Cognitive-function-improving agent

Abstract

To provide a pharmaceutical composition used to treat or prevent a cognitive-function disease or disorder.SOLUTION: The present invention provides a pharmaceutical composition used to treat or prevent a disease or disorder caused by activation of Ca2+ / calmodulin-dependent kinase II, the pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a Ca-containing N-pyridyl urea derivative. 2+ The present invention relates to a pharmaceutical composition for use in the treatment or prevention of a disease or disorder caused by activation of calmodulin-dependent kinase II, particularly a pharmaceutical composition for use in improving cognitive function, and a method for treating or preventing a disease associated with cognitive impairment using the compound. [Background technology]

[0002] N-methyl-D-aspartate (NMDA) receptors (NMDA receptors, NMDARs), which are glutamate-gated cation channels in neurons, are known to regulate synaptic plasticity, which is the basis of neural development, connectivity, and cognition, through their abundance and activity. NMDA receptors are distributed ubiquitously throughout the brain, and NMDA receptors have properties that are distinct from the other major subtypes of ionotropic glutamate receptors (AMPA and kainate receptors). Mammalian NMDA receptors are thought to be composed of four subunits, consisting of two sets of heterodimers of GluN1 and GluN2, with a glycine-binding site on the GluN1 subunit and a glutamate-binding site on the GluN2 subunit. Four types of GluN2 subunits have been cloned, GluN2A, GluN2B, GluN2C, and GluN2D, and each has different expression sites and timing in vivo. There have been reports on the regulation of NMDA receptors via GluN2B (Patent Documents 1 and 2).

[0003] Ca 2+ Calmodulin-dependent protein kinase II (CaMKII) is a Ca 2+CaMKII is a serine / threonine-specific protein kinase controlled by the NR2A / calmodulin complex, and is known to be involved in many signal transduction cascades and is thought to play an important role in the plasticity of synaptic transmission and higher brain functions including learning and memory. It has been reported that the binding of CaMKII to GluN2B is involved in signal transduction, particularly in the long-term potentiation (LTP) phenomenon of synaptic responses (Non-Patent Documents 1-3). It has also been reported that GluN2A of CaMKII is involved in LTP (Non-Patent Document 2). Genome-wide association analysis has suggested that NR2A of CaMKII is strongly correlated with schizophrenia, depression, and the like (Non-Patent Document 4).

[0004] There have been many reports on N-pyridyl urea derivatives having pharmaceutical activity (for example, Patent Documents 3 and 4). There has also been a report on a method for synthesizing N-pyridyl urea derivatives (Non-Patent Document 6). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special table number 2018-520170 [Patent Document 2] Special table number 2018-504854 [Patent Document 3] Japanese Patent Application Publication No. 9-241243 [Patent Document 4] WO2019 / 099307 A1 [Non-patent literature]

[0006] [Non-Patent Document 1] Halt, AR et al., The EMBO Journal (2012) 31, 1203-1216 [Non-Patent Document 2] Incontro, S. et al., Nat Commun. 2018; 9: 2069. doi: 10.1038 / s41467-018-04439-7 [Non-Patent Document 3] Barcomb, K. et al., The Journal of Biological Chemistry 291, 31, 16082-16089 [Non-Patent Document 4] Cross-Disorder Group of the Psychiatric Genomics Consortium, Lancet 2013; 381: 1371-79 [Non-Patent Document 5] Poltavskaya, EG et al., Life 2021, 11, 997. https: / / doi.org / 10.3390 / life11100997 [Non-Patent Document 6] Arisawa, M. et al.,Org. Lett. 2021, 23, 9382-9386 DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0007] It cannot be said that there are any established therapeutic or preventive methods that are sufficiently effective against cognitive function diseases or disorders such as Alzheimer's disease, and there is a demand for new therapeutic and preventive agents that have a mechanism of action different from that of existing drugs.

[0008] In one aspect, the present invention aims to provide a pharmaceutical composition for use in treating or preventing a cognitive function disease or disorder.Further, the present invention aims to provide a method for treating or preventing a cognitive function disease or disorder using a specific N-pyridyl urea derivative.

[0009] In one aspect, the present invention aims to provide a GluN2A activator. Furthermore, the present invention aims to provide a method for activating GluN2A using a specific N-pyridyl urea derivative. In one aspect, the present invention provides a method for the preparation of a Ca 2+ The present invention aims to provide a calmodulin-dependent protein kinase II (CaMKII) activator. The present invention also aims to provide a pharmaceutical composition for use in treating or preventing a disease involving CaMKII. The present invention also aims to provide a method for treating or preventing a disease involving CaMKII using a specific N-pyridyl urea derivative. [Means for solving the problem]

[0010] The present inventors have conducted intensive research to achieve the above object, and have found that N-pyridyl urea derivatives have GluN2A activation activity, CaMKII activation activity, and therapeutic effects on cognitive function diseases or disorders, and have completed the present invention. The disclosure of this specification encompasses the inventions described below.

[0011] [1] Formula (I):

[0012] [ka]

[0013] [In the formula, R 1 and R 2 are each independently a hydrogen atom, and C 1-6 alkyl; X is a direct bond, O, or S; Q is R a pyridyl optionally substituted by 1 to 4 substituents selected from Y is a hydrogen atom, R a R a Phenyl optionally substituted with 1 to 4 substituents selected from b C which may be substituted with 1 to 4 substituents selected from 3-10 cycloalkyl, or R b C which may be substituted with 1 to 4 substituents selected from 6-10is cycloalkenyl; R a each independently represents a C group optionally substituted by hydroxy, cyano, or one or more halogen atoms; 1-6 Alkyl, optionally substituted with one or more halogen atoms 1-6 selected from alkoxy, halogen atoms, and phenyl; R b each independently represents a C which may be substituted by one or more halogen atoms; 1-6 Alkyl, optionally substituted with one or more halogen atoms 1-6 alkoxy, hydroxy, and halogen atoms. A pharmaceutical composition comprising a compound represented by the formula:

[0014] [2]R 1 and R 2 The pharmaceutical composition according to [1], wherein [3] The pharmaceutical composition according to [1] or [2], wherein X is O. [4] Q is R a The pharmaceutical composition according to any one of [1] to [3], wherein the 2-pyridyl is optionally substituted with 1 to 4 substituents selected from the following:

[0015] [5] The pharmaceutical composition according to any one of [1] to [4], wherein the 5- to 10-membered heteroaryl is pyridyl, quinolyl, thiazolyl, oxazolyl, benzothiazolyl, or benzoxazolyl.

[0016] [6]R a is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

[0017] [7]R b is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

[0018] [8]N-(4-methoxy-2-pyridyl)-N'-(3-methyl-2-pyridyl)urea; N-(4-Methoxy-2-pyridyl)-N'-2-pyridylurea; N-(4-methoxy-2-pyridyl)-N'-(4-chloro-3-pyridyl)urea; N-(4-Methoxy-2-pyridyl)-N'-(4-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4,6-dimethyl-2-pyridyl)urea; Bis-N,N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethyl-2-pyridyl)urea; Bis-N-(4-trifluoromethyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(5-quinolyl)urea; N-(6-methyl-2-benzothiazolyl)-N'-2-pyridylurea; N-(2-benzoxazolyl)-N'-2-pyridylurea; N-(4-Methoxy-2-pyridyl)-N'-2-thiazolylurea; N-(4-Methoxy-2-pyridyl)-N'-2-pyridylthiourea; Bis-N,N'-(4-methoxy-2-pyridyl)thiourea; Bis-N,N'-(2-pyridyl)thiourea; Bis-N,N'-(4-pyridyl)urea; Bis-N,N'-(3-pyridyl)urea; N-(2-pyridyl)-N'-(3-methylphenyl)urea; N-(4-Methoxy-2-pyridyl)-N'-phenylurea; N-(4-methoxy-2-pyridyl)urea; N-(6-trifluoromethyl-3-pyridyl)urea; N-(6-chloro-2-pyridyl)urea; N-(4-trifluoromethyl-2-pyridyl)urea; N-(6-chloro-3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-trifluoromethylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-chlorophenyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-cyclohexylurea; and [(1R,5R,7aR)-2,3,5,6,7,7a-Hexahydro-5-tert-butyldimethylsilyloxy-7a-methyl-1H-indenyl]-N'-(3-pyridyl)urea The pharmaceutical composition according to [1], comprising a compound selected from the group consisting of:

[0019] [9] The pharmaceutical composition according to any one of [1] to [8] for use in treating or preventing a disease or disorder caused by long-term potentiation of synaptic responses.

[10] Ca 2+ / The pharmaceutical composition according to any one of [1] to [9] for use in treating or preventing a disease or disorder caused by activation of calmodulin-dependent kinase II.

[0020]

[11] GluN2A-mediated Ca 2+ / The pharmaceutical composition according to any one of [1] to

[10] for use in treating or preventing a disease or disorder caused by activation of calmodulin-dependent kinase II.

[0021]

[12] The pharmaceutical composition according to any one of [1] to

[11] for use in the treatment or prevention of a cognitive function disease or disorder.

[13] The pharmaceutical composition described in

[12] , wherein the cognitive function disease or disorder is selected from Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease, psychiatric disorders, and neurodegenerative diseases.

[0022]

[14] The pharmaceutical composition according to any one of [1] to

[11] for use in the treatment or prevention of autism, depression, major depressive disorder, schizophrenia, or bipolar disorder.

[15] Formula (I):

[0023] [ka]

[0024] [In the formula, R 1 and R 2 are each independently a hydrogen atom, and C 1-6 alkyl; X is a direct bond, O, or S; Q is R a 2-pyridyl optionally substituted by 1 to 4 substituents selected from Y is R a R a Phenyl optionally substituted with 1 to 4 substituents selected from b C which may be substituted with 1 to 4 substituents selected from 5-7 cycloalkyl, or R b C which may be substituted with 1 to 4 substituents selected from 6-10 is cycloalkenyl; 5-10 membered heteroaryl is pyridyl, quinolyl, thiazolyl, oxazolyl, benzothiazolyl, or benzoxazolyl; R a each independently represents a C group optionally substituted by hydroxy, cyano, or one or more halogen atoms; 1-6 Alkyl, optionally substituted with one or more halogen atoms 1-6 selected from alkoxy, halogen atoms, and phenyl; R b each independently represents a C which may be substituted by one or more halogen atoms; 1-6 Alkyl, optionally substituted with one or more halogen atoms 1-6 alkoxy, hydroxy, and halogen atoms. or a pharma- ceutical acceptable salt thereof.

[0025]

[16] R 1 and R 2 is a hydrogen atom, or a pharma- ceutical acceptable salt thereof.

[17] The compound according to

[15] or

[16] , or a pharma- ceutical acceptable salt thereof, wherein X is O.

[0026]

[18] R a The compound according to any one of

[15] to

[17] , or a pharma- ceutical acceptable salt thereof, wherein is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

[0027]

[19] R b The compound according to any one of

[15] to

[18] , or a pharma- ceutical acceptable salt thereof, wherein is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

[0028]

[20] N-(4-methoxy-2-pyridyl)-N'-(3-methyl-2-pyridyl)urea; N-(4-Methoxy-2-pyridyl)-N'-2-pyridylurea; N-(4-methoxy-2-pyridyl)-N'-(4-chloro-3-pyridyl)urea; N-(4-Methoxy-2-pyridyl)-N'-(4-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4,6-dimethyl-2-pyridyl)urea; Bis-N,N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethyl-2-pyridyl)urea; Bis-N-(4-trifluoromethyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(5-quinolyl)urea; N-(6-methyl-2-benzothiazolyl)-N'-2-pyridylurea; N-(2-benzoxazolyl)-N'-2-pyridylurea; N-(4-Methoxy-2-pyridyl)-N'-2-thiazolylurea; N-(4-Methoxy-2-pyridyl)-N'-2-pyridylthiourea; Bis-N,N'-(4-methoxy-2-pyridyl)thiourea; Bis-N,N'-(2-pyridyl)thiourea; N-(2-pyridyl)-N'-(3-methylphenyl)urea; N-(4-Methoxy-2-pyridyl)-N'-phenylurea; N-(4-methoxy-2-pyridyl)urea; N-(6-chloro-2-pyridyl)urea; N-(4-trifluoromethyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-trifluoromethylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-chlorophenyl)urea; and The compound according to

[15] , or a pharma- ceutical acceptable salt thereof, selected from N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethylphenyl)urea. Effect of the Invention

[0029] In one aspect, the present invention provides a pharmaceutical composition for use in treating or preventing a cognitive function disease or disorder. In another aspect, the present invention provides a GluN2A activator or a CaMKII activator. [Brief description of the drawings]

[0030] [Figure 1] FIG. 1 shows the results of measuring the expression level of phosphorylated CaMKII by immunoblotting when a test compound (1 μM) was administered to GluN2A-overexpressing cells. [Diagram 2] Figure 2 shows the results of measuring the expression level of phosphorylated CaMKII when a test compound (1 μM) was administered to cells overexpressing NMDA receptor subunits. a11 means compound No. 11. [Figure 3a] Figure 3a is a graph showing a test for improving cognitive function by the Y-maze method using olfactory bulbectomized mice (OBX mice) that were chronically treated (orally administered) with a test compound (1 mg / kg) once a day for two weeks. The vertical axis represents alternation (%) as an index of normal alternation behavior (spatial working memory accuracy rate). a2, a11, and a12 represent compounds No. 2, No. 11, and No. 12, respectively. [Figure 3b] Figure 3b is a graph showing the effect of improving attention function (cognitive function) by a novel object recognition test using olfactory bulbectomized mice (OBX mice) chronically treated (orally administered) with a test compound (1 mg / kg) once a day for 2 weeks. The vertical axis shows the discrimination index calculated as the ratio (%) of the number of contacts with the replaced building block to the total number of contacts in the retention trial. a2, a11, and a12 represent compounds No. 2, No. 11, and No. 12, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention will now be described in more detail. According to one aspect of the present invention, a pharmaceutical composition is provided, comprising a compound represented by formula (I) or a pharma- ceutical acceptable salt thereof.In one embodiment, the composition is used in the treatment or prevention of cognitive function disease or disorder.The compound of the present invention includes the compounds represented by the following formulas (I) and (II).

[0032] [ka]

[0033] In the formula, R 1 , R 2 , X, Y, and Ra are as defined above, and n represents an integer of 0 to 4. In this specification, "C 1-6 "Alkyl" means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropylmethyl, and the like, for example, C 1-4 Alkyl and C 1-3 Alkyl is also included.

[0034] In this specification, "C 1-6 "Alkoxy" refers to an alkyloxy group [-O-(C 1-6alkyl), and includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, and the like. 1-4 Alkoxy and C 1-3 Also, in the present specification, "C 1-4 Alkoxy" includes, for example, C 1-3 Alkoxy is also included.

[0035] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present specification, "C optionally substituted with one or more halogen atoms" 1-6 Examples of "alkyl" include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, and the like.

[0036] In the present specification, "C optionally substituted with one or more halogen atoms" 1-6 "Alkoxy" refers to the above C 1-6 The alkoxy group may be substituted with one or more, for example, 1 to 5, specifically 1 to 3, halogen atoms, and the alkoxy may be unsubstituted. Examples thereof include trifluoromethoxy, pentafluoroethoxy, and 2,2,2-trifluoroethoxy.

[0037] In this specification, "C 3-10 "Cycloalkyl" refers to a monocyclic or bicyclic alkyl group having 3 to 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4,4,0]decanyl, bicyclo[4,3,0]nonanyl, and bicyclo[3,3,0]octanyl.

[0038] In this specification, "C 6-10 "Cycloalkenyl" means a monocyclic or bicyclic alkenyl group having 6 to 10 carbon atoms and containing 1, 2 or 3 double bonds, for example, one double bond. Examples include cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[4,4,0]decenyl, bicyclo[4,3,0]nonanyl, and bicyclo[3,3,0]octenyl.

[0039] When the compound of formula (I) forms a solvate such as a hydrate, the present invention can be practiced using the solvate. Furthermore, the compound of the present invention can be suitably practiced as a mixture, a solution, a crystalline polymorph, etc.

[0040] In the present specification, when a group is substituted with one or more substituents, it is substituted with, for example, 1 to 3 substituents. As the compound of the present invention, for example, the compounds described in the Examples of this specification can be used. More specifically, the following compounds can be used: N-(4-Methoxy-2-pyridyl)-N'-(3-methyl-2-pyridyl)urea (No. 1); N-(4-Methoxy-2-pyridyl)-N'-2-pyridylurea (No. 2); N-(4-Methoxy-2-pyridyl)-N'-(4-chloro-3-pyridyl)urea (No. 4); N-(4-Methoxy-2-pyridyl)-N'-(4-pyridyl)urea (No. 5); N-(4-Methoxy-2-pyridyl)-N'-(3-pyridyl)urea (No. 6); N-(4-Methoxy-2-pyridyl)-N'-(4,6-dimethyl-2-pyridyl)urea (No. 7); Bis-N,N'-(6-chloro-2-pyridyl)urea (No. 9); N-(4-Methoxy-2-pyridyl)-N'-(4-trifluoromethyl-2-pyridyl)urea (No. 10); Bis-N-(4-trifluoromethyl-2-pyridyl)urea (No. 11); N-(4-Methoxy-2-pyridyl)-N'-(6-chloro-2-pyridyl)urea (No. 12); N-(4-Methoxy-2-pyridyl)-N'-(5-quinolyl)urea (No. 16); N-(6-methyl-2-benzothiazolyl)-N'-2-pyridylurea (No. 17); N-(2-benzoxazolyl)-N'-2-pyridylurea (No. 18); N-(4-Methoxy-2-pyridyl)-N'-2-thiazolylurea (No. 19); N-(4-Methoxy-2-pyridyl)-N'-2-pyridylthiourea (No. 20); Bis-N,N'-(4-methoxy-2-pyridyl)thiourea (No. 21); Bis-N,N'-(2-pyridyl)thiourea (No. 22); Bis-N,N'-(4-pyridyl)urea (No. 28); Bis-N,N'-(3-pyridyl)urea (No. 29); N-(2-pyridyl)-N'-(3-methylphenyl)urea (No. 38); N-(4-Methoxy-2-pyridyl)-N'-phenylurea (No. 40); N-(4-Methoxy-2-pyridyl)urea (No.43) N-(6-trifluoromethyl-3-pyridyl)urea (No. 45); N-(6-chloro-2-pyridyl)urea (No. 46); N-(4-trifluoromethyl-2-pyridyl)urea (No. 48); N-(6-chloro-3-pyridyl)urea (No. 49); N-(4-Methoxy-2-pyridyl)-N'-(3-trifluoromethylphenyl)urea (No. 53); N-(4-Methoxy-2-pyridyl)-N'-(3-chlorophenyl)urea (No. 54); N-(4-Methoxy-2-pyridyl)-N'-(4-trifluoromethylphenyl)urea (No. 59); N-(4-Methoxy-2-pyridyl)-N'-cyclohexylurea (No. 61); and [(1R,5R,7aR)-2,3,5,6,7,7a-Hexahydro-5-tert-butyldimethylsilyloxy-7a-methyl-1H-indenyl]-N'-(3-pyridyl)urea (No. 66).

[0041] [Table 1-1]

[0042] [Table 1-2]

[0043] [Table 2-1]

[0044] [Table 2-2]

[0045] The "pharmaceutical acceptable salt" of the compound of formula (I) is not particularly limited as long as it is a salt that can be used as a pharmaceutical. Examples of the salt that the compound of the present invention forms with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; and salts with organic bases such as methylamine, ethylamine, and ethanolamine. The salt may be an acid addition salt, and specific examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid.

[0046] Atoms contained in the compound represented by formula (I) (e.g., hydrogen atom, carbon atom, oxygen atom, nitrogen atom, sulfur atom, etc.) may be isotope atoms other than the most abundant isotope of each isotope in nature, and the isotope atom may be a radioisotope atom. That is, according to one aspect of the present invention, there is provided a compound of formula (I) as defined herein, or a salt thereof, which is labeled with an isotope atom. Here, labeling with an isotope atom includes, for example, labeling with a radioisotope ( 3 H, 14 C. 32 P, etc.), and from the viewpoint of ease of preparation of the compound, 3 Labeling with 3H is preferred.

[0047] In one embodiment of the invention, the compounds of formula (I), or a pharma- ceutically acceptable salt thereof, are administered as prodrugs, which are converted in vivo to the active compound. The treatment of cognitive disease or disorder in the present invention includes treatment of Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disease, and neurodegenerative disease. The pharmaceutical composition in the present invention also includes improvement of brain dysfunction, for example, improvement of brain dysfunction caused by cerebrovascular disease, brain trauma, brain tumor, viral encephalitis, hypoxic encephalopathy, alcoholism, etc. The present invention can be particularly applied to cognitive dysfunction such as memory disorder, attention disorder, executive dysfunction, and social behavior disorder. Cognitive dysfunction includes, for example, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc.), psychiatric diseases (schizophrenia, bipolar disorder, depression, phobia, sleep disorder, drug addiction, etc.), and pervasive developmental disorder (autism, Asperger's syndrome, mental retardation, hyperactivity disorder, tic disorder, etc.).

[0048] In one embodiment of the present invention, the compound of formula (I) or a pharma- ceutical acceptable salt thereof is used as a GluN2A activator or a CaMKII activator. That is, the compound of formula (I), its enantiomer, its diastereomer, or its pharma- ceutical acceptable salt thereof can be used for treating or preventing diseases related to GluN2A and CaMKII, such as cognitive function diseases or disorders, and psychiatric diseases.

[0049] The pharmaceutical composition of the present invention can be in various dosage forms, for example, for oral administration, tablets, capsules, powders, granules, pills, liquids, emulsions, suspensions, solutions, spirits, syrups, extracts, elixirs, and for parenteral administration, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, and intraperitoneal injections; transdermal administration or patch, ointment or lotion; sublingual preparations and oral patch preparations for oral administration; and aerosol preparations for nasal administration, but not limited thereto.These preparations can be manufactured by known methods commonly used in the preparation process.

[0050] The pharmaceutical composition may contain various commonly used ingredients, for example, one or more pharma- ceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, coloring agents, sweeteners, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffers, binders, stabilizers, coating agents, etc. The pharmaceutical composition of the present invention may also be in a sustained or sustained release dosage form.

[0051] The dosage of the therapeutic agent, preventive agent, or pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, the patient's body type, age, physical condition, degree of disease, time since onset, etc., and the pharmaceutical composition of the present invention can contain a therapeutically effective amount and / or a prophylactically effective amount of the compound of formula (I). In the present invention, the compound of formula (I) can be generally used at a dose of 1 to 1000 mg / day / adult or 0.01 to 20 mg / day / kg body weight. The pharmaceutical composition may be administered in a single dose or multiple doses.

[0052] The pharmaceutical composition of the present invention may contain, as necessary, conventionally known coloring agents, preservatives, fragrances, flavorings, coating agents, antioxidants, vitamins, amino acids, peptides, proteins, and minerals (iron, zinc, magnesium, iodine, etc.). The therapeutic or prophylactic agent of the present invention may be prepared in a form suitable for pharmaceutical compositions, functional foods, health foods, beverages, supplements, etc., such as various solid preparations such as granules (including dry syrups), capsules (soft capsules, hard capsules), tablets (including chewable agents, etc.), powders (powdered agents), and pills, or liquid preparations such as oral liquids (including liquids, suspensions, and syrups). The therapeutic or prophylactic agent of the present invention may also be used as a pharmaceutical composition, functional food, health food, supplement, etc. as it is.

[0053] Examples of additives for formulation include excipients, lubricants, binders, disintegrants, fluidizers, dispersants, wetting agents, preservatives, thickeners, pH adjusters, colorants, flavorings, surfactants, and dissolution aids. When the formulation is in the form of a liquid, a thickener such as pectin, xanthan gum, or guar gum can be added. In addition, the formulation can be made into a coated tablet using a coating agent, or into a paste-like glue. Furthermore, when preparing other forms, conventional methods can be followed. EXAMPLES

[0054] The present invention will be described in more detail below by showing examples, but the present invention is not limited to these examples. [Example 1] Preparation of N-(4-methoxy-2-pyridyl)-N'-(3-methyl-2-pyridyl)urea (No. 1)

[0055] [ka]

[0056] Under an argon atmosphere, a solution (1.0 mL) of N,N'-bis(4-methoxy-2-pyridyl)urea (compound 1, 0.25 mmol, 68.5 mg) and N,N'-bis(2-methyl-2-pyridyl)urea (compound 2, 0.75 mmol, 181.5 mg) in dehydrated toluene (1.0 mL) was added with separately prepared rhodium hydride tetrakistriphenylphosphine complex (14.4 mg, 5 mol%, Ahmad, N. et al., Inorg. Synth., 15, 58 (1974)) and 1,2-bis(diphenylphosphino)benzene (11.2 mg, 10 mol%) at room temperature, and the mixture was heated to reflux for 3 hours. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (No. 1, 90.5 mg, 70%) as a white solid.

[0057] Yield 70%.; White solid (90.5 mg, 70%). Mp 176.0-177.0 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ10.54 (2H, bs), 8.15 (1H, d, J = 5.6 Hz), 7.68 (1H, t, J = 7.6 Hz), 7.55 (1H, bs), 7.33 (1H, bs), 6.94 (1H, d, J = 7.2 Hz), 6.70 (1H, dd, J = 5.6, 2.0 Hz), 3.86 (3H, s), 2.46 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 166.7, 155.9, 154.1, 151.9, 151.7, 148.5, 138.7, 117.3, 109.2, 105.6, 97.0, 55.3, 23.6. 3444, 3234, 3008, 1704, 1575, 1447, 1274, 780cm -1 MS (EI) m / z 258 (M + , 9%), 108 (M +-150, 100%). HRMS (EI) Calcd. for C 13 H 14 N4O2: 258.1117. Found: 258.1116.

[0058] The following compounds (No. 2, No. 4 to No. 7, No. 10, No. 12, No. 16, No. 19, No. 20, No. 38, No. 40, No. 53, No. 54, No. 59) were synthesized in the same manner as in Example 1 using raw materials corresponding to the target compounds. Regarding the equivalent ratio of raw materials, No. 2, 4, 5, 6, 7, 10, 12, 40, 53, 54, and 59 used 1 equivalent of N,N'-bis(4-methoxy-2-pyridyl)urea and 3 equivalents of the other symmetrical urea. No. 16, 19, and 20 used 3 equivalents of N,N'-bis(4-methoxy-2-pyridyl)urea and 1 equivalent of the other symmetrical urea. No. 38 used 3 equivalents of N,N'-bis(m-tolyl)urea and 1 equivalent of the other symmetrical urea.

[0059] No.2: N-(4-methoxy-2-pyridyl)-N'-2-pyridylurea Yield 75%.; White solid. Mp 178.0-179.0 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ10.78 (1H, bs), 10.45 (1H, bs), 8.32 (1H, dt, J = 4.8, 1.6 Hz), 8.15 (1H, d, J = 6.0 Hz), 7.75-7.83 (2H, m), 7.29 (1H, bs), 7.07-7.10 (1H, m), 6.71 (1H, dd, J = 5.6, 2.4 Hz), 3.86 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 166.7, 154.0, 152.3, 151.9, 148.4, 147.3, 138.4, 118.2, 112.4, 105.6, 97.0, 55.3. IR (KBr) 3378, 3122, 3009, 1697, 1576, 1549, 1433, 1312, 1025 cm -1 MS (EI) m / z 244 (M+ , 8%), 94 (M + -150, 100%). HRMS (EI) Calcd. for C 12 H 12 N4O2: 244.0960. Found: 244.0976.

[0060] No.4: N-(4-methoxy-2-pyridyl)-N'-(4-chloro-3-pyridyl)urea Yield 75%.; White solid. Mp 225.0-226.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ11.05 (1H, bs), 9.58 (1H, bs), 8.54 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 6.0 Hz), 8.08 (1H, dd, J = 8.4, 2.2 Hz), 7.45 (1H, d, J = 8.8 Hz), 6.99 (1H, d, J = 2.0 Hz), 6.66 (1H, dd, J = 6.0, 2.4 Hz), 3.81 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 166.9, 154.2, 152.3, 148.0, 142.9, 140.1, 135.4, 129.5, 124.2, 105.7, 96.3, 55.4. IR (KBr) 3231, 3124, 2979, 1708, 1590, 1461, 1278, 1030 cm -1 . MS (EI) m / z 278 (M + , 3%), 124 (M + -154, 100%). HRMS (EI) Calcd. for C 12 H 11 ClN4O2: 278.0571. Found: 278.0597.

[0061] No.5: N-(4-methoxy-2-pyridyl)-N'-(4-pyridyl)urea Yield 69%.; White solid. Mp 216.0-217.0 ℃ (エタノール). 1H-NMR (400 MHz, DMSO-d6) δ10.90 (1H, bs), 9.55 (1H, s), 8.39 (2H, dd, J = 14.8, 1.2 Hz), 8.12 (1H, d, J = 6.0 Hz), 7.50 (2H, dd, J = 4.8, 1.2 Hz), 7.08 (1H, d, J = 1.6 Hz), 6.68 (1H, dd, J = 6.0, 2.4 Hz), 3.81 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 166.9, 154.1, 152.0, 150.3, 148.2, 145.8, 112.9, 105.8, 96.5, 55.4. IR (KBr) 3381, 3116, 3023, 1704, 1580, 1281, 1201, 1021, 823cm -1 . MS (EI) m / z 244 (M + , 10%), 124 (M + -120, 100%). HRMS (EI) Calcd. for C 12 H 12 N4O2: 244.0960. Found: 244.0980.

[0062] No.6: N-(4-methoxy-2-pyridyl)-N'-(3-pyridyl)urea Yield 70%.; White solid. Mp 220.0-221.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ10.90 (1H, s), 9.52 (1H, bs), 8.23 ​​(1H, dd, J = 4.8, 1.2 Hz), 8.12 (1H, d, J = 6.0 Hz), 8.02 (1H, ddd, J = 8.4, 3.6, 1.6 Hz), 7.34 (1H, dd, J = 8.4, 4.8 Hz), 7.02 (1H, d, J = 2.0 Hz), 6.66 (1H, dd, J = 6.0, 2.4 Hz), 3.81 (3H, s). 13C-NMR (100 MHz, DMSO-d6) δ 167.1, 154.6, 152.6, 148.3, 143.8, 140.8, 136.0, 126.1, 124.0, 105.8, 96.5, 55.6. IR (KBr) 3226, 3157, 2932, 1700, 1599, 1482, 1268, 1174, 820 cm -1 . MS (EI) m / z 244 (M + , 20%), 124 (M + -120, 100%). HRMS (EI) Calcd. for C 12 H 12 N4O2: 244.0960. Found: 244.0970.

[0063] No.7: N-(4-methoxy-2-pyridyl)-N'-(4,6-dimethyl-2-pyridyl)urea Yield 69%.; White solid. Mp 207.0-208.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ10.41 (2H, bs), 8.11 (1H, d, J = 5.6 Hz), 7.31 (2H, bs), 6.74 (1H, s), 6.65 (1H, dd, J = 6.0, 2.4 Hz), 3.81 (3H, s), 2.37 (3H, s), 2.25 (3H, s). 13 IR (KBr) 3350, 3220, 3011, 1686, 1543, 1413, 1041 cm -1 . MS (EI) m / z 272 (M + , 3%), 122 (M + -150, 100%). HRMS (EI-TOF) Calcd. for C 14 H 16 N4O2: 272.1273. Found: 272.1300.

[0064] No.10: N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethyl-2-pyridyl)urea Yield 70%.; White solid. Mp 247.0-248.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ11.30 (1H, bs), 10.05 (1H, bs), 8.56 (1H, d, J = 5.6 Hz), 8.23 ​​(1H, s), 8.13 (1H, d, J = 5.6 Hz), 7.41 (1H, dd, J = 5.2, 1.2 Hz), 7.15 (1H, bs), 6.69 (1H, dd, J = 6.0, 2.4 Hz), 3.83 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 166.9, 153.9, 153.3, 151.9, 149.8, 148.3, 138.4 (d, J = 32.7 Hz), 122.9 (q, J = 271.9 Hz), 113.7 (d, J = 3.0 Hz), 107.7 (d, J = 4.5 Hz), 106.0, 96.9, 55.4. IR (KBr) 3244, 1704, 1561, 1426, 1309, 1171 cm -1 . MS (EI) m / z 312 (M + , 8%), 151 (M + -161, 100%). HRMS (EI) Calcd. for C 13 H 11 F3N4O2: 312.0834. Found: 312.0828.

[0065] No.12: N-(4-methoxy-2-pyridyl)-N'-(6-chloro-2-pyridyl)urea Yield 73%.; White solid. Mp 216.0-217.0 ℃ (エタノール). 1H-NMR (400 MHz, DMSO-d6) δ11.03 (1H, s), 9.78 (1H, bs), 8.13 (1H, d, J = 6.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.81 (1H, t, J = 8.0 Hz), 7.15 (1H, d, J = 0.4 Hz), 7.13 (1H, s), 6.68 (1H, dd, J = 6.0, 2.4 Hz), 3.82 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 166.9, 153.9, 152.3, 151.6, 148.4, 147.8, 141.7, 118.0, 111.1, 105.8, 96.8, 55.4. IR (KBr) 3371, 3221, 3053, 1727, 1684, 1591, 1441, 1213 cm -1 . MS (EI) m / z 278 (M + , 1%), 150 (M + -128, 100%). HRMS (EI) Calcd. for C 12 H 11 ClN4O2: 278.0571. Found: 278.0592.

[0066] No.16: N-(4-methoxy-2-pyridyl)-N'-(5-quinolyl)urea Yield 60%.; White solid. Mp 250.0-251.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ11.66 (1H, s), 9.81 (1H, s), 8.95 (1H, dd, J = 4.0, 1.2 Hz), 8.54 (1H, d, J = 8.4 Hz), 8.22-8.27 (2H, m), 7.73-7.76 (2H, m), 7.67 (1H, dd, J = 8.4, 4.0 Hz), 6.95 (1H, s), 6.71 (1H, dd, J = 6.0, 2.0 Hz), 3.83 (3H, s). 13C-NMR (100 MHz, DMSO-d6) δ 167.0, 154.7, 152.6, 150.4, 148.2, 147.9, 134.5, 129.8, 129.6, 124.0, 121.4, 120.7, 117.0, 105.6, 96.1, 55.4. IR (KBr) 3214, 1701, 1619, 1586, 1282 cm -1 MS (EI) m / z 294 (M + , 1%), 170 (M + -124, 100%). HRMS (EI) Calcd. for C 16 H 14 N4O2: 294.1117. Found: 294.1114.

[0067] No.19: N-(4-Methoxy-2-pyridyl)-N'-2-thiazolyl urea Yield 69% (reaction was carried out in DMSO instead of toluene at 140 °C). White solid. Mp 231.5-232.5 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ 12.2 (1H, bs), 9.83 (1H, bs), 8.14 (1H, d, J = 6.0 Hz), 7.42 (1H, d, J = 3.6 Hz), 7.18 (1H, d, J = 3.2 Hz), 7.18 (1H, d, J = 3.2 Hz), 7.04 (1H, bs), 6.71 (1H, dd, J = 6.0, 2.4 Hz), 2.98 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 167.0, 158.5, 153.8, 151.4, 148.1, 137.7, 113.2, 106.1, 96.6, 55.4. IR (KBr) 3370, 3105, 3082, 1694, 1557, 1272cm -1 MS (EI) m / z 250 (M + , 12%), 151 (M + -99, 100%). HRMS (EI) Calcd. for C 10 H10 N4O2S: 250.0525. Found: 250.0552。

[0068] No.20: N-(4-Methoxy-2-pyridyl)-N'-2-pyridylthiourea Yield 73% (reaction time was 24 h).; White solid. M.p. 130.0 - 131.0 °C (toluene / hexane = 1 / 5). 1 1H-NMR (600 MHz, DMSO-d6) δ 12.88 (1H, bs), 12.12 (1H, bs), 8.37 (1H, s), 8.19 (1H, d, J = 6.0 Hz), 8.12 (1H, bs), 7.83 (1H, t, J = 1.2 Hz), 7.62 (1H, bs), 7.16 (1H, d, J = 1.8 Hz), 6.77 (1H, d, J = 3.0 Hz). 13 13C-NMR (150 MHz, DMSO-d6) δ 177.0, 166.5, 154.2, 152.4, 147.6, 146.7, 137.8, 119.2, 114.5, 106.6, 98.9, 55.1. IR (KBr) 3236, 3052, 1609, 1557, 1354, 1204, 1033 cm -1 . MS (EI) m / z 260 (M + , 5%), 226 (M + -34, 100%). HRMS (EI) Calcd. for C 12 H 12 N4OS: 260.0732. Found: 260.0740。

[0069] No.38: N-(2-pyridyl)-N'-(3-methylphenyl)urea Yield 71%. MS (EI) m / z 227 (M + , 43%), 94 (M + -133, 100%). HRMS (EI) Calcd. for C 13 H 13 N3O: 227.1059. Found: 227.1049。

[0070] No.40: N-(4-methoxy-2-pyridyl)-N'-phenylurea Yield 74%. MS (EI) m / z 243 (M + , 30%), 124 (M + -119, 100%). HRMS (EI) Calcd. for C 13 H 13 N3O2: 243.1008. Found: 243.1010.

[0071] No.53: N-(4-methoxy-2-pyridyl)-N'-(3-trifluoromethylphenyl)urea Yield 73%. White solid. Mp 201.0-202.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ11.00 (1H, s), 9.49 (1H, s), 8.13 (1H, d, J = 6.0 Hz), 8.08 (1H, s), 7.66 (1H, d, J = 8.8 Hz), 7.54 (1H, t, J = 8.0 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.04 (1H, d, J = 1.6 Hz) 6.66 (1H, dd, J = 5.8, 2.4 Hz), 3.82 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 167.8, 155.3, 153.3, 149.0, 140.9, 131.0, 130.6 (q, J = 31.4 Hz), 125.1 (q, J = 270.7 Hz), 123.5, 119.7 (q, J = 3.8 Hz), 115.7 (q, J = 3.8 Hz), 106.6, 97.2, 56.3. 19 F-NMR (375 MHz, DMSO-d6) δ -61.5. IR (KBr) 2984, 1698, 1614, 1579, 1448, 1269, 1118 cm -1 . HRMS (ESI) Calcd. for C 12 H 13 N4OS (M + +H): 312.0954. Found: 312.0976.

[0072] No.54: N-(4-methoxy-2-pyridyl)-N'-(3-chlorophenyl)urea Yield 75%. White solid. Mp 226.0-227.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ10.90 (1H, s), 9.46 (1H, s), 8.12 (1H, d, J = 6.0 Hz), 7.79 (1H, m), 7.30-7.36 (2H, m), 7.06 (1H, dt, J = 6.8, 2.0 Hz), 7.02 (1H, d, J = 2.4 Hz), 6.65 (1H, dd, J = 5.8, 2.0 Hz), 3.81 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 167.8, 155.3, 153.1, 149.0, 141.5, 134.5, 131.5, 123.1, 119.1, 118.2, 106.5, 97.2, 56.3. IR (KBr) 3030, 1702, 1584, 1389, 1088, 1025cm -1 . HRMS (ESI) Calcd. for C 13 H 12 N3O2Cl (M + +H): 278.0691. Found: 278.0702.

[0073] No.59: N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethylphenyl)urea Yield 75%. White solid. Mp 189.0-190.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ9.71 (1H, s), 9.65 (1H, s), 8.53 (1H, d, J = 4.8 Hz), 8.06 (1H, s), 7.34 (1H, d, J = 5.6 Hz), 7.19-7.23 (2H, m), 6.98 (1H, m), 6.62 (1H, dd, J = 8.0, 2.4 Hz), 3.75 (3H, s). 13C-NMR (100 MHz, DMSO-d6) δ 160.7, 154.6, 152.8, 150.5, 140.9, 139.4 (q, J = 33.4 Hz), 130.7, 123.9 (q, J = 271.7 Hz), 113.9, 112.1, 109.2, 108.2 (q, J = 3.8 Hz), 105.5, 56.0. IR (KBr) 3128, 3035, 1705, 1580, 1526, 1425, 1394, 1183, 1087 cm -1 .HRMS (ESI) Calcd. for C 14 H 12 N3O2F3(M + +H): 312.0954. Found: 312.0978.

[0074] [Example 2]: Preparation of N-(2-benzoxazolyl)-N'-2-pyridylurea (No. 18)

[0075] [ka]

[0076] Under an argon atmosphere, 2-aminobenzoxazole (1 mmol, 134.1 mg) was reacted with phenyl isocyanate (1 mmol, 119.0 mg) in tetrahydrofuran (2 mL) to give N-(2-benzoxazolyl)-N'-phenylurea (234.5 mg, 93%). Next, N,N'-bis(2-pyridyl)urea (0.25 mmol, 53.5 mg), rhodium hydride tetrakistriphenylphosphine complex (14.4 mg, 5 mol%), and 1,2-bis(diphenylphosphino)benzene (11.2 mg, 10 mol%) were added to the obtained N-(2-benzoxazolyl)-N'-phenylurea (0.25 mmol, 63.1 mg) at room temperature, and the mixture was heated to reflux for 3 hours. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain No. 18 (22.2 mg, 35%) as a white solid.

[0077] Yield 60%.; White solid. Mp 199.0-200.0 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ11.79 (1H, bs), 11.00 (1H, bs), 8.35-8.36 (1H, m), 8.00 (1H, d, J = 8.0 Hz), 7.84 (1H, td, J = 7.6, 1.6 Hz), 7.62 (1H, d, J = 8.4 Hz), 7.33 (1H, td, J = 7.6, 1.2 Hz), 7.27 (1H, td, J = 7.6, 1.6 Hz), 7.15 (1H, dd, J = 5.6, 1.2 Hz). 13 C-NMR (100MHz, DMSO-d6) δ 156.5, 151.4, 149.5, 148.0, 147.1, 140.0, 138.6, 124.8, 123.4, 119.4, 117.5, 112.7, 110.0. 3226, 3127, 3012, 1685, 1629, 1602cm -1 MS (EI) m / z 254 (M+ , 4%), 134 (M + -120, 100%). HRMS (EI) Calcd. for C 13 H 10 N4O2: 254.0804. Found: 254.0817.

[0078] The following compound (No. 17) was synthesized in the same manner as in Example 2 using raw materials corresponding to the target compound. No.17: N-(6-methyl-2-benzothiazolyl)-N'-2-pyridylurea Yield 60%.; White solid. Mp 276.0-277.0 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ12.22 (1H, bs), 10.06 (1H, bs), 8.36 (1H, dd, J = 5.2, 1.2 Hz), 7.83 (1H, td, J = 8.4, 1.6 Hz), 7.74 (1H, s), 7.60 (1H, d, J = 8.0 Hz), 7.53 (1H, bt, J = 7.2 Hz), 7.22 (1H, dd, J = 8.0, 1.2 Hz), 7.11 (1H, dd, J = 7.2, 5.6 Hz), 2.40 (3H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 157.6, 151.9, 151.5, 147.1, 146.8, 139.1, 132.6, 131.8, 127.3, 121.2, 119.8, 118.6, 112.4, 21.0. IR (KBr) 3367, 1698, 1571, 1267 cm -1 MS (EI) m / z 284 (M + , 3%), 164 (M + -120, 100%). HRMS (EI) Calcd. for C 14 H 12 N4O2S: 284.0732. Found: 284.0732.

[0079] [Example 3] Preparation of bis-N,N'-(6-chloro-2-pyridyl)urea (No. 9)

[0080] [ka]

[0081] A solution of 6-chloro-2-pyridylamine (2 mmol, 256.0 mg) and carbonyldiimidazole (1 mmol, 162.0 mg) in tetrahydrofuran was stirred at room temperature for 10 hours. The solvent was then removed under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain No. 9 (253.8 mg, 90%) as a white solid.

[0082] Yield 90%.; White solid. Mp 259.0-260.0 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ9.90 (2H, s), 7.86 (2H, dd, J = 8.4, 2.4 Hz), 7.83 (2H, t, J = 8.4 Hz), 7.16 (2H, dd, J = 7.2, 2.4 Hz). 13 C-NMR (100 MHz, DMSO-d6) δ 152.1, 151.1, 147.8, 141.8, 118.1, 110.8. IR (KBr) 3205, 3128, 3054, 2985, 1703, 1571, 1439, 1403, 1167cm -1 MS (EI) m / z 282 (M + , 1%), 128 (M + -154, 100%). HRMS (EI) Calcd. for C 11 H8Cl2N4O: 282.0075. Found: 282.0075. The following compounds (No. 11, No. 28, No. 29) were synthesized in the same manner as in Example 3 using raw materials corresponding to the target compounds.

[0083] No.11: Bis-N-(4-trifluoromethyl-2-pyridyl)urea Yield 84%.; White solid. Mp 250.0-251.0 ℃ (エタノール, decomposition). 1 H-NMR (400 MHz, DMSO-d6) δ 10.5 (2H, bs), 8.58 (2H, d, J = 5.2 Hz), 8.15 (2H, s), 7.44 (2H, dd, J = 5.2, 1.2 Hz). 13 C-NMR (100 MHz, DMSO-d6) δ 153.0, 151.7, 149.8, 136.8 (q, J = 32.8 Hz), 122.9 (q, J = 271.9 Hz), 113.9 (d, J = 3.0 Hz), 107.7 (d, J = 4.5 Hz). 19 F-NMR (376 MHz, DMSO-d6) δ -65.3. IR (KBr) 3293, 1704, 1578, 1422, 1183 cm -1 . MS (EI) m / z 350 (M + , 1%), 162 (M + -188, 100%). HRMS (EI) Calcd. for C 13 H8F6N4O: 350.0602. Found: 350.0576. No.28: Bis-N,N'-(4-pyridyl)urea Yield 86%.; White solid.; Mp 235.0-236.0 ℃ (エタノール).; 1 H-NMR (400 MHz, DMSO-d6) δ 9.34 (2H,s), 8.43 (4H, d, J = 5.4 Hz), 7.49 (4H, dd, J = 4.8, 1.2 Hz). 13 C-NMR (100 MHz, DMSO-d6) δ152.8, 151.3, 147.0, 113.6. IR (KBr) 3403, 3013, 1739, 1586, 1518, 1496, 1192 cm -1 . HRMS (ESI) Calcd for C 11 H 11 N4O [M+H] + :215.0927. Found:215.0930. No.29: Bis-N,N'-(3-pyridyl)urea Yield 92%.; White solid.; Mp 237.0-238.0 °C (ethanol).; 1 H-NMR (400 MHz, DMSO-d6) δ 9.03 (2H, s), 8.66 (2H, s), 8.25 (2H, d, J = 4.4 Hz), 7.99 (2H, d, J = 8.0 Hz), 7.36 (2H, dd, J = 8.0, 4.8 Hz). 13 C-NMR (100 MHz, DMSO-d6) δ 153.7, 144.1, 141.3, 137.2, 126.4, 124.6. IR (KBr) 3246, 3045, 2993, 1690, 1585, 1547, 1420, 1276, 1228 cm -1 . HRMS (ESI) Calcd for C 11 H 11 NO [M+H] + :215.0927. Found:215.0924. [Example 4] Preparation of bis-N,N'-(4-methoxy-2-pyridyl)thiourea (No. 21)

[0084] [ka]

[0085] Under an argon atmosphere, a solution (3.0 mL) of (4-methoxy-2-pyridyl)amine (2 mmol, 248.0 mg) and bis(1-benzotriazolyl)methanethione (1 mmol, 280.3 mg) in tetrahydrofuran was heated to reflux for 5 hours, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate = 1:1) to obtain bis-N,N'-(4-methoxy-2-pyridyl)thiourea (No. 21, 110.6 mg, 38%) as a white solid.

[0086] White solid. Mp. 177.0-178.0 °C (ethanol).; 1H-NMR (400 MHz, DMSO-d6) δ 8.23 ​​(2H, d, J = 6.0 Hz), 7.94 (2H, dd, J = 5.6, 3.2 Hz), 7.47 (2H, dd, J = 6.4, 3.2 Hz), 6.82 (2H, dd, J = 6.0, 2.4 Hz), 3.87 (6H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 177.9, 167.5, 155.3, 149.0, 126.3, 107.9, 56.5. IR (KBr) 3230, 3053, 2942, 1616, 1572, 1404, 1354, 1289, 1038cm -1 . HRMS (ESI) Calcd for C 13 H 15 N4O2S [M+H] + :291.0910. Found: 291.0917. The following compound (No. 22) was synthesized in the same manner as in Example 4 using raw materials corresponding to the target compound.

[0087] No.22: Bis-N,N'-(2-pyridyl)thiourea Yield 78%.; White solid.; Mp 169.5-170.5 °C (ethanol).; White solid. Mp 169.5-170.5 °C (ethanol). 1 H-NMR (400 MHz, CO(CD3)2) δ 8.43 (2H, d, J = 5.2 Hz), 7.88 (2H, t, J = 7.6 Hz), 7.20 (2H, dd, J = 8.0, 5.2 Hz). 13 C-NMR (100 MHz,CO(CD3)2) δ 169.6, 145.1, 139.2, 130.1, 111.4, 106.2. IR (KBr) 1603, 1560, 1523, 1460, 1351, 1183 cm -1 . HRMS (ESI) Calcd for C 11 H 11 N4S [M+H] +:231.0699. Found: 231.0685.

[0088] [Example 5] Preparation of N-(4-methoxy-2-pyridyl)urea (No. 43)

[0089] [ka]

[0090] Under an argon atmosphere, chlorosulfonyl isocyanate (3.75 mmol, 0.33 mL) was added dropwise to a solution of 4-methoxy-2-pyridylamine (2.5 mmol, 0.31 g) in dehydrated dichloromethane (20 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. 4 M HCl in 1,4-dioxane (20 mL, 1,4-dioxane:water = 3:1) was added to the residue at 10 °C, and the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. 10% NaHCO3 aqueous solution (30 mL) was added to the resulting solid, and the mixture was extracted three times with dichloromethane (30 mL). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain No. 43 (85%, 357.1 mg) as a white solid.

[0091] Yield 85%.; White solid.; Mp. 213.0-214.0 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) d 9.05 (1H, s), 8.03 (1H, d, J = 5.6 hz), 7.00 (1H, s), 6.58 (1H, dd, J = 5.6, 2.4 Hz), 3.81 (3H, s), 3.39 (2H, s). 13 C-NMR (100 MHz, DMSO-d6) d 167.5, 156.5, 156.2, 149.0, 105.8, 96.8, 56.1. IR (KBr) 3323, 1708, 1598, 1418, 1397, 1300, 1272, 1191, 1173cm -1MS (EI) m / z 167 (M + , 10%), 124 (M + -43, 100%). HRMS (EI) Calcd. for C7H9N3O2: 167.0695. Found: 167.0701.

[0092] The following compounds (No. 45, No. 46, No. 48, No. 49) were synthesized in the same manner as in Example 5 using raw materials corresponding to the target compounds. No.45: N-(6-trifluoromethyl-3-pyridyl)urea Yield 78%.; White solid. Mp 194.5-195.5 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ 9.22 (1H, s), 8.69 (1H, d, J = 2.4 Hz), 8.21 (1H, dd, J = 8.8, 2.4 Hz), 7.78 (1H, d, J = 8.8 Hz), 6.25 (2H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 156.6, 141.3, 140.3, 139.4 (q, J = 34.3 Hz), 125.5, 123.1 (q, J = 271.7 Hz), 122.0. IR (KBr) 3432, 3333, 1711, 1585, 1542, 1338, 1130, 1089cm -1 . HRMS (ESI) Calcd for C7H7N3OF3[M+H] + :206.0536. Found:206.0530.

[0093] No.46: N-(6-chloro-2-pyridyl)urea Yield 83%.; White solid. Mp 246.0-247.0 °C (ethanol). 1 H-NMR (400 MHz, DMSO-d6) δ 9.42 (1H, s), 7.75 (1H, t, J = 8.0 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.04 (1H, d, J = 8.0 Hz), 6.61 (2H, s). 13C-NMR (100 MHz, DMSO-d6) δ 156.0, 154.5, 148.4, 142.2, 117.4, 111.1. IR (KBr) 3351, 3054, 1748, 1600, 1416, 1170 cm -1 . HRMS (ESI) Calcd for C6H7ClN3O [M+H] + :172.0272. Found:172.0275.

[0094] No.48: N-(4-trifluoromethyl-2-pyridyl)urea Yield 85%.; White solid. Mp 237.0-238.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ 9.57 (1H, s), 8.44 (1H, d, J = 5.2 Hz), 7.99 (1H, s), 7.20 (1H, d, J = 4.4 Hz), 6.89 (2H, s). 13 C-NMR (100 MHz, DMSO-d6) δ 156.5, 155.4, 150.2, 139.4 (q, J = 32.4 Hz), 124.0 (q, J = 271.7 Hz), 113.1, 108.1. IR (KBr) 3353, 1706, 1608, 1580, 1392, 1348, 1174, 1134, 1019 cm -1 . HRMS (ESI) Calcd for C7H7N3OF3[M+H] + :206.0536. Found:206.0544. No.49: N-(6-chloro-3-pyridyl)urea Yield 80%.; White solid. Mp 222.0-223.0 ℃ (エタノール). 1 H-NMR (400 MHz, DMSO-d6) δ 8.91 (1H, s), 8.42 (1H, d, J = 2.8 Hz), 7.99 (1H, dd, J = 8.8, 5.2 Hz), 7.39 (1H, d, J = 8.8 Hz), 6.12 (2H, s). 13C-NMR (100 MHz, DMSO-d6) δ 153.7, 144.1, 141.2, 137.2, 126.4, 124.6. IR (KBr) 3396, 3280, 3182, 2550, 1670, 1632, 1536, 1468 cm -1 . HRMS (ESI) [M+H] + Calcd for C6H7ClN3O [M+H] + :172.0272. Found:172.0303. [Example 6] Preparation of N-(4-methoxy-2-pyridyl)-N'-cyclohexylurea (No. 61)

[0095] [ka]

[0096] Under an argon atmosphere, 4-methoxy-2-pyridylamine (1 mmol, 124.1 mg) was reacted with cyclohexyl isocyanate (1 mmol, 125.0 mg) in tetrahydrofuran (2 mL) at room temperature for 5 hours, and then the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate = 5:1) to obtain N-(4-methoxy-2-pyridyl)-N'-cyclohexylurea No. 61 (247.6 mg, 99%) as a white solid.

[0097] Yield 99%. White solid. Mp 133.0-134.0 °C (ethyl acetate). 1H-NMR (400 MHz, acetone-d6) δ 8.84 (1H, bs), 8.44 (1H, s), 8.01 (1H, d, J = 5.6 Hz), 6.79 (1H, d, J = 2.0 Hz), 6.52 (1H, dd, J = 6.0, 2.0 Hz), 3.82 (3H, s), 3.73-3.66 (1H, m), 1,90-1.95 (2H, m), 1.70-1.75 (2H, m), 1.55-1.59 (1H, m), 1.26-1.44 (5H, m). 13 C-NMR (100 MHz, acetone-d6) δ 167.3, 155.9, 154.3, 147.6, 105.0, 95.3, 54.8, 48.2, 33.1, 25.6, 24.5. IR (KBr) 2932, 2854, 1683, 1617, 1588, 1542, 1481 cm -1 .HRMS (ESI) Calcd. for C 13 H 19 N3O2(M + +H): 250.1550. Found: 250.1563. [Example 7] Preparation of [(1R,5R,7aR)-2,3,5,6,7,7a-hexahydro-5-tert-butyldimethylsilyloxy-7a-methyl-1H-indenyl]-N'-(3-pyridyl)urea (No. 66)

[0098] [ka]

[0099] (1R,5R,7aR)-2,3,5,6,7,7a-Hexahydro-5-tert-butyldimethylsilyloxy-7a-methyl-1H-inden-1-amine (0.1 mmol, 28.1 mg) and 3-pyridyl isocyanate (0.1 mmol, 12.0 mg) were reacted in toluene (1 mL) at 100°C for 2 hours, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate = 5:1) to obtain N-[(1R,5R,7aR)-2,3,5,6,7,7a-hexahydro-5-tert-butyldimethylsilyloxy-7a-methyl-1H-indelyl]-N'-(3-pyridyl)urea (30.8 mg, 77%) as a white solid. The obtained compound was dissolved in tetrahydrofuran and treated with tetrabutylammonium fluoride (3 equiv.) at 40 degrees for 5 hours. The solvent was then removed under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate = 5:1) to obtain No. 66 (18.9 mg, 86%) as a white solid.

[0100] Yield 66% (2 steps). White solid. Mp 97.2-98.6 °C (hexane:acetone = 5:1). 1 H-NMR (400 MHz, acetone-d6) δ 8.50 (1H, d, J = 2.8 Hz), 8.09 (1H, dd, J = 4.8, 1.2 Hz), 8.08 (1H, bs), 7.97 (1H, ddd, J = 8.0, 2.8, 1.2 Hz), 7.17 (1H, dd, J = 8.0, 4.8 Hz), 5.89 (1H, d, J = 8.8 Hz), 5.32 (1H, bs), 4.16 (1H, s), 3.75 (1H, dd, J = 19.6, 8.8 Hz), 3.10 (1H, bs), 2.34-2.42 (1H, m), 2.05-2.14 (1H, m), 1.86-2.01 (3H, m), 1.45-1.66 (4H, m), 0.94 (3H, s). 13C-NMR (100 MHz, acetone-d6) δ 154.9, 147.2, 142.5, 139.9, 137.4, 124.6, 124.2, 123.3, 67.6, 59.6, 43.3, 34.3, 29.8, 27.4, 25.6, 17.0. IR (KBr) 3363, 2933, 1678, 1551, 1484, 1421, 1259, 1095, 980 cm -1 .HRMS (ESI) Calcd. for C 16 H 22 N3O2(M + +H): 288.1707. Found: 288.1707.

[0101] [Test Example 1] Measurement of expression level of phosphorylated CaMKII The plasmid vector pcDNA1.1, into which the cDNA of the NMDA receptor subunit GluN2A was inserted, was obtained from Addgene (Addgene plasmid: # 17924; pEGFP-NR2A; https: / / www.addgene.org / 17924 / ; RRID:Addgene_17924). The plasmid vector was prepared using the GenElute HP Plasmid Maxiprep Kit (Sigma-Aldrich) according to the attached manual. Neuro2 A cells (N2A cells, National Institute of Biomedical Innovation) cultured in DMEM culture medium (Gibco) were replaced with Opti-Mem (Gibco) (Lipofectamine R2000 was added at 1μg / 1ml) containing the plasmid vector pcDNA1.1 (1μg / μl) prepared above, and cultured for 5 hours to obtain N2A cells overexpressing GluN2A. After replacing with DMEM culture medium again, the cells were cultured for 2 days. Then, the compound of the present invention (n=4 for each group) was added to the culture medium (DMEM, Gibco) to a concentration of 1μM, and the cells were harvested 1 hour later. The cells were suspended in SDS sample buffer, and CaMKII activation was measured by immunoblotting using anti-phosphorylated CaMKII antibody (Fukunaga K et al., J. Biol. Chem. 1992, 267, 22527-22533) as the primary antibody and anti-rabbit IgG antibody (SouthernBiotech) as the secondary antibody (other than the use of the above-mentioned antibodies, the conditions were the same as for conventional immunoblotting).

[0102] The results are shown in Figure 1. The results were evaluated by post hoc Bonferroni's multiple comparison test. **<0.01, *<0.05 indicate significance. [Test Example 2] Measurement of phosphorylated CaMKII expression levels when this product is added to cells overexpressing each NMDA receptor subunit In addition to the above-mentioned plasmid vector into which the cDNA of the NMDA receptor subunit GluN2A was inserted, the plasmid vector into which the cDNA of the NMDA receptor subunit GluN1 was inserted: pcDNA3.1, and the plasmid vector into which the cDNA of the NMDA receptor subunit GluN2B was inserted: pRK5 were obtained from Addgene, and plasmid vectors were prepared (Addgene plasmid: # 17926; pEGFP-NR1a; https: / / www.addgene.org / 17926 / ; RRID:Addgene_17926; # 17925; pEGFP-NR2B; https: / / www.addgene.org / 17925 / ; RRID:Addgene_17925). The compound of the present invention (n=4 for each group) was added to the cells overexpressing each NMDA receptor subunit at a concentration of 1 μM in the culture medium (DMEM, Gibco), and the cells were collected after 1 hour. (The conditions were as described above for the immunoblotting method). The cells were suspended in SDS sample buffer, and the activation of CaMKII was measured by immunoblotting using anti-phosphorylated CaMKII antibody (Fukunaga K et al., J. Biol. Chem. 1992, 267, 22527-22533) as the primary antibody and anti-rabbit IgG antibody (SouthernBiotech) as the secondary antibody. The results are shown in Figure 2. The results were evaluated by post hoc Bonferroni's multiple comparison test. Significance is indicated as *<0.01, *<0.05 (vs. cells to which the compound of the present invention was not added), and +<0.05 (vs. cells to which the compound of the present invention was added but not transfected with the plasmid vector).

[0103] [Test Example 3] Confirmation test of cognitive function improvement effect The cognitive impairment of olfactory bulbectomized mice (OBX mice) (10 weeks old), a model mouse with cognitive impairment, was confirmed by chronic treatment (oral administration) of the test compound (1 mg / kg) once a day for 2 weeks, and a significant improvement in cognitive function was confirmed. The results of the confirmation test are shown in Figure 4a-c. OBX mice were generated using 10-week-old DDY male mice (Nippon SLC, Hamamatsu, Japan). Olfactory bulbectomy surgery was performed under conditions of anesthesia with sodium pentobarbital (50 mg / kg, intraperitoneal administration; Dainippon, Osaka, Japan). The mice were fixed in a brain fixator, and a hole with a diameter of 1 mm was drilled in the skull above the olfactory bulb. The olfactory bulb and prefrontal cortex were aspirated and removed using a suction pump. In the Sham group, the same procedures as in the OBX group were performed except for the aspirated removal of the olfactory bulb.

[0104] Figure 3a-b shows the results of behavioral analysis. Figure 3a shows the results of examining the attention function of sham mice and OBX mice (n=5 each) using the conventional Y-maze method, and treatment with the test compound (1mg / kg) showed a significant improvement in attention function. The Y-maze method is a method in which mice are allowed to walk freely through three arms for 8 minutes. If the arms are designated A, B, and C, a mouse in A will enter either arm B or C. If a mouse enters arm B, the mouse will then enter arm C. In this way, entering ABC is considered a correct answer. On the other hand, entering ABA or not entering a new arm is considered an incorrect answer. The positions of the arms that the mouse moved to are recorded in the order of selection, and the number of times the mouse moved to each arm during the measurement time is counted, which is considered to be total arm entries. Furthermore, the number of correct answers (combinations in which three different arms were selected consecutively) was counted, and this number was taken as the number of alternations. The ratio of the number of alternations to the total arm entries minus 2 was expressed as Alternation (%) as an index of normal alternation behavior (correct rate of spatial working memory). *<0.05 (vs. Sham), +<0.05 (vs. OBX) indicate significance. Figure 3b shows the results of a conventional novel object recognition test in which memory for novel objects was measured in sham mice, OBX mice, and OBX mice treated with a test compound (1 mg / kg) (n=5 each), and a significant improvement in memory impairment was observed by treatment with the test compound (1 mg / kg). In the novel object recognition test, two blocks of the same shape were placed in a mouse cage and the mouse was allowed to freely explore the object for 10 minutes (training trial). After 1 hour, one of the blocks was replaced with a novel object, and the mouse was allowed to freely explore the object for another 5 minutes (retention trial). In the training and retention trials, the number of contacts with each of the two objects was measured, and the discrimination index was calculated as the percentage of contacts with the swapped block to the total number of contacts in the retention trial. *<0.05 (vs. Sham), +<0.05 (vs. OBX) indicate significance.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R １ and R ２ Each independently represents a hydrogen atom, and C １－６ alkyl; X is a direct bond, O, or S; Q is R ａ pyridyl optionally substituted with 1 to 4 substituents selected from Y is a hydrogen atom, R ａ R ａ Phenyl optionally substituted with 1 to 4 substituents selected from ｂ C which is optionally substituted with 1 to 4 substituents selected from ３－１０ cycloalkyl, or R ｂ C which is optionally substituted with 1 to 4 substituents selected from ６－１０ is cycloalkenyl; R ａ each independently represents a C group optionally substituted by hydroxy, cyano, or one or more halogen atoms; １－６ alkyl, C optionally substituted with one or more halogen atoms; １－６ selected from alkoxy, halogen atoms, and phenyl; R ｂ each independently represents a C which may be substituted with one or more halogen atoms; １－６ alkyl, C optionally substituted with one or more halogen atoms; １－６ alkoxy, hydroxy, and halogen atoms. A pharmaceutical composition comprising a compound represented by the formula:

2. R １ and R ２ The pharmaceutical composition according to claim 1 , wherein is a hydrogen atom.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein X is O.

4. Q is R ａ The pharmaceutical composition according to any one of claims 1 to 3, wherein the 2-pyridyl is optionally substituted with 1 to 4 substituents selected from the following:

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the 5-10 membered heteroaryl is pyridyl, quinolyl, thiazolyl, oxazolyl, benzothiazolyl, or benzoxazolyl.

6. R ａ The pharmaceutical composition according to any one of claims 1 to 5, wherein is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

7. R ｂ The pharmaceutical composition according to any one of claims 1 to 6, wherein is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

8. N-(4-methoxy-2-pyridyl)-N'-(3-methyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-2-pyridylurea; N-(4-methoxy-2-pyridyl)-N'-(4-chloro-3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4,6-dimethyl-2-pyridyl)urea; Bis-N,N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethyl-2-pyridyl)urea; Bis-N-(4-trifluoromethyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(5-quinolyl)urea; N-(6-methyl-2-benzothiazolyl)-N'-2-pyridylurea; N-(2-benzoxazolyl)-N'-2-pyridylurea; N-(4-methoxy-2-pyridyl)-N'-2-thiazolyl urea; N-(4-methoxy-2-pyridyl)-N'-2-pyridylthiourea; Bis-N,N'-(4-methoxy-2-pyridyl)thiourea; Bis-N,N'-(2-pyridyl)thiourea; Bis-N,N'-(4-pyridyl)urea; Bis-N,N'-(3-pyridyl)urea; N-(2-pyridyl)-N'-(3-methylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-phenylurea; N-(4-methoxy-2-pyridyl)urea; N-(6-trifluoromethyl-3-pyridyl)urea; N-(6-chloro-2-pyridyl)urea; N-(4-trifluoromethyl-2-pyridyl)urea; N-(6-chloro-3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-trifluoromethylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-chlorophenyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-cyclohexylurea; and [(1R,5R,7aR)-2,3,5,6,7,7a-hexahydro-5-tert-butyldimethylsilyloxy-7a-methyl-1H-indenyl]-N'-(3-pyridyl)urea 2. The pharmaceutical composition of claim 1, comprising a compound selected from the group consisting of:

9. The pharmaceutical composition according to any one of claims 1 to 8 for use in treating or preventing a disease or disorder caused by long-term potentiation of synaptic responses.

10. Ca ２＋ / A pharmaceutical composition according to any one of claims 1 to 9 for use in the treatment or prevention of a disease or disorder caused by activation of calmodulin-dependent kinase II.

11. GluN2A-mediated Ca ２＋ / A pharmaceutical composition according to any one of claims 1 to 10 for use in the treatment or prevention of a disease or disorder caused by activation of calmodulin-dependent kinase II.

12. The pharmaceutical composition according to any one of claims 1 to 11, for use in treating or preventing a cognitive function disease or disorder.

13. The pharmaceutical composition according to claim 12, wherein the cognitive function disease or disorder is selected from Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease, psychiatric diseases, and neurodegenerative diseases.

14. The pharmaceutical composition according to any one of claims 1 to 11 for use in the treatment or prevention of autism, depression, major depressive disorder, schizophrenia, or bipolar disorder.

15. Formula (I): 【Chemistry 2】 [In the formula, R １ and R ２ Each independently represents a hydrogen atom, and C １－６ alkyl; X is a direct bond, O, or S; Q is R ａ 2-pyridyl optionally substituted by 1 to 4 substituents selected from Y is R ａ R ａ Phenyl optionally substituted with 1 to 4 substituents selected from ｂ C which is optionally substituted with 1 to 4 substituents selected from ５－７ cycloalkyl, or R ｂ C which is optionally substituted with 1 to 4 substituents selected from ６－１０ is cycloalkenyl; 5-10 membered heteroaryl is pyridyl, quinolyl, thiazolyl, oxazolyl, benzothiazolyl, or benzoxazolyl; R ａ each independently represents a C group optionally substituted by hydroxy, cyano, or one or more halogen atoms; １－６ alkyl, C optionally substituted with one or more halogen atoms; １－６ selected from alkoxy, halogen atoms, and phenyl; R ｂ each independently represents a C which may be substituted with one or more halogen atoms; １－６ alkyl, C optionally substituted with one or more halogen atoms; １－６ alkoxy, hydroxy, and halogen atoms. or a pharma- ceutical acceptable salt thereof.

16. R １ and R ２ 16. The compound according to claim 15, or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

17. 17. The compound of claim 15 or 16, or a pharma- ceutically acceptable salt thereof, wherein X is O.

18. R ａ The compound according to any one of claims 15 to 17, or a pharma- ceutical acceptable salt thereof, wherein is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

19. R ｂ The compound according to any one of claims 15 to 18, or a pharma- ceutically acceptable salt thereof, wherein is a fluorine atom, a chlorine atom, a bromine atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or hydroxy.

20. N-(4-methoxy-2-pyridyl)-N'-(3-methyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-2-pyridylurea; N-(4-methoxy-2-pyridyl)-N'-(4-chloro-3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4,6-dimethyl-2-pyridyl)urea; Bis-N,N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethyl-2-pyridyl)urea; Bis-N-(4-trifluoromethyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(6-chloro-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(5-quinolyl)urea; N-(6-methyl-2-benzothiazolyl)-N'-2-pyridylurea; N-(2-benzoxazolyl)-N'-2-pyridylurea; N-(4-methoxy-2-pyridyl)-N'-2-thiazolyl urea; N-(4-methoxy-2-pyridyl)-N'-2-pyridylthiourea; Bis-N,N'-(4-methoxy-2-pyridyl)thiourea; Bis-N,N'-(2-pyridyl)thiourea; N-(2-pyridyl)-N'-(3-methylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-phenylurea; N-(4-methoxy-2-pyridyl)urea; N-(6-chloro-2-pyridyl)urea; N-(4-trifluoromethyl-2-pyridyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-trifluoromethylphenyl)urea; N-(4-methoxy-2-pyridyl)-N'-(3-chlorophenyl)urea; and N-(4-methoxy-2-pyridyl)-N'-(4-trifluoromethylphenyl)urea; 16. The compound of claim 15 selected from: or a pharma- ceutically acceptable salt thereof.

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