JP2023045508A - Isoxazoline derivative - Google Patents

Abstract

To provide a compound which is useful as a medicine for various diseases caused by abnormality in balance between excitation and depression of brain nerve cells, especially epilepsy.SOLUTION: Provided are: a compound represented in formula (1) or a pharmaceutically acceptable salt thereof (in the formula, R1 to R4 represent a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, and the like; X represents a bond and the like; and Y represents a carboxamide such as CONH2 or a sulfonamide group and the like); and a therapeutic agent and/or a preventive agent containing the same for diseases such as epilepsy.SELECTED DRAWING: None

Description

The present invention provides pharmaceutically useful isoxazoline derivatives and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them as active ingredients, or agents for treating and/or preventing diseases such as epilepsy and/or depressive syndrome. Regarding agents.

Epilepsy is a chronic disease in which hyperexcitability of cerebral neurons causes sudden and recurrent abnormal physical symptoms and changes in movement, consciousness, and sensation. Epileptic seizures are classified by the International League Against Epilepsy (ILAE) into generalized seizures, focal seizures, and unclassified seizures. Generalized seizures are further classified into tonic, clonic, absence, myoclonic, and atonic seizures. (Patent Document 1). The etiology underlying the disease is roughly classified into genetic, structural/metabolic, and unknown. Epilepsy is classified into various disease types and syndromes based on characteristics such as electroencephalogram, clinical symptoms, age of onset, and etiology. For example, infancy-onset West syndrome and Dravet syndrome, childhood-onset Lennox-Gastaut syndrome and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), and medial temporal lobe epilepsy with hippocampal sclerosis as a distinct cluster. and Rasmussen's syndrome and many others (Non-Patent Document 2). Since the 1990s, international collaborative research has progressed, especially in molecular pathophysiological analysis of epilepsy, and many causative genes have been identified up to the present. These genes include ion channels such as Na, K, Ca, Cl, GABA-A, and ACh, and it is presumed that epilepsy develops as one of the causes of abnormal ion homeostasis.

Epilepsy is a serious disease that affects life prognosis and is known to affect about 1% of the world's population. Drug therapy is the main treatment for these epileptic seizures, and although various antiepileptic drugs have been prescribed for a long time, 1 out of 3 patients with epilepsy shows resistance to multidrug therapy with existing drugs. Intractable epilepsy. Existing drugs also cause dose-dependent neurological side effects such as excessive drowsiness, light-headedness, cognitive impairment, psychiatric symptoms, rare but idiosyncratic serious side effects such as Stevens-Johnson syndrome, and teratogenicity. There are also risks such as sexuality, etc., and there is also a risk of problems such as loss of efficacy and increased side effects due to drug interactions. In addition, epileptic patients are at high risk of concurrent psychiatric symptoms such as depression, anxiety, and cognitive impairment (Non-Patent Document 3). However, existing drugs have no therapeutic effect on these accompanying psychiatric symptoms. Based on the above, there is a strong need to develop new antiepileptic drugs with characteristics such as high efficacy against intractable epilepsy, excellent pharmacokinetic and safety profiles, and efficacy against both epilepsy and associated psychiatric symptoms. It has been demanded.

Epilepsy presents seizures due to overexcitation of brain neurons, but excitatory nerves work strongly or inhibitory nerves weaken, that is, the balance between excitation (E) and inhibition (I) (E/I balance). is thought to be caused by the anomaly of In addition to epilepsy, diseases caused by E/I imbalance are known. GABA nervous system activators that activate inhibitory nerves have been shown to have therapeutic effects on REM sleep disorders associated with anxiety disorders, obsessive-compulsive disorders, Parkinson's disease and dementia with Lewy bodies. E/I imbalance is also involved in neuropathic pain, developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, and Parkinson's disease. known to do. In fact, some of the antiepileptic drugs that ameliorate E/I imbalance have been widely applied in these other diseases. However, their efficacy in diseases other than epilepsy is limited, and side effects and pharmacokinetic problems remain. Therefore, antiepileptic drugs with new efficacy and side effect profiles may be applicable to many of these psychiatric and nervous system diseases, and the development is of great significance.

Patent document 1 describes isoxazolines having a therapeutic effect on bladder cancer, but their chemical structures are different from those of compounds represented by formula (1) described below.

WO2011/091040

Robert S. Fisher et al. Epilepsia, (2017), 58(4), 522-530 Anne T. Berg et al. Epilepsia, (2010) 51(4), 676-85 Schmitz B. Epilepsia, (2005) 46 (Suppl. 4), 45-49

An object of the present invention is to provide a compound useful as an antiepileptic drug.

As a result of intensive studies, the present inventors have found that a compound represented by the following formula (1) exhibits strong anticonvulsant action, that is, exhibits antiepileptic action, and completed the present invention. According to the present invention, an isoxazoline derivative represented by the following formula (1) (hereinafter sometimes referred to as "the compound of the present invention") is provided.

That is, the present invention is as follows.

［式中、
Ｒ^１及びＲ^２は、同一又は異なって、水素原子、ハロゲン、Ｃ_１－６アルキル（該アルキルは、ハロゲン、水酸基、Ｃ_３－６シクロアルキル、及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、Ｃ_１－３アルキル、及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表すか、あるいは、それらが結合する炭素原子と一緒になってＣ_３－６シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、Ｃ_１－３アルキル、及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を構成した基を表し、
Ｒ^３及びＲ^４は、同一又は異なって、水素原子、ハロゲン、Ｃ_１－６アルキル（該アルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－６シクロアルキル、Ｃ_１－３アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_６－１０アリール、及び置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい５～１０員のヘテロアリールからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、Ｃ_１－３アルキル、及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_６－１０アリール（該アリールは、ハロゲン、１～５個のハロゲンで置換されていてもよいＣ_１－５アルキル、１～５個のハロゲンで置換されていてもよいＣ_３－６シクロアルキル、１～５個のハロゲンで置換されていてもよいＣ_１－５アルコキシ、シアノ、及びニトロからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又は５～１０員のヘテロアリール（該ヘテロアリールは、ハロゲン、１～５個のハロゲンで置換されていてもよいＣ_１－５アルキル、１～５個のハロゲンで置換されていてもよいＣ_３－６シクロアルキル、１～５個のハロゲンで置換されていてもよいＣ_１－５アルコキシ、シアノ、及びニトロからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、但し、Ｒ^３及びＲ^４のいずれか一方は、上記で定義のＣ_６－１０アリール、上記で定義の５～１０員のヘテロアリール、又はＣ_１－６アルキル（但し、該アルキルは、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_６－１０アリール又は置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい５～１０員のヘテロアリールによって１個置換されている）を表し、
Ｘは、結合、酸素、硫黄、ＮＲ^５、又は直鎖のＣ_１－６アルキレン（該アルキレンは、ハロゲン、水酸基、及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｙは、ＣＯＲ^６、ＣＯＮＲ^７Ｒ^８、Ｓ（Ｏ）_ｎＲ^６、Ｓ（Ｏ）_ｎＮＲ^７Ｒ^８、又はＯＳ（Ｏ）_ｎＮＲ^７Ｒ^８を表し、
Ｒ^５、Ｒ^６、Ｒ^７、及びＲ^８は、同一又は異なって、水素原子、Ｃ_１－６アルキル（該アルキルは、ハロゲン、水酸基、Ｃ_３－６シクロアルキル、及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、Ｃ_１－３アルキル、及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
ｎは、０～２の整数を表し、
置換基群Ａは、ハロゲン、水酸基、Ｃ_１－３アルキル、及びＣ_１－３アルコキシを表し、及び
置換基群Ｂは、ハロゲン、１～５個のハロゲンで置換されていてもよいＣ_１－５アルキル、１～５個のハロゲンで置換されていてもよいＣ_３－６シクロアルキル、１～５個のハロゲンで置換されていてもよいＣ_１－５アルコキシ、シアノ、及びニトロを表す。］ [Item 1] A compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[In the formula,
R ¹ and R ² are the same or different, hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is independently from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy) optionally substituted with 1 to 3 substituents selected by ), or C _3-6 cycloalkyl (wherein the cycloalkyl is selected from halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or together with the carbon atom to which they are attached, C _3-6 cycloalkyl (the cycloalkyl Alkyl represents a group consisting of halogen, hydroxyl, C _1-3 alkyl, and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy. ,
R ³ and R ⁴ are the same or different, hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A optionally substituted C _3-6 cycloalkyl, C _1-3 alkoxy, C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, and 1 to 3 substituents independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B ), C _3-6 cycloalkyl (wherein the cycloalkyl is 1-3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with one substituent), C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 halogens, 1 to 5 halogens 1-3 independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with , C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro or 5- to 10-membered heteroaryl (wherein the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, 1 to independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with 5 halogens, C _1-5 alkoxy optionally substituted with 1 to 5 halogens, cyano, and nitro (optionally substituted ^with 1 to ³ _substituents such as or C _1-6 alkyl (wherein said alkyl is C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B or a substituent 1 substituted with 5- to 10-membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from Group B);
X is a bond, oxygen, sulfur, NR ⁵ , or linear C _1-6 alkylene (the alkylene being 1 to 3 groups independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy; It may be substituted with a substituent of
Y represents ^COR6 , ^{CONR7R8 , S(O)nR6, S(O)nNR7R8 , or} _OS ^{( O} _{) nNR7R8} ;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different, and are hydrogen atom, C _1-6 alkyl (where alkyl is selected from halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl, and C optionally substituted with 1 to 3 substituents independently selected from the group consisting of _1-3 alkoxy),
n represents an integer from 0 to 2,
Substituent group A represents halogen, hydroxyl group, C _1-3 alkyl and C _1-3 alkoxy, and Substituent group B represents halogen, C _1- optionally substituted with 1 to 5 halogens ₅ alkyl, C _3-6 cycloalkyl optionally substituted by 1 to 5 halogens, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano and nitro. ]

[Claim 2] R ³ is a hydrogen atom, halogen, or C _1-6 alkyl (the alkyl being 1 to 3 substituted groups independently selected from the group consisting of halogen, hydroxyl group and C _1-3 alkoxy Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is optionally substituted with a group.

[Item ³ ] The compound or a pharmaceutically acceptable salt thereof according to item 1 or 2, wherein R3 is a hydrogen atom, fluorine, or methyl.

[Item 4] The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 3, wherein R ³ is a hydrogen atom.

[Item 5] R ⁴ is C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, substituted by 1 to 5 halogens with 1 to 3 substituents independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with 1 to 5 halogens, C _1-5 alkoxy optionally substituted with 1 to 5 halogens, cyano, and nitro; optionally substituted), 5-10 membered heteroaryl (heteroaryl is halogen, C _1-5 alkyl optionally substituted with 1-5 halogens, substituted with 1-5 halogens 1 to 3 independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with 1 to 5 halogens, C _1-5 alkoxy optionally substituted with 1 to 5 halogens, cyano, and nitro optionally substituted with substituents), or C _6-10 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected _from Substituent Group B) substituted one by aryl);
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.

[Claim 6] R ⁴ is C _6-10 aryl (the aryl is halogen, C _1-3 alkyl optionally substituted with 1 to 5 fluorines, substituted with 1 to 5 fluorines optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy, and cyano), 5- to 10-membered heteroaryl (wherein said heteroaryl is halogen , C _1-3 alkyl optionally substituted with 1 to 5 fluorines, and optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano), or C _1-3 alkyl (wherein the alkyl is substituted once with C _6-10 aryl optionally substituted with 1 to 3 halogens);
Item 6. The compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.

[Claim 7] R ⁴ is phenyl (the phenyl is halogen, C _1-3 alkyl optionally substituted with 1 to 5 fluorines, C ₁ optionally substituted by 1 to 5 fluorines _-3 alkoxy, optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano), pyridyl (the pyridyl is substituted with halogen, 1 to 5 fluorines) optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkyl, and cyano), or methyl (wherein the methyl is 1 to 3 fluorine is substituted with one optionally substituted phenyl),
Item 7. The compound according to any one of Items 1 to 6 or a pharmaceutically acceptable salt thereof.

[Claim 8] X is a bond or C _1-6 alkylene (the alkylene is 1 to 3 groups independently selected from the group consisting of fluorine, hydroxyl group, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with a substituent),
^Y is ^CONR7R8 , ^S (O) _nNR7R8 , or OS ⁽ O) _nNR7R8 , and n is ^{2 ;}
Item 8. The compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof.

[Claim 9] R ⁷ and R ⁸ are the same or different and are 1 to 3 independently selected from the group consisting of hydrogen atom, C _1-6 alkyl (wherein said alkyl is halogen and C _3-6 cycloalkyl) or C _3-6 cycloalkyl, wherein the cycloalkyl is independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with 1 to 3 substituents) is
Item 9. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8.

[Claim 10] R ⁷ and R ⁸ are the same or different and are 1 to 3 independently selected from the group consisting of a hydrogen atom, C _1-6 alkyl (wherein said alkyl is fluorine and C _3-6 cycloalkyl) optionally substituted with 1 substituent), or C _3-6 cycloalkyl (wherein the cycloalkyl is optionally substituted with 1 to 3 fluorines),
Item 10. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 9.

[Item 11] R ¹ and R ² are the same or different and are C _1-4 alkyl (said alkyl may be substituted with 1 to 3 fluorine atoms) or C _3-5 cycloalkyl (said cycloalkyl optionally substituted with 1 to 3 fluorines), or together with the carbon atom to which they are attached are C _3-5 cycloalkyls (the cycloalkyls are optionally substituted by 1 to 3 fluorines optionally substituted),
Item 11. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 10.

[Item 12] R ¹ and R ² are the same or different and are C _1-2 alkyl (the alkyl may be substituted with 1 to 3 fluorines), or the carbon to which they are attached a group that together with the atoms constitutes a C _3-5 cycloalkyl (the cycloalkyl may be substituted with 1 to 3 fluorines);
Item 12. The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.

[Item 13] R ¹ and R ² are the same or different and are C _1-4 alkyl (said alkyl may be substituted with 1 to 3 fluorine atoms) or C _3-5 cycloalkyl (said cycloalkyl optionally substituted with 1 to 3 fluorines), or together with the carbon atom to which they are attached are C _3-5 cycloalkyls (the cycloalkyls are optionally substituted by 1 to 3 fluorines optionally substituted) is a group that constitutes
R ³ is hydrogen, halogen, or C _1-6 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy; ) and
R ⁴ is C _6-10 aryl (the aryl is halogen, C _1-3 alkyl optionally substituted with 1 to 5 fluorines, C ₁ optionally substituted by 1 to 5 fluorines _-3 alkoxy, optionally substituted with 1-3 substituents independently selected from the group consisting of cyano), 5-10 membered heteroaryl (wherein the heteroaryl is halogen, 1-5 optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkyl optionally substituted with 1 fluorine, and cyano), or C _1-3 alkyl (the alkyl is substituted once with C _6-10 aryl optionally substituted with 1 to 3 halogens);
X is a bond or C _1-6 alkylene substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; ) and
Y is ^CONR7R8 , ^S (O) ^nNR7R8 , or ^OS ( ^O ) ^nNR7R8 ;
R ⁷ and R ⁸ are the same or different and are a hydrogen atom, C _1-6 alkyl (wherein the alkyl is 1 to 3 substituents independently selected from the group consisting of halogen and C _3-6 cycloalkyl) or C _3-6 cycloalkyl, wherein the cycloalkyl is independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy 1 to optionally substituted with 3 substituents), and n is 2;
Item 1. The compound according to item 1 or a pharmaceutically acceptable salt thereof.

[Item 14] A racemic form, an optically active form, or a pharmaceutically acceptable salt thereof of the compound according to Item 1, which is selected from the following compounds:
5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 1),
4-(2-fluorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 2),
4-(4-fluorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 4),
4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 7),
4-(4-bromophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 8),
7-(4-chlorophenyl)-4-oxa-5-azaspiro[2.4]hept-5-ene-6-carboxamide (Example 14),
8-phenyl-5-oxa-6-azaspiro[3.4]oct-6-ene-7-carboxamide (Example 15),
N,N,5,5-tetramethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 28),
N,5,5-trimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 29),
N-ethyl-5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 30),
N-cyclopropyl-5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 31),
5,5-dimethyl-4-phenyl-N-(propan-2-yl)-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 32),
5,5-dimethyl-4-phenyl-N-propyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 33),
4-(4-chlorophenyl)-N-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 34),
4-(4-chlorophenyl)-5,5-dimethyl-N-(2,2,2-trifluoroethyl)-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 35), and (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methyl sulfamate (Example 36).

[Item 15] A racemic form, an optically active form, or a pharmaceutically acceptable salt thereof of the compound according to Item 1, which is selected from the following compounds:
5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 1),
4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 7),
4-(4-bromophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 8), and N-cyclopropyl-5,5-dimethyl-4- Phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide (Example 31).

[Item 16] A pharmaceutical composition containing the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof.

[Claim 17] A therapeutic agent for diseases associated with GABA nervous system hypofunction, containing the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient and/or prophylactic agent.

[Item 18] The therapeutic and/or prophylactic agent according to Item 17, wherein the disease associated with GABA nervous system dysfunction is a nervous system disease or a psychiatric disease.

[Item 19] Neurological or psychiatric disease is epileptic seizure (tonic seizure, clonic seizure, absence seizure, myoclonic seizure, generalized seizure including atonic seizure, focal seizure, unclassified seizure), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a distinct cluster, Rasmussen's syndrome, depressive symptoms with or without epilepsy , anxiety disorder, obsessive-compulsive disorder, REM sleep disorder associated with Parkinson's disease and dementia with Lewy bodies, neuropathic pain, developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, muscle Item 19. The therapeutic and/or prophylactic agent according to Item 18, which is atrophic lateral sclerosis or Parkinson's disease.

[Claim 20] A therapeutically effective amount of the compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment, GABA nerve A method for treating and/or preventing diseases involving systemic dysfunction.

[Claim 21] The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable compound thereof, for producing a therapeutic and/or preventive agent for diseases associated with GABA nervous system hypofunction use of salt.

[Item 22] The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of diseases associated with GABA nervous system hypofunction.

[Claim 23] A therapeutic and/or prophylactic agent for epilepsy, containing the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Item 24] Epilepsy is epileptic seizure (tonic seizure, clonic seizure, absence seizure, myoclonic seizure, generalized seizure including atonic seizure, focal seizure, unclassified seizure), status epilepticus, West syndrome, Dravet syndrome, 24. The therapeutic agent and/or according to Item 23, which is Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a distinct specific symptom group, or Rasmussen's syndrome. prophylactic agent.

[Claim 25] A treatment for epilepsy, comprising administering a therapeutically effective amount of the compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment. Methods for treatment and/or prevention.

[Item 26] Use of the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof for manufacturing a therapeutic and/or preventive agent for epilepsy.

[Claim 27] A drug containing the compound of any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof, and a drug classified as an antiepileptic drug, an antidepressant drug, or an antipsychotic drug A medicament in combination with at least one drug selected from

[Claim 28] A disease associated with GABA nervous system dysfunction, characterized by being used in combination with at least one drug selected from drugs classified as antiepileptic drugs, antidepressants, or antipsychotic drugs A medicament containing the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof for treatment.

The compounds of the present invention are potent in multiple convulsive model animals caused by decreased GABA signal (decreased GABA nervous system function) (subcutaneous injection pentetrazole model in Test Example 2, Drave model mouse febrile convulsion in Test Example 4). showed significant anticonvulsant activity. The subcutaneous injection pentetrazole model of Test Example 2 is a phenotype of generalized absence seizures and myoclonic seizures, and is a model exhibiting a seizure type with a low remission rate of existing antiepileptic drugs. The Dravet model mouse febrile convulsion of Test Example 4 is an animal model that has the same genetic background as Dravet syndrome, which exhibits treatment-resistant convulsions, and the effects of existing antiepileptic drugs on this model are very limited. . The maximal electroconvulsive seizure model (MES) of Test Example 1 is a phenotype of generalized tonic-clonic seizures and secondary generalized partial seizures, and the compounds of the present invention exhibited anticonvulsant activity. The compounds of the present invention are therefore useful in epilepsy (e.g., epileptic seizures (tonic, clonic, absence, myoclonic, generalized including atonic, focal, unclassified), status epilepticus, West ( West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a distinct cluster, Rasmussen (Rasmussen's syndrome, etc.). In addition, West syndrome, Dravet syndrome, and Lennox-Gastaut syndrome present treatment-resistant convulsions and are serious diseases accompanied by developmental delay, etc., and provide prophylactic and/or therapeutic agents for intractable epilepsy including these. is of great significance. It is also useful as a prophylactic and/or therapeutic agent for REM sleep disorders associated with anxiety disorder, obsessive-compulsive disorder, Parkinson's disease and dementia with Lewy bodies, for which therapeutic effects of existing GABA nervous system activators have been recognized. In addition, neuropathic pain with abnormalities in the GABA nervous system, developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, Parkinson's disease It is thought that the improvement effect will be exhibited.

The results of Test Example 4 are shown.

The terms used in this specification are explained below.

In this specification, unless otherwise indicated, the description of each group also applies when that group is part or a substituent of another group.

"Halogen" includes, for example, fluorine, chlorine, bromine, or iodine. Fluorine or chlorine is preferred. Fluorine is more preferred.

“C _1-6 alkyl” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, “C ₆ alkyl” means alkyl having 6 carbon atoms means The same is true for other numbers. "C _1-6 alkyl" preferably includes "C _1-4 alkyl", more preferably "C _1-3 alkyl". Specific examples of “C _1-2 alkyl” include methyl, ethyl and the like. Specific examples of “C _1-3 alkyl” include, in addition to the specific examples of “C _1-2 alkyl” above, propyl, 1-methylethyl and the like. Specific examples of "C _1-4 alkyl" include, in addition to those listed above as specific examples of "C _1-3 alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methyl propyl and the like. Specific examples of "C _1-5 alkyl" include, in addition to those listed above as specific examples of "C _1-4 alkyl", pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl and the like. Specific examples of "C _1-6 alkyl" include, in addition to the specific examples of "C _1-5 alkyl", 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1- Methylpentyl, hexyl and the like can be mentioned.

“C _3-6 cycloalkyl” means a cyclic alkyl having 3 to 6 carbon atoms, including partially crosslinked structures. “C _3-6 cycloalkyl” preferably includes “C _3-5 cycloalkyl”. Specific examples of “C _3-5 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and the like. Specific examples of “C _3-6 cycloalkyl” include, in addition to those exemplified above for ““C _3-5 cycloalkyl”, cyclohexyl and the like.

“C _1-5 alkoxy” means an oxy group substituted with the above “C _1-5 alkyl”. The “C _1-5 alkoxy group” preferably includes “C _1-4 alkoxy”, more preferably “C _1-3 alkoxy”. Specific examples of “C _1-3 alkoxy” include methoxy, ethoxy, propoxy, 1-methylethoxy and the like. Specific examples of "C _1-5 alkoxy" include, in addition to those listed above as specific examples of "C _1-3 alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methyl propoxy, pentyloxy, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy and the like.

“C _6-10 aryl” means an aromatic hydrocarbon having 6 to 10 carbon atoms. Specific examples of “C _6-10 aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like. “C _6-10 aryl” preferably includes phenyl.

"5- to 10-membered heteroaryl" means a monocyclic ring composed of 5 to 10 atoms containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom It means a formula or bicyclic aromatic heterocyclic group. "5- to 10-membered heteroaryl" preferably includes "5- to 7-membered heteroaryl", more preferably "5- to 7-membered nitrogen-containing heteroaryl" having 1 to 3 nitrogen atoms in the ring. aryl", more preferably pyridyl, pyrimidinyl, quinolyl, isoquinolyl, etc., and particularly preferably pyridyl.
Specific examples of "5- to 7-membered nitrogen-containing heteroaryl" include, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl , triazolyl, tetrazolyl and the like. Specific examples of the "5- to 7-membered heteroaryl" include furyl, thienyl and the like in addition to the specific examples of the above-mentioned "5- to 7-membered nitrogen-containing heteroaryl". Specific examples of "5- to 10-membered heteroaryl" include, for example, indolyl, indazolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, 6,11-dihydrodibenzo[b,e]thiepinyl groups and the like.

“C _1-6 alkylene” means a linear or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms, or a divalent divalent hydrocarbon group containing a cyclic structure having 3 to 6 carbon atoms. means a saturated hydrocarbon group. “C _1-6 alkylene” preferably includes “C _1-4 alkylene”, and more preferably includes linear “C _1-3 alkylene”.
Specific examples of linear or branched “C _1-6 alkylene” include methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1- Methylethylene, 2-methylethylene, 1-ethylethylene and the like, preferably methylene and ethylene.
Specific examples of “C _3-6 alkylene” containing a cyclic structure include groups represented by the following groups.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y and n are preferably as follows, and the technical scope of the present invention is as follows. The scope of compounds listed is not intended to be limiting.

A preferred embodiment of R ¹ and R ² is that R ¹ and R ² are the same or different,
(1) C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; may be present),
(2) a hydrogen atom,
(3) C _3-6 cycloalkyl, wherein the cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy; may have been),
(4) halogen,
Alternatively, together with the carbon atoms to which R ¹ and R ² are attached (5) C _3-6 cycloalkyl (wherein said cycloalkyl consists of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group).

A more preferred embodiment of R ¹ and R ² is that R ¹ and R ² are the same or different,
(1) C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; may be present),
(2) a hydrogen atom,
(3) C _3-6 cycloalkyl, wherein the cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy; may have been),
Alternatively, together with the carbon atoms to which R ¹ and R ² are attached (4) C _3-6 cycloalkyl (wherein said cycloalkyl consists of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group).

A more preferred embodiment of R ¹ and R ² is that R ¹ and R ² are the same or different,
(1) C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; may be present),
(2) a hydrogen atom,
Alternatively, together with the carbon atoms to which R ¹ and R ² are attached (3) C _3-6 cycloalkyl (wherein said cycloalkyl consists of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group).

In the most preferred embodiment of R ¹ and R ² , R ¹ and R ² are the same or different,
(1) C _1-3 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl and C _1-3 alkoxy),
Alternatively, together with the carbon atom to which R ¹ and R ² are attached, (2) C _3-6 cycloalkyl (wherein said cycloalkyl is independently selected from the group consisting of fluorine, hydroxyl and C _1-3 alkoxy) optionally substituted with 1 to 3 substituents).

In preferred embodiments of R ³ and R ⁴ , R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) halogen,
(3) C _1-6 alkyl (wherein the alkyl is C _3-6 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, Substituent Group A, C _1-3 alkoxy, C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, and 1 to 1 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted by 3 substituents),
(4) C _3-6 cycloalkyl, wherein the cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy; may have been),
(5) C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 halogens, C _3- optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₆ cycloalkyl, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano, and nitro good),
(6) 5- to 10-membered heteroaryl (heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, optionally substituted by 1 to 5 halogens substituted with 1-3 substituents independently selected from the group consisting of C _3-6 cycloalkyl, C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro may be present),
provided that either one of R ³ and R ⁴ is C _6-10 aryl as defined above, 5- to 10-membered heteroaryl as defined above, or C _1-6 alkyl (wherein said alkyl is a substituent C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Group B or substituted with 1 to 3 substituents independently selected from Substituent Group B one substituted with a 5- to 10-membered heteroaryl that may be substituted), and the like.

In a more preferred embodiment of R ³ and R ⁴ , R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) halogen,
(3) C _1-6 alkyl (the alkyl is C ₆ optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, C _1-3 alkoxy and Substituent Group B _-10 aryl, and 1 to 3 independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with one substituent),
(4) C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 halogens, C _3- optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₆ cycloalkyl, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano, and nitro good),
(5) 5- to 10-membered heteroaryl (heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, optionally substituted by 1 to 5 halogens substituted with 1-3 substituents independently selected from the group consisting of C _3-6 cycloalkyl, C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro may be present),
provided that either one of R ³ and R ⁴ is C _6-10 aryl as defined above, 5- to 10-membered heteroaryl as defined above, or C _1-6 alkyl (wherein said alkyl is a substituent C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Group B or substituted with 1 to 3 substituents independently selected from Substituent Group B one substituted with a 5- to 10-membered heteroaryl that may be substituted), and the like.

In a more preferred embodiment of R ³ and R ⁴ , R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) fluorine,
(3) C _1-3 alkyl (the alkyl is C ₆ optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, C _1-3 alkoxy and Substituent Group B _-10 aryl, and 1 to 3 independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with one substituent),
(4) C ₆ aryl (the aryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, C _3-6 cyclo optionally substituted by 1 to 5 halogens optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano, and nitro) ,
(5) 5- to 6-membered heteroaryl (the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, optionally substituted by 1 to 5 halogens substituted with 1-3 substituents independently selected from the group consisting of C _3-6 cycloalkyl, C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro may be present),
provided that either one of R ³ and R ⁴ is C ₆ aryl as defined above, 5- to 6-membered heteroaryl as defined above, or C _1-3 alkyl (wherein said alkyl is C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from or substituted with 1 to 3 substituents independently selected from Substituent Group B one substituted with a 5- to 10-membered heteroaryl which is also good), and the like.

In the most preferred embodiment of R ³ and R ⁴ , R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) fluorine,
(3) a methyl group,
(4) C ₆ aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 fluorine groups, C _1- optionally substituted with 1 to 3 substituents independently selected from the group consisting of _5alkoxy and cyano),
(5) 6-membered heteroaryl (the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 fluorine groups, optionally substituted by 1 to 5 fluorine groups optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-5 alkoxy and cyano),
provided that either one of R ³ and R ⁴ is C ₆ aryl as defined above or 6-membered heteroaryl as defined above.

Preferred embodiments of X include a bond, oxygen, sulfur, NR ⁵ , or linear C _1-6 alkylene (wherein the alkylene is independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents).
A more preferred embodiment of X is a bond or a linear C _1-3 alkylene (the alkylene being 1 to 3 substituted groups independently selected from the group consisting of halogen, hydroxyl group and C _1-3 alkoxy optionally substituted with a group).
A most preferred aspect of X is a bond.

Preferred aspects of Y are (1) COR ⁶ ,
(2) ^{CONR7R8 ,}
(3) S(O) _nR6 ^,
( 4) S ⁽ O) _nNR7R8
⁽ 5) OS(O) _nNR7R8 ^,
R ⁶ , R ⁷ and R ⁸ are the same or different and are hydrogen atom, C _1-6 alkyl (where alkyl is independently from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of
n represents an integer of 0 to 2;
A more preferred embodiment of Y is
(1) ^{CONR7R8 ,}
R ⁷ and R ⁸ are the same or different and are independently selected from the group consisting of hydrogen atom, C _1-6 alkyl (wherein said alkyl is independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from ).
A most preferred embodiment of Y includes _CONH2 .

Among the compounds represented by formula (1), preferred compounds include the following compounds or pharmaceutically acceptable salts thereof.

One aspect of the compound represented by Formula (1) includes the following (A).
(A)
R ¹ and R ² are the same or different,
(1) C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; may be present),
(2) a hydrogen atom,
(3) C _3-6 cycloalkyl, wherein the cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy; or (4) halogen,
Alternatively, together with the carbon atoms to which R ¹ and R ² are attached (5) C _3-6 cycloalkyl (wherein said cycloalkyl consists of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group;
R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) halogen,
(3) C _1-6 alkyl (wherein the alkyl is C _3-6 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, Substituent Group A, C _1-3 alkoxy, C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, and 1 to 1 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted by 3 substituents),
(4) C _3-6 cycloalkyl, wherein the cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy; may have been),
(5) C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 halogens, C _3- optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₆ cycloalkyl, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano, and nitro or (6) 5- to 10-membered heteroaryl (wherein the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, substituted by 1 to 5 halogens 1-3 substitutions independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with 1-5 halogens, C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro optionally substituted with a group),
provided that either one of R ³ and R ⁴ is C _6-10 aryl as defined above, 5- to 10-membered heteroaryl as defined above, or C _1-6 alkyl (wherein said alkyl is C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from or substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted one by a 5- to 10-membered heteroaryl);
X is a bond, oxygen, sulfur, NR ⁵ , or linear C _1-6 alkylene (the alkylene being 1 to 3 independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy; optionally substituted with a substituent of);
Y is ^COR6 , ^{CONR7R8 , S(O)nR6, S(O)nNR7R8} _, ^or _OS ^{( O} ₎ ^nNR7R8 ;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different, hydrogen atom, C _1-6 alkyl (wherein alkyl consists of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy) optionally substituted with 1 to 3 substituents independently selected from the group) or C _3-6 cycloalkyl (wherein said cycloalkyl is halogen, hydroxyl, C _1-3 alkyl, and C _1- optionally substituted with ₁ to 3 substituents independently selected from the group consisting of 3alkoxy;
n represents an integer from 0 to 2;
Substituent Group A is halogen, hydroxyl group, C _1-3 alkyl, and C _1-3 alkoxy; and Substituent Group B is halogen, C _1- optionally substituted with 1 to 5 halogens ₅ alkyl, C _3-6 cycloalkyl optionally substituted by 1 to 5 halogens, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano, and nitro;
A compound or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by Formula (1) includes the following (B).
(B)
R ¹ and R ² are the same or different,
(1) C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; may be present),
(2) _a hydrogen _atom , or (3) C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to optionally substituted with 3 substituents) or
Alternatively, together with the carbon atoms to which R ¹ and R ² are attached (4) C _3-6 cycloalkyl (wherein said cycloalkyl consists of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group;
R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) halogen,
(3) C _1-6 alkyl (the alkyl is C ₆ optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, C _1-3 alkoxy and Substituent Group B _-10 aryl, and 1 to 3 independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with one substituent),
(4) C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 halogens, C _3- optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₆ cycloalkyl, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano, and nitro or (5) 5- to 10-membered heteroaryl (wherein the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, substituted by 1 to 5 halogens 1-3 substitutions independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with 1-5 halogens, C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro optionally substituted with a group),
provided that either one of R ³ and R ⁴ is C _6-10 aryl as defined above, 5- to 10-membered heteroaryl as defined above, or C _1-6 alkyl (wherein said alkyl is C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from or substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted one by a 5- to 10-membered heteroaryl);
X is a bond or a linear C _1-3 alkylene (the alkylene is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy; may be);
Y is CONR ⁷ R ⁸ ; and R ⁷ and R ⁸ are the same or different and are hydrogen atom _, C _1-6 alkyl ( _where alkyl is halogen, hydroxyl group, C optionally substituted with 1 to ₃ substituents independently selected from the group consisting of 3alkoxy) or C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of
A compound or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by formula (1) includes the following (C).
(C)
R ¹ and R ² are the same or different,
(1) C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or (2) a hydrogen atom,
Alternatively, together with the carbon atoms to which R ¹ and R ² are attached (3) C _3-6 cycloalkyl (wherein said cycloalkyl consists of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group;
R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) fluorine,
(3) C _1-3 alkyl (the alkyl is C ₆ optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, C _1-3 alkoxy and Substituent Group B _-10 aryl, and 1 to 3 independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with one substituent),
(4) C ₆ aryl (the aryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, C _3-6 cyclo optionally substituted by 1 to 5 halogens optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano, and nitro) , or (5) 5- to 6-membered heteroaryl (the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, substituted by 1 to 5 halogens with 1 to 3 substituents independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with 1 to 5 halogens, C _1-5 alkoxy optionally substituted with 1 to 5 halogens, cyano, and nitro; may be substituted) and
provided that either one of R ³ and R ⁴ is C ₆ aryl as defined above, 5- to 6-membered heteroaryl as defined above, or C _1-3 alkyl (wherein said alkyl is independently optionally substituted with 1 to 3 substituents independently selected from C _6-10 aryl or substituent group B optionally substituted by 1 to 3 substituents selected as substituted one by a 5- to 10-membered heteroaryl);
X is a bond;
Y is CONR ⁷ R ⁸ ; and R ⁷ and R ⁸ are the same or different and are hydrogen atom _, C _1-6 alkyl ( _where alkyl is halogen, hydroxyl group, C optionally substituted with 1 to ₃ substituents independently selected from the group consisting of 3alkoxy), or C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of
A compound or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by formula (1) includes the following (D).
(D)
R ¹ and R ² are the same or different,
(1) C _1-3 alkyl (the alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl and C _1-3 alkoxy); mosquito,
Alternatively, together with the carbon atoms to which R ¹ and R ² are attached,
(2) C _3-6 cycloalkyl (the cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl and C _1-3 alkoxy); is;
R ³ and R ⁴ are the same or different,
(1) a hydrogen atom,
(2) fluorine,
(3) a methyl group,
(4) C ₆ aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 fluorine groups, C _1- optionally substituted with 1 to 3 substituents independently selected from the group consisting of _5alkoxy and cyano), or (5) 6-membered heteroaryl (wherein the heteroaryl is halogen, 1 to independently selected from the group consisting of C _1-5 alkyl optionally substituted with 5 fluorine groups, C _1-5 alkoxy optionally substituted with 1 to 5 fluorine groups, and cyano optionally substituted with 1 to 3 substituents),
provided that either one of ^R3 and ^R4 is _C6 aryl as defined above or 6-membered heteroaryl as defined above;
X is a bond; and Y is CONR ⁷ R ⁸ (R ⁷ is a hydrogen atom and R ⁸ is a hydrogen atom or cyclopropyl),
A compound or a pharmaceutically acceptable salt thereof.

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

Suitable salts and pharmaceutically acceptable salts of starting compounds and intermediates are the conventional non-toxic salts, including organic acid salts (e.g. acetates, trifluoroacetates, maleates, fumaric acid salts). salt, citrate, tartrate, methanesulfonate, benzenesulfonate, formate or para-toluenesulfonate, etc.) and inorganic acid salts (e.g. hydrochloride, hydrobromide, hydroiodide) , sulfates, nitrates or phosphates), salts with amino acids (eg arginine, aspartic acid or glutamic acid), alkali metal salts (eg sodium or potassium salts) and alkaline earth metals Metal salts such as salts (e.g. calcium salts or magnesium salts), ammonium salts, or organic base salts (e.g. trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts or N,N'-dibenzylethylenediamine salts, etc.) ), etc., can be appropriately selected by those skilled in the art.

When obtaining a salt of the compound of the present invention, when the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and when it is obtained in the free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended, and an acid or base may be added to form a salt by a conventional method.

In the present invention, a deuterium conversion product obtained by converting any one or two or more ¹ H of the compound represented by formula (1) to ² H(D) is also a compound represented by formula (1). included.
The present invention includes a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. In addition, the compounds of the present invention may exist in the form of hydrates and/or solvates with various solvents (ethanolates, etc.), so these hydrates and/or solvates are also Included in the compounds of the invention. Furthermore, the present invention includes all tautomers, all existing stereoisomers, and all forms of crystalline forms of compound (1) of the present invention, as well as mixtures thereof.

The compound (1) of the present invention includes optical isomers based on an optically active center, atropisomers based on axial or planar chirality caused by restriction of intramolecular rotation, other stereoisomers, and tautomers. All possible isomers and mixtures thereof are included within the scope of the present invention, including the possible existence of isomers, geometric isomers, and the like.

In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. If necessary, at an appropriate stage in the production process below, the corresponding starting material, intermediate or racemate of the final product can be physically separated by a known separation method such as a method using an optically active column or a fractional crystallization method. or chemically into their optical antipodes. Specifically, for example, in the diastereomer method, two diastereomers are formed from a racemate by a reaction using an optically active resolving agent. The different diastereomers generally have different physical properties and can be resolved by known methods such as fractional crystallization.

Methods for producing the compounds of the present invention are described below, but the methods for producing the compounds of the present invention are not limited to these.

（式中、Ｒ^１～Ｒ^４及びＸは項１の定義に同じであり、ＲはＣ_１－６アルキルである。） Manufacturing method 1
The compound of formula (1) [compound of formula (Ia) below] can be produced by the following production method.

(In the formula, R ¹ to R ⁴ and X are the same as defined in Item 1, and R is C _1-6 alkyl.)

Compound (Ia) is obtained by reacting compound (IIa) with ammonia.

The reaction of compound (IIa) and ammonia is carried out in a solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc. Examples include toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO, methanol, ethanol, ethylene. Glycol, water and the like can be mentioned and can be used alone or as a mixed solvent. Although the reaction temperature varies depending on the type of starting compound used, it is usually about -30°C to about 150°C, preferably about -10°C to about 70°C.

（式中、Ｒ^１～Ｒ^４、Ｘ、Ｒ^７及びＲ^８は項１の定義に同じである。） Manufacturing method 2
The compound of formula (1) in which at least one of R ⁷ and R ⁸ is other than hydrogen [compound of formula (1b) below] can be produced by the following production method.

(In the formula, R ¹ to R ⁴ , X, R ⁷ and R ⁸ are the same as defined in Item 1.)

Amidation of compound (III) gives compound (Ib).

Amidation reaction of compound (III) can be carried out according to a conventional method. For example, this reaction is accomplished by converting compound (III) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting it with various amines. Specific examples of active esters include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and the like. Specific examples of acid anhydrides include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid and the like.

Compound (Ib) can also be produced by reacting compound (III) with various amines or ammonium salts such as (NH ₄ ) ₂ CO ₃ in the presence of a condensing agent. Specific examples of condensing agents include N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride, N,N'-carbonyldiimidazole, and benzotriazol-1-yl. -oxytris(pyrrolidino)phosphonium-hexafluorophosphate and the like. These condensing agents can be used alone or in combination with peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole.

The reaction between compound (III) and various amines is carried out in a solvent or in the absence of a solvent. Specific examples of the solvent should be selected according to the type of starting compound, etc. Examples include toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO and the like. Alternatively, it can be used as a mixed solvent. Various amines may be used in the form of acid addition salts such as hydrochlorides to generate free bases in the reaction system. This reaction is usually carried out in the presence of a base, and specific examples of the base used include inorganic bases such as potassium carbonate and sodium hydrogencarbonate, or triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. , 4-dimethylaminopyridine and the like. Although the reaction temperature varies depending on the type of starting compound used, it is usually about -30°C to about 150°C, preferably about -10°C to about 70°C.

The compounds of formulas (Ia) and (Ib) produced by production methods 1 and 2 above can be isolated and purified by conventional methods such as chromatography and recrystallization.

Next, the raw material compounds used in the production methods 1 and 2 can be produced by the following method.

（式中、Ｒ^１～Ｒ^４及びＸは、項１の定義に同じであり、Ｒは、Ｃ_１－６アルキル、ベンジル、又は４－ニトロベンジルである。） The compounds (II: the compound represented by IIa is a part of the compound represented by II) and (III) used in the above manufacturing methods 1 and 2 are manufactured according to the method shown by the following reaction scheme.

(In the formula, R ¹ to R ⁴ and X are the same as defined in Item 1, and R is C _1-6 alkyl, benzyl, or 4-nitrobenzyl.)

(Step 1): Cycloaddition of compounds (IV) and (V) gives (II).

The esterification reaction of step 1 can be carried out according to a conventional method. For example, this reaction is carried out by contacting compounds (IV) and (V) in the presence or absence of a base in a suitable solvent. Specific examples of the solvent should be selected according to the type of raw material compound and the like. Can be used as a solvent. Specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkoxy alkali metals such as potassium t-butoxy, sodium carbonate, sodium hydrogen carbonate, potassium carbonate and lithium carbonate. and other alkali metal carbonates. The reaction temperature varies depending on the kind of raw material compounds and reagents used, but is usually 0 to 200°C, preferably 20 to 150°C.

(Step 2): Compound (II) is hydrolyzed to give compound (III).

The hydrolysis reaction in step 2 can be carried out according to a conventional method. For example, this reaction is carried out by contacting compound (II) with water under acidic or basic conditions in a suitable solvent. Specific examples of the solvent should be selected according to the type of raw material compound, and include alcohols such as THF, dioxane, DME, acetone, acetonitrile, DMF, DMSO, methanol, ethanol, and isopropanol, and water. can be used alone or as a mixed solvent. Specific examples of acids used include mineral acids such as hydrochloric acid and sulfuric acid. Further, specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkoxy alkali metals such as potassium t-butoxy, sodium carbonate, potassium carbonate, lithium carbonate and the like. Alkali metal carbonates are mentioned. The reaction temperature varies depending on the starting material compounds and reagents used, but is usually 0 to 150°C, preferably 20 to 100°C.

（式中、Ｒ^１～Ｒ^４及びＸは、項１の定義に同じであり、Ｒは、Ｃ_１－６アルキル、ベンジル、又は４－ニトロベンジルである。） Manufacturing method 3
The compound of formula (1) [compound of formula (VII) below] can be produced by the following production method.

(In the formula, R ¹ to R ⁴ and X are the same as defined in Item 1, and R is C _1-6 alkyl, benzyl, or 4-nitrobenzyl.)

(Step 3): Compound (II) is reduced to give (VI).

The reduction reaction in step 3 can be carried out according to a conventional method. For example, this reaction is carried out by contacting a reducing agent in a suitable solvent. Specific examples of the solvent should be selected according to the type of the raw material compound, and examples thereof include ethers such as Et ₂ O, THF, dioxane, and DME, alcohols such as methanol, ethanol, and isopropyl alcohol, and toluene. and can be used singly or as a mixed solvent. Specific examples of the reducing agent used include NaBH ₄ , LiBH ₄ , lithium triethylborohydride, lithium tri(sec-butyl)borohydride, potassium tri(sec-butyl)borohydride, diborane and the like. Examples include boron reagents, aluminum hydride reagents such as LiAlH ₄ , sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride and the like. The reaction temperature is usually -100°C to 200°C, preferably -78°C to 100°C, although it varies depending on the kind of starting compound and reagent used.

(Step 4): Sulfamation of compound (VI) gives compound (VII).

Sulfamation in step 4 can be carried out according to a conventional method. For example, this reaction is carried out by contacting compound (VI) with sulfamoyl chloride in the presence or absence of a base in a suitable solvent. Specific examples of the solvent should be selected according to the type of starting compound, etc. Examples include THF, dioxane, DME, acetone, acetonitrile, DMF, DMSO, dimethylacetamide, etc., which may be used alone or as a mixed solvent. be able to. Specific examples of the base used include alkoxy alkali metals such as t-butoxy potassium, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, amines such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine. is mentioned. The reaction temperature is usually -20°C to 150°C, preferably 0°C to 100°C, although it varies depending on the kind of starting compounds and reagents used.

（式中、Ｒ^１～Ｒ^４は項１の定義に同じである。） Manufacturing method 4
The compound of formula (1) [compound of formula (X) below] can be produced by the following production method.

(In the formula, R ¹ to R ⁴ are the same as defined in item 1.)

(Step 1): Compound (VIII) is obtained by chlorinating the hydroxyl group of compound (VIa). For example, this reaction is carried out by contacting a chlorinating agent in a suitable solvent or in the absence of a solvent. Specific examples of the solvent should be selected according to the type of the raw material compound, and include ethers such as Et ₂ O, THF, dioxane, and DME, and halogen-based solvents such as dichloromethane, chloroform, and carbon tetrachloride. and can be used alone or as a mixed solvent. Specific examples of chlorination reagents include triphenylphosphine and carbon tetrachloride, thionyl chloride, 1-chloro-N,N-trimethylpropenylamine, phosphorus oxychloride, phosphorus pentachloride and the like. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

(Step 2): Compound (IX) is obtained by reacting compound (VIII) with sodium sulfite. The substitution reaction in step 2 can be carried out according to a conventional method. For example, this reaction is carried out by contacting sodium sulfite in a suitable solvent. Specific examples of the solvent should be selected according to the type of the raw material compound, and examples thereof include ethers such as Et ₂ O, THF, dioxane, and DME, alcohols such as methanol, ethanol, and isopropyl alcohol, and toluene. and can be used singly or as a mixed solvent. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

(Step 3): Compound (X) is obtained by sulfonamidating compound (IX). Sulfonamidation in step 2 can be carried out according to a conventional method. For example, this reaction is accomplished by converting compound (IX) to a sulfonyl chloride and then reacting it with an amine. Conversion to sulfonyl chloride is carried out by reacting phosphorus oxychloride in a solvent or in the absence of solvent. Specific examples of the solvent should be selected according to the kind of the raw material compound, etc. Examples include Et ₂ O, THF, dioxane, DME, toluene, etc., and can be used alone or as a mixed solvent. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

The conversion of the sulfonyl chloride, which is an intermediate in Step 2, to the sulfonamide is carried out by reacting an ammonia solution in a solvent or ammonia gas. Specific examples of the solvent should be selected according to the type of raw material compound, etc. Examples include Et ₂ O, THF, dioxane, DME, DMF, acetonitrile, toluene, etc., and may be used alone or as a mixed solvent. can be done. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

Among the raw materials and intermediates in each of the production methods described above, those for which the production method is not described again are commercially available compounds, or methods known to those skilled in the art from commercially available compounds, or methods according to them. can be synthesized by the method.

Since the novel oxadiazole derivative of the present invention has anticonvulsant activity and GABA-A receptor activating action (GABA nervous system activating action), it is a therapeutic agent for diseases associated with GABA nervous system hypofunction and/or Can be prophylactic. In addition, the novel oxadiazole derivative of the present invention exhibits GABA-A receptor activating action and/or enhancing inhibition (I) in the balance between excitation (E) and inhibition (I) (E/I balance). Since it has, it can be used as a therapeutic and/or preventive agent for nervous system diseases or psychiatric diseases. Neurological or psychiatric disorders include epilepsy (e.g., epileptic seizures (tonic, clonic, absence, myoclonic, generalized, including atonic, focal, unclassified seizures), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a clear specific symptom group, Rasmussen syndrome, etc.), neuropathic pain, Developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, Parkinson's disease, depression with or without epilepsy, anxiety, obsessive-compulsive disorder, Parkinson's and REM sleep disorder associated with dementia with Lewy bodies. The novel oxadiazole derivatives of the present invention are preferably used in epileptic seizures (epileptic seizures (tonic, clonic, absence, myoclonic, generalized seizures including atonic seizures, focal seizures, unclassified seizures), status epilepticus. , West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), medial temporal lobe epilepsy with hippocampal sclerosis as a distinct group of symptoms, Rasmussen syndrome, etc.) and/or Or it can be a preventive agent.

The isoxazoline derivative of the present invention has an effect on GABA nervous system dysfunction and/or abnormalities in the balance between excitation (E) and inhibition (I) (E/I balance), so that nervous system diseases or psychiatric diseases can be a therapeutic and/or prophylactic agent for In addition, the novel oxadiazole derivative of the present invention can serve as a therapeutic and/or prophylactic agent for diseases in which excitation (E) is increased and/or inhibition (I) is decreased in the E/I balance. Neurological or psychiatric disorders include epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar and related disorders, schizophrenia spectrum disorders, Alzheimer's disease and other neurocognitive disorders, and amyotrophic lateral sclerosis. Parkinson's disease, depressive syndromes, anxiety disorders, obsessive-compulsive disorders, trauma- and stressor-related disorders, sleep-wake disorders, and/or REM sleep disorders associated with Parkinson's disease and dementia with Lewy bodies. .

The isoxazoline derivative of the present invention has anticonvulsant activity, GABA-A receptor activating action (GABA nervous system activating action), and therefore is a therapeutic and/or preventive agent for diseases associated with GABA nervous system hypofunction. can be. Diseases associated with GABA nervous system dysfunction include epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar disorder and related disorders, schizophrenia spectrum disorders, Alzheimer's disease and other neurocognitive disorders, muscle atrophy Lateral sclerosis, Parkinson's disease, depressive syndrome, anxiety disorders, obsessive-compulsive disorder, trauma- and stressor-related disorders, sleep-wake disorders, and/or REM sleep disturbance associated with Parkinson's disease/dementia with Lewy bodies is mentioned.

The epilepsy includes, for example, epileptic seizures (tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, unclassified seizures), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Angelman's syndrome, tuberous sclerosis, mesial temporal lobe epilepsy with hippocampal sclerosis as a distinct cluster, and/or Rasmussen's syndrome, etc. mentioned. In particular, it can be preferably used for Dravet syndrome, Lennox-Gastaut syndrome and/or Angelman syndrome.

The depressive syndromes include, for example, depressive disorders with anxiety distress, depressive disorders with mixed features, depressive disorders with melancholia features, depressive disorders with atypical features, mood-consistent depressive disorders with psychotic features, mood-inconsistent depressive disorders with psychotic features, depressive disorders with catatonia, perinatal onset, seasonal depressive disorders, severe dysthymia, Depression/Major Depressive Disorder, Persistent Depressive Disorder, Premenstrual Dysphoric Disorder, Substance/Pharmaceutical-Induced Depressive Disorder, Depressive Disorder Due to Other Medical Disorders, Other Depressive Disorders Identified, and/or Unspecified and depressive disorders. In particular, it can be preferably used for depression/major depressive disorder.

The anxiety disorder group includes, for example, separation anxiety, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance/drug-induced anxiety disorder, and others. Anxiety disorders due to medical conditions, other specified anxiety disorders, and/or unspecified anxiety disorders are included.

The bipolar disorders and related disorders include, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance/pharmaceutical-induced bipolar disorder and related disorders, bipolar disorders caused by other medical diseases and Related disorders, other specified bipolar and related disorders, and/or unspecified bipolar and related disorders, and the like. These further include symptoms of depression, depression or anxiety associated with said bipolar disorder and related disorders.

In the present invention, "prevention" means the act of administering the active ingredient of the present invention to a healthy person who has not developed a disease, for example, for the purpose of preventing the development of a disease. be. “Treatment” is the act of administering the active ingredient of the present invention to a person (patient) diagnosed by a doctor as having a disease. The action taken by a patient suffering from such a disease to suppress seizures associated with such a disease also falls under "prevention" or "treatment" herein.

The administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, and the daily dose varies depending on the type of compound, administration method, patient's symptoms, age and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per 1 kg body weight of humans or mammals can be administered in 1 to several divided doses. For parenteral administration such as intravenous injection, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per 1 kg body weight of a human or mammal can be administered.

The compounds of the present invention can be formulated and administered directly or using appropriate dosage forms, either orally or parenterally. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices and the like. Formulations are manufactured by known methods using pharmaceutically acceptable additives.
Additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , fragrance, etc. can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, stearin. Magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc and the like.

The compounds of the present invention can be used in combination with at least one or more drugs classified as antiepileptics, antidepressants, or antipsychotics. The term "combination" as used herein refers to a form in which a preparation prepared separately from the compound of the present invention is administered. may be administered after Drugs classified as antiepileptic drugs include, for example, sodium channel blockers such as phenytoin, valproic acid, carbamazepine, lamotrigine, and topiramate; calcium channel blockers such as ethosuximide and zonisamide; and AMPA receptor blockers such as perampanel and GABA. Examples include benzodiazepine drugs (diazepam, clonazepam, clobazam, etc.), barbital drugs (phenobarbital, etc.), gabapentin, vigabatrin, and the like, which enhance the action of the nervous system. Examples of drugs classified as antidepressants include SSRIs such as fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram; SNRIs such as duloxetine and milnacipran; and tricyclic antidepressants such as imipramine, amitriptyline, and clomipramine. , amoxapine and the like. Examples of drugs classified as antipsychotics include typical antipsychotics such as haloperidol, spiperone, and chlorpromazine, and SDA such as risperidone, quetiapine, olanzapine, clozapine, perospirone, and aripiprazole.

The present invention will be described in more detail with reference examples, examples and test examples below, but the present invention is by no means limited thereto. The compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

In order to simplify the description of the specification, the following abbreviations may be used in Reference Examples, Examples, and tables in Examples. Abbreviations used as substituents are Me for methyl and Ph for phenyl. THF means tetrahydrofuran, DMF means N,N-dimethylformamide, DME means 1,2-dimethoxyethane, and DMSO means dimethylsulfoxide. The symbols used in NMR are as follows: s is a singlet, d is a doublet, dd is a doublet of doublets, t is a triplet, td is a doublet of triplets, q is a quartet, m is multiplet, br is broad multiplet, brs is broad singlet, and J is coupling constant.

High performance liquid chromatographic mass spectrometer; LCMS measurement conditions are as follows, where the observed mass spectrometric value [MS (m/z)] is indicated by MH ⁺ and the retention time is indicated by Rt (min).

Instrumentation: Waters ACQUITYTM UltraPerformance LC
Column: ACQUITY UPLC BEH C18 1.7μm 2.1×30mm column
Solvent: A solution: 0.05% HCOOH/H ₂ O, B solution: CH ₃ CN
Gradient conditions:
0.0-1.3 minutes; A/B = 90/10-5/95 (linear gradient)
1.3-1.5 minutes; A/B = 90/10
Flow rate: 0.80 mL/min
UV: 220nm, 254nm
Column temperature: 40°C

エチル ２－クロロ－２－ヒドロキシイミノアセテート（１０．８３ｇ）のトルエン（２５０ｍＬ）溶液を加熱還流下の２－メチル－１－フェニルプロペン（９．４５ｇ）のトルエン（１５ｍＬ）溶液に滴下後、２０時間加熱還流した。反応溶液を減圧濃縮後、シリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル；９：１）で生成し、エチル ５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボキシレート（８．６０ｇ）を油状物として得た。
¹H-NMR (CDCl₃)δ: 1.02 (s, 3H), 1.21-1.26 (m, 3H), 1.48 (s,3H), 4.15 (s, 1H), 4.17-4.28 (m, 2H), 7.00-7.02 (m, 2H), 7.27-7.34 (m, 3H) Reference example 1 :
Ethyl 5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylate

After dropping a toluene (250 mL) solution of ethyl 2-chloro-2-hydroxyiminoacetate (10.83 g) into a toluene (15 mL) solution of 2-methyl-1-phenylpropene (9.45 g) under reflux, 20 It was heated to reflux for 1 hour. After concentrating the reaction solution under reduced pressure, it was purified by silica gel column chromatography (n-hexane:ethyl acetate; 9:1) to give ethyl 5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole- 3-carboxylate (8.60 g) was obtained as an oil.
¹ H-NMR (CDCl ₃ )δ: 1.02 (s, 3H), 1.21-1.26 (m, 3H), 1.48 (s, 3H), 4.15 (s, 1H), 4.17-4.28 (m, 2H), 7.00 -7.02 (m, 2H), 7.27-7.34 (m, 3H)

Reference example 2-25 :
The compounds shown in Table 1 were obtained by reacting and treating in the same manner as in Reference Example 1 using the corresponding starting compounds.

参考例１で得られたエチル ５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボキシレート（４５２ｍｇ）をＴＨＦ（５ｍＬ）とメタノール（５ｍＬ）の混合溶媒に溶解し、そこに水酸化リチウム１水和物（２３０ｍｇ）の水溶液（５ｍＬ）を加え、室温で１時間撹拌した。反応溶液を１０％クエン酸水溶液で酸性に調整後、酢酸エチルで抽出、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボン酸（３４０ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.05 (s, 3H), 1.51 (s, 3H), 4.17 (s, 1H), 7.01-7.03 (m, 2H), 7.28- 7.37 (m, 3H).
MS(m/z)220(MH+),Rt= 0.63 min. Reference Example 28 :
5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylic acid

Ethyl 5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylate (452 mg) obtained in Reference Example 1 was dissolved in a mixed solvent of THF (5 mL) and methanol (5 mL). , an aqueous solution (5 mL) of lithium hydroxide monohydrate (230 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was acidified with a 10% aqueous citric acid solution, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylic acid (340 mg) as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.05 (s, 3H), 1.51 (s, 3H), 4.17 (s, 1H), 7.01-7.03 (m, 2H), 7.28- 7.37 (m, 3H).
MS(m/z)220(MH+), Rt= 0.63 min.

Reference Example 29 :
4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxylic acid Using the corresponding starting compound, reaction and treatment in the same manner as in Reference Example 28 to obtain the compounds shown below.

参考例１で得られたエチル ５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボキシレート（６７１ｍｇ）のエタノール（１５ｍＬ）に水素化ホウ素ナトリウム（１．０３ｇ）を加え室温で１５時間撹拌した。水で希釈しクロロホルムで抽出、硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル；３：１）で精製し、（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）メタノール（４８５ｍｇ）を油状物として得た。
¹H-NMR (CDCl₃)δ: 0.99 (s, 3H), 1.46 (s, 3H), 1.90 (br, 1H), 3.97 (s, 3H), 4.21-4.26 (m, 1H), 4.38-4.43 (m, 1H), 7.03- 7.06 (m, 2H), 7.29- 7.38 (m, 3H). Reference Example 30 :
(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanol

To ethanol (15 mL) was added sodium borohydride (1. 03 g) was added and stirred at room temperature for 15 hours. The extract was diluted with water, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 3:1) and treated with (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanol. (485 mg) was obtained as an oil.
¹ H-NMR (CDCl ₃ )δ: 0.99 (s, 3H), 1.46 (s, 3H), 1.90 (br, 1H), 3.97 (s, 3H), 4.21-4.26 (m, 1H), 4.38-4.43 (m, 1H), 7.03- 7.06 (m, 2H), 7.29- 7.38 (m, 3H).

参考例３０で得られた（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）メタノール（４８５ｍｇ）のトルエン溶液（１０ｍＬ）にチオニルクロリド（０．５１４ｍＬ）を加え８０℃加熱下で４時間撹拌後、減圧濃縮した。得られた残渣のアセトン（１０ｍＬ）溶液にスルフィン酸ナトリウム（２９８ｍｇ）水溶液（１０ｍＬ）を加え、３日間加熱還流した。アセトンを減圧留去し残った水層をジエチルエーテルで洗浄後、減圧濃縮して（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）メタンスルホン酸（６８８ｍｇ）のナトリウム塩を固体として得た。
MS(m/z) 269 (MH+), Rt = 0.68 min. Reference Example 31 :
(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanesulfonic acid

To a toluene solution (10 mL) of (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanol (485 mg) obtained in Reference Example 30 was added thionyl chloride (0. 514 mL) was added, and the mixture was stirred under heating at 80° C. for 4 hours, and then concentrated under reduced pressure. A sodium sulfinate (298 mg) aqueous solution (10 mL) was added to an acetone (10 mL) solution of the obtained residue, and the mixture was heated under reflux for 3 days. Acetone was distilled off under reduced pressure, and the remaining aqueous layer was washed with diethyl ether and concentrated under reduced pressure to give (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanesulfone. The sodium salt of the acid (688mg) was obtained as a solid.
MS(m/z) 269 (MH+), Rt = 0.68 min.

Reference Example 32 :
(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)acetic acid

[Step 1]: Production of ethyl (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)acetate (Compound Q1) 5,5 obtained in Reference Example 28 -Dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylic acid (0.56 g) in chloroform (6.0 mL) was added with oxalyl chloride (0.44 mL) and a few drops of DMF. added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The obtained crude product was dissolved in THF (30 mL), and triethylamine (0.94 mL) and trimethylsilyldiazomethane (0.6 mol/L hexane solution) (5.6 mL) were added. After stirring at room temperature for 2 hours, saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium bicarbonate and then dried over magnesium sulfate. The solvent in the dried organic layer was distilled off under reduced pressure. Further, the obtained crude product was dissolved in ethanol/chloroform (4/1) (30 mL), and silver oxide (1.2 g) was added. After stirring at room temperature for 2 hours, the mixture was filtered through celite and the residue was washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=90:10→50:50) to give the title compound (0.20 g).
MS(m/z)262 (MH+), Rt = 0.90 min.

[Step 2]: Preparation of (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)acetic acid (Compound Q2) Compound Q1 (0.10 g) in THF/H Lithium hydroxide (92 mg) was added to a solution of ₂ O (1:1) (4 mL) and stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., added with water, adjusted to pH 5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was washed with saturated saline and then dried with magnesium sulfate. The solvent in the dried organic layer was distilled off under reduced pressure to obtain the title compound (90 mg) as a crude product.
MS(m/z) 234 (MH+), Rt = 0.66 min.

参考例１で得られたエチル ５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボキシレート（６．００ｇ）を７ｍｏｌ／Ｌのアンモニアメタノール溶液（６９ｍＬ）に溶解し、６５℃加温下で４時間撹拌後減圧濃縮した。得られた固体を水で洗浄し減圧乾燥後、シリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル；１：１）で精製し、５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボキサミド（３．０７ｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.01 (s, 3H), 1.46 (s, 3H), 4.22 (s, 1H), 5.34 (br s, 1H), 6.56 (br s, 1H), 7.00-7.02 (m, 2H), 7.25-7.34 (m, 3H)
MS(m/z) 219 (MH+), Rt = 0.63 min. Example 1 :
5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide

Ethyl 5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylate (6.00 g) obtained in Reference Example 1 was added to a 7 mol/L ammonia methanol solution (69 mL). and the mixture was stirred for 4 hours while heating at 65° C. and then concentrated under reduced pressure. The resulting solid was washed with water, dried under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to yield 5,5-dimethyl-4-phenyl-4,5-dihydro-1. , 2-oxazole-3-carboxamide (3.07 g) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.01 (s, 3H), 1.46 (s, 3H), 4.22 (s, 1H), 5.34 (br s, 1H), 6.56 (br s, 1H), 7.00-7.02 (m, 2H), 7.25-7.34 (m, 3H)
MS(m/z) 219 (MH+), Rt = 0.63 min.

Examples 2-27 :
The compounds shown in Table 2 were obtained by reacting and treating in the same manner as in Example 1 using corresponding starting compounds.

参考例２８で得られた５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボン酸（１４０ｍｇ）のジクロロメタン(２ｍＬ)溶液に、ジメチルアミン塩酸塩（６３ｍｇ）、１－ヒドロキシ－７－アザベンゾトリアゾール（２１７ｍｇ）、Ｎ－（３－ジメチルアミノプロピル）－Ｎ’－エチルカルボジイミド塩酸塩（１８４ｍｇ）を加えた。０℃まで冷却しＮ，Ｎ－ジイソプロピルエチルアミン（０．４４ｍＬ）を滴下後、室温で４時間撹拌した。反応溶液を１０％クエン酸水溶液、水の順で洗浄し硫酸マグネシウムで洗浄後、減圧濃縮した。シリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル；４：１）で精製し、Ｎ，Ｎ，５，５－テトラメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－カルボキサミド（１１３ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.02 (s, 3H), 1.48 (s, 3H), 2.96 (s, 3H), 3.34 (s, 3H), 4.41 (s, 1H), 7.25-7.32 (m, 5H).
MS(m/z) 247 (MH+), Rt = 0.76 min. Example 28 :
N,N,5,5-tetramethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide

Dimethylamine hydrochloride (63 mg ), 1-hydroxy-7-azabenzotriazole (217 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (184 mg) were added. After cooling to 0° C. and N,N-diisopropylethylamine (0.44 mL) was added dropwise, the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with a 10% aqueous citric acid solution and water in this order, washed with magnesium sulfate, and then concentrated under reduced pressure. Purification by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate; 4:1) gave N,N,5,5-tetramethyl-4-phenyl-4,5-dihydro-1,2-oxazole- 3-carboxamide (113 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.02 (s, 3H), 1.48 (s, 3H), 2.96 (s, 3H), 3.34 (s, 3H), 4.41 (s, 1H), 7.25-7.32 (m , 5H).
MS(m/z) 247 (MH+), Rt = 0.76 min.

Examples 29-35 :
The compounds shown in Table 3 were obtained by reacting and treating in the same manner as in Example 28 using corresponding starting compounds.

参考例３０で得られた（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）メタノール（１７８ｍｇ）のジメチルアセトアミド（５ｍＬ）溶液にスルファモイルクロリド（１．００ｇ）のジメチルアセトアミド（３ｍＬ）溶液を加え、室温で１５時間撹拌した。反応溶液を水で希釈し酢酸エチルで抽出、有機層を水と食塩水で洗浄後、硫酸ナトリウムで乾燥した。溶媒を減圧留去後、シリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル；１：１）で精製し、（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）メチル スルファメート（１８４ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.01 (s, 3H), 1.47 (s, 3H), 4.03 (s, 1H), 4.66-4.70 (m、1H), 4.79 (br、1H), 4.88 ( br, 1H), 5.00 (d, 1H), 7.03 (d, 2H), 7.31-7.39 (m, 3H).
MS(m/z) 285(MH+), Rt = 0.71 min. Example 36 :
(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methyl sulfamate

Sulfamoyl chloride was added to a dimethylacetamide (5 mL) solution of (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanol (178 mg) obtained in Reference Example 30. (1.00 g) in dimethylacetamide (3 mL) was added and stirred at room temperature for 15 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the product was purified by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate; 1:1) to obtain (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2 -oxazol-3-yl)methyl sulfamate (184 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.01 (s, 3H), 1.47 (s, 3H), 4.03 (s, 1H), 4.66-4.70 (m, 1H), 4.79 (br, 1H), 4.88 (br , 1H), 5.00 (d, 1H), 7.03 (d, 2H), 7.31-7.39 (m, 3H).
MS(m/z) 285(MH+), Rt = 0.71 min.

参考例３１で得られた（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）メタンスルホン酸のナトリウム塩（６８８ｍｇ）をジクロロメタン（１０ｍＬ）に懸濁させ、そこにオキサリルクロリド（０．８１ｍＬ）とジメチルホルムアミド１滴を加えた。室温で２時間撹拌後に減圧濃縮、続いてトルエンで共沸した。残渣のテトラヒドロフラン（１０ｍＬ）懸濁液にアンモニア溶液を加え、室温で２時間撹拌後、酢酸エチルで抽出した。得られた有機層を食塩水で洗浄し硫酸マグネシウムで乾燥後、減圧濃縮した。シリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル；１：１）で精製し、１－（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）メタンスルホンアミド（１８０ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.02 (s, 3H), 1.49 (s, 3H), 3.81 (d, 1H), 4.21 (s, 1H), 4.22 (d, 1H), 4.90 (s, 2H), 7.02-7.04 (m, 2H), 7.31-7.40 (m, 3H)
MS(m/z) 269 (MH+), Rt = 0.64 min. Example 37 :
1-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanesulfonamide

The sodium salt of (5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methanesulfonic acid (688 mg) obtained in Reference Example 31 was suspended in dichloromethane (10 mL). It became cloudy and oxalyl chloride (0.81 mL) and 1 drop of dimethylformamide were added thereto. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure and then azeotroped with toluene. Ammonia solution was added to a suspension of the residue in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hours and then extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate; 1:1) gave 1-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3- yl)methanesulfonamide (180 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.02 (s, 3H), 1.49 (s, 3H), 3.81 (d, 1H), 4.21 (s, 1H), 4.22 (d, 1H), 4.90 (s, 2H) ), 7.02-7.04 (m, 2H), 7.31-7.40 (m, 3H)
MS(m/z) 269 (MH+), Rt = 0.64 min.

参考例３２で得られた（５，５－ジメチル－４－フェニル－４，５－ジヒドロ－１，２－オキサゾール－３－イル）酢酸（９０ｍｇ）をクロロホルム（１ｍＬ）に溶解しオキサリルクロリド（０．０６６ｍＬ）及びＤＭＦ（１滴）を加え、室温で３０分間撹拌した。７ｍｏｌ／Ｌのアンモニアメタノール溶液（５ｍＬ）を加え室温で３０分間撹拌後、減圧濃縮した。シリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル；９０：１０→１：９９）で精製し、２－（５，５－ジメチル－４－フェニル－４，５－ジヒドロイソキサゾール－３－イル）アセタミド（３０ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 0.98 (s, 3H), 1.45 (s, 3H), 3.01 (d, 1H), 3.35 (d, 1H), 3.96 (s, 1H), 6.98-7.02 (m, 2H), 7.27-7.36 (m, 3H)
MS(m/z) 233 (MH+), Rt = 0.55 min. Example 38 :
2-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)acetamide

(5,5-Dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)acetic acid (90 mg) obtained in Reference Example 32 was dissolved in chloroform (1 mL) and oxalyl chloride (0 .066 mL) and DMF (1 drop) were added and stirred at room temperature for 30 minutes. A 7 mol/L ammonia methanol solution (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Purification by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate; 90:10→1:99) gave 2-(5,5-dimethyl-4-phenyl-4,5-dihydroisoxazole-3 -yl)acetamide (30 mg) was obtained as a solid.
¹ H-NMR (CDCl ₃ )δ: 0.98 (s, 3H), 1.45 (s, 3H), 3.01 (d, 1H), 3.35 (d, 1H), 3.96 (s, 1H), 6.98-7.02 (m , 2H), 7.27-7.36 (m, 3H)
MS(m/z) 233 (MH+), Rt = 0.55 min.

実施例１の化合物をダイセル社製CHIRALPAK^TM IG（移動相：100％ MeOH）で分取し、前ピーク（エナンチオマーＡ、絶対配置未決定）及び後ピーク（エナンチオマーＢ、絶対配置未決定）を得た。 Examples 39 and 40 :
(4R)-5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide and (4S)-5,5-dimethyl-4-phenyl-4,5-dihydro- 1,2-oxazole-3-carboxamide

The compound of Example 1 was fractionated with Daicel CHIRALPAK ^™ IG (mobile phase: 100% MeOH) to obtain a front peak (enantiomer A, absolute configuration undetermined) and a rear peak (enantiomer B, absolute configuration undetermined). rice field.

Example 39 (Enantiomer A): retention time 4.11 minutes Chiral HPLC (Chiralpak ^TM IG, 0.46 cmI.D. x 25 cmL, mobile phase: 100% MeOH, flow rate: 1.0 mL/min, temperature: 40°C, wavelength: 245 nm)
Example 40 (Enantiomer B): retention time 5.44 minutes Chiral HPLC (Chiralpak ^TM IG, 0.46 cmI.D. x 25 cmL, mobile phase: 100% MeOH, flow rate: 1.0 mL/min, temperature: 40°C, wavelength: 260 nm)

実施例７の化合物をダイセル社製CHIRALPAK^TM IG（移動相：100% MeCN）で分取し、前
ピーク（エナンチオマーＡ、絶対配置未決定）及び後ピーク（エナンチオマーＢ、絶対配置未決定）を得た。
実施例４１（エナンチオマーＡ）：保持時間 4.61分 Chiral HPLC (Chiralpak^TM IG, 0.46cmI.D. x 25 cmL, 移動相：100% MeCN、流量：1.0 mL/min、温度：40℃、波長：235 nm )
実施例４２（エナンチオマーＢ）：保持時間 5.77分 Chiral HPLC (Chiralpak^TM IG, 0.46cmI.D. x 25 cmL, 移動相：100% MeCN、流量：1.0 mL/min、温度：40℃、波長：235 nm ) Examples 41-42 :
(4R)-4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide and (4S)-4-(4-chlorophenyl)-5,5- Dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide

The compound of Example 7 was fractionated with Daicel CHIRALPAK ^™ IG (mobile phase: 100% MeCN) to obtain a front peak (enantiomer A, absolute configuration undetermined) and a rear peak (enantiomer B, absolute configuration undetermined). rice field.
Example 41 (Enantiomer A): retention time 4.61 minutes Chiral HPLC (Chiralpak ^TM IG, 0.46 cmI.D. x 25 cmL, mobile phase: 100% MeCN, flow rate: 1.0 mL/min, temperature: 40°C, wavelength: 235 nm)
Example 42 (Enantiomer B): retention time 5.77 minutes Chiral HPLC (Chiralpak ^TM IG, 0.46 cmI.D. x 25 cmL, mobile phase: 100% MeCN, flow rate: 1.0 mL/min, temperature: 40°C, wavelength: 235 nm)

Test Examples Pharmacological test results of representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are described, but the present invention is not limited to these test examples.

Test Example 1: Maximum Electric Convulsion Model (MES) Evaluation This test is for evaluating the anticonvulsant action of a drug. The animal model used in this study is the generalized tonic-clonic seizure and secondary generalized partial seizure phenotypes. Slc: ddY male mice (obtained from Japan SLC Co., Ltd.; 3 mice per group; body weight: 20-30 g) were orally administered with 100 mg/kg of the test compound, and after 1 hour, electrical stimulation (60 Hz, 25 mA, 0.25 mA) was applied from the cornea. 2 seconds), and the suppression of the induced tonic extensor cramps of the hind limbs was observed. As a control, 0.5% methylcellulose solution was administered. The results are shown in Table 4 below. The number of animals showing suppression of convulsions among the 3 animals was indicated by "A" when 3 animals, "B" when 2 animals, and "C" when 1 animal or less. In Table 4, "-" means unimplemented.

Test Example 2 Subcutaneous Injection Pentetrazole Model (Minimum Convulsive Model, scPTZ) Evaluation This test is similar to Test Example 1 to evaluate the anticonvulsant action of drugs. The animal model used in this test is a phenotype of generalized absence seizures and myoclonic seizures, unlike the phenotype of Test Example 1. Slc: ddY male mice (obtained from Japan SLC Co., Ltd., 5 mice per group, body weight 20-30 g) were orally administered with 100 mg/kg of the test compound, and 1 hour later, 85 mg/kg of pentetrazole was administered subcutaneously. Thereafter, the presence or absence of clonic convulsions for 30 minutes was observed. As a control, 0.5% methylcellulose solution was administered. The results are shown in Table 4 below. The number of animals showing suppression of convulsions among the 5 animals was indicated by "A" when 4 or more, "B" when 2 or more and less than 4, and "C" when 1 or less. .

Test Example 3: Evaluation of rotarod This test is a test for evaluating the inhibitory effect of drugs on coordination ability. A rotarod is a device that rotates a cylindrical rod with a diameter of 4 cm. Mice are made to walk on the rotated rod, and their coordination ability is evaluated using the ability to walk as an index. Slc:ddy male mice (obtained from Japan SLC Co., Ltd., body weight: 20-30 g) were trained to walk without falling for 5 minutes on a rotarod device rotated at 12 rpm 3 hours before the test. , only ambulatory mice are used for testing. A test compound was orally administered to a group of 5 animals, and after 1 hour, the animals were placed on a rotarod device rotated at 15 revolutions/minute, and the walking condition was observed for 180 seconds. The number of animals successfully walking for 180 seconds was counted. As a control, 0.5% methylcellulose solution was administered. The results are shown in Table 4 below. Among the 5 animals, the number of animals that successfully walked was indicated by "A" when 4 or more, "B" when 2 or more and less than 4, and "C" when 1 or less.

As shown in Table 4, compounds of the present invention exhibited anticonvulsant activity in the maximal electroshock seizure model (MES) evaluation and/or the subcutaneous injection pentetrazole model (minimal seizure model, scPTZ) evaluation upon oral administration. The compounds of Examples 1, 7, 8, 31, 39, 41 and 42 exhibited strong anticonvulsant activity and no anticoordination activity in both evaluations.

Test Example 4: Evaluation of Febrile Convulsion in Dravet Model Mouse This test is a test to evaluate the anticonvulsant effect of a drug on febrile convulsion in Dravet model mouse. In this test, BALB/c-Scn1a <+/-> mice (catalog number: RBRC06422; can be provided from the National Research and Development Agency RIKEN BioResource Center via the Ministry of Education, Culture, Sports, Science and Technology National BioResource Project). Using. This model mouse has a mutation in Scn1A, which is the causative gene of Dravet syndrome patients, and has a phenotype that exhibits a pathology similar to febrile convulsions due to increased body temperature, which is a symptom of Dravet syndrome patients. (Reference: Epilepsy Treatment Research Promotion Foundation Research Annual Report 2015: 26: 69-76). A test compound was orally administered to Dravet model male mice (3 to 11 mice per group, body weight 18 to 30 g), and after 60 minutes, the mice were placed in a hot water bath to induce febrile convulsions due to an increase in body temperature. The duration of febrile convulsions was measured and the convulsive severity score was determined (score 0: no change, score 1: tremor, head up and down, score 2: forelimb clonus, score 3: hindlimb clonus, stage 4: fall , stage 5: jumping, sprinting, score 6: clonic convulsions with loss of righting reflex). As a control, 0.5% methylcellulose solution was administered as a test compound, and the same test was performed. The results are shown in Figure 1 below.

As shown in FIG. 1, in Example 39, even in a model mouse of Dravet syndrome, which is known as one of the intractable generalized epilepsy and the causative mutation gene has been identified, at an administration dose that does not affect coordination ability Reduced febrile seizure severity score and duration (statistically significant by t-test). Accordingly, the compounds of the present invention are useful as antiepileptic agents (e.g., partial seizures, including simple partial seizures, complex partial seizures and persistent secondary generalized seizures with loss of consciousness, absence seizures, myoclonic seizures, clonic seizures, It is useful as a prophylactic and/or therapeutic agent for generalized seizures such as tonic seizures, tonic-clonic seizures, atonic seizures, West syndrome and Lennox-Gastaut syndrome. In addition, this group of compounds of the present invention is also expected as prophylactic and/or therapeutic agents for intractable epileptic seizures for which drug therapy has not yet been successful.

The compounds of the present invention exhibit potent anticonvulsant activity in multiple animal models and are useful as antiepileptic drugs with a broad therapeutic spectrum. Furthermore, a preferred group of compounds among the compounds of the present invention are also expected as prophylactic and/or therapeutic agents for intractable epileptic seizures for which conventional drug treatments are unsuccessful.

Claims (28)

A compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[In the formula,
R ¹ and R ² are the same or different, hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is independently from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy) optionally substituted with 1 to 3 substituents selected by ), or C _3-6 cycloalkyl (wherein the cycloalkyl is selected from halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or together with the carbon atom to which they are attached, C _3-6 cycloalkyl (the cycloalkyl Alkyl represents a group consisting of halogen, hydroxyl, C _1-3 alkyl, and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy. ,
R ³ and R ⁴ are the same or different, hydrogen atom, halogen, C _1-6 alkyl (wherein said alkyl is 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A optionally substituted C _3-6 cycloalkyl, C _1-3 alkoxy, C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, and 1 to 3 substituents independently selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B ), C _3-6 cycloalkyl (wherein the cycloalkyl is 1-3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy optionally substituted with one substituent), C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted with 1 to 5 halogens, 1 to 5 halogens 1-3 independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with , C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro or 5- to 10-membered heteroaryl (wherein the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, 1 to independently selected from the group consisting of C _3-6 cycloalkyl optionally substituted with 5 halogens, C _1-5 alkoxy optionally substituted with 1 to 5 halogens, cyano, and nitro (optionally substituted ^with 1 to ³ _substituents such as or C _1-6 alkyl (wherein said alkyl is C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B or a substituent 1 substituted with 5- to 10-membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from Group B);
X is a bond, oxygen, sulfur, NR ⁵ , or linear C _1-6 alkylene (the alkylene being 1 to 3 groups independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy; It may be substituted with a substituent of
Y represents ^COR6 , ^CONR7R8 , ^{S (} O) ^nR6 , _S ⁽ O) ^nNR7R8 , or _OS (O ₎ ^nNR7R8 ;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different, and are hydrogen atom, C _1-6 alkyl (where alkyl is selected from halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl, and C optionally substituted with 1 to 3 substituents independently selected from the group consisting of _1-3 alkoxy),
n represents an integer from 0 to 2,
Substituent group A represents halogen, hydroxyl group, C _1-3 alkyl and C _1-3 alkoxy, and substituent group B represents halogen, C _1-5 optionally substituted with 1 to 5 halogens represents alkyl, C _3-6 cycloalkyl optionally substituted by 1 to 5 halogens, C _1-5 alkoxy optionally substituted by 1 to 5 halogens, cyano and nitro. ] R ³ is a hydrogen atom, halogen, or C _1-6 alkyl (wherein the alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy; or a pharmaceutically acceptable salt thereof according to claim 1, wherein ^3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R3 is a hydrogen atom, fluorine, or methyl. ^4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R3 is a hydrogen atom. R ⁴ is C _6-10 aryl (the aryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, C ₃ optionally substituted by 1 to 5 halogens substituted with 1 to 3 substituents independently selected from the group consisting of _-6 cycloalkyl, C _1-5 alkoxy optionally substituted with 1 to 5 halogens, cyano, and nitro ), 5- to 10-membered heteroaryl (the heteroaryl is halogen, C _1-5 alkyl optionally substituted by 1 to 5 halogens, optionally substituted by 1 to 5 halogens substituted with 1-3 substituents independently selected from the group consisting of optionally C _3-6 cycloalkyl, C _1-5 alkoxy optionally substituted with 1-5 halogens, cyano, and nitro or C _1-6 alkyl (wherein said alkyl is C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B) is replaced),
A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. R ⁴ is C _6-10 aryl (the aryl is halogen, C _1-3 alkyl optionally substituted with 1 to 5 fluorines, C ₁ optionally substituted by 1 to 5 fluorines _-3 alkoxy, and optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano), 5- to 10-membered heteroaryl (wherein said heteroaryl is halogen, 1-5 optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkyl optionally substituted with fluorine, and cyano) or C _1-3 alkyl ( the alkyl is substituted once with C _6-10 aryl optionally substituted with 1 to 3 halogens);
A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. R ⁴ is phenyl (the phenyl is halogen, C _1-3 alkyl optionally substituted with 1 to 5 fluorines, C _1-3 alkoxy optionally substituted by 1 to 5 fluorines, and cyano optionally substituted with 1 to 3 substituents independently selected from the group consisting of C optionally substituted with 1 to 3 substituents independently selected from the group consisting of _1-3 alkyl and cyano), or methyl (the methyl is substituted with 1 to 3 fluorine is substituted with one phenyl,
A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. X is a bond or C _1-6 alkylene substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; Y ^{is CONR7R8} , _S (O ^{) nNR7R8} , or OS(O ₎ ^nNR7R8 , and n is ² ;
A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. R ⁷ and R ⁸ are the same or different and are a hydrogen atom, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen and C _3-6 cycloalkyl; or C _3-6 cycloalkyl, wherein the cycloalkyl is independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy 1 to optionally substituted with 3 substituents),
A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. R ⁷ and R ⁸ are the same or different and are a hydrogen atom, C _1-6 alkyl (wherein the alkyl is 1 to 3 substituents independently selected from the group consisting of fluorine and C _3-6 cycloalkyl; optionally substituted with ), or C _3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 3 fluorines,
A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof. R ¹ and R ² are the same or different and are C _1-4 alkyl (wherein said alkyl is optionally substituted with 1 to 3 fluorines) or C _3-5 cycloalkyl (wherein said cycloalkyl is 1 to 3 optionally substituted with 1 to 3 fluorines), or together with the carbon atom to which they are attached, C _3-5 cycloalkyl (wherein the cycloalkyl is substituted with 1 to 3 fluorines) ), which is the group that made up
A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. R ¹ and R ² are the same or different and are C _1-2 alkyl (wherein the alkyl is optionally substituted with 1 to 3 fluorines), or together with the carbon atom to which they are attached is a group consisting of C _3-5 cycloalkyl (the cycloalkyl may be substituted with 1 to 3 fluorines),
A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11. R ¹ and R ² are the same or different and are C _1-4 alkyl (wherein said alkyl is optionally substituted with 1 to 3 fluorines) or C _3-5 cycloalkyl (wherein said cycloalkyl is 1 to 3 optionally substituted with 1 to 3 fluorines), or together with the carbon atom to which they are attached, C _3-5 cycloalkyl (wherein the cycloalkyl is substituted with 1 to 3 fluorines) ) is a group that constitutes
R ³ is hydrogen, halogen, or C _1-6 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and C _1-3 alkoxy; ) and
R ⁴ is C _6-10 aryl (the aryl is halogen, C _1-3 alkyl optionally substituted with 1 to 5 fluorines, C ₁ optionally substituted by 1 to 5 fluorines _-3 alkoxy, optionally substituted with 1-3 substituents independently selected from the group consisting of cyano), 5-10 membered heteroaryl (wherein the heteroaryl is halogen, 1-5 optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkyl optionally substituted with 1 fluorine, and cyano), or C _1-3 alkyl (the alkyl is substituted once with C _6-10 aryl optionally substituted with 1 to 3 halogens);
X is a bond or C _1-6 alkylene substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; ) and
Y is ^CONR7R8 , ^S (O) ^nNR7R8 , or ^OS ( ^O ) ^nNR7R8 ;
R ⁷ and R ⁸ are the same or different and are a hydrogen atom, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen and C _3-6 cycloalkyl; or C _3-6 cycloalkyl, wherein the cycloalkyl is independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl, and C _1-3 alkoxy 1 to optionally substituted with 3 substituents), and n is 2;
A compound according to claim 1 or a pharmaceutically acceptable salt thereof. A racemate, an optically active form, or a pharmaceutically acceptable salt thereof of the compound of claim 1, selected from the following compounds:
5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(2-fluorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(4-fluorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(4-bromophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
7-(4-chlorophenyl)-4-oxa-5-azaspiro[2.4]hept-5-ene-6-carboxamide,
8-phenyl-5-oxa-6-azaspiro[3.4]oct-6-ene-7-carboxamide,
N,N,5,5-tetramethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
N,5,5-trimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
N-ethyl-5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
N-cyclopropyl-5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
5,5-dimethyl-4-phenyl-N-(propan-2-yl)-4,5-dihydro-1,2-oxazole-3-carboxamide,
5,5-dimethyl-4-phenyl-N-propyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(4-chlorophenyl)-N-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(4-chlorophenyl)-5,5-dimethyl-N-(2,2,2-trifluoroethyl)-4,5-dihydro-1,2-oxazole-3-carboxamide, and (5,5- Dimethyl-4-phenyl-4,5-dihydro-1,2-oxazol-3-yl)methyl sulfamate. A racemate, an optically active form, or a pharmaceutically acceptable salt thereof of the compound of claim 1, selected from the following compounds:
5,5-dimethyl-4-phenyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide,
4-(4-bromophenyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3-carboxamide, and N-cyclopropyl-5,5-dimethyl-4-phenyl-4,5 -dihydro-1,2-oxazole-3-carboxamide. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof. A therapeutic and/or prophylactic agent for diseases associated with GABA nervous system hypofunction, comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient. 18. The therapeutic and/or prophylactic agent according to claim 17, wherein the disease associated with GABA nervous system hypofunction is a nervous system disease or a psychiatric disease. A neurological or psychiatric disorder that causes epileptic seizures (tonic, clonic, absence, myoclonic, generalized seizures including cataplexy, focal seizures, unclassified seizures), status epilepticus, West syndrome, Dravet syndrome , Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a distinct cluster, Rasmussen syndrome, depressive symptoms with or without epilepsy, anxiety disorders, Obsessive-compulsive disorder, REM sleep disorder associated with Parkinson's disease and dementia with Lewy bodies, neuropathic pain, developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral tendons 19. The therapeutic and/or prophylactic agent according to claim 18, which is sclerosis or Parkinson's disease. GABA nervous system hypofunction, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment A method for treating and/or preventing diseases involving Use of the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for producing a therapeutic and/or preventive agent for diseases associated with GABA nervous system hypofunction . 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in treating and/or preventing diseases associated with GABA nervous system hypofunction. A therapeutic and/or preventive agent for epilepsy, comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient. Epilepsy, epileptic seizures (tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, unclassified seizures), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome , autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), medial temporal lobe epilepsy with hippocampal sclerosis as a distinct group of symptoms, or Rasmussen's syndrome. Treatment of epilepsy and/or treatment of epilepsy, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Or a method for prevention. Use of the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for manufacturing a therapeutic and/or preventive agent for epilepsy. Selected from a drug containing the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a drug classified as an antiepileptic drug, an antidepressant drug, or an antipsychotic drug A medicament in combination with at least one or more drugs. For treating diseases associated with GABA nervous system hypofunction, characterized in that it is used in combination with at least one drug selected from drugs classified as antiepileptic drugs, antidepressants, or antipsychotic drugs. , a medicament containing the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

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