Oxadiazole derivative

Abstract

To provide a compound useful as an antiepileptic drug.SOLUTION: The present invention relates to: a compound represented by formula (1) (where 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 given structure) or a pharmaceutically acceptable salt thereof; and a medicaments comprising them for treating and / or preventing a disease such as epilepsy.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an oxadiazole derivative useful as a medicine, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them as an active ingredient, or a therapeutic agent and / or prophylactic agent for diseases such as epilepsy and / or depressive syndrome.

Background Art

[0002] Epilepsy is a chronic disease in which abnormal physical symptoms, movements, consciousness, and sensations suddenly and repeatedly occur due to the overexcitation of nerve cells in the brain. The seizure types of epilepsy are classified by the International League Against Epilepsy (ILAE) into generalized seizures, focal seizures, and seizures of unknown classification. Generalized seizures are further classified into tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, etc. (Non-Patent Document 1). The etiologies underlying the disease are roughly classified into genetic, structural / metabolic, and unknown causes. In addition, epilepsy is classified into various disease types and syndromes based on characteristics such as electroencephalogram, clinical symptoms, onset age, and etiology. For example, West syndrome and Doose syndrome that occur in infancy, Lennox-Gastaut syndrome and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) that occur in childhood, medial temporal lobe epilepsy and Rasmussen syndrome accompanied by hippocampal sclerosis as a clear specific symptom group, and many others are included (Non-Patent Document 2). Since the 1990s, especially the international joint research on the molecular pathology analysis of epilepsy has advanced, and a large number of causative genes have been identified to date. These genes include ion channels such as Na, K, Ca, Cl, GABA-A, and ACh, and it is inferred that epilepsy develops due to an abnormality in ion homeostasis as one of the causes.

[0003] Epilepsy is a severe disease that also affects life prognosis, and it is known that approximately 1% of the world's population suffers from it. The treatment of these epileptic seizures mainly relies on drug therapy. Despite various anti-epileptic drugs having been prescribed for a long time, one in three epilepsy cases is intractable epilepsy that shows resistance to combination therapy with existing drugs. In addition, existing drugs have risks such as dose-dependent side effects on the nervous system like excessive drowsiness, dizziness, cognitive impairment, and psychiatric symptoms, rare but severe idiosyncratic side effects like Stevens-Johnson syndrome, teratogenicity, etc., and there is also a risk of drug efficacy loss or side effect enhancement due to drug interactions. Moreover, epilepsy patients have a high risk of concurrent psychiatric symptoms such as depression, anxiety, and cognitive impairment (Non-Patent Document 3). However, existing drugs do not have a therapeutic effect on these concurrent psychiatric symptoms. From the above, there is a strong demand for the development of new anti-epileptic drugs with characteristics such as high efficacy against intractable epilepsy, excellent profiles in terms of pharmacokinetics and safety, and efficacy for both epilepsy and concurrent psychiatric symptoms. Epilepsy presents seizures due to the excessive excitation of brain nerve cells, and it is considered to be caused by the strong activation of excitatory nerves or the weakening of the power of inhibitory nerves, that is, the imbalance of excitation (E) and inhibition (I) (E / I balance). In addition to epilepsy, diseases caused by E / I balance abnormalities are known. GABAergic drugs that activate inhibitory nerves have shown a therapeutic effect on anxiety disorders, obsessive-compulsive disorder, and REM sleep disorder associated with Parkinson's disease with Lewy body dementia. Also, E / I balance abnormalities are known to be involved in neuropathic pain, developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, Parkinson's disease, etc. In fact, some anti-epileptic drugs that improve E / I balance have been widely applied to these other diseases. However, the drug efficacy intensity in these diseases other than epilepsy is also limited, and problems in terms of side effects and pharmacokinetics remain. Therefore, anti-epileptic drugs with new drug efficacy and side effect profiles may be applicable to many of these mental and nervous system diseases, and the significance of development is great.

[0004] Patent Document 1 describes oxadiazoles having a sweet taste modifying effect, but they have a chemical structure different from that of the compound represented by the following formula (1).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a compound useful as an antiepileptic drug.

Means for Solving the Problems

[0008] As a result of intensive studies, the present inventors have clarified that the compound represented by the following formula (1) exhibits a strong antispasmodic effect, that is, an antiepileptic effect, and has a GABA-A receptor activating effect, and completed the present invention. According to the present invention, there is provided an oxadiazole derivative represented by the following formula (1) (hereinafter, sometimes referred to as "the compound of the present invention").

[0009] That is, the present invention is as follows.

[0010] [Item 1] A compound represented by formula (1), or a pharmaceutically acceptable salt thereof. [Chemical formula] [In the formula, Q 1 represents a halogen, Q 2 represents hydrogen, a halogen, cyano, C 1-3 alkyl (the alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 3-6 cycloalkyl and C 1-3 alkoxy) or C 1-3 alkoxy (the alkoxy may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 3-6 cycloalkyl and C 1-3 alkoxy), X, Y, and Z are the same or different and each represents a nitrogen atom or an oxygen atom, provided that the ring containing X, Y, and Z is a heteroaryl in which two of X, Y, and Z are nitrogen atoms and the remaining one is an oxygen atom, R 1 represents any one of the following (2) to (4), [Chemical formula] R 2 and R 3 are the same or different and each represents C 1-6 alkyl (the alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 3-6 cycloalkyl and C 1-3 alkoxy) or C 3-6 cycloalkyl (the cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy), or together with the carbon atom to which they are attached, form C 3-6Cycloalkyl (the cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, 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 nitrogen atom and oxygen atom (the saturated heterocyclic ring may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-3 alkyl and C 1-3 alkoxy), represents a group formed by R 4 and R 5 are the same or different and are hydrogen, halogen, hydroxyl group, C 1-6 alkyl (the alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C 3-6 cycloalkyl and C 1-3 alkoxy), or C 3-6 cycloalkyl (the cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-3 alkyl and C 1-3 alkoxy), or when R 4 and R 5 are present on the same carbon atom or adjacent carbon atoms, together with the carbon atoms to which they are attached, form a C 3-6 cycloalkyl (the cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, 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 nitrogen atom and oxygen atom (the saturated heterocyclic ring may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-3 alkyl and C 1-3 alkoxy) may be formed, n represents an integer from 0 to 2.]

[0011] [Item 2] R 2 and R 3 are the same or different and are C 1-3 alkyl (the alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, and C 1-3 alkoxy), or together with the carbon atom to which they are attached form C 3-6 cycloalkyl (the cycloalkyl may be 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 group containing 1 or 2 heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom and forming C 4-6 saturated heterocyclic ring (the saturated heterocyclic ring may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C 1-3 alkyl, and C 1-3 alkoxy), which is the compound according to item 1 or a pharmaceutically acceptable salt thereof. The compound according to item 1 or a pharmaceutically acceptable salt thereof.

[0012] [Item 3] R 2 and R 3 are the same or different and are C 1-3 alkyl (the alkyl may be substituted with fluorine), or together with the carbon atom to which they are attached form C 3-6 cycloalkyl (the cycloalkyl may be substituted with fluorine), or a group containing 1 or 2 heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom and forming C 4-6 saturated heterocyclic ring (the saturated heterocyclic ring may be substituted with fluorine), which is the compound according to item 2 or a pharmaceutically acceptable salt thereof. The compound according to item 2 or a pharmaceutically acceptable salt thereof.

[0013] [Item 4] R 4 and R 5 are the same or different and are hydrogen, fluorine, hydroxyl, C 1-3 alkyl (the alkyl is fluorine, hydroxyl, and C 1-3(which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), or C 3-6 cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy, and may be substituted with 1 to 3 substituents independently selected from the group consisting thereof), or R 4 and R 5 when present on the same carbon atom or adjacent carbon atoms, together with the carbon atom to which they are attached, form a C 3-6 cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy, and may be substituted with 1 to 3 substituents independently selected from the group consisting thereof), or a group formed by 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 is fluorine, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy, and may be substituted with 1 to 3 substituents independently selected from the group consisting thereof) may be formed, The compound according to any one of items 1 to 3 or a pharmaceutically acceptable salt thereof.

[0014] [Item 5] R 4 and R 5 are the same or different and are hydrogen, fluorine, hydroxyl, C 1-3 alkyl (the alkyl may be substituted with fluorine), or C 3-6 cycloalkyl (the cycloalkyl may be substituted with fluorine), or R 4 and R 5 when present on the same carbon atom or adjacent carbon atoms, together with the carbon atom to which they are attached, form a 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 be formed, The compound according to item 4 or a pharmaceutically acceptable salt thereof.

[0015] [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), The compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.

[0016] [Item 7] The ring containing X, Y and Z is the following (5a), (5b), or (5c), [Chemical formula] The compound according to any one of Items 1 to 6 or a pharmaceutically acceptable salt thereof.

[0017] [Item 8] The ring containing X, Y and Z is the following (5a) or (5b), [Chemical formula] The compound according to Item 7 or a pharmaceutically acceptable salt thereof.

[0018] [Item 9] R 1 is the following (2) or (3), [Chemical formula] The compound according to any one of Items 1 to 3, or 6 to 8 or a pharmaceutically acceptable salt thereof.

[0019] [Item 10] R 1 is the following (4), [Chemical formula] The compound according to Item 1, or any one of Items 4 to 8 or a pharmaceutically acceptable salt thereof.

[0020] [Item 11] The compound according to Item 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 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).

[0021] [Item 12] The compound according to Item 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 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).

[0022] [Item 13] A pharmaceutical composition containing the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[0023] [Item 14] A therapeutic and / or prophylactic agent for a nervous system disease or a mental disease, containing the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0024] [Item 15] A therapeutic and / or prophylactic agent for a disease in which excitation (E) in the E / I balance is enhanced and / or inhibition (I) is reduced, containing the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0025] [Item 16] A therapeutic and / or prophylactic agent for a disease involving reduced GABA nervous system function, containing the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] [Item 17] The therapeutic and / or prophylactic agent according to Item 16, wherein the disease involving reduced GABA nervous system function is a nervous system disease or a mental disease.

[0027] [Item 18] The nervous system disease or mental disorder is epilepsy seizure (generalized seizure including tonic seizure, clonic seizure, absence seizure, myoclonic seizure, atonic seizure, focal seizure, seizure of unknown classification), 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 specific symptom group, Rasmussen syndrome, depressive symptoms with or without epilepsy, anxiety disorder, obsessive-compulsive disorder, REM sleep disorder associated with Parkinson's disease-dementia with Lewy bodies, neuropathic pain, developmental disorder, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, or Parkinson's disease, the therapeutic agent and / or prophylactic agent according to Item 14 or 17.

[0028] [Item 19] The nervous system disease or mental disorder is epilepsy, neuropathic pain, neurodevelopmental disorder group, bipolar disorder and related disorder group, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorder group, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndrome, anxiety disorder group, obsessive-compulsive disorder, mental trauma and stress factor-related disorder, sleep-wake disorder group, and / or REM sleep disorder associated with Parkinson's disease-dementia with Lewy bodies, the therapeutic agent and / or prophylactic agent according to Item 14 or 17.

[0029] [Item 20] A method for treating and / or preventing a disease involving reduced GABA nervous system function, which comprises administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[0030] [Item 21] Use of the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof, for manufacturing a therapeutic agent and / or prophylactic agent for a disease involving reduced GABA nervous system function.

[0031] [Item 22] The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving reduced GABA nervous system function.

[0032] [Item 23] A therapeutic and / or prophylactic agent for epilepsy, containing, as an active ingredient, the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[0033] [Item 24] The therapeutic and / or prophylactic agent according to Item 23, wherein the epilepsy is epilepsy seizure (generalized seizure including tonic seizure, clonic seizure, absence seizure, myoclonic seizure, atonic seizure, focal seizure, seizure of unknown classification), 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 definite specific symptom group, or Rasmussen syndrome.

[0034] [Item 25] A method for treating and / or preventing epilepsy, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[0035] [Item 26] Use of the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof, for manufacturing a therapeutic and / or prophylactic agent for epilepsy.

[0036] [Item 27] The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of epilepsy.

[0037] [Item 28] A pharmaceutical composition comprising a pharmaceutical containing the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof, and at least one agent selected from the group consisting of anti-epileptic drugs, antidepressants, or antipsychotics.

[0038] [Item 29] A pharmaceutical containing the compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof, for treating a disease involving reduced GABA nervous system function, characterized by being used in combination with at least one agent selected from the group consisting of anti-epileptic drugs, antidepressants, or antipsychotics.

[0039] [Item 30] The following formula: [Chemical formula] A process for producing compound (Ic) comprising reacting compound (IIc1) and compound (IIc2) shown in the formula to obtain compound (IIc'), and methylating compound (IIc') (the symbols in the formula have the same meanings as described above).

[0040] [Item 31] The following formula: [Chemical formula] A process for producing compound (Ic') comprising reacting compound (IIc1') and compound (IIc2') shown in the formula (the symbols in the formula have the same meanings as described above). [Advantages of the Invention]

[0041] The compounds of the present invention exhibited potent antispasmodic activity in multiple spasm model animals caused by reduced GABA signaling (the subcutaneous pentylenetetrazole model in Test Example 1, the febrile convulsion in the Dravet model mice in Test Example 3). The subcutaneous pentylenetetrazole model in Test Example 1 is a manifestation system of generalized absence seizures and myoclonic seizures, and is a model presenting a seizure type with a low remission rate of existing antiepileptic drugs. The febrile convulsion in the Dravet model mice in Test Example 3 is an animal model having the same genetic background as the Dravet syndrome presenting treatment-resistant spasms, and the effects of existing antiepileptic drugs on this model are very limited. Therefore, the compounds of the present invention are useful as prophylactic and / or therapeutic agents for epilepsy (for example, epileptic seizures (generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, focal seizures, seizures of unknown classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), medial temporal lobe epilepsy associated with hippocampal sclerosis as a specific symptom group, Rasmussen syndrome, etc.). Incidentally, West syndrome, Dravet syndrome, and Lennox-Gastaut syndrome present treatment-resistant spasms and are severe diseases accompanied by developmental delay, etc., and it is of great significance to provide prophylactic and / or therapeutic agents for intractable epilepsy including these. The GABA-A receptor activating activity of the compounds of the present invention is exerted in a mode different from that of benzodiazepine, which is one of the existing GABA nervous system activating agents, and since it exerted an effect on the depressive symptoms in the rat forced swimming model in which benzodiazepine showed no effect (Test Example 5), it has an effect on depressive symptoms with or without epilepsy, and has usefulness not possessed by existing antiepileptic drugs. Since the compounds of the present invention have GABA-A receptor activating activity, they are also useful as prophylactic and / or therapeutic agents for anxiety disorders, obsessive-compulsive disorder, and REM sleep disorder associated with Parkinson's disease and Lewy body dementia, for which therapeutic effects of existing GABA nervous system activating agents have been recognized.In addition, it is considered to exhibit a pathological improvement effect on neuropathic pain, developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, and Parkinson's disease, which are caused by abnormalities in the GABA nervous system. Furthermore, it is also useful as a prophylactic and / or therapeutic agent for other diseases described in this specification. In addition, since the compound of the present invention has an action of enhancing inhibition (I) in the balance between excitation (E) and inhibition (I) (E / I balance), it can be a therapeutic and / or prophylactic agent for nervous system diseases or mental diseases, particularly for diseases in which excitation (E) in the E / I balance is enhanced and / or inhibition (I) is decreased.

Mode for Carrying Out the Invention

[0042] The terms used in this specification are explained below.

[0043] In this specification, unless otherwise indicated, the description of each group applies also when the group is a part of another group or a substituent.

[0044] Examples of the "halogen" include fluorine, chlorine, bromine, or iodine. Fluorine, chlorine, or bromine is preferred. More preferably, fluorine or chlorine is used, and even more preferably, fluorine is used.

[0045] "C 1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and "C 6 alkyl" means an alkyl having 6 carbon atoms. The same applies to other numbers. "C 1-6 alkyl" preferably includes "C 1-3 alkyl", and more preferably includes "C 1-2 alkyl". "C 1-3 alkyl" preferably includes "C 1-2 alkyl", and more preferably includes methyl. Specific examples of "C 1-2 alkyl" include, for example, methyl, ethyl, and the like. "C1-3 Specific examples of "alkyl" include, for example, the above-mentioned "C" 1-2 In addition to those exemplified as specific examples of "alkyl", propyl, 1-methylethyl, etc. can be mentioned. "C" 1-6 Specific examples of "alkyl" include, for example, the above-mentioned "C" 1-3 In addition to those exemplified as specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, etc. can be mentioned.

[0046] "C" 3-6 "Cycloalkyl" means a cyclic alkyl having 3 to 6 carbon atoms and also includes those having a partially bridged structure. "C" 3-6 As "cycloalkyl", preferably "C" 3-5 "Cycloalkyl" can be mentioned. "C" 3-5 Specific examples of "cycloalkyl" include, for example, cyclopropyl, cyclobutyl, cyclopentyl, etc. "C" 3-6 Specific examples of "cycloalkyl" include, for example, the above-mentioned ""C" 3-5 In addition to those exemplified as specific examples of "cycloalkyl", cyclohexyl, etc. can be mentioned.

[0047] "C" 1-3 "Alkoxy" means an oxy group substituted by the above-mentioned "C" 1-3 "alkyl". As the "alkoxy group", preferably "C" 1-3 "alkoxy" can be mentioned, and more preferably "methoxy" can be mentioned. "C" 1-2 Specific examples of "alkoxy" include, for example, methoxy, ethoxy, etc. "C" 1-2 Specific examples of "alkoxy" include, for example, the above-mentioned "C" 1-3 In addition to those exemplified as specific examples of "alkoxy", propoxy, 1-methylethoxy, etc. can be mentioned. 1-2 Specific examples of "alkoxy" include, for example, the above-mentioned "C"

[0048] "C"4-6 The term "saturated heterocyclic ring" 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, and also includes those having a partially bridged structure. Preferably, it contains 1 or 2 heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom, and is a C 4-6 saturated heterocyclic ring. "C 4-6 saturated heterocyclic ring", preferably "C 4-5 saturated heterocyclic ring". "C 4-5 saturated heterocyclic ring" includes, for example, oxetane, azetidine, tetrahydrofuran, pyrrolidine, etc. as specific examples. "C 4-6 saturated heterocyclic ring" includes, for example, in addition to those exemplified as the specific examples of the "saturated heterocyclic ring", tetrahydropyran, piperidine, morpholine, piperazine, etc. 4-5

[0049] R 1 R 2 R 3 R 4 R 5 X, Y, Z, Q 1 Q 2 and n, and the preferred ones are as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.

[0050] R 1 Examples of the embodiment of R include the following (2) to (4).

Chemical formula

Chemical formula

Chemical formula

[0051] ​ R 2 and R 3 Preferred embodiments of R 2 and R 3 are the same or different and (1)C 1-3 alkyl (the alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, and C 1-3 alkoxy), or (2)R 2 and R 3 together with the carbon atom to which they are attached form C 3-6 cycloalkyl (the cycloalkyl may be 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 (3)R 2 and R 3 together with the carbon atom to which they are attached form a C 4-6 saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms (the cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy). Examples thereof are given below.

[0052] R 2 and R 3 More preferred embodiments of R 2 and R 3 are the same or different and (1)C 1-3 alkyl (the alkyl may be substituted with fluorine), or (2)together with the carbon atom to which they are attached form C 3-6 cycloalkyl (the cycloalkyl may be substituted with fluorine), or (3)a C 4-6A group constituting a saturated complex ring (the saturated complex ring may be substituted with fluorine). include the following.

[0053] R 2 and R 3 together with the carbon atom to which they are attached to form a C 3-6 Examples of the cycloalkyl include the following groups.

Chemical formula

[0054] R 2 and R 3 together with the carbon atom to which they are attached to form a C 4-6 Examples of the saturated complex ring include a 4- to 6-membered saturated ring containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms, such as the following groups.

Chemical formula

[0055] R 4 and R 5 In a preferred embodiment of R 4 and R 5 are the same or different and (1) hydrogen, (2) fluorine, (3) a hydroxyl group, (4) C 1-3 alkyl (the alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, a hydroxyl group, and C 1-3 alkoxy), (5) C 3-6 cycloalkyl (the cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, a hydroxyl group, C 1-3 alkyl, and C 1-3 alkoxy), or R 4 and R 5 when present on the carbon atom to which they are attached or on an adjacent carbon atom, (6) together with the carbon atom to which they are attached, C 3-6 cycloalkyl (the cycloalkyl may be 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 (7) together with the carbon atom to which they are attached, C 4-6 saturated heterocycle (the cycloalkyl may be 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 form a group Examples include. Here, the "adjacent carbon atoms" refer to the state in which the ring-constituting carbons to which R 4 and R 5 are respectively attached are adjacent and bonded.

[0056] R 4 and R 5 In a more preferred embodiment, R 4 and R 5 are the same or different, and (1) hydrogen, (2) fluorine, (3) hydroxyl, (4) C 1-3 alkyl (the alkyl may be substituted with fluorine), (5) C 3-6 cycloalkyl (the cycloalkyl may be substituted with fluorine), or R 4 and R 5 are present on the same carbon atom or adjacent carbon atoms, (6) together with the carbon atom to which they are attached, 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 form a group Examples include.

[0057] R 4 and R 5 When they are present on the same carbon atom or adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a C 3-6 Examples of cycloalkyl include the following groups and the like.

Chemical formula

[0058] R 4 and R 5 When they are present on the same carbon atom or adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a C 4-6 Examples of saturated heterocycles include the following groups and the like.

Chemical formula

Chemical formula

Chemical formula

[0059] Preferred embodiments of X, Y, and Z are the same or different and represent a nitrogen atom or an oxygen atom. However, the ring containing X, Y, and Z includes the following oxadiazoles in which two of X, Y, and Z are nitrogen atoms and the remaining one is an oxygen atom.

Chemical formula

[0060] More preferred embodiments of X, Y, and Z include the following oxadiazoles.

Chemical formula

[0061] Examples of n include integers of 0, 1, or 2, and preferred examples include 0 or 1.

[0062] Q 1 Preferred examples of include fluorine, chlorine, bromine, or iodine, and more preferred examples include fluorine, chlorine, or bromine.

[0063] Q 2 Preferred examples of include (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) are included.

[0064] Q 2 More preferred examples of include (1) hydrogen, (2) fluorine, (3) chlorine, or (4) cyano are included.

[0065] Among the compounds represented by formula (1), preferred compounds include the following compounds or pharmaceutically acceptable salts thereof.

[0066] One example of the compound represented by formula (1) includes the following (A). (A) R 1 is any of the following,

Chemical formula

Chemical formula

[0067] One embodiment of the compound represented by formula (1) includes the following (B). (B) R 1 Is the following (4),

Chemical formula

Chemical formula

[0068] One embodiment of the compound represented by formula (1) includes the following (C). (C) R 1 is any of the following,

Chemical formula

Chemical formula

[0069] One embodiment of the compound represented by formula (1) includes the following (D). (D) R 1 is as follows (4),

Chemical formula

Chemical Structure

[0070] Examples of "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, phosphate, etc., or organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, camphorsulfonate, etc. Base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, aluminum salt, etc., or organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylamine, etc. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic amino acids or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0071] Suitable salts of the starting compounds and intermediates and pharmaceutically acceptable salts are conventional non-toxic salts, such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate or para-toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate, etc.) such as acid addition salts, salts with amino acids (e.g., arginine, aspartic acid or glutamic acid, etc.), metal salts such as alkali metal salts (e.g., sodium salt or potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt or magnesium salt, etc.), ammonium salts, or organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picolinate, dicyclohexylamine salt or N,N'-dibenzylethylenediamine salt, etc.), etc., which can be appropriately selected by those skilled in the art.

[0072] When it is desired to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it may be purified as it is. If it is obtained in the free form, it may be dissolved or suspended in a suitable organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0073] In the present invention, any one or two or more of the compounds represented by formula (1) 1 H is 2 The deuterium-converted product obtained by converting H to H(D) is also included in the compound represented by formula (1). The present invention includes the compound represented by formula (1), or a pharmaceutically acceptable salt thereof. Further, since the compound of the present invention may exist in the form of a hydrate and / or a solvate with various solvents (such as an ethanol solvate, etc.), these hydrates and / or solvates are also included in the compound of the present invention. Furthermore, the present invention includes all tautomers of the compound (1) of the present invention, all existing stereoisomers, and all forms of crystal forms, and mixtures thereof.

[0074] Among the compounds (1) of the present invention, there may be optical isomers based on an optically active center, atropisomers based on axial or planar chirality caused by the restriction of intramolecular rotation, other stereoisomers, tautomers, and geometric isomers, etc. All possible isomers including these and their mixtures are included within the scope of the present invention.

[0075] In particular, optical isomers and atropisomers can be obtained as racemates or as optically active forms when optically active starting materials or intermediates are used. If necessary, at appropriate stages of the following production methods, the racemates of the corresponding raw materials, intermediates or final products can be physically or chemically separated into their optical antipodes by known separation methods such as methods using an optically active column or fractional crystallization method. Specifically, for example, in the diastereomer method, two kinds of diastereomers are formed from the racemate by a reaction using an optically active resolving agent. Since these different diastereomers generally have different physical properties, they can be separated by known methods such as fractional crystallization.

[0076] The production methods of the compounds of the present invention are described below, but the production methods of the compounds of the present invention are not limited thereto.

[0077] Manufacturing Method 1 Among the compounds of formula (I), the compounds of formula (Ia) below can be produced by the following production method.

Chemical formula

[0078] Compound (Ia) is obtained by the amidation reaction of (IIa) and ammonia. The amidation reaction of compound (IIa) can be carried out according to a conventional method. For example, this reaction is achieved by converting compound (IIa) into a reactive derivative (e.g., lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting it with ammonia. Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester, etc. Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chloroformate, isobutyl chloroformate, isovaleric acid, pivalic acid, etc. Specific examples of the solvent should be selected according to the type of raw material compound, etc. For example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, etc. can be mentioned and can be used alone or as a mixed solvent. 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.

[0079] Also, compound (Ia) is compound (IIa) and (NH 4 ) 2 CO 3It can also be produced by reacting with an ammonium salt such as etc. in the presence of a condensing agent. Specific examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·1 hydrochloride, N,N'-carbonyldiimidazole, benzotriazol-1-yl-oxytri-(pyrrolidino)phosphonium-hexafluorophosphate, etc. 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 raw material compound, etc. For example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, etc. can be mentioned and can be used alone or as a mixed solvent. 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.

[0080] Manufacturing Method 2 Among the compounds of formula (I), the compound of the following formula (1b) can be produced by the following production method. [Chemical formula] (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 protecting group for a nitrogen atom that can be removed under acidic conditions, such as a 2,4-dimethoxybenzyl group or a p-methoxybenzyl group, and P 2 is hydrogen or a protecting group for a nitrogen atom that can be removed under acidic conditions, such as a 2,4-dimethoxybenzyl group or a p-methoxybenzyl group.)

[0081] Compound (Ib) is obtained by deprotecting compound (IIb). The deprotection of compound (IIb) can be carried out according to conventional methods. For example, this reaction is achieved by reacting compound (IIb) with an organic strong acid such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or an inorganic strong acid such as hydrochloric acid, sulfuric acid, nitric acid, etc.

[0082] The deprotection of compound (IIb) is carried out in a solvent or without a solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc. For example, toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, acetonitrile, DMF, DMSO, etc. can be mentioned and can be used alone or as a mixed solvent. In addition, as the protecting group for the nitrogen atom in compound (IIb), in addition to the 2,4-dimethoxybenzyl group, protecting groups that cleave under acidic conditions such as the t-butoxycarbonyl group, t-butyl group, p-methoxybenzyl group, etc. can be used, and depending on the type of protecting group, the number of protecting groups may be one. The reaction temperature varies depending on the type of raw material compound used, etc., but 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.

[0083] Manufacturing Method 3 Among the compounds of formula (I), the compound of the following formula (1c) can be produced by the following production method.

Chemical formula

[0084] Compound (Ic) is obtained by methylating compound (IIc). The methylation of compound (IIc) can be carried out according to conventional methods. For example, this reaction is achieved by reacting compound (IIc) with a methylating agent such as methyl iodide, methyl bromide, dimethyl sulfate, 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, etc. For example, toluene, THF, dioxane, DME, ethyl acetate, isopropyl acetate, acetone, acetonitrile, DMF, NMP, etc. can be mentioned and can be used alone or as a mixed solvent. Specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal hydrides such as sodium hydride, potassium hydride, alkoxyalkali metals such as potassium t-butoxide, sodium methoxide, and alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate. The reaction temperature varies depending on the type of raw material compound and reagent used, etc., but 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.

[0085] The compounds of formulas (Ia), (Ib) and (Ic) produced by the above production methods 1, 2 and 3 can be isolated and purified by ordinary methods such as chromatography and recrystallization.

[0086] The raw material compounds used in the above production methods 1, 2 and 3 can be produced by the following methods.

[0087] Manufacturing Method 4 Among the compounds of formula (I), the compound of the following formula (1c') can also be produced by the following production method.

Chemical formula

[0088] Compound (Ic’) is produced by reacting compound (IIc1’) with 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·1 hydrochloride, N,N’-carbonyldiimidazole, 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 anhydride, 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 raw material compound and the like. For example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, ethyl acetate, isopropyl acetate, and the like can be mentioned, and they can be used alone or as a mixed solvent. The reaction temperature varies depending on the type of raw material compounds and reagents used, but is usually -100 to 200 °C, preferably -30 to 150 °C. The reaction time is usually 30 minutes to 24 hours.

[0089] Manufacturing Method 5 Compound (IIa) used in the above Production Method 1 is produced according to the method represented by the following reaction formula.

Chemical formula

[0090] (Step 1) Compound (IIIa) is obtained by alkylating compound (IVa). The alkylation reaction in Step 1 can be carried out according to conventional methods. For example, this reaction can be 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. Also, for a compound in which R 2 and R 3 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 4- to 6-membered saturated heterocyclic ring, the above reaction conditions are used to react compound (IVa) with the corresponding dihalide (e.g., X-(CH 2 ) n -X (n represents an integer from 3 to 6, and X represents a halogen)). Specific examples of the solvent should be selected according to the type of raw material compound, etc. For example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, etc. can be mentioned and can be used alone or as a mixed solvent. Specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal hydrides such as sodium hydride, potassium hydride, alkoxyalkali metals such as potassium t-butoxide, sodium methoxide, and alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate. The reaction temperature varies depending on the types of raw material compounds and reagents used, etc., but is usually 0 to 200 °C, preferably 20 to 150 °C. The reaction time is usually 30 minutes to 24 hours.

[0091] (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 the starting compound, etc. For example, THF, dioxane, DME, acetone, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, water, etc. can be mentioned and can be used alone or as a mixed solvent. Specific examples of the acid used include mineral acids such as hydrochloric acid and sulfuric acid. Also, specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkoxy alkali metals such as potassium t-butoxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate. The reaction temperature varies depending on the type of the starting compound and reagent used, etc., but is usually 0 to 150 °C, preferably 20 to 100 °C. The reaction time is usually 30 minutes to 24 hours.

[0092] Manufacturing Method 6 Among the compounds (IIIa) used in the above Production Method 5, (IIIa’) is produced by a condensation dehydration cyclization reaction of compound (IIIa1) and compound (IIIa2).

Chemical formula

[0093] The condensation dehydration cyclization reaction of compound (IIIa1) and compound (IIIa2) can be carried out according to conventional methods. For example, this reaction is achieved by converting compound (IIIa2) into a reactive derivative (e.g., lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting it with compound (IIIa1). Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester, etc. Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chloroformate, isobutyl chloroformate, isovaleric acid, pivalic acid, etc. Specific examples of the solvent should be selected according to the type of raw material compound, etc. For example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine or esters such as ethyl acetate and isopropyl acetate can be mentioned and can be used alone or as a mixed solvent. The reaction temperature varies depending on the types of raw material compounds and reagents used, etc., but is usually -100 to 200 °C, preferably -30 to 150 °C. The reaction time is usually 30 minutes to 24 hours.

[0094] 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·1 hydrochloride, N,N’-carbonyldiimidazole, 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 starting compound, etc. For example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, ethyl acetate, isopropyl acetate, etc. can be mentioned, and they can be used alone or as a mixed solvent. The reaction temperature varies depending on the type of the starting compound and reagent used, etc., but is usually -100 to 200 °C, preferably -30 to 150 °C. The reaction time is usually 30 minutes to 24 hours.

[0095] Manufacturing Method 7 Among the compounds (IVa) used in the above Production Method 5, (IVa’) is produced by the condensation dehydration cyclization reaction of compound (IVa1) and compound (IVa2). [Chemical formula] (In the formula, Q 1 and Q 2 are the same as defined in item 1, and R is C 1-6 alkyl.)

[0096] Compound (IVa’) is produced according to the method described in Production Method 6 using compound (IVa1) and compound (IVa2).

[0097] Manufacturing Method 8 Among the compounds (IVa) used in the above Production Method 5, (IVa’’) is produced by the condensation dehydration cyclization reaction of compound (IVa3) and compound (IVa4). [Chemical formula] (In the formula, Q 1 and Q 2 are the same as defined in item 1, and R is C 1-6 alkyl. )

[0098] Compound (IVa'') is produced according to the method described in Production Method 6 using Compound (IVa3) and Compound (IVa4).

[0099] Manufacturing Method 9 Among the compounds (IVa) used in the above Production Method 5, (IVa''') is produced by the condensation dehydration cyclization reaction of Compound (IVa5) and Compound (IVa6). [Chemical formula] (In the formula, Q 1 and Q 2 are the same as defined in item 1, and R is C 1-6 alkyl. )

[0100] Compound (IVa''') is produced according to the method described in Production Method 6 using Compound (IVa5) and Compound (IVa6). When producing a 1,3,4-oxadiazole ring by a dehydration cyclization reaction, it is produced by coexisting a dehydrating agent such as phosphorus oxychloride or a Burgess reagent as an additive.

[0101] Manufacturing Method 10 The compound (IIb) used in the above Production Method 2 is produced according to the method shown in the following reaction formula. [Chemical formula] (In the formula, R 2 , R 3 , Q 1 , Q 2 , X, Y and Z are the same as defined in item 1. P 1is a protecting group for a nitrogen atom that can be removed under acidic conditions, such as a 2,4 - dimethoxybenzyl group, a p - methoxybenzyl group, etc., and P 2 is hydrogen, or a protecting group for a nitrogen atom that can be removed under acidic conditions, such as a 2,4 - dimethoxybenzyl group, a p - methoxybenzyl group, etc.).)

[0102] (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 raw material compound, etc., but for example, Et 2 ethers such as O, THF, dioxane, DME, alcohols such as methanol, ethanol, isopropyl alcohol, toluene, etc. can be mentioned, and they can be used alone or as a mixed solvent. The reaction temperature varies depending on the types of raw material compounds and reagents used, etc., but is usually - 100°C to 200°C, preferably 0°C to 150°C. The reaction time is usually 30 minutes to 24 hours.

[0103] (Step 2) Compound (IIIb) is obtained by sulfonamidating compound (IVb). The sulfonamidation in Step 2 can be carried out according to a conventional method. For example, this reaction is achieved by converting compound (IVb) to a sulfonyl chloride and then reacting it with an amine. The conversion to sulfonyl chloride is carried out by the action of phosphorus oxychloride in a solvent or without a solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc., but for example, Et 2 O, THF, dioxane, DME, toluene, etc. can be mentioned, and they can be used alone or as a mixed solvent. The reaction temperature varies depending on the types of raw material compounds and reagents used, etc., but is usually - 100°C to 200°C, preferably 0°C to 150°C. The reaction time is usually 30 minutes to 24 hours.

[0104] The conversion of the sulfonyl chloride, which is an intermediate of Step 2, into a sulfonamide is carried out by reacting with a mono- or di-substituted amine NHP having a protecting group that can be removed under acidic conditions, in the presence or absence of a base in a solvent. 1 P 2 The specific examples of the solvent should be selected according to the type of the starting compound and the like. For example, Et 2 O, THF, dioxane, DME, DMF, acetonitrile, toluene and the like can be mentioned and they can be used alone or as a mixed solvent. Specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkoxyalkali metals such as potassium t-butoxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, and organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine. The reaction temperature varies depending on the type of the starting compound and reagent used, etc., but is usually -100°C to 200°C, preferably 0°C to 150°C. The reaction time is usually 30 minutes to 24 hours.

[0105] (Step 3) Compound (IIb) is obtained by alkylating compound (IIIb). Compound (IIb) is produced according to the method described in Step 1 of Production Method 5 using compound (IIIb).

[0106] Manufacturing Method 11 Among the compounds (Vb) used in Production Method 10, (Vb’) is produced by a condensation dehydration cyclization reaction of compound (Vb1) and compound (Vb2). [Chemical formula] (In the formula, Q 1 and Q 2 are the same as defined in Item 1.)

[0107] Compound (Vb’) is produced according to the method described in Production Method 6 using compound (Vb1) and compound (Vb2).

[0108] Manufacturing Method 12 Among the compounds (Vb) used in the production method 10, (Vb'') is produced by a condensation dehydration cyclization reaction of compound (Vb3) and compound (Vb4). [Chemical formula] (In the formula, Q 1 and Q 2 are the same as defined in item 1.)

[0109] Compound (Vb'') is produced according to the method described in production method 6 using compound (Vb3) and compound (Vab).

[0110] Manufacturing Method 13 Among the compounds (Vb) used in the production method 10, (Vb''') is produced by a condensation dehydration cyclization reaction of compound (Vb5) and compound (Vb6). [Chemical formula] (In the formula, Q 1 and Q 2 are the same as defined in item 1.)

[0111] Compound (Vb''') is produced according to the method described in production method 9 using compound (Vb5) and compound (Vb6).

[0112] Manufacturing Method 14 Among the compounds (IIc) used in the production method 3, (IIc') is produced by a condensation dehydration cyclization reaction of compound (IIc1) and compound (IIc2). [Chemical formula] (In the formula, R 4 , R 5 , Q 1 , Q 2 , and n are the same as defined in item 1.)

[0113] Compound (IIc’) is produced according to the method described in Production Method 6 using Compound (IIc1) and Compound (IIc2).

[0114] Manufacturing Method 15 Among the compounds (IIc) used in Production Method 3, (IIc’’) is produced by a condensation dehydration cyclization reaction of Compound (IIc3) and Compound (IIc4).

Chemical formula

[0115] Compound (IIc’’) is produced according to the method described in Production Method 6 using Compound (IIc3) and Compound (IIc4).

[0116] Manufacturing Method 16 Among the compounds (IIc) used in Production Method 3, (IIc’’’) is produced by a condensation dehydration cyclization reaction of Compound (IIc5) and Compound (IIc6).

Chemical formula

[0117] Compound (IIc’’’) is produced according to the method described in Production Method 9 using Compound (IIc5) and Compound (IIc6).

[0118] The compound of the present invention represented by formula (1) or its intermediate can be separated and purified by methods known to those skilled in the art. For example, extraction, partition, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization, etc. can be mentioned. As the recrystallization solvent, for example, 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, ketone solvents such as acetone, halogen solvents such as dichloromethane or chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide or acetonitrile, water, or a mixed solvent thereof, etc. can be used. As other purification methods, methods described in Experimental Chemistry Course (edited by The Chemical Society of Japan, Maruzen) Volume 1, etc. can be used. In addition, the determination of the molecular structure of the compound of the present invention can be easily carried out by spectroscopic methods such as nuclear magnetic resonance method, infrared absorption method, circular dichroism spectrum analysis method, etc. and mass spectrometry method with reference to the structure derived from each starting compound.

[0119] In addition, the intermediate or the final product in the above production method can be converted into other compounds included in the present invention by appropriately converting its functional group, especially by extending various side chains from amino, hydroxyl, carbonyl, halogen, etc., and performing the above protection and deprotection as necessary. The conversion of the functional group and the extension of the side chain can be carried out by general methods commonly used (for example, refer to Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons Inc. (1999), etc.).

[0120] The compound of the present invention represented by formula (1) or a pharmaceutically acceptable salt thereof may have asymmetry or a substituent having an asymmetric carbon, and in such a compound, optical isomers exist. The compound of the present invention includes mixtures and isolated forms of these isomers, and they can be produced according to ordinary methods. Examples of the production methods include a method using a raw material having an asymmetric point or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using an optically active raw material or performing optical resolution or the like at an appropriate stage of the production process. Examples of the optical resolution method include, when the compound represented by formula (1) or an intermediate thereof has a basic functional group, in an inert solvent (for example, an alcohol-based solvent such as methanol, ethanol, 2-propanol, etc., an ether-based solvent such as diethyl ether, an ester-based solvent such as ethyl acetate, a hydrocarbon-based solvent such as toluene, an aprotic solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents), an optically active acid (for example, a monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, a dicarboxylic acid such as tartaric acid, o-diisopropylidene tartaric acid, malic acid, a sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid) is used to form a salt, and a diastereomer method can be mentioned. When the compound of the present invention represented by formula (1) or an intermediate thereof has an acidic functional group such as a carboxyl group, optical resolution can also be performed by forming a salt using an optically active amine (for example, an organic amine such as 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine).

[0121] The temperature for forming the salt 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 filtering the precipitated salt, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably around 1 equivalent, relative to the substrate. If necessary, the crystals can be recrystallized in an inert solvent (for example, alcohol solvents such as methanol, ethanol, 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) to obtain a highly pure optically active salt. Further, if necessary, the optically resolved salt can be treated with an acid or a base by a usual method to obtain the free form.

[0122] Among the raw materials and intermediates in each of the production methods described above, those for which the production method has not been particularly described again can be commercially available compounds or can be synthesized from commercially available compounds by methods known to those skilled in the art or methods analogous thereto.

[0123] Since the novel oxadiazole derivative of the present invention has an anticonvulsant activity and a GABA-A receptor activating action (GABA nervous system activating action), it can be a therapeutic agent and / or a prophylactic agent for diseases involving a decrease in GABA nervous system function. Further, since the novel 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), it can be a therapeutic agent and / or a prophylactic agent for nervous system diseases or mental diseases. Examples of nervous system diseases or mental diseases include epilepsy (for example, epileptic seizures (generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, focal seizures, seizures of unknown classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), medial temporal lobe epilepsy associated with hippocampal sclerosis as a distinct 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, depressive symptoms with or without epilepsy, anxiety disorders, obsessive-compulsive disorder, REM sleep disorder associated with Parkinson's disease-Lewy body dementia. The novel oxadiazole derivative of the present invention can preferably be a therapeutic agent and / or a prophylactic agent for epilepsy (epileptic seizures (generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, focal seizures, seizures of unknown classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), medial temporal lobe epilepsy associated with hippocampal sclerosis as a distinct specific symptom group, Rasmussen syndrome, etc.). In the present invention, "prevention" refers to 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 onset of a disease. "Treatment" refers to the act of administering the active ingredient of the present invention to a person (patient) diagnosed by a doctor as having developed a disease. The act of a patient suffering from such a disease taking the medicine to suppress seizures related to such a disease also falls within the scope of "prevention" or "treatment" here.

[0124] The novel oxadiazole derivative of the present invention has a GABA-A receptor activating effect and / or an effect of enhancing inhibition (I) in the balance between excitation (E) and inhibition (I) (E / I balance), and thus can be a therapeutic agent and / or a prophylactic agent for nervous system diseases or mental diseases. In addition, the novel oxadiazole derivative of the present invention can be a therapeutic agent and / or a prophylactic agent for diseases in which excitation (E) in the E / I balance is enhanced and / or inhibition (I) is decreased. Examples of the nervous system disease or mental disease include epilepsy, neuropathic pain, neurodevelopmental disorder group, bipolar disorder and related disorder group, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorder group, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndrome, anxiety disorder group, obsessive-compulsive disorder, mental trauma and stress factor-related disorder, sleep-wake disorder group, and / or REM sleep disorder associated with Parkinson's disease-dementia with Lewy bodies.

[0125] Since the novel oxadiazole derivative of the present invention has an anticonvulsant activity and a GABA-A receptor activating effect (GABA nervous system activating effect), it can be a therapeutic agent and / or a prophylactic agent for diseases involving a decrease in GABA nervous system function. Examples of the diseases involving a decrease in GABA nervous system function include epilepsy, neuropathic pain, neurodevelopmental disorder group, bipolar disorder and related disorder group, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorder group, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndrome, anxiety disorder group, obsessive-compulsive disorder, mental trauma and stress factor-related disorder, sleep-wake disorder group, and / or REM sleep disorder associated with Parkinson's disease-dementia with Lewy bodies.

[0126] Examples of the epilepsy include, for example, epileptic seizures (generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, focal seizures, seizures of unknown classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Angelman syndrome, tuberous sclerosis, medial temporal lobe epilepsy associated with hippocampal sclerosis as a clear specific symptom group, and / or Rasmussen syndrome, etc. It can be preferably used particularly for Dravet syndrome, Lennox-Gastaut syndrome and / or Angelman syndrome.

[0127] Examples of the depressive syndrome include, for example, depressive disorder groups with anxious distress, depressive disorder groups with mixed features, depressive disorder groups with melancholic features, depressive disorder groups with atypical features, depressive disorder groups with mood-congruent psychotic features, depressive disorder groups with mood-incongruent psychotic features, depressive disorder groups with catatonia, perinatal onset, seasonal pattern depressive disorder groups, severe mood dysregulation, major depressive disorder / major depressive disorder, persistent depressive disorder, premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to other medical conditions, other specified depressive disorder, and / or unspecified depressive disorder, etc. It can be preferably used particularly for major depressive disorder / major depressive disorder.

[0128] Examples of the anxiety disorder group include, for example, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, anxiety disorder due to other medical conditions, other specified anxiety disorder, and / or unspecified anxiety disorder, etc.

[0129] Examples of the bipolar disorder and related disorder group include, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorder, bipolar disorder and related disorder due to other medical conditions, other specified bipolar disorder and related disorder, and / or unspecified bipolar disorder and related disorder, etc. These further include depressive symptoms, depressive states or anxiety symptoms associated with the bipolar disorder and related disorder group.

[0130] In the present invention, "prevention" refers to the act of administering the active ingredient of the present invention to a healthy person who has not developed the disease, for example, for the purpose of preventing the onset of the disease. "Treatment" refers to the act of administering the active ingredient of the present invention to a person (patient) diagnosed by a doctor as having developed the disease. The act of a patient suffering from such a disease taking the medicine to suppress seizures related to such a disease also falls within the scope of "prevention" or "treatment" here.

[0131] As the administration route of the compound of the present invention, any of oral administration, parenteral administration or rectal administration may be used, and the daily dosage varies depending on the type of the compound, the administration method, the symptoms and age of the patient, etc. 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 a human or mammal can be administered in divided doses of 1 to several times. In the case of parenteral administration such as intravenous injection, usually, 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.

[0132] The compound of the present invention can be formulated and administered directly or using an appropriate dosage form by oral administration or parenteral administration. Examples of the dosage form include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, cataplasms, etc. The preparation is manufactured by a known method using pharmaceutically acceptable additives. Depending on the purpose, excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizing aids, thickeners, dispersants, stabilizers, sweeteners, fragrances, etc. can be used as the additives. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, pregelatinized starch, calcium carmellose, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc. can be mentioned.

[0133] The compounds of the present invention can be used in combination with at least one drug classified as an antiepileptic drug, antidepressant drug, or antipsychotic drug. Here, the combined use means a form of administration as a preparation separately prepared from the compound of the present invention, and it may be administered to the administration subject simultaneously with the preparation containing the compound of the present invention or at a time interval. Examples of drugs classified as antiepileptic drugs include phenytoin, valproic acid, carbamazepine, lamotrigine, topiramate, etc. that inhibit sodium channels, ethosuximide, zonisamide, etc. that inhibit calcium channels, perampanel that inhibits AMPA receptors, benzodiazepine drugs (diazepam, clonazepam, clobazam, etc.) that enhance the function of the GABA nervous system, barbiturate drugs (phenobarbital, etc.), gabapentin, vigabatrin, etc. Examples of drugs classified as antidepressant drugs include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, etc. called SSRI, duloxetine, milnacipran, etc. called SNRI, imipramine, amitriptyline, clomipramine, amoxapine, etc. called tricyclic antidepressants. Examples of drugs classified as antipsychotic drugs include haloperidol, spiperone, chlorpromazine, etc. called typical antipsychotics, risperidone, quetiapine, olanzapine, clozapine, perospirone, aripiprazole, etc. called SDA.

Example

[0134] The present invention will be described in more detail below with reference to reference examples, examples, and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following reference examples and examples do not necessarily follow the IUPAC nomenclature.

[0135] For the sake of simplifying the description in the specification, the following abbreviations may be used in reference examples, examples, and tables in the examples. As abbreviations used as substituents, Me means methyl, and Ph means phenyl. THF means tetrahydrofuran, DMF means N,N-dimethylformamide, DME means 1,2-dimethoxyethane, DMSO means dimethyl sulfoxide, TFA means trifluoroacetic acid, and MeCN means acetonitrile. n- means normal-, and t- means tert-. As symbols used in NMR, s means singlet, d means doublet, dd means doublet of doublets, t means triplet, td means triplet of doublets, q means quartet, m means multiplet, br means broad, brs means broad singlet, brm means broad multiplet, and J means coupling constant.

[0136] High-performance liquid chromatography mass spectrometer; The measurement conditions of LCMS are as follows, and the observed mass spectrometry value [MS (m / z)] is MH + is shown with the retention time as Rt (min).

[0137] Measuring instrument: Waters ACQUITYTM UltraPerformance LC Column: ACQUITY UPLC BEH C18 1.7μm 2.1 × 30 mm column Solvent: Solution A: 0.05% HCOOH / H 2 O, Solution B: CH 3 CN Gradient conditions: 0.0 - 1.3 min; A / B = 90 / 10~5 / 95 (linear gradient) 1.3 - 1.5 min; A / B = 90 / 10 Flow rate: 0.80 mL / min UV: 220 nm, 254 nm Column temperature: 40 °C

[0138] Reference Example 1 : Ethyl 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxylate

Chemical Structure

[0139] Reference Examples 2 - 11 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as described in Reference Example 1 to obtain the compounds shown in Table 1.

Table 1

[0140] Reference Example 12 : Ethyl 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]acetate

Chemical formula

[0141] Reference Examples 13 - 14 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as described in Reference Example 12 to obtain the compounds shown in Table 2.

Table 2

[0142] Reference Example 15 : Ethyl 2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]acetate

Chemical formula

[0143] Reference Example 16 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as the method described in Reference Example 15 to obtain the compound of Reference Example 16.

Chemical formula

[0144] Reference Example 17 : Ethyl 2 - [5 - (4 - chlorophenyl) - 1,2,4 - oxadiazol - 3 - yl] - 2 - methylpropanoate

Chemical formula

[0145] Reference Examples 18 - 21 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as the method described in Reference Example 17 to obtain the compounds shown in Table 3.

Table 3

[0146] Reference Example 22 : 2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanoic acid

Chem.

[0147] Reference Examples 23 - 37 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as described in Reference Example 22 to obtain the compounds shown in Table 4.

Table 4

[0148] Reference Example 38 : Sodium [3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]methanesulfonate

Chem.

[0149] Reference Examples 39 - 45 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Reference Example 38 to obtain the compounds shown in Table 5.

Table 5

[0150] Reference Example 46 : 1-[3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl]-N,N-bis(2,4-dimethoxybenzyl)methanesulfonamide

Chemical formula

[0151] Reference Examples 47 - 53 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Reference Example 46 to obtain the compounds shown in Table 6.

Table 6

[0152] Reference Example 54 : 2-[3-(4-Bromophenyl)-1,2,4-oxazol-5-yl]-N,N-bis(2,4-dimethoxybenzyl)propane-2-sulfonamide

Chemical formula

[0153] Reference Examples 55 - 61 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as described in Reference Example 54 to obtain the compounds shown in Table 7.

Table 7

[0154] Reference Example 62 : 5-[3(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-2-one

Chemical formula

[0155] Reference Examples 63 - 68 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as described in Reference Example 62 to obtain the compounds shown in Table 8.

Table 8

[0156] Example 1 : 2-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide

Chemical formula

[0157] Examples 2 - 16 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds shown in Table 9.

Table 9

[0158] Example 17 : 2-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide

Chemical formula

[0159] Examples 18 - 24 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Example 18 to obtain the compounds shown in Table 10.

Table 10

[0160] Example 25 : 5-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one

Chemical formula

[0161] Examples 26 - 31 : Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Example 25 to obtain the compounds shown in Table 11.

Table 11

[0162] 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

Chemical formula

[0163] Example 33:(S)-5-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one

Chemical formula

[0164] The pharmacological test results of the representative compounds of the present invention are shown below to explain the pharmacological effects of the compounds, but the present invention is not limited to these test examples.

[0165] Test Example 1: Evaluation of Subcutaneous Pentetrazole Model (Minimum Convulsion Model, scPTZ) For the evaluation of antiepileptic drugs, a subcutaneous pentylenetetrazol model (minimal seizure model, scPTZ) with high clinical predictability is used. Compounds showing an antispasmodic effect in this model are expected to be antiepileptic drugs clinically. In this test, an animal model that is an expression system of generalized absence seizures and myoclonic seizures was used. The test compound was orally administered to Slc:ddY male mice (obtained from Japan SLC, Inc., 5 mice per group, body weight 20 - 30 g), and 1 hour later, 85 mg / kg of pentylenetetrazol was subcutaneously administered. Thereafter, the presence or absence of the occurrence of metoclonic seizures within 30 minutes was observed. Note that as a control, a 0.5% methylcellulose solution was administered as the test compound, and the same test was conducted. The results are shown in Table 12 below. It was expressed as the number of mice showing suppression of the occurrence of seizures out of 5 mice. For the control, the test was considered valid when 4 out of 5 mice had seizures.

Table 12

[0166] As shown in Table 12, the compounds of the present invention showed an antispasmodic effect in the subcutaneous pentylenetetrazol model (minimal seizure model, scPTZ) evaluation by oral administration. The compounds of Examples 11, 16, 25, 28, 30, and 31 showed an antispasmodic effect in more than half of the cases even at an oral administration of 25 mg / kg.

[0167] Test Example 2: Rotarod Evaluation This test is to evaluate the inhibitory effect of drugs on coordinated motor ability. The rotor rod is a device that rotates a cylindrical rod with a diameter of 4 cm. Mice are made to walk on the rotating rod, and the coordinated motor ability is evaluated based on whether they can walk or not. Slc:ddy male mice (obtained from Japan SLC, Inc., weighing 20 - 30 g) were trained 3 hours before the test to be able to walk on the rotor rod device rotating at 12 revolutions per minute for 5 minutes without falling. Only the mice that could walk were used in the test. The test compound was orally administered to a group of 5 mice. One hour later, they were placed on the rotor rod device rotating at 15 revolutions per minute, and the walking state was observed for 180 seconds and the walking time was measured. For the control, a 0.5% methylcellulose solution was administered as the test compound, and the same test was conducted. The coordinated motor ability was expressed as the average value of the walking times (seconds) of 5 mice. The results are shown in Table 13. The control was able to walk for 180 seconds.

Table 13

[0168] As shown in Table 13, in any of the examples, when orally administered at 25 mg / kg or more, it was possible to continue walking without falling from the rotor rod device for 180 seconds, and it did not affect the coordinated motor ability. Therefore, in the example compounds for which the subcutaneous injection pentetrazole model (minimum convulsion model, scPTZ) evaluation was conducted in Test Example 1, although they showed an anticonvulsant effect as described above, it was confirmed that at the doses at which the effect was obtained, they had almost no effect on the coordinated motor ability.

[0169] Test Example 3: Evaluation of Heat - Induced Convulsion in Draize Model Mice This test is to evaluate the antispasmodic effect of a drug on febrile seizures in a drave model mouse. In this test, BALB / c-Scn1a<+ / -> mice (catalog number: RBRC06422; can be obtained from the Bioresource Center of the National Institute of Advanced Industrial Science and Technology through the Ministry of Education, Culture, Sports, Science and Technology National Bioresource Project) were used. These model mice have a mutation in Scn1A, which is the causative gene of patients with the drave syndrome, and exhibit a phenotype similar to the pathological condition of febrile seizures caused by body temperature elevation, which is a symptom of patients with the drave syndrome, and can be used as a model animal for spontaneous drave syndrome (reference: Research Annual Report of the Epilepsy Treatment Research Promotion Foundation 2015:26:69-76). The test compound was orally administered to drave model male mice (5-8 mice per group, body weight 20-30 g). After 50 minutes, the mice were placed in a chamber with a water bath to induce a body temperature increase, and the occurrence of febrile seizures was observed. Immediately after the occurrence of febrile seizures, the rectal body temperature was measured and used as the seizure threshold body temperature. For the control, a 0.5% methylcellulose solution was administered as the test compound, and the same test was conducted. The antispasmodic activity was expressed as the drug dose that significantly increased the seizure threshold body temperature compared to the control group and the difference in seizure threshold body temperature between the control group and the test group. The results are shown in Table 14.

Table 14

[0170] As shown in Table 14, the compound of the present invention showed an effect of increasing the seizure threshold body temperature of drave febrile seizures, indicating that it has an antiseizure effect on the drave model. In the compounds of all examples, an antiseizure effect on the drave model was shown at a dose that did not affect the coordinated motor ability in the rotarod evaluation of Test Example 2.

[0171] Test Example 4: Evaluation of GABA - A Receptor Activation Effect This test uses GABA-A receptor-expressing cells that can be obtained by the method described in the guidelines for creating stable cell lines (Roche Japan website; Non-Patent Document 4), and evaluates the GABA-A receptor activation effect of drugs using the current induced by GABA as an index. GABA-A receptor-expressing cells were subjected to electrophysiological experiments, and the current observed when a 2 μM GABA solution and subsequently a mixture of 2 μM GABA and the test compound were added was measured. The GABA activation activity was indicated by the increase rate of the current observed when a mixture of 2 μM GABA and the test compound was added, relative to the current observed with GABA alone, and the concentration of the test compound that increased the current by 20% was represented as EC20. Similarly, the current observed when a mixture of 2 μM GABA, the test compound, and 10 μM flumazenil was added was measured, and the inhibition rate by flumazenil against the current increase in the absence of flumazenil was calculated. The results are shown in Table 15.

Table 15

[0172] As shown in Table 15, the compounds of the present invention exhibited GABA-A receptor activation activity. Clobazam and diazepam, which are classified as benzodiazepines, have their GABA-A receptor activation activity strongly inhibited by flumazenil, a benzodiazepine antagonist. In contrast, the GABA-A receptor activation activity of the compounds of the present invention was weakly inhibited by flumazenil against the current increase, indicating that the GABA-A receptor activation activity of the compounds of the present invention occurs through a mechanism different from that of benzodiazepines.

[0173] Test Example 5: Evaluation of Rat Forced Swimming Model This test is to evaluate the antidepressant effect of a drug. When a rat is placed in an inescapable water tank and made to swim, immobility is observed after the escape behavior. When the rat is placed back in the water tank the next day, immobility appears earlier than the first time. The duration of this immobility time is used as a depressive-like behavior to evaluate the antidepressant effect of the test compound. Wistar male rats (obtained from Japan Charles River Co., Ltd., body weight 260 - 300 g) were made to swim in the water tank for 15 minutes on the day before the test. On the test day, the test compound was administered orally (10 - 12 rats per group), and 1 hour later, the rats were made to swim in the water tank for 5 minutes again to measure the immobility time. Note that the control group was administered a 0.5% methylcellulose solution as the test compound and the same test was conducted. The antidepressant activity was represented by the average value of the reduction rate of the immobility time compared to the control group. The results are shown in Table 16.

Table 16

[0174] As shown in Table 16, Examples 29 and 32 were shown to significantly reduce the immobility time in the rat forced swimming model and have an antidepressant effect. On the other hand, diazepam has the same GABA-A receptor activation effect as the compounds of the present invention as shown in Experimental Example 4, but did not show an antidepressant effect in the rat forced swimming model. Diazepam is one of the benzodiazepines also used as an anticonvulsant drug. The fact that the compounds of the present invention showed an effect on a depressive model in which benzodiazepines did not show an effect indicates that, as shown in Experimental Example 4, the GABA-A receptor activation mechanism of action of the compounds of the present invention is different from that of benzodiazepines, and it is considered that an antidepressant effect not possessed by benzodiazepines was shown due to some unknown mechanism of action of the compounds of the present invention. From this, it was suggested that the compounds of the present invention have a combined therapeutic / preventive effect not only on epileptic seizures but also on depressive symptoms that frequently co-occur in epileptic patients.

[0175] As described above, the compound of the present invention showed a strong antispasmodic effect in the subcutaneous injection pentetrazole model (minimum convulsion model, scPTZ) evaluation. Also, in a model mouse of Dravet syndrome, which is known as one of intractable generalized epilepsy and for which a causative mutant gene has been identified, the convulsion onset threshold body temperature of febrile convulsion was increased at a dosage that does not affect the coordinated motor ability. Therefore, the compound of the present invention is useful as an antiepileptic drug (a therapeutic and / or prophylactic drug for generalized seizures including tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, focal seizures, seizures of unknown classification, Dravet syndrome classified as intractable epilepsy for which drug treatment has not yet been effective, West syndrome, Lennox-Gastaut syndrome, etc.). Since the compound of the present invention also has GABA-A receptor activating activity, it is also useful as a therapeutic and / or prophylactic drug for anxiety disorders, obsessive-compulsive disorder, and REM sleep disorder associated with Parkinson's disease and dementia with Lewy bodies, for which a therapeutic effect by existing GABA nervous system activating drugs has been recognized. The GABA-A receptor activating activity of the compound of the present invention is exerted in a mode different from that of benzodiazepine, which is one of the existing GABA nervous system activating drugs, and has an effect on the depressive symptoms in a rat forced swimming model in which benzodiazepine showed no effect. Therefore, it has an effect on depressive symptoms that may or may not coexist with epilepsy, and is useful as a therapeutic and / or prophylactic drug for depressive syndrome, etc., and has a usefulness that existing antiepileptic drugs do not have. Also, it is considered to exert a pathological improvement effect on developmental disorders, autism, bipolar disorder and related disorder groups, schizophrenia spectrum disorders, Alzheimer's disease and other neurocognitive disorder groups, amyotrophic lateral sclerosis, and Parkinson's disease, which are based on abnormalities in the GABA nervous system.

Industrial Applicability

[0176] Since the compound of the present invention has a strong antispasmodic effect and also has a GABA-A receptor agonistic effect, it is useful as a therapeutic agent and / or prophylactic agent for diseases involving reduced GABA nervous system function. In addition, since the compound of the present invention has an effect of enhancing inhibition (I) in the balance between excitation (E) and inhibition (I) (E / I balance), it is useful as a therapeutic agent and / or prophylactic agent for diseases in which E is enhanced and / or I is reduced in the E / I balance.

Claims

1. A compound represented by formula (1) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, Q １ represents a halogen, Q ２ is hydrogen, halogen, cyano, C １－３ Alkyl (the alkyl is halogen, hydroxyl, C ３－６ Cycloalkyl and C １－３ alkoxy), or C １－３ Alkoxy (the alkoxy is a halogen, a hydroxyl group, C ３－６ Cycloalkyl and C １－３ alkoxy), X, Y and Z are the same or different and each represents a nitrogen atom or an oxygen atom, provided that the ring containing X, Y and Z is a heteroaryl in which two of X, Y and Z are nitrogen atoms and the remaining one is an oxygen atom; R １ represents any one of the following (2) to (4): 【Chemistry 2】 R ２ and R ３ are the same or different, C １－６ Alkyl (the alkyl is halogen, hydroxyl, C ３－６ Cycloalkyl and C １－３ alkoxy), or C ３－６ Cycloalkyl (the cycloalkyl is halogen, hydroxyl, C １－３ Alkyl and C １－３ alkoxy), or together with the carbon atom to which they are attached, represent C ３－６ Cycloalkyl (the cycloalkyl is halogen, hydroxyl, C １－３ Alkyl and C １－３ alkoxy), or C containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms ４－６ Saturated heterocyclic ring (the saturated heterocyclic ring is not substituted with halogen, hydroxyl group, C １－３ Alkyl and C １－３ alkoxy), R ４ and R ５ are the same or different and are hydrogen, halogen, hydroxyl group, C １－６ Alkyl (the alkyl is halogen, hydroxyl, C ３－６ Cycloalkyl and C １－３ alkoxy), or C ３－６ Cycloalkyl (the cycloalkyl is halogen, hydroxyl, C １－３ Alkyl and C １－３ alkoxy), or R ４ and R ５ When they are present on the same carbon atom or on adjacent carbon atoms, together with the carbon atoms to which they are attached, ３－６ Cycloalkyl (the cycloalkyl is halogen, hydroxyl, C １－３ Alkyl and C １－３ alkoxy) or C containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms ４－６ Saturated heterocyclic ring (the saturated heterocyclic ring is not substituted with halogen, hydroxyl group, C １－３ Alkyl and C １－３ alkoxy), n represents an integer of 0 to 2.

2. R ２ and R ３ is the same or different, C １－３ Alkyl (the alkyl is fluorine, hydroxyl and C １－３ alkoxy), or together with the carbon atom to which they are attached, represent C ３－６ Cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C １－３ Alkyl and C １－３ alkoxy) or a C group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms. ４－６ Saturated heterocyclic ring (the saturated heterocyclic ring is not fluorine, hydroxyl group, C １－３ Alkyl and C １－３ alkoxy), 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. R ２ and R ３ is the same or different, C １－３ alkyl (which may be substituted with fluorine), or together with the carbon atom to which they are attached, C ３－６ A group consisting of a cycloalkyl (which may be substituted with fluorine), or a C group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms. ４－６ a group constituting a saturated heterocyclic ring (the saturated heterocyclic ring may be substituted with fluorine); 3. The compound according to claim 2 or a pharma- ceutically acceptable salt thereof.

4. R ４ and R ５ are the same or different and are hydrogen, fluorine, a hydroxyl group, C １－３ Alkyl (the alkyl is fluorine, hydroxyl, and C １－３ alkoxy), or C ３－６ Cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C １－３ Alkyl and C １－３ alkoxy), or R ４ and R ５ When they are present on the same carbon atom or on adjacent carbon atoms, together with the carbon atoms to which they are attached, ３－６ Cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C １－３ Alkyl and C １－３ alkoxy) or a C group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms. ４－６ Saturated heterocyclic ring (the saturated heterocyclic ring is not fluorine, hydroxyl group, C １－３ Alkyl and C １－３ alkoxy), The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. R ４ and R ５ are the same or different and are hydrogen, fluorine, a hydroxyl group, C １－３ Alkyl (the alkyl may be substituted with fluorine), or C ３－６ cycloalkyl, which may be substituted with fluorine; or R ４ and R ５ When they are present on the same carbon atom or on adjacent carbon atoms, together with the carbon atoms to which they are attached, ３－６ Cycloalkyl (the cycloalkyl is fluorine and C １－３ alkyl), 5. The compound according to claim 4 or a pharma- ceutically acceptable salt thereof.

6. Q １ is fluorine, chlorine or bromine, Q ２ are hydrogen, fluorine, chlorine, bromine, cyano, C １－３ Alkyl (the alkyl may be substituted with fluorine) or C １－３ alkoxy (which may be substituted with fluorine); The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

7. The ring containing X, Y and Z is the following (5a), (5b) or (5c): 【Chemistry 3】 The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. The ring containing X, Y and Z is the following (5a) or (5b): 【Chemistry 4】 8. The compound according to claim 7 or a pharma- ceutically acceptable salt thereof.

9. R １ But it is the following (4): 【Chemistry 5】 9. The compound according to claim 1, or any one of claims 4 to 8, or a pharma- ceutically acceptable salt thereof.

10. 2. The compound of claim 1, selected from the following compounds: 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.

11. 2. The compound of claim 1, selected from the following compounds: 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.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof.

13. 12. A therapeutic and / or prophylactic agent for a disease associated with decreased function of the GABAergic nervous system, comprising the compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof as an active ingredient.

14. The therapeutic and / or prophylactic agent according to claim 13, wherein the disease associated with decreased function of the GABAergic nervous system is a nervous system disease or a psychiatric disease.

15. The therapeutic and / or prophylactic agent according to claim 14, wherein the nervous system disease or psychiatric disease is epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar disorder and related disorders, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndromes, anxiety disorders, obsessive-compulsive disorder, trauma- and stress-related disorders, sleep-wake disorders, and / or REM sleep disorder associated with Parkinson's disease / dementia with Lewy bodies.

16. A method for treating and / or preventing a disease associated with decreased function of the GABAergic nervous system, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharma- ceutical acceptable salt thereof.

17. Use of the compound according to any one of claims 1 to 11, or a pharma- ceutical acceptable salt thereof, for the manufacture of an agent for treating and / or preventing a disease involving decreased function of the GABAergic nervous system.

18. 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving decreased function of the GABAergic nervous system.

19. A medicine comprising the compound according to any one of claims 1 to 11 or a pharma- ceutical acceptable salt thereof in combination with at least one drug selected from drugs classified as antiepileptics, antidepressants, or antipsychotics.

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharma- ceutical acceptable salt thereof for treating a disease associated with decreased function of the GABAergic nervous system, the pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharma- ceutical agent selected from the group consisting of antiepileptic drugs, antidepressants, and antipsychotic drugs.

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