Heterocyclic compound and use thereof

Abstract

To provide a compound of formula (I) or a salt thereof that may have an antagonistic action against an NMDA receptor that includes an NR2B subunit and may be useful as a prophylactic or therapeutic agent for depression, bipolar disorder, migraine, pain, or symptoms peripheral to dementia.SOLUTION: The salt of the compound of formula (I) is a pharmacologically acceptable salt. Non-limiting examples of such salts include, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to Japanese Patent Application No. 2019-206311, filed November 14, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to heterocyclic compounds that may have an antagonistic effect on N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit and may be useful as agents for the prevention or treatment of depression, bipolar disorder, migraine, pain, dementia-related symptoms, and the like. [Background technology]

[0003] Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS), including the brain and spinal cord. Its signaling is mediated by ionotropic receptors, including N-methyl-D-aspartate (NMDA) receptors, gamma-amino-3-hydroxy-5-methyloxazole-4-propionic acid (AMPA) / kainate (KA) receptors, and metabotropic glutamate receptors. NMDA receptors are highly permeable to certain cations, including calcium ions, and mediate excitatory neurotransmission by depolarizing neurons. Furthermore, calcium influx through NMDA receptors acts as a second messenger, inducing plastic neuronal function through changes in intracellular phosphorylation signaling and the regulation of gene transcription and translation. Thus, NMDA receptors play an important role in regulating CNS function.

[0004] NMDA receptors are tetramers composed of two or three of the following subunits: NR1, NR2A, NR2B, NR2C, NR2D, NR3A, and NR3B. The presence of the NR1 subunit is believed to be essential for the receptor's excitatory neurotransmission function. Because the NR1 subunit is a functional NMDA receptor, it is widely distributed throughout the central nervous system. However, the distribution and timing of expression of the NR2 subunit differs for each subunit. For example, NR2A and NR2C subunits are first detected shortly before birth, whereas NR2B and NR2D subunits are observed from early fetal development. Furthermore, while the NR2A subunit is widely distributed throughout the brain, the NR2B subunit is expressed in the forebrain and the NR2C subunit is restricted to the cerebellum.

[0005] The NMDA receptor containing the NR2B subunit, which is the target of the present disclosure, is highly expressed in the cerebral cortex (particularly layers 2 and 3), hippocampus, amygdala, ventral nucleus of the thalamus, and olfactory bulb in the brain of adult rodents. In the spinal cord, it is also localized to the dorsal horn of the spinal cord, particularly layer 2. Furthermore, in single cells, NMDA receptors containing the NR2B subunit are most highly expressed in the postsynaptic density, with expression also observed in extrasynaptic regions. This suggests that NMDA receptors containing the NR2B subunit have widespread functions in the brain and may be effective in the prevention or treatment of central nervous system disorders. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides heterocyclic compounds and pharmaceutical compositions containing the same that may have an antagonistic effect on NMDA receptors containing the NR2B subunit and may be useful as preventive or therapeutic agents for depression, bipolar disorder, migraine, pain, or dementia-related symptoms, etc.

[0007] In this specification, [1] Formula (I): [ka] or a salt thereof (herein, may be abbreviated as "compound (I)"), wherein R 1 is a C optionally substituted with halogen and at least one fluorine; 1-3 alkyl groups; R 2 is a C optionally substituted with at least one fluorine 1-3 alkyl groups; R 3 is selected from hydrogen and a hydroxy group; Ring A is selected from an optionally substituted benzene group; Ring B has the formula: [ka] is selected from the group X and Y are each independently selected from carbon and nitrogen; Ring B 1 is selected from an optionally substituted benzene group, an optionally substituted pyridine group, and an optionally substituted pyrazine group; Ring B 2 is selected from an optionally substituted pyrimidine group; and Ring B 3 is selected from an optionally substituted pyrimidine group; and Z is selected from CH2, CF2, O, and NH.

[0008] Also in this specification, [2] R 1 is C optionally substituted with halogen and 1 to 3 fluorines 1-3 alkyl groups; R 2 is a C optionally substituted with 1 to 3 fluorines 1-3 alkyl groups; R 3is selected from hydrogen and a hydroxyl group; Ring A is selected from a benzene group optionally substituted with 1 to 4 halogens; Ring B has the formula: [ka] is selected from the group X and Y are each independently selected from carbon and nitrogen; Ring B 1 is selected from an unsubstituted benzene group, an unsubstituted pyridine group, and an unsubstituted pyrazine group; Ring B 2 is an unsubstituted pyrimidine group; and Ring B 3 is an unsubstituted pyrimidine group; and Z is selected from CH2, CF2, O, and NH; The compound or salt thereof according to [1] is disclosed.

[0009] Also in this specification, [3] R 1 is a C optionally substituted with halogen and one or two fluorines 1-3 alkyl groups; R 2 is the unsubstituted C 1-3 alkyl groups; R 3 is selected from hydrogen and a hydroxyl group; Ring A is selected from a benzene group optionally substituted with one or two halogens; Ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen; Ring B 1 is selected from unsubstituted pyridine groups; and Ring B 2is an unsubstituted pyrimidine group; and Z is CH2 or O; The compound or salt thereof according to [1] is disclosed.

[0010] Also in this specification, [4] R 1 is a C optionally substituted with halogen and one or two fluorines 1-3 alkyl groups; R 2 is the unsubstituted C 1-3 alkyl groups; R 3 is selected from hydrogen and a hydroxyl group; Ring A is a group represented by the formula: [ka] is selected from the group R v is selected from halogens; and R w is selected from hydrogen and halogen; Ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen; Ring B 1 is selected from unsubstituted pyridine groups; and Ring B 2 is an unsubstituted pyrimidine group; and Z is CH2 or O; The compound or salt thereof according to [1] is disclosed.

[0011] Also in this specification, [5] Disclosed is a compound which is (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidin-2-one and salts thereof.

[0012] [6] Disclosed is a compound which is (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidin-2-one and salts thereof.

[0013] Also in this specification, [7] Disclosed is a compound which is (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one and salts thereof.

[0014] Also in this specification, [8] A pharmaceutical composition containing at least one entity selected from the compounds according to [1] and salts thereof is disclosed.

[0015] Also herein, [9] [8] The pharmaceutical composition according to [8] is disclosed, wherein the at least one entity is an antagonist of an NMDA receptor containing the NR2B subunit.

[0016] Also herein,

[10] The pharmaceutical composition according to [8] is disclosed, wherein the at least one entity is an agent for preventing or treating depression, bipolar disorder, migraine, pain, or dementia-related symptoms.

[0017] Also herein,

[11] The compound or salt thereof according to [1] is disclosed for use in the prevention or treatment of depression, bipolar disorder, migraine, pain, or dementia-related symptoms.

[0018] Also herein,

[12] Disclosed is a method for antagonizing an NMDA receptor containing the NR2B subunit in a mammal, comprising administering to the mammal an effective dose of at least one entity selected from the compounds described in [1] and salts thereof.

[0019] Also herein,

[13] Disclosed is a method for preventing or treating depression, bipolar disorder, migraine, pain, or cognitive-behavioral symptoms in a mammal, the method comprising administering to the mammal an effective dose of at least one entity selected from the compounds described in [1] and salts thereof.

[0020] Also herein,

[14] The present invention discloses use of at least one compound selected from the compounds according to [1] and salts thereof in the manufacture of an agent for the prophylaxis or treatment of depression, bipolar disorder, migraine, pain, or dementia-related symptoms. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure provides heterocyclic compounds and pharmaceutical compositions containing the same that may have an antagonistic effect on NMDA receptors containing the NR2B subunit and may be useful as preventive or therapeutic agents for depression, bipolar disorder, migraine, pain, or dementia-related symptoms, etc.

[0022] The definition of each substituent used in the present specification will be described in detail below. Unless otherwise specified, each substituent has the following definition.

[0023] Non-limiting examples of "halogen" include fluorine, chlorine, bromine, and iodine.

[0024] In this specification, "C 1-6 Non-limiting examples of "alkyl groups" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl groups.

[0025] As used herein, "C optionally substituted with at least one halogen" refers to1-6 The alkyl group may be a C alkyl group which may be substituted with 1 to 7, for example 1 to 5, halogen atoms. 1-6 Non-limiting examples include alkyl groups, such as methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl.

[0026] In this specification, "C 2-6 Non-limiting examples of "alkenyl groups" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl groups.

[0027] In this specification, "C 2-6 Non-limiting examples of "alkynyl groups" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.

[0028] In this specification, "C 3-10Non-limiting examples of "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl groups.

[0029] As used herein, "optionally halogenated C 3-10 cycloalkyl group" (i.e., "C optionally substituted with at least one halogen) 3-10 The cycloalkyl group includes a C substituted with 1 to 7, for example 1 to 5, halogen atoms. 3-10 Non-limiting examples of cycloalkyl groups include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0030] In this specification, "C 3-10 Non-limiting examples of "cycloalkenyl groups" include cyclopropenyl groups, cyclobutenyl groups, cyclopentenyl groups, cyclohexenyl groups, cycloheptenyl groups, and cyclooctenyl groups.

[0031] In this specification, "C 6-14 Non-limiting examples of "aryl groups" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl groups.

[0032] In this specification, "C 7-16 Non-limiting examples of "aralkyl groups" include benzyl groups, phenethyl groups, naphthylmethyl groups, and phenylpropyl groups.

[0033] In this specification, "C 1-6Non-limiting examples of "alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0034] As used herein, "optionally halogenated C 1-6 an alkoxy group" (i.e., "C optionally substituted with at least one halogen) 1-6 The alkoxy group includes a C alkoxy group which may be substituted with 1 to 7, for example 1 to 5, halogen atoms. 1-6 Non-limiting examples of alkoxy groups include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy groups.

[0035] In this specification, "C 3-10 Non-limiting examples of "cycloalkyloxy groups" include cyclopropyloxy groups, cyclobutyloxy groups, cyclopentyloxy groups, cyclohexyloxy groups, cycloheptyloxy groups, and cyclooctyloxy groups.

[0036] In this specification, "C 1-6 Non-limiting examples of "alkylthio groups" include methylthio groups, ethylthio groups, propylthio groups, isopropylthio groups, butylthio groups, sec-butylthio groups, tert-butylthio groups, pentylthio groups, and hexylthio groups.

[0037] As used herein, "optionally halogenated C 1-6 alkylthio group" (i.e., "C optionally substituted with at least one halogen) 1-6 The alkylthio group is a C alkylthio group which may be substituted with 1 to 7, for example 1 to 5, halogen atoms. 1-6Non-limiting examples of alkylthio groups include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio groups.

[0038] In this specification, "C 1-6 Non-limiting examples of "alkyl-carbonyl groups" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl groups.

[0039] As used herein, "halogenated C 1-6 alkyl-carbonyl group" (i.e., "C optionally substituted with at least one halogen) 1-6 The alkyl-carbonyl group is a C alkyl group which may be substituted with 1 to 7, for example 1 to 5, halogen atoms. 1-6 Non-limiting examples include alkyl-carbonyl groups, such as acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl groups.

[0040] In this specification, "C 1-6 Non-limiting examples of "alkoxy-carbonyl groups" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups.

[0041] In this specification, "C 6-14 Non-limiting examples of "aryl-carbonyl groups" include benzoyl, 1-naphthoyl, and 2-naphthoyl groups.

[0042] In this specification, "C 7-16 Non-limiting examples of "aralkyl-carbonyl groups" include phenylacetyl and phenylpropionyl groups.

[0043] As used herein, non-limiting examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include a nicotinoyl group, an isonicotinoyl group, a thenoyl group, and a furoyl group.

[0044] As used herein, non-limiting examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include a morpholinylcarbonyl group, a piperidinylcarbonyl group, and a pyrrolidinylcarbonyl group.

[0045] As used herein, "mono- or di-C 1-6 Non-limiting examples of "alkyl-carbamoyl groups" include methylcarbamoyl groups, ethylcarbamoyl groups, dimethylcarbamoyl groups, diethylcarbamoyl groups, and N-ethyl-N-methylcarbamoyl groups.

[0046] As used herein, "mono- or di-C 7-16 Non-limiting examples of "aralkyl-carbamoyl groups" include benzylcarbamoyl and phenethylcarbamoyl groups.

[0047] In this specification, "C 1-6 Non-limiting examples of "alkylsulfonyl groups" include methylsulfonyl groups, ethylsulfonyl groups, propylsulfonyl groups, isopropylsulfonyl groups, butylsulfonyl groups, sec-butylsulfonyl groups, and tert-butylsulfonyl groups.

[0048] As used herein, "halogenated C 1-6 alkylsulfonyl group" (i.e., "C optionally substituted with at least one halogen) 1-6 Non-limiting examples of alkylsulfonyl groups include C alkylsulfonyl groups which may be substituted with 1 to 7, for example 1 to 5, halogens. 1-6Non-limiting examples include alkylsulfonyl groups, such as methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl groups.

[0049] In this specification, "C 6-14 Non-limiting examples of "arylsulfonyl groups" include phenylsulfonyl groups, 1-naphthylsulfonyl groups, and 2-naphthylsulfonyl groups.

[0050] As used herein, non-limiting examples of "substituents" include halogen, cyano group, nitro group, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, acyl group, optionally substituted amino group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted sulfamoyl group, optionally substituted hydroxy group, optionally substituted sulfanyl (SH) group, and optionally substituted silyl group.

[0051] As used herein, non-limiting examples of the "hydrocarbon group" (for example, the "hydrocarbon group" in the "hydrocarbon group which may be substituted" or "optionally substituted hydrogen carbon group") include C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl groups, and C 7-16 Examples include aralkyl groups.

[0052] As used herein, non-limiting examples of "hydrocarbon groups which may be substituted" (i.e., "optionally substituted hydrocarbon groups") include hydrocarbon groups which may be substituted with at least one substituent selected from the following Substituent Group A. [Substituent group A] (1) halogen; (2) nitro group; (3) cyano group; (4) oxo group; (5) hydroxy group; (6) C optionally substituted with at least one halogen 1-6 alkoxy groups; (7) C 6-14 Aryloxy groups (e.g., phenoxy or naphthoxy groups); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy groups, etc.); (9) 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy groups, etc.); (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy and piperidinyloxy groups); (11)C 1-6 alkyl-carbonyloxy groups (such as acetoxy or propanoyloxy groups); (12)C 6-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, or 2-naphthoyloxy groups); (13)C 1-6 alkoxy-carbonyloxy groups (for example, methoxycarbonyloxy groups, ethoxycarbonyloxy groups, propoxycarbonyloxy groups, or butoxycarbonyloxy groups); (14) Mono- or di-C 1-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy groups, ethylcarbamoyloxy groups, dimethylcarbamoyloxy groups, diethylcarbamoyloxy groups, etc.); (15)C 6-14 aryl-carbamoyloxy groups (for example, phenylcarbamoyloxy groups or naphthylcarbamoyloxy groups); (16) 5- to 14-membered aromatic heterocyclic carbonyloxy groups (e.g., nicotinoyloxy groups, etc.); (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy groups, piperidinylcarbonyloxy groups, etc.); (18) C optionally substituted with at least one halogen 1-6 alkylsulfonyloxy groups (for example, methylsulfonyloxy groups or trifluoromethylsulfonyloxy groups); (19)C 1-6 C optionally substituted with alkyl groups 6-14 arylsulfonyloxy groups (for example, phenylsulfonyloxy groups or toluenesulfonyloxy groups); (20) C optionally substituted with at least one halogen 1-6 (21) an alkylthio group; (22) a 5- to 14-membered aromatic heterocyclic group; (22) 3- to 14-membered non-aromatic heterocyclic groups; (23) formyl group; (24) Carboxy group; (25) C optionally substituted with at least one halogen 1-6 Alkyl-carbonyl group; (26)C 6-14 aryl-carbonyl group; (27) 5- to 14-membered aromatic heterocyclic carbonyl group; (28) 3- to 14-membered non-aromatic heterocyclic carbonyl group; (29)C 1-6 Alkoxy-carbonyl groups; (30)C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, or 2-naphthyloxycarbonyl groups); (31) C 7-16 aralkyloxy-carbonyl groups (such as benzyloxycarbonyl or phenethyloxycarbonyl groups); (32) Carbamoyl group; (33) Thiocarbamoyl group; (34) Mono- or di-C 1-6 Alkyl-carbamoyl group; (35)C 6-14aryl-carbamoyl groups (for example, phenylcarbamoyl groups, etc.); (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl groups, thienylcarbamoyl groups, etc.); (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl groups, piperidinylcarbamoyl groups, etc.); (38) C optionally substituted with at least one halogen 1-6 Alkylsulfonyl groups; (39)C 6-14 arylsulfonyl groups; (40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl groups or thienylsulfonyl groups); (41) C optionally substituted with at least one halogen 1-6 alkylsulfinyl group; (42)C 6-14 arylsulfinyl groups (for example, phenylsulfinyl groups, 1-naphthylsulfinyl groups, or 2-naphthylsulfinyl groups); (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., a pyridylsulfinyl group, a thienylsulfinyl group, etc.); (44) Amino group; (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, or N-ethyl-N-methylamino groups); (46) Mono- or di-C 6-14 arylamino groups (e.g., phenylamino groups, etc.); (47) 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino groups, etc.); (48)C 7-16 aralkylamino groups (e.g., benzylamino groups, etc.); (49) Formylamino group; (50)C 1-6alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, or butanoylamino groups); (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino groups, etc.); (52)C 6-14 aryl-carbonylamino groups (for example, phenylcarbonylamino groups or naphthylcarbonylamino groups); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino groups, ethoxycarbonylamino groups, propoxycarbonylamino groups, butoxycarbonylamino groups, or tert-butoxycarbonylamino groups); (54)C 7-16 aralkyloxy-carbonylamino groups (e.g., benzyloxycarbonylamino groups, etc.); (55)C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino groups or ethylsulfonylamino groups); (56)C 1-6 C optionally substituted with alkyl group 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino groups and toluenesulfonylamino groups); (57) C optionally substituted with at least one halogen 1-6 alkyl groups; (58)C 2-6 alkenyl groups; (59)C 2-6 Alkynyl groups; (60)C 3-10 cycloalkyl groups; (61)C 3-10 cycloalkenyl groups; and (62)C 6-14 Aryl groups.

[0053] Non-limiting examples of the number of substituents in an "optionally substituted hydrocarbon group" (i.e., an "optionally substituted hydrocarbon group") are 1 to 5, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

[0054] As used herein, non-limiting examples of "heterocyclic groups" (including "heterocyclic groups" in "optionally substituted heterocyclic groups" or "optionally substituted heterocyclic groups") include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered bridged heterocyclic groups, each of which contains at least one carbon and 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen as ring-constituting atoms.

[0055] As used herein, non-limiting examples of "aromatic heterocyclic groups" (for example, "5- to 14-membered aromatic heterocyclic groups") include 5- to 14-membered (for example, 5- to 10-membered) aromatic heterocyclic groups containing at least one carbon and 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen as ring-constituting atoms.

[0056] Non-limiting examples of "aromatic heterocyclic groups" include a thienyl group, a furyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a 1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a 1,2,4-thiadiazolyl group, a 1,3,4-thiadiazolyl group, a triaryl group, a thiazolyl ... 5- or 6-membered monocyclic aromatic heterocyclic groups such as azolyl, tetrazolyl, and triazinyl groups; and benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopy ... benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, pyraz Lysinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazopyrazinyl group, imidazopyrimidinyl group, thienopyrimidinyl group, furopyrimidinyl group, pyrrolopyrimidinyl group, pyrazolopyrimidinyl group, oxazolopyrimidinyl group, thiazolopyrimidinyl group, pyrazolotriazinyl group, naphtho[2,3-b]thienyl group, phenoxathiinyl group, indolyl group, isoindolyl group, 1H-indolyl group, Examples thereof include 8- to 14-membered fused polycyclic (e.g., bicyclic or tricyclic) aromatic heterocyclic groups such as a dazolyl group, a purinyl group, an isoquinolyl group, a quinolyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, a β-carbolinyl group, a phenanthridinyl group, an acridinyl group, a phenazinyl group, a phenothiazinyl group, and a phenoxazinyl group.

[0057] As used herein, non-limiting examples of "non-aromatic heterocyclic groups" (including, for example, 3- to 14-membered non-aromatic heterocyclic groups) include 3- to 14-membered (e.g., 4- to 10-membered) non-aromatic heterocyclic groups containing at least one carbon and 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen as ring-constituting atoms.

[0058] Non-limiting examples of "non-aromatic heterocyclic groups" include aziridinyl groups, oxiranyl groups, thiiranyl groups, azetidinyl groups, oxetanyl groups, thietanyl groups, tetrahydrothienyl groups, tetrahydrofuranyl groups, pyrrolinyl groups, pyrrolidinyl groups, imidazolinyl groups, imidazolidinyl groups, oxazolinyl groups, oxazolidinyl groups, pyrazolinyl groups, pyrazolidinyl groups, thiazolinyl groups, thiazolidinyl groups, tetrahydroisothiazolyl groups, tetrahydrooxazolyl groups, tetrahydroisooxazolyl groups, and tetrahydroisooxazolyl groups. 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as azazolyl group, piperidinyl group, piperazinyl group, tetrahydropyridinyl group, dihydropyridinyl group, dihydrothiopyranyl group, tetrahydropyrimidinyl group, tetrahydropyridazinyl group, dihydropyranyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group, azepanyl group, diazepanyl group, azepinyl group, oxepanyl group, azocanyl group, and diazocanyl group; and dihydrobenzoyl groups. Zofuranyl group, dihydrobenzimidazolyl group, dihydrobenzoxazolyl group, dihydrobenzothiazolyl group, dihydrobenzisothiazolyl group, dihydronaphtho[2,3-b]thienyl group, tetrahydroisoquinolyl group, tetrahydroquinolyl group, 4H-quinolidinyl group, indolinyl group, isoindolinyl group, tetrahydrothieno[2,3-c]pyridinyl group, tetrahydrobenzazepinyl group, tetrahydroquinoxalinyl group, tetrahydrophenanthridinyl group, hexahydro and 9- to 14-membered fused polycyclic (e.g., bicyclic or tricyclic) non-aromatic heterocyclic groups such as iphenothiazinyl group, hexahydrophenoxazinyl group, tetrahydrophthalazinyl group, tetrahydronaphthyridinyl group, tetrahydroquinazolinyl group, tetrahydrocinnolinyl group, tetrahydrocarbazolyl group, tetrahydro-β-carbolinyl group, tetrahydroacridinyl group, tetrahydrophenazinyl group, tetrahydrothioxanthenyl group, and octahydroisoquinolyl group.

[0059] As used herein, non-limiting examples of the "7- to 10-membered heterobridged ring group" include a quinuclidinyl group and a 7-azabicyclo[2.2.1]heptanyl group.

[0060] In the present specification, non-limiting examples of the "nitrogen-containing heterocyclic group" include heterocyclic groups containing at least one nitrogen atom as a ring-constituting atom.

[0061] As used herein, examples of the "heterocyclic group which may be substituted" (i.e., "optionally substituted heterocyclic group") include, but are not limited to, heterocyclic groups which may be substituted with one or more substituents selected from the above-mentioned Substituent Group A.

[0062] Non-limiting examples of the number of substituents in an "optionally substituted heterocyclic group" (i.e., an "optionally substituted heterocyclic group") are 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

[0063] As used herein, non-limiting examples of "acyl groups" include formyl groups, carboxy groups, carbamoyl groups, thiocarbamoyl groups, sulfino groups, sulfo groups, sulfamoyl groups, and phosphono groups, each of which is defined as "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 one or two substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group, each of which may be halogenated, 1-6 It can be substituted with "one that can be substituted with 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group."

[0064] Further, non-limiting examples of "acyl groups" include hydrocarbon-sulfonyl groups, heterocyclic-sulfonyl groups, hydrocarbon-sulfinyl groups, and heterocyclic-sulfinyl groups.

[0065] As used herein, a hydrocarbon-sulfonyl group refers to a sulfonyl group having a hydrocarbon group attached thereto, a heterocyclic-sulfonyl group refers to a sulfonyl group having a heterocyclic group attached thereto, a hydrocarbon-sulfinyl group refers to a sulfonyl group having a hydrocarbon group attached thereto, and a heterocyclic-sulfinyl group refers to a sulfonyl group having a heterocyclic group attached thereto.

[0066] Non-limiting examples of "acyl groups" include formyl groups, carboxy groups, C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl group), C 3-10 Cycloalkyl-carbonyl groups (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, or cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl group), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl group or naphthyloxycarbonyl group), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl group or phenethyloxycarbonyl group), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl group), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl group), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl group), mono- or di-C 7-16Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl group, etc.), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl group or N-ethyl-N-methylthiocarbamoyl group), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl group), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl group or cyclohexylthiocarbamoyl group), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl group), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl group or phenethylthiocarbamoyl group), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl group), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl group or ethyl sulfinyl group), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, and mono- or di-C 1-6 Examples include alkylphosphono groups (for example, a dimethylphosphono group, a diethylphosphono group, a diisopropylphosphono group, or a dibutylphosphono group).

[0067] As used herein, examples of "amino groups that may be substituted" (i.e., "optionally substituted amino groups") include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group, and C 6-14 arylsulfonyl groups, each of which may be substituted with 1 to 3 substituents selected from Substituent Group A, but are not limited to these.

[0068] Non-limiting examples of "amino groups that may be substituted" (i.e., "optionally substituted amino groups") include amino groups, mono- or di-(C 1-6 alkyl)amino group, where C 1-6 alkyl optionally substituted with at least one halogen (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, or dibutylamino); mono- or di-C 2-6 Alkenylamino group (e.g., diallylamino group), mono- or di-C 3-10 Mono- or di-C such as cycloalkylamino groups (e.g., cyclopropylamino or cyclohexylamino groups), 6-14 Arylamino group (e.g., phenylamino group), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino or dibenzylamino groups), mono- or di-(C 1-6 alkyl)-carbonylamino group, where C 1-6 The alkyl may be optionally substituted with at least one halogen (e.g., acetylamino or propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino group), mono- or di-C 7-16Aralkyl-carbonylamino group (e.g., benzylcarbonylamino group, etc.), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino group (e.g., nicotinoylamino group and isonicotinoylamino group, etc.), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino group (e.g., piperidinylcarbonylamino group, etc.), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino group, etc.), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino group, etc.), carbamoylamino group, (mono- or di-C 1-6 alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino group), (mono- or di-C 7-16 Aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino, etc.), C 1-6 Alkyl sulfonyl amino group (e.g., methyl sulfonyl amino group or ethyl sulfonyl amino group), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino group), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino groups), and (C 1-6 Alkyl)(C 6-14 and aryl-carbonyl)amino groups (for example, N-benzoyl-N-methylamino groups).

[0069] As used herein, examples of "carbamoyl groups that may be substituted" (i.e., "optionally substituted carbamoyl groups") include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl groups, and mono- or di-C 7-16 aralkyl-carbamoyl groups, each of which may be substituted with 1 to 3 substituents selected from Substituent Group A, but are not limited to these.

[0070] Non-limiting examples of carbamoyl groups that can be substituted (i.e., optionally substituted carbamoyl groups) include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl group), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl group or cyclohexylcarbamoyl group), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl group), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl group or propionylcarbamoyl group), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-carbamoyl groups (for example, benzoylcarbamoyl groups, etc.) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (for example, pyridylcarbamoyl groups, etc.).

[0071] As used herein, examples of "thiocarbamoyl groups that may be substituted" (i.e., "optionally substituted thiocarbamoyl groups") include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl groups, and mono- or di-C 7-16 aralkyl-carbamoyl groups, each of which may be substituted with 1 to 3 substituents selected from Substituent Group A, but are not limited to these.

[0072] Non-limiting examples of thiocarbamoyl groups that can be substituted (i.e., optionally substituted thiocarbamoyl groups) include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl group, ethylthiocarbamoyl group, dimethylthiocarbamoyl group, diethylthiocarbamoyl group, or N-ethyl-N-methylthiocarbamoyl group), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl group), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl group or cyclohexylthiocarbamoyl group), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl group), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl group or phenethylthiocarbamoyl group), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl group or propionylthiocarbamoyl group), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-thiocarbamoyl groups (for example, benzoylthiocarbamoyl groups, etc.) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (for example, pyridylthiocarbamoyl groups, etc.).

[0073] As used herein, examples of "optionally substituted sulfamoyl groups" (i.e., "optionally substituted sulfamoyl groups") include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl groups, and mono- or di-C 7-16 aralkyl-carbamoyl groups, each of which may be substituted with 1 to 3 substituents selected from Substituent Group A, but are not limited to these.

[0074] Non-limiting examples of sulfamoyl groups that can be substituted (i.e., optionally substituted sulfamoyl groups) include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl group, ethylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, or N-ethyl-N-methylsulfamoyl group), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl group), mono- or di-C 3-10 Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl group or cyclohexylsulfamoyl group), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl group), mono- or di-C 7-16Mono- or di-C, such as aralkyl-sulfamoyl groups (e.g., benzylsulfamoyl or phenethylsulfamoyl groups), 1-6 Mono- or di-C alkyl-carbonyl-sulfamoyl groups (e.g., acetylsulfamoyl or propionylsulfamoyl groups) 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (for example, benzoylsulfamoyl groups, etc.) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (for example, pyridylsulfamoyl groups, etc.).

[0075] As used herein, examples of "hydroxy groups that may be substituted" (i.e., "optionally substituted hydroxy groups") include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group, and C 6-14 arylsulfonyl groups, each of which may be substituted with 1 to 3 substituents selected from Substituent Group A, but are not limited to these.

[0076] Non-limiting examples of hydroxy groups that can be substituted (i.e., optionally substituted hydroxy groups) include hydroxy groups, C 1-6 Alkoxy group, C 2-6Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, and 3-hexenyloxy groups), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy group), C 6-14 Aryloxy groups (e.g., phenoxy or naphthyloxy groups), C 7-16 Aralkyloxy groups (e.g., benzyloxy or phenethyloxy groups), C 1-6 Alkyl-carbonyloxy groups (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, or pivaloyloxy groups), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy group), C 7-16 aralkyl-carbonyloxy groups (e.g., benzylcarbonyloxy groups, etc.), 5- to 14-membered aromatic heterocyclic carbonyloxy groups (e.g., nicotinoyloxy groups, etc.), 3- to 14-membered non-aromatic heterocyclic carbonyloxy groups (e.g., piperidinylcarbonyloxy groups, etc.), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy group, etc.), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy group, etc.), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy groups), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy group), C 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy groups or ethyl sulfonyloxy groups), and C 6-14 Examples include arylsulfonyloxy groups (for example, phenylsulfonyloxy groups).

[0077] As used herein, examples of "optionally substituted sulfanyl groups" (i.e., "optionally substituted sulfanyl groups") include sulfanyl groups having at least one "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Examples of the substituents include, but are not limited to, a sulfanyl group which may be substituted with a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic carbonyl group, each of which may be substituted with 1 to 3 substituents selected from Substituent Group A.

[0078] Non-limiting examples of sulfanyl groups that can be substituted (i.e., optionally substituted sulfanyl groups) include sulfanyl (—SH) groups, C 1-6 Alkylthio group, C 2-6 alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, or 3-hexenylthio groups), C 3-10 Cycloalkylthio groups (e.g., cyclohexylthio groups), C 6-14 Arylthio groups (e.g., phenylthio or naphthylthio groups), C 7-16 Aralkylthio groups (e.g., benzylthio or phenethylthio groups), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, or pivaloylthio groups), C 6-14 Examples include aryl-carbonylthio groups (such as a benzoylthio group), 5- to 14-membered aromatic heterocyclic thio groups (such as a pyridylthio group), and halogenated thio groups (such as a pentafluorothio group).

[0079] As used herein, examples of "optionally substituted silyl groups" (i.e., "optionally substituted silyl groups") include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups, and C 7-16 Examples of the silyl group include, but are not limited to, a silyl group that may be substituted with 1 to 3 substituents selected from aralkyl groups, each of which may be optionally substituted with 1 to 3 substituents selected from Substituent group A.

[0080] Non-limiting examples of silyl groups that can be substituted (i.e., optionally substituted silyl groups) include tri-C 1-6 Examples include alkylsilyl groups (for example, trimethylsilyl and tert-butyl(dimethyl)silyl groups).

[0081] In this specification, "C 1-3 Non-limiting examples of "alkyl groups" include C alkyl groups having 1 to 3 carbon atoms. 1-3 Examples of suitable alkyl groups include:

[0082] As used herein, "C which may be substituted with fluorine atom(s)" refers to 1-3 alkyl group "(i.e., "C optionally substituted with at least one fluorine 1-3 The term "alkyl group") refers to, for example, a C alkyl group which may be substituted with 1 to 5 (e.g., 1 to 3, 1 or 2, etc.) fluorines. 1-3 It means an alkyl group.

[0083] In this specification, the benzene group in the "benzene group which may be further substituted" (i.e., "optionally substituted benzene group") may have, for example, 1 to 4 (e.g., 1 to 3, 1 or 2, etc.) substituents selected from the above-mentioned Substituent Group A.

[0084] As used herein, among the "benzene group, pyridine group, or pyrazine group, each of which may be further substituted" (i.e., "an optionally substituted benzene group, an optionally substituted pyridine group, and an optionally substituted pyrazine group"), the benzene group may be substituted with a substituent similar to the above-mentioned "benzene group which may be further substituted," the pyridine group may be substituted with, for example, 1 to 3 (e.g., 1 or 2) substituents selected from the above-mentioned Substituent Group A, and the pyrazine group may be substituted with, for example, 1 or 2 (e.g., 1) substituents selected from the above-mentioned Substituent Group A.

[0085] As used herein, the pyrimidine group of the "pyrimidine group which may be further substituted" (i.e., "optionally substituted pyrimidine group") may be substituted with, for example, one or two (e.g., one) substituents selected from the above-mentioned Substituent Group A.

[0086] The definition of each symbol in formula (I) is described in detail below.

[0087] In some embodiments, R 1 is a C optionally substituted with halogen and at least one fluorine; 1-3 The alkyl group is selected from the group consisting of:

[0088] In some embodiments, R 1 is a halogen (e.g., fluorine or chlorine), and C optionally substituted with 1 to 3 (e.g., 1 or 2) fluorines; 1-3 The group is selected from alkyl groups (such as methyl groups).

[0089] In some embodiments, R 2 is a C optionally substituted with at least one fluorine 1-3 The alkyl group is selected from the group consisting of:

[0090] In some embodiments, R 2 is a C optionally substituted with 1 to 3 fluorines 1-3 In some embodiments, R is selected from alkyl groups (e.g., methyl or ethyl groups). 2 is the unsubstituted C 1-3 The group is selected from alkyl groups (such as methyl groups).

[0091] In some embodiments, R 3 is selected from hydrogen and a hydroxy group.

[0092] In some embodiments, ring A is selected from an optionally substituted benzene group.

[0093] In some embodiments, the benzene group in ring A is R 1 In addition to -O-ring B-, it may be substituted with 1 to 4 (e.g., 1 or 2) substituents. Non-limiting examples of the substituents include at least one substituent selected from the above-mentioned substituent group A, such as a halogen (e.g., fluorine).

[0094] In some embodiments, ring A is selected from a benzene group optionally substituted with 1 to 4 (e.g., 1 or 2) halogens (e.g., fluorine, etc.). In some embodiments, ring A is selected from a benzene group optionally substituted with 1 or 2 (e.g., 1) halogens (e.g., fluorine, etc.).

[0095] In some embodiments of the present disclosure, Ring A is selected from a benzene group substituted with at least one halogen (such as fluorine) at one or two positions ortho to -O-Ring B-.

[0096] In some embodiments, ring A has the formula: [ka] is selected from the group R 1 is as defined above; R v is selected from halogens (e.g., fluorine); and R w is selected from hydrogen and halogen (such as fluorine).

[0097] In some embodiments, ring B has the formula: [ka] is selected from the group

[0098] In some embodiments, X and Y are each independently selected from carbon and nitrogen.

[0099] In some embodiments, ring B 1 is selected from an optionally substituted benzene group, an optionally substituted pyridine group, and an optionally substituted pyrazine group.

[0100] In some embodiments, ring B 2 is selected from optionally substituted pyrimidine groups.

[0101] In some embodiments, ring B 3 is selected from optionally substituted pyrimidine groups.

[0102] In some embodiments, ring B 1 is selected from an optionally substituted benzene group, an optionally substituted pyridine group, and an optionally substituted pyrazine group.

[0103] In some embodiments, ring B 1 An optionally substituted benzene group (where both X and Y are carbon), an optionally substituted pyridine group (where one of X and Y is carbon and the other is nitrogen), or an optionally substituted pyrazine group (where both X and Y are nitrogen), represented by the formula (I) may be substituted with 1 to 4 (e.g., 1 or 2) substituents. Non-limiting examples of the substituents include substituents selected from the above-mentioned substituent group A.

[0104] In some embodiments, ring B 1 is selected from an unsubstituted benzene group, an unsubstituted pyridine group, and an unsubstituted pyrazine group.

[0105] In some embodiments, ring B 1is selected from unsubstituted pyridine groups, where one of X and Y is carbon and the other is nitrogen, e.g., X is nitrogen and Y is carbon, etc.

[0106] In some embodiments, ring B 2 is optionally substituted with one or two (e.g., one) substituents. Non-limiting examples of substituents include those selected from Substituent Group A above.

[0107] In some embodiments, ring B 3 is optionally substituted with one or two (e.g., one) substituents. Non-limiting examples of substituents include those selected from Substituent Group A above.

[0108] In some embodiments, ring B 2 is an unsubstituted pyrimidine group.

[0109] In some embodiments, ring B 3 is an unsubstituted pyrimidine group.

[0110] In some embodiments, ring B has the formula: [ka] is selected from the group X and Y are each independently selected from carbon and nitrogen; Ring B 1 is selected from an unsubstituted benzene group, an unsubstituted pyridine group, and an unsubstituted pyrazine group; Ring B 2 is an unsubstituted pyrimidine group; and Ring B 3 is an unsubstituted pyrimidine group.

[0111] In some embodiments, ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen; Ring B 1 is selected from unsubstituted pyridine groups; and Ring B 2 is an unsubstituted pyrimidine group.

[0112] In some embodiments, ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen (e.g., X is nitrogen and Y is carbon); and Ring B 1 is non-substituted.

[0113] In some embodiments, Z is selected from CH2, CF2, O, and NH.

[0114] In some embodiments of the present disclosure, Z is selected from CH2, O, and NH.

[0115] In some embodiments, Z is CH2 or O.

[0116] Non-limiting examples of compounds of formula (I) and salts thereof include the following compounds and salts thereof: [Compound I-1]

[0117] A compound of formula (I), or a salt thereof, wherein R 1 is a halogen (e.g., fluorine and chlorine), and C optionally substituted with 1 to 3 fluorines 1-3 alkyl groups (e.g., methyl groups); R 2 is a C optionally substituted with 1 to 3 fluorines 1-3alkyl groups (such as methyl and ethyl groups); R 3 is selected from hydrogen and a hydroxyl group; Ring A is selected from a benzene group optionally substituted with 1 to 4 (e.g., 1 or 2) halogens (e.g., fluorine); Ring B has the formula: [ka] is selected from the group X and Y are each independently selected from carbon and nitrogen; Ring B 1 is selected from an unsubstituted benzene group, an unsubstituted pyridine group, and an unsubstituted pyrazine group; Ring B 2 is an unsubstituted pyrimidine group; and Ring B 3 is an unsubstituted pyrimidine group; and Z is selected from CH2, CF2, O, and NH. [Compound I-2]

[0118] A compound of formula (I), or a salt thereof, wherein R 1 is a halogen (e.g., fluorine and chlorine), and C optionally substituted with one or two fluorines; 1-3 alkyl groups (e.g., methyl groups); R 2 is the unsubstituted C 1-3 alkyl groups (e.g., methyl groups); R 3 is selected from hydrogen and a hydroxyl group; Ring A is selected from a benzene group optionally substituted with one or two (e.g., one) halogens (e.g., fluorine); Ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen (e.g., X is nitrogen and Y is carbon); Ring B 1 is selected from unsubstituted pyridine groups; and Ring B 2 is an unsubstituted pyrimidine group; and Z is CH2 or O. [Compound I-3]

[0119] A compound of formula (I), or a salt thereof, wherein R 1 is a halogen (e.g., fluorine and chlorine), and C optionally substituted with one or two fluorines; 1-3 alkyl groups (e.g., methyl groups); R 2 is the unsubstituted C 1-3 alkyl groups (e.g., methyl groups); R 3 is selected from hydrogen and a hydroxyl group; Ring A is a group represented by the formula: [ka] is selected from the group R v is selected from halogens (e.g., fluorine); and R w is selected from hydrogen and halogen (such as fluorine); Ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen (e.g., X is nitrogen and Y is carbon); Ring B 1 is selected from unsubstituted pyridine groups; and Ring B 2is an unsubstituted pyrimidine group; and Z is CH2 or O.

[0120] Non-limiting examples of the compound of formula (I) include the compounds of Examples 1 to 50 described below.

[0121] The salt of the compound of formula (I) is a pharmacologically acceptable salt, and non-limiting examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0122] Non-limiting examples of salts with inorganic bases include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts; and ammonium salts.

[0123] Non-limiting examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, or N,N-dibenzylethylenediamine.

[0124] Non-limiting examples of salts with inorganic acids include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, or phosphoric acid.

[0125] Non-limiting examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

[0126] Non-limiting examples of salts with basic amino acids include salts with arginine, lysine, or ornithine.

[0127] Non-limiting examples of salts with acidic amino acids include salts with aspartic acid or glutamic acid.

[0128] In some embodiments, the compounds of formula (I) may be administered as prodrugs.

[0129] In some embodiments, the prodrug of the compound of formula (I) is a compound that is converted to the compound of formula (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, i.e., a compound that is converted to the compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, or the like, and a compound that is converted to the compound of formula (I) by hydrolysis, or the like, with gastric acid, or the like.

[0130] Non-limiting examples of prodrugs of compounds of formula (I) include: a compound of formula (I) in which the amino group has been acylated, alkylated or phosphorylated (e.g., a compound of formula (I) in which the amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); Examples of such compounds include compounds in which the hydroxy group of the compound of formula (I) is acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxy group of the compound of formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated); and compounds in which the carboxy group of the compound of formula (I) is esterified or amidated (for example, compounds in which the carboxy group of the compound of formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidized). These compounds can be produced from the compound of formula (I) by methods known to those skilled in the art.

[0131] In some embodiments, the prodrug of the compound of formula (I) may be converted into the compound of formula (I) under physiological conditions, as described in "Drug Development," Hirokawa Publishing, 1990, Vol. 7, Molecular Design, pp. 163-198.

[0132] In some embodiments, the prodrug may form a salt, and examples of such salts include those exemplified as salts of the compound of formula (I) above.

[0133] In some embodiments, compounds of formula (I) may be isotopically modified (e.g., 3 H, 13 C. 14 C. 18 F, 35 S, and 125 I) or the like.

[0134] In some embodiments, isotopically labeled or substituted compounds of formula (I) may be used, for example, as tracers for use in positron emission tomography (PET) (PET tracers), and may be useful in fields such as medical diagnostics.

[0135] In some embodiments, the compound of formula (I) may be hydrated, non-hydrated, ansolvated, or solvated.

[0136] In some embodiments, the compound of formula (I) also comprises 1 H 2 This includes deuterium conversion products converted to H(D).

[0137] In some embodiments, the compound of Formula (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. In some embodiments, a co-crystal or co-crystal salt is a crystalline substance composed of two or more distinct solids at room temperature, each with different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Co-crystals or co-crystal salts can be prepared according to co-crystallization methods known to those skilled in the art.

[0138] In some embodiments, the compound of formula (I), a salt thereof, or a prodrug thereof may be used as is or as a pharmaceutical composition prepared by mixing with a pharmacologically acceptable carrier, etc. In some embodiments, the compound of formula (I), a salt thereof, or a prodrug thereof may be used as a prophylactic or therapeutic agent for various diseases described below in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.).

[0139] Non-limiting examples of pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials. In some embodiments, solid formulations contain excipients, lubricants, binders, disintegrants, etc. In some embodiments, liquid formulations contain solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. In some embodiments, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners, etc. may be added.

[0140] Non-limiting examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0141] Non-limiting examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.

[0142] Non-limiting examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

[0143] Non-limiting examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

[0144] Non-limiting examples of solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

[0145] Non-limiting examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

[0146] Non-limiting examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.

[0147] Non-limiting examples of tonicity agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose.

[0148] Non-limiting examples of buffering agents include phosphate, acetate, carbonate, and citrate buffers.

[0149] Non-limiting examples of soothing agents include benzyl alcohol.

[0150] Non-limiting examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0151] Non-limiting examples of antioxidants include sulfites and ascorbates.

[0152] Non-limiting examples of coloring agents include water-soluble food tar dyes (e.g., food dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, and Food Blue Nos. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide).

[0153] Non-limiting examples of sweetening agents include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0154] Non-limiting examples of dosage forms of the pharmaceutical of the present invention include oral preparations such as tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, and buccal tablets), pills, powders, granules, capsules (e.g., soft capsules and microcapsules), troches, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films and oral mucosal patch films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (e.g., inhalants), and eye drops.

[0155] The compound of formula (I), a salt thereof, or a prodrug thereof, or a pharmaceutical composition of the present disclosure may be administered orally or parenterally (e.g., intravenously, intraarterially, intramuscularly, subcutaneously, intraorgan, intranasally, intradermally, by ophthalmic drop, intracerebrally, intrarectally, intravaginally, intraperitoneally, intratumorally, proximal to a tumor, etc.), or may be administered directly to a lesion.

[0156] In some embodiments, the pharmaceutical compositions of the present disclosure may be in a controlled release formulation, such as an immediate release formulation or a sustained release formulation (e.g., sustained release microcapsules, etc.).

[0157] In some embodiments, pharmaceutical compositions of the present disclosure may be manufactured by methods commonly used in the pharmaceutical arts, such as those described in the Japanese Pharmacopoeia.

[0158] In some embodiments, the content of the compound of the present disclosure in the pharmaceutical composition of the present disclosure may be, for example, about 0.1 to 100 wt %, depending on the dosage form, the dosage amount of the compound, etc.

[0159] In some embodiments, when an oral preparation is produced, a coating may be performed, if necessary, for the purpose of masking the taste, improving enteric properties, or improving durability.

[0160] Non-limiting examples of coating bases include, for example, sugar-coated bases, water-soluble film-coating bases, enteric film-coating bases, and sustained-release film-coating bases.

[0161] In some embodiments, sucrose is used as the coating base. In some embodiments, one or more of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, and carnauba wax may be used in combination.

[0162] Non-limiting examples of water-soluble film coating bases include cellulosic high molecular weight molecules such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic high molecular weight molecules such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan.

[0163] Non-limiting examples of enteric film coating bases include cellulose-based high molecular weight molecules such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid-based high molecular weight molecules such as methacrylic acid copolymer L (Eudragit L (trade name)), methacrylic acid copolymer LD (Eudragit L-30D55 ​​(trade name)), and methacrylic acid copolymer S (Eudragit S (trade name)); and natural products such as shellac.

[0164] Non-limiting examples of sustained-release film coating bases include cellulose-based high molecular weight molecules such as ethyl cellulose; and acrylic acid-based high molecular weight molecules such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS (trade name)) and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE (trade name)).

[0165] In some embodiments, two or more of the above-mentioned coating bases may be mixed in an appropriate ratio. In some embodiments, a light-blocking agent such as titanium oxide and ferric oxide may be used during coating.

[0166] The compound of formula (I), a salt thereof, or a prodrug thereof may have an antagonistic effect on an NMDA receptor containing the NR2B subunit. In some embodiments, the antagonism of an NMDA receptor containing the NR2B subunit is, for example, due to activation of the receptor (e.g., glutamate-induced increase in intracellular calcium ions (Ca 2+ ) inflow, etc.).

[0167] In some embodiments, the NMDA receptor containing the NR2B subunit is a receptor composed of a total of four subunits, including one NR2B subunit and three subunits of two or three types selected from NR1, NR2A, NR2B, NR2C, NR2D, NR3A, and NR3B.

[0168] In some embodiments, the NMDA receptor containing the NR2B subunit is a receptor composed of four subunits, including a heterodimer of NR1 and NR2B, one type of subunit selected from NR2A, NR2B, NR2C, and NR2D, and a heterodimer of NR1.

[0169] In some embodiments, the NMDA receptor containing the NR2B subunit is a receptor composed of four subunits consisting of two sets of heterodimers of NR1 and NR2B.

[0170] In some embodiments, the compound of formula (I), its salt, or prodrug thereof is expected to exhibit low toxicity (e.g., cardiotoxicity, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, pulmonary toxicity, and carcinogenicity) and few side effects (e.g., psychotomimetic side effects). In some embodiments, the compound of formula (I), its salt, or prodrug thereof can be used in mammals as a preventive, therapeutic, or diagnostic agent for various diseases.

[0171] In some embodiments, the compound of formula (I), a salt thereof, or a prodrug thereof is expected to have low mutagenicity in the Ames test and / or low hERG (human ether-a-go-go related gene) inhibitory activity. In some embodiments, the compound of formula (I), a salt thereof, or a prodrug thereof is expected to have low brain efflux via the BCRP (breast cancer resistance protein) transporter and excellent stability against conjugation metabolism.

[0172] In some embodiments, the compound of formula (I), a salt thereof, or a prodrug thereof is expected to have excellent brain penetration.

[0173] The compound of formula (I), its salt, or its prodrug can be used as a preventive or therapeutic agent for central and peripheral diseases. In some embodiments, the compound of formula (I), its salt, or its prodrug can be used as a preventive or therapeutic agent for central and peripheral diseases. (1) Psychiatric disorders [e.g., major depression (including treatment-refractory major depression and treatment-resistant depression), minor depressive disorder, bipolar depression, recurrent depression, postpartum depression, stress disorder, major depressive disorder comorbid with psychosis (including delusional disorder and schizophrenia), manic or mixed mood episode, hypomanic mood episode, depressive episode with atypical features, depressive episode with melancholic features, depressive episode with catatonic features, depressive episode after stroke (all of which are referred to as "depression" in this specification) ), dysthymic disorder, affective disorder (e.g., seasonal affective disorder), delirium, cognitive impairment (e.g., psychotic or behavioral abnormalities), anxiety, generalized anxiety disorder, anxiety syndrome, irritability, mood disorder, cyclothymic disorder, premenstrual dysphoric disorder, panic disorder, phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, post-traumatic stress disorder, schizoaffective disorder with paranoid or depressive type, paranoid personality disorder, Taurette's syndrome, autism, fragile X syndrome, Levish personality disorder, syndrome, adjustment disorder, bipolar disorder (including bipolar disorder type I and bipolar disorder type II), neurosis, schizophrenia (e.g., positive symptoms, negative symptoms, memory impairment, paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, and residual schizophrenia), schizophreniform disorder, chronic fatigue syndrome, obsessive-compulsive disorder, epilepsy, refractory childhood epilepsy syndrome, West syndrome, anxiety-dysphoric mental state, dysthymia, cyclothymia, syncope, addiction, decreased libido, attention-deficit hyperactivity disorder (ADHD), psychiatric psychotic disorders (e.g., brief psychotic disorder and shared psychotic disorder), alcohol-, amphetamine-, cannabis-, cocaine-, hallucinogen-, obesity-, inhalant-, opioid-, or phencyclidine-induced psychosis, delusional disorder, Noonan syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedimann syndrome, Silver-Russell syndrome, tuberous sclerosis complex, Williams syndrome, Kallmann syndrome, Rubinstein-Taybi syndrome, movement disorders, mental retardation, paranoid tendencies, etc.); (2) Neurodegenerative diseases [e.g., Alzheimer's disease, Alzheimer's-type senile dementia, Parkinson's disease, Huntington's chorea, multi-infarct dementia, frontotemporal dementia, Parkinson's-type frontotemporal dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, dementia associated with Huntington's disease or Parkinson's disease, neurodegeneration associated with brain trauma, neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction, neurodegeneration associated with hypoglycemia, seizures] Neurodegeneration associated with cancer seizures, neurodegeneration associated with neurotoxicity, multiple system atrophy, spinal cord injury, AIDS-related dementia, progressive supranuclear palsy, Pick's syndrome, Niemann-Pick syndrome, corticobasal degeneration, Down's syndrome, vascular dementia, post-encephalitic Parkinson's disease, dementia with Lewy bodies, HIV-associated dementia, amyotrophic lateral sclerosis (ALS), motor neurogenic diseases (MND), Creutzfeldt-Jakob disease or prion diseases, cerebral palsy, multiple sclerosis, and neuromyopathy; (3) amnesic disorders, mild cognitive impairment, learning disabilities (e.g., dyslexia, dysgraphia, and dyscalculia), and age-related cognitive and memory disorders (e.g., age-related memory impairment and senile dementia); (4) Sleep disorders (e.g., endogenous sleep disorders (e.g., psychophysiological insomnia), exogenous sleep disorders, circadian rhythm disorders (e.g., jet lag, shift work sleep disorder, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake patterns), parasomnia, sleep disorders associated with medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, and anxiety), stress insomnia, insomnia, insomnia neurosis, and sleep apnea syndrome); (5) Respiratory depression caused by anesthetics, trauma, or neurodegenerative diseases, etc. (6) Pain [e.g., psychogenic pain (e.g., somatoform disorder, pain disorder, somatization disorder, hypochondriasis, conversion disorder, and chronic pain with depression), inflammatory pain, peripheral neuropathic pain, central neuropathic pain, neuropathic pain, acute pain, intractable pain, persistent cancer pain, breakthrough cancer pain, cancer pain, persistent pain, somatic pain, breakthrough pain, chronic pain, tenderness, generalized pain, dull pain, cutaneous pain syndrome, radiating pain, pain, and post-thoracotomy pain syndrome]; (7) Hearing loss [e.g., kanamycin hearing loss, streptomycin hearing loss, toxic hearing loss, presbycusis, idiopathic bilateral sensorineural hearing loss, sudden hearing loss, acquired deafness, hereditary hearing loss, organic hearing loss, high-frequency hearing loss, occupational hearing loss, occupational hearing loss, and low-frequency hearing loss, etc.]; (8) Traumatic brain injury and its associated disorders or complications, post-concussion syndrome, shaken baby syndrome, stroke, age-related macular degeneration, oculopalatal tremor, convulsions, phantom limb pain, radiation lethargy syndrome, anorexia nervosa, eating disorders, anorexia nervosa, bulimia, other eating disorders, alcoholism, alcohol abuse, alcoholic amnesia, alcoholic paranoia, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcoholism, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, hepatic encephalopathy, drug preference, drug phobia, drug mania, drug abuse, drug dependence, drug withdrawal, migraine, Stress headaches, tension headaches, diabetic neuropathy, obesity, diabetes, muscle spasms, Meniere's disease, autonomic imbalance, alopecia, glaucoma, high blood pressure, heart disease, tachycardia, congestive heart failure, hyperventilation, bronchial asthma, apnea, sudden infant death syndrome, inflammatory diseases, allergic diseases, systemic lupus erythematosus, impotence, menopausal disorders, infertility, cancer, HIV infection-related immunodeficiency syndrome, stress-related immunodeficiency syndrome, cerebrospinal meningitis, acromegaly, incontinence, metabolic syndrome, osteoporosis, peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress-related gastrointestinal disorders, nervous vomiting, diarrhea, constipation, and postoperative ileus These compounds may be useful as preventive or therapeutic agents for various diseases such as the above.

[0174] In some embodiments, the compounds of formula (I), salts thereof, or prodrugs thereof may be useful for the prevention or treatment of depression (including major depression, treatment-refractory major depression, treatment-resistant depression, etc.), bipolar disorder, migraine, pain, or cognitive impairment.

[0175] Both depression and bipolar disorder can be characterized by prolonged periods of depression or periods of depression and mania. Recently, it has been found that a single intravenous administration of ketamine, an NMDA receptor antagonist, rapidly and sustainably alleviates depressive symptoms associated with major depression and bipolar disorder [Therapeutic Advances in Psychopharmacology (Ther. Adv. Psychopharmacol.) Vol. 4, pp. 75-99, 2014]. Furthermore, it has been reported that continuous intravenous administration of CP-101,606, an antagonist of NMDA receptors containing the NR2B subunit, significantly improves treatment-resistant depressive symptoms [Journal of Clinical Psychopharmacology (J. Clin. Psychopharmacol.) Vol. 28, pp. 631-637, 2008]. Therefore, the compounds disclosed herein are promising as preventive or therapeutic agents for treatment-resistant depression.

[0176] Migraine is a chronic, episodic primary headache. While its pathogenesis remains unknown, it is believed to be associated with abnormalities in central nervous system processing and the trigeminovascular system. In the pathophysiology of migraine, particularly aura, the phenomenon of cortical spreading depression has attracted attention. In experimental cortical spreading depression tests using rodents, CP-101,606 and Ro25-6981, antagonists of NMDA receptors containing the NR2B subunit, have been reported to suppress the frequency and depth of cortical spreading depression [The Journal of Pharmacology and Experimental Therapeutics (J. Pharmacol. Exp. Ther.) Vol. 321, pp. 564-572, 2007]. Therefore, the compound of formula (I), its salt, or its prodrug may be useful as a prophylactic or therapeutic agent for migraine.

[0177] Pain can be classified into acute pain, which lasts for a relatively short period of time, and chronic pain, which persists or recurs for three months or longer, persists for more than one month after recovery from acute tissue damage, or is accompanied by non-healing lesions. NMDA receptors containing the NR2B subunit are highly expressed in the dorsal horn of the spinal cord, where they play an important role in pain reception. It has been suggested that pain can be controlled by regulating the function of NMDA receptors containing the NR2B subunit. Genetic manipulations that reduce the function of the NR2B subunit have been shown to increase pain thresholds [European Journal of Neuroscience (Eur. J. Neurosci.) Vol. 32, pp. 798-810, 2010]. Furthermore, ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, has been shown to increase pain thresholds [Pain Vol. 153, pp. 1022-1029, 2012]. Therefore, the compound of formula (I), its salt, or its prodrug may be useful as a preventive or therapeutic agent for pain.

[0178] Dementia is a chronic, global, and usually irreversible cognitive decline. While cognitive decline significantly reduces the patient's quality of life, cognitive-related symptoms (e.g., psychiatric symptoms or behavioral abnormalities) are also considered to be significant factors that significantly affect the quality of life of patients and / or caregivers. Although effective therapeutic interventions for cognitive-related symptoms have not been established, it has been reported that administration of memantine, an NMDA receptor antagonist, partially improves cognitive-related symptoms [The Annals of Pharmacotherapy (Ann. Pharmacother.) Vol. 42, pp. 32-38, 2007]. NR2B subunit-containing NMDA receptors are widely distributed throughout the brain, excluding the cerebellum, and cognitive-related symptoms have been reported to be associated with white matter abnormalities in brain regions other than the cerebellum [Journal of the Neurological Sciences (J. Neurol. Sci.) Vol. 337, pp. 162-166, 2014]. Therefore, the compound of formula (I), its salt, or a prodrug thereof may be useful as a preventive or therapeutic agent for cognitive-related symptoms.

[0179] The dosage of the compound of formula (I), a salt thereof, or a prodrug thereof may vary depending on the subject, route of administration, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the single dose may usually be about 0.01 to 100 mg / kg body weight, for example, 0.1 to 50 mg / kg body weight, for example, 0.5 to 20 mg / kg body weight, and this amount may be administered once to three times a day.

[0180] The compound of formula (I), a salt thereof, or a prodrug thereof can be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).

[0181] Non-limiting examples of concomitant drugs include the following: acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, etc.), anti-dementia drugs (e.g., memantine, etc.), beta-amyloid protein production, secretion, accumulation, aggregation, and / or deposition inhibitors, beta-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyl Tetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2- (N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, optically active substances thereof, salts thereof and hydrates thereof, as well as OM99-2 (International Publication No. 01 / 00663)), gamma secretase inhibitors, beta amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED ( NC-531), PPI-368 (JP Patent Publication No. Hei 11-514333), PPI-558 (JP Patent Publication No. 2001-500852), SKF-74652 (Biochem.J.(1999),340(1),283-289)), beta-amyloid vaccines and beta-amyloid degrading enzymes, brain function activators (e.g., aniracetam and nicergoline), Parkinson's disease treatment drugs (e.g., dopamine receptor agonists (e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, and amantadine),Monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selgiline (selegiline), remacemide, and riluzole), anticholinergic agents (e.g., trihexyphenidyl and biperiden), COMT inhibitors (e.g., entacapone), etc.), drugs for treating amyotrophic lateral sclerosis (e.g., neurotrophic factors such as riluzole), drugs for treating abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives and anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, and CEP-1347), neuronal differentiation and regeneration promoters ( For example, leteprinim, Xaliproden (SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-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-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active substances, salts, and hydrates, etc.), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroid drugs (e.g., dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors, antihistamines and MAP kinase inhibitors, etc.), urinary incontinence and frequent urination treatments (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride, etc.), phosphodiesterase inhibitors (e.g., sildenafil citrate, etc.), dopamine agonists (e.g., apomorphine, etc.), antiarrhythmic drugs (e.g., mexiletine, etc.), sex hormones or their derivatives (e.g., progesterone, estradiol, and estradiol benzoate, etc.), osteoporosis treatments (e.g., alfacalcidol, calcitriol, elcatonin, salmon calcitonin,estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, and incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, drugs for treating insomnia (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, and orexin receptor antagonists), drugs for treating schizophrenia (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; drugs acting on metabotropic or ionotropic glutamate receptors; and phosphodiesterase inhibitors), benzodiazepines (e.g., chlordiazepoxide, diazepam, clorazepate potassium, lorazepam , clonazepam, alprazolam, etc.), L-type calcium channel blockers (e.g., pregabalin, etc.), tricyclic or tetracyclic antidepressants (e.g., imipramine hydrochloride, amitriptyline hydrochloride, clomipramine hydrochloride, mianserin hydrochloride, setiptiline maleate, etc.), selective serotonin reuptake inhibitors (e.g., fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, escitalopram oxalate, sertraline hydrochloride, paroxetine hydrochloride hydrate, etc.), serotonin-noradrenaline reuptake inhibitors (e.g., venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine, etc.), noradrenaline reuptake inhibitors (e.g., reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, bupropion hydrochloride, 5-HT, 1A agonists (e.g., buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, 5-HT3 antagonists (e.g., cyamemazine, etc.), non-cardioselective beta-blockers (e.g., propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists, CRF antagonists, other anxiolytics (e.g., meprobamate, etc.), tachykinin antagonists, drugs acting on metabotropic glutamate receptors, CCK antagonists, beta3-adrenergic antagonists (e.g., amibegron hydrochloride, etc.), GAT-1 inhibitors, N-type calcium channel blockers, type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists, NMDA antagonists (e.g., memantine, ketamine, esketamine, etc.), peripheral benzodiazepine receptor agonists, vasopressin receptor antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones, thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), MAO inhibitors (e.g., phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), drugs for treating bipolar disorder (e.g., lithium carbonate, sodium valproate, lamotrigine, riluzole, etc.), ol, felbamate, etc.), cannabinoid CB1 antagonists, FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (e.g., methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), drugs for treating alcoholism, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia, drugs for treating headaches, drugs for smoking cessation, drugs for treating myasthenia gravis, drugs for treating cerebral infarction, drugs for treating mania, drugs for treating hypersomnia, drugs for treating pain, drugs for treating dysthymia, drugs for treating autonomic nervous system disorders, drugs for treating male and female sexual dysfunction, drugs for treating migraines, drugs for treating pathological gambling , drugs for treating restless leg syndrome, drugs for treating substance dependence, drugs for treating alcohol-related disorders, drugs for treating irritable bowel syndrome, drugs for treating dyslipidemia such as cholesterol-lowering drugs (e.g., statins, etc.), fibrates, and squalene synthesis inhibitors), drugs for treating abnormal behavior or drugs to suppress wanderlust due to dementia (e.g., sedatives, anti-anxiety drugs, etc.), anti-obesity drugs, drugs for treating diabetes, drugs for treating diabetic complications, drugs for treating hypertension, drugs for treating hypotension, diuretics, chemotherapy agents, immunotherapy agents, antithrombotic agents, anti-cancer agents, antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, etc.

[0182] The above concomitant drugs may be used in combination of two or more kinds in an appropriate ratio.

[0183] Furthermore, when the compound of formula (I), a salt thereof, or a prodrug thereof is used in the treatment or prevention of any of the above-mentioned diseases, the compound, a salt thereof, or a prodrug thereof may be used in combination with a biologic (e.g., an antibody drug, a nucleic acid or a nucleic acid derivative, an aptamer drug, a vaccine preparation, etc.), in combination with a gene therapy method, etc., or in combination with a drug-free psychiatric therapy.

[0184] Non-drug psychiatric treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy, including cognitive behavioral therapy.

[0185] In some embodiments, the compound of formula (I), a salt thereof, or a prodrug thereof may be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and vascular regeneration, cell transplantation therapy using bone marrow cells (such as bone marrow mononuclear cells and bone marrow stem cells), and artificial organs using tissue engineering (such as artificial blood vessels and cardiomyocyte sheets).

[0186] By combining the compound of formula (I), a salt thereof, or a prodrug thereof with a concomitant drug, (1) The dose of the compound of formula (I), a salt thereof, a prodrug thereof, or a combination drug can be reduced compared to when the compound of formula (I), a salt thereof, a prodrug thereof, or a combination drug is administered alone. (2) The compound of formula (I), a salt thereof, or a prodrug thereof and a drug to be used in combination can be selected depending on the patient's symptoms (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of formula (I), a salt thereof, or a prodrug thereof, the treatment period can be extended. (4) By selecting a concomitant drug having a different mechanism of action from the compound of formula (I), a salt thereof, or a prodrug thereof, it is possible to achieve a sustained therapeutic effect; and (5) By using the compound of the present disclosure in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0187] Hereinafter, the combination of a compound of formula (I), a salt thereof, or a prodrug thereof with a concomitant drug is referred to as "the combination therapy of the present disclosure."

[0188] When using the combination therapy of the present disclosure, the administration time of the compound of formula (I), its salt, or prodrug thereof, and the concomitant drug is not limited, and the compound of formula (I), its salt, or prodrug, or pharmaceutical composition containing them, and the concomitant drug or pharmaceutical composition containing them, can be administered to a subject simultaneously (as a single formulation or separate formulations), or at different times. When administered at different times, the order of administration can be such that the compound of formula (I), its salt, or prodrug, or the concomitant drug is administered first. Furthermore, the compound of formula (I), its salt, or prodrug, or the concomitant drug can be administered after the concomitant drug has been continuously administered for a certain period of time.

[0189] The dosage of the concomitant drug may be in accordance with the dosage used clinically, and can be appropriately selected depending on the subject, route of administration, disease, combination, etc.

[0190] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage, and the compounding ratio of the compound of formula (I), a salt thereof, or a prodrug thereof to the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the target disease, symptoms, combination, etc.

[0191] The method for producing the compound of formula (I) is described below.

[0192] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compounds of the present disclosure described above.

[0193] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known to those skilled in the art. Conversely, when the compound obtained in each step is a salt, it can be converted into the free compound or another desired type of salt by a method known to those skilled in the art.

[0194] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product. Alternatively, the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc., according to a conventional method in the field to which the present disclosure pertains.

[0195] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0196] In the reaction of each step, the reaction time may vary depending on the reagent or solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, for example, 10 minutes to 8 hours.

[0197] In the reaction of each step, the reaction temperature may vary depending on the reagents and solvent used, but is usually −78° C. to 300° C., for example −78° C. to 150° C., unless otherwise specified.

[0198] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, for example 1 atm to 3 atm.

[0199] In the reactions of each step, a microwave synthesis apparatus such as Biotage's Initiator may be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300°C, for example, 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, for example, 1 minute to 8 hours.

[0200] In the reactions of each step, unless otherwise specified, the reagent may be used in an amount of 0.5 to 20 equivalents, for example, 0.8 to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent may be used in an amount of 0.001 to 1 equivalent, for example, 0.01 to 0.2 equivalents, relative to the substrate. When a reagent also serves as a reaction solvent, the reagent may be used in an amount equivalent to the solvent.

[0201] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending in a suitable solvent. Non-limiting examples of solvents include those described in the Examples and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water.

[0202] The above solvents may be used by mixing two or more of them in an appropriate ratio.

[0203] When a base is used in the reaction of each step, the base shown below or the base described in the Examples is used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0204] When an acid or an acid catalyst is used in the reaction of each step, the acid or acid catalyst shown below or the acid or acid catalyst described in the Examples can be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0205] Unless otherwise specified, the reactions in each step are taken from, for example, Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); Organic Syntheses Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, Oxford University Press); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); or Comprehensive Organic Transformations (VCH Publishers Inc., 1989, or the like, or may be carried out in accordance with a method known to those skilled in the art, or a method described in the Examples.

[0206] In each step, the protection or deprotection reaction of functional groups is carried out according to a method known to those skilled in the art, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene and Peter G.M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (P.J. Kocienski), published by Thieme in 2004, or a method described in the Examples.

[0207] Non-limiting examples of protecting groups for hydroxyl groups of alcohols and the like and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as tert-butyl carbonate.

[0208] Non-limiting examples of the protecting group for the carbonyl group of an aldehyde include, for example, acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as 1,3-dioxane.

[0209] Non-limiting examples of protecting groups for the carbonyl group of ketones include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone.

[0210] Non-limiting examples of the protecting group for a carboxyl group include, for example, ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide.

[0211] Non-limiting examples of thiol protecting groups include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate; and the like.

[0212] Non-limiting examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include, for example, carbamate-type protecting groups such as benzyl carbamate and tert-butyl carbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; sulfonamide-type protecting groups such as methanesulfonamide; 2-(trimethylsilyl)ethoxymethyl group;

[0213] The protecting group can be removed by a method known to those skilled in the art, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0214] In each step, when a reduction reaction is performed, non-limiting examples of reducing agents include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; and the like. When reducing carbon-carbon double or triple bonds, methods using catalysts such as palladium-carbon or Lindlar catalyst are available. When reducing nitro groups, methods using catalysts such as rhodium-carbon in the presence of iron(II) acetate are available. When reducing azide groups, methods using triphenylphosphine in the presence of water are available.

[0215] In the case of carrying out an oxidation reaction in each step, non-limiting examples of the oxidizing agent include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, potassium peroxymonosulfate (OXONE®), and tert-butylhydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodides such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0216] When a radical cyclization reaction is carried out in each step, non-limiting examples of radical initiators include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Non-limiting examples of radical reaction reagents include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0217] When a Wittig reaction is carried out in each step, non-limiting examples of the Wittig reagent include alkylidenephosphoranes, etc. The alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0218] In each step, when the Horner-Emmons reaction is carried out, non-limiting examples of the reagent include phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides or organolithium compounds.

[0219] In each step, when a Friedel-Crafts reaction is carried out, non-limiting examples of the reagent include a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0220] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (for example, a phenol, an amine, or imidazole) and a base (for example, an inorganic base or an organic base) can be used as the reagent.

[0221] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is performed, non-limiting examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0222] When a Grignard reaction is carried out in each step, non-limiting examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0223] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, and inorganic bases) can be used as reagents.

[0224] When the Vilsmeier-Haack reaction is carried out in each step, the reagent used may be a combination of phosphoryl chloride and an amide derivative (for example, N,N-dimethylformamide), or (chloromethylene)dimethyliminium chloride (Vilsmeier reagent).

[0225] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, non-limiting examples of the azidation agent include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are methods using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and methods using trimethylsilyl azide and a Lewis acid.

[0226] When a reductive amination reaction is performed in each step, non-limiting examples of reducing agents include sodium triacetoxyborohydride, borane-2-methylpyridine complex, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, non-limiting examples of carbonyl compounds include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of amines include primary amines such as ammonia and methylamine, and secondary amines such as dimethylamine.

[0227] When Mitsunobu reaction is carried out in each step, azodicarboxylic acid esters (for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine can be used as reagents.

[0228] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is performed, non-limiting examples of the reagent include acyl halides such as acid chlorides and acid bromides; and activated carboxylic acids such as acid anhydrides, activated esters, and sulfates. When an amidation reaction is performed using an unactivated ester, trimethylaluminum or the like can be used as an activating agent. Examples of activating agents for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be further added to the reaction.

[0229] In each step, when a coupling reaction is carried out, non-limiting examples of the metal catalyst include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases.

[0230] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide can be used as the thiocarbonylating agent. However, in addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0231] In each step, when the Wohl-Ziegler reaction is carried out, non-limiting examples of the halogenating agent include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0232] When a halogenation reaction of a hydroxy group is carried out in each step, non-limiting examples of the halogenating agent include hydrohalic acid and acid halides of inorganic acids, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc., may be used. Alternatively, a method may be used in which an alkyl halide is obtained from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. Alternatively, a method may be used in which an alkyl halide is synthesized via a two-step reaction, such as converting an alcohol to a sulfonic acid ester and then reacting it with lithium bromide, lithium chloride, or sodium iodide.

[0233] In each step, when Arbuzov reaction is carried out, non-limiting examples of reagents include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0234] When a sulfonate esterification reaction is carried out in each step, non-limiting examples of the sulfonylating agent include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0235] In each step, when a hydrolysis reaction is carried out, an acid or a base can be used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid, triethylsilane, or the like may be added to reductively trap the by-product tert-butyl cation.

[0236] When a dehydration reaction is carried out in each step, non-limiting examples of the dehydrating agent include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0237] In the case of carrying out an alkylation reaction in each step, non-limiting examples of the base include potassium carbonate, tripotassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, n-butyllithium, and the like.

[0238] In each step, when an aromatic electrophilic substitution reaction is carried out, an electrophilic agent (e.g., a halogenating agent, a nitrating agent, etc.) can be used as a reagent. Non-limiting examples of halogenating agents include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectFluor®), etc. Non-limiting examples of nitrating agents include nitric acid, etc.

[0239] When the Leimgruber-Batcho indole synthesis reaction is carried out in each step, a carbon chain homologation reagent (e.g., N,N-dimethylformamide dimethyl acetal, etc.) and a reducing agent (e.g., catalytic amounts of iron(II) acetate and rhodium-carbon, etc. under a hydrogen atmosphere) can be used as reagents.

[0240] In each step, when a deoxygenative fluorination reaction is carried out, non-limiting examples of the fluorinating agent include bis(2-methoxyethyl)aminosulfur trifluoride, diethylaminosulfur trifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, N,N-diethyl-S,S-difluorosulfiliminium tetrafluoroborate, difluoro-4-morpholinylsulfonium tetrafluoroborate, and the like.

[0241] When a decarboxylative fluorination reaction is carried out in each step, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectFluor (registered trademark)) and an inorganic base (e.g., lithium carbonate, lithium acetate, potassium fluoride, etc.) can be used as the reagent.

[0242] The compound of formula (I) or a salt thereof can be synthesized according to the methods exemplified in the following Production Methods A to H or methods similar thereto.

[0243] Unless otherwise specified, the symbols in each general formula in the reaction scheme have the same meanings as above. a is replaced by C 1-3 alkyl groups, optionally substituted C 1-3 Examples of the alkyl group include C substituted with 1 to 3 substituents selected from the above-mentioned substituent group A as needed. 1-3 In some embodiments, R a is the unsubstituted C 1-3 In the formula, X is selected from halogens (e.g., fluorine, chlorine, bromine, or iodine). 1 is selected from protecting groups for alcoholic hydroxyl groups (e.g., tert-butyldimethylsilyl ether, etc.). 2 is selected from protecting groups for phenolic hydroxyl groups (such as benzyl ethers).

[0244] The starting compounds used in each production method are commercially available or can be produced by methods known to those skilled in the art.

[0245] Among the compounds of formula (I), the compound of formula (Ia) in which Z is selected from CH2, CF2, and O, or a salt thereof can be produced from compound (2) by the following method. [Manufacturing method A] [ka]

[0246] In the formula, Z a is selected from CH2, CF2, and O, and the other symbols have the same meanings as above.

[0247] Compound (4) can be produced by subjecting compound (2) to a nucleophilic aromatic substitution reaction with compound (3). Potassium carbonate or the like can be used as a base. Compound (6) can be produced by subjecting compound (4) to a reduction reaction. Compound (6) can also be produced by subjecting compound (5), obtained by hydrolysis of compound (4), to a reduction reaction. Compound (7) can be produced by halogenating the hydroxy group of compound (6). Examples of reagents include phosphorus tribromide. Compounds of formula (Ia) can be produced by subjecting compound (7) to an alkylation reaction with compound (8).

[0248] Among the compounds of formula (Ia), Z a is CH2 and R 3 The compound of formula (Ib) or a salt thereof, wherein is a hydroxy group, can be produced from compound (7) by the following method. [Manufacturing method B] [ka]

[0249] The compound of formula (Ib) can also be prepared by alkylating compound (7) with compound (9) to give compound (10), followed by deprotection.

[0250] Among the compounds of formula (Ia), R 1 The compound of formula (Ic) or a salt thereof in which is a difluoromethyl group can also be produced from compound (2) by the following method. [Manufacturing method C] [ka]

[0251] Compound (12) can be produced by subjecting compound (2) to a nucleophilic aromatic substitution reaction with compound (11). Compound (4b) can be produced by subjecting compound (12) to a deoxygenative fluorination reaction. Compound (6b) can be produced by subjecting compound (4b) to a reduction reaction. Compound (6b) can also be produced by subjecting compound (5b), which is obtained by hydrolyzing compound (4b), to a reduction reaction. Compound (7b) can be produced by halogenating the hydroxy group of compound (6b). Compound (Ic) can be produced by subjecting compound (7b) to an alkylation reaction with compound (8).

[0252] Among the compounds of formula (Ic), Z a is CH2 and R 3 The compound of formula (Id) or a salt thereof, wherein is a hydroxy group, can also be produced from compound (7b) by the following method. [Manufacturing method D] [ka]

[0253] The compound of formula (Id) can be produced by alkylating compound (7b) with compound (9) to give compound (10b), followed by deprotection.

[0254] Among the compounds of formula (Ia), Z a is O and R 2 The compound of formula (Ie) or a salt thereof in which R is a monofluoromethyl group or a difluoromethyl group can also be produced from compound (7) by the following method. [Manufacturing method E] [ka]

[0255] In the formula, R 2a is a monofluoromethyl group or a difluoromethyl group, and the other symbols have the same meanings as above.

[0256] Compound (14) can be produced by alkylating compound (7) with compound (13). Compound (15) can be produced by cyclizing compound (14) in the presence of a base. Non-limiting examples of the cyclizing agent include triphosgene, and examples of the base include triethylamine. Compound (Ie) can be produced by deoxygenative fluorination of compound (15). Alternatively, the compound of formula (Ie) can be produced by oxidizing compound (15) to give compound (16), which can then be subjected to deoxygenative fluorination.

[0257] Among the compounds of formula (I), Z is NH and R 3 The compound of formula (If) or a salt thereof, wherein is a hydrogen atom, can be produced from compound (7) by the following method. [Manufacturing method F] [ka]

[0258] Compound (18) can be produced by alkylating compound (7) with compound (17). Compound (19) can be produced by cyclizing compound (18) in the presence of a base. An example of the cyclizing agent is triphosgene, and an example of the base is triethylamine. A compound of formula (If) can be produced by deprotecting compound (19).

[0259] Among the compounds of formula (I), the compound of formula (Ia) in which Z is CH, CF, or O, or a salt thereof, can also be produced from compound (20) by the following method. [Production Method G] [ka]

[0260] Compound (21) can be prepared by alkylating compound (20) with compound (8). Compound (22) can be obtained by deprotecting compound (21). Compound (Ia) can be prepared by coupling compound (22) with compound (23).

[0261] Among the compounds of formula (Ia), Z a is CH2 and R 3 The compound of formula (Ib) or a salt thereof, wherein is a hydroxy group, can also be produced from compound (20) by the following method. [Manufacturing method H] [ka]

[0262] Compound (24) can be produced by alkylating compound (20) with compound (9). Compound (25) can be produced by the alkylation of P of compound (24). 2 The compound of formula (Ib) can be prepared by coupling compound (25) with compound (23) to obtain compound (26), which is obtained by deprotecting the P group. 1 The compound can be prepared by deprotecting the hydroxyl group.

[0263] In the compound of formula (I), the functional groups in the molecule can be converted to the desired functional group by combining chemical reactions known to those skilled in the art, including, but not limited to, oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0264] The compound of formula (I) obtained by the above production method can be isolated and purified by known means, such as solvent extraction, pH change of the solution, dissolution transfer, crystallization, recrystallization, chromatography, and the like.

[0265] When the compound of formula (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also included in the compound of formula (I), and each can be obtained as a single product by synthetic methods and separation methods known to those skilled in the art. For example, when the compound of formula (I) contains optical isomers, the optical isomers resolved from the compound are also included in the compound of formula (I).

[0266] Optical isomers can be prepared by methods known to those skilled in the art.

[0267] The compounds of formula (I) may be in crystalline form.

[0268] The crystal of the compound of formula (I) (hereinafter, sometimes referred to as the crystal of the present disclosure) can be produced by crystallizing the compound of formula (I) using a crystallization method known to those skilled in the art.

[0269] The crystals of the present disclosure may have excellent physicochemical properties (e.g., melting point, solubility, stability, etc.) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion, etc.), and efficacy), and are expected to be useful as pharmaceuticals. [Example]

[0270] The present disclosure will be further described in detail below by referring to examples, test examples, and formulation examples. These examples do not limit the present disclosure in any way and can be modified as long as they do not deviate from the scope of the present disclosure.

[0271] In the following examples, "room temperature" generally refers to about 10°C to about 35°C. Ratios shown for mixed solvents are by volume unless otherwise specified. % means % by weight unless otherwise specified.

[0272] Unless otherwise specified, elution in column chromatography in the examples was carried out under observation by TLC (thin layer chromatography). In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The solvent used in column chromatography was the same as the elution solvent used in column chromatography. A UV detector was used for detection. In silica gel column chromatography, NH refers to the use of aminopropylsilane-bonded silica gel, and Diol refers to the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high-performance liquid chromatography), C18 refers to the use of octadecyl-bonded silica gel. The ratios shown for elution solvents are by volume unless otherwise specified.

[0273] 1 H NMR analysis was performed using ACD / SpecManager (trade name) software. Peaks with very gentle proton peaks, such as those of hydroxyl or amino groups, may not be recorded.

[0274] MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shown are actual measurements (found values). Molecular ion peaks are usually observed, but fragment ions may also be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0275] Optical rotation ([α] D The unit of sample concentration (c) in (a) is g / 100 mL.

[0276] Elemental analyses (anal.) are given as calculated (calcd) and found (found).

[0277] The peaks in the powder X-ray diffraction in the examples were obtained using Cu Kα radiation as the radiation source, and Ultima The peaks are measured at room temperature using IV (Rigaku Corporation, Japan).

[0278] The measurement conditions are as follows. Voltage (electric pressure) / current: 40kV / 50mA Scanning speed: 6 degrees / min 2θ scanning range: 2~35 degrees

[0279] In the examples, the crystallinity measured by powder X-ray diffraction was calculated by the Hermans method.

[0280] The following abbreviations are used in the following examples: mp: melting point MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization IPE: Diisopropyl ether DMF: N,N-dimethylformamide THF: tetrahydrofuran MeOH: Methanol MeCN: acetonitrile NMP: N-methylpyrrolidone Example 13 (4S,5S)-4-Hydroxy-5-methyl-1-{[6-(4-methylphenoxy)pyridin-3-yl]methyl}pyrrolidin-2-one A) Methyl 6-(p-tolyloxy)nicotinate

[0281] To a suspension of methyl 6-fluoronicotinate (8.00 g) and p-cresol (5.96 mL) in DMF (80 mL) was added potassium carbonate (8.55 g) at room temperature, and the mixture was stirred at 80° C. for 3 hours. After dilution with water, the resulting precipitate was collected by filtration and washed with water to obtain the title compound (12.5 g).

[0282] MS: [M+H] + 244.1. B) (6-(p-tolyloxy)pyridin-3-yl)methanol

[0283] To a suspension of methyl 6-(p-tolyloxy)nicotinate (11.5 g) in THF (100 mL) / MeOH (20 mL), sodium borohydride (6.61 g) was added at room temperature and stirred overnight. The mixture was then stirred at 60°C for 3 hours. The mixture was diluted with aqueous ammonium chloride and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane to give the title compound (9.46 g).

[0284] MS: [M+H] + 216.1. C) 5-(bromomethyl)-2-(p-tolyloxy)pyridine

[0285] To a mixture of (6-(p-tolyloxy)pyridin-3-yl)methanol (740 mg) and THF (10 mL) was added phosphorus tribromide (0.389 mL) at 0° C., followed by stirring at room temperature for 3 hours.

[0286] The mixture was diluted with ethyl acetate and water, and then extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane / ethyl acetate to give the title compound (842 mg).

[0287] MS: [M+H] + 278.0. D) (4S,5S)-4-Hydroxy-5-methyl-1-{[6-(4-methylphenoxy)pyridin-3-yl]methyl}pyrrolidin-2-one

[0288] To a mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidin-2-one (2.00 g), 5-(bromomethyl)-2-(p-tolyloxy)pyridine (3.64 g), and THF (20 mL) was added a 0.5 M solution of potassium hexamethyldisilazide in toluene (19.2 mL) at 0° C., and the mixture was stirred at room temperature overnight.

[0289] The mixture was diluted with ethyl acetate and water and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methyl-1-((6-(p-tolyloxy)pyridin-3-yl)methyl)pyrrolidin-2-one (2.13 g). This was dissolved in THF (10 mL), and 4 M hydrogen chloride solution in cyclopentyl methyl ether (20 mL) was added at room temperature. The mixture was stirred at 60 °C for 3 hours.

[0290] The mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate, then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, and ethyl acetate / methanol) and triturated with hexane / ethyl acetate to give the title compound (1.24 g).

[0291] 1 H NMR (300 MHz, DMSO-d6) δ 1.05 (3H, d, J = 6.8 Hz), 2.15(1H, dd, J = 16.6, 3.4 Hz), 2.31(3H, s), 2.52-2.61 (1H, m), 3.43-3.55 (1H, m), 4.07 (1H, d, J = 15.4 Hz),4.11-4.21 (1H, m), 4.59 (1H, d, J = 15.4 Hz), 5.06 (1H, d, J = 4.9 Hz), 6.90-7.02 (3H,m), 7.20 (2H, d, J = 7.9 Hz), 7.66 (1H, dd, J = 8.5, 2.4 Hz), 8.01 (1H, d, J =1.9 Hz). Example 17 (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidin-2-one

[0292] A 2M hydrogen chloride-ethanol solution (240 mL) was added dropwise to a solution of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2-fluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidin-2-one (140 g) obtained in Steps A) to E) of Example 38 in ethanol (100 mL) at 0°C, followed by the addition of a 5% hydrogen chloride-methanol solution (218 mL). The resulting mixture was slowly warmed to room temperature and stirred overnight (using a granular silica gel tube). The mixture was concentrated, ethyl acetate (500 mL) was added to the residue, and the mixture was cooled to 0°C. An aqueous sodium carbonate solution (500 mL) was slowly added, and the organic and aqueous layers were separated. The aqueous layer was washed with ethyl acetate (1000 mL), and the organic layer was separated. The resulting organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. After dissolving the residue in ethyl acetate (500 mL), it was filtered through an NH silica gel pad (eluted with ethyl acetate (2000 mL)) and concentrated under reduced pressure. Toluene / ethyl acetate (1:0.5) was added to the residue and heated to 50° C. with stirring, then filtered to obtain the crude product (90.5 g). After further concentration of the filtrate, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (6.37 g).

[0293] All steps up to this point were repeated seven times to finally obtain 525 g of the title compound.

[0294] Ethyl acetate (1630 mL) was added to the title compound (523 g) thus obtained, heated to 50° C., and stirred until dissolved. The solution was filtered and cooled to room temperature, and then heptane (2120 mL) was added dropwise with stirring. After stirring the mixture for 1 hour, heptane (4230 mL) was added dropwise. Heptane (4230 mL) was added dropwise to the mixture, and the mixture was further stirred overnight. The precipitate was collected by filtration and washed with heptane, then dried under reduced pressure at 50° C. to give the title compound (500 g) as crystals.

[0295] 1 H NMR (300 MHz, DMSO-d6) δ 1.04 (3H, d, J = 6.6 Hz) 2.15(1H, dd, J = 16.7, 3.3 Hz) 2.52-2.60 (1H, m) 3.45-3.54 (1H, m) 4.07-4.19 (2H,m) 4.59 (1H, d, J = 15.5 Hz) 5.07 (1H, d, J = 4.5 Hz) 6.86-7.27 (2H, m) 7.47 (2H, d, J = 4.1 Hz) 7.61 (1H, d, J =11.3 Hz) 7.74 (1H, dd, J = 8.5, 2.5 Hz) 7.99 (1H, d, J = 1.9 Hz).

[0296] X-ray powder diffraction patterns were measured using a Rigaku Ultima IV (Rigaku, Tok The ion beam was generated using copper K-α radiation using a ion beam splitter (Yokohama, Japan).

[0297] The obtained crystals were characterized by having distinct peaks at 2θ of 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2°, and 22.5°±0.2° in the powder X-ray diffraction pattern. Example 37 (4S,5S)-1-{[6-(2,4-difluorophenoxy)pyridin-3-yl]methyl}-4-hydroxy-5-methylpyrrolidin-2-one A) Methyl 6-(2,4-difluorophenoxy)nicotinate

[0298] A mixture of methyl 6-fluoronicotinate (4.31 g), 2,4-difluorophenol (3.80 g), potassium carbonate (5.76 g), and MeCN (30 mL) was stirred at 60° C. for 16 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated brine, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure to give the title compound (7.37 g).

[0299] MS: [M+H] + 266.3. B) (6-(2,4-difluorophenoxy)pyridin-3-yl)methanol

[0300] To a suspension of methyl 6-(2,4-difluorophenoxy)nicotinate (7.37 g) in THF (60 mL) / MeOH (15 mL) was added sodium borohydride (4.21 g) at room temperature, and the mixture was stirred at 60° C. for 3 hours.

[0301] Sodium borohydride (4.21 g) was then added at room temperature, and the mixture was stirred at 60° C. for an additional 3 hours. The solvent was evaporated, and the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure to give the title compound (6.59 g).

[0302] MS: [M+H] + 238.3. C) 5-(bromomethyl)-2-(2,4-difluorophenoxy)pyridine

[0303] To a mixture of (6-(2,4-difluorophenoxy)pyridin-3-yl)methanol (6.59 g) and THF (70 mL) was added phosphorus tribromide (2.90 mL) at 0° C., followed by stirring at room temperature for 16 hours.

[0304] The mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (7.07 g).

[0305] 1 H NMR (300 MHz, DMSO-d6) δ 4.72 (2H, s), 7.10-7.20 (2H,m), 7.36-7.50 (2H, m), 7.96 (1H, dd, J = 8.5, 2.4 Hz), 8.18 (1H, d, J = 2.3 Hz). D) (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidin-2-one

[0306] To a mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidin-2-one (2.26 g) and THF (40 mL), 1.6 M butyllithium solution in hexane (6.16 mL) was added at -78°C and stirred at 0°C for 30 minutes. 5-(Bromomethyl)-2-(2,4-difluorophenoxy)pyridine (2.96 g) was added to the mixture, and the mixture was stirred at room temperature for 1 hour and then at 50°C for an additional 7.5 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.30 g).

[0307] MS: [M+H] + 449.2. E) (4S,5S)-1-{[6-(2,4-difluorophenoxy)pyridin-3-yl]methyl}-4-hydroxy-5-methylpyrrolidin-2-one

[0308] A mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidin-2-one (2.29 g) and a 2 M solution of hydrogen chloride in ethanol (40 mL) was stirred at room temperature for 1 hour.

[0309] The mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane and ethyl acetate / methanol) to obtain a crude product. This was dissolved in ethyl acetate at 80°C, and heptane was added dropwise to the solution. The resulting suspension was stirred at room temperature for 18 hours.

[0310] The precipitate was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (1.47 g).

[0311] 1 H NMR (300 MHz, DMSO-d6) δ 1.04 (3H, d, J = 6.8 Hz), 2.14(1H, dd, J = 16.6, 3.0 Hz),2.52-2.63 (1H, m), 3.44-3.54 (1H, m), 4.04-4.21 (2H, m), 4.59 (1H, d, J = 15.4Hz), 5.05 (1H, d, J = 4.9 Hz), 7.06-7.19 (2H, m), 7.32-7.48 (2H, m), 7.71 (1H,dd, J = 8.5, 2.4 Hz), 7.97 (1H, d, J = 1.9 Hz). Example 38 (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidin-2-one A) Methyl 6-(2-fluoro-4-formylphenoxy)nicotinate

[0312] A mixture of methyl 6-fluoronicotinate (12.2 g), 3-fluoro-4-hydroxybenzaldehyde (11.0 g), potassium carbonate (16.3 g), and NMP (75 mL) was stirred at 90° C. in a nitrogen atmosphere for 16 hours.

[0313] The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from hexane to give the title compound (17.4 g).

[0314] MS: [M+H] + 276.0. B) Methyl 6-(4-(difluoromethyl)-2-fluorophenoxy)nicotinate

[0315] (Diethylamino)sulfur trifluoride (11.5 mL) was added to a solution of methyl 6-(2-fluoro-4-formylphenoxy)nicotinate (8.00 g) in toluene (90 mL) at 0°C, and the mixture was stirred at room temperature for 1 day. After quenching the reaction with MeOH (10 mL), the mixture was diluted with 10% aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.14 g).

[0316] MS: [M+H] + 298.0. C) (6-(4-(difluoromethyl)-2-fluorophenoxy)pyridin-3-yl)methanol

[0317] To a suspension of methyl 6-(4-(difluoromethyl)-2-fluorophenoxy)nicotinate (8.14 g) in THF (60 mL) / MeOH (15 mL), sodium borohydride (4.14 g) was added at room temperature, and the mixture was stirred at 60°C for 1 hour. Sodium borohydride (4.14 g) was added at room temperature, and the mixture was stirred at 60°C for an additional 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (5.33 g).

[0318] MS: [M+H] + 270.0. D) 5-(bromomethyl)-2-(4-(difluoromethyl)-2-fluorophenoxy)pyridine

[0319] To a mixture of (6-(4-(difluoromethyl)-2-fluorophenoxy)pyridin-3-yl)methanol (920 mg) and THF (10 mL), phosphorus tribromide (0.357 mL) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. After diluting the mixture with ethyl acetate, the solution was washed with aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (977 mg).

[0320] MS: [M+H] + 332.0. E) (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2-fluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidin-2-one

[0321] To a mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidin-2-one (1.65 g) and THF (24 mL), a 1.6 M butyllithium solution in hexane (4.50 mL) was added dropwise at -78°C, followed by stirring at 0°C for 30 minutes. 5-(bromomethyl)-2-(4-(difluoromethyl)-2-fluorophenoxy)pyridine (2.39 g) was added to the mixture, and the mixture was stirred at room temperature for 20 minutes, then at 50°C for 22 hours and at 40°C for 48 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.15 g).

[0322] MS: [M+H] + 481.2. F) (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidin-2-one

[0323] A mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2-fluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidin-2-one (2.14 g) and 2 M hydrogen chloride solution in ethanol (40 mL) was stirred at room temperature for 18 hours. After concentration, the residue was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine. It was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, and ethyl acetate / methanol) to give the crude product (1.61 g). This crude product was dissolved in warm ethyl acetate (5 mL), and heptane (8 mL) was added dropwise to the solution at room temperature, and the mixture was stirred for 15 minutes. Heptane (16 mL) was added dropwise to the resulting mixture at room temperature, and the mixture was stirred for an additional 30 minutes. To the resulting mixture was added heptane (16 mL) dropwise at room temperature, and the mixture was stirred for an additional 72 hours. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (1.52 g) as crystals.

[0324] 1 H NMR (300 MHz, DMSO-d6) δ 1.04 (3H, d, J = 6.8 Hz), 2.15(1H, dd, J = 16.6, 3.4 Hz),2.52-2.61 (1H, m), 3.45-3.55 (1H, m), 4.06-4.21 (2H, m), 4.59 (1H, d, J = 15.4Hz), 5.07 (1H, d, J = 4.9 Hz), 7.07 (1H, t, J = 57.0 Hz), 7.15 (1H, d, J = 8.7Hz), 7.47 (2H, d, J = 4.1 Hz), 7.61 (1H, d, J = 10.9 Hz), 7.74 (1H, dd, J =8.5, 2.4 Hz), 7.99 (1H, d, J = 1.9Hz).

[0325] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with copper K-α radiation.

[0326] The obtained crystals were characterized by having distinct peaks at 2θ of 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2°, and 25.2°±0.2° in a powder X-ray diffraction pattern. Example 45 (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidin-2-one A) 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylic acid methyl ester

[0327] A mixture of methyl 2-chloropyrimidine-5-carboxylate (5.00 g), 2,4-difluorophenol (2.77 mL), potassium carbonate (6.01 g), and MeCN (60 mL) was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated brine, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was crystallized from hexane to give the title compound (7.18 g).

[0328] MS: [M+H] + 267.0. B) 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylic acid

[0329] To a mixture of methyl 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylate (7.18 g) and THF (80 mL), 2 M aqueous sodium hydroxide (20.2 mL) was added at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (40 mL), and neutralized with 1 M hydrochloric acid (40 mL). The resulting precipitate was collected and washed with water to give the title compound (4.98 g).

[0330] MS: [MH] + 250.9. C) (2-(2,4-difluorophenoxy)pyrimidin-5-yl)methanol

[0331] To a mixture of 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylic acid (4.97 g) and THF (80 mL), isobutyl chloroformate (3.07 mL) and 4-methylmorpholine (3.25 mL) were added at 0°C, and the mixture was stirred at the same temperature for 1 hour. Sodium borohydride (1.86 g) and water (20 mL) were added dropwise at 0°C, and the mixture was stirred at room temperature for an additional 16 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.93 g).

[0332] 1 H NMR (300 MHz, DMSO-d6) δ 4.50 (2H, d, J = 5.7 Hz), 5.38(1H, t, J = 5.7 Hz), 7.11-7.21 (1H, m), 7.41-7.53 (2H, m), 8.59 (2H, s). D) 5-(bromomethyl)-2-(2,4-difluorophenoxy)pyrimidine

[0333] To a mixture of (2-(2,4-difluorophenoxy)pyrimidin-5-yl)methanol (2.93 g) and THF (30 mL), phosphorus tribromide (1.29 mL) was added at 0°C and stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, and the solution was washed with aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.34 g).

[0334] MS: [M+H] + 300.9. E) (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidin-2-one

[0335] To a mixture of (S)-5-methylpyrrolidin-2-one (0.364 g) and THF (12 mL), 1.6 M butyllithium solution in hexane (2.30 mL) was added dropwise at -78 °C and stirred at 0 °C for 30 minutes. 5-(Bromomethyl)-2-(2,4-difluorophenoxy)pyrimidine (1.11 g) was added to the mixture and stirred at room temperature for 1.5 hours. The mixture was diluted with ethyl acetate and aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, passed through a silica gel / NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and recrystallized from ethyl acetate / heptane to give the title compound (0.621 g) as crystals.

[0336] 1 H NMR (300 MHz, DMSO-d6) δ 1.13 (3H, d, J = 6.4 Hz),1.44-1.59 (1H, m), 2.06-2.34 (3H, m), 3.52-3.64 (1H, m), 4.17 (1H, d, J = 15.8Hz), 4.56 (1H, d, J = 15.4 Hz), 7.11-7.21 (1H, m), 7.41-7.53 (2H, m), 8.55 (2H,s).

[0337] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with copper K-α radiation.

[0338] The obtained crystals were characterized by having clear peaks at 2θ of 7.4°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 20.6°±0.2°, and 21.3°±0.2° in a powder X-ray diffraction pattern. was assigned. Example 49 (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one A) 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylic acid methyl ester

[0339] A mixture of methyl 2-chloropyrimidine-5-carboxylate (5.00 g), 4-chloro-2-fluorophenol (3.08 mL), potassium carbonate (6.01 g), and MeCN (60 mL) was stirred at room temperature under a nitrogen atmosphere for 16 hours. 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 sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was crystallized from hexane to give the title compound (7.39 g).

[0340] MS: [M+H] + 283.0. B) 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylic acid

[0341] To a mixture of methyl 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylate (7.39 g) and THF (50 mL), 2 M aqueous sodium hydroxide (14.4 mL) was added at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL), and neutralized with 1 M hydrochloric acid (29 mL). The resulting precipitate was collected by filtration and washed with water to give the title compound (6.35 g).

[0342] MS: [MH] + 266.8. C) (2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl)methanol

[0343] To a mixture of 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylic acid (6.33 g) and THF (100 mL), isobutyl chloroformate (3.67 mL) and 4-methylmorpholine (3.89 mL) were added at 0°C, and the mixture was stirred at the same temperature for 1 hour. Sodium borohydride (2.23 g) and water (25 mL) were added dropwise at 0°C, and the mixture was stirred at room temperature for an additional 16 hours. 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 sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the resulting solid was washed with IPE to give the title compound (2.80 g).

[0344] 1 H NMR (300 MHz, DMSO-d6) δ 4.50 (2H, d, J = 5.3 Hz), 5.39(1H, t, J = 5.7 Hz), 7.33-7.40 (1H, m), 7.42-7.51 (1H, m), 7.65 (1H, dd, J =10.5, 2.3 Hz), 8.59 (2H, s). D) 5-(bromomethyl)-2-(4-chloro-2-fluorophenoxy)pyrimidine

[0345] To a mixture of (2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl)methanol (2.80 g) and THF (25 mL), phosphorus tribromide (1.15 mL) was added at 0° C. and stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, and the solution was washed with aqueous sodium bicarbonate and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from hexane to give the title compound (2.22 g).

[0346] MS: [M+H] + 316.9. E) (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

[0347] To a mixture of (S)-4-methyloxazolidin-2-one (0.103 g) and THF (8 mL), 1.6 M butyllithium solution (0.637 mL) in hexane was added at −78° C., and the mixture was stirred at 0° C. for 30 minutes. To the mixture, 5-(bromomethyl)-2-(4-chloro-2-fluorophenoxy)pyrimidine (0.323 g) was added, and the mixture was stirred at room temperature for 60 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and recrystallized from ethyl acetate / heptane to give the title compound (0.233 g) as crystals.

[0348] 1 H NMR (300 MHz, DMSO-d6) δ 1.18 (3H, d, J = 6.0 Hz),3.77-3.87 (2H, m), 4.27 (1H, d, J =15.0 Hz), 4.35-4.50 (2H, m), 7.34-7.41 (1H, m), 7.43-7.51 (1H, m), 7.66 (1H,dd, J = 10.4, 2.4 Hz), 8.63 (2H, s).

[0349] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with copper K-α radiation.

[0350] The obtained crystals were characterized by having distinct peaks at 2θ of 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 24.5°±0.2° in the powder X-ray diffraction pattern.

[0351] The example compounds are shown in the table below. MS in the table indicates measured values. The compounds of Examples 1 to 12, 14 to 16, 18 to 36, 39 to 44, 46 to 48, and 50 in the table below were produced according to the methods shown in the above examples or methods similar thereto. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Test Example 1: NR2B Ca 2+ Influx assay

[0352] To confirm that the compounds of the present disclosure exhibit antagonistic activity against NMDA receptors containing the NR2B subunit, the inhibitory effect on the activation of the receptor was measured using human embryonic kidney cells expressing an NMDA receptor composed of four subunits, each consisting of two sets of heterodimers of NR1 and NR2B, specifically HEK293 cells expressing human glutamate ionotropic receptor NMDA subunit 1 (GRIN1) and human glutamate ionotropic receptor NMDA subunit 2B (GRIN2B).

[0353] HEK293 cells expressing GRIN1 and GRIN2B were purchased from ChanTest (Human NMDA (NR1 / NR2B) receptor expressing stably replicating cell line (HEK293) Catalog No. CT6121).

[0354] As an indicator of NMDA receptor activation, intracellular calcium ions (Ca) are released by the binding of glycine and glutamate to NR1 and NR2B, respectively. 2+ ) inflow was used.

[0355] HEK293 cells expressing GRIN1 and GRIN2B were cultured in cell culture flasks in an incubator (37°C, 5% CO2) using DMEM / F-12 medium (Cosmo Bio, 10-092-CM) supplemented with 10% FBS (fetal bovine serum, Ausgene), 100 units / mL penicillin, 100 μg / mL streptomycin, 500 μg / mL neomycin, 100 μg / mL Zeocin (Invitrogen registered trademark), and 5 μg / mL blasticidin.

[0356] The day before the assay, cells were detached from the flask by trypsinization and plated at 8 × 10 5The cells were suspended in seeding medium (DMEM (Invitrogen, 31053) supplemented with 10% FBS, 100 units / mL penicillin, and 100 μg / mL streptomycin) to a concentration of 10,000 cells / mL. 25 μL of the cells were seeded into a 384-well plate (Falcon, 356663) at 20,000 cells / well, and cultured overnight in an incubator. On the day of the assay, tetracycline (Wako Pure Chemical Industries, 209-16561) was diluted to 2 μg / mL in the seeding medium and added at 25 μL / well to the plate. The plate was then cultured for 2 hours in an incubator. The medium was then removed, and the plate was washed with 50 μL / well of assay buffer (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl, 10 mM HEPES (pH 7.2), 10 mM glucose, 0.1% BSA). Next, 25 μL / well of loading buffer (assay buffer supplemented with 2.5 μM Fluo-4AM, 2 mM amaranth, and 1 mM tartrazine) was added, followed by incubation in an incubator for 30 minutes and at room temperature for 15 minutes. A solution of the example compound diluted with the assay buffer to 30 μM (final concentration 10 μM) was added at 25 μL / well, and the plate was left to stand at room temperature for 15 minutes. Using an FDSS7000EX / μCELL (Hamamatsu Photonics), 25 μL of assay buffer containing 30 μM glutamic acid and 30 μM glycine was added per well, and the fluorescence signal was measured every 3 seconds for 5 minutes at an excitation wavelength of 480 nm and an emission wavelength of 540 nm. The inhibitory activity was calculated as a relative activity value (inhibition rate) with the integrated fluorescence value of each well taken as 100% inhibition compared to the integrated fluorescence value of a well to which assay buffer containing no glutamic acid or glycine was added. The results are shown in Table 2. [Table 2]

[0357] As shown in Table 2 above, the compounds of the present disclosure inhibit the intracellular calcium ion (Ca 2+) influx was inhibited. That is, it was confirmed that the compounds of the present disclosure exert an antagonistic effect on NMDA receptors containing the NR2B subunit. Test Example 2: In vivo 3 H]MK-801 binding assay

[0358] To confirm that compounds of the present disclosure exert functional antagonism on NMDA receptors containing the NR2B subunit in vivo, binding studies were performed using a tritium-labeled form of MK-801 ((5R,10S)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene) ([ 3 This was performed using [H]MK-801, a compound that can bind to the opening site of the NMDA receptor.

[0359] The example compound (3 mg / kg / 2 mL, 0.5% MC water) or the vehicle (2 mL of 0.5% MC water) was orally administered (po) to Sprague Dawley rats (body weight 180-260 g). After a certain period of time (approximately the time until the maximum blood concentration), 3[H]MK-801 (20 μCi / kg / mL, Muromachi Kikai) was administered intravenously. After 10 minutes, the rats were euthanized by decapitation and subjected to craniotomy, and the hippocampi were collected. The collected hippocampi were homogenized in 30 volumes (30 mL per gram of tissue) of ice-cold 20 mM HEPES (pH 7.5, Hampton Research) using a homogenizer (T10 basic Ultra-Turrax) for 10 minutes. 600 μL of the homogenate was then immediately filtered through a GF / B Whatman glass filter (GE Health Care), which had been presoaked in 0.5% polyethyleneimine (FUJIFILM Wako Pure Chemical Corporation), and placed in a manifold filtration system (Millipore) by suction. The filter was washed four times with ice-cold saline (5 mL, Otsuka Pharmaceutical), placed in a scintillation vial, and then washed with 10 mL of liquid scintillator A (FUJIFILM Wako Pure Chemical Corporation) was added thereto, and the residual radioactivity was counted using a liquid scintillation counter (ALOKA LSC-6100).

[0360] Separately, the residual radioactivity of 100 μL of the homogenate was counted in the same manner. The value of [residual radioactivity of the filter / residual radioactivity of 100 μL of the homogenate] was calculated as the [ 3 The percentage of [H]MK-801 bound to the vehicle control group was then calculated. 3 The [H]MK-801 binding rate was considered as 100%, and the [H]MK-801 binding rate in the group subcutaneously administered with an excess amount of MK-801 maleate (2 mg / kg / 2 mL, 0.5% MC water) was considered as 100%. 3 The [H]MK-801 binding rate in the group orally administered with the example compound was considered to be 0%. 3 The difference between the percentage of 3HMK-801 binding rate and the percentage in the vehicle control group (100%) was used as the [ 3The results are shown in Table 3. [Table 3]

[0361] As shown in Table 3 above, the compounds of the present disclosure are compounds capable of binding to the opening site of an NMDA receptor containing the NR2B subunit, [ 3 3H]MK-801 binding. That is, it was confirmed that the compounds of the present disclosure have functional antagonistic activity against NMDA receptors containing the NR2B subunit in vivo. Formulation Example 1 (Capsule Production) 1) 30 mg of the compound of Example 1 2) Finely powdered cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg Total 60mg

[0362] 1), 2), 3) and 4) are mixed and filled into a gelatin capsule. Formulation Example 2 (Tablet Production) 1) 30 g of the compound of Example 1 2) Lactose 50g 3) 15g corn starch 4) Carboxymethylcellulose calcium 44g 5) Magnesium stearate 1g 1000 tablets total 140g

[0363] The total amount of 1), 2), 3) and 30 g of 4) are mixed with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder and compressed into tablets using a tablet press. 1000 tablets containing 30 mg of the compound of Example 1 per tablet are thus obtained. The present invention provides, for example, the following items. (Item 1) Formula (I): [ka] or a salt thereof, wherein R 1 is a C optionally substituted with halogen and at least one fluorine; 1-3 alkyl groups; R 2 is a C optionally substituted with at least one fluorine 1-3 alkyl groups; R 3 is selected from hydrogen and a hydroxy group; Ring A is selected from an optionally substituted benzene group; Ring B has the formula: [ka] is selected from the group X and Y are each independently selected from carbon and nitrogen; Ring B 1 is selected from an optionally substituted benzene group, an optionally substituted pyridine group, and an optionally substituted pyrazine group; Ring B 2 is selected from an optionally substituted pyrimidine group; and Ring B 3 is selected from an optionally substituted pyrimidine group; and Z is selected from CH2, CF2, O, and NH; A compound or a salt thereof. (Item 2) R 1 is C optionally substituted with halogen and 1 to 3 fluorines 1-3 alkyl groups; R 2 is a C optionally substituted with 1 to 3 fluorines 1-3 alkyl groups; R 3 is selected from hydrogen and a hydroxyl group; Ring A is selected from a benzene group optionally substituted with 1 to 4 halogens; Ring B has the formula: [ka] is selected from the group X and Y are each independently selected from carbon and nitrogen; Ring B 1 is selected from an unsubstituted benzene group, an unsubstituted pyridine group, and an unsubstituted pyrazine group; Ring B 2 is an unsubstituted pyrimidine group; and Ring B 3 is an unsubstituted pyrimidine group; and Z is selected from CH2, CF2, O, and NH; Item 1. The compound or a salt thereof according to item 1. (Item 3) R 1 is a C optionally substituted with halogen and one or two fluorines 1-3 alkyl groups; R 2 is the unsubstituted C 1-3 alkyl groups; R 3 is selected from hydrogen and a hydroxyl group; Ring A is selected from a benzene group optionally substituted with one or two halogens; Ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen; Ring B 1 is selected from unsubstituted pyridine groups; and Ring B 2 is an unsubstituted pyrimidine group; and Z is CH2 or O; Item 1. The compound or a salt thereof according to item 1. (Item 4) R 1 is a C optionally substituted with halogen and one or two fluorines 1-3 alkyl groups; R 2 is the unsubstituted C 1-3 alkyl groups; R 3 is selected from hydrogen and a hydroxyl group; Ring A is a group represented by the formula: [ka] is selected from the group R v is selected from halogens; and R w is selected from hydrogen and halogen; Ring B has the formula: [ka] is selected from the group one of X and Y is carbon and the other is nitrogen; Ring B 1 is selected from unsubstituted pyridine groups; and Ring B 2 is an unsubstituted pyrimidine group; and Z is CH2 or O; Item 1. The compound or a salt thereof according to item 1. (Item 5) A compound which is (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidin-2-one or a salt thereof. (Item 6) A compound which is (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidin-2-one or a salt thereof. (Item 7) A compound which is (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one or a salt thereof. (Item 8) A pharmaceutical composition containing at least one entity selected from the compounds according to item 1 and salts thereof. (Item 9) 9. The pharmaceutical composition of claim 8, wherein the at least one entity is an antagonist of an NMDA receptor containing the NR2B subunit. (Item 10) 9. The pharmaceutical composition according to item 8, wherein the at least one entity is an agent for preventing or treating depression, bipolar disorder, migraine, pain, or cognitive impairment. (Item 11) Item 1. The compound or salt thereof according to item 1 for use in the prevention or treatment of depression, bipolar disorder, migraine, pain, or cognitive-related symptoms. (Item 12) A method for antagonizing an NMDA receptor containing the NR2B subunit in a mammal, comprising administering to the mammal an effective dose of at least one entity selected from the compounds described in item 1 and salts thereof. (Item 13) A method for preventing or treating depression, bipolar disorder, migraine, pain, or cognitive-behavioral symptoms in a mammal, comprising administering to the mammal an effective dose of at least one entity selected from the compounds described in item 1 and salts thereof. (Item 14) Use of at least one compound selected from the compounds according to item 1 and salts thereof in the manufacture of an agent for the prophylaxis or treatment of depression, bipolar disorder, migraine, pain, or dementia-related symptoms.

Claims

1. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, and 22.5°±0.2°.

2. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 8.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, and 22.5°±0.2°.

3. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 11.2°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, and 22.5°±0.2°.

4. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, and 22.5°±0.2°.

5. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2°, and 22.5°±0.2°.

6. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 8.5°±0.2°, 11.2°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, and 22.5°±0.2°.

7. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 8.5°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, and 22.5°±0.2°.

8. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 8.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2°, and 22.5°±0.2°.

9. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, and 22.5°±0.2°.

10. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 11.2°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2°, and 22.5°±0.2°.

11. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2°, and 22.5°±0.2°.

12. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2° and 22.5°±0.2°.

13. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 8.5°±0.2°, 11.2°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2°.

14. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 8.5°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2°, and 22.5°±0.2°.

15. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 11.5°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2°.

16. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 10.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, and 25.2°±0.2°.

17. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 5.1°±0.2°, 16.5°±0.2°, 17.6°±0.2°, and 25.2°±0.2°.

18. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 5.1°±0.2°, 10.3°±0.2°, 17.6°±0.2°, and 25.2°±0.2°.

19. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 5.1°±0.2°, 10.3°±0.2°, 16.5°±0.2°, and 25.2°±0.2°.

20. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 5.1°±0.2°, 10.3°±0.2°, 16.5°±0.2°, and 17.6°±0.2°.

21. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 5.1°±0.2°, 10.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, and 25.2°±0.2°.

22. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 5.1°±0.2°, 10.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2°, and 25.2°±0.2°.

23. A crystal of (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern including 2θ peaks at 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, and 25.2°±0.2°.