Composition for preventing or treating tumor necrosis factor-related diseases comprising 4-benzopyrone derivative

Abstract

The present invention relates to a composition for preventing or treating a tumor necrosis factor-related disease, comprising a 4-benzopyrone derivative, and more specifically, to a composition for preventing or treating a tumor necrosis factor-related disease, the present invention relates to a 4-benzopyrone derivative, a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof, a composition for preventing, ameliorating and treating tumor necrosis factor-related diseases comprising the same as an active ingredient, a method for treating tumor necrosis factor-related diseases using the same, and a method for inhibiting tumor necrosis factor (TNF) According to the reagent composition and the tumor necrosis factor inhibition method, the composition can be orally administered, so that injection side effects are avoided, immunogenic resistance is avoided, the composition can be easily administered in combination with an existing oral preparation, the dosage of the composition can be easily adjusted, and the activity of a tumor necrosis factor can be effectively inhibited by directly binding the composition to the tumor necrosis factor.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201880067639.8, filing date July 12, 2018, and invention name “Composition for preventing or treating tumor necrosis factor-related diseases containing novel derivatives as active ingredients and method for inhibiting tumor necrosis factor activity using the same”. Technical Field

[0002] The present invention relates to a novel 4-benzopyrone compound derivative, a composition containing the novel 4-benzopyrone compound derivative as an effective ingredient for preventing, improving or treating tumor necrosis factor-related diseases, and a method for inhibiting tumor necrosis factor (TNF) activity using the novel 4-benzopyrone compound derivative. Background Art

[0003] Tumor necrosis factor (TNF) is a key inflammatory cytokine and has garnered significant attention as a major cause of autoimmune inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and ankylosing spondylitis. Several blockbuster anti-TNF biologics, including etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), are being actively used as treatments for various TNF-related diseases, including rheumatoid arthritis. While these anti-TNF biologics demonstrate excellent short-term efficacy, their high cost and the need for repeated injections have led to significant patient rejection. Approximately one-third of patients experience no therapeutic effect, and those who do respond often develop resistance within a few years due to immunogenic side effects. Furthermore, they require low-temperature storage, resulting in significant storage difficulties and unmet medical needs.

[0004] As a strategy to overcome this problem, efforts have been made to discover cytokines or low-molecular-weight substances that can be orally administered by directly binding to their receptors [He et al. (2005). Science 310(5750): 1022-1025]. However, the binding of cytokines to their receptors is protein-protein binding and occurs over a large area. So far, the use of low-molecular-weight substances to inhibit this has been ineffective.

[0005] A low-molecular-weight substance that directly binds to TNF and dissociates TNF trimers has been published [He et al. (2005). Science 310(5750):1022-1025], but further research appears to have been discontinued due to weak activity. Meanwhile, many low-molecular-weight signaling inhibitors that block intracellular signaling are under development. Although papers have been published on inhibitors of TNF expression or secretion whose mechanisms are unclear, no in vivo activity data are available. Furthermore, to date, there have been no successful cases of developing low-molecular-weight drugs that directly inhibit the binding between TNF and TNF receptors (TNFRs). Summary of the Invention

[0006] Technical issues

[0007] An object of the present invention is to provide a novel compound having an excellent tumor necrosis factor activity inhibitory effect.

[0008] Another object of the present invention is to provide a pharmaceutical composition that can effectively prevent or treat diseases due to its excellent tumor necrosis factor activity inhibitory effect.

[0009] Another object of the present invention is to provide a health functional food composition that can effectively prevent or improve diseases due to its excellent tumor necrosis factor activity inhibitory effect.

[0010] Another object of the present invention is to provide an effective method for treating tumor necrosis factor-related diseases.

[0011] Another object of the present invention is to provide a reagent composition for inhibiting the activity of tumor necrosis factor in vitro.

[0012] Another object of the present invention is to provide a method for inhibiting tumor necrosis factor activity in animals other than humans.

[0013] Solutions to the Problem

[0014] To achieve the above object, the present invention provides a 4-benzopyrone derivative represented by the following Chemical Formula 1, and a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof.

[0015] In order to achieve the further object, the present invention provides a pharmaceutical composition for preventing or treating tumor necrosis factor-related diseases, comprising a 4-benzopyrone derivative represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof as an active ingredient, and inhibiting the activity of tumor necrosis factor by directly binding to tumor necrosis factor.

[0016] In order to achieve the other object, the present invention provides a health functional food composition for preventing or improving tumor necrosis factor-related diseases, comprising a 4-benzopyrone derivative represented by the following chemical formula 1, or a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof as an active ingredient, and inhibiting the activity of tumor necrosis factor by directly binding to tumor necrosis factor.

[0017] To achieve another object, the present invention provides a method for treating tumor necrosis factor-related diseases, comprising the step of treating a pharmaceutically effective amount of a 4-benzopyrone derivative represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof.

[0018] In order to achieve the further object, the present invention provides a reagent composition for inhibiting the activity of tumor necrosis factor in vitro, comprising a 4-benzopyrone derivative represented by the following chemical formula 1, or a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof as an active ingredient.

[0019] To achieve the further object, the present invention provides a method for inhibiting tumor necrosis factor activity, comprising the step of treating an animal other than a human with a 4-benzopyrone derivative represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof.

[0020] Chemical formula 1:

[0021] In the chemical formula 1, R 1 is heteroaryl or substituted phenyl;

[0022] R 2 is hydrogen or (C1-C4) lower alkyl;

[0023] R 3 、R 4 、R 5 and R 6 Each independently represents hydrogen, halogen or (C1-C4)alkoxy.

[0024] Effects of the Invention

[0025] The present application relates to a composition for preventing or treating tumor necrosis factor-related diseases, comprising a 4-benzopyrone derivative compound as an active ingredient. Existing protein tumor necrosis factor-inhibiting biological drugs are difficult to be administered in combination with other compound therapeutic agents and complex preparations cannot be developed. However, the tumor necrosis factor-inhibiting compound provided in the present application is very convenient for being administered in combination with other existing compound therapeutic agents or for developing complex preparations. In addition, it has the advantages of excellent efficacy, low cost, non-invasive oral administration, no immunogenicity, and no need for refrigeration. Therefore, it can be effectively used as a composition for preventing or treating tumor necrosis factor-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The graph shows the tumor necrosis factor-inhibitory ability of representative compounds (Compound of Example 46, Compound of Example 61, and Compound of Example 51) among the low molecular weight compounds synthesized in one example of the present invention at different concentrations.

[0027] Figures 2a to 2e The results show whether the compounds of the present invention directly bind to TNF and their competitive inhibitory activity on TNF-etanercept binding. Figure 2a ): The results of confirming the binding of tumor necrosis factor bound to the chip and the compound of Example 61 were obtained by surface plasmon resonance (Biacore T200); ( Figure 2b ): Measurement of the binding affinity (K) of tumor necrosis factor and the compound of Example 61 bound to the chip D ) result;( Figure 2c ): The results of measuring whether the compound binds to etanercept, a tumor necrosis factor receptor, by a surface plasmon resonance method; ( Figure 2d ): Results of measuring the binding capacity of the compound of Example 30, which has a weak tumor necrosis factor-inhibiting effect, as a control group to tumor necrosis factor; ( Figure 2e ) : Results of confirming the inhibitory ability of the compound of Example 61 on tumor necrosis factor-etanercept binding using the surface plasmon resonance method).

[0028] Figure 3a to Figure 3b To show the tumor necrosis factor-cell binding inhibitory activity of the tumor necrosis factor-inhibitory compound according to one embodiment of the present invention ( Figure 3a ) and the tumor necrosis factor-induced signaling inhibitory activity of the compound of Example 61 ( Figure 3b ).

[0029] Figures 4a to 4b To illustrate the therapeutic effect of the tumor necrosis factor-inhibiting compound according to one embodiment of the present invention on sepsis (( Figure 4a): Results of measuring the in vivo tumor necrosis factor-inhibitory activity of the compound of Example 61 in a tumor necrosis factor-induced septic lethality model; ( Figure 4b ): Results of an in vivo efficacy experiment using a lipopolysaccharide (LPS)-induced sepsis model to examine the combined administration of the tumor necrosis factor-inhibiting compound of Example 61 and LMT-28, an interleukin-6 (IL-6)-inhibiting compound.

[0030] Figures 5a to 5c To confirm the preventive or therapeutic effect of the tumor necrosis factor-inhibiting compound according to one embodiment of the present invention on rheumatoid arthritis (( Figure 5a ): Confirming the preventive effect of the compound of Example 61 on rheumatoid arthritis in a tumor necrosis factor-overexpressing mouse model; ( Figure 5b ): Confirming the therapeutic effect of the compound of Example 61 on rheumatoid arthritis in a tumor necrosis factor-overexpressing mouse model; ( Figure 5c ): Confirmation of the therapeutic effect of Example 61 compound on rheumatoid arthritis in the CIA mouse model).

[0031] Figure 6 To demonstrate the therapeutic effect of combined administration of the compounds in an animal model of inflammatory bowel disease induced by dextran sulfate sodium (DSS).

[0032] Figure 7 To show the protective effect of compounds against acute kidney injury in a cecal ligation and puncture (CLP)-induced sepsis animal model.

[0033] Figure 8 These are the results of confirming the therapeutic synergistic effect of combined administration of the compound of Example 61 and methotrexate (MTX) in a rheumatoid arthritis animal model. DETAILED DESCRIPTION

[0034] Hereinafter, the present invention will be described in detail.

[0035] The present invention provides a 4-benzopyrone derivative, a pharmaceutically acceptable salt, a solvate, a racemate or a stereoisomer thereof, characterized by being represented by the following chemical formula 1:

[0036] Chemical formula 1:

[0037] In the chemical formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or (C1-C4) lower alkyl; R 3 、R4 、R 5 and R 6 Each independently represents hydrogen, halogen or (C1-C4)alkoxy.

[0038] In one embodiment of the present invention, the 4-benzopyrone derivative having a carboxyl group at the 3-position of the 4-benzopyrone compound as described above can be prepared by the following reaction formula 1:

[0039] Reaction 1:

[0040] A step of preparing compound (3) by reacting compound (2) with an acid chloride in the presence of a base and a catalyst (step 1); a step of preparing compound (4) by subjecting compound (3) prepared in step 1 to an intermolecular Wittig reaction (step 2); and a step of preparing compound (5) by removing the tert-butyl group by deesterifying compound (4) prepared in step 2 under acidic conditions (step 3).

[0041] Each preparation step of the present invention is described in detail below; Step 1 is a step of preparing compound (3) by reacting compound (2) with a heteroaromatic or benzoyl chloride in the presence of a base and a catalyst.

[0042] The base can be N, N-diisopropylethylamine, triethylamine or pyridine, and the catalyst can be 4-dimethylaminopyridine. A slightly excessive amount of the acyl chloride is used, preferably 1.05 equivalents, to cause an esterification reaction. The remaining acyl chloride can be removed by a post-reaction treatment method using a chromatographic purification or a Girard-Ti (H2NNHCOCH2N(CH3)3Cl) reagent instead of a chromatographic purification. The acyl chloride reacts with the Girard-Ti reagent to form a hydrazine derivative soluble in water, so that only the target compound (3) remains in the organic layer, and the rest is contained in the aqueous layer, thereby being easily removed.

[0043] Compound (2) as a starting material in step 1 can be obtained by reacting an o-acetyl salicylic acid chloride compound with a tert-butoxycarbonylmethylenetriphenylphosphine compound in the presence of benzene or tetrahydrofuran as a reaction solvent and N,O-dimethylsilylacetamide as a catalyst to prepare a phosphine compound, and then deacetylating the acetyl group with a base such as dimethylamine, methylamine or ammonia using tetrahydrofuran, methanol or ethanol as a reaction solvent.

[0044] Then, step 2 is a step of preparing compound (4) by subjecting compound (3) prepared in step 1 to an intermolecular Wittig reaction. In this case, the reaction solvent may be benzene, toluene, xylene, or mesitylene. Preferably, the reaction is carried out by heating under reflux at a temperature of 80° C. to 140° C. for 8 to 24 hours.

[0045] Then, step 3 is a step of preparing compound (5) by removing the tert-butyl group from compound (4) prepared in step 2 under acidic conditions. The deesterification reaction is carried out by reacting the compound with trifluoroacetic acid in a carbon dichloride solvent, but by these reactions, the tert-butyl group is removed from the butyl carboxylate compound (4), thereby obtaining 4-benzopyrone compound (5) having a carboxyl group at position 3 of Chemical Formula 1.

[0046] In addition to the compounds specified as the base substance, solvent, and catalyst in each of the above reactions, compounds that can cause the reaction to proceed can be used as the base substance, solvent, and catalyst.

[0047] The product after completion of each reaction or all reactions can be isolated and purified by conventional post-treatment methods, for example, chromatography or recrystallization.

[0048] The compound of Chemical Formula 1 of the present application is synthesized and used by the synthesis method, and can be obtained by all conventional methods, or by using commercially available reagents.

[0049] 4-chromenone compound of the present invention can be in the form of its pharmaceutically acceptable salt (salt).Described salt comprises conventional acid addition salt commonly used in compound inhibitor field, for example, derived from the salt of mineral acid such as hydrochloric acid, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid and derived from the salt of organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid.And, described salt comprises conventional metal salt form, for example, derived from the salt of metal such as lithium, sodium, potassium, magnesium or calcium.Described acid addition salt or metal salt can be prepared according to conventional method well known in the field of organic chemistry.

[0050] The 4-benzopyrone compound of the present invention may also be in the form of a solvate thereof. The term "solvate" refers to a complex or aggregate formed by one or more solute molecules, i.e., a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and one or more solvent molecules. The solvate may be, for example, a complex or aggregate formed with water, methanol, ethanol, isopropanol, or acetic acid.

[0051] The 4-benzopyrone compound of the present invention can also be in the form of its stereoisomers. The stereoisomers include all stereoisomers, such as enantiomers and diastereomers. The compound can be a stereoisomerically pure form or a mixture of more than one stereoisomer, for example, it can be a racemic mixture. The separation of specific stereoisomers can be carried out by one of the conventional methods known in the art. In detail, in the chemical formula 1, R 1 is furyl, thiophenyl or represents a substituted phenyl group, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 11 They may each independently be hydrogen, chlorine, bromine, fluorine or methoxy.

[0052] In more detail, the 4-benzopyrone derivative can be selected from 2-(2-chlorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; benzopyrone; 2-(2-furyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7 -methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; -4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone;2-(2-Thiophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone Benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone )-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,5 -difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone;2-(2,3-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2, 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)- benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone -methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; and 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone. ;

[0053] In one embodiment of the present invention, the 4-benzopyrone derivative compound can inhibit the activity of tumor necrosis factor (TNF) by directly binding to TNF.

[0054] At the same time, the present invention provides a pharmaceutical composition for preventing or treating tumor necrosis factor-related diseases, or a health functional food composition for preventing or ameliorating tumor necrosis factor-related diseases, comprising a 4-benzopyrone derivative represented by the following chemical formula 1, or a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof as an active ingredient, which inhibits the activity of tumor necrosis factor by directly binding to tumor necrosis factor:

[0055] Chemical formula 1:

[0056] In the chemical formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or (C1-C4) lower alkyl; R 3 、R 4 、R 5 and R 6 Each independently represents hydrogen, halogen or (C1-C4)alkoxy.

[0057] In detail, in the chemical formula 1, R 1 is furyl, thiophenyl or represents a substituted phenyl group, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 11 They may each independently be hydrogen, chlorine, bromine, fluorine or methoxy.

[0058] In more detail, the 4-benzopyrone derivative can be selected from 2-(2-chlorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; benzopyrone; 2-(2-furyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7 -methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; -4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone;2-(2-Thiophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone Benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone )-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,5 -difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone;2-(2,3-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2, 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)- benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone -methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; and 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone. ;

[0059] Here, the tumor necrosis factor-related disease may be a disease selected from the group consisting of autoimmune diseases, inflammatory diseases, cardiovascular diseases, metabolic diseases, immune disorders, neurological diseases, ophthalmic diseases, skin diseases, mental illnesses, infectious diseases and cancer, but is not limited thereto.

[0060] In detail, the tumor necrosis factor-related disease can be selected from rheumatoid arthritis, pediatric rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, pediatric plaque psoriasis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, Behcet's colitis, ankylosing spondylitis, axial spondyloarthritis, arthritis associated with pediatric enthesitis, polymyalgia rheumatica, multiple sclerosis, thyroiditis, delayed hypersensitivity reaction, allergy, contact dermatitis, atopic dermatitis, systemic lupus erythematosus, systemic sclerosis, adult-onset Still's disease, asthma, autoimmune thyroid disorder, Sjögren's syndrome, Kawasaki disease, pancreatitis, nephritis, hepatitis, pneumonia, chronic obstructive pulmonary disease, otitis media, angioproliferative nephritis, myelodysplastic syndrome, osteoarthritis, sarcoidosis, granuloma annulare, Wegener's granulomatosis, lupus, hemolytic uremic syndrome, arteriosclerosis, vasculitis, heart failure, stroke, myocardial infarction, myocardial ischemia-reperfusion injury, sexual dysfunction, obesity, hypertension, diabetes and diabetic complications, hyperlipidemia, preeclampsia, kidney disease, liver disease, kidney damage, liver damage, snake bites, allograft rejection, organ transplantation, graft-versus-host disease, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pain, central nervous system diseases, uveitis, Behçet's disease, diabetic macular edema, macular degeneration, orbital disease, glaucoma, hidradenitis suppurativa, multicentric reticulohistiocytosis, pityriasis rubra pilaris, eosinophilic fasciitis, panniculitis, diabetic fat necrosis of the breast, cicatricial pemphigoid, pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatosis, scleroderma The present invention also includes, but is not limited to, a disease selected from the group consisting of dermatosis, neutrophilic dermatitis, toxic epidermal necrolysis, pustular dermatitis, dermatomyositis, polymyositis, bullous dermatosis, erythema nodosum, alopecia, depression, bipolar disorder, anxiety disorder, tuberculosis, viral infection, bacterial infection, fungal infection, protozoal infection, cerebral malaria, sepsis, septic shock, prostate cancer, skin cancer, colon cancer, kidney cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, lymphoma, glioma, osteosarcoma, leukemia, multiple myeloma and cachexia.

[0061] In one embodiment of the present invention, the composition may further comprise a drug. In this case, the composition can be administered in combination with the drug to more effectively prevent, improve or treat tumor necrosis factor-related diseases.

[0062] The "drug" used in the present invention is a substance that can promote or inhibit physiological functions in animals or humans to induce biological or pharmacological effects, and refers to a chemical or biological substance or compound suitable for administration to animals or humans, which can play the following roles: (1) have a preventive effect on the organism by preventing harmful biological effects such as infection; (2) alleviate the physical condition caused by the disease, for example, relieve pain or infection caused by the disease; and (3) alleviate, reduce or completely eliminate the disease from the organism.

[0063] In detail, the drug can be selected from anti-rheumatic drugs (DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs), steroids, antimetabolites, anti-inflammatory substances, antibiotics, signal transduction / enzyme inhibitors, receptor inhibitors, high mobility group protein B1 (HMGB1) inhibitors, antithrombotic agents, autophagy agonists, cytokine inhibitors, hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors, antihypertensive agents, anticancer agents, immune activators, B cell inhibitors and T cell inhibitors, but is not limited thereto.

[0064] In more detail, the drug can be selected from methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, bucillamine, cyclosporine, tacrolimus, azathioprine, cyclophosphamide, mizoribine, penicillamine, oral preparations, antimalarial agents, 6-mercaptopurine, indomethacin, naproxen, sulindac, diclofenac sodium, aceclofenac, mefenamic acid, aspirin, fenoprofen, salsalate, piroxicam, etodolac, flurbiprofen, ibuprofen, loxoprofen, nabumetone, lonazolac, meloxicam, fenbufen, ketorolac tromethamine, indoibuprofen, ketoprofen, suprofen, carprofen, tiaprofenic acid, flufenamic acid, ebselen, felbinac, tolmetin, flunixin, celecoxib, rofecoxib, hydrocortisone, cortisone, prednisone Dragon, methylprednisolone, triamcinolone acetonide, betamethasone, dexamethasone, fludrocortisone, budesonide, 5-aminosalicylate, 6-thioguanine, cytarabine, 5-fluorouracil, dacarbazine, nitrogen mustard, thiotepa, chlorambucil, melphalan, carmustine, lomustine, busulfan, sestrin2, withaferin A, celastrol, quercetin, luteolin, curcumin, metformin, dibromomannitol, GR270773, pentoxifylline, N-acetylcysteine, melatonin, resveratrol, mesilamine, single-chain fatty acids, glutamine, gemfibrozil, tretinoin, hydroxyurea sulfate, trihydroxyisoflavones, deoxykaempferol, kaempferol, gingerol, caffeic acid, anthocyanins, cryptotanshinone, deguelin, delphinidin , equol, fisetin, myricetin, proanthocyanidin B2, metronidazole, ciprofloxacin, niclosamide, thiabendazole, imipenem-cilastine sodium, fluoroquinolones, tofacitinib, glibenclamide, rolipram, doxycycline, VX-166, zVAD, L-97-1, ISO-1, tauroursodeoxycholic acid, HK-156, A-285222, CP-0127, Bis-N-norgliovictin, aurin tricarboxylic acid, chloramidine, ouabain, terazosin, prazosin, tranilast, apremilast, monobenzone, phenazopyridine, 546C88, NOX-100, gabexate mesylate, ulinastatin, somatostatin, octreotide, IKK inhibitors, caspase (cas ase inhibitors, TAK-242, eritoran, ki16425, camptothecin, caffeic acid phenethyl ester, sulforaphane, Tim-3, BN-52021, BB-882, TCV-309, CT-400, ethyl pyruvate, hemin, CORM-2, tanshinone IIA sulfonate, nicotine, EGCG, isorhamnetin-3-o-galactoside, polygonum multiflorum, catechin, carbenoxolone, glabridin, emodin-6-ObD-glucoside, verbascoside, forsythiaside B, rosmarinic acid, chlorogenic acid, inflachromene, cilostazol, clopidogrel, sarpogrelate, drotrecogen α, carbamazepine, chloroquine, anakinra, tocilizumab, LMT-28,1-(3-Dimethylaminopropyl)-3-ethylurea, gp130Fc, beta-arrestin 2, IL-30, diacerein, secukinumab, ustekinumab, ixekizumab, thalidomide, adalimumab, infliximab, pravastatin, atorvastatin, rosuvastatin, simvastatin, losartan, telmisartan, hydrochlorothiazide, furosemide, propranolol, metoprolol, captopril Prilosec, amlodipine, clonidine, methyldopa, minoxidil, streptozotocin, mitomycin, cisplatin, daunorubicin, doxorubicin, dactinomycin, bleomycin, mithramycin, anthramycin, calicheamicin, dukamycin, paclitaxel, docetaxel, cyclin B, gramicidin D, ethyl bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, autumn The present invention includes, but is not limited to, the group consisting of narcissine, dihydroxyanthraquinone, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, procaine, tetracaine, lidocaine, propranolol, tamoxifen, bazedoxifene, puromycin, anetrolol, nivolumab, pembrolizumab, ipilimumab, atezolizumab, α-galactosylceramide, SRT3025, DTA-1, interleukin-7 (IL-7), interleukin-2 (IL-2), interleukin-15 (IL-15), CXCL1, all-trans retinoic acid, gemcitabine, carboplatin, NCX-4016, CDDO-Me, sunitinib, zoledronic acid, astragalus polysaccharide, rituximab, imuran, abatacept, GW9662, rosiglitazone, Y-27632, and alefacept.

[0065] Relative to the total weight of the composition, the composition may contain 0.0001 weight percent to 10 weight percent of a 4-benzopyrone derivative, a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof, preferably, 0.001 weight percent to 1 weight percent, but is not limited thereto.

[0066] In one embodiment of the present invention, the pharmaceutical composition for preventing or treating tumor necrosis factor-related diseases, comprising the 4-benzopyrone derivative, a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof as an active ingredient, can be used in the form of one selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, titrants or liquids according to conventional methods.

[0067] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, expanders, glidants, flavoring agents, antioxidants, buffers, antibacterial agents, diluents, dispersants, surfactants, binders and lubricants commonly used in the preparation of the pharmaceutical composition.

[0068] Specifically, the carrier, excipient, and diluent may include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid preparations can be prepared by mixing one or more excipients into the composition, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition, lubricants such as magnesium stearate and talc may also be used in addition to simple excipients. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., which, in addition to water and liquid paraffin commonly used as simple diluents, may include a variety of excipients, such as wetting agents, sweeteners, aromatics, preservatives, etc. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents, suppositories, etc. Non-aqueous solvents and suspensions can use vegetable oils such as propylene glycol, polyethylene glycol, olive oil, injectable esters such as ethyl oleate, etc. The base of the suppository can use witepsol, polyethylene glycol, Tween 61, cocoa butter, lauric acid esters, glycerin gelatin, etc.

[0069] The preferred dosage of the 4-benzopyrone derivative, its pharmaceutically acceptable salt, solvate, racemate or stereoisomer may vary according to the state and weight of the subject, the type and extent of the disease, the pharmaceutical form, the route of administration and the time, and may be appropriately selected by one of ordinary skill in the art. However, in order to obtain a preferred effect, preferably, the compound of the present invention is administered at 0.0001 mg / kg to 100 mg / kg per day, preferably, at 0.001 mg / kg to 100 mg / kg per day. Administration may be once a day or divided into several doses, and the scope of the present invention is not limited thereto.

[0070] In one embodiment of the present invention, the pharmaceutical composition can be administered to mammals such as rats, mice, livestock, and humans via a variety of routes. All routes of administration are contemplated, for example, administration can be performed orally, parenterally, or by intravenous, intramuscular, subcutaneous, intrauterine dural, or intracerebral broventricular injection.

[0071] In one embodiment of the present invention, the health functional food composition may include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, colorants and fillers (cheese, chocolate, etc.), pectin acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerol, alcohol, carbonating agents used in carbonated beverages, etc. In addition, it may include pulp used to prepare natural fruit juice, synthetic fruit juice, and vegetable juice. These ingredients can be used alone or in combination. In addition, the health functional food composition can be a form selected from meat, sausage, bread, chocolate, candy, fast food, biscuits, pizza, ramen, chewing gum, ice cream, soup, beverage, tea, functional water, drink, alcohol, and vitamin complex.

[0072] In addition, the health functional food composition may also contain food additives. Unless otherwise specified, whether it meets the requirements of "food additives" should be determined in accordance with the general principles and general test methods of the Food Additives Codex approved by the Food and Drug Safety Administration, and in accordance with the regulations and standards related to such varieties.

[0073] Examples of the food additives listed in the Food Additives Code include chemically synthesized products such as ketones, glycine, potassium citrate, niacin, and cinnamic acid, natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sorghum pigment, and guar gum, sodium L-glutamate preparations, and mixed preparations such as noodles containing added alkali agents, preservatives, and tar pigment preparations.

[0074] At this time, the 4-benzopyrone derivative, its pharmaceutically acceptable salt, solvate, racemate or stereoisomer added in the process of preparing the health functional food composition can be appropriately increased or decreased as needed, preferably, added in an amount of 1 weight percent to 90 weight percent.

[0075] At the same time, the present invention provides a method for treating tumor necrosis factor-related diseases, comprising the step of treating a pharmaceutically effective amount of a 4-benzopyrone derivative represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof:

[0076] Chemical formula 1:

[0077] In the chemical formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or (C1-C4) lower alkyl; R 3 、R 4 、R 5 and R 6 Each is independently hydrogen, halogen or (C1-C4)alkoxy.

[0078] In detail, in the chemical formula 1, R 1 is furyl, thiophenyl or represents a substituted phenyl group, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 11 They may each independently be hydrogen, chlorine, bromine, fluorine or methoxy.

[0079] In more detail, the 4-benzopyrone derivative can be selected from 2-(2-chlorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; benzopyrone; 2-(2-furyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7 -methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; -4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone;2-(2-Thiophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone Benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone )-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,5 -difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone;2-(2,3-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2, 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)- benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone -methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; and 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone. ;

[0080] Here, the tumor necrosis factor-related disease may be a disease selected from the group consisting of autoimmune diseases, inflammatory diseases, cardiovascular diseases, metabolic diseases, immune disorders, neurological diseases, ophthalmic diseases, skin diseases, mental illnesses, infectious diseases and cancer, but is not limited thereto.

[0081] In detail, the tumor necrosis factor-related disease can be selected from rheumatoid arthritis, pediatric rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, pediatric plaque psoriasis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, Behcet's colitis, ankylosing spondylitis, axial spondyloarthritis, arthritis associated with pediatric enthesitis, polymyalgia rheumatica, multiple sclerosis, thyroiditis, delayed hypersensitivity reaction, allergy, contact dermatitis, atopic dermatitis, systemic lupus erythematosus, systemic sclerosis, dyslipidemia, adult-onset Still's disease, asthma, autoimmune thyroid disorder, Sjögren's syndrome, Kawasaki disease, pancreatitis, nephritis, hepatitis, pneumonia, chronic obstructive pulmonary disease, otitis media, angioproliferative nephritis, myelodysplastic syndrome, osteoarthritis, sarcoidosis, granuloma annulare, Wegener's granulomatosis, lupus, hemolytic uremic syndrome, arteriosclerosis, vasculitis, heart failure, stroke, myocardial infarction, myocardial ischemia-reperfusion injury, sexual dysfunction, obesity, hypertension, diabetes and diabetic complications, hyperlipidemia, preeclampsia, kidney disease, liver disease, kidney damage, liver damage, snake bites, allograft rejection, organ transplantation, graft-versus-host disease, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pain, central nervous system diseases, uveitis, Behçet's disease, diabetic macular edema, macular degeneration, orbital disease, glaucoma, hidradenitis suppurativa, multicentric reticulohistiocytosis, pityriasis rubra pilaris, eosinophilic fasciitis, panniculitis, diabetic breast fat necrosis, cicatricial pemphigoid, pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatosis, The present invention also includes one selected from the group consisting of scleroderma, neutrophilic dermatitis, toxic epidermal necrolysis, pustular dermatitis, dermatomyositis, polymyositis, bullous dermatosis, erythema nodosum, alopecia, depression, bipolar disorder, anxiety disorder, tuberculosis, viral infection, bacterial infection, fungal infection, protozoal infection, cerebral malaria, sepsis, septic shock, prostate cancer, skin cancer, colon cancer, kidney cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, lymphoma, glioma, osteosarcoma, leukemia, multiple myeloma and cachexia, but is not limited thereto.

[0082] In the present invention, "pharmaceutically effective amount" refers to an amount sufficient to administer a drug to an animal or human to have the desired physiological or pharmacological activity. However, the pharmaceutically effective amount may vary appropriately depending on the age, weight, health status, sex, route of administration, and duration of treatment of the subject.

[0083] In addition, "pharmaceutically acceptable" refers to physiologically acceptable, and when applied to humans, does not usually cause allergic reactions such as gastrointestinal disorders and dizziness or expect similar reactions. Examples of the carrier, excipient, and diluent include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, spices, emulsifiers, and preservatives may also be included.

[0084] Furthermore, the present invention provides a reagent composition for inhibiting the activity of tumor necrosis factor in vitro, comprising a 4-benzopyrone derivative represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof as an active ingredient:

[0085] Chemical formula 1:

[0086] In the chemical formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or (C1-C4) lower alkyl; R 3 、R 4 、R 5 and R 6 Each is independently hydrogen, halogen or (C1-C4)alkoxy.

[0087] At the same time, the present invention provides a method for inhibiting the activity of tumor necrosis factor, comprising the step of treating an animal other than a human with the 4-benzopyrone derivative represented by Chemical Formula 1, or a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof.

[0088] In detail, in the chemical formula 1, R 1 is furyl, thiophenyl or represents a substituted phenyl group, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 11 They may each independently be hydrogen, chlorine, bromine, fluorine or methoxy.

[0089] In more detail, the 4-benzopyrone derivative can be selected from 2-(2-chlorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; benzopyrone; 2-(2-furyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7 -methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; -4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2-thiophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone;2-(2-Thiophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2-Thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone Benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone )-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-(4H)-4-benzopyrone; 2-(3,5 -difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone;2-(2,3-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(2, 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)- benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone -methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone; 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone; and 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone. ;

[0090] Specific embodiments of the present invention

[0091] Below, in order to facilitate understanding of the present invention, detailed description is given by enumerating examples. However, the following examples are provided to more fully illustrate the present invention to those of ordinary skill in the art, and are merely used to illustrate the contents of the present invention. Therefore, the scope of the present invention is not limited to the following examples.

[0092] Preparation Example 1.4 General reaction process of benzopyrone compound derivatives

[0093] Reaction 1:

[0094] First, a 2-hydroxybenzophosphine derivative compound (2) is dissolved in carbon dichloride, and pyridine (2 equivalents) is titrated followed by a heteroaromatic or benzoyl chloride derivative (1.5 equivalents), and then 4-dimethylaminopyridine (0.05 equivalents). Subsequently, the reaction mixture is stirred under nitrogen for 1 to 5 hours. After the reaction is completed, acetic acid (1 mL) is added to the reaction solution and Girard reagent T (1 eq) is titrated, followed by stirring under nitrogen for 1 hour. The mixture is then extracted with a 1N HCl and NaHCO3 saturated solution, and the organic layer is dried over anhydrous MgSO4. The obtained compound (3) is then dissolved in toluene solvent by vacuum distillation. After heating under reflux for 5 to 18 hours under nitrogen, the reaction is completed, the solvent is removed by vacuum distillation, and the reaction mixture is purified by chromatography. The thus obtained 4-benzopyrone compound (4) is dissolved in carbon dichloride, trifluoroacetic acid (TFA) is titrated, and the mixture is stirred under nitrogen for 1 to 5 hours. After the reaction is completed, the solvent is removed by distillation under reduced pressure, and then the crystals formed by crystallization in diethyl ether are filtered and dried in a vacuum oven to obtain the final target compound (5).

[0095] Example 1. Synthesis of 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone

[0096] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphine compound (150 mg, 0.28 mmol), pyridine (0.05 mL, 0.57 mmol, 2 eq), and 3-fluorobenzoyl chloride (0.05 mL, 0.43 mmol, 1.5 eq) were stirred in carbon chloride (5 mL) for 4 hours and 30 minutes, stirred in toluene (10 mL) for 2 hours and 30 minutes, and then stirred in trifluoroacetic acid (2 mL) and carbon dichloride (2 mL) for 1 hour and 30 minutes to obtain 60 mg (67.0%) of 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone as the final target compound.

[0097] mp214~215℃. 1 H NMR (300MHz, CDCl3): δ3.96 (s, 3H), 6.97 (d, J=2.3Hz, 1H), 7.15 (dd, J=9.1, 2.3Hz, 1H), 7.26-7.50 (m, 4H), 8.24 (d, J=9.1Hz, 1H); 13C NMR (75MHz, CDCl3): δ56.22, 100.21, 110.10, 115.48, 116.14, 116.91, 118.53, 12 4.96, 127.77, 129.86, 134.56, 157.54, 160.45, 163.56, 166.12, 172.04, 179.62.

[0098] Example 2. Synthesis of 2-(2-furyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone

[0099] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-furoyl chloride (0.029 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in methylene chloride (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then stirred in trifluoroacetic acid (3 mL) and methylene chloride (3 mL) for 1 hour to obtain 25.2 mg (47.6%) of the final target compound 2-(2-furyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone.

[0100] mp195~197℃. 1 H NMR (300MHz, CDCl3): δ2.53 (s, 3H), 6.71 (dd, J=3.7, 1.7Hz, 1H), 7.55 (d, J=8.6Hz, 1H), 7.66 (d d, J=8.6, 2.0Hz, 1H), 7.79 (d, J=1.7Hz, 1H), 7.99 (d, J=3.7Hz, 1H), 8.09 (s, 1H), 14.55 (s, 1H).

[0101] Example 3. Synthesis of 2-(2-furyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone

[0102] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 equivalents), and 2-furoyl chloride (0.05 mL, 0.57 mmol, 1.5 equivalents) were stirred in carbon dichloride (4 mL) for 1 hour, stirred in toluene (15 mL) for 10 hours, and then stirred in trifluoroacetic acid (2 mL) and carbon dichloride (2 mL) for 4 hours to obtain 50 mg (46.0%) of the final target compound 2-(2-furyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone.

[0103] mp217~219℃. 1 H NMR (300MHz, CDCl3): δ3.99 (s, 3H), 6.71 (dd, J=3.7, 1.6Hz, 1H), 7.03 (d, J=2.3Hz, 1H), 7.11 (dd, J= 9.0, 2.3Hz, 1H), 7.78 (d, J=1.6Hz, 1H), 8.01 (d, J=3.7Hz, 1H), 8.21 (d, J=9.0Hz, 1H), 15.00 (s, 1H).

[0104] Example 4. Synthesis of 2-(2-furyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone

[0105] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 eq), and 2-furoyl chloride (0.05 mL, 0.57 mmol, 1.5 eq) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (15 mL) for 10 hours, and then stirred in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) for 4 hours to obtain 70 mg (64.0%) of the final target compound 2-(2-furyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone.

[0106] mp205~207℃. 1 H NMR (300MHz, CDCl3): δ3.97 (s, 3H), 6.71 (dd, J=3.7, 1.7Hz, 1H), 7.43 (dd, J=9.2, 3.1Hz, 1H), 7.60 ( d, J=9.2Hz, 1H), 7.64 (d, J=3.1Hz, 1H), 7.79 (d, J=1.7Hz, 1H), 7.99 (d, J=3.7Hz, 1H), 14.60 (s, 1H).

[0107] Example 5. Synthesis of 2-(3-methylphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone

[0108] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluoyl chloride (m-toluoly chloride; 0.031 mL, 0.24 mmol, 1.2 eq), and 4-(dimethylamino)pyridine (4-(dimethylamino)pyridine; 5 mg) were stirred in dichloromethane (3 mL) for 24 hours, then in toluene (6 mL) for 14 hours, and then in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour and 30 minutes to obtain 23.1 mg (40.1%) of the final target compound 2-(3-methylphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone.

[0109] mp192~195℃. 1 H NMR (300MHz, CDCl3): δ2.46 (s, 3H), 2.55 (s, 3H), 7.41-7.47 (m, 4H), 7.52 (d, J =8.6Hz, 1H), 7.67 (dd, J=8.6, 2.1Hz, 1H), 8.14 (d, J=0.9Hz, 1H), 14.30 (s, 1H).

[0110] Example 6. Synthesis of 2-(3-methylphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone

[0111] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 equivalents), and m-toluoyl chloride (0.05 mL, 0.57 mmol, 1.5 equivalents) were stirred in dichloromethane (4 mL) for 19 hours, stirred in toluene (15 mL) for 17 hours, and then stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 76.3 mg (65.0%) of the final target compound 2-(3-methylphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone.

[0112] mp183~184℃. 1H NMR (300MHz, CDCl3): δ2.46 (s, 3H), 3.96 (s, 3H), 6.98 (d, J=2.3Hz, 1H), 7.14 ( dd, J=9.0, 2.3Hz, 1H), 7.40-7.46 (m, 4H), 8.25 (d, J=9.0Hz, 1H), 14.45 (s, 1H).

[0113] Example 7. Synthesis of 2-(3-methylphenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone

[0114] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 eq), and m-toluoyl chloride (0.05 mL, 0.57 mmol, 1.5 eq) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (15 mL) for 71 hours, and then stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 49.5 mg (42.0%) of the final target compound 2-(3-methylphenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone.

[0115] mp198~199℃. 1 H NMR (300MHz, CDCl3): δ2.46 (s, 3H), 3.98 (s, 3H), 7.27-7.46 (m, 5H), 7.56 (d, J=9.2Hz, 1H), 7.67 (d, J=3.0Hz, 1H), 14.35 (s, 1H).

[0116] Example 8. Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-(4H)-4-benzopyrone

[0117] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (200 mg, 0.4 mmol), pyridine (0.05 mL, 0.6 mmol, 1.5 eq), and 3,4-dimethoxybenzoyl chloride (dimethoxybenzoyl chloride; 96 mg, 0.48 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 150 hours, stirred in toluene (15 mL) for 72 hours, and then stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 34.9 mg (63.0%) of the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-(4H)-4-benzopyrone.

[0118] mp237~238℃. 1H NMR (300MHz, CDCl3): δ3.94 (s, 3H), 3.99 (s, 3H), 7.00 (d, J = 8.4Hz, 1H), 7.23 (d, J = 2.1Hz, 1H), 7.39 (d d, J=8.4, 2.1Hz, 1H), 7.56-7.64 (m, 2H), 7.64-7.90 (m, 1H), 8.36 (dd, J=8.0, 1.6Hz, 1H), 14.50 (s, 1H).

[0119] Example 9. Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone

[0120] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), and 3,4-dimethoxybenzoyl chloride (92 mg, 0.46 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 12 hours, stirred in benzene (10 mL) for 45 hours, and then stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 59.7 mg (89.0%) of the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone.

[0121] mp208~210℃. 1 H NMR (300MHz, CDCl3): δ3.94 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H), 6.97-6.99 (m, 2H), 7.12 (dd, J =8.9, 2.3Hz, 1H), 7.20 (d, J=1.9Hz, 1H), 7.34 (dd, J=8.4, 1.9Hz, 1H), 8.22 (d, J=8.9Hz, 1H).

[0122] Example 10. Synthesis of 2-(2-chlorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone

[0123] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), and 2-chlorobenzoyl chloride (0.06 mL, 0.46 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (15 mL) for 8 hours, and then stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 70 mg (88.0%) of the target compound 2-(2-chlorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone.

[0124] mp130~132℃. 1 H NMR (300MHz, CDCl3): δ3.96 (s, 3H), 6.98 (d, J=2.4Hz, 1H), 7.17 (dd, J=9.0, 2.4Hz , 1H), 7.43-7.44 (m, 2H), 7.48-7.56 (m, 2H), 8.28 (d, J=9.0Hz, 1H), 14.40 (s, 1H).

[0125] Example 11. Synthesis of 2-(2-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone

[0126] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (200 mg, 0.40 mmol), pyridine (0.05 mL, 0.60 mmol, 1.5 eq), and 2-chlorobenzoyl chloride (0.06 mL, 0.48 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (15 mL) for 120 hours, and then stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 6 hours and 30 minutes to obtain 34 mg (44.0%) of the final target compound 2-(2-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone.

[0127] mp133~135℃. 1 H NMR (300MHz, CDCl3): δ7.44-7.46 (m, 2H), 7.49-7.55 (m, 2H), 7.61-7.66 (m, 2H), 7.87-7.93 (m, 1H), 8.40 (dd, J=8.3, 1.7Hz, 1H).

[0128] Example 12. Synthesis of 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone

[0129] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), and 2-thiophenecarbonyl chloride (2-thiophenecarbonylchloride; 0.05 mL, 0.46 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 2 hours and 30 minutes, and then stirred in toluene (15 mL) for 36 hours. Then, the mixture was stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 52.4 mg (56.0%) of the final target compound 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone.

[0130] mp196~198℃. 1 H NMR (300MHz, CDCl3): δ4.07 (s, 3H), 7.25 (dd, J=5.0, 4.0Hz, 1H), 7.31 (dd, J=8.1, 1.3Hz, 1H) , 7.46 (dd, J=8.1, 8.1Hz, 1H), 7.81-7.85 (m, 2H), 8.38 (dd, J=4.0, 1.2Hz, 1H), 14.80 (s, 1H).

[0131] Example 13. Synthesis of 2-(2-thiophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone

[0132] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), and 2-thiophenecarbonyl chloride (0.05 mL, 0.46 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 2 hours and 30 minutes, and then stirred in toluene (15 mL) for 28 hours. Then, the mixture was stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 41 mg (77.0%) of the final target compound 2-(2-thiophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyrone.

[0133] mp205~207℃. 1H NMR (300MHz, CDCl3): δ3.97 (s, 3H), 6.95 (d, J=2.3Hz, 1H), 7.09 (dd, J=9.0, 2.3Hz, 1H), 7.22 (dd, J=5.0, 4 .0Hz, 1H), 7.79 (dd, J=5.0, 1.1Hz, 1H), 8.19 (d, J=9.0Hz, 1H), 8.25 (dd, J=4.0, 1.1Hz, 1H), 14.98 (s, 1H).

[0134] Example 14. Synthesis of 2-(2-thiophenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone

[0135] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methoxybenzophosphine compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), and 2-thiophenecarbonyl chloride (0.05 mL, 0.46 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 2 hours and 30 minutes, and then stirred in toluene (15 mL) for 42 hours. Then, the mixture was stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 1 hour and 30 minutes to obtain 50 mg (68.0%) of the final target compound 2-(2-thiophenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyrone.

[0136] mp172~174℃. 1 H NMR (300MHz, CDCl3): δ3.96 (s, 3H), 7.24 (dd, J=5.0, 4.0Hz, 1H), 7.43 (dd, J=9.2, 3.0Hz, 1H), 7.55 (d, J=9 .2Hz, 1H), 7.63 (d, J=3.0Hz, 1H), 7.81 (dd, J=5.0, 1.2Hz, 1H), 8.25 (dd, J=4.0, 1.2Hz, 1H), 14.78 (s, 1H).

[0137] Example 15. Synthesis of 2-(2-thiophenyl)-3-carboxy-(4H)-4-benzopyrone

[0138] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (200 mg, 0.40 mmol), pyridine (0.05 mL, 0.60 mmol, 1.5 eq), and 2-thiophenecarbonyl chloride (0.05 mL, 0.48 mmol, 1.2 eq) were stirred in dichloromethane (4 mL) for 3 hours, stirred in toluene (15 mL) for 23 hours and 30 minutes, and then stirred in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) for 2 hours to obtain 52.3 mg (78.0%) of the final target compound 2-(2-thiophenyl)-3-carboxyl-(4H)-4-benzopyrone.

[0139] mp175~176℃. 1 H NMR (300MHz, CDCl3): δ7.25 (dd, J=5.0, 4.1Hz,

[0140] 1H), 7.55-7.64(m, 2H), 7.83-7.89(m, 2H), 8.29-8.34(m, 2H), 14.70(s, 1H).

[0141] Example 16. Synthesis of 2-(3-fluorophenyl)-3-carboxy-(4H)-4-benzopyrone

[0142] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (300 mg, 0.6 mmol), diisopropylethylamine (0.314 mL, 1.8 mmol, 3 eq), 3-fluorobenzoyl chloride (0.118 mL, 1.2 mmol, 2 eq), and 4-(dimethylamino)pyridine (10 mg) were stirred in dichloromethane (5 mL) for 1 hour, stirred in toluene (15 mL) for 4 hours and 30 minutes, and then stirred in trifluoroacetic acid (7 mL) and dichloromethane (7 mL) for 1 hour and 30 minutes to obtain 154 mg (90.0%) of the final target compound 2-(3-fluorophenyl)-3-carboxy-(4H)-4-benzopyrone.

[0143] mp193~196℃. 1 H NMR (300MHz, CDCl3): δ7.29-7.55 (m, 4H), 7.60-7.65 (m, 2H), 7.87-7.93 (m, 1H), 8.37-8.40 (m, 1H), 14.19 (s, 1H).

[0144] Example 17. Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-(4H)-4-benzopyrone

[0145] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (300 mg, 0.6 mmol), diisopropylethylamine (0.314 mL, 1.8 mmol, 3 eq), 3,5-difluorobenzoyl chloride (0.15 mL, 1.2 mmol, 2 eq), and 4-(dimethylamino)pyridine (10 mg) were stirred in dichloromethane (5 mL) for 1 hour, stirred in toluene (15 mL) for 2 hours and 30 minutes, and then stirred in trifluoroacetic acid (7 mL) and dichloromethane (7 mL) for 1 hour to obtain 22 mg (12.0%) of the final target compound 2-(3,5-difluorophenyl)-3-carboxy-(4H)-4-benzopyrone.

[0146] mp208~209℃. 1 H NMR (300MHz, CDCl3): δ7.02-7.08 (m, 1H), 7.16-7.19 (m, 2H), 7.62-66 (m, 2H), 7.89-7.94 (m, 1H), 8.38 (d, J = 8.3Hz, 1H).

[0147] Example 18. Synthesis of 2-(2-furyl)-3-carboxy-(4H)-4-benzopyrone

[0148] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (300 mg, 0.6 mmol), diisopropylethylamine (0.314 mL, 1.8 mmol, 3 eq), 2-furoyl chloride (0.118 mL, 1.2 mmol, 2 eq), and 4-(dimethylamino)pyridine (10 mg) were stirred in dichloromethane (5 mL) for 1 hour, stirred in toluene (15 mL) for 8 hours, and then stirred in trifluoroacetic acid (7 mL) and dichloromethane (7 mL) for 1 hour to obtain 96 mg (62.0%) of the final target compound 2-(2-furyl)-3-carboxy-(4H)-4-benzopyrone.

[0149] mp202~205℃. 1 H NMR (300MHz, CDCl3): δ6.72 (dd, J=3.8, 1.7Hz,

[0150] 1H), 7.54-7.60 (m, 1H), 7.65 (d, J=8.4Hz, 1H), 7.81-7.89 (m, 2H), 8.01-8.03 (m, 1H), 8.32 (dd, J=8.0, 1.5Hz, 1H), 14.45 (s, 1H).

[0151] Example 19. Synthesis of 2-(3-methylphenyl)-3-carboxyl-(4H)-4-benzopyrone

[0152] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (300 mg, 0.6 mmol), diisopropylethylamine (0.314 mL, 1.8 mmol, 3 eq), m-toluoyl chloride (0.158 mL, 1.2 mmol, 2 eq), and 4-(dimethylamino)pyridine (10 mg) were stirred in dichloromethane (5 mL) for 1 hour, stirred in toluene (15 mL) for 72 hours, and then stirred in trifluoroacetic acid (7 mL) and dichloromethane (7 mL) for 1 hour to obtain 73 mg (43.0%) of the final target compound 2-(3-methylphenyl)-3-carboxy-(4H)-4-benzopyrone.

[0153] mp162~164℃. 1 H NMR (300MHz, CDCl3): δ2.48 (s, 3H), 7.43-7.50 (m, 4H), 7.59-7.65 (m, 2H), 7.86-7.92 (m, 1H), 8.38 (dd, J=8.0, 1.5Hz, 1H), 14.20 (s, 1H).

[0154] Example 20. Synthesis of 2-(2-furyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0155] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-furoyl chloride (0.029 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 31.4 mg (59.3%) of the final target compound 2-(2-furyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0156] mp227~228℃. 1 H NMR (300MHz, CDCl3): δ2.58 (s, 3H), 6.69 (dd, J=3.6, 1.7Hz, 1H), 7.32-7.36 (m, 2H), 7.59 (d, J=7.3Hz, 1H), 7.76-7.77 (m, 1H), 7.98 (d, J=7.3Hz, 1H).

[0157] Example 21. Synthesis of 2-(2-furyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0158] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-furoyl chloride (0.029 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 19.1 mg (36.1%) of the final target compound 2-(2-furyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0159] mp217~218℃. 1 H NMR (300MHz, CDCl3): δ2.57 (s, 3H), 6.71 (dd, J=3.7, 1.7Hz, 1H), 7.37 (dd, J=8.2, 0.8Hz, 1H), 7 .46 (s, 1H), 7.79 (d, J=1.7Hz, 1H), 8.00 (d, J=3.7Hz, 1H), 8.18 (d, J=8.2Hz, 1H), 14.55 (s, 1H).

[0160] Example 22. Synthesis of 2-(2-furyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0161] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-furoyl chloride (0.029 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 25.2 mg (47.6%) of the final target compound 2-(2-furyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0162] mp195~197℃. 1H NMR (300MHz, CDCl3): δ2.53 (s, 3H), 6.71 (dd, J=3.7, 1.7Hz, 1H), 7.55 (d, J=8.6Hz, 1H), 7.66 (d d, J=8.6, 2.0Hz, 1H), 7.79 (d, J=1.7Hz, 1H), 7.99 (d, J=3.7Hz, 1H), 8.09 (s, 1H), 14.55 (s, 1H).

[0163] Example 23. Synthesis of 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone. Using the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 2-furoyl chloride (0.028 mL, 0.29 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 20.20 mg (36.9%) of the final target compound 2-(2-furyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0164] mp196~198℃. 1 H NMR (300MHz, CDCl3): δ6.73 (dd, J=3.8, 1.7Hz,

[0165] 1H), 7.62 (d, J=9.0Hz, 1H), 7.77-7.81 (m, 2H), 8.04 (dd, J=3.8, 0.5Hz, 1H), 8.27 (d, J=2.5Hz, 1H), 14.00 (s, 1H).

[0166] Example 24. Synthesis of 2-(2-furyl)-3-carboxy-6-stin-(4H)-4-benzopyrone

[0167] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 2-furoyl chloride (0.026 mL, 0.26 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 41.9 mg (71.9%) of the final target compound 2-(2-furyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0168] mp209~211℃. 1 H NMR (300MHz, CDCl3): δ6.73 (dd, J=3.8, 1.6Hz,

[0169] 1H), 7.55 (d, J=8.9Hz, 1H), 7.80-7.81 (m, 1H), 7.93 (dd, J=8.9, 2.4Hz, 1H), 8.03 (d, J=3.8Hz, 1H), 8.43 (d, J=2.4Hz, 1H), 14.25 (s, 1H).

[0170] Example 25. Synthesis of 2-(3-methylphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0171] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluoyl chloride (0.031 mL, 0.24 mmol, 1.2 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour and 30 minutes to obtain 14.0 mg (24.3%) of the final target compound 2-(3-methylphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0172] mp209~211℃. 1 H NMR (300MHz, CDCl3): δ2.47 (s, 3H), 2.55 (s, 3H), 7.42-7.51 (m, 5H), 7.70 (d, J=7.1Hz, 1H), 8.19 (d, J=7.1Hz, 1H), 14.25 (s, 1H).

[0173] Example 26. Synthesis of 2-(3-methylphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0174] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluoyl chloride (0.031 mL, 0.24 mmol, 1.2 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour and 30 minutes to obtain 23.2 mg (40.4%) of the final target compound 2-(3-methylphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0175] mp152~155℃. 1 H NMR (300MHz, CDCl3): δ2.46 (s, 3H), 2.57 (s, 3H), 7.39-7.47 (m, 6H), 8.24 (d, J = 8.5Hz, 1H), 14.30 (s, 1H).

[0176] Example 27. Synthesis of 2-(3-methylphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0177] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluoyl chloride (0.031 mL, 0.24 mmol, 1.2 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour and 30 minutes to obtain 23.1 mg (40.1%) of the final target compound 2-(3-methylphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0178] mp192~195℃. 1 H NMR (300MHz, CDCl3): δ2.46 (s, 3H), 2.55 (s, 3H), 7.41-7.47 (m, 4H), 7.52 (d, J =8.6Hz, 1H), 7.67 (dd, J=8.6, 2.1Hz, 1H), 8.14 (d, J=0.9Hz, 1H), 14.30 (s, 1H).

[0179] Example 28. Synthesis of 2-(3-methylphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone

[0180] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), m-toluoyl chloride (0.030 mL, 0.23 mmol, 1.2 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour and 30 minutes to obtain 28.4 mg (48.0%) of the final target compound 2-(3-methylphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone.

[0181] mp179~181℃. 1 H NMR (300MHz, CDCl3): δ2.46 (s, 3H), 7.43-7.46 (m, 4H), 7.56 (dd, J=8.6, 1.5Hz, 1H), 7.66 (s, 1H), 8.30 (d, J=8.6Hz, 1H), 13.95 (s, 1H).

[0182] Example 29. Synthesis of 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone

[0183] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), m-toluoyl chloride (0.030 mL, 0.23 mmol, 1.2 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour and 30 minutes to obtain 13.4 mg (22.6%) of the final target compound 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0184] mp218~220℃. 1 H NMR (300MHz, CDCl3): δ2.46 (s, 3H), 7.44-7.47 (m, 4H), 7.52 (d, J=8.9Hz, 1H), 7.95 (dd, J=8.9, 2.4Hz, 1H), 8.49 (d, J=2.4Hz, 1H), 13.80 (s, 1H).

[0185] Example 30. Synthesis of 2-(3-methylphenyl)-3-carboxy-6-odor-(4H)-4-benzopyrone

[0186] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), m-toluoyl chloride (0.027 mL, 0.20 mmol, 1.2 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour and 30 minutes to obtain 21.6 mg (34.6%) of the final target compound 2-(3-methylphenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0187] mp208~210℃. 1 H NMR (300MHz, CDCl3): δ2.47 (s, 3H), 7.42-7.47 (m, 4H), 7.59 (d, J=8.9Hz, 1H), 7.80 (dd, J=8.9, 2.5Hz, 1H), 8.32 (d, J=2.5Hz, 1H), 13.90 (s, 1H).

[0188] Example 31. Synthesis of 2-(2-thiophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0189] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-thiophenecarbonyl chloride (0.031 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 21 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 26.5 mg (47.3%) of the final target compound 2-(2-thiophenyl)-3-carboxyl-8-methyl-(4H)-4-benzopyrone.

[0190] mp205~206℃. 1H NMR (300MHz, CDCl3): δ2.63 (s, 3H), 7.25-7.26 (m, 4H), 7.45 (dd, J=7.7, 7.7Hz, 1H), 7.68 (d, J =7.7Hz, 1H), 7.83 (dd, J=5.0, 1.0Hz, 1H), 8.14 (d, J=7.7Hz, 1H), 8.38 (dd, J=4.0, 1.0Hz, 1H).

[0191] Example 32. Synthesis of 2-(2-thiophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0192] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-thiophenecarbonyl chloride (0.031 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 21 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 30.1 mg (53.8%) of the final target compound 2-(2-thiophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0193] mp202~203℃. 1 H NMR (300MHz, CDCl3): δ2.58 (s, 3H), 7.24 (dd, J=5.0, 4.0Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 7.42 (s, 1 H), 7.82 (dd, J=5.0, 1.1Hz, 1H), 8.18 (d, J=8.2Hz, 1H), 8.28 (dd, J=4.0, 1.1Hz, 1H), 14.80 (s, 1H).

[0194] Example 33. Synthesis of 2-(2-thiophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0195] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-thiophenecarbonyl chloride (0.031 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 30 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 50 mg (89%) of the final target compound 2-(2-thiophenyl)-3-carboxyl-6-methyl-(4H)-4-benzopyrone.

[0196] mp153~155℃. 1 H NMR (300MHz, CDCl3): δ2.54 (s, 3H), 7.24 (dd, J=5.0, 4.0Hz, 1H), 7.52 (d, J=8.6Hz, 1H), 7.66 (dd, J=8 .6, 2.0Hz, 1H), 7.82 (dd, J=5.0, 1.1Hz, 1H), 8.09 (s, 1H), 8.28 (dd, J=4.0, 1.1Hz, 1H), 14.75 (s, 1H).

[0197] Example 34. Synthesis of 2-(2-thiophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone

[0198] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 2-thiophenecarbonyl chloride (0.030 mL, 0.29 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 24 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 37.0 mg (63.8%) of the final target compound 2-(2-thiophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone.

[0199] mp232~233℃. 1 H NMR (300MHz, CDCl3): δ7.20 (dd, J=5.0, 4.0Hz,

[0200] 1H), 7.42 (dd, J=8.5, 1.8Hz, 1H), 7.60 (d, J=1.8Hz, 1H), 7.73 (dd, J=5.0, 1.0Hz, 1H), 7.93 (dd, J=4.0, 1.0Hz, 1H), 8.15 (d, J=8.5Hz, 1H).

[0201] Example 35. Synthesis of 2-(2-thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone

[0202] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 2-thiophenecarbonyl chloride (0.030 mL, 0.29 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 72 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 36.7 mg (63.3%) of the final target compound 2-(2-thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0203] mp202~204℃. 1 H NMR (300MHz, CDCl3): δ7.24 (dd, J=5.0, 4.0Hz,

[0204] 1H), 7.57 (d, J=8.9Hz, 1H), 7.77 (dd, J=8.9, 2.5Hz, 1H), 7.84 (dd, J=5.0, 1. 1Hz, 1H), 8.25 (d, J=2.5Hz, 1H), 8.28 (dd, J=4.0, 1.1Hz, 1H), 14.45 (s, 1H).

[0205] Example 36. Synthesis of 2-(2-thiophenyl)-3-carboxy-6-stin-(4H)-4-benzopyrone

[0206] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 2-thiophenecarbonyl chloride (0.028 mL, 0.26 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 72 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 46.2 mg (75.7%) of the final target compound 2-(2-thiophenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0207] mp210~212℃. 1 H NMR (300MHz, CDCl3): δ7.25 (dd, J=5.0, 4.1Hz,

[0208] 1H), 7.52 (d, J=8.9Hz, 1H), 7.86 (dd, J=5.0, 1.1Hz, 1H), 7.93 (dd, J=8.9, 2. 4Hz, 1H), 8.30 (dd, J=4.1, 1.1Hz, 1H), 8.44 (d, J=2.4Hz, 1H), 14.30 (s, 1H).

[0209] Example 37. Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0210] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3,4-dimethoxybenzoyl chloride (3,4-dimethoxybenzoyl chloride; 59 mg, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 96 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 20.3 mg (30.3%) of the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0211] mp210~212℃. 1H NMR (300MHz, CDCl3): δ2.58 (s, 3H), 3.96 (s, 3H), 4.00 (s, 3H), 7.01 (d, J = 8.5Hz, 1H), 7.27 (d, J = 2.1Hz, 1H), 7.43 (dd, J=8.5, 2.1Hz, 1H), 7.48 (dd, J=7.7, 7.7Hz, 1H), 7.69 (d, J=7.7Hz, 1H), 8.18 (d, J=7.7Hz, 1H), 14.45 (s, 1H).

[0212] Example 38. Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0213] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3,4-dimethoxybenzoyl chloride (59 mg, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 24 hours, stirred in toluene (6 mL) for 96 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 28.4 mg (42.4%) of the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0214] mp200~201℃. 1 H NMR (300MHz, CDCl3): δ2.58 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 6.99 (d, J=8.5Hz, 1 H), 7.22 (d, J=2.0Hz, 1H), 7.36-7.43 (m, 3H), 8.22 (d, J=8.1Hz, 1H), 14.45 (s, 1H).

[0215] Example 39. Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone

[0216] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 3,4-dimethoxybenzoyl chloride (57 mg, 0.29 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 100 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 34.8 mg (51.2%) of the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone.

[0217] mp226~227℃. 1 H NMR (300MHz, CDCl3): δ3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J=8.4Hz, 1H), 7.21 (d, J=2.1Hz, 1H), 7.38 (dd, J= 8.4, 2.1Hz, 1H), 7.54 (dd, J=8.6, 1.8Hz, 1H), 7.66 (dd, J=1.8Hz, 1H), 8.28 (d, J=8.6Hz, 1H), 14.10 (s, 1H).

[0218] Example 40. Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-6-odor-(4H)-4-benzopyrone

[0219] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 2-thiophenecarbonyl chloride (0.028 mL, 0.26 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 92 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 34 mg (48%) of the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0220] mp242~243℃. 1H NMR (300MHz, CDCl3): δ3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J = 8.4Hz, 1H), 7.22 (d, J = 2.1Hz, 1H), 7.3 8 (dd, J=8.4, 2.1Hz, 1H), 7.53 (d, J=8.9Hz, 1H), 7.94 (dd, J=8.9, 2.4Hz, 1H), 8.48 (d, J=2.4Hz, 1H).

[0221] Example 41. Synthesis of 2-(3-fluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0222] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3-fluorobenzoyl chloride (0.036 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 12 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 2 hours to obtain 18.7 mg (32.2%) of the final target compound 2-(3-fluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0223] mp227~229℃. 1 H NMR (300MHz, CDCl3): δ2.54 (s, 3H), 7.28-7.33 (m, 1H), 7.39 (d, J=9.3Hz, 1H), 7.46-7.49 (m.3H), 7.71 (d, J=7.5Hz, 1H), 8.19 (d, J=8.0Hz, 1H).

[0224] Example 42. Synthesis of 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0225] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3-fluorobenzoyl chloride (0.036 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 10 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 2 hours to obtain 16.1 mg (27.8%) of the final target compound 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0226] mp178~181℃. 1 H NMR (300MHz, CDCl3): δ2.58 (s, 3H), 7.28-7.38 (m, 2H), 7.42-7.44 (m, 3H), 7.47-7.54 (m.1H), 8.23-8.26 (m, 1H), 14.33 (s, 1H).

[0227] Example 43. Synthesis of 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0228] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3-fluorobenzoyl chloride (0.036 mL, 0.30 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 21 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 2 hours to obtain 34.2 mg (59.0%) of the final target compound 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0229] mp214~215℃. 1 H NMR (300MHz, CDCl3): δ2.56 (s, 3H), 7.30-7.33 (m, 1H), 7.35-7.39 (m, 1H), 7.42-7.4 5 (m, 1H), 7.47-7.54 (m.2H), 7.69 (dd, J=8.6, 2.0Hz, 1H), 8.14 (s, 1H), 14.30 (s, 1H).

[0230] Example 44. Synthesis of 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone

[0231] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 3-fluorobenzoyl chloride (0.034 mL, 0.29 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 19 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 2 hours to obtain 43 mg (71.6%) of the final target compound 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone.

[0232] mp160~163℃. 1 H NMR (300MHz, CDCl3): δ7.30-7.44 (m, 2H), 7.51 (dd, J=8.0, 5.4Hz, 1H), 7.58 (dd, J=8.6, 1 .8Hz, 1H), 7.66 (d, J=1.8Hz, 1H), 7.71-7.75 (m, 1H), 8.31 (d, J=8.6Hz, 1H), 15.35 (s, 1H).

[0233] Example 45. Synthesis of 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone

[0234] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 3-fluorobenzoyl chloride (0.034 mL, 0.29 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 2 hours, stirred in toluene (6 mL) for 24 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 2 hours to obtain 48.0 mg (80.0%) of the final target compound 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0235] mp216~217℃. 1 H NMR (300MHz, CDCl3): δ7.29-7.39 (m, 2H), 7.42-7.46 (m, 1H), 7.49-7.56 (m, 1H), 7.6 0 (d, J=8.9Hz, 1H), 7.83 (dd, J=8.9, 2.5Hz, 1H), 8.33 (d, J=2.5Hz, 1H), 13.80 (s, 1H).

[0236] Example 46. Synthesis of 2-(3-fluorophenyl)-3-carboxy-6-ol-(4H)-4-benzopyrone

[0237] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 3-fluorobenzoyl chloride (0.032 m, 0.26 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (3 mL) for 1 hour, stirred in toluene (6 mL) for 24 hours, and then stirred in trifluoroacetic acid (3 mL) and dichloromethane (3 mL) for 1 hour to obtain 44.9 mg (71.3%) of the final target compound 2-(3-fluorophenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0238] mp222~223℃. 1 H NMR (300MHz, CDCl3): δ7.32-7.38 (m, 2H), 7.44 (d, J=7.8Hz, 1H), 7.48-7.55 (m.2H), 7.97 (dd, J=9.7, 2.3Hz, 1H), 8.50 (d, J=2.3Hz, 1H), 13.85 (s, 1H).

[0239] Example 47. Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0240] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3,5-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, stirred in toluene (9 mL) for 7 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 92.2 mg (75.0%) of the final target compound 2-(3,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0241] mp243~244℃. 1H NMR (300MHz, CDCl3): δ2.53 (s, 3H), 7.01-7.06 (m, 1H), 7.26-7.33 (m, 2H), 7.42-7.47 (m.1H), 7.67 (d, J=7.0Hz, 1H), 8.13 (d, J=7.9Hz, 1H).

[0242] Example 48. Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0243] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3,5-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, stirred in toluene (9 mL) for 7 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 77.3 mg (62.9%) of the final target compound 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0244] mp220~222℃. 1 H NMR (300MHz, CDCl3): δ2.65 (s, 3H), 7.07-7.15 (m, 1H), 7.18-7.26 (m, 2H), 7.50 (d, J=8.2Hz, 2H), 8.31 (d, J=8.2Hz, 1H), 14.34 (s, 1H).

[0245] Example 49. Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0246] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (200 mg, 0.40 mml), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3,5-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, and then stirred in toluene (9 mL) for 10 hours. Then, the mixture was stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 75.7 mg (61.5%) of the final target compound 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0247] mp238~240℃. 1 H NMR (300MHz, CDCl3): δ2.63 (s, 3H), 7.07-7.15 (m, 1H), 7.20-7.34 (m, 2H), 7. 59 (d, J=8.6Hz, 1H), 7.77 (dd, J=8.6, 2.1Hz, 1H), 8.21 (s, 1H), 14.12 (s, 1H).

[0248] Example 50. Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone

[0249] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 3,5-difluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 10 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 99.0 mg (78.6%) of the final target compound 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0250] mp207~209℃. 1 H NMR (300MHz, CDCl3): δ7.09-7.17 (m, 1H), 7.20-7.12 (m, 2H), 7.66 (d, J=8.9Hz, 1H), 7.91 (dd, J=8.9, 2.5Hz, 1H), 8.40 (d, J=2.5Hz, 1H), 14.00 (s, 1H).

[0251] Example 51. Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-6-(4H)-4-benzopyrone

[0252] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 3,5-difluorobenzoyl chloride (0.066 mL, 0.52 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 10 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 91.3 mg (69.2%) of the final target compound 2-(3,5-difluorophenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0253] mp216~218℃. 1 H NMR (300MHz, CDCl3): δ7.01-7.08 (m, 1H), 7.14-7.18 (m, 2H), 7.51 (d, J=8.9Hz, 1H), 7.97 (dd, J=8.9, 2.3Hz, 1H), 8.48 (d, J=2.3Hz, 1H), 13.60 (s, 1H).

[0254] Example 52. Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0255] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.3-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 68.0 mg (55.3%) of the final target compound 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0256] mp167-169℃. 1 H NMR (300MHz, CDCl3): δ2.51 (s, 3H), 7.26-7.31 (m, 2H), 7.36-7.43 (m, 1H), 7. 48-7.53 (m, 1H), 7.71 (d, J=7.3Hz, 1H), 8.20 (d, J=7.9Hz, 1H), 14.21 (s, 1H).

[0257] Example 53. Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0258] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.3-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, and then stirred in toluene (9 mL) for 15 hours. Then, the mixture was stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 78.0 mg (63.4%) of the final target compound 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0259] mp155~156℃. 1 H NMR (300MHz, CDCl3): δ2.57 (s, 3H), 7.17-7.27 (m, 3H), 7.42 (d, J=8.2Hz, 2H), 8.24 (d, J=8.2Hz, 1H), 14.20 (s, 1H).

[0260] Example 54. Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0261] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.3-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, and then stirred in toluene (9 mL) for 15 hours. Then, the mixture was stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 32.0 mg (26.0%) of the final target compound 2-(2,3-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0262] mp120~122℃. 1 H NMR (300MHz, CDCl3): δ2.55 (s, 3H), 7.24-7.30 (m, 2H), 7.35-7.43 (m, 1H), 7. 51 (d, J=8.6Hz, 1H), 7.69 (dd, J=8.6, 2.0Hz, 1H), 8.14 (s, 1H), 14.15 (s, 1H).

[0263] Example 55. Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone

[0264] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.3-difluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 26.0 mg (20.6%) of the final target compound 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone.

[0265] mp220℃ or above. 1 H NMR (300MHz, CDCl3): δ6.95-7.31 (m, 2H), 7.38-7.46 (m, 1H), 7.69 (dd, J=8.6, 1.8Hz, 1H), 7.65 (d, J=1.8Hz, 1H), 8.32 (d, J=8.6Hz, 1H), 13.85 (s, 1H).

[0266] Example 56. Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone

[0267] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.3-difluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 34.0 mg (27.0%) of the final target compound 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0268] mp120℃ or above. 1H NMR (300MHz, CDCl3): δ7.24-7.32 (m, 2H), 7.38-7.47 (m, 1H), 7.60 (d, J=8.9Hz, 1H), 7.84 (dd, J=8.9, 2.5Hz, 1H), 8.35 (d, J=2.5Hz, 1H), 13.81 (s, 1H).

[0269] Example 57. Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-6-ol-(4H)-4-benzopyrone

[0270] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 3,5-difluorobenzoyl chloride (0.066 mL, 0.52 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour and 30 minutes, and then stirred in toluene (9 mL) for 15 hours. Then, the mixture was stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 90.0 mg (68.2%) of the final target compound 2-(2,3-difluorophenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0271] mp120℃ or above. 1 H NMR (300MHz, CDCl3): δ7.17-7.53 (m, 3H), 7.61 (dd, J=8.8, 2.3Hz, 1H), 7.91-7.98 (m, 1H), 8.43 (d, J=2.3Hz, 1H), 11.80 (s, 1H).

[0272] Example 58. Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0273] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.5-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 104.5 mg (85.0%) of the final target compound 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0274] mp170~172℃. 1 H NMR (300MHz, CDCl3): δ2.54 (s, 3H), 7.20-7.31 (m, 3H), 7.51 (dd, J=7.6, 7.6Hz, 1H), 7.73 (d, J=7.6Hz, 1H), 8.21 (d, J=7.6Hz, 1H), 14.19 (s, 1H).

[0275] Example 59. Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0276] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.5-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 84.9 mg (69.0%) of the final target compound 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0277] mp156~158℃. 1 H NMR (300MHz, CDCl3): δ2.59 (s, 3H), 7.15-7.29 (m, 3H), 7.43 (d, J=8.0Hz, 2H), 8.12 (d, J=8.0Hz, 1H), 14.21 (s, 1H).

[0278] Example 60. Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0279] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.5-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 82.3 mg (66.9%) of the final target compound 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0280] mp120℃ or above. 1 H NMR (300MHz, CDCl3): δ2.57 (s, 3H), 7.15-7.30 (m, 3H), 7.52 (d, J=8.6Hz, 1H), 7.70 (dd, J=8.6, 1.9Hz, 1H), 8.15 (s, 1H), 14.17 (s, 1H).

[0281] Example 61. Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone

[0282] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.5-difluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 37.6 mg (29.8%) of the final target compound 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyrone.

[0283] mp147~150℃. 1 H NMR (300MHz, CDCl3): δ7.26-7.43 (m, 3H), 7.69 (dd, J=8.6, 1.8Hz, 1H), 7.75 (d, J=1.8Hz, 1H), 8.41 (d, J=8.6Hz, 1H), 13.94 (s, 1H).

[0284] Example 62. Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone

[0285] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.5-difluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 108.8 mg (86.4%) of the final target compound 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0286] mp168~170℃. 1 H NMR (300MHz, CDCl3): δ7.16-7.33 (m, 3H), 7.60 (d, J=8.9Hz, 1H), 7.84 (dd, J=8.9, 2.5Hz, 1H), 8.34 (d, J=2.5Hz, 1H), 13.77 (s, 1H).

[0287] Example 63. Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-6-ol-(4H)-4-benzopyrone

[0288] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 2,5-difluorobenzoyl chloride (0.066 mL, 0.52 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 15 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 65.2 mg (49.4%) of the final target compound 2-(2,5-difluorophenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0289] mp152~153℃. 1 H NMR (300MHz, CDCl3): δ7.16-7.32 (m, 3H), 7.53 (d, J=8.9Hz, 1H), 7.98 (dd, J=8.9, 2.3Hz, 1H), 8.50 (d, J=2.3Hz, 1H), 13.77 (s, 1H).

[0290] Example 64. Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0291] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3.4-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 10 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 81 mg (66%) of the final target compound 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0292] mp203~204℃. 1 H NMR (300MHz, CDCl3): δ2.55 (s, 3H), 7.29-7.38 (m, 1H), 7.45-7.58 (m, 3H), 7.73 (d, J=6.7Hz, 1H), 8.20 (d, J=8.1Hz, 1H), 14.30 (s, 1H).

[0293] Example 65. Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0294] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3.4-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 10 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 47 mg (38%) of the final target compound 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0295] mp202~204℃. 1 H NMR (300MHz, CDCl3): δ7.30-7.36 (m, 1H), 7.43 (d, J=6.9Hz, 3H), 7.49-7.55 (m, 1H), 8.24 (d, J=8.7Hz, 1H), 14.30 (s, 1H).

[0296] Example 66. Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0297] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3.4-difluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 10 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 70.9 mg (57.6%) of the final target compound 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0298] mp222~223℃. 1 H NMR (300MHz, CDCl3): δ2.56 (s, 3H), 7.30-7.36 (m, 1H), 7.42-7.47 (m, 1H), 7.49-7.56 (m, 2H), 7.70 (dd, J=8.5, 1.8Hz, 1H), 8.14 (s, 1H), 14.20 (s, 1H).

[0299] Example 67. Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone

[0300] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 3,4-difluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 10 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 100.8 mg (80.0%) of the final target compound 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0301] mp195~198℃. 1 H NMR (300MHz, CDCl3): δ7.31-7.37 (m, 1H), 7.43-7.47 (m, 1H), 7.50-7.61 (m, 2H), 7.83 (dd, J=8.9, 2.4Hz, 1H), 8.32 (d, J=2.4Hz, 1H).

[0302] Example 68. Synthesis of 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone

[0303] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (9 mL) for 40 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 99 mg (81%) of the final target compound 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyrone.

[0304] mp217~219℃. 1 H NMR (300MHz, CDCl3): δ2.53 (s, 3H), 7.46-7.53 (m, 3H), 7.63 (dd, J=6.7, 2.0Hz, 2H), 7.70 (d, J=6.7Hz, 1H), 8.18 (d, J=8.0Hz, 1H), 14.35 (s, 1H).

[0305] Example 69. Synthesis of 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone

[0306] By the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (9 mL) for 70 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 105 mg (85%) of the final target compound 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyrone.

[0307] mp220~222℃. 1 H NMR (300MHz, CDCl3): δ2.56 (s, 3H), 7.40 (d, J=6.7Hz, 2H), 7.48 (dd, J=6.7, 2.0Hz, 2H), 7.60 (dd, J=6.7, 2.0Hz, 2H), 8.22 (d, J=8.6Hz, 1H), 14.35 (s, 1H).

[0308] Example 70. Synthesis of 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone

[0309] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (9 mL) for 60 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 57.0 mg (46.3%) of the final target compound 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyrone.

[0310] mp212~227℃. 1 H NMR (300MHz, CDCl3): δ2.54 (s, 3H), 7.49 (dd, J=8.6, 2.7Hz, 3H), 7.60 (dd, J=8.6, 1.8Hz, 2H), 7.67 (dd, J=8.6, 2.1Hz, 1H), 8.12 (s, 1H), 14.50 (s, 1H).

[0311] Example 71. Synthesis of 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone. Using the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 4-chlorobenzoyl chloride (0.072 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (9 mL) for 80 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 48.2 mg (38.3%) of the final target compound 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyrone.

[0312] mp227~228℃. 1 H NMR (300MHz, CDCl3): δ7.50 (d, J=8.5Hz,

[0313] 2H), 7.55-7.62 (m, 3H), 7.80 (dd, J=8.9, 2.5Hz, 1H), 8.30 (d, J=2.5Hz, 1H), 14.20 (s, 1H).

[0314] Example 72. Synthesis of 2-(4-chlorophenyl)-3-carboxy-6-odor-(4H)-4-benzopyrone

[0315] By the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphine compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 4-chlorobenzoyl chloride (0.066 mL, 0.52 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 1 hour, stirred in toluene (9 mL) for 40 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 61.4 mg (46.5%) of the final target compound 2-(4-chlorophenyl)-3-carboxy-6-stinky-(4H)-4-benzopyrone.

[0316] mp211~213℃. 1 H NMR (300MHz, CDCl3): δ7.47-7.50 (m, 3H), 7.73 (d, J=8.5Hz, 2H), 7.87 (dd, J=8.8, 2.3Hz, 1H), 8.39 (d, J=2.3Hz, 1H).

[0317] Example 73. Synthesis of 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone

[0318] By the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphine compound (200 mg, 0.40 mmol), diisopropylethylamine (0.140 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride (0.077 mL, 0.60 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 17 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 47.1 mg (38.9%) of the final target compound 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyrone.

[0319] mp212~213℃. 1 H NMR (300MHz, CDCl3): δ7.50 (d, J=8.6Hz,

[0320] 2H), 7.58-7.63 (m, 4H), 7.84-7.90 (m, 1H), 8.35 (dd, J=8.2, 1.7Hz, 1H), 14.35 (s, 1H).

[0321] Example 74. Synthesis of 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone

[0322] By the general synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphine compound (200 mg, 0.38 mmol), diisopropylethylamine (0.132 mL, 0.76 mmol, 2 eq), 4-chlorobenzoyl chloride (0.072 mL, 0.57 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (5 mg) were stirred in dichloromethane (4 mL) for 2 hours, stirred in toluene (9 mL) for 20 hours, and then stirred in trifluoroacetic acid (6 mL) and dichloromethane (6 mL) for 2 hours to obtain 30.8 mg (24.4%) of the final target compound 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyrone.

[0323] mp238~239℃. 1 H NMR (300MHz, CDCl3): δ4.02 (s, 3H), 7.34 (d, J=8.0Hz, 1H), 7.49-7.54 (m, 3H), 7.67 (d, J=8.5Hz, 2H), 7.88 (dd, J=8.0, 1.2Hz, 1H), 14.30 (s, 1H).

[0324] Experimental Example 1. Measurement of Tumor Necrosis Factor-Induced Apoptosis Inhibitory Activity of Synthesized 4-Benzopyrone Derivative Compounds

[0325] First, recombinant tumor necrosis factor was added to LM cells, which are mouse fibroblasts, to induce apoptosis, and a tumor necrosis factor-neutralization bioassay was established using this. Specifically, tumor necrosis factor (20 ng / ml) and various concentrations of the compounds synthesized in the examples (5×10 4 Cells / well), actinomycin D (0.5 μg / ml) was added as a sensitizer and cultured in a CO2 incubator for 24 hours, and then MTT measurement was performed. At this time, 10 μl of MTT (5 mg / ml stock solution) was added and reacted for 4 hours, then dissolved in dimethyl sulfoxide (DMSO) and the absorbance was measured at 570 nm. First, the tumor necrosis factor-targeted expected compound at a single concentration (50 μM or 10 μM) was measured for tumor necrosis factor apoptosis inhibition / neutralization. Second, the compound with an effective effect was treated with various concentrations of the compound and the IC was calculated. 50 The percentage inhibition of tumor necrosis factor (%inhibition of TNF) was calculated by the following formula:

[0326] TNF inhibition percentage = (OD value of TNF and compound treated groups - OD value of TNF treated group) / (OD value of TNF untreated group - OD value of TNF treated group) × 100.

[0327] IC was statistically analyzed using Prism 6 (GraphPad) 50 Value (IC 50 : 50% inhibition concentration, CC 50 : 50% cytotoxic concentration).

[0328] As shown in Tables 1 and 2 below, the cytotoxicity of tumor necrosis factor was inhibited by up to 100% when the cells were treated with the listed compounds, compared to the case of treating with tumor necrosis factor alone.

[0329] Table 1

[0330]

[0331]

[0332] Table 2

[0333]

[0334]

[0335]

[0336] Among them, the IC of the compound of Example 61 is 50 The value and cytotoxicity were the lowest, so we further studied the mechanism of action and activity of this compound. Figure 1 To show the extent of TNF-inhibition at various concentrations of representative compounds including Example 61.

[0337] Experimental Example 2. Measurement of the Inhibitory Activity of 4-Benzopyrone Derivatives Against Direct Binding of Tumor Necrosis Factor and Binding of Tumor Necrosis Factor-Etanercept

[0338] (1) Real-time binding of 4-benzopyrone derivatives to tumor necrosis factor using surface plasmon resonance (SPR) analysis

[0339] The binding kinetics of tumor necrosis factor and 4-benzopyrone derivative compounds were measured by surface plasmon resonance (SPR). First, after determining the appropriate buffer pH based on the results of pH screening (10mM acetate buffer, pH 4.0, 4.5, 5.0 and 5.5), the recombinant tumor necrosis factor was fixed on the CM5 chip (4000-5000RU). In order to correct the effect of dimethyl sulfoxide, a solvent correction standard was prepared, and dimethyl sulfoxide was added to HBS-EP+ buffer (GE) until it reached 5%. Subsequently, the 4-benzopyrone derivative compound was prepared according to the concentration and flowed into the chip (20μl / min, 500s), and the sensorgram results obtained by dissolution (500s) were analyzed by a dedicated program to calculate the affinity value (K D At this time, the running buffer was HBS-EP+ buffer (GE), the regeneration buffer was 10 mM glycine (pH 2.5), and the analysis instrument used was Biacore T200 (GE).

[0340] The results, such as Figures 2a to 2e As shown, the direct binding of tumor necrosis factor to the compound of Example 61 was measured using surface plasmon resonance measurement, and the binding affinity (K D ) is 1.439×10 -6 (M)( Figure 2a and Figure 2b ). It was confirmed that the compound of Example 61 does not bind to Etanercept ( Figure 2c ), while the compound of Example 30, which had almost no tumor necrosis factor neutralization effect, did not bind to tumor necrosis factor (Table 1, inhibition 7.4%) ( Figure 2d ).

[0341] (2) Surface plasmon resonance measurement of the inhibitory activity of 4-benzopyrone derivatives on the binding between tumor necrosis factor and etanercept

[0342] Surface plasmon resonance was used to measure the binding competition of etanercept and its derivatives, both TNF-inhibitory biopharmaceuticals, against TNF. After determining the appropriate buffer pH based on pH screening (10 mM acetate buffer, pH 4.0, 4.5, 5.0, and 5.5), recombinant TNF was immobilized on a CM5 chip (4000-5000 RU). To correct for the effects of dimethyl sulfoxide (DMSO), a solvent calibration standard was prepared by adding DMSO to 5% in phosphate-buffered saline (PBST) (1× PBS, pH 7.4, 0.05% Tween 20, 0.01% Triton X-100, and 5% DMSO). Sensorgrams were analyzed using a dedicated program after etanercept alone or mixed with the compounds was flowed onto the chip (20 μl / min, 300 s) and dissolved (700 s). Changes in RU values for the compound mixture samples relative to the biopharmaceutical alone control group were observed. At this time, the running buffer was phosphate-Tween buffer, the regeneration buffer was 10 mM glycine (pH 2.5), and the instrument was Biacore T200 (GE).

[0343] The results, such as Figure 2e As shown, the compound of Example 61 significantly inhibited the binding between tumor necrosis factor and etanercept, thereby demonstrating that the compound and etanercept compete with each other for binding to tumor necrosis factor, and the compound hinders the binding of tumor necrosis factor to the tumor necrosis factor receptor (etanercept) by binding to tumor necrosis factor.

[0344] Experimental Example 3. Analysis of TNF-cell binding and TNF-cell signaling inhibitory activities of 4-benzopyrone derivatives

[0345] (1) Measurement of the tumor necrosis factor-binding inhibitory activity of 4-benzopyrone derivatives on Raw264.7 cells using flow cytometry analysis

[0346] First, prepare macrophage Raw 264.7 cells (4×10 6Cells were treated with 10 μL of avidin-fluorescein isothiocyanate (FITC) reagent (10 μL / mL) of biotinylated TNF-α alone or mixed with a 4-benzopyrone derivative (800, 200, or 5 μM) and reacted in the dark for 30 minutes at 4°C. After washing with RDF1 buffer, cells were separated by flow cytometry (FACS) analysis (BD Canto). The R&D Systems Human TNF-α Biotinylated Fluorokine Flow Cytometry Kit (Cat#: NFTA0) was used for these experiments.

[0347] The results, such as Figure 3a shown, with the lowest IC 50 Compound Example 61, which has a high IC50 value (1.8 μM in Table 2), reduced target cell binding of tumor necrosis factor to the basal level in a concentration-dependent manner. Compound Example 51, which has a relatively high IC50 value (4.5 μM in Table 2), exhibited a significant degree of inhibitory activity against tumor necrosis factor-cell binding. Compound Example 30 (Table 1), which had almost no inhibitory activity against tumor necrosis factor cytotoxicity, did not inhibit tumor necrosis factor cell binding at all. This indicates that the inhibitory effect against tumor necrosis factor cytotoxicity is closely related to the inhibitory effect against tumor necrosis factor cell binding.

[0348] (2) Western blot analysis to measure the tumor necrosis factor-induced LM cell signaling inhibitory activity of 4-benzopyrone derivatives

[0349] First, LM cells were treated with tumor necrosis factor (TNF) alone (50 ng / ml) or a mixture of TNF and the compound of Example 61 (0 μM, 10 μM, 25 μM, and 50 μM) for 1 hour, then washed and prepared. Cytoplasmic and nuclear fractions were separated using NE-PER nuclear and cytoplasmic extraction reagents (Thermo Scientific, cat#78833). NF-κB p65 protein was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Anti-NF-κB p65 rabbit monoclonal antibody (Cell Signaling Technology, cat#D14E12) was used as the primary antibody, and goat anti-rabbit HRP-conjugated antibody (Invitrogen, cat#656120) was used as the secondary antibody. As Western blot control proteins (housekeeping proteins), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used in the cytoplasmic fraction, and lamin B1 was used in the nuclear fraction. The primary antibody for glyceraldehyde-3-phosphate dehydrogenase was an anti-GAPDH mouse monoclonal antibody (GenScript, cat#A01622), and the secondary antibody was a goat anti-mouse HRP-conjugated antibody (BETHYL laboratories, cat#A90-116P). The primary antibody for lamin B1 was an anti-lamin B1 rabbit monoclonal antibody (Cell Signaling Technology, cat#12586S), and the secondary antibody was an anti-rabbit HRP-conjugated antibody (Invitrogen, cat#656120).

[0350] The results, such as Figure 3b As shown, it was found that the translocation of NF-κB from the cytoplasm to the nucleus activated by treatment with tumor necrosis factor was almost completely inhibited by treatment with about 25 μM of the compound of Example 61.

[0351] In summary, Figure 3a to Figure 3b The results showed that the compound of Example 61 also inhibited tumor necrosis factor-based cell signaling by fundamentally blocking the cell binding of tumor necrosis factor.

[0352] Experimental Example 4. Analysis of the therapeutic effect of 4-benzopyrone derivative compounds on sepsis

[0353] (1) In vivo TNF neutralization measurement (TNF-induced sepsis)

[0354] In an in vivo mouse model, treatment with tumor necrosis factor (TNF) and the sensitizer D-galactosamine (D-galactosamine) leads to acute liver failure and induced lethality. To this end, BALB / c mice were orally administered with the compound of Example 61 (3.3 mpk or 16.5 mpk) and, 30 minutes later, IP-treated with a mixture of D-galactosamine (21 mg / mouse) and tumor necrosis factor (0.3 μg / mouse). Survival rates were recorded every 3 hours for up to 24 hours, and statistical analysis was performed using Prism 6 (GraphPad) using the Log-rank (Mantel-Cox) test (N=13 / group, **P<0.005, ***P<0.001). mpk, mg / kg). This confirmed the in vivo neutralizing activity of the compound against tumor necrosis factor binding in a tumor necrosis factor-induced lethality model.

[0355] The results, such as Figure 4a As shown, oral (PO) administration of the compound of Example 61 suppressed the death of mice caused by acute hepatotoxicity induced by D-galactosamine and tumor necrosis factor in a concentration-dependent manner (3.3, 16.5 mpk).

[0356] (2) Lipopolysaccharide (LPS)-induced sepsis model

[0357] A sepsis mouse model was induced by intraperitoneal injection of lipopolysaccharide (45 mg / kg; Sigma, E. coli 055:B5). Mouse survival was assessed by co-administering the compound of Example 61 (50 mg / kg) and LMT-28 (50 mg / kg) immediately after lipopolysaccharide injection. Survival rates were monitored every 24 hours for three days.

[0358] The results, such as Figure 4b As shown, the survival rate in the group treated with the compound of Example 61 in combination with LMT-28 was 100% compared to the LPS-alone-treated group which recorded a survival rate of 20% after 72 hours (N=5 / group, ***P<0.001).

[0359] Experimental Example 5. Analysis of the preventive or therapeutic effects of 4-benzopyrone derivatives on rheumatoid arthritis

[0360] (1) Rheumatoid arthritis preventive effect (tumor necrosis factor-overexpression mouse model)

[0361] Tumor necrosis factor-overexpressing C57BL / 6 mice are recombinant mice that overexpress human tumor necrosis factor, leading to age-related arthritis. Tumor necrosis factor-overexpressing mice were orally administered the compound of Example 61 (3.3 mpk or 33 mpk) three times per week from 8 to 24 weeks, and symptoms were measured and recorded from 7 to 24 weeks. Symptom scores were measured with a score of 1 = erythema or flexed foot, 2 = flexed foot and mild swelling, 3 = flexed foot and moderate swelling, 4 = flexed ankle and mild swelling, and 5 = flexed ankle with severe swelling (N = 4 / group, *P < 0.01, **P < 0.005, ***P < 0.001).

[0362] The results, such as Figure 5a As shown, the tumor necrosis factor-inhibitory compound inhibited the occurrence of rheumatoid arthritis caused by tumor necrosis factor in a concentration-dependent manner, showing significant efficacy even at a low dose of 3.3 mpk. Compared with the negative control, a significant preventive effect of rheumatoid arthritis was observed at a dose of 33 mpk.

[0363] (2) Therapeutic effect on rheumatoid arthritis (tumor necrosis factor-overexpression mouse model)

[0364] First, tumor necrosis factor-overexpressing mice were bred until their average arthritis score reached 8. Thus, mice with rheumatoid arthritis were orally administered etanercept (4.5 mpk), adalimumab (1.2 mpk), and the compound of Example 61 (25 mpk, 50 mpk, or 100 mpk) three times a week from 15 to 23 weeks, and symptoms were measured and recorded from 7 to 24 weeks (N = 5-6 / group, *P < 0.01, **P < 0.005, ***P < 0.001).

[0365] The results, such as Figure 5b As shown, the tumor necrosis factor-inhibiting compound exhibits concentration-dependent therapeutic efficacy against rheumatoid arthritis induced by tumor necrosis factor. Significant rheumatoid arthritis therapeutic effects were observed at all doses of 25 mpk, 50 mpk, and 100 mpk compared to the negative control group. Oral administration of the compound of Example 61 at doses of 50 mpk and 100 mpk was comparable in efficacy to the commercially available injectable biopharmaceuticals adalimumab and etanercept, respectively.

[0366] (3) Synergistic effect in the treatment of rheumatoid arthritis when combined with tofacitinib (CIA mouse model)

[0367] The CIA mouse model is a model of arthritis induced by collagen in DBA / 1 mice. To this end, in 8-week-old DBA / 1 mice, type II collagen and complete Freund's adjuvant (CFA) were mixed in a 1:1 ratio and injected intradermally (ID) at the base of the tail. Two weeks after the first immunization, type II collagen and incomplete Freund's adjuvant (IFA) were mixed in a 1:1 ratio and injected intradermally at the base of the tail. After the second immunization, the disease was measured twice a week and divided equally into groups with an average score of 4 points per group. After the first immunization, etanercept (4.5 mpk), adalimumab (1.2 mpk), and Example 61 compound (25 mpk, 50 mpk, or 100 mpk) were orally administered 3 times a week starting from day 35, and the symptoms were measured and recorded. Symptom score measures severity as 1 = inflammation and swelling of one toe, 2 = inflammation of more than one toe or mild swelling of the entire sole, 3 = severe swelling of the entire sole and swelling of the ankle, 4 = very severe inflammation of the entire foot or a bent and stiff foot (N = 7-9 / group, *P < 0.01, **P < 0.005, ***P < 0.001).

[0368] The results, such as Figure 5c As shown, tumor necrosis factor-inhibiting compounds exhibit significant therapeutic efficacy against rheumatoid arthritis induced by collagen injection. Significant rheumatoid arthritis therapeutic effects were observed at all doses of 25 mpk, 50 mpk, and 100 mpk compared to the negative control group. Tofacitinib (25 mpk), a commercially available oral Janus kinase (JAK) inhibitor, and the compound of Example 61 (25 mpk) exhibited comparable efficacy, and their efficacy was comparable to that of the injectable biopharmaceutical etanercept.

[0369] (4) Synergistic effect in the treatment of rheumatoid arthritis when combined with methotrexate (CIA mouse model)

[0370] In DBA / 1 mice, type II collagen and Freund's complete adjuvant were mixed at a 1:1 ratio and injected intradermally (ID) at the base of the tail. Two weeks after the first immunization, type II collagen and incomplete Freund's adjuvant (IFA) were mixed at a 1:1 ratio and injected intradermally at the base of the tail to establish a rheumatoid arthritis animal model. The mice prepared in this way were divided into three groups, namely, a positive control group (5 mpk methotrexate treatment group; 10 mice), an Example 61 compound alone treatment group (10 mpk methotrexate treatment group; 9 mice), a methotrexate and Example 61 compound combined treatment group (5 mpk and 10 mpk respectively; 9 mice) and a vehicle treatment group (0.05% CMC diluted in distilled water treatment group; 15 mice). Each drug was administered intraperitoneally or orally three times a week (License #2016-018-02) at the time point when symptoms first appeared (25 days after the first immunization), and the Example 61 compound was administered orally once a day.

[0371] The severity of arthritis was determined by confirming the average arthritis score on the forefoot and hindfoot twice a week from day 0 to day 73 after the first immunization according to the following standard score: 0 = normal foot, 1 = inflammation and swelling of one toe, 2 = inflammation and swelling of more than one toe but not all toes, or mild swelling of all toes, 3 = inflammation and swelling of all toes, and 4 = severe inflammation and swelling or occlusion of the foot.

[0372] The results, such as Figure 8 As shown, when the compound of Example 61 alone or methotrexate alone was used, an arthritis therapeutic effect was also exhibited, but when both substances were used together, a significantly superior arthritis therapeutic effect was exhibited, thus confirming a significant synergistic effect.

[0373] Experimental Example 6. Analysis of the therapeutic effect of inflammatory bowel disease (IBD) based on 4-benzopyrone derivative compounds

[0374] Oral administration of dextran sulfate sodium induces inflammatory bowel disease in mice. Seven-week-old C57BL / 6 mice were induced with dextran sulfate sodium (2.5% for 6 days) and simultaneously orally administered with the compound of Example 61 (100 mpk) and metformin (100 mpk). After 9 days, colon length was measured in each treatment group to statistically analyze the drug's therapeutic effect on inflammatory bowel disease (N = 5 / group, *P < 0.05, mean ± standard deviation (SEM)).

[0375] The results, such as Figure 6As shown, in in vivo / in vitro experiments using the compound of Example 61, after confirming the tumor necrosis factor inhibitory efficacy, the efficacy on inflammatory bowel disease was analyzed. The results confirmed that the reduction in large intestine length based on dextran sulfate sodium was significantly inhibited when the compound of Example 61 and metformin were administered in combination.

[0376] Experimental Example 7. Analysis of the Effect of 4-Benzopyrone Derivative Compounds on Sepsis-Induced Acute Kidney Injury

[0377] Mice (male, C57 / BL6, 12-14 weeks old, 25-30 g, N=5) underwent cecal ligation and puncture (CLP) or a sham surgery and were maintained for 48 hours. Example 61 compound (50 mpk) was administered intraperitoneally (IP) directly after CLP. Serum urea nitrogen (BUN) and creatinine were analyzed 48 hours later to measure renal function.

[0378] The results, such as Figure 7 As shown in Figure 2, the incidence of acute kidney injury (AKI) 48 hours after cecal ligation and puncture surgery was approximately 75%. In contrast, in the compound-treated groups, there was no significant increase in kidney injury markers or a slight increase.

[0379] While specific portions of the present invention have been described above, it will be apparent to those skilled in the art that these specific descriptions are merely exemplary embodiments and are not intended to limit the scope of the present invention. The substantive scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Use of a composition in the preparation of a medicament for preventing or treating a disease caused by overexpression of tumor necrosis factor, characterized in that: The tumor necrosis factor-overexpressing disease is rheumatoid arthritis, and the composition comprises 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-chromenone or a pharmaceutically acceptable salt thereof.

2. Use of a composition in the preparation of a medicament for preventing or treating a disease caused by overexpression of tumor necrosis factor, characterized in that: The composition comprises 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-chromenone or a pharmaceutically acceptable salt thereof and a drug; and the tumor necrosis factor-overexpressing disease is rheumatoid arthritis.

3. Use of the composition according to claim 2 in the preparation of a medicament for preventing or treating a disease caused by overexpression of tumor necrosis factor, characterized in that: The drug is selected from methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, bucillamine, cyclosporine, tacrolimus, azathioprine, cyclophosphamide, mizoribine, penicillamine, oral preparations, antimalarial agents, 6-mercaptopurine, indomethacin, naproxen, sulindac, diclofenac sodium, aceclofenac, mefenamic acid, aspirin, fenoprofen, salsalate, piroxicam, etodolac, flurbiprofen, ibuprofen, loxoprofen, nabumetone, lonazolac, meloxicam, fenbufen, ketorolac tromethamine, indoibuprofen, ketoprofen, suprofen, carprofen, tiaprofenic acid, flufenamic acid, ebselen, felbinac, tolmetin, flunixin, celecoxib, rofecoxib, hydrocortisone, cortisone, prednisolone, methylprednisolone Dragon, triamcinolone acetonide, betamethasone, dexamethasone, fludrocortisone, budesonide, 5-aminosalicylate, 6-thioguanine, cytarabine, 5-fluorouracil, dacarbazine, nitrogen mustard, thiotepa, chlorambucil, melphalan, carmustine, lomustine, busulfan, sestrin2, withaferin A, celastrol, quercetin, luteolin, curcumin, metformin, dibromomannitol, GR270773, pentoxifylline, N-acetylcysteine, melatonin, resveratrol, mesilamine, single-chain fatty acids, glutamine, gemfibrozil, retinoic acid, hydroxyurea sulfate, trihydroxyisoflavones, deoxykaempferol, kaempferol, gingerol, caffeic acid, anthocyanins, cryptotanshinone, deguelin, delphinidin, equol, fisetin, Myricetin, proanthocyanidin B2, metronidazole, ciprofloxacin, niclosamide, thiabendazole, imipenem-cilastine sodium, fluoroquinolones, tofacitinib, glibenclamide, rolipram, doxycycline, VX-166, zVAD, L-97-1, ISO-1, tauroursodeoxycholic acid, HK-156, A-285222, CP-0127, Bis-N-norgliovictin, aurin tricarboxylic acid, chloramidine, ouabain, terazosin, prazosin, tranilast, apremilast, monobenzone, phenazopyridine, 546C88, NOX-100, gabexate mesylate, ulinastatin, somatostatin, octreotide, IKK inhibitors, caspase inhibitors, TAK-242, erithidone Tolan, ki16425, camptothecin, caffeic acid phenethyl ester, sulforaphane, Tim-3, BN-52021, BB-882, TCV-309, CT-400, ethyl pyruvate, hemin, CORM-2, tanshinone IIA sulfonate, nicotine, EGCG, isorhamnetin-3-o-galactoside, polygonum multiflorum, catechin, carbenoxolone, glabridin, emodin-6-ObD-glucoside, verbascoside, forsythiaside B, rosmarinic acid, chlorogenic acid, inflachromene, cilostazol, clopidogrel, sarpogrelate, drotrecoside α, carbamazepine, chloroquine, anakinra, tocilizumab, LMT-28, 1-(3-dimethylaminopropyl)-3-ethylurea,gp130Fc, beta-arrestin 2, interleukin-30, diacerein, secukinumab, ustekinumab, ixekizumab, thalidomide, adalimumab, infliximab, pravastatin, atorvastatin, rosuvastatin, simvastatin, losartan, telmisartan, hydrochlorothiazide, furosemide, propranolol, metoprolol, captopril, amlodipine, clonidine, methyldopa, minoxidil, streptozotocin, mitomycin, cisplatin, daunorubicin, doxorubicin, dactinomycin, bleomycin, mithramycin, anthramycin, calicheamicin, dukatomycin, paclitaxel, docetaxel, cyclin B, gramicidin D, ethyl bromide, emetine, mitomycin, etoposide, teniposide, vincristine, The group consisting of vinblastine, colchicine, dihydroxyanthraquinone, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, procaine, tetracaine, lidocaine, propranolol, tamoxifen, bazedoxifene, puromycin, anetrolol, nivolumab, pembrolizumab, ipilimumab, atezolizumab, α-galactosylceramide, SRT3025, DTA-1, interleukin-7, interleukin-2, interleukin-15, CXCL1, all-trans retinoic acid, gemcitabine, carboplatin, NCX-4016, CDDO-Me, sunitinib, zoledronic acid, astragalus polysaccharide, rituximab, imuran, abatacept, GW9662, rosiglitazone, Y-27632 and alefacept.

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