JP2023046323A - Pharmaceutical composition containing oxadiazole derivative - Google Patents

Abstract

To provide a pharmaceutical composition useful as an antiepileptic.SOLUTION: The pharmaceutical composition contains a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. (In the formula, Q1 represents halogen; Q2 represents hydrogen or the like; X, Y and Z each represent a nitrogen atom or oxygen atom; and R1 has a prescribed structure.)SELECTED DRAWING: None

Description

The present invention provides oxadiazole derivatives and pharmaceutically acceptable salts thereof which are useful as medicines, pharmaceutical compositions containing them as active ingredients, therapeutic agents for diseases such as epilepsy and/or depressive syndrome, and/or Regarding prophylaxis.

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. (Non-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 oxadiazoles having a sweetness modifying effect, but they have a different chemical structure from the compound represented by formula (1) described below.

WO2006/138512

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 pharmaceutical composition useful as an antiepileptic drug.

As a result of intensive research, the present inventors have found that a compound represented by the following formula (1) exhibits a strong anticonvulsant action, that is, exhibits an antiepileptic action and also has a GABA-A receptor activating action. clarified and completed the present invention. According to the present invention, a pharmaceutical composition containing an oxadiazole derivative represented by the following formula (1) (hereinafter sometimes referred to as "the present compound") is provided.

That is, the present invention is as follows.

［式中、
Ｑ^１はハロゲンを表し、
Ｑ^２は水素、ハロゲン、シアノ、Ｃ_１－３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_１－３アルコキシ（該アルコキシはハロゲン、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）を表し、
Ｘ、Ｙ及びＺは、同一又は異なって、窒素原子又は酸素原子を表し、ただし、Ｘ、Ｙ及びＺを含む環は、Ｘ、Ｙ及びＺのうちの２つが窒素原子であり、残りの１つが酸素原子であるヘテロアリールであり、
Ｒ^１は以下の（２）～（４）のいずれかを表し、

Ｒ^２及びＲ^３は、同一又は異なって、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）、又は窒素原子及び酸素原子からなる群から独立して選択される１または２個のヘテロ原子を含むＣ_４－６飽和複素環（該飽和複素環はハロゲン、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^４及びＲ^５は、同一又は異なって、水素、ハロゲン、水酸基、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、Ｒ^４及びＲ^５が同一の炭素原子上又は隣接する炭素原子上に存在する場合、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）又は窒素原子及び酸素原子からなる群から独立して選択される１または２個のヘテロ原子を含むＣ_４－６飽和複素環（該飽和複素環はハロゲン、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）を構成した基を形成してもよく、
ｎは、０～２の整数を表す。］ [Item 1] A pharmaceutical composition containing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[In the formula,
Q ¹ represents halogen,
Q ² is hydrogen, halogen, cyano, C _1-3 alkyl (wherein alkyl is 1 to 3 substituted groups independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _1-3 alkoxy (wherein said alkoxy is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy) It may be substituted with a substituent) represents,
X, Y and Z are the same or different and represent a nitrogen atom or an oxygen atom, provided that a ring containing X, Y and Z has two of X, Y and Z being nitrogen atoms and the remaining one is a heteroaryl wherein one is an oxygen atom,
R ¹ represents any one of the following (2) to (4),

R ² and R ³ are the same or different and C _1-6 alkyl (wherein said alkyl is 1 to 3 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 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), or together with the carbon atom to which they are attached, represents C _3-6 cycloalkyl (wherein said cycloalkyl is halogen, hydroxyl, C _1- optionally substituted with ₁ to 3 substituents independently selected from the group consisting of 3 alkyl and C _1-3 alkoxy), or independently selected from the group consisting of a nitrogen atom and an oxygen atom C _4-6 saturated heterocycle containing 1 or 2 heteroatoms, wherein the saturated heterocycle is 1-3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy may be substituted with one substituent),
R ⁴ and R ⁵ are the same or different, hydrogen, halogen, hydroxyl group, 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 optionally substituted with 1 to 3 selected substituents), or C _3-6 cycloalkyl (wherein the cycloalkyl is from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 independently selected substituents), or when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms, they are C _3-6 cycloalkyl together with the carbon atom to which is attached, wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy or a C _4-6 saturated heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms (wherein the saturated heterocycle is a halogen , hydroxyl group, 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; ]

[Claim 2] R ² and R ³ are the same or different and have 1 to 3 substituted groups independently selected from _{the group consisting of fluorine, hydroxyl group and C 1-3 alkoxy} ; or C _3-6 cycloalkyl together with the carbon atom to which they are attached, wherein said cycloalkyl is fluorine, hydroxyl, C _1-3 alkyl and C _1- optionally substituted with ₁ to 3 substituents independently selected from the group consisting of 3alkoxy), or 1 independently selected from the group consisting of a nitrogen atom and an oxygen atom, or a C _4-6 saturated heterocyclic ring containing 2 heteroatoms, wherein the saturated heterocyclic ring comprises 1 to 3 independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; optionally substituted with a substituent),
Item 1. The pharmaceutical composition according to item 1.

[Claim 3] R ² and R ³ are the same or different and represent C _1-3 alkyl (the alkyl may be substituted with fluorine), or together with the carbon atom to which they are attached a group constituting a C _3-6 cycloalkyl (the cycloalkyl may be substituted with fluorine), or 1 or 2 heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom; A group constituting a C _4-6 saturated heterocyclic ring (the saturated heterocyclic ring may be substituted with fluorine) containing
Item 3. The pharmaceutical composition according to item 2.

[Claim 4] R ⁴ and R ⁵ are the same or different and are independently selected from the group consisting of hydrogen, fluorine, hydroxyl group and C _1-3 alkyl (wherein said alkyl is independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy) or C _3-6 cycloalkyl (wherein the cycloalkyl is independently from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy) optionally substituted with 1 to 3 substituents selected by ), or when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms, they are bonded C _3-6 cycloalkyl together with the carbon atom, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy or a C _4-6 saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom (the saturated heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group, C _1-3 alkyl and C _1-3 alkoxy) good,
The pharmaceutical composition according to any one of Items 1 to 3.

[Claim 5] R ⁴ and R ⁵ are the same or different, hydrogen, fluorine, hydroxyl group, C _1-3 alkyl (said alkyl may be substituted with fluorine), or C _3-6 cycloalkyl (said Cycloalkyl may be optionally substituted with fluorine), or when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms, together with the carbon atom to which they are attached, form a group constituting C _3-6 cycloalkyl (the cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine and C _1-3 alkyl) may
Item 5. The pharmaceutical composition according to item 4.

[Item 6] Q ¹ is fluorine, chlorine or bromine;
Q ² is hydrogen, fluorine, chlorine, bromine, cyano, C _1-3 alkyl (the alkyl may be substituted with fluorine) or C _1-3 alkoxy (the alkoxy may be substituted with fluorine) is
Item 6. The pharmaceutical composition according to any one of items 1 to 5.

項１～６のいずれか一項に記載の医薬組成物。 [Claim 7] The ring containing X, Y and Z is (5a), (5b), or (5c) below.

The pharmaceutical composition according to any one of Items 1-6.

項７に記載の医薬組成物。 [Claim 8] The ring containing X, Y and Z is (5a) or (5b) below.

Item 8. The pharmaceutical composition according to item 7.

項１～３、又は６～８のいずれか一項に記載の医薬組成物。 [Claim 9] R ¹ is the following (2) or (3),

9. The pharmaceutical composition according to any one of Items 1 to 3 or 6 to 8.

項１、又は４～８のいずれか一項に記載の医薬組成物。 [Clause 10] R ¹ is the following (4),

Item 1, or the pharmaceutical composition according to any one of items 4 to 8.

[Claim 11] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof is selected from the compounds represented by the following compound names or pharmaceutically acceptable salts thereof: Item 1. The pharmaceutical composition of item 1:
2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide (Example 1),
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide (Example 2),
2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide (Example 3),
1-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide (Example 4),
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide (Example 5),
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-fluorocyclobutane-1-carboxamide (Example 6),
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3,3-difluorocyclobutane-1-carboxamide (Example 7),
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxamide (Example 8),
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclopentane-1-carboxamide (Example 9),
4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]tetrahydro-2H-pyran-4-carboxamide (Example 10),
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-ethylbutanamide (Example 11),
2-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide (Example 12),
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide (Example 13),
2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide (Example 14),
2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropanamide (Example 15),
2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropanamide (Example 16),
2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide (Example 17),
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide (Example 18),
2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide (Example 19),
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide (Example 20),
2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide (Example 21),
2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide (Example 22),
2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide (Example 23),
2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide (Example 24),
5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 25),
5-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 26),
5-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 27),
5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1,5-dimethylpyrrolidin-2-one (Example 28),
5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 29),
5-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 30),
(S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 31), and (R)- 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 32).

[Claim 12] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof is selected from the compounds represented by the following compound names or pharmaceutically acceptable salts thereof: Item 1. The pharmaceutical composition of item 1:
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide (Example 2),
2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide (Example 3),
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide (Example 13),
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide (Example 20),
5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 25),
5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 29),
(S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 31), and (R)- 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 32).

[Item 13] A therapeutic and/or preventive agent for a nervous system disease or a psychiatric disorder, comprising the pharmaceutical composition according to any one of items 1 to 12.

[Claim 14] A disease in which excitation (E) is increased and/or inhibition (I) is decreased in the E/I balance, which contains the pharmaceutical composition according to any one of items 1 to 12. Therapeutic and / or prophylactic agent of.

[Item 15] A therapeutic and/or preventive agent for diseases associated with GABA nervous system hypofunction, containing the pharmaceutical composition according to any one of items 1 to 12.

[Item 16] The therapeutic and/or prophylactic agent according to Item 15, wherein the disease associated with GABA nervous system dysfunction is a nervous system disease or a psychiatric disease.

[Item 17] 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 17. The therapeutic and/or prophylactic agent according to item 13 or 16, which is atrophic lateral sclerosis or Parkinson's disease.

[Item 18] Nervous system disease or psychiatric disease is epilepsy, neuropathic pain, neurodevelopmental disorder group, bipolar disorder and related disorder group, schizophrenia spectrum disorder, Alzheimer's disease or other neurocognitive disorder group, 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 17. The therapeutic and/or prophylactic agent according to Item 13 or 16, which is

[Claim 19] Treating a disease associated with GABA nervous system dysfunction, comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of Items 1 to 12 to a patient in need of treatment and/or preventive methods.

[Item 20] Use of the pharmaceutical composition according to any one of Items 1 to 12 for manufacturing a therapeutic and/or preventive agent for a disease associated with GABA nervous system dysfunction.

[Item 21] The pharmaceutical composition according to any one of Items 1 to 12, for use in the treatment and/or prevention of diseases associated with GABA nervous system dysfunction.

[Item 22] A therapeutic and/or preventive agent for epilepsy, comprising the pharmaceutical composition according to any one of items 1 to 12.

[Item 23] 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, 23. The therapeutic agent and/or according to item 22, 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.

[Item 24] A method for treating and/or preventing epilepsy, comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of Items 1 to 12 to a patient in need of treatment. .

[Item 25] Use of the pharmaceutical composition according to any one of Items 1 to 12 for manufacturing a therapeutic and/or preventive agent for epilepsy.

[Item 26] The pharmaceutical composition according to any one of Items 1 to 12, which is used for the treatment and/or prevention of epilepsy.

[Claim 27] The pharmaceutical composition according to any one of items 1 to 12 and at least one drug selected from drugs classified as antiepileptic drugs, antidepressants, or antipsychotic drugs medicines in combination.

[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 13. The pharmaceutical composition according to any one of Items 1 to 12, for treatment.

に示す化合物（ＩＩｃ１）と化合物（ＩＩｃ２）を反応させて化合物（ＩＩｃ’）を得る工程と、化合物（ＩＩｃ’）をメチル化する工程を含む、化合物（Ｉｃ）の製造方法（式中の記号は前記と同じ意味を有する）。 [Section 29] The following formula:

A method for producing compound (Ic), comprising a step of reacting compound (IIc1) with compound (IIc2) shown in to obtain compound (IIc′), and a step of methylating compound (IIc′) (the symbol in the formula have the same meaning as above).

に示す化合物（ＩＩｃ１’）と化合物（ＩＩｃ２’）を反応させる工程を含む、化合物（Ｉｃ’）の製造方法（式中の記号は前記と同じ意味を有する）。 [Section 30] The following formula:

A method for producing compound (Ic'), comprising the step of reacting compound (IIc1') shown in 1 with compound (IIc2') (the symbols in the formula have the same meanings as above).

This compound showed potent anticonvulsant activity in multiple convulsive model animals caused by decreased GABA signal (subcutaneous injection pentetrazole model in Test Example 1, Drave model mouse febrile convulsion in Test Example 3). The subcutaneous injection pentetrazole model of Test Example 1 is a phenotype of generalized absence seizures and myoclonic seizures, and is a model exhibiting a seizure type in which the remission rate of existing antiepileptic drugs is low. The Dravet model mouse febrile convulsion in Test Example 3 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 compounds are therefore useful in epileptic seizures (e.g., epileptic seizures (tonic, clonic, absence, myoclonic, generalized including atonic seizures, 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, etc.) as a prophylactic and/or therapeutic agent. 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. The GABA-A receptor activating activity of this compound is exerted in a mode of action different from that of benzodiazepines, which are one of the existing GABA nervous system activating agents, and depression in a forced swimming rat model in which benzodiazepines did not show any effect. Since it exhibited an effect on symptoms (Test Example 5), it has an effect on depressive symptoms that occur or do not occur with epilepsy, and has utility that existing antiepileptic drugs do not have. Since this compound has GABA-A receptor activating activity, it has been shown to be therapeutically effective with existing GABA nervous system activators. It is also useful as a prophylactic and/or therapeutic agent for sleep disorders. 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. Furthermore, it is useful as a prophylactic and/or therapeutic agent for other diseases described herein.
In addition, since the present compound has an effect of enhancing inhibition (I) in the balance between excitation (E) and inhibition (I) (E/I balance), it is a therapeutic and / or preventive agent for nervous system diseases or psychiatric diseases. In particular, it can be 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.

1 is an example of the X-ray powder diffraction pattern of the compound of Example 33 (crystalline form A). The x-axis indicates the 2θ value and the y-axis indicates the intensity. An example of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) for the compound of Example 33 (crystalline form A) is shown. The x-axis shows temperature (° C.) and the left y-axis shows heat flow (Watts/g). Also, the right y-axis indicates weight variation (%).

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, chlorine, or bromine is preferred. Fluorine or chlorine is more preferred, and fluorine is even 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 _1-3 alkyl”, more preferably “C _1-2 alkyl”. “C _1-3 alkyl” preferably includes “C _1-2 alkyl”, more preferably methyl. 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 _1-6 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, pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl , hexyl and the like.

“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 _1-3 alkoxy” means an oxy group substituted with the above “C _1-3 alkyl”. The “C _1-3 alkoxy group” is preferably “C _1-2 alkoxy”, more preferably “methoxy”. Specific examples of “C _1-2 alkoxy” include methoxy, ethoxy and the like. Specific examples of “C _1-3 alkoxy” include propoxy, 1-methylethoxy and the like in addition to the specific examples of “C _1-2 alkoxy”.

“C _4-6 saturated heterocycle” means a 4- to 6-membered saturated ring containing one or more identical or different heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; Partially bridged structures are also included. Preferred are C _4-6 saturated heterocycles containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. "C _4-6 saturated heterocycle" preferably includes "C _4-5 saturated heterocycle". Specific examples of the “C _4-5 saturated heterocycle” include oxetane, azetidine, tetrahydrofuran, pyrrolidine and the like. Specific examples of the "C _4-6 saturated heterocyclic ring" include, in addition to the specific examples of the above ""C _4-5 saturated heterocyclic ring", tetrahydropyran, piperidine, morpholine, piperazine and the like. .

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y, Z, Q ¹ , Q ² and n are preferably as follows, and the technical scope of the present invention is listed below. The range of compounds is not limited.

Ｒ^１の別の態様としては、以下の（２）または（３）が挙げられる。

Ｒ^１の別の態様としては、以下の（４）が挙げられる。

Embodiments of R ¹ include the following (2) to (4).

Another aspect of R ¹ includes the following (2) or (3).

Another aspect of R ¹ includes the following (4).

In preferred embodiments of R ² and R ³ , R ² and R ³ are the same or different,
(1) C _1-3 alkyl (wherein said alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl and C _1-3 alkoxy); or
(2) C _3-6 cycloalkyl together with the carbon atom to which R ² and R ³ are attached, wherein said cycloalkyl is independently from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; optionally substituted with 1 to 3 substituents selected by ), or (3) from a nitrogen atom and an oxygen atom together with the carbon atom to which R ² and R ³ are bonded C _4-6 saturated heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy (optionally substituted with 1 to 3 independently selected substituents).

A more preferred embodiment of R ² and R ³ is that R ² and R ³ are the same or different,
(1) C _1-3 alkyl (which alkyl may be substituted with fluorine), or
(2) a group which together with the carbon atoms to which they are attached constitutes a C _3-6 cycloalkyl (the cycloalkyl may be substituted with fluorine), or (3) consists of a nitrogen atom and an oxygen atom Groups constituting a C _4-6 saturated heterocyclic ring (the saturated heterocyclic ring may be substituted with fluorine) containing 1 or 2 heteroatoms independently selected from the group are exemplified.

The C _3-6 cycloalkyl formed together with the carbon atoms to which R ² and R ³ are attached includes, for example, the following groups.

The C _4-6 saturated heterocyclic ring formed together with the carbon atoms to which R ² and R ³ are attached includes 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. 4- to 6-membered saturated rings containing, for example, the following groups.

In preferred embodiments of R ⁴ and R ⁵ , R ⁴ and R ⁵ are the same or different,
(1) hydrogen,
(2) fluorine,
(3) a hydroxyl group,
(4) 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);
(5) C _3-6 cycloalkyl (wherein said cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; may be), or
when R ⁴ and R ⁵ are present on the carbon atom to which they are attached or on adjacent carbon atoms,
(6) C _3-6 cycloalkyl together with the carbon atom to which they are attached, said cycloalkyl being independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy (optionally substituted with 1 to 3 substituents), or (7) together with the carbon atom to which they are attached, a C _4-6 saturated heterocyclic ring (the cycloalkyl is fluorine, hydroxyl group , optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkyl and C _1-3 alkoxy). be done. The term "adjacent carbon atoms" as used herein refers to a state in which the ring-constituting carbon atoms to which ^R4 and ^R5 are respectively bonded are adjacent to each other and bonded.

A more preferred embodiment of R ⁴ and R ⁵ is that R ⁴ and R ⁵ are the same or different,
(1) hydrogen,
(2) fluorine,
(3) a hydroxyl group,
(4) C _1-3 alkyl (which alkyl may be substituted with fluorine),
(5) is C _3-6 cycloalkyl (wherein the cycloalkyl is optionally substituted with fluorine), or
when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms,
(6) C _3-6 cycloalkyl together with the carbon atom to which they are attached, wherein the cycloalkyl is 1 to 3 substituents independently selected from the group consisting of fluorine and C _1-3 alkyl; (optionally substituted) may be formed.

When R ⁴ and R ⁵ are present on the same carbon atom or on adjacent carbon atoms, the C _3-6 cycloalkyl formed together with the carbon atom to which they are attached includes, for example, the following groups, etc. mentioned.

When R ⁴ and R ⁵ are present on the same carbon atom or on adjacent carbon atoms, the C _4-6 saturated heterocyclic ring formed together with the carbon atom to which they are attached includes, for example, the following groups, etc. is mentioned.

図（５ａ）～（５ｃ）において、左側の結合手はベンゼン環と結合し、右側の結合手はＲ^１と結合する。 Preferred embodiments of X, Y, and Z are the same or different and represent a nitrogen atom or an oxygen atom, provided that the ring containing X, Y, and Z is a ring in which two of X, Y, and Z are nitrogen atoms. , and the remaining one is an oxygen atom.

In Figures (5a) to (5c), the bond on the left bonds to the benzene ring and the bond on the right bonds to ^R1 .

More preferred embodiments of X, Y and Z include the following oxadiazoles.

Embodiments of n include integers of 0, 1, or 2, and preferred embodiments include 0 or 1.

Preferred embodiments of Q ¹ include fluorine, chlorine, bromine, or iodine, more preferably fluorine, chlorine, or bromine.

A preferred embodiment of ^Q2 is
(1) hydrogen,
(2) fluorine,
(3) chlorine,
(4) bromine,
(5) cyano,
(6) C _1-3 alkyl (the alkyl may be substituted with fluorine), or (7) C _1-3 alkoxy (the alkoxy may be substituted with fluorine)
is mentioned.

As a more preferable aspect of ^Q2 ,
(1) hydrogen,
(2) fluorine,
(3) chlorine, or (4) cyano.

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

Ｒ^２及びＲ^３が、同一又は異なって、
（１）Ｃ_１－３アルキル（該アルキルはフッ素、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）、
（２）Ｃ_３－６シクロアルキル（該シクロアルキルはフッ素、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）であるか、あるいは、
（３）Ｒ^２及びＲ^３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フッ素、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、または
（４）Ｒ^２及びＲ^３が結合する炭素原子と一緒になって窒素原子及び酸素原子からなる群から独立して選択される１または２個のヘテロ原子を含むＣ_４－６飽和複素環（該飽和複素環はハロゲン、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
であり、
Ｘ、Ｙ、Ｚを含むヘテロアリールが、以下の（５ａ）～（５ｃ）のいずれかであり、

Ｑ^１が、フッ素、塩素、又は臭素であり、
Ｑ^２が、水素、フッ素、塩素、シアノ、Ｃ_１－３アルキル（該アルキルはフッ素、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）、またはＣ_１－３アルコキシ（該アルコキシはフッ素、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）
である、化合物又はその製薬学的に許容される塩。 One aspect of the compound represented by Formula (1) includes the following (A).
(A)
R ¹ is any of the following,

R ² and R ³ are the same or different,
(1) C _1-3 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; can also be used),
(2) C _3-6 cycloalkyl (wherein said cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; may be), or
(3) C _3-6 cycloalkyl together with the carbon atom to which R ² and R ³ are attached, wherein said cycloalkyl is independently from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; or (4) consisting of a nitrogen atom and an oxygen atom together with the carbon atom to which R ² and R ³ are bonded C _4-6 saturated heterocycle containing 1 or 2 heteroatoms independently selected from the group, wherein said saturated heterocycle is independently from the group consisting of halogen, hydroxy, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents selected by
heteroaryl containing X, Y and Z is any of (5a) to (5c) below;

Q ¹ is fluorine, chlorine, or bromine;
Q ² is 1 to 3 groups independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, C _1-3 alkyl, wherein the alkyl is fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy; optionally substituted with a substituent), or C _1-3 alkoxy (wherein the alkoxy is 1 to 3 independently selected from the group consisting of fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy) optionally substituted with a substituent)
is a compound or a pharmaceutically acceptable salt thereof.

Ｒ^４及びＲ^５が、同一又は異なって、
（１）水素、
（２）ハロゲン、
（３）水酸基、
（４）Ｃ_１－３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）、
（５）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）であるか、あるいは、
Ｒ^４及びＲ^５が結合する炭素原子上または隣接する炭素原子上に存在する場合、
（６）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、または
（７）それらが結合する炭素原子と一緒になって窒素原子及び酸素原子からなる群から独立して選択される１または２個のヘテロ原子を含むＣ_４－６飽和複素環（該飽和複素環はハロゲン、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）を構成した基を形成してもよく、
Ｘ、Ｙ、Ｚを含むヘテロアリールが、以下の（５ａ）～（５ｃ）のいずれかであり、

Ｑ^１が、フッ素、塩素、又は臭素であり、
Ｑ^２が、水素、フッ素、塩素、シアノ、Ｃ_１－３アルキル（該アルキルはフッ素、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）、Ｃ_１－３アルコキシ（該アルコキシはフッ素、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）であり、
ｎの好ましい態様としては０、１、２の整数
である、化合物又はその製薬学的に許容される塩。 One aspect of the compound represented by Formula (1) includes the following (B).
(B)
R ¹ is (4) below,

R ⁴ and R ⁵ are the same or different,
(1) hydrogen,
(2) halogen,
(3) a hydroxyl group,
(4) C _1-3 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; can also be used),
(5) C _3-6 cycloalkyl, wherein said 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 be), or
when R ⁴ and R ⁵ are present on the carbon atom to which they are attached or on adjacent carbon atoms,
(6) C _3-6 cycloalkyl together with the carbon atom to which they are attached, wherein said cycloalkyl is independently selected from the group consisting of halogen, hydroxy, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents), or (7) together with the carbon atom to which they are attached are independently selected from the group consisting of nitrogen and oxygen atoms C _4-6 saturated heterocycle containing 1 or 2 heteroatoms, wherein the saturated heterocycle is 1-3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy may be substituted with one substituent) may form a group,
heteroaryl containing X, Y and Z is any of (5a) to (5c) below;

Q ¹ is fluorine, chlorine, or bromine;
Q ² is 1 to 3 groups independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, C _1-3 alkyl, wherein the alkyl is fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy; optionally substituted with substituents), C _1-3 alkoxy (wherein said alkoxy has 1 to 3 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy) optionally substituted with a group),
A preferred embodiment of n is an integer of 0, 1 or 2, or a compound or a pharmaceutically acceptable salt thereof.

Ｒ^２及びＲ^３が、同一又は異なって、
（１）Ｃ_１－３アルキル（該アルキルはフッ素で置換されていてもよい）であるか、あるいは、
（２）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フッ素で置換されていてもよい）を構成した基、または
（３）窒素原子及び酸素原子からなる群から独立して選択される１または２個のヘテロ原子を含むＣ_４－６飽和複素環（該飽和複素環はフッ素で置換されていてもよい）を構成した基
であり、
Ｘ、Ｙ、Ｚを含むヘテロアリールが、以下の（５ａ）または（５ｂ）であり、

Ｑ^１が、フッ素、塩素、または臭素であり、
Ｑ^２が、水素、フッ素、塩素、シアノである化合物又はその製薬学的に許容される塩。 One aspect of the compound represented by Formula (1) includes the following (C).
(C)
R ¹ is any of the following,

R ² and R ³ are the same or different,
(1) C _1-3 alkyl (which alkyl may be substituted with fluorine), or
(2) a group that together with the carbon atoms to which they are attached constitutes a C _3-6 cycloalkyl (the cycloalkyl may be substituted with fluorine), or (3) consists of a nitrogen atom and an oxygen atom a group constituting a C _4-6 saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group (the saturated heterocyclic ring may be substituted with fluorine),
heteroaryl containing X, Y, Z is (5a) or (5b) below,

Q ¹ is fluorine, chlorine, or bromine;
A compound wherein ^Q2 is hydrogen, fluorine, chlorine, cyano, or a pharmaceutically acceptable salt thereof.

Ｒ^４及びＲ^５が、同一又は異なって、
（１）水素、
（２）フッ素、
（３）水酸基、
（４）Ｃ_１－３アルキル（該アルキルはフッ素で置換されていてもよい）、
（５）Ｃ_３－６シクロアルキル（該シクロアルキルはフッ素で置換されていてもよい）であるか、あるいは、
Ｒ^４及びＲ^５が同一の炭素原子上又は隣接する炭素原子上に存在する場合、
（６）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フッ素及びＣ_１－３アルキ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）を構成した基を形成してもよく、
Ｘ、Ｙ、Ｚを含むヘテロアリールが、以下の（５ａ）または（５ｂ）であり、

Ｑ^１が、フッ素、塩素、または臭素であり、
Ｑ^２が、水素、フッ素、塩素、シアノである化合物又はその製薬学的に許容される塩。 One aspect of the compound represented by formula (1) includes the following (D).
(D)
R ¹ is the following (4),

R ⁴ and R ⁵ are the same or different,
(1) hydrogen,
(2) fluorine,
(3) a hydroxyl group,
(4) C _1-3 alkyl (which alkyl may be substituted with fluorine),
(5) is C _3-6 cycloalkyl (wherein the cycloalkyl is optionally substituted with fluorine), or
when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms,
(6) C _3-6 cycloalkyl together with the carbon atom to which they are attached, wherein the cycloalkyl is 1 to 3 substituents independently selected from the group consisting of fluorine and C _1-3 alkyl; optionally substituted) may form a group that constitutes,
heteroaryl containing X, Y, Z is (5a) or (5b) below,

Q ¹ is fluorine, chlorine, or bromine;
A compound wherein ^Q2 is hydrogen, fluorine, chlorine, cyano, or a pharmaceutically acceptable salt thereof.

The crystalline forms of the compound of formula (1) can be determined by conventional techniques such as X-ray powder diffraction (hereinafter "XRPD") analysis, differential scanning calorimetry (hereinafter "DSC"), thermogravimetric analysis (hereinafter "TGA"). It is generally known that analysis can be performed using

For example, the compound of Example 33 exists in one crystalline form, identified herein as crystalline form A, but the crystalline form of the present invention is not limited to this crystalline form.

As a further aspect of the invention, (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidine-2 as crystalline form A - include on.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , 2-theta, having an X-ray powder diffraction pattern with characteristic peaks at at least 13.6°±0.2°.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , 2-theta, having an X-ray powder diffraction pattern with characteristic peaks at at least 14.7°±0.2°.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , 2-theta, having an X-ray powder diffraction pattern with characteristic peaks at at least 21.7°±0.2°.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , 2-theta, having an X-ray powder diffraction pattern with characteristic peaks at least at 25.0°±0.2°.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , expressed in 2-theta, characteristic of at least 13.6°±0.2°, 14.7°±0.2°, 21.7°±0.2° and 25.0°±0.2° Crystalline form A has a peaked powder X-ray diffraction pattern.

As a further aspect of the invention, crystalline form A of (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2- 5.9 ± 0.2°, 13.6 ± 0.2°, 14.7 ± 0.2°, 15.8 ± 0.2°, 16.0 ± 0.2°, 16.7±0.2°, 18.1±0.2°, 21.7±0.2°, 25.0±0.2°, 27.4±0.2° Those having a powder X-ray diffraction pattern with characteristic peaks are included. The crystal is identified by having 4 or 5 selected from these 10 peaks.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , a crystalline form A having an endothermic peak associated with melting with an extrapolated onset temperature (Tim) at 83.6°C ± 5°C in differential scanning calorimetry (DSC).

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , which has a DSC thermogram substantially the same as the DSC thermogram shown in FIG.

A further aspect of the present invention is (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one , which has a TGA graph substantially the same as the TGA graph shown in FIG.

Crystalline Form A of Example 33 can be prepared in the organic solvents of Example 33 (e.g., tert-butyl methyl ether, 2-propanol, ethyl acetate, toluene, diisopropyl ether, and ethyl acetate/heptane, toluene/heptane and ethyl acetate/heptane etc.) or a mixed solvent with water (e.g., 2-propanol / water mixture) suspension at room temperature or under heating conditions (preferably 25 ° C. to boiling point, more preferably 25 to 60 ° C.) It can be produced by dissolving at , cooling (preferably 0° C. to 25° C., more preferably 0° C.), stirring, and filtering. Alternatively, after dissolving the compound of Example 33 in the above-described organic solvent or a mixed solvent with water at room temperature or under heating conditions, the temperature at the time of dissolution, or cooling to room temperature, ice cooling, etc. During or after cooling, a poorly soluble organic solvent (e.g., hexane, heptane, etc.) or water is further added, or the dissolved solution is added to a poorly soluble organic solvent (e.g., hexane, heptane, etc.) or water. It can also be produced by dripping.

The 2-theta values of X-ray powder diffraction patterns can vary slightly from instrument to instrument or sample to sample, so the numbers given here are not absolute (Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), see X-Ray Diffraction Procedures). Generally, the measurement error of diffraction angles in X-ray powder diffraction spectra is, for example, about ±0.2° in 2θ, and that degree of measurement error should be taken into account when considering X-ray powder diffraction data. . Furthermore, the intensity can vary depending on experimental conditions and sample preparation (preferred orientation). In the present application, measurements are given when carried out using copper radiation (Cu Kα1, λ=1.5406 Å, Kα2, λ=1.5444 Å).

It is also known that X-ray powder diffraction patterns can be obtained with one or more measurement errors depending on the measurement conditions (eg the instrumentation or equipment used). For example, grains with non-uniform sizes and aspect ratios greater than 30 microns can affect the relative intensities of the peaks. Also, the position of the reflection can be affected by the exact height at which the sample is placed in the diffractometer and the zero calibration of the diffractometer. The planarity of the sample surface can also have some effect. Thus, unless otherwise stated, the crystalline forms of the present invention described above are not limited to crystals that provide the X-ray powder diffraction patterns shown in FIG. Any crystals that give the same X-ray powder diffraction pattern are within the scope of the invention.

Moreover, ±5° C. is allowed for the extrapolation start temperature (Tim) of differential scanning calorimetry (DSC), the endothermic peak temperature (Tpm), and the like. The extrapolation start temperature (Tim) of differential scanning calorimetry (DSC) refers to the temperature at the intersection of the extrapolated line of the rising portion of the endothermic peak curve and the baseline, and the endothermic peak temperature (Tpm) , refers to the peak top temperature of the endothermic peak.

"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 it is desired to obtain a salt of the present compound, when the present compound is obtained in the form of a salt, it may be purified as it is, and when obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent. , an acid or a base may be added to form a salt in the usual manner.

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). subsumed.
The present invention includes a pharmaceutical composition containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. In addition, since the present compound may exist in the form of hydrates and/or solvates with various solvents (ethanolates, etc.), these hydrates and/or solvates are also included in the present compound. included. Furthermore, the present invention includes all tautomers, all existing stereoisomers, and all forms of crystalline forms of the compounds of formula (1), as well as mixtures thereof.

Among the compounds represented by formula (1), there are optical isomers based on the optically active center, atropisomers based on axial or planar chirality caused by restriction of intramolecular rotation, other stereoisomers, All possible isomers and mixtures thereof, including tautomers, geometric isomers, etc., which may exist, are included within the scope of the present invention.

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.

The method for producing the present compound will be described below, but the method for producing the present compound is not limited to these.

（式中、Ｒ^２、Ｒ^３、Ｑ^１、Ｑ^２、Ｘ、Ｙ及びＺは項１の定義に同じである。） Manufacturing method 1
Among the compounds of the formula (I), the compound of the following formula (Ia) can be produced by the following production method.

(Wherein, R ² , R ³ , Q ¹ , Q ² , X, Y and Z are the same as defined in item 1.)

Compound (Ia) is obtained by an amidation reaction between (IIa) and ammonia. Amidation reaction of compound (IIa) can be carried out according to a conventional method. For example, this reaction is accomplished by converting compound (IIa) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting it with ammonia. 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. Specific examples of the solvent should be selected according to the type of starting compound, etc. Examples include THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, etc., which may be used alone or as a mixed solvent. can do. The reaction temperature is not particularly limited, but is usually selected from the range of -20°C to the boiling point of the solvent used, preferably 0°C to 30°C. The reaction time is usually 30 minutes to 24 hours.

Compound (Ia) can also be produced by reacting compound (IIa) with an ammonium salt such as (NH ₄ ) ₂ CO ₃ in the presence of a condensing agent. Specific examples of the condensing agent 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. Specific examples of the solvent should be selected according to the type of starting compound, etc. Examples include THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, etc., which may be used alone or as a mixed solvent. can do. The reaction temperature is not particularly limited, but is usually selected from the range of -20°C to the boiling point of the solvent used, preferably 0°C to 30°C. The reaction time is usually 30 minutes to 24 hours.

（式中、Ｒ^２、Ｒ^３、Ｑ^１、Ｑ^２、Ｘ、Ｙ及びＺは項１の定義に同じである。Ｐ^１は、２，４－ジメトキシベンジル基、ｐ－メトキシベンジル基等の、酸性条件で除去することのできる窒素原子の保護基であり、Ｐ^２は、水素、または２，４－ジメトキシベンジル基、ｐ－メトキシベンジル基等の、酸性条件で除去することのできる窒素原子の保護基である。） Manufacturing method 2
Among the compounds of the formula (I), the compound of the following formula (1b) can be produced by the following production method.

(In the formula, R ² , R ³ , Q ¹ , Q ² , X, Y and Z are the same as defined in item 1. ^{P 1} is a 2,4-dimethoxybenzyl group, p-methoxybenzyl group, etc. is a nitrogen atom-protecting group that can be removed under acidic conditions, and ^P2 is hydrogen or a nitrogen atom that can be removed under acidic conditions, such as a 2,4-dimethoxybenzyl group or a p-methoxybenzyl group. is a protecting group of

Compound (Ib) is obtained by deprotecting compound (IIb). Deprotection of compound (IIb) can be carried out according to a conventional method. For example, this reaction is achieved by reacting compound (IIb) with strong organic acids such as trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid, or strong inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid.

Deprotection of compound (IIb) is carried out in a solvent or without solvent. Specific examples of the solvent should be selected according to the type of the raw material compound and the like. can be used alone or as a mixed solvent. As the nitrogen atom-protecting group in compound (IIb), in addition to 2,4-dimethoxybenzyl group, a protecting group that is cleaved under acidic conditions, such as t-butoxycarbonyl group, t-butyl group, p-methoxybenzyl group, etc. can be used, and the number of protecting groups may be one depending on the type of protecting group. 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 reaction time is usually 30 minutes to 24 hours.

（式中、Ｒ^４、Ｒ^５、Ｑ^１、Ｑ^２、Ｘ、Ｙ、Ｚ及びｎは項１の定義に同じである。） Manufacturing method 3
Among the compounds of formula (I), the compound of formula (1c) below can be produced by the following production method.

(In the formula, R ⁴ , R ⁵ , Q ¹ , Q ² , X, Y, Z and n are the same as defined in item 1.)

Compound (Ic) is obtained by methylating compound (IIc). Methylation of compound (IIc) can be carried out according to a conventional method. For example, this reaction is achieved by reacting compound (IIc) with a methylating agent such as methyl iodide, methyl bromide, dimethylsulfate, etc. in the presence 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. It can be used as a mixed solvent. Specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, potassium t-butoxy, sodium methoxide and the like. and alkali metal carbonates such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate and cesium carbonate. The reaction temperature is usually about -30°C to about 150°C, preferably about -10°C to about 70°C, although it varies depending on the kind of starting compound and reagent used. The reaction time is usually 30 minutes to 24 hours.

The compounds of formulas (Ia), (Ib) and (Ic) produced by production methods 1, 2 and 3 above can be isolated and purified by conventional methods such as chromatography and recrystallization.

The starting compounds used in Production Methods 1, 2 and 3 above can be produced by the following methods.

（式中、Ｒ^４、Ｒ^５、Ｑ^１、Ｑ^２、及びｎは項１の定義に同じである。） Manufacturing method 4
Among the compounds of formula (I), the compound of formula (1c') below can also be produced by the following production method.

(In the formula, R ⁴ , R ⁵ , Q ¹ , Q ² and n are the same as defined in item 1.)

Compound (Ic') is produced by reacting compound (IIc1') and compound (IIc2') in the presence of a condensing agent. Specific examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride, N,N'-carbonyldiimidazole, and benzotriazol-1-yl. -oxytris(pyrrolidino)phosphonium-hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide-hexafluorophosphate, 2 -chloro-1,3-dimethylimidazolinium-hexafluorophosphate, 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium-hexafluorophosphate, bromotris(pyrrolidino)phosphonium-hexafluorophosphate, propylphosphonic acid and anhydrides. These condensing agents can be used alone or in combination with peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole. Specific examples of the solvent should be selected according to the type of the raw material compound and the like. can be used as The reaction temperature is usually -100 to 200.degree. C., preferably -30 to 150.degree. The reaction time is usually 30 minutes to 24 hours.

（式中、Ｒ^２、Ｒ^３、Ｑ^１、Ｑ^２、Ｘ、Ｙ及びＺ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 5
Compound (IIa) used in Production Method 1 is produced according to the method shown by the following reaction scheme.

(Wherein, R ² , R ³ , Q ¹ , Q ² , X, Y and Z are the same as defined in item 1, and R is C _1-6 alkyl.)

(Step 1)
Compound (IIIa) is obtained by alkylating compound (IVa). The alkylation reaction of step 1 can be carried out according to a conventional method. For example, this reaction is carried out by reacting compound (IVa) with an alkyl halide or cycloalkyl halide represented by R ² X or R ³ X in the presence of a base in a suitable solvent. In addition, for a compound that forms a C _3-6 cycloalkyl or a 4-6-membered saturated heterocyclic ring together with the carbon atoms to which R ² and R ³ are attached, the compound (IVa) and the corresponding It is carried out by reacting a dihalide (for example, X—(CH ₂ ) _n —X (n represents an integer of 3 to 6 and X represents a halogen)). Specific examples of the solvent should be selected according to the type of the raw material compound and the like. can do. Specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, potassium t-butoxy, sodium methoxide and the like. and alkali metal carbonates such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate and cesium carbonate. 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. The reaction time is usually 30 minutes to 24 hours.

(Step 2)
Compound (IIa) is obtained by hydrolyzing compound (IIIa). 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 (IIIa) 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 the like. It can be used 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 kind of starting compound and reagent used, but is usually 0 to 150°C, preferably 20 to 100°C. The reaction time is usually 30 minutes to 24 hours.

（式中、Ｒ^２、Ｒ^３、Ｑ^１及びＱ^２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 6
Of the compounds (IIIa) used in Production Method 5, (IIIa') is produced by a condensation dehydration cyclization reaction between compound (IIIa1) and compound (IIIa2).

(In the formula, R ² , R ³ , Q ¹ and Q ² are the same as defined in Item 1, and R is C _1-6 alkyl.)

The condensation dehydration cyclization reaction of compound (IIIa1) and compound (IIIa2) can be carried out according to a conventional method. For example, this reaction is achieved by converting compound (IIIa2) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting it with compound (IIIa1). 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. Specific examples of the solvent should be selected according to the type of the raw material compound and the like. Alternatively, it can be used as a mixed solvent. The reaction temperature is usually -100 to 200.degree. C., preferably -30 to 150.degree. The reaction time is usually 30 minutes to 24 hours.

Compound (IIIa') can also be produced by reacting compound (IIIa1) with compound (IIIa2) in the presence of a condensing agent. Specific examples of the condensing agent 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. Specific examples of the solvent should be selected according to the type of the raw material compound and the like. can be used as The reaction temperature is usually -100 to 200.degree. C., preferably -30 to 150.degree. The reaction time is usually 30 minutes to 24 hours.

（式中、Ｑ^１及びＱ^２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 7
Of the compounds (IVa) used in Production Method 5, (IVa') is produced by a condensation dehydration cyclization reaction between compound (IVa1) and compound (IVa2).

(In the formula, Q ¹ and Q ² are the same as defined in item 1, and R is C _1-6 alkyl.)

Compound (IVa') is produced according to the method described in Production Method 6 using compound (IVa1) and compound (IVa2).

（式中、Ｑ^１及びＱ^２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 8
Of the compounds (IVa) used in Production Method 5, (IVa'') is produced by a condensation dehydration cyclization reaction between compound (IVa3) and compound (IVa4).

(In the formula, Q ¹ and Q ² are the same as defined in item 1, and R is C _1-6 alkyl.)

Compound (IVa'') is produced according to the method described in Production Method 6 using compound (IVa3) and compound (IVa4).

（式中、Ｑ^１及びＱ^２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 9
Among the compounds (IVa) used in Production Method 5, (IVa''') is produced by a condensation dehydration cyclization reaction between compound (IVa5) and compound (IVa6).

(In the formula, Q ¹ and Q ² are the same as defined in item 1, and R is C _1-6 alkyl.)

Compound (IVa''') is produced according to the method described in Production Method 6 using compound (IVa5) and compound (IVa6). When the 1,3,4-oxadiazole ring is produced by the cyclodehydration reaction, it is produced by coexisting a dehydrating agent such as phosphorus oxychloride or Burgess reagent as an additive.

（式中、Ｒ^２、Ｒ^３、Ｑ^１、Ｑ^２、Ｘ、Ｙ及びＺは項１の定義に同じである。Ｐ^１は、２，４－ジメトキシベンジル基、ｐ－メトキシベンジル基等の、酸性条件で除去することのできる窒素原子の保護基であり、Ｐ^２は、水素、または２，４－ジメトキシベンジル基、ｐ－メトキシベンジル基等の、酸性条件で除去することのできる窒素原子の保護基である。） Manufacturing method 10
Compound (IIb) used in Production Method 2 is produced according to the method shown by the following reaction scheme.

(In the formula, R ² , R ³ , Q ¹ , Q ² , X, Y and Z are the same as defined in item 1. ^{P 1} is a 2,4-dimethoxybenzyl group, p-methoxybenzyl group, etc. is a nitrogen atom-protecting group that can be removed under acidic conditions, and ^P2 is hydrogen or a nitrogen atom that can be removed under acidic conditions, such as a 2,4-dimethoxybenzyl group or a p-methoxybenzyl group. is a protecting group of

(Step 1)
Compound (IVb) is obtained by reacting compound (Vb) with sodium sulfite. The substitution reaction in step 1 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 2)
Compound (IIIb) is obtained by sulfonamidating compound (IVb). Sulfonamidation in step 2 can be carried out according to a conventional method. For example, this reaction is accomplished by converting compound (IVb) 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 intermediate sulfonyl chloride of step 2 to the sulfonamide, in a solvent with or without base, is carried out on the amine NHP ¹ P ² mono- or di-substituted by protecting groups that can be removed under acidic conditions. is performed by acting Specific examples of the solvent should be selected according to the _type of the raw material compound and the like. can be done. 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. Organic bases such as alkali metal carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine and 4-dimethylaminopyridine can be mentioned. 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 (IIb) is obtained by alkylating compound (IIIb). Compound (IIb) is produced using compound (IIIb) according to the method described in Production Method 5, Step 1.

（式中、Ｑ^１及びＱ^２は項１の定義に同じである。） Manufacturing method 11
Of the compounds (Vb) used in Production Method 10, (Vb') is produced by a condensation dehydration cyclization reaction between compound (Vb1) and compound (Vb2).

(In the formula, Q ¹ and Q ² are the same as defined in item 1.)

Compound (Vb') is produced according to the method described in Production Method 6 using compound (Vb1) and compound (Vb2).

（式中、Ｑ^１及びＱ^２は項１の定義に同じである。） Manufacturing method 12
Of the compounds (Vb) used in Production Method 10, (Vb'') is produced by a condensation dehydration cyclization reaction between compounds (Vb3) and (Vb4).

(In the formula, Q ¹ and Q ² are the same as defined in item 1.)

Compound (Vb'') is produced according to the method described in Production Method 6 using compound (Vb3) and compound (Vab).

（式中、Ｑ^１及びＱ^２は項１の定義に同じである。） Manufacturing method 13
Of the compounds (Vb) used in Production Method 10, (Vb''') is produced by a condensation dehydration cyclization reaction between compound (Vb5) and compound (Vb6).

(In the formula, Q ¹ and Q ² are the same as defined in item 1.)

Compound (Vb''') is produced according to the method described in Production Method 9 using compound (Vb5) and compound (Vb6).

（式中、Ｒ^４、Ｒ^５、Ｑ^１、Ｑ^２、及びｎは項１の定義に同じである。） Manufacturing method 14
Of the compounds (IIc) used in Production Method 3, (IIc') is produced by a condensation dehydration cyclization reaction between compound (IIc1) and compound (IIc2).

(In the formula, R ⁴ , R ⁵ , Q ¹ , Q ² and n are the same as defined in item 1.)

Compound (IIc') is produced according to the method described in Production Method 6 using compound (IIc1) and compound (IIc2).

（式中、Ｒ^４、Ｒ^５、Ｑ^１、Ｑ^２、及びｎは項１の定義に同じである。） Manufacturing method 15
Of the compounds (IIc) used in Production Method 3, (IIc'') is produced by a condensation dehydration cyclization reaction between compound (IIc3) and compound (IIc4).

(In the formula, R ⁴ , R ⁵ , Q ¹ , Q ² and n are the same as defined in item 1.)

Compound (IIc'') is produced according to the method described in Production Method 6 using compound (IIc3) and compound (IIc4).

（式中、Ｒ^４、Ｒ^５、Ｑ^１、Ｑ^２、及びｎは項１の定義に同じである。） Manufacturing method 16
Of the compounds (IIc) used in Production Method 3, (IIc''') is produced by a condensation dehydration cyclization reaction between compound (IIc5) and compound (IIc6).

(In the formula, R ⁴ , R ⁵ , Q ¹ , Q ² and n are the same as defined in item 1.)

Compound (IIc''') is produced according to the method described in Production Method 9 using compound (IIc5) and compound (IIc6).

The compound represented by formula (1) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. Examples include extraction, distribution, reprecipitation, column chromatography (eg, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography), recrystallization, and the like.
Examples of recrystallization solvents include alcohol solvents such as methanol, ethanol or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene or toluene, and acetone. , halogen solvents such as dichloromethane or chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide or acetonitrile, water, or mixed solvents thereof. As other purification methods, the method described in Jikken Kagaku Koza (Edited by The Chemical Society of Japan, Maruzen) Vol. 1 and the like can be used. In addition, the determination of the molecular structure of this compound is performed by referring to the structure derived from each raw material compound, spectroscopic methods such as nuclear magnetic resonance, infrared absorption, circular dichroism spectrometry, and mass It can be easily done by an analytical method.

In addition, the intermediates or final products in the above production method are required to convert their functional groups as appropriate, and in particular, to extend various side chains from amino, hydroxyl, carbonyl, halogen, etc., and at that time, It is also possible to lead to other compounds included in the present invention by performing the above protection and deprotection according to the above. Transformation of functional groups and elongation of side chains can be carried out by conventional methods (see, for example, Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999), etc.).

The compound represented by formula (1) or a pharmaceutically acceptable salt thereof may be asymmetric or have a substituent having an asymmetric carbon. Isomers exist. The present compound includes mixtures and isolated isomers of these isomers, and can be produced according to conventional methods. The production method includes, for example, a method using a raw material having an asymmetric point, or a method of introducing asymmetry in an intermediate step. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution or the like at an appropriate stage in the production process. As an optical resolution method, for example, when the compound represented by formula (1) or an intermediate thereof has a basic functional group, in an inert solvent (e.g., methanol, ethanol, alcoholic solvent such as 2-propanol , ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, or a mixed solvent of two or more selected from the above solvents), optical activity acids (e.g., monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid; dicarboxylic acids such as tartaric acid, o-diisopropylidenetartaric acid and malic acid; sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) A diastereomer method is used to form a salt. When the compound represented by formula (1) or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (e.g., 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.) Optical resolution can also be performed by forming a salt with an organic amine).

The temperature at which the salt is formed is selected from the range of -50°C to the boiling point of the solvent, preferably from 0°C to the boiling point, more preferably from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to once raise the temperature to near the boiling point of the solvent. When the precipitated salt is collected by filtration, the yield can be improved by cooling as necessary. The amount of optically active acid or amine to be used is appropriately in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, crystals are placed in an inert solvent (e.g., alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; or a mixed solvent of two or more selected from the above solvents) to obtain a highly pure optically active salt. In addition, if necessary, the optically resolved salt can be treated with an acid or base in a conventional manner to obtain a free form.

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 oxadiazole derivative of the present invention has anticonvulsant activity and GABA-A receptor activating action (GABA nervous system activating action), it is a therapeutic and/or preventive agent for diseases associated with GABA nervous system hypofunction. can be a drug. 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.
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 oxadiazole derivative of the present invention has a GABA-A receptor activating action and/or an action of enhancing inhibition (I) in the balance between excitation (E) and inhibition (I) (E/I balance). , a therapeutic and/or prophylactic agent for nervous system diseases or psychiatric diseases.
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, 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. .

Since the 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.
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 route of administration of this compound may be oral administration, parenteral administration or rectal administration, and the daily dose varies depending on the type of compound, administration method, symptoms and age of the patient, 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 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 present compounds 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 administered as a formulation prepared separately from the present compound, and may be administered simultaneously with a formulation containing the present compound, or may be administered with a time lag to the administration subject. You may 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, DMSO means dimethylsulfoxide, TFA means trifluoroacetic acid and MeCN means acetonitrile. n- means normal- and t- means tert-. 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, brs is broad singlet, brm is broad multiplet, 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 1.7 μm 2.1 × 30 mm 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

シクロブタン－１，１－ジカルボン酸モノエチルエステル（１００ｍｇ）にチオニルクロリド（９３μｌ）を加え、５時間加熱還流した。減圧濃縮後、トルエンで共沸して１－（クロロカルボニル）シクロブタン－１－カルボン酸エチルを油状物として得た。これをアセトン（２．６４ｍｌ）に溶解し、４－クロロベンズアミドオキシム（９０ｍｇ）と炭酸カリウム（１０９ｍｇ）を加え、５０度加熱下で１時間撹拌した。固体をろ過により除去し濾液を濃縮後、残渣をトルエン（２．６４ｍｌ）に溶解し６時間加熱還流した。溶媒を減圧留去後、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；６：１）で精製し、参考例１の化合物（１３８ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.25 (t, 3H), 2.08-2.23 (m, 2H), 2.76-2.84 (m, 2H), 2.86-2.94 (m, 2H), 4.24 (q, 2H), 7.45-7.48 (m, 2H), 8.04-8.07 (m, 2H). Reference Example 1 : 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxylic acid ethyl

Thionyl chloride (93 μl) was added to cyclobutane-1,1-dicarboxylic acid monoethyl ester (100 mg), and the mixture was heated under reflux for 5 hours. After concentration under reduced pressure, ethyl 1-(chlorocarbonyl)cyclobutane-1-carboxylate was obtained as an oil by azeotroping with toluene. This was dissolved in acetone (2.64 ml), 4-chlorobenzamide oxime (90 mg) and potassium carbonate (109 mg) were added, and the mixture was stirred under heating at 50°C for 1 hour. After removing the solid by filtration and concentrating the filtrate, the residue was dissolved in toluene (2.64 ml) and heated under reflux for 6 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 6:1) to obtain the compound of Reference Example 1 (138 mg) as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.25 (t, 3H), 2.08-2.23 (m, 2H), 2.76-2.84 (m, 2H), 2.86-2.94 (m, 2H), 4.24 (q, 2H) , 7.45-7.48 (m, 2H), 8.04-8.07 (m, 2H).

Reference Examples 2-11 :
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.

３－（ヒドロキシアミノ）－３－イミノプロパン酸エチル（４．００ｇ）のピリジン（４０ｍｌ）溶液に４－クロロ安息香酸クロリド（３．４８ｍｌ）を加え、室温で２時間撹拌した。さらに９０度加温下で２０時間撹拌後、反応溶液を減圧濃縮し残渣を酢酸エチルに溶解した。１０％クエン酸水溶液、飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。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；２：１）で精製し、参考例１２の化合物（４．６０ｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.28 (t, 3H), 3.86 (s, 2H), 4.23 (q, 2H), 7.49 (d, 2H), 8.05 (d, 2H). Reference Example 12 : 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl acetate

4-Chlorobenzoyl chloride (3.48 ml) was added to a solution of ethyl 3-(hydroxyamino)-3-iminopropanoate (4.00 g) in pyridine (40 ml), and the mixture was stirred at room temperature for 2 hours. After stirring for 20 hours while heating at 90° C., the reaction solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. After washing with a 10% aqueous citric acid solution and saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to give the compound of Reference Example 12 (4.60 g) as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.28 (t, 3H), 3.86 (s, 2H), 4.23 (q, 2H), 7.49 (d, 2H), 8.05 (d, 2H).

Reference Examples 13-14 :
Using the corresponding starting compounds, the compounds shown in Table 2 were obtained by reacting and treating in the same manner as in Reference Example 12.

４－クロロベンズヒドラジド（５００ｍｇ）とエチルマロニルクロリド（０．３７ｍｌ）のＴＨＦ（１０ｍｌ）懸濁液にトリエチルアミン（０．８６ｍｌ）を加え室温で２時間撹拌後、減圧濃縮した。得られた残渣をクロロホルム（１０ｍｌ）に溶解しバージェス試薬（１．５４ｇ）を加え６時間加熱還流後、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；２：１）で精製し、参考例１５の化合物（５９８ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.28 (t, 3H), 4.01 (s, 2H), 4.23 (q, 2H), 7.45-7.50 (m, 2H), 7.96-7.99 (m, 2H). Reference Example 15 : 2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]ethyl acetate

Triethylamine (0.86 ml) was added to a suspension of 4-chlorobenzhydrazide (500 mg) and ethylmalonyl chloride (0.37 ml) in THF (10 ml), and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting residue was dissolved in chloroform (10 ml), Burgess reagent (1.54 g) was added, and the mixture was heated under reflux for 6 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to give the compound of Reference Example 15 (598 mg) as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.28 (t, 3H), 4.01 (s, 2H), 4.23 (q, 2H), 7.45-7.50 (m, 2H), 7.96-7.99 (m, 2H).

Reference Example 16 :
A compound of Reference Example 16 was obtained by reacting and treating in the same manner as in Reference Example 15 using the corresponding starting compound.

参考例１２の化合物（１．６０ｇ）のＤＭＦ（１６ｍｌ）溶液に炭酸セシウム（７．８２ｇ）とヨードメタン（１．１２ｍｌ）を加え、室温で終夜撹拌した。反応溶液に水を加え酢酸エチルで抽出、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、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；９：１）で精製し、参考例１７の化合物（１．１１ｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.21 (t, 3H), 1.67 (s, 6H), 4.17 (q, 2H), 7.47-7.50 (m, 2H), 8.04-8.07 (m, 2H). Reference Example 17 : Ethyl 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanoate

Cesium carbonate (7.82 g) and iodomethane (1.12 ml) were added to a solution of the compound of Reference Example 12 (1.60 g) in DMF (16 ml), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 9:1) to obtain the compound of Reference Example 17 (1.11 g) as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.21 (t, 3H), 1.67 (s, 6H), 4.17 (q, 2H), 7.47-7.50 (m, 2H), 8.04-8.07 (m, 2H).

Reference Examples 18-21 :
The compounds shown in Table 3 were obtained by reacting and treating in the same manner as in Reference Example 17 using corresponding starting compounds.

参考例３の化合物（３．１０ｇ）のメタノール（２０ｍｌ）溶液に５ｍоｌ／Ｌ水酸化ナトリウム水溶液（７．３ｍｌ）を加え、６時間加熱還流した。室温まで冷却後１０％クエン酸水溶液を加えｐＨ４に調整し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、参考例２２の化合物（２．８９ｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.78 (s, 6H), 7.42-7.46 (m, 2H), 8.00-8.03 (m, 2H). Reference Example 22 : 2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanoic acid

A 5 mol/L sodium hydroxide aqueous solution (7.3 ml) was added to a solution of the compound of Reference Example 3 (3.10 g) in methanol (20 ml), and the mixture was heated under reflux for 6 hours. After cooling to room temperature, a 10% aqueous citric acid solution was added to adjust the pH to 4, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the compound of Reference Example 22 (2.89 g) as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.78 (s, 6H), 7.42-7.46 (m, 2H), 8.00-8.03 (m, 2H).

Reference Examples 23-37 :
Using the corresponding starting compounds, the compounds shown in Table 4 were obtained by reacting and treating in the same manner as in Reference Example 22.

３－（４－ブロモフェニル）－５－（クロロメチル）－１，２，４－オキサジアゾール（１．３５ｇ）のエタノール（５ｍｌ）溶液に亜硫酸ナトリウム（０．６２ｇ）の水溶液（５ｍｌ）を加え、４時間加熱還流した。溶媒を減圧留去し、参考例３８の化合物（２．０４ｇ）を固体として得た。
MS (m/z) 317 (MNa^-), Rt = 0.52 min. Reference Example 38 : [3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl] sodium methanesulfonate

An aqueous solution (5 ml) of sodium sulfite (0.62 g) was added to a solution of 3-(4-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (1.35 g) in ethanol (5 ml). The mixture was added and heated under reflux for 4 hours. The solvent was distilled off under reduced pressure to obtain the compound of Reference Example 38 (2.04 g) as a solid.
MS (m/z) 317 (MNa ^- ), Rt = 0.52 min.

Reference Examples 39-45 :
Using the corresponding starting compounds, the compounds shown in Table 5 were obtained by reacting and treating in the same manner as in Reference Example 38.

参考例３８の化合物（１．６８ｇ）にオキシ塩化リン（２２．５ｍｌ）を加え、５時間加熱還流後、減圧濃縮した。残渣をＴＨＦ（２０ｍｌ）に加え、これをビス（２，４－ジメトキシベンジル）アミン（１．５６ｇ）、トリエチルアミン（２．７５ｍｌ）、４－ジメチルアミノピリジン（０．０６ｇ）のＴＨＦ（２０ｍｌ）溶液に滴下後、室温で終夜撹拌した。反応溶液を１０％クエン酸水溶液で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、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；２：１）で精製し、参考例４６の化合物（１．３２ｇ）をアモルファスとして得た。
¹H-NMR (CDCl₃)δ: 3.78 (s, 12H), 4.38 (s, 2H), 4.38 (s, 4H), 6.43-6.46 (m, 4H), 7.20 (d, 2H), 7.58-7.61 (m, 2H),7.89-7.93 (m, 2H). Reference Example 46 : 1-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-N,N-bis(2,4-dimethoxybenzyl)methanesulfonamide

Phosphorus oxychloride (22.5 ml) was added to the compound of Reference Example 38 (1.68 g), and the mixture was heated under reflux for 5 hours and then concentrated under reduced pressure. The residue was added to THF (20 ml) and this was treated with bis(2,4-dimethoxybenzyl)amine (1.56 g), triethylamine (2.75 ml) and 4-dimethylaminopyridine (0.06 g) in THF (20 ml). and stirred overnight at room temperature. The reaction solution was diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to obtain the compound of Reference Example 46 (1.32 g) as an amorphous substance.
¹ H-NMR (CDCl ₃ )δ: 3.78 (s, 12H), 4.38 (s, 2H), 4.38 (s, 4H), 6.43-6.46 (m, 4H), 7.20 (d, 2H), 7.58-7.61 (m, 2H),7.89-7.93 (m, 2H).

Reference Examples 47-53 :
Using the corresponding starting compounds, the compounds shown in Table 6 were obtained by reacting and treating in the same manner as in Reference Example 46.

参考例４６の化合物（２５０ｍｇ）のＤＭＦ（５ｍｌ）溶液に炭酸セシウム（５２７ｍｇ）とヨードメタン（０．０７５ｍｌ）を加え、室温で終夜撹拌した。反応溶液に水を加え酢酸エチルで抽出、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、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；１：１）で精製し、参考例５４の化合物（２４１ｍｇ）をアモルファスとして得た。
¹H-NMR (CDCl₃)δ: 1.93 (s, 6H), 3.57 (s, 6H), 3.71 (s, 6H), 4.27 (br s, 4H), 5.43 (br s, 1H), 6.77 (br s, 1H), 7.14-7.19 (m, 2H), 8.05-8.10 (m, 2H). Reference Example 54 : 2-[3-(4-bromophenyl)-1,2,4-oxazol-5-yl]-N,N-bis(2,4-dimethoxybenzyl)propane-2-sulfonamide

Cesium carbonate (527 mg) and iodomethane (0.075 ml) were added to a solution of the compound of Reference Example 46 (250 mg) in DMF (5 ml), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to obtain the compound of Reference Example 54 (241 mg) as an amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.93 (s, 6H), 3.57 (s, 6H), 3.71 (s, 6H), 4.27 (br s, 4H), 5.43 (br s, 1H), 6.77 (br s, 1H), 7.14-7.19 (m, 2H), 8.05-8.10 (m, 2H).

Reference Examples 55-61 :
Using the corresponding starting compounds, the compounds shown in Table 7 were obtained by reacting and treating in the same manner as in Reference Example 54.

４－フルオロベンズアミドキシム（１．９０ｇ）、２－ピロリドン－５－カルボン酸（１．５９ｇ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロリン酸塩（５．１６ｇ）のＤＭＥ（５０ｍｌ）溶液にＮ，Ｎ－ジイソプロピルエチルアミン（４．３ｍｌ）を加え、室温で２時間、８０℃加温下で２時間撹拌した。反応溶液に水を加え酢酸エチルで抽出、有機層を飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、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；１：４）で精製し、参考例６２の化合物（２．３０ｇ）を固体として得た。
¹H-NMR (d6-DMSO) δ: 2.21-2.40 (m, 3H), 2.51-2.62 (m, 1H), 5.09-5.12 (m, 1H), 7.38-7.44 (m, 2H), 8.04-8.09 (m, 2H), 8.37 (br ｓ, 1H). Reference Example 62 : 5-[3(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-2-one

4-fluorobenzamidoxime (1.90 g), 2-pyrrolidone-5-carboxylic acid (1.59 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetra N,N-diisopropylethylamine (4.3 ml) was added to a solution of methyluronium hexafluorophosphate (5.16 g) in DME (50 ml), and the mixture was stirred at room temperature for 2 hours and then heated at 80°C for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:4) to give the compound of Reference Example 62 (2.30 g) as a solid.
¹ H-NMR (d6-DMSO) δ: 2.21-2.40 (m, 3H), 2.51-2.62 (m, 1H), 5.09-5.12 (m, 1H), 7.38-7.44 (m, 2H), 8.04-8.09 (m, 2H), 8.37 (br s, 1H).

Reference Examples 63-68 :
Using the corresponding starting compounds, the compounds shown in Table 8 were obtained by reacting and treating in the same manner as in Reference Example 62.

参考例２３で得られた化合物（２８０ｍｇ）と塩化オキサリル（０．３８４ｍｌ）を脱水クロロホルム（１０ｍｌ）に溶解しＤＭＦを２滴加えた後に、室温で１時間撹拌した。反応溶液を減圧濃縮後、残渣を脱水ＴＨＦ（５ｍｌ）に溶解し、２８％アンモニア水溶液（１ｍｌ）を加え室温で終夜撹拌した。反応溶液を減圧濃縮後、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；１：１）で精製し、実施例１の化合物（２０６ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.75 (s, 6H), 5.43 (br s, 1H),6.77 (br s, 1H), 7.14-7.19 (m, 2H), 8.05-8.10 (m, 2H).
MS (m/z) 250 (MH⁺), Rt = 0.69 min. Example 1 : 2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide

The compound (280 mg) obtained in Reference Example 23 and oxalyl chloride (0.384 ml) were dissolved in dehydrated chloroform (10 ml), 2 drops of DMF were added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in dehydrated THF (5 ml), 28% aqueous ammonia solution (1 ml) was added, and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to obtain the compound of Example 1 (206 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 1.75 (s, 6H), 5.43 (br s, 1H), 6.77 (br s, 1H), 7.14-7.19 (m, 2H), 8.05-8.10 (m, 2H) .
MS (m/z) 250 (MH ⁺ ), Rt = 0.69 min.

Examples 2-16 :
The compounds shown in Table 9 were obtained by reacting and treating in the same manner as in Example 1 using the corresponding starting compounds.

参考例５５で得られた化合物のトルエン(２０ｍｌ)溶液に、トリフルオロ酢酸（１０ｍｌ）を加え、室温で１５時間撹拌した。反応溶液を減圧濃縮後、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；１：１）で精製し、実施例１７の化合物（１０３ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 1.98 (s, 6H), 4.95 (br s, 2H), 7.14-7.19 (m, 2H), 8.03-8.08 (m, 2H).
MS (m/z) 286 (MH⁺), Rt = 0.71 min. Example 17 : 2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide

Trifluoroacetic acid (10 ml) was added to a toluene (20 ml) solution of the compound obtained in Reference Example 55, and the mixture was stirred at room temperature for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to give the compound of Example 17 (103 mg) as a solid.
¹ H-NMR (CDCl ₃ )δ: 1.98 (s, 6H), 4.95 (br s, 2H), 7.14-7.19 (m, 2H), 8.03-8.08 (m, 2H).
MS (m/z) 286 (MH ⁺ ), Rt = 0.71 min.

Examples 18-24 :
The compounds shown in Table 10 were obtained by reacting and treating in the same manner as in Example 18 using corresponding starting compounds.

参考例６２で得られた化合物（５００ｍｇ）とヨウ化メチル（０．１９ｍｌ）のＤＭＦ(４ｍｌ)溶液に、炭酸セシウム（０．９８８ｍｇ）を加え、室温で２．５時間撹拌した。反応溶液に１０％クエン酸水溶液を加え酢酸エチルで抽出、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮後、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；１：３）で精製し、実施例２５の化合物（４８３ｍｇ）を固体として得た。
¹H-NMR (CDCl₃)δ: 2.27-2.33 (m, 1H), 2.40-2.67 (m, 3H), 2.85 (s，3H), 4.84-4.87 (m, 1H), 7.09-7.15 (m, 2H), 7.99-8.04 (m, 2H).
MS (m/z) 262 (MH⁺), Rt = 0.71 min. Example 25 : 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one

Cesium carbonate (0.988 mg) was added to a DMF (4 ml) solution of the compound (500 mg) obtained in Reference Example 62 and methyl iodide (0.19 ml), and the mixture was stirred at room temperature for 2.5 hours. A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:3) to give the compound of Example 25 (483 mg) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 2.27-2.33 (m, 1H), 2.40-2.67 (m, 3H), 2.85 (s, 3H), 4.84-4.87 (m, 1H), 7.09-7.15 (m, 2H), 7.99-8.04 (m, 2H).
MS (m/z) 262 (MH ⁺ ), Rt = 0.71 min.

Examples 26-31 :
The compounds shown in Table 11 were obtained by reacting and treating in the same manner as in Example 25 using corresponding starting compounds.

実施例２５の化合物をダイセル社製カラム（CHIRALPAK^TM AD-H（移動相：100％ MeCN））で分取し、前ピーク（エナンチオマーＡ）及び後ピーク（エナンチオマーＢ）を得た。なお、エナンチオマーＡ及びＢの絶対配置は、Ｓ体の原料化合物を用いた参考例６８から製造した化合物（＝実施例３１）との比較により、エナンチオマーＡがＳ体、エナンチオマーＢがＲ体であると決定した。
実施例３１（エナンチオマーＡ）：保持時間 4.78分 Chiral HPLC (Chiralpak^TM AD-H, 0.46 cm I.D. x 25 cm L, 移動相：100％ MeCN、流量：1.0 ml/min、温度：４０℃、波長：237 nm)
実施例３２（エナンチオマーＢ）：保持時間 5.99分 Chiral HPLC (Chiralpak^TM AD-H, 0.46 cm I.D. x 25 cm L, 移動相：100％ MeCN、流量：1.0 ml/min、温度：４０℃、波長：237 nm) Examples 31 and 32 : (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one and (R)- 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one

The compound of Example 25 was fractionated with a Daicel column (CHIRALPAK ^™ AD-H (mobile phase: 100% MeCN)) to give a front peak (enantiomer A) and a rear peak (enantiomer B). The absolute configurations of enantiomers A and B are compared with the compound prepared from Reference Example 68 (=Example 31) using the S-form starting compound, and enantiomer A is the S-form and enantiomer B is the R-form. decided.
Example 31 (Enantiomer A): retention time 4.78 minutes Chiral HPLC (Chiralpak ^™ AD-H, 0.46 cm ID x 25 cm L, mobile phase: 100% MeCN, flow rate: 1.0 ml/min, temperature: 40°C, wavelength: 237 nm)
Example 32 (enantiomer B): retention time 5.99 minutes Chiral HPLC (Chiralpak ^™ AD-H, 0.46 cm ID x 25 cm L, mobile phase: 100% MeCN, flow rate: 1.0 ml/min, temperature: 40°C, wavelength: 237 nm)

実施例３１の化合物は以下の方法によっても製造することができる。
４－フルオロベンズアミドキシム（１．０８ｋｇ）、（Ｓ）－２－ピロリドン－５－カルボン酸（８４０ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（２．５６Ｌ）と酢酸エチル（７．３Ｌ）の混合物に、プロパンホスホン酸無水物の５０％酢酸エチル溶液（４．４８ｋｇ）を加え、室温で１．５時間、続いて７５℃加温下で２．５時間撹拌した。放冷後、反応溶液に０．１ｍｏｌ／Ｌ塩酸（３．３６Ｌ）を加えて分液し、水層を酢酸エチル（１．８６Ｌ）で２回抽出した。有機層を合一し、５％リン酸水素二カリウム水溶液（３．３６ｋｇ）、水（１．６８Ｌ）で順次洗浄したのち、有機層を３．３６ｋｇまで減圧濃縮し、攪拌しつつ０℃まで冷却した。生じたスラリーにｎ－ヘプタン（３．０２ｋｇ）を滴下し、結晶を濾過で集め、４０％酢酸エチル／ヘプタン混合溶媒（１．６８ｋｇ）で洗浄、４０℃で真空乾燥することにより、粗結晶（１．１４ｋｇ）を淡褐色固体として得た。この粗結晶（１．００ｋｇ）を２－プロパノール／水（５０％、１．６ｋｇ）に溶解後、活性炭６０ｇを加えて２５℃で攪拌し、活性炭を濾過で除いた。濾液を２－プロパノール／水（５０％）で３．０ｋｇになるよう希釈し、０℃の水（６．０Ｌ）に攪拌しながら滴下した。結晶を濾過で集め、２－プロパノール／水混合溶媒（１２．５％、２．０ｋｇ）で洗浄後、４０℃で真空乾燥することにより、実施例３３の化合物（９４４ｇ）を結晶形Ａ（白色固体）として得た。ＮＭＲとＨＰＬＣの確認により、この化合物が実施例３１の化合物と同一であることを確認した。 Example 33 : (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one

The compound of Example 31 can also be prepared by the following method.
To a mixture of 4-fluorobenzamidoxime (1.08 kg), (S)-2-pyrrolidone-5-carboxylic acid (840 g), N,N-diisopropylethylamine (2.56 L) and ethyl acetate (7.3 L), A 50% ethyl acetate solution (4.48 kg) of propanephosphonic anhydride was added, and the mixture was stirred at room temperature for 1.5 hours and then heated at 75°C for 2.5 hours. After allowing to cool, 0.1 mol/L hydrochloric acid (3.36 L) was added to the reaction solution to separate the layers, and the aqueous layer was extracted twice with ethyl acetate (1.86 L). The organic layers were combined and washed successively with a 5% dipotassium hydrogen phosphate aqueous solution (3.36 kg) and water (1.68 L). cooled. n-Heptane (3.02 kg) was added dropwise to the resulting slurry, and the crystals were collected by filtration, washed with a 40% ethyl acetate/heptane mixed solvent (1.68 kg), and dried in vacuo at 40°C to obtain crude crystals ( 1.14 kg) was obtained as a pale brown solid. After dissolving the crude crystals (1.00 kg) in 2-propanol/water (50%, 1.6 kg), 60 g of activated carbon was added and the mixture was stirred at 25° C., and the activated carbon was removed by filtration. The filtrate was diluted with 2-propanol/water (50%) to 3.0 kg and added dropwise with stirring to water (6.0 L) at 0°C. The crystals were collected by filtration, washed with a mixed solvent of 2-propanol/water (12.5%, 2.0 kg), and dried in vacuo at 40° C. to give the compound of Example 33 (944 g) as crystalline form A (white solid). Confirmation by NMR and HPLC confirmed that this compound was identical to the compound of Example 31.

The crystalline forms of the present invention were characterized by various analytical techniques including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) using the following procedures.

X-ray powder analysis (XRPD) of the compound obtained in Example 33
X-ray powder analysis of crystalline Form A of Example 33 was performed by the following procedure.
X-ray powder diffraction: XRPD analysis was performed on a diffractometer (Bruker AXS D8 ADVANCE, Bruker, Billerica, Massachusetts, America) using a copper tube (Cu Kα1, λ=1.5406 Å, Kα2, λ=1.5444 Å) was measured at a voltage of 40 kV and an amperage of 40 mA. A measurement sample was formed by filling a sample into a filling portion of a glass sample plate (inner diameter: 20 mm, depth: 0.2 mm). The slits used were Soller slit 2.5°, divergence slit 0.2°, anti-scatter slit 5.5 mm. The sample rotation speed was 0.25 revolutions/second. The measurement range was 2θ, scanning was performed from 4 to 40° with a step size of 0.015° and an irradiation time of 48 seconds per step. Data analysis was performed using DIFFRAC. Performed by EVA (Bruker, Billerica, Massachusetts, USA).
The XRPD pattern of Form A of Example 33 is shown below and in FIG.
Powder XRD (°, 2θ ± 0.2): 5.86, 13.61, 14.66, 15.76, 16.03, 16.74, 17.55, 18.13, 21.40, 21.66, 23.47, 25.03, 27.38, 28.18, 29.41 (of which ten characteristic The peaks were 5.86, 13.61, 14.66, 15.76, 16.03, 16.74, 18.13, 21.66, 25.03, 27.38, and the four characteristic peaks were 13.61, 14.66, 21.66, 25.03.)

Differential scanning calorimetry (DSC) of the compound obtained in Example 33
Differential scanning calorimetry of crystalline Form A of Example 33 was performed by the following procedure.
Differential Scanning Calorimetry: Thermal properties were evaluated using a Differential Scanning Calorimetry (DSC) instrument (DSC2500, TA Instruments, New Castle, DE, USA). Approximately 1-10 mg of solid sample was placed in a T_ZERO sample container (TA Instruments) for each experiment and heated at a rate of 2° C./min under a nitrogen purge of 50 mL/min. Data analysis was performed using TRIOS (TA Instruments).

The DSC of Form A of Example 33 is shown in FIG. The crystal form A has a melting point of around 83°C.

Thermogravimetric analysis (TGA) of the compound obtained in Example 33
Thermogravimetric analysis of crystalline Form A of Example 33 was performed by the following procedure.
Thermogravimetric analysis: Thermogravimetric analysis (TGA) was performed on a TGA instrument (TGA 5500, TA Instruments). Approximately 1-10 mg of solid sample was placed in an open aluminum container and heated at a rate of 5° C./min under a nitrogen purge of 25 mL/min for each experiment. Data analysis was performed using TRIOS (TA Instruments).

The TGA of Form A of Example 33 is shown in FIG. Crystal form A has no weight loss up to its melting temperature and is suitable for formulation.

The 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: Subcutaneous Injection Pentetrazole Model (Minimal Convulsion Model, scPTZ) Evaluation For the evaluation of antiepileptic drugs, a subcutaneous injection pentetrazole model (minimal convulsion model, scPTZ) evaluation with high clinical predictability is used. Compounds that exhibit anticonvulsant activity in this model are expected to be clinically useful antiepileptic drugs. This study used an animal model representing generalized absence seizures and myoclonic seizures. A test compound was orally administered to Slc:ddY male mice (obtained from Japan SLC Co., Ltd., 5 mice per group, body weight 20-30 g), and 85 mg/kg of pentetrazole was subcutaneously administered 1 hour later. Thereafter, the presence or absence of clonic convulsions for 30 minutes was observed. As a control, 0.5% methylcellulose solution was administered as a test compound, and the same test was performed. The results are shown in Table 12 below. The number of mice showing suppression of convulsions out of 5 mice was shown. For the control, the test was completed when 4 out of 5 animals developed convulsions.

As shown in Table 12, this compound showed anticonvulsant activity in a subcutaneous pentetrazole model (minimal convulsive model, scPTZ) evaluation upon oral administration. The compounds of Examples 11, 16, 25, 28, 30 and 31 exhibited anticonvulsant activity in more than half of the cases even when administered orally at 25 mg/kg.

Test Example 2: 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. and only ambulatory mice are used for testing. A test compound was orally administered to each group of 5 animals, and after 1 hour, the animals were placed on a rotarod device rotated at 15 times/min, and walking conditions were observed for 180 seconds to measure the walking time. As a control, 0.5% methylcellulose solution was administered as a test compound, and the same test was performed. Coordinated motor ability was expressed as the average walking time (seconds) of 5 mice. The results are shown in Table 13. Controls were ambulatory for 180 seconds.

As shown in Table 13, oral administration of 25 mg/kg or more in any of the Examples allowed walking to continue for 180 seconds without falling off the rotarod apparatus, and did not affect coordination. Therefore, the example compounds evaluated in the subcutaneous injection pentetrazole model (minimum convulsion model, scPTZ) in Test Example 1 showed anticonvulsant action as described above, but at the dose at which the effect was obtained, coordination exercise capacity was confirmed to have little effect on

Test Example 3: 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 (5 to 8 mice per group, body weight 20 to 30 g), and after 50 minutes, the mice were placed in a chamber bathed in hot water to induce a rise in body temperature, and the occurrence of febrile convulsions was observed. Immediately after the onset of febrile convulsions, the rectal body temperature was measured and used as the convulsive threshold body temperature. As a control, 0.5% methylcellulose solution was administered as a test compound, and the same test was performed. Anticonvulsant activity was expressed as the difference between the drug dose that significantly increased the convulsive threshold body temperature compared to the control group and the convulsive threshold body temperature from the control group. The results are shown in Table 14.

As shown in Table 14, this compound showed convulsive threshold body temperature raising action in Dravet febrile convulsion, and was shown to have anticonvulsant action on Dravet model. All of the compounds of Examples showed anticonvulsant action on the Dravet model in the rotarod evaluation of Test Example 2 at doses that did not affect coordination.

Test Example 4: Evaluation of GABA-A Receptor Activation Effect In this test, GABA-A receptor-expressing cells that can be obtained by the method described in the guidelines for creating stable cell lines (Lonza Japan website; Non-Patent Document 4) is used to evaluate the GABA-A receptor activating effect of a drug using the current induced by GABA as an indicator. GABA-A receptor-expressing cells were subjected to electrophysiology experiments, measuring currents observed upon addition of 2 μM GABA solution followed by a mixture of 2 μM GABA and test compound. The GABA-stimulating activity was expressed as the rate of increase in the current observed when a mixture of 2 μM GABA and the test compound was added, relative to the current observed with GABA alone. represented by Similarly, the current observed when 2 μM GABA and 10 μM flumazenil mixed solution was added to the test compound was measured, and the rate of inhibition by flumazenil against the current increase in the absence of flumazenil was calculated. The results are shown in Table 15.

As shown in Table 15, this compound exhibited GABA-A receptor activation activity. The GABA-A receptor activation activity of clobazam and diazepam, which are classified as benzodiazepines, is strongly inhibited by the benzodiazepine antagonist flumazenil. The inhibition of the current increase by the compound was weak, indicating that the GABA-A receptor activating activity of this compound occurs through a mechanism different from that of benzodiazepines.

Test Example 5: Rat Forced Swimming Model Evaluation This test is for evaluating the antidepressant effects of drugs. When rats are placed in a tank from which they cannot escape and allowed to swim, immobility is observed after escape behavior. When the rats were placed in the tank again the next day, immobility appeared earlier than the first time. This is a method for evaluating the antidepressant effect of a test compound, using the duration of this immobility time as depression-like behavior. Male Wister rats (obtained from Charles River Laboratories Japan, Ltd., body weight 260-300 g) were allowed to swim in a water tank for 15 minutes on the day before the test. On the day of the test, the test compound was orally administered (10 to 12 animals per group), and after 1 hour, the animals were again allowed to swim in the water tank for 5 minutes, and the immobility time was measured. For the control group, 0.5% methylcellulose solution was administered as a test compound, and the same test was performed. The antidepressant activity was expressed as the average reduction rate of immobility time compared to the control group. The results are shown in Table 16.

As shown in Table 16, Examples 29 and 32 significantly reduced the immobility time of the rat forced swimming model, indicating that they had an antidepressant effect. On the other hand, as shown in Experimental Example 4, diazepam has the same GABA-A receptor activating action as the present compound, but did not exhibit antidepressant effects in the rat forced swimming model. Diazepam is one of the benzodiazepines that are also used as anticonvulsants. The fact that the present compound showed an effect on the depression model in which benzodiazepines do not show an effect is because, as shown in Experimental Example 4, the GABA-A receptor activation action mechanism of the present compound is different from that of benzodiazepines. Therefore, it is thought that this compound exhibits an antidepressant effect that benzodiazepines do not possess due to some unknown mechanism of action. From this, it was suggested that the present compound has therapeutic/preventive effects not only on epileptic seizures but also on depressive symptoms that frequently occur concurrently in epileptic patients.

As explained above, this compound showed potent anticonvulsant activity in the subcutaneous injection pentetrazole model (minimal convulsion model, scPTZ) evaluation. In addition, in a model mouse of Dravet syndrome, one of the intractable generalized epilepsies, the causative mutation gene has been identified. . Therefore, this compound is classified as an antiepileptic drug (tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, unclassified seizures, and refractory epilepsy that has not yet been successfully treated with drugs). It is useful as a therapeutic and/or prophylactic agent for generalized seizures such as Dravet syndrome, West syndrome and Lennox-Gastaut syndrome. Since this compound also has GABA-A receptor activating activity, it is associated with anxiety disorders, obsessive-compulsive disorder, Parkinson's disease and dementia with Lewy bodies, for which therapeutic effects of existing GABA nervous system activators have been recognized. It is also useful as a therapeutic and/or prophylactic agent for REM sleep disorders. The GABA-A receptor activating activity of this compound is exerted in a mode of action different from that of benzodiazepines, which are one of the existing GABA nervous system activating agents, and depression in a forced swimming rat model in which benzodiazepines did not show any effect. Since it was effective against symptoms, it is effective against depressive symptoms that may or may not be associated with epilepsy, and is useful as a therapeutic and/or prophylactic agent for depressive syndrome, etc., and is useful not found in existing antiepileptic drugs. have a nature. In addition, developmental disorders with abnormalities in the GABA nervous system, autism, bipolar disorder and related disorders, schizophrenia spectrum disorders, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's. It is thought that it exerts an effect of improving the condition of the disease.

Since the pharmaceutical composition of the present invention has a strong anticonvulsant effect and also has a GABA-A receptor activating effect, it can be used as a therapeutic and / or preventive agent for diseases associated with GABA nervous system hypofunction. Useful. In addition, the pharmaceutical composition of the present invention has the effect of enhancing inhibition (I) in the balance between excitation (E) and inhibition (I) (E/I balance), so that E in E/I balance is enhanced. and/or is useful as a therapeutic and/or prophylactic agent for diseases in which I is low.

Claims (18)

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

[In the formula,
Q ¹ represents halogen,
Q ² is hydrogen, halogen, cyano, C _1-3 alkyl (wherein alkyl is 1 to 3 substituted groups independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _1-3 alkoxy (wherein said alkoxy is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy) It may be substituted with a substituent) represents,
X, Y and Z are the same or different and represent a nitrogen atom or an oxygen atom, provided that a ring containing X, Y and Z has two of X, Y and Z being nitrogen atoms and the remaining one is a heteroaryl wherein one is an oxygen atom,
R ¹ represents any one of the following (2) to (4),

R ² and R ³ are the same or different and C _1-6 alkyl (wherein said alkyl is 1 to 3 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 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), or together with the carbon atom to which they are attached, represents C _3-6 cycloalkyl (wherein said cycloalkyl is halogen, hydroxyl, C _1- optionally substituted with ₁ to 3 substituents independently selected from the group consisting of 3 alkyl and C _1-3 alkoxy), or independently selected from the group consisting of a nitrogen atom and an oxygen atom C _4-6 saturated heterocycle containing 1 or 2 heteroatoms, wherein the saturated heterocycle is 1-3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy may be substituted with one substituent),
R ⁴ and R ⁵ are the same or different, hydrogen, halogen, hydroxyl group, 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 optionally substituted with 1 to 3 selected substituents), or C _3-6 cycloalkyl (wherein the cycloalkyl is from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 independently selected substituents), or when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms, they are C _3-6 cycloalkyl together with the carbon atom to which is attached, wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy or a _C4-6 saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the saturated heterocyclic ring is a halogen , hydroxyl group, 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; ] R ² and R ³ are the same or different and are substituted with 1 to 3 substituents independently selected from _{the group consisting of fluorine, hydroxyl and C 1-3 alkoxy} ; or C _3-6 cycloalkyl together with the carbon atom to which they are attached, said cycloalkyl consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group), or 1 or 2 hetero groups independently selected from the group consisting of a nitrogen atom and an oxygen atom C _4-6 saturated heterocycle containing atoms, said saturated heterocycle substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It is a group that constituted the
Pharmaceutical composition according to claim 1 R ² and R ³ are the same or different and represent C _1-3 alkyl (which alkyl may be substituted with fluorine), or together with the carbon atom to which they are attached, C _3- C _4- containing 1 or 2 heteroatoms independently selected from a group consisting of ₆ cycloalkyl (which cycloalkyl may be substituted with fluorine), or a nitrogen atom and an oxygen atom; A group constituting a _6- saturated heterocyclic ring (the saturated heterocyclic ring may be substituted with fluorine),
Pharmaceutical composition according to claim 2 1 to 3 in which R ⁴ and R ⁵ are the same or different and are independently selected from the group consisting of hydrogen, fluorine, hydroxyl group, C _1-3 alkyl (wherein said alkyl is fluorine, hydroxyl group and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl is independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents), or when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms, the carbon atom to which they are attached and taken together, C _3-6 cycloalkyl, said cycloalkyl substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy; or a _C4-6 saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom (the saturated heterocyclic ring being fluorine, (optionally substituted with 1 to 3 substituents independently selected from the group consisting of a hydroxyl group, C _1-3 alkyl and C _1-3 alkoxy)),
The pharmaceutical composition according to any one of claims 1-3 R ⁴ and R ⁵ are the same or different, hydrogen, fluorine, hydroxyl group, C _1-3 alkyl (which alkyl may be substituted with fluorine), or C _3-6 cycloalkyl (wherein said cycloalkyl is fluorine ), or when R ⁴ and R ⁵ are on the same carbon atom or on adjacent carbon atoms, together with the carbon atom to which they are attached, C _{3- 6} cycloalkyl (the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine and C _1-3 alkyl). ,
A pharmaceutical composition according to claim 4 . Q ¹ is fluorine, chlorine or bromine,
Q ² is hydrogen, fluorine, chlorine, bromine, cyano, C _1-3 alkyl (the alkyl may be substituted with fluorine) or C _1-3 alkoxy (the alkoxy may be substituted with fluorine) is
The pharmaceutical composition according to any one of claims 1-5. The ring containing X, Y and Z is (5a), (5b), or (5c) below,

The pharmaceutical composition according to any one of claims 1-6. The ring containing X, Y and Z is (5a) or (5b) below,

A pharmaceutical composition according to claim 7 . R ¹ is (4) below;

The pharmaceutical composition according to claim 1 or any one of claims 4-8. The compound represented by formula (1) or a pharmaceutically acceptable salt thereof is selected from the compounds represented by the following compound names or pharmaceutically acceptable salts thereof, according to claim 1 The described pharmaceutical composition:
2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide,
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide,
2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide,
1-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide,
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide,
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-fluorocyclobutane-1-carboxamide,
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3,3-difluorocyclobutane-1-carboxamide,
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxamide,
1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclopentane-1-carboxamide,
4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]tetrahydro-2H-pyran-4-carboxamide,
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-ethylbutanamide,
2-[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide,
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide,
2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide,
2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropanamide,
2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropanamide,
2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide,
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide,
2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide,
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide,
2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide,
2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide,
2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide,
2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]propane-2-sulfonamide,
5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one,
5-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one,
5-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one,
5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1,5-dimethylpyrrolidin-2-one,
5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one,
5-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one,
(S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, and (R)-5-[3- (4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one. The compound represented by formula (1) or a pharmaceutically acceptable salt thereof is selected from the compounds represented by the following compound names or pharmaceutically acceptable salts thereof, according to claim 1 The described pharmaceutical composition:
2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide,
2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide,
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide,
2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide,
5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one,
5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one,
(S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one, and (R)-5-[3- (4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one. A therapeutic and/or preventive agent for diseases associated with GABA nervous system dysfunction, containing the pharmaceutical composition according to any one of claims 1 to 11. 13. The therapeutic and/or prophylactic agent according to claim 12, wherein the disease associated with GABA nervous system dysfunction is a nervous system disease or a psychiatric disease. Nervous system or psychiatric disorders such as epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar and related disorders, schizophrenia spectrum disorders, Alzheimer's disease and other neurocognitive disorders, 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. Item 14. The therapeutic and/or prophylactic agent according to item 13. Use of the pharmaceutical composition according to any one of claims 1 to 11 for producing a therapeutic and/or preventive agent for diseases associated with GABA nervous system hypofunction. The pharmaceutical composition according to any one of claims 1 to 11, for use in treating and/or preventing diseases associated with GABA nervous system hypofunction. A combination of the pharmaceutical composition according to any one of claims 1 to 11 and at least one drug selected from drugs classified as antiepileptic drugs, antidepressants, or antipsychotic drugs Medicine. 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 pharmaceutical composition according to any one of claims 1 to 11.

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