KR101997108B1 - Antiviral compound, preparation method thereof, and pharmaceutical composition for use in preventing or treating viral diseases containing the same as an active ingredient - Google Patents

Abstract

In one aspect of the present invention, there is provided a novel antiviral compound, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a method for producing the same, and a pharmaceutical composition for preventing or treating viral diseases containing the same as an active ingredient .

Description

TECHNICAL FIELD [0001] The present invention relates to an antiviral compound, a method for producing the same, and a pharmaceutical composition for preventing or treating a viral disease containing the same as an active ingredient. The antiviral compound, preparation method thereof, and pharmaceutical composition for use in treating or treating viral diseases containing the same as an active ingredient}

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

The picornavirus is a 7.2 to 8.5 Kb positive single stranded RNA virus, a very small, spherical virus of about 22-30 nm, free of hull and the oldest known virus.

The diseases caused by the picornavirus include, but are not limited to, polio, acute hemorrhagic conjunctivitis, viral meningitis, aquatic diseases, waterborne disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, encephalitis, encephalitis, , Respiratory diseases such as foot and mouth disease, gastrointestinal diseases, circulatory diseases and skin diseases.

In addition, picornavirus is transmitted through food or water and is often contained in tap water, but it is very stable and is not easily disinfected. Therefore, viruses belonging to the picornaviruses 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 picornavirus class includes Rhinovirus, Poliovirus, Coxsackie virus A, Coxsackie virus B, echovirus, Hepatitis A virus And enteroviruses such as < RTI ID = 0.0 >

Specifically, human rhinovirus (hRV) is a type of respiratory virus and is known as the most common asthma exacerbation factor. Human rhinovirus is also known to exist in the bronchial tissues of a large number of stable asthmatic patients. The frequency of detection of human rhinovirus was significantly higher in the asthmatic group than in the non-asthmatic group, and the presence of human rhinovirus and asthma There is also a correlation with the clinical severity of the disease. In addition, symptoms that are caused by human rhinovirus include chronic obstructive pulmonary disease, pneumonia, sinusitis and otitis media besides asthma, and it is one of the main viruses causing colds, but currently effective therapeutic agents have not been developed.

In addition, poliovirus is transmitted through ingestion of food, and the virus propagates in the oropharyngeal mucosa or the intestinal mucosa. After infiltrating lymphatic tissues and proliferating, they enter the bloodstream and induce primary viremia. Most infections stop at this stage and become 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 widely available, they are still developing.

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 Enterovirus. The particle is a regular icosahedron with a diameter of 27-28 nm, the genome is a (+) chain RNA of 7,401 bases, Infected. The coxsackievirus exists in two groups, coxsackievirus A and coxsvirus B, coxsackievirus A causes relaxation 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 in severe cases. At present, effective therapeutic agents have not yet been developed.

In addition, Hepatitis A virus causes hepatitis A. While a vaccine against hepatitis A virus has been developed, a vaccine against an eco virus that causes enterovirus and aseptic meningitis, diarrhea, and airway infections that cause meningitis and respiratory infections has not yet been developed.

On the other hand, the development of a therapeutic agent for diseases related to the above-mentioned picornavirus group has been studied, and the nivirocyz derivatives have been studied as promising candidates 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). However, in clinical studies, it has been observed to have normal or no effect, insufficient pharmacokinetics and undesirable side effects have been observed.

In addition, the protease inhibitor AG 7088 was studied based on knowledge of the sophisticated structure and function of viral protease 2C. In cell cultures in the range of nanomolar concentrations, AG 7088 was shown to have an effect on 48 rhinovirus types and coxsackieviruses A21, B3, enterovirus 70 and eco virus 11.

Furthermore, as the molecular structure of the picornavirus capside became clear, the preconditions for the critical design of the "WIN material", a capsid blocker, were studied. They inhibit the adsorption and / or de-epithelization of rhinovirus and enteroviruses. Some of the WIN substances have a highly specific effect only on the individual genus or virus type of the picornavirus. Other derivatives inhibit replication of both rhinoviruses and enteric viruses. Arylon, disoxaril and pirodavir belong, for example, to the WIN substance. These compounds showed very good antiviral effect in cell culture medium. However, side effects such as inadequate solubility (aryldon), low bioavailability (aryldone and dyssaryl), rapid metabolism and excretion (Dyssaril and WIN 54954) as well as skin rashes (WIN 54954) made.

In addition, another WIN compound, plconaryl, has very good oral bioavailability which, after binding to the hydrophobic pocket in the viral capsid, inhibits the penetration of the rhinovirus, eco-virus and coxsackievirus. Thus, plconalil is potentially effective against a wide range of viral diseases ranging from common colds to viral meningitis or myocarditis. Resistance was observed for rhinovirus, enterovirus 71 and coxsackievirus B3. However, the proven therapeutic efficacy was not sufficient in the United States to label plcnaril (Picovir, Viropharma, USA) as a treatment for rhinovirus infection. In March 2002, the corresponding application was rejected by the Food and Drug Administration (FDA) because side effects were observed and the treatment success rate was too low.

Furthermore, BTA-798 compounds, which are more active than flconilyl in in vitro and in vivo antiviral drug efficacy assays using rhinoviruses, are currently in clinical trials.

Despite these various studies, no approved antiviral drug has yet been developed for the treatment of enterovirus or rhinovirus.

Accordingly, the present inventors have been studying antiviral compounds against Coxsackie virus, poliovirus and rhinovirus belonging to the picornavirus group,

It is confirmed that the compound provided in one aspect of the present invention exhibits excellent antiviral activity against poliovirus and rhinovirus belonging to the picornavirus group and consequently is useful as a pharmaceutical composition for the prevention or treatment of viral diseases And the present invention has been completed.

Heinz BA and Vance LM: J Virol, 1995, 69 (7), 4189-97.

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.

Another object of the present invention is to provide a method for producing an antiviral compound of the novel structure.

Another object of the present invention is to provide an antiviral pharmaceutical composition containing an antiviral compound of the novel structure, a pharmaceutically acceptable salt thereof and an optical isomer thereof as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating viral diseases containing the above-described novel structure of an antiviral compound, a pharmaceutically acceptable salt thereof or an optical isomer thereof as an active ingredient .

Another object of the present invention is to provide a health functional food composition for preventing or ameliorating a viral disease containing an antiviral compound of the novel structure, a pharmaceutically acceptable salt thereof or an optical isomer thereof as an active ingredient .

In order to achieve the above object,

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.

[Chemical Formula 1]

In Formula 1,

,

,

,

, 또는

이고, 여기서 상기 A¹, A² 및 A³는 독립적으로 -H, 또는 C_1-10의 직쇄 또는 측쇄 알킬이고,Ring

,

,

,

, or

Wherein A ¹ , A ² and A ³ are independently -H, or C _1-10 straight-chain or branched alkyl,

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently -H or an unsubstituted or mono-, di-, or trisubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of N, is a heteroaryl of from 5 to 10 atoms substituted by G ^1, wherein -G ¹ is linear or branched linear or branched alkyl, C _1-7 of the unsubstituted or one or more halogen substituted C _1-7 alkoxy C _{1 -7} straight or branched chain alkyl, or unsubstituted C _3-6 cycloalkyl;

R ¹ is selected from the group consisting of -H, halogen, -OH, -CN, -NO ₂ , C _1-10 linear or branched alkyl, C _1-10 straight or branched alkoxy, C _1-5 straight or branched alkylaminocarbonyl , Or straight or branched chain alkylaminocarbonyl of dC < ₁ >_-5;

X is = CH-, or = N-; And

L is a single bond, or -O-.

In another aspect of the present invention, as shown in Reaction Scheme 1 below,

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).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , X and Ring 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 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, there is provided a pharmaceutical composition for preventing or treating viral diseases, which comprises the compound represented by the formula (I), an optical 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 .

The novel antiviral compound according to one aspect of the present invention not only has low cytotoxicity but also exhibits a very excellent antiviral activity against picornaviruses such as poliovirus and rhinovirus,

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 , Vomiting, or otitis media. The pharmaceutical composition of the present invention is useful as a pharmaceutical composition for preventing or treating viral diseases.

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.

[Chemical Formula 1]

In Formula 1,

,

,

,

, 또는

이고, 여기서 상기 A¹, A² 및 A³는 독립적으로 -H, 또는 C_1-10의 직쇄 또는 측쇄 알킬이고,Ring

,

,

,

, or

Wherein A ¹ , A ² and A ³ are independently -H, or C _1-10 straight-chain or branched alkyl,

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently -H or an unsubstituted or mono-, di-, or trisubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of N, is a heteroaryl of from 5 to 10 atoms substituted by G ^1, wherein -G ¹ is linear or branched linear or branched alkyl, C _1-7 of the unsubstituted or one or more halogen substituted C _1-7 alkoxy C _{1 -7} straight or branched chain alkyl, or unsubstituted C _3-6 cycloalkyl;

R ¹ is selected from the group consisting of -H, halogen, -OH, -CN, -NO ₂ , C _1-10 linear or branched alkyl, C _1-10 straight or branched alkoxy, C _1-5 straight or branched alkylaminocarbonyl , Or straight or branched chain alkylaminocarbonyl of dC < ₁ >_-5;

X is = CH-, or = N-; And

L is a single bond, or -O-.

In another aspect,

,

,

,

, 또는

이고, 여기서 상기 A¹, A² 및 A³는 독립적으로 -H, 또는 C_1-5의 직쇄 또는 측쇄 알킬이고,Ring

,

,

,

, or

Wherein A ¹ , A ² and A ³ are independently -H, or a straight or branched alkyl of C _1-5 ,

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently -H or an unsubstituted or mono-, di-, or trisubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of N, is a heteroaryl of from 5 to 8 atoms substituted by G ^1, wherein -G ¹ is linear or branched linear or branched alkyl, C _1-5 of the unsubstituted or one or more halogen substituted C _1-5 alkoxy C _{1 -5} straight or branched chain alkyl, or unsubstituted C _3-4 cycloalkyl;

R ¹ is straight or branched alkyl of C _1-3 aminocarbonyl carbonyl, or di-C _{1 -3} straight or branched chain alkyl aminocarbonyl, and the;

X is = N-; And

L may be a single bond, or -O-.

In another aspect,

,

,

,

, 또는

이고, 여기서 상기 A¹, A² 및 A³는 독립적으로 -H, 또는 메틸이고,Ring

,

,

,

, or

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

,

,

,

,

,

, 또는

이고;R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently -H,

,

,

,

,

,

, or

ego;

R < ¹ > is methylaminocarbonyl, or dimethylaminocarbonyl;

X is = N-; And

L may be a single bond, or -O-.

In another aspect, the compound represented by Formula 1 may be any one selected from the group consisting of the following 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-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-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;

(10) 4- [3- (5- (Methoxymethyl) -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-oxadiazol-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-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] Picolinamide;

(19) Synthesis of 4 - [(2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -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) -N-methylpicolinamide; And

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

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, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, benzenesulfonates, benzenesulfonates, benzenesulfonates, phenylenesulfonates, -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, the derivative of formula (1) is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., Filtration and drying of the resulting precipitate, or distillation of 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 an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, 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.

In another aspect of the present invention, as shown in Reaction Scheme 1 below,

There is provided a process for preparing a compound represented by the above formula (1) comprising 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).

[Reaction Scheme 1]

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, etc. used in carrying out the reaction may be easily changed or adopted by those skilled in the art, and it is not particularly limited. When the reaction temperature range is specifically specified, it can be performed in the range of 0 ° C to 300 ° C, can be performed in the range of 20 ° C to 280 ° C, can be performed in the range of 40 ° C to 260 ° C, And can be carried out in the range of 80 to 220 캜 and can be carried out in the range of 100 to 200 캜 and can be carried out in the range of 120 to 180 캜 and can be carried out in the range of 140 to 160 캜 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, And may be performed in the range of 40 to 140 hours, may be performed in the range of 50 to 130 hours, may be performed in the range of 60 to 120 hours, may be performed in the range of 70 to 110 hours And can be carried out in the range of 80 to 100 hours, and can be carried out for 90 hours. The reaction pressure can be generally carried out at atmospheric pressure (1 atm), but is not particularly limited.

Further, in one aspect of the present invention, there is provided a pharmaceutical composition for antiviral comprising the compound represented by the formula (1), an optical isomer thereof 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, myositis, myocarditis paralysis, idiopathic dilated cardiomyopathy, myocarditis, pericarditis, meningitis, otitis media, viral diabetes, acute hemorrhagic conjunctivitis, Asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, general cold, acute respiratory tract infection, and the like, as well as other diseases such as diabetes mellitus, diabetes mellitus, poliomyelitis, poliomyelitis, Respiratory tract infections, sinusitis, cystic fibrosis, bronchitis, waterborne disease, hepatitis A, pancreatitis, epidemic muscle pain, foot and mouth disease and the like.

In another aspect of the present invention, the compound represented by Chemical Formula 1 is subjected to antiviral drug screening. As a result, the compound represented by Chemical Formula 1 according to the present invention can be used as an antiviral drug, Viruses (HRV14, HRV21 and HRV71), and the compounds of the Examples show excellent antiviral activity even at a very low concentration of less than micromolar.

Accordingly, in another aspect of the present invention, the compounds represented by Formula 1 have excellent antiviral activity against coxsakiovirus, polovirus, and rhinovirus belonging to the picornavirus group, Mechanical 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 various dosage forms during clinical administration. In the case of formulation, the compound commonly used in the form of a filler, an extender, a binder, a wetting agent, Or a diluent or an excipient such as a surfactant.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. 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 and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

In another aspect of the present invention, the effective dose of the compound in the human body may vary depending on the patient's age, weight, sex, dosage form, health condition and disease severity, and is generally 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, It may be divided into several doses.

Hereinafter, the contents according to one aspect of the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following Examples and Experiments exemplify the present invention, but the present invention is not limited thereto.

< Example  1 > N- methyl -4- [4- (5- methyl -1,2,4- Oxadiazole -3 days) Phenoxy ] Picoline ami De

Step 1. N ', 4- Dihydroxybenzimidamide

4-Cyanophenol (1.043 g, 8.756 mmol) was dissolved in a mixed solution of 50% NH ₂ OH aqueous solution (8 mL) and EtOH (2 mL), followed by stirring at 90 ° C for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain N ', 4-dihydroxybenzimidamide (1.319 g, 99%).

Step 2. Preparation of 4- (5- methyl -1,2,4- Oxadiazole 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 resulting mixture. 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 mixture was purified by silica gel column chromatography (EtOAc: Hx = 1: 3) to obtain 4- (5-methyl-1,2,4-oxadiazol-3-yl) phenol (245.3 mg, 79% .

Step 3. N- methyl -4- [4- (5- methyl -1,2,4- Oxadiazole -3 days) Phenoxy ] Picolinamide

A mixture of 4- (5-methyl-1,2,4-oxadiazol-3-yl) phenol (99.7 mg, 0.566 mmol) and 4- chloro- N-methylpicolinamide (96.8 mg, 0.566 mmol) Was stirred at 150 &lt; 0 &gt; C for 90 hours. The reaction mixture was cooled to room temperature, and then CH ₂ Cl ₂ (100 mL) and distilled water (100 mL) were added thereto. The aqueous layer was extracted with CH ₂ Cl ₂ (50 mL × 3). The combined organic layer was washed with brine (10 mL) and concentrated under reduced pressure after drying was in MgSO _4. The resulting mixture was purified by silica gel column chromatography (EtOAc: Hx = 2: 3) to obtain the target compound (57.6 mg, 33%).

^{1 H NMR (300 MHz, CDCl} 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] &lt; ⁺ &gt; = 311.03.

< Example  2 > 4- [4- (5-Ethyl-1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpicolinamide De

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

N, 4-dihydroxybenzimidamide (247.6 mg, 1.627 mmol) as a starting material and propionyl chloride (181 mg, 1.95 mmol) instead of acetyl chloride as reaction materials. - (5-ethyl-1,2,4-oxadiazol-3-yl) phenol (245.3 mg, 79%).

Step 2. Preparation of 4- [4- (5-ethyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

The objective compound was obtained by the same procedure as in Example 1, Step 3, using the starting material of 4- (5-ethyl-1,2,4-oxadiazol-3-yl) phenol (101.5 mg, 0.5336 mmol) , 21%).

^{1 H NMR (300 MHz, CDCl} 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 1H), 7.21 (d, J = 8.7 Hz, 2H), 7.02 (dd, J = 5.6,2.6 Hz, 1H), 3.08 2.93 (m, 5H), 1.48 (t, J = 7.6 Hz, 3H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 325.27.

< Example  3 > 4- [4- (5- Cyclopropyl -1,2,4- Oxadiazole -3 days) Phenoxy ] -N- methyl Picolinamide

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

(245.4 mg, 2.344 mmol) instead of acetyl chloride as the starting material and N, N ', 4-dihydroxybenzimidamide (297.2 mg, 1.953 mmol) To obtain 238.5 mg (53%) of 4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenol.

Step 2. Preparation of 4- [4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

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) mg, 18%).

^{1 H NMR (300 MHz, CDCl} 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 = J = 5.6, 2.5 Hz, 1H), 3.04 (d, J = 5.1 Hz, 3H), 2.29 (tt, J = 8.2, 5.0 Hz, 1 H), 1.41 1.22 (m, 4 H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 337.15.

< Example  4> 4- [4- (5-Isopropyl-1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpicol Linamide

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

N ', 4-dihydroxybenzimidamide (193.4 mg, 1.271 mmol) as a starting material and isobutyryl chloride (162.7 mg, 1.525 mmol) instead of acetyl chloride as a starting material, 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol (204.0 mg, 79%).

Step 2. Preparation of 4- [4- (5-isopropyl-l, 2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

The objective compound was obtained by the same procedure as in Example 1, Step 3, using the starting material of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol (101.4 mg, 0.4964 mmol) mg, 29%).

^{1 H NMR (300 MHz, CDCl} 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, (Dd, J = 5.5, 2.6 Hz, 1H), 3.32 (hept, J = 7.0 Hz, 1H), 3.04 d, J = 5.1 Hz, 3H), 1.50 (d, J = 7.0 Hz, 6H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 339.31.

< Example  5> 4- [4- (5-Isobutyl-1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpicoline amides

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

N, 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 a starting material. To obtain 4- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenol (109.0 mg, 51%).

Step 2. Preparation of 4- [4- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

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

^{1 H NMR (300 MHz, CDCl} 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 = J = 5.0 Hz, 3H), 2.86 (d, J = 6.9 Hz, 2H), 7.01 (d, 7.1 Hz, 2H), 2.40 2.21 (m, 1H), 1.08 (d, J = 6.7 Hz, 6H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 353.22.

< Example  6> 4- [4- (5- ( Methoxymethyl ) -1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpyridine Cholinamide

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

(150.0 mg, 0.9859 mmol) as a starting material and methoxyacetyl chloride (112.4 mg, 1.035 mmol) instead of acetyl chloride as a starting material, the title compound was obtained as a white amorphous solid by the method of Example 1, Step 2 To obtain 4- [5- (methoxymethyl) -1,2,4-oxadiazol-3-yl] phenol (114.5 mg, 56%).

Step 2. Preparation of 4- [4- (5- ( Methoxymethyl ) -1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpicolinamide

The objective compound was obtained by the same procedure as in Example 1, Step 3 using 4- [5- (methoxymethyl) -1,2,4-oxadiazol-3-yl] phenol (98.2 mg, 0.476 mmol) (49.7 mg, 31%).

^{1 H NMR (300 MHz, CDCl} 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 = 2H), 3.60 (s, 3H), 3.04 (d, J = 5.8 Hz, J = 5.1 Hz, 3H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 341.20.

< Example  7> N- methyl -4- [4- (5- ( Trifluoromethyl ) -1,2,4- Oxadiazole -3 days) Fenok Yl] picolinamide

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

N, 4-dihydroxybenzimidamide (299.7 mg, 1.970 mmol) as a starting material and trifluoroacetic anhydride (620.1 mg, 2.955 mmol) instead of acetyl chloride as starting materials, 2-yl] phenol (328.9 mg, 73%) was obtained by the method of 2-

Step 2. Synthesis of N-methyl-4- [4- (5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl) phenoxy] picolinamide

(102.1 mg, 0.4436 mmol) was used as starting material in the same manner as in Example 1, Step 3, except that the title compound was obtained as a colorless powder starting from 4- [5- (trifluoromethyl) -1,2,4-oxadiazol- (33.2 mg, 17%).

^{1 H NMR (300 MHz, CDCl} 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 (d, J = 5.1 Hz, 3H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 365.23.

< Example  8> 4- [3- (5-Isopropyl-1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpicolinamide

Step 1. Preparation of N ', 3-dihydroxybenzimidamide

3-Hydroxybenzoic acid (3.014 g, 21.82 mmol) was added to SOCl ₂ (20 mL), DMF (77.4 mg, 1.06 mmol) was added and the reaction was refluxed at 70 ° C for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Toluene (10 mL) was added to the resulting mixture, and the mixture was concentrated under reduced pressure. The resulting mixture 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 reaction mixture was concentrated under reduced pressure. 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 give 3-hydroxybenzamide (2.6485 g). 3-Hydroxybenzamide (2.649 g, 19.18 mmol) was added to THF (100 mL), then cooled to 0 占 폚 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 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (100 mL) and distilled water (100 mL) were added to the mixture. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (10 mL), dried over MgSO ₄ and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EtOAc: Hx = 1: 2) to give 3-hydroxybenzonitrile &Lt; / RTI &gt; To this mixture was added a 50% NH ₂ OH aqueous solution (20 mL), followed by stirring 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

(125.3 mg, 1.176 mmol) was used instead of acetyl chloride as the starting material and N, N ', 3-dihydroxybenzimidamide (150.0 mg, 0.9859 mmol) 3- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol (92.5 mg, 46%).

Step 3. Preparation of 4- [3- (5-isopropyl-l, 2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

The objective compound was obtained by the same procedure as in Example 1, Step 3, using 3- (5-isopropyl-1,2,4-oxadiazol-3-yl) phenol (92.5 mg, 0.453 mmol) as a starting material (31.8 mg, 21%).

^{1 H NMR (300 MHz, CDCl} 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] &lt; ⁺ &gt; = 339.11.

< Example  9> 4- [3- (5-Isobutyl-1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpicolinamide

Step 1. Preparation of 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) instead of acetyl chloride as a starting material. To obtain 3- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenol (109.9 mg, 51%).

Step 2. Preparation of 4- [3- (5-isobutyl-1,2,4-oxadiazol-3-yl) phenoxy] -N-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) δ 8.42 (dd, J = 5.6, 0.5 Hz, 1H), 8.09 - 7.96 (m, 2H), 7.84 (dd, J = 2.5, 1.5 Hz, 1H), 7.75 ( J = 2.6, 0.5 Hz, 1H), 7.63-7.51 (m, 1H), 7.26 (ddd, J = 8.2, 2.5, 1.0 Hz, , 3.03 (d, J = 5.1 Hz, 3H), 2.85 (d, J = 7.2 Hz, 2H), 2.38-2.21 (m, 1H), 1.06 (d, J = 6.7 Hz, 6H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 353.22.

< Example  10> 4- [3- (5- ( Methoxymethyl ) -1,2,4- Oxadiazole -3 days) Phenoxy ] -N- Methylpyridine Cholinamide

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

N ', 3-dihydroxybenzimidamide (150.0 mg, 0.9859 mmol) as a starting material and methoxyacetyl chloride (112.4 mg, 1.035 mmol) instead of acetyl chloride as a starting material, To obtain 3- (5- (methoxymethyl) -1,2,4-oxadiazol-3-yl) phenol (114.5 mg, 56%).

Step 2. Preparation of 4- [3- (5- (methoxymethyl) -1,2,4-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide

The objective compound was prepared by the same procedure as in Example 1, Step 3, using 3- (5- (methoxymethyl) -1,2,4-oxadiazol-3-yl) phenol (96.1 mg, 0.466 mmol) (41.5 mg, 26%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.43 (d, J = 5.6 Hz, 1H), 8.10 - 7.97 (m, 2H), 7.91 - 7.82 (m, 1H), 7.75 (d, J = 2.5 Hz, 2H), 3.58 (s, 3H), 3.03 (m, IH), 7.63-7.22 (d, J = 5.1 Hz, 3 H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 341.07.

< Example  11> 4- (4- (5-Isopropyl-1,2,4- Oxadiazole Yl) -2- Methylphenoxy ) -N-methylpicolinamide

Step 1. 4- Hydroxy -3- Methylbenzamide

4-hydroxy-3-methylbenzamide (241 mg, 24%) was obtained by the method of Example 8, Step 1 using 4-hydroxy-3-methylbenzoic acid (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 mmol).

Step 3. Synthesis of (Z) -N ', 4- Dihydroxy -3- Methylbenzimidamide

(Z) -N ', 4-dihydroxy-3-methylbenzimide (352 mg, 2.64 mmol) was obtained by the method of Example 1, step 1, using 4-hydroxy- Amide (423 mg, 96%).

Step 4. Preparation of 4- (5-isopropyl-l, 2,4- Oxadiazole Yl) -2- Methylphenol

(5-isopropyl-1, 3-dihydroxy-benzoimidazol-1-yl) -ethanone was prepared by the same procedure for the example 1, step 2, using (Z) Oxadiazol-3-yl) -2-methylphenol (304 mg, 52%).

Step 5. Preparation of 4- (4- (5-isopropyl-l, 2,4- Oxadiazole Yl) -2- Methylphenoxy ) -N- Methylpicolinamide

(100 mg, 0.458 mmol) was used as starting material in the same manner as in Example 1, Step 3, except that the target compound &Lt; / RTI &gt; (26.9 mg, 17%).

^{1 H NMR (300 MHz, CDCl} 3) 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), (D, J = 8.4 Hz, 1H), 6.92 (dd, J = 5.6,2.6 Hz, 1H), 3.42 3.24 3H), 1.50 (d, J = 7.0 Hz, 6H).

< Example  12> 4- (4- (5-Isopropyl-1,2,4- Oxadiazole Yl) -2,6- Dimethylphenoxy ) -N-methylpicolinamide

Step 1. Synthesis of (Z) -N ', 4- Dihydroxy -3,5- Dimethylbenzimidamide

(Z) -N ', 4-dihydroxy-3,5-dihydroxy-3, 5-dihydroxy- -Dimethylbenzimidamide (1.31 g, 100%).

Step 2. Preparation of 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenol

(5-isopropyl-piperidin-4-yl) -ethanone was obtained by the same procedure as in Example 1, Step 2, using (Z) -N'4-dihydroxy-3,5-dimethylbenzimidamide (500 mg, 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) -N-methylpicolinamide

Using the procedure of Example 1, Step 3, starting from 4- (5-isopropyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenol (100 mg, 0.431 mmol) The target compound was obtained (13.1 mg, 8%).

^{1 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> N- methyl -4 - [(6- (5- methyl -1,2,4- Oxadiazole Yl) naphthalen-2-yl) Oxy ] Picolinamide

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

Dihydroxy-2-naphthimidamide (651.2 mg, 30 [Eta]) was obtained as a starting material according to the method for example 8, step 1, using 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-

(5- (4-fluorobenzyl) -2,3-dihydro-2-naphthyridin-2-ylamine was obtained in the same manner as in Example 1, Step 2, Methyl-1,2,4-oxadiazol-3-yl) naphthalen-2-ol (64.4 mg, 38%).

Step 3. Preparation of N-methyl-4 - [(6- (5-methyl-1,2,4-oxadiazol-3- yl) naphthalen-2-yl) oxy] picolinamide

The objective compound was prepared by the same procedure as in Example 1, Step 3, using 6- (5-methyl-1,2,4-oxadiazol-3-yl) naphthalen-2-ol (64.4 mg, (21.8 mg, 21%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.65 (s, 1H), 8.45 (dd, J = 5.6, 0.6 Hz, 1H), 8.20 (dd, J = 8.6, 1.7 Hz, 1H), 8.10 - 7.98 ( (d, J = 8.9, 2.4 Hz, 1H), 7.90 (d, J = 1H), 7.06 (dd, J = 5.6,2.6 Hz, 1H), 3.04 (d, J = 5.1 Hz, 3H), 2.74 (s, 3H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 361.18.

< Example  14> 4- (4- (5-Isopropyl-1,2,4- Oxadiazole -3 days) Phenoxy ) - N, N - Dimethylpicolinamide

Step 1. 4-Chloro-N, N-dimethylpicolinamide

After dissolving 4-chloro-N-methylpicolinamide (1.00 g, 5.86 mmol) in DMF (20 mL), the mixture was cooled to 0 ° C and NaH (dissolved in mineral oil 60%, 235 mg, 5.86 mmol) And stirred for 25 minutes. After the reaction was cooled to 0 ° C, MeI (1.66 g, 11.7 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting mixture 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 distilled water (10 mL) and brine (5 mL), dried over MgSO 4 and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (CH ₂ Cl ₂ / acetone = 30: 1) Chloro-N-methylpicolinamide (887 mg, 82%).

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

Chloro-N, N-dimethylpicolinamide (90.5 mg, 0.490 mmol) was reacted with 4- (5-isopropyl-1,2,4-oxadiazol- (26.3 mg, 15%) as a starting material, by the method of Example 1, Step 3.

^{1 H NMR (300 MHz, CDCl} 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> 4- (4- (5-Isopropyl-1,2,4- Oxadiazole Yl) -2,6- Dimethylphenoxy ) -N, N-dimethylpicolinamide

(150 mg, 0.646 mmol) 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%).

^{1 H NMR (300 MHz, CDCl} 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> N- methyl -4 - [(3- methyl -2- (5-methyl-1,2,4-oxadiazol-3-yl) benzo [b] thiophen-6-yl) oxy] picolinamide

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

(1.558 g, 7.010 mmol) was added to SOCl ₂ (14 mL), DMF (47.2 mg, 0.646 mmol) was added and the reaction was stirred at 80 &lt;Lt; 0 &gt; C for 4 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Toluene (20 mL) was added to the obtained precipitate, and the filtrate was concentrated under reduced pressure. The resulting mixture was added to THF (20 mL), and 40% NH ₃ aqueous solution (20 mL) was added thereto, followed by stirring 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 washed successively with 0.05 N HCl aqueous solution (10 mL) and brine (10 mL), dried over MgSO ₄ and concentrated under reduced pressure to give 6-methoxy-3-methylbenzo [b] thiophene-2-carboxamide 1.1682 g, 75%).

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

To a solution of 6-methoxy-3-methylbenzo [b] thiophene-2-carboxamide (1.1672 g, 5.2750 mmol) in 1,2-dichloroethane (25 mL), trifluoroacetic anhydride 3.325 g, 15.83 mmol) was added thereto, and the mixture was stirred at room temperature for 3 minutes. To the reaction was added pyridine (2.087 g, 26.38 mmol) and the reaction was stirred at room temperature for 1.5 hours. The reaction was diluted with CH ₂ Cl ₂ (30 mL), 1 N 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 resulting mixture was purified by silica gel column chromatography (EtOAc: Hx = 1: 10) to give 6-methoxy- b] thiophene-2-carbonitrile (757.6 mg, 71%).

Step 3. N'-Hydroxy-6-methoxy-3-methylbenzo [b] thiophene-2-carboximidamide

6-methoxy-3-methyl-benzo [b] thiophene-2-carbonitrile is stirred at 90 ℃ after adding a mixed solution of 50% NH ₂ OH aqueous solution (15 mL) and EtOH (5 mL) for 48 hours. . The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain N'-hydroxy-6-methoxy-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

(249.8 mg, 1.056 mmol) and acetyl chloride (99.7 mg, 1.27 mmol) as starting materials, the title compound was obtained as a yellow amorphous solid in the same manner as in Example 5-methyl-1,2,4-oxadiazole (135.1 mg, 49%) was obtained as a white amorphous solid in the same manner as in Step 2 of Example 1, .

Step 5. Preparation of 3-methyl-2- (5-methyl-1,2,4-oxadiazol-3-yl) benzo [b] thiophen-

Methyl-1,2,4-oxadiazole (124.3 mg, 0.4775 mmol) was dissolved in CH ₂ Cl ₂ (4 (4-methoxy-3-methylbenzo [ after which was added in mL) cooled to -78 was added dropwise a ℃ _{BBr 3 (1.0 M CH 2 Cl} 2 solution, 1.4 mL, 1.4 mmol). The reaction was stirred at room temperature for 16 h and then the reaction was added to a mixture of H ₂ O (30 mL) and CH ₂ Cl ₂ (40 mL). The aqueous layer was neutralized with NaHCO ₃ to pH = 8 and extracted with CH ₂ Cl ₂ (50 mL x 3). The organic layer was washed with brine (10 mL), dried over MgSO ₄ and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (CH ₂ Cl ₂ : acetone = 30: 1) Methyl-1,2,4-oxadiazol-3-yl) benzo [b] thiophen-6-ol (108.0 mg, 92%).

Step 6. N- methyl -4 - [(3- methyl -2- (5-methyl-1,2,4-oxadiazol-3-yl) benzo [b] thiophen-6-yl) Oxy ] Picolinamide

(98.0 mg, 0.398 mmol) was used as starting material instead of 3-methyl-2- (5-methyl-1,2,4-oxadiazol- , The target compound was obtained by the method of Step 3 (42.6 mg, 28%).

^{1 H NMR (300 MHz, CDCl} 3) 8.42 (dd, J = 5.6, 0.6 Hz, 1H), 8.02 (br. S, 1H), 7.86 (dd, J = 8.7, 0.5 Hz, 1H), 7.76 (dd (Dd, J = 5.6, 2.6 Hz, 1H), 7.20 (dd, J = 1H), 3.03 (d, J = 5.1 Hz, 3H), 2.83 (s, 3H), 2.70 (s, 3H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 381.10.

< Example  17> 4 - [(2- (5-Ethyl-1,2,4- Oxadiazole Yl) -3- Methylbenzo [b] thiophene -6-yl) oxy] -N-methylpicolinamide

Step 1. Preparation of 5-ethyl-3- (6-methoxy-3-methylbenzo [b] thiophen-

Carboximidamide (251.2 mg, 1.063 mmol) and propionyl chloride (117.5 mg, 1.271 mmol) as starting materials (757.6 mg, 71%) was obtained as white crystals from 5-ethyl-3- (6-methoxy-3-methylbenzo [b] thiophen- ).

Step 2. Preparation of 2- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-

(137.9 mg, 0.5027 mmol) as starting materials, the title compound was obtained as a colorless powder starting from 5-ethyl-3- (6-methoxy- Oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-ol (116.5 mg, 89% .

Step 3. Preparation of 4 - [(2- (5-ethyl-1,2,4- Oxadiazole Yl) -3- Methylbenzo [b] thiophene Yl) Oxy ] -N- Methylpicolinamide

(100.0 mg, 0.3842 mmol) was used as starting material instead of 2- (5-ethyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [ , The target compound was obtained by the method of Step 3 (36.2 mg, 21%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.43 (dd, J = 5.6, 0.6 Hz, 1H), 8.03 (br. S, 1H), 7.86 (dd, J = 8.7, 0.5 Hz, 1H), 7.76 ( (dd, J = 2.6, 0.5 Hz, 1H), 7.60 (dd, J = 2.3, 0.5 Hz, 1H), 7.20 , 1H), 3.10 2.96 (m, 5H), 2.84 (s, 3H), 1.50 (t, J = 7.6 Hz, 3H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 395.14.

< Example  18 > 4 - [(2- (5- Cyclopropyl -1,2,4- Oxadiazole Yl) -3- Methylbenzo [b] thiophene -6-yl) oxy] -N-methylpicolinamide

Step 1. Preparation of 5-cyclopropyl-3- (6-methoxy-3-methylbenzo [b] thiophen-

(161.2 mg, 0.6822 mmol) and cyclopropanecarbonyl chloride (85.6 mg, 0.819 mmol) were used as starting materials, and the title compound was obtained as a yellow amorphous solid 2-yl) -1,2,4-oxadiazole (81.6 mg, 0.25 mmol) was obtained as a colorless oil from the fraction eluted with ethyl acetate-hexane , 39%).

Step 2. Preparation of 2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-

As starting material, 5-cyclopropyl-3- (6-methoxy-3-methylbenzo [b] thiophen-2-yl) -1,2,4- oxadiazole (81.6 mg, 0.285 mmol) (45.1 mg, 58%) was prepared by the method of Example 12, Step 5 from 2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) ).

Step 3. Preparation of 4 - [(2- (5- Cyclopropyl -1,2,4- Oxadiazole Yl) -3- Methylbenzo [b] thiophene Yl) Oxy ] -N- Methylpicolinamide

Using the starting material of 2- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-6-ol (45.1 mg, 0.1656 mmol) 1, &lt; / RTI &gt; step 3, the desired compound was obtained (11.9 mg, 21%).

^{1 H NMR (300 MHz, CDCl} 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, J = (Dd, J = 5.6, 2.6 Hz, 1H), 3.03 (d, J = J = 5.1 Hz, 3H), 2.82 (s, 3H), 2.32 (tt, J = 8.2, 5.0 Hz, 1H), 1.42 1.24 (m, 4H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 407.02.

< Example  19> 4 - [(2- (5-Isopropyl-1,2,4- Oxadiazole Yl) -3- Methylbenzo [b] thiophene -6-yl) oxy] -N-methylpicolinamide

Step 1. Preparation of 5-isopropyl-3- (6-methoxy-3-methylbenzo [b] thiophen-2-yl) -1,2,4-oxadiazole

Carboximidamide (239.2 mg, 1.012 mmol) and isobutyryl chloride (129.0 mg, 1.210 mmol) as starting materials, to a solution of (3-methylbenzo [b] thiophen-2-yl) -1,2,4-oxadiazole (235.3 mg, 81%).

Step 2. Synthesis of 2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -3-methylbenzo [b] thiophen-

(189.6 mg, 0.657 mmol) as a starting material was used as starting material instead of 2-ethoxy-5-isopropyl-3- (6-methoxy- 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-l, 2,4- Oxadiazole Yl) -3- Methylbenzo [b] thiophene Yl) Oxy ] -N- Methylpicolinamide

(108.5 mg, 0.3955 mmol) as starting materials, the title compound was obtained as a yellow amorphous solid in the same manner as in Example 1, step 3, the desired compound was obtained (38.8 mg, 24%).

^{1 H NMR (300 MHz, CDCl} 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 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), 7.68 7.51 Hz, 1H), 3.03 (d, J = 5.1 Hz, 3H), 2.84 (s, 3H), 1.50 (d, J = 7.0 Hz, 6H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 409.25.

< Example  20> N- methyl -4 - [(3- methyl -2- (5- ( Trifluoromethyl ) -1,2,4- Oxadiazole Yl) benzo [b] thiophen-6-yl) oxy] picolinamide

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

Hydroxybenzo [b] thiophene-2-carboxamide (1.000 g, 4.519 mmol) was used as starting material instead of 6-methoxy-3- [b] thiophene-2-carboxamide (615.3 mg, 66%).

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

4 - [(2-Carbamoyl-pyridin-2-yl) -ethanone was obtained by the method of Example 1, Step 3, using 6-hydroxy-3-methylbenzo [ Methylbenzo [b] thiophen-6-yl) oxy] -N-methylpicolinamide (63.3 mg, 13%).

Step 3. N- methyl -4 - [(3- methyl -2- (5- ( Trifluoromethyl ) -1,2,4- Oxadiazole -3 days) Benzo [b] thiophene Yl) oxy] picolinamide &lt; RTI ID = 0.0 &gt;

Methylpicolinamide (63.3 mg, 0.188 mmol) was added to CH ₂ Cl ₂ (2 mL) and a solution of 4 - [(2-carbamoyl-3-methylbenzo [b] thiophen-6-yl) oxy] After cooling to 0 [deg.] 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 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction was diluted with CH ₂ Cl ₂ (30 mL), then 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 brine (10 mL), dried over MgSO ₄ and concentrated under reduced pressure. Purification of the resulting mixture by silica gel column chromatography _{(CH 2 Cl 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- Lt; / RTI &gt; The resulting mixture 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. The resulting mixture was added to pyridine (3 mL), trifluoroacetic acid (74.1 mg, 0.353 mmol) was added, and the mixture was refluxed at 120 ° C for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting mixture was added to a mixed solution of THF (2 mL) and distilled water (0.5 mL), 1 N aqueous NaOH solution (0.5 mL) was added thereto, and the mixture was 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 layer was extracted with CH ₂ Cl ₂ (30 mL × 3). The organic layer was washed with brine (5 mL), dried over MgSO ₄ and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (EtOAc: Hx = 1: 1) to obtain the target compound (18.2 mg, 22% .

^{1 H NMR (300 MHz, CDCl} 3) δ 8.45 (dd, J = 5.6, 0.6 Hz, 1H), 8.04 (br. S, 1H), 7.91 (dd, J = 8.8, 0.6 Hz, 1H), 7.75 ( (dd, J = 2.6, 0.5 Hz, 1H), 7.62 (dd, J = 2.2, 0.5 Hz, 1H), 7.24 , 1 H), 3.04 (d, J = 5.1 Hz, 3H), 2.88 (s, 3H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 435.17.

< Example  21> 4 - ((6- (5-Isopropyl-1,2,4- Oxadiazole Yl) pyridin-3-yl) Oxy ) -N- Methylpicolinamide

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

(Z) -N'-hydroxy-5-methoxypicoline imidamide (546.9 mg, 0.355 mmol) was obtained by the same procedure for the Example 1, Step 1, , 98%).

Step 2. 5-Isopropyl-3- (5-methoxypyridin-2-yl) -1,2,4-oxadiazole

(382 mg, 3.59 mmol) instead of acetyl chloride as starting materials and (Z) -N'-hydroxy-5-methoxypicolinimidamide (500.1 mg, 2.994 mmol) (5-methoxypyridin-2-yl) -1,2,4-oxadiazole (550.5 mg, 84%).

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, 2.280 mmol) - (5-isopropyl-1,2,4-oxadiazol-3-yl) pyridin-3-ol (321.8 mg, 69%).

Step 4. Synthesis of 4 - ((6- (5-isopropyl-1,2,4-oxadiazol-3-yl) pyridin-3- yl) oxy)

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

^{1 H NMR (500 MHz, CDCl} 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 = 7.0 Hz, 1 H), 3.04 (d, J = 5.1 Hz, 3H), 1.51 (d, J = 7.0 Hz, 6H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 340.26.

< Example  22> 5- (5-Isopropyl-1,2,4- Oxadiazole Yl) -N- methyl -2-oxo-2H- [1,4 ' Bipyridine ]-2'- Carboxamide

Step 1. Preparation of (Z) -N'-hydroxy-6-methoxy nicotinimidamide

(Z) -N'-hydroxy-6-methoxy nicotineimidamide (1.921 g, 11.46 mmol) was obtained by the method of Example 1, Step 1, using 6-methoxynicotinonitrile , 99%).

Step 2. 5-Isopropyl-3- (6-methoxypyridin-3-yl) -1,2,4-oxadiazole

(192.3 mg, 1.805 mmol) instead of acetyl chloride as starting materials and (Z) -N'-hydroxy-6-methoxy nicotineimidamide (251.4 mg, 1.504 mmol) 1-isopropyl-3- (6-methoxypyridin-3-yl) -1,2,4-oxadiazole (72.6 mg, 22%).

Step 3. Preparation of 5- (5-isopropyl-l, 2,4-oxadiazol-3-yl) pyridin-

The starting material was prepared from 5-isopropyl-3- (6-methoxypyridin-3-yl) -1,2,4-oxadiazole (718.14 mg, 3.275 mmol) - (5-isopropyl-1,2,4-oxadiazol-3-yl) pyridin-2-ol (340.9 mg, 51%).

Step 4. Preparation of 5- (5-isopropyl-l, 2,4-oxadiazol-3-yl) -N-methyl-2-oxo-2H- [1,4'-bipyridine] Vox amide

(150.0 mng, 0.7309 mmol) as starting materials and carrying out the same procedures as in Example 1, Step 3, the title compound (17.8 mg, 7%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.70 (dd, J = 5.3, 0.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.14 J = 9.7, 0.6 Hz, 1H), 3.25 (hept, J = 6.9 Hz, 1H), 3.08 (d, J = , J = 5.1 Hz, 3H), 1.43 (d, J = 7.0 Hz, 6H); LC / MS (ESI) [M + H] &lt; ⁺ &gt; = 340.26.

The specific chemical structures of Examples 1 to 22 according to the present invention are summarized in Table 1 below.

Example Chemical structure Example Chemical structure One

12

2

13

3

14

4

15

5

16

6

17

7

18

8

19

9

20

10

21

11

22

< Experimental Example  1> Saito Pachi  effect( CPE , Cytopathic  Effect) Viper cornavirus  How to search for medicines

In the experimental materials, first, HeLa (human cervical cancerous malignant tumor cells), MRC-5 (human embryonic lung cells) and RD (human embryonic muscle cells) were used. Standard drugs were ribavirin (Riv) Pleconaril, pleco, and BTA-798 (BTA) were used. The 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. 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, when the cells were all killed by virus infection, the CPE inhibition rate was 0%. When the cell survival rate was 100% due to the antiviral activity, the CPE inhibition rate was calculated as 100% Respectively. The CPE inhibition rate, i.e., the cell survival rate, was determined by MTT [3- (4,5-dimethylthiazol-2) -2,5-diphenyltetrazolium bromide], MTS [3- (4,5- -Yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium] or FDA (Fluorescein diacetate). Cells suitable for viruses were grown in 96-well plates and then virus diluted with DME (DME / 2% FBS) containing 2% FBS or MEM (MEM / 2% FBS) containing 2% FBS the inoculum size ㎕ inoculated by 100 so that the 100 CCID ₅₀ (50% cell culture inhibitory dose) and to remove the culture medium was absorbed in 33 ℃ or 37 ℃ for 30 minutes to 1 hour. 100 μl of each diluted drug was added to each well at a concentration of 3 or 5 times at a constant concentration of 3 or 5 times, and the remaining viruses except HRV (human rhinovirus) cultured at 33 ° C were incubated in a 37 ° C CO ₂ incubator for 2 After culturing for 3 days, the results were measured. 50 占 퐇 of double-concentration drug was added to the cells, followed by addition of 50 占 퐇 of viral solution, 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.

virus Reference Host cell Incubation temperature Incubation period Culture solution Cock Saki B1 - HeLa 37 ℃ 2 days DME / 2% FBS Cock Saki B3 - HeLa 37 ℃ 2 days DME / 2% FBS Poliovirus 3 - HeLa 37 ℃ 2 days DME / 2% FBS Rhinovirus - HeLa 37 ℃ 3 days DME / 2% FBS

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 method was carried out by removing 50 쨉 l of the MTT solution diluted with the culture medium, and culturing for 30 minutes at 37 째 C. To dissolve the reduced formazan, 100 쨉 l of the organic solvent was added, The OD (optical density) value of each cell at 540 nm and 690 nm was measured using a microplate reader, and the difference between the absorbance at 540 nm and 690 nm was determined and used for the calculation. , 90 [mu] l of the culture solution and 10 [mu] l of MTS-phenazine methosulfate (Promega, Rayon, Netherlands) were added to each well. After incubation at 37 [deg.] C for 2 hours, For the RD and MRC-5 cells, the CPE was determined by FDA. After removing all the medium, 100 ㎕ of 3 ug / ml FDA solution was added, and 37 캜 The fluorescence values were read using a 485 nm excitation filter and a 538 nm emission filter using a microplate fluorescence meter (Fluoroskan Ascent, Labsystem).

To determine the effect of drug toxicity on the drug efficacy results, the virus-free culture was added to the cells at the time of virus inoculation and then treated in the same manner as mock-infected cells inoculated with virus. Next, after one hour of culture, the medium was removed and the diluted drug was added to the culture once more. The number of cells survived in each simulated infected well with MTT, MTS or FDA added drug was compared with that of non-drug-treated cell compared to 50% Was determined as 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 infected cell survival rate (% survival) for cytotoxicity measurement was calculated by the following equation (1).

If the survival rate is 100%, there is no toxicity. If the survival rate is 0%, the 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 toxic.

In addition, the antiviral effect can be calculated by the following equation (2).

If the survival rate is 100%, the antiviral effect is 100%. If the survival rate is 0%, there is no antiviral effect. The concentration of the drug, which cells in the virus-infected well can exhibit 50% survival, is calculated by EC ₅₀ , which means that the lower the value, the better the antiviral efficacy.

< Experimental Example  2> Multicycle Saito Pachi  effect( CPE ) Reduction analysis method Picornavirus  Drug search

We conducted a multi - cycle CPE reduction assay to investigate the pharmacopoeial effect of antimicrobial virus. The antiviral activity of the compound is determined by the MTS [3- (4,5-dimethylthiazol-2-yl) -5- (3- carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium] It was first determined by a basic CPE reduction assay.

Specifically, each virus was inoculated into the cells proliferated for fusion in a 96-well dish so that each well dose was 100 CCID ₅₀ (50% inhibition of cell culture). After adsorption at 37 ° C for 2 hours, the virus was removed and stair-diluted compounds were added. Cultured cells were further cultured at 37 ° C. for 3 days until the control virus (VC), which was induced but not treated, was measured as complete CPE. The medium was then removed and 90 [mu] l of cultured cell vehicle and 10 [mu] l of MTS-penazine methosulfate (Promega, Rayon, Netherlands) were added to each well. After incubation at 37 ° C for 2 hours, the OD (optical density) value of each cell was measured at 498 nm using a microplate reader. The% CPE value for evaluating the antiviral drug efficacy was calculated by the following equation (3).

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

In the above equations (3) and (4)

OD (CC) is the OD of the culture solution of the culture solution which is not induced in the virus and not treated with the compound,

OD (VC) is the OD of the control cultured cells that are virus induced and not compound treated,

The OD (virus + compound) is the OD of the cultured cells infected with the virus treated with the concentrated compound,

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

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 interpolation). The cytotoxicity results are shown in Table 3 below.

Example rhino tox
CC ₅₀ ([mu] M) pico tox
CC ₅₀ ([mu] M) EV tox
CC ₅₀ ([mu] M) One > 10 > 10 > 10 2 > 10 > 10 > 10 3 > 10 > 10 > 10 4 > 10 > 10 > 10 5 > 10 > 10 - 6 > 10 > 10 - 7 > 10 > 10 > 10 8 > 10 > 10 - 9 > 10 > 10 - 10 > 10 > 10 - 13 6.9 5.6 - 16 > 10 > 10 > 10 17 5.2 9.1 > 10 18 6.8 2.0 2.6 19 5.5 2.9 - 20 > 10 > 10 > 10

In addition, the effective concentration (EC ₅₀ ) for the compounds of the examples according to the present invention against Coxsackie virus B1 (CoxB1), Coxsackievirus B3 (CoxB3), Poliovirus 3 (PV3) and 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.

Example HRV14
EC ₅₀ ([mu] M) HRV21
EC ₅₀ ([mu] M) HRV71
EC ₅₀ ([mu] M) Cox B1
EC ₅₀ ([mu] M) Cox B3
EC ₅₀ ([mu] M) PV 3
EC ₅₀ ([mu] M) One > 10 8.7 1.6 > 10 > 10 > 10 2 1.1 0.13 0.031 > 10 > 10 1.7 3 0.52 0.4 0.05 1.2 > 10 0.29 4 0.073 0.38 0.034 8.7 > 10 0.95 5 > 10 2.2 0.34 > 10 > 10 > 10 6 8.3 2.1 1.7 > 10 > 10 > 10 7 9.3 > 10 1.6 2.8 > 10 0.34 8 > 10 2.1 0.15 > 10 > 10 0.34 9 > 10 2.7 0.37 > 10 > 10 > 10 10 > 10 > 10 2 > 10 > 10 5 13 1.7 0.11 0.0084 > 5.6 > 5.6 0.64 16 0.65 0.059 0.061 > 10 > 10 <0.16 17 0.43 0.077 0.014 > 9.1 > 9.1 <0.16 18 0.47 0.06 0.0031 > 2.0 > 2.0 0.07 19 0.073 0.3 0.013 > 2.9 > 2.9 0.22 20 2 0.99 0.3 > 10 > 10 0.31

Example EV 68
EC ₅₀ ([mu] M) EV 71
EC ₅₀ ([mu] M) One > 10 > 10 2 9.1 3.2 3 2.1 1.2 4 8 1.1 5 - - 6 - - 7 > 10 8.4 8 - - 9 - - 10 - - 13 - - 16 > 10 > 10 17 1.6 5.8 18 > 2.6 > 2.6 19 - - 20 > 10 > 10

As shown in Tables 4 and 5,

The compounds according to the present invention exhibited excellent antiviral activity against poliovirus 3 (PV3) and rhinovirus (HRV14, HRV21 and HRV71) belonging to the picornavirus group and enterovirus (EV) It was found that the compound of the present invention exhibits excellent antiviral activity even at a very low EC ₅₀ value of 10 μM 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)

Lactose 1 g

After mixing the above components, the mixture was packed in an airtight container to prepare a powder.

<1-2> Preparation of tablets

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

&Lt; 1-3 > Preparation of capsules

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<1-4> Preparation of Injection Solution

10 [micro] g / ml of the compound represented by formula (1)

Until dilute hydrochloric acid BP pH 3.5

Sodium chloride BP injected up to 1 ml

The compound according to the invention was dissolved in a suitable volume of injected sodium chloride BP and the pH of the resulting solution was adjusted to pH 3.5 using dilute hydrochloric acid BP and the volume was adjusted using injectable sodium chloride BP and mixed thoroughly. The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed in an upper lattice of air by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and an injection solution was prepared.

Claims (11)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
Ring

,

,

,

, or

Wherein A ¹ , A ² and A ³ are independently -H or methyl,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently

,

,

,

,

,

, or

ego;

R &lt; ¹ &gt; is methylaminocarbonyl, or dimethylaminocarbonyl;

X is = N-; And

The ring

, L is a single bond, or
The ring

, L is -O-).
delete delete The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following 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] -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-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-oxadiazol-3-yl) phenoxy] -N-methylpicolinamide;
(10) 4- [3- (5- (Methoxymethyl) -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-oxadiazol-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-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] Picolinamide;
(19) Synthesis of 4 - [(2- (5-isopropyl-1,2,4-oxadiazol-3-yl) -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) -N-methylpicolinamide; And
(22) 5- (5-Isopropyl-1,2,4-oxadiazol-3-yl) -N-methyl-2-oxo-2H- [1,4'-bipyridine] Vox amide.
As shown in Scheme 1 below,
A process for producing a compound represented by the general formula (1), comprising the step of reacting a compound represented by the general formula (2) with a compound represented by the general formula (3) to prepare a compound represented by the general formula
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ , X and Ring are independently as defined in formula 1 of claim 1; And
Halo is a halogen.
An antiviral pharmaceutical composition comprising a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

(In the formula 1,
Ring

,

, or

Wherein A ¹ , A ² and A ³ are independently -H or methyl,
R ² , R ³ , R ⁴ , and R ⁵ are independently

,

,

,

,

,

, or

ego;

R &lt; ¹ &gt; is methylaminocarbonyl, or dimethylaminocarbonyl;

X is = N-; And

L is -O-).
A pharmaceutical composition for the prevention or treatment of a viral disease comprising a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

(In the formula 1,
Ring

,

, or

Wherein A ¹ , A ² and A ³ are independently -H or methyl,
R ² , R ³ , R ⁴ , and R ⁵ are independently

,

,

,

,

,

, or

ego;

R &lt; ¹ &gt; is methylaminocarbonyl, or dimethylaminocarbonyl;

X is = N-; And

L is -O-).
8. The method of claim 7,
Wherein the viral disease is a disease caused by rhinovirus, picornavirus, or poliovirus.
8. The method of claim 7,
Wherein said viral disease is a disease caused by human rhinovirus.
8. The method of claim 7,
The viral diseases are selected from the group consisting of poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, waterborne disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, encephalitis, cold, herpes zoster, Wherein the disease is lung disease, obstructive pulmonary disease, pneumonia, sinusitis or otitis media.
A health functional food composition for preventing or ameliorating a viral disease comprising a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

(In the formula 1,
Ring

,

, or

Wherein A ¹ , A ² and A ³ are independently -H or methyl,
R ² , R ³ , R ⁴ , and R ⁵ are independently

,

,

,

,

,

, or

ego;

R &lt; ¹ &gt; is methylaminocarbonyl, or dimethylaminocarbonyl;

X is = N-; And

L is -O-).