Pharmaceutical composed of 2-heteroaryl aminoquinazolinone derivative

Abstract

To provide a pharmaceutical composed of a 2-heteroaryl aminoquinazolinone derivative.SOLUTION: A pharmaceutical contains a compound represented by formula (1) [where X1 is CR1 or N, X2 is CR2 or N, X3 is CR3 or N, X4 is CR4 or N, Y is optionally substituted C1-6 alkyl or the like, Z is optionally substituted 6-10 membered heteroaryl, R1, R2, R3 and R4 independently represent a hydrogen atom, halogen, cyano, optionally substituted C1-6 alkyl, or optionally substituted C1-6 alkoxy or the like] or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates to 2-heteroarylaminoquinazolinone derivatives and pharmaceutically acceptable salts thereof that have an inhibitory effect on neural circuit hyperexcitability and are useful as pharmaceuticals, as well as pharmaceutical compositions containing them as active ingredients. [Background technology]

[0002] Abnormal excitation of brain neural circuits is known to be associated with various central nervous system diseases. For example, epilepsy is a chronic disease characterized by recurrent episodes of paroxysmal motor, consciousness, sensory, and behavioral abnormalities resulting from excessive excitation of neural circuits. For the nervous system to function normally, excitatory and inhibitory signals must be skillfully regulated, but in epilepsy, it is thought that excessive excitation occurs due to an imbalance between excitatory and inhibitory signals. The causes of the disease are diverse and can be broadly classified into predisposing etiologies, where known genetic abnormalities are the direct cause, and structural etiologies, where abnormalities in brain structure are the cause (Non-Patent Literature 1). For example, Dravet syndrome, in which approximately 80% of patients have a pathogenic mutation in the SCN1A gene, is a predisposing etiology, while medial temporal lobe epilepsy with hippocampal sclerosis is a representative example of a structural etiology. Both types of epilepsy are diagnosed through medical history and electroencephalography (EEG), and excessive excitation of neural circuits is observed as abnormal EEG waves called spike waves and spike-and-slow waves.

[0003] Treatment for epileptic seizures primarily involves medication, with antiepileptic drugs suppressing excessive excitation of neural circuits mainly by inhibiting or enhancing excitatory signals. Despite the numerous antiepileptic drugs approved and marketed to date, one in three cases of epilepsy is refractory, showing resistance to existing drug treatments. Furthermore, existing antiepileptic drugs have a relatively narrow effective concentration range (therapeutic range), and undesirable side effects (e.g., ataxia, sedation, dizziness, etc.) are likely to occur at doses necessary to achieve anticonvulsant activity. In addition, epilepsy patients have a high risk of developing comorbidities such as developmental disorders, psychiatric disorders, and cognitive impairments (Non-patent documents 2, 3), but existing drugs do not have therapeutic effects on these comorbid neurological and psychiatric symptoms.

[0004] Abnormalities in the balance between excitatory and inhibitory signals in neural circuits are thought to be underlying factors in various central nervous system disorders, including not only epilepsy, but also developmental disorders (autism spectrum disorder, Rett syndrome, Angelman syndrome, fragile X syndrome, attention deficit hyperactivity disorder, etc.), mental disorders (schizophrenia, bipolar disorder, depression, anxiety disorders, obsessive-compulsive disorder, etc.), cognitive disorders (Alzheimer's disease and other dementias, Parkinson's disease, etc.) (Non-patent literature 4, 5, 6). Therefore, drugs that regulate excessive excitation are expected to have a pathological effect on these disorders. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Scheffer, IE. et al. Epilepsia, (2017), 58(4), 512-521. [Non-Patent Document 2] Aaberg, KM. et al. Pediatrics, (2016), 138(3), e2016921. [Non-Patent Document 3] Gaitatzis, A. et al. Epilepsia, (2004), 45(12), 1613-1622. [Non-Patent Document 4] Selten, M. et al. F1000Research, (2018), 7. [Non-Patent Document 5] Palop, JJ. et al. Nature Review Neuroscience, (2016), 17(12), 777-792. [Non-Patent Document 6] Charvin, D. et al. Nature Review Drug Discovery, (2018), 17(11), 804-822. [Overview of the Initiative] [Means for solving the problem]

[0006] The present disclosure provides a 2-heteroaryl aminoquinazolinone derivative and a pharmaceutically acceptable salt thereof, a nerve overexcitation inhibitor containing the compound or the like as an active ingredient, a medicine, a pharmaceutical composition, and uses thereof that are useful for the treatment or prevention of epilepsy, developmental disorders, and the like, and a method for prevention or treatment using the compound.

[0007] As a result of intensive studies, the present inventors have found that the compound represented by the following formula (1) exhibits a strong inhibitory effect on nerve circuit overexcitation, and have completed the present disclosure. According to the present disclosure, a 2-heteroaryl aminoquinazolinone derivative represented by the following formula (1) (hereinafter, may also be referred to as "the compound of the present disclosure") is provided.

[0008] That is, the present disclosure is as follows.

[0009] (Item 1) Formula (1): [Chemical formula] [In the formula, X 1 represents CR 1 or N, X 2 represents CR 2 or N, X 3 represents CR 3 or N, X 4 represents CR 4 or N, Here, (1) when X 1 is N, X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 (2) when X 2 is N, X 1 is CR 1 and X 3 is CR 3and X 4 CR 4 (3)X 3 If X is N, 1 CR 1 and X 2 CR 2 and X 4 CR 4 (4)X 4 If X is N, 1 CR 1 and X 2 CR 2 and X 3 CR 3 And, Y may be substituted for C 1-6 Alkyl, possibly substituted C 3-10 Alicyclic group, optionally substituted 4-10 membered nonaryl heteroring, optionally substituted C 6-10 Represents an aryl or optionally substituted 5-10 member heteroaryl, Z represents a 5-10 member heteroaryl that may be substituted, R 1 , R 2 , R 3 and R 4 These are, independently, hydrogen, halogen, cyano, and C. 1-6 Alkyl sulfonyl, -SO2-NR 5 R 6 , -NR 7 R 8 , -NR 9 -C(=O)R 10 , -NR 11 -SO2-R 12 -C(=O)NR 13 R 14 , -C(=O)OR 15 , C which may be substituted 1-6 Alkyl or optionally substituted C 1-6 Represents alkoxy, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R12 、 R 13 、 R 14 and R 15 are each independently, when there are a plurality, each independently, the same or different, a hydrogen atom, C 3-6 alicyclic group, and C 1-6 alkyl (the alicyclic group and the alkyl are each independently substituted by the same or different 1 to 3 substituents selected from the group consisting of halogen, hydroxyl group, C 3-10 alicyclic group, C 1-6 alkoxy, and 4- to 6-membered non-aryl heterocyclic group), and herein, R 5 and R 6 、 R 7 and R 8 、 R 13 and R 14 together with the nitrogen atom to which they are attached may form a 4- to 10-membered nitrogen-containing non-aryl heterocyclic group (the ring may be substituted by the same or different 1 to 5 substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy)] represented by, A medicament containing a compound or a pharmaceutically acceptable salt thereof. (Item 2) Formula (1):

Chemical formula

[0010] In this disclosure, the one or more of the above features are intended to be provided in combinations other than those explicitly stated. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary. [Effects of the Invention]

[0011] The compounds disclosed herein have activity that suppresses the excessive excitation of neural circuits thought to be underlying various epileptic pathologies, and have shown strong anticonvulsant activity in human cell epilepsy models and multiple animal seizure models. Therefore, they are useful as antiepileptic drugs with a broad therapeutic spectrum (for epileptic seizures (generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, and atonic seizures, focal seizures, epileptic spasms, and seizures of unknown classification), status epilepticus, epileptic syndromes (Dravet syndrome, Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy, medial temporal lobe epilepsy with hippocampal sclerosis, Rasmussen syndrome, etc.), epilepsy attributable to structural / metabolic causes (cortical dysplasia, neurocutaneous syndromes (tuberous sclerosis complex, Sturge-Weber syndrome, etc.), etc.), and for treating and / or prophylactic conditions such as developmental disorders, mental disorders, and cognitive disorders that occur concurrently with these conditions). Furthermore, it is expected to exhibit a pathological improvement effect on disorders or diseases that are based on an imbalance between excitatory and inhibitory signals in neural circuits (developmental disorders (autism spectrum disorder, Rett syndrome, Angelman syndrome, fragile X syndrome, attention deficit hyperactivity disorder, etc.), mental disorders (schizophrenia, bipolar disorder, depression, anxiety disorders, obsessive-compulsive disorder, etc.), cognitive disorders (Alzheimer's disease and other dementias, Parkinson's disease, etc.)). [Brief explanation of the drawing]

[0012] [Figure 1] The powder X-ray diffraction patterns of the type I crystal of the compound from Example 3 are shown. The horizontal axis represents the diffraction angle 2θ (°), and the vertical axis represents the count (the same applies to Figures 2 to 5 below). [Figure 2] The powder X-ray diffraction pattern of the form II crystal of the compound in Example 234 is shown. [Figure 3] The powder X-ray diffraction pattern of the form III crystal of the compound of Example 235 is shown. [Figure 4] The powder X-ray diffraction pattern of the form IV crystal of the compound in Example 236 is shown. [Figure 5] The powder X-ray diffraction pattern of the V-shaped crystal of the compound in Example 237 is shown. [Modes for carrying out the invention]

[0013] The present disclosure is described in further detail below. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0014] In this specification, if there are instances where a group is described with and without the word "group," such as "phenyl" and "phenyl group," they shall be interpreted as referring to the same group.

[0015] The number of substituents on a group defined as "may be substituted" or "substituted" is not particularly limited as long as substitution is possible. Also, unless otherwise specified, the description of each group applies even if that group is part of or a substituent of another group.

[0016] The substituents in "may be substituted" are selected from the group of substituents α consisting of the following, and may be substituted with the same or different 1 to 5 substituents. There are no particular restrictions on the type of substituent, however, if the atom to which the substituent is bonded is an oxygen atom, nitrogen atom, or sulfur atom, then the substituents are limited to those from the following list to which the bonded atom is a carbon atom. The substituent group α is, 1) Halogen atom 2) Hydroxyl group 3) Carboxyl group 4) Cyano group 5) C 1-6 alkyl group 6) C 2-6 Alkenyl group 7)C 2-6 Alkynyl group 8)C 1-6 Alkoxy group 9)C 1-6 Alkylthio group 10)C 1-6 Alkylcarbonyl group 11)C 1-6 Alkyl sulfonyl group (However, each substituent from 5) to 11) may be replaced by one to five identical or different substituents selected from substituent group β.) 12)C 3-10 alicyclic group 13)C 3-10 Alicyclic oxy group 14)C 6-10 Aryloxy group 15) Five-membered or six-membered heteroaryloxy group 16) 4-10 member non-aryl heterocyclic oxy groups 17)C 3-10 alicyclic thio group 18)C 6-10 Arylthio group 19) Five-membered or six-membered heteroarylthio group 20) 4-10 member nonaryl heterocyclic thio groups 21)C 6-10 Ariel 22) Five-membered or six-membered heteroaryl 23) 4-10 member non-aryl heterocyclic groups 24)C 3-10 Alicyclic carbonyl group 25)C 6-10 Arylcarbonyl group 26) Five-membered or six-membered heteroarylcarbonyl group 27) 4-10 member non-aryl heterocyclic carbonyl group 28)C 3-10 Alicyclic sulfonyl group 29)C 6-10 Arylsulfonyl group 30) 5-membered or 6-membered heteroarylsulfonyl group 31) 4-10 member non-aryl heterocyclic sulfonyl group (However, each substituent from 12) to 31) is either a group of 1 to 5 substituents β or the C mentioned in 1) above. 1-6 (May be substituted with an alkyl group) 32)-NR 16 R 17 These include, The substituent group β is, 1) Halogen atom, 2) Hydroxyl group, 3) Carboxyl group, 4) Cyano group, 5) C 3-10 alicyclic group, 6) C 1-6 Alkoxy group, 7)C 3-10 Alicyclic oxy group, 8)C 1-6 Alkylthio group, 9) 5-membered or 6-membered heteroarylthio group, 10)C 6-10 Ariel, 11) 5-membered or 6-membered heteroaryl, 12) 4-10 member non-aryl heterocyclic group, 13)C 1-6 Alkylcarbonyl group, 14)C 3-10 Alicyclic carbonyl group, 15)C 6-10 Arylcarbonyl group, 16) 5-membered or 6-membered heteroarylcarbonyl group, 17) 4-10 member non-aryl heterocyclic carbonyl group, 18)-NR 18 R 19 , (However, among the substituent group β, each substituent from 5) to 17) is a halogen atom, hydroxyl group, cyano group, carboxyl group, -NR 20 R 21 A group consisting of (which may be substituted by 1 to 5 substituents selected from the group consisting of) R 16 , R 17 , R 18 , R 19 Each is independently, identical or different, a hydrogen atom or C 1-6 Alkyl group (The alkyl group is a hydroxyl group, a cyano group, C 1-6 Alkoxy group, -NR 20 R 21 (May be substituted by 1 to 3 identical or different substituents, which are more selected) R 20 , R 21 Each is independently, identical or different, a hydrogen atom or C 1-6 It is an alkyl group.

[0017] The substituents in "may be substituted" are preferably the following substituents. The substituent group α is preferably, 1) Halogen atom 2) Hydroxyl group 3) Carboxyl group 4) Cyano group 5) C 1-6 alkyl group 6) C 1-6 Alkoxy group 7)C 1-6 Alkylthio group 8)C 1-6 Alkylcarbonyl group (However, each substituent in 5) to 8) may be replaced by one to five identical or different substituents selected from substituent group β.) 9)C 3-10 alicyclic group 10)C 3-10 Alicyclic oxy group 11)C 6-10 Aryloxy group 12) Five-membered or six-membered heteroaryloxy group 13) 4-10 member non-aryl heterocyclic oxy groups 14)C 3-10 alicyclic thio group 15)C 6-10 Arylthio group 16) Five-membered or six-membered heteroarylthio group 17) 4-10 member nonaryl heterocyclic thio groups 18)C 6-10 Ariel 19) Five-membered or six-membered heteroaryl 20) 4-10 member non-aryl heterocyclic groups 21)C 3-10 Alicyclic carbonyl group 22)C 6-10 Arylcarbonyl group 23) 5-membered or 6-membered heteroarylcarbonyl group 24) 4-10 member non-aryl heterocyclic carbonyl group (However, each substituent in 9) to 24) is either a group of 1 to 5 substituents β or the C in 1) above. 1-6 (May be substituted with an alkyl group) 25)-NR 16 R 17 These include, The substituent group β is preferably, 1) Halogen atom 2) Hydroxyl group 3) Cyano group 4) C 3-10 alicyclic group 5) C 1-6 Alkoxy group 6) C 1-6 Alkylthio group 7) Five-membered or six-membered heteroarylthio group 8) Five-membered or six-membered heteroaryl 9) 4-10 member nonaryl heterocyclic groups 10)C 1-6 Alkylcarbonyl group 11)C 3-10 Alicyclic carbonyl group 12)C 6-10 Arylcarbonyl group 13) 5-membered or 6-membered heteroarylcarbonyl group 14) 4-10 member non-aryl heterocyclic carbonyl group 15)-NR 18 R 19 (However, among the substituent group β, each substituent from 4) to 14) is a halogen atom, hydroxyl group, cyano group, carboxyl group, -NR 20 R 21 A group consisting of (which may be substituted by 1 to 5 substituents selected from the group consisting of) R 16 , R 17 , R 18 , R 19 Each is independently, identical or different, a hydrogen atom or C 1-6 Alkyl group (The alkyl group is a hydroxyl group, a cyano group, C 1-6 Alkoxy group, -NR 20 R 21 (May be substituted by 1 to 3 identical or different substituents, which are more selected) R 20 , R 21 Each is independently, identical or different, a hydrogen atom or C 1-6 It is an alkyl group.

[0018] The substituents in "may be substituted" are more preferably the following substituents. The substituent group α is more preferably, 1) Halogen atom 2) Hydroxyl group 3) Cyano group 4) C 1-6 alkyl group 5) C 1-6 Alkoxy group 6) C 1-6 Alkylthio group 7)C 1-6 Alkylcarbonyl group (However, each substituent in 4) to 7) may be replaced by one to five identical or different substituents selected from substituent group β.) 8) Five-membered or six-membered heteroaryloxy group 9) 4-10 member non-aryl heterocyclic oxy groups 10) 5-membered or 6-membered heteroarylthio group 11) 4-10 member nonaryl heterocyclic thio groups 12)C 6-10 Ariel 13) 5-membered or 6-membered heteroaryl 14) 4-10 member non-aryl heterocyclic groups (However, each substituent in 4) to 14) is either a group of 1 to 5 substituents β or the C in 1) above. 1-6 (May be substituted with an alkyl group) 15)-NR 16 R 17 These include, The substituent group β is more preferably, 1) Halogen atom, 2) Hydroxyl group, 3) Cyano group, 4)-NR 18 R 19 , And R 16 , R 17 , R 18 , R 19 Each is independently, identical or different, a hydrogen atom or C 1-6 Alkyl group (The alkyl group is a hydroxyl group, a cyano group, C 1-6 Alkoxy group, -NR 20 R 21 (May be substituted by 1 to 3 identical or different substituents, which are more selected) R 20 , R 21 Each is independently, identical or different, a hydrogen atom or C 1-6 It is an alkyl group.

[0019] "C 1-6 " means that the number of carbon atoms is between 1 and 6. The same applies to other numbers, for example, "C 1-4 " means that the number of carbon atoms is between 1 and 4.

[0020] "Heteroatoms" refer to oxygen atoms, nitrogen atoms, sulfur atoms, etc.

[0021] A "halogen atom" refers to any atom other than carbon and hydrogen atoms, and includes fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are preferred among these. Sometimes, "halogen atom" is simply referred to as "halogen."

[0022] "C 1-6 "Alkyl" or "C 1-6 "Alkyl group" refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms. 1-6 Preferably, the alkyl group is "C 1-4 Examples include "alkyl groups", and more preferably "C 1-3 "alkyl group" or "C 2-3 "Alkyl group" is one example. 1-3 Specific examples of alkyl groups include methyl, ethyl, propyl, and 1-methylethyl. 2-3 Specific examples of alkyl groups include ethyl, propyl, and 1-methylethyl. 1-4 A specific example of an alkyl group is, for example, the aforementioned "C 1-3 In addition to the examples listed as specific examples of "alkyl groups," other examples include butyl, 1,1-dimethylethyl, 1-methylpropyl, and 2-methylpropyl. 1-6 A specific example of an alkyl group is, for example, the aforementioned "C 1-4 In addition to the examples listed for "alkyl groups," pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl These are some examples.

[0023] "C 2-6 "Alkenil" or "C 2-6 An "alkenyl group" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds. 2-6As the "alkenyl group", preferably "C 2-4 It is an "alkenyl group" "C 2-6 Specific examples of "alkenyl groups" are not limited to these, but include vinyl groups, 1-propyrenyl groups, 2-propyrenyl groups, 1-butenyl groups, 2-butenyl groups, 3-butenyl groups, 2-methyl-1-propyrenyl groups, and 2-methyl-2-propyrenyl groups.

[0024] "C 2-6 "Alkinyl" or "C 2-6 The term "alkynyl group" refers to a linear or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds. 2-6 "Alkynyl group" is preferably "C 2-4 These are "alkynyl groups." Specifically, although not limited to these, examples include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, and 1-hexynyl group.

[0025] "C 3-10 "Alicyclic group" refers to a monocyclic or bicyclic monovalent non-aromatic hydrocarbon ring group having 3 to 10 carbon atoms, and includes those with some unsaturated bonds, some bridging structures, some spirated structures, and those with one or more carbonyl structures. "Alicyclic group" includes cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups. 3-10 Preferably, "C" is used as the "alicyclic group". 3-6 "Alicyclic group", more preferably "C 5-6 "Alicyclic group" is one example. 5-6 Specific examples of "alicyclic groups" include, for example, cyclopentyl and cyclohexyl. 3-6 A specific example of an "alicyclic group" is, for example, the aforementioned "C 5-6 In addition to the examples given for "alicyclic groups," other examples include cyclopropyl and cyclobutyl. 3-10 A specific example of an "alicyclic group" is, for example, the aforementioned "C 3-6In addition to the examples given for "alicyclic groups," other examples include cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and adamantyl.

[0026] "C" has a partially cross-linked structure. 3-10 Specific examples of "alicyclic groups" are not limited to those shown below, but include, for example, those with the structures shown below. [ka]

[0027] Also, "C 3-10 The term "alicyclic group" also includes compounds formed by fusion with an aromatic ring. Specific examples include the groups shown below. [ka]

[0028] "C 6-10 "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 carbon atoms. 6-10 The "aryl" may be condensed with the "alicyclic group" or "non-aryl heterocycle" at all possible positions. 6-10 Specific examples of "aryl" include, for example, phenyl, 1-naphthyl, and 2-naphthyl. 6-10 Phenyne is a preferred example of the "aryl" group. Specific examples of the fused ring structure include, for example, the group represented below. [ka] [ka]

[0029] "5-10 membered heteroaryl" means a monocyclic or bicyclic aromatic heterocyclic group composed of 5-10 atoms, including 1-4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. "5-10 membered heteroaryl" may be condensed with the "alicyclic group" or "non-aryl heterocycle" at all possible positions. Preferred "5-10 membered heteroaryl" groups include "5 membered heteroaryl," "6 membered heteroaryl," "5 membered or 6 membered heteroaryl," "6-10 membered heteroaryl," or "9 membered or 10 membered heteroaryl." Specific examples of "5 membered heteroaryl" groups include furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, and thiadiazolyl. Specific examples of "6 membered heteroaryl" groups include pyridyl, pyrazinyl, pyrimidinyl, and pyridadinyl. Specific examples of "5-membered or 6-membered heteroaryls" include, for example, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridadinyl. Specific examples of "6- to 10-membered heteroaryls" include pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinoxalyl, triazolopyridyl, etc. Specific examples of "5- to 10-membered heteroaryls" include the aforementioned "6- to 10-membered heteroaryls" and "5- or 6-membered heteroaryls".

[0030] In Formula 1, if Y is a "5- to 10-membered heteroaryl," a "5- or 6-membered heteroaryl," or a "6-membered heteroaryl," the nitrogen atom is bonded to the carbon atom on the ring of the heteroaryl group.

[0031] In Formula 1, a "5-10 membered heteroaryl" or a Z group that is a "5-10 membered heteroaryl," such as "pyridyl," "pyrimidinyl," "indazolyl," or "imidazopyridyl," is bonded to a nitrogen atom at a carbon atom on the ring of the Z group. In one embodiment, a 5-10 membered heteroaryl, such as the 5-10 membered heteroaryl of Z, is not bonded to a nitrogen atom on the ring of the heteroaryl group.

[0032] Specific examples of "9-membered or 10-membered heteroaryls" include, but are not limited to, those with the structures shown below. [ka] [ka]

[0033] The aforementioned "5-membered or 6-membered heteroaryl" or "5- to 10-membered heteroaryl" is C 5-10 It may form a fused ring structure with an alicyclic group, or a fused ring structure with a 5-10 membered non-aryl heteroring. Specific examples include the groups shown below. [ka] [ka] [ka]

[0034] A "4-10 member non-aryl heterocyclic group" refers to a monocyclic or bicyclic non-aromatic heterocyclic group composed of 4 to 10 atoms, including 1 to 2 identical or different heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, in addition to carbon atoms, and includes those having some unsaturated bonds, some bridging structures, and / or some spirogenic structures. A "4-10 member non-aryl heterocyclic group" is preferably a "4-6 member non-aryl heterocyclic group" or a "4-10 member nitrogen-containing non-aryl heterocyclic group." Specific examples of "4-6 member non-aryl heterocyclic groups" include, for example, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranil, and tetrahydropyranil. Among these, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, and oxetanyl are preferred. The non-aryl heterocyclic group may form a fused ring with an aryl or heteroaryl group. For example, C 6-10 Non-aryl heterocycles are also included when fused with aryl or 5-membered or 6-membered heteroaryl groups. Furthermore, the non-aryl heterocycle may contain one or more carbonyl, thiocarbonyl, sulfinyl, or sulfonyl atoms. For example, cyclic groups such as lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate, and cyclic thiocarbamate are also included in the non-aryl heterocycle. Here, the oxygen atoms of carbonyl, sulfinyl, and sulfonyl groups, and the sulfur atoms of thiocarbonyl groups are not included in the number of members (ring size) and the number of heteroatoms constituting the ring. As for "4- to 10-membered non-aryl heterocycles," "4- to 6-membered non-aryl heterocycles" are preferred. Specific examples of "4- to 6-membered non-aryl heterocycles" include, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, and tetrahydropyran. Specific examples of "4- to 10-membered non-aryl heterorings" include, for example, those with the structures shown below, in addition to those listed above as specific examples of "4- to 6-membered non-aryl heterorings." [ka]

[0035] Furthermore, specific examples of "4- to 10-membered non-aryl heterocycles" having partial cross-linking and / or spiro structures include, but are not limited to, those with the structures shown below. [ka]

[0036] "Oxetanyl" is a monovalent group with a saturated four-membered ring containing one oxygen atom, for example, phenyloxetanyl. [ka] These are some examples.

[0037] A "4-10 member nitrogen-containing non-aryl heterocycle" refers to a monocyclic or bicyclic non-aromatic heterocycle composed of 4 to 10 atoms, containing one nitrogen atom and zero or one or more identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. This includes those with some unsaturated bonds, some bridged structures, and / or those that are partially spirated. Preferably, a "4-10 member nitrogen-containing non-aryl heterocycle" is a "4-6 member nitrogen-containing non-aryl heterocycle" or a "5- or 6-member nitrogen-containing non-aryl heterocycle." Specific examples of a "5- or 6-member nitrogen-containing non-aryl heterocycle" include pyrrolidine, piperidine, piperazine, morpholine, etc. Specific examples of a "4-6 member nitrogen-containing non-aryl heterocycle" include those listed above as examples of a "5- or 6-member nitrogen-containing non-aryl heterocycle," as well as azetidine, etc. Specific examples of "4- to 10-membered nitrogen-containing non-aryl heterocycles" include, in addition to those listed above as specific examples of "5- or 6-membered nitrogen-containing non-aryl heterocycles," azetidine, azepane, azocane, and the like.

[0038] Furthermore, specific examples of "4-10 member nitrogen-containing non-aryl heterocycles" having partial crosslinking and / or spiro structures include, but are not limited to, those with the structures shown below. [ka]

[0039] In Formula 1, if Y is a "4- to 10-membered nitrogen-containing nonaryl heterocyclic group" or a "5- or 6-membered nitrogen-containing nonaryl heterocyclic group," the nitrogen atom is bonded to the carbon atoms on the ring of the nitrogen-containing nonaryl heterocyclic group.

[0040] Furthermore, specific examples of "four-membered non-aryl heterocycles" having some unsaturated bonds include, but are not limited to, those with the structures shown below. [ka]

[0041] Furthermore, specific examples of "5-membered non-aryl heterocycles" that have some unsaturated bonds include, but are not limited to, those with the structures shown below. [ka]

[0042] Furthermore, specific examples of "5-membered non-aryl heterocycles" having a partially cross-linked structure include, but are not limited to, those with the structures shown below. [ka]

[0043] Furthermore, specific examples of "5-membered non-aryl heterocycles" containing carbonyl or thiocarbonyl molecules, etc., are not limited to these, but include, for example, structures like those shown below. [ka]

[0044] Furthermore, while not limited to these examples, specific examples of "six-membered non-aryl heterocycles" that have some unsaturated bonds include those with the structures shown below. [ka]

[0045] Furthermore, specific examples of "six-membered non-aryl heterocycles" having a partially cross-linked structure include, but are not limited to, those with the structures shown below. [ka]

[0046] "C 1-6 "alkoxy" or "C 1-6 An "alkoxy group" is a "C 1-6 This refers to "alkyloxy," and "C 1-6 The "alkyl" portion is the aforementioned "C 1-6 It is synonymous with "alkyl". 1-6 Preferably, "C" is used as the "alkoxy" 1-4 "alkoxy" or "C 2-6 "Alkoxy" is one example, and more preferably "C 1-3 "alkoxy" is one example. 1-3 Specific examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and 1-methylethoxy. 1-4 A specific example of "alkoxy" is, for example, the aforementioned "C 1-3 In addition to the examples given for "alkoxy," other examples include butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methylpropoxy. 2-6Specific examples of "alkoxy" include, for example, ethoxy, propoxy, 1-methylethoxy, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, etc. 1-6 A specific example of "alkoxy" is, for example, the aforementioned "C 1-4 In addition to the examples given for "alkoxy," other examples include pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, and hexyloxy.

[0047] "C 3-6 "Alicyclic oxy" or "C 3-6 "Alicyclic oxy group" refers to (C 3-6 (Alicyclic group)-O- group, and the C 3-6 The alicyclic part is C 3-6 It is synonymous with an alicyclic group. 3-6 "Alicyclic oxy group" is "C 3-6 Contains a "cycloalkoxy group". A "cycloalkoxy group" is the same as "cycloalkyloxy", and the "cycloalkyl" part is synonymous with the aforementioned "cycloalkyl". 3-6 Specific examples of "alicyclic oxy groups" include, for example, cyclopropoxy groups, cyclobutoxy groups, cyclopentoxy groups, and cyclohexoxy groups.

[0048] "C 6-10 C of "aryloxy group" 6-10 The aryl portion is C above. 6-10 It is synonymous with "aryl". 6-10 Preferably, the "aryloxy group" is "C6 or C6". 10 "The aryloxy group of C" is one example. 6-10Specific examples of "aryloxy groups" are not limited to these, but include, for example, phenoxy group, 1-naphthyloxy group, and 2-naphthyloxy group.

[0049] The 5-membered or 6-membered heteroaryl portion of "5-membered or 6-membered heteroaryloxy group" is synonymous with the above-mentioned "5-membered heteroaryl" or "6-membered heteroaryl." Specific examples of "5-membered or 6-membered heteroaryloxy groups" are not limited to these, but include, for example, pyrazoyloxy, triazoyloxy, thiazoyloxy, thiadiazoyloxy, pyridyloxy, and pyridazoyloxy groups.

[0050] The 4-10 member non-aryl heterocyclic portion of "4-10 member non-aryl heterocyclic oxy group" is synonymous with the above-mentioned "4-10 member non-aryl heterocyclic ring". Preferably, the "4-10 member non-aryl heterocyclic oxy group" is a "4-6 member non-aryl heterocyclic oxy group". Specific examples of the "4-10 member non-aryl heterocyclic oxy group" are not limited to these, but include, for example, tetrahydrofuranyloxy group, tetrahydropyranyloxy group, azetidinyloxy group, pyrrolidinyloxy group, piperidinyloxy group, etc.

[0051] "C 1-6 C of alkylthio group 1-6 The alkyl portion is the above C 1-6 It is synonymous with alkyl. 1-6 Preferably, "C" is used as the alkylthio group. 1-4 "alkylthio group", more preferably "C 1-3 It is an alkylthio group. 1-6 Specific examples of "alkylthio groups" include, but are not limited to, methylthio group, ethylthio group, propylthio group, butylthio group, isopropylthio group, isobutylthio group, tert-butylthio group, sec-butylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1,2-dimethylpropylthio group, and others.

[0052] "C3-10 "Alipidic thio" or "C 3-10 "Alicyclic thio group" is (C 3-10 (Alicyclic group) -S- group, and the C 3-10 The alicyclic portion is C above. 3-10 It is synonymous with an alicyclic group. 3-10 Preferably, "C" is used as the "alicyclic thio group". 3-6 It is an alicyclic thio group. 3-6 Specific examples of "alicyclic thio groups" include, but are not limited to, cyclopropylthio groups, cyclobutylthio groups, cyclopentylthio groups, and cyclohexylthio groups.

[0053] "C 6-10 "Alylthio" or "C 6-10 C of the arylthio group 6-10 The aryl portion is C above. 6-10 It is synonymous with "aryl". 6-10 The "arylthio group" is preferably "C6 or C6". 10 One example is the "arylthio group of C". 6-10 Specific examples of "arylthio groups" are not limited to these, but include, for example, phenylthio groups, 1-naphthylthio groups, and 2-naphthylthio groups.

[0054] The 5-membered or 6-membered heteroaryl portion of "5-membered or 6-membered heteroarylthio" or "5-membered or 6-membered heteroarylthio group" is synonymous with the above-mentioned "5-membered heteroaryl" or "6-membered heteroaryl". Specific examples of "5-membered or 6-membered heteroarylthio groups" are not limited to these, but include, for example, pyrazoylthio groups, triazoylthio groups, thiazoylthio groups, thiadiazoylthio groups, pyridylthio groups, pyridazoylthio groups, etc.

[0055] The 4-10 member non-aryl heterocyclic portion of "4-10 member non-aryl heterocyclic thio" or "4-10 member non-aryl heterocyclic thio group" is synonymous with the above-mentioned "4-10 member non-aryl heterocyclic." Preferably, the "4-10 member non-aryl heterocyclic thio group" is a "4-6 member non-aryl heterocyclic thio group." Specific examples of the "4-10 member non-aryl heterocyclic thio group" are not limited to these, but include, for example, a tetrahydropyranylthio group and a piperidinylthio group.

[0056] "C 1-6 "Alkylcarbonyl" or "C 1-6 The "alkylcarbonyl group" refers to the above "C 1-6 This refers to a carbonyl group substituted with an alkyl group. 1-6 Preferably, "C" is used as the "alkylcarbonyl group". 1-4 It is an alkylcarbonyl group. 1-6 Specific examples of "alkylcarbonyl groups" include, but are not limited to, acetyl groups, propionyl groups, and butyryl groups.

[0057] "C 3-10 "Alicyclic carbonyl" or "C 3-10 "Alicyclic carbonyl group" refers to the above "C 3-10 This refers to a carbonyl group substituted with an alicyclic group. 3-10 Preferably, "C" is used as the "alicyclic carbonyl group". 3-6 It is an "alicyclic carbonyl group". 3-10 Specific examples of "alicyclic carbonyl groups" include, but are not limited to, cyclopropyl carbonyl groups and cyclopentyl carbonyl groups.

[0058] "C 6-10 "Arylcarbonyl" or "C 6-10 The term "arylcarbonyl group" refers to the above "C 6-10 This refers to a carbonyl group substituted with "aryl". 6-10 Preferably, the "arylcarbonyl group" is "C6 or C6". 10 It is the arylcarbonyl group of "C 6-10Specific examples of "arylcarbonyl groups" are not limited to these, but include, for example, benzoyl groups, 1-naphthylcarbonyl groups, and 2-naphthylcarbonyl groups.

[0059] "Five-membered or six-membered heteroarylcarbonyl" or "five-membered or six-membered heteroarylcarbonyl group" means a carbonyl group substituted with the above-mentioned "five-membered or six-membered heteroaryl." Specific examples of "five-membered or six-membered heteroarylcarbonyl groups" are not limited to these, but include, for example, pyrazoylcarbonyl group, triazoylcarbonyl group, thiazoylcarbonyl group, thiadiazoylcarbonyl group, pyridylcarbonyl group, pyridazoylcarbonyl group, etc.

[0060] "4-10 member non-aryl heterocyclic carbonyl" or "4-10 member non-aryl heterocyclic carbonyl group" means a carbonyl group substituted with the above-mentioned "4-10 member non-aryl heterocyclic" group. Preferably, the "4-10 member non-aryl heterocyclic carbonyl group" is a "4-6 member non-aryl heterocyclic carbonyl group". Specific examples of the "4-10 member non-aryl heterocyclic carbonyl group" are, but are not limited to, azetidinyl carbonyl group, pyrrolidinyl carbonyl group, piperidinyl carbonyl group, morpholinyl carbonyl group, etc.

[0061] "C 1-6 "Alkylsulfonyl" or "C 1-6 The "alkylsulfonyl group" refers to the above "C 1-6 This refers to a sulfonyl group substituted with an alkyl group. 1-6 Preferably, "C" is used as the alkylsulfonyl group. 1-4 It is an alkylsulfonyl group. 1-6 Specific examples of "alkylsulfonyl groups" are not limited to these, but include, for example, methylsulfonyl groups, propionylsulfonyl groups, and butyrylsulfonyl groups.

[0062] "C 3-10 "Alicyclic sulfonyl" or "C 3-10"Alicyclic sulfonyl group" refers to the above "C 3-10 This refers to a sulfonyl group substituted with an alicyclic group. 3-10 As an "alicyclic sulfonyl group", preferably "C 3-6 It is an "alicyclic sulfonyl group". 3-10 Specific examples of "alicyclic sulfonyl groups" include, but are not limited to, cyclopropylsulfonyl groups, cyclobutylsulfonyl groups, cyclopentylsulfonyl groups, and cyclohexylsulfonyl groups.

[0063] "C 6-10 "Aryl sulfonyl" or "C 6-10 The term "arylsulfonyl group" refers to the above "C 6-10 This refers to a sulfonyl group substituted with "aryl". 6-10 The "aryl sulfonyl group" is preferably "C6 or C6". 10 It is the aryl sulfonyl group of "C 6-10 Specific examples of "arylsulfonyl groups" include, but are not limited to, phenylsulfonyl groups, 1-naphthylsulfonyl groups, and 2-naphthylsulfonyl groups.

[0064] "Five-membered or six-membered heteroarylsulfonyl" or "five-membered or six-membered heteroarylsulfonyl group" means a sulfonyl group substituted with the above-mentioned "five-membered or six-membered heteroaryl". Specific examples of "five-membered or six-membered heteroarylsulfonyl groups" include pyrazoylsulfonyl group, triazoylsulfonyl group, thiazoylsulfonyl group, thiadiazoylsulfonyl group, pyridylsulfonyl group, pyridazoylsulfonyl group, etc.

[0065] In the compound of the present disclosure represented by formula (1), X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 Preferred Y and Z are as follows, but the technical scope of this disclosure is not limited to the compounds listed below.

[0066] X 1 A preferred embodiment is CR 1 These are some examples.

[0067] X 2 A preferred embodiment is CR 2 These are some examples.

[0068] X 3 A preferred embodiment is CR 3 These are some examples.

[0069] X 4 A preferred embodiment is CR 4 These are some examples.

[0070] R 1 , R 2 , R 3 and R 4 A preferred embodiment is, (1) Hydrogen atom, (2) Fluorine, (3) Cyano, (4)C 1-6 Alkoxy, or (5)C 1-6 Alkyl (the alkyl is a halogen, hydroxy, and C 1-6 Examples include those that are substituted with one to three identical or different substituents selected from the group consisting of alkoxys.

[0071] R 1 , R 2 , R 3 and R 4 A more preferred embodiment is, (1) Hydrogen atom, (2) Fluorine (3) Cyano is an example.

[0072] R 1 , R 3 and R 4 A more preferred embodiment is a hydrogen atom.

[0073] R 2 A more preferred embodiment includes fluorine or cyanoacrylate.

[0074] A preferred embodiment of Y is: (1) Halogen, hydroxy, amino, dimethylamino, C 3-6 Alicyclic group, 4-10 member nitrogen-containing nonaryl heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing nonaryl heterocycle, the alkoxy, and the aryl group are each independently a halogen, cyano, C 3-6 Alicyclic group, C which may be substituted with 1 to 5 fluorine atoms. 1-6 Alkyl and C 1-6 (These may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys), and a 5 to 10-membered heteroaryl group (the heteroaryl group is a halogen, cyano, or C 3-6 Alicyclic group, C which may be substituted with 1 to 5 fluorine atoms. 1-6 Alkyl and C 1-6 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys) 1-6 Alkyl, (2) C which may be substituted with halogens, hydroxyl, amino, dimethylamino, or 1 to 5 fluorines. 1-6 Alkyl, C 3-6 Alicyclic group, 4-10 member nitrogen-containing nonaryl heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing nonaryl heterocycle, the alkoxy, and the aryl group are each independently a halogen, cyano, C 3-6 Alicyclic group, C which may be substituted with 1 to 5 fluorine atoms. 1-6 Alkyl and C 1-6 (These may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys), and a 5 to 10-membered heteroaryl group (the heteroaryl group is a halogen, cyano, or C 3-6Alicyclic group, C which may be substituted with 1 to 5 fluorine atoms. 1-6 Alkyl and C 1-6 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys) 3-10 alicyclic group, (3) C which may be substituted with halogens, hydroxyl, amino, dimethylamino, or 1 to 5 fluorines. 1-6 Alkyl, C 3-6 Alicyclic groups and C 1-6 A 4-10 member nonaryl heterocyclic group which may be substituted with 1-3 identical or different substituents selected from the group consisting of alkoxys, (4) Halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C 1-6 C may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys (which may be substituted with one to three identical or different substituents). 6-10 Aryl, or (5) Halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C 1-6 Examples include 5-10 member heteroaryls which may be substituted with 1-3 identical or different substituents selected from the group consisting of alkoxys.

[0075] A preferred embodiment of Y is: (1) Fluorine, C 3-6 A alicyclic group, a 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing nonaryl heterocyclic group, and the phenyl group may each be independently substituted with fluorine, cyano, or 1 to 3 fluorine atoms). 1-3(The heteroaryl group may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) and a five-membered heteroaryl group (the heteroaryl group may be substituted with fluorine, cyano, or one to three fluorine atoms) 1-3 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) 1-3 Alkyl, (2) Fluorine, amino, dimethylamino, or C which may be substituted with 1 to 3 fluorine atoms. 2-3 Alkyl, 5-6 member nitrogen-containing nonaryl heterocyclic group, phenyl (the phenyl group may be substituted with fluorine, cyano, or 1-3 fluorine atoms) 1-3 (The heteroaryl group may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) and a 5-6 member heteroaryl group (the heteroaryl group may be substituted with fluorine, cyano, or one to three fluorine atoms) 1-3 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) 5-6 Alicyclic group or phenylcyclopropyl, (3) Fluorine, amino, dimethylamino, or C which may be substituted with 1 to 3 fluorine atoms. 2-3 Alkyl and phenyl (the phenyl group may be substituted with fluorine, cyano, or 1 to 3 fluorine atoms) 1-3 A 4-6 member nitrogen-containing nonaryl heterocyclic group, phenyloxetanyl, or tetrahydropyranyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy. (4) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Phenyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (5) Halogen, cyano, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Examples include six-membered heteroaryls which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0076] Furthermore, preferred embodiments of Y include (1) fluorine, C 3-6 A alicyclic group, a 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing nonaryl heterocyclic group, and the phenyl group may each be independently substituted with fluorine, cyano, or 1 to 3 fluorine atoms). 1-3 (The heteroaryl group may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) and a 5-6 member heteroaryl group (the heteroaryl group may be substituted with fluorine, cyano, or one to three fluorine atoms) 1-3 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) 1-3 Alkyl, (2) Fluorine, amino, dimethylamino, or C which may be substituted with 1 to 3 fluorine atoms. 1-3 Alkyl, 5-6 member nitrogen-containing nonaryl heterocyclic group, phenyl (the nitrogen-containing nonaryl heterocyclic group and the phenyl group may each be independently substituted with fluorine, cyano, or 1-3 fluorine atoms) 1-3 (The heteroaryl group may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) and a 5-6 member heteroaryl group (the heteroaryl group may be substituted with fluorine, cyano, or one to three fluorine atoms) 1-3 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) 3-6 alicyclic group, (3) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 1-3A 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (4) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Phenyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (5) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Examples include five-membered or six-membered heteroaryls which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0077] A more preferred embodiment of Y is, (1) C may be substituted with 1 to 3 fluorine atoms. 1-3 Alkyl, (2) C which may be substituted with fluorine, amino, dimethylamino, and 1 to 3 fluorine atoms. 1-3 C may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. 5-6 alicyclic group, (3) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 1-3 A 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (4) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Phenyl or which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. (5) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 A 5-membered or 6-membered heteroaryl compound which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0078] A more preferred embodiment of Y is: (1) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 1-3 C may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. 5-6 alicyclic group, (2) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 1-3 A 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (3) C which may be substituted with halogens, cyano, methoxy and 1 to 3 fluorines. 1-3 Phenyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (4) C which may be substituted with halogen, cyano, methoxy and 1 to 3 fluorine atoms. 1-3 Examples include five-membered or six-membered heteroaryls which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0079] A more preferred embodiment of Y is: (1) Phenyl which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy and methyl, (2) Examples include five-membered or six-membered heteroaryls which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy, and methyl.

[0080] The most preferred embodiment of Y is, (1) Phenyl which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy and methyl, (2) Examples include six-membered heteroaryls which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy, and methyl.

[0081] Preferred embodiments of Z include halogens, cyano, dimethylamino, and C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C) 1-6 Examples include 6-10 member heteroaryls, which may be substituted with 1-3 identical or different substituents selected from the group consisting of alkoxys.

[0082] Preferred embodiments of Z include halogens, cyanoacrylates, and C 2-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C 1-6 Examples include 6-10 member heteroaryls, which may be substituted with 1-3 identical or different substituents selected from the group consisting of alkoxys.

[0083] Preferred embodiments of Z include fluorine, cyano, and C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C 1-6 Examples include 6-10 membered heteroaryls, thienyls, pyrrolyls, thiazolyls, isothiazolyls, isoxazolyls, or thiadiazolyls, which may be substituted with one or three identical or different substituents selected from the group consisting of alkoxys.

[0084] A more preferred embodiment of Z is fluorine, chloro, cyano, C 1-6 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3Examples include 6-10 member heteroaryls that are substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0085] A more preferred embodiment of Z is C which may be substituted with fluorine, chloro, cyano, methoxy, and 1 to 3 fluorine atoms. 1-3 Examples include pyridyl, pyrimidinyl, indazolyl, or imidazopyridyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0086] A more preferred embodiment of Z is C which may be substituted with fluorine, chloro, cyano, and 1 to 3 fluorine atoms. 1-3 Examples include pyridyl, pyrimidinyl, indazolyl, or imidazopyridyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0087] The most preferred embodiment of Z is C which may be substituted with fluorine, chloro, cyano, and 1 to 3 fluorine atoms. 1-3 Examples of pyridyls include those which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0088] One embodiment of the compound represented by formula (1) is (A) below. (A) X 1 However, CR 1 or N, X 2 However, CR 2 or N, X 3 However, CR 3 or N, X 4 However, CR 4 or N, Herein, (1)X 1 If X is N, 2 CR 2 and X 3 CR 3 and X 4is CR 4 and when (2) X 2 is N, X 1 is CR 1 and X 3 is CR 3 and X 4 is CR 4 and when (3) X 3 is N, X 1 is CR 1 and X 2 is CR 2 and X 4 is CR 4 and when (4) X 4 is N, X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and R 1 , R 2 , R 3 and R 4 are each independently (1) a hydrogen atom, (2) a halogen, (3) cyano, (4) C 1-6 alkoxy, or (5) C 1-6 alkyl (the alkyl may be substituted by the same or different 1 to 3 substituents selected from the group consisting of halogen, hydroxy, and C 1-6 alkoxy), and Y is (1) a halogen, hydroxy, amino, dimethylamino, C 3-6 alicyclic group, a 4- to 10-member nitrogen-containing non-aryl heterocyclic group, C 1-6 alkoxy, C 6-10 aryl (the alicyclic group, the nitrogen-containing non-aryl heterocyclic group, the alkoxy, and the aryl group are each independently halogen, cyano, C 3-6 alicyclic group, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C 1-6(These may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys), and a 5 to 10-membered heteroaryl group (the heteroaryl group is a halogen, cyano, or C 3-6 Alicyclic group, C which may be substituted with 1 to 5 fluorine atoms. 1-6 Alkyl and C 1-6 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys) 1-6 Alkyl, (2) C which may be substituted with halogens, hydroxyl, amino, dimethylamino, or 1 to 5 fluorines. 1-6 Alkyl, C 3-6 Alicyclic group, 4-10 member nitrogen-containing nonaryl heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing nonaryl heterocycle, the alkoxy, and the aryl group are each independently a halogen, cyano, C 3-6 Alicyclic group, C which may be substituted with 1 to 5 fluorine atoms. 1-6 Alkyl and C 1-6 (These may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys), and a 5 to 10-membered heteroaryl group (the heteroaryl group is a halogen, cyano, or C 3-6 Alicyclic group, C which may be substituted with 1 to 5 fluorine atoms. 1-6 Alkyl and C 1-6 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys) 3-10 alicyclic group, (3) C which may be substituted with halogens, hydroxyl, amino, dimethylamino, or 1 to 5 fluorines. 1-6 Alkyl, C 3-6 Alicyclic groups and C 1-6 A 4-10 member nitrogen-containing nonaryl heterocyclic group which may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys, (4) Halogen, cyano, dimethylamino, C1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C 1-6 C may be substituted with one to three identical or different substituents selected from the group consisting of alkoxys (which may be substituted with one to three identical or different substituents). 6-10 Aryl, or (5) Halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C 1-6 A 5-10 member heteroaryl, which may be substituted with one or three identical or different substituents selected from the group consisting of alkoxys, Z is halogen, cyano, dimethylamino, C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently halogen, hydroxy, and C) 1-6 A 6-10 member heteroaryl, which may be substituted with one or three identical or different substituents selected from the group consisting of alkoxys, A compound or a pharmaceutically acceptable salt thereof.

[0089] One embodiment of the compound represented by formula (1) is (B) below. (B) X 1 However, CR 1 And, X 2 However, CR 2 And, X 3 However, CR 3 And, X 4 However, CR 4 And, R 1 , R3 and R 4 However, both are hydrogen atoms, R 2 but, (1) Hydrogen atom, (2) Fluorine, (3) Chlorophyll, (4) Cyano (5)C 1-6 Alkoxy, or (6)C 1-6 Alkyl (the alkyl is a halogen, hydroxy, and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkoxys) Y (1) Fluorine, C 3-6 Alicyclic group, 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group, phenyl (the alicyclic group, the nitrogen-containing nonaryl heterocyclic group, and the phenyl group may each be independently substituted with fluorine, cyano, or 1 to 3 fluorine atoms) 1-3 (The heteroaryl group may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) and a 5-6 member heteroaryl group (the heteroaryl group may be substituted with fluorine, cyano, or one to three fluorine atoms) 1-3 C (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) 1-3 Alkyl, (2) Fluorine, amino, dimethylamino, or C which may be substituted with 1 to 3 fluorine atoms. 1-3 Alkyl, 5-6 member nitrogen-containing nonaryl heterocyclic group, phenyl (the nitrogen-containing nonaryl heterocyclic group and the phenyl group may each be independently substituted with fluorine, cyano, or 1-3 fluorine atoms) 1-3 (The heteroaryl group may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy) and a 5-6 member heteroaryl group (the heteroaryl group may be substituted with fluorine, cyano, or one to three fluorine atoms) 1-3C optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl and methoxy 3-6 alicyclic group, (3) fluorine, amino, dimethylamino, and C optionally substituted with 1 to 3 fluorines 1-3 a 5- or 6-membered nitrogen-containing non-aryl heterocyclic group optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl (4) halogen, cyano, dimethylamino, C 1-3 alkoxy, and C optionally substituted with 1 to 3 fluorines 1-3 phenyl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl, or (5) halogen, cyano, dimethylamino, C 1-3 alkoxy, and C optionally substituted with 1 to 3 fluorines 1-3 a 5- or 6-membered heteroaryl optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl, and Z is fluorine, chloro, cyano, C 1-6 alkoxy, and 1 C 1-6 alkoxy or C optionally substituted with 1 to 3 fluorines 1-3 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl, and is a 6- to 10-membered heteroaryl containing 1 to 2 atoms independently selected from the group consisting of nitrogen atoms and oxygen atoms, a compound or a pharmaceutically acceptable salt thereof.

[0090] One embodiment of the compound represented by formula (1) includes the following (C). (C) X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4However, CR 4 And, R 1 , R 3 and R 4 However, both are hydrogen atoms, R 2 However, it is fluorine or cyano, Y (1) C may be substituted with 1 to 3 fluorine atoms. 1-3 Alkyl, (2) C which may be substituted with fluorine, amino, dimethylamino, and 1 to 3 fluorine atoms. 1-3 C may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. 5-6 alicyclic group, (3) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 1-3 A 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (4) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Phenyl or which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. (5) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 A 5-membered or 6-membered heteroaryl which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, Z is fluorine, chloro, cyano, C 1-6 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 It is a 6-10 member heteroaryl compound that may be substituted with one to three identical or different substituents selected from the group consisting of alkyl atoms, and contains one to two atoms independently selected from the group consisting of nitrogen and oxygen atoms. A compound or a pharmaceutically acceptable salt thereof.

[0091] One embodiment of the compound represented by formula (1) is (D) below. (D) X 1 However, CR 1 And, X 2 However, CR 2 And, X 3 However, CR 3 And, X 4 However, CR 4 And, R 1 , R 3 and R 4 However, both are hydrogen atoms, R 2 However, it is fluorine or cyano, Y (1) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 1-3 C may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. 5-6 alicyclic group, (2) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 1-3 A 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (3) C which may be substituted with halogens, cyano, methoxy and 1 to 3 fluorines. 1-3 Phenyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (4) C which may be substituted with halogen, cyano, methoxy and 1 to 3 fluorine atoms. 1-3 A 5-membered or 6-membered heteroaryl which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, Z may be substituted with fluorine, chloro, cyano, methoxy, and C with 1 to 3 fluorine atoms. 1-3A compound or a pharmaceutically acceptable salt thereof that is pyridyl, pyrimidinyl, indazolyl, or imidazopyridyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0092] One embodiment of the compound represented by formula (1) is (E) below. (E) X 1 However, CR 1 And, X 2 However, CR 2 And, X 3 However, CR 3 And, X 4 However, CR 4 And, R 1 , R 3 and R 4 However, both are hydrogen atoms, R 2 However, it is fluorine or cyano, Y (1) Phenyl which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy and methyl, (2) A 5-membered or 6-membered heteroaryl which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy and methyl, Z may be substituted with fluorine, chloro, cyano, and C with 1 to 3 fluorine atoms. 1-3 A compound or a pharmaceutically acceptable salt thereof that is pyridyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0093] One embodiment of the compound represented by formula (1) is (F) below. (F) X 1 However, CR 1 And, X 2 However, CR 2 And, X 3 However, CR 3 And, X 4 However, CR 4 And, R 1 , R 3 and R 4 However, both are hydrogen atoms, R 2 However, it is fluorine or cyano, Y (1) C may be substituted with 1 to 3 fluorine atoms. 1-3 Alkyl, (2) C which may be substituted with fluorine, amino, dimethylamino, and 1 to 3 fluorine atoms. 2-3 C may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. 5-6 Alicyclic group or phenylcyclopropyl, (3) Fluorine, amino, dimethylamino, or C which may be substituted with 1 to 3 fluorine atoms. 2-3 Alkyl and phenyl (the phenyl group may be substituted with fluorine, cyano, or 1 to 3 fluorine atoms) 1-3 A 4-6 member nitrogen-containing nonaryl heterocyclic group, phenyloxetanyl, or tetrahydropyranyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy. (4) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Phenyl or which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. (5) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 A six-membered heteroaryl which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, Z is fluorine, chloro, cyano, C 2-6C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 A compound or a pharmaceutically acceptable salt thereof that is a 6-10 member heteroaryl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0094] One embodiment of the compound represented by formula (1) is (G) below. (G) X 1 However, CR 1 And, X 2 However, CR 2 And, X 3 However, CR 3 And, X 4 However, CR 4 And, R 1 , R 3 and R 4 However, both are hydrogen atoms, R 2 However, it is fluorine or cyano, Y (1) C may be substituted with 1 to 3 fluorine atoms. 1-3 Alkyl, (2) C which may be substituted with fluorine, amino, dimethylamino, and 1 to 3 fluorine atoms. 2-3 C may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. 5-6 Alicyclic group or phenylcyclopropyl, (3) Fluorine, amino, dimethylamino, or C which may be substituted with 1 to 3 fluorine atoms. 2-3 Alkyl and phenyl (the phenyl group may be substituted with fluorine, cyano, or 1 to 3 fluorine atoms) 1-3 A 4-6 member nitrogen-containing nonaryl heterocyclic group, phenyloxetanyl, or tetrahydropyranyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl and methoxy. (4) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 Phenyl or which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. (5) Halogen, cyano, dimethylamino, C 1-3 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 A six-membered heteroaryl which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, Z is fluorine, cyano, C 2-6 C may be substituted with alkoxy and 1 to 3 fluorine atoms. 1-3 A compound or a pharmaceutically acceptable salt thereof that is a 6-10 membered heteroaryl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, or thiadiazolyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0095] One embodiment of the compound represented by formula (1) is (H) below. (H) X 1 However, CR 1 And, X 2 However, CR 2 And, X 3 However, CR 3 And, X 4 However, CR 4 And, R 1 , R 3 and R 4 However, both are hydrogen atoms, R 2 However, it is fluorine or cyano, Y (1) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 2-3 C may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. 5-6alicyclic group, (2) C which may be substituted with fluorine, amino, dimethylamino and 1 to 3 fluorine atoms. 2-3 A 5-membered or 6-membered nitrogen-containing nonaryl heterocyclic group which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (3) C which may be substituted with halogens, cyano, methoxy and 1 to 3 fluorines. 1-3 Phenyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, (4) C which may be substituted with halogen, cyano, methoxy and 1 to 3 fluorine atoms. 1-3 A six-membered heteroaryl which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups, Z may be substituted with fluorine, chloro, cyano, and C with 1 to 3 fluorine atoms. 1-3 A compound or a pharmaceutically acceptable salt thereof that is pyridyl, pyrimidinyl, indazolyl, or imidazopyridyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0096] One embodiment of the compound represented by formula (1) is (I) below. (I) X 1 However, CR 1 And, X 2 However, CR 2 And, X 3 However, CR 3 And, X 4 However, CR 4 And, R 1 , R 3 and R 4 However, both are hydrogen atoms, R 2 However, it is fluorine or cyano, Y (1) Phenyl which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy and methyl, (2) A six-membered heteroaryl which may be substituted with one or two identical or different substituents selected from the group consisting of fluorine, cyano, methoxy and methyl, Z may be substituted with fluorine, chloro, cyano, and C with 1 to 3 fluorine atoms. 1-3 A compound or a pharmaceutically acceptable salt thereof that is pyridyl, which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.

[0097] Examples of "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, or organic salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Examples of base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, or organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylatelethylamine. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0098] Suitable salts of raw material compounds and intermediates, and salts acceptable as pharmaceutical raw materials, are conventional non-toxic salts, including acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, or p-toluenesulfonate) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, or phosphate), salts with amino acids (e.g., arginine, aspartic acid, or glutamic acid), metal salts such as alkali metal salts (e.g., sodium salt or potassium salt) and alkaline earth metal salts (e.g., calcium salt or magnesium salt), ammonium salts, or organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, or N,N'-dibenzylethylenediamine salt), which can be appropriately selected by those skilled in the art.

[0099] When it is desired to obtain a salt of the compound of this disclosure, if the compound of this disclosure is obtained in the form of a salt, it can be purified as is, and if it is obtained in the form of a free compound, it can be dissolved or suspended in a suitable organic solvent and a salt can be formed by adding an acid or base in the usual manner.

[0100] In this disclosure, deuterium converters obtained by converting one or more 1H atoms in any of the compounds represented by formula (1) to 2H(D) are also included in the compounds represented by formula (1). This disclosure includes compounds represented by formula (1), or pharmaceutically acceptable salts thereof. The compounds of this disclosure may also exist in the form of hydrates and / or solvates with various solvents (e.g., ethanol hydrates), and these hydrates and / or solvates are also included in the compounds of this disclosure. Furthermore, this disclosure includes all tautomers, all stereoisomers, and all modes of crystalline form of compound (1) of this disclosure, as well as mixtures thereof.

[0101] Some of the compounds (1) of this disclosure may have optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from the constraint of intramolecular rotation, other stereoisomers, tautomers, and geometric isomers, but all possible isomers and mixtures thereof, including these, are included in the scope of this disclosure.

[0102] In particular, optical isomers and atrop isomers can be obtained as racemates, or as optically active compounds if optically active starting materials or intermediates are used. If necessary, at an appropriate stage of the manufacturing process described below, the corresponding racemates of the starting materials, intermediates, or final products can be physically or chemically separated into their optical isomers by known separation methods such as optically active column methods or fractional crystallization. Specifically, for example, in the diastereomer method, two diastereomers are formed from a racemate by a reaction using an optically active resolving agent. Since these different diastereomers generally have different physical properties, they can be separated by known methods such as fractional crystallization.

[0103] The methods for producing the compounds disclosed herein are described below, but the methods for producing the compounds disclosed herein are not limited to these.

[0104] The compounds disclosed herein, but are not limited to those described below, can be produced by the following manufacturing methods. These manufacturing methods can be appropriately modified based on the knowledge of a person proficient in organic synthesis chemistry. In the manufacturing methods described below, salts of the compounds may be used as raw materials, provided that they do not interfere with the reaction.

[0105] In the manufacturing method described below, even if the use of protecting groups is not explicitly stated, if any functional group other than the reaction site changes under the reaction conditions, or if it is unsuitable for post-reaction processing, the target compound can be obtained by protecting the non-reaction site as necessary and deprotecting it after the reaction is complete or after the series of reactions have been carried out. Protecting groups used in these processes are described in the reference (TW Greene and PGM Wuts, “Protective Group in Organic Synthesis”, 3 rd Conventional protecting groups as described in Ed., John Wiley and Sons, Inc., New York (1999) can be used. Furthermore, the introduction and removal of protecting groups can be carried out by methods commonly used in organic synthesis chemistry (e.g., the methods described in the above-mentioned literature) or by methods similar thereto.

[0106] The starting materials and intermediates used in the following manufacturing method are either commercially available or can be obtained by methods described in public literature or by synthesis from known compounds according to known methods. Furthermore, salts of these starting materials and intermediates may be used, provided they do not interfere with the reaction.

[0107] The intermediates and target compounds in the manufacturing method described below can also be converted into other compounds included in this disclosure by appropriately changing their functional groups. The conversion of functional groups in this case can be carried out using methods commonly used in organic synthesis chemistry (e.g., RC Larock, “Comprehensive Organic Transformations”, 2 nd This can be done by the method described in Ed., John Wiley and Sons, Inc., New York (1999), or by a similar method.

[0108] In the manufacturing method described below, an inert solvent means a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. (hereinafter sometimes referred to as "raw materials, etc." used in the reaction) used in the reaction. Furthermore, even if the solvent used in each step reacts with the raw materials, etc. used in the reaction, it can still be used as an inert solvent as long as the desired reaction proceeds and the target compound is obtained.

[0109] The compound of this disclosure represented by formula (1) can be produced, for example, by the following production methods 1 to 4.

[0110] Manufacturing method 1 Of the compounds represented by formula (1), the compound represented by formula [A1] can be produced, for example, by the following method. [ka]

[0111] (In the formula, X 11 CR 1 X 21 CR 2 X 31 CR 3 X 41 CR 4 And R 1 , R 2 , R 3 , R 4 , Y, and Z are equivalent to those in item 1.

[0112] Compound a1 can be obtained using commercially available materials or manufactured by known methods, such as those described in Anais da Academia Brasileira de Ciencias 2015, 87(3), 1525-1529.

[0113] Compound a2 can be used commercially or produced by known methods, such as those described in Synthetic Communications (2013), 43(24), 3342-3351, Journal of Organic Chemistry (1986), 51(13), 2613-15, etc.

[0114] [Step 1-1: Cyclization reaction] Compound a3 can be produced by reacting compound a1 and compound a2 in the presence of a suitable base, in a solvent-free environment or in a suitable solvent, under atmospheric pressure or under pressure. The base can be appropriately selected from the bases exemplified below, but triethylamine or N,N-diisopropylethylamine is preferred. The solvent can be appropriately selected from the solvents exemplified below, but ethanol or isopropanol is preferred. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 12 hours. The reaction temperature is usually -78°C to 150°C, preferably 25°C to 150°C.

[0115] This reaction can be carried out according to the methods described in European Journal of Medicinal Chemistry 2016, 112, 106-113, Synthetic Communications 2017, 47(11), 1040-1045, etc.

[0116] [Step 1-2: Chlorination reaction] Compound a4 can be produced by reacting compound a3 with a suitable chlorinating reagent in a solvent-free environment or a suitable solvent. The solvent can be appropriately selected from the solvents exemplified below, but toluene or chloroform are preferred. The chlorinating reagent should be appropriately selected according to the type of starting compound, but examples include phosphoryl chloride, phosphorus pentachloride, thionyl chloride, and sulfuryl chloride. These chlorinating reagents can be used individually or as a mixture of two or more, preferably a mixture of phosphoryl chloride and phosphorus pentachloride. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 12 hours. The reaction temperature is usually -78°C to 150°C, preferably 25°C to 150°C.

[0117] This reaction can be carried out according to the methods described in Journal of Medicinal Chemistry 2014, 57(5), 2091-2106, Bioorganic & Medicinal Chemistry 2010, 18(8), 2836-2848, etc.

[0118] [Steps 1-3: Substitution reaction] Compound A1 can be produced by reacting compound a4 and compound a5 in the absence of a solvent or in a suitable solvent under atmospheric pressure or under pressure. The solvent can be appropriately selected from the solvents exemplified below, but examples include N-methylpyrrolidone and dimethyl sulfoxide. The reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 12 hours. The reaction temperature is usually 0°C to 250°C, preferably 25°C to 200°C. This reaction may be carried out in the presence of a base if necessary. The base can be appropriately selected from the bases exemplified below, but examples include lithium (bistrimethylsilyl)amide or potassium fluoride.

[0119] Compound a5 can be used commercially or produced by known methods, such as those described in The Journal of Organic Chemistry 2009, 74 (12), 4542-4546, Organometalics 2017, 36(2), 251-254, etc.

[0120] Manufacturing method 2 Among the compounds represented by formula (1), the compound represented by formula [A1] can also be produced, for example, by the following method. [ka]

[0121] (In the formula, X 11 CR 1 X 21 CR 2 X 31 CR 3 X 41 CR 4 And R 1 , R 2 , R 3 , R 4 , Y, and Z are equivalent to those in item 1.

[0122] [Step 2-1: Coupling reaction] Compound A1 is produced by coupling compound a4 with compound a5 in a suitable solvent in the presence of a catalyst and a base. Examples of catalysts include transition metals such as palladium, their salts, complexes, and polymers supported on a carrier. The base can be appropriately selected from the bases exemplified below, but preferably cesium carbonate, potassium carbonate, or sodium t-butoxide. The solvent can be appropriately selected from the solvents exemplified below, but preferably toluene, xylene, dioxane, or N,N-dimethylformamide. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 20°C to 160°C.

[0123] This reaction can be carried out in accordance with the method described in International Publication No. 2016 / 105564.

[0124] Manufacturing method 3 Among the compounds represented by formula (1), the compound represented by formula [C1] is, for example, the following compound It can be manufactured by law. [ka]

[0125] (In the formula, X 1 , X 2 , X 3 , X 4 (Y and Z are equivalent to those in item 1.)

[0126] [Step 3-1: Cyclization reaction] Compound C1 can be produced by reacting compound c1 and compound c2 in the presence of copper bromide and a base, in the absence of a solvent or in a suitable solvent, under atmospheric pressure or under pressure, according to the method described in Helvetica Chimica Acta (2016), 99(5), 378-383. The base can be appropriately selected from the bases exemplified below, but triethylamine or N,N-diisopropylethylamine is preferred. The solvent can be appropriately selected from the solvents exemplified below, but N,N-dimethylformamide is preferred. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 48 hours. The reaction temperature is usually 0°C to 150°C, preferably 25°C to 100°C.

[0127] Compound c1 can be used commercially or produced by known methods, such as those described in International Publication No. 2001 / 018536, International Publication No. 2001 / 19788, Journal of Medicinal Chemistry 1986, 29(8), 1534-1537, etc.

[0128] Compound c2 can be a commercially available product, or it can be produced from compound a5 in accordance with the method for producing compound a2 in Production Method 1.

[0129] Manufacturing method 4 Among the compounds represented by formula (1), the compound represented by formula [C1] is, for example, the following compound It can also be manufactured by law. [ka]

[0130] (In the formula, X 1 , X 2 , X 3 , X 4 (Y and Z are equivalent to those in item 1.)

[0131] [Step 4-1: One-pot reaction] Compound C1 can be produced by reacting a solution obtained by reacting compound d1 and compound d2 in a suitable solvent under atmospheric pressure or pressurized pressure with compound c2 in the presence of copper bromide and a base under atmospheric pressure or pressurized pressure. The base can be appropriately selected from the bases exemplified below, but triethylamine or N,N-diisopropylethylamine is preferred. The solvent can be appropriately selected from the solvents exemplified below, but N,N-dimethylformamide is preferred. The reaction time for both the reaction with compound d2 and the reaction with compound c2 is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature for both the reaction with compound d2 and the reaction with compound c2 is usually 0°C to 150°C, preferably 25°C to 100°C.

[0132] Compound d1 can be used from a commercially available source or can be manufactured by known methods, such as those described in Journal of Medicinal Chemistry 2019, 62(3), 1468-1483.

[0133] Compound d2 can be a commercially available product, or it can be manufactured in accordance with the manufacturing method of compound a5 in Manufacturing Method 1.

[0134] Manufacturing method 5 Among the compounds represented by formula (1), the compound represented by formula [A1] can also be produced, for example, by the following method. [ka]

[0135] (In the formula, X 11 CR 1 X 21 CR 2 X 31 CR 3 X 41 CR 4 And R 1 , R 2 , R 3 , R 4 , Y, and Z are equivalent to those in item 1.

[0136] Compound b1 can be produced in accordance with the method for producing compound a3 in Production Method 1.

[0137] [Step 5-1: Methylation reaction] Compound b2 can be produced by reacting compound b1 with a suitable methylation reagent in the presence of a suitable base, either in the absence of a solvent or in a suitable solvent. The solvent can be appropriately selected from the solvents exemplified below, but N,N-dimethylformamide is preferred. The methylation reagent should be appropriately selected according to the type of starting compound, but examples include iodomethane and dimethyl sulfate. The base can be appropriately selected from the bases exemplified below, but potassium carbonate is preferred. The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually -78°C to 150°C, preferably 0°C to 100°C.

[0138] This reaction can be carried out according to the method described in ChemMedChem 2009, 4(5), 866-876, etc.

[0139] [Step 5-2: Substitution reaction] Compound A1 can be produced by reacting compound b2 and compound d2 in the absence of a solvent or in a suitable solvent, in the presence of a suitable base, at atmospheric pressure or under pressure. The solvent can be appropriately selected from the solvents exemplified below, but examples include tetrahydrofuran. The base can be appropriately selected from the bases exemplified below, but potassium t-butoxide is preferred. The reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 12 hours. The reaction temperature is usually -78°C to 150°C, preferably 0°C to 100°C.

[0140] The bases used in each step of each of the above manufacturing methods should be selected appropriately depending on the reaction and the type of raw material compound, but examples include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, metal fluorides such as potassium fluoride and cesium fluoride, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium t-butoxide and potassium t-butoxide, organometallic bases such as butyllithium, lithium diisopropylamide and lithium (bistrimethylsilyl)amide, and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0141] The solvent used in each step of each of the above manufacturing methods should be selected appropriately depending on the reaction and the type of raw material compound. Examples include alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ketone; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran (THF) and dioxane; aromatic hydrocarbons such as toluene, benzene, and xylene; aliphatic hydrocarbons such as hexane and heptane; esters such as ethyl acetate and propyl acetate; amides such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide (DMSO); and nitriles such as acetonitrile. These solvents can be used alone or in mixtures of two or more. Depending on the type of reaction, organic bases may also be used as solvents.

[0142] The compounds of the present disclosure represented by formula (1) or their intermediates can be separated and purified by methods known to those skilled in the art. Examples include extraction, partitioning, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion-exchange column chromatography, or preparative liquid chromatography), or recrystallization.

[0143] As recrystallization solvents, for example, alcohol-based solvents such as methanol, ethanol, or 2-propanol; ether-based solvents such as diethyl ether; ester-based solvents such as ethyl acetate; aromatic hydrocarbon-based solvents such as benzene or toluene; ketone-based solvents such as acetone; halogen-based solvents such as dichloromethane or chloroform; hydrocarbon-based solvents such as hexane; aprotic solvents such as dimethylformamide or acetonitrile; water; or mixtures thereof can be used. Other purification methods include those described in Volume 1 of "Experimental Chemistry Series" (edited by the Chemical Society of Japan, Maruzen). Furthermore, the molecular structure of the compounds disclosed herein can be easily determined by referring to the structures derived from each starting compound and using spectroscopic techniques such as nuclear magnetic resonance spectroscopy, infrared absorption spectroscopy, and circular dichroism spectroscopy, as well as mass spectrometry.

[0144] Furthermore, the intermediates or final products in the above manufacturing method can be converted to other compounds included in this disclosure by appropriately changing their functional groups, particularly by extending various side chains from amino, hydroxyl, carbonyl, halogen, etc., and by performing the protection and deprotection described below as necessary. The conversion of functional groups and the extension of side chains can be carried out by commonly used methods (see, for example, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

[0145] Examples of amino protecting groups include alkylcarbonyl (e.g., acetyl, propionyl), formyl, phenylcarbonyl, alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), phenyloxycarbonyl, arylalkyloxycarbonyl (e.g., benzyloxycarbonyl), trityl, phthaloyl, tosyl, and benzyl.

[0146] Examples of protecting groups for carboxyls include alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, benzyl, trityl, and silyl groups (e.g., trimethylsilyl, tert-butyldimethylsilyl).

[0147] Examples of hydroxyl protecting groups include methyl, tert-butyl, allyl, substituted methyl (e.g., methoxymethyl, methoxyethoxymethyl), ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trityl, arylalkyl (e.g., benzyl), alkylcarbonyl (e.g., acetyl, propionyl), formyl, benzoyl, arylalkyloxycarbonyl (e.g., benzyloxycarbonyl), and silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl).

[0148] Carbonyl protection can be achieved by converting the carbonyl to an acyclic ketal (such as dimethyl ketal or diethyl ketal) or a cyclic ketal (such as 1,3-dioxolane or 1,3-dioxane).

[0149] The compounds of the present disclosure represented by formula (1) or pharmaceutically acceptable salts thereof may exhibit chirality or have substituents with chiral carbons, and in such compounds, optical isomers exist. The compounds of the present disclosure include mixtures of these isomers and isolated compounds, which can be prepared by conventional methods.

[0150] Examples of manufacturing methods include using a raw material with a chiral center, or introducing chirality at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using an optically active raw material or by performing optical resolution at an appropriate stage in the manufacturing process. As for optical resolution methods, for example, if the compound represented by formula (1) or its intermediate has a basic functional group, a diastereomer method can be used to form a salt using an optically active acid (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropylidene tartaric acid, malic acid, camphor sulfonic acid, bromocamphor sulfonic acid, etc.) in an inert solvent (e.g., alcohol-based solvents such as methanol, ethanol, 2-propanol, diethyl ether, ester-based solvents such as ethyl acetate, hydrocarbon-based solvents such as toluene, aprotic solvents such as acetonitrile, or a mixed solvent of two or more solvents selected from the above).

[0151] If the compound of the present disclosure represented by formula (1) or its intermediate has an acidic functional group such as a carboxyl group, optical resolution can also be performed by forming a salt using an optically active amine (for example, an organic amine such as 1-phenylethylamine, quinine, quinidine, cinconidine, cinconine, or strychnine).

[0152] The temperature for salt formation is selected from a range of -50°C to the boiling point of the solvent, preferably from 0°C to the boiling point, and more preferably from room temperature to the boiling point of the solvent. To improve optical purity, it is desirable to raise the temperature to near the boiling point of the solvent. When filtering the precipitated salt, cooling can be performed as needed to improve the yield. The amount of optically active acid or amine used is suitable in the range of about 0.5 to about 2.0 equivalents relative to the substrate, preferably around 1 equivalent. If necessary, the crystals can be recrystallized in an inert solvent (for example, alcoholic solvents such as methanol, ethanol, 2-propanol; etheric solvents such as diethyl ether; esteric solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more solvents selected from the above) to obtain a high-purity optically active salt. Alternatively, if necessary, the optically resolved salt can be treated with an acid or base in a conventional manner to obtain a free form.

[0153] Of the raw materials and intermediates used in each of the manufacturing methods described above, those whose manufacturing methods are not specifically mentioned can be commercially available compounds or synthesized from commercially available compounds by methods known to those skilled in the art, or by similar methods.

[0154] This disclosure provides a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient for treating or preventing disorders or diseases involving abnormal nerve excitation. "Disorders or diseases involving abnormal nerve excitation" refers to central nervous system disorders or diseases resulting from an imbalance between excitatory and inhibitory signals in neural circuits. Examples include epilepsy, developmental disorders (autism spectrum disorder, Rett syndrome, Angelman syndrome, fragile X syndrome, attention deficit hyperactivity disorder, etc.), mental disorders (schizophrenia, bipolar disorder, depression, anxiety disorders, obsessive-compulsive disorder, etc.), and cognitive disorders (Alzheimer's disease and other dementias, Parkinson's disease, etc.). "Epilepsy" includes epileptic seizures, status epilepticus, epileptic syndromes (such as Dravet syndrome, Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy, medial temporal lobe epilepsy with hippocampal sclerosis, and Rasmussen syndrome), epilepsy attributable to structural / metabolic causes (such as cortical dysplasia, neurocutaneous syndromes (such as tuberous sclerosis complex and Sturge-Weber syndrome)), and developmental disorders, mental disorders, and cognitive impairments that may occur in conjunction with these conditions. An "epileptic seizure" is defined as "a transient sign or symptom caused by excessive and / or synchronous abnormal neuronal activity in the brain" (Operational Classification of Seizure Types, Fisher, 2017, by the International League Against Epilepsy: Official Statement of the ILAE Classification and Terminology Committee), and includes, for example, generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, focal seizures, and seizures of unknown classification. Preferably, "a disorder or disease involving abnormal neuronal excitation" is epilepsy or a developmental disorder.

[0155] The effects of the compounds disclosed herein on epilepsy can be evaluated, for example, by inhibitory activity against hyperexcitation of cultured nerve cells, or by inhibitory activity against convulsions or abnormal electroencephalograms (such as spike waves or spike-and-slow waves) in epileptic model animals. The effects on developmental disorders, mental disorders, and cognitive disorders can be evaluated, for example, by using the three-chamber test, which uses social interaction in model animals as an indicator, the repetitive grooming behavior test, the glass bead cover test, the spontaneous movement test, which uses hyperactivity as an indicator, the forced swimming test, which uses depressive-like behavior as an indicator, and the novel object recognition test or Y-maze test, which use cognitive function as an indicator. These tests are described in Buccafusco, Jerry J. "Methods of behavior analysis in neuroscience" Crc Press, 2008., Silverman and Jill L., et al. "Behavioural phenotyping assays for mouse models of autism." Nature Reviews Neuroscience 11.7 (2010): 490-502.

[0156] In this disclosure, "prevention" refers to the act of administering the active ingredient of this disclosure to healthy individuals who have not yet developed a disease, for example, with the aim of preventing the onset of the disease. "Treatment" refers to the act of administering the active ingredient of this disclosure to individuals (patients) who have been diagnosed by a physician as having developed a disease.

[0157] The compounds disclosed herein may be administered orally, parenterally, or rectally, and the daily dose will vary depending on the type of compound, the method of administration, and the patient's symptoms and age. For example, in the case of oral administration, typically about 0.01 to 1000 mg per kg of human or mammalian body weight, more preferably about 0.1 to 500 mg, can be administered in one to several divided doses. In the case of parenteral administration, such as intravenous injection, typically, for example, about 0.01 mg to 300 mg per kg of human or mammalian body weight, more preferably about 0.01 mg to 100 mg can be administered.

[0158] The compounds of this disclosure can be administered orally or parenterally, either directly or in a suitable dosage form. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices. The formulations are manufactured by known methods using pharmaceutically acceptable excipients. Depending on the purpose, excipients may include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solvents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavorings. Specifically, examples include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, stearyl fumarate sodium, polyethylene glycol, propylene glycol, titanium dioxide, and talc.

[0159] The compounds of this disclosure can be used in combination with at least one other drug classified as an antiepileptic, antidepressant, anxiolytic, or antipsychotic, and these can be administered for treatment or prevention. Examples of drugs classified as antiepileptic drugs include phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine acetate, retigabine, lamotrigine, zonisamide, topiramate, sodium valproate, gabapentin, vigabatrin, pregabalin, phenobarbital, clonazepam, clobazam, diazepam, felbamate, rufinamide, ethosuximide, levetiracetam, brivalacetam, perampanel, stiripentol, cannabidiol, and fenfluramine. Preferably, these are carbamazepine, lamotrigine, topiramate, sodium valproate, clonazepam, clobazam, ethosuximide, levetiracetam, stiripentol, cannabidiol, and fenfluramine. Drugs classified as antidepressants include, for example, SSRIs such as fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram; SNRIs such as duloxetine and milnacipran; and tricyclic antidepressants such as imipramine, amitriptyline, clomipramine, and amoxapine. Drugs classified as anxiolytics include, for example, benzodiazepine anxiolytics such as etizolam and lorazepam, and azapirone anxiolytics such as tandospirone. Drugs classified as antipsychotics include, for example, typical antipsychotics such as haloperidol, spiperone, and chlorpromazine, and SDAs such as risperidone, quetiapine, olanzapine, clozapine, perospirone, and aripiprazole. Hereinafter, drugs that can be used in combination with the compound of the present invention will be abbreviated as "combination drugs."

[0160] The administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the target patient simultaneously or with a time difference. Alternatively, the compound of the present invention and the concomitant drug may be used as a combination preparation. The dosage of the concomitant drug can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, and combination. For example, if the target patient is a human, 0.01 to 100 parts by weight of the concomitant drug may be used for 1 part by weight of the compound of the present invention. In addition, for the purpose of suppressing side effects, it can be used in combination with drugs such as antiemetics, hypnotics, and anticonvulsants (concomitant drugs).

[0161] In this specification, "or" is used when "at least one" of the items listed in the text can be adopted. The same applies to "or else". In this specification, when it is specified as "within the range of two values", that range includes the two values ​​themselves.

[0162] References such as scientific literature, patents, and patent applications cited herein are incorporated herein by reference to the same extent as they are specifically described herein.

[0163] The present disclosure has been described above with reference to preferred embodiments for ease of understanding. The present disclosure will now be described based on examples, but the above description and the following examples are provided for illustrative purposes only and not to limit the present disclosure. Accordingly, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the claims. [Examples]

[0164] The present disclosure will be further described below with reference examples, examples, and test examples, but this disclosure is not limited thereto. Note that the compound names shown in the following reference examples and examples do not necessarily follow IUPAC nomenclature.

[0165] To simplify the description in the specification, the following abbreviations may be used in the reference examples, examples, and tables within the examples. Abbreviations used for substituents include Ph, which means phenyl. Abbreviations used for reagents include TFA, which means trifluoroacetic acid; DMF, which means N,N-dimethylformamide; and HATU, which means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate. Symbols used in NMR include s for single line, d for double line, dd for double line of double lines, dt for triple line of triple lines, t for triple line, q for quadruple line, m for multiple line, br for broad line, brs for broad single line, and J for bond constant.

[0166] The measurement conditions for high-performance liquid chromatography-mass spectrometry (LCMS) are as follows, and the observed mass spectrometry value [MS(m / z)] is measured in MH. + The retention time is indicated by Rt (minutes). The measurement conditions used for each measured value are also noted.

[0167] Measurement condition A Detection equipment: ACQUITY® SQ detector (Waters Corporation) HPLC: ACQUITY UPLC (registered trademark) SYSTEM Column:Waters ACQUITY UPLC(registered trademark)BEH C18(1.7um, 2.1mm × 30mm) Solvent: Solution A: 0.05% formic acid / H2O, Solution B: acetonitrile Gradient Condition: 0.0-1.3 minutes (linear gradient from B 10% to 95%) 1.3-1.5 minutes (B 10%) Flow rate: 0.8 ml / min UV: 220nm and 254nm Column temperature: 40℃

[0168] Measurement condition B Detection equipment: ACQUITY® SQ detector (Waters Corporation) HPLC: ACQUITY UPLC (registered trademark) SYSTEM Column:Waters ACQUITY UPLC(registered trademark)BEH C18(1.7um, 2.1mm × 30mm) Solvent: Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / acetonitrile Gradient Condition: 0.0-1.3 minutes (linear gradient from B 2% to 96%) 1.3-1.5 minutes (B 96%) 1.5-2.2 minutes (B 2%) Flow rate: 0.8 ml / min UV: 220nm and 254nm Column temperature: 40℃

[0169] Measurement conditions C Detection equipment: Shimadzu LCMS-2020 Column: Phenomenex Kinetex(1.7μm C18,50 mm×2.10 mm) Solvent: Solution A: 0.05% TFA / H2O, Solution B: 0.05% TFA / acetonitrile Gradient Condition: 0.0-1.7min(linear gradient from B 1% to 99%) 1.7-1.9 minutes (B 99%) 1.9-3.0 minutes (B 1%) Flow rate: 0.5 ml / min UV: 254 nm Column temperature: 40℃

[0170] Reference example 1 2-Chloro-3-phenylquinazoline-4(3H)-one [ka]

[0171] a) Preparation of 3-phenyl-2-thioxo-2,3-dihydroquinazoline-4(1H)-one (compound A3) A solution of anthranilic acid (2.0 g) and N,N-diisopropylethylamine (6.4 ml) in ethanol (70 ml) was mixed with phenyl isothiocyanate (2.6 ml) and stirred under superheated reflux for 16 hours. After the reaction mixture was cooled to room temperature, the resulting solid was filtered and washed with ethyl acetate and hexane. Compound A3 (3.2 g) was obtained by drying the solid under reduced pressure at room temperature. 1 H NMR (300 MHz, DMSO-d6) δ:7.24-7.30 (2H, m), 7.32-7.52 (5H, m), 7.76-7.82 (1H, m), 7.96 (1H, dd, J = 8.0, 1.4 Hz), 13.05 (1H, s).

[0172] b) Preparation of 2-chloro-3-phenylquinazoline-4(3H)-one (Reference Example 1) A mixture of compound A3 (2.8 g), phosphorus pentachloride (3.7 g), and phosphorus oxychloride (21 ml) was stirred at 130°C for 16 hours. The reaction mixture was poured into ice water, the resulting solid was filtered, and washed with water. The crude product was dissolved in ethyl acetate and washed with saturated brine, followed by saturated sodium bicarbonate water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain Reference Example 1 (2.0 g). 1 H NMR (300 MHz, CDCl3) δ: 7.30-7.35 (2H, m), 7.50-7.64 (4H,m), 7.79-7.92 (2H, m), 8.30 (1H, dd, J = 7.9, 1.4 Hz).

[0173] Reference example 2 2-amino-5-cyano-N-phenylbenzamide [ka]

[0174] To a solution of 2-amino-5-cyanobenzoic acid (2.00 g) in DMF (12 ml), aniline (1.15 g), N,N-diisopropylethylamine (1.75 g), and HATU (4.69 g) were added and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the precipitated solid was filtered to obtain Reference Example 2 (2.78 g). LC-MS (measurement conditions A), m / z; 238 (M+H)+ ESI, Rt; 0.76.

[0175] Reference example 3 3-Fluoro-5-isothiocyanatopyridine [ka]

[0176] 1,1'-thiocarbonylbis(pyridine-2(1H)-one) (1.15 g) was added to a solution of 5-fluoropyridine-3-amine (0.56 g) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (eluent: hexane:ethyl acetate) to obtain Reference Example 3 (0.5 g). 1 H-NMR (400 MHz, DMSO-d6) δ:8.60-8.61 (2H, m), 8.03 (1H, d, J = 9.6 Hz).

[0177] Reference example 4 6-Fluoro-3-(5-Fluoropyridine-3-yl)-2-(methylthio)quinazoline-4(3H)-one [ka]

[0178] c) Preparation of 6-fluoro-3-(5-fluoropyridine-3-yl)-2-thioxo-2,3-dihydroquinazoline-4(1H)-one (compound B1) To a solution of 2-amino-5-fluorobenzoic acid (4.0 g) in dioxane (80 ml), 3-fluoro-5-isothiocyanatopyridine (5.8 g) and triethylamine (5.4 ml) were added, and the mixture was stirred at 85°C for 2 hours. After the reaction mixture cooled to room temperature, the resulting solid was filtered and washed with toluene. Compound B1 (6.5 g) was obtained by drying the solid under reduced pressure at room temperature. 1 H-NMR (400 MHz, DMSO-d6) δ:7.51 (1H, dd, J = 9.2, 4.3 Hz), 7.69-7.76 (2H, m), 7.87-7.91 (1H, m), 8.43-8.44 (1H, m), 8.65-8.66 (1H, m), 13.29 (1H, s).

[0179] b) Preparation of 6-fluoro-3-(5-fluoropyridine-3-yl)-2-(methylthio)quinazoline-4(3H)-one (Reference Example 4) Potassium carbonate (2.8g) was added to a solution of compound B1 (4.3g) in DMF (30ml), and iodomethane (1.0ml) was added dropwise at 8-15°C, stirring for 1.5 hours at the same temperature. Water was added to the reaction mixture, and after stirring at room temperature for 1 hour, the resulting solid was filtered and washed with water. Reference Example 4 (4.3g) was obtained by drying the solid under reduced pressure at room temperature. 1 H-NMR (400 MHz, DMSO-d6) δ:2.53 (3H, s), 7.70-7.79 (3H, m), 8.16-8.19 (1H, m), 8.64-8.65 (1H, m), 8.82 (1H, d, J = 3.1 Hz).

[0180] Reference example 5 2-amino-5-cyano-N-(o-toluyl)benzamide [ka]

[0181] It was synthesized using the same method as in Reference Example 2. LC-MS (measurement conditions A), m / z; 252 (M+H)+ ESI, Rt; 0.76.

[0182] Example 1 2-(benzo[d]oxazole-5-ylamino)-3-phenylquinazoline-4(3H)-one [ka] A solution of Reference Example 1 (100 mg), N,N-dimethyl-4-aminopyridine (14 mg), and 1,3-benzoxazole-5-amine (104 mg) in DMF (2 ml) was stirred at 130°C for 24 hours. After concentrating the reaction mixture, the crude product was purified by high-performance liquid chromatography (elution solvent: water:acetonitrile) to obtain Example 1 (10 mg). 1 H-NMR (300 MHz, CDCl3) δ:6.16 (1H, brs), 7.25-7.33 (2H, m), 7.44-7.59 (4H, m), 7.64-7.74 (4H, m), 8.12 (1H, s), 8.21 (1H, dd, J = 7.9, 1.6 Hz), 8.25 (1H, d, J = 2.1 Hz).

[0183] Example 2 2-((1-methyl-1H-benzo[d]imidazole-6-yl)amino)-3-phenylquinazoline-4(3H)-one [ka] Reference Example 1 (100 mg), 1-methyl-1H-benzimidazole-6-amine (63 mg), and cesium carbonate (250 mg) were dissolved in a dioxane / DMF (1.2 / 0.4 ml) solution. 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (23 mg) and palladium acetate (9 mg) were added, and the mixture was stirred at 160°C for 40 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude product. The resulting crude product was purified by high-performance liquid chromatography (elution solvent: water:acetonitrile) to obtain Example 2 (13.0 mg). 1 H-NMR (300 MHz, CDCl3) δ:3.90 (3H, s), 6.13 (1H, brs), 6.87 (1H, dd, J = 9.0, 3.0 Hz), 7.27-7.32 (1H, m), 7.46-7.55 (3H, m), 7.62-7.74 (5H, m), 7.89 (1H, s), 8.20-8.25 (2H, m).

[0184] Example 3 4-Oxo-3-phenyl-2-(pyridine-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile [ka] To a 17 ml solution of DMF containing Reference Example 2 (4.0 g), N,N-diisopropylethylamine (4.3 ml), 3-isothiocyanatopyridine (2.26 ml), and copper bromide (2.9 g) were added, and the mixture was stirred at 85°C for 3 hours. Ammonia water was added to the reaction mixture, filtered by Celite, and the filtrate was extracted with chloroform. The mixture was then washed with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was recrystallized from acetonitrile to obtain Example 3 (1.52 g) as crystals (crystal I). 1H-NMR (400 MHz, DMSO-d6) δ:7.33-7.36 (2H, m), 7.51-7.63 (5H, m), 7.85 (1H, brs), 7.95 (1H, dd, J = 8.5, 1.8 Hz), 8.19 (1H, brs), 8.29-8.30 (2H, m), 8.59 (1H, brs). The powder X-ray diffraction pattern of [I crystal] is shown in Figure 1. Major diffractential peaks: 2θ(°) = 7.75, 10.32, 13.91, 15.50, 16.35, 21.23, 23.36, 23.87, 25.11, 25.93 Characteristic diffraction peaks: 2θ(°) = 7.75, 10.32, 15.50, 23.36

[0185] Example 4 6-Fluoro-2-((5-Fluoropyridine-3-yl)amino)-3-(o-Toluyl)quinazoline-4(3H)-one [ka] A solution of 6-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (181 mg) and o-toluidine (113 mg) in DMF (1 ml) was stirred at 85°C for 6 hours. Then, at room temperature, N,N-diisopropylethylamine (0.27 ml), Reference Example 3 (200 mg), and copper bromide (186 mg) were added to the reaction mixture and stirred at 85°C for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was extracted with chloroform. The mixture was then washed with saturated ammonium chloride aqueous solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was recrystallized from acetonitrile to obtain Example 4 (83 mg). 1 H-NMR (400 MHz, DMSO-d6) δ:2.10 (3H, s), 7.41-7.48 (5H, m), 7.57-7.68 (2H, m), 8.02 (2H, m), 8.25 (1H, d, J = 1.8 Hz), 8.54 (1H, brs).

[0186] Examples 5-232 Using the corresponding raw material compounds, the compounds shown in Tables 1-1 to 1-35 were obtained by the same method as in Examples 1 to 4. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 [Table 1-42] [Table 1-43] [Table 1-44] [Table 1-45] [Table 1-46]

[0187] Example 233 6-Fluoro-2-((5-Fluoropyridine-3-yl)amino)-3-phenylquinazoline-4(3H)-one [ka] To a solution of potassium t-butoxide (587 mg) in THF (15 ml), aniline (0.5 ml) and Reference Example 4 (1.5 g) were added and stirred at room temperature for 2.5 hours. Potassium t-butoxide (588 mg) was added and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, the resulting solid was filtered and washed with water. The solid was dried under reduced pressure at room temperature to obtain the title compound (964 mg). 1 H-NMR (400 MHz, DMSO-d6) δ:7.53-7.59 (3H, m), 7.65-7.75 (5H, m), 8.07-8.11 (2H, m), 8.32 (1H, d, J = 2.4 Hz), 8.62 (1H, brs).

[0188] Example 234 6-Fluoro-3-phenyl-2-(pyridine-3-ylamino)quinazoline-4(3H)-one [ka] The title compound (3.25 g) was obtained as a crystal (Crystal II) by recrystallizing Example 12 (3.79 g) from acetonitrile. The powder X-ray diffraction pattern of [II crystal] is shown in Figure 2. Major diffraction peaks: 2θ(°) = 7.80, 10.82, 13.67, 15.59, 16.62, 18.41, 21.32, 23.47, 24.33, 25.46 Characteristic diffraction peaks: 2θ(°) = 7.80, 10.82, 13.67, 15.59

[0189] Example 235 6-Fluoro-2-((5-Fluoropyridine-3-yl)amino)-3-phenylquinazoline-4(3H)-one [ka] The title compound (11.6 g) was obtained as a crystal (III crystal) by recrystallizing Example 233 (12.0 g) from ethanol. The powder X-ray diffraction pattern for [III crystal] is shown in Figure 3. Major diffraction peaks: 2θ(°) = 7.79, 8.40, 10.66, 13.80, 15.62, 16.46, 21.52, 23.53, 23.95, 25.38 Characteristic diffraction peaks: 2θ(°) = 7.79, 8.40, 13.80, 25.38

[0190] Example 236 4-Oxo-2-(pyridine-3-ylamino)-3-(o-toluyl)-3,4-dihydroquinazoline-6-carbonitrile [ka] To a 10 ml solution of Reference Example 5 (2.4 g) in DMF, N,N-diisopropylethylamine (2.4 ml), 3-isothiocyanatopyridine (1.3 ml), and copper bromide (1.6 g) were added and the mixture was stirred at 85°C for 3 hours. Ammonia water was added to the reaction mixture, filtered by Celite, and the filtrate was extracted with chloroform. The mixture was then washed with saturated ammonium chloride aqueous solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: hexane:ethyl acetate). The resulting crude product was recrystallized from ethanol to obtain the title compound (1.3 g) as crystals (IV crystals). The powder X-ray diffraction pattern of the [IV crystal] is shown in Figure 4. Major diffractential peaks: 2θ(°) = 8.15, 13.66, 13.92, 16.32, 21.04, 21.22, 22.10, 25.12, 25.37, 25.83 Characteristic diffraction peaks: 2θ(°) = 8.15, 16.32, 25.37, 25.83

[0191] Example 237 2-((5-fluoropyridine-3-yl)amino)-4-oxo-3-(o-toluyl)-3,4-dihydroquinazoline-6-carbonitrile [ka] The title compound (2.3g) was obtained as a crystal (V crystal) by recrystallizing Example 114 (5.4g) from ethanol. The powder X-ray diffraction pattern of the [V crystal] is shown in Figure 5. Major diffraction peaks: 2θ(°) = 8.07, 10.19, 11.62, 15.86, 16.18, 22.13, 24.51, 26.43, 26.83, 27.54 Characteristic diffraction peaks: 2θ(°) = 8.07, 15.86, 16.18, 26.43

[0192] The powder X-ray diffraction measurements in the above examples were performed under the following conditions. The obtained diffraction patterns (XRD spectra) are shown in Figures 1 to 5.

[0193] To identify the crystal form, one can make a determination based on the characteristic diffraction peaks of each crystal shown in the diffraction diagrams in Figures 1 to 5.

[0194] The main diffraction peaks and characteristic diffraction peaks identified from the diffraction patterns in Figures 1 to 5 are shown in Examples 3, 234, 235, 236, and 237. Note that the diffraction peak values ​​at a diffraction angle of 2θ(°) described in the examples may have some measurement error depending on the measuring instrument or measurement conditions. Specifically, the measurement error may be within the range of ±0.2, preferably ±0.1.

[0195] Powder X-ray diffraction measurement method: Detection equipment: Spectris Power X-ray diffraction system Empyrean X-ray tube: CuKα (wavelength: 1.54 angstroms) Tube voltage: 45kV Tube current: 40mA Measurement range: 4-40 degrees (2θ) Step length: 0.013 degrees Cumulative time: 100 seconds / step

[0196] Test example The following shows the results of pharmacological tests on representative compounds of this disclosure and explains their pharmacological effects, but this disclosure is not limited to these test examples.

[0197] Test Example 1: Measurement of hyperexcitability inhibitory activity using nerve cells differentiated from SCN1A gene-deficient human iPS cells. (1) Differentiation induction from human iPS cells into nerve cells SCN1A gene mutant cells established from a healthy human-derived iPS cell line (clone name 201B7, obtained from the Center for iPS Cell Research and Application, Kyoto University) were differentiated into glutamatergic excitatory neurons or γ-aminobutyric acid (GABA) agonist inhibitory neurons and maintained using BrainPhys Neuronal Medium (STEMCELL Technologies, cat#ST-05793) containing NeuroCult SM1 Neuronal Supplement, N2 Supplement-A, 20 ng / mL BDNF, 20 ng / mL GDNF, 1 mM dibutyryl cAMP, and 200 nM ascorbic acid. Seven days after differentiation induction, glutamatergic excitatory neurons and GABAergic inhibitory neurons were mixed in a 4:1 ratio and seeded onto 384-well plates (Corning, Cat#353962) coated with poly-L-lysine (Sigma-Aldrich, cat#P4707) and iMatrix-511 silk (Matrixome, cat#892021). The culture medium was changed by half every 3-4 days.

[0198] (2) Treatment with fluorescent calcium probe, compound addition, and evaluation of intracellular calcium concentration After 60 days of differentiation induction, half of the culture medium was removed, and an equal volume of measurement medium containing a fluorescent calcium probe (Molecular Devices, product name FLIPR Calcium 6 Assay Bulk Kit, cat#R8191) was added to the remaining medium. After standing for 30 minutes, the culture was subjected to measurement. The measurement medium used was 20 mM Hepes (Thermo Fisher Scientific, cat#15630-080) and Hank's buffer containing 0.1% bovine serum albumin (Sigma-Aldrich, cat#A9576) (Thermo Fisher Scientific, cat#14065-056).

[0199] The test compounds were serially diluted in a dimethyl sulfoxide (DMSO) solution to obtain final concentrations ranging from 0.1 to 100 μM, and solutions were prepared at six times the final concentration.

[0200] The fluorescence intensity of calcium probes was measured over time using an FDSS7000EX (Hamamatsu Photonics), and changes in intracellular calcium concentration were evaluated. First, fluorescence intensity was measured for 2 minutes, then the compound solution was added using the FDSS7000EX, and fluorescence intensity was measured again for 8 minutes. The frequency of spontaneous calcium oscillations was quantified as an indicator of nerve excitation, and the frequency for the last 2 minutes after the addition of the compound solution was calculated as the ratio of the frequency for the 2 minutes before the addition of the compound solution to 100%. The inhibitory activity (%) at each serial dilution concentration was determined for each test compound, and the inhibition rate (%) at the 50% inhibitory concentration (IC50) or a certain concentration (the concentration indicated after @ in Tables 2-1 and 2-2) was determined for each test compound. The inhibitory activity data for representative compounds are shown in Tables 2-1 and 2-2. [Table 2-1] [Table 2-2]

[0201] As shown in the table above, the compounds of this disclosure showed inhibitory activity in an activity measurement test for hyperexcitation using nerve cells differentiated from SCN1A gene-deficient human iPS cells.

[0202] Example 2: Epileptic spike wave evaluation using SCN1A mutant animals This study evaluates the inhibitory effect of drugs on epileptic spikes expressed in association with SCN1A gene loss-of-function mutations. The animal model used in this study is the F1 generation produced by crossing BALB / c-Scn1a<+ / -> mice (catalog number: RBRC06422; this model mouse can be obtained from the RIKEN BioResource Research Center (RIKEN BRC) through the Ministry of Education, Culture, Sports, Science and Technology's National BioResource Project, and, like patients with Dravet syndrome, has a deletion-type gene mutation in the SCN1A gene, exhibiting the phenotype of Dravet syndrome, which includes febrile seizures associated with elevated body temperature, and can be used as an animal model for spontaneously occurring Dravet syndrome (Reference: Research Annual Report of the Foundation for the Promotion of Epilepsy Treatment Research 2015:26:69-76)) with C57BL / 6J mice. SCN1A gene mutant mice (6-10 weeks old) were placed in a plastic chamber whose internal temperature was raised by using a warm bath at approximately 43°C. Febrile seizures were induced by continuously raising the body temperature through this process. Two weeks after the induction of febrile seizures, a head mount (cat#8201-SS, Pinnacle Technology) was attached to the heads of the mice. Two weeks after head mount attachment, the SCN1A gene mutant mice (25-32g) were connected to a seizure electroencephalogram (EEG) recording system (Pinnacle Technology), and the test compound was administered. The frequency of epileptic spikes was measured three hours before and after compound administration, and the dose (ED50) at which the frequency of epileptic spikes was suppressed by 50% after administration was calculated. The results are shown in Table 3 below. [Table 3]

[0203] Test Example 3: Evaluation of a subcutaneous injection pentetrazol model (minimal seizure model, scPTZ) This study evaluates the anticonvulsant effect of a drug. The animal model used in this study exhibits generalized absence seizures and myoclonic seizures. Male Slc:ddY mice (5 mice per group, 20-30g body weight) were orally administered the test compound, followed by a subcutaneous administration of pentetrazol 85 mg / kg 1 hour later. The presence or absence of clonic seizures was then observed over a 30-minute period, and the dose at which clonic seizures occurred in 50% of the animals (ED50) was calculated. A 0.5% methylcellulose solution was administered as a control. The results are shown in Table 4 below. [Table 4]

[0204] Test Example 4: Evaluation of Maximum Electrical Stress Model (MES) This study, like Study Example 3, evaluates the anticonvulsant effect of a drug. The animal models used in this study are those exhibiting generalized tonic-clonic seizures and secondary generalized partial seizures. Male Slc:ddY mice (5 mice per group, 20-30g body weight) were orally administered the test compound. One hour later, electrical stimulation (60Hz, 50mA, 0.2 seconds) was applied to the cornea, and the suppression of induced tonic extension seizures of the hind limbs was observed. The dose at which 50% of the animals exhibited tonic extension seizures (ED50) was calculated. The control group was administered 0.5% methylcellulose solution. The results are shown in Table 5 below. [Table 5]

[0205] As shown in the table above, the compounds of this disclosure showed anticonvulsant activity when administered orally in the evaluation of epileptic spike waves in SCN1A mutant animals and / or in the evaluation of a subcutaneous injection pentetrazol model (minimal convulsion model, scPTZ) and / or in the evaluation of a maximal electroconvulsion model (MES).

[0206] Test Example 5: Rotor Rod Evaluation This study evaluated the inhibitory effect of a drug on motor coordination. Male Slc:ddy mice (body weight 20-30g) were trained to walk for 5 minutes on a rotor rod device (a device that rotates a 4cm diameter cylindrical rod, 12 revolutions / minute) on the day of the study. Five mice were orally administered the test compound, and 50 minutes later, they were placed on a rotor rod device (15 revolutions / minute) and their walking ability was observed for 180 seconds. The number of animals that fell due to impaired motor coordination within 180 seconds was counted, and the dose at which 50% of the animals fell (TD50) was calculated. A control group was administered 0.5% methylcellulose solution. The results are shown in Table 6. [Table 6]

[0207] Test Example 6: 3-Chamber Test Evaluation This study evaluates the drug's effect on improving social impairment, a core symptom of autism spectrum disorder. The animal model used in this study is the F1 generation, produced by crossing BALB / c-Scn1a<+ / -> mice with C57BL / 6J mice, similar to Study Example 2.

[0208] SCN1A gene mutant mice (6-10 weeks old) described above were placed in a plastic chamber whose internal temperature was raised by using a warm bath at approximately 43°C. Febrile seizures were induced by continuously raising the body temperature through this process. A three-chamber test was conducted two weeks after the induction of febrile seizures. A cage containing a decoy mouse was placed in one chamber of the three-chamber test apparatus, and a cage containing an object was placed in the other chamber. The test compound was orally administered to F1 SCN1A gene function loss mutant mice (25-32g), and one hour later, the mice were allowed to freely explore the apparatus for 10 minutes. The sniffing time of the decoy mouse and the object was measured during this time.

[0209] Test Example 7: Cognitive function assessment using the Novel Object Recognition Test (NORT). This study evaluates the cognitive function-improving effects of the compound. In the NORT (Non-Autonomous Rehabilitation Test) using APP-Tg mice or rTg4510 mice, which are AD (Alzheimer's disease) model mice, a time-dependent decline in memory for known objects was observed between the first trial (training) and the second trial (test). For example, when the second trial was performed 3 hours after the first trial, APP-Tg mice and rTg4510 mice showed no difference in search time for novel and known objects compared to healthy mice, indicating significant forgetting.

[0210] The APP-Tg mice used in this study are created by constructing an expression cassette in which human APP751 isoforms with Swedish (K670N / M671L) and Indiana (V717F) mutations introduced downstream of the mouse Thy-1 promoter are linked. This cassette is then injected into mouse fertilized eggs and transplanted into surrogate parents. The resulting mice exhibit Aβ accumulation in the brain and cognitive impairment from an early stage, making them suitable for cognitive function evaluation.

[0211] The rTg4510 mice used in this study will be produced by crossing Tg(tauP301L)4510 mice (Stock No. 015815) and CaMKII-tTA mice (Stock No. 007004) purchased from The Jackson Laboratory and breeding them. The resulting mice will overexpress human-type FTDP-17 mutant tau in the forebrain and exhibit age-dependent accumulation of tau aggregates in the brain and cognitive impairment, making them suitable for cognitive function evaluation.

[0212] The test compound is administered to the generated APP-Tg mice or rTg4510 mice, and the first trial is performed 30-60 minutes after administration or after 1 month of mixed diet administration. The second trial is performed 3 hours after the first trial, and the search time for novel and known objects in the second trial is evaluated. The discrimination index is calculated from the search time for novel and known objects in the second trial, and this is used as an indicator of cognitive function to confirm the cognitive function-improving effect of the test compound by comparing it with the group that did not receive the test compound. The discrimination index is calculated using the following formula. Discrimination index = {(Time spent searching for novel objects) - (Time spent searching for known objects)} / {(Time spent searching for novel objects) + (Time spent searching for known objects)}

[0213] As described above, the compounds of this disclosure have the activity to suppress the excessive excitation of neural circuits that are thought to be underlying various epileptic pathologies, and have shown strong anticonvulsant activity in epilepsy models using human cells and in multiple animal seizure models. Therefore, they are useful as antiepileptic drugs with a broad therapeutic spectrum (for epileptic seizures (generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, and atonic seizures), status epilepticus, epileptic syndromes (Dravet syndrome, Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy, medial temporal lobe epilepsy with hippocampal sclerosis, Rasmussen syndrome, etc.), epilepsy attributable to structural / metabolic causes (cortical dysplasia, neurocutaneous syndromes (tuberous sclerosis complex, Sturge-Weber syndrome, etc.), etc.), and for the treatment and / or prevention of developmental disorders, mental disorders, cognitive disorders, etc. that occur concurrently with these). Furthermore, it is expected to exhibit a pathological improvement effect on disorders or diseases that are based on an imbalance between excitatory and inhibitory signals in neural circuits (developmental disorders (autism spectrum disorder, Rett syndrome, Angelman syndrome, fragile X syndrome, attention deficit hyperactivity disorder, etc.), mental disorders (schizophrenia, bipolar disorder, depression, anxiety disorders, obsessive-compulsive disorder, etc.), and cognitive disorders (Alzheimer's disease and other dementias, Parkinson's disease, etc.).

[0214] As described above, the Disclosure has been illustrated using preferred embodiments thereof, but it is understood that the scope of the Disclosure should be interpreted solely by the claims. This Application claims priority over Japanese Patent Application No. 2021-173154 (filed October 22, 2021), the contents of which are incorporated herein by reference in their entirety. It is understood that the contents of any patents, patent applications and documents cited herein should be incorporated herein by reference as if their contents were specifically described herein. [Industrial applicability]

[0215] The compounds disclosed herein have activity that suppresses excessive excitation of neural circuits, and are therefore useful as therapeutic and / or prophylactic agents for disorders or diseases involving abnormalities in neural excitation, such as epilepsy.

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, X １ is CR １ or N, X ２ is CR ２ or N, X ３ is CR ３ or N, X ４ is CR ４ or N, Here, (1) X １ If N, then X ２ is CR ２ and X ３ is CR ３ and X ４ is CR ４ and (2) X ２ If N, then X １ is CR １ and X ３ is CR ３ and X ４ is CR ４ and (3) X ３ If N, then X １ is CR １ and X ２ is CR ２ and X ４ is CR ４ and (4) X ４ If N, then X １ is CR １ and X ２ is CR ２ and X ３ is CR ３ and Y is an optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ an alicyclic group, an optionally substituted 4- to 10-membered non-aryl heterocycle, an optionally substituted C ６－１０ represents an aryl or an optionally substituted 5- to 10-membered heteroaryl; Z represents an optionally substituted 5- to 10-membered heteroaryl; R １ , R ２ , R ３ and R ４ each independently represents a hydrogen atom, halogen, cyano, C 1-6 alkoxy, or C 1-6 alkyl (the alkoxy and the alkyl may each independently be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen, hydroxy, and C 1-6 alkoxy), A pharmaceutical containing a compound as an active ingredient, provided that the pharmaceutical Formula (W-1): 【Chemistry 2】 {During the ceremony, and Z a is an optionally substituted 5- to 10-membered heteroaryl}, a compound represented by formula (W-2): 【Transformation 3】 {During the ceremony, X a is O or S, and Y b is ethyl, unsubstituted phenyl, 4-chlorophenyl, or 4-methoxyphenyl; Formula (W-3): 【Chemistry 4】 {During the ceremony, X c is —S— or —SO 2 —, and Y c is unsubstituted phenyl, 4-methylphenyl, 4-chlorophenyl, or 4-methoxyphenyl; Formula (W-4): 【Transformation 5】 {During the ceremony, X d is methoxy, chloro or dimethylamino, and Y d is ethyl, unsubstituted phenyl, 4-chlorophenyl or 4-methoxyphenyl; 2-{(4,6-dimethylpyrimidin-2-yl)amino}-3-isopentylquinazolin-4(3H)-one, 3-(pyridin-2-yl)-2-(pyridin-2-ylamino)quinazolin-4(3H)-one, 3-methyl-2-{[2-((1-methylpiperidin-4-yl)methoxy)pyridin-3-yl]amino}pyrido[3,4-d]pyrimidin-4(3H)-one, 3-methyl-2-{[2-((1-methylpiperidin-4-yl)methoxy)pyridin-3-yl]amino}pyrido[2,3-d]pyrimidin-4(3H)-one, 3-ethyl-2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)quinazolin-4(3H)-one, 3-allyl-2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)quinazolin-4(3H)-one, 2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-3-phenylquinazolin-4(3H)-one, 2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-3-(pyridin-4-yl)quinazolin-4(3H)-one, 2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-3-(p-tolyl)quinazolin-4(3H)-one, 3-(4-nitrophenyl)-2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)quinazolin-4(3H)-one, 3-(4-chlorophenyl)-2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)quinazolin-4(3H)-one, 3-(2-chlorophenyl)-2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)quinazolin-4(3H)-one, 3-(2-methoxyphenyl)-2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)quinazolin-4(3H)-one, and 3-(4-Methoxyphenyl)-2-((4-oxo-2-phenylquinazolin-3(4H)-yl)amino)quinazolin-4(3H)-one Contains no medicines.

2. X １ But, CR １ That is, The pharmaceutical composition according to claim 1.

3. X ２ But, CR ２ That is, The pharmaceutical composition according to claim 1.

4. X ３ But, CR ３ That is, The pharmaceutical composition according to claim 1.

5. X ４ But, CR ４ That is, The pharmaceutical composition according to claim 1.

6. R １ , R ３ and R ４ are both hydrogen atoms, and R ２ is a hydrogen atom, halogen, cyano, C １－６ alkyl (the alkyl may be substituted with 1 to 3 fluorine atoms or methoxy groups), or C １－６ is an alkoxy, The pharmaceutical composition according to claim 1.

7. R １ , R ３ and R ４ are both hydrogen atoms, and R ２ is a hydrogen atom, fluorine, chloro, cyano or C １－６ alkyl (the alkyl may be substituted with 1 to 3 fluorine atoms or a methoxy group); The pharmaceutical composition according to claim 1.

8. R １ , R ３ and R ４ are both hydrogen atoms, and R ２ is fluorine or cyano; The pharmaceutical composition according to claim 1.

9. Y is, (1) Halogen, hydroxy, amino, dimethylamino, C ３－６ Alicyclic groups, 4- to 10-membered nitrogen-containing non-aryl heterocyclic groups, C １－６ Alkoxy, C ６－１０ Aryl (the alicyclic group, the nitrogen-containing non-aryl heterocyclic group, the alkoxy, and the aryl group each independently represent halogen, cyano, C ３－６ an alicyclic group, a C optionally substituted with 1 to 5 fluorines １－６ Alkyl, and C １－６ alkoxy), and 5- to 10-membered heteroaryl (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen, cyano, C ３－６ an alicyclic group, a C optionally substituted with 1 to 5 fluorines １－６ Alkyl, and C １－６ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkoxy １－６ Alkyl, (2) C optionally substituted with halogen, hydroxy, amino, dimethylamino, or 1 to 5 fluorines １－６ Alkyl, C ３－６ Alicyclic groups, 4- to 10-membered nitrogen-containing non-aryl heterocyclic groups, C １－６ Alkoxy, C ６－１０ Aryl (the alicyclic group, the nitrogen-containing non-aryl heterocyclic group, the alkoxy, and the aryl group each independently represent halogen, cyano, C ３－６ an alicyclic group, a C optionally substituted with 1 to 5 fluorines １－６ Alkyl, and C １－６ alkoxy), and 5- to 10-membered heteroaryl (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen, cyano, C ３－６ an alicyclic group, a C optionally substituted with 1 to 5 fluorines １－６ Alkyl, and C １－６ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkoxy ３－１０ alicyclic group, (3) C optionally substituted with halogen, hydroxy, amino, dimethylamino, or 1 to 5 fluorines １－６ Alkyl, C ３－６ Alicyclic group, C １－６ Alkoxy and C ６－１０ Aryl (the alicyclic group, the alkoxy, and the aryl group are each independently selected from halogen, cyano, C ３－６ an alicyclic group, a C optionally substituted with 1 to 5 fluorines １－６ Alkyl, and C １－６ a 4- to 10-membered non-aryl heterocyclic group optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of alkoxy; (4) Halogen, cyano, dimethylamino, C １－６ Alkoxy and C １－６ alkyl (the alkoxy and the alkyl are each independently selected from halogen, hydroxy, and C １－６ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkoxy ６－１０ aryl, or (5) Halogen, cyano, dimethylamino, C １－６ Alkoxy and C １－６ alkyl (the alkoxy and the alkyl are each independently selected from halogen, hydroxy, and C １－６ 5-10 membered heteroaryl optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of alkoxy; The pharmaceutical composition according to claim 1.

10. Y is, (1) Fluorine, C ３－６ an alicyclic group, a 5- or 6-membered nitrogen-containing non-aryl heterocyclic group, a phenyl (the alicyclic group, the nitrogen-containing non-aryl heterocyclic ring, and the phenyl group each independently represent a C group optionally substituted with fluorine, cyano, or 1 to 3 fluorines); １－３ and 5- to 6-membered heteroaryl (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine, cyano, C １－３ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, methyl ... １－３ Alkyl, (2) Fluorine, amino, dimethylamino, C optionally substituted with 1 to 3 fluorines １－３ alkyl, a 5- to 6-membered nitrogen-containing non-aryl heterocyclic group, phenyl (the phenyl group may be substituted with fluorine, cyano, or C １－３ and 5- to 6-membered heteroaryl (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine, cyano, C １－３ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, methyl ... ３－６ alicyclic group, (3) C optionally substituted with fluorine, amino, dimethylamino, or 1 to 3 fluorines １－３ a 5- or 6-membered nitrogen-containing non-aryl heterocyclic group optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl; (4) Halogen, cyano, dimethylamino, C １－３ C optionally substituted with alkoxy and 1 to 3 fluorines １－３ phenyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or (5) Halogen, cyano, dimethylamino, C １－３ C optionally substituted with alkoxy and 1 to 3 fluorines １－３ alkyl, 5- or 6-membered heteroaryl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of The pharmaceutical composition according to claim 1.

11. Y is, (1) Fluorine, C ３－６ an alicyclic group, a 5- or 6-membered nitrogen-containing non-aryl heterocyclic group, a phenyl (the alicyclic group, the nitrogen-containing non-aryl heterocyclic ring, and the phenyl group each independently represent a C group optionally substituted with fluorine, cyano, or 1 to 3 fluorines); １－３ and 5-membered heteroaryl (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine, cyano, C １－３ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, methyl ... １－３ Alkyl, (2) Fluorine, amino, dimethylamino, C optionally substituted with 1 to 3 fluorines ２－３ alkyl, a 5- to 6-membered nitrogen-containing non-aryl heterocyclic group, phenyl (the phenyl group may be substituted with fluorine, cyano, or C １－３ and 5- to 6-membered heteroaryl (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine, cyano, C １－３ C is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, methyl ... ５－６ an alicyclic group or phenylcyclopropyl, (3) fluorine, amino, dimethylamino, C optionally substituted with 1 to 3 fluorines ２－３ Alkyl and phenyl (the phenyl group may be substituted with fluorine, cyano, 1 to 3 fluorines, C １－３ a 4- to 6-membered nitrogen-containing non-aryl heterocyclic group optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, phenyloxetanyl, and tetrahydropyranyl; (4) Halogen, cyano, dimethylamino, C １－３ C optionally substituted with alkoxy and 1 to 3 fluorines １－３ phenyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or (5) Halogen, cyano, C １－３ C optionally substituted with alkoxy and 1 to 3 fluorines １－３ a 6-membered heteroaryl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl; The pharmaceutical composition according to claim 1.

12. Y is, (1) C optionally substituted with 1 to 3 fluorines １－３ Alkyl, (2) Fluorine, amino, dimethylamino, and C optionally substituted with 1 to 3 fluorines １－３ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl ５－６ alicyclic group, (3) C optionally substituted with fluorine, amino, dimethylamino, or 1 to 3 fluorines １－３ a 5- or 6-membered nitrogen-containing non-aryl heterocyclic group optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl; (4) Halogen, cyano, dimethylamino, C １－３ C optionally substituted with alkoxy and 1 to 3 fluorines １－３ Phenyl or alkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of (5) Halogen, cyano, dimethylamino, C １－３ C optionally substituted with alkoxy and 1 to 3 fluorines １－３ alkyl, 5- or 6-membered heteroaryl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of The pharmaceutical composition according to claim 1.

13. Y is, (1) Fluorine, amino, dimethylamino, and C optionally substituted with 1 to 3 fluorines １－３ C optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl ５－６ alicyclic group, (2) C optionally substituted with fluorine, amino, dimethylamino, or 1 to 3 fluorines １－３ a 5- or 6-membered nitrogen-containing non-aryl heterocyclic group optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl; (3) C optionally substituted with halogen, cyano, methoxy, and 1 to 3 fluorines １－３ phenyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or (4) C optionally substituted with halogen, cyano, methoxy, and 1 to 3 fluorines １－３ alkyl, 5- or 6-membered heteroaryl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of The pharmaceutical composition according to claim 1.

14. Y is, (1) phenyl optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of fluorine, cyano, methoxy, and methyl, or (2) a 5- or 6-membered heteroaryl optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of fluorine, cyano, methoxy, and methyl; The pharmaceutical composition according to claim 1.

15. Y is, (1) phenyl optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of fluorine, cyano, methoxy, and methyl, or (2) a 6-membered heteroaryl optionally substituted with 1 to 2 identical or different substituents selected from the group consisting of fluorine, cyano, methoxy, and methyl; The pharmaceutical composition according to claim 1.

16. Z is halogen, cyano, dimethylamino, C １－６ Alkoxy, and C １－６ alkyl (the alkoxy and the alkyl are each independently selected from halogen, hydroxy, and C １－６ 5-10 membered heteroaryl optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of alkoxy; The pharmaceutical composition according to claim 1.

17. Z is halogen, cyano, C ２－６ Alkoxy, and C １－６ alkyl (the alkoxy and the alkyl are each independently selected from halogen, hydroxy, and C １－６ 6- to 10-membered heteroaryl optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of alkoxy; The pharmaceutical composition according to claim 1.

18. Z is fluorine, cyano, C ２－６ Alkoxy, and C １－６ alkyl (the alkoxy and the alkyl are each independently selected from halogen, hydroxy, and C １－６ 6-10 membered heteroaryl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl, optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of alkoxy; The pharmaceutical composition according to claim 1.

19. Z is fluorine, chloro, cyano, C １－６ Alkoxy and C optionally substituted with 1 to 3 fluorines １－３ alkyl, 6-10 membered heteroaryl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of The pharmaceutical composition according to claim 1.

20. Z is fluorine, chloro, cyano, methoxy, or C optionally substituted with 1 to 3 fluorines. １－３ The pharmaceutical agent according to claim 1, which is pyridyl, pyrimidinyl, indazolyl or imidazopyridyl, optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

21. Z is fluorine, chloro, cyano, or C optionally substituted with 1 to 3 fluorines １－３ pyridyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl; The pharmaceutical composition according to claim 1.

22. The pharmaceutical composition according to claim 1, comprising a compound selected from the following compounds as an active ingredient: 4-oxo-3-phenyl-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile, 6-fluoro-2-((5-fluoropyridin-3-yl)amino)-3-(o-toluyl)quinazolin-4(3H)-one, 6-chloro-2-((2-methoxypyridin-3-yl)amino)-3-phenylquinazolin-4(3H)-one, 6-fluoro-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 6-chloro-3-(2-chlorophenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 6-chloro-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 6,8-difluoro-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 6-fluoro-3-(pyridin-3-yl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 6-chloro-3-phenyl-2-(pyrazin-2-ylamino)quinazolin-4(3H)-one, 6-fluoro-3-phenyl-2-(pyrazin-2-ylamino)quinazolin-4(3H)-one, 6-fluoro-2-((5-fluoropyridin-3-yl)amino)-3-phenylquinazolin-4(3H)-one, 5-((6-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)amino)nicotinonitrile, 6-methyl-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 2-((5-chloropyridin-3-yl)amino)-6-fluoro-3-phenylquinazolin-4(3H)-one, 6-chloro-3-(2-fluorophenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 2-((1-methyl-1H-indazol-6-yl)amino)-3-phenylquinazolin-4(3H)-one, 2-(imidazo[1,5-a]pyridin-8-ylamino)-3-phenylquinazolin-4(3H)-one, 3-(4-methoxy-2-methylphenyl)-4-oxo-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile, 3-(5-fluoro-2-methylphenyl)-4-oxo-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile, 6-fluoro-2-(pyridin-3-ylamino)-3-(p-toluyl)quinazolin-4(3H)-one, 6-fluoro-2-(pyridin-3-ylamino)-3-(o-toluyl)quinazolin-4(3H)-one, 6-fluoro-3-(2-fluorophenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one, 4-oxo-2-(pyridin-3-ylamino)-3-(o-toluyl)-3,4-dihydroquinazoline-6-carbonitrile, 6-fluoro-3-(2-fluorophenyl)-2-((5-fluoropyridin-3-yl)amino)quinazolin-4(3H)-one, 2-((5-fluoropyridin-3-yl)amino)-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-carbonitrile, 3-(2-fluorophenyl)-2-((5-fluoropyridin-3-yl)amino)-4-oxo-3,4-dihydroquinazoline-6-carbonitrile, 2-((5-fluoropyridin-3-yl)amino)-4-oxo-3-(o-toluyl)-3,4-dihydroquinazoline-6-carbonitrile, 6-fluoro-2-((4-fluoropyridin-2-yl)amino)-3-phenylquinazolin-4(3H)-one, 6-fluoro-2-((5-methylpyridin-2-yl)amino)-3-phenylquinazolin-4(3H)-one, 6-fluoro-2-((2-fluoropyridin-4-yl)amino)-3-phenylquinazolin-4(3H)-one, 6-fluoro-3-(2-methoxyphenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one and 3-(2-Chlorophenyl)-6-fluoro-2-(pyridin-3-ylamino)quinazolin-4(3H)-one.

23. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

24. A drug for the treatment or prevention of epilepsy or developmental disorders, The pharmaceutical composition according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 23.

25. A therapeutic or preventive agent for disorders or diseases involving abnormalities in nerve excitation, comprising the pharmaceutical agent according to any one of claims 1 to 22 or the pharmaceutical composition according to claim 23.

26. Use of the medicament according to any one of claims 1 to 22 or the pharmaceutical composition according to claim 23 for the manufacture of a therapeutic or preventive drug for a disorder or disease involving abnormalities in nerve excitation.

27. A pharmaceutical composition according to any one of claims 1 to 22 or a pharmaceutical composition according to claim 23 for use in treating or preventing a disorder or disease involving abnormalities in nerve excitation.

28. A pharmaceutical composition comprising a combination of the medicament according to any one of claims 1 to 22, or the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one or more drugs selected from drugs classified as antiepileptics, antidepressants, antianxiety drugs, or antipsychotic drugs.

29. The medicament according to any one of claims 1 to 22 or the pharmaceutical composition according to claim 23, for treating or preventing a disorder or disease involving abnormalities in neural excitation, in combination with at least one or more drugs selected from drugs classified as antiepileptics, antidepressants, antianxiety drugs, or antipsychotic drugs.

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