WO2019074219A1

WO2019074219A1 - Anti-viral compound, method for preparing same, and pharmaceutical composition containing same as active ingredient for prevention or treatment of viral disease

Info

Publication number: WO2019074219A1
Application number: PCT/KR2018/010849
Authority: WO
Inventors: 정영식; 한수봉; 김진우; 신진수
Original assignee: 한국화학연구원
Priority date: 2017-10-12
Filing date: 2018-09-14
Publication date: 2019-04-18
Also published as: KR101997108B1; KR20190041202A

Abstract

Provided are a novel anti-viral compound, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for prevention or treatment of a viral disease.

Description

Sexy bulbs

However,

, ^ ¾ ^ mouth [specification]

Title of the Invention

An antiviral compound, a method for producing the same, and a pharmaceutical composition for preventing or treating viral diseases containing the same as an active ingredient

TECHNICAL FIELD

An antiviral compound, a process for producing the same, and a pharmaceutical composition for preventing or treating viral diseases containing the same as an active ingredient. BACKGROUND ART [0002]

The picornavirus is a positive single stranded RNA virus of 7.2-8.5 Kb. It is a very small spherical virus of about 22-30 nm and has no coat and is the oldest known virus. The diseases caused by picornavirus include respiratory diseases such as poliomyelitis, acute conjunctivitis, viral meningitis, waterborne diseases, waterborne diseases, hepatitis A, myocarditis, pancreatitis, diabetes mellitus, encephalomyelitis, encephalitis, Diseases, circulatory diseases, skin diseases, etc.

In addition, picornavirus is transmitted through food or water, and is often contained in water, but it is very stable and is not suitable for disinfection. Therefore, viruses belonging to the picornavirus cause various diseases that cause health, social and economic problems. Accordingly, the development of therapeutic agents for picornavirus-related diseases is actively under way. However, to date, no therapeutic agent has been developed to treat it, and most of the drugs under development are uncoating inhibitors. The virus belonging to the picornaviridae is the rhinovirus

(Rhinovirus), poliovirus (Po? Rvus), coxsakiovirus

Coxsackie virus A, coxsackievirus B, echoviruses, enteroviruses including hepatitis A virus, and the like. Specifically, the human rhinovirus (hRV) is known as one of the most common asthma exacerbations as a kind of respiratory virus, and human rhinovirus is also known to exist in bronchial tissues of a large number of stable asthmatic patients. In the asthmatic and non-asthmatic patients, bronchial mucosal biopsy specimens were collected and compared. The incidence of human rhinovirus was significantly higher in asthmatic group than in non-asthmatic group, and the presence of human rhinovirus And the clinical severity of asthma Naha

"

. In addition, human rhinovirus causes asthma as a symptom of foot disease. In addition, chronic obstructive pulmonary disease, pneumonia, and also cause a lot of fungus, a virus that is a major cause of the cold, or effective treatment has not been developed at present. In addition, poliovirus is transmitted through ingestion of food, and viruses proliferate in the oropharyngeal mucosa or the intestinal mucosa (i nt est i na 1 mucosa). It infiltrates lymphatic tissues, proliferates, enters the bloodstream, induces primary viremia, and most infections stop at this stage, leading to an inapparent infection. On the other hand, in about 1% of infected people, the virus can penetrate the central nervous system and cause paralytic diseases, especially infecting children and causing polio. Currently, effective vaccines can be developed and prevented, but in countries where vaccines such as Niger, Nigeria, Egypt, India, Pakistan and Afghanistan are not well supplied, the disease is still prevalent. Furthermore, the Coxsackie virus has been isolated from the feces of infected children in Coxsackie, New York, and is a virus belonging to the genus Enterobacteria. The genus 20-dc helicoid with a diameter of 27 to 28 n has a (+) chain of dibasic RNA, which is orally infected. Coxsackie virus exists in two groups, coxsackievirus A and coccyvirus B. Coxsackievirus A causes this paralysis, and B causes spastic paralysis. Coxsackie virus B is known to be the cause of idiopathic dilated cardiomyopathy, myocarditis, which is required for heart transplantation even if it is a serious complication of meningitis, myositis, and myocarditis paralysis. . Currently, effective therapeutic agents have not yet been developed. In addition, hepatitis A virus causes hepatitis A virus. While a vaccine against hepatitis A virus has been developed, a vaccine against an eco virus that causes enteritis, aseptic meningitis, diarrhea, and airway infections that cause meningitis, respiratory infections, etc. has not yet been developed . Meanwhile, the development of a therapeutic agent for diseases related to the above-mentioned picornavirus group has been studied, and the nivioxerc derivative has been studied as a promising candidate substance having broad anti-enterovirus (enterovirus) and anti-rhinovirus activity . Enviroxym inhibits the synthesis of plus-strand RNA by binding to the viral protein 3A required for the formation of RNA intermediates during viral regeneration (Non-Patent Document 1, Heinz BA and Vance LM: J Virol, 1995, 69 (7) , 4189-97.). However, clinical studies have shown normal or no effect, and insufficient drug power Studies and unwanted side effects were observed. In addition, protease inhibition AG 7088 has been studied based on knowledge of the precise structure and function of viral protease 2C. In cell cultures with a range of nanomolar concentrations, AG 7088 has 48 rhinovirus types and coxsackieviruses A21, B3 , The intestinal virus 70 and the eco virus 11. Furthermore, as the molecular structure of picornavirus capsids became clear, preliminary conditions for the increased design of the "WIN substance", a capsid blocker, have been investigated, which include adsorption and / or excretion of rhinovirus and enterovirus Some of the WIN substances have a highly specific effect only on the individual genus or virus type of the picornavirus. Other derivatives inhibit the replication of both rhinoviruses and enteric viruses. , Disoxaril and pi rodavir belong to the WIN substance, for example. These compounds showed a very good antiviral effect in cell culture fluids. However, sufficient solubility (aryldon) , Such as skin rashes (WIN 54954), as well as low bioavailability (aryldone and dyssaryl), rapid metabolism and excretion (Dysaryl and WIN 54954) In addition, another WIN compound, plconaryl, has a very good oral bioavailability, which, after binding to the hydrophobic pocket in the viral capsid, leads to penetration of the rhinovirus, eco-virus and coxsackie virus Thus, plconaril is potentially effective against a wide range of viral diseases ranging from common colds to viral meningitis or myocarditis. Resistance is observed for rhinovirus, enterovirus 71 and coxsackievirus B3. However, the proven therapeutic effect was not sufficient to label plconaril (Picovir, Viropharma, USA) as an agent for the treatment of rhinovirus infections in the US In March 2002, adverse events were observed and the treatment success rate was too low Because of this, countermeasures are rejected by the Food and Drug Administration (FDA) Furthermore, BTA-798 compounds, which are more active than flconilyl in in vitro and in vivo antiviral efficacy assays using the rhinovirus, are currently in clinical trials. , Antiviral drugs approved for the treatment of enteroviruses or rhinoviruses have not yet been developed. Thus, the inventors of the present invention have found that Cockovirus

Blank Light

Chemical flow

In studying antiviral compounds against poliovirus and rhinovirus,

It has been confirmed that the compound provided in this aspect of the present invention exhibits excellent anti-virus activity against poliovirus and rhinovirus belonging to the picornavirus group, and consequently, the pharmaceutical composition for the prevention or treatment of viral diseases And the present invention has been completed.

DETAILED DESCRIPTION OF THE INVENTION

[Technical Problem]

An object of one aspect of the present invention is to provide a novel structure of an antiviral compound, a pharmaceutically acceptable salt thereof, and an optical isomer thereof.

neck

Enemy

Another object of the present invention is to provide a process for preparing an anti-virus compound of novel structure based on functionality. Han

ᅧ상

However,

In another aspect of the present invention,

The God

A compound of the formula (I), a pharmaceutically acceptable salt thereof,

Tuggy

As an active ingredient, an antiviral pharmaceutical composition

Is a light

to be

Graduate School

In another aspect of the present invention, there is provided a novel zwitterionic compound of the structure, its pharmaceutically acceptable salt, its optical isomerism

For the prevention or treatment of viral diseases containing active ingredients,

The present invention relates to a composition for preparing a composition. In another aspect of the present invention,

The iris compound, its pharmacologically acceptable

Viral < RTI ID = 0.0 >

Functional food composition. In another aspect of the present invention, there is provided a method for the treatment or prevention of cancer, comprising administering a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a subject (subj ecct) And to provide a method for treating a viral disease. Another object of the present invention is to provide a pharmaceutical composition or health composition containing, as an active ingredient, a compound represented by the formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of viral diseases (Us e) of the functional food composition. Another object of the present invention is to provide a compound represented by the general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention, alleviation or treatment of a viral disease The use of the salt is to be provided.

[Technical Solution]

In order to achieve the above object,

To In one aspect of the present invention are represented by formula 1 ^τ ΰΖ ^"are provided compounds, ό its optical isomer, or a pharmaceutically acceptable salt thereof.

One

In Formula 1,

d- ₇ straight or branched alkyl, straight or branched alkoxy d- ₇ of the straight-chain or branched alkyl, or unsubstituted C ₃ - ₆ cycloalkyl, in which p is 1 to 100;

R ¹ is -H, _{halogen, OH, -CN, -N0 2)} - ₁₀ straight or branched chain alkyl, straight or branched chain alkoxy of C _o, _C-5 straight or branched chain alkyl aminocarbonyl, or di (^ - ₅ < / RTI > linear or branched alkylaminocarbonyl;

X is

Or = N-; And

Mystery work

Yu Chemical

And L is a single bond or -O-. In another aspect of the present invention,

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1).

However,

2 3 1

In the above Reaction Scheme 1,

R X and R ng are independently as defined in Formula 1 above; And

Halo is a halogen. Further, in another aspect of the present invention, there is provided an antiviral pharmaceutical composition containing, as an active ingredient, a compound represented by the above formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, It does.

Hashan

To

In another aspect of the present invention,

The present invention provides a pharmaceutical composition for the prevention or treatment of a viral disease, which comprises, as an active ingredient, an optically isomer thereof, or a pharmaceutically acceptable salt thereof _, as an active ingredient. Further, in another aspect of the present invention, there is provided a health functional food composition for preventing or ameliorating a viral disease comprising the compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient . In another aspect of the present invention,

Water, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

To a subject in need thereof (subj ec t)

The present invention provides a method for treating a disease of a female. Furthermore, in another aspect of the present invention, there is provided a pharmaceutical composition or a pharmaceutical composition comprising the compound represented by the formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient in the prevention or treatment of viral diseases The use of the food composition Wind

In another aspect of the present invention, there is provided a medicament for the prevention of viral diseases,

A compound, an optical isomer thereof, or a pharmaceutically acceptable use thereof.

【Advantageous effect】

The novel antiviral compound according to one aspect of the present invention is not only low in cytotoxicity but also exhibits a very excellent antiviral activity against picornavirus such as poliovirus and rhinovirus. Therefore, the novel antiviral compound of the present invention can be used for poliomyelitis, acute hemorrhagic conjunctivitis, , Viral diseases such as water-borne diseases, waterborne diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epilepsy, encephalitis, herpes zoster, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, Prevention of or. And can be usefully used as therapeutic pharmaceutical compositions.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail. In one aspect of the present invention, there is provided a compound represented by the following formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Pentagon

Hashih

One

The above-

Ring

, Wherein A &^lt; ¹ >, A &^lt; j > j is independently or (^ - ^

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently -H, or one or more heteroatoms selected from the group consisting of N 0 and S ^; Include Is a heteroaryl of 5 to 10 atoms substituted by an unsubstituted or a -G ^1, wherein -G ¹ is a linear of straight or branched chain of the unsubstituted or substituted with one or more halogen d- ₇ alkyl, d- ₇ or branched alkoxy d- ₇ straight-chain or branched alkyl, or unsubstituted C ₃ - ₆ of the cycloalkyl;

R ¹ is -H, _{halogen, -OH, -CN, - N0 2} , 10 straight or branched alkyl, (^ - ^ straight or branched alkoxy, straight-chain or branched alkylamino of d- _5-carbonyl, or di ^ - straight or branched chain alkyl aminocarbonyl and _5; X is = CH-, or = N- gt; and.

L is a single bond, or -O-.

Linear or branched alkyl of d-5 or d-5,

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently -H or an unsubstituted or substituted one or more heteroatoms containing one or more heteroatoms selected from the group consisting of N, Is a 5- or 8-membered heteroaryl substituted by G ¹ , wherein -G ¹ is straight or branched alkyl of d-5, unsubstituted or substituted by one or more halogens, straight or branched alkoxy d- ₅ straight or branched alkyl, or unsubstituted C ₃ - ₄ cycloalkyl, in which p is 1 to 100; R < ¹ > is straight or branched chain alkylaminocarbonyl of d- ₃ or straight or branched chain alkylaminocarbonyl of di (^ - ₃ ;

X is = N-; And L may be a single bond, or -O-. In another aspect,

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently an unsubstituted or substituted oxadiazole Being a solicitor,

Wherein said substituted oxadiazolyl is unsubstituted or substituted with one or more halogen-substituted straight or branched chain alkyl, d- ₅ linear or branched alkoxy d-

₅ straight or branched alkyl, or unsubstituted C ₃ - yi-cycloalkyl of ₄ may be a sol-one days oxadiazole substituted. In another aspect,

A ¹ , A ² and A ³ are independently -H or methyl

Lt; / RTI > is methylaminocarbonyl, or dimethylaminocarbonyl

X is = N-; And

L may be a single bond, or -

or

, Wherein A ¹ , A ² and A ³ are independently H or methyl,

Methylaminocarbonyl, or dimethylaminocarbonyl < / RTI >

X is = N-; And

L may be -O-. In another aspect, the compound represented by Formula 1 may be any compound selected from the following group of compounds.

(1) N-methyl-4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy] picolinamide;

(2) 4- [4- (5-ethyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(3) 4- [4- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(4) 4- [4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(5) 4- [4- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide; (6) 4- [4- (5- (Methoxymethyl) -1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(7) N-Methyl-4- [4- (5 (trifluoromethyl) -1,2,4-oxadiazolyl-3-yl) phenoxy] picolinamide;

(8) 4- [3- (5-Isopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(9) 4- [3- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(10) 4- [3- (5- (Methylmethyl) -1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(11) 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2-methylphenoxy) -N-methylpicolinamide;

(12) 4- (4- (5-Isopropyl-1,2,4-oxadiazolyl-3-yl) -2,6-dimethylphenoxy) -N-methylpicolinamide;

(13) N-methyl-4 - [(6- (5-methyl-1,2,4-oxadiazol-3-yl) naphthalen-2-yl) oxy] picolinamide;

(14) 4- (4- (5-Isopropyl-1,2,4-oxadiazol-3-yl) phenoxy) -N, N-dimethylpicolinamide;

(15) 4? (4- (5-isopropyl-1,2,4-oxadiazolyl-3-yl) -2,6-dimethylphenoxy) -N, N-dimethylpicolinamide;

B) thiophen-6-yl) oxy] piperidine-2-carboxylic acid (16) Choline amide;

(17) 4 - [(2- (5-Ethyl-1,2,4-oxadiazole-3-yl) -3-methylbenzo [b] thiophen- Picolinamide;

B) thiophen-6-yl) oxy] -N- (3-methylpiperazin-1- Methylpicolinamide;

(19) Synthesis of 4 - [(2- (5-isopropyl-1,2,4-oxadiazolyl) -3- methylbenzo [b] thiophen-6-yl) oxy] Picolinamide;

(20) Synthesis of N-methyl-4 - [(3-methyl-2- (5- (trifluoromethyl) -1,2,4-oxadiazol- Yl) oxy] picolinamide;

(21) 4 - ((6- (5-isopropyl-1,2,4-oxadiazol-3-yl) pyridin-3-yl) oxy) methylpicolinamide; And

(22) Synthesis of 5- (5-isopropyl-1,2,4-oxadiazol-3-yl) -N-methyl-2-oxo-2H- [1,4'-bipyridine] -2'- amides. In another aspect of the present invention, the compound represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Do. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Is obtained from organic acids such as nontoxic organic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4- with rubenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphate chlorides, But are not limited to, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , Succinate, suverate, sebacate, fumarate, malate, butyne ᅳ 1, 4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate , Hydroxybenzoate, methoxybenzoate, phthalate Terephthalate, benzenesulfonate, rubenesulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, Maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to another aspect of the present invention can be prepared by a conventional method, for example, by dissolving the derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like, And then precipitating the resulting precipitate by filtration and drying. Alternatively, the precipitate may be produced by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. As the metal salt, Or a calcium salt. In addition, a salt thereof is obtained by reacting an alkali metal or an alkaline earth metal salt with a suitable salt (for example, silver nitrate). Further, in another aspect of the present invention, the compound represented by the formula (1) and pharmaceutically acceptable salts thereof, as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom are all included. Further, in another aspect of the present invention, as shown in the following Equation 1,

(2) and a compound represented by the general formula (3) to produce a compound represented by the general formula (1).

However,

2 3

In the above Reaction Scheme 1,

R ¹ , X and Ring are independently as defined in Formula 1 above; And

Halo is halogen or may be selected from -F, -Cl, -Br, -I. Here, the solvent, temperature, reagent, and the like used in carrying out the reaction may be easily changed or adopted by those skilled in the art without any particular limitation. If the particular reaction temperature ranges in detail may be performed on CC to 3001 range, 20 ^° C to can be carried out at 280 ^° C range, can be carried out at 40 ^° C to 260 ^° C range, 60 ^° C to may be carried out at 240 ^° C range, 80 ^° C to can be carried out at 220 ^° C range, it can be carried out at 100 ^° C to 200 ^° C range, to perform at 120 ^° C to 180 ^° C range And can be performed in the range of 140 ^° C to 160 ^° C and can be carried out at 150 ^° C. When the reaction time is specifically specified, the reaction can be carried out in the range of 1 hour to 180 hours, in the range of 10 hours to 170 hours, in the range of 20 hours to 160 hours, To 150 hours, can be carried out in the range of 40 to 140 hours, can be carried out in the range of 50 to 130 hours, can be carried out in the range of 60 to 120 hours, and can be carried out in the range of 70 to 110 Time range, can be carried out in the range of 80 to 100 hours, and can be carried out for 90 hours. Barometric pressure can generally be performed at atmospheric pressure (latm), but is not particularly limited. Further, in one aspect of the present invention, there is provided a pharmaceutical composition for antiviral containing an optical isomer of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, or a pharmaceutical composition for preventing or treating a viral disease A pharmaceutical composition is provided.

At this time, the viral disease is a disease caused by the picornavirus group. The viral disease is a disease caused by at least one virus selected from the group consisting of coxsacki virus, poliovirus and rhinovirus.

Wherein the viral disease is selected from the group consisting of encephalitis, viral meningitis, muscle warts, myocarditis paralysis, idiopathic dilated cardiomyopathy, myocarditis, pericarditis, meningitis, hydrocephalus, viral diabetes, acute hemorrhagic conjunctivitis, Constipation, aseptic meningitis, poliomyelitis, relaxant paralysis, adverse recurrences, non-anemic whiskers, paralytic whiskers, progressive whiskers, muscle weakness Chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, common cold, acute respiratory tract infection, respiratory tract infection, sinusitis, cystic fibrosis, gastroenteritis, waterborne disease, hepatitis A, pancreatitis, epidemic muscle pain, foot and mouth disease . &Lt; / RTI >

In another aspect of the present invention, the compound represented by the formula (1) according to the present invention has been found to be useful as an antiviral drug for the poliovirus 3 (PV3) belonging to the picornavirus group and Showed excellent antiviral activity against rhinoviruses (HRV14, HRV21 and HRV71), and the compounds of the examples showed excellent antiviral activity even at very low concentrations below micromolar. Accordingly, in another aspect of the present invention, the compounds represented by Formula 1 show excellent antiviral activity against Coxsackie virus, polyovirus, and rhinovirus belonging to the picornavirus group, Cardiovascular system diseases, neurological diseases, and the like. In another aspect of the present invention, the compound represented by Formula 1 may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of preparing the compound, the compounding agent, diluent, binder, Solid preparations for oral administration, prepared using a diluent or excipient such as a disintegrating agent, a surfactant, etc., include tablets, patients, powders, granules, capsules, troches and the like, The compound of the present invention is mixed with at least one excipient such as starch, calcium carbonate, sucrose, lactose (1 actose), or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be added in addition to water and liquid paraffin, May be included. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oil such as rib oil, injectable ester such as ethyl oleate, and the like can be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used. Drop

^ Name.

^ ᅦ's.

In ¹ I geothi from one to the other aspect of the invention, the effective dosage for humans of the compound may vary according to the degree of age, weight, sex and dosage forms of the patient, health conditions and diseases, in general, Is about 0.001 to 100 mg / kg / day, preferably 0.01 to 35 mg / kg / day. It is generally 0.07 to 7000 mg / day, preferably 0.7 to 2500 mg / day, based on an adult patient weighing 70 kg, and may be administered once a day at a predetermined time interval according to the judgment of a doctor or pharmacist It may be divided into several doses. Form for Implementation]

, Contents according to one aspect of the present invention and experiment examples will be described. However, the present invention is not limited to the following examples and the present invention,

Example 1 Synthesis of N-methyl-4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy]

Yes Yes

Step 1. N-4-Dihydroxybenzimidamide

4-Cyanophenol (1.043 g, 8.756 mol) was dissolved in a solution of 50% aqueous NH ₄ OH (8 mL) and EtOH (2 mL) and stirred at 9 ° C for 16 h. Dihydroxybenzimidamide (1.319 g, 99%). Step 2. Preparation of 4- (5-methyl-1,2,4-oxadiazol-3- Yl) phenol

N ', 4-dihydroxybenzimidamide (249.7 mg, 1.641 mmol) was dissolved in pyridine (4 mL), acetyl chloride (155 mg, 1.969 mmol) was added and the mixture was stirred at 120 ^° C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and EtOAc (100 mL) and H ₂ O (100 mL) were added to the residue. The aqueous layer was extracted with EtOAc (50 mL x 3) and the organic layer was washed with brine (10 mL), dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel column chromatography (EtOAc: Hx = 1: 3) to obtain 245.3 mg (79%) 4- (5-methyl-1,2,4-oxadiazol- . Step 3. Preparation of N-methyl ᅳ 4- [4- (5-methylphenyl) -1,4-oxadiazol-3-yl) phenoxy] picolinamide

A shake of 4- (5-methyl-1,2,4,5-oxadiazol-3-yl) phenol (99.7 mg, 0.566 mmol) and 4-chloro-Nmethylpicolinamide (96.8 mg, Compound Stir at 150 ^° C for 90 hours. After the reaction mixture was cooled to room temperature, CH ₂ Cl ₂ (100 mL) and distilled water (100 mL) were added. The aqueous layer was extracted with CH ₂ Cl ₂ (50 niL x 3). The combined organic layer was washed with brine (10 mL) and concentrated under reduced pressure after which dried MgS0 _4. The obtained residue was purified by silica gel column chromatography (EtOAc: Hx = 2: 3) to obtain the target compound (57.6 mg, 33%).

^{: H NMR (300 MHz, CDC1} 3) δ 8.45 (dd, J = 5.6, 0.5 Hz, 1H), 8.16 (d, J = 6.7 Hz, 2H), 8.03 (. Br s, 1H), 7.80 (dd, J = 2.6, 0.5 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.04 (dd, J = 5.6, 2.5 Hz, 1H), 3.04 s, 3H); LC / MS (ESI) [M + H] < ⁺ > = 311.03.

Example 2 Synthesis of 4- [4- (5-ethyl-1,2,4-oxadiazol-3-yl) phenoxy]

Step 1. Preparation of 4- (5-ethyl-1,2,4-oxadiazol-3-yl) phenol

N, N ', 4-dihydroxybenzimidamide (247.6 mg, 1.627 mmol) was used as a starting material and propionyl chloride (181 mg, 1.95 mmol) was used instead of acetyl chloride as a starting material. 4- (5-ethyl-1,2,4-oxadiazole-3-yl) phenol (245.3 mg, 79%). Step 2. Synthesis of 4- [4- (5-ethyl-1,2,4-oxadiazolyl-3-yl) phenoxy] -? - methylpicolinamide

The target compound was obtained by the method of Example 1, Step 3, using the starting material of 4- (5-ethyl-1,2,4-oxadiazole-3-yl) phenol (101.5 mg, 0.5336 mmol) , 21%).

^匪R (300 MHz, CDCI 3) δ 8.43 (dd, J = 5.6, 0.6 Hz, 1H), 8.16 (d, J = 8.8 Hz, 2H), 8.03 (br. S, 1H), 7.85 7.75 (m J = 5.6, 2.6 Hz, 1H), 3.08 2.93 (m, 5H), 1.48 (t, J = 7.6 Hz, 2H), 7.01 (d, J = ); LC / MS (ESI) [M + H] < + > = 325.27.

Example 3 Synthesis of 4- [4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

Step 1. Preparation of 4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenol

N, N ', 4-dihydroxybenzimidamide (297.2 mg, 1.953 mmol) as a starting material and cyclopropanecarbonyl chloride (245.4 mg, 2.344  ol) instead of acetyl chloride as a starting material, 2) to obtain 4- (5-cyclopropyl-1,2,4-oxadiazole-3-yl) phenol (238.5 mg 53%). Step 2. Preparation of 4- [4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenoxy]

The target compound was obtained by the method of Example 1, Step 3, using the starting material of 4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenol (101.0 mg, 0.4995 mmol) , 18%).

^{X H匿(300 MHz, CDCI} 3) δ 8.44 (d, J = 5.6 Hz, 1H), 8.13 (d J = 8.7 Hz, 2H), 8.02 (br. S, 1H), 7.80 (d, J = 2.6 (Dt, J = 8.2 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.02 5.0 Hz, 1 H), 1.41 1.22 (m, 4H); LC / MS (ESI) [M + H] ⁺ = 337.15.

Example 4 Synthesis of 4- [4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenoxy]

Step 1. Preparation of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol

N, N ', 4-dihydroxybenzimidamide (193.4 mg, 1.271  ol) was used as a starting material and isobutyryl chloride (162.7 mg, 1.525  ol) was used instead of acetyl chloride as a starting material. (4-isopropyl-1,2,4-oxadiazol-3-yl) phenol (204.0 mg, 79%). Step 2. 4- [4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenoxy] - ^{methyl-6-picoline}

4- (5-isopropylphenyl) -1,4-oxadiazol-3-yl) phenol (101.4 mg, 0.4964 mmol) as a starting material, the target compound was obtained by the method of Example 1, Step 3 (48.2 mg, 29%).

^{: H NMR (300 MHz, CDC1} 3) δ 8.44 (dd, J = 5.6, 0.6 Hz, 1H), 8.18 (d, J = 8.9 Hz, 2H), 8.02 (. Br s, 1H), 7.80 (dd, J = 2.6, 0.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.02 (del, J = 5.5, 2.6 Hz, 1H), 3.32 LC / MS (ESI) [M + H] < + > = 339.31 (d, J = 5.1 Hz, 3H), 1.50

Example 5 Synthesis of 4- [4- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy]

Step 1. Preparation of 4- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenol

N ', 4-dihydroxybenzimidamide (150.0 mg, 0.9859 mmol) as a starting material and isobalyl chloride (142.6 mg, 1.183 mmol) instead of acetyl chloride as starting materials, (109.0 mg, 51%) of 4- (5-isobutylphenyl) 1,2,4-oxadiazolyl 3-yl) phenol. Step 2. Preparation of 4- [4- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy] -methylpicolinamide

The target compound was obtained by the same procedure as in Example 1, Step 3, using 4 (5-isobutyl-1,2,4-oxadiazol-3-yl) phenol (105.3 mg, 0.4825 mmol) as starting materials (52.1 mg, 31%).

_{H NMR (300 MHz, CDC1 3} ) δ 8.43 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.03 (br. S, 1H), 7.79 (d, J = 2.5 Hz, 1 H), 7.21

(d, J = 6.9 Hz, 2H), 7.02 (dd, J = 5.6, 2.5 Hz,

(D, J = 7.1 Hz, 2H), 2.40 2.21 (m, 1H), 1.08

(d, J = 6.7 Hz, 6 H); LC / MS (ESI) [M + H] < ⁺ > = 353.22.

Example 6 Synthesis of 4- [4- (5- (methoxymethyl) -2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

Step 1. Preparation of 4- [5- (mexemethyl) -1,2,4-oxadiazol-3-yl] phenol

(150 mg, 0.9859 mmol) as a starting material, and using carboxylacetyl chloride (112.4 mg, 1.035 mmol) instead of acetyl chloride as the starting material, the title compound was obtained as a white amorphous solid in the same manner as in Example 1, Step 2 Oxaziazol-3-yl] phenol (114.5 mg, 56.4)) was obtained as a colorless oil. Step 2. Preparation of 4- [4- (5- (mexemethyl) -1,2,4-oxadiazol-3-yl) phenoxy]

N-methylpicolinamide

The title compound was obtained by the same procedure as Example 1, step 3, using the title compound as a starting material and 4 ᅳ [5 (meroethyl) -1,2,4-oxadiazol-3-yl] phenol (98.2 mg, 0.476 mmol) (49.7 mg, 31%).

^{X H NMR (300 MHz, CDC1} 3) δ 8.45 (d, J = 5.5 Hz, 1H), 8.20 (d

J = 8.8 Hz, 2H), 8.02 (br s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.23 Hz, < / RTI > 1H), 4.79 (s, 2H)

LC / MS (ESI) [M + H] < ⁺ > = 3.60 (s, 3H)

341.20.

Example 7 Synthesis of N-methyl-4- [4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-phenoxy] picolinamide

Step 1. 4- [5- (Trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenol N ', 4-dihydroxybenzimidamide (299.7 mg, 1.970 mmol) (620.1 mg, 2.955 mmol) was used instead of acetyl chloride as a starting material to give 4- [5- (trifluoromethyl) ᅳ 1,2,3,4-tetrahydroisoquinoline- 4-oxadiazolyl 3-yl] phenol (328.9 mg, 73.4). Step 2. N-methyl-4- [4- (5- (trifluoromethyl) -1,2,4- oxadiazole - 3-yl) phenoxy] picolinamide

The starting material was prepared by the method of Example 1, Step 3 using the starting material of 4- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenol (102.1 mg, 0.4436 mmol) (33.2 mg, 17%).

_{ln NMR (300 MHz, CDC1 3} ) δ 8.47 (dd, J = 5.6, 0.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 2H), 8.03 (br. s, 1H), 7.80 (dd, J = 2.6, 0.5 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.07 (dd, J = 5.6, 2.5 Hz, 1H), 3.04 (ESI) [M + H] < ⁺ > = 365.23. Example 8 Synthesis of 4- [3- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-

Step 1. Preparation of N ', 3-dihydroxybenzimidamide

3-hydroxybenzoic acid (3.014 g, 21.82 ol ol) was added to SOCl ₂ (20 mL), DMF (77.4 mg, 1.06 mol) was added and the reaction was heated to reflux at 70 ^° C for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then diluted with toluene (10 mL) and concentrated under reduced pressure. The resulting residue was dissolved in THF (20 mL), cooled to 0 ^° C, and 50% NH ₃ aqueous solution (10 mL) was added thereto. The reaction mixture was stirred at room temperature for 16 hours. The resulting precipitate was diluted with EtOAc (100 mL) and distilled water (100 mL), and the aqueous layer was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (10 mL), dried over MgSO ₄ and concentrated under reduced pressure to obtain 3-hydroxybenzamide (2.6485 g). 3-Hvdroxybenzamide (2.649 g, 19.18 mmol) was added to THF (100 mL), and the mixture was stirred at 0 ^° C and trifluoroacetic anhydride (12.09 g, 57.54 mmol) was added. After stirring at room temperature for 30 minutes, pyridine (7.581 g, 95.90 匪 ol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. After the reaction mixture was concentrated under reduced pressure, EtOAc (100 mL) and distilled water (100 mL) were added to the residue. The aqueous layer was extracted with EtOAc (100 mL × 3). The collected organic layer was washed with brine (10 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc: Hx = 1: 2) to give 3-hydroxybenzonitrile . To this mixture was added 50% NH ₂ OH aqueous solution (20 mL), stirred at 70 ^° C for 16 hours and then at 90 ^° C for 4 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give N ', 3-dihydroxybenzimidamide (1.7332 g, 53%). Step 2. Preparation of 3- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol

N ', 3- dihydroxy benjeuyi mid-amide (150.0 mg, 0.9859 mmol) ^■ the embodiment as a starting material, to obtain isobutyryl chloride (125.3 mg, 1.176隱ol) instead of acetyl chloride in water banung Example 1, step 2 (92.5 mg, 46%) of 3- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol. Step 3. Use the following procedure to remove the solvent ^.

3 (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol (92.5 mg, 0.453 mmol) as a starting material, the target compound was obtained by the method of Example 1, Step 3 (31.8 mg, 21%).

^{: H NMR (300 MHz, CDC1} 3) δ 8.43 (dd, J = 5.6, 0.6 Hz, 1H), 8.08 - 7.94 (m, 2H), 7.85 - 7.83 (m, 1H), 7.75 (d, J = 2.4 (Dd, J = 8.2, 2.5, 1.0 Hz, 1H), 7.02 (dd, J = 5.6,2.6 Hz, 1H), 3.30 (hept, J = 7.1 Hz, 1H), 3.03 (d, J = 5.1 Hz, 3H), 1.47 (d, J = 7.0 Hz, 6H). LC / MS (ESI) [M + H] ⁺ = 339.11.

Example 9 Synthesis of 4- [3- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy]

Step L 3- (5-Isobutyl-1,2,4-oxadiazol-3-yl) phenol

N, N ', 3-dihydroxybenzimidamide (150.0 mg, 0.9859 mmol) as a starting material and isobalyl chloride (142.6 mg, 1.183 mmol) (109.9 mg, 51%) of 3- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenol. Step 2. Preparation of 4- [3- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy] -methylpicolinamide

The objective compound was obtained by the same procedure as in Example 1, Step 3, using 3- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenol (109.9 mg, 0.5035 mmol) as a starting material (44.7 mg, 25%).

: 1 H NMR (300 MHz, CDCl ₃ ) 隆 8.42 (dd, J = 5.6, 0.5 Hz, 1H)

(M, 2H), 7.84 (dd, J = 2.5,1.5 Hz, 1H), 7.75 (dd, J = 2.6, 0.5 Hz, 1H), 7.63-7.51 J = 8.2, 1.0 Hz, 1H), 7.02 (dd, J = 5.6,2.6 Hz, 1H), 3.03 (d, J = 5.1 Hz, 2.38-2.21 (m, 1H), 1.06 (d, J = 6.7 Hz, 6H). LC / MS (ESI) [M + H] ⁺ = 353.22.

Example 10 Synthesis of 4- [3- (5- (methoxymethyl) -1,2,4-oxadiazol-3-yl)

Step 1. 3- (5- (Methoxymethyl) -1,2,4-oxadiazol-3-yl) phenol ^.

N ', 3-dihydroxybenzimidamide (150.0 mg, 0.9859 mmol) (112 mg, 1.035 mmol) instead of acetyl chloride in place of acetyl chloride in step 1, the title compound was obtained as a yellow solid from 3- (5- (methicillmethyl) -1,2,4-oxa Diol-3-yl) phenol (114.5 mg, 56%). Step 2. Synthesis of 4- [3- (5- (mexemethyl) -1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

The title compound was obtained by the same procedure as Example 1, step 3, using 3- (5- (methxymethyl) -1,2,4-oxadiazol-3-yl) phenol (96.1 mg, 0.466 mmol) (41.5 mg, 26%).

_{lW NMR (300 MHz, CDC1 3} ) δ 8.43 (d, J = 5.6 Hz, 1H), 8.10 - 7.97 (m, 2H), 7.91 eu 7.82 (m, 1H), 7.75 (d, J = 2.5 Hz, 1H 2H), 3.58 (s, 3H), 3.03 (m, 2H), 7.64 (s, d, J = 5.1 Hz, 3H); LC / MS (ESI) [M + H] + = 341.07.

Example 11 Synthesis of 4- (4- (5-isopropyl-, 2,4-oxadiazol-3-yl) -2-methylphenoxy) -N-methylpicolinamide

Step 1 - Preparation of 4-hydroxy-3-methylbenz omeptide

4-hydroxy-3-methylbenzamide (241 mg, 24%) was obtained by the method of Example 8, Step 1, using 4-hydroxy-3-methylbenzoic acid as a starting material (1.00 g, 6.59 mmol) . Step 2. 4-Hydroxy-3-methylbenzonitrile

4-hydroxy-3-methylbenzonitrile (268 mg, 81%) was obtained by the method of Example 8, Step 1 using 4-hydroxy-3-methylbenzamide (376 mg, 2.49  ol) . Step 3. Preparation of (Z) -N ', 4-dihydroxy-3-methylbenzimidamide

(Z) -N ', 4-dihydroxy-3-methyl (4-hydroxyphenyl) propanoate was obtained by the method of Example 1, Step 1, using 4-hydroxy-3-methylbenzonitrile (352 mg, Benzimidamide (423 mg, 96%). Step 4. Preparation of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2-methylphenol

(Z) -N ', 4-dihydroxy-3-methylbenzimidamide (300 mg, 1.81 (4-isopropenyl-1,2,4-oxadiazol-3-yl) -2-methylphenol (304 mg, 52%) was obtained by the method of Example 1, Step 2, %). Step 5. Preparation of 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2-methylphenoxy) -N-methylpicolinamide

The procedure of Example 1, Step 3 was repeated with the use of 4- (5-isopropyl-1,2,4-oxadiazolyl) -3- methylphenol (100 mg, 0.458  ol) The compound was obtained. (26.9 mg, 17%).

^! H丽R (300 MHz, CDCls ) δ 8.41 (d, J = 5.6 Hz, 1H), 8.06 (s: 1H), 8.05 7.88 (m, 2H), 7.71 (d, J = 2.5 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 5.6,2.6 Hz, 1H), 3.42 3.24 ), 1.50 (d, J = 7.0 Hz, 6H).

Example 12 Synthesis of 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl)

(Z) -N ', 4-dihydroxy-3 (4'-hydroxyphenyl) propanoic acid was obtained by the method of Example 1, Step 1, using 4-hydroxyphenyl 3,5-dimethylbenzonitrile , 5-dimethylbenzimidamide (1.31 g, 100%). Step 2. Preparation of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenol

(5-isopropyl (4-hydroxyphenyl) propyl) amine was prepared by the same procedure for the example 1, step 2, using -1,2,4-oxadiazol-3-yl) -2,6-dimethylphenol (232 mg, 36%). Step 3. Preparation of 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy)

The title compound was prepared by the method of Example 1, Step 3 using as starting material 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenol (100 mg, The title compound was obtained (13.1 mg, 8%).

^{: H NMR (300 MHz, Chloroform-} d) δ 8.38 (d, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.88 (s, 2H), 7.65 (d, J = 2.5 Hz, 1H), J = 5.1 Hz, 3H), 2.18 (s, 6H), 1.50 (d, J = 7.0Hz, 1H), 6.81 (dd, J = 5.6,2.6Hz, 1H) 6H). Example 13 Synthesis of N-methyl-4 - [(6- (5-methyl-1,2,4-oxadiazol-3-yl) naphthalen-2-yl)] picolinamide

Step 1. Preparation of N ', 6-dihydroxy-2-naphthimidamide

Dihydroxy 2-naphthimidamide (651.2 mg, 30 [Eta]) was obtained as a starting material from 6-hydroxy-2-naphthoic acid (2.002 g, 10.64 mmol) %). Step 2. Preparation of 6- (5-methyl-1,2,4-oxadiazol-3-yl) naphthalene-

The title compound was prepared by the same method as in Example 1, Step 2, using N, N'-dihydroxy-2-naphthimideamide (150.0 mg, 0.7418 mmol) and acetyl chloride (61.2 mg, 0.779 隱 ol) Methyl-1,2,4-oxadiazol-3-yl) naphthalen-2-ol (64.4 mg, 38%). Step 3. Preparation of ^ methyl- 4 - [(6- (5-methyl-1,2,4-oxadiazol-3-yl) naphthalen-2-yl) oxy] picolinamide

Using the procedure of Example 1, Step 3, and using the target compound as a starting material, 6- (5-methyl-1,2,4-oxadiazol-3-yl) naphthalen- (21.8 mg, 21%).

_{¾ NMR (300 MHz, CDC1 3} ) δ 8.65 (s, 1Η), 8.45 (dd, J = 5.6, 0.6 Hz, 1H), 8.20 (dd, J = 8.6, 1.7 Hz, 1H), 8.10 - 7.98 (m J = 8.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.90 , 2.4 Hz, 1H), 7.06 (dd, J = 5.6,2.6 Hz, 1H), 3.04 (d, J = 5.1 Hz, 3H), 2.74 (s, 3H); LC / ] ⁺ = 361.18.

Example 14 Synthesis of 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenoxy) -N, N-dimethylpicolinamide

Step 1. Preparation of 4-chloro-N, N-dimethylpicolinamide

4-Chloro-N-methylpicolinamide (1.00 g, 5.86 mmol) was dissolved in DMF (20 mL), and incubated ^at 0 ^° C. NaH (60% solution in mineral oil, 235 mg, 5.86 mmol) was added and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was cooled to 0 ^° C, and Mel (1.66 g, 11.7 mmol) was added thereto. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL) and distilled water (100 mL), and the aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layer was washed with distilled water (10 mL) and brine (5 mL), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / acetone = 30: 1) -Chloro-N-methylpicolinamide (887 mg, 82%). Step 2. Synthesis of 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenoxy) -N, N-dimethylpicolinamide

(100 mg, 0.490 mmol) and 4-chloro-N, N-dimethylpicolinamide (90.5 mg, 0.490 mmol ) As a starting material, the target compound was obtained by the method in Example 1, Step 3 (26.3 mg, 15%).

^{: H NMR (300 MHz, CDC1} 3) δ 8.49 (d, J = 5.7 Hz, 1H), 8.18 (d J = 8.8 Hz, 2H), 7.26 - 7.17 (m, 3H), 6.94 (dd, J = 5.7 , 2.5 Hz, 1H), 3.41-3.24 (m, 1H), 3.12 (d, J = 8.5 Hz, 6H), 1.49 (d, J = 7.0 Hz, 6H).

Example 15 Synthesis of 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy) -N, N-dimethylpicolinamide

A mixture of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenol (150 mg, 0.646 Â ol) and 4-chloro-N, N-dimethylpicolinamide (119 mg, 0.646 mmol) as starting materials, the target compound was obtained by the method of Example 1, Step 3 (46.1 mg, 19%).

^! _{H NMR (300 MHz, CDC1 3} ) δ 8.43 (d, J = 5.7 Hz, 1H), 7.88 (s 2H), 7.06 (d, J = 2.4 Hz, 1H) 6.73 (dd, J = 5.7, 2.5 Hz, 1H), 3.42-3.24 (m, 1H), 3.10 (d, J = 12.5 Hz, 6H), 2.19 (s, 6H), 1.49 (d, J = 7.0 Hz, 6H).

Example 16 Synthesis of N-methyl-4 - [(3-methyl-2- (5-methyl-1,2,4-oxadiazol- ] Picolinamide

Step 1. 6-Methoxy-3-methylbenzo [b] thiophene-2-carboxamide

(1.558 g, 7.010  ol) was added to SOCl ₂ (14 mL) followed by the addition of DMF (47.2 mg, 0.646 mol) and a solution of 6-hydroxy- The reaction was stirred at 80 ° C for 4 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting precipitate was diluted with toluene (20 mL) and concentrated under reduced pressure. The resulting residue was added to THF (20 mL), and then 40% NH ₃ aqueous solution (20 mL) was added thereto and stirred at room temperature for 16 hours. The reaction was neutralized to pH = 7 with 2N HCl aqueous solution and the aqueous solution was extracted with EtOAc (50 mL x 3). The organic layer was 0.05 N HC1 solution (10 mL) and brine, then washed successively with (10 mL) M _g S0 ₄ was dried and concentrated reduced pressure meteuk eu 6-3-methyl-benzo [b] thiophene-2-car (1.1682 g, 75%). Step 2. 6-Methoxy-3-methylbenzo [b] thiophene-2-carbonitrile

3-Methylbenzo [b] thiophene-2-carboxamide (1.1672 g, 5.2750 mmol) was added to 1,2-dichloroethane (25 mL) and trifluoroacetic anhydride 3.325 g, 15.83 ol ol) was added and stirred at room temperature for 3 minutes. To the reaction mixture was added pyridine (2.087 g, 26.38 mmol), and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with CH ₂ Cl ₂ (30 mL), IN HCl aqueous solution (50 mL) was added, and the aqueous layer was extracted with CH ₂ Cl ₂ (50 mL × 3). The combined organic layer was washed with brine (10 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc: Hx = 1: 10) Benzo [b] thiophene-2-carbonitrile (757.6 mg, 71%). Step 3. Synthesis of N'-hydroxy-6-carboxy-3-methylbenzo [b] thiophene-2-carboxy n de

The 6-methoxy-3-methylbenzo [b] thiophene-2-carbonitrile was added to a mixed solution of 50% NH ₂ OH aqueous solution (15 mL) and EtOH (5 mL) Lt; / RTI > The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain N ¹ -hydroxy-6-meperoxy-3-methylbenzo [b] thiophene-2-carboximidamide (956.3 mg, 99%). Step 4. Preparation of 3- (6-methoxy-3-methylbenzo [b] thiophen-2-yl) -5-methyl-1,2,4-oxadiazole

Hydroxybenzo [b] thiophene-2-carboximidamide (249.8 mg, 1.056  ol) and acetyl chloride (99.7 mg, 1.27 3-methylbenzo [b] thiophen-2-yl) -5-methyl-1,2,4-oxazin- (135.1 mg, 49%). Step 5. Preparation of 3-methyl ᅳ 2- (5-methyl-1,2,4-oxadiazol-3-yl) benzo [b] thiophene

-6-ol

Methyl-1,2,4-oxadiazole (124.3 mg, 0.4775 sleep ol) was dissolved in CH ₂ Cl ₂ (4 (4-methylbenzo [b] thiophene 2-yl) mL), and incubated ^at -78 ^° C. BBr ₃ (1.0 M CH 2 Cl 2 solution, 1.4 mL, 1.4 Å _{10 I} ) was added to the solution. The reaction was stirred at room temperature for 16 hours and then the reaction mixture was added to a solution of H ₂ O (30 mL) and CH ₂ Cl ₂ (40 mL). The aqueous layer was neutralized to NaHCO ₃ i 0 and extracted with CH ₂ Cl ₂ (50 mL x 3). The combined organic brine (10 mL) after a MgS0 ₄ dried over silica gel and concentrated under reduced pressure to a common compound pipe claw Mato our washed with _{_{(CH 2 C1 2: acetone =}} 30 to give 3-methyl-2- (5-methyl-1 Yl) benzo [b] thiophen-6-ol (108.0 mg, 92% (5-methyl-1,2,4-oxadiazol-3-yl) benzo [b] thiophene-6-yl) oxy] picoline

3-methyl ᅳ 2- (5-methyl-1,2,4-oxadiazol-3-yl) benzo [b] thiophen-

(98.0 mg, 0.398 mmol) as starting materials, the target compound was obtained in the same manner as in Example 1, Step 3 (42.6 mg, 28%).

_{^ NMR (300 MHz, CDC1 3} ) 8.42 (dd, J = 5.6, 0.6 Hz, 1H), 8.02

(dd, J = 2.2, 0.5 Hz, 1H), 7.86 (d, J = 8.7, 0.5 Hz, 1H) Hz, 1 H), 7.20 (dd, J = 8.7,

ί the path

2.2 Hz, 1H), 7.02 (dd, J = 5.6,2.6 Hz, 1H), 3.03 (d,

3H), 2.83 (s, 3H), 2.70 (s, 3H); LC / MS (ESI) [M + H] ⁺ = 381.10.

Example 17 Synthesis of 4 - [(2- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thi-6-yl) oxy] Picolinamide

Oxadiazole

Hydroxybenzo [b] thiophene-2-carboximidamide (251.2 mg, 1.063 mmol) and propionyl chloride (117.5 mg, 1.271  ol) . 3-methylbenzo [b] thiophen-2-yl) -1,2,4-oxadiazole (757.6 mg, 71% . Step 2. Preparation of 2- (5-ethyl-1,2,4-oxadiazolyl 3-yl) -3-methylbenzo [b] thiophene

-6 mol

(137.9 mg, 0.5027  ol) as the starting material as a starting material, the title compound was obtained as a colorless oil from the fraction eluted with ethyl acetate-hexane Yl) -3-methylbenzo [b] thiophen-6-ol (116.5 mg, 89%) was prepared by the method of Example 12, Step 5 from 2- (5-ethyl-1,2,4-oxadiazol- &Lt; / RTI > Step 3. Preparation of 4 - [(2- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [ Picolinamide

As starting materials, the title compound was obtained as a colorless powder starting from 2- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-ol (100.0 mg, 1, < / RTI > step 3, the title compound was obtained (36.2 mg, 21%).

_{^ NMR (300 MHz, CDC1 3} ) δ 8.43 (dd, J = 5.6, 0.6 Hz, 1H),

(Dd, J = 2.3, 0.5 Hz, 1H), 7.76 (dd, J = 2.6, 0.5 Hz, 1H) , 7.20 (dd, J = 8.7,2.2 Hz, 1H), 7.02 (dd, J = 5.6,2.6 Hz, 1H), 3.10 2.96 (m, 5H), 2.84 Hz, 3H); LC / MS (ESI) [M + H] < ⁺ > = 395.14.

Example 18 Synthesis of 4 - [(2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-me-yl) oxy] -N-methylpicolinamide

Yl) -1,2,4-oxadiazole

(161.2 mg, 0.6822  ol) and cyclopropanecarbonyl chloride (85.6 mg, 0.819 mmol) were added to a solution of 5-amino-5-methoxy- The title compound was obtained as the material of Example 1, step 2 from 5-cyclopropyl-3- (6-methoxy-3-methylbenzo [b] thiophen- (81.6 mg, 39%). Step 2. Preparation of 2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-

Starting from 5-cyclopropyl-3- (6-methoxybenzylmethylbenzo [b] thiophen-2-yl) - 1,2,4- oxadiazole (81.6 mg, 0.285 sleep ol) (45.1 mg, 58%) was obtained as white crystals from 2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) %). Step 3. Preparation of 4 - [(2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenyl 3-thylbenzo [b] thiophen-6-yl) oxy] Picolinamide

Using 45 mg (0.1656 mmol) of 2- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-ol as starting materials The target compound was obtained by the method of Example 1, Step 3 (11.9 mg, 21%).

^{X H NMR (300 MHz, CDC1} 3) δ 8.42 (d, J = 5.6 Hz, 1H), 8.03 (br. S, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.76 (d eu J = (Dd, J = 5.6, 2.6 Hz, 1H), 3.03 (d, J = (M, 4H); LC / MS (ESI) [M + H] < ⁺ > = 407.02 .

Example 19 Synthesis of 4 - [(2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzene [b] thiophen- - methylpicoline ^azine

Step 5-Isopropyl-3- (6-methoxy-3-methylbenzo [b] thiophen-

1,2,4-oxadiazole

3-methylbenzo [b] thiophene-2-carboximidamide (239.2 mg, 1.012 mmol) and isobutyryl chloride (129.0 mg, 1.210 mmol) 3-methylbenzo [b] thiophene-2-yl) -1,2,4-oxadiazole was obtained by the method of Example 1,

(235.3 mg, 81%). Step 2. Preparation of 2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [

(189.6 mg, 0.657 mmol) as starting materials, the title compound was obtained as a colorless oil from 5-isopropyl-3- (6-methyloxy-3-methylbenzo [b] thiophen- Oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-ol (119.4 mg, 66%) was prepared by the method of Example 12, Step 5 from 2- (5-isopropyl- ). Step 3. Preparation of 4 - [(2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen- Methylpicolinamide

(108.5 mg, 0.3955 mmol) as a starting material, the title compound was obtained as a colorless powder from the fraction obtained in Example (2) using 2 (5-isopropyl-1,2,4-oxadiazol- 1, step 3, the desired compound was obtained (38.8 mg, 24%).

ln NMR (300匪z, CDC1 3) δ 8.42 (dd, J = 5.6, 0.5 Hz, 1H), 8.03 (br. s, 1H), 7.95-7.80 (m, 1H), 7.76 (dd, J = 2.6 , 0.5 Hz, 1H), 7.68 7.51 (m, 1H), 7.19 (dd, J = 8.7, 2.2 Hz, 1H), 7.02 (dd _; J = 5.6,2.6 Hz, 1H), 3.34 (hept, J = 7.0 Hz, 1H), 3.03 (d, J = 5.1 Hz, 3H), 2.84 6H); LC / MS (ESI) [M + H] < ⁺ > = 409.25.

Example 20 Synthesis of N-methyl-4 - [(3-methyl-2- (5- (trifluoromethyl) -1,2,4- Yl) oxy] picolinamide

Step 1. 6-Hydroxy-3-methylbenzo [b] thiophene-2-carboxamide

6-hydroxy-3-methyl (3-methylpiperazin-1-yl) -3-methylbenzo [b] thiophene- Benzo [b] thiophene-2-carboxamide (615.3 mg, 66%).

Step 2. Preparation of 4 - [(2-Carbamoyl-3-methylbenzo [b] thiophen-6-yl) oxy] -N-methylpicolinamide

The title compound was synthesized in the same manner as in Example 1, Step 3, using 6-hydroxy-3-methylbenzo [b] thiophene-2-carboxamide (300.0 mg, 1.449 隱 ol) -3-methylbenzo [b] thiophen-6-yl) oxy] -N-methylpicolinamide (63.3 mg, 13%). Step 3-methyl-4 - [(3-Methyl-2- (5- (trifluoromethyl) - 1, _{2,4-oxadiazol-eu-3-yl)} benzo _[b] _{thiophen-6-il} ) Oxy] picoline ami

A [(2-carbamoyl-3-methyl-benzo [b] thiophen-6-yl) oxy] -N- methyl-picoline Oh imide (63.3 mg, 0.188 mmol) to _{_{CH 2 C1 2 (2 mL)}} - 4 After cooling to 0 ^° C, trifluoroacetic anhydride (157.6 mg, 0.752 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, cooled to 0 ^° C, and then pyridine (74.3 mg, 0.940 ol ol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (30 mL), distilled water (30 mL) was added, and the aqueous layer was extracted with CH ₂ Cl ₂ (50 mL × 3). The combined organic layers were washed with 10 mL of brine Dried over MgSO ₄ and concentrated under reduced pressure. Purification of the common compound obtained by silica gel column chromatography _{_{(CH 2 C1 2: acetone =}} 1: 2) 4 - [(2- cyano-3-methyl-benzo [b] thiophen-6-yl) oxy] -N- Methylpyrimidine and 4 - [(2-cyano-3-methylbenzo [b] thiophen-6-yl) oxy] -N- methyl-N- (2,2,2- A mixture of choline amides was obtained. The resulting residue was added to a 50% aqueous NH ₃ OH solution (3 mL), followed by stirring at 85 ^° C for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to give pyridine (3 mL). Trifluoroacetic acid (74.1 mg, 0.353 mmol) was added and the mixture was refluxed at 120 T for 16 hours. reaction The water was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in THF (2 mL) and distilled water (0.5 mL). 1 N NaOH aqueous solution (0.5 mL) was added thereto and stirred at room temperature for 2 hours. To the reaction was added 2 N HCl aqueous solution, diluted with CH ₂ Cl ₂ (50 mL) and H ₂ O (30 mL), and the aqueous solution was extracted with CH ₂ Cl ₂ (30 mL × 3). The collected organic layer was washed with brine (5 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc: Hx = 1: 1) to obtain the desired compound (18.2 mg, 22%).

_{ln NMR (300 MHz, CDC1 3} ) δ 8.45 (dd, J = 5.6 0.6 Hz, 1H), 88..0044 (bbrr .. ss ,, 11HH),, 77..9911 ((dddd ,, JJ == J = 2.2, 0.5 Hz, 1H), 7.24 (dd, J = 8.8, 2.2 Hz, 1H), 7.75 , 7.06 (dd, J = 5.6, 2.6 Hz, 1H) 3.04 (d, J =

3H), 2.88 (s, 3H); LC / MS (ESI) [M + H] + = 435.17.

Example 21 Synthesis of 4 - ((6- (5-isopropyl-, 2,4-oxadiazol-3-yl) pyridin-3- yl) oxy) -N-methylpicolinamide

Step 1. Synthesis of (Z) -N'-hydroxy-5-mechsypicoline imidamide

(Z) -N'-hydroxy-5-meroxypicolinimideamide (546.9 mg, 3.355 mmol) was obtained by the same method as in Example 1, Step 1, using 5-methoxypicolinonitrile mg, 98%). Step 2. 5-Isopropyl-3- (5-methoxypyridin-2-yl) -1,2,4-oxadiazole

(382 mg, 3.59 mmol) was used instead of acetyl chloride as starting materials and (Z) -N'-hydroxy-5-megestipicin imidamide (500.1 mg, 2.994 mmol) 5-isopropyl-3- (5-methoxypyridin-2-yl) -1,2,4-oxadiazole (550.5 mg, 84%) was obtained by the method of Example 1, Step 2. Step 3. Preparation of 6- (5-isopropyl-l, 2,4-oxadiazol-3-yl) pyridin-

The title compound was prepared by the method of Example 12, Step 5 using 5-isopropyl-3- (5-methoxypyridin-2-yl) -1,2,4- oxadiazole (499.9 mg, To give 6- (5-isopropyl-1,2,4-oxadiazol-3-yl) pyridin-3-ol (321.8 mg, 69%). Step 4. Preparation of 4 - ((6- (5-isopropyl-1,2,4,5-oxadiazol-3-yl) pyridin- Yl) oxy) -N-methylpicolinamide

3-yl) pyridin-3-ol (150.0 mg, 0.7309 mmol) as starting materials, the target compound (117.6 mg, 47%).

^{: H NMR (500 MHz, CDC1} 3) δ 8.65 (d, J = 2.7 Hz, 1H), 8.48 (d J = 5.6 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.02 (s, J = 8.6, 2.8 Hz, 1H), 7.05 (dd, J = 5.6,2.6 Hz, 1H), 3.36 (hept, J = 7.0Hz, 1H) LC / MS (ESI) [M + H] < ⁺ > = 340.26 (d, J = 5.1 Hz, 3H), 1.51 (d, J = 7.0 Hz, 6H).

Example 22: Synthesis of 5- (5-isopropyl-1,2,4-oxadiazol-3-yl) -N-methyl-2-oxo- - [1,4'-bipyridine] Carboxamide

(Z) -N'-hydroxy-6-methicinicotinimidamide (1.921 (3H)) was obtained by the method of Example 1, Step 1, using 6-mexylicycotinonitrile as a starting material (1.5366 g, 11.46 mmol) g, 99%). Step 2. 5-Isopropyl-3- (6-methoxypyridin-3-yl) -1,2,4-oxadiazole.

(192.3 mg, 1.805 mmol) instead of acetyl chloride was used as the starting material and the reaction was carried out using (Z) -N'-hydroxy-6-mexylicinotineimidamide (251.4 mg, 1.504 mmol) as a starting material and isobutyryl chloride 3-yl) -1,2,4-oxadiazole (72.6 mg, 22%) was obtained by the method of Example 1, Step 2. Step 3. Preparation of (5-isopropyl-l, 2,4-oxadiazol-3-yl) pyridin-

5-isopropylphenyl 3- (6-mexylpyridin-3-yl) -1,2,4-oxadiazole

(5-isopropyl-1,2,4-oxadiazol-3-yl) pyridin-2-ol (340.9 mg) obtained in the same manner as in Example 12, Step 5, mg ᅳ 51%). Step 4. Preparation of 5- (5-isopropyl-1,2,4-oxadiazol-3-yl) -N-methyl-2-oxo-2H- [1,4'-bipyridine] Vox 0

5- (5-isopropyl-1,2,4,5-oxadiazol-3-yl) pyridin-2-ol (150.0 mng

0.7309 mmol) as starting materials _. (17.8 mg, 7%).

_{¾ NMR (300 MHz, CDC1 3} ) δ 8.70 (dd, J = 5.3, 0.6 Hz, 1H), (Dd, J = 8.7 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H) 0.6 Hz,

<Experimental Example 1> A method of searching for the pharmacological effect of the antimicrobial virus using the cytopathic effect (CPE)

In the experimental materials, first, the cells were HeLa (human cervical malignant tumor cells) MRC-5 human embryonic lung cells) and RD (human embryonic muscle cells), and standard drugs were ribavirin (Riv) Pleconar Π, pleco) and ΒΤΑ-798 (ΒΤΑ). Samples were dissolved in 100% dimethyl sulfoxide (DMSO) at 10 to 40 mg / ml. The water-soluble samples were dissolved in PBS (-) solution and stored ^at -20 ^° C. 5 times consecutive dilution, and the concentration of dimethylsulfoxide in the wells was controlled so as not to exceed 0.5% or 1%. The pharmacological screening used virus - induced cytopathic effect (CPE) inhibition. In other words, the survival rate of the treated cells was calculated based on the CPE inhibition rate of 100% when the cell viability was 100% by the antiviral activity, Inhibition rate was calculated. The CPE inhibition rate, i.e. the cell viability, was determined by MTT [3- (4,5-dimethylthiazoline) -2,5-diphenyltetrazolium bromide], MTS [3- (4,5- (3-carboxymethylphenyl) -2- (4-sulfophenyl) -2H-tetrazolium] or FDA (Fluorescein diacetate). The cells diluted with MEM containing 2% FBS (DME / 2% FBS) or MEM containing 2% FBS (MEM / 2% FBS) were added to each well by 100 ^ inoculated to an inoculum size is 100 CCID ₅₀ (50% cell culture inhibitory dose) in culture medium was removed, and then adsorbed at 33 ^° C or 37 ^° C for 30 minutes to 1 hour. In each concentration by two wells per concentration by the drug diluted three times or five times in a row, by 100 ^ was added to each well, except for HRVOuiman rhinovirus) were incubated in the 33 ^° C the remaining viruses at 37 ^° C C0 ₂ incubator After culturing for 2 ~ 3 days, the results were measured. 50 μl of double-concentration drug was added to the cells, and the virus solution 50 was added, followed by culturing for 2 to 3 days without removing the culture solution. The test conditions for each virus are shown in Table 2 below. [Table 2]

In the case of HeLa cells, the cell viability (or CPE ratio) was measured using MTT or MTS, and the average value of 2 wells was used to determine the EC ₅₀ (50% effective concentration) . MTT detection was performed by removing all of the culture medium, adding 50 ^ of the MTT solution diluted with the culture medium to each well, and culturing for 30 minutes at 37 ^° C. To dissolve the reduced formazan, organic solvent 100 was added The optical density of 0D (optical density) of each sal at 540 nm and 690 nm was measured using a microplate reader, and the difference between absorbance at 540 nm and 690 nm was determined and used for the calculation. The culture medium was removed and 90 [mu] L of culture medium and 10 [mu] M of MTS-phenazine methosulfate (Promega, Rayon, Netherlands) were added to each well. After incubation at 37 [ ^deg .] C for 2 hours, Fletcher The ODD of each well at 498 ηηι was measured using a reader reader.The CPE was determined by the FDA for RD and MRC-5 cells.To remove all of the culture medium and add 3 ug / ml FDA solution And fluorescence values were read using a 485 nm excitation filter and a 538 nm emission filter using a microplate fluorescence meter (F 1 uoroskan Ascent, Labsystem). To investigate the toxic effects of viruses, virus-free culture media were added to the cells at the time of virus inoculation and then treated in the same manner as mock-infected cells inoculated with virus. After incubation, the medium was removed and the diluted drug was added once more. The cells were incubated for the same time as those infected with the virus, A and together, MTT or MTS or FDA concentration of drug that kills 50% of cells by the drug is compared to the number of cells that survived the well infected with each simulation was added and the cell control group-well drug is not added to the CC _{50 (50} % Cytotoxic concentration). As with viral infection, the mean value was calculated by adding to two wells for each concentration. That is, the simulated survival rate of infected cells for cytotoxicity measurement) was calculated by the following equation (1).

Equation (1) is based on the equation (1) _; The survival rate is 100% Waga

Toxicity is the strongest. The concentration of the drug capable of killing 50% of the cells is indicated by CC ₅₀ , which means that the higher the value, the less toxicity. In addition, the antiviral effect can be calculated by the following equation (2)

(There is no antiviral effect with an antiviral effect of 10M and a survival rate of 0 when the survival rate of the virus is 100%).

The concentration of drug in EC ₅₀ that may indicate an 50% survival

The lower the value, the better the antiviral efficacy.

Experimental Example 2: Anticancer virus effect detection using the multicycle cytopathic effect (CPE) reduction assay

The anti - cornavirus effect detection was performed using the multi - cycle CPE reduction assay. The antiviral activity of the compound is determined by the MTS [3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethylphenyl) -2- (4-sulfophenyl) It was first determined by a basic CPE reduction assay. Specifically, each cell was inoculated with each virus to 100 CCID ₅₀ (50% cell culture inhibiting amount) for each well in the cells proliferated for fusion in a 96-well dish. After adsorption at 37 ^° C for 2 hours, the virus was removed and the stair-diluted compounds added. Cultured cells were further cultured for 3 days at 37 ^° C until the untreated control virus (VC) was measured as complete CPE. The medium was then removed and 90 [mu] L of cultured cell vehicle and 10 MTS-phenazine methosulfate (Promega, Rayon, NJ) were added to each well. After incubation at 37 ° C for 2 hours, 0D (optical density) value of each sal at 498 nm was measured using a microplate reader. The% CPE value for the efficacy evaluation was calculated by the following equation (3).

[Equation 3]

The% CPE value for measuring the cytotoxicity of the drug was calculated by the following equation (4)

. ∞ (water)

&Lt; tb >

In the above equations (3) and (4) The OD (CC) is 0D of the cell culture solution which is not induced in the virus and not treated with the compound,

OD (VC) is 0D of virus-induced and compound-treated control cultured cells,

0D (virus + compound) is 0D of cultured cells infected with the virus treated with the concentrated compound,

0D (compound) is 0D of the cultured cells treated with only the concentrated compound,

OD (Blank) is the OD of the well to which only the culture medium is added. The effective concentration (EC ₅₀ ) is the concentration of the drug that causes 50% of the cells to survive by the CPE of the induced virus, and the cytotoxic concentration (CC ₅₀ ) is the concentration of the drug that killed 50% (logarithmic interpolat ion). The cytotoxicity results are shown in Table 3 below.

[Table 3]

In addition, the compounds of the examples according to the present invention,

The effective concentrations (EC ₅₀ ) for the Coxsackie virus B3 (CoxB3), the poliovirus 3 (PV3) and the rhinovirus (HRV14, HRV21 and HRV71) are shown in Table 4 below. Furthermore, the effective concentration (EC ₅₀ ) of the compounds of the examples according to the present invention against Enterovirus (EV) was also measured and shown in Table 5 below.

[Table 4] _// : _/ O ₆₀ S8S2MI _> d ₆ ss-06szAV

The compound according to the present invention was found to have excellent antiviral activity against Enterovirus (EV) and Poliovirus myiasis 3 (PV3) and rhinovirus (HRV14, HRV21 and HRV71) belonging to the picornavirus group, , And that the compound of the present invention exhibits excellent antiviral activity even at a very low EC ₅₀ value of 10 y M or less.

&Lt; Formulation Example 1 > Preparation of pharmaceutical preparation

<1-1> Preparation of powder

2 g of the compound represented by the formula 1

1 g

Were mixed and filled in an airtight container to prepare a powder.

<1-2> Preparation of tablets

Compound represented by formula (1) 100 mg Corn starch 100 mg Lactose 100 mg Magnesium stearate 2 mg Tablets were prepared by tableting according to a conventional method for producing tablets common to the above components.

<1-3> Manufacture of camphor

Compound represented by formula (1) 100 mg Corn starch 100 mg Milk 100 mg Stearic acid mannitol 2 mg After the above ingredients were mixed, capsules were prepared by layering into gelatin capsules according to the conventional preparation method of capsules. <1-4> Preparation of Injection Solution

The compound 10 // g / mi represented by the formula (1)

Until diluted hydrochloric acid BP 3.5

Sodium chloride BP injected up to 1 m Pore volume of a suitable volume The compound according to the invention is dissolved in the BP and the pH of the resulting solution is adjusted to pH 3.5 with diluted hydrochloric acid BP and the injected sodium chloride BP is used The volume was adjusted and the layers were shaved. The solution was charged into a 5-type I ampoule made of transparent glass, sealed in the upper lattice of the air by dissolving the glass, sterilized by autoclaving at 120 ^° C for 15 minutes or longer, and an injection solution was prepared. [Industrial applicability]

The novel antiviral compound according to one aspect of the present invention not only has low cytotoxicity but also exhibits excellent antiviral activity against picornavirus such as poliovirus, rhinovirus, etc. Therefore,

Acute hemorrhagic conjunctivitis, viral meningitis, foot and mouth disease, waterborne disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, encephalitis, encephalitis, cold, herpes zoster, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia , Vasculitis, or otitis media. The term " pharmaceutical composition "

Claims

[Claims] [Claims]

[Claim 1]

1, an optical isomer thereof, and

C

Lt; RTI ID = 0.0 > pharmaceutically < / RTI &

- With

One

A ¹ , A ² and A ³ are independent

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^{6 π} and - ¹ RR ^{77 each} independently represents a hydrogen atom or a substituent group selected from the group consisting of N, O and S, and b include a non-substituted or a -G ¹ a heteroaryl of from 5 to 10 atoms substituted by Advanced group - _G i is the side chain of a straight chain is unsubstituted or substituted with one or more halogen d- ₇ alkyl, d- ₇ a straight or branched alkoxy d- a straight-chain or branched chain ₇ t kill, or unsubstituted C ₃ - ₆ cycloalkyl, in which p is 1 to 100; Gen -OH, -CN, -N0 _2, the CO straight-chain or branched alkyl, alkoxy chain, a straight or branched alkyl-amino-carbonyl-chain or branched alkyl and aminocarbonyl;

X is = CH-, or = N-; And L is a single bond, or -O-).

[Claim 2]

The method according to claim 1, Ring

Or wherein AA < ² > and

Is linear or branched alkyl of-H, or d- ₅ ,

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently -H or an unsubstituted or monovalent group comprising at least one heteroatom selected from the group consisting of N, O and S and a heteroaryl substituted with 0 to 5 to 8 atoms -G ^1, wherein -G ¹ is of the unsubstituted or substituted with one or more halogen dE straight or branched chain alkyl, straight or branched alkoxy d-5 straight or branched alkyl, or unsubstituted C ₃ - ₄ cycloalkyl, in which p is 1 to 100;

R < ¹ > is straight or branched chain alkylaminocarbonyl of d- ₃ or straight-chain or branched alkylaminocarbonyl of di- ₃ ;

X is = N-; And

L is a single bond, or -O-, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Claim 3]

The method according to claim 1,

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently an unsubstituted or substituted oxadiazolyl,

The substituted oxadiazole thing linear or branched linear or branched unsubstituted or at least one of a halogen-substituted d-5-alkyl, ₅ straight or branched alkoxy d- ₅ alkyl, or unsubstituted C ₃ - ₄ cycloalkyl Wherein the alkyl is substituted oxadiazolyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Claim 4

The method of claim 1, wherein

_R < 1 > is methylaminocarbonyl, or dimethylaminocarbonyl; X is = N -; and

[Claim 5]

The method of claim 1, wherein

or

, Wherein A ¹ , A "and are independently -H or methyl;

Methylaminocarbonyl, or dimethylaminocarbonyl;

X is = N-; And

L is -O-, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[Claim 6]

In Item 1,

The compound represented by the formula (1) is any one selected from the following group of compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

(1) N-methyl-4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy] picolinamide;

(2) 4 [4- (5-ethyl-1,2,4-oxadiazol-3-yl) phenoxy] methyl N-methylpicolinamide;

(3) 4- [4- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(4) 4- [4 (5-isopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(5) 4- [4- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide; (6) 4- [4- (5- (Methylmethyl) -1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(7) N-Methyl-4 - [4- (5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl) phenoxy] picolinamide;

(8) 4- [3- (5-Isopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(9) 4- [3 (5-isobutyl-1,2,4-oxadiazolyl-3-yl) phenoxy] -N-methylpicolinamide;

(10) 4? [3- (5- (Methylmethyl) -1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(12) 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy) -N-methylpicolinamide;

(15) 4- (4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy) -N, N-dimethylpicolinamide;

(16) Synthesis of N-methyl-4 - [(3-methyl-2- (5-methyl-1,2,4-oxadiazol- Choline amide;

(17) Synthesis of 4- [2- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-yl) oxy] Choline amide;

(18) Synthesis of 4 - [(2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-yl) oxy] Methylpicolinamide;

(19) Synthesis of 4 - [(2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-yl) oxy] Picolinamide;

(21) 4- ((6- (5-Isopropyl-1,2,4-oxadiazol-3-yl) pyridin-3-yl) oxy) -N-methylpicolinamide; And

(22) 5- (5-Isopropyl-1,2,4-oxadiazol-3-yl) -N-methyl-2-oxo- 2H- [1,4'- bipyridine] Vox amide.

7.

A compound represented by the general formula (1) of claim 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof,

A pharmaceutical composition.

8.

A compound represented by the general formula (1) of claim 1, an optical isomer thereof, A pharmaceutical composition for preventing or treating a viral disease containing a pharmaceutically acceptable salt thereof as an active ingredient.

[Claim 9]

9. The method according to claim 8,

Wherein the viral disease is a disease caused by a rhinovirus, a picornavirus, or a poliovirus.

Claim 10

9. The method of claim 8,

Wherein said viral disease is a disease caused by human rhinovirus.

Claim 11

9. The method of claim 8,

The viral diseases are selected from the group consisting of poliomyelitis, acute hemorrhagic conjunctivitis, biliary meningitis, waterborne disease, hepatitis A, myositis, myocarditis, pancreatitis, epidemic pain, encephalitis, cold, herpetic ischemia, foot and mouth disease, asthma, A disease, a pneumonia, an emesis, or otitis media. ^'

Claim 12

A health functional food composition for preventing or ameliorating a viral disease comprising a compound represented by the general formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

Claim 13

A method for the treatment of a viral disease comprising administering to a subject in need thereof a compound represented by the general formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

14.

The use of a compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of viral diseases,

15.

Use of a compound of formula (1), an optically isomeric form thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention, alleviation or treatment of viral diseases.