Oxadiazole Derivatives

Abstract

The present invention relates to the compound represented in formula (1) or a pharmaceutically acceptable salt thereof (in the formula, Q1 represents a halogen, Q2 represents a hydrogen, etc., X, Y and Z represent a nitrogen atom or an oxygen atom, and R1 represents a prescribed structure), and the present invention further relates to a therapeutic and / or prophylactic agent for disease such as epilepsy that contains these.

Description

[Technical field]

[0001] The present invention relates to oxadiazole derivatives and pharma- ceutically acceptable salts thereof which are useful as medicines, as well as pharmaceutical compositions or therapeutic and / or prophylactic agents for diseases such as epilepsy and / or depressive syndromes, each of which contains the derivative or a pharma- ceutical composition as an active ingredient. [Background technology]

[0002] Epilepsy is a chronic disease in which abnormal physical symptoms and changes in movement, consciousness, and sensation occur suddenly and repeatedly due to hyperexcitation of cerebral nerve cells. The International League Against Epilepsy (ILAE) classifies epilepsy seizure types into generalized seizures, focal seizures, and unclassified seizures, and generalized seizures are further classified into tonic seizures, clonic seizures, absence seizures, myoclonic seizures, atonic seizures, and the like (Non-Patent Document 1). The etiology of the disease background is broadly classified into genetic, structural / metabolic, and unknown causes. Epilepsy is also classified into various disease types and syndromes based on characteristics such as electroencephalograms, clinical symptoms, age at onset, and etiology. For example, these include West syndrome and Dravet syndrome that develop in infancy, Lennox-Gastaut syndrome and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) that develop in childhood, mesial temporal lobe epilepsy with hippocampal sclerosis and Rasmussen syndrome as clear specific symptom groups, and many others (Non-Patent Document 2). Since the 1990s, international collaborative research on molecular pathology analysis of epilepsy has progressed, and many 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 in part to abnormalities in ion homeostasis.

[0003] Epilepsy is a severe disease that affects the prognosis of life, and it is known that approximately 1% of the world's population suffers from it. The treatment of these epileptic seizures is mainly drug therapy, and although various antiepileptic drugs have been prescribed for a long time, one in three cases of epilepsy is refractory epilepsy that shows resistance to combination therapy with existing drugs. In addition, existing drugs have the risk of dose-dependent side effects on the nervous system such as excessive drowsiness, dizziness, cognitive impairment, and psychiatric symptoms, rare but serious idiosyncratic side effects such as Stevens-Johnson syndrome, and teratogenicity, and there is also a risk of problems such as loss of efficacy and enhanced side effects due to drug interactions. In addition, epilepsy patients are at high risk of developing psychiatric symptoms such as depression, anxiety, and cognitive impairment (Non-Patent Document 3). However, existing drugs do not have a therapeutic effect on these psychiatric symptoms. For these reasons, there is a strong need for the development of new antiepileptic drugs that have the following characteristics: high efficacy against refractory epilepsy, excellent pharmacokinetic and safety profiles, and efficacy in treating both epilepsy and concomitant psychiatric symptoms. Epilepsy is caused by the overexcitation of brain neurons, and is believed to be caused by an abnormality in the balance between excitation (E) and inhibition (I) (E / I balance), where the excitatory nerves are too strong or the inhibitory nerves are too weak. In addition to epilepsy, there are other known diseases caused by E / I balance abnormalities. GABAergic neuroactivators that activate inhibitory nerves have been shown to be effective in treating anxiety, obsessive-compulsive disorder, and REM sleep disorders associated with Parkinson's disease and dementia with Lewy bodies. E / I balance abnormalities are also 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, and other conditions. In fact, some of the antiepileptic drugs that improve E / I balance abnormalities have been widely applied to these other diseases. However, the efficacy of these drugs in diseases other than epilepsy is limited, and there are still problems with side effects and pharmacokinetics. Therefore, the development of antiepileptic drugs with new efficacy and side effect profiles may be applicable to many of these psychiatric and neurological disorders, and is of great significance.

[0004] Patent Document 1 describes oxadiazoles having a sweetness-modifying effect, but the chemical structure of these oxadiazoles is different from that of the compound represented by formula (1) described below. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2006 / 138512 [Non-patent literature]

[0006] [Non-Patent Document 1] Robert S. Fisher et al. Epilepsia, (2017), 58(4), 522-530 [Non-Patent Document 2] Anne T. Berg et al. Epilepsia, (2010) 51(4), 676-85 [Non-Patent Document 3] Schmitz B. Epilepsia, (2005) 46 (Suppl. 4), 45-49 Summary of the Invention [Problem 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 problem]

[0008] As a result of intensive research, the present inventors have found that a compound represented by the following formula (1) exhibits a strong anticonvulsant effect, i.e., an antiepileptic effect, and also has a GABA-A receptor activation effect, and have completed the present invention. According to the present invention, an oxadiazole derivative represented by the following formula (1) (hereinafter, sometimes referred to as the "compound of the present invention") is provided.

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

[0010] [Item 1] A compound represented by formula (1) or a pharma- ceutically acceptable salt thereof. [ka] [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 halogen, 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), [ka] 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, represents C 3-6Cycloalkyl (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 does not contain 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, 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 does not contain halogen, hydroxyl group, C 1-3 Alkyl and C 1-3 alkoxy), n represents an integer of 0 to 2.

[0011] [Section 2] R 2 and R 3 However, 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, represents 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 does not contain fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), Item 1. The compound according to item 1 or a pharma- ceutically acceptable salt thereof.

[0012] [Section 3] R 2 and R 3 However, 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); Item 3. The compound according to item 2 or a pharma- ceutically acceptable salt thereof.

[0013] [Section 4]R 4 and R 5 are the same or different and are hydrogen, fluorine, hydroxyl group, C 1-3 Alkyl (the alkyl is fluorine, hydroxyl, and C 1-3alkoxy), 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, 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 does not contain fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), Item 4. The compound according to any one of Items 1 to 3, or a pharma- ceutically acceptable salt thereof.

[0014] [Section 5] R 4 and R 5 are the same or different and are hydrogen, fluorine, 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, C 3-6 Cycloalkyl (wherein the cycloalkyl is fluorine and C 1-3 alkyl), Item 5. The compound according to item 4 or a pharma- ceutically acceptable salt thereof.

[0015] [Section 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); Item 6. The compound according to any one of Items 1 to 5, or a pharma- ceutically acceptable salt thereof.

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

[0017] [Item 8] The ring containing X, Y and Z is the following (5a) or (5b): [ka] Item 8. The compound according to item 7 or a pharma- ceutically acceptable salt thereof.

[0018] [Section 9]R 1 is either (2) or (3) below, [ka] Item 9. The compound according to any one of items 1 to 3, or 6 to 8, or a pharma- ceutically acceptable salt thereof.

[0019] [Section 10] R 1 However, the following (4) is true. [ka] Item 10. The compound according to any one of items 1, or 4 to 8, or a pharma- ceutically acceptable salt thereof.

[0020] [Item 11] The compound according to item 1, or a pharma- ceutically 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, selected from the following compounds, or a pharma- ceutically acceptable salt thereof: 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 comprising the compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof.

[0023] [Item 14] A therapeutic and / or prophylactic agent for a nervous system disorder or a psychiatric disorder, comprising the compound according to any one of items 1 to 12 or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0024] [Item 15] A therapeutic and / or prophylactic agent for a disease in which excitation (E) is increased and / or inhibition (I) is decreased in the E / I balance, the therapeutic and / or prophylactic agent comprising the compound according to any one of items 1 to 12 or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0025] [Item 16] 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 items 1 to 12 or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0026] [Item 17] The therapeutic and / or prophylactic agent according to Item 16, wherein the disease associated with decreased function of the GABAergic nervous system is a nervous system disease or a psychiatric disease.

[0027] [Item 18] The therapeutic and / or prophylactic agent according to Item 14 or 17, wherein the nervous system disease or psychiatric disease is epileptic seizures (tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, and seizures of unspecified classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a clearly defined specific symptom group, Rasmussen syndrome, depressive symptoms with or without comorbidity with epilepsy, anxiety disorder, obsessive-compulsive disorder, REM sleep disorder associated with Parkinson's disease or dementia with Lewy bodies, neuropathic pain, developmental disorder, autism, bipolar disorder, schizophrenia, Alzheimer's disease or other dementia, amyotrophic lateral sclerosis, or Parkinson's disease.

[0028] [Item 19] The therapeutic and / or prophylactic agent according to Item 14 or 17, 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.

[0029] [Item 20] 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 treatment a therapeutically effective amount of the compound according to any one of items 1 to 12, or a pharma- ceutical acceptable salt thereof.

[0030] [Item 21] Use of the compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing a disease associated with decreased function of the GABAergic nervous system.

[0031] [Item 22] The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease associated with decreased function of the GABAergic nervous system.

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

[0033] [Item 24] The therapeutic and / or prophylactic agent according to Item 23, wherein the epilepsy is epileptic seizures (tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, and seizures of unspecified classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a distinct 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 pharma- ceutically acceptable salt thereof.

[0035] [Item 26] Use of the compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic and / or prophylactic agent for epilepsy.

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

[0037] [Item 28] A medicine comprising the compound according to any one of items 1 to 12 or a pharma- ceutical acceptable salt thereof in combination with at least one drug selected from drugs classified as antiepileptics, antidepressants, or antipsychotics.

[0038] [Item 29] A medicine comprising the compound according to any one of items 1 to 12 or a pharma- ceutical acceptable salt thereof for treating a disease associated with decreased function of the GABAergic nervous system, the medicine being used in combination with at least one drug selected from drugs classified as antiepileptics, antidepressants, or antipsychotics.

[0039] [Section 30] Below formula: [ka] The method for producing compound (Ic), comprising the steps of reacting compound (IIc1) and compound (IIc2) shown in the formula (Ic) to obtain compound (IIc'), and methylating compound (IIc') (the symbols in the formula have the same meanings as defined above).

[0040] [Section 31] The following formula: [ka] The symbols in the formula have the same meanings as defined above. Effect of the Invention

[0041] The compound of the present invention showed strong anticonvulsant activity in several animal models of convulsions caused by decreased GABA signals (subcutaneous injection pentetrazol model in Test Example 1, Dravet model mouse febrile convulsions in Test Example 3). The subcutaneous injection pentetrazol model in Test Example 1 is a model that has a generalized absence seizure or myoclonic seizure phenotype and exhibits a seizure type with a low remission rate for existing antiepileptic drugs. The Dravet model mouse febrile convulsions in Test Example 3 is an animal model with the same genetic background as Dravet syndrome, which exhibits treatment-resistant convulsions, and the effect of existing antiepileptic drugs on this model is very limited. Therefore, the compound of the present invention is useful as a preventive and / or therapeutic agent for epilepsy (e.g., epileptic seizures (tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, and seizures of unknown classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a clear specific symptom group, Rasmussen syndrome, etc.). Note that West syndrome, Dravet syndrome, and Lennox-Gastaut syndrome are serious diseases that exhibit treatment-resistant convulsions and are accompanied by developmental delay, etc., and it is of great significance to provide a preventive and / or therapeutic agent for intractable epilepsy including these. The GABA-A receptor activating activity of the compound of the present invention is exerted by a different mode of action from benzodiazepine, which is one of the existing GABA nervous system activators, and since it was effective against depressive symptoms in a rat forced swimming model in which benzodiazepines were ineffective (Test Example 5), it is effective against depressive symptoms that may or may not occur concomitantly with epilepsy, and has usefulness not found in existing antiepileptic drugs. Since the compound of the present invention has GABA-A receptor activating activity, it is also useful as a preventive and / or therapeutic agent for anxiety disorder, obsessive-compulsive disorder, and REM sleep disorder associated with Parkinson's disease / dementia with Lewy bodies, for which the therapeutic effect of existing GABA nervous system activators has been recognized.In addition, it is believed to have an effect of improving the pathology of 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 effect of strengthening inhibition (I) in the balance between excitation (E) and inhibition (I) (E / I balance), it can be used as a therapeutic and / or preventive agent for nervous system diseases or psychiatric diseases, particularly a therapeutic and / or preventive agent for diseases in which excitation (E) is enhanced and / or inhibition (I) is decreased in the E / I balance. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

[0044] Examples of "halogen" include fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine, and bromine. More preferred are fluorine and chlorine, and further preferred is fluorine.

[0045] "C 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and "C6 alkyl" means an alkyl group having 6 carbon atoms. The same applies to other numbers. 1-6 As "alkyl", preferably "C 1-3 alkyl" and more preferably "C 1-2 "C alkyl" is one example. 1-3 As "alkyl", preferably "C 1-2 "Alkyl" is preferred, and methyl is more preferred. 1-2 Specific examples of "alkyl" include methyl and ethyl. 1-3Specific examples of "alkyl" include the above-mentioned "C 1-2 In addition to the specific examples of "alkyl", propyl, 1-methylethyl, etc. are also included. 1-6 Specific examples of "alkyl" include the above-mentioned "C 1-3 In addition to the examples given as "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, and the like can be mentioned.

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

[0047] "C 1-3 The term "alkoxy" refers to the above-mentioned "C 1-3 "C" means an oxy group substituted with "alkyl". 1-3 As the "alkoxy group", preferably "C 1-2 "Alkoxy" is preferred, and "methoxy" is more preferred. 1-2 Specific examples of "alkoxy" include, for example, methoxy and ethoxy. 1-3 Specific examples of "alkoxy" include the above-mentioned "C 1-2 In addition to the specific examples of "alkoxy", propoxy, 1-methylethoxy, etc. are included.

[0048] "C 4-6The term "saturated heterocycle" refers to 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 a partially bridged structure. Preferably, it is a C ring containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. 4-6 It is a saturated heterocyclic ring. 4-6 As the "saturated heterocycle", preferably "C 4-5 "C 4-5 Specific examples of "saturated heterocycle" include oxetane, azetidine, tetrahydrofuran, pyrrolidine, etc. 4-6 Specific examples of the "saturated heterocycle" include the above-mentioned "C 4-5 In addition to those given as specific examples of the "saturated heterocycle," there may be mentioned tetrahydropyran, piperidine, morpholine, piperazine, and the like.

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

[0050] R 1 The embodiments include the following (2) to (4). [ka] R 1 Other embodiments of the above include the following (2) or (3). [ka] R 1 Another aspect of the above is the following (4). [ka]

[0051] R 2 and R 3 A preferred embodiment of R 2 and R 3 are the same or different, (1) C 1-3 Alkyl (the alkyl is fluorine, hydroxyl, and C 1-3 alkoxy), or (2)R 2 and R 3 Together with the carbon atom to which it is bonded, C 3-6 Cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), or (3)R 2 and R 3 C, which, together with the carbon atom to which it is attached, contains one or two heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms. 4-6 Saturated heterocycle (the cycloalkyl is fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy) Examples include:

[0052] R 2 and R 3 In a more preferred embodiment, R 2 and R 3 are the same or different, (1) C 1-3 alkyl, which may be substituted with fluorine; or (2) Together with the carbon atoms to which they are attached, C 3-6 a group consisting of a cycloalkyl (wherein the cycloalkyl may be substituted with fluorine); or (3) C containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms 4-6A group constituting a saturated heterocyclic ring (the saturated heterocyclic ring may be substituted with fluorine). Examples include:

[0053] R 2 and R 3 Together with the carbon atom to which it is bonded, it forms C 3-6 Cycloalkyl includes, for example, the following groups: [ka]

[0054] R 2 and R 3 Together with the carbon atom to which it is bonded, it forms C 4-6 The saturated heterocyclic ring includes a 4- to 6-membered saturated ring containing one or two heteroatoms independently selected from the group consisting of a nitrogen atom and an oxygen atom, and examples thereof include the following groups. [ka]

[0055] R 4 and R 5 A preferred embodiment of R 4 and R 5 are the same or different, (1) Hydrogen, (2) Fluorine, (3) hydroxyl group, (4) C 1-3 Alkyl (the alkyl is fluorine, hydroxyl, and C 1-3 alkoxy), (5) C 3-6 Cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), or R 4 and R 5 is present on the carbon atom to which it is bonded or on an adjacent carbon atom, (6) Together with the carbon atoms to which they are attached, C 3-6 Cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), or (7) Together with the carbon atoms to which they are attached, C 4-6 Saturated heterocycle (the cycloalkyl is fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy) may be formed. In this case, the "adjacent carbon atom" is R 4 and R 5 is bonded adjacent to the ring carbon atoms to which they are bonded.

[0056] R 4 and R 5 In a more preferred embodiment, R 4 and R 5 are the same or different, (1) Hydrogen, (2) Fluorine, (3) hydroxyl group, (4) C 1-3 Alkyl (which may be substituted with fluorine); (5) C 3-6 cycloalkyl, which 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 atoms to which they are attached, C 3-6 Cycloalkyl (wherein the cycloalkyl is fluorine and C 1-3 alkyl) may be formed. Examples include:

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

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

[0059] Preferred embodiments of X, Y, and Z are the same or different and represent a nitrogen atom or an oxygen atom, provided that in the ring containing X, Y, and Z, two of X, Y, and Z are nitrogen atoms and the remaining one is an oxygen atom, such as the following oxadiazole. [ka] In Figures (5a) to (5c), the bond on the left is connected to the benzene ring, and the bond on the right is connected to R 1 and combine.

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

[0061] In one embodiment, n is an integer of 0, 1, or 2, and in a preferred embodiment, n is 0 or 1.

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

[0063] Q 2 A preferred embodiment of the above is as follows: (1) Hydrogen, (2) Fluorine, (3) Chlorine, (4) bromine, (5) Cyano, (6) C 1-3 Alkyl (which may be substituted with fluorine), or (7) C 1-3 Alkoxy (the alkoxy may be substituted with fluorine) Examples include:

[0064] Q 2 As a more preferred embodiment, (1) Hydrogen, (2) Fluorine, (3) Chlorine, or (4) Cyano Examples include:

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

[0066] One embodiment of the compound represented by formula (1) is the following (A). (A) R 1 is one of the following, [ka] R 2 and R 3 However, the same or different, (1) C 1-3Alkyl (the alkyl is fluorine, hydroxyl, C 3-6 Cycloalkyl and C 1-3 alkoxy), (2) C 3-6 Cycloalkyl (the cycloalkyl is 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 it is bonded, C 3-6 Cycloalkyl (the cycloalkyl is fluorine, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), or (4)R 2 and R 3 C, which, together with the carbon atom to which it is bonded, contains one or two heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms. 4-6 Saturated heterocyclic ring (the saturated heterocyclic ring does not contain halogen, hydroxyl group, C 1-3 Alkyl and C 1-3 alkoxy) and The heteroaryl including X, Y, and Z is any one of the following (5a) to (5c): [ka] Q 1 is fluorine, chlorine, or bromine; Q 2 But hydrogen, fluorine, chlorine, cyano, C 1-3 Alkyl (the alkyl is fluorine, C 3-6 Cycloalkyl and C 1-3 alkoxy), or C 1-3 Alkoxy (the alkoxy is fluorine, C3-6 Cycloalkyl and C 1-3 alkoxy) or a pharma- ceutically acceptable salt thereof.

[0067] One embodiment of the compound represented by formula (1) is the following (B). (B) R 1 is (4) below, [ka] R 4 and R 5 However, the same or different, (1) Hydrogen, (2) halogens, (3) hydroxyl group, (4) C 1-3 Alkyl (the alkyl is halogen, hydroxyl, C 3-6 Cycloalkyl and C 1-3 alkoxy), (5) C 3-6 Cycloalkyl (the cycloalkyl is halogen, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), or R 4 and R 5 is present on the carbon atom to which it is bonded or on an adjacent carbon atom, (6) Together with the carbon atoms to which they are attached, C 3-6 Cycloalkyl (the cycloalkyl is halogen, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), or (7) C containing, together with the carbon atom to which they are attached, one or two heteroatoms independently selected from the group consisting of nitrogen atoms and oxygen atoms. 4-6Saturated heterocycle (the cycloalkyl is halogen, hydroxyl, C 1-3 Alkyl and C 1-3 alkoxy), The heteroaryl including X, Y, and Z is any one of the following (5a) to (5c): [ka] Q 1 is fluorine, chlorine, or bromine; Q 2 But hydrogen, fluorine, chlorine, cyano, C 1-3 Alkyl (the alkyl is fluorine, C 3-6 Cycloalkyl and C 1-3 alkoxy), C 1-3 Alkoxy (the alkoxy is fluorine, C 3-6 Cycloalkyl and C 1-3 alkoxy), Preferred embodiments of n include integers of 0, 1, and 2. or a pharma- ceutically acceptable salt thereof.

[0068] One embodiment of the compound represented by formula (1) is the following (C). (C) R 1 is one of the following, [ka] R 2 and R 3 However, the same or different, (1) C 1-3 alkyl, which may be substituted with fluorine; or (2) Together with the carbon atoms to which they are attached, C 3-6 a group consisting of a cycloalkyl (wherein the cycloalkyl may be substituted with fluorine); or (3) C 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). and The heteroaryl containing X, Y, and Z is the following (5a) or (5b), [ka] Q 1 is fluorine, chlorine, or bromine; Q 2 is hydrogen, fluorine, chlorine, or cyano, or a pharma- ceutically acceptable salt thereof.

[0069] One embodiment of the compound represented by formula (1) is the following (D). (D) R 1 is (4) below, [ka] R 4 and R 5 However, the same or different, (1) Hydrogen, (2) Fluorine, (3) hydroxyl group, (4) C 1-3 Alkyl (which may be substituted with fluorine); (5) C 3-6 cycloalkyl, which 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 atoms to which they are attached, C 3-6 Cycloalkyl (wherein the cycloalkyl is fluorine and C 1-3 alkyl), The heteroaryl containing X, Y, and Z is the following (5a) or (5b), [ka] Q 1 is fluorine, chlorine, or bromine; Q 2 is hydrogen, fluorine, chlorine, or cyano, or a pharma- ceutically acceptable salt thereof.

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

[0071] Suitable salts of raw materials and intermediates, and salts acceptable as raw materials for pharmaceutical products, are conventional non-toxic salts, including acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, para-toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.), metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salts, and organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), and others that 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, or 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 more compounds represented by formula (1) 1 H 2 Deuterium converted to H(D) is also included in the compound represented by formula (1). The present invention includes a compound represented by formula (1) or a pharma- ceutically acceptable salt thereof. The compound of the present invention may also exist in the form of a hydrate and / or a solvate with various solvents (such as an ethanolate), and these hydrates and / or solvates are also included in the compound of the present invention. Furthermore, the present invention includes all tautomers, all existing stereoisomers, and all forms of crystal forms of the compound (1) of the present invention, as well as mixtures thereof.

[0074] Among the compounds (1) of the present invention, there may exist optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from the restriction of intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and the like, and all possible isomers and mixtures thereof, including these, are included within the scope of the present invention.

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

[0076] Methods for producing the compounds of the present invention are described below, but the methods for producing the compounds of the present invention are not limited to these.

[0077] Manufacturing method 1 Among the compounds of formula (I), the compound of formula (Ia) can be produced by the following production method. [ka] (In the formula, R 2 , R 3 , Q 1 , Q 2 , X, Y and Z are defined as in item 1.)

[0078] Compound (Ia) is obtained by the amidation reaction of (IIa) with 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 active esters include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester, etc. Specific examples of acid anhydrides include mixed acid anhydrides of ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid, etc. Specific examples of solvents should be selected according to the type of raw material compound, and include, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, etc., which 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, and is preferably 0°C to 30°C. The reaction time is usually 30 minutes to 24 hours.

[0079] Compound (Ia) can also be produced by reacting compound (IIa) with an ammonium salt such as (NH4)2CO3 in the presence of a condensing agent. Specific examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride, N,N'-carbonyldiimidazole, 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 raw material compound, and include, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, and the like, which can be used alone or as a mixed solvent. The reaction temperature is not particularly limited, but is usually selected within the range from −20° C. to the boiling point of the solvent used, and is 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 formula (1b) can be produced by the following production method. [ka] (In the formula, R 2 , R 3 , Q 1 , Q 2 , X, Y and Z are defined as in item 1. 1 is a nitrogen atom protecting group that can be removed under acidic conditions, such as 2,4-dimethoxybenzyl group or 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 2,4-dimethoxybenzyl or p-methoxybenzyl.

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

[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, and include, for example, toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, acetonitrile, DMF, DMSO, etc., which can be used alone or as a mixed solvent. In addition to the 2,4-dimethoxybenzyl group, a protecting group that is cleaved under acidic conditions, such as a t-butoxycarbonyl group, a t-butyl group, a p-methoxybenzyl group, etc., can be used as the protecting group of the nitrogen atom in compound (IIb), and the number of protecting groups may be one depending on the type of the protecting group. The reaction temperature varies depending on the type of raw material compound used, and 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 formula (1c) can be produced by the following production method. [ka] (In the formula, R 4 , R 5 , Q 1 , Q 2 , X, Y, Z and n are defined as in item 1.)

[0084] Compound (Ic) is obtained by methylating compound (IIc). Methylation of compound (IIc) can be carried out according to a conventional method. For example, this reaction is achieved by reacting compound (IIc) with a methylating agent such as methyl iodide, methyl bromide, dimethyl sulfate, etc. in a suitable solvent in the presence of a base. Specific examples of the solvent should be selected according to the type of raw material compound, etc., and include, for example, toluene, THF, dioxane, DME, ethyl acetate, isopropyl acetate, acetone, acetonitrile, DMF, NMP, etc., which 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, and lithium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxy alkali metals such as potassium t-butoxide and sodium methoxide, and alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, and 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 formulae (Ia), (Ib) and (Ic) produced by the above Production Methods 1, 2 and 3 can be isolated and purified by conventional methods such as chromatography and recrystallization.

[0086] The starting 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 formula (1c') can also be produced by the following production method. [ka] (In the formula, R 4 , R 5 , Q 1 , Q 2 , and n are defined as in Item 1.)

[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 monohydrochloride, 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, and propylphosphonic anhydride. 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 include, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, ethyl acetate, isopropyl acetate, and the like, which can be used alone or as a mixed solvent. The reaction temperature varies depending on the type of raw material compound and reagent used, and 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 The compound (IIa) used in the above-mentioned Production Method 1 is produced according to the method shown in the following reaction scheme. [ka] (In the formula, R 2 , R 3 , Q 1 , Q 2 , X, Y and Z are defined as in Item 1, and R is C 1-6 It is an alkyl group.

[0090] (Process 1) Compound (IIIa) can be obtained by alkylating compound (IVa). The alkylation reaction in step 1 can be carried out according to a conventional method. For example, this reaction can be carried out by reacting compound (IVa) with R 2 X or R 3 This is carried out by reacting with an alkyl halide or cycloalkyl halide represented by X. 2 and R 3 Together with the carbon atom to which it is bonded, C 3-6 For compounds forming a cycloalkyl or 4-6 membered saturated heterocycle, compound (IVa) and the corresponding dihalide (e.g., X-(CH2) n -X (n represents an integer of 3 to 6, and X represents a halogen)). Specific examples of the solvent should be selected according to the type of raw material compound, and examples include THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, isopropyl acetate, and the like, which 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, and lithium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxy alkali metals such as potassium t-butoxide and sodium methoxide, and alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, and cesium carbonate. The reaction temperature varies depending on the type of raw material compound and reagent used, and is usually 0 to 200°C, preferably 20 to 150°C. The reaction time is usually 30 minutes to 24 hours.

[0091] (Process 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 in an appropriate solvent under acidic or basic conditions. Specific examples of the solvent should be selected according to the type of raw material compound, and include, for example, THF, dioxane, DME, acetone, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol, water, and the like, which 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. Specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, alkoxy alkali metals such as potassium t-butoxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate. The reaction temperature varies depending on the type of raw material compound and reagent used, and 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 Of the compounds (IIIa) used in the above Production Method 5, (IIIa') is produced by a condensation-dehydration cyclization reaction between a compound (IIIa1) and a compound (IIIa2). [ka] (In the formula, R 2 , R 3 , Q 1 and Q 2 is the same as the definition of Term 1, and R is C 1-6 It is an alkyl group.

[0093] The condensation dehydration cyclization reaction of compound (IIIa1) and compound (IIIa2) can be carried out according to a conventional method. For example, this reaction is achieved by converting compound (IIIa2) into a reactive derivative (e.g., lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting it with compound (IIIa1). Specific examples of active esters include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester, etc. Specific examples of acid anhydrides include mixed acid anhydrides of ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid, etc. Specific examples of solvents should be selected according to the type of raw material compound, etc., and include, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, or esters such as ethyl acetate and isopropyl acetate, which can be used alone or as a mixed solvent. The reaction temperature varies depending on the type of raw material 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.

[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 monohydrochloride, 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 raw material compound, and include, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, ethyl acetate, isopropyl acetate, and the like, which can be used alone or as a mixed solvent. The reaction temperature varies depending on the types of starting compounds and reagents used, but is usually −100 to 200° C., and preferably −30 to 150° C. The reaction time is usually 30 minutes to 24 hours.

[0095] Manufacturing method 7 Of the compounds (IVa) used in the above Production Method 5, (IVa') is produced by a condensation-dehydration cyclization reaction between a compound (IVa1) and a compound (IVa2). [ka] (In the formula, Q 1 and Q 2 is the same as the definition of Term 1, and R is C 1-6 It is an alkyl group.

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

[0097] Manufacturing method 8 Of the compounds (IVa) used in the above Production Method 5, (IVa″) is produced by a condensation-dehydration cyclization reaction between a compound (IVa3) and a compound (IVa4). [ka] (In the formula, Q 1 and Q 2 is the same as the definition of Term 1, and R is C 1-6 It is an alkyl group.

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

[0099] Manufacturing method 9 Of the compounds (IVa) used in the above Production Method 5, (IVa''') is produced by a condensation-dehydration cyclization reaction between a compound (IVa5) and a compound (IVa6). [ka] (In the formula, Q 1 and Q 2 is the same as the definition of Term 1, and R is C 1-6 It is an alkyl group.

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

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

[0102] (Process 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, and include ethers such as Et2O, THF, dioxane, and DME, alcohols such as methanol, ethanol, and isopropyl alcohol, and toluene, which can be used alone or as a mixed solvent. The reaction temperature varies depending on the type of raw material compound and reagent used, and is usually -100°C to 200°C, preferably 0°C to 150°C. The reaction time is usually 30 minutes to 24 hours.

[0103] (Process 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 a sulfonyl chloride is carried out by reacting 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, and include, for example, Et2O, THF, dioxane, DME, toluene, etc., which can be used alone or as a mixed solvent. The reaction temperature varies depending on the type of raw material compound and reagent used, and 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 intermediate sulfonyl chloride in step 2 to a sulfonamide can be carried out by the addition of a mono- or di-substituted amine NHP with a protecting group that can be removed under acidic conditions in a solvent with or without a base. 1 P 2 The reaction is carried out by reacting with. Specific examples of the solvent should be selected according to the type of raw material compound, and include, for example, Et2O, THF, dioxane, DME, DMF, acetonitrile, toluene, etc., 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, and lithium hydroxide, alkoxy alkali metals such as t-butoxy potassium, alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate, and organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, and 4-dimethylaminopyridine. The reaction temperature varies depending on the type of raw material compound and reagent used, and 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) can be obtained by alkylating compound (IIIb). Compound (IIb) can be produced from compound (IIIb) according to the method described in Production Method 5, Step 1.

[0106] Manufacturing method 11 Of the compounds (Vb) used in the above-mentioned Production Method 10, (Vb') is produced by a condensation-dehydration cyclization reaction between a compound (Vb1) and a compound (Vb2). [ka] (In the formula, Q 1 and Q 2 is defined as in Item 1.)

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

[0108] Manufacturing method 12 Of the compounds (Vb) used in the above-mentioned Production Method 10, (Vb″) is produced by a condensation-dehydration cyclization reaction between a compound (Vb3) and a compound (Vb4). [ka] (In the formula, Q 1 and Q 2 is defined as in Item 1.)

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

[0110] Manufacturing method 13 Of the compounds (Vb) used in the above-mentioned Production Method 10, (Vb''') is produced by a condensation-dehydration cyclization reaction between a compound (Vb5) and a compound (Vb6). [ka] (In the formula, Q 1 and Q 2 is defined as in Item 1.)

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

[0112] Manufacturing method 14 Of the compounds (IIc) used in the above Production Method 3, (IIc') is produced by a condensation-dehydration cyclization reaction between a compound (IIc1) and a compound (IIc2). [ka] (In the formula, R 4 , R 5 , Q 1 , Q 2 , and n are defined as in Item 1.)

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

[0114] Manufacturing method 15 Of the compounds (IIc) used in the above Production Method 3, (IIc″) is produced by a condensation-dehydration cyclization reaction between a compound (IIc3) and a compound (IIc4). [ka] (In the formula, R 4 , R 5 , Q 1 , Q 2 , and n are defined as in Item 1.)

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

[0116] Manufacturing method 16 Of the compounds (IIc) used in the above Production Method 3, (IIc''') is produced by a condensation-dehydration cyclization reaction between a compound (IIc5) and a compound (IIc6). [ka] (In the formula, R 4 , R 5 , Q 1 , Q 2 , and n are defined as in Item 1.)

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

[0118] The compound of the present invention represented by formula (1) or an intermediate thereof can be separated and purified by a method known to those skilled in the art, such as extraction, distribution, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion exchange column chromatography, or preparative liquid chromatography), or recrystallization. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol, or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene or toluene, 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 mixture of these solvents. Other purification methods include those described in Experimental Chemistry Lectures (edited by the Chemical Society of Japan, Maruzen) Vol. 1, etc. In addition, the molecular structure of the compound of the present invention can be easily determined by spectroscopic methods such as nuclear magnetic resonance, infrared absorption, and circular dichroism spectroscopy, and mass spectrometry, with reference to the structures derived from the respective raw materials.

[0119] In addition, the intermediate or final product in the above-mentioned production method can be converted into another compound included in the present invention by appropriately converting its functional group, particularly by extending various side chains from amino, hydroxyl, carbonyl, halogen, etc., and, if necessary, by carrying out the above-mentioned protection and deprotection. The conversion of the functional group and the extension of the side chain can be carried out by a general method that is usually performed (see, for example, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999)).

[0120] The compound of the present invention represented by formula (1) or a pharma- ceutically acceptable salt thereof may have asymmetry or a substituent having an asymmetric carbon, and such a compound has optical isomers. The compound of the present invention includes mixtures or isolated isomers of these isomers, and can be produced according to a conventional method. Examples of the production method include a method using a raw material having an asymmetric center, or a method of introducing asymmetry at an intermediate stage. For example, in the case of an optical isomer, an optical isomer can be obtained by using an optically active raw material or by performing optical resolution or the like at an appropriate stage of the production process. For example, when the compound represented by formula (1) or an intermediate thereof has a basic functional group, the optical resolution method includes a diastereomeric method in which a salt is formed using an optically active acid (e.g., monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, etc., dicarboxylic acid such as tartaric acid, o-diisopropylidenetartaric acid, malic acid, etc., sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid, etc.) in an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, 2-propanol, etc., 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 of the above solvents). When the compound represented by formula (1) of the present invention or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (e.g., organic amines such as 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.) is used to form a salt, thereby performing optical resolution.

[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 out the precipitated salt, the yield can be improved by cooling as necessary. The amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents relative to the substrate, preferably about 1 equivalent. If necessary, the crystals can be recrystallized in an inert solvent (e.g., alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more of the above solvents) to obtain a high-purity optically active salt. If necessary, the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.

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

[0123] The novel oxadiazole derivative of the present invention has anticonvulsant activity and GABA-A receptor activating action (GABA nervous system activating action), and therefore can be used as a therapeutic and / or preventive agent for diseases associated with decreased function of the GABA nervous system. In addition, the novel oxadiazole derivative of the present invention has GABA-A receptor activating action and / or an action of strengthening inhibition (I) in the balance between excitation (E) and inhibition (I) (E / I balance), and therefore can be used as a therapeutic and / or preventive agent for nervous system diseases or psychiatric diseases. Nervous system or psychiatric disorders include epilepsy (e.g., epileptic seizures (tonic, clonic, absence, myoclonic, generalized seizures including atonic, focal, and unclassified seizures), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a distinct specific syndrome group, Rasmussen syndrome, etc.), neuropathic pain, developmental disorders, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, Parkinson's disease, depression with or without comorbidity with epilepsy, anxiety, obsessive-compulsive disorder, REM sleep disorder associated with Parkinson's disease and dementia with Lewy bodies. The novel oxadiazole derivative of the present invention can preferably be an agent for treating and / or preventing epilepsy (epileptic seizures (tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, and seizures of unknown classification), status epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy with hippocampal sclerosis as a clear specific symptom group, Rasmussen syndrome, etc.). In the present invention, "prevention" refers to the administration of the active ingredient of the present invention to a healthy person who has not developed a disease, for example, with the aim of preventing the onset of a disease. "Treatment" refers to the administration of the active ingredient of the present invention to a person (patient) who has been diagnosed by a doctor as having a disease. The act of a patient suffering from such a disease taking the medicine to suppress attacks related to the disease also falls under the category 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 therefore can be used as a therapeutic and / or prophylactic agent for nervous system disorders or psychiatric disorders. Furthermore, the novel oxadiazole derivative of the present invention can be used as a therapeutic and / or preventive agent for diseases in which excitation (E) is enhanced and / or inhibition (I) is reduced in the E / I balance. The neurological or psychiatric disorders include epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar disorder and related disorders, schizophrenia spectrum disorders, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndromes, anxiety disorders, obsessive-compulsive disorder, trauma and stress-related disorders, sleep-wake disorders, and / or REM sleep disorders associated with Parkinson's disease-Lewy body dementia.

[0125] The novel oxadiazole derivative of the present invention has anticonvulsant activity and GABA-A receptor activating activity (GABAergic nervous system activating activity), and therefore can be used as a therapeutic and / or preventive agent for diseases associated with decreased function of the GABAergic nervous system. Diseases in which GABAergic dysfunction is implicated include epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar and related disorders, schizophrenia spectrum disorders, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndromes, anxiety disorders, obsessive-compulsive disorder, trauma- and stress-related disorders, sleep-wake disorders, and / or REM sleep disorders associated with Parkinson's disease-Lewy body dementia.

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

[0127] Examples of the depressive syndrome include depressive disorders with anxiety distress, depressive disorders with mixed features, depressive disorders with melancholic features, depressive disorders with atypical features, depressive disorders with psychotic features consistent with mood, depressive disorders with psychotic features inconsistent with mood, depressive disorders with catatonia, perinatal onset, seasonal depressive disorder, severe mood dysregulation disorder, depression / major depressive disorder, persistent depressive disorder, premenstrual dysphoric disorder, substance- or drug-induced depressive disorder, depressive disorder due to other medical illnesses, other specified depressive disorder, and / or unspecified depressive disorder. In particular, it can be preferably used for depression / major depressive disorder.

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

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

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

[0131] The route of administration of the compound of the present invention may be oral, parenteral or rectal administration, and the daily dosage varies depending on the type of compound, the administration method, the symptoms and age of the patient, etc. For example, in the case of oral administration, about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered once or in several divided doses. In the case of parenteral administration such as intravenous injection, usually, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.

[0132] The compound of the present invention can be administered orally or parenterally, directly or after preparation using a suitable dosage form. The dosage form includes, but is not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices, etc. The preparation is produced by a known method using pharma- ceutically acceptable additives. The additives that can be used depending on the purpose include excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizing aids, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. Specific examples include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0133] The compound of the present invention can be used in combination with at least one or more drugs classified as antiepileptics, antidepressants, or antipsychotics. The term "combined use" refers to a form of administration in which the compound of the present invention is prepared separately from the compound of the present invention, and the compound of the present invention may be administered to the subject at the same time as the compound of the present invention or at a later time. Drugs classified as antiepileptics include, for example, phenytoin, valproic acid, carbamazepine, lamotrigine, topiramate, etc., which inhibit sodium channels; ethosuximide, zonisamide, etc., which inhibit calcium channels; perampanel, which inhibits AMPA receptors; benzodiazepine drugs (diazepam, clonazepam, clobazam, etc.), which enhance the activity of the GABA nervous system; barbituric drugs (phenobarbital, etc.), gabapentin, vigabatrin, etc. Examples of drugs classified as antidepressants include SSRIs such as fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, etc., SNRIs such as duloxetine, milnacipran, etc., and tricyclic antidepressants such as imipramine, amitriptyline, clomipramine, amoxapine, etc. Examples of drugs classified as antipsychotics include typical antipsychotics such as haloperidol, spiperone, chlorpromazine, etc., and SDAs such as risperidone, quetiapine, olanzapine, clozapine, perospirone, aripiprazole, etc. EXAMPLES

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

[0135] In order to simplify the description in the specification, the following abbreviations may be used in the Reference Examples, Examples, and Tables in the Examples. As for the 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 dimethylsulfoxide, TFA means trifluoroacetic acid, and MeCN means acetonitrile. n- means normal-, and t- means tert-. As for the symbols used in NMR, s means singlet, d means doublet, dd means doublet of doublets, t means triplet, td means doublet of triplets, q means quartet, m means multiplet, br means broad, brs means broad singlet, brm means broad multiplet, and J means coupling constant.

[0136] The measurement conditions for the high-performance liquid chromatography mass spectrometer (LCMS) were as follows. The observed mass spectrometry values ​​[MS (m / z)] were calculated as MH + and retention time is shown as Rt (min).

[0137] Measurement equipment: Waters ACQUITYTM UltraPerformance LC Column: ACQUITY UPLC BEH C18 1.7μm 2.1 × 30 mm column Solvent: A liquid: 0.05% HCOOH / H2O, B liquid: CH3CN Gradient conditions: 0.0-1.3 minutes;A / B=90 / 10~5 / 95(linear gradient) 1.3-1.5 minutes; A / B=90 / 10 Flow rate: 0.80mL / min UV: 220nm, 254nm Column temperature: 40℃

[0138] Reference example 1 :Ethyl 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxylate [ka] Thionyl chloride (93μl) was added to cyclobutane-1,1-dicarboxylic acid monoethyl ester (100mg) and heated under reflux for 5 hours. After vacuum concentration, azeotropic distillation with toluene was performed to obtain 1-(chlorocarbonyl)cyclobutane-1-carboxylate ethyl as an oil. This was dissolved in acetone (2.64ml), 4-chlorobenzamide oxime (90mg) and potassium carbonate (109mg) were added, and the mixture was stirred for 1 hour under heating at 50°C. The solid was removed by filtration, and the filtrate was concentrated, after which the residue was dissolved in toluene (2.64ml) and heated under reflux for 6 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 6:1) to obtain the compound of Reference Example 1 (138mg) as a solid. 1 H-NMR (CDCl3)δ: 1.25 (t, 3H), 2.08-2.23 (m, 2H), 2.76-2.84 (m, 2H), 2.86-2.94 (m, 2H), 4.24 (q, 2H), 7.45-7.48 (m, 2H), 8.04-8.07 (m, 2H).

[0139] Reference examples 2~11 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 1. [Table 1]

[0140] Reference example 12 : 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl acetate [ka] 4-Chlorobenzoyl chloride (3.48 ml) was added to a solution of ethyl 3-(hydroxyamino)-3-iminopropanoate (4.00 g) in pyridine (40 ml) and stirred at room temperature for 2 hours. After stirring for 20 hours at 90°C, the reaction solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. After washing with 10% citric acid aqueous solution and saturated saline, and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to obtain the compound of Reference Example 12 (4.60 g) as a solid. 1 H-NMR (CDCl3)δ: 1.28 (t, 3H), 3.86 (s, 2H), 4.23 (q, 2H), 7.49 (d, 2H), 8.05 (d, 2H).

[0141] Reference examples 13~14 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 12 to obtain the compounds shown in Table 2. [Table 2]

[0142] Reference example 15 : 2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]ethyl acetate [ka] Triethylamine (0.86 ml) was added to a suspension of 4-chlorobenzhydrazide (500 mg) and ethyl malonyl chloride (0.37 ml) in THF (10 ml), and the mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (10 ml), Burgess reagent (1.54 g) was added, and the mixture was heated under reflux for 6 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to obtain the compound of Reference Example 15 (598 mg) as a solid. 1H-NMR (CDCl3)δ: 1.28 (t, 3H), 4.01 (s, 2H), 4.23 (q, 2H), 7.45-7.50 (m, 2H), 7.96-7.99 (m, 2H).

[0143] Reference example 16 : The corresponding starting compound was reacted and treated in the same manner as in Reference Example 15 to give the compound of Reference Example 16. [ka]

[0144] Reference example 17 : Ethyl 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanoate [ka] Cesium carbonate (7.82 g) and iodomethane (1.12 ml) were added to a solution of the compound of Reference Example 12 (1.60 g) in DMF (16 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 9:1) to obtain the compound of Reference Example 17 (1.11 g) as a solid. 1 H-NMR (CDCl3)δ: 1.21 (t, 3H), 1.67 (s, 6H), 4.17 (q, 2H), 7.47-7.50 (m, 2H), 8.04-8.07 (m, 2H).

[0145] Reference examples 18~21 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 17 to obtain the compounds shown in Table 3. [Table 3]

[0146] Reference example 222-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanoic acid [ka] A 5 mol / L aqueous sodium hydroxide solution (7.3 ml) was added to a solution of the compound of Reference Example 3 (3.10 g) in methanol (20 ml) and the mixture was heated under reflux for 6 hours. After cooling to room temperature, a 10% aqueous citric acid solution was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the compound of Reference Example 22 (2.89 g) as a solid. 1 H-NMR (CDCl3)δ: 1.78 (s, 6H), 7.42-7.46 (m, 2H), 8.00-8.03 (m, 2H).

[0147] Reference examples 23~37 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 22 to give the compounds shown in Table 4. [Table 4]

[0148] Reference example 38 :Sodium [3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]methanesulfonate [ka] A solution of 3-(4-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (1.35 g) in ethanol (5 ml) was added with an aqueous solution (5 ml) of sodium sulfite (0.62 g) and refluxed for 4 hours. The solvent was distilled off under reduced pressure to obtain the compound of Reference Example 38 (2.04 g) as a solid. MS (m / z) 317 (MNa - ), Rt = 0.52 min.

[0149] Reference examples 39~45 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 38 to give 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 [ka] Phosphorus oxychloride (22.5 ml) was added to the compound of Reference Example 38 (1.68 g), heated under reflux for 5 hours, and then concentrated under reduced pressure. The residue was added to THF (20 ml), and this was added dropwise to a solution of bis(2,4-dimethoxybenzyl)amine (1.56 g), triethylamine (2.75 ml), and 4-dimethylaminopyridine (0.06 g) in THF (20 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to obtain the compound of Reference Example 46 (1.32 g) as an amorphous substance. 1 H-NMR (CDCl3)δ: 3.78 (s, 12H), 4.38 (s, 2H), 4.38 (s, 4H), 6.43-6.46 (m, 4H), 7.20 (d, 2H), 7.58-7.61 (m, 2H),7.89-7.93 (m, 2H).

[0151] Reference examples 47~53 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 46 to give the compounds shown in Table 6. [Table 6]

[0152] Reference example 542-[3-(4-bromophenyl)-1,2,4-oxazol-5-yl]-N,N-bis(2,4-dimethoxybenzyl)propane-2-sulfonamide [ka] Cesium carbonate (527 mg) and iodomethane (0.075 ml) were added to a solution of the compound of Reference Example 46 (250 mg) in DMF (5 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to obtain the compound of Reference Example 54 (241 mg) as an amorphous substance. 1 H-NMR (CDCl3)δ: 1.93 (s, 6H), 3.57 (s, 6H), 3.71 (s, 6H), 4.27 (br s, 4H), 5.43 (br s, 1H), 6.77 (br s, 1H), 7.14-7.19 (m, 2H), 8.05-8.10 (m, 2H).

[0153] Reference examples 55~61 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 54 to give 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 [ka] N,N-diisopropylethylamine (4.3 ml) was added to a solution of 4-fluorobenzamidoxime (1.90 g), 2-pyrrolidone-5-carboxylic acid (1.59 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.16 g) in DME (50 ml), and the mixture was stirred at room temperature for 2 hours and at 80°C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:4) to obtain the compound of Reference Example 62 (2.30 g) as a solid. 1 H-NMR (d6-DMSO) δ: 2.21-2.40 (m, 3H), 2.51-2.62 (m, 1H), 5.09-5.12 (m, 1H), 7.38-7.44 (m, 2H), 8.04-8.09 (m, 2H), 8.37 (br s, 1H).

[0155] Reference examples 63~68 : The corresponding starting compounds were reacted and treated in the same manner as in Reference Example 62 to give the compounds shown in Table 8. [Table 8]

[0156] Example 1 2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide [ka] The compound (280 mg) obtained in Reference Example 23 and oxalyl chloride (0.384 ml) were dissolved in dehydrated chloroform (10 ml), and two drops of DMF were added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dehydrated THF (5 ml), and 28% aqueous ammonia solution (1 ml) was added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1), to obtain the compound of Example 1 (206 mg) as a solid. 1 H-NMR (CDCl3)δ: 1.75 (s, 6H), 5.43 (br s, 1H),6.77 (br s, 1H), 7.14-7.19 (m, 2H), 8.05-8.10 (m, 2H). MS (m / z) 250 (MH + ), Rt = 0.69 min.

[0157] Example 2-16 : The corresponding starting compounds were used in the same manner as in Example 1 to carry out the reactions and treatments, thereby obtaining the compounds shown in Table 9. [Table 9] TIFF0007637121000064.tif160158

[0158] Example 17 2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide [ka] Trifluoroacetic acid (10 ml) was added to a toluene (20 ml) solution of the compound obtained in Reference Example 55, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to obtain the compound of Example 17 (103 mg) as a solid. 1H-NMR (CDCl3)δ: 1.98 (s, 6H), 4.95 (br s, 2H), 7.14-7.19 (m, 2H), 8.03-8.08 (m, 2H). MS (m / z) 286 (MH + ), Rt = 0.71 min.

[0159] Examples 18-24 : The corresponding starting compounds were used in the same manner as in Example 18 to prepare 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 [ka] Cesium carbonate (0.988 mg) was added to a solution of the compound obtained in Reference Example 62 (500 mg) and methyl iodide (0.19 ml) in DMF (4 ml), and the mixture was stirred at room temperature for 2.5 hours. A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:3) to obtain the compound of Example 25 (483 mg) as a solid. 1 H-NMR (CDCl3)δ: 2.27-2.33 (m, 1H), 2.40-2.67 (m, 3H), 2.85 (s,3H), 4.84-4.87 (m, 1H), 7.09-7.15 (m, 2H), 7.99-8.04 (m, 2H). MS (m / z) 262 (MH + ), Rt = 0.71 min.

[0161] Examples 26-31 : The corresponding starting compounds were used in the same manner as in Example 25 to prepare 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 [ka] The compound of Example 25 was passed through a column (CHIRALPAK TM The mixture was separated using AD-H (mobile phase: 100% MeCN) to obtain a front peak (enantiomer A) and a rear peak (enantiomer B). The absolute configurations of enantiomers A and B were determined to be S-configuration and R-configuration, respectively, by comparison with the compound (Example 31) produced from Reference Example 68 using the S-configuration starting compound. Example 31 (Enantiomer A): Retention time 4.78 min Chiral HPLC (Chiralpak TM AD-H, 0.46 cm ID x 25 cm L, mobile phase: 100% MeCN, flow rate: 1.0 ml / min, temperature: 40°C, wavelength: 237 nm) Example 32 (Enantiomer B): Retention time 5.99 minutes Chiral HPLC (Chiralpak TM AD-H, 0.46 cm ID x 25 cm L, mobile phase: 100% MeCN, flow rate: 1.0 ml / min, temperature: 40°C, wavelength: 237 nm)

[0163] Example 33 (S)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one [ka] The compound of Example 31 can also be prepared by the following method. A 50% ethyl acetate solution of propanephosphonic anhydride (4.48 kg) was added to a mixture of 4-fluorobenzamidoxime (840 g), (S)-2-pyrrolidone-5-carboxylic acid (1.08 kg), N,N-diisopropylethylamine (2.56 L) and ethyl acetate (7.3 L), and the mixture was stirred at room temperature for 1.5 hours, and then heated to 75°C for 2.5 hours. After cooling, 0.1 mol / L hydrochloric acid (3.36 L) was added to the reaction solution to separate the liquid, and the aqueous layer was extracted twice with ethyl acetate (1.86 L). The organic layers were combined and washed with 5% dipotassium hydrogen phosphate aqueous solution (3.36 kg) and water (1.68 L) in that order, after which the organic layer was concentrated under reduced pressure to 3.36 kg and cooled to 0°C with stirring. n-Heptane (3.02 kg) was added dropwise to the resulting slurry, and the crystals were collected by filtration, washed with a 40% ethyl acetate / heptane mixed solvent (1.68 kg), and dried under vacuum at 40°C to obtain crude crystals (1.14 g) as a light brown solid. The crude crystals (1.00 kg) were dissolved in 2-propanol / water (50%, 1.6 kg), and then 60 g of activated carbon was added and stirred at 25°C, and the activated carbon was removed by filtration. The filtrate was diluted with 2-propanol / water (50%) to 3.0 kg, and added dropwise to water (6.0 L) at 0°C while stirring. The crystals were collected by filtration, washed with a 2-propanol / water mixed solvent (12.5%, 2.0 kg), and then dried under vacuum at 40°C to obtain the compound of Example 33 (944 g) as a white solid. It was confirmed by NMR and HPLC that this compound was identical to the compound of Example 31.

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

[0165] Test Example 1: Subcutaneous injection pentetrazol model (minimal convulsion model, scPTZ) evaluation For the evaluation of antiepileptic drugs, a subcutaneous injection pentetrazol model (minimal convulsion model, scPTZ) evaluation is used, which has high clinical predictability. Compounds that show anticonvulsant effects in this model are expected to be used as antiepileptic drugs in clinical practice. In this test, an animal model that expresses generalized absence seizures and myoclonic seizures was used. The test compound was orally administered to male Slc:ddY mice (obtained from Japan SLC Co., Ltd., 5 mice per group, weighing 20-30 g), and 85 mg / kg of pentetrazol was administered subcutaneously 1 hour later. The presence or absence of clonic convulsions was then observed for 30 minutes. As a control, a 0.5% methylcellulose solution was administered as the test compound, and a similar test was performed. The results are shown in Table 12 below. The results are expressed as the number of mice that showed suppression of convulsion expression out of 5 mice. The control test was considered to be successful when 4 out of 5 mice showed convulsions. [Table 12]

[0166] As shown in Table 12, the compounds of the present invention showed anticonvulsant effects when orally administered in the subcutaneous injection pentetrazol model (minimal convulsion model, scPTZ) evaluation. The compounds of Examples 11, 16, 25, 28, 30 and 31 showed anticonvulsant effects in more than half of the cases even when orally administered at 25 mg / kg.

[0167] Test Example 2: Rotarod Evaluation This test is a test to evaluate the inhibitory effect of drugs on coordinated movement ability. The rotarod is a device that rotates a cylindrical rod with a diameter of 4 cm, and mice are made to walk on the rotating rod, and the ability to walk is used as an index to evaluate coordinated movement ability. Slc:ddy male mice (obtained from Japan SLC Co., Ltd., weighing 20 to 30 g) are trained to walk on the rotarod device rotating at 12 revolutions per minute for 5 minutes without falling 3 hours before the test, and only mice that can walk are used in the test. A test compound was orally administered to a group of 5 mice, and 1 hour later, the mice were placed on the rotarod device rotating at 15 revolutions per minute, and their walking state was observed for 180 seconds and the walking time was measured. The control was administered 0.5% methylcellulose solution as the test compound and the same test was performed. Coordinated movement ability was expressed as the average walking time (seconds) of the 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 all of the Examples, oral administration of 25 mg / kg or more enabled the rats to continue walking for 180 seconds without falling from the rotor rod apparatus, and did not affect coordinated motor function. Therefore, the Example compounds evaluated in the subcutaneous injection pentetrazol model (minimal convulsion model, scPTZ) in Test Example 1 showed anticonvulsant effects as described above, but it was confirmed that the doses at which such effects were obtained had little effect on coordinated motor function.

[0169] Test Example 3: Evaluation of febrile convulsions in Dravet model mice This test was conducted to evaluate the anticonvulsant effect of drugs on febrile convulsions in Dravet model mice. In this test, BALB / c-Scn1a<+ / -> mice (catalog number: RBRC06422; available from the RIKEN Bioresource Center through the Ministry of Education, Culture, Sports, Science and Technology's National Bioresource Project) were used. This model mouse has a mutation in Scn1A, the causative gene of Dravet syndrome patients, and has a phenotype that exhibits a pathological condition similar to febrile convulsions caused by body temperature increase, which is a symptom of Dravet syndrome patients, and can be used as a model animal for spontaneous Dravet syndrome (reference: Research Annual Report of the Foundation for the Promotion of Epilepsy Treatment Research 2015:26:69-76). The test compound was orally administered to male Dravet model mice (groups of 5-8 mice, weighing 20-30 g), and 50 minutes later, the mice were placed in a chamber immersed in a hot water bath to induce an increase in body temperature, and the onset of febrile convulsions was observed. After the onset of febrile convulsions, the rectal temperature was measured immediately and used as the convulsion threshold temperature. As a control, a 0.5% methylcellulose solution was administered as the test compound, and the same test was performed. The anticonvulsant activity was expressed as the drug dose that significantly increased the convulsion threshold body temperature compared to the control group, and the difference in the convulsion threshold body temperature from the control group. The results are shown in Table 14. [Table 14]

[0170] As shown in Table 14, the compounds of the present invention showed a seizure threshold body temperature increasing effect in Dravet febrile convulsions, and were shown to have an anticonvulsant effect in the Dravet model. All of the compounds of the Examples showed an anticonvulsant effect in the Dravet model at a dose that did not affect coordinated movement 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 obtained by the method described in the Guidelines for Creating Stable Cell Lines (Lonza Japan website; Non-Patent Document 4) to evaluate the GABA-A receptor activating 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 was added, followed by a mixture of 2 μM GABA and the test compound was measured. GABA activation activity was expressed as 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 increases the current by 20% was expressed as EC20. Similarly, the current observed when a mixture of 10 μM flumazenil was added to 2 μM GABA and the test compound was measured, and the inhibition rate by flumazenil against the increase in current 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. The GABA-A receptor activation activity of clobazam and diazepam, which are classified as benzodiazepines, is strongly inhibited by the benzodiazepine antagonist flumazenil. In contrast, the GABA-A receptor activation activity of the compounds of the present invention was weakly inhibited by flumazenil against the increase in current, 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: Rat forced swimming model evaluation This test is a test to evaluate the antidepressant effect of drugs. When rats are placed in a water tank from which they cannot escape and made to swim, immobility is observed after the escape behavior. When the rats are placed in the water tank again the next day, immobility appears earlier than the first time. The duration of this immobility is regarded as depression-like behavior, and this method evaluates the antidepressant effect of the test compound. Male Wister rats (obtained from Charles River Japan Co., Ltd., weighing 260-300g) were made to swim in the water tank for 15 minutes on the day before the test. On the day of the test, the test compound was orally administered (10-12 rats per group), and after 1 hour, the rats were made to swim in the water tank again for 5 minutes and the immobility time was measured. The control group was administered 0.5% methylcellulose solution as the test compound and the same test was performed. The antidepressant activity was expressed as the average reduction rate of immobility time compared to the control group. The results are shown in Table 16. [Table 16]

[0174] As shown in Table 16, Examples 29 and 32 significantly reduced the immobility time in the rat forced swimming model, and were shown to have an antidepressant effect. On the other hand, diazepam has a GABA-A receptor activating effect similar to the compound 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 that are also used as anticonvulsants. The fact that the compound of the present invention was effective against a depression model in which benzodiazepines were ineffective is thought to be due to the fact that the GABA-A receptor activating mechanism of the compound of the present invention is different from that of benzodiazepines as shown in Experimental Example 4, and that the compound of the present invention showed an antidepressant effect not found in benzodiazepines due to some unknown mechanism of action. This suggests that the compound of the present invention has a therapeutic / prophylactic effect not only against epileptic seizures but also against depressive symptoms that occur frequently in epilepsy patients.

[0175] As described above, the compound of the present invention showed a strong anticonvulsant effect in the subcutaneous injection pentetrazol model (minimal convulsion model, scPTZ) evaluation. In addition, in a mouse model of Dravet syndrome, known as one of the intractable generalized epilepsies and for which the causative mutation gene has been identified, the compound increased the threshold body temperature for febrile convulsions at an administration dose that does not affect coordination. Therefore, the compound of the present invention is useful as an antiepileptic drug (a therapeutic and / or preventive drug for generalized seizures such as tonic seizures, clonic seizures, absence seizures, myoclonic seizures, generalized seizures including atonic seizures, focal seizures, unclassified seizures, and Dravet syndrome, West syndrome, and Lennox-Gastaut syndrome, which are classified as intractable epilepsy for which drug treatment has not yet been effective). Since the compound of the present invention also has GABA-A receptor activating activity, it is also useful as a therapeutic and / or preventive drug for anxiety disorders, obsessive-compulsive disorder, and REM sleep disorder associated with Parkinson's disease and dementia with Lewy bodies, for which the therapeutic effect of existing GABA nervous system activators has been recognized. The GABA-A receptor activating activity of the compound of the present invention is exerted by a different mode of action from benzodiazepine, which is one of the existing GABA nervous system activators, and since it was effective against depressive symptoms in a rat forced swimming model, which benzodiazepines did not show any effect on, it is effective against depressive symptoms with or without epilepsy, and is useful as a therapeutic and / or preventive drug for depressive syndrome, etc., and has usefulness not found in existing antiepileptic drugs. It is also considered that the compound of the present invention has an effect of improving the pathology of developmental disorders, autism, bipolar disorder and related disorders, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, and Parkinson's disease, which are caused by abnormalities in the GABA nervous system. [Industrial Applicability]

[0176] The compound of the present invention has a strong anticonvulsant effect and also has a GABA-A receptor activating effect, and therefore is useful as a therapeutic and / or preventive agent for diseases associated with decreased function of the GABA nervous system. In addition, the compound of the present invention has an effect of strengthening inhibition (I) in the balance (E / I balance) between excitation (E) and inhibition (I), and therefore is useful as a therapeutic and / or preventive agent for diseases in which E is enhanced and / or I is decreased 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 and n represents an integer of 0 to 2.] However, the following compounds are excluded: 2-[3-(3,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide, 2-[3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide, 1-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxamide, 1-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxamide, 6-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpiperidin-2-one, 6-[3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpiperidin-2-one, and 2-[3-(2-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide.

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.

Images