EA048061B1 - OXADIAZOLE DERIVATIVE - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to an oxadiazole derivative or a pharmaceutically acceptable salt thereof, which can be used as a medicine, and to a pharmaceutical composition or medicine for the treatment and/or prevention of epilepsy and/or depressive syndrome and other similar diseases, containing this derivative as an active ingredient.

State of the art

Epilepsy is a chronic disease caused by increased excitability of neurons in the brain, the symptom of which is this unusual somatic symptom or change in body movement, consciousness or perception, suddenly occurring repeatedly. The International League Against Epilepsy (ILAE) divides the type of epileptic seizure into generalized seizure, focal seizure and seizure of unknown etiology, where generalized seizure is further divided into tonic seizure, clonic seizure, petit mal seizure, myoclonic seizure, atonic seizure and other similar types of seizures (Non-patent document 1). The etiologies of epilepsy can be roughly divided into genetic, structural/metabolic and unknown. In addition, epilepsy is divided into various disease types and syndromes based on characteristics such as electroencephalogram/clinical symptom, time from the onset of the disease manifestation and pathogenesis of the disease. These include, for example, West syndrome and Dravet syndrome, which occur in infancy, Lennox-Gastaut syndrome and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), which occur in childhood, mesial temporal lobe epilepsy associated with hippocampal sclerosis, which is a clearly identifiable symptom, Rasmussen syndrome and many other symptoms (Non-patent document 2). Since the 1990s, international collaborative research has been conducted, in particular on the molecular pathology of epilepsy, and many genes causing this disease have now been identified. These genes include ion channels such as Na, K, Ca, Cl, GABA-A and ACh, and it is believed that epilepsy is caused by a disturbance in ion homeostasis, which is one of the causes of the disease.

Epilepsy is a serious disease that can have a negative impact on prognosis, and it is known that epilepsy affects approximately 1% of the world's population. Drug therapy is mainly used to treat these epileptic seizures. Although various antiepileptic drugs have been prescribed for treatment for many years, however, in one out of three cases of treatment, epilepsy is resistant and refractory to drug therapy with many existing drugs. In addition, existing epilepsy drugs have dose-dependent side effects on the nervous system, such as excessive sleepiness, loss of balance when walking, cognitive impairment, and psychiatric symptoms; severe idiosyncratic side effects, such as Stevens-Johnson syndrome, although rare; teratogenic risks; and drug interaction risks, such as loss of drug efficacy and increased side effects. In addition, patients suffering from epilepsy have a high risk of developing psychiatric symptoms such as depressive syndrome, anxiety and cognitive impairment as complications (Non-patent document 3). However, existing epilepsy drugs do not have a therapeutic effect on such psychiatric symptoms that arise as complications. Therefore, there has been a great need for a long time to create a new antiepileptic drug that would have many positive properties, such as high efficacy against refractory epilepsy, a significantly improved pharmacokinetic and safety profile, and efficacy against both epilepsy and psychiatric symptoms that arise as complications.

Epilepsy causes a seizure due to increased excitability of a brain neuron, which occurs when the excitatory neuron is strongly activated or the inhibitory neuron is weakened, i.e., it is assumed that the cause is an imbalance between excitation (E) and inhibition (I) (E/I balance). In addition to epilepsy, some diseases are also known to be caused by an imbalance of E/I. Drugs that enhance the GABAergic system by activating inhibitory neurons have shown some therapeutic effects in anxiety disorder, obsessive-compulsive disorder, and REM sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies. And it is known that E/I imbalance is also associated with neuropathic pain, developmental disabilities, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis, Parkinson's disease and other similar diseases. In fact, some antiepileptic drugs that may have a positive effect on E/I imbalance are widely used in the treatment of these diseases. However, these drugs have limited efficacy in the above-mentioned non-epilepsy diseases and also have disadvantages related to side effects and pharmacokinetics. It follows that if a new antiepileptic drug with a higher

- 1 048061 efficiency and with weaker side effects, this drug can find application in the treatment of many mental or neurological diseases, and the creation of such a drug is of great importance.

Patent Document 1 discloses oxadiazoles which have a sweet taste modifier effect but whose structures are different from the structure of the compound of formula (1) shown below.

Prior art (References to patent documents).

[Patent Document 1] WO 2006/138512.

(References to non-patent documents).

[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.

The essence of the invention

Technical challenge.

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

Solving a technical problem.

In order to solve the above problem, the inventors of the present invention conducted extensive studies and as a result found that the compound of the following formula (1) has a strong anticonvulsant effect, that is, the inventors of the present invention found that the compound has an antiepileptic effect, as well as a potentiating effect on the GABA receptor. Based on the obtained data, the present invention was created. According to the present invention, an oxadiazole derivative of the following formula (1) is provided (hereinafter, where appropriate, referred to as the compound of the present invention).

Accordingly, the present invention is described as follows.

Point 1.

Compound of formula (1):

^Q XJ0>- _R 1

L'Chu'g CO or its pharmaceutically acceptable salt, where Q ¹ is a halogen,

Q ² is hydrogen or halogen, the ring containing X, Y and Z has the following formulas (5a), (5b) or (5c):

NO ON NN _Ч Л А/ νΛ X/ %Л X/ 3 Ν < Ч Ν Т Ч ^Х О ^? (5a) (5Ь) (5с)

R ¹ has any one of the following formulas (2)-(4):

θ O ,O Me

A JL A Jst AN 'nh ₂ Avo

R ² R ³ (2) R ² R ³ (3) UD (4) R ⁵

R ² and R ³ are the same or different and represent C1-6 alkyl; or R ² and R ³ may be taken together with the carbon atom to which they are attached to form _C3.6 cycloalkyl (which may be substituted with from 1 to 3 substituents independently selected from halogen) or a C4-6 saturated heterocyclic ring containing one oxygen atom,

R ⁴ and R ⁵ are the same or different and are hydrogen, halogen or C _1-6 alkyl, and n is 1, provided that the following compounds are excluded from the compound of formula (1) 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-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxamide, 1-[3-(3,4-dichloro ...

- 2 048061 (4-bromophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxamide, 2-[3-(2-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide.

Point 2.

A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are the same or different and represent C 1-3 alkyl; or R ² and R ³ may be taken together with the carbon atom to which they are attached to form a C 3-6 cycloalkyl (which may be substituted with 1 to 3 fluorines) or a C _4-6 saturated heterocyclic ring containing one oxygen atom.

Item 3.

The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein

R ⁴ and R ⁵ are the same or different and represent hydrogen or C _1-3 alkyl.

Item 4.

The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein

Q ¹ is fluorine, chlorine or bromine, and

Q ² is hydrogen, fluorine, chlorine or bromine.

Item 5.

The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the ring containing X, Y and Z has the following formulas (5a) or (5b).

N-0 O-N

(5a) (Sb)

Item 6.

The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein

R ¹ has the following formula (4). Me

Item 7.

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is 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-difluorocyclobutan-1-carboxamide (example 7), 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutan-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),

- 3 048061

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), (R)-5-|3-(4-(|)tor(|)enyl)-1.2.4-oxadiazol-5-yl|-1-methylpyrrolidin-2-one (Example 31), and (B)-5-|3-(4-(|)tor(|)enyl)-1.2.4-oxadiazol-5-yl|-1-methylpyrrolidin-2-one (Example 32). Point 8.

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide (Example 2), 2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide (Example 3), 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanamide (Example 13), 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propane-2-sulfonamide (Example 20), 5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 25), 5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 29), (^)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 31), and (^)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one (Example 32). Item 9.

A pharmaceutical composition comprising a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof.

Item 10.

A medicinal product for the treatment and/or prevention of diseases associated with hypofunction of the GABAergic system, containing a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 11.

The medicinal product according to claim 10, wherein the diseases associated with hypofunction of the GABAergic system are a neurological disease or a mental illness.

Item 12.

The medicinal product according to claim 11, wherein the neurological disease or mental illness is epilepsy, neuropathic pain, neurological developmental disorders, bipolar disorder and related disorders, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndrome, anxiety disorders, obsessive-compulsive disorder, trauma- and stress-related disorders, sleep-wake cycle disorders and/or rapid eye movement sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies.

Item 13.

A method for treating and/or preventing diseases associated with hypofunction of the GABAergic system, comprising administering a therapeutically effective amount of a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Item 14.

The use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicinal product for the treatment and/or prevention of diseases associated with hypofunction of the GABAergic system.

Item 15.

The use of a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the treatment and/or prevention of diseases associated with hypofunction of the GABAergic system.

Item 16.

A pharmaceutical combination comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and at least one medicinal agent selected from medicinal agents related to an antiepileptic medicinal agent, an antidepressant or a neuroleptic medicinal agent.

Item 17.

A medicinal product for the treatment of diseases associated with hypofunction of the GABAergic system, containing a combination according to item 16.

Positive effect of the invention

The compounds of the present invention exhibited potent anticonvulsant activity in a number of animal models of seizures induced by GABA signal reduction (the subcutaneous pentetrazole model in Test 1 and the mouse model of Dravet syndrome with febrile seizures in Test 3). The subcutaneous pentetrazole model in Test 1 is an animal model with a seizure type

- 4 048061 erysipelas, which is an expression of generalized petit mal or myoclonic seizures, and is characterized by a low remission rate with existing antiepileptic drugs. The Dravet syndrome febrile seizure model in test 3 is an animal model that shares the same genetic background as Dravet syndrome, which is characterized by seizure resistance to current drug treatment. The effect of existing antiepileptic drugs in this model is very limited. It follows that the compounds of the present invention can be used as a medicine for the treatment or prevention of epilepsy such as epileptic seizure (tonic seizures, clonic seizures, petit mal seizure, myoclonic seizures, generalized seizure including atonic seizures, focal seizure, seizure of unknown etiology), epileptic condition, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy associated with hippocampal sclerosis, which is a clearly identifiable symptom, and Rasmussen syndrome. Among these diseases, West syndrome, Dravet syndrome and Lennox-Gastaut syndrome are severe diseases characterized by seizure resistant to the effect of drug treatment and include mental retardation and other similar disorders, therefore, it is very important to develop a drug for preventing and/or treating intractable epilepsy including these diseases. The potentiating effect of the compounds of the present invention on GABA receptors is carried out by a mechanism different from that of benzodiazepine, which is one of the existing GABA receptor agonists, and, in fact, the result of test 5 showed that the compounds of the present invention exhibited a positive effect on depressive syndrome in rats in the forced swim test, on which benzodiazepine had no effect. Therefore, the compounds of the present invention have a beneficial effect on depressive symptom accompanied or not accompanied by epilepsy, and can be used in cases in which existing antiepileptic drugs have no therapeutic effect. The potentiating effect of the compounds of the present invention on GABA receptors can also have a beneficial effect when used as a drug for treating or preventing anxiety disorder, obsessive-compulsive disorder, REM sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies, which can be treated with existing GABA receptor agonists. And it is expected that the compounds of the present invention can improve pathological conditions of neuropathic pain, developmental disorder, autism, bipolar disorder, schizophrenia, Alzheimer's disease and other types of dementia, amyotrophic lateral sclerosis and Parkinson's disease, which are caused by dysfunction of the GABAergic system. In addition, the compounds of the present invention can also be used as a medicine for the prevention and/or treatment of other diseases mentioned in the invention.

In addition, the compounds of the present invention have the effect of enhancing inhibition (I) in the balance of excitation (E) and inhibition (I) (in the E/I balance), and therefore, the compounds of the present invention can be used as a medicine for treating or preventing a neurological disease or a mental disease, in particular, a medicine for treating or preventing a disease in which excitation (E) increases and/or inhibition (I) decreases in the E/I balance.

Description of embodiments of the invention

The following is an explanation of the terms used in the invention.

Unless otherwise stated, the definition of each substituent group also applies to the case of partial inclusion of the substituent group or the case where the substituent group is present in another substituent group.

The halogen includes, for example, fluorine, chlorine, bromine, and iodine. The preferred halogen is fluorine or chlorine, and fluorine is more preferred.

C _1-6 alkyl denotes a linear or branched saturated hydrocarbon group having from 1 to 6 carbon atoms, and C ₆ alkyl denotes alkyl having 6 carbon atoms. This applies equally in case of another number of carbon atoms. C _1-6 alkyl preferably includes C _1-3 alkyl, more preferably C _1-2 alkyl. C _1-3 alkyl preferably includes C _1-2 alkyl, more preferably methyl. C _1-2 alkyl includes, for example, methyl, ethyl and the like. C _1-3 alkyl includes, for example, propyl, 1-methylethyl and the like, along with the examples given for said C _1-2 alkyl. C _1-6 alkyl includes, for example, 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 other similar alkyls, along with the examples given for the said C _1-3 alkyl.

- 5 048061

C3-6 cycloalkyl means a cyclic alkyl having from 3 to 6 carbon atoms, which may have a bridged structure. _C3-6 cycloalkyl includes preferably _C3-5 cycloalkyl. _C3-5 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and other similar cycloalkyls. _C3-6 cycloalkyl includes, for example, cyclohexyl and other similar cycloalkyls, along with the examples given for said _C3-5 cycloalkyl.

C _1-3 alkoxy means an oxyl group substituted by the above-mentioned C _1-3 alkyl. C _1-3 alkoxy preferably includes C _1-2 alkoxy, more preferably methoxy. C _1-2 alkoxy includes, for example, methoxy, ethoxy and other similar oxyl groups. C _1-3 alkoxy includes, for example, propoxy, 1-methylethoxy and other similar alkoxy groups, along with the examples given for said C _1-2 alkoxy.

The _C4-6 saturated heterocyclic ring means a 4-6-membered saturated ring which has the same or different one or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a bridged structure. A preferred ring is a C4-6 saturated heterocyclic ring containing one or two heteroatoms independently selected from a nitrogen atom and an oxygen atom. The _C4-6 saturated heterocyclic ring includes preferably a _C4-5 saturated heterocyclic ring. The _C4-5 saturated heterocyclic ring includes, for example, oxetane, azetidine, tetrahydrofuran, pyrrolidine and the like. The _C4-6 saturated heterocyclic ring includes, for example, tetrahydropyran, piperidine, morpholine, piperazine and the like, along with the examples given for said _C4-5 saturated heterocyclic ring.

Preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y, Z, Q ¹ , Q ² and n are shown below, but the scope of the present invention is not limited to the scope of the compounds listed below.

In an embodiment, R ¹ has the following formulas (2)-(4).

In another embodiment, R ¹ has the following formulas (2) or (3).

In another embodiment, R ¹ has the following formula (4).

In a preferred embodiment, R ² and R ³ , R ² and R ³ are the same or different and represent (1) C _1-3 alkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy and C _1-3 alkoxy; or (2) R ² and R ³ are taken together with the carbon atom to which they are attached to form a C _3-6 cycloalkyl which may be substituted with from 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl and C _1-3 alkoxy, or (3) R ² and R ³ are taken together with the carbon atom to which they are attached to form a C _4-6 saturated heterocyclic ring containing one or two heteroatoms independently selected from a nitrogen atom and an oxygen atom, wherein said saturated heterocyclic ring may be substituted with from 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl and C _1-3 alkoxy.

In a more preferred embodiment, R ² and R ³ , R ² and R ³ are the same or different and are (1) C _1-3 alkyl which may be substituted with fluorine; or (2) R ² and R ³ are taken together with the carbon atom to which they are attached to form C _3-6

- 6 048061 cycloalkyl which may be substituted with fluorine, or (3) R ² and R ³ are taken together with the carbon atom to which they are attached to form a C _4-6 saturated heterocyclic ring containing one or two heteroatoms selected independently from a nitrogen atom and an oxygen atom, wherein said saturated heterocyclic ring may be substituted with fluorine.

C _3-6 cycloalkyl, which is formed by taking R ² and R ³ together with the carbon atom to which they are attached, includes, for example, the following groups.

(6a) (6b) (6c) (6d)

A C4-6 saturated heterocyclic ring which is formed by taking ^R2 and ^R3 together with the carbon atom to which they are attached includes a 4- to 6-membered saturated ring which has one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom, which includes, for example, the following groups.

(7a) (7b) (7c) (7d) (7e) (7f) (7g) (7h) (7i)

In a preferred embodiment, R ⁴ and R ⁵ , R ⁴ and R ⁵ are the same or different and represent (1) hydrogen, (2) fluoro, (3) hydroxy, (4) C _1-3 alkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy and C _1-3 alkoxy, (5) C _3-6 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl and C _1-3 alkoxy; or when R ⁴ and R ⁵ are attached to the same carbon atom or to two adjacent carbon atoms, respectively, (6) R ⁴ and R ⁵ may be taken together with the carbon atom(s) to which they are attached to form a C _3-6 cycloalkyl which may be substituted with from 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl and C _1-3 alkoxy, and (7) R ⁴ and R ⁵ may be taken together with the carbon atom(s) to which they are attached to form a C4-6 saturated heterocyclic ring which may be substituted with from 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C 1-3 alkyl and C _1-3 alkoxy. As used in the invention, the term adjacent carbon atoms means that two carbon atoms forming a ring are bonded to each other, and said carbon atoms are bonded to R ⁴ or R ⁵ , respectively.

In a more preferred embodiment, R ⁴ and R ⁵ , R ⁴ and R ⁵ are the same or different and represent (1) hydrogen, (2) fluoro, (3) hydroxy, (4) C _1-3 alkyl which may be substituted with fluoro, (5) C _3-6 cycloalkyl which may be substituted with fluoro; or when R ⁴ and R ⁵ are attached to the same carbon atom or to two adjacent carbon atoms, respectively, (6) R ⁴ and R ⁵ may be taken together with the carbon atom(s) to which they are attached to form C3-6 cycloalkyl which may be substituted with from 1 to 3 substituents independently selected from the group consisting of fluoro and C _1-3 alkyl.

When R ⁴ and R ⁵ are attached to the same carbon atom or to two adjacent carbon atoms, respectively, the C3-6 cycloalkyl that is formed by taking R ⁴ and R ⁵ together with the carbon atom(s) to which they are attached includes, for example, the following groups:

- 7 048061

When R ⁴ and R ⁵ are attached to the same carbon atom or to two adjacent carbon atoms, respectively, the C _4-6 saturated heterocyclic ring which is formed by taking R ⁴ and R ⁵ together with the carbon atom(s) to which they are attached includes, for example, the following groups:

- 8 048061

Me

Y >=O o (9a)

Me

Me N

0-1 (9b) =0 n

Me

Me Me Me Me Me Me

Sfcifr £Й° ₀ £Й°дЙ° hn£Й° (9c) (9d)

Me (9e) (9f) (9g) (9h)

Me

Me

Me

Me

Me (9i) (9j) (9k)

Me

Me

Me (91)

Me (9m) H

Me (9n) (9o)

Me Me (9p)

Me mt me ivic -·- ivic , , i (9q) (9r) (9s) (9t) (9u)

Me Me Me Me _Me (9y) (9z) (9aa) (9ab) (9ac)

Me Me Me _ψ Me

A D ¢¢- -¾ i (9ae) (9af) (9ag) (9ah) (9v) (9w) (9x)

Me

L-A ⁰ (9ad) w Me

J-N .

4 ^0HN (9ai)

Me --hi )=0

A (9aj) γ Me w Me γ Me w Me y Me γ Me (9ak)

Me (9al)

Me I (9am)

Me (9an)

Me (9ao) (9ap)

..- .— ,- Me Me Me γίγθΑγ-Νψ,ο A

V °V γ hnA ζΥ Η (9aq) (9ar) (9as) (9at) (9au) (9av) (9aw)

Me Me Me Me Me Me

X ^th ex (9ax) (9ay) (9az) (9ba) (9bb) (9bc)(9bd)

Me Me Me Me Me Me Me Me

ΑγΝγ-ο 1 bo Λ N -ο <Cbo Αγίγο Αχγο Λ, ιγο A no

0η Cj hnCJ °0h ^H kJ <0 ^H k>

(9be) ^H (9bf) (9bg) (9bh) (9bi) (9bj) (9bk)(9bl)

- 9 048061

In a preferred embodiment, X, Y and Z are the same or different and represent a nitrogen atom or an oxygen atom, provided that the ring containing X, Y and Z includes the following oxadiazoles, wherein any two of X, Y and Z represent a nitrogen atom and the other represents an oxygen atom.

(5a) (Sb) (5c)

In the above compounds (5a)-(5c), the left-hand side bonding site is attached to the benzene ring, and the right-hand side bonding site is attached to R ¹ .

In a preferred embodiment, the ring containing X, Y and Z comprises the following oxadiazoles:

N-O O-N

(5a) (5b)

In an embodiment, n is an integer of 0, 1 or 2; preferably 0 or 1. In a preferred embodiment, Q ¹ is fluorine, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine.

In a preferred embodiment, Q ² is (1) hydrogen, (2) fluoro, (3) chlorine, (4) bromine, (5) cyano, (6) C _1-3 alkyl which may be substituted with fluoro, or (7) C _1-3 alkoxy which may be substituted with fluoro.

In a more preferred embodiment, Q ² is (1) hydrogen, (2) fluorine, (3) chlorine, or (4) cyano.

Preferred compounds of formula (1) include the following compounds or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of the present invention of formula (1) comprises the following definition (A).

(A) A compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ has one of the following formulas (2) and (3):

- 10 048061

R ² and R ³ are the same or different and represent (1) C1. ₃ alkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C _3-6 cycloalkyl and C1. ₃ alkoxy, or (2) C _3-6 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl and C _1-3 alkoxy; or (3) R ² and R ³ are taken together with the carbon atom to which they are attached to form a C _3-6 cycloalkyl which may be substituted with from 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C _1-3 alkyl and C _1-3 alkoxy, or (4) R ² and R ³ are taken together with the carbon atom to which they are attached to form a C _4-6 saturated heterocyclic ring containing one or two heteroatoms independently selected from a nitrogen atom and an oxygen atom, wherein said saturated heterocyclic ring may be substituted with from 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C _1-3 alkyl and C _1-3 alkoxy, the ring containing X, Y and Z having one of the following formulae (5a) to (5c):

Q ¹ is fluorine, chlorine or bromine, and

Q ² is hydrogen, fluorine, chlorine, cyano, C _1-3 alkyl (which may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy), or C _1-3 alkoxy (which may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy).

In an embodiment, the compound of the present invention of formula (1) comprises the following definition (B).

(B) A compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ has the following formula (4):

R ⁴ and R ⁵ are the same or different and represent (1) hydrogen, (2) halogen, (3) hydroxy, (4) C1-3 alkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C _3-6 cycloalkyl and C _1-3 alkoxy, or (5) C _3-6 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1. ₃ alkyl and C1-3 alkoxy; or when R ⁴ and R ⁵ are attached to the same carbon atom or to two adjacent carbon atoms, respectively, (6) R ⁴ and R ⁵ may be taken together with the carbon atom(s) to which they are attached to form a C3-6 cycloalkyl which may be substituted with from 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-3 alkyl and C1-3 alkoxy, or (7) R ⁴ and R ⁵ may be taken together with the carbon atom(s) to which they are attached to form a C _4-6 saturated heterocyclic ring containing one or two heteroatoms independently selected from a nitrogen atom and an oxygen atom, wherein said saturated heterocyclic ring may be substituted with from 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C _1-3 alkyl and C _1-3 alkoxy, a ring containing X, Y and Z, has one of the following formulas (5a)-(5c):

- 11 048061

Q ¹ is fluorine, chlorine or bromine,

Q ² is hydrogen, fluorine, chlorine, cyano, C _1-3 alkyl (which may be substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy), or C _1-3 alkoxy (which may be substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl and C _1-3 alkoxy), and n is preferably an integer of 0, 1 or 2.

In an embodiment, the compound of the present invention of formula (1) comprises the following definition (C).

(C) A compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ has one of the following formulas (2) and (3) o O _4z O

A A A JsC

X nh ₂

^R2R3 ( ^{2)R2R3 ( 3} )

R ² and R ³ are the same or different and are (1) C _1-3 alkyl which may be substituted with fluorine; or (2) R ² and R ³ are taken together with the carbon atom to which they are attached to form a C _3-6 cycloalkyl which may be substituted with fluorine, or (3) R ² and R ³ are taken together with the carbon atom to which they are attached to form a C _4-6 saturated heterocyclic ring containing one or two heteroatoms independently selected from a nitrogen atom and an oxygen atom, wherein said saturated heterocyclic ring may be substituted with fluorine, the aryl ring containing X, Y and Z having the following formulae (5a) or (5b):

N-0 O-N .Τ' Ac Ac (5a) (5b)

Q ¹ is fluorine, chlorine or bromine, and Q ² is hydrogen, fluorine, chlorine or cyano.

In an embodiment, the compound of the present invention of formula (1) comprises the following definition (D).

(D) A compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ has the following formula (4):

Me Λν-Ν. R ⁴ -r, Λ ⁰ 7V)n (4)

R ^s

R ⁴ and R ⁵ are the same or different and represent (1) hydrogen, (2) fluoro, (3) hydroxy, (4) C _1-3 alkyl which may be substituted by fluoro, or (5) C _3-6 cycloalkyl which may be substituted by fluoro; or when R ⁴ and R ⁵ are attached to the same carbon atom or to two adjacent carbon atoms, respectively, (6) R ⁴ and R ⁵ may be taken together with the carbon atom(s) to which they are attached to form C3-6 cycloalkyl which may be substituted with from 1 to 3 substituents independently selected from the group consisting of fluoro and C _1-3 alkyl, the aryl ring containing X, Y and Z has the following formulae (5a) or (5b):

- 12 048061

N-0 O-N

(5a) (5b)

Q ¹ is fluorine, chlorine or bromine, and

Q ² is hydrogen, fluorine, chlorine or cyano.

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

Suitable salts of the starting materials and intermediates and suitable salts of the drug substances are conventional non-toxic salts. Suitable salt includes, for example, acid addition salts such as organic acid salts (including acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate and paratoluenesulfonate) and inorganic acid salts (including hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate); salts with amino acids (including arginine, aspartate and glutamate); metal salts such as alkali metal salts (including sodium salts and potassium salts) and alkaline earth metal salts (including calcium salts and magnesium salts); ammonium salts; organic base salts (including trimethylamine salts, triethylamine salts, pyridine salts, picolinates, dicyclohexylamine salts and N,N'-dibenzylethylenediamine salts; and other salts that a person skilled in the art may wish to select.

When it is necessary to obtain the compound of the present invention in the form of its salt, when the compound of the present invention is obtained in the form of a salt, it can be purified as such in the salt form, and when the compound is obtained in free form, it can be purified, dissolved or suspended in an appropriate organic solvent, and an acid or base can be added to the solution or suspension of the compound to form a salt in a conventional manner.

A compound of formula (1) in which one or more 1H atoms are replaced by ^2H (D) atoms is also included within the scope of the compound of the present invention of formula (1).

The present invention includes compounds of formula (1) or pharmaceutically acceptable salts thereof. Since the compound of the present invention may exist in the form of a hydrate and/or solvate of various solvents, including a solvate (ethanolate and other similar solvate), and these hydrate and/or solvate are included in the scope of the compound of the present invention. In addition, the present invention includes all tautomers of the compound of formula (1), all its possible stereoisomers, its crystalline forms in various states and mixtures thereof.

The compound of formula (1) includes optical isomers based on the optically active center, atropisomers based on axial or planar chirality due to the restriction of intramolecular rotation, and all other isomers that can exist as stereoisomers, tautomers and geometric isomers and mixtures thereof.

In particular, each optical isomer and atropisomer can be obtained as a racemate or as an optically active substance when an optically active starting material or intermediate is used. If necessary, the racemates of the respective starting materials, intermediates or final products can also be physically or chemically separated into optical enantiomers by a known separation method such as an optically active column method and a fractional crystallization method at an appropriate stage in the above-mentioned production processes. These enantiomer separation methods include a diastereomeric method in which, for example, a racemate is reacted with an optically active resolving agent to form two kinds of diastereomers, which are separated by fractional crystallization or the like due to differences in physical properties.

Methods for producing the compounds of the present invention are shown below, but these methods for producing the compound of the present invention do not limit the scope of the invention in any way.

- 13 048061

Method of obtaining 1.

With reference to the compound of formula (I), the compound of the following formula (Ia) can be obtained by the following production method.

Where R ² , R ³ , Q ¹ , Q ² , X, Y and Z are defined in paragraph 1.

The compound (Ia) can be obtained by amidating the compound (IIa) with ammonia. The amidation of the compound (IIa) can be carried out in a conventional manner. For example, the reaction can be carried out by converting the compound (IIa) into a reactive derivative (such as a lower alkyl ester, an activated ester, an acid anhydride and an acid halide) and reacting the obtained reactive derivative with ammonia. The activated ester includes, for example, p-nitrophenyl ester, N-hydroxysuccinimide ester and pentafluorophenyl ester. The acid anhydride includes, for example, a mixed anhydride of the compound (IIa) which is obtained with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid and the like. The solvent used here should be selected in consideration of the starting compound used and other factors, and includes, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, and isopropyl acetate. The solvent may be used alone or in combination with another solvent. The reaction temperature is not limited to a specific temperature, and is generally selected from a temperature range of -20°C to the boiling point of the solvent used, and is preferably 0°C to 30°C. The reaction time is generally 30 minutes to 24 hours.

In addition, the compound (Ia) can also be produced by reacting the compound (IIa) with an ammonium salt such as ( _NH4 ) _2CO3 in the presence of a condensing reagent. The condensing reagent used herein includes, for example, N, _{N'dicyclohexylcarbodiimide} , 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide monohydrochloride, N,N'carbonyldiimidazole and benzotriazol-1-yloxytris(pyrrolidino)-phosphonium hexafluorophosphate. These condensing reagents can be used alone or in combination with a peptide synthesizing reagent such as N-hydroxysuccinimide and N-hydroxybenzotriazole. The solvent used here should be selected in consideration of the starting compound used and other factors, and includes, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, and isopropyl acetate. The solvent may be used alone or in combination with another solvent. The reaction temperature is not limited to a specific temperature, and is generally selected from a temperature range of -20°C to the boiling point of the solvent used, and is preferably 0°C to 30°C. The reaction time is generally 30 minutes to 24 hours.

Method of obtaining 2.

With reference to the compound of formula (I), the compound of the following formula (1b) can be obtained by the following production method.

(lib) (ib)

Where R ² , R ³ , Q ¹ , Q ² , X, Y and Z are defined in paragraph 1;

P ¹ is a protecting group for the nitrogen atom, such as 2,4-dimethoxybenzyl group and p-methoxybenzyl group, which can be removed using acidic conditions; and

^P2 represents hydrogen or a protecting group for the nitrogen atom such as 2,4-dimethoxybenzyl group and p-methoxybenzyl group, which can be removed by using

- 14 048061 using acidic conditions.

The compound (Ib) can be obtained by removing the protecting group from the compound (IIb). The removal of the protecting group from the compound (IIb) can be carried out in a conventional manner. For example, the reaction of removing the protecting group can be carried out by reacting the compound (IIb) with a strong organic acid such as trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid, or with a strong inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid.

The deprotection of the compound (IIb) can be carried out in a solvent or in the absence of solvents. The solvent used here should be selected taking into account the starting compound used and other factors, and the solvent includes, for example, toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, acetonitrile, DMF and DMSO. The solvent can be used as the sole solvent or in combination with another solvent. As the protecting group for the nitrogen atom in the compound (IIb), in addition to the 2,4-dimethoxybenzyl group, tert-butoxycarbonyl group, tert-butyl group, p-methoxybenzyl group and the like can also be used, which can be removed by using acidic conditions. Depending on the type of the protecting group, only one protecting group can be selected to protect the nitrogen atom. The reaction temperature may vary depending on the starting compound and other factors, and it is usually from about -30°C to about 150°C, and preferably from about -10°C to about 70°C. The reaction time is usually from 30 minutes to 24 hours.

Method of obtaining 3.

With reference to the compound of formula (I), the compound of the following formula (1c) can be obtained by the following production method.

(PS) (1s)

Where R ⁴ , R ⁵ , Q ¹ , Q ² , X, Y, Z and n are defined in paragraph 1.

The compound (Ic) can be obtained by methylating the compound (IIc). The methylation of the compound (IIc) can be carried out in a conventional manner. For example, the methylation reaction can be carried out by reacting the compound (IIc) with a methylating reagent such as methyl iodide, methyl bromide and dimethyl sulfate in the presence of a base in an appropriate solvent. The solvent used here should be selected in consideration of the starting material used and other factors, and the solvent includes, for example, toluene, THF, dioxane, DME, ethyl acetate, isopropyl acetate, acetone, acetonitrile, DMF and NMP. The solvent can be used alone or in combination with another solvent. The base used includes, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as potassium tert-butoxide and sodium methoxide; and alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate and cesium carbonate. The reaction temperature may vary depending on the starting compound and other factors, and is usually about -30°C to about 150°C, and preferably about -10°C to about 70°C. The reaction time is usually 30 minutes to 24 hours.

The compounds of formulas (Ia), (Ib) and (Ic), which are obtained by the above methods for preparing 1, 2 and 3, can be isolated and purified by a conventional method such as chromatography and recrystallization.

The starting compounds used in the above methods for preparing 1, 2 and 3 can be prepared by the methods mentioned below.

Method of obtaining 4.

With reference to the compound of formula (I), the compound of the following formula (1c') can also be obtained by the following production method.

- 15 048061

Where R ⁴ , R ⁵ , Q ¹ , Q ² and n are defined in paragraph 1.

Compound (Ic') can be obtained by reacting compound (IIcl') and compound (IIc2') in the presence of a condensing reagent. The condensing reagent used herein includes, for example, NI-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide monohydrochloride, NI-carbonyldiimidazole, benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triα-zolo[4,5-b]pyrimidinium 3-oxide hexafluorophosphate, 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate, 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate, bromotris(pyrrolidino)phosphonium hexafluorophosphate and propylphosphonic anhydride. These condensing reagents can be used singly or in combination with a peptide synthesizing reagent such as N-hydroxysuccinimide and N-hydroxybenzotriazole. The solvent used here should be selected in consideration of the starting compound used and other factors, and includes, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, ethyl acetate and isopropyl acetate. The solvent can be used as a sole solvent or in combination with another solvent. The reaction temperature may vary depending on the starting compound and other factors, and it is usually about -100°C to about 200°C, and preferably -30°C to 150°C. The reaction time is usually 30 minutes to 24 hours.

Method of obtaining 5.

Compound (IIa), which is used in the above-described method for producing 1, can be obtained according to the method shown in the following scheme.

O O

(IVa) (Illa)

ABOUT

(On)

Where ^R2 , ^R3 , ^Q1 , ^Q2 , X, Y and Z are defined in paragraph 1, and R is _C1-6 alkyl.

Stage 1.

Compound (IIIa) can be obtained by alkylating compound (IVa). The alkylation in step 1 can be carried out in a conventional manner. For example, the reaction can be carried out by reacting compound (IVa) with an alkyl halide or cycloalkyl halide, which are represented by R ² X or R ³ X, in the presence of a base in an appropriate solvent. Compound (IIIa), wherein R ² and R ³ are taken together with the carbon atom to which they are attached to form C _3-6 cycloalkyl or a 4- to 6-membered saturated heterocyclic ring, can be obtained by reacting compound (IVa) with a corresponding dihalogenated compound (e.g., X-(CH ₂ ) _n -X, where n is an integer from 3 to 6, and X is halogen) under the above-described reaction conditions. The solvent used herein should be selected taking into account the starting compound used and other factors, and includes, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, ethyl acetate, and isopropyl acetate. The solvent can be used alone or in combination with another solvent. The base used herein includes, for example, alkali metal hydroxides such as hydroxide

- 16 048061 sodium, potassium hydroxide and lithium hydroxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides 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 may vary depending on the starting compound and other factors, and is usually from 0°C to 200°C, and preferably from 20°C to 150°C. The reaction time is usually from 30 minutes to 24 hours.

Stage 2.

The compound (IIa) can be obtained by hydrolyzing the compound (IIIa). The hydrolysis in step 2 can be carried out in a conventional manner. For example, the reaction can be carried out by treating the compound (IIIa) with water under acidic or basic conditions in an appropriate solvent. The solvent used herein should be selected in consideration of the starting material used and other factors, and the solvent includes, for example, THF, dioxane, DME, acetone, acetonitrile, DMF, DMSO, methanol, ethanol, isopropanol and water. The solvent can be used alone or in combination with another solvent. The acid used herein includes, for example, a mineral acid such as hydrochloric acid and sulfuric acid. The base used herein includes, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal alkoxides such as potassium tert-butoxide; and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate. The reaction temperature may vary depending on the starting compound and other factors, and it is usually 0°C to 150°C, and preferably 20°C to 100°C. The reaction time is usually 30 minutes. Method 6.

With reference to the compound (IIIa) used in the above-described production method 5, a compound of the following formula (IIIa') can be obtained by carrying out a condensation reaction accompanied by a dehydration reaction and cyclization of the compound (IIIa1) and the compound (IIIa2).

Where R ² , R ³ , Q ¹ and Q ² are defined in paragraph 1, and R is C _1-6 alkyl.

The condensation reaction accompanied by the dehydration and cyclization reaction of the compound (IIIa1) and the compound (IIIa2) can be carried out in a conventional manner. For example, the reaction can be carried out by converting the compound (IIIa2) into a reactive derivative (such as an alkyl ester, an activated ester, an acid anhydride, and an acid halide), and then reacting the resulting reactive derivative with the compound (IIIa1). The active ester includes, for example, p-nitrophenyl ester, N-hydroxysuccinimide ester, and pentafluorophenyl ester. The acid anhydride includes, for example, a mixed anhydride derived from ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid, and the like. The solvent used here should be selected in consideration of the starting compound used and other factors, and includes, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, and ethers such as ethyl acetate, isopropyl acetate. The solvent may be used alone or in combination with another solvent. The reaction temperature may vary depending on the starting compound and other factors, and is usually from -100°C to 200°C, and preferably from -30°C to 150°C. The reaction time is usually from 30 minutes to 24 hours.

In addition, the compound (IIIa') can also be obtained by reacting the compound (IIIa1) and the compound (IIIa2) in the presence of a condensing reagent. The condensing reagent used herein includes, for example, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide monohydrochloride, N,N'-carbonyldiimidazole and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate. These condensing reagents can be used individually or in combination with a peptide synthesizing reagent such as N-hydroxysuccinimide and N-hydroxybenzotriazole. The solvent used here should be selected in consideration of the starting compound used and other factors, and includes, for example, THF, dioxane, DME, acetonitrile, DMF, toluene, pyridine, ethyl acetate and isopropyl acetate. The solvent may be used alone or in combination with another solvent. The reaction temperature may vary depending on the starting compound and other factors, and it is usually from -100°C to 200°C, and preferably from -30°C.

- 17 048061 up to 150°C. The reaction time is usually from 30 minutes to 24 hours.

Method of obtaining 7.

With reference to the compound (IVa) used in the above-described production method 5, a compound of the following formula (IVa') can be obtained by carrying out a condensation reaction accompanied by a dehydration reaction and cyclization of the compound (IVa1) and the compound (IVa2).

Where Q ¹ and Q ² are defined in paragraph 1, and R is C _1-6 alkyl.

Compound (IVa') can be obtained from compound (IVa1) and compound (IVa2) according to the production method 6.

Method of obtaining 8.

With reference to the compound (IVa) used in the above-described production method 5, a compound of the following formula (IVa) can be obtained by carrying out a condensation reaction accompanied by a dehydration reaction and cyclization of the compound (IVa3) and the compound (IVa4).

Where Q ¹ and Q ² are defined in paragraph 1, and R is C _1-6 alkyl.

Compound (IVa) can be obtained from compound (IVa3) and compound (IVa4) according to the production method 6.

Method of obtaining 9.

With reference to the compound (IVa) used in the above-described production method 5, a compound of the following formula (IVa''') can be obtained by carrying out a condensation reaction accompanied by a dehydration reaction and cyclization of the compound (IVa5) and the compound (IVa6).

Where Q ¹ and Q ² are defined in paragraph 1, and R is C _1-6 alkyl.

Compound (IVa') can be obtained from compound (IVa5) and compound (IVa6) according to Production Method 6. The preparation of 1,3,4-oxadiazole ring subjected to dehydration and cyclization reaction can be carried out in the joint presence of a dehydrating reagent such as phosphorus oxychloride and Burgess reagent as an additive.

Method of obtaining 10.

Compound (IIb), which is used in the above-described method for producing 2, can be prepared by the method shown in the following scheme.

- 18 048061

(lllb) (lib)

Where R ² , R ³ , Q ¹ , Q ² , X, Y and Z are defined in paragraph 1;

P ¹ is a protecting group for the nitrogen atom, such as 2,4-dimethoxybenzyl group and p-methoxybenzyl group, which can be removed using acidic conditions; and

^P2 represents hydrogen or a protecting group for the nitrogen atom such as 2,4-dimethoxybenzyl group and p-methoxybenzyl group, which can be removed using acidic conditions.

Stage 1.

The compound (IVb) can be obtained by reacting the compound (Vb) with sodium sulfite. The substitution reaction in step 1 can be carried out in a conventional manner. For example, the reaction can be carried out by treating the compound (Vb) with sodium sulfite in a suitable solvent. The solvent used here should be selected in consideration of the starting compound used and other factors, and the solvent includes, for example, ethers such as _Et2O , THF, dioxane and DME; alcohols such as methanol, ethanol and isopropyl alcohol; and toluene. The solvent can be used alone or in combination with another solvent. The reaction temperature may vary depending on the starting compound and other factors, and it is usually from -100°C to 200°C, and preferably from 0°C to 150°C. The reaction time is usually from 30 minutes to 24 hours.

Stage 2.

The compound (IIIb) can be obtained by sulfonamidation of the compound (IVb). The sulfonamidation in step 2 can be carried out in a conventional manner. For example, the reaction can be carried out by converting the compound (IVb) into a sulfonyl chloride compound and then reacting the obtained compound with an amine compound. The conversion into a sulfonyl chloride compound can be carried out using phosphorus oxychloride in a solvent or in the absence of solvents. The solvent used here should be selected in consideration of the starting compound used and other factors, and the solvent includes, for example, Et ₂ O, THF, dioxane, DME and toluene. The solvent may be used alone or in combination with another solvent. The reaction temperature may vary depending on the starting compound and other factors, and it is usually from -100°C to 200°C, and preferably from 0°C to 150°C. The reaction time usually ranges from 30 minutes to 24 hours.

The conversion of a sulfonyl chloride compound, which is an intermediate compound in step 2, into a corresponding sulfonamide compound can be carried out in the presence or absence of a base in a solvent with ^NHP'P2 , which is an amine compound mono- or disubstituted by a protecting group which can be removed by using acidic conditions. The solvent used herein should be selected in consideration of the starting material used and other factors, and the solvent includes, for example, _Et2O , THF, dioxane, DME, DMF, acetonitrile and toluene. The solvent can be used alone or in combination with another solvent. The base used herein includes, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal alkoxides such as potassium tert-butoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; and organic bases such as triethylamine, MX-diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine and 4-dimethylaminopyridine. The reaction temperature may vary depending on the starting compound and other factors, and is usually -100°C to 200°C, and preferably 0°C to 150°C. The reaction time is usually 30 minutes to 24 hours.

- 19 048061

Stage 3.

Compound (IIb) can be obtained by alkylating compound (IIIb). Compound (IIb) can be obtained from compound (IIIb) according to Production Method 5, Step 1.

Method of obtaining 11.

With reference to the compound (Vb) which is used in the above-described production method 10, the compound of the following formula (Vb') can be obtained by carrying out a condensation-cyclodehydration reaction of the compound (Vb1) and the compound (Vb2).

(Vb1) (Vb2) (Vb')

Where Q ¹ and Q ² are defined in paragraph 1.

Compound (Vb') can be obtained from compound (Vb1) and compound (Vb2) according to the production method 6.

Method of obtaining 12.

With reference to the compound (Vb) used in the above-described production method 10, a compound of the following formula (Vb) can be obtained by carrying out a condensation reaction accompanied by a dehydration and cyclization reaction of the compound (Vb3) and the compound (Vb4).

(Vb3) (Vb4) (Vb)

Where Q ¹ and Q ² are defined in paragraph 1.

Compound (Vb) can be obtained from compound (Vb3) and compound (Vb4) according to the production method 6.

Method of obtaining 13.

With reference to the compound (Vb) which is used in the above-described production method of 10, a compound of the following formula (Vb''') can be obtained by carrying out a condensation reaction accompanied by a dehydration and cyclization reaction of the compound (Vb5) and the compound (Vb6).

Where Q ¹ and Q ² are defined in paragraph 1.

Compound (Vb') can be obtained from compound (Vb5) and compound (Vb6) according to the production method 9.

Method of obtaining 14.

With reference to the compound (IIc) used in the above-described production method 3, a compound of the following formula (IIc') can be obtained by carrying out a condensation reaction accompanied by a dehydration and cyclization reaction of compound (IIc1) and compound (IIc2).

(lid) (Нс2) (НС)

Where R ⁴ , R ⁵ , Q ¹ , Q ² and n are defined in paragraph 1.

Compound (IIc') can be obtained from compound (IIc1) and compound (IIc2) according to the production method 6.

- 20 048061

Method of obtaining 15.

With reference to the compound (IIc) used in the above-described production method 3, a compound of the following formula (IIc) can be obtained by carrying out a condensation reaction accompanied by a dehydration and cyclization reaction of the compound (IIc3) and the compound (IIc4).

Where R ⁴ , R ⁵ , Q ¹ , Q ² and n are defined in paragraph 1.

Compound (IIc) can be obtained from compound (IIc3) and compound (IIc4) according to the preparation method 6.

Method of obtaining 16.

With reference to the compound (IIc) used in the above-described production method 3, a compound of the following formula (IIc''') can be obtained by carrying out a condensation reaction accompanied by a dehydration and cyclization reaction of compound (IIc5) and compound (IIc6).

(NS5) (NSb) (NS)

Where R ⁴ , R ⁵ , Q ¹ , Q ² and n are defined in paragraph 1.

Compound (IIc') can be obtained from compound (IIc5) and compound (IIc6) according to the production method 9.

The compounds of the present invention of formula (1) and their intermediates can be isolated and purified by a method well known to a person skilled in the art. This method includes, for example, extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography and preparative liquid chromatography), and recrystallization.

The solvent used here for the recrystallization includes, for example, an alcohol solvent such as methanol, ethanol and 2-propanol; an ether solvent such as diethyl ether; an ester solvent such as ethyl acetate; an aromatic hydrocarbon solvent such as benzene and toluene; a ketone solvent such as acetone; a halogenated solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane; an aprotic solvent such as dimethylformamide and acetonitrile; water and a mixed solvent. As for other purification methods, for example, methods described in Experimental Chemistry Publication Series, Volume 1 or other volumes (Jikken Kagaku Kouza, edited by the Chemical Society of Japan, issued by MARUZEN) can be used. And the structure of the compounds of the present invention can be easily determined by a spectral analysis method such as a nuclear magnetic resonance method, an infrared absorption method and a circular dichroism spectroscopy method, and a mass spectrometry method, taking into account the structure of each starting compound.

In addition, if necessary, each intermediate compound or each final product in the above-described production methods can also be converted into another compound of the present invention by appropriately modifying their functional group, namely, lengthening various side chains on the side of amine, hydroxy, carbonyl, halogen, etc.; and by optionally installing the above-mentioned protective groups and removing them. The modification of the functional group and the lengthening of the side chain can be carried out in a conventional manner (for example, see the monograph Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999), etc.).

The compounds of the present invention of formula (1) or a pharmaceutically acceptable salt thereof are sometimes asymmetric compounds or sometimes have a substituent comprising an asymmetric carbon atom. In this case, the compounds have optical isomers. The compounds of the present invention include a mixture of these isomers and an individual isomer which can be obtained by a conventional method. The compounds having an asymmetric structure can be obtained, for example, by using a starting material having an asymmetric center or by introducing

- 21 048061 the formation of an asymmetric structure at any stage of the process. For example, in the case of optical isomers, the optical isomers can be obtained by using an optically active starting material or by separating a mixture of optical isomers at an appropriate stage. In the case where the compound of formula (1) or an intermediate thereof has a functional group with basic properties, its optical resolution includes, for example, a diastereomeric method where the compound is converted into a salt thereof by reaction with an optically active acid (for example, a monocarboxylic acid such as mandelic acid, N-benzyloxyalanine and lactic acid; a dicarboxylic acid such as tartaric acid, o-diisopropylidene tartaric acid and malic acid; or a sulfonic acid such as camphorsulfonic acid and bromocamphorsulfonic acid) in inert solvents (for example, alcohols such as methanol, ethanol and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; a hydrocarbon solvent such as toluene; an aprotic solvent such as acetonitrile; or a mixture of solvents). In the case where the compound of formula (1) or an intermediate thereof has a functional group with acidic properties, such as a carboxyl group, the compound can also be optically resolved by forming a salt thereof with an optically active amine (for example, an organic amine such as 1-phenylethylamine, kinine, quinidine, cinchonidine, cinchonine and strychnine).

The temperature for forming the salt is usually selected in the range of -50°C to the boiling point of the solvent used in the specific case, preferably from 0°C to the boiling point, and more preferably from room temperature to the boiling point. In order to increase the optical purity, it is desirable to increase the temperature to about the boiling point of the solvent used in the specific case. When collecting the precipitated crystals on a filter, optimal cooling can lead to an increase in the yield. A suitable amount of the optically active acid or amine used is about 0.5 to about 2.0 equivalents relative to the amount of the compound, preferably about one equivalent. In an appropriate case, the obtained crystal can be recrystallized in an inert solvent (for example, an alcohol such as methanol, ethanol and 2-propanol; an ether solvent such as diethyl ether; an ester solvent such as ethyl acetate; a hydrocarbon solvent such as toluene; an aprotic solvent such as acetonitrile; or a mixture of solvents) to obtain a highly pure salt thereof. And, in an appropriate case, the optically resolved salt can also be treated with an acid or a base to obtain a free form of the compound.

Among the starting materials and intermediate compounds in each of the above-mentioned production methods, compounds that are not described in each method are commercially available or can be obtained by a person skilled in the art from a commercially available material by a known method or a method similar thereto.

The novel oxadiazole derivative of the present invention has an anticonvulsant effect and a potentiating effect on GABA receptors (activation of the GABAergic system), due to which this derivative can be used as a drug for the treatment or prevention of diseases associated with hypofunction of the GABAergic system. In addition, the novel oxadiazole derivative of the present invention has a potentiating effect on GABA receptors and/or an effect of enhancing inhibition (I) in the balance of excitation (E) and inhibition (I) (E/I balance), due to which this derivative can be used as a drug for the treatment or prevention of a neurological disease or a mental disease. Neurological disorder or mental disorder includes epilepsy such as seizure disorder (tonic seizure, clonic seizure, petit mal seizure, myoclonic seizure, generalized seizure including atonic seizure, focal seizure, seizure of unknown etiology), state epilepticus, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy associated with hippocampal sclerosis, which is a clearly identifiable symptom, and Rasmussen syndrome; neuropathic pain; developmental disorder; autism; bipolar disorder; schizophrenia; Alzheimer's disease and other types of dementia; amyotrophic lateral sclerosis; Parkinson's disease; depressive symptom, with or without epilepsy; anxiety disorder; obsessive-compulsive disorder; and REM sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies. The novel oxadiazole derivative of the present invention can be preferably used as a drug for the treatment or prevention of epilepsy, such as epileptic seizure (tonic seizures, clonic seizures, petit mal seizure, myoclonic seizures, generalized seizure including atonic seizures, focal seizure, seizure of unknown etiology), epileptic condition, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), mesial temporal lobe epilepsy associated with hippocampal sclerosis, which is precisely identified

- 22 048061 cited symptom, and Rasmussen's syndrome.

In the present invention, prevention means that the active ingredient of the present invention is administered to a healthy subject who does not suffer from a disease, and, for example, said purpose of administration is to prevent the onset of the disease. Treatment means that the active ingredient of the present invention is administered to a subject who has been diagnosed with a disease by a physician (i.e., a patient). Administration of the active ingredient to a patient suffering from a disease for the purpose of blocking a seizure associated with the disease refers to the term prevention or the term treatment.

The novel oxadiazole derivative of the present invention has a potentiating effect on GABA receptors and/or an effect of enhancing inhibition (I) in the balance of excitation (E) and inhibition (I) (E/I balance), whereby this derivative can be used as a medicine for the treatment or prevention of a neurological disease or a mental disease.

In addition, the novel oxadiazole derivative of the present invention can be used as a medicine for treating or preventing a disease in which excitation (E) is increased and/or inhibition (I) is decreased in the E/I balance.

Neurological disorder or mental illness includes epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar and related disorders, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's disease, depressive disorder, anxiety disorders, obsessive-compulsive disorder, trauma-related and stress-related disorders, sleep-wake cycle disorders, and/or REM sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies.

The new oxadiazole derivative of the present invention has an anticonvulsant effect and a potentiating effect on GABA receptors (activation of the GABA-ergic system), due to which this derivative can be used as a drug for the treatment or prevention of diseases associated with hypofunction of the GABA-ergic system.

Disorders associated with hypofunction of the GABAergic system include epilepsy, neuropathic pain, neurodevelopmental disorders, bipolar and related disorders, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndrome, anxiety disorders, obsessive-compulsive disorder, trauma-related and stress-related disorders, sleep-wake cycle disorders, and/or REM sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies.

Epilepsy includes, for example, epileptic seizure (tonic seizures, clonic seizures, petit mal seizure, myoclonic seizures, generalized seizure including atonic seizures, focal epileptic seizure, seizure of unknown etiology), epileptic condition, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Angelman syndrome, tuberous sclerosis, mesial temporal lobe epilepsy associated with hippocampal sclerosis, which is a clearly identifiable symptom, and/or Rasmussen syndrome. The present invention can be advantageously used in the treatment of, in particular, Dravet syndrome, Lennox-Gastaut syndrome and/or Angelman syndrome.

Depressive syndrome includes, for example, depressive disorders with anxiety disorder, depressive disorders with mixed features, depressive disorders with melancholia features, depressive disorders with atypical features, depressive disorders with mood-congruent psychopathic features, depressive disorders with mood-discongruent psychopathic features, depressive disorders with catatonic syndrome, postpartum depression, seasonal depressive disorder, disruptive mood dysregulation disorder, depression/major depressive disorder, persistent depressive disorder, premenstrual dysphoric disorder, substance/drug-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and/or unspecified depressive disorder. In particular, the present invention is preferably used for depression/major depressive disorder.

Anxiety disorders include, for example, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attack, fear of open spaces, generalized anxiety disorder, substance/drug-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and/or unspecified depressive disorder.

Bipolar or related disorders include, for example, bipolar I disorder, bipolar II disorder, substance-induced cyclothymic disorder, and schizophrenia.

- 23 048061 vom/drug bipolar disorder and related disorders, bipolar disorder and related disorders due to another medical condition, other established bipolar disorder and related disorders and/or unspecified bipolar disorder and related disorders. These disorders additionally include a depressive symptom, a depressive state or an anxiety symptom that is associated with the above-mentioned bipolar and related disorders.

In the present invention, prevention means that the active ingredient of the present invention is administered to a healthy subject who does not suffer from a disease, and, for example, said purpose of administration is to prevent the onset of the disease. Treatment means that the active ingredient of the present invention is administered to a subject who has been diagnosed with a disease by a physician (i.e., a patient). Administration of the active ingredient to a patient suffering from a disease for the purpose of blocking a seizure associated with the disease refers to the term prevention or the term treatment.

The compounds of the present invention can be administered orally, parenterally or rectally, and the daily dose may vary depending on the compound, the route of administration, the condition/age of the patient and other factors. For oral administration, for example, the compounds of the present invention can be administered generally at a dose of about 0.01 to 1000 mg, preferably about 0.1 to 500 mg per day per kilogram of body weight of a human or mammal, and from one to several times. For parenteral administration such as intravenous injection, for example, the compounds of the present invention can be administered generally at a dose of about 0.01 to 300 mg, preferably about 1 to 100 mg per day per kilogram of body weight of a human or mammal.

The compounds of the present invention can be administered orally or parenterally, alone or in a suitable dosage form containing them. Their dosage form can be, for example, a tablet, a capsule, a powder, a granule, a liquid suspension, an injection, a patch, a gel patch and other similar forms, but these forms are not limitations for the invention. The dosage form can be prepared together with pharmaceutically acceptable additives by known methods.

The additives can be selected based on achieving any purpose, and they include an auxiliary substance, a disintegrant, a binder, a fluidizing agent, a lubricant, a coating agent, a solubilizer, a solubilizing agent, a thickener, a dispersant, a stabilizer, a sweetener, a substance correcting the taste and smell of the drug and other similar additives. In particular, they include, for example, lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, calcium carmellose, sodium croscarmellose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc and other similar additives.

The compounds of the present invention can be used in combination with at least one other drug selected from drugs belonging to an antiepileptic drug, an antidepressant or a neuroleptic drug. In this case, the combination with another drug means that the other drug is prepared separately from the compound of the present invention, and the dosage form containing the other drug can be administered to a subject simultaneously with the dosage form including the compound of the present invention or at an interval with the dosage form including the compound of the present invention. The drug belonging to an antiepileptic drug includes, for example, phenytoin, valproic acid, carbamazepine, lamotrigine, topiramate and other agents that can inhibit sodium channels; ethosuximide, zonisamide and other agents that can inhibit calcium channels; perampanel, which may inhibit the AMPA receptor; benzodiazepine, which may enhance the activity of the GABAergic system (such as diazepam, clonazepam, and clobazam); barbiturate (such as phenobarbital); gabapentin; and vigabatrin. The drug belonging to the antidepressant includes, for example, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and other similar agents, which are referred to as selective serotonin reuptake inhibitors (SSRIs); duloxetine, milnacipran and other similar agents, which are referred to as selective serotonin-norepinephrine reuptake inhibitors (SNRIs); and imipramine, amitriptyline, clomipramine, amoxapine and other similar agents, which are referred to as tricyclic antidepressants. The drug belonging to neuroleptic drugs includes, for example, haloperidol, spiperone, chlorpromazine and other similar drugs, which are classified as typical antipsychotic drugs; and risperidone, quetiapine, olanzapine, clozapine, perospirone, aripiprazole and other similar drugs, which are classified as serotonin and dopamine antagonists (SDA).

- 24 048061

Examples

Reference examples, examples and tests are given below to explain the present invention in more detail, but they do not limit the scope of the invention in any way. The names of the compounds used in the invention are not always based on the IUPAC nomenclature system.

For the purpose of simplifying the description, the following conventional abbreviations may sometimes be used in the Reference Examples, Examples, and Tables in Examples. Me: methyl, Ph: phenyl, THF: tetrahydrofuran, DMF: NH-dimethylformamide. DME: 1,2-dimethoxyethane, DMSO: dimethyl sulfoxide, TFA: trifluoroacetic acid, MeCN: acetonitrile, n-: normal-, t-: tert-. The symbols used in NMR are defined as follows, s: singlet, d: doublet, dd: doublet of doublet, t: triplet, td: triplet of doublet, q: quartet, m: multiplet, br: broad, brs: broadened singlet, brm: broadened multiplet, and J: coupling constant.

Liquid chromatography with mass spectrometry. The analytical conditions for LC/MS are given below. The observed mass spectrum value [MS(m/z)] is presented in MH ⁺ , and the retention time is presented as Rt (minutes).

Device: Waters ACQUITYTM UltraPerformance LC.

Column: ACQUITY UPLC VEN C18 1.7 µm 2.1x30 mm.

Solvent: A: 0.05% HCOOH/ _H2O , B: _CH3CN .

Conditions for carrying out gradient elution: 0.0-1.3 minutes; A/B=90/10-5/95 (linear gradient) 1.3-1.5 minutes; A/B=90/10.

Flow rate: 0.80 ml/min.

UV: 220 nm, 254 nm.

Column temperature: 40°C.

Reference example 1. Ethyl 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]cyclobutane-1-carboxylate.

To cyclobutane-1,1-dicarboxylic acid monoethyl ester (100 mg) was added thionyl chloride (93 μl), and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was azeotropically dried with toluene to give ethyl 1-(chlorocarbonyl)cyclobutane-1-carboxylate as an oil. The oil product was dissolved in acetone (2.64 ml). To the solution were added 4-chlorobenzamidoxime (90 mg) and potassium carbonate (109 mg), and the mixture was stirred at 50°C for one hour. The solid in the reaction mixture was removed by filtration, and the filtrate was concentrated. The residue was dissolved in toluene (2.64 ml), and the solution was heated under reflux for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 6:1) to give the compound of Reference Example 1 (138 mg) as a solid.

1H NMR ( _CDCl3 ) δ: 1.25 (t, 3H), 2.08-2.23 (m, 2H), 2.76-2.84 (m, 2H), 2.86-2.94 (m, 2H), 4.24 (q, 2H), 7.45-7.48 (m, 2H), 8.04-8.07 (m, 2H).

Reference examples 2-11.

Each compound listed in Table 1 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 1.

- 25 048061

Table 1 Reference example Structure Reference example Structure 2 f A 3 О )^~ОМе Г ¹ С Η о jfy ⁿ h ₃ c ³ 4 O J^-OMe If y ^N H ₃ C ⁵ Br-X^ 5 π 4-7 ξ/ν ⁰ o s η 6 O N-O'^-OMe yy^N 7 H ₃ C η )~ ^CH 3 Ν-Ο Α- _ο ³ 1' y—X. F 8 F 9 10 X ϋ X J f ° οχΐ O^z 'Ь 11 0 Ho W _C |>X ^CH 3

Reference example 12.

Ethyl 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]acetate.

To a solution of ethyl 3-(hydroxyamino)-3-iminopropionate (4.00 g) in pyridine (40 ml) was added 4-chlorobenzoyl chloride (3.48 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was then stirred at 90°C for 20 hours, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 10% aqueous citric acid solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed from the solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate; 2:1) to give the compound of Reference Example 12 (4.60 g) as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (t, 3H), 3.86 (s, 2H), 4.23 (q, 2H), 7.49 (d, 2H), 8.05 (d, 2H).

Reference examples 13-14.

Each compound listed in Table 2 was prepared from each corresponding starting material by carrying out a reaction and treatment similar to that in the method described in Reference Example 12.

Table 2 Reference example Structure Reference example Structure 13 F ON Vr™ ³ •^y^N 14 ί VG η X o h, 0*4

- 26 048061

Reference example 15.

Ethyl 2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]acetate.

To a suspension of 4-chlorobenzhydrazide (500 mg) and ethyl malonyl chloride (0.37 ml) in THF (10 ml) was added triethylamine (0.86 ml), and the mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (10 ml), and Burgess reagent (154 g) was added to the solution. The mixture was refluxed for 6 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to give the compound of Reference Example 15 (598 mg) as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (t, 3H), 4.01 (s, 2H), 4.23 (q, 2H), 7.45-750 (m, 2H), 7.96-7.99 (m, 2H).

Reference example 16.

The compound of Reference Example 16 was obtained from the corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 15.

Reference example 17.

Ethyl 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]-2-methylpropanoate.

To a solution of the compound of Reference Example 12 (1.60 g) in DMF (16 ml) were added cesium carbonate (7.82 g) and methyl iodide (1.12 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 brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 9:1) to give the compound of Reference Example 17 (1.11 g) as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (t, 3H), 1.67 (s, 6H), 4.17 (q, 2H), 7.47-750 (m, 2H), 8.04-8.07 (m, 2H).

Reference examples 18-21.

Each compound shown in Table 3 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 17.

Table 3 Reference example Structure Reference example Structure 18 Jl F ON><T ^CHl V ^N ^A ^CHi 19 if In g ON A<C ^CH = Ϋν ¹ · 20 With g Ά° ζ O O = ы 21 jf Вг^ 7=z “°А° ^Χ °Ί О Ζ ω

- 27 048061

Reference example 22.

2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanoic acid.

To a solution of the compound of Reference Example 3 (3.10 g) in methanol (20 ml) was added 5 mol/L aqueous sodium hydroxide solution (7.3 ml), and the mixture was heated under reflux for 6 hours. The reaction solution was cooled to room temperature, and then 10% aqueous citric acid solution was added to the solution to adjust the pH value to pH 4. The solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the compound of Reference Example 22 (2.89 g) as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.78 (s, 6H), 7.42-7.46 (m, 2H), 8.00-8.03 (m, 2H).

Reference examples 23-37.

Each compound shown in Table 4 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 22.

Table 4 Reference book Structure Reference example) Structure 23 O N-CI^-OH n ₃ with ^CH3 24 O jfU ^N H ₃ c ^CH ' 25 O ^N '°\ A° ⁿ jj y—z F'^X 26 O NO. $-ОН _ 1'</—к jfj **я ^> 27 0 NO. D-OH _F 28 O ^N '°\ Mr. xGYA, F 29 0 N-0 D-OH 30 O N-θ >-on 31 o N-0 D- _0N X 32 about N-°. 'VoH 33 0 °'NV _0H rV^ ^N HC ^CH3 J| J n ₃ c F^U 34 O O-NvJ^-OH jfy ^N n ₃ c ³ 35 s ъ co 36 O jfy °H ₃ C ³ 37 0 JXh° ^H jT J °H ₃ C ³

- 28 048061

Reference example 38.

Sodium [3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]methanesulfonate.

To a solution of 3-(4-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (1.35 g) in ethanol (5 ml) was added a solution of sodium sulfite (0.62 g) in water (5 ml), and the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure to give the compound of Reference Example 38 (2.04 g) as a solid.

MS (m/z) 317 (MNa ^- ), Rt=0.52 min.

Reference examples 39-45.

Each compound shown in Table 5 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 38.

Table 5 Reference example Structure Reference example Structure 39 N-θ 'S-ONa 11 40 η°-? Ν- ⁰ . 'S-ONa _ 1' jfj ^Ν 41 o.9 O-N__'S-ONa 42 0.9 Ο-Ν JS-ONa ίΥ ^Ν 43 O..9 NN 'S-ONa jl Ό—/ jPj ⁰ 44 ο.,9 N-N 'S-ONa ji ρ—У jTj ° 45 o.,9 N'N 'S-ONa ji 'Y—/ °

Reference example 46.

1-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]^A-bis(2,4-dimethoxybenzyl)methanesulfonamide.

To the compound of Reference Example 38 (1.68 g) was added phosphorus oxychloride (225 ml), and the mixture was heated under reflux for 5 hours and then concentrated under reduced pressure. The residue was dissolved in THF (20 ml), and the solution was added dropwise to a solution of bis(2,4-dimethoxybenzyl)amine (156 g), triethylamine (2.75 ml), and 4-dimethylaminopyridine (0.06 g) in THF (20 ml). The solution was stirred at room temperature overnight. The reaction solution was diluted with 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed at low

- 29 048061 at reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to give the compound of Reference Example 46 (1.32 g) as an amorphous substance.

Ή-NMR (CDCl ₃ ) δ: 3.78 (s, 12H), 4.38 (s, 2H), 4.38 (s, 4H), 6.43-6.46 (m, 4H), 7 .20 (d, 2H), 758-7.61 (m, 2H), 7.89-7.93 (m, 2H).

Reference examples 47-53.

Each compound shown in Table 6 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 46.

Table b Reference example Structure Reference example Structure 47 ч.ъ * ? Ь-о w I 48 O h Λ TA if ы θ P l I ^υ- ο ы I w 49 n ₃ s*°^— ? ^NZ ο,θ Ο-Ν_>- ^Ν ~, An A ^o ' ^{s n} z P J f and sk ^7 °'CH ₃ 50 n ₃ с-°х__ 9 ⁿ s oA° rL ^CH2 °'CH ₃ 51 N ₃ C-°x_ R ⁿ z 0.0 ^Ν 'λ / ^S ~ ^N -| A°' ^СНз °-Сн ₃ 52 H ₃ C'° _S __ _{_} P ^H 3 XV-O o,9 /—Ά-Μ NN 'S-ГЫ A,°'CH ₃ Л J гч °'CH ₃ 53 n ₃ s-<\_ 9 ⁿ z 0.9 GkZ N-“ 'SN^ )__z°-ch ₃ Jj °'CH ₃

Reference example 54.

2-[3-(4-bromophenyl)-1,2,4-oxazol-5-yl]-H,H-bis(2,4-dimethoxybenzyl)propane-2-sulfonamide.

°'СН ₃

To a solution of the compound of Reference Example 46 (250 mg) in DMF (5 ml) were added cesium carbonate (527 mg) and methyl iodide (0.075 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 brine and dried over anhydrous sodium sulfate. The solvent was removed from the solution under reduced pressure. The residue was purified by silica gel column chromatography (nhexane:ethyl acetate; 1:1) to give the compound of Reference Example 54 (241 mg) as an amorphous substance.

¹ H-NMR (CDCl ₃ ) δ: 1.93 (s, 6H), 357 (s, 6H), 3.71 (s, 6H), 4.27 (br.s, 4H), 5.43 ( br.s, 1H), 6.77 (br.s, 1H), 7.14-7.19 (m, 2H), 8.05-8.10 (m, 2H).

Reference examples 55-61.

Each compound shown in Table 7 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 54.

- 30 048061

Table 7 Reference example Structure Reference example Structure 55 n ₃ s-°h^. 9 ⁿ s ο,.θ γΆ-У n-° ;sN^ ⁿ Х' ^СНз _F JU ^HiC Q °-ch ₃ 56 SP Ζ g> O-l I O η o ? ¹ X X ъ о 57 h ₃ c-°x__ 0.5? !— CN /S-nR rtwXAwXAcH ³ Il ^{J n s} Λ °'CH ₃ 58 w h o-JL,o x O 1 - o ω x z^ Q y θ ζ ω χ ω 59 rt T <0 O’-Г» I О u .w О ГЧ X 60 <η X m Ο ο ^Λ Ο ? X χ ^Ο: λΖ Λ ο 61 Z tn Ο·η I О о _£ w and ? xf oW O' X X co

Reference example 62.

5-[3(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-2-one.

To a solution of 4-fluorobenzamidoxime (1.90 g), 2-pyrrolidone-5-carboxylic acid (159 g) and O-(7-azabenzotriazol-1-yl)-IIK,A'-tetramethyluronium hexafluorophosphate (5.16 g) in DME (50 ml) was added N,N-diisopropylethylamine (4.3 ml), and the mixture was stirred at room temperature for 2 hours and then 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 brine and dried over anhydrous sodium sulfate. The solvent was removed from the solution under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:4) to give the compound of Reference Example 62 (2.30 g) as a solid.

¹ H-NMR ^6-DMSO) δ: 2.21-2.40 (m, 3H), 251-2.62 (m, 1H), 5.09-5.12 (m, 1H), 7. 38-7.44 (m, 2H), 8.048.09 (m, 2H), 8.37 (br.s, 1H).

Reference examples 63-68.

Each compound shown in Table 8 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to the reaction and treatment in the method described in Reference Example 62.

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Table 8

Example 1.

2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide.

The compound of Reference Example 23 (280 mg) and oxalyl chloride (0.384 ml) were dissolved in dried chloroform (10 ml), two drops of DMF were added to the solution, and the solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dried THF (5 ml). A 28% aqueous ammonia solution (1 ml) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to give the compound of Example 1 (206 mg) as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (s, 6H), 5.43 (br.s, 1H), 6.77 (br.s, 1H), 7.14-7.19 (m , 2H), 8.05-8.10 (m, 2H).

MS (m/z) 250 (MH ⁺ ), Rt=0.69 min.

Examples 2-16.

Each compound listed in Table 9 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to that in the method described in Example 1.

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Table 9 Example Structure ¹ H-NMR δ: LC-MS [M+H] +/Rt 2 0 N'°xA“NH ₂ jPj ^N H ₃ C ³ CDC1 ₃ : 1.75 (s, 6H), 5.45 (br.s, 1H), 6.74 (br.s, 1H), 7.44-7.47 (m, 2H), 7.99 -8, 03 (m, 2N) 266/ 0.80 min 3 0 Ν'θΑ~ ^ΝΗ 2 A'nL CDC1 ₃ : 1.77 (s, 6H), 5.49 (br.s, 1H), 6.75 (br.s, 1H), 7.62-7.65 (m, 2H), 7.94 -7.98 (m, 2H) 310/ 0.80 min 4 O ,e^ CDC1 ₃ : 1.70-1.81 (m, 2H), 1.93-2.03 (m, 2H), 5.75 (br.s, 1H), 7.10-7.15 (m, 2H), 7.97-8.02 (m, 2H) , 8.89 (br.s, 1H) 248/ 0.74 min 5 ABOUT CDC1 ₃ : 1.75-1.86 (m, 2H), 1.98-2.08 (m, 2H), 5.80 (br.s, 1H), 7.45-7.48 (m, 2Н), 7.97-8.00 (m, 2Н) , 8.91 (br.s, 1Н) 264/ 0.83 min

- 33 048061

11 ABOUT CDC1 ₃ : 0.80 (t, 6H), 2.03-2.12 (m, 2H), 2.24-2.33 (M, 2H), 5.78 (br.s, 1H), 7 ,45750 (μ, 2Η) , 8.00-8.03 (m, 2Η) , 8.45 (br. s, 1Η) 294/ 0.94 min 12 o O'N/-N ^h ₂ G ί ⁿ h ₃ c ³ CDC1 ₃ : 1.70 (s, 6Η), 5.47 (br.s, 1H), 654 (br.s, 1Η), 7.18-7.24 (μ, 2Η), 8.12-8 .17 (m, 2Η) 250/ 0.65 min 13 0 ⁰ 'a_J^ ^NH 2 jfy ^N H ₃ C ³ CDC1 ₃ : 1.70 (s, 6H), 5.40 (br.s, 1H), 651 (br.s, 1H), 7.49-752 (m, 2H), 8.05-8.08 (m, 2H) 266/ 0.73 min 14 N) CDCb: 1.72 (s, 6H), 5.46 (b.s., 1H), 652 (b.s., 1H), 7.69-7.71 (m, 2H), 8.00-8 .02 (m, 2H) 310/ 0.77 min 15 0 yw jfy °H ₃ C ³ CDCb: 1.70 (s, 6H), 5.39 (br.s, 1H), 657 (br.s, 1H), 7.42-7.45 (m, 2H), 7.91-7, 94 (m, 2H) 266/ 0, 62 min 16 0 n-nJnh ₂ G/°нД ^СН1 SBS1 _E : 1.74 (s, 6H), 556 (br.s, 1H), 6.62 (br.s, 1H), 7.63 (d, 2H), 7.88 (d, 2H) 310/ 0.65 min

Example 17.

2-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]propane-2-sulfonamide.

To a solution of the compound of Reference Example 55 in toluene (20 ml) was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography.

- 34 048061 by silica gel chromatography (n-hexane:ethyl acetate; 1:1) to give the compound of Example 17 (103 mg) as a solid.

¹ H-NMR (CDCi ₃ ) δ: 1.98 (s, 6H), 4.95 (br.s, 2H), 7.14-7.19 (m, 2H), 8.03-8.08 (m, 2H).

MS (m/z) 286 (MH ⁺ ), Rt=0.71 min.

Examples 18-24.

Each compound listed in Table 10 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to that in the method described in Example 18.

Table 10 Example Structure ^{X H} -NMR (CDC1 ₃ ) δ LC-MS [M+H] ⁺ /Rt 18 o°-? N-° 'S-NH ₂ hi PSNz jfy ^N H ₃ C ³ 1.98 (s, 6H), 4.93 (br.s, 2H), 7.44-7.47 (m, 2H), 7.98-8.01 (m, 2H) 302/ 0.81 min 19 l °'° N'° _v )S-NH ₂ jfy ⁿ h ₃ c ³ Β|Ά 1.98 (s, 6H), 4.96 (br.s, 2H), 7.61 (d, 2H) / 7.92 (d _f 2H) 346/ 0.83 min 20 o.9 ^Ο ΆΧ ^ΝΗ 2 jfy ^N H ₃ C ³ 1.93 (s, 6H), 4.96 (br.s, 2H), 750-753 (m, 2H), 8.03-8.07 (m, 2H) 302/ 0.75 min 21 0.5? °'\JS-N ^h ₂ /NzPS H ₃ [f У h ₃ c ³ 1.95 (s, 6H), 4.98 (br.s, 2H), 7.68-7.71 (m, 2H), 7.97-8.01 (m, 2H) 346/ 0.87 min 22 4 ft; O <f'O Ni 2.01 (s, 6H), 4.87 (br.s, 2H), 7.19-7.23 (m, 2H), 8.04-8.09 (m, 2H) 286/ 0.57 min 23 o.,9 Ν' ¹ } 'S-NH ₂ Jfy °H ₃ C ³ 2.01 (s, 6H), 4.88 (br.s, 2H), 7.48-752 (m, 2H), 7.97-8.00 (m, 2H) 302/ 0, 68 min 24 0.9 nn ;s-nh ₂ /^bА/ТНз Jfy °H ₃ C ³ 1.98 (s, 6H), 4.99 (br. s, 2H), 7.62 (d, 2H), 7.86 (d, 2H) 346/ 0, 68 min

Example 25.

5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one.

- 35 048061

To a solution of the compound of Reference Example 62 (500 mg) and methyl iodide (0.19 ml) in DMF (4 ml) was added cesium carbonate (0.988 g), and the mixture was stirred at room temperature for 25 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 brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:3) to give the compound of Example 25 (483 mg) as a solid.

¹ H-NMR (CDCl ₃ ) δ: 2.27-2.33 (m, 1H), 2.40-2.67 (m, 3H), 2.85 (s, 3H), 4.84-4.87 (m, 1H), 7.09-7.15 (m, 2H), 7.99-8.04 (m, 2H).

MS (m/z) 262 (MH ⁺ ), Rt=0.71 min.

Examples 26-31.

Each compound listed in Table 11 was prepared from each corresponding starting compound by carrying out a reaction and treatment similar to that in the method described in Example 25.

Table 11 Example Structure CN-NMR (CDC1.J δ LC-MS [Μ+Η] %Rt 26 F N-0 N^.0 1 1' Y—< g 2.27-2.34 (Μ, 1Η), 2.41-2.67 (m, ZN), 2.85 (s, ZN), 4.87-4.90 (m, 1Η), 6, 91-7.00 (m, 2Η), 7.98-8.04 (Μ, 1Η) 280/ 0.74 min 27 part 5- 2.31-2.38 (Μ, 1Η), 2.45-2.71 (μ, 3Η), 2.89 (s, 3Η), 4.89-4.92 (μ, 1Η), 7, 26-7.32 (Μ, 1Η), 7.82-7.86 (Μ, 1Η), 7.87-7.86 (Μ, 1Η) 280/ 0.80 min 28 Part 5 1.80 (s, 3Η), 2.10-2.19 (μ, 1Η), 2.45-2.68 (μ, 3Η), 2.83 (s, 3Η), 7, 137.18 ( μ, 2Η), 8.04-8.08 (μ, 2Η) 276/ 0.82 min 29 h.h. 2.27-2.33 (μ, 1Η), 2.40-2.67 (Μ, 3Η), 2.84 (s, ZN), 4.84-4.87 (m, 1Η), 7, 39-7.42 (m, 2Η), 7.94-7.97 (μ, 2Η) 278/ 0.85 min 30 Ν-θ N^<O p v—< G iTj ^N 2.32-2.38 (μ, 1Η), 2.45-2.71 (Μ, 3Η), 2.89 (s, ZN), 4.89-4.92 (m, 1Η), 7, 60-7, 63 (m, 2Η), 7.91-7.95 (μ, 2Η) 322/ 0.87 min

31 Ν'θ Ν^χ,Ο ₁ ! G jTj ^N 2.27-2.33 (m, 1H), 2.40-2.67 (μ, 3H), 2.85 (s, ZN), 4, 84-4.87 (m, 1H), 7, 09-7.15 (m, 2Η), 7.99-8.04 (μ, 2Η) 262/ 0.71 min

- 36 048061

Examples 31 and 32.

(R)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one and (R)-5-[3-(4-fluorophenyl)1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one.

The compound obtained in Example 25 was separated on a DAICEL column (CHIRALPAK™ AD-H (mobile phase: 100% MeCN)) to obtain the first peak (enantiomer A) and the second peak (enantiomer B). The absolute configurations of enantiomers A and B were estimated by comparison with the corresponding product obtained in Reference Example 68, formed from the S-form of the starting compound (i.e., the compound of Example 31), to determine that enantiomer A is in the S form and enantiomer B is in the R form.

Example 31 (enantiomer A): Rt 4.78 minutes, Chiral HPLC (Chiralpak™ AD-H, 0.46 cm i.d. x 25 cm long, mobile phase: 100% MeCN, flow rate: 1.0 mL/min, temperature: 40°C, wavelength: 237 nm).

Example 32 (enantiomer B): Rt 5.99 minutes, Chiral HPLC (Chiralpak™ AD-H, 0.46 cm ID x 25 cm length, mobile phase: 100% MeCN, flow rate: 1.0 mL/min, temperature: 40°C, wavelength: 237 nm).

Example 33.

^)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylpyrrolidin-2-one.

The compound of Example 31 can also be prepared by the method described below.

To a mixture of 4-fluorobenzamidoxime (840 g), (N)-2-pyrrolidone-5-carboxylic acid (1.08 kg), N,N-diisopropylethylamine (256 L) and ethyl acetate (7.3 L) was added a 50% solution of propylphosphonic acid anhydride in ethyl acetate (4.48 kg), and the mixture was stirred at room temperature for 15 hours and then at 75°C for 25 hours. Then, the reaction solution was cooled to room temperature, 0.1 mol/L aqueous hydrochloric acid solution (3.36 L) was added to the reaction solution. The mixture was separated in a separatory funnel, and the aqueous layer was extracted twice with ethyl acetate (1.86 L). The combined organic layer was washed with 5% aqueous potassium hydrogen phosphate solution (3.36 kg) and then with water (1.68 L), and the organic layer was concentrated under reduced pressure to a weight of 3.36 kg. The concentrated solution was cooled to 0 °C with stirring. To the resulting suspension, n-heptane (3.02 kg) was added dropwise, and the resulting crystal was collected on a filter, washed with 40% ethyl acetate/heptane (1.68 kg), and dried under vacuum at 40 °C to give an impure crystal (1.14 kg) of pale brown color. The resulting impure crystal (1.00 kg) was dissolved in 2-propanol/water (50%, 1.6 kg), and then 60 g of activated carbon was added. The mixture was stirred at 25 °C, and the activated carbon was removed by filtration. The filtrate was diluted with 2-propanol/water (50%) to bring the total weight to 3.0 kg, and the diluted solution was added dropwise into water (6.0 L) at 0°C with stirring. The resulting crystal was collected on the filter, washed with 2-propanol/water (12.5%, 2.0 kg), and dried under vacuum at 40°C to give the compound of Example 33 (944 g) as a white solid. NMR and HPLC analysis showed that the present compound is identical to the compound of Example 31.

The results of pharmacological experiments with some typical compounds of the present invention are given below, and in addition, an interpretation of the pharmacological activities of the compounds of the present invention is given, but these results in no way limit the scope of the present invention.

Test 1: Test using a model created by subcutaneous injection of pentetrazole (minimal seizure model, scPTZ).

A model commonly used to evaluate antiepileptic drugs is the subcutaneous injection of pentetrazole (minimal seizure model, scPTZ), which has a high degree of clinical predictive validity. It is assumed that a compound that exhibits anticonvulsant activity in this model may be used clinically as an antiepileptic drug. In this trial,

- 37 048061 used an animal model showing generalized petit mal seizure or myoclonic jerks. The test compounds were orally administered to male Slc:ddY mice (purchased from Japan SLC, Inc., 5 mice in each group, body weight 20-30 g). One hour later, pentetrazole (85 mg/kg) was subcutaneously administered. Then, the mice were observed for 30 minutes to see whether clonic jerks developed or not. The control mice were injected with 0.5% methylcellulose solution and the same test was conducted. The results are shown in Table 12. The results are presented as the number of mice without seizures out of a total of 5 mice. The present test was considered to yield reliable results when 4 mice out of 5 mice in the control group developed seizures.

-: testing not performed.

- 38 048061

As shown in Table 12, the compounds of the present invention exhibited anticonvulsant activity in this study in which the compounds of the present invention were orally administered in a model created by subcutaneous injection of pentetrazole (minimal seizure model, scPTZ). As for the compounds of Examples 11, 16, 25, 28, 30 and 31, more than half of the animals in each test showed anticonvulsant activity of the compounds even when orally administered at a dose of 25 mg/kg.

Test 2. Test on a rotating shaft.

This test is a test to evaluate the probability of causing locomotor coordination disorder under the influence of the test compound. The apparatus for conducting this test is equipped with a rotating cylindrical shaft of 4 cm in diameter, in which the mouse is forced to run on the rotating shaft, and the locomotor coordination is evaluated based on the result of this running (can run or cannot run). Male Sic:ddy mice (purchased from Japan SLC, Inc., body weight: 20-30 g) were trained 3 hours before the test to run on the rotating shaft at a rotation speed of 12 revolutions per minute for 5 minutes without falling. Only those mice that were able to run during training were used in this test. The test compound was orally administered to a group of 5 mice. One hour after the administration, the mice were placed on the rotating shaft at a speed of 15 revolutions per minute, and their locomotor characteristics were recorded for 180 seconds and the time they ran was measured. Control mice were given 0.5% methylcellulose solution instead of the test compound and the same test was performed. Movement coordination was assessed by the average running time of five mice (in seconds). The results are shown in Table 13. The control group ran for 180 seconds.

Table 13 Example Dose 100 mg/kg 50 mg/kg 25 mg/kg 1 180 - -

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2 180 - - 3 180 - - 4 180 - - 5 180 - - 6 180 - - 7 180 - - 8 180 - - 9 180 - - 10 180 - - AND 180 - - 12 180 - - 13 180 - - 14 180 - - 15 180 - - 16 180 - - 17 180 - - 18 180 - - 19 180 - - 20 180 - - 21 180 - - 22 180 - - 23 180 - - 24 180 - - 25 - 144.8 180 26 - 180 - 27 - 180 - 28 - 180 - 29 - 146.4 180 30 - 180 - 31 0 53.2 180 32 65.3 180 -

-: not tested As shown in Table 13, according to the results for all the example compounds, mice orally administered the compound at a dose of 25 mg/kg or more ran on a rotating shaft without falling for 180 seconds, which means that all the example compounds did not impair motor coordination. It follows that the example compounds evaluated in the model created by subcutaneous injection of pentetrazole (in the minimal seizure model, scPTZ) in Test 1 showed anticonvulsant activity, and in Test 2 showed that the doses in Test 1 did not impair motor coordination.

Trial 3: Evaluation of anticonvulsant activity in a mouse model of Dravet syndrome with febrile seizures.

This test is carried out to evaluate the anticonvulsant effect of the test compounds in

- 40 048061 febrile seizures in a mouse model of Dravet syndrome. BALB/c-ScnlA <+/-> mice (catalog number: RBRC06422; available from the National BioResource Project at RIKEN BioResource Research Center) were used in this study. This mouse model, which has a mutation in the ScnlA gene responsible for Dravet syndrome, can simulate symptoms similar to febrile seizures induced by hyperthermia, which is a symptom in a patient with Dravet syndrome, and can be used as an animal model of spontaneous Dravet syndrome (Publication reference: Japan Epilepsy Research Foundation, Annual Report 2015: 26: 69-76). Male mice in the Dravet syndrome model (one group: 5-8 mice, body weight: 20-30 g) were orally administered the test compound. After 50 min, the mice were placed in a chamber heated by a hot bath to induce hyperthermia, and the development of febrile seizures was observed. Immediately after the development of febrile seizures, the rectal temperature was measured and used as the threshold body temperature for inducing febrile seizures. Control mice were administered 0.5% methylcellulose solution instead of the test compound and the same test was conducted. The anticonvulsant effect in this test was evaluated by the dose required to significantly increase the threshold body temperature for causing febrile seizures compared with the control group and by the difference in threshold body temperature for causing febrile seizures compared with the control group.

As shown in Table 14, the compounds of the present invention exhibited some effect of increasing the threshold temperature of seizure onset in the mouse model of Dravet syndrome with febrile seizures, and therefore, the obtained results indicate that the compounds of the present invention have an anticonvulsant effect in the Dravet syndrome model. For all the compounds of the examples, the anticonvulsant effect in the Dravet syndrome model was exhibited at a dose that did not disturb the coordination of movements in Test 2, that is, the test of movement on a rotating shaft.

Test 4. Evaluation of the potentiating effect on GABAA receptors.

This test is performed to evaluate the potentiating effect of a drug on GABA receptors, as determined by the electric current generated by GABA, using GABA receptor-expressing cells prepared in accordance with the Guideline for Generation of Stable Cell Lines (Lonza Japan website; Non-patent document 4). The GABA receptor-expressing cells were used in an electrophysiological assay in which the electric current was measured when a 2 μM GABA solution and then a mixture of 2 μM GABA and a test compound were added to the cells. The potentiating effect on GABA receptors was evaluated by the increase in the ratio of the electric current generated by 2 μM GABA alone to the electric current generated by a mixture of 2 μM GABA and a test compound, and the concentration of the test compound at which the ratio increased by 20% was determined and designated as EC20. In addition, the electric current generated by a mixture of 2 μM GABA solution and the test compound with 10 μM flumazenil was measured, and the degree of inhibition of electric current generation by the addition of flumazenil was calculated compared to the electric current generated in the absence of flumazenil. The results are presented in Table 15.

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Table 15 Example Potentiating effect on GABAA receptors EC20 (μM) Degree of inhibition of the increase in electric current with the addition of flumazenil (%) 1 55 - 2 29 <0 3 29 <0 4 >100 - 5 >300 - 6 3,3 - 7 5.4 - 8 3.2 - 9 2.7 - 10 247 - AND 5.1 - 12 234 - 13 71 <0 14 32 - 15 >300 - 16 >300 - 17 45 - 18 37 <0 19 34 - 20 20 55 21 9.6 - 22 >300 - 23 190 - 24 86 - 25 16 12 26 >100 - 27 39 <0 28 9.3 24 29 1,1 7 31 15 <0 32 3.6 <0 clobazam 0.34 88 diazepam 0,03 93

-: not rated.

As shown in Table 15, the compounds of the present invention exerted potentiating action

- 42 048061 on GABA receptors. The potentiating effect on GABA receptors of clobazam and diazepam, which belong to benzodiazepines, was strongly inhibited by flumazenil, which is a benzodiazepine antagonist, while the potentiating effect of the compounds of the present invention on GABA receptors was inhibited by flumazenil very weakly, which allowed us to assume that the potentiating effect of the compounds of the present invention on GABA receptors occurs by a mechanism different from the mechanism of action of benzodiazepines.

Test 5. Evaluation of antidepressant effect in the forced swim test on rats.

This test allows the antidepressant effect of a drug to be assessed. When a rat is thrown into a bath of water from which the rat cannot escape, with the aim of forcing it to swim, the rat first tries to escape and then becomes immobile. The next day, when the rat is thrown into the bath of water again, immobility occurs earlier than in the first test. This method allows the antidepressant effect of the test compound to be assessed using the duration of immobility as an index of depressive behavior. The day before the test, male Wister rats (purchased from Charles River Laboratories Japan, body weight 260-300 g) were forced to swim in a bath of water for 15 minutes. On the day of the test, the rats were orally administered the test compound (10-12 rats per group). An hour later, the rats were again forced to swim for 5 minutes and the time of each instance of immobility was measured. In the control group, rats were given 0.5% methylcellulose instead of the test compound and subjected to the same behavioral test. The presence of antidepressant action was indicated by the average reduction in immobility time compared to the control group.

*: statistically significant difference.

As shown in Table 16, the compounds of Examples 29 and 32 statistically significantly decreased the immobility time of rats in the forced swimming model, suggesting that these compounds have an antidepressant effect. On the other hand, diazepam did not show an antidepressant effect in the forced swimming test on rats, although Test 4 showed that diazepam has a potentiating effect on GABA receptors like the compounds of the present invention. Diazepam is one of the benzodiazepines, which is used as an anticonvulsant drug. This result, showing that the compounds of the present invention showed an effect and benzodiazepines did not show an effect in this model, suggests that the mechanism of the potentiating effect of the compounds of the present invention on GABA receptors is different from that of benzodiazepines, as shown in Test 4, and due to this unknown mechanism of action that the compounds of the present invention have, they may have an antidepressant effect that benzodiazepines do not. As a result, it was hypothesized that the compounds of the present invention may have a therapeutic or prophylactic effect not only on epileptic seizure but also on depressive symptom, which is very often a concomitant symptom in patients suffering from epilepsy.

As shown above, the compounds of the present invention exhibited potent anticonvulsant activity when tested in a model created by subcutaneous injection of pentetrazole (minimal seizure model, scPTZ). In a mouse model of Dravet syndrome, which is known as a resistant generalized epilepsy and whose mutated gene responsible has been identified, it was shown that the compounds of the present invention could increase the threshold body temperature for inducing febrile seizures at a dose that did not impair motor coordination. Therefore, the compounds of the present invention can be used as an antiepileptic drug, that is, a drug for treating or preventing generalized seizure including tonic seizures, clonic seizures, petit mal seizure, myoclonic seizures and atonic seizures; focal epileptic seizure; seizure of unknown etiology; and generalized seizure including Dravet syndrome, West syndrome and Lennox-Gastaut syndrome, which refers to drug-resistant epilepsy. The compounds of the present invention also have a potentiating

- 43 048061 action on GABA receptors, and therefore, the compounds of the present invention can be used as a drug for the treatment or prevention of anxiety disorders, obsessive-compulsive disorder, rapid eye movement disorder associated with Parkinson's disease/dementia with Lewy bodies, which can be treated with existing GABA receptor agonists. The potentiating effect of the compounds of the present invention on GABA receptors is exerted by a mechanism different from that of benzodiazepine, which is one of the existing agonists of GABAergic neurons, that is, the compounds of the present invention exhibited an antidepressant effect on rats in a forced swimming test, on which benzodiazepine did not have this effect, as a result of which it is assumed that the compounds of the present invention have some effect on a depressive symptom accompanied or not accompanied by epilepsy, and can be used as a drug for the treatment or prevention of depressive syndrome and other similar disorders, and also have useful therapeutic effects that existing antiepileptic drugs do not have. In addition, the compounds of the present invention are expected to improve the pathological conditions 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, the underlying cause of which is dysfunction of the GABAergic system.

Industrial applicability

The compounds of the present invention have a strong anticonvulsant effect, as well as a potentiating effect on GABA receptors, as a result of which the compounds of the present invention can be used as a drug for the treatment or prevention of diseases associated with hypofunctions of the GABAergic system. In addition, the compounds of the present invention have an effect of enhancing inhibition (I) in the balance of excitation (E) and inhibition (I) (E/I balance), as a result of which the compounds of the present invention can be used as a drug for the treatment or prevention of a disease in which E increases and/or I decreases in the E/I balance.

Claims (17)

1. Compound of formula (1): or a pharmaceutically acceptable salt thereof, wherein Q ¹ is a halogen, Q ² is hydrogen or halogen, the ring containing X, Y and Z has the following formulas (5a), (5b) or (5c): R ¹ has any one of the following formulas (2)-(4): R ² and R ³ are the same or different and represent C 1-6 alkyl; or R ² and R ³ may be taken together with the carbon atom to which they are attached to form a C 3-6 cycloalkyl (which may be substituted with from 1 to 3 substituents independently selected from halogen) or a C _4-6 saturated heterocyclic ring containing one oxygen atom, - 44 048061 R ⁴ and R ⁵ are the same or different and represent hydrogen, halogen or C _1-6 alkyl, and n represents 1, provided that the following compounds are excluded from the compound of formula (1): 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, 2-[3-(2-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropanamide. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are the same or different and represent C1.3 alkyl; or R ² and R ³ may be taken together with the carbon atom to which they are attached to form a C3-6 cycloalkyl (which may be substituted with from 1 to 3 fluorines) or a C _4-6 saturated heterocyclic ring containing one oxygen atom. 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ are the same or different and represent hydrogen or C _1-3 alkyl. 4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Q ¹ is fluorine, chlorine or bromine, and Q ² is hydrogen, fluorine, chlorine or bromine. 5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the ring containing X, Y and Z has the following formulas (5a) or (5b). N-0 O-N and L L, L, A s (5a) (5b) 6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ¹ has the following formula (4). Me A_,n R ⁴ —Г. ^=° ^L Mn (4) R ⁵ 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is 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]propan-2-sulfonamide, 2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]propan-2-sulfonamide, 2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]propan-2-sulfonamide, 2-[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]propan-2-sulfonamide, 2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]propan-2-sulfonamide, 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]propan-2-sulfonamide, 2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]propan-2-sulfonamide, 2-[5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl]propan-2-sulfonamide, - 45 048061 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, (b)-5-|3-(4-(|)tor(| )enyl)-1,2,4-oxadiazol-5-yl|-1-methylpyrrolidin-2-one, and (K)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5 -yl]-1-methylpyrrolidin-2-one. 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is 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]propan-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, (b)-5-|3-(4-(()torphenyl)- 1.2.4-oxadiazol-5-yl|-1-methylpyrrolidin-2-one and (K)-5-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1- methylpyrrolidin-2-one. 9. A pharmaceutical composition containing a compound according to any one of claims 1 to 8 or its (an aromatically acceptable salt). 10. A medicinal product for the treatment and/or prevention of diseases associated with hypofunction of the GABAergic system, containing a compound according to any one of claims 1 to 8 or its (an aromatically acceptable salt) as an active ingredient. 11. The medicinal product according to item 10, wherein the diseases associated with hypofunction of the GABAergic system are a neurological disease or a mental illness. 12. The medicinal product of claim 11, wherein the neurological disease or mental illness is epilepsy, neuropathic pain, neurological developmental disorders, bipolar disorder and related disorders, schizophrenia spectrum disorder, Alzheimer's disease and other neurocognitive disorders, amyotrophic lateral sclerosis, Parkinson's disease, depressive syndrome, anxiety disorders, obsessive-compulsive disorder, trauma- and stress-related disorders, sleep-wake cycle disorders and/or rapid eye movement sleep behavior disorder associated with Parkinson's disease/dementia with Lewy bodies. 13. A method for treating and/or preventing diseases associated with hypofunction of the GABAergic system, comprising administering a therapeutically effective amount of a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof to a patient in need thereof. 14. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicinal product for the treatment and/or prevention of diseases associated with hypofunction of the GABAergic system. 15. Use of a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the treatment and/or prevention of diseases associated with hypofunction of the GABAergic system. 16. A pharmaceutical combination comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and at least one medicinal product selected from medicinal products related to an antiepileptic medicinal product, an antidepressant or a neuroleptic medicinal product. 17. A medicinal product for the treatment of diseases associated with hypofunction of the GABAergic system, containing a combination according to item 16.