2-Heteroarylaminoquinazolinone derivatives

Abstract

Provided are 2-heteroarylaminoquinazolinone derivatives. Compounds represented by formula (1) or pharmaceutically acceptable salts thereof, [wherein, X 1 Indicates CR 1 or N, X 2 Indicates CR 2 or N, X 3 Indicates CR 3 or N, X 4 Indicates CR 4 or N, Y represents an optionally substituted C 1‑6 Alkyl, optionally substituted C 3‑10 alicyclic group, an optionally substituted 4-10 membered non-aromatic heterocyclic ring, an optionally substituted C 6‑10 aryl or an optionally substituted 5- to 10-membered heteroaryl, Z represents an optionally substituted 6- to 10-membered heteroaryl, R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, an optionally substituted C 1‑6 Alkyl, or optionally substituted C 1‑6 Alkoxy, etc.].

Description

[0001] The present disclosure relates to 2-heteroarylaminoquinazolinone derivatives and pharmaceutically acceptable salts thereof having an effect of inhibiting excessive excitation of a neural circuit and useful as pharmaceuticals, as well as pharmaceutical compositions containing the same as active ingredients. Background Art

[0002] Abnormal excitability of brain neural circuits is known to be associated with various central nervous system diseases. For example, epilepsy is a chronic disease characterized by recurring paroxysmal abnormalities in movement, consciousness, perception, and behavior, caused by overexcitability of neural circuits. While it is believed that the normal functioning of the nervous system requires a delicate regulation of excitatory and inhibitory signals, epilepsy results in overexcitability due to an imbalance in this balance. Diseases can be caused by a variety of factors, broadly categorized as genetic, with known genetic abnormalities acting as direct causes, and structural, with abnormalities in brain structure acting as causes (Non-Patent Document 1). For example, Dravet syndrome, in which approximately 80% of patients have been found to have lesions in the SCN1A gene, is a representative example of a genetic cause, while mesial temporal lobe epilepsy with hippocampal sclerosis is a representative example of a structural cause. Both types of epilepsy are diagnosed through interviews and electroencephalogram (EEG) testing, where overexcitability of neural circuits is detected as abnormal EEG waves called spikes and slow spike waves.

[0003] The treatment of epileptic seizures is centered around drug therapy, and antiepileptic drugs primarily inhibit the overexcitation of neural circuits by suppressing excitatory signals or enhancing inhibitory signals. Although a variety of antiepileptic drugs have been approved and marketed to date, one in three cases of epilepsy is refractory and resistant to existing drug treatments. In addition, the effective concentration (therapeutic range) of existing antiepileptic drugs is relatively narrow, and they are prone to producing undesirable side effects (e.g., movement disorders, sedation, dizziness, etc.) at the doses required to achieve anticonvulsant activity. Moreover, patients with epilepsy are at high risk of developing complications such as mental development disorders, mental disorders, and cognitive impairment (Non-Patent Literature 2, 3), and existing drugs do not have therapeutic effects on these concurrent neurological / psychiatric symptoms.

[0004] It is believed that the abnormal balance between excitatory and inhibitory signals in neural circuits is not only present in epilepsy, but also has a background in diseases related to mental development disorders (autism spectrum disorder, Rett syndrome, Angelman syndrome, fragile X syndrome, attention deficit hyperactivity disorder, etc.), diseases related to mental disorders (schizophrenia, bipolar disorder, depression, anxiety, obsessive-compulsive disorder, etc.), diseases related to cognitive impairment (Alzheimer's disease or other dementias, Parkinson's disease, etc.), and various central nervous system diseases (Non-Patent Documents 4, 5, 6). Therefore, it is expected that drugs that regulate excessive excitement will have a disease-modifying effect on these diseases.

[0005] Prior art literature

[0006] Non-patent literature

[0007] Non-patent document 1: Scheffer, IE. et al., Epilepsia, (2017), 58(4), 512-521.

[0008] Non-patent document 2: Aaberg, KM. et al., Pediatrics, (2016), 138(3), e2016921.

[0009] Non-patent document 3: Gaitatzis, A. et al., Epilepsia, (2004), 45(12), 1613-1622.

[0010] Non-patent literature 4: Selten, M. et al., F1000Research, (2018), 7.

[0011] Non-patent literature 5: Palop, JJ. et al., Nature Review Neuroscience, (2016), 17(12), 777-792.

[0012] Non-patent literature 6: Charvin, D. et al., Nature Review Drug Discovery, (2018), 17(11), 804-822. Summary of the Invention

[0013] Problems to be solved by the invention

[0014] The present inventors have diligently researched and discovered that compounds represented by the following formula (1) exhibit potent inhibitory effects on neural circuit hyperexcitation, leading to the completion of the present disclosure. According to the present disclosure, 2-heteroarylaminoquinazolinone derivatives represented by the following formula (1) (hereinafter sometimes referred to as "compounds of the present disclosure") are provided.

[0015] That is, the present disclosure is as follows.

[0016] (Item 1) a compound represented by formula (1) or a pharmaceutically acceptable salt thereof,

[0017] [Chemical Formula 14]

[0018]

[0019] [Where,

[0020] X 1 Indicates CR1 or N,

[0021] X 2 Indicates CR 2 or N,

[0022] X 3 Indicates CR 3 or N,

[0023] X 4 Indicates CR 4 or N,

[0024] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1 CR 1 , and X 2 CR 2 , and X 3 CR 3 ,

[0025] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 alicyclic group, an optionally substituted 4-10 membered non-aromatic heterocyclic ring, an optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0026] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0027] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -SO2-NR 5R 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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0028] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R 6 、R 7 and R 8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic group (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 substituted by 1 to 5 substituents which may be the same or different in the alkoxy group),

[0029] Except for the following compounds:

[0030] Compound represented by formula (W-1)

[0031] [Chemical Formula 15]

[0032]

[0033] {Where Z a is an optionally substituted 5- to 10-membered heteroaryl},

[0034] Compound represented by formula (W-2)

[0035] [Chemical Formula 16]

[0036]

[0037] {Where, X a O or S, Y b is ethyl, unsubstituted phenyl, 4-chlorophenyl, or 4-methoxyphenyl},

[0038] Compound represented by formula (W-3)

[0039] [Chemical Formula 17]

[0040]

[0041] {Where, X c -S- or -SO2-, Y c is unsubstituted phenyl, 4-chlorophenyl, or 4-methoxyphenyl},

[0042] Compound represented by formula (W-4)

[0043] [Chemical Formula 18]

[0044]

[0045] {Where, X d is methoxy, chlorine or dimethylamino, Y d is ethyl, unsubstituted phenyl, 4-chlorophenyl, or 4-methoxyphenyl},

[0046] 2-{(4,6-dimethylpyrimidin-2-yl)amino}-3-isopentylquinazolin-4(3H)-one,

[0047] 3-(pyridin-2-yl)-2-(pyridin-2-ylamino)quinazolin-4(3H)-one,

[0048] 3-methyl-2-{[2-((1-methylpiperidin-4-yl)methoxy)pyridin-3-yl]amino}pyrido[3,4-d]pyrimidin-4(3H)-one and

[0049] 3-methyl-2-{[2-((1-methylpiperidin-4-yl)methoxy)pyridin-3-yl]amino}pyrido[2,3-d]pyrimidin-4(3H)-one].

[0050] (Item 2) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein X 1 CR 1 .

[0051] (Item 3) The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 2 CR 2 .

[0052] (Item 4) The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X 3 CR 3 .

[0053] (Item 5) The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X 4 CR 4 .

[0054] (Item 6) The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 and R 4 are independently a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkoxy, or C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 The alkoxy group is substituted by 1 to 3 substituents which may be the same or different.

[0055] (Item 7) The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 3 and R 4 are all hydrogen atoms, R 2 For hydrogen atoms, halogen, cyano, C 1-6 Alkyl (the alkyl group is optionally substituted by 1 to 3 fluorine or methoxy groups), or C 1-6 Alkoxy.

[0056] (Item 8) The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 3 and R 4 are all hydrogen atoms, R 2 is a hydrogen atom, fluorine, chlorine, cyano or C 1-6 Alkyl (the alkyl group may be substituted by 1 to 3 fluorine or methoxy groups).

[0057] (Item 9) The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 、R 3 and R 4 are all hydrogen atoms, R 2 It is fluorine or cyano.

[0058] (Item 10) The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0059] Y is

[0060] (1) optionally selected from halogen, hydroxy, amino, dimethylamino, C 3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic group, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 1-6 alkyl,

[0061] (2) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C 3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic group, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 3-10 alicyclic groups,

[0062] (3) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C 3-6 Alicyclic group, C 1-6 Alkoxy and C 6-10Aryl (the alicyclic group, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 a 4- to 10-membered non-aromatic heterocyclic group substituted with the same or different 1 to 3 substituents in an alkoxy group,

[0063] (4) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 6-10 Aryl, or

[0064] (5) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 5- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0065] (Item 11) The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0066] Y is

[0067] (1) optionally selected from fluorine, C 3-6 alicyclic group, a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic ring, and the phenyl group are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 1-3 alkyl,

[0068] (2) C optionally substituted with 1 to 3 fluorine groups, fluorine, amino, dimethylamino, 1-3 Alkyl, 5-6 membered nitrogen-containing non-aromatic heterocyclic group, phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 3-6 alicyclic groups,

[0069] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0070] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0071] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 A 5-membered or 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0072] (Item 11a) The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0073] Y is

[0074] (1) optionally selected from fluorine, C 3-6 alicyclic group, a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic ring, and the phenyl group are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5-membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 1-3 alkyl,

[0075] (2) C optionally substituted with 1 to 3 fluorine groups, fluorine, amino, dimethylamino, 2-3 Alkyl, 5-6 membered nitrogen-containing non-aromatic heterocyclic group, phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 5-6 alicyclic or phenylcyclopropyl,

[0076] (3) C optionally substituted with 1 to 3 fluorine groups, amino, dimethylamino, 2-3 Alkyl and phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) in 4 to 6 membered nitrogen-containing non-aromatic heterocyclic group, phenyloxetane or tetrahydropyranyl,

[0077] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0078] (5) optionally selected from halogen, cyano, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 A 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0079] (Item 12) The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0080] Y is

[0081] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0082] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0083] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0084] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0085] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 A 5-membered or 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0086] (Item 13) The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0087] Y is

[0088] (1) C optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino and 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0089] (2) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0090] (3) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0091] (4) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 A 5-membered or 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0092] (Item 14) The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0093] Y is

[0094] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0095] (2) A 5-membered or 6-membered heteroaryl group optionally substituted by 1 to 2 substituents which are the same or different and are selected from fluorine, cyano, methoxy and methyl.

[0096] (Item 14a) The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0097] Y is

[0098] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0099] (2) A 6-membered heteroaryl group optionally substituted by 1 to 2 substituents which are the same or different and selected from fluorine, cyano, methoxy and methyl.

[0100] (Item 15) The compound according to any one of Items 1 to 14, Item 11a, and Item 14a, or a pharmaceutically acceptable salt thereof, wherein:

[0101] Z is optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 5- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0102] (Item 15a) The compound according to any one of Items 1 to 14, Item 11a, and Item 14a, or a pharmaceutically acceptable salt thereof, wherein

[0103] Z is optionally selected from halogen, cyano, C 2-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 6- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0104] (Item 15b) The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, Item 11a, and Item 14a, wherein:

[0105] Z is optionally selected from fluoro, cyano, C 2-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 6- to 10-membered heteroaryl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an isoxazolyl group or a thiadiazolyl group substituted with the same or different 1 to 3 substituents in the alkyloxy group (substituted with the same or different 1 to 3 substituents in the alkyloxy group).

[0106] (Item 16) The compound according to any one of Items 1 to 14, Item 11a, and Item 14a, or a pharmaceutically acceptable salt thereof, wherein:

[0107] Z is optionally selected from fluorine, chlorine, cyano, C 1-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine1-3 A 6- to 10-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0108] (Item 17) The compound according to any one of Items 1 to 14, Item 11a, and Item 14a, or a pharmaceutically acceptable salt thereof, wherein:

[0109] Z is optionally selected from fluorine, chlorine, cyano, methoxy, and C optionally substituted with 1 to 3 fluorine 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

[0110] (Item 18) The compound according to any one of Items 1 to 14, Item 11a, and Item 14a, or a pharmaceutically acceptable salt thereof, wherein:

[0111] Z is a C group optionally selected from fluorine, chlorine, cyano and optionally substituted with 1 to 3 fluorine groups. 1-3 Pyridyl substituted with 1 to 3 substituents which may be the same or different in the alkyl group.

[0112] (Item 19) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0113] X 1 CR 1 or N,

[0114] X 2 CR 2 or N,

[0115] X 3 CR 3 or N,

[0116] X 4 CR 4 or N,

[0117] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1 CR 1 , and X 2 CR 2 , and X 3 CR 3 ,

[0118] R 1 、R 2 、R 3 and R 4 Each independently

[0119] (1) Hydrogen atoms,

[0120] (2) Halogen,

[0121] (3) cyano,

[0122] (4) C 1-6 Alkoxy, or

[0123] (5) C 1-6 Alkyl (the alkyl group is optionally selected from halogen, hydroxy, and C 1-6 substituted by 1 to 3 identical or different substituents in the alkoxy group),

[0124] Y is

[0125] (1) optionally selected from halogen, hydroxy, amino, dimethylamino, C 3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocycle, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 1-6 alkyl,

[0126] (2) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocycle, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 3-10 alicyclic groups,

[0127] (3) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C 3-6 Alicyclic groups and C 1-6 a 4- to 10-membered nitrogen-containing non-aromatic heterocyclic group substituted with the same or different 1-3 substituents in the alkoxy group,

[0128] (4) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 6-10 Aryl, or

[0129] (5) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 5- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group,

[0130] Z is optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy, and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 6- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0131] (Item 20)

[0132] X 1 CR 1 ,

[0133] X 2 CR 2 ,

[0134] X 3 CR 3 ,

[0135] X 4 CR 4 ,

[0136] R 1 、R 3 and R 4 are all hydrogen atoms,

[0137] R 2 for

[0138] (1) Hydrogen atoms,

[0139] (2) Fluorine,

[0140] (3) Chlorine,

[0141] (4) Cyano

[0142] (5) C 1-6 Alkoxy, or

[0143] (6) C 1-6 Alkyl (the alkyl group is optionally selected from halogen, hydroxy, and C 1-6 substituted by 1 to 3 identical or different substituents in the alkoxy group),

[0144] Y is

[0145] (1) optionally selected from fluorine, C 3-6 alicyclic group, a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic group, and the phenyl group are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 1-3 alkyl,

[0146] (2) C optionally substituted with 1 to 3 fluorine groups, fluorine, amino, dimethylamino,1-3 Alkyl, 5-6 membered nitrogen-containing non-aromatic heterocyclic group, phenyl (the nitrogen-containing non-aromatic heterocyclic group, and the phenyl are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 3-6 alicyclic groups,

[0147] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0148] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0149] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 5-membered or 6-membered heteroaryl group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0150] Z is optionally selected from fluorine, chlorine, cyano, C 1-6 Alkoxy, and 1 C 1-6 Alkoxy or C optionally substituted by 1 to 3 fluorine groups 1-3 A 6- to 10-membered heteroaryl group containing 1 to 2 atoms independently selected from nitrogen and oxygen atoms and substituted with 1 to 3 substituents which are the same or different in the alkyl group.

[0151] (Item 21) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0152] X 1 CR 1 ,

[0153] X 2 CR 2 ,

[0154] X 3 CR 3 ,

[0155] X 4 CR 4 ,

[0156] R 1 、R 3 and R 4 are all hydrogen atoms,

[0157] R 2 is fluorine or cyano,

[0158] Y is

[0159] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0160] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0161] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0162] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0163] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 5-membered or 6-membered heteroaryl group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0164] Z is optionally selected from fluorine, chlorine, cyano, C 1-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine 1-3 A 6- to 10-membered heteroaryl group containing 1 to 2 atoms independently selected from nitrogen and oxygen atoms, substituted with 1 to 3 identical or different substituents in the alkyl group.

[0165] (Item 22) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0166] X 1 CR 1 ,

[0167] X 2 CR 2 ,

[0168] X 3 CR3 ,

[0169] X 4 CR 4 ,

[0170] R 1 、R 3 and R 4 are all hydrogen atoms,

[0171] R 2 is fluorine or cyano,

[0172] Y is

[0173] (1) C optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino and 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0174] (2) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0175] (3) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0176] (4) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 a 5-membered or 6-membered heteroaryl group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0177] Z is optionally selected from fluorine, chlorine, cyano, methoxy, and C optionally substituted with 1 to 3 fluorine 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

[0178] (Item 23) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0179] X 1 CR 1 ,

[0180] X 2 CR 2 ,

[0181] X 3 CR 3 ,

[0182] X 4CR 4 ,

[0183] R 1 、R 3 and R 4 are all hydrogen atoms,

[0184] R 2 is fluorine or cyano,

[0185] Y is

[0186] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0187] (2) a 5-membered or 6-membered heteroaryl group optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl,

[0188] Z is a C group optionally selected from fluorine, chlorine, cyano and optionally substituted with 1 to 3 fluorine groups. 1-3 Pyridyl substituted with 1 to 3 substituents which may be the same or different in the alkyl group.

[0189] (Item 24) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0190] X 1 CR 1 ,

[0191] X 2 CR 2 ,

[0192] X 3 CR 3 ,

[0193] X 4 CR 4 ,

[0194] R 1 、R 3 and R 4 are all hydrogen atoms,

[0195] R 2 is fluorine or cyano,

[0196] Y is

[0197] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0198] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 2-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6alicyclic or phenylcyclopropyl,

[0199] (3) C optionally substituted with 1 to 3 fluorine groups, amino, dimethylamino, 2-3 Alkyl and phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) in 4 to 6 membered nitrogen-containing non-aromatic heterocyclic group, phenyloxetane or tetrahydropyranyl,

[0200] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and optionally substituted by 1 to 3 fluorine groups C 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0201] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group,

[0202] Z is optionally selected from fluorine, chlorine, cyano, C 2-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine 1-3 A 6- to 10-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0203] (Item 25) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0204] X 1 CR 1 ,

[0205] X 2 CR 2 ,

[0206] X 3 CR 3 ,

[0207] X 4 CR 4 ,

[0208] R 1 、R 3 and R 4 are all hydrogen atoms,

[0209] R 2 is fluorine or cyano,

[0210] Y is

[0211] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0212] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 2-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic or phenylcyclopropyl,

[0213] (3) C optionally substituted with 1 to 3 fluorine groups, amino, dimethylamino, 2-3 Alkyl and phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) in 4 to 6 membered nitrogen-containing non-aromatic heterocyclic group, phenyloxetane or tetrahydropyranyl,

[0214] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0215] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group,

[0216] Z is optionally selected from fluoro, cyano, C 2-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine 1-3 6-10 membered heteroaryl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl substituted by 1 to 3 identical or different substituents in the alkyl group.

[0217] (Item 26) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0218] X 1 CR 1 ,

[0219] X 2 CR 2 ,

[0220] X 3 CR 3 ,

[0221] X 4 CR 4 ,

[0222] R 1 、R 3 and R 4 are all hydrogen atoms,

[0223] R 2 is fluorine or cyano,

[0224] Y is

[0225] (1) C optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino and 2-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0226] (2) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 2-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0227] (3) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0228] (4) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 a 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group,

[0229] Z is a C group optionally selected from fluorine, chlorine, cyano and optionally substituted with 1 to 3 fluorine groups. 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

[0230] (Item 27) The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0231] X 1 CR 1 ,

[0232] X 2 CR 2 ,

[0233] X 3 CR 3 ,

[0234] X 4 CR 4 ,

[0235] R 1 、R 3 and R 4are all hydrogen atoms,

[0236] R 2 is fluorine or cyano,

[0237] Y is

[0238] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0239] (2) a 6-membered heteroaryl group optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl,

[0240] Z is optionally selected from fluorine, chlorine, cyano, and C optionally substituted with 1 to 3 fluorines. 1-3 Pyridyl substituted with 1 to 3 substituents which may be the same or different in the alkyl group.

[0241] (Item 24) The compound according to Items 1 to 23, Item 11a, Item 14a, Item 15a, or Item 15b, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

[0242] 4-oxo-3-phenyl-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile (Example 3),

[0243] 6-fluoro-2-((5-fluoropyridin-3-yl)amino)-3-(o-tolyl)quinazolin-4(3H)-one (Example 4),

[0244] 6-chloro-2-((2-methoxypyridin-3-yl)amino)-3-phenylquinazolin-4(3H)-one (Example 10),

[0245] 6-fluoro-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 12),

[0246] 3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 14),

[0247] 6-chloro-3-(2-chlorophenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 15),

[0248] 6-chloro-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 31),

[0249] 6,8-difluoro-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 32),

[0250] 6-fluoro-3-(pyridin-3-yl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 35),

[0251] 6-chloro-3-phenyl-2-(pyrazin-2-ylamino)quinazolin-4(3H)-one (Example 38),

[0252] 6-fluoro-3-phenyl-2-(pyrazin-2-ylamino)quinazolin-4(3H)-one (Example 39),

[0253] 6-fluoro-2-((5-fluoropyridin-3-yl)amino)-3-phenylquinazolin-4(3H)-one (Example 40),

[0254] 5-((6-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)amino)nicotinonitrile (Example 41),

[0255] 6-methyl-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 42),

[0256] 2-((5-chloropyridin-3-yl)amino)-6-fluoro-3-phenylquinazolin-4(3H)-one (Example 45),

[0257] 6-chloro-3-(2-fluorophenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 51),

[0258] 2-((1-methyl-1H-indazol-6-yl)amino)-3-phenylquinazolin-4(3H)-one (Example 54),

[0259] 2-(Imidazolo[1,5-a]pyridin-8-ylamino)-3-phenylquinazolin-4(3H)-one (Example 69),

[0260] 3-(4-methoxy-2-methylphenyl)-4-oxo-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile (Example 102),

[0261] 3-(5-fluoro-2-methylphenyl)-4-oxo-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile (Example 104),

[0262] 6-fluoro-2-(pyridin-3-ylamino)-3-(p-tolyl)quinazolin-4(3H)-one (Example 105),

[0263] 6-fluoro-2-(pyridin-3-ylamino)-3-(o-tolyl)quinazolin-4(3H)-one (Example 107),

[0264] 6-fluoro-3-(2-fluorophenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 108),

[0265] 4-oxo-2-(pyridin-3-ylamino)-3-(o-tolyl)-3,4-dihydroquinazoline-6-carbonitrile (Example 109),

[0266] 6-fluoro-3-(2-fluorophenyl)-2-((5-fluoropyridin-3-yl)amino)quinazolin-4(3H)-one (Example 111),

[0267] 2-((5-fluoropyridin-3-yl)amino)-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-carbonitrile (Example 112),

[0268] 3-(2-fluorophenyl)-2-((5-fluoropyridin-3-yl)amino)-4-oxo-3,4-dihydroquinazoline-6-carbonitrile (Example 113),

[0269] 2-((5-fluoropyridin-3-yl)amino)-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-carbonitrile (Example 114),

[0270] 6-fluoro-2-((4-fluoropyridin-2-yl)amino)-3-phenylquinazolin-4(3H)-one (Example 127),

[0271] 6-fluoro-2-((5-methylpyridin-2-yl)amino)-3-phenylquinazolin-4(3H)-one (Example 137),

[0272] 6-fluoro-2-((2-fluoropyridin-4-yl)amino)-3-phenylquinazolin-4(3H)-one (Example 141),

[0273] 6-fluoro-3-(2-methoxyphenyl)-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 142) and

[0274] 3-(2-Chlorophenyl)-6-fluoro-2-(pyridin-3-ylamino)quinazolin-4(3H)-one (Example 145).

[0275] (Item 25) A drug comprising the compound according to any one of Items 1 to 24, Item 11a, Item 14a, Item 15a, and Item 15b, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0276] (Item 26) The drug according to Item 25, which is a therapeutic or preventive drug for epilepsy or mental developmental disorders.

[0277] (Item 27) A therapeutic or preventive agent for a disorder or disease associated with abnormal neural excitability, comprising as an active ingredient the compound described in any one of Items 1 to 26, Item 11a, Item 14a, Item 15a, and Item 15b, or a pharmaceutically acceptable salt thereof.

[0278] (Item 28) The therapeutic or preventive agent according to Item 27, wherein the disorder or disease associated with abnormal neural excitability is a disease involving epilepsy or mental development disorder.

[0279] (Item 29) A pharmaceutical composition comprising the compound according to any one of Items 1 to 24, Item 11a, Item 14a, Item 15a, and Item 15b, or a pharmaceutically acceptable salt thereof.

[0280] (Item 30) The pharmaceutical composition according to Item 29, which is used for treating or preventing a disorder or disease associated with abnormal neural excitability.

[0281] (Item 31) The pharmaceutical composition according to Item 29 or 30, which is a therapeutic or preventive drug for epilepsy or mental developmental disorders.

[0282] (Item 32) A method for treating or preventing a disorder or disease associated with abnormal neural excitation, comprising administering a therapeutically or preventively effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of Items 1 to 24, Item 11a, Item 14a, Item 15a, and Item 15b to a patient in need of treatment or prevention.

[0283] (Item 33) Use of the compound according to any one of Items 1 to 24, Item 11a, Item 14a, Item 15a, and Item 15b, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic or preventive agent for a disorder or disease associated with abnormal neural excitability.

[0284] (Item 34) The compound according to any one of Items 1 to 24, Item 11a, Item 14a, Item 15a, and Item 15b, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disorder or disease associated with abnormal neural excitability.

[0285] (Item 35) A pharmaceutical composition comprising a compound according to any one of Items 1 to 24, Item 11a, Item 14a, Item 15a, and Item 15b, or a pharmaceutically acceptable salt thereof, and at least one drug selected from the group consisting of antiepileptic drugs, antidepressants, antianxiety drugs, and antipsychotic drugs.

[0286] (Item 36) A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof described in any one of Items 1 to 24, Item 11a, Item 14a, Item 15a, and Item 15b, used in combination with at least one drug selected from antiepileptic drugs, antidepressants, antianxiety drugs, or antipsychotic drugs for the treatment or prevention of disorders or diseases associated with abnormal nervous excitation.

[0287] (Item 37) A drug for treating or preventing a disorder or disease associated with abnormal neuroexcitability, comprising as an active ingredient a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0288] [Chemical Formula 19]

[0289]

[0290] [Where,

[0291] X 1 Indicates CR 1 or N,

[0292] X 2 Indicates CR 2 or N,

[0293] X 3 Indicates CR 3 or N,

[0294] X 4 Indicates CR 4 or N,

[0295] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1 CR 1 , and X2 CR 2 , and X 3 CR 3 ,

[0296] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0297] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0298] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0299] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R 6 、R 7 and R8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0300] (Item 38) A therapeutic or preventive drug for a disorder or disease associated with abnormal nerve excitability, comprising as an active ingredient a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0301] [Chemical Formula 20]

[0302]

[0303] [Where,

[0304] X 1 Indicates CR 1 or N,

[0305] X 2 Indicates CR 2 or N,

[0306] X 3 Indicates CR 3 or N,

[0307] X 4 Indicates CR 4 or N,

[0308] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1 CR 1 , and X2 CR 2 , and X 3 CR 3 ,

[0309] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0310] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0311] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0312] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R 6 、R 7 and R8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0313] (Item 39) A pharmaceutical composition, which is a therapeutic or preventive agent for a disorder or disease associated with abnormal neural excitability, comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0314] [Chemical Formula 21]

[0315]

[0316] [Where,

[0317] X 1 Indicates CR 1 or N,

[0318] X 2 Indicates CR 2 or N,

[0319] X 3 Indicates CR 3 or N,

[0320] X 4 Indicates CR 4 or N,

[0321] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1 CR 1 , and X2 CR 2 , and X 3 CR 3 ,

[0322] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0323] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0324] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0325] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R 6 、R 7 and R8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0326] (Item 40) A method for treating or preventing a disorder or disease associated with abnormal neural excitability, comprising administering a therapeutically or preventively effective amount of a compound represented by the following formula or a pharmaceutically acceptable salt thereof to a patient in need of treatment or prevention:

[0327] [Chemical Formula 22]

[0328]

[0329] [Where,

[0330] X 1 Indicates CR 1 or N,

[0331] X 2 Indicates CR 2 or N,

[0332] X 3 Indicates CR 3 or N,

[0333] X 4 Indicates CR 4 or N,

[0334] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1CR 1 , and X 2 CR 2 , and X 3 CR 3 ,

[0335] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0336] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0337] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0338] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R 6 、R7 and R 8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0339] (Item 41)

[0340] Use of a compound represented by the following formula or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic or preventive drug for a disorder or disease associated with abnormal nerve excitability,

[0341] [Chemical Formula 23]

[0342]

[0343] [Where,

[0344] X 1 Indicates CR 1 or N,

[0345] X 2 Indicates CR 2 or N,

[0346] X 3 Indicates CR 3 or N,

[0347] X 4 Indicates CR 4 or N,

[0348] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X1 CR 1 , and X 2 CR 2 , and X 3 CR 3 ,

[0349] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0350] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0351] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0352] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R6 、R 7 and R 8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0353] (Item 42) A compound represented by the following formula or a pharmaceutically acceptable salt thereof for use in treating or preventing a disorder or disease associated with abnormal neural excitability,

[0354] [Chemical Formula 24]

[0355]

[0356] [Where,

[0357] X 1 Indicates CR 1 or N,

[0358] X 2 Indicates CR 2 or N,

[0359] X 3 Indicates CR 3 or N,

[0360] X 4 Indicates CR 4 or N,

[0361] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1 CR1 , and X 2 CR 2 , and X 3 CR 3 ,

[0362] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0363] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0364] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0365] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R 6 、R7 and R 8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0366] (Item 43) A drug comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof, and at least one drug selected from the group consisting of antiepileptic drugs, antidepressants, anxiolytics, and antipsychotics.

[0367] [Chemical Formula 25]

[0368]

[0369] [Where,

[0370] X 1 Indicates CR 1 or N,

[0371] X 2 Indicates CR 2 or N,

[0372] X 3 Indicates CR 3 or N,

[0373] X 4 Indicates CR 4 or N,

[0374] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X1 CR 1 , and X 2 CR 2 , and X 3 CR 3 ,

[0375] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0376] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0377] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0378] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6 alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R6 、R 7 and R 8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0379] (Item 44) A pharmaceutical composition comprising a compound represented by the following formula or a pharmaceutically acceptable salt thereof, used in combination with at least one drug selected from the group consisting of antiepileptic drugs, antidepressants, antianxiety drugs, and antipsychotic drugs, for treating or preventing a disorder or disease associated with abnormal nervous excitability.

[0380] [Chemical Formula 26]

[0381]

[0382] [Where,

[0383] X 1 Indicates CR 1 or N,

[0384] X 2 Indicates CR 2 or N,

[0385] X 3 Indicates CR 3 or N,

[0386] X 4 Indicates CR 4 or N,

[0387] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR4 , (4) X 4 When N, X 1 CR 1 , and X 2 CR 2 , and X 3 CR 3 ,

[0388] Y represents an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered non-aromatic heterocyclic group, optionally substituted C 6-10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0389] Z represents an optionally substituted 5- to 10-membered heteroaryl group,

[0390] R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, a halogen, a cyano group, a C 1-6 Alkylsulfonyl, -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 , optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 Alkoxy,

[0391] R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 When there are multiple independently, they are the same or different and represent a hydrogen atom, C 3-6 Alicyclic group, and C 1-6 Alkyl (the alicyclic group, and the alkyl group are each independently optionally selected from halogen, hydroxyl, C 3-10 Alicyclic group, C 1-6alkoxy, and 1 to 3 substituents which are the same or different in a 4- to 6-membered non-aromatic heterocyclic group), wherein R 5 and R 6 、R 7 and R 8 、R 13 and R 14 Optionally, together with the nitrogen atom to which it is bonded, it forms a 4-10 membered nitrogen-containing non-aromatic heterocyclic ring (the ring is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 the alkoxy group is substituted by 1 to 5 substituents which may be the same or different).

[0392] In the present disclosure, the above one or more features are intended to be provided in combination in addition to the combinations explicitly stated. Those skilled in the art will recognize further embodiments and advantages of the present disclosure by reading and understanding the following detailed description as needed.

[0393] Effects of the Invention

[0394] The compounds disclosed herein have the activity of inhibiting the hyperexcitability of neural circuits, which is believed to be present in the background of various epileptic conditions. Since they exhibit strong anticonvulsant activity in epilepsy models using human cells and various animal models of spasm, they are useful as antiepileptic drugs with a broad therapeutic spectrum (for epileptic seizures (including generalized seizures such as tonic seizures, clonic seizures, absence seizures, myoclonic seizures, and atonic seizures, focal seizures, epileptic spasms, and unclassified seizures), status epilepticus, epileptic syndromes (such as Dravet syndrome, Ohtawara syndrome, West syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy, mesial temporal lobe epilepsy with hippocampal sclerosis, and Rasmussen syndrome), epilepsy due to structural or metabolic causes (such as cortical dysplasia, neurocutaneous syndromes (such as tuberous sclerosis and Stevens-Willi syndrome), and mental developmental disorders, mental disorders, cognitive impairment, etc., as well as those complicated by these diseases). Furthermore, it is expected to have an ameliorative effect on disorders or diseases based on an abnormal balance between excitatory and inhibitory signals in neural circuits, including 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, other dementias, Parkinson's disease, etc.).

[0395] Brief description of the accompanying drawings

[0396] Figure 1: Shows the powder X-ray diffraction pattern of the crystalline form I of the compound of Example 3. The horizontal axis represents the diffraction angle 2θ (°), and the vertical axis represents the count (hereinafter, for Figures 2 to 5 same).

[0397] Figure 2 : Shows the powder X-ray diffraction pattern of Form II of the compound of Example 234.

[0398] Figure 3 : Shows the powder X-ray diffraction pattern of Form III of the compound of Example 235.

[0399] Figure 4 : Shows the powder X-ray diffraction pattern of Form IV of the compound of Example 236.

[0400] Figure 5 : This shows the powder X-ray diffraction pattern of Form V of the compound of Example 237. DETAILED DESCRIPTION

[0401] The present disclosure will be described in detail below. Throughout this specification, expressions in the singular form should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (such as "a", "an", "the", etc. in the case of English) should be understood to include the concept of their plural form unless otherwise specified. In addition, the terms used in this specification should be understood to be used in the sense commonly used in the art unless otherwise specified. Therefore, all technical terms and scientific and technical terms used in this specification have the same meaning as those commonly understood by those skilled in the art in the field to which the present invention belongs, unless otherwise defined. In the event of a conflict, this specification (including definitions) takes precedence.

[0402] Regarding the groups described in this specification, such as "phenyl" and "phenyl group", whether they have the "group" or not, they are interpreted as representing the same group.

[0403] The number of substituents in a group defined as "optionally substituted" or "substituted with" is not particularly limited as long as the group is capable of substitution. Furthermore, unless otherwise specified, the description of each group also applies to the case where the group is part of another group or a substituent.

[0404] The substituent in "optionally substituted with..." is selected from the following substituent group α, and may be optionally substituted with 1 to 5 substituents, the same or different. While not particularly limited in type, when the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the atom to which the substituent is bonded in the following substituent is limited to a carbon atom.

[0405] Examples of the substituent group α include:

[0406] 1) Halogen atoms

[0407] 2) Hydroxyl

[0408] 3) Carboxyl

[0409] 4) Cyano

[0410] 5) C 1-6 alkyl

[0411] 6) C 2-6 alkenyl

[0412] 7) C 2-6 Alkynyl

[0413] 8) C 1-6 Alkoxy

[0414] 9) C 1-6 Alkylthio

[0415] 10) C 1-6 Alkylcarbonyl

[0416] 11) C 1-6 Alkylsulfonyl

[0417] wherein each substituent in 5) to 11) is optionally substituted by 1 to 5 substituents, which may be the same or different, selected from substituent group β.

[0418] 12) C 3-10 Alicyclic group

[0419] 13) C 3-10 Alicyclic oxy group

[0420] 14) C 6-10 Aryloxy

[0421] 15) 5-membered or 6-membered heteroaryloxy

[0422] 16) 4-10 membered non-aromatic heterocyclic oxy group

[0423] 17) C 3-10 Alicyclic sulfhydryl

[0424] 18) C 6-10 Arylthio

[0425] 19) 5-membered or 6-membered heteroarylthio

[0426] 20) 4-10 membered non-aromatic heterocyclic thio group

[0427] 21) C 6-10 Aryl

[0428] 22) 5-membered or 6-membered heteroaryl

[0429] 23) 4-10 membered non-aromatic heterocyclic group

[0430] 24) C 3-10 Alicyclic carbonyl

[0431] 25) C 6-10 Arylcarbonyl

[0432] 26) 5-membered or 6-membered heteroarylcarbonyl

[0433] 27) 4-10 membered non-aromatic heterocyclic carbonyl

[0434] 28) C 3-10 Alicyclic sulfonyl

[0435] 29) C 6-10 Arylsulfonyl

[0436] 30) 5-membered or 6-membered heteroarylsulfonyl

[0437] 31) 4-10 membered non-aromatic heterocyclic sulfonyl

[0438] Wherein, each substituent in 12) to 31) is optionally replaced by 1 to 5 substituents of group β or the aforementioned 1) C 1-6 Alkyl substitution,

[0439] 32) -NR 16 R 17 ,

[0440] Substituent group β is the group consisting of,

[0441] 1) Halogen atoms,

[0442] 2) Hydroxyl,

[0443] 3) Carboxyl,

[0444] 4) cyano,

[0445] 5) C 3-10 alicyclic groups,

[0446] 6) C 1-6 Alkoxy,

[0447] 7) C 3-10 Alicyclic oxygen group,

[0448] 8) C 1-6 Alkylthio,

[0449] 9) 5-membered or 6-membered heteroarylthio group,

[0450] 10) C 6-10 Aryl,

[0451] 11) 5-membered or 6-membered heteroaryl,

[0452] 12) 4-10 membered non-aromatic heterocyclic group,

[0453] 13) C 1-6 Alkylcarbonyl,

[0454] 14) C 3-10 Alicyclic carbonyl,

[0455] 15) C 6-10 Arylcarbonyl,

[0456] 16) 5-membered or 6-membered heteroarylcarbonyl,

[0457] 17) 4-10 membered non-aromatic heterocyclic carbonyl,

[0458] 18) -NR 18 R 19 、

[0459] In the substituent group β, each substituent of 5) to 17) is optionally selected from a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, a -NR 20 R 21 substituted with 1 to 5 substituents,

[0460] R 16 、R 17 、R 18 、R 19 are independently the same or different and are hydrogen or C 1-6 Alkyl (the alkyl group is optionally selected from hydroxyl, cyano, C 1-6 Alkoxy, -NR 20 R 21 substituted by 1 to 3 identical or different substituents in

[0461] R 20 、R 21 are independently the same or different and are hydrogen or C 1-6 alkyl.

[0462] As the substituent in "optionally substituted with...", preferably the following substituents can be mentioned.

[0463] Preferred examples of the substituent group α include:

[0464] 1) Halogen atoms

[0465] 2) Hydroxyl

[0466] 3) Carboxyl

[0467] 4) Cyano

[0468] 5) C 1-6 alkyl

[0469] 6) C 1-6 Alkoxy

[0470] 7) C 1-6 Alkylthio

[0471] 8) C 1-6 Alkylcarbonyl

[0472] wherein each substituent in 5) to 8) is optionally substituted by 1 to 5 substituents, which may be the same or different, selected from substituent group β.

[0473] 9) C 3-10 Alicyclic group

[0474] 10) C 3-10 Alicyclic oxy group

[0475] 11) C 6-10 Aryloxy

[0476] 12) 5-membered or 6-membered heteroaryloxy

[0477] 13) 4-10 membered non-aromatic heterocyclic oxy group

[0478] 14) C 3-10 Alicyclic sulfhydryl

[0479] 15) C 6-10 Arylthio

[0480] 16) 5-membered or 6-membered heteroarylthio

[0481] 17) 4-10 membered non-aromatic heterocyclic thio group

[0482] 18) C 6-10 Aryl

[0483] 19) 5-membered or 6-membered heteroaryl

[0484] 20) 4-10 membered non-aromatic heterocyclic group

[0485] 21) C 3-10 Alicyclic carbonyl

[0486] 22) C 6-10 Arylcarbonyl

[0487] 23) 5-membered or 6-membered heteroarylcarbonyl

[0488] 24) 4-10 membered non-aromatic heterocyclic carbonyl

[0489] Wherein, each substituent in 9) to 24) is optionally replaced by 1 to 5 substituent groups β or the aforementioned 1) C 1-6 Alkyl substitution,

[0490] 25) -NR16 R 17 ,

[0491] The substituent group β is preferably a group consisting of,

[0492] 1) Halogen atoms

[0493] 2) Hydroxyl

[0494] 3) Cyano

[0495] 4) C 3-10 Alicyclic group

[0496] 5) C 1-6 Alkoxy

[0497] 6) C 1-6 Alkylthio

[0498] 7) 5-membered or 6-membered heteroarylthio

[0499] 8) 5-membered or 6-membered heteroaryl

[0500] 9) 4-10 membered non-aromatic heterocyclic group

[0501] 10) C 1-6 Alkylcarbonyl

[0502] 11) C 3-10 Alicyclic carbonyl

[0503] 12) C 6-10 Arylcarbonyl

[0504] 13) 5-membered or 6-membered heteroarylcarbonyl

[0505] 14) 4-10 membered non-aromatic heterocyclic carbonyl

[0506] 15) -NR 18 R 19

[0507] In the substituent group β, each substituent of 4) to 14) is optionally selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups, -NR 20 R 21 substituted with 1 to 5 substituents,

[0508] R 16 、R 17 、R 18 、R 19 are independently the same or different and are hydrogen or C 1-6 Alkyl (the alkyl group is optionally selected from hydroxyl, cyano, C 1-6 Alkoxy, -NR 20 R 21 substituted by 1 to 3 substituents, which may be the same or different),

[0509] R 20 、R 21 are independently the same or different and are hydrogen or C 1-6 alkyl.

[0510] As the substituent in "optionally substituted with...", the following substituents are more preferably mentioned.

[0511] More preferably, the substituent group α includes:

[0512] 1) Halogen atoms

[0513] 2) Hydroxyl

[0514] 3) Cyano

[0515] 4) C 1-6 alkyl

[0516] 5) C 1-6 Alkoxy

[0517] 6) C 1-6 Alkylthio

[0518] 7) C 1-6 Alkylcarbonyl

[0519] wherein each substituent in 4) to 7) is optionally substituted by 1 to 5 substituents, which may be the same or different, selected from substituent group β.

[0520] 8) 5-membered or 6-membered heteroaryloxy

[0521] 9) 4-10 membered non-aromatic heterocyclic oxy group

[0522] 10) 5-membered or 6-membered heteroarylthio

[0523] 11) 4-10 membered non-aromatic heterocyclic thio group

[0524] 12) C 6-10 Aryl

[0525] 13) 5-membered or 6-membered heteroaryl

[0526] 14) 4-10 membered non-aromatic heterocyclic group

[0527] Wherein, each substituent in 4) to 14) is optionally replaced by 1 to 5 substituent groups β or the aforementioned 1) C 1-6 Alkyl substitution,

[0528] 15) -NR 16 R 17 ,

[0529] Substituent group β is more preferably

[0530] 1) Halogen atoms,

[0531] 2) Hydroxyl,

[0532] 3) cyano,

[0533] 4) -NR 18 R 19 ,

[0534] R 16 、R 17 、R 18 、R 19 are independently the same or different and are hydrogen or C 1-6 Alkyl (the alkyl group is optionally selected from hydroxyl, cyano, C 1-6 Alkoxy, -NR 20 R 21 substituted by 1 to 3 identical or different substituents in

[0535] R 20 、R 21 are independently the same or different and are hydrogen or C 1-6 alkyl.

[0536] “C 1-6 ” means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, “C 1-4 ” means the number of carbon atoms is 1 to 4.

[0537] The "hetero atom" means an oxygen atom, a nitrogen atom, a sulfur atom or the like.

[0538] A "halogen atom" refers to any atom other than a carbon atom and a hydrogen atom, and includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a fluorine atom and a chlorine atom are preferred. A "halogen atom" is sometimes referred to as "halogen."

[0539] “C 1-6 Alkyl" or "C 1-6 "Alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Alkyl, preferably "C 1-4 Alkyl", more preferably "C 1-3 Alkyl" or "C 2-3 Alkyl. As "C 1-3 Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. As "C 2-3 Specific examples of "alkyl" include ethyl, propyl, 1-methylethyl, etc. As "C 1-4 Specific examples of "alkyl" include, for example, in addition to the aforementioned "C 1-3In addition to those mentioned as specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl and the like can also be mentioned. As "C 1-6 Specific examples of "alkyl" include, for example, 1-4 In addition to those listed as specific examples of the "alkyl group", there can be mentioned pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.

[0540] “C 2-6 Alkenyl" or "C 2-6 Alkenyl refers to a linear or branched unsaturated hydrocarbon group with 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds. 2-6 Alkenyl", preferably "C 2-4 Alkenyl". As "C 2-6 Specific examples of the "alkenyl group" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.

[0541] “C 2-6 Alkynyl" or "C 2-6 Alkynyl "group" means a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds. 2-6 Alkynyl", preferably "C 2-4 Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, and 1-hexynyl.

[0542] “C 3-10 "Alicyclic group" means a monocyclic or bicyclic monovalent non-aromatic hydrocarbon ring group having 3 to 10 carbon atoms, including those having a portion of unsaturated bonds, those having a portion of bridged structures, those having a portion of spiro groups, and those having one or more carbonyl structures. "Alicyclic group" includes cycloalkyl, cycloalkenyl, and cycloalkynyl groups. As "C 3-10 Alicyclic group", preferably "C 3-6 Alicyclic group", more preferably "C 5-6 Alicyclic group". As "C 5-6 Specific examples of "alicyclic group" include cyclopentyl and cyclohexyl. 3-6 Specific examples of "alicyclic group" include, for example, 5-6 In addition to those mentioned as specific examples of "alicyclic group", cyclopropyl, cyclobutyl, etc. can also be mentioned. 3-10Specific examples of "alicyclic group" include, for example, 3-6 In addition to those exemplified as specific examples of the “alicyclic group”, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and adamantyl groups may be mentioned.

[0543] As a "C 3-10 Specific examples of the "alicyclic group" include, for example, those having the following structures, but are not limited thereto.

[0544] [Chemical Formula 27]

[0545]

[0546] In addition, "C 3-10 The term "alicyclic group" also includes compounds condensed with an aromatic ring. Specific examples include the following groups.

[0547] [Chemical Formula 28]

[0548]

[0549] “C 6-10 "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 The "aryl group" can be fused with the aforementioned "alicyclic group" or "non-aromatic heterocycle" at all possible positions. 6-10 Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. As "C 6-10 "Aryl" preferably includes phenyl. Specific examples of the condensed ring structure include the following groups.

[0550] [Chemical Formula 29]

[0551]

[0552] [Chemical formula 30]

[0553]

[0554] A "5- to 10-membered heteroaryl group" refers to a monocyclic or bicyclic aromatic heterocyclic group consisting of 5 to 10 atoms, containing 1 to 4 atoms independently selected from nitrogen, oxygen, and sulfur atoms. The "5- to 10-membered heteroaryl group" may be fused with the aforementioned "alicyclic group" or "non-aromatic heterocyclic ring" at all possible positions. Preferred examples of the "5- to 10-membered heteroaryl group" include a "5-membered heteroaryl group," a "6-membered heteroaryl group," a "5- or 6-membered heteroaryl group," a "6- to 10-membered heteroaryl group," or a "9- or 10-membered heteroaryl group." Specific examples of the "5-membered heteroaryl group" include furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, and thiadiazolyl. Specific examples of the "6-membered heteroaryl group" include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Specific examples of "5- or 6-membered heteroaryl groups" include furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Specific examples of "6- to 10-membered heteroaryl groups" include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, and triazolopyridinyl. Specific examples of "5- to 10-membered heteroaryl groups" include the aforementioned specific examples of "6- to 10-membered heteroaryl groups" and "5- or 6-membered heteroaryl groups."

[0555] In Formula 1, when Y is a "5- to 10-membered heteroaryl group", a "5- or 6-membered heteroaryl group" or a "6-membered heteroaryl group", it is bonded to a nitrogen atom on a carbon atom on the ring of the heteroaryl group.

[0556] In Formula 1, the Z group as a "5- to 10-membered heteroaryl group" or a "5- to 10-membered heteroaryl group", for example, a "pyridyl group", a "pyrimidinyl group", an "indazolyl group", or an "imidazopyridinyl group", is bonded to a nitrogen atom on a carbon atom on the ring of the Z group. In one embodiment, the 5- to 10-membered heteroaryl group, for example, the 5- to 10-membered heteroaryl group of Z, is not bonded to a nitrogen atom on the ring of the heteroaryl group.

[0557] Specific examples of the "9-membered or 10-membered heteroaryl group" include, but are not limited to, those having the following structures.

[0558] [Chemical Formula 31]

[0559]

[0560] [Chemical Formula 32]

[0561]

[0562] The aforementioned "5-membered or 6-membered heteroaryl" or "5- to 10-membered heteroaryl" may also form a 5-10The alicyclic group may form a condensed ring structure or a condensed ring structure with a 5- to 10-membered non-aromatic heterocyclic ring. Specific examples include the following groups.

[0563] [Chemical Formula 33]

[0564]

[0565] [Chemical Formula 34]

[0566]

[0567] [Chemical Formula 35]

[0568]

[0569] "4-10 membered non-aromatic heterocyclic group" means a monocyclic or bicyclic non-aromatic heterocyclic ring composed of 4 to 10 atoms, which contains 1 to 2 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms, and includes those having a portion of unsaturated bonds, those having a portion of bridged structures and / or those that are partially spiro-formed. As a "4-10 membered non-aromatic heterocyclic group", a "4-6 membered non-aromatic heterocyclic group" or a "4-10 membered nitrogen-containing non-aromatic heterocyclic group" is preferred. Specific examples of "4-6 membered non-aromatic heterocyclic groups" include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and the like. Among them, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and oxetanyl are preferred. The non-aromatic heterocyclic ring may form a condensed ring with an aryl or heteroaryl group. For example, with C 6-10 Non-aromatic heterocyclic rings also include aryl groups or rings fused with 5- or 6-membered heteroaryl groups. Furthermore, non-aromatic heterocyclic rings may contain one or more carbonyl, thiocarbonyl, sulfinyl, or sulfonyl groups. Examples of cyclic groups include lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates. The oxygen atoms of carbonyl, sulfinyl, and sulfonyl groups, and the sulfur atom of thiocarbonyl groups are not included in the number of 4-10 members (ring size) and the number of heteroatoms constituting the ring. "4- to 10-membered non-aromatic heterocyclic rings" are preferably "4- to 6-membered non-aromatic heterocyclic rings." Specific examples of "4- to 6-membered non-aromatic heterocyclic rings" include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, and tetrahydropyran. Specific examples of the "4- to 10-membered non-aryl heterocycle" include, in addition to the heterocycles listed as specific examples of the "4- to 6-membered non-aryl heterocycle" described above, heterocycles having the structures shown below.

[0570] [Chemical Formula 36]

[0571]

[0572] Specific examples of the "4- to 10-membered non-aryl heterocycle" having a partially bridged and / or spiro structure include, but are not limited to, those having the following structures.

[0573] [Chemical Formula 37]

[0574]

[0575] "Oxetane" is a monovalent group containing one oxygen in a saturated 4-membered ring, and examples thereof include phenyloxetane

[0576] [Chemical Formula 38]

[0577]

[0578] A "4- to 10-membered nitrogen-containing non-aromatic heterocycle" refers to a monocyclic or bicyclic non-aromatic heterocycle composed of 4 to 10 atoms, containing, in addition to one nitrogen atom, zero or more heteroatoms selected from oxygen, nitrogen, and sulfur atoms, which may be the same or different. These include those having a partially unsaturated bond, a partially bridged structure, and / or a partially spirocyclic structure. Preferred examples of the "4- to 10-membered nitrogen-containing non-aromatic heterocycle" include a "4- to 6-membered nitrogen-containing non-aromatic heterocycle" or a "5- or 6-membered nitrogen-containing non-aromatic heterocycle." Specific examples of the "5- or 6-membered nitrogen-containing non-aromatic heterocycle" include pyrrolidine, piperidine, piperazine, and morpholine. Specific examples of the "4- to 6-membered nitrogen-containing non-aromatic heterocycle" include, in addition to those listed above as specific examples of the "5- or 6-membered nitrogen-containing non-aromatic heterocycle," azetidine, and the like. Specific examples of the "4- to 10-membered nitrogen-containing non-aromatic heterocycle" include, in addition to those listed as specific examples of the "5- or 6-membered nitrogen-containing non-aromatic heterocycle", azetidine, azepane, azoctane, and the like.

[0579] Specific examples of the "4- to 10-membered nitrogen-containing non-aromatic heterocyclic ring" having a partially bridged and / or spiro structure include, but are not limited to, those having the following structures.

[0580] [Chemical Formula 39]

[0581]

[0582] In Formula 1, when Y is a "4- to 10-membered nitrogen-containing non-aromatic heterocyclic group" or a "5- or 6-membered nitrogen-containing non-aromatic heterocyclic group", the nitrogen atom is bonded to a carbon atom on the ring of the nitrogen-containing non-aromatic heterocyclic group.

[0583] Specific examples of the "4-membered non-aromatic heterocycle" having a partially unsaturated bond include, for example, those having the following structures, but are not limited thereto.

[0584] [Chemical Formula 40]

[0585]

[0586] Specific examples of the "5-membered non-aromatic heterocycle" having a partially unsaturated bond include, for example, those having the following structures, but are not limited thereto.

[0587] [Chemical Formula 41]

[0588]

[0589] Specific examples of the "5-membered non-aryl heterocycle" having a partially bridged structure include, but are not limited to, those having the following structures.

[0590] [Chemical Formula 42]

[0591]

[0592] Specific examples of the "5-membered non-aryl heterocycle" containing a carbonyl group, a thiocarbonyl group, and the like include, for example, those having the following structures, but are not limited thereto.

[0593] [Chemical Formula 43]

[0594]

[0595] Specific examples of the "6-membered non-aryl heterocycle" having a partially unsaturated bond include, for example, those having the following structures, but are not limited thereto.

[0596] [Chemical Formula 44]

[0597]

[0598] Specific examples of the "6-membered non-aryl heterocycle" having a partially bridged structure include, but are not limited to, those having the following structures.

[0599] [Chemical Formula 45]

[0600] .

[0601] “C 1-6 Alkoxy" or "C 1-6 "Alkoxy group" refers to "C 1-6 Alkyloxy", "C 1-6The "alkyl" part is the same as the aforementioned "C 1-6 Alkyl" has the same meaning. 1-6 Alkoxy group", preferably "C 1-4 Alkoxy" or "C 2-6 Alkoxy", more preferably "C 1-3 Alkoxy". As "C 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. As "C 1-4 Specific examples of "alkoxy" include, for example, in addition to the aforementioned "C 1-3 In addition to those listed as specific examples of "alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. can also be mentioned. 2-6 Specific examples of the "alkoxy group" include ethoxy, propoxy, 1-methylethoxy, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, pentoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, and hexyloxy. As "C 1-6 Specific examples of "alkoxy" include, for example, in addition to the aforementioned "C 1-4 In addition to those mentioned as specific examples of "alkoxy", there can be mentioned pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

[0602] “C 3-6 Alicyclic oxy" or "C 3-6 "alicyclic oxy group" means (C 3-6 Alicyclic)-O-group, the C 3-6 The alicyclic part and C 3-6 Alicyclic groups have the same meaning. 3-6 Alicyclic oxy" contains "C 3-6 Cycloalkoxy". "Cycloalkoxy" means "cycloalkyloxy", and the "cycloalkyl" part has the same meaning as the aforementioned "cycloalkyl". As "C 3-6 Specific examples of the “alicyclic oxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0603] “C 6-10 Aryloxy" C 6-10 The aryl moiety and the above C 6-10 Aryl has the same meaning as “C 6-10 Aryloxy", preferably "C6 or C 10As "C 6-10 Specific examples of the "aryloxy group" include phenoxy, 1-naphthyloxy, and 2-naphthyloxy, but are not limited thereto.

[0604] The 5-membered or 6-membered heteroaryl moiety of the "5-membered or 6-membered heteroaryloxy" has the same meaning as the "5-membered heteroaryl" or "6-membered heteroaryl" described above. Specific examples of the "5-membered or 6-membered heteroaryloxy" include, but are not limited to, pyrazolyloxy, triazolyloxy, thiazolyloxy, thiadiazolyloxy, pyridyloxy, and pyridazinyloxy.

[0605] The 4- to 10-membered non-aryl heterocyclic ring portion of a "4- to 10-membered non-aryl heterocyclic group" has the same meaning as the "4- to 10-membered non-aryl heterocyclic group" described above. A "4- to 10-membered non-aryl heterocyclic group" is preferably a "4- to 6-membered non-aryl heterocyclic group." Specific examples of "4- to 10-membered non-aryl heterocyclic groups" include, but are not limited to, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, and piperidinyloxy.

[0606] “C 1-6 Alkylthio" C 1-6 The alkyl part is the same as the above C 1-6 Alkyl has the same meaning. 1-6 Alkylthio", preferably "C 1-4 Alkylthio", more preferably "C 1-3 Alkylthio". As "C 1-6 Specific examples of the "alkylthio group" include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, and 1,2-dimethylpropylthio.

[0607] “C 3-10 Alicyclic thio" or "C 3-10 "alicyclic thio group" means (C 3-10 Alicyclic)-S-group, the C 3-10 The alicyclic part and the above C 3-10 Alicyclic groups have the same meaning. 3-10 Alicyclic thio group", preferably "C 3-6 Alicyclic thio group". As "C 3-6 Specific examples of the “alicyclic thio group” include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio.

[0608] “C 6-10 Arylthio" or "C 6-10Arylthio group" C 6-10 The aryl moiety and the above C 6-10 Aryl has the same meaning as “C 6-10 Arylthio", preferably "C6 or C 10 Arylthio". As "C 6-10 Specific examples of the "arylthio group" include phenylthio, 1-naphthylthio, 2-naphthylthio, etc., but are not limited to these.

[0609] The 5-membered or 6-membered heteroaryl moiety of a "5-membered or 6-membered heteroarylthio group" or a "5-membered or 6-membered heteroarylthio group" has the same meaning as the "5-membered heteroaryl" or "6-membered heteroaryl" described above. Specific examples of the "5-membered or 6-membered heteroarylthio group" include, but are not limited to, pyrazolylthio, triazolylthio, thiazolylthio, thiadiazolylthio, pyridylthio, and pyridazinylthio.

[0610] The 4- to 10-membered non-aryl heterocyclic ring portion of a "4- to 10-membered non-aryl heterocyclic thio group" or a "4- to 10-membered non-aryl heterocyclic thio group" has the same meaning as the "4- to 10-membered non-aryl heterocyclic ring" described above. A "4- to 10-membered non-aryl heterocyclic thio group" is preferably a "4- to 6-membered non-aryl heterocyclic thio group." Specific examples of "4- to 10-membered non-aryl heterocyclic thio groups" include, but are not limited to, tetrahydropyranylthio and piperidinylthio.

[0611] “C 1-6 Alkylcarbonyl" or "C 1-6 "Alkylcarbonyl group" means an alkylcarbonyl group replaced by the above-mentioned "C 1-6 Alkyl" substituted carbonyl. As "C 1-6 Alkylcarbonyl", preferably "C 1-4 Alkylcarbonyl. As "C 1-6 Specific examples of the "alkylcarbonyl group" include, but are not limited to, acetyl, propionyl, and butyryl.

[0612] “C 3-10 Alicyclic carbonyl" or "C 3-10 "Alicyclic carbonyl group" means an alicyclic carbonyl group 3-10 Alicyclic group" substituted carbonyl. As "C 3-10 Alicyclic carbonyl", preferably "C 3-6 Alicyclic carbonyl. As "C 3-10 Specific examples of the "alicyclic carbonyl group" include, but are not limited to, cyclopropylcarbonyl and cyclopentylcarbonyl.

[0613] “C 6-10 Arylcarbonyl" or "C 6-10 "Arylcarbonyl group" means an arylcarbonyl group replaced by the above-mentioned "C 6-10Aryl" substituted carbonyl. As "C 6-10 Arylcarbonyl", preferably "C6 or C 10 Arylcarbonyl. As "C 6-10 Specific examples of the "arylcarbonyl group" include benzoyl, 1-naphthylcarbonyl, and 2-naphthylcarbonyl, but are not limited thereto.

[0614] A "5-membered or 6-membered heteroarylcarbonyl group" or a "5-membered or 6-membered heteroarylcarbonyl group" refers to a carbonyl group substituted with the above-mentioned "5-membered or 6-membered heteroaryl group." Specific examples of the "5-membered or 6-membered heteroarylcarbonyl group" include, but are not limited to, pyrazolylcarbonyl, triazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl, pyridylcarbonyl, and pyridazinylcarbonyl groups.

[0615] A "4- to 10-membered non-aryl heterocyclic carbonyl group" or a "4- to 10-membered non-aryl heterocyclic carbonyl group" refers to a carbonyl group substituted with the above-mentioned "4- to 10-membered non-aryl heterocyclic ring." A "4- to 10-membered non-aryl heterocyclic carbonyl group" is preferably a "4- to 6-membered non-aryl heterocyclic carbonyl group." Specific examples of "4- to 10-membered non-aryl heterocyclic carbonyl groups" include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, and morpholinylcarbonyl groups.

[0616] “C 1-6 Alkylsulfonyl" or "C 1-6 "Alkylsulfonyl group" means an alkylsulfonyl group replaced by the above-mentioned "C 1-6 Alkyl" substituted sulfonyl. As "C 1-6 Alkylsulfonyl", preferably "C 1-4 Alkylsulfonyl. As "C 1-6 Specific examples of the "alkylsulfonyl group" include, but are not limited to, methylsulfonyl, propionylsulfonyl, and butyrylsulfonyl.

[0617] “C 3-10 Alicyclic sulfonyl" or "C 3-10 "Alicyclic sulfonyl group" means a group replaced by the above-mentioned "C 3-10 Alicyclic group" substituted sulfonyl. As "C 3-10 Alicyclic sulfonyl", preferably "C 3-6 Alicyclic sulfonyl. As "C 3-10 Specific examples of the “alicyclic sulfonyl group” include, but are not limited to, a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, and a cyclohexylsulfonyl group.

[0618] “C 6-10 Arylsulfonyl" or "C 6-10 "Arylsulfonyl group" means an arylsulfonyl group replaced by the above-mentioned "C 6-10 Aryl" substituted sulfonyl. As "C 6-10Arylsulfonyl", preferably "C6 or C 10 Arylsulfonyl. As "C 6-10 Specific examples of the “arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl, but are not limited thereto.

[0619] The "5-membered or 6-membered heteroarylsulfonyl group" or "5-membered or 6-membered heteroarylsulfonyl group" means a sulfonyl group substituted with the above-mentioned "5-membered or 6-membered heteroaryl group". Specific examples of the "5-membered or 6-membered heteroarylsulfonyl group" include pyrazolylsulfonyl, triazolylsulfonyl, thiazolylsulfonyl, thiadiazolylsulfonyl, pyridylsulfonyl, and pyridazinylsulfonyl.

[0620] 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 embodiments of , Y and Z are described below, but the technical scope of the present disclosure is not limited to the scope of the compounds listed below.

[0621] As X 1 A preferred embodiment of the present invention includes CR 1 .

[0622] As X 2 A preferred embodiment of the present invention includes CR 2 .

[0623] As X 3 A preferred embodiment of the present invention includes CR 3 .

[0624] As X 4 A preferred embodiment of the present invention includes CR 4 .

[0625] As R 1 、R 2 、R 3 and R 4 The preferred embodiment includes:

[0626] (1) Hydrogen atoms,

[0627] (2) Fluorine,

[0628] (3) cyano,

[0629] (4) C 1-6 Alkoxy, or

[0630] (5) C 1-6Alkyl (the alkyl group is optionally selected from halogen, hydroxy, and C 1-6 The alkoxy group is substituted by 1 to 3 substituents which may be the same or different.

[0631] As R 1 、R 2 、R 3 and R 4 A more preferred embodiment of the present invention includes:

[0632] (1) Hydrogen atoms,

[0633] (2) Fluorine

[0634] (3) Cyano group.

[0635] As R 1 、R 3 and R 4 A further preferred embodiment of includes a hydrogen atom.

[0636] As R 2 A further preferred embodiment of includes fluorine and cyano.

[0637] Preferred embodiments of Y include:

[0638] (1) optionally selected from halogen, hydroxy, amino, dimethylamino, C 3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocycle, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 1-6 alkyl,

[0639] (2) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C 3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocycle, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 3-10 alicyclic groups,

[0640] (3) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C 3-6 Alicyclic groups and C 1-6 a 4- to 10-membered non-aromatic heterocyclic group substituted with 1 to 3 identical or different substituents in the alkoxy group,

[0641] (4) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 6-10 Aryl, or

[0642] (5) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 5- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0643] Preferred embodiments of Y include:

[0644] (1) optionally selected from fluorine, C 3-6 alicyclic group, a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic ring, and the phenyl group are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5-membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 1-3 alkyl,

[0645] (2) C optionally substituted with 1 to 3 fluorine groups, fluorine, amino, dimethylamino, 2-3 Alkyl, 5-6 membered nitrogen-containing non-aromatic heterocyclic group, phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with 1 to 3 substituents which are the same or different), C 5-6 Alicyclic or phenylcyclopropyl

[0646] (3) C optionally substituted with 1 to 3 fluorine groups, amino, dimethylamino, 2-3 Alkyl and phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with 1 to 3 substituents which are the same or different, 4 to 6-membered nitrogen-containing non-aromatic heterocyclic group, phenyloxetane or tetrahydropyranyl,

[0647] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0648] (5) optionally selected from halogen, cyano, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 A 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0649] In addition, as a preferred embodiment of Y, there are also mentioned: (1) optionally selected from fluorine, C 3-6 alicyclic group, a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic ring, and the phenyl group are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 1-3 alkyl,

[0650] (2) C optionally substituted with 1 to 3 fluorine groups, fluorine, amino, dimethylamino, 1-3 Alkyl, 5-6 membered nitrogen-containing non-aromatic heterocyclic group, phenyl (the nitrogen-containing non-aromatic heterocyclic group and the phenyl are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 3-6 alicyclic groups,

[0651] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0652] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0653] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 A 5-membered or 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0654] As a more preferable embodiment of Y, the following can be mentioned:

[0655] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0656] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0657] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0658] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0659] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 A 5-membered or 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0660] As a further preferred embodiment of Y, there can be mentioned:

[0661] (1) C optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino and 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0662] (2) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0663] (3) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0664] (4) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 A 5-membered or 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0665] As a further preferred embodiment of Y, there can be mentioned:

[0666] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0667] (2) A 5-membered or 6-membered heteroaryl group optionally substituted by 1 to 2 substituents which are the same or different and are selected from fluorine, cyano, methoxy and methyl.

[0668] The most preferred embodiment of Y includes:

[0669] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0670] (2) A 6-membered heteroaryl group optionally substituted by 1 to 2 substituents which are the same or different and selected from fluorine, cyano, methoxy and methyl.

[0671] Preferred embodiments of Z include: optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy, and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 6- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0672] Preferred embodiments of Z include: optionally selected from halogen, cyano, C 2-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 6- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0673] Preferred embodiments of Z include: optionally selected from fluorine, cyano, C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group), a 6- to 10-membered heteroaryl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an isoxazolyl group or a thiadiazolyl group.

[0674] As a more preferred embodiment of Z, fluorine, chlorine, cyano, C 1-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine 1-3 A 6- to 10-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0675] As a further preferred embodiment of Z, there can be mentioned: C optionally substituted with 1 to 3 fluorine groups, fluorine, chlorine, cyano, methoxy, and 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

[0676] As a further preferred embodiment of Z, there are mentioned: C optionally substituted with 1 to 3 fluorine groups, fluorine, chlorine, cyano, and 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

[0677] The most preferred embodiment of Z includes: C optionally substituted with 1 to 3 fluorine groups, optionally fluorine groups, optionally chlorine groups, and cyano groups. 1-3 Pyridyl substituted with 1 to 3 substituents which may be the same or different in the alkyl group.

[0678] As one embodiment of the compound represented by formula (1), the following (A) can be mentioned.

[0679] (A) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0680] X 1 CR 1 or N,

[0681] X 2 CR 2 or N,

[0682] X 3 CR 3 or N,

[0683] X 4 CR 4 or N,

[0684] Among them, (1)X 1 When N, X 2 CR 2 , and X 3 CR 3 , and X 4 CR 4 , (2) X 2 When N, X 1 CR 1 , and X 3 CR 3 , and X 4 CR 4 , (3) X 3 When N, X 1 CR 1 , and X 2 CR 2 , and X 4 CR 4 , (4) X 4 When N, X 1 CR 1 , and X 2 CR 2 , and X 3 CR 3 ,

[0685] R 1 、R 2 、R 3 and R 4 Each independently

[0686] (1) Hydrogen atoms,

[0687] (2) Halogen,

[0688] (3) cyano,

[0689] (4) C 1-6 Alkoxy, or

[0690] (5) C 1-6 Alkyl (the alkyl group is optionally selected from halogen, hydroxy, and C 1-6 substituted by 1 to 3 identical or different substituents in the alkoxy group),

[0691] Y is (1) optionally selected from halogen, hydroxy, amino, dimethylamino, C 3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocycle, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 1-6 alkyl,

[0692] (2) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C 3-6 Alicyclic group, 4-10 membered nitrogen-containing non-aromatic heterocyclic group, C 1-6 Alkoxy, C 6-10 Aryl (the alicyclic group, the nitrogen-containing non-aromatic heterocycle, the alkoxy group, and the aryl group are each independently optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6 substituted with the same or different 1 to 3 substituents in the alkoxy group), and a 5- to 10-membered heteroaryl group (the heteroaryl group is optionally selected from halogen, cyano, C 3-6 Alicyclic group, C optionally substituted by 1 to 5 fluorine groups 1-6 Alkyl, and C 1-6substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 3-10 alicyclic groups,

[0693] (3) optionally substituted with 1 to 5 fluorine groups, selected from halogen, hydroxy, amino, dimethylamino, C 1-6 Alkyl, C 3-6 Alicyclic groups and C 1-6 a 4- to 10-membered nitrogen-containing non-aromatic heterocyclic group substituted with the same or different 1-3 substituents in the alkoxy group,

[0694] (4) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 substituted by the same or different 1 to 3 substituents in the alkoxy group) and substituted by the same or different 1 to 3 substituents in the C 6-10 Aryl, or

[0695] (5) optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy and C 1-6 Alkyl (the alkoxy and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 5- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group,

[0696] Z is optionally selected from halogen, cyano, dimethylamino, C 1-6 Alkoxy, and C 1-6 Alkyl (the alkoxy, and the alkyl are each independently optionally selected from halogen, hydroxy, and C 1-6 a 6- to 10-membered heteroaryl group substituted with the same or different 1 to 3 substituents in the alkoxy group.

[0697] One embodiment of the compound represented by formula (1) includes the following (B).

[0698] (B) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0699] X 1 CR 1 ,

[0700] X 2 CR 2 ,

[0701] X 3 CR 3 ,

[0702] X 4 CR 4 ,

[0703] R 1 、R 3 and R 4 are all hydrogen atoms,

[0704] R 2 for

[0705] (1) Hydrogen atoms,

[0706] (2) Fluorine,

[0707] (3) Chlorine,

[0708] (4) Cyano

[0709] (5) C 1-6 Alkoxy, or

[0710] (6) C 1-6 Alkyl (the alkyl group is optionally selected from halogen, hydroxy, and C 1-6 substituted by 1 to 3 identical or different substituents in the alkoxy group),

[0711] Y is

[0712] (1) optionally selected from fluorine, C 3-6 alicyclic group, a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group, a phenyl group (the alicyclic group, the nitrogen-containing non-aromatic heterocyclic group, and the phenyl group are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C 1-3 alkyl,

[0713] (2) C optionally substituted with 1 to 3 fluorine groups, fluorine, amino, dimethylamino, 1-3 Alkyl, 5-6 membered nitrogen-containing non-aromatic heterocyclic group, phenyl (the nitrogen-containing non-aromatic heterocyclic group, and the phenyl are each independently optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with the same or different 1 to 3 substituents) and 5 to 6 membered heteroaryl (the heteroaryl is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy (substituted with 1 to 3 substituents which are the same or different) substituted with 1 to 3 substituents which are the same or different C3-6 alicyclic groups,

[0714] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0715] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0716] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 5-membered or 6-membered heteroaryl group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0717] Z is optionally selected from fluorine, chlorine, cyano, C 1-6 Alkoxy, and 1 C 1-6 Alkoxy or C optionally substituted by 1 to 3 fluorine groups 1-3 A 6- to 10-membered heteroaryl group containing 1 to 2 atoms independently selected from nitrogen and oxygen atoms and substituted with 1 to 3 substituents which are the same or different in the alkyl group.

[0718] One embodiment of the compound represented by formula (1) includes the following (C).

[0719] (C) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0720] X 1 CR 1 ,

[0721] X 2 CR 2 ,

[0722] X 3 CR 3 ,

[0723] X 4 CR 4 ,

[0724] R 1 、R 3 and R 4 are all hydrogen atoms,

[0725] R 2 is fluorine or cyano,

[0726] Y is

[0727] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0728] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0729] (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0730] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0731] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 5-membered or 6-membered heteroaryl group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0732] Z is optionally selected from fluorine, chlorine, cyano, C 1-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine 1-3 A 6- to 10-membered heteroaryl group containing 1 to 2 atoms independently selected from nitrogen and oxygen atoms and substituted with 1 to 3 substituents which are the same or different in the alkyl group.

[0733] One embodiment of the compound represented by formula (1) includes the following (D).

[0734] (D) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0735] X 1 CR 1 ,

[0736] X 2 CR 2 ,

[0737] X 3 CR 3 ,

[0738] X 4 CR 4 ,

[0739] R 1 、R3 and R 4 are all hydrogen atoms,

[0740] R 2 is fluorine or cyano,

[0741] Y is

[0742] (1) C optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino and 1-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0743] (2) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0744] (3) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0745] (4) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 a 5-membered or 6-membered heteroaryl group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0746] Z is optionally selected from fluorine, chlorine, cyano, methoxy, and C optionally substituted with 1 to 3 fluorine 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

[0747] One embodiment of the compound represented by formula (1) includes the following (E).

[0748] (E) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0749] X 1 CR 1 ,

[0750] X 2 CR 2 ,

[0751] X 3 CR 3 ,

[0752] X 4 CR 4 ,

[0753] R 1 、R3 and R 4 are all hydrogen atoms,

[0754] R 2 is fluorine or cyano,

[0755] Y is

[0756] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0757] (2) a 5-membered or 6-membered heteroaryl group optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl,

[0758] Z is optionally selected from fluorine, chlorine, cyano, and C optionally substituted with 1 to 3 fluorines. 1-3 Pyridyl substituted with 1 to 3 substituents which may be the same or different in the alkyl group.

[0759] As one embodiment of the compound represented by formula (1), the following (F) can be mentioned.

[0760] (F) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0761] X 1 CR 1 ,

[0762] X 2 CR 2 ,

[0763] X 3 CR 3 ,

[0764] X 4 CR 4 ,

[0765] R 1 、R 3 and R 4 are all hydrogen atoms,

[0766] R 2 is fluorine or cyano,

[0767] Y is

[0768] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0769] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 2-3 Alkyl substituted with 1 to 3 identical or different substituents, C 5-6 alicyclic or phenylcyclopropyl,

[0770] (3) C optionally substituted with 1 to 3 fluorine groups, amino, dimethylamino, 2-3 Alkyl and phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with 1 to 3 substituents which are the same or different, 4 to 6-membered nitrogen-containing non-aromatic heterocyclic group, phenyloxetane or tetrahydropyranyl,

[0771] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0772] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group,

[0773] Z is optionally selected from fluorine, chlorine, cyano, C 2-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine 1-3 A 6- to 10-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group.

[0774] One embodiment of the compound represented by formula (1) includes the following (G).

[0775] (G) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0776] X 1 CR 1 ,

[0777] X 2 CR 2 ,

[0778] X 3 CR 3 ,

[0779] X 4 CR 4 ,

[0780] R 1 、R 3 and R 4 are all hydrogen atoms,

[0781] R 2 is fluorine or cyano,

[0782] Y is

[0783] (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl,

[0784] (2) optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino, and C 2-3 Alkyl substituted with 1 to 3 identical or different substituents, C 5-6 alicyclic or phenylcyclopropyl,

[0785] (3) C optionally substituted with 1 to 3 fluorine groups, amino, dimethylamino, 2-3 Alkyl and phenyl (the phenyl group is optionally selected from fluorine, cyano, C 1-3 alkyl, and methoxy substituted with 1 to 3 substituents which are the same or different, 4 to 6-membered nitrogen-containing non-aromatic heterocyclic group, phenyloxetane or tetrahydropyranyl,

[0786] (4) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or

[0787] (5) optionally selected from halogen, cyano, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 a 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group,

[0788] Z is optionally selected from fluoro, cyano, C 2-6 Alkoxy, and C optionally substituted by 1 to 3 fluorine 1-3 alkyl, 6- to 10-membered heteroaryl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl or thiadiazolyl.

[0789] As one embodiment of the compound represented by formula (1), the following (H) can be mentioned.

[0790] (H) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0791] X 1 CR 1 ,

[0792] X 2 CR 2 ,

[0793] X 3 CR 3 ,

[0794] X 4 CR 4 ,

[0795] R 1 、R 3 and R 4 are all hydrogen atoms,

[0796] R 2 is fluorine or cyano,

[0797] Y is

[0798] (1) C optionally substituted with 1 to 3 fluorine groups, selected from fluorine, amino, dimethylamino and 2-3 The same or different 1 to 3 substituents in the alkyl group substituted C 5-6 alicyclic groups,

[0799] (2) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 2-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group,

[0800] (3) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or

[0801] (4) optionally selected from halogen, cyano, methoxy and C optionally substituted with 1 to 3 fluorine 1-3 a 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkyl group,

[0802] Z is a C group optionally selected from fluorine, chlorine, cyano and optionally substituted with 1 to 3 fluorine groups. 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

[0803] One embodiment of the compound represented by formula (1) includes the following (I).

[0804] (I) The following compound or a pharmaceutically acceptable salt thereof, wherein:

[0805] X 1 CR 1 ,

[0806] X 2 CR 2 ,

[0807] X 3 CR 3 ,

[0808] X 4 CR 4 ,

[0809] R 1 、R 3 and R 4 are all hydrogen atoms,

[0810] R 2 is fluorine or cyano,

[0811] Y is

[0812] (1) phenyl optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl, or

[0813] (2) a 6-membered heteroaryl group optionally substituted by 1 to 2 substituents, which may be the same or different, selected from fluorine, cyano, methoxy and methyl,

[0814] Z is optionally selected from fluorine, chlorine, cyano, and C optionally substituted with 1 to 3 fluorines. 1-3 Pyridyl substituted with 1 to 3 substituents which may be the same or different in the alkyl group.

[0815] Examples of "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, hydroiodides, nitrates, and phosphates, and organic acid salts such as citrates, oxalates, phthalates, fumarates, maleates, succinates, malates, acetates, formates, propionates, benzoates, trifluoroacetates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, and camphorsulfonates. Base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, and aluminum salts, and 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-dibenzylethylamine. Furthermore, examples of the "pharmaceutically acceptable salt" include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0816] Suitable salts of the starting compounds and intermediates, and salts acceptable as pharmaceutical raw materials are conventional non-toxic salts. Such salts include 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, pyridinium salt, picoline salt, dicyclohexylamine salt, or N,N'-dibenzylethylenediamine salt), and can be appropriately selected by those skilled in the art.

[0817] When a salt of the compound of the present disclosure is desired, if the compound of the present disclosure is obtained as a salt, it can be directly purified. If it is obtained in a free form, it can be dissolved or suspended in a suitable organic solvent, and an acid or base can be added to form a salt by a conventional method.

[0818] In the present disclosure, deuterated forms obtained by converting any one or two or more 1H groups of the compound represented by formula (1) to 2H (D) are also included in the compound represented by formula (1).

[0819] The present disclosure includes compounds represented by formula (1), or pharmaceutically acceptable salts thereof. Furthermore, the compounds of the present disclosure may exist in the form of hydrates and / or solvates with various solvents (e.g., ethanolates), and therefore these hydrates and / or solvates are also included in the compounds of the present disclosure. Furthermore, the present disclosure also includes all tautomers, all existing stereoisomers, and all crystalline forms of the compound (1) of the present disclosure, as well as mixtures thereof.

[0820] Compound (1) of the present disclosure may contain optical isomers based on the optically active center, atropisomers based on axial or planar chirality resulting from the restraint of intramolecular rotation, other stereoisomers, tautomers, and geometric isomers, and all possible isomers and mixtures thereof are included within the scope of the present disclosure.

[0821] In particular, optical isomers and atropisomers can be obtained in racemic form, or when using optically active starting materials or intermediates, can be obtained in optically active form. As required, in the appropriate stage of the following manufacturing method, the racemate of the corresponding raw material, intermediate or final product can be physically or chemically split into their optical enantiomers by using a method using an optically active column, a fractional crystallization method or other known separation methods. Specifically, for example, in a diastereoisomer method, two diastereomers are formed from a racemate by the reaction using an optically active resolving agent. The different diastereomers usually have different physical properties and can therefore be split by known methods such as fractional crystallization.

[0822] The method for producing the compound of the present disclosure will be described below, but the method for producing the compound of the present disclosure is not limited thereto.

[0823] The compounds disclosed herein can be manufactured by, for example, the following manufacturing methods, but are not limited thereto. These manufacturing methods can be suitably modified based on the knowledge of a technician familiar with organic synthetic chemistry. In the following manufacturing methods, the compounds used as raw materials can be used as long as they do not affect the reaction.

[0824] In the following production methods, even if the use of a protecting group is not specifically indicated, when any functional group other than the reaction site changes under the reaction conditions or when it is not suitable for post-reaction treatment, the functional group other than the reaction site may be protected as needed, and deprotected after the reaction is completed or after a series of reactions, thereby obtaining the target compound. As protecting groups that can be used in these processes, those described in the literature (TW Greene and PGM Wuts, "Protective Group in Organic Synthesis", 3 rd Ed., John Wiley and Sons, Inc., New York (1999)) etc. In addition, the introduction and removal of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, the method described in the above-mentioned literature) or a method based thereon.

[0825] The starting materials and intermediates in the following manufacture methods can be purchased as commercially available products, or can be synthesized and obtained according to the method described in the known literature or by known compounds according to a known method. In addition, these starting materials and intermediates can also be used as long as they do not affect the reaction.

[0826] The intermediates and target compounds in the following production methods can also be transformed into other compounds included in the present disclosure by appropriately transforming their functional groups. The functional group transformation in this case can be carried out by methods commonly used in organic synthetic chemistry (e.g., RC Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, Inc., New York (1999)) or a method based thereon.

[0827] In the production methods described below, an inert solvent refers to a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction (hereinafter sometimes referred to as "raw materials, etc."). Furthermore, even if the solvent used in each step reacts with the raw materials, etc. used in the reaction, it can be used as an inert solvent as long as the target reaction proceeds to produce the target compound.

[0828] The compound of the present disclosure represented by formula (1) can be produced by, for example, the following Production Methods 1 to 4.

[0829] Method 1

[0830] Among the compounds represented by formula (1), the compound represented by formula [A1] can be produced by, for example, the following production method.

[0831] [Chemical Formula 46]

[0832]

[0833] (Where X 11 CR 1 , X 21 CR 2 , X 31 CR 3 , X 41 CR 4 , R 1 、R 2 、R 3 、R 4 , Y, and Z have the same meanings as in item 1. ).

[0834] Compound a1 can be produced using a commercially available product or according to a known method, for example, the method described in Anais da Academia Brasileira de Ciencias 2015, 87(3), 1525-1529.

[0835] Compound a2 can be produced using a commercially available product or according to a known method, for example, the method described in Synthetic Communications (2013), 43(24), 3342-3351, Journal of Organic Chemistry (1986), 51(13), 2613-15, etc.

[0836] [Step 1-1: Cyclization reaction]

[0837] Compound a3 can be produced by reacting compound a1 with compound a2 in the presence of a suitable base, in the absence of a solvent or in a suitable solvent, at normal pressure or under pressure. As the base, it can be appropriately selected from the bases exemplified below, and preferably triethylamine or N,N-diisopropylethylamine can be mentioned. As the solvent, it can be appropriately selected from the solvents exemplified below, and preferably ethanol or isopropanol can be mentioned. The reaction time is generally 5 minutes to 48 hours, preferably 1 hour to 12 hours. The reaction temperature is generally -78°C to 150°C, preferably 25°C to 150°C.

[0838] This reaction can be carried out according to the method described in European Journal of Medicinal Chemistry 2016, 112, 106-113, Synthetic Communications 2017, 47(11), 1040-1045, etc.

[0839] [Step 1-2: Chlorination reaction]

[0840] Compound a4 can be prepared by reacting compound a3 with a suitable chlorinating agent in a solvent-free or suitable solvent. As a solvent, it can be appropriately selected from the solvents exemplified below, and preferably toluene or chloroform can be mentioned. As a chlorinating agent, it should be appropriately selected according to the type of raw material compound, and for example, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, sulfuryl chloride, etc. can be mentioned. These chlorinating agents can be used alone or in the form of a mixture of two or more, preferably a mixture of phosphorus oxychloride and phosphorus pentachloride. The reaction time is generally 5 minutes to 48 hours, preferably 1 hour to 12 hours. The reaction temperature is generally -78°C to 150°C, preferably 25°C to 150°C.

[0841] 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.

[0842] [Step 1-3: Substitution reaction]

[0843] Compound A1 can be produced by reacting Compound a4 with Compound a5 in the absence of a solvent or in an appropriate solvent, under normal pressure or under pressure. The solvent can be appropriately selected from the solvents exemplified below, and examples thereof include N-methylpyrrolidone and dimethyl sulfoxide. The reaction time is generally 5 minutes to 48 hours, preferably 5 minutes to 12 hours. The reaction temperature is generally 0°C to 250°C, preferably 25°C to 200°C. This reaction can be carried out in the presence of a base as needed. The base can be appropriately selected from the bases exemplified below, and preferably lithium (bistrimethylsilyl)amide or potassium fluoride.

[0844] Compound a5 can be produced using a commercially available product or according to a known method, for example, the method described in The Journal of Organic Chemistry 2009, 74 (12), 4542-4546, Organometallics 2017, 36 (2), 251-254, etc.

[0845] Method 2

[0846] Among the compounds represented by formula (1), the compound represented by formula [A1] can be produced by, for example, the following production method.

[0847] [Chemical Formula 47]

[0848]

[0849] (Where X 11 CR 1 , X 21 CR 2 , X 31 CR 3 , X 41 CR 4 , R 1 、R 2 、R 3 、R 4 , Y, and Z have the same meanings as in item 1. ).

[0850] [Step 2-1: Coupling reaction]

[0851] Compound A1 is prepared by coupling compound a4 with compound a5 in a suitable solvent in the presence of a catalyst and a base. Examples of the catalyst include transition metals such as palladium or their salts, complexes thereof, and substances supported on a carrier such as a polymer. As a base, it can be appropriately selected from the bases exemplified below, and preferably cesium carbonate, potassium carbonate, or sodium tert-butoxide. As a solvent, it can be appropriately selected from the solvents exemplified below, and preferably toluene, xylene, dioxane, or N,N-dimethylformamide. The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is generally 0°C to 200°C, preferably 20°C to 160°C.

[0852] This reaction can be carried out according to the method described in International Publication No. 2016 / 105564.

[0853] Method 3

[0854] Among the compounds represented by formula (1), the compound represented by formula [C1] can be produced, for example, by the following production method.

[0855] [Chemical Formula 48]

[0856]

[0857] (Where X 1 、X 2 、X 3 、X 4 , Y, and Z have the same meanings as in item 1).

[0858] [Step 3-1: Cyclization reaction]

[0859] Compound C1 can be produced by reacting Compound C1 with Compound C2 in the presence of copper bromide and a base, in the absence of a solvent or in an appropriate solvent, under normal 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, and preferably triethylamine or N,N-diisopropylethylamine can be mentioned. The solvent can be appropriately selected from the solvents exemplified below, and preferably dimethylformamide can be mentioned. The reaction time is generally 5 minutes to 48 hours, and preferably 1 hour to 48 hours. The reaction temperature is generally 0°C to 150°C, and preferably 25°C to 100°C.

[0860] Compound c1 can be produced using a commercially available product or according to a known method, for example, the method described in International Publication No. 2001 / 018536, International Publication No. 2001 / 19788, Journal of Medicinal Chemistry 1986, 29(8), 1534-1537.

[0861] Compound c2 may be a commercially available product, or may be produced from Compound a5 according to the method for producing Compound a2 in Production Method 1.

[0862] Method 4

[0863] Among the compounds represented by formula (1), the compound represented by formula [C1] can also be produced by the following production method, for example.

[0864] [Chemical Formula 49]

[0865]

[0866] (Where X 1 、X 2 、X 3 、X 4 , Y, and Z have the same meanings as in item 1).

[0867] [Step 4-1: One-pot reaction]

[0868] Compound C1 can be produced by reacting Compound d1 with Compound d2 in a suitable solvent at normal pressure or under pressure to obtain a solution, and reacting the solution with Compound c2 in the presence of copper bromide and a base at normal pressure or under pressure. The base can be appropriately selected from the bases exemplified below, with triethylamine or N,N-diisopropylethylamine being preferred. The solvent can be appropriately selected from the solvents exemplified below, with N,N-dimethylformamide being preferred. The reaction time for both the reaction with Compound d2 and the reaction with Compound c2 is generally 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 generally 0°C to 150°C, preferably 25°C to 100°C.

[0869] Compound d1 can be a commercially available product or can be produced according to a known method, for example, a method described in Journal of Medicinal Chemistry 2019, 62(3), 1468-1483.

[0870] Compound d2 can be a commercially available product, or can be produced according to the production method of compound a5 in Production Method 1.

[0871] Method 5

[0872] Among the compounds represented by formula (1), the compound represented by formula [A1] can also be produced by the following production method, for example.

[0873] [Chemical Formula 50]

[0874]

[0875] (Where X 11 CR 1 , X 21 CR 2 , X 31 CR 3 , X 41 CR 4 , R 1 、R 2 、R 3 、R 4 , Y, and Z have the same meanings as in item 1. ).

[0876] Compound b1 can be produced according to the production method of Compound a3 in Production Method 1.

[0877] [Step 5-1: Methylation reaction]

[0878] Compound b2 can be prepared by reacting compound b1 with a suitable methylating agent in the presence of a suitable base in the absence of a solvent or in a suitable solvent. As a solvent, it can be appropriately selected from the solvents exemplified below, and N,N-dimethylformamide is preferably cited. As a methylating agent, it should be appropriately selected according to the type of raw material compound, and examples include iodomethane, dimethyl sulfate, etc. As a base, it can be appropriately selected from the bases exemplified below, and potassium carbonate is preferably cited. The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is generally -78°C to 150°C, preferably 0°C to 100°C.

[0879] This reaction can be carried out according to the method described in ChemMedChem 2009, 4(5), 866-876, etc.

[0880] [Step 5-2: Substitution reaction]

[0881] Compound A1 can be prepared by reacting compound b2 with compound d2 in the absence of a solvent or in a suitable solvent, in the presence of a suitable base, at normal pressure or under pressure. As a solvent, it is appropriately selected from the solvents exemplified below, and tetrahydrofuran and the like can be mentioned. As a base, it is appropriately selected from the bases exemplified below, and potassium tert-butoxide is preferably mentioned. The reaction time is generally 5 minutes to 48 hours, preferably 5 minutes to 12 hours. The reaction temperature is generally -78°C to 150°C, preferably 0°C to 100°C.

[0882] The base used in each step of each of the above-mentioned production methods should be appropriately selected depending on the reaction, the type of the starting compound, etc., and examples thereof include bicarbonate bases such as sodium bicarbonate and potassium bicarbonate, carbonate bases 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 tert-butoxide, and potassium tert-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).

[0883] The solvent used in each step of the above-mentioned production methods should be appropriately selected depending on the reaction and the type of starting compound. Examples include alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ketone; halogenated hydrocarbons such as dichloromethane 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 may be used alone or in mixtures of two or more. Depending on the type of reaction, an organic base may also be used as a solvent.

[0884] The compounds of the present disclosure represented by formula (1) or their intermediates can be isolated 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.

[0885] As the recrystallization solvent, for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as ether, an ester solvent such as ethyl acetate, an aromatic hydrocarbon solvent such as benzene or toluene, a ketone solvent such as acetone, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aprotic solvent such as dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used. As other purification methods, the method of recording in volume 1 of Experimental Chemistry Lecture (edited by the Chemical Society of Japan, Maruzen) can be used. In addition, the determination of the molecular structure of the compound of the present disclosure can be easily carried out by spectroscopic methods such as nuclear magnetic resonance, infrared absorption, circular dichroism spectroscopy, and mass spectrometry with reference to the structure of each raw material compound.

[0886] Furthermore, the intermediates or final products in the above-described production methods can be converted into other compounds encompassed by the present disclosure by appropriately modifying their functional groups, particularly by extending various side chains from amino, hydroxyl, carbonyl, halogen, and the like, and then performing the following protection and deprotection procedures as needed. Functional group conversion and side chain extension can be performed by commonly used methods (e.g., see Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons Inc. (1999)).

[0887] As the protecting group for the amino group, for example, an alkylcarbonyl group (e.g., acetyl, propionyl), formyl, phenylcarbonyl, alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), phenyloxycarbonyl, arylalkyloxycarbonyl (e.g., benzyloxycarbonyl), trityl, phthaloyl, tosyl, benzyl group can be used.

[0888] Examples of carboxyl-protecting groups include alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl), phenyl, benzyl, trityl, and silyl groups (e.g., trimethylsilyl and tert-butyldimethylsilyl).

[0889] As the protecting group for the hydroxy group, for example, a methyl group, a tert-butyl group, an allyl group, a substituted methyl group (e.g., a methoxymethyl group, a methoxyethoxymethyl group), an ethoxyethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a trityl group, an arylalkyl group (e.g., a benzyl group), an alkylcarbonyl group (e.g., an acetyl group, a propionyl group), a formyl group, a benzoyl group, an arylalkyloxycarbonyl group (e.g., a benzyloxycarbonyl group), a silyl group (e.g., a trimethylsilyl group, a tert-butyldimethylsilyl group) can be used.

[0890] The protection of the carbonyl group can be performed by converting the carbonyl group into an acyclic ketal (such as dimethyl ketal and diethyl ketal) or a cyclic ketal (such as 1,3-dioxolane and 1,3-dioxane).

[0891] The compounds of the present disclosure represented by formula (1) or their pharmaceutically acceptable salts may be asymmetric or have a substituent containing an asymmetric carbon, and such compounds may exist as optical isomers. The compounds of the present disclosure include mixtures and isolated forms of these isomers, and can be produced by conventional methods.

[0892] As a production method, for example, a method using a raw material having an asymmetric point or a method introducing asymmetry at an intermediate stage can be mentioned. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or performing optical resolution at an appropriate stage in the production process. As an optical resolution method, for example, when the compound represented by formula (1) or its intermediate has a basic functional group, a diastereoisomer method can be mentioned, in which a salt is formed in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, or 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents) using an optically active acid (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, or lactic acid, dicarboxylic acids such as tartaric acid, o-diisopropyltartaric acid, or malic acid, or a sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid).

[0893] When the compound of the present disclosure represented by formula (1) or an intermediate thereof 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 (e.g., an organic amine such as 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, or strychnine).

[0894] The temperature for salt formation can be selected from the 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, the temperature is preferably temporarily raised to near the boiling point of the solvent. When filtering out the precipitated salt, cooling can be performed as needed to improve yield. The amount of the optically active acid or amine used is preferably in the range of approximately 0.5 to 2.0 equivalents, preferably approximately 1 equivalent, relative to the substrate. If desired, the crystals can be recrystallized from an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or mixed solvents of two or more selected from the foregoing) to obtain high-purity optically active salts. Furthermore, if desired, the salt obtained through optical resolution can be treated with an acid or base by conventional methods to obtain the free form.

[0895] The raw materials and intermediates in the various production methods described above, for which the production method is not particularly described, may be commercially available compounds, or may be synthesized from commercially available compounds according to methods known to those skilled in the art, or methods based thereon.

[0896] The present disclosure provides pharmaceutical compositions containing a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient for treating or preventing disorders or diseases associated with abnormal neural excitation. "Disorders or diseases associated with abnormal neural excitation" refer to disorders or diseases of the central nervous system caused by a disturbance in the balance between excitatory and inhibitory signals in neural circuits. Examples include epilepsy, mental 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, other dementias, Parkinson's disease, etc.). "Epilepsy" includes epileptic seizures, status epilepticus, epilepsy syndromes (Dravet syndrome, Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy, mesial temporal lobe epilepsy with hippocampal sclerosis, Rasmussen syndrome, etc.), epilepsy due to structural / metabolic causes (cortical dysplasia, neurocutaneous syndromes (tuberous sclerosis, Stevens-Willi syndrome, etc.), etc.), as well as mental developmental disorders, mental disorders, cognitive disorders, etc. that are concurrent with these diseases. An "epileptic seizure" is "a transient sign or symptom caused by excessive and / or simultaneous abnormal neuronal activity in the brain" (Operational Classification of Seizure Types published by the International League Against Epilepsy: Formulated Statement by the ILAE Classification and Terminology Committee (Fisher, 2017). Examples include generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, and atonic seizures, focal seizures, and seizures of unclassified types. Preferred examples of "disorders or diseases related to abnormal neuronal excitability" include epilepsy and mental developmental disorders.

[0897] The effect of the compound of the present disclosure on epilepsy can be evaluated, for example, by the inhibitory activity for the overexcitement of cultured nerve cells, the inhibitory activity for convulsions or abnormal brain waves (spikes, spike-slow waves, etc.) of epilepsy model animals as an indicator. The effect on mental development disorder, mental disorder, and cognitive disorder can be evaluated using, for example, a 3-chamber test with social interaction of model animals as an indicator, a repetitive sorting behavior test with repeated / identical actions as an indicator, a glass bead burying test, a spontaneous exercise test with hyperactivity as an indicator, a forced swimming test with depression-like behavior as an indicator, a novel object recognition test or a Y-shaped labyrinth test with cognitive function as an indicator, as 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.

[0898] It should be noted that, in this disclosure, "prevention" refers to the act of administering the active ingredient of this disclosure to a healthy person who does not have a disease, for example, to prevent the onset of a disease. "Treatment" refers to the act of administering the active ingredient of this disclosure to a person (patient) diagnosed by a physician as having a disease.

[0899] The administration route of the compound of the present invention may be oral administration, parenteral administration, or rectal administration, and the daily dosage varies depending on the type of compound, the method of administration, the symptoms / age of the patient, etc. For example, in the case of oral administration, about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg, per kg body weight of a human or mammal can be administered in one to several divided doses. In the case of parenteral administration such as intravenous infusion, about 0.01 mg to 300 mg, more preferably about 0.01 mg to 100 mg, can be administered per kg body weight of a human or mammal.

[0900] The compounds of the present disclosure can be administered orally or non-orally, or can be administered by preparing a preparation using an appropriate dosage form. The dosage form includes, for example, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices, but is not limited thereto. The preparation can be manufactured using pharmaceutically acceptable additives and by known methods. Additives can include excipients, disintegrants, binders, flow agents, lubricants, coating agents, solubilizers, cosolvents, thickeners, dispersants, stabilizers, sweeteners, spices, etc., depending on the purpose. Specifically, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially alpha-starch, carboxymethyl cellulose calcium, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc. can be mentioned.

[0901] The compounds of the present disclosure can be used in combination with at least one or more pharmaceutical agents classified as antiepileptics, antidepressants, antianxiety drugs, or antipsychotics, and these can be administered for treatment or prevention. As pharmaceutical agents classified as antiepileptics, for example, phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine acetate, retigabine, lamotrigine, zonisamide, topiramate, sodium valproate, gabapentin, vigabatrin, pregabalin, phenobarbital, clonazepam, clobazam, diazepam, felbamate, rufinamide, ethosuximide, levetiracetam, brivaracetam, perampanel, stiripentol, cannabidiol, fenfluramine, etc. are mentioned, preferably carbamazepine, lamotrigine, topiramate, sodium valproate, clonazepam, clobazam, ethosuximide, levetiracetam, stiripentol, cannabidiol, fenfluramine. Drugs classified as antidepressants include, for example, SSRIs such as fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, duloxetine and milnacipran, and tricyclic antidepressants such as imipramine, amitriptyline, clomipramine, and amoxapine. Drugs classified as antianxiety drugs include, for example, benzodiazepine antianxiety drugs such as etizolam and lorazepam, and azaspirone antianxiety drugs such as tandospirone. Drugs classified as antipsychotics include, for example, typical antipsychotics such as haloperidol, spiroperidone, and chlorpromazine, and SDAs such as risperidone, quetiapine, olanzapine, clozapine, perospirone, and aripiprazole. Hereinafter, drugs that can be used in combination with the compounds of the present invention are referred to as combined drugs.

[0902] There is no specific time limit for administering the compound of the present invention and the concomitant drug; they can be administered to the subject simultaneously or with a time difference. Alternatively, the compound of the present invention and the concomitant drug can be combined. The dosage of the concomitant drug can be appropriately selected based on clinically used dosages. Furthermore, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected based on the subject, route of administration, target disease, symptoms, and combination. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug can be used per 1 part by weight of the compound of the present invention. Furthermore, to suppress side effects, the compound of the present invention can be used in combination with drugs (concomitant drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants.

[0903] In this specification, "or" is used when "at least one or more" of the items listed in the text can be used. The same applies to "or". In this specification, when the format of "within the range of two values" is described, the range also includes the two values ​​themselves.

[0904] The scientific literature, patents, patent applications and other references cited in this specification are incorporated herein by reference in their entirety to the same extent as if each were specifically described.

[0905] The present disclosure has been described above by way of preferred embodiments for ease of understanding. The present disclosure is described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the specific embodiments or examples described in this specification, but is defined solely by the claims. Example

[0906] The present disclosure is further described in detail below by reference examples, examples, and test examples, but the present disclosure is of course not limited thereto. It should be noted that the names of the compounds shown in the following reference examples and examples are not necessarily based on the IUPAC nomenclature.

[0907] To simplify the description, the following abbreviations may also be used in the Reference Examples, Examples, and Tables in the Examples. As abbreviations for substituents, Ph means phenyl. As abbreviations for reagents, TFA means trifluoroacetic acid, DMF means N,N-dimethylformamide, and HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. As symbols used in NMR, s means singlet, d means doublet, dd means doublet of doublets, dt means doublet of triplets, td means triplet of doublets, t means triplet, q means quartet, m means multiplet, br means broad, brs means broad singlet, and J means bond constant.

[0908] High performance liquid chromatography-mass spectrometry; LCMS measurement conditions are as follows, and the observed mass spectrum values ​​[MS (m / z)] are expressed as MH ＋ The retention time is expressed as Rt (minutes). In addition, the measurement conditions used in the measurement are mentioned in addition to each measured value.

[0909] Measurement Condition A

[0910] Detection equipment: ACQUITY (registered trademark) SQ detector (Waters)

[0911] HPLC: ACQUITY UPLC (registered trademark) SYSTEM

[0912] Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm)

[0913] Solvent:

[0914] Solution A: 0.05% formic acid / H2O, Solution B: acetonitrile

[0915] Gradient conditions:

[0916] 0.0-1.3 minutes (linear gradient from B 10% to 95%)

[0917] 1.3-1.5 minutes (B 10%)

[0918] Flow rate: 0.8 ml / min

[0919] UV: 220nm and 254nm

[0920] Column temperature: 40℃.

[0921] Measurement Condition B

[0922] Detection equipment: ACQUITY (registered trademark) SQ detector (Waters)

[0923] HPLC: ACQUITY UPLC (registered trademark) SYSTEM

[0924] Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm)

[0925] Solvent:

[0926] Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / acetonitrile

[0927] Gradient conditions:

[0928] 0.0-1.3 minutes (linear gradient from B 2% to 96%)

[0929] 1.3-1.5 minutes (B 96%)

[0930] 1.5-2.2 minutes (B 2%)

[0931] Flow rate: 0.8 ml / min

[0932] UV: 220nm and 254nm

[0933] Column temperature: 40℃.

[0934] Assay Condition C

[0935] Detection equipment: Shimadzu LCMS-2020

[0936] Column: Phenomenex Kinetex (1.7 μm C18, 50 mm × 2.10 mm)

[0937] Solvent:

[0938] Solution A: 0.05% TFA / H2O, Solution B: 0.05% TFA / acetonitrile

[0939] Gradient conditions:

[0940] 0.0-1.7 minutes (linear gradient from B 1% to 99%)

[0941] 1.7-1.9 minutes (B 99%)

[0942] 1.9-3.0 minutes (B 1%)

[0943] Flow rate: 0.5 ml / min

[0944] UV: 254 nm

[0945] Column temperature: 40℃.

[0946] Reference Example 1

[0947] 2-Chloro-3-phenylquinazolin-4(3H)-one

[0948] [Chemical Formula 51]

[0949]

[0950] a) Production of 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound A3)

[0951] To a solution of anthranilic acid (2.0 g) and N,N-diisopropylethylamine (6.4 ml) in ethanol (70 ml) was added phenyl isothiocyanate (2.6 ml), and the mixture was stirred under reflux for 16 hours. After cooling the reaction mixture to room temperature, the resulting solid was collected by filtration and washed with ethyl acetate and hexane. The solid was dried under reduced pressure at room temperature to obtain Compound A3 (3.2 g).

[0952]

[0953] b) Production of 2-chloro-3-phenylquinazolin-4(3H)-one (Reference Example 1)

[0954] 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, and the resulting solid was filtered and washed with water. The crude product was dissolved in ethyl acetate and washed with saturated brine, followed by a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain Reference Example 1 (2.0 g).

[0955]

[0956] Reference Example 2

[0957] 2-Amino-5-cyano-N-phenylbenzamide

[0958] [Chemical Formula 52]

[0959]

[0960] To a solution of 2-amino-5-cyanobenzoic acid (2.00 g) in DMF (12 ml) were added aniline (1.15 g), N,N-diisopropylethylamine (1.75 g), and HATU (4.69 g), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain Reference Example 2 (2.78 g).

[0961] LC-MS (determination conditions A), m / z; 238 (M+H)+ ESI, Rt; 0.76.

[0962] Reference Example 3

[0963] 3-Fluoro-5-isothiocyanatopyridine

[0964] [Chemical Formula 53]

[0965]

[0966] To a solution of 5-fluoropyridin-3-amine (0.56 g) in dichloromethane (10 ml) was added 1,1'-thiocarbonylbis(pyridin-2(1H)-one) (1.15 g), 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).

[0967]

[0968] Reference Example 4

[0969] 6-Fluoro-3-(5-fluoropyridin-3-yl)-2-(methylthio)quinazolin-4(3H)-one

[0970] [Chemical Formula 54]

[0971]

[0972] c) Production of 6-fluoro-3-(5-fluoropyridin-3-yl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (Compound B1)

[0973] To a solution of 2-amino-5-fluorobenzoic acid (4.0 g) in dioxane (80 ml) were added 3-fluoro-5-isothiocyanatopyridine (5.8 g) and triethylamine (5.4 ml), and the mixture was stirred at 85°C for 2 hours. After the reaction mixture was cooled to room temperature, the resulting solid was collected by filtration and washed with toluene. The solid was dried under reduced pressure at room temperature to obtain Compound B1 (6.5 g).

[0974]

[0975] b) Production of 6-fluoro-3-(5-fluoropyridin-3-yl)-2-(methylthio)quinazolin-4(3H)-one (Reference Example 4)

[0976] Potassium carbonate (2.8 g) was added to a solution of Compound B1 (4.3 g) in DMF (30 ml). Methyl iodide (1.0 ml) was added dropwise at 8-15°C, and the mixture was stirred at the same temperature for 1.5 hours. 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. The solid was dried under reduced pressure at room temperature to obtain Reference Example 4 (4.3 g).

[0977]

[0978] Reference Example 5

[0979] 2-Amino-5-cyano-N-(o-tolyl)benzamide

[0980] [Chemical Formula 55]

[0981]

[0982] The same method as in Reference Example 2 was used for synthesis.

[0983] LC-MS (determination conditions A), m / z; 252 (M+H)+ ESI, Rt; 0.76.

[0984] Example 1

[0985] 2-(Benzo[d]oxazol-5-ylamino)-3-phenylquinazolin-4(3H)-one

[0986] [Chemical Formula 56]

[0987]

[0988] A solution of Reference Example 1 (100 mg), N,N-dimethyl-4-aminopyridine (14 mg), and 1,3-benzoxazol-5-amine (104 mg) in DMF (2 ml) was stirred at 130°C for 24 hours. The reaction solution was concentrated, and the crude product was purified by high-performance liquid chromatography (eluting solvent: water:acetonitrile) to obtain Example 1 (10 mg).

[0989]

[0990] Example 2

[0991] 2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)-3-phenylquinazolin-4(3H)-one

[0992] [Chemical Formula 57]

[0993]

[0994] To a solution of Reference Example 1 (100 mg), 1-methyl-1H-benzimidazol-6-amine (63 mg), and cesium carbonate (250 mg) in dioxane / DMF (1.2 / 0.4 ml) were added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg) and palladium acetate (9 mg), 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 a crude product. This crude product was purified by high-performance liquid chromatography (eluting solvent: water:acetonitrile) to obtain Example 2 (13.0 mg).

[0995]

[0996] Example 3

[0997] 4-Oxo-3-phenyl-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile

[0998] [Chemical Formula 58]

[0999]

[1000] To a solution of Reference Example 2 (4.0 g) in DMF (17 ml) were added N,N-diisopropylethylamine (4.3 ml), 3-isothiocyanatopyridine (2.26 ml), and copper bromide (2.9 g), and the mixture was stirred at 85°C for 3 hours. Aqueous ammonia was added to the reaction mixture, which was filtered through Celite. The filtrate was extracted with chloroform and then washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was recrystallized from acetonitrile to obtain Example 3 (1.52 g) as crystals (Crystals I).

[1001]

[1002] [Crystal I] Powder X-ray diffraction pattern is shown in Figure 1 .

[1003] Main diffraction peaks: 2θ (°) = 7.75, 10.32, 13.91, 15.50, 16.35, 21.23, 23.36, 23.87, 25.11, 25.93

[1004] Characteristic diffraction peaks: 2θ (°) = 7.75, 10.32, 15.50, 23.36.

[1005] Example 4

[1006] 6-Fluoro-2-((5-fluoropyridin-3-yl)amino)-3-(o-tolyl)quinazolin-4(3H)-one

[1007] [Chemical Formula 59]

[1008]

[1009] 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. N,N-diisopropylethylamine (0.27 ml), Reference Example 3 (200 mg), and copper bromide (186 mg) were then added to the reaction mixture at room temperature, followed by stirring at 85°C for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was extracted with chloroform and washed with saturated aqueous ammonium chloride, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was then recrystallized from acetonitrile to obtain Example 4 (83 mg).

[1010]

[1011] Examples 5 to 232

[1012] The compounds shown in Table 1-1 to Table 1-35 were obtained by the same method as in Examples 1 to 4 using the corresponding starting compounds.

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055] Example 233

[1056] 6-Fluoro-2-((5-fluoropyridin-3-yl)amino)-3-phenylquinazolin-4(3H)-one

[1057] [Chemical Formula 60]

[1058]

[1059] To a solution of potassium tert-butoxide (587 mg) in THF (15 ml) was added aniline (0.5 ml) and Reference Example 4 (1.5 g), and the mixture was stirred at room temperature for 2.5 hours. Potassium tert-butoxide (588 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and 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).

[1060]

[1061] Example 234

[1062] 6-Fluoro-3-phenyl-2-(pyridin-3-ylamino)quinazolin-4(3H)-one

[1063] [Chemical Formula 61]

[1064]

[1065] The title compound (3.25 g) was obtained as crystals (Crystal II) by recrystallizing Example 12 (3.79 g) from acetonitrile.

[1066] [Crystal II] Powder X-ray diffraction pattern is shown in Figure 2 .

[1067] Main diffraction peaks: 2θ (°) = 7.80, 10.82, 13.67, 15.59, 16.62, 18.41, 21.32, 23.47, 24.33, 25.46

[1068] Characteristic diffraction peaks: 2θ (°) = 7.80, 10.82, 13.67, 15.59.

[1069] Example 235

[1070] 6-Fluoro-2-((5-fluoropyridin-3-yl)amino)-3-phenylquinazolin-4(3H)-one

[1071] [Chemical Formula 62]

[1072]

[1073] The title compound (11.6 g) was obtained as crystals (Crystal III) by recrystallizing Example 233 (12.0 g) from ethanol.

[1074] [Crystal III] Powder X-ray diffraction pattern is shown in Figure 3 .

[1075] Main diffraction peaks: 2θ (°) = 7.79, 8.40, 10.66, 13.80, 15.62, 16.46, 21.52, 23.53, 23.95, 25.38

[1076] Characteristic diffraction peaks: 2θ (°) = 7.79, 8.40, 13.80, 25.38.

[1077] Example 236

[1078] 4-Oxo-2-(pyridin-3-ylamino)-3-(o-tolyl)-3,4-dihydroquinazoline-6-carbonitrile

[1079] [Chemical Formula 63]

[1080]

[1081] To a solution of Reference Example 5 (2.4 g) in DMF (10 ml) were added N,N-diisopropylethylamine (2.4 ml), 3-isothiocyanatopyridine (1.3 ml), and copper bromide (1.6 g), and the mixture was stirred at 85°C for 3 hours. Aqueous ammonia was added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was extracted with chloroform and washed with saturated aqueous ammonium chloride, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which 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 (Crystal IV).

[1082] [Crystal IV] Powder X-ray diffraction pattern is shown in Figure 4 .

[1083] Main diffraction peaks: 2θ (°) = 8.15, 13.66, 13.92, 16.32, 21.04, 21.22, 22.10, 25.12, 25.37, 25.83

[1084] Characteristic diffraction peaks: 2θ (°) = 8.15, 16.32, 25.37, 25.83.

[1085] Example 237

[1086] 2-((5-fluoropyridin-3-yl)amino)-4-oxo-3-(o-tolyl)-3,4-dihydroquinazoline-6-carbonitrile

[1087] [Chemical Formula 64]

[1088]

[1089] The title compound (2.3 g) was obtained as crystals (Crystal V) by recrystallizing Example 114 (5.4 g) from ethanol.

[1090] [Crystal V] Powder X-ray diffraction pattern is shown in Figure 5 .

[1091] Main diffraction peaks: 2θ (°) = 8.07, 10.19, 11.62, 15.86, 16.18, 22.13, 24.51, 26.43, 26.83, 27.54

[1092] Characteristic diffraction peaks: 2θ (°) = 8.07, 15.86, 16.18, 26.43.

[1093] 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 .

[1094] When determining the crystal form, based on Figures 1 to 5 It can be judged by the characteristic diffraction peaks of each crystal shown in the diffraction pattern.

[1095] Depend on Figures 1 to 5 The main diffraction peaks and characteristic diffraction peaks determined from the diffraction patterns are shown in Examples 3, 234, 235, 236, and 237. It should be noted that the diffraction peaks at diffraction angles 2θ (°) described in the Examples may be subject to some measurement error depending on the measurement equipment and conditions. Specifically, the measurement error can be within a range of ±0.2, preferably ±0.1.

[1096] Powder X-ray diffraction determination method:

[1097] Testing equipment: Spectris Power X-ray diffraction system Empyrean

[1098] X-ray tube: CuKα (wavelength: 1.54 angstroms)

[1099] Tube voltage: 45kV

[1100] Tube current: 40mA

[1101] Measuring range: 4 to 40 degrees (2θ)

[1102] Stride: 0.013 degrees

[1103] Cumulative time: 100 seconds / step.

[1104] Test example

[1105] The following shows the results of pharmacological tests on representative compounds of the present disclosure, and describes the pharmacological effects of these compounds. However, the present disclosure is not limited to these test examples.

[1106] Experimental Example 1: Hyperexcitability suppression of neural cells induced by differentiation of SCN1A gene-deficient human iPS cells Activity assay

[1107] (1) Induction of differentiation from human iPS cells to neural cells

[1108] SCN1A gene-mutated cells, established from a human-derived iPS cell line (strain 201B7, obtained from the iPS Cell Research Institute, Kyoto University), were differentiated into either glutamate-stimulated excitatory neurons or γ-aminobutyric acid (GABA)-stimulated inhibitory neurons and maintained in 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. After seven days of differentiation induction, glutamate-stimulated excitatory neurons and GABA-stimulated inhibitory neurons were mixed at a ratio of 4:1 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 replaced by half every three to four days.

[1109] (2) Fluorescent calcium probe treatment, compound addition, and evaluation of intracellular calcium concentration

[1110] After 60 days of differentiation induction, half of the culture medium was removed and an equal amount of assay medium containing a fluorescent calcium probe (Molecular Devices, trade name FLIPR Calcium 6 Assay Bulk Kit, cat# R8191) was added. The cells were allowed to stand for 30 minutes before being assayed. The assay medium used was Hank's buffer (Thermo Fisher Scientific, cat# 14065-056) containing 20 mM Hepes (ThermoFisher Scientific, cat# 15630-080) and 0.1% bovine serum albumin (Sigma-Aldrich, cat# A9576).

[1111] The test compound was serially diluted with a dimethyl sulfoxide (DMSO) solution so that the final concentration became 0.1 to 100 μM, and a 6-fold concentration solution of the final concentration was prepared.

[1112] Fluorescence intensity of the calcium probe was measured over time using an FDSS7000EX (Hamamatsu Photonic Co., Ltd.) to evaluate changes in intracellular calcium concentration. After measuring fluorescence intensity for 2 minutes, the compound solution was added using the FDSS7000EX and fluorescence intensity was further measured for 8 minutes. The frequency of spontaneous calcium oscillations was quantified as an indicator of neural excitation. The frequency in the 2 minutes before compound solution addition was set as 100%, and the ratio of the frequency in the last 2 minutes after compound solution addition was calculated. For each test compound, the inhibitory activity (%) was determined at each concentration in a serial dilution series. The 50% inhibitory concentration (IC50) or the inhibition rate (%) at a specific concentration (denoted by @ in Tables 2-1 and 2-2) was determined for each test compound. Inhibitory activity data for representative compounds are shown in Tables 2-1 and 2-2.

[1113] .

[1114] .

[1115] As shown in the above table, the compounds of the present disclosure exhibited inhibitory activity in a hyperexcitability inhibitory activity assay using neural cells differentiated from SCN1A gene-deficient human iPS cells.

[1116] Test Example 2: Evaluation of epileptic spikes using SCN1A mutant animals

[1117] This study evaluated the inhibitory effects of drugs on epileptic spikes associated with loss-of-function mutations in the SCN1A gene. The animal model used was an F1 hybrid generated by mating BALB / c-Scn1a<+ / -> mice (Catalog No. RBRC06422; this model mouse was provided by the RIKEN BioResource Research Center (RIKEN BRC) through the Ministry of Education, Culture, Sports, Science and Technology's National Bioresource Project. Similar to Dravet syndrome patients, these mice harbor a deletion mutation in the SCN1A gene, resulting in a Dravet syndrome phenotype characterized by febrile seizures accompanied by elevated body temperature (see: Epilepsy Treatment Research Promotion Foundation Research Annual Report 2015: 26: 69-76) with C57BL / 6J mice.

[1118] The aforementioned SCN1A gene mutant mice (6-10 weeks old) were placed in a plastic chamber heated to a high internal temperature of approximately 43°C using a hot water bath. This temperature was maintained to elevate the body temperature, thereby inducing febrile seizures. Two weeks after the induction of febrile seizures, a helmet (cat#8201-SS, Pinnacle Technology) was placed on the mice's heads. Two weeks after the helmet was applied, F1 SCN1A gene loss-of-function mutant mice (25-32 g) were connected to a seizure EEG recording system (Pinnacle Technology) and administered with the test compound. The frequency of epileptic spikes was measured three hours before and after compound administration, and the dose that suppressed the epileptic spike frequency by 50% (ED50) was calculated. The results are shown in Table 3 below.

[1119]

[1120] Test Example 3: Evaluation of the Subcutaneous Pentylenetetrazol Model (Minimal Spasm Model, scPTZ)

[1121] This test evaluates the anticonvulsant effects of a drug. The animal model used is characterized by generalized absence or myoclonic seizures. Slc:ddY male mice (5 per group, weighing 20-30 g) were orally administered the test compound, followed one hour later by subcutaneous administration of 85 mg / kg pentylenetetrazol. The mice were then observed for 30 minutes for signs of clonic seizures, and the dose required to induce clonic seizures 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.

[1122]

[1123] Test Example 4: Maximum Electric Shock (MES) Model Evaluation

[1124] This test evaluated the anticonvulsant effects of a drug in the same manner as in Test Example 3. The animal model used in this test exhibited a phenotype of generalized tonic-clonic seizures or secondary generalized partial seizures. Slc:ddY male mice (5 mice per group, weighing 20-30 g) were orally administered the test compound. One hour later, electrical stimulation (60 Hz, 50 mA, 0.2 seconds) was applied to the cornea. The inhibition of the induced tonic extension spasm in the hind limbs was observed, and the dose that produced tonic extension spasms in 50% of the animals (ED50) was calculated. A 0.5% methylcellulose solution was administered as a control. The results are shown in Table 5 below.

[1125]

[1126] As shown in the table above, the compounds of the present disclosure exhibited anticonvulsant effects in epileptic spike wave evaluation using SCN1A mutant animals and / or subcutaneous PTZ model (minimal seizure model, scPTZ) evaluation and / or maximal electric shock seizure model (MES) evaluation.

[1127] Test Example 5: Rotarod Evaluation

[1128] This test evaluates the inhibitory effect of a drug on motor coordination. On the day of the test, Slc:ddy male mice (weighing 20-30 g) were trained to walk for 5 minutes using a rotarod apparatus (a device that rotates a 4 cm diameter cylindrical rod at 12 rpm). Fifty minutes after oral administration of the test compound, each group of five mice were placed on a rotarod apparatus (15 rpm) and observed for 180 seconds. The number of animals falling due to motor impairment within 180 seconds was counted, and the dose required for 50% of animals to fall (TD50) was calculated. A control was administered with a 0.5% methylcellulose solution. The results are shown in Table 6.

[1129]

[1130] Test Example 6: 3-chamber test evaluation

[1131] This study evaluated the drug's effect on improving social impairment, a core symptom of autism spectrum disorder. The animal model used in this study was the same as in Experimental Example 2: F1 mice were generated by mating BALB / c-Scn1a<+ / -> mice with C57BL / 6J mice.

[1132] The aforementioned SCN1A gene mutant mice (6-10 weeks old) were placed in a plastic chamber heated to a high internal temperature using a hot water bath at approximately 43°C. This heat was continued to raise the body temperature, inducing febrile seizures. Two weeks after the induction of febrile seizures, a three-chamber test was conducted. A cage containing a baited mouse was placed in one chamber of the three-chamber test apparatus, while a cage containing an object was placed in the other chamber. F1 SCN1A gene loss-of-function mutant mice (25-32 g) were orally administered with the test compound. One hour later, the mice were allowed to freely explore the chamber for 10 minutes. The sniffing time of the baited mouse and the object was measured.

[1133] Test Example 7: Cognitive Function Evaluation Based on the Novel Object Recognition Test (hereinafter sometimes referred to as “NORT”)

[1134] This study evaluates the cognitive function-improving effects of a compound. In a NORT experiment using APP-Tg mice or rTg4510 mice, which serve as models of AD (Alzheimer's disease), a decrease in memory for known objects was observed, depending on the time between the first trial (training) and the second trial (test). For example, when the second trial was performed three hours after the first trial, the APP-Tg and rTg4510 mice showed no difference in exploration time for novel and known objects compared to healthy mice, indicating significant forgetting.

[1135] The APP-Tg mice used in this experiment were generated by constructing an expression cassette for human APP751 isoforms with Swedish (K670N / M671L) and Indiana (V717F) mutations downstream of the mouse Thy-1 promoter. This expression cassette was then injected into fertilized mouse eggs and transplanted into surrogate mothers. These mice exhibit early brain Aβ accumulation and cognitive impairment, making them suitable for use in cognitive function assessments.

[1136] The rTg4510 mice used in this experiment were generated by mating and breeding Tg(tauP301L)4510 mice (Stock No. 015815) purchased from The Jackson Laboratory with CaMKII-tTA mice (Stock No. 007004). These mice overexpress human FTDP-17 mutant tau in the forebrain and exhibit age-dependent brain accumulation of tau aggregates and cognitive impairment, making them suitable for use in cognitive function assessments.

[1137] The test compound was administered to the prepared APP-Tg mice or rTg4510 mice, and a first trial was performed 30 to 60 minutes after administration or after one month of mixed diet administration. A second trial was performed 3 hours after the first trial, and the exploration time for the novel object and known objects in the second trial was evaluated. The recognition index was calculated from the exploration time for the novel object and known objects in the second trial, and this was compared with the group not administered the test compound as an indicator of cognitive function to confirm the cognitive function-improving effect of the test compound. It should be noted that the recognition index was calculated using the following mathematical formula.

[1138] Recognition index = {(exploration time for novel objects) - (exploration time for known objects)} / {(exploration time for novel objects) + (exploration time for known objects)}

[1139] As described above, the compounds of the present disclosure have activity that inhibits the hyperexcitability of neural circuits thought to be present in the background of various epileptic conditions. They exhibit strong anticonvulsant activity in epilepsy models using human cells and various animal models of spasm. Therefore, they are useful as antiepileptic drugs with a broad therapeutic spectrum (e.g., for epileptic seizures (including generalized seizures such as tonic seizures, clonic seizures, absence seizures, myoclonic seizures, and atonic seizures, focal seizures, epileptic spasms, and unclassified seizures), status epilepticus, epileptic syndromes (e.g., Dravet syndrome, Ohtawara syndrome, West syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy, mesial temporal lobe epilepsy with hippocampal sclerosis, Rasmussen syndrome), epilepsy due to structural / metabolic causes (e.g., cortical dysplasia, neurocutaneous syndromes (e.g., tuberous sclerosis, Stevens-Willi syndrome), etc.), and for the treatment and / or prevention of mental developmental disorders, mental disorders, cognitive impairment, etc., which are complications of these diseases). Furthermore, it is expected to have a symptom-modifying effect on disorders or diseases based on an abnormal balance between excitatory and inhibitory signals in neural circuits, including developmental disorders (autism spectrum disorder, Rett syndrome, Angelman syndrome, fragile X syndrome, attention deficit hyperactivity disorder, etc.), mental disorders (schizophrenia, bipolar disorder, depression, anxiety, obsessive-compulsive disorder, etc.), and cognitive disorders (Alzheimer's disease and other dementias, Parkinson's disease, etc.).

[1140] As described above, the present disclosure has been illustrated using preferred embodiments thereof. However, it should be understood that the scope of the present disclosure should be construed solely by the claims. This application claims priority to Japanese Patent Application No. 2020-77487 (filed on April 24, 2020), the contents of which are incorporated herein by reference in their entirety. It should be understood that all patents, patent applications, and references cited in this specification are incorporated herein by reference as if their contents were specifically set forth in this specification.

[1141] Industrial Availability

[1142] The compounds disclosed herein have an activity of suppressing excessive excitation of neural circuits and are therefore useful as therapeutic and / or preventive drugs for disorders or diseases associated with abnormal neural excitation, such as epilepsy.

Claims

1. A compound represented by formula (1) or a pharmaceutically acceptable salt thereof, Where, X 1 Indicates CR 1 , X 2 Indicates CR 2 , X 3 Indicates CR 3 , X 4 Indicates CR 4 , in, R 1 、R 3 and R 4 are all hydrogen atoms, R 2 is fluorine or cyano, Y is (1) C optionally substituted with 1 to 3 fluorine groups 1-3 alkyl, (2) C optionally substituted with 1 to 3 substituents, the same or different, selected from fluorine, amino and dimethylamino 5-6 alicyclic groups, (3) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group, (4) optionally selected from halogen, dimethylamino, C 1-3 Alkoxy and C optionally substituted by 1 to 3 fluorine 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group or (5) optionally selected from halogen and C 1-3 a 5-membered or 6-membered heteroaryl group substituted with 1 to 3 identical or different substituents in the alkoxy group, Z is optionally selected from fluorine, chlorine and C optionally substituted with 1 to 3 fluorines. 1-3 A 6- to 10-membered heteroaryl group containing 1 to 2 atoms independently selected from nitrogen and oxygen atoms and substituted with 1 to 3 substituents which are the same or different in the alkyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is (1) C optionally substituted with 1 to 3 substituents, the same or different, selected from fluorine, amino and dimethylamino 5-6 alicyclic groups, (2) optionally substituted with 1 to 3 fluorine groups selected from fluorine, amino, dimethylamino and C 1-3 a 5-membered or 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by 1 to 3 identical or different substituents in the alkyl group, (3) optionally substituted with 1 to 3 fluorine groups selected from halogen, methoxy and C 1-3 Phenyl substituted with the same or different 1 to 3 substituents in the alkyl group, or (4) A 5-membered or 6-membered heteroaryl group optionally substituted by 1 to 3 substituents which are the same or different and are selected from halogen and methoxy.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Y is (1) phenyl optionally substituted by 1 to 2 substituents which may be the same or different and selected from fluorine, methoxy and methyl, or (2) 5- or 6-membered heteroaryl optionally substituted by 1 to 2 substituents which may be the same or different and selected from fluorine and methoxy.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Y is (1) phenyl optionally substituted by 1 to 2 substituents which may be the same or different and selected from fluorine, methoxy and methyl, or (2) 6-membered heteroaryl optionally substituted by 1 to 2 substituents which may be the same or different and selected from fluorine and methoxy.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Z is optionally selected from fluorine, chlorine, and C optionally substituted with 1 to 3 fluorines. 1-3 The alkyl group may be substituted with 1 to 3 substituents which may be the same or different, pyridyl, pyrimidinyl, indazolyl or imidazopyridyl.

6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Z is optionally selected from fluorine, chlorine and C optionally substituted with 1 to 3 fluorines. 1-3 Pyridyl substituted with 1 to 3 substituents which may be the same or different in the alkyl group.

7. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds: 4-Oxo-3-phenyl-2-(pyridin-3-ylamino)-3,4-dihydroquinazoline-6-carbonitrile, 6-fluoro-2-((5-fluoropyridin-3-yl)amino)-3-(o-tolyl)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-tolyl)quinazolin-4(3H)-one, 6-fluoro-2-(pyridin-3-ylamino)-3-(o-tolyl)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-tolyl)-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-tolyl)-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.

8. A medicine comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. A therapeutic or preventive drug for a disorder or disease associated with abnormal nerve excitability, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient. 10 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or preventive drug for a disorder or disease associated with abnormal neural excitability.

12. A pharmaceutical composition, wherein A combination of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and at least one drug selected from drugs classified as antiepileptic drugs, antidepressants, anxiolytics, or antipsychotics.

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