1.03 g).

[0469] 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

[0470] A mixture of 2-{2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]hydrazine}propionic acid azide (1.59 g) and toluene (15 mL) was stirred at 110 °C for 2 hours. The mixture was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (1.09 g).

[0471] 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-(propane-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0472] Cyanomethylenetributylphosphine (703 mg) was added to a mixture of 2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (495 mg), [1-(propane-2-yl)-1H-pyrazol-4-yl]methanol (408 mg), and THF (10 mL), and the mixture was stirred at 80 °C for 4 hours. The mixture was purified by silicone column chromatography (NH4+, ethyl acetate / hexane) to obtain the title compound (463 mg).

[0473] MS: [M+H]+ 462.1. G) 2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propane-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0474] A mixture of 2-[5-bromo-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-4-{[1-(propane-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), Pd2(dba)3 (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 silicone column chromatography (NH, ethyl acetate / hexane) and HPLC (C18, mobile phase: water / CH3CN (10 mM ammonium bicarbonate system)) and concentrated under reduced pressure to obtain the title compound (12.6 mg).

[0475] 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-dimethoxypropane-2-amine

[0476] First, 1,1-dimethoxypropane-2-amine (331 mg) was added to a mixture of 1-ethyl-1H-pyrazole-4-carboxaldehyde (300 mg) and toluene (4 mL), 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 silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (510 mg).

[0477] MS: [M+H]+ 228.1. B) Ethyl 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0478] Methyl sulfonate (1.54 g) and TEA (1.36 g) were added to a mixture of 2-cyclobutylethane-1-ol (900 mg) and THF (20 mL), and stirred at room temperature for 30 minutes. The mixture was neutralized with a saturated sodium bicarbonate aqueous solution at 0 °C and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated brine solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 2-cyclobutyl methanesulfonate (1.6 g). The crude 2-cyclobutyl methanesulfonate (1.6 g) and potassium carbonate (1.55 g) were added to a mixture of ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1.56 g) and DMF (15 mL), and stirred overnight at room temperature. Water was added to the mixture, and then extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (1.99 g).

[0479] MS: [M+H]+ 291.1. C) N'-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(1,1-dimethoxypropane-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]urea

[0480] A 4 M lithium hydroxide aqueous solution (5.14 mL) was added to a mixture of ethyl 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (1.99 g), THF (15 mL), and MeOH (5 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 obtain crude 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid. At room temperature, TEA (46.3 mg) and DPPA (126 mg) were added to the crude 1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (100 mg) and toluene (1 mL). After stirring the mixture at room temperature for 30 minutes, N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1-dimethoxypropane-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 obtain the title compound (185 mg).

[0481] 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

[0482] At room temperature, TFA (1 mL) was added to a mixture of N'-[1-(2-cyclobutylethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(1,1-dimethoxypropane-2-yl)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]urea (185 mg), CH3CN (2 mL), and water (0.4 mL), and the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (104 g).

[0483] 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]

[0103] [] 4-Methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propane-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

[0484] Proprynil-1-amine (1.07 g) was added to a mixture of 1-isopropyl-1H-pyrazole-4-carboxaldehyde (2.07 g) and toluene (30 mL), 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. NBH4 (0.851 g) was added 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 silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (2.00 g).

[0485] 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-ylurea

[0486] At 0 °C, bis(trichloromethyl) carbonate (115 mg) and TEA (117 mg) were added to a mixture of 6-[(2R)-methylmorpholino-4-yl]-4-(trifluoromethyl)pyridin-2-amine (202.0 mg) and THF (15 mL), and stirred at room temperature for 30 minutes. After concentrating the mixture, the residue was suspended in THF (15 mL). A mixture of N-[(1-propane-2-yl)-1H-pyrazol-4-yl]methylprop-2-yn-1-amine (144 mg), THF (4 mL), and TEA (218 mg) was added, and the mixture was stirred at room temperature overnight. The mixture was added to a saturated aqueous solution of 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 silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (58.0 mg).

[0487] MS: [M+H]+ 465.3. C) 4-Methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propane-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one

[0488] A 1 M TBAF / THF solution (0.118 mL) was added 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), and the mixture was stirred in a sealed tube at 80 °C for 2 hours. After cooling the mixture, a 4 N hydrogen chloride / ethyl acetate solution (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 5 minutes, followed by concentration of the reaction solution. The residue was purified by silicone column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (20 mg).

[0489] 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]

[0110] [] 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)pyridine-2-amine

[0490] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (1 g), diphenylmethaneimine (1.1 g), Pd2(dba)3 (0.21 g), BINAP (0.29 g), sodium tert-butoxide (0.67 g), and toluene (17 mL) was irradiated with a microwave at 140 °C for 1 hour. A 2 N hydrogen chloride / ethanol solution (10 mL) was added to the mixture at room temperature. After stirring the mixture at room temperature for 1 hour, a saturated aqueous solution of sodium bicarbonate 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 silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (277 mg).

[0491] 1H 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-ylurea

[0492] At 0 °C, TEA (0.13 g) and bis(trichloromethyl) carbonate (0.18 g) were added to a mixture of 6-chloro-4-(trifluoromethyl)pyridin-2-amine (0.24 g) and THF (8 mL). After stirring the reaction mixture at room temperature for 1 hour, 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) was added. The mixture was stirred at room temperature for 12 hours. Water was added to the mixture, and the mixture 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 silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (0.32 g).

[0493] 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

[0494] A 1 M TBAF / THF solution (0.91 mL) was added 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), and the mixture was stirred at 80 °C for 1 hour. At room temperature, a 2 N hydrogen chloride / ethanol solution (1 mL) was added to the reaction mixture and stirred for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the mixture and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (0.11 g).

[0495] 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

[0496] A mixture of 1-(1-fluorocyclobutyl)methylamine hydrochloride (21.7 mg), sodium tributoxide (49.8 mg), and DME (1 mL) was stirred at room temperature for 10 minutes. At room temperature, a THF (0.5 mL) 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), 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'-diisopropoxybiphenyl-2-yl)phosphine (6.1 mg) were added to the mixture. The mixture was irradiated with microwave at 110°C for 1 hour and purified by silicone column chromatography (ethyl acetate / hexane), followed by further purification by HPLC (C18, mobile phase: water / CH3CN (10 mM TFA system)). The fraction obtained was concentrated under reduced pressure to obtain the title compound (26 mg).

[0497] 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]

[0127] [] 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-dimethoxyethane-1-imine

[0498] Dimethoxyacetaldehyde (1.27 g) was added to a mixture of 1-(1-ethyl-1H-pyrazol-4-yl)methylamine (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).

[0499] 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-dimethoxypropane-2-amine

[0500] TFA (228 mg) was added to a mixture of (1E)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2,2-dimethoxyethane-1-imine (423 mg), potassium hydrogen fluoride (117 mg), DMF (439 mg), and CH3 CN (4 mL) at 0 °C, and stirred for 5 min at the same temperature. Trimethyl(trifluoromethylmethyl)silane (355 mg) was added to the mixture at 0 °C, and the mixture was stirred for 15 min at room temperature. The residue was purified by HPLC (C18, mobile phase: water / CH3 CN (10 mM ammonium bicarbonate system)). The fraction obtained was concentrated under reduced pressure to obtain the title compound (75 mg).

[0501] 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-dimethoxypropane-2-yl)urea

[0502] Bis(trichloromethyl) carbonate (26.4 mg) was added to a mixture of 3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]4-(trifluoromethyl)pyridine-2-amine (62 mg), TEA (53.9 mg), and THF (2 mL), and the mixture was stirred at the same temperature for 30 minutes. At 0 °C, a solution of N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,1,1-trifluoro-3,3-dimethoxypropane-2-amine (73 mg) and TEA (33.7 mg) in THF (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (116 mg).

[0503] MS: [M+H]+ 587.3. D) 3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1-{3-fluoro-6-[(2R)-2--4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-(trifluoromethyl)-1,3-dihydro-2H-imidazol-2-one

[0504] 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-dimethoxypropane-2-yl)urea (116 mg), TFA (666 mg), CH3CN (3 mL), and water (0.3 mL) was microwave-irradiated at 130 °C for 3 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was purified by silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (64 mg).

[0505] 1 H 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]

[0134] [] 3-[4-(2,2-dimethylmorpholino-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-Dimethylmorpholino-4-yl)-6-(trifluoromethyl)pyrimidin-2-amine

[0506] 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-butanol (1 mL) was stirred overnight at 120 °C. The mixture was purified by silicone column chromatography (NH4, ethyl acetate / hexane) to obtain the title compound (90.0 mg).

[0507] 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-prop-2-yn-1-ylurea

[0508] At 0 °C, bis(trichloromethyl) carbonate (19.3 mg) was added to a mixture of 4-(2,2-dimethylmorpholino-4-yl)-6-(trifluoromethyl)pyrimidin-2-amine and THF (2 mL), and the mixture was stirred at room temperature for 4 hours. Then, N-[(1-ethyl-1H-pyrazol-4-yl)methyl]prop-2-yn-1-amine (31.9 mg) and TEA (24.7 mg) were added to the mixture, and the mixture was stirred overnight at room temperature. 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 silicone column chromatography (ethyl acetate / hexane) to obtain the title compound (73.1 mg).

[0509] 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

[0510] 0.2 mL of 1 M TBAF / THF solution was added to a mixture of N'-[4-(2,2-dimethylmorpholino-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), and the mixture was stirred at 60 °C for 2 h. After cooling the mixture to room temperature, 0.12 mL of 2 M hydrogen chloride / ethanol solution was added. The mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by silicone column chromatography (NH, ethyl acetate / hexane). The product was purified by HPLC (C18, mobile phase: water / CH3CN (10 mM ammonium bicarbonate system)). The fraction was concentrated under reduced pressure to obtain the title compound (34.1 mg).

[0511] 1 H 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).

[0512] The table below shows the compounds used in the examples. In the table, MS represents the actual measured value. The compounds in the table below were produced according to the methods described in the examples above or similar methods. Table 1 [Instance Number] [IUPAC] [name] [structure] [Salt] [MS] 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 431.2 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 454.2 3 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 445.2 4 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 468.3 5 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[3-(4-fluorophenoxy)-5-(trifluoromethyl)phenyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 461.2 6 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 451.2 7 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 471.2 8 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 450.2 9 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 468.3 10 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 468.2 11 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 454.2 12 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 468.3 13 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 468.2 14 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 450.3 15 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 470.2 16 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 464.3 17 3-[3-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 421.3 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 451.3 19 3-[3-(4,4-difluorohexahydropyridin-1-yl)-5-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 470.3 20 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 486.2 twenty 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 431.2 twenty two 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 457.2 twenty three 3-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-(trifluoromethyl)phenyl}-1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 464.3 twenty four 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 456.2 25 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 468.3 26 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 455.2 27 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 455.2 28 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 450.2 29 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 464.3 30 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 469.2 31 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 468.3 32 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 420.2 33 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 469.2 34 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 468.2 35 1-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 468.3 36 1-[5-(4,4-difluorohexahydropyridin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one 474.2 37 1-[5-(3,3-difluorohexahydropyridin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one 474.3 38 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 464.3 39 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 460.2 40 1-[5-(2,2-difluoromorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one 476.2 41 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 472.2 42 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 451.3 43 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[2-fluoro-5-(4-oxa-7-azaspiro[2.5]oct-7-yl)-3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one 466.2 44 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 426.3 45 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 465.3 46 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 476.3 47 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 494.3 48 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[3-(methoxymethoxy)-5-(trifluoromethyl)phenyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 411.2 49 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{3-[(oxecyclobut-2-yl)methoxy]-5-(trifluoromethyl)phenyl}-1,3-dihydro-2H-imidazol-2-one 437.3 50 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 457.2 51 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 457.2 52 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 453.3 53 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 482.3 54 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 490.1 55 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 498.3 56 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 439.3 57 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 484.2 58 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 498.3 59 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 483.2 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 465.3 61 1-{2-fluoro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 482.3 62 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 464.3 63 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 486.2 64 1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 483.3 65 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 481.1 66 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-[3-{[(2S)-oxacyclopentan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one 451.2 67 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 443.3 68 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 453.3 69 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 473.2 70 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 504.2 71 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 462.3 72 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 480.3 73 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 508.3 74 1-{3-vinyl-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one 412.4 75 1-{3-fluoro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 469.3 76 1-{3-(difluoromethyl)-5-[methyl(oxan-4-yl)amino]phenyl}-4,5-dimethyl-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 474.3 77 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 423.3 78 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 462.2 79 1-[3-(difluoromethyl)-5-(2,2-dimethylmorpholin-4-yl)-2-fluorophenyl]-4-methyl-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 478.2 80 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 414.3 81 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 428.3 82 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 484.1 83 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 499.2 84 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 485.1 85 1-{3-chloro-6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-4-methyl-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 499.2 86 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 465.2 87 1-{2-fluoro-3-methyl-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-4-methyl-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 428.3 88 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 494.2 89 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 460.1 90 2-{2-fluoro-5-[(2S)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 483.2 91 2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 483.3 92 2-{2-fluoro-5-[methyl(oxan-4-yl)amino]-3-(trifluoromethyl)phenyl}-5-methyl-4-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 497.2 93 2-[5-(2,2-dimethylmorpholin-4-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-4-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 497.2 94 2-[5-(3,3-difluoropyrrolidin-1-yl)-2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-4-{[1-(propyl-2-yl)-1H-pyrazole-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 489.2 95 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 483.2 96 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 483.2 97 2-[5-(4,4-difluorohexahydropyridin-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 489.2 98 1-{3-(difluoromethyl)-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-4-methyl-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 464.2 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 423.3 100 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-[3-{[(2S)-oxacyclopentan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one 465.2 101 4-Methyl-3-[3-{[(2S)-oxacyclopentan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 465.2 102 1-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 451.2 103 4-Methyl-3-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 465.2 104 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 422.3 105 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 481.2 106 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[(oxepyl-2-yl)methoxy]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one 452.2 107 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[2-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-3-(trifluoromethyl)phenyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 469.1 108 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[(oxepyl-2-yl)methoxy]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one 452.2 109 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-3-{6-[(oxepyl-2-yl)methoxy]-4-(trifluoromethyl)pyridin-2-yl}-1,3-dihydro-2H-imidazol-2-one 452.2 110 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 453.2 111 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 473.2 112 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 469.2 113 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-3-(2-hydroxypropyl-2-yl)-5-[methyl(oxan-4-yl)amino]phenyl}-1,3-dihydro-2H-imidazol-2-one 458.3 114 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-[6-{[(2R)-oxacyclopentan-2-yl]methoxy}-4-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-imidazol-2-one 466.2 115 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4,5-dimethyl-3-[6-{[(2S)-oxacyclopentan-2-yl]methoxy}-4-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-imidazol-2-one 466.3 116 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 455.2 117 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 469.2 118 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-[2-fluoro-5-{[(2S)-oxacyclopentan-2-yl]methoxy}-3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one 455.2 119 1-{2-fluoro-5-[(oxan-4-yl)oxy]-3-(trifluoromethyl)phenyl}-4-methyl-3-{[1-(prop-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 483.2 120 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 479.2 121 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 457.2 122 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-{2-fluoro-3-(2-fluoroprop-2-yl)-5-[methyl(oxan-4-yl)amino]phenyl}-1,3-dihydro-2H-imidazol-2-one 460.3 123 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 477.1 124 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 452.2 125 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 465.3 126 3-{4-cyclopropyl-6-[(2R)-2-methylmorpholin-4-yl]pyridin-2-yl}-4-methyl-1-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 437.3 127 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 523.2 128 4-Methyl-3-{6-[methyl(oxan-4-yl)amino]-4-(trifluoromethyl)pyridin-2-yl}-1-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 479.3 129 4-Methyl-1-{6-[(2R)-2-methylmorpholin-4-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 465.3 130 3-[4-cyclopropyl-6-(2,2-dimethylmorpholin-4-yl)pyridin-2-yl]-4-methyl-1-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 451.3 131 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 457.3 132 1-[6-(2,2-dimethylmorpholin-4-yl)-3-fluoro-4-(trifluoromethyl)pyridin-2-yl]-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 483.2 133 1-[3-fluoro-6-{[(1-fluorocyclobutyl)methyl]amino}-4-(trifluoromethyl)pyridin-2-yl]-3-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 471.2 134 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 466.3 135 3-[4-(2,2-dimethylmorpholin-4-yl)-6-(trifluoromethyl)pyrimidin-2-yl]-4-methyl-1-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 480.3 136 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 497.3 137 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 474.1 138 2-[5-(4,4-difluorohexahydropyridin-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 503.3 139 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 434.2 140 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 440.3 141 2-[6-(4,4-difluorohexahydropyridin-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 472.2 142 2-[6-(4,4-difluorohexahydropyridin-1-yl)-4-(trifluoromethyl)pyridin-2-yl]-5-methyl-4-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 486.2 143 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 530.2 144 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 457.2 145 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 457.2 146 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 478.1 147 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 436.3 148 4-Methyl-3-[6-{[(2S)-oxacyclopentan-2-yl]methoxy}-4-(trifluoromethyl)pyridin-2-yl]-1-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one 466.2 149 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 469.3 150 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 483.3 151 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 476.2 152 1-[3,5-bis(4,4-difluorohexahydropyridin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one 525.3 153 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 470.2 154 2-[6-(4,4-difluorohexahydropyridin-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 490.2 155 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 489.2 156 1-[3-(2,2-difluorocyclopropyl)-5-(4,4-difluorohexahydropyridin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one 482.3 157 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 465.3 158 1-[3-(2,2-difluorocyclopropyl)-5-(4,4-difluorohexahydropyridin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-dihydro-2H-imidazol-2-one 482.2 159 2-{2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]-3-(trifluoromethoxy)phenyl}-5-methyl-4-{[1-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one 499.2 160 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 440.3 161 2-[5-(4,4-difluorohexahydropyridin-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 485.2 162 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 437.3 163 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 397.3 164 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 454.3 165 1-[3-Cyclopropyl-5-(4,4-Difluorohexahydropyridin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 460.2 166 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 448.2 167 1-[3-chloro-5-(4,4-difluorohexahydropyridin-1-yl)-2-fluorophenyl]-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-methyl-1,3-dihydro-2H-imidazol-2-one 454.2 [Test Example] [1] Measurement of the inhibition rate of IP1 in 30 μM of the compound in Example 2 in CHO cells expressing GPR139

[0513] The changes in IP1 levels in CHO cells induced by GPR139 were measured to assess the activity of compounds via GPR139. GPR139 alters the intracellular calcium Gq-coupled receptor (Liu C et al., Mol Pharmacol. 2015 Nov; 88(5):911-25), therefore the amount of IP1, a stable metabolite of the second messenger IP3, varies with the activity of GPR139. Given that GPR139 exhibits structural activity during recombinant expression in mammalian cells, compounds with GPR139 receptor inverse agonist activity are expected to reduce IP1 production.

[0514] IP1 was measured using the IP-ONE HTFR assay kit (cis-bio) and CHO-TREx (Life Technologies) cells stably transfected with GPR139. CHO-TREx cells expressed human GPR139 using a tetracycline-inducible element. Cells were cultured in FBS containing F12K and 10% tetracycline-free medium and induced to express human GPR139 in growth medium at 37°C and 5% CO2 for 17 hours the day before analysis. On the day of testing, cells were washed with 10 mL PBS, dissected with TrypLE Express (Life Technologies), centrifuged at 1,000 rpm to form a pellet, and then a cell suspension was prepared using stimulation buffer (cis-bio, included in the IP-ONE HTFR assay kit).

[0515] The compound was diluted with stimulation buffer, and 4 μL was added to a 384-well white Greiner plate. Cell suspension was added to achieve a concentration of 2000 cells / well, and the plate was incubated at 37°C for 40 minutes. Equal volumes of IP1-d2 and Ab-Crp solutions (both purchased from cis-bio and included in the IP-ONE HTRF analysis kit) prepared with dissolution buffer (cis-bio) were mixed, and 4 μL was added to the plate and incubated at room temperature for 1 hour. The fluorescence intensity at two wavelengths was measured using the HTRF settings of the Envision (PerkinElmer) instrument, and the ratio was calculated as {(signal 665 nm) / (signal 615 nm)} × 10000. When the mediator was set to 0% and the IP1 concentration was set to 100%, the inhibition rate of IP1 in the 30 μM compound of Example 2 was 84%.

[0516] In CHO cells expressing GPR139, the compound of Example 2 inhibited the amount of IP1, a stable metabolite of IP3, a downstream second messenger of GPR139 signaling. That is, the compound of Example 2 exhibited a reverse agonist effect on the GPR139 receptor. [Test Example] [2] Measurement of the inhibition rate of IP1 levels in CHO cells expressing GPR139 (inverse agonist analysis)

[0517] The inhibition rate of IP1 was measured using the same method as in Test Example 1, and the inhibition rate of IP1 in Example Compound 2 in Test Example 1 was defined as 100%. The activities of the compounds in Examples 1 and 3 to 167 are expressed as relative values ​​in Table 2. [surface] [2] [Instance Number] [30 µM] [Inhibition rate below] 1 99% 2 100% 3 101% 4 102% 5 99% 6 102% 7 102% 8 101% 9 102% 10 100% 11 98% 12 98% 13 101% 14 99% 15 101% 16 100% 17 99% 18 101% 19 100% 20 99% twenty one 99% twenty two 100% twenty three 100% 24 100% 25 100% 26 100% 27 99% 28 99% 29 99% 30 99% 31 100% 32 98% 33 100% 34 100% 35 99% 36 101% 37 99% 38 99% 39 99% 40 101% 41 101% 42 99% 43 100% 44 100% 45 101% 46 100% 47 101% 48 101% 49 102% 50 102% 51 102% 52 99% 53 101% 54 101% 55 101% 56 98% 57 101% 58 98% 59 102% 60 101% 61 102% 62 99% 63 100% 64 98% 65 98% 66 99% 67 98% 68 98% 69 95% 70 100% 71 98% 72 99% 73 99% 74 98% 75 99% 76 97% 77 100% 78 99% 79 98% 80 99% 81 98% 82 100% 83 99% 84 99% 85 97% 86 101% 87 98% 88 99% 89 101% 90 99% 91 100% 92 99% 93 99% 94 99% 95 100% 96 101% 97 102% 98 99% 99 101% 100 99% 101 99% 102 105% 103 103% 104 104% 105 103% 106 102% 107 104% 108 102% 109 101% 110 101% 111 105% 112 100% 113 103% 114 103% 115 103% 116 101% 117 100% 118 100% 119 101% 120 102% 121 101% 122 103% 123 102% 124 103% 125 101% 126 100% 127 99% 128 101% 129 100% 130 100% 131 96% 132 99% 133 99% 134 98% 135 102% 136 100% 137 98% 138 100% 139 98% 140 98% 141 101% 142 100% 143 101% 144 101% 145 102% 146 103% 147 100% 148 101% 149 101% 150 101% 151 98% 152 98% 153 100% 154 98% 155 101% 156 98% 157 101% 158 98% 159 99% 160 98% 161 100% 162 101% 163 96% 164 97% 165 97% 166 98% 167 97%

[0518] As shown in Table 2, in CHO cells expressing GPR139, the compound disclosed herein inhibited the amount of IP1, a stable metabolite of IP3, the second messenger downstream of GPR139 signaling. That is, the compound disclosed herein has GPR139 receptor antagonist activity (inverse agonist activity). [Examples of blended ingredients] []

[0519] In some embodiments, pharmaceutical preparations containing the compounds disclosed herein as active ingredients may be manufactured using the following non-limiting examples of formulations. [surface] [3] (1) The compound obtained in Example 1 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg

[0520] The total amount of (1), (2) and (3) and 5 mg (4) were mixed and granulated. The remaining 5 mg (4) was then added, and the entire mixture was sealed in a gelatin capsule. [surface] [4] (1) The compound obtained in Example 1 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg

[0521] The total amount of (1), (2) and (3), 20 mg (4) and 2.5 mg (5) were mixed and granulated. The remaining 10 mg (4) and 2.5 mg (5) were added to the capsule and pressure molded to form tablets.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, (I), wherein: R1 is represented by the following groups: or; Cycle A1 is selected from a 6-membered aromatic ring further substituted with 1 to 3 independently selected substituents: (a) halogen atom; (b) C1-6 alkyl group substituted with 1 to 3 independently selected substituents: (i) halogen atom; and (ii) hydroxyl group; (c) C1-6 alkoxy group substituted with halogenation as appropriate; (d) C3-10 cycloalkyl group substituted with 1 to 3 halogen atoms as appropriate; (e) C2-6 alkenyl group; and (f) 3 to 14-membered non-aromatic heterocyclic group substituted with 1 to 3 halogen atoms as appropriate; Cycle A2 is selected from a 5-membered monocyclic aromatic heterocycle substituted with 1 to 3 C1-6 alkyl group substituted with halogenation as appropriate; Z-R2; R2 and R3 are each independently selected from hydrogen, halogen, and C1-6 alkyl group substituted with halogenation as appropriate; R4 and R5 are each independently selected from hydrogen and C1-6 alkyl; R6a is selected from: (1) substituted C3-10 cycloalkyl; (2) substituted C6-14 aryl; (3) substituted 3 to 14 non-aromatic heterocyclic groups; (4) substituted 5 to 14 aromatic heterocyclic groups; (5) substituted mono- or di-C1-6 alkylamino; (6) substituted N-C1-6 alkyl-N-3 to 14 non-aromatic heterocyclic amino; (7) substituted C1-6 alkoxy; (8) substituted C6-14 aryloxy; and (9) substituted 3 to 14 non-aromatic heterocyclic groups. R6b is selected from C1-6 alkyl groups substituted with 1 to 3 C3-10 cycloalkyl groups as appropriate; and ring B is selected from 5-membered monocyclic aromatic heterocycles substituted with 1 to 3 C1-6 alkyl groups as appropriate, wherein the 5-membered monocyclic aromatic heterocycle contains 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen, provided that the compound or its pharmaceutically acceptable 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 compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein R1 is represented by a group consisting of: , where: The cyclic A1 group is selected from: (1) a benzene ring further substituted with one to three independently selected substituents: (a) a halogen atom; (b) a C1-6 alkyl group substituted with one to three independently selected substituents: (i) a halogen atom; and (ii) a hydroxyl group; (c) a C1-6 alkoxy group substituted with one to three halogen atoms; (d) a C3-6 cycloalkyl group substituted with one to three halogen atoms; (e) a C2-6 alkenyl group; and (f) a hexahydropyridyl group substituted with one to three halogen atoms; (2) a pyridine ring further substituted with one to three independently selected substituents: (a) a halogen atom; (b) a C1-6 alkyl group substituted with one to three independently selected substituents: (a) a halogen atom; (b) a C1-6 alkyl group substituted with one to three independently selected substituents: (c) a C1-6 alkoxy group substituted with one to three independently selected substituents; and (d) a C3-6 cycloalkyl group; and (3) Further, as appropriate, a pyrimidine ring substituted with one or two, as appropriate, C1-6 alkyl groups; and R6a is selected from: (1) a C3-6 cycloalkyl group substituted with one to three halogen atoms, as appropriate; (2) a phenyl group substituted with one to three halogen atoms, as appropriate; (3) a morpholino group substituted with one to three, independently selected from: (a) a halogen atom; and (b) a, as appropriate, a C1-6 alkyl group substituted with halogen atoms; (4) a hexahydropyridyl group substituted with one to three halogen atoms, as appropriate; (5) a pyrrolidyl group substituted with one to three halogen atoms, as appropriate; (6) 4-oxa-7-azaspiro[2.5]octyl; (7) an imidazolyl group substituted with one to three, as appropriate; (8) (9) N-C1-6 alkyl-N-tetrahydropyranylamino group, substituted with 1 to 3 halogen atoms as appropriate; (10) C1-6 alkoxy group, substituted with 1 to 3 substituents independently selected from: (a) C1-6 alkoxy group; (b) C3-6 cycloalkyl group, substituted with 1 to 3 halogen atoms as appropriate; (c) oxacyclobutyl group; and (d) tetrahydrofuranyl group; (11) phenoxy group, substituted with 1 to 3 halogen atoms as appropriate; and (12) tetrahydropyranyloxy group.

3. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein the following groups are represented: [group name missing], where: R6a is selected from: (1) substituted C3-10 cycloalkyl groups, as appropriate; (2) substituted C6-14 aryl groups, as appropriate; (3) substituted 3 to 14-membered non-aromatic heterocyclic groups, as appropriate; (4) substituted 5 to 14-membered aromatic heterocyclic groups, as appropriate; (5) substituted mono- or di-C1-6 alkylamino groups, as appropriate; (6) substituted N-C1-6 alkyl-N-3 to 14-membered non-aromatic heterocyclic amino groups, as appropriate; (7) substituted C1-6 alkoxy groups, as appropriate; (8) substituted C6-14 aryloxy groups, as appropriate; and (9) substituted 3 to 14-membered non-aromatic heterocyclic oxygen groups, as appropriate; R7a is selected from: (a) hydrogen atoms; (b) halogen atoms; (c) The C1-6 alkyl group, substituted as appropriate with one to three independently selected substituents: (i) a halogen atom; and (ii) a hydroxyl group; (d) a C1-6 alkoxy group, halogenated as appropriate; (e) a C3-10 cycloalkyl group, substituted as appropriate with one to three halogen atoms; (f) a C2-6 alkenyl group; and (g) a 3 to 14 non-aromatic heterocyclic group, substituted as appropriate with one to three halogen atoms; and R8a is selected from: (a) a hydrogen atom; (b) a halogen atom; and (c) a C1-6 alkyl group.

4. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein the following groups are represented: [group name missing], where: R6a is selected from: (1) a substituted C3-10 cycloalkyl group, as appropriate; (2) a substituted C6-14 aryl group, as appropriate; (3) a substituted 3 to 14 non-aromatic heterocyclic group, as appropriate; (4) a substituted 5 to 14 aromatic heterocyclic group, as appropriate; (5) a substituted mono- or di-C1-6 alkylamino group, as appropriate; (6) a substituted N-C1-6 alkyl-N-3 to 14 non-aromatic heterocyclic amino group, as appropriate; (7) a substituted C1-6 alkoxy group, as appropriate; (8) a substituted C6-14 aryloxy group, as appropriate; and (9) a substituted 3 to 14 non-aromatic heterocyclic oxygen group, as appropriate; R7a1 is selected from: (a) a halogen atom; (b) a C1-6 alkyl group, as appropriate, substituted with 1 to 3 substituents independently selected from a halogen atom and a hydroxyl group; (c) a C1-6 alkoxy group halogenated as appropriate; (d) a C3-6 cycloalkyl group substituted with 1 to 3 halogen atoms as appropriate; (e) a C2-6 alkenyl group; and (f) a hexahydropyridyl group substituted with 1 to 3 halogen atoms as appropriate; R7a2 is selected from: (a) a hydrogen atom; (b) a C1-6 alkyl group halogenated as appropriate; (c) a C1-6 alkoxy group halogenated as appropriate; and (d) a C3-6 cycloalkyl group; R7a3 is selected from a C1-6 alkyl group halogenated as appropriate; R8a1 is selected from: (a) a hydrogen atom; (b) a halogen atom; and (c) a C1-6 alkyl group; and R8a2 is selected from: (a) a hydrogen atom; (b) a halogen atom; and (c) a C1-6 alkyl group.

5. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein the following groups are represented: [group name missing], where: R6a is selected from: (1) substituted C3-10 cycloalkyl; (2) substituted C6-14 aryl; (3) substituted 3 to 14 non-aromatic heterocyclic groups; (4) substituted 5 to 14 aromatic heterocyclic groups; (5) substituted mono- or di-C1-6 alkylamino; (6) substituted N-C1-6 alkyl-N-3 to 14 non-aromatic heterocyclic amino; (7) substituted C1-6 alkoxy; (8) substituted C6-14 aryloxy; and (9) substituted 3 to 14 non-aromatic heterocyclic groups; R7a2 is selected from halogenated C1-6 alkyl; and R8a2 is selected from hydrogen atoms and halogen atoms.

6. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein the following groups are represented: [group name missing], where: R6a is selected from: (1) substituted C3-10 cycloalkyl; (2) substituted C6-14 aryl; (3) substituted 3 to 14 non-aromatic heterocyclic groups; (4) substituted 5 to 14 aromatic heterocyclic groups; (5) substituted mono- or di-C1-6 alkylamino; (6) substituted N-C1-6 alkyl-N-3 to 14 non-aromatic heterocyclic amino; (7) substituted C1-6 alkoxy; (8) substituted C6-14 aryloxy; and (9) substituted 3 to 14 non-aromatic heterocyclic groups; R7a2 is selected from halogenated C1-6 alkyl; and R8a2 is a hydrogen atom.

7. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein R1 is represented by a group consisting of: , where: The ring A1 is selected from a pyridine ring further substituted by one or two independent substituents selected from: (a) a halogen atom; and (b) a halogenated C1-6 alkyl group; and R6a is selected from a morpholino group substituted by one to three C1-6 alkyl groups, as appropriate.

8. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein R1 is represented by a group consisting of: , where: The ring A1 is selected from a pyridine ring further substituted with a halogenated C1-6 alkyl group; and the R6a is selected from a morpholino group substituted with a C1-6 alkyl group.

9. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein R1 is a group represented by: , where: Cyclone A2 is selected from pyrazole rings that are further substituted with 1 to 3 halogenated C1-6 alkyl groups as appropriate; and R6b is selected from C1-6 alkyl groups that are substituted with 1 to 3 C3-6 cycloalkyl groups as appropriate.

10. A compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein the following groups are represented by: [group name missing], where: R6b is selected from C1-6 alkyl groups that are substituted with 1 to 3 C3-10 cycloalkyl groups as appropriate; and R7b is selected from C1-6 alkyl groups that are halogenated as appropriate.

11. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, wherein ring B is selected from a pyrazole ring further substituted with one to three C1-6 alkyl groups, as appropriate.

12. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, wherein ring B is selected from a pyrazole ring further substituted with a C1-6 alkyl group.

13. A compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate, as claimed in any of claims 1 to 10, wherein the cyclic B group is: , where: R1c is selected from hydrogen atoms and C1-6 alkyl groups; and R2c and R3c are each independently selected from hydrogen atoms and C1-6 alkyl groups.

14. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, wherein the ring B group is: , wherein the R1c group is selected from C1-6 alkyl groups.

15. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein: Z-series C-R2; and R2 series is selected from hydrogen atoms and C1-3 alkyl groups.

16. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein: Z-series C-R2; and R2 series selected from C1-3 alkyl groups.

17. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, wherein R3 is selected from hydrogen atoms and C1-3 alkyl groups.

18. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, wherein R3 is selected from C1-3 alkyl groups.

19. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein: R4 is selected from hydrogen atoms and C1-6 alkyl groups; and R5 is selected from hydrogen atoms.

20. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, wherein R4 and R5 are both hydrogen atoms.

21. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein the compound is selected from: 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(oxalan-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-difluorohexahydropyridin-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]-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; 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-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-one; 1-[5-(4,4-difluorohexahydropyridin-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-difluorohexahydropyridin-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(oxalan-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)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]oct-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-[(oxecyclobut-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(oxalan-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-(prop-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-(propyl-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)-oxacyclopentan-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-vinyl-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-(propyl-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-(propyl-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-(propyl-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-(propyl-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-(prop-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; 1-{3-(difluoromethyl)-2-fluoro-5-[(2R)-2-methylmorpholin-4-yl]phenyl}-4-methyl-3-{[1-(propyl-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)-oxacyclopentan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one; 4-methyl-3-[3-{[(2S)-oxacyclopentan-2-yl]methoxy}-5-(trifluoromethyl)phenyl]-1-{[1-(propyl-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-(propyl-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-(propyl-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-[(oxacyclopent-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)-oxacyclopentan-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-hydroxypropyl-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)-oxacyclopentan-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)-oxacyclopentan-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)-oxacyclopentan-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-(prop-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-fluoroprop-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-(propyl-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-(propyl-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-(propyl-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-(propyl-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-(propyl-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-(propyl-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-(propyl-2-yl)-1H-pyrazol-4-yl]methyl}-1,3-dihydro-2H-imidazol-2-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; 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; 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)-oxacyclopentan-2-yl]methoxy}-4-(trifluoromethyl)pyridin-2-yl]-1-{[1-(propyl-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; 1-[3,5-bis(4,4-difluorohexahydropyridin-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; 1-[3-(2,2-difluorocyclopropyl)-5-(4,4-difluorohexahydropyridin-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; 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; 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-Difluorohexahydropyridin-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-difluorohexahydropyridin-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.

22. A pharmaceutical composition comprising: at least one compound as claimed in any one of claims 1 to 21, or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof; and at least one pharmaceutically acceptable carrier.

23. Use of any compound of claims 1 to 21 or a pharmaceutically acceptable salt, stereoisomer, tautomer or hydrate thereof, or a pharmaceutical composition of claim 22, for the preparation of a pharmaceutical product for the treatment or prevention of GPR139-mediated diseases in mammals of need.

24. As requested in claim 23, wherein the disease is selected from depression, Alzheimer's disease, schizophrenia, drug addiction, sleep disorder, pain, and attention deficit hyperactivity disorder.

25. As claimed in claim 23 or 24, wherein the treatment further comprises administering at least one combination drug to the mammal.