KR20220162642A - Novel fluoro-substituted flavonoid derivative and pharmaceutical composition for preventing or treating allergic diseases comprising the same - Google Patents

Abstract

The present invention provides a fluorine-substituted flavonoid derivative compound, and a pharmaceutical composition for preventing or treating allergic diseases, comprising the same. A fluorine-substituted flavonoid derivative compound of the present invention controls intracellular signaling mediated by TSLP, to exhibit the effect of inhibiting the phosphorylation of intracellular STAT5 and exhibit an excellent inhibitory effect on reactions of TSLP and TSLP receptors, thereby being effectively used as a pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopic dermatitis.

Description

Novel fluoro-substituted flavonoid derivative and pharmaceutical composition for preventing or treating allergic diseases comprising the same {Novel fluoro-substituted flavonoid derivative and pharmaceutical composition for preventing or treating allergic diseases comprising the same}

The present invention relates to novel fluorine-substituted flavonoid derivatives, and more particularly, to novel fluorine-substituted flavonoid derivatives exhibiting preventive or therapeutic effects on allergic diseases.

Bronchodilators or anti-inflammatory drugs used in the treatment of allergic inflammatory diseases are drugs that are mainly applied symptomatically and can temporarily relieve symptoms, but cannot fundamentally treat the disease because it is impossible to control the allergic disease in the fundamental stage. has the disadvantage of not being able to Environmental diseases such as bronchial asthma, atopic skin disease, and allergic rhinitis are known as immune diseases, and Th2 cells are well known to play a pivotal role in inducing allergic reactions. When CD4 T cells are stimulated by antigens in lymphocytes, they can differentiate into various types of Th cells depending on the cytokines they simultaneously recognize, and the cytokines recognized at this time are thymic stromal lymphoprotein (TSLP). Alternatively, in the case of type 2 cytokines such as IL-4, these cells differentiate into Th2 and induce an allergic response.

These various cytokines include TSLP, IL-25, IL-33, etc., and among them, TSLP is expected to play the most effective role. For example, it has been shown that suppression of TSLP secretion in animal models makes it difficult to generate and activate Th2 cells and thus does not cause disease in animals. Inhibition of TSLP in diseased animals has also been reported to cure disease. there is a bar Taken together, TSLP is an important cytokine that acts on both the differentiation and activation of Th2 cells, and its control is recognized as important for the treatment of allergic diseases.

US Patent US 8242130 B2 (2012.08.14)

An object to be solved by the present invention is to provide a novel fluorine-substituted flavonoid derivative that can be used as a treatment for allergic diseases such as asthma or atopy.

In addition, an object of the present invention is to provide a method for preparing the novel fluorine-substituted flavonoid derivative.

In addition, an object of the present invention is to provide a pharmaceutical composition for preventing or treating thymic stromal lymphoprotein (TSLP)-related diseases, comprising the novel fluorine-substituted flavonoid derivative as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating allergic diseases comprising the novel fluorine-substituted flavonoid derivative as an active ingredient.

In addition, the problem to be solved by the present invention is to treat at least one allergy selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis, containing the novel fluorine-substituted flavonoid derivative as an active ingredient. sexually transmitted disease; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And to provide a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.

In addition, the problem of the present invention is to treat asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneity, including the step of administering the novel fluorine-substituted flavonoid derivative to a subject in need thereof. at least one allergic disease selected from urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And to provide a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.

In addition, one or more allergic diseases selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And to provide a use of the novel fluorine-substituted flavonoid derivative to prepare a medicament for use in preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.

In addition, an object of the present invention is to provide a functional health food composition for improving symptoms of allergic diseases, which includes the novel fluorine-substituted flavonoid derivative.

The problem to be solved by the present invention is not limited to the above-mentioned problem, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.

In order to solve the above problems, according to one aspect of the present invention, a fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.

<Formula Ⅰ>

In the above formula,

R _a and R _b are hydrogen or linked to each other to form a single bond,

X and Y are independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxy, or OCO-alkyl;

Z is hydrogen, halogen, or OCO-alkyl;

R ₁ is hydrogen, C ₁ -C ₄ alkoxy, hydroxy, or COO-R _c ;

R ₂ is hydrogen or COO-R _c ;

R _c is hydrogen or C ₁ -C ₄ straight or branched chain alkyl.

According to another aspect of the present invention, a treatment for thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for prevention or treatment is provided.

According to another aspect of the present invention, a fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient for preventing or treating allergic diseases. A pharmaceutical composition is provided.

According to another aspect of the present invention, a fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient, asthma, allergic rhinitis, chronic sinusitis At least one allergic disease selected from allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.

According to another aspect of the present invention, the step of administering the fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof one or more allergic diseases selected from asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.

According to another aspect of the present invention, the fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used for asthma, allergic rhinitis, chronic sinusitis, and allergic contact dermatitis. , atopic dermatitis, chronic spontaneous urticaria, and at least one allergic disease selected from anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a use for preparing a medicament for use in the prevention or treatment of one or more diseases selected from the group consisting of chronic obstructive pulmonary disease is provided.

According to another aspect of the present invention, a health functional food composition for improving the symptoms of allergic diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. is provided.

The novel fluorine-substituted flavonoid derivative compound provided in one aspect of the present invention controls intracellular signal transduction by TSLP (thymic stromal lymphoprotein) to exert an effect of inhibiting intracellular STAT5 phosphorylation and reacts with TSLP and TSLP receptors By exhibiting an excellent inhibitory effect on, it can be usefully used as a pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopy.

The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be inferred from the description of the present invention or the configuration of the invention described in the claims.

1 is a ¹ H 1D NMR spectrum showing the oxidation of baicalein over time.
2 shows baicalein quinone produced by oxidation of baicalein.
3 is a result of evaluating the stability of compound 5e using NMR.
Figure 4 is a schematic diagram schematically showing an ELISA test method for measuring inhibition of TSLP and TSLP receptor (TSLPR) binding.
5 is a dose-response graph measuring IC ₅₀ values of compound 7.

The present invention provides a fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

<Formula Ⅰ>

In the above formula,

R _a and R _b are hydrogen or linked to each other to form a single bond,

X and Y are independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxy, or OCO-alkyl;

Z is hydrogen, halogen, or OCO-alkyl;

R ₁ is hydrogen, C ₁ -C ₄ alkoxy, hydroxy, or COO-R _c ;

R ₂ is hydrogen or COO-R _c ;

R _c is hydrogen or C ₁ -C ₄ straight or branched chain alkyl.

In defining the compound of Formula I throughout this specification, the concepts defined for the following substituents are used.

The term “alkyl” is a straight-chain or branched hydrocarbon, which may contain single, double or triple bonds, and is preferably C ₁ -C ₁₀ alkyl. For example, the alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl, and the like.

The term "alkoxy", unless otherwise defined, means an alkyloxy having from 1 to 10 carbon atoms.

The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

In one embodiment, the fluorine-substituted flavonoid derivative compound represented by Formula 1 may be a compound represented by Formula 1a below.

<Formula Ia>

In the above formula,

X and Y are independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, C ₁ -C ₄ alkoxy, or halogen;

Z is hydrogen or halogen;

R ₁ is hydrogen, C ₁ -C ₄ alkoxy, hydroxy, or COO-R _c ;

R ₂ is hydrogen or COO-R _c ;

R _c is C ₁ -C ₄ straight or branched chain alkyl.

In one embodiment, the fluorine-substituted flavonoid derivative compound represented by Formula 1 may be a compound represented by Formula 1b below.

<Formula Ib>

In the above formula,

X and Y are independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxy, or OCO-alkyl;

Z is hydrogen, halogen, or OCO-alkyl;

R ₁ is hydrogen, C ₁ -C ₄ alkoxy, hydroxy, or COO-R _c ;

R ₂ is hydrogen or COO-R _c ;

R _c is hydrogen or C ₁ -C ₄ straight or branched chain alkyl.

In one embodiment, X and Y may independently be hydrogen, methyl, methoxy, F, Cl, hydroxy, or acetate.

In one embodiment, the Z can be hydrogen, F, or acetate.

In one embodiment, R ₁ can be hydrogen, methoxy, hydroxy, carboxyl, or methyl carboxylate.

In one embodiment, R ₂ can be hydrogen, carboxyl, or methyl carboxylate.

Specific examples of the fluorine-substituted flavonoid derivative compounds according to the present invention are as follows:

(E) -1- (4-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3a );

(E) -1- (4-fluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3b ),

(E) -1- (5-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3c ),

(E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3d );

(E) -1- (2-fluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3e );

(E) -1- (2-fluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3f ),

(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3g ),

(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3h ),

(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3i ),

(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3j ),

(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3k ),

(E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3l );

(E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3m );

(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3n ),

(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3o ),

(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3p ),

(E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3q );

(E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3r );

(E) -1- (2-hydroxy-4,5-dimethoxyphenyl) -3-phenylprop-2-en-1-one ( 3s ),

(E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3t ),

(E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3u );

(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3-phenylprop-2-en-1-one ( 3v ),

(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3w ),

(E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3x );

(E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3y );

(E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3z );

7-fluoro-2-phenyl-4H-chromen-4-one ( 4a );

7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4b );

6-fluoro-2-phenyl-4H-chromen-4-one ( 4c );

6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4d );

5-fluoro-2-phenyl-4H-chromen-4-one ( 4e );

5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4f );

5,7-difluoro-2-phenyl-4H-chromen-4-one ( 4g );

5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4h );

6,7-difluoro-2-phenyl-4H-chromen-4-one ( 4i );

6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4j );

methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4k );

methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4l );

6,7-dichloro-2-phenyl-4H-chromen-4-one ( 4m );

6,7-dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4n );

methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4o );

methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4p );

6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 4q );

methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4r );

methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4s );

6,7-dimethyl-2-phenyl-4H-chromen-4-one ( 4t );

2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 4u );

methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4v );

methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4w );

methyl 4-(4-oxo-4H-chromen-2-yl)benzoate ( 4x );

7-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5a );

6-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5b );

5-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5c );

5,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5d );

3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5e );

4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5f );

6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5g ),

3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5h );

4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5i );

6,7-dihydroxy-2-phenyl-4H-chromen-4-one ( 5j );

4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5k );

3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5l ),

2-(4-hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 5m );

4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5n );

3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5o );

4-(4-oxo-4H-chromen-2-yl)benzoic acid ( 5p );

4-oxo-2-phenyl-4H-chromene-5,6,7-triyl triacetate ( 7 ).

Since the compound represented by Formula I according to the present invention can be used in the form of a prodrug, hydrate, solvate, or pharmaceutically acceptable salt in order to improve absorption or solubility in vivo, the prodrug, Hydrates, solvates and pharmaceutically acceptable salts are also within the scope of this invention.

The term “prodrug” refers to a substance that is transformed into the parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may obtain bioactivity by oral administration whereas the parent agent may not. A prodrug may also have improved solubility in a pharmaceutical composition than the parent drug. For example, a prodrug may be an in vivo hydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug would be a short peptide (polyamino acid) attached to an acid group that is metabolized to reveal an active site.

The term "hydrate" refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof.

The term “solvate” refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.

The term “isomer” refers to compounds of the present invention or salts thereof that have the same chemical formula or molecular formula but differ structurally or sterically. These isomers include both structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, and stereoisomers such as geometric isomers (trans, cis). All these isomers and mixtures thereof are also included within the scope of the present invention.

The term “pharmaceutically acceptable salt” refers to a salt form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salt is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed with sulfonic acids and the like are included. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine; and the like. The compounds of formula (I) according to the present invention may be converted into their salts by conventional methods.

Fluorine-substituted flavonoid derivatives of formula (I) of the present invention can be synthesized according to Scheme 1 and Scheme 2 described below. The method for preparing the compound of Formula I according to the present invention is not limited to the method for preparing the compound of Formula I according to the present invention. The preparation methods of Reaction Scheme 1 and Reaction Scheme 2 are only examples, and it is obvious that they can be easily modified by a person skilled in the art according to specific substituents.

The present invention also relates to prevention or treatment of thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for use.

The present invention also provides a pharmaceutical composition for the prevention or treatment of allergic diseases comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

The present invention also relates to asthma, allergic rhinitis, chronic sinusitis, and allergic contact, comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. at least one allergic disease selected from sexual dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And it provides a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.

The present invention also provides a step of administering a fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof, one or more allergic diseases selected from allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And it provides a method for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.

The present invention also relates to a fluorine-substituted flavonoid derivative compound represented by Formula I, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, for asthma, allergic rhinitis, chronic sinusitis, allergic contact dermatitis, atopic dermatitis, at least one allergic disease selected from chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; and chronic obstructive pulmonary disease.

The present invention also provides a health functional food composition for improving symptoms of allergic diseases, comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition comprising the fluorine-substituted flavonoid derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. provides

The additives may include pharmaceutically acceptable carriers or diluents, and oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterilization according to conventional methods, respectively. It can be formulated in the form of an injection solution.

The pharmaceutically acceptable carrier is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil; and the like. In addition, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants are included. Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose. ), gelatin, and the like, and may include lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, internal solutions, emulsions, syrups, and the like, and may include diluents such as water and liquid paraffin, wetting agents, sweeteners, aromatics, and preservatives. Parenteral formulations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, lyophilized formulations, and suppositories, and non-aqueous solvents and suspensions include vegetable oils, injectable esters such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

The dose of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of active ingredient, the route and period of administration, and may be appropriately adjusted according to the patient. For example, the active ingredient may be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the administration may be administered once or several times a day. In addition, the pharmaceutical composition of the present invention may include the active ingredient in a weight percentage of 0.001 to 90% based on the total weight of the composition.

The pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans through various routes, for example, oral, dermal, abdominal, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebral vascular (intracerebroventricular) It may be administered by injection.

Hereinafter, the present invention will be described in more detail through synthesis examples, examples and experimental examples. However, the following synthesis examples, examples and experimental examples are for exemplifying the present invention, but the scope of the present invention is not limited thereto.

Synthesis Example 1. Overall process of synthesizing flavonoid compounds

Scheme 1 below shows the synthetic process of flavonoid derivatives ( 5a-5p ).

<Scheme 1>

[Reagents and conditions: (i) a. Acetyl chloride, pyridine, CH ₂ Cl ₂ , room temperature, 30 minutes for 2a-2d or acetyl chloride, acetic anhydride, 110° C., 3 hours for 2e -2f ; b. AlCl ₃ , 120 °C-150 °C, 10 minutes-3 hours; (ii) a suitable aldehyde for 3a-3h , Ba(OH) ₂ , MeOH (or EtOH), 40 °C-50 °C, 1 h-17 h, 44%-95% yield or a suitable aldehyde for 3i-3z ; 25% (w/v) NaOMe solution, THF, room temperature, 5-12 hours, 12%-97% yield; (iii) I 2 , DMSO, 100 °C-110 °C, 6h-24h for 4a- 4x , ₄₇ %-97% yield; (iv) for 5a-5d, 5g, 5j , and 5m , 1.0 M BBr ₃ in CH ₂ Cl ₂ , CH ₂ Cl ₂ , 50° C., 14 hr-18 hr, 13%-97% yield or 5e-5f; 1 N NaOH, MeOH, 70 °C-80 °C, 1 h-4 h for 5h-5i, 5k-5l and 5n-5p , 49%-78% yield.]

Scheme 1 describes the synthesis of flavonoid derivatives in which two phenyl rings of the compound are substituted with various functional groups. The acetophenone compounds 2a-2c and 2g-2i were commercially available and used as starting materials. However, compounds 2d-2f having two substituents were synthesized in two steps (see Scheme 1). In addition, starting material 1a was reacted with acetyl chloride in the presence of pyridine in dichloromethane at room temperature. After monitoring the progress of the reaction by TLC, aluminum chloride was added to the reaction mixture and a subsequent reaction was conducted at 150° C. to obtain compound 2d . Meanwhile, 3,4-difluorophenol ( 1b ) and 3,4-dichlorophenol ( 1c ) were reacted with sodium acetate in acetic anhydride at 110 °C. After purification, the acetylated compound was dissolved in dichloromethane, aluminum chloride was added little by little, and the mixture was stirred at 120 °C. After monitoring the progress of the reaction by TLC, it was neutralized with 10% HCl and extracted with dichloromethane. Purification by silica gel column chromatography gave compounds 2e and 2f . Compounds 3a-3z were obtained via the Claisen-Schmidt condensation reaction of compounds 2a-2i with appropriate aldehydes, and for 3a-3h with barium hydroxide in methanol (or ethanol) at 40 °C-50 °C. for 1-17 hours, or 25% (w/v) NaOMe solution in THF for 3i-3z from 0°C to room temperature for 12 hours. Compounds 4a-4h were obtained in 47%-97% yields through intramolecular cyclization by reacting compounds 3a-3h with iodine in DMSO at 110 °C for 6-24 hours. Compounds 5a-5d, 5g, 5j and 5m were obtained by reacting compounds 4b, 4d, 4f, 4h, 4j, 4q and 4u with boron tribromide in dichloromethane for 14 to 20 hours to obtain a concentration of 13% to 97%. Obtained in % yield. Compounds 5e-5f, 5h-5i, 5k-5l and 5n-5p reacted with compounds 4k-4l, 4o-4p, 4r-4s and 4v-4x with 1 N NaOH in MeOH at 70 °C for 1-4 hours. It was obtained in 49%-78% yield.

The synthetic process of the acetyl-substituted flavonoid ( 7 ) is shown in Scheme 2 below.

<Scheme 2>

[Reagents and conditions: (i) acetyl chloride, diisopropylethylamine, DMF, 0 ° C to room temperature, 15 hours, 93% yield.]

Reaction Scheme 2 shows the synthetic process of flavonoid derivatives having an acetyl group of the A ring. 5,6,7-Trihydroxyflavone ( 6 ) [Trihydroxyflavone ( 6 )] was commercially available and was used as the starting material. 5,6,7-trihydroxyflavone ( 6 ) was reacted with acetyl chloride in the presence of diisopropylethylamine as base in DMF at 0°C to room temperature. After monitoring the reaction progress by TLC, it was concentrated with toluene and purified by silica gel column chromatography to obtain compound 7 in 93% yield.

Synthesis Example 2. Common synthetic procedure for compounds 3a-3z

To a stirred solution of the substituted acetophenone compound ( 2a-2d ) in methanol (MeOH) or ethanol (EtOH) was added barium hydroxide (2.0 equiv.) and the appropriate aldehyde (1.2 equiv.) at room temperature. The reaction mixture was stirred under argon at 40° C. to 50° C. until complete conversion was confirmed by TLC analysis (usually 1 hour to 20 hours), quenched with acetic acid (1.5 mL), EtOAc (30 mL) and H ₂ Extraction with O (30 mL) gave 3a-3h . Alternatively, to a stirred solution of the substituted acetophenone compound ( 2e-2i ) in THF was added a 25% (w/v) sodium methoxide solution (1.2 equiv-1.4 equiv) at 0°C under argon. After 20 min, the appropriate aldehyde (1.2 eq) was added to the reaction mixture and stirred at room temperature under argon until complete conversion was confirmed by TLC analysis (typically 12 hours). The mixture was concentrated and extracted with EtOAc, 3N HCl solution and NH ₄ Cl solution. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 3i-3z . The organic layer was washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give compounds 3a-3z .

Example 1. (E)-1-(4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3a) [ (E)-1-(4-Fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3a)]

Compound 3a is 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2a ; 200 mg, 1.3 mmol) [ 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ], Benzaldehyde (159 μL, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) were stirred in methanol (8.0 mL) at 50 ° C. for 1 hour, followed by the same method as described in Synthesis Example 2, yielding 72% as a yellow powder. was obtained with The crude residue was purified by column chromatography on silica gel. ^1H NMR (600 MHz, CDCl ₃ ) δ 13.2 (s, 1H), 7.97-7.90 (m, 2H), 7.70-7.64 (m, 2H), 7.58 (d, J = 15.6 Hz, 1H), 7.48- 7.43 (m, 3H), 6.71 (dd, J = 2.6 Hz and J = 10.3 Hz, 1H), and 6.69–6.65 (m, 1H).

Example 2. (E)-1-(4-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3b) [ (E)-1-(4-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3b)]

Compound 3b was 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2a ; 200 mg, 1.3 mmol), p-anisaldehyde ( p- anisaldehyde, 190 μL, 1.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was stirred in methanol (10 mL) at 50 °C for 17 hours to obtain a yellow powder in 44% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.33 (s, 1H), 7.96–7.89 (m, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 15.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H) ), 6.70 (dd, J = 2.5 Hz and J = 10.3 Hz, 1H), 6.68–6.63 (m, 1H), 3.87 (s, 3H).

Example 3. (E)-1-(5-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3c) [ (E)-1-(5-Fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3c)]

Compound 3c was 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one ( 2b ; 200 mg, 1.3 mmol), benzaldehyde (159 μL, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) was stirred in methanol (8.0 mL) at 50 °C for 1 hour to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 12.53 (s, 1H), 7.95 (d, J = 15.4 Hz, 1H), 7.72-7.66 (m, 2H), 7.59 (dd, J = 3.0 Hz and J = 9.0 Hz, 1H), 7.55 (d, J = 15.4 Hz, 1H), 7.47–7.44 (m, 3H), 7.29–7.22 (m, 2H), 7.0 (dd, J = 4.6 Hz and J = 9.1 Hz, 1H).

Example 4. (E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3d) [ (E)-1-(5-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3d)]

Compound 3d was 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one ( 2b ; 200 mg, 1.3 mmol), p-anisaldehyde (190 μL, 2.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was used in methanol (10 mL) at 40° C. for 4 hours to obtain a yellow powder in 76% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 12.65 (s, 1H), 7.93 (d, J = 15.3 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 2.9 Hz and J = 9.1 Hz, 1H), 7.43 ( d, J = 15.3 Hz, 1H), 7.25–7.21 (m, 1H), 7.02–6.94 (m, 3H), 3.88 (s, 3H).

Example 5. (E)-1-(2-fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3e) [ (E)-1-(2-Fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3e)]

Compound 3e was 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one ( 2c ; 166 μL, 1.3 mmol), benzaldehyde (159 μL, 1.6 mmol) and barium hydroxide (446 mg, 2.6 mmol) was stirred in methanol (8.0 mL) at 50 °C for 3 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.94 (dd, J = 3.5 Hz and J = 16.0 Hz, 1H), 7.72-7.64 (m, 3H), 7.49-7.38 (m, 4H), 6.58 (d, J = 8.5 Hz, 1H), 6.71–6.61 (m, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 192.49, 164.68, 163.74, 162.05, 145.72, 136.07, 135.98, 134.66, 131.00, 129.04, 128.86, 125.39, 125.28, 114.47, 106.40, 106.23 HRMS m / z calculated for C ₁₅ H ₁₁ FO ₂ [MH] ^- : 241.0670; found: 241.0681.

Example 6. (E)-1-(2-fluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3f) [ (E)-1-(2-Fluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3f)]

Compound 3f was 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one ( 2c ; 200 mg, 1.3 mmol), p-anisaldehyde (190 μL, 1.6 mmol) and barium hydroxide (445 mg, 2.6 mmol) was used in methanol (10 mL) at 50 °C for 6 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 13.17 (s, 1H), 7.93 (dd, J = 3.4 Hz and J = 15.2 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.56 (dd, J =1.8 Hz and J = 15.4 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.3 Hz and J = 12.1 Hz, 1H), 3.87 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 192.35, 164.68, 163.72, 162.13, 162.02, 145.77, 135.75, 135.67, 130.80, 130.78, 127.45, 122.99, 122.88, 114.55, 114.53, 114.40, 110.73, 110.63 HRMS m / z calculated for C ₁₆ H ₁₆ F ₁ O ₃ [MH] ^- : 271.0776; found: 271.0780.

Example 7. (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3g) [ (E)-1-(2,4-Difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one (3g)]

Compound 3g was 1-(2,4-difluoro-6-hydroxyphenyl)ethan-1-one ( 2d ; 200 mg, 1.2 mmol), benzaldehyde (142 μL, 1.4 mmol) and barium hydroxide (398 mg, 2.3 mmol) was used in methanol (8.0 mL) at 50 °C for 2 hours to obtain a yellow powder in 95% yield in the same manner as described in Synthesis Example 2. The crude residue was used in the next step without further purification. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.98 (dd, J = 3.3 Hz and J = 15.4 Hz, 1H), 7.71-7.66 (m, 2H), 7.64 (dd, J = 2.2 Hz and J = 15.4 Hz , 1H), 7.50-7.44 (m, 3H), 6.59-6.53 (m, 1H), 6.47-6.41 (m, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 191.64, 191.60, 167.64, 166.78, 166.71, 165.09, 164.98, 163.39, 163.28, 146.20, 134.53, 131.13, 129.07, 128.88, 124.78, 124.67, 101.59, 101.43, 96.08, 96.08, 96.08. HRMS m / z calculated for C ₁₅ H ₁₀ F ₂ O ₂ [MH] ^- : 259.0576; found: 259.0587.

Example 8. (E) -1- (2,4-difluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3h) [ (E)-1-(2,4-Difluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3h)]

Compound 3h was 1-(2,4-difluoro-6-hydroxyphenyl)ethan-1-one ( 2d ; 200 mg, 1.2 mmol), p-anisaldehyde (169 μL, 1.4 mmol) and barium hydroxide ( 398 mg, 2.3 mmol) was stirred in methanol (8.0 mL) at 50 °C for 3 hours to obtain a yellow powder in 85% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.94 (dd, J = 3.5 and J = 15.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.50 (dd, J = 1.9 Hz and J = 15.3 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.55–6.50 (m, 1H), 6.43–6.36 (m, 1H), 3.87 (s, 3H); ¹³ C NMR (150 MHz, DMSO _- d6 ) δ 191.39, 162.23, 146.22, 130.82, 127.30, 122.29, 122.17, 114.55, 101.47, 101.34, 96.13, 95.94, 55.46 . HRMS m / z calculated for C ₁₆ H ₁₂ F ₂ O ₅ [MH] ^- : 289.0682; found: 289.0696.

Example 9. (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3i) [ (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3i)]

Compound 3i was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 200 mg, 1.2 mmol), benzaldehyde (142 μL, 1.7 mmol) and sodium methoxide solution (397.8 μL, 1.7 μL). mmol) in THF (7.5 mL) at room temperature for 24 hours to obtain a yellow powder in 57% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.96 (d, J = 15.0 Hz), 7.73 (dd, J = 9.0 Hz and J = 10.2 Hz, 1H), 7.69-7.67 (m, 2H), 7.49-7.45 (m, 4H), 6.84 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 192.02, 161.41, 156.36, 156.27, 146.61, 134.23, 131.35, 129.16, 128.83, 119.36, 116.97, 116.95, 116.85, 107.11, 106.99. HRMS m / z calculated for C ₁₅ H ₁₀ F ₂ O ₂ [MH] ^- : 259.0576; found: 259.0587.

Example 10. (E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3j) [ (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3j)]

Compound 3j was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 300 mg, 1.7 mmol), p-anisaldehyde (254 μL, 2.6 mmol) and sodium methoxide solution (596.8 μL, 2.6 mmol) was stirred in THF (11 mL) at room temperature for 5 hours to obtain a yellow powder in 90% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.94 (d, J = 15.6 Hz, 1H), 7.72 (dd, J = 8.7 Hz and J = 10.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H) ), 7.35 (d, J = 15.3 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H), 3.89 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 192.02, 161.41, 156.36, 156.27, 146.61, 134.23, 131.35, 129.16, 12.83, 119.36, 116.97, 116.95, 116.1, 1.107.19 HRMS m / z calculated for C ₁₆ H ₁₂ F ₂ O ₃ [MH] ^- : 289.0682; found: 289.0695.

Example 11. (E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one (3k) [ (E)-1-(4,5-Difluoro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (3k)]

Compound 3k was prepared from 1-(4,5-difluoro-2-hydroxyphenyl)ethenone ( 2e ; 300 mg, 1.7 mmol), hydroxybenzaldehyde (173 mg, 2.6 mmol) and sodium methoxide solution (398 μL, 2.6 mmol) was used in THF (7.5 mL) at room temperature to 50 ° C. for 24 hours to obtain a yellow powder in 12% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ^1H NMR (600 MHz, MeOD) δ 8.15 (dd, J = 9.0 Hz and J =11.4 Hz, 1H), 7.92 (d, J = 15.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H) , 7.65 (d, J = 15.6 Hz, 1H), 6.89–6.86 (m, 3H).

Example 12. (E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3l) [ (E)-Methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3l)]

Compound 3l is 1- (4,5-difluoro-2-hydroxyphenyl) ethanone ( 2e ; 150 mg, 0.87 mmol), methyl-3-formylbenzoate (methyl-3-formylbenzoate, 171 mg, 1.3 mmol) and sodium methoxide solution (298 μL, 1.3 mmol) were stirred in THF (5.7 mL) at room temperature for 5 hours to obtain a yellow powder in 23% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from EtOH. ^1H NMR (600 MHz, MeOD) δ 8.44 (brs, 1H), 8.24 (t, J = 10.2 Hz, 1H), 8.10 (dd, J = 7.2 Hz and J = 16.2 Hz, 2H), 8.03-7.91 ( m, 3H), 7.61 (t, J = 7.8 Hz, 1H), 6.92 (dd, J = 6.6 Hz and J = 11.4 Hz, 1H), 3.98 (s, 3H).

Example 13. (E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3m) [ (E)-Methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3m)]

Compound 3m is 1-(4,5-difluoro-2-hydroxyphenyl)ethanone ( 2e ; 350 mg, 2.0 mmol), methyl terephthalaldehydate (400 mg, 3.0 mmol) and sodium methoxide The solution (696 μL, 3.0 mmol) was stirred in THF (13 mL) at room temperature for 5 hours to obtain a yellow powder in 28% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.14 (d, J = 7.8 Hz, 2H), 7.97 (d, J = 15.6 Hz, 1H), 7.76-7.73 (m, 3H), 7.56 (d, J = 15.3 Hz, 1H), 6.85 (dd, J = 6.6 Hz and J = 10.8 Hz, 1H), 3.97 (s 3H).

Example 14. (E) -1- (4,5-dichloro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one (3n) [ (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3n)]

Compound 3n was 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 150 mg, 0.73 mmol), benzaldehyde (89.4 μL, 1.1 mmol) and sodium methoxide solution (250 μL, 1.1 mmol) ) was stirred in THF (4.8 mL) at room temperature for 5 hours to obtain a yellow powder in 73% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.98 (d, J = 15.6, 1H), 7.71-7.69 (m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.48-7.46 (m, 3H), 7.18 (s, 1H).

Example 15. (E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3o) [ (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3o)]

Compound 3o was prepared from 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 300 mg, 1.5 mmol), p-anisaldehyde (213 μL, 2.2 mmol) and sodium methoxide solution (501 μL). , 2.2 mmol) was stirred in THF (9.6 mL) at room temperature for 5 hours to obtain a yellow powder in 82% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from n-hexane. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.95 (d, J = 15.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 15.3 Hz , H), 7.17 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H).

Example 16. (E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one (3p) [ (E)-1-(4,5-Dichloro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (3p)]

Compound 3p was prepared from 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 200 mg, 0.98 mmol), hydroxybenzaldehyde (182 mg, 1.5 mmol) and sodium methoxide solution (334 μL). , 1.5 mmol) was used in THF (6.3 mL) at room temperature to 70 ° C. for 24 hours to obtain a yellow powder in 15% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.94 (d, J = 15.0 Hz, 1H), 7.63 (d, J = 9.0 Hz), 7.40 (d, J = 15.6 Hz, 1H) ), 7.17 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H).

Example 17. (E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3q) [ (E)-Methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3q)]

Compound 3q was 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 150 mg, 0.73 mmol), methyl-3-formylbenzoate (144 mg, 1.1 mmol) and sodium methoxide The solution (250 μL, 1.1 mmol) was stirred in THF (4.75 mL) at room temperature for 5 hours to obtain a yellow powder in 42% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from EtOH. ^1H NMR (600 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J = 15.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 15.6 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 4.00 (s, 3H).

Example 18. (E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3r) [ (E)-Methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3r)]

Compound 3r was obtained from 1-(4,5-dichloro-2-hydroxyphenyl)ethanone ( 2f ; 350 mg, 1.7 mmol), methyl terephthalaldehyde (336 mg, 2.6 mmol) and sodium methoxide solution (585 μL). , 2.6 mmol) was stirred in THF (11 mL) at room temperature for 5 hours to obtain a yellow powder in 59% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ^1H NMR (600 MHz, CDCl ₃ ) δ 8.14 (d, J = 8.4 Hz, 1H), 8.01-7.97 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 15.3 Hz, 1H), 7.21 (s, 1H), 3.98 (s, 3H).

Example 19. (E) -1- (2-hydroxy-4,5-dimethoxyphenyl) -3-phenylprop-2-en-1-one (3s) [ (E)-1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-phenylprop-2-en-1-one (3s)]

Compound 3s was 2'-hydroxy-4',5'-dimethoxyacetophenone ( 2 g ; 300 mg, 1.5 mmol), benzaldehyde (188 μL, 1.8 mmol) and sodium methoxide solution (510 μL, 2.1 mmol) was stirred in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 97% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.93 (d, J = 15.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.48-7.45 (m, 3H), 7.28 (s, 1H), 6.54 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H).

Example 20. (E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3t) [ (E)-Methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3t)]

Compound 3t was prepared by mixing 2'-hydroxy-4',5'-dimethoxyacetophenone ( 2 g ; 1.0 g, 5.1 mmol), methyl terephthalaldehyde (1.0 g, 6.1 mmol) and sodium methoxide solution (1.4 mL, 6.1 mmol) was used in THF (40 mL) at room temperature for 12 hours to obtain a yellow powder in 50% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.12 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 15.0 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 15.6 Hz, 1H), 7.20 ( s, 1H), 6.55 (s, 1H), 3.97–3.95 (m, 9H).

Example 21. (E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3u) [ (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3u)]

Compound 3u was prepared by 2'-hydroxy-4',5'-dimethoxyacetophenone ( 2 g ; 600 mg, 3.1 mmol), methyl 3-formylbenzoate (602 mg, 3.7 mmol) and sodium methoxide solution ( 0.84 mL, 3.7 mmol) was stirred in THF (40 mL) at room temperature for 12 hours to obtain a yellow powder in 22% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 15.6 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 15.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.96 (s, 3H).

Example 22. (E) -1- (2-hydroxy-4,5-dimethylphenyl) -3-phenylprop-2-en-1-one (3v) [ (E)-1-(2-Hydroxy-4,5-dimethylphenyl)-3-phenylprop-2-en-1-one (3v)]

Compound 3v was prepared by mixing 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), benzaldehyde (0.22 mL, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mmol). was stirred in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 73% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by recrystallization from ethanol. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.92 (d, J = 15.0 Hz, 1H), 7.71–7.70 (m, 2H), 7.69–7.66 (m, 2H), 7.48–7.45 (m, 3H), 6.86 (s, 1H), 2.32 (s, 3H), 2.29 (s, 3H).

Example 23. (E) -1- (2-hydroxy-4,5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one (3w) [ (E)-1-(2-Hydroxy-4,5-dimethylphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3w)]

Compound 3w was 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), p-anisaldehyde (0.27 mL, 2.2 mol) and sodium methoxide solution (0.6 mL, 2.6 mL). mmol) in THF (10 mL) at room temperature for 12 hours to obtain an orange powder in 95% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.90 (d, J = 15.0 Hz, 1H), 7.67-7.66 (m, 3H), 7.55 (d, J = 15.0 Hz, 1H), 6.99-6.98 (m, 2H), 6.85 (s, 1H), 3.90 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H).

Example 24. (E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3x) [ (E)-Methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3x)]

compound3xis 2'-hydroxy-4',5'-dimethylacetophenone (2h; 300 mg, 1.8 mmol), methyl terephthalaldehyde (361 mg, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mmol) were stirred in THF (10 mL) at room temperature for 12 hours to obtain Synthesis Example 2. It was obtained in 57% yield as an orange powder in the same manner as described. The crude residue was purified by column chromatography on silica gel.^OneH NMR (600 MHz, CDCl₃) δ 8.12 (d,J = 8.4 Hz, 2H), 7.91 (d,J = 15.6 Hz, 1H), 7.76-7.72 (m, 3H), 7.65 (s, 1H), 6.86 (s, 1H), 3.98 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H) .

Example 25. (E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3y) [ (E)-Methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate (3y)]

Compound 3y was prepared by 2'-hydroxy-4',5'-dimethylacetophenone ( 2h ; 300 mg, 1.8 mmol), methyl 3-formylbenzoate (361 mg, 2.2 mmol) and sodium methoxide solution (0.6 mL, 2.6 mmol) was stirred in THF (10 mL) at room temperature for 12 hours to obtain a yellow powder in 30% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 15.6 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 7.68 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 6.86 (s, 1H), 4.00 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H) ).

Example 26. (E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3z) [ (E)-Methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate (3z)]

Compound 3z was prepared in THF (10 mL) using 2'-hydroxyacetophenone ( 2i ; 200 mg, 1.5 mmol), methyl terephthalaldehyde (289 mg, 1.8 mmol) and sodium methoxide solution (0.40 mL, 1.8 mmol). ) was stirred at room temperature for 12 hours to obtain a yellow powder in 67% yield in the same manner as described in Synthesis Example 2. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.13 (d, J = 8.4 Hz, 2H), 7.96–7.93 (m, 2H), 7.77–7.75 (m, 3H), 7.57–7.54 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H) , 7.01–6.98 (m, 1H), 3.98 (s, 3H).

Synthesis Example 3. Common Synthetic Procedure for Compounds 4a - 4x

To a stirred solution of the chalcone intermediates ( 3a - 3z ) in DMSO was added iodine (0.1 eq.) at room temperature. The reaction mixture was stirred under argon at 100 °C until complete conversion was confirmed by TLC analysis (typically 6 to 24 hours), quenched with 1.0 M sodium thiosulfate solution (10 mL), EtOAc (30 mL) and H Extracted with ₂ O (30 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (n-hexane/EtOAc or CH ₂ Cl ₂ /MeOH) to give compounds 4a-4x .

Example 27. 7-fluoro-2-phenyl-4H-chromen-4-one (4a) [ 7-Fluoro-2-phenyl-4H-chromen-4-one (4a)]

Compound 4a was (E)-1-(4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3a ; 194 mg, 0.80 mmol) and iodine (20.3 mg, 0.08 mmol) was used in DMSO (6.0 mL) and stirred for 24 hours to obtain a white powder in 90% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.26 (dd, J = 6.4 Hz and J = 8.8 Hz, 1H), 7.91 (dd, J = 1.3 Hz and J = 7.8 Hz, 2H), 7.60-7.51 (m, 3H), 7.28 (d, J = 2.2 Hz, 1H), 7.20-7.14 (m, 1H), 6.82 (s, 1H); ¹³ C NMR (150 MHz, CDCL ₃ ) δ 177.48, 166.60, 164.91, 163.75, 157.31, 157.23, 131.80, 131.46, 129.14, 128.30, 126.28, 120.87, 114.09, 113.94, 107.69, 104.92, 104.75. HRMS m / z calculated for C ₁₅ H ₉ FO ₂ [M+H] ⁺ : 241.0660; found: 241.0654.

Example 28. 7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4b) [ 7-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4b)]

Compound 4b was (E)-1-(4-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3b ; 137 mg, 0.50 mmol) And iodine (12.7 mg, 0.05 mmol) was stirred in DMSO (7.0 mL) for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.24 (dd, J = 6.4 Hz and J = 8.8 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.24 (dd, J = 2.3 Hz and J = 9.1 Hz, 1H), 7.17-7.12 ( m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 3.90 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 177.45, 166.49, 164.80, 163.77, 162.57, 157.22, 128.21, 128.14, 128.01, 123.67, 120.82, 114.56, 113.88, 113.74, 106.21.5, 104.88 HRMS m / z calculated for C ₁₆ H ₁₁ FO ₃ [M+H] ⁺ : 271.0765; found: 271.0753.

Example 29. 6-Fluoro-2-phenyl-4H-chromen-4-one (4c) [ 6-Fluoro-2-phenyl-4H-chromen-4-one (4c)]

Compound 4c was (E)-1-(5-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3c ; 304 mg, 1.3 mmol) and iodine (31.7 mg, 0.13 mmol) was used in DMSO (6.0 mL) and stirred for 15 hours to obtain a white powder in 91% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.93 (d, J = 7.1 Hz, 2H), 7.88 (dd, J = 3.2 and J = 8.1 Hz, 1H), 7.61-7.58 (m, 1H), 7.57-7.52 (m, 3H), 7.46-7.41 ( m, 1H), 6.83 (s, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 177.63, 163.71, 160.44, 158.81, 152.47, 131.82, 131.54, 129.12, 126.34, 125.21, 125.16, 122.01, 121.85, 120.22, 120.16, 9,910.7 HRMS m / z calculated for C ₁₅ H ₉ FO ₂ [M+H] ⁺ : 241.0660; found: 241.0648.

Example 30. 6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4d) [ 6-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4d)]

Compound 4d was (E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3d ; 240 mg, 0.88 mmol) And iodine (22.3 mg, 0.09 mmol) was stirred in DMSO (10 mL) for 15 hours to obtain a white powder in 97% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.90-7.85 (m, 3H), 7.56 (dd, J = 4.1 Hz and J = 9.1 Hz, 1H), 7.44-7.39 (m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 6.74 (s , 1H), 3.90 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 177.55, 163.72, 162.58, 160.38, 158.74, 152.39, 128.07, 125.18, 123.75, 121.74, 121.57, 120.04, 119.99, 114.54, 110.5.5, 4,10.57 HRMS m / z calculated for C ₁₆ H ₁₁ FO ₃ [M+H] ⁺ : 271.0765; found: 271.0751.

Example 31. 5-fluoro-2-phenyl-4H-chromen-4-one (4e) [ 5-Fluoro-2-phenyl-4H-chromen-4-one (4e)]

Compound 4e was (E)-1-(2-fluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3e ; 200 mg, 0.83 mmol) and iodine (21.1 mg, 0.08 mmol) was used in DMSO (5.0 mL) and stirred for 20 hours to obtain a white powder in 86% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.91 (d, J = 7.8 Hz, 2H), 7.66-7.61 (m, 1H), 7.58-7.51 (m, 3H), 7.39 (d, J = 8.5 Hz, 1H), 7.12-7.05 (m, 1H) , 6.78 (s, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.79, 162.46, 133.74, 133.67, 131.81, 131.23, 129.13, 126.27, 114.06, 114.03, 112.23, 112.09, 108.69. HRMS m / z calculated for C ₁₅ H ₉ FO ₂ [M+H] ⁺ : 241.0660; found: 241.0647.

Example 32. 5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4f) [ 5-Fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4f)]

Compound 4f was (E)-1-(2-fluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3f ; 380 mg, 1.40 mmol) And iodine (35.5 mg, 0.14 mmol) was stirred in DMSO (10 mL) for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.87-7.84 (m, 2H), 7.63-7.58 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.08-7.04 (m, 1H), 7.04-7.01 (m, 2H), 6.69 ( s, 1H), 3.90 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 176.63, 162.52, 162.35, 161.47, 159.72, 157.14, 157.12, 133.50, 133.43, 127.88, 123.20, 114.48, 114.28, 114.21, 113.94, 113.91, 112.02, 111.88, 107.04, 55.50 HRMS m / z calculated for C ₁₆ H ₁₁ FO ₃ [M+H] ⁺ : 271.0765; found: 271.0773.

Example 33. 5,7-difluoro-2-phenyl-4H-chromen-4-one (4g) [ 5,7-Difluoro-2-phenyl-4H-chromen-4-one (4g)]

Compound 4g was (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3g ; 280 mg, 0.96 mmol) and iodine ( 24.4 mg, 0.09 mmol) was stirred in DMSO (10 mL) for 14 hours to obtain a white powder in 88% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.88 (d, J = 7.0 Hz, 2H), 7.59–7.51 (m, 3H), 7.10 (d, J = 8.8 Hz, 1H), 6.88–6.83 (m, 1H), 6.75 (s, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 175.75, 165.74, 165.64, 164.05, 163.95, 162.78, 162.68, 162.56, 161.01, 160.91, 158.07, 158.03, 157.96, 157.93, 131.97, 130.78, 129.17, 126.18, 111.58, 111.53, 111.51, 108.62, 102.19, 102.03, 101.86, 101.41, 101.38, 101.25, 101.22. HRMS m / z calculated for C ₁₅ H ₈ F ₂ O ₂ [MH] ^- : 259.0565; found: 259.0562.

Example 34. 5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4h) [ 5,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4h)]

Compound 4h is (E)-1-(2,4-difluoro-6-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3h ; 270 mg, 0.93 mmol) and iodine (23.6 mg, 0.09 mmol) were stirred in DMSO (6.0 mL) for 10 hours to obtain a white powder in 47% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.03 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 9.4 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (d, J = 8.9 Hz, 2H), 6.88 (s, 1H) ), 3.85 (s, 3H); ¹³ C NMR (150 MHz, DMSO _- d6 ) δ 175.01, 165.48, 162.88, 162.34, 128.69, 123.01, 115.14, 106.97, 102.55, 102.46, 102.43, 102.38, 102.29, 102.26, 102.21, 56.08. HRMS m / z calculated for C ₁₆ H ₁₀ F ₂ O ₃ [M+H] ⁺ : 289.0671; found: 289.0657.

Example 35. 6,7-difluoro-2-phenyl-4H-chromen-4-one (4i) [ 6,7-Difluoro-2-phenyl-4H-chromen-4-one (4i)]

Compound 4i is (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3i ; 100 mg, 0.38 mmol) and iodine ( 106.6 mg, 0.42 mmol) was stirred in DMSO (5.6 mL) at 100° C. for 24 hours to obtain a white powder in 89% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ^1H NMR (600 MHz, CDCl ₃ ) δ 8.02 (t, J = 9.3 Hz, 1H), 7.90 (d, J = 6.6 Hz, 2H), 7.58-7.55 (m, 3H), 7.43 (dd, J = 6.6 Hz and J = 9.6 Hz, 1H), 6.82 (s, 1H); ¹³ C NMR (150 MHz, CDCL ₃ ) Δ 176.68, 164.06, 154.93, 154.82, 153.21, 153.11, 152.49, 152.42, 149.49, 149.40, 147.83, 147.74, 131.98, 131.21, 129.18 , 113.02, 113.01, 107.30, 107.15, 107.09. HRMS m/z calculated for C ₁₅ H ₈ F ₂ O ₂ [MH] ^- : 259.0565; found: 259.0564.

Example 36. 6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4j) [ 6,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (4j)]

Compound 4j is (E)-1-(4,5-difluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3j ; 100 mg, 0.38 mmol) and iodine (107 mg, 0.42 mmol) were stirred in DMSO (5.6 mL) at 100 ° C. for 24 hours to obtain a white powder in 89% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.03-8.00 (m, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.41 (dd, J = 6.0 Hz and J = 9.6 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.74 (s, 1H), 3.93 (s, 3H); ¹³ C NMR (150 MHz, DMSO _- d6 ) δ 176.05, 163.81, 162.85, 152.69, 128.80, 123.28, 121.12, 115.13, 112.65, 112.52, 108.87, 108.73, 105.39, 56.07. HRMS m / z calculated for C ₁₆ H ₁₀ F ₂ O ₃ [M+H] ⁺ : 289.0671; found: 289.0656.

Example 37. Methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4k) [ Methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4k)]

Compound 4k is (E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3l ; 100 mg , 0.31 mmol) and iodine (87.5 mg, 0.35 mmol) were stirred in DMSO (4.6 mL) at 100 ° C. for 16 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.23 (d, J = 9.6 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.03-7.99 (m, 1H), 7.64 (t, J = 8.1 Hz, 1H) ), 7.47 (dd, J = 6.6 Hz and J = 10.2 Hz, 1H), 6.86 (s, 1H), 4.00 (s, 3H).

Example 38. Methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4l) [ Methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate (4l)]

Compound 4l is (E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3m ; 100 mg , 0.31 mmol) and iodine (87.5 mg, 0.35 mmol) were stirred in DMSO (4.6 mL) at 100 ° C. for 16 hours to obtain a white powder in 88% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.21 (d, J = 8.4 Hz, 2H), 8.02 (t, J = 9.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 6.0 Hz and J = 10.2 Hz, 1H), 6.87 (s, 1H), 3.99 (s, 3H).

Example 39. 6,7-dichloro-2-phenyl-4H-chromen-4-one (4m) [ 6,7-Dichloro-2-phenyl-4H-chromen-4-one (4m)]

Compound 4m is (E)-1-(4,5-dichloro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one ( 3n ; 100 mg, 0.34 mmol) and iodine (95 mg, 0.37 mmol) was stirred in DMSO (5.0 mL) at 100 °C for 24 hours to obtain a white powder in 67% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.76 (s, 1H), 7.59–7.54 (m, 3H), 6.83 (s, 1H).

Example 40. 6,7-dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one (4n) [ 6,7-Dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one (4n)]

Compound 4n was (E)-1-(4,5-dichloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3o ; 100 mg, 0.34 mmol) and iodine (95 mg, 0.37 mmol) in DMSO (5.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in 67% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.29 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 7.05 (s, 1H), 3.88 (s, 3H) ).

Example 41. Methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4o) [ Methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4o)]

Compound 4o is (E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3q ; 100 mg; 0.29 mmol) and iodine (79.5 mg, 0.31 mmol) were stirred in DMSO (4.2 mL) at 100 ° C. for 24 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 8.31 (s, 1H), 8.25 (t, J = 8.1 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 6.88 (s, 1H), 4.01 (s, 3H).

Example 42. Methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4p) [ Methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate (4p)]

Compound 4p is (E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3r ; 100 mg, 0.29 mmol) and iodine (79.5 mg, 0.31 mmol) were stirred in DMSO (4.2 mL) at 100 ° C. for 24 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.21 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 7.78 (s, 1H), 6.88 (s, 1H), 3.99 (s, 3H) ).

Example 43. 6,7-dimethoxy-2-phenyl-4H-chromen-4-one (4q) [ 6,7-Dimethoxy-2-phenyl-4H-chromen-4-one (4q)]

Compound 4q was (E)-1-(2-hydroxy-4,5-dimethoxyphenyl)-3-phenylprop-2-en-1-one ( 3s ; 200 mg, 0.70 mmol) and iodine ( 196 mg, 0.77 mmol) was stirred in DMSO (10 mL) at 110 ° C. for 24 hours to obtain a white powder in 76% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.94-7.93 (m, 2H), 7.60 (s, 1H), 7.55-7.54 (m, 3H), 7.03 (s, 1H), 6.82 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H).

Example 44. Methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4r) [ Methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4r)]

Compound 4r is (E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3t ; 200 mg , 0.58 mmol) and iodine (178 mg, 0.70 mmol) in DMSO (5.0 mL) and stirred at 100 ° C. for 24 hours to obtain a brown powder in 62% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.19 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.04 (s, 1H), 4.05 (s, 3H), 4.02 (s, 3H) ), 3.99 (s, 3H).

Example 45. Methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4s) [ Methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate (4s)]

Compound 4s was (E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3u ; 100 mg , 0.29 mmol) and iodine (89 mg, 0.35 mmol) in DMSO (3.0 mL) and stirred at 100 ° C. for 24 hours to obtain a brown powder in 71% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.07 (s, 1H), 6.86 (s, 1H), 4.06 (s, 3H), 4.01 (s, 6H).

Example 46. 6,7-dimethyl-2-phenyl-4H-chromen-4-one (4t) [ 6,7-Dimethyl-2-phenyl-4H-chromen-4-one (4t)]

Compound 4t was prepared from (E)-1-(2-hydroxy-4,5-dimethylphenyl)-3-phenylprop-2-en-1-one ( 3v ; 100 mg, 0.40 mmol) and iodine (121 mg). . The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.95-7.94 (m, 2H), 7.56-7.53 (m, 3H), 7.39 (s, 1H), 6.82 (s, 1H), 2.44 (s, 3H), 2.40 (s, 3H).

Example 47. 2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (4u) [ 2-(4-Methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (4u)]

Compound 4u was (E)-1-(2-hydroxy-4,5-dimethylphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3w ; 200 mg, 0.71 mmol ) and iodine (216 mg, 0.85 mmol) were stirred in DMSO (5.0 mL) at 100 ° C. for 24 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.33 (s, 1H), 7.03-7.01 (m, 2H), 6.70 (s, 1H), 3.89 (s, 3H), 2.41 (s, 3H), 2.36 (s, 3H).

Example 48. Methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4v) [ Methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4v)]

Compound 4v was (E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3x ; 200 mg, 0.64 mmol) and iodine (196 mg, 0.77 mmol) in DMSO (5.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.18 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.37 (s, 1H), 6.84 (s, 1H), 3.98 (s, 3H) ), 2.43 (s, 3H), 2.38 (s, 3H).

Example 49. Methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4w) [ Methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate (4w)]

Compound 4w was (E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3y ; 120 mg, 0.39 mmol) and iodine (118 mg, 0.46 mmol) in DMSO (3.0 mL) and stirred at 100 °C for 24 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.43 (s, 1H), 6.87 (s, 1H), 4.02 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H).

Example 50. Methyl 4-(4-oxo-4H-chromen-2-yl)benzoate (4x) [ Methyl 4-(4-oxo-4H-chromen-2-yl)benzoate (4x)]

Compound 4x was (E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3z ; 200 mg, 0.71 mmol) and iodine (198 mg, 0.78 mmol) was stirred in DMSO (10 mL) at 100 °C for 24 hours to obtain a white powder in 79% yield in the same manner as described in Synthesis Example 3. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, MeOD) δ 8.17-8.13 (m, 5H), 7.86-7.83 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 6.99 (s, 1H), 3.96 (s, 3H).

Synthesis Example 4. Common synthetic procedure for compounds 5a-5d, 5g, 5j and 5m

To stirred solutions of cyclized compounds ( 4b, 4d, 4f, 4h, 4j, 4q and 4u ) in dichloromethane was added 1.0 M BBr ₃ (5.0 equiv-12 equiv) in dichloromethane at 0 °C. The reaction mixture was stirred at 50° C. under argon and quenched with ice water and conc. dichloromethane until complete conversion was confirmed by TLC analysis (usually 14 to 20 hours). It was then extracted with EtOAc (30 mL) and H ₂ O (30 mL). The crude residue was purified by column chromatography on silica gel (CH ₂ Cl ₂ /MeOH or n-hexane/EtOAc) or washed with an organic solvent such as ether or n-hexane to give compounds 5a-5d, 5g, 5j and 5m . got it

Synthesis Example 5. Common Synthesis Procedure for Compounds 5e-5f, 5h-5i, 5k-5l and 5n-5p

To a stirred solution of the cyclized compounds ( 4k-4l, 4o-4p, 4r-4s and 4v-4x ) in methanol was added 1 N NaOH (2.0 equiv-4.0 equiv) at room temperature. The reaction mixture was stirred at 70 °C-80 °C until complete conversion was confirmed by TLC analysis (generally 1 h - 4 h). It was then extracted with EtOAc (30 mL) and H ₂ O (30 mL). The crude residue was purified by column chromatography on silica gel (CH ₂ Cl ₂ /MeOH) or washed with an organic solvent such as ether to give compounds 5e-5f, 5h-5i, 5k-5l and 5n-5p .

Example 51. 7-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5a) [ 7-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5a)]

Compound 5a was distilled using 7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4b ; 76 mg, 0.28 mmol) and boron tribromide (3.4 mL, 3.4 mmol). It was stirred in chloromethane (30 mL) at 50 °C for 18 hours to obtain a brown powder in quantitative yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 10.32 (s, 1H), 8.07 (dd, J = 6.5 Hz and J = 8.8 Hz, 1H), 7.97-7.92 (m, 2H), 7.69 (dd, J = 2.4 Hz and J = 9.6 Hz, 1H), 7.37-7.32 (m, 1H), 6.95-6.90 (m, 2H), 6.86 (s, 1H); ¹³ C NMR (150 MHz, DMSO _- d6 ) δ 176.54, 166.18, 164.51, 163.87, 161.56, 157.15, 157.06, 128.86, 128.03, 127.96, 121.75, 120.94, 116.43, 114.36, 114.20, 114.20, 2,240.5.7 HRMS m / z calculated for C ₁₅ H ₉ FO ₃ [M+H] ⁺ : 257.0609; found: 257.0616.

Example 52. 6-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5b) [ 6-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5b)]

Compound 5b was distilled using 6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4d ; 100 mg, 0.37 mmol) and boron tribromide (4.4 mL, 4.4 mmol). After stirring in chloromethane (15 mL) for 11 hours, it was obtained as a yellow powder in 97% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, MeOD) δ 7.96-7.89 (m, 2H), 7.81-7.74 (m, 2H), 7.63-7.55 (m, 1H), 6.98-6.93 (m, 2H), 6.81 (s, 1H); ¹³ C NMR (150 MHz, DMSO _- d6 ) δ 176.79, 164.00, 160.19, 158.62, 152.49, 128.98, 124.97, 122.56, 122.39, 121.65, 121.59, 116.47, 109.94, 109.79, 104.59. HRMS m / z calculated for C ₁₅ H ₉ FO ₃ [MH] ^- : 257.0609; found: 257.0599.

Example 53. 5-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5c) [ 5-Fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5c)]

Compound 5c was distilled using 5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4f ; 100 mg, 0.37 mmol) and boron tribromide (4.4 mL, 4.4 mmol). It was stirred in chloromethane (30 mL) at 50 °C for 18 hours to obtain a white powder in 96% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 10.31 (brs, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.81-7.73 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.3 Hz and J = 10.7 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H); ¹³ C NMR (150 MHz, DMSO _- d6 ) δ 175.81, 162.53, 161.56, 160.89, 159.16, 157.13, 134.81, 134.74, 128.84, 121.47, 116.44, 115.03, 115.01, 113.99, 113.92, 113.2.6, 112.5 HRMS m / z calculated for C ₁₅ H ₉ FO ₃ [M+H] ⁺ : 257.0609; found: 257.0618.

Example 54. 5,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5d) [ 5,7-Difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5d)]

Compound 5d was prepared by combining 5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4h ; 100 mg, 0.35 mmol) and boron tribromide (4.2 mL, 4.2 mmol). was stirred in dichloromethane (30 mL) at 50 °C for 14 hours to obtain a white powder in 94% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 10.34 (brs, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 9.0 Hz, 1H), 7.35-7.28 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H) ), 6.78 (s, 1H); ¹³ C NMR (150 MHz, DMSO _- d6 ) δ 175.07, 162.66, 161.77, 157.95, 128.84, 121.08, 116.47, 111.49, 106.15, 102.38, 49.07 . HRMS m / z calculated for C ₁₅ H ₈ F ₂ O ₃ [M+H] ⁺ : 275.0515; found: 275.0524.

Example 55. 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5e) [ 3-(6,7-Difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5e)]

Compound 5e was prepared from methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4k ; 50 mg, 0.16 mmol) and 1 N NaOH in MeOH (3.0 mL) ( 3.9 mL, 0.40 mmol) was stirred at 70 °C for 2 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, MeOD) δ 8.66 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 10.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (d, J = 6.6 Hz, 1H), 6.93 (s, 1H). HRMS m / z calculated for C ₁₆ H ₈ F ₂ O ₄ [MH] ^- : 301.0318; found: 301.0298.

Example 56. 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5f) [ 4-(6,7-Difluoro-4-oxo-4H-chromen-2-yl)benzoic acid (5f)]

Compound 5f was prepared from methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4l ; 88 mg, 0.28 mmol) and 1 N NaOH in MeOH (1.8 mL) ( 0.55 mL, 0.56 mmol) was used and stirred at 80° C. for 1 hour to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.14 (d, J = 7.8 Hz, 2H), 8.07 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 11.4 Hz, 1H), 7.67 (d, J = 6.6 Hz, 1H), 7.06 ( s, 1H).

Example 57. 6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5 g) [ 6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one (5g)]

Compound 5g was prepared by combining 6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4j ; 65 mg, 0.23 mmol) and boron tribromide (0.6 mL, 3.8 mmol). was stirred in dichloromethane (2.6 mL) at 60 °C for 24 hours to obtain a white powder in 13% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, MeOD) δ 7.96 (t, J = 9.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.73 (dd, J = 6.6 Hz and J = 10.2 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.80 (s, 1H); ¹³ C NMR (150 MHz, DMSO- d6 ) δ 175.93, 164.19, 161.69, 152.52, 128.92 _, 121.59, 121.09, 116.45, 112.60, 112.47, 108.76, 108.61, 104.72. HRMS m / z calculated for C ₁₅ H ₈ F ₂ O ₃ [M+H] ⁺ : 275.0515; found: 275.0527.

Example 58. 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5h) [ 3-(6,7-Dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5h)]

Compound 5h was obtained from methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4o ; 100 mg, 0.29 mmol) and 1 N NaOH (0.57 mL in MeOH (2.0 mL)). , 0.57 mmol) was stirred at 80 °C for 1 hour to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.60 (t, J = 1.5 Hz, 1H), 8.41 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.18-8.17 (m, 2H), 7.74 (t, J = 7.8 Hz, 1H) ), 7.20 (s, 1H).

Example 59. 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5i) [ 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid (5i)]

Compound 5i was prepared from methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4p ; 150 mg, 0.43 mmol) and 1 N NaOH (0.86 mL, 0.86 mmol) was stirred at 70 °C for 2 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, MeOD) δ 8.12-8.11 (m, 2H), 8.10 (s, 1H), 8.06-8.05 (m, 2H), 7.92 (s, 1H), 7.10 (s, 1H).

Example 60. 6,7-dihydroxy-2-phenyl-4H-chromen-4-one (5j) [ 6,7-Dihydroxy-2-phenyl-4H-chromen-4-one (5j)]

Compound 5j was prepared using 6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 4q ; 93 mg, 0.33 mmol) and boron tribromide (3.3 mL, 3.3 mmol) in dichloromethane ( 5.0 mL) was stirred at 50 °C for 15 hours to obtain an ivory-colored powder in 52% yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, MeOD) δ 7.96-7.94 (m, 2H), 7.56-7.51 (m, 3H), 7.41 (s, 1H), 7.03 (s, 1H), 6.76 (s, 1H).

Example 61. 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5k) [ 4-(6,7-Dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5k)]

Compound 5k was prepared from methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4r ; 100 mg, 0.29 mmol) and 1 N NaOH in methanol (5.0 mL) ( 0.60 mL, 0.59 mmol) was used and stirred at 70° C. for 2 hours to obtain an ivory-colored powder in 54% yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.22 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 9.0 Hz, 2H), 7.44 (s, 1H), 7.39 (s, 1H), 7.08 (s, 1H), 3.96 (s, 3H) ), 3.89 (s, 3H).

Example 62. 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5l) [ 3-(6,7-Dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid (5l)]

Compound 5l was obtained from methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4s ; 100 mg, 0.29 mmol) and 1 N NaOH (5.0 mL) in methanol. 0.60 mL, 0.59 mmol) was used and stirred at 70° C. for 2 hours to obtain a yellow powder in 78% yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.57 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.72-7.70 (m, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.39 (s, 1H), 3.97 (s, 3H), 3.89 (s, 3H).

Example 63. 2-(4-hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one (5m) [ 2-(4-Hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one (5m)]

Compound 5m was prepared using 2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 4u ; 85 mg, 0.29 mmol) and boron tribromide (4.5 mL, 4.4 mmol). was stirred in dichloromethane (5.0 mL) at room temperature for 6 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 4. The crude residue was purified by column chromatography on silica gel. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 7.93 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 7.55 (s, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.79 (s, 1H), 2.39 (s, 3H) ), 2.34 (s, 3H).

Example 64. 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5n) [ 4-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5n)]

Compound 5n was obtained from methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4v ; 70 mg, 0.23 mmol) and 1 N NaOH (0.68 mL) in methanol (5.0 mL). mL, 0.68 mmol) was stirred at 70 °C for 3 hours to obtain a yellow powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.20 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.63 (s, 1H), 7.08 (s, 1H), 2.41 (s, 3H) ), 2.40 (s, 3H).

Example 65. 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5o) [ 3-(6,7-Dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid (5o)]

Compound 5o was obtained from methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4w ; 109 mg, 0.35 mmol) and 1 N NaOH (1.1 mL, 1.1 mmol) was stirred at 70 °C for 2 hours to obtain a white powder in quantitative yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.55 (s, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.32-8.31 (m, 1H), 8.16-8.15 (m, 1H), 7.12 (s, 1H), 7.02 (s, 1H) , 2.40 (s, 3H), 2.35 (s, 3H).

Example 66. 4-(4-oxo-4H-chromen-2-yl)benzoic acid (5p) [ 4-(4-Oxo-4H-chromen-2-yl)benzoic acid (5p)]

Compound 5p was prepared using methyl 4-(4-oxo-4H-chromen-2-yl)benzoate ( 4x ; 100 mg, 0.36 mmol) using 1 N NaOH (0.70 mL, 0.71 mmol) in methanol (5.0 mL). It was stirred at 70° C. for 1 hour and obtained as a white powder in 49% yield in the same manner as described in Synthesis Example 5. The crude residue was washed with ether and water. ¹ H NMR (600 MHz, DMSO _- d6 ) δ 8.14 (d, J = 7.8 Hz, 2H), 8.08–8.05 (m, 3H), 7.88–7.85 (m, 1H), 7.84–7.82 (m, 1H), 7.54–7.52 (m, 1H), 7.10 ( s, 1H).

Example 67. 4-oxo-2-phenyl-4H-chromen-5,6,7-triyl triacetate (7) [ 4-Oxo-2-phenyl-4H-chromene-5,6,7-triyl triacetate (7)]

To a stirred solution of baicalein ( 6 ) (300 mg, 1.1 mmol) in DMF (5.0 mL) at room temperature under argon was added diisopropylethylamine (1.2 mL, 6.6 mmol). After 20 minutes, acetyl chloride (0.5 mL, 6.6 mmol) was added dropwise to the reaction mixture at 0 °C and then stirred at room temperature for 15 hours. The reaction mixture was concentrated with toluene. The crude residue was purified by column chromatography on silica gel. Compound 7 was obtained as a pale orange powder in 93% yield. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.89–7.87 (m, 2H), 7.59–7.53 (m, 4H), 6.68 (s, 1H), 2.47 (s, 3H), 2.38–2.37 (m, 6H).

Experimental Example 1. Evaluation of compound stability: Stability Test

In order to confirm the stability of baicalein in a solution, 1H 1D NMR spectrum over time was observed under PBS conditions. By comparing the signal intensity of 1D NMR at room temperature (25 ℃) for 2-26 hours, it was possible to observe the change in NMR signal according to the structural change of baicalein, which was observed by the change in intensity The half life (T _1/2 ) of baicalein was about 22 hours. It was observed that the H2' and H6' signals at the 7.9 ppm position decreased with time, and the H2' and H6' signals at the new position around 7.8 ppm appeared quantitatively. In addition, it was observed that the H8 signal near 6.5 ppm was reduced over time, and the H8 signal at a new position appeared quantitatively (see FIG. 1). When analyzing these signal changes, it can be expected that baicalein has a structural transformation due to oxidation to baicalein quinone (see FIG. 2).

On the other hand, compound 5e was substituted with fluorine groups instead of hydroxyl groups at positions 6 and 7 so that it could not be oxidized to quinone, so it did not undergo structural transformation by oxidation in solution, and as a result, 26 It was confirmed that no change in the 1D NMR signal was observed even with time, and the same structure was maintained (see FIG. 3).

Experimental Example 2. Compound in vitro ( in vitro ) active evaluation result

4 schematically shows an ELISA test method for measuring inhibition of TSLP and TSLP receptor (TSLPR) binding.

2.1. Coating

After preparing 100 nM of TSLP receptor (TSLPR) human recombinant protein in 1X coating buffer (Biolegend), put it into a 96 well microplate (Corning) using a multichannel pipette (Multichannel pipette, Gilson), and coat for more than 12 hours at 4℃. did

2.2. Blocking

After washing three times with PBST (1X PBS (Welgene), 1% Tween 20 (sigma)), it was reacted with 1% BSA (Bovogen) blocking buffer at room temperature for 1 hour.

2.3. Binding

Samples containing 100 nM of TSLP wildtype human recombinant protein and 10 μM or 100 μM of each of the example compounds were prepared, put into the same volume, and reacted at room temperature for 2 hours or longer.

2.4. detection

After washing three times with PBST (1X PBS (Welgene), 1% Tween 20 (sigma)), the anti-TSLP (Abcam) antibody was diluted 1:7500 and reacted at room temperature for 1 hour or longer.

After washing three times with PBST (1X PBS (Welgene), 0.05% Tween 20 (sigma)), anti-rabbit IgG and HRP-linked Antibody (Cell signaling) antibodies were diluted 1:1000 and reacted at room temperature for more than 1 hour. made it

2.5. reaction

After washing three times with PBST (1X PBS (Welgene), 1% Tween 20 (sigma)), TMB substrate solution (Thermo) was added and reacted for 5 minutes or longer. After stopping the reaction by adding 1 N HCl (Samchun), orbital shaking was performed for 5 seconds using a Microplate reader (Tecan, Spark ^® ), and the absorbance value was obtained at 450 nm.

2.6. assay

The result values derived from the program linked with the microplate reader were analyzed using the Excel program. The average of the three values obtained through triplicate is obtained and the vehicle value is converted to 100% to obtain the binding % or the vehicle value is converted to 100% to obtain the TSLP-TSLPR binding % saved The binding rate (%) value of each compound was obtained by subtracting the TSLP-TSLPR binding % from 100%, and the error range of triplicate was also obtained, which was reflected when deriving the compound inhibition rate graph.

2.7. result

The results of inhibition % of TSLP and TSLP receptor (TSLPR) binding are shown in Tables 1 and 2 below.

Example compound number ELISA (Inhibition %) ELISA
IC ₅₀ (μM) 10 µM 100 µM 300 µM 9 3i 13 11 - - 10 3j 19 22 - - 11 3k 34 50 - - 12 3l 20 20 - - 13 3m 13 21 - - 14 3n 15 29 - - 15 3o 22 49 - - 16 3p 35 78 - - 17 3q 14 37 - - 18 3r 21 37 - - 19 3s 4 7 - - 20 3t 36 70 - - 21 3u 8 10 - - 22 3v One -6 - - 24 3x 3 7 - - 25 3y 6 23 - - 35 4i 4 54 - - 36 4j 39 87 - - 39 4m 33 39 - - 40 4n 47 79 - - 43 4q 9 43 - - 46 4t 20 46 - -

Example compound number ELISA (Inhibition %) ELISA
IC ₅₀ (μM) 10 µM 100 µM 300 µM 55 5e 15 15 - - 56 5f 26 59 - - 57 5g 30 54 - - 58 5h 42 49 - - 59 5i 17 85 - - 60 5j 53 76 61 5k 15 40 - - 62 5l 11 38 - - 63 5m 44 71 - - 64 5n 14 24 - - 66 5p 37 32 67 7 48 71 - 1.9

The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims (13)

A fluorine-substituted flavonoid derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
<Formula Ⅰ>

In the above formula,
R _a and R _b are hydrogen or linked to each other to form a single bond,
X and Y are independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxy, or OCO-alkyl;
Z is hydrogen, halogen, or OCO-alkyl;
R ₁ is hydrogen, C ₁ -C ₄ alkoxy, hydroxy, or COO-R _c ;
R ₂ is hydrogen or COO-R _c ;
R _c is hydrogen or C ₁ -C ₄ straight or branched chain alkyl.
The fluorine-substituted flavonoid derivative compound according to claim 1, characterized by being represented by the following formula (Ia), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
<Formula Ia>

In the above formula,
X and Y are independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, C ₁ -C ₄ alkoxy, or halogen;
Z is hydrogen or halogen;
R ₁ is hydrogen, C ₁ -C ₄ alkoxy, hydroxy, or COO-R _c ;
R ₂ is hydrogen or COO-R _c ;
R _c is C ₁ -C ₄ straight or branched chain alkyl.
The fluorine-substituted flavonoid derivative compound according to claim 1, characterized by being represented by the following formula (Ib), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
<Formula Ib>

In the above formula,
X and Y are independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxy, or OCO-alkyl;
Z is hydrogen, halogen, or OCO-alkyl;
R ₁ is hydrogen, C ₁ -C ₄ alkoxy, hydroxy, or COO-R _c ;
R ₂ is hydrogen or COO-R _c ;
R _c is hydrogen or C ₁ -C ₄ straight or branched chain alkyl.
The fluorine-substituted flavonoid derivative compound according to claim 1, wherein X and Y are independently hydrogen, methyl, methoxy, F, Cl, hydroxy, or acetate, a hydrate thereof, a solvate thereof, or a pharmaceutical thereof. an acceptable salt.
The fluorine-substituted flavonoid derivative compound according to claim 1, wherein Z is hydrogen, F, or acetate, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
The fluorine-substituted flavonoid derivative compound according to claim 1, wherein R ₁ is hydrogen, methoxy, hydroxy, carboxyl, or methyl carboxylate, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable compound thereof. salt possible.
The fluorine-substituted flavonoid derivative compound according to claim 1, wherein R ₂ is hydrogen, carboxyl, or methyl carboxylate, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
The fluorine-substituted flavonoid derivative compound according to claim 1, wherein the fluorine-substituted flavonoid derivative compound represented by Formula 1 is any one selected from the group consisting of the following compounds, a hydrate thereof, a solvate thereof, or a fluorine-substituted flavonoid derivative compound thereof. Pharmaceutically acceptable salts:
(E) -1- (4-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3a );
(E) -1- (4-fluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3b ),
(E) -1- (5-fluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3c ),
(E)-1-(5-fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one ( 3d );
(E) -1- (2-fluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3e );
(E) -1- (2-fluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3f ),
(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3g ),
(E) -1- (2,4-difluoro-6-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3h ),
(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3i ),
(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3j ),
(E) -1- (4,5-difluoro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3k ),
(E)-methyl 3-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3l );
(E)-methyl 4-(3-(4,5-difluoro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3m );
(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3-phenylprop-2-en-1-one ( 3n ),
(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3o ),
(E) -1- (4,5-dichloro-2-hydroxyphenyl) -3- (4-hydroxyphenyl) prop-2-en-1-one ( 3p ),
(E)-methyl 3-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3q );
(E)-methyl 4-(3-(4,5-dichloro-2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3r );
(E) -1- (2-hydroxy-4,5-dimethoxyphenyl) -3-phenylprop-2-en-1-one ( 3s ),
(E)-methyl 4-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3t ),
(E)-methyl 3-(3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3u );
(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3-phenylprop-2-en-1-one ( 3v ),
(E) -1- (2-hydroxy-4,5-dimethylphenyl) -3- (4-methoxyphenyl) prop-2-en-1-one ( 3w ),
(E)-methyl 4-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3x );
(E)-methyl 3-(3-(2-hydroxy-4,5-dimethylphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3y );
(E)-methyl 4-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoate ( 3z );
7-fluoro-2-phenyl-4H-chromen-4-one ( 4a );
7-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4b );
6-fluoro-2-phenyl-4H-chromen-4-one ( 4c );
6-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4d );
5-fluoro-2-phenyl-4H-chromen-4-one ( 4e );
5-fluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4f );
5,7-difluoro-2-phenyl-4H-chromen-4-one ( 4g );
5,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4h );
6,7-difluoro-2-phenyl-4H-chromen-4-one ( 4i );
6,7-difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4j );
methyl 3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4k );
methyl 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoate ( 4l );
6,7-dichloro-2-phenyl-4H-chromen-4-one ( 4m );
6,7-dichloro-2-(4-methoxyphenyl)-4H-chromen-4-one ( 4n );
methyl 3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4o );
methyl 4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoate ( 4p );
6,7-dimethoxy-2-phenyl-4H-chromen-4-one ( 4q );
methyl 4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4r );
methyl 3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoate ( 4s );
6,7-dimethyl-2-phenyl-4H-chromen-4-one ( 4t );
2-(4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 4u );
methyl 4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4v );
methyl 3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoate ( 4w );
methyl 4-(4-oxo-4H-chromen-2-yl)benzoate ( 4x );
7-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5a );
6-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5b );
5-fluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5c );
5,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5d );
3-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5e );
4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5f );
6,7-difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one ( 5g ),
3-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5h );
4-(6,7-dichloro-4-oxo-4H-chromen-2-yl)benzoic acid ( 5i );
6,7-dihydroxy-2-phenyl-4H-chromen-4-one ( 5j );
4-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5k );
3-(6,7-dimethoxy-4-oxo-4H-chromen-2-yl)benzoic acid ( 5l ),
2-(4-hydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one ( 5m );
4-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5n );
3-(6,7-dimethyl-4-oxo-4H-chromen-2-yl)benzoic acid ( 5o );
4-(4-oxo-4H-chromen-2-yl)benzoic acid ( 5p ) and
4-oxo-2-phenyl-4H-chromene-5,6,7-triyl triacetate ( 7 ).
Prevention or treatment of thymic stromal lymphoprotein (TSLP)-related diseases comprising the fluorine-substituted flavonoid derivative compound of any one of claims 1 to 8, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient pharmaceutical composition for use.
A pharmaceutical composition for preventing or treating allergic diseases, comprising the fluorine-substituted flavonoid derivative compound according to any one of claims 1 to 8, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
Asthma, allergic rhinitis, chronic sinusitis, allergic contact comprising the fluorine-substituted flavonoid derivative compound according to any one of claims 1 to 8, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. at least one allergic disease selected from the group consisting of sexual dermatitis, atopic dermatitis, chronic spontaneous urticaria and anaphylaxis; at least one autoimmune disease selected from the group consisting of Graves' disease, Sjogren's syndrome, immune thrombocytopenia, autoimmune hemolytic anemia, inflammatory bowel disease, and primary biliary cholangitis; And a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of chronic obstructive pulmonary disease.
A pharmaceutical composition comprising the fluorine-substituted flavonoid derivative compound of any one of claims 1 to 8, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. .
A food composition for improving the symptoms of an allergic disease, comprising the fluorine-substituted flavonoid derivative compound according to any one of claims 1 to 8, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

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