KR102049140B1 - Isoquinolinone derivatives, preparation method thereof and pharmaceutical composition for treating influenza virus containing the same - Google Patents

Abstract

The present invention relates to an isoquinolinone derivative, a method for preparing the same, and a pharmaceutical composition for treating influenza virus containing the same, wherein the isoquinolinone derivative of formula 1 according to the present invention is low in toxicity to normal cells, Since it has very good antiviral activity against influenza virus, it can be usefully used as a pharmaceutical composition for the prevention or treatment of influenza.

Description

Isoquinolinone derivatives, preparation method etc. and pharmaceutical composition for treating influenza virus containing the same}

The present invention relates to an isoquinolinone derivative, a preparation method thereof and a pharmaceutical composition for treating influenza virus containing the same.

The flu (influenza) is an infectious disease caused by the influenza virus (virus) of the Oxomyxovirus family. Influenza viruses cause pandemic influenza worldwide, killing thousands to tens of thousands of people every season. In the 20th century, there were three global epidemics of influenza caused by new viruses, killing tens of millions of people. These strains of viruses often occur when infections occur from other animals to humans, and when a species of humans receives genes from species that host other animals. The emergence of H5N1, which emerged in Asia in 1990, has generated great interest in the pandemic of influenza, but the species has not changed to specialize in human-to-human infections. In April 2009, a variant of H1N1 emerged in Mexico from several countries. The International Health Organization (WHO) declared this fad as 'global fad' on 11 July 2009.

Influenza viruses are divided into three types, A, B, and C, depending on the antigen type. Virus type A can host many animals, while virus types B and C are primarily human. Influenza epidemics are mostly caused by type A and B infections, and viral C infections are not common and usually follow a mild course. On the surface of the virus particles are antigenic projections. Type A and B processes include specific hemagglutinin (HA) and neuraminidase (NA), and type C lacks neuraminidase. Hemagglutinin is involved in adhesion to cells of the host animal. Neuraminidase eliminates neuramic acid in airway mucin (mucin has an inhibitory effect on hemagglutinin, preventing the virus from attaching to the cell), preventing the virus from freeing and inter-virus aggregation from the host It is known to work. Type A is subclassed according to the hemagglutinin and neuraminidase antigen types. There are 16 types of hemagglutinin of H-type influenza virus that cause human infection, and 9 types of neuraminidase such as N1 and N2, and they are classified as H3N2, H1N1, H2N2, etc. do. Influenza virus names are listed in the order of type / location / separation number / year of separation (subtype). For example, it is written as A / Hong Kong / 8/68 (H3N2).

The presence or absence of specific antibodies to influenza virus antigens determines immunity. Influenza viruses have two types of antigenic mutations, such as a change in the HA or NA caused by gene rearrangement, such as a change from H1 to H2. A slight change in sex is called the drift of the antigen. The pandemic of influenza virus A occurs every 10 to 40 years due to antigenic mutations, and between 2 and 3 years due to urine. The big outbreak of type B usually occurs every four to seven years. In case of a pandemic, the highest incidence of infection is 50% among children aged 5-14 years, and it is known that the same age infection rate is about 15%. In Korea, influenza A was reported annually and influenza B every two years.

Two classes of antiviral drugs are used to treat influenza. Neuraminidase inhibitors and M2 protein inhibitors (adamantane derivatives) are used as antiviral drugs. Neuraminidase inhibitors are currently preferred for the treatment of influenza virus infection because they are very toxic and very effective. The U.S. Centers for Disease Control and Prevention recommended prescribing neuraminidase inhibitors over M2 inhibitors during the influenza season during 2005-2006 because of the high levels of drug resistance. Pregnant women are advised to prescribe anti-influenza drugs immediately, as they are likely to be more seriously affected by the 2009 H1N1 virus than the general population. Neuraminidase Inhibitors Neuraminidase inhibitors, such as oseltamivir (commercial Tamiflu) and zanamivir (commercial Relenza), are drugs designed to prevent the spread of the virus in the body. These drugs are effective against both influenza viruses A and B. Different influenza virus strains show different degrees of resistance to these antiviral drugs. M2 Inhibitors Antiviral drugs amantadine and rimantadine inhibit viral ion channels (M2 proteins) and prevent viruses from infecting cells. These drugs are sometimes effective against influenza virus A if prescribed early in the infection. However, it is not effective against influenza virus B. This is because the M2 protein of influenza B virus is structurally different from the M2 protein of type A virus and does not bind amantadine. The measured resistance of H3N2 to amantadine and rimantadine in the United States increased 91% in 2005. High levels of resistance may be due to the easiest use of amantadine among over-the-counter cold medicines in China and Russia. It may also be because amantadine is easily used by poultry to prevent influenza on farms.

Therefore, the development of new therapeutics that can overcome the resistance of existing antiviral drugs is continuously needed.

Accordingly, the present inventors, while studying a compound having activity against the influenza virus, confirmed that the isoquinolinone derivatives selectively have excellent activity against the influenza virus while having low toxicity to normal cells, thereby completing the present invention. It was.

United States Patent Application Publication No. US2005 / 0136065

It is an object of the present invention to provide isoquinolinone derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide methods 1 and 2 for preparing the isoquinolinone derivatives.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of influenza virus containing the isoquinolinone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object,

The present invention provides an isoquinolinone derivative represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

R ¹ is hydrogen or C _1-6 linear or branched alkyl;

R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently hydrogen, C _1-6 straight or branched chain alkyl, or C _1-6 straight or branched alkoxy, wherein R ^2c and R ^2d are Together with the carbon atom to which it is linked may form a 5-8 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;

R ³ is hydrogen;

R ⁴ is hydrogen or C _1-6 straight or branched alkyl;

R ⁵ is hydrogen or C _1-6 straight or branched alkoxy;

R ⁶ is hydrogen or C _1-6 straight or branched alkoxy;

R ⁷ is hydrogen or hydroxy;

However, the compound represented by Formula 1 excludes the following compound groups:

1) 7,8-dimethoxy-2-methyl-3- (6-vinylbenzo [d] [1,3] dioxol-5-yl) isoquinolin-1 (2H) -one;

2) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one;

4) 5- (dimethylamino) -3-p-tolylisoquinolin-1 (2H) -one;

5) 5- (dimethylamino) -3- (4-methoxyphenyl) isoquinolin-1 (2H) -one;

6) 3- (4-chlorophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;

7) 3- (4-bromophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;

8) 3- (2,6-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;

9) 3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;

12) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl)-[1,3] dioxolo [4,5-h] isoquinoline-9 ( 8H) -one;

13) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxyisoquinolin-1 (2H) -one;

14) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -8-methyl- [1,3] dioxolo [4,5-h] iso Quinolin-9 (8H) -one;

15) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one ;

16) 4-bromo-3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;

17) 4-bromo-3- (3,5-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;

18) 2- (2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl) benzaldehyde;

19) 2- (6-methyl-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzaldehyde; And

20) 6- (4-bromo-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzo [d] [1,3] dioxol-5-carbaldehyde.

In addition, the present invention as shown in Scheme 1,

Compound 101 was added dropwise to the first organic solvent, water was added to remove the precipitate, the filtrate was dissolved in the second organic solvent, and dimethyl sulfate was added while refluxing to obtain compound 102 (step 1);

Compound 102 was added to the third organic solvent, and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added to the filtrate of the organic layer obtained by extraction with CHCl ₃ and stirred. Next, adding NaHCO ₃ and separating the organic layer to obtain a compound 103 (step 2);

Dissolving compound 103 in a fourth organic solvent and stirring with Pd / C, concentrating the filtrate and diluting with CH ₂ Cl ₂ , then separating the organic layer to obtain compound 104 (step 3); And

Dissolving compound 104 and p-TsOH in a fifth organic solvent and refluxing to remove the fifth organic solvent, and then separating the organic layer obtained by dissolving the residue in a sixth organic solvent to obtain Compound 1A (step 4);

It provides a method of preparing Compound 1A.

Scheme 1

In Scheme 1,

Compound 1A is included in the isoquinolinone derivative represented by Chemical Formula 1.

Furthermore, the present invention, as shown in Scheme 2 below,

Provided is a method for preparing Compound 1B comprising the step of adding Compound 105 and 106 to a mixed solution of the first organic solvent and n-BuLi to obtain Compound 1B.

Scheme 2

In Scheme 2,

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined in Formula 1 of claim 1,

Compound 1B is included in the isoquinolinone derivative represented by Chemical Formula 1.

In addition, the present invention provides a pharmaceutical composition for preventing or treating influenza virus containing an isoquinolinone derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.

[Formula 1]

In Chemical Formula 1,

R ¹ is hydrogen, C _1-6 straight or branched alkyl or C _1-6 straight or branched alkenyl;

R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently C _1-6 straight or branched chain alkyl, C _1-6 straight or branched chain substituted with hydrogen, halogen, unsubstituted or one or more hydroxy; Kenyl, C _1-6 straight or branched alkoxy, or formyl,

Wherein R ^2c and R ^2d together with the carbon atom to which they are linked may form a 5-8 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;

R ³ is hydrogen or halogen;

R ⁴ is hydrogen, C _1-6 straight or branched alkyl, or —NR ^4a R ^4b , wherein R ^4a and R ^4b are independently C _1-6 straight or branched alkyl;

R ⁵ is hydrogen, C _1-6 straight or branched alkyl, or C _1-6 straight or branched alkoxy;

R ⁶ is hydrogen or C _1-6 straight or branched alkoxy;

R ⁷ is hydrogen, hydroxy, or C _1-6 straight or branched alkoxy;

R ⁶ and R ⁷ may form a 5-8 membered heterocycle including one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are linked.

The isoquinolinone derivatives of the general formula (1) according to the present invention not only have low toxicity to normal cells but also have very good antiviral activity against influenza viruses, and thus can be usefully used as pharmaceutical compositions for the prevention or treatment of influenza. have.

Hereinafter, the present invention will be described in detail.

Isoquinolinone  Derivatives, pharmaceutically thereof Acceptable  Salts or optical isomers thereof

The present invention provides an isoquinolinone derivative represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

R ¹ is hydrogen or C _1-6 linear or branched alkyl;

R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently hydrogen, C _1-6 straight or branched chain alkyl, or C _1-6 straight or branched alkoxy, wherein R ^2c and R ^2d are Together with the carbon atom to which it is linked may form a 5-8 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;

R ³ is hydrogen;

R ⁴ is hydrogen or C _1-6 straight or branched alkyl;

R ⁵ is hydrogen or C _1-6 straight or branched alkoxy;

R ⁶ is hydrogen or C _1-6 straight or branched alkoxy;

R ⁷ is hydrogen or hydroxy;

However, the compound represented by Formula 1 excludes the following compound groups:

1) 7,8-dimethoxy-2-methyl-3- (6-vinylbenzo [d] [1,3] dioxol-5-yl) isoquinolin-1 (2H) -one;

2) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one;

4) 5- (dimethylamino) -3-p-tolylisoquinolin-1 (2H) -one;

5) 5- (dimethylamino) -3- (4-methoxyphenyl) isoquinolin-1 (2H) -one;

6) 3- (4-chlorophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;

7) 3- (4-bromophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;

8) 3- (2,6-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;

9) 3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;

12) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl)-[1,3] dioxolo [4,5-h] isoquinoline-9 ( 8H) -one;

13) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxyisoquinolin-1 (2H) -one;

14) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -8-methyl- [1,3] dioxolo [4,5-h] iso Quinolin-9 (8H) -one;

15) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one ;

16) 4-bromo-3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;

17) 4-bromo-3- (3,5-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;

18) 2- (2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl) benzaldehyde;

19) 2- (6-methyl-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzaldehyde; And

20) 6- (4-bromo-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzo [d] [1,3] dioxol-5-carbaldehyde.

Preferably,

R ¹ is hydrogen or methyl;

R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently hydrogen, ethyl, or methoxy, wherein R ^2c and R ^2d are 5-membered hetero, including two O atoms with the carbon atom to which they are linked Can form a cycle;

R ³ is hydrogen;

R ⁴ is hydrogen or methyl;

R ⁵ is hydrogen or methoxy;

R ⁶ is hydrogen or methoxy;

R ⁷ is hydrogen or hydroxy.

Preferred examples of the isoquinolinone derivative represented by Formula 1 according to the present invention include the following compound groups.

3) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -8-hydroxy-7-methoxy-2-methylisoquinolin-1 (2H) -one;

10) 6,7-dimethoxy-3-phenylisoquinolin-1 (2H) -one; And

11) 3- (3-methoxyphenyl) -5-methylisoquinolin-1 (2H) -one.

The derivative represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The expression pharmaceutically acceptable salt is a concentration that has a relatively nontoxic and harmless effect on the patient and that any side effects due to the salt do not degrade the beneficial efficacy of the base compound of formula 1, or Means inorganic addition salts. These salts may include inorganic acids and organic acids as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, and the like, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine as organic acids. Acids, Gluconic Acid, Methanesulfonic Acid, Glyconic Acid, Succinic Acid, Tartaric Acid, Galluturonic Acid, Embonic Acid, Glutamic Acid, Aspartic Acid, Oxalic Acid, (D) or (L) Malic Acid, Maleic Acid, Methanesulphonic Acid, Ethene Sulfur Phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid and the like can be used. These salts also include alkali metal salts (sodium salts, potassium salts, and the like), alkaline earth metal salts (calcium salts, magnesium salts, and the like) and the like. For example, acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, disylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Mali Eate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccha Laterate, stearate, succinate, tartrate, tosylate, trifluoroacete , Aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like. Heavy hydrochloride or trifluoroacetate are preferred.

Acid addition salt according to the present invention is a conventional method, for example, a precipitate formed by dissolving the derivative represented by the formula (1) in an organic solvent, for example methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, and adding an organic or inorganic acid The solvent may be prepared by filtration, drying, or by distillation under reduced pressure of the solvent and excess acid, followed by drying or crystallization under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Furthermore, the present invention includes not only derivatives of Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, isomers, optical isomers and the like that can be prepared therefrom.

Manufacturing Method 1

As the present invention is shown in Scheme 1,

Compound 101 was added dropwise to the first organic solvent, water was added to remove the precipitate, the filtrate was dissolved in the second organic solvent, and dimethyl sulfate was added while refluxing to obtain compound 102 (step 1);

Compound 102 was added to the third organic solvent, and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added to the filtrate of the organic layer obtained by extraction with CHCl ₃ and stirred. Next, adding NaHCO ₃ and separating the organic layer to obtain a compound 103 (step 2);

Dissolving compound 103 in a fourth organic solvent and stirring with Pd / C, concentrating the filtrate and diluting with CH ₂ Cl ₂ , then separating the organic layer to obtain compound 104 (step 3); And

Dissolving compound 104 and p-TsOH in a fifth organic solvent and refluxing to remove the fifth organic solvent, and then separating the organic layer obtained by dissolving the residue in a sixth organic solvent to obtain Compound 1A (step 4);

It provides a method of preparing Compound 1A.

Scheme 1

In Scheme 1,

Compound 1A is included in the isoquinolinone derivative represented by Chemical Formula 1.

In the preparation method 1 according to the present invention, the first to sixth organic solvents are anhydrous tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH ₂ Cl ₂ , hexane, dimethylformamide ( DMF), ethanol, diisopropyl ether, diethyl ether, dioxane, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetone, chlorobenzene and the like can be used alone or in combination. Further, the first organic solvent may include LiAlH ₄ .

In the preparation method 1 according to the present invention, the reaction temperature of step 1 may be 0-100 ° C., preferably 20-50 ° C., and the reaction time may be 1-10 hours, preferably 1-5 hours. have.

In the preparation method 1 according to the present invention, the reaction temperature of step 2 may be 0-100 ° C, preferably 20-50 ° C, and the reaction time may be 0.1-24 hours, preferably 0.1-12 hours. have.

In the preparation method 1 according to the present invention, the reaction temperature of step 3 may be 0-100 ° C., preferably 20-50 ° C., and the reaction time may be 1-24 hours, preferably 5-16 hours. have. In addition, the reaction of step 3 may be reacted under a hydrogen atmosphere.

In the preparation method 1 according to the present invention, the reaction temperature of step 4 may be 0-100 ° C, preferably 20-100 ° C, and the reaction time may be 0.1-10 hours, preferably 1-5 hours. have.

Manufacturing Method 2

As the present invention is shown in Scheme 2,

Provided is a method for preparing Compound 1B comprising the step of adding Compound 105 and 106 to a mixed solution of a first organic solvent and n-BuLi to obtain Compound 1B.

Scheme 2

In Scheme 2,

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined in Formula 1 of claim 1,

Compound 1B is included in the isoquinolinone derivative represented by Chemical Formula 1.

In the preparation method 2 according to the present invention, the first organic solvent is anhydrous tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH ₂ Cl ₂ , hexane, dimethylformamide (DMF), ethanol, Diisopropyl ether, diethyl ether, dioxane, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), chlorobenzene and the like can be used alone or in combination.

In the preparation method 1 according to the present invention, the reaction temperature of the step 1 may be -100 to 0 ℃, preferably -70 to -50 ℃, the reaction time is 10-50 hours, preferably 20-40 It can be time.

Pharmaceutical composition for preventing or treating influenza virus

The present invention provides a pharmaceutical composition for preventing or treating influenza virus containing an isoquinolinone derivative represented by Formula 1 below, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient.

[Formula 1]

In Chemical Formula 1,

R ¹ is hydrogen, C _1-6 straight or branched alkyl or C _1-6 straight or branched alkenyl;

R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently C _1-6 straight or branched chain alkyl, C _1-6 straight or branched chain substituted with hydrogen, halogen, unsubstituted or one or more hydroxy; Kenyl, C _1-6 straight or branched alkoxy, or formyl,

Wherein R ^2c and R ^2d together with the carbon atom to which they are linked may form a 5-8 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;

R ³ is hydrogen or halogen;

R ⁴ is hydrogen, C _1-6 straight or branched alkyl, or —NR ^4a R ^4b , wherein R ^4a and R ^4b are independently C _1-6 straight or branched alkyl;

R ⁵ is hydrogen, C _1-6 straight or branched alkyl, or C _1-6 straight or branched alkoxy;

R ⁶ is hydrogen or C _1-6 straight or branched alkoxy;

R ⁷ is hydrogen, hydroxy, or C _1-6 straight or branched alkoxy;

R ⁶ and R ⁷ may form a 5-8 membered heterocycle including one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are linked.

Preferably,

R ¹ is hydrogen, C _1-3 straight or branched alkyl or C _1-3 straight or branched alkenyl;

R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently C _1-3 straight or branched chain alkyl of C _1-3 substituted with hydrogen, halogen, unsubstituted or one or more hydroxy, C _1-3 straight or branched chain al Kenyl, C _1-3 straight or branched alkoxy, or formyl,

Wherein R ^2c and R ^2d together with the carbon atom to which they are linked may form a 5-6 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;

R ³ is hydrogen or halogen;

R ⁴ is hydrogen, C _1-3 straight or branched alkyl, or —NR ^4a R ^4b , wherein R ^4a and R ^4b are independently C _1-3 straight or branched alkyl;

R ⁵ is hydrogen, C _1-3 straight or branched alkyl, or C _1-3 straight or branched alkoxy;

R ⁶ is hydrogen or C _1-3 straight or branched alkoxy;

R ⁷ is hydrogen, hydroxy, or C _1-3 straight or branched alkoxy;

R ⁶ and R ⁷ may form a 5-6 membered heterocycle including one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are linked.

More preferably,

R ¹ is hydrogen, methyl or vinyl;

R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently hydrogen, Cl, Br, methyl, ethyl, hydroxyethyl, vinyl, methoxy, or formyl,

Wherein R ^2c and R ^2d together with the carbon atom to which they are linked may form a five membered heterocycle comprising two O atoms;

R ³ is hydrogen or Br;

R ⁴ is hydrogen, methyl, or —N (CH ₃ ) ₂ ;

R ⁵ is hydrogen, methyl, or methoxy;

R ⁶ is hydrogen or methoxy;

R ⁷ is hydrogen, hydroxy, or methoxy;

R ⁶ and R ⁷ together with the carbon atoms to which they are linked may form a five membered heterocycle comprising two O atoms.

In the pharmaceutical composition according to the present invention, preferred examples of the isoquinolinone derivative represented by Formula 1 include the following compound groups.

1) 7,8-dimethoxy-2-methyl-3- (6-vinylbenzo [d] [1,3] dioxol-5-yl) isoquinolin-1 (2H) -one;

2) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one;

3) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -8-hydroxy-7-methoxy-2-methylisoquinolin-1 (2H) -one;

4) 5- (dimethylamino) -3-p-tolylisoquinolin-1 (2H) -one;

5) 5- (dimethylamino) -3- (4-methoxyphenyl) isoquinolin-1 (2H) -one;

6) 3- (4-chlorophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;

7) 3- (4-bromophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;

8) 3- (2,6-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;

9) 3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;

10) 6,7-dimethoxy-3-phenylisoquinolin-1 (2H) -one;

11) 3- (3-methoxyphenyl) -5-methylisoquinolin-1 (2H) -one;

12) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl)-[1,3] dioxolo [4,5-h] isoquinoline-9 ( 8H) -one;

13) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxyisoquinolin-1 (2H) -one;

14) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -8-methyl- [1,3] dioxolo [4,5-h] iso Quinolin-9 (8H) -one;

15) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one ;

16) 4-bromo-3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;

17) 4-bromo-3- (3,5-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;

18) 2- (2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl) benzaldehyde;

19) 2- (6-methyl-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzaldehyde; And

20) 6- (4-bromo-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzo [d] [1,3] dioxol-5-carbaldehyde.

Table 1 shows the chemical structural formulas of Compounds 1 to 20.

compound Chemical structure compound Chemical structure One

11


Example 3

2

12

3


Example 1

13

4

14

5

15

6

16

7

17

8

18

9

19

10


Example 2

20

In the pharmaceutical composition according to the present invention, the influenza virus may be influenza virus A, influenza virus B, influenza virus C, preferably influenza virus A and / or influenza virus B.

The influenza virus type A is not only strains of H1N1, H3N2 including A / Puerto Rico / 8/34 (H1N1, PR8), and A / Hong Kong / 8/68 (H3N2, HK), but also H3N8, H5N1, H5N8 And various subtype viruses such as H7N9, H9N2.

The influenza virus type B may be a virus of various Yamagata lineages and Victoria lineages including B / Lee / 40 (Lee).

The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

< EXAMPLE  1> 3- (6- Ethylbenzo [d] [1,3] dioxol -5-day) -8- Hydroxy -7- Methoxy Preparation of 2-methylisoquinolin-1 (2H) -one (Compound 3 = Compound 1A = CWJILQ-3)

Step 1: Preparation of Compound 102

Berberine chloride (Compound 101) (10 g, 26.89 mmol) was added dropwise while stirring the suspension suspended in LiAlH ₄ (3.07 g, 81.1 mmol) in anhydrous tetrahydrofuran (340 mL) at 0 ° C. Stir for hours. Next, water was added, the precipitate was filtered off and the resulting filtrate was concentrated to obtain a dehydrogenated derivative, which was dissolved in anhydrous benzene (200 mL) and then refluxed. Dimethylsulfate (10.2 g, 81.1 mmol) was added to the refluxing benzene solution and further refluxed for 1.5 h. After the mixture was cooled, the reaction precipitate was filtered, screened and dried to give compound 102 (9.75 g, 78%).

Step 2: Preparation of Compound 103

Compound 102 (2 g, 4.4 mmol) obtained in step 1 was added to refluxing 25% KOH / MeOH solution (50 mL), heated under reflux for 10 minutes, poured into ice water and extracted with CHCl ₃ . . The organic layer was washed with water, dried over brine, concentrated under reduced pressure and filtered. To the filtrate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.18 g, 5.18 mmol) was added in portions at room temperature and stirred overnight. Saturated NaHCO ₃ solution was added to the reaction mixture, the organic layer was separated, dried over brine, and the residue obtained by concentration under reduced pressure was purified by column chromatography to obtain Compound 103 (490 mg, 31%).

Step 3: Preparation of Compound 104

The solution of Compound 103 (300 mg, 0.82 mmol) obtained in step 2 in MeOH (30 mL) was stirred with 5% Pd / C (120 mg) overnight under a hydrogen atmosphere at room temperature. The filtrate obtained by filtration of the reaction mixture was concentrated under reduced pressure and diluted with CH ₂ Cl ₂ . The organic layer was washed with water, dried over brine, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 104 (290 mg, 96%).

Step 4: Compound 1A (Compound 3 = CWJILQ - 3)  Produce

A solution of compound 104 (200 mg, 0.54 mmol) and p- TsOH (140 mg, 0.81 mmol) obtained in step 3 in toluene (15 mL) was refluxed. Toluene was removed by evaporation and the residue dissolved in CH ₂ Cl ₂ . The organic layer was washed with water, dried over brine and concentrated under reduced pressure to give a residue that was purified by column chromatography to give compound 1A (146 mg, 76%).

¹ H-NMR (300 MHz, CDCL ₃ ) δ: 13.20 (d, J = 0.6 Hz, 1H), 7.30-7.26 (m, 1H, partially overlapped with CHCl ₃ peak), 6.90 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H), 6.66 (s, 1H), 6.39 (s, 1H), 6.01 (t, J = 1.5 Hz, 2H), 3.97 (s, 3H), 3.25 (s, 3H), 2.50-2.29 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H).

The compound of Example 2-3 was prepared using the following scheme.

Example 2: R ^2a to R ^2e = H; R ³ , R ⁴ , R ⁷ = H; R ⁵ , R ⁶ = OMe

Example 3: R ^2a , R ^2c -R ^2e = H; R ^2b = OMe; R ³ , R ⁵ , R ⁶ , R ⁷ = H; R ⁴ = Me

< EXAMPLE  2> 6,7- Dimethoxy -3- Phenylisoquinoline Preparation of -1 (2H) -one (Compound 10 = CWJILQ-10)

Which was cooled to less than -70 ℃ being maintained below -60 ℃ hexane (3.2 mL, 7.96 mmol) and anhydrous THF (20 mL) and 2.5 M n in a mixture of -BuLi, N, N - diethyl 4,5 A solution of dimethoxy-2-methylbenzamide (1 g, 3.98 mmol) and benzonitrile (468 mg, 4.53 mmol) dissolved in anhydrous THF (7 mL) was added. The reaction mixture was stirred at −78 ° C. for 38.5 hours, then warmed to room temperature and terminated with saturated NH ₄ Cl. The precipitate was filtered off and the filtrate was washed with water and EtOAc, then extracted with CH ₂ Cl ₂ , washed with water and concentrated under reduced pressure. Fractions not dissolved in EtOAc were again filtered off and washed with EtOAc to afford the desired compound 10 (98 mg, 8%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.06 (s, 1H), 7.78 (s, 1H), 7.65-7.62 (m, 2H), 7.53-7.43 (m, 3H), 6.97 (s, 1H ), 6.71 (s, 1 H), 4.03 (s, 3 H), 4.02 (s, 3 H).

< EXAMPLE  3> 3- (3- Methoxyphenyl ) -5- Methylisoquinoline Preparation of -1 (2H) -one (Compound No. 11, CWJILQ-11)

Hexane (5 mL, 12 mmol) which was cooled to less than -70 ℃ being maintained below -60 ℃ and anhydrous THF (30 mL) and a mixture of 2.5 M n -BuLi, N, N - diethyl -2,3 A solution of dimethylbenzamide (1.02 g, 5 mmol) and 3-methoxybenzonitrile (832 mg, 6.25 mmol) in anhydrous THF (7 mL) was added. The reaction mixture was stirred at −78 ° C. for 38.5 hours, then warmed to room temperature and terminated with saturated NH ₄ Cl. The precipitate was filtered off and the filtrate was washed with water and EtOAc, then extracted with CH ₂ Cl ₂ , washed with water and concentrated under reduced pressure. Fractions not dissolved in EtOAc were again filtered off and washed with EtOAc to afford the desired compound 11 (1 g, 75%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.42 (s, 1H), 8.28 (d, J = 8.0, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.45-7.41 (m, 1H ), 7.39-7.31 (m, 3H), 7.03-7.00 (m, 1H), 6.89 (s, 1H), 3.92 (s, 3H), 2.59 (s, 3H).

Preparation of the experiment

Influenza virus A / Puerto Rico / 8/34 (H1N1, PR8), A / Hong Kong / 8/68 (H3N2, HK) and B / Lee / 40 (Lee) are American Type Culture Collection (ATCC, Rockville, MD) Used from Both of the influenza virus type A were infected with 10 day old eggs and amplified at 37 ° C. for 3 days. The influenza virus type B (Lee) was a MDCK (Madin-Darby canine kidney) cell under serum-free conditions. Infected and amplified. Partially purified virus was collected by centrifugation (3,000 rpm) for 5 minutes of the collected egg ureter or cell culture supernatant.

Virus titers were measured by hemagglutinin assay or plaque assay and stored at −70 ° C. prior to use. MDCK cells were maintained at 37 ° C. and 5% CO ₂ conditions in MEM (Minimum Essential Medium) supplied with 10% FBS (fetal bovine serum, Invitrogen).

As a positive control antiviral agent, amantadine hydrochloride (AMT), ribavirin (RBV) and OSV-P (oseltamivir phosphate, Tamiflu; US Biological, Swampscott, MA) were used. Test compounds were dissolved in DMSO at a concentration of 40 mg / mL and stored at -20 ° C.

< Experimental Example  1> cytopathic effect ( Cytopathic  effect, CPE ) Inhibition assessment ( in vitro )

In order to determine the cytotoxicity and antiviral activity of the isoquinolinone derivative compound 1-20 according to the present invention, the following experiment was performed, and the results are shown in Table 2 below.

Specifically, MDCK cells were dispensed into 96-well plates and incubated until 100% fusion. Next, the cells were washed with PBS (phosphate-buffered saline) and then mocked with influenza virus at a multiplicity of infection of 0.001 for 1 hour at 35 ° C. in a serum-free condition. -infected) or infected. Unabsorbed virus was removed by PBS wash and three-fold serial dilutions of the Example compound dissolved in MEM and 2 mg / mL TPCK-trypsin were added to each well. Three days after infection, cell viability was measured using MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide; Sigma-Aldrich). After reading the absorbance at 540/690 nm wavelength, 50% cytotoxic concentration (CC ₅₀ ) and 50% effective concentration (EC ₅₀ ) were calculated using GraphPad Prism 6 (GraphPad Software, La Jolla, Calif.). In Table 2 below, “Selectivity index” means a ratio of CC ₅₀ to EC ₅₀ .

Compd No. Toxicity (CC ₅₀ , μM) Antiviral activity
(EC ₅₀ , μM) Selectivity index PR8 HK Lee PR8 HK Lee One 44 <1.2 <1.2 <1.2 > 36.7 > 36.7 > 36.7 2 43.7 0.4 0.3 0.2 106.6 161.9 273.1 3 174.5 5.6 4 1.2 31.2 43.6 145.4 4 > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 5 > 100.0 > 100.0 93.4 > 100.0 ND > 1.1 ND 6 > 100.0 > 100.0 41.1 > 100.0 ND  > 2.4 ND 7 > 100.0 > 100.0 71.5 > 100.0 ND > 1.4 ND 8 > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 9 > 100.0 > 100.0 18.6 > 100.0 ND > 5.4 ND 10 > 100.0 11.6 <11.1 <11.1 > 8.6 > 9.0 > 9.0 11 > 100.0 > 100.0 43 > 100.0 ND > 2.3 ND 12 > 100.0 > 100.0 38.6 > 100.0 ND > 2.6 ND 13 > 100.0 33.3 <11.1 <11.1 > 3.0 > 9.0 > 9.0 14 > 100.0 > 100.0 33.3 100 ND > 3.0 > 1.0 15 > 100.0 > 100.0 <11.1 <11.1 ND > 9.0 > 9.0 16 > 100.0 90.5 17.5 74.5 > 1.1 > 5.7 > 1.3 17 > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 18 > 100.0 > 100.0 <11.1 > 100.0 ND > 9.0 ND 19 > 100.0 66.5 36.8 56 > 1.5 > 2.7 > 1.8 20 > 100.0 > 100.0 68.9 > 100.0 ND > 1.5 ND

As shown in Table 2, Example compounds 1, 2, 3, 10, 13 according to the present invention was low in cytotoxicity, it was found that the antiviral activity is very good.

Preparation Example 1 Preparation of Pharmaceutical Formulation

<1-1> Powder  Produce

2 g of a compound of formula 1

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of Tablet

100 mg of compound of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

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

<1-3> Preparation of Capsule

100 mg of compound of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> Preparation of Injection Solution

10 μg / ml of the compound of Formula 1

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

Dissolve the compound of formula 1 according to the invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and adjust the volume with sodium chloride BP for injection and sufficiently Mixed. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

<1-5> Preparation of Nasal Spray

1.0 g of compound of formula 1

0.3 g of sodium acetate

0.1 g of methyl paraben

Propylparaben 0.02 g

Sodium Chloride

HCl or NaOH pH adjustment

Purified water

According to the conventional method for preparing a nasal absorbent, 3 mg of the compound of formula 1 is contained per mL of saline (0.9% NaCl, w / v, purified water is solvent), and it is packed into an opaque spray container and sterilized. An absorbent was prepared.

<1-6> Preparation of Liquid

100 mg of compound of Formula 1

10 g of isomerized sugar

5 g of mannitol

Purified water

According to the conventional method for preparing a liquid solution, each component is added to the purified water to dissolve, lemon flavor is added, the above components are mixed, adjusted to 100 mL by adding purified water, and then filled into a brown bottle and sterilized to prepare a liquid solution. It was.

Claims (15)

Isoquinolinone derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula 1,
R ¹ is hydrogen or C _1-6 linear or branched alkyl;
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently hydrogen, C _1-6 straight or branched chain alkyl, or C _1-6 straight or branched alkoxy, wherein R ^2c and R ^2d are Together with the carbon atom to which it is linked may form a 5-8 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;
R ³ is hydrogen;
R ⁴ is hydrogen or C _1-6 straight or branched alkyl;
R ⁵ is hydrogen or C _1-6 straight or branched alkoxy;
R ⁶ is hydrogen or C _1-6 straight or branched alkoxy;
R ⁷ is hydrogen or hydroxy;
However, the compound represented by Formula 1 excludes the following compound groups:
3) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -8-hydroxy-7-methoxy-2-methylisoquinolin-1 (2H) -one; And
10) 6,7-dimethoxy-3-phenylisoquinolin-1 (2H) -one).
The method of claim 1,
R ¹ is hydrogen;
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently hydrogen or methoxy;
R ³ is hydrogen;
R ⁴ is methyl;
R ⁵ is hydrogen;
R ⁶ is hydrogen;
R ⁷ is hydrogen isoquinolinone derivative, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
The isoquinolinone derivative represented by Formula 1 is an isoquinolinone derivative, or a pharmaceutically acceptable salt thereof, wherein the isoquinolinone derivative is the following compound:
11) 3- (3-methoxyphenyl) -5-methylisoquinolin-1 (2H) -one.
As shown in Scheme 1 below,
Compound 101 was added dropwise to the first organic solvent, water was added to remove the precipitate, the filtrate was dissolved in the second organic solvent, and dimethyl sulfate was added while refluxing to obtain compound 102 (step 1);
Compound 102 was added to the third organic solvent, and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added to the filtrate of the organic layer obtained by extraction with CHCl ₃ and stirred. Next, adding NaHCO ₃ and separating the organic layer to obtain a compound 103 (step 2);
Dissolving compound 103 in a fourth organic solvent and stirring with Pd / C, concentrating the filtrate and diluting with CH ₂ Cl ₂ , then separating the organic layer to obtain compound 104 (step 3); And
Dissolving compound 104 and p-TsOH in a fifth organic solvent and refluxing to remove the fifth organic solvent, and then separating the organic layer obtained by dissolving the residue in a sixth organic solvent to obtain Compound 1A (step 4);
Method for the preparation of compound 1A comprising:
Scheme 1

(In Scheme 1,
Compound 1A is included in the isoquinolinone derivative represented by Formula 1 of claim 1).
The method of claim 4, wherein
The first to sixth organic solvents are anhydrous tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH ₂ Cl ₂ , hexane, dimethylformamide (DMF), ethanol, diisopropyl ether, At least one member selected from the group consisting of diethyl ether, dioxane, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetone and chlorobenzene.
The method of claim 5,
The first organic solvent is a manufacturing method, characterized in that LiAlH ₄ is further included as a reducing agent.
As shown in Scheme 2 below,
A method for preparing compound 1B comprising the step of adding compound 105 and 106 to a mixture of first organic solvent and n-BuLi to obtain compound 1B:
Scheme 2

(In Scheme 2,
R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined in Formula 1 of claim 1,
Compound 1B is included in the isoquinolinone derivative represented by Formula 1 of claim 1).
The method of claim 7, wherein
The first organic solvent is anhydrous tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH ₂ Cl ₂ , hexane, dimethylformamide (DMF), ethanol, diisopropyl ether, diethyl ether, dioxane And dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and chlorobenzene.
A pharmaceutical composition for preventing or treating influenza virus containing an isoquinolinone derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as an active ingredient:
[Formula 1]

(In the above formula 1,
R ¹ is hydrogen, C _1-6 straight or branched alkyl or C _1-6 straight or branched alkenyl;
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently C _1-6 straight or branched chain alkyl, C _1-6 straight or branched chain substituted with hydrogen, halogen, unsubstituted or one or more hydroxy; Kenyl, C _1-6 straight or branched alkoxy, or formyl,
Wherein R ^2c and R ^2d together with the carbon atom to which they are linked may form a 5-8 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;
R ³ is hydrogen or halogen;
R ⁴ is hydrogen, C _1-6 straight or branched alkyl, or —NR ^4a R ^4b , wherein R ^4a and R ^4b are independently C _1-6 straight or branched alkyl;
R ⁵ is hydrogen, C _1-6 straight or branched alkyl, or C _1-6 straight or branched alkoxy;
R ⁶ is hydrogen or C _1-6 straight or branched alkoxy;
R ⁷ is hydrogen, hydroxy, or C _1-6 straight or branched alkoxy;
R ⁶ and R ⁷ may form a 5-8 membered heterocycle including one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are linked).
The method of claim 9,
R ¹ is hydrogen, C _1-3 straight or branched alkyl or C _1-3 straight or branched alkenyl;
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently C _1-3 straight or branched chain alkyl of C _1-3 substituted with hydrogen, halogen, unsubstituted or one or more hydroxy, C _1-3 straight or branched chain al Kenyl, C _1-3 straight or branched alkoxy, or formyl,
Wherein R ^2c and R ^2d together with the carbon atom to which they are linked may form a 5-6 membered heterocycle comprising at least one hetero atom selected from the group consisting of N, O and S;
R ³ is hydrogen or halogen;
R ⁴ is hydrogen, C _1-3 straight or branched alkyl, or —NR ^4a R ^4b , wherein R ^4a and R ^4b are independently C _1-3 straight or branched alkyl;
R ⁵ is hydrogen, C _1-3 straight or branched alkyl, or C _1-3 straight or branched alkoxy;
R ⁶ is hydrogen or C _1-3 straight or branched alkoxy;
R ⁷ is hydrogen, hydroxy, or C _1-3 straight or branched alkoxy;
Wherein R ⁶ and R ⁷ together with the carbon atoms to which they are linked may form a 5-6 membered heterocycle comprising one or more heteroatoms selected from the group consisting of N, O and S Composition.
The method of claim 9,
R ¹ is hydrogen, methyl or vinyl;
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e are independently hydrogen, Cl, Br, methyl, ethyl, hydroxyethyl, vinyl, methoxy, or formyl,
Wherein R ^2c and R ^2d together with the carbon atom to which they are linked may form a five membered heterocycle comprising two O atoms;
R ³ is hydrogen or Br;
R ⁴ is hydrogen, methyl, or —N (CH ₃ ) ₂ ;
R ⁵ is hydrogen, methyl, or methoxy;
R ⁶ is hydrogen or methoxy;
R ⁷ is hydrogen, hydroxy, or methoxy;
Wherein R ⁶ and R ⁷ together with the carbon atoms to which they are linked may form a five membered heterocycle comprising two O atoms.
The method of claim 9,
The isoquinolinone derivative represented by Formula 1 is any one selected from the following compound group:
1) 7,8-dimethoxy-2-methyl-3- (6-vinylbenzo [d] [1,3] dioxol-5-yl) isoquinolin-1 (2H) -one;
2) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one;
3) 3- (6-ethylbenzo [d] [1,3] dioxol-5-yl) -8-hydroxy-7-methoxy-2-methylisoquinolin-1 (2H) -one;
4) 5- (dimethylamino) -3-p-tolylisoquinolin-1 (2H) -one;
5) 5- (dimethylamino) -3- (4-methoxyphenyl) isoquinolin-1 (2H) -one;
6) 3- (4-chlorophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;
7) 3- (4-bromophenyl) -5- (dimethylamino) isoquinolin-1 (2H) -one;
8) 3- (2,6-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;
9) 3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;
10) 6,7-dimethoxy-3-phenylisoquinolin-1 (2H) -one;
11) 3- (3-methoxyphenyl) -5-methylisoquinolin-1 (2H) -one;
12) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl)-[1,3] dioxolo [4,5-h] isoquinoline-9 ( 8H) -one;
13) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxyisoquinolin-1 (2H) -one;
14) 7- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -8-methyl- [1,3] dioxolo [4,5-h] iso Quinolin-9 (8H) -one;
15) 3- (6- (2-hydroxyethyl) benzo [d] [1,3] dioxol-5-yl) -7,8-dimethoxy-2-methylisoquinolin-1 (2H) -one ;
16) 4-bromo-3- (3,4-dimethoxyphenyl) -6-methylisoquinolin-1 (2H) -one;
17) 4-bromo-3- (3,5-dimethylphenyl) -6-methylisoquinolin-1 (2H) -one;
18) 2- (2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl) benzaldehyde;
19) 2- (6-methyl-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzaldehyde; And
20) 6- (4-bromo-1-oxo-2-vinyl-1,2-dihydroisoquinolin-3-yl) benzo [d] [1,3] dioxol-5-carbaldehyde.
The method of claim 9,
The influenza virus is a pharmaceutical composition, characterized in that at least one selected from the group consisting of influenza virus type A and influenza virus type B.
The method of claim 13,
The influenza virus type A is at least one member selected from the group consisting of H1N1, H3N2, H3N8, H5N1, H5N8, H7N9 and H9N2.
The method of claim 13,
The influenza virus type B is at least one member selected from the group consisting of Yamagata lineage and Victoria lineage.