Novel benzofuranylhydroxyphenylmethanone derivative compounds or pharmaceutically acceptable salts thereof

Abstract

The present invention provides a pharmaceutical composition for inhibiting HSP47, which contains a benzofuranylhydroxyphenylmethanone derivative compound having a specific chemical structure or a pharma- ceutical acceptable salt thereof, and a method for producing the same. The benzofuranylhydroxyphenylmethanone derivative compound contained in the pharmaceutical composition for inhibiting HSP47 according to the present invention can be usefully used in the fields of medicine and pharmacy for inhibiting HSP47, such as for the prevention or treatment of fibrosis, inflammatory diseases, and cancer.

Description

[Technical Field]

[0001] The present invention relates to novel benzofuranylhydroxyphenylmethanone derivative compounds, and more particularly to pharmaceutical compositions for HSP47 inhibition containing benzofuranylhydroxyphenylmethanone derivatives and methods for producing the same. [Background technology]

[0002] HSP47 (Heat shock protein 47) is a stress-induced protein present in the endoplasmic reticulum that acts as a chaperone protein for the formation of the three-dimensional structure of collagen and its extracellular secretion. HSP47 expression has been reported to increase in various tissue fibrosis conditions, including hepatic sclerosis, pulmonary fibrosis, keloids, hypertrophic scars, and glomerulosclerosis. According to the literature, inhibiting the HSP47 protein suppresses collagen secretion in collagen-producing cells. Furthermore, inhibiting HSP47 protein has been reported to induce cell death in collagen-producing cells (Ito S et al., 2017). These results suggest that inhibiting the HSP47 protein is an effective and specific therapeutic target in fibrosis prevention therapy.

[0003] Fibrosis, or fibrosis, refers to the abnormal accumulation of collagen due to damage or inflammation that alters the structure and function of various tissues. Regardless of the location of fibrosis, many etiologies involve an excessive accumulation of collagen that replaces normal tissue. Progressive fibrosis in the liver, lungs, or skin is a disease with unmet medical needs for which there are currently no specific treatments.

[0004] It has been reported that the function of HSP47 is not limited to collagen production, and it also promotes the expression of MCP-1 (Monocyte chemoattractant protein-1), which is one of the inflammatory mediator proteins, in bladder cancer cells that are cancer cells, thereby promoting inflammation and neovascularization (Ma Wenlong et al., 2021).

[0005] Furthermore, it has been reported that HSP47 is also expressed in cancer cells, and it was reported that an increase in the expression level of HSP47 facilitates metastasis of many cancer cells and increases mortality regardless of the presence or absence of collagen expression. It has also been reported that suppressing the expression of HSP47 by a genetic method inhibits cancer progression (Parveen A et al., 2020).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

[0008] The problem that this invention aims to solve is to recognize that there is a close relationship between HSP47 and excessive collagen accumulation, and to provide an HSP47 inhibitor that has therapeutic efficacy against diseases such as fibrosis and cancer by suppressing the HSP47 protein.

[0009] Furthermore, the problem that the present invention aims to solve is to provide a pharmaceutical composition for the prevention or treatment of HSP47-related diseases, which contains the benzofuranylhydroxyphenylmethanone derivative compound as an active ingredient.

[0010] Furthermore, the problem that the present invention aims to solve is to provide a method for preventing or treating HSP47-related diseases using the benzofuranylhydroxyphenylmethanone derivative compound or a pharmaceutically acceptable salt thereof.

[0011] Furthermore, the problem that the present invention aims to solve is to provide the use of the benzofuranylhydroxyphenylmethanone derivative compound, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of HSP47-related diseases.

[0012] Furthermore, the problem that the present invention aims to solve is to provide a method for producing the benzofuranylhydroxyphenylmethanone derivative compound or a pharmaceutically acceptable salt thereof.

[0013] On the other hand, the problems that the present invention aims to solve are not limited to those described above, and other technical problems not mentioned will be clearly understood by those with ordinary skill in the art to which the present invention belongs from the following description. [Means for solving the problem]

[0014] To solve the above problems, according to one aspect of the present invention, a benzofuranylhydroxyphenylmethanone derivative compound represented by the following chemical formula I, or a pharmaceutically acceptable salt thereof, is provided.

[0015] [ka]

[0016] In the above formula, R 1 and R 2 It is a halogen, R 3 is hydrogen or C1-C3 alkyl, R a , R b and R d These are independently hydrogen, C1-C3 alkyl, or halogen. R c These are hydrogen C1-C3 alkyl, halogen, or C1-C3 haloalkyl.

[0017] In another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of HSP47-related diseases is provided, comprising a benzofuranylhydroxyphenylmethanone derivative compound represented by the chemical formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0018] In another aspect of the present invention, a method for preventing or treating HSP47-related diseases is provided using a benzofuranylhydroxyphenylmethanone derivative compound represented by chemical formula I, or a pharmaceutically acceptable salt thereof.

[0019] In another aspect of the present invention, a benzofuranylhydroxyphenylmethanone derivative compound represented by chemical formula I, or a pharmaceutically acceptable salt thereof, is provided for use in the prevention or treatment of HSP47-related diseases.

[0020] A further aspect of the present invention provides a method for producing a benzofuranylhydroxyphenylmethanone derivative compound represented by the following chemical formula I, or a pharmaceutically acceptable salt thereof, comprising the steps of: producing a compound of the following chemical formula I-2 from a compound of the following chemical formula I-1 by a nucleophilic substitution reaction; reducing the obtained compound of chemical formula I-2 to produce a compound of the following chemical formula I-3; reacting the obtained compound of chemical formula I-3 with 4-anisoyl chloride to produce a compound of the following chemical formula I-4; removing the methyl methoxy from the obtained compound of chemical formula I-4 to produce a compound of the following chemical formula I-5 having a hydroxy substituent; and obtaining a compound of the following chemical formula I from the obtained compound of chemical formula I-5.

[0021] [ka]

[0022] In the aforementioned Chemical Formula I, Chemical Formula I-1, Chemical Formula I-2, Chemical Formula I-3, Chemical Formula I-4 and Chemical Formula I-5, R 1 , R 2 , R 3 , R a , R b , R c and R d are the same as the definitions described above. [Effects of the Invention]

[0023] According to the present invention, it has been clarified that the benzofuranyl hydroxyphenyl methanone derivative compound represented by Chemical Formula I exhibits HSP47 inhibitory effects such as suppressing collagen accumulation in liver, lung, kidney and skin tissues, and killing cells that overproduce collagen in pathological conditions, and thus can be used for HSP47 inhibitory applications such as prevention or treatment of fibrosis and cancer.

[0024] Therefore, the benzofuranyl hydroxyphenyl methanone derivative compound of the present invention can be usefully used as an HSP47 inhibitory application for the prevention or treatment of fibrosis and cancer in the fields of medicine and pharmaceuticals.

[0025] It should be understood that the effects of the present invention are not limited to the above-described effects, but include all effects that can be inferred from the configuration of the invention described in the detailed description of the present invention or the appended claims. [Brief Description of the Drawings]

[0026] [Figure 1] This is the result of fibrosis inhibition in KEL FIB skin fibroblasts of the test substance (Compound 9). [Mode for Carrying Out the Invention]

[0027] The present invention provides a benzofuranyl hydroxyphenyl methanone derivative compound represented by the following Chemical Formula I, or a pharmaceutically acceptable salt thereof.

[0028] [Chemical Formula]

[0029] In the above formula, R 1 and R 2 It is a halogen, R 3 is hydrogen or C1-C3 alkyl, R a , R b and R d These are independently hydrogen, C1-C3 alkyl, or halogen. R c These are hydrogen C1-C3 alkyl, halogen, or C1-C3 haloalkyl.

[0030] In one example, the R 1 and R 2 This could be bromo or iodine.

[0031] In one example, the R 3 This substituent may be selected from the group consisting of hydrogen, methyl, and ethyl.

[0032] In one example, the R a This can be a substituent selected from the group consisting of hydrogen, methyl, fluoro, and chloro.

[0033] In one example, the R b This substituent may be selected from the group consisting of hydrogen, methyl, ethyl, and bromo.

[0034] In one example, the R c This can be a substituent selected from the group consisting of hydrogen, methyl, ethyl, trifluoromethyl, chloro, and bromo.

[0035] In one example, the R d This can be a substituent selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, and bromo.

[0036] In the present invention, preferred examples of benzofuranylhydroxyphenylmethanone derivative compounds represented by the chemical formula I are as follows:

[0037] (4-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2,6-diethylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-methylbenzofuran-3-yl)methanone, (7-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (7-bromo-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-fluorobenzofuran-3-yl)methanone, (2-ethyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (5-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (2-ethyl-6-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (6-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (6-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (2-ethyl-7-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (7-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (7-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, Benzofuran-3-yl(3,5-dibromo-4-hydroxyphenyl)methanone, (6-bromo-2-methylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (5-bromo-2-methylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (6-chloro-2-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2,5-diethylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2,7-diethylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hyde-roxcypenyl)(2-ethyl-6-(trifluoromethyl)benzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-4-methylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-4-fluorobenzofuran-3-yl)methanone.

[0038] In this specification, unless otherwise specified, the following definitions apply to compounds of chemical formula I.

[0039] As used herein, the term "alkyl" refers to a linear or branched saturated hydrocarbon, preferably a C1-C10 alkyl group. For example, the alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0040] As used herein, the terms "halogen" or "halo" refer to fluorine / fluoro(F), chlorine(Cl), bromine(Br), or iodine(I).

[0041] As used in this application, “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). The group non-limitingly includes chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutetyl.

[0042] Since the compound represented by chemical formula I according to the present invention can be used in the form of a prodrug, hydrate, solvide, and pharmaceutically acceptable salt to enhance bioavailability or increase solubility, the prodrug, hydrate, solvide, and pharmaceutically acceptable salt also fall within the scope of the present invention.

[0043] The term "prodrug" refers to a substance that is converted into a parent drug in the body. Prodrugs are often used because, in some cases, they are easier to administer than parent drugs. For example, they may become bioavailable through oral administration, whereas the parent drug may not. Also, prodrugs may have improved solubility in pharmaceutical compositions than parent drugs. For example, a prodrug may be a biohydrolyzable ester of a compound according to the present invention and its pharmaceutically acceptable salt. Yet another example of a prodrug may be a short peptide (polyamino acid) to which an acid group is bound, and the peptide is converted by metabolism to reveal its active site.

[0044] The term "hydrate" refers to a compound or salt of the present invention that contains a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces.

[0045] The term "solvate" refers to a compound or salt thereof of the present invention that contains a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. Preferred solvents include volatile, non-toxic, and / or suitable for administration to humans.

[0046] The term "isomer" refers to a compound or salt of the present invention that has the same chemical or molecular formula but is structurally or stereochemically different. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included in the scope of the present invention.

[0047] The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not impair the biological activity and properties of the compound without inducing serious irritation in the organism to which the compound is administered. Such pharmaceutically acceptable salts include acid addition salts formed by acids that form nontoxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic carboxylic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. For example, pharmaceutically acceptable carboxylates include metal salts or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, and guanidine, and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine. The compound of chemical formula I according to the present invention can be converted to its salt by conventional methods.

[0048] Furthermore, the present invention provides a method for producing the chemical formula I, and includes the following steps.

[0049] (1) The step of producing the compound of chemical formula I-2 below from the compound of chemical formula I-1 below by a nucleophilic substitution reaction. This step involves the reaction of the compound of chemical formula I-1 below with chloroacetone in the presence of potassium carbonate to synthesize a benzofuran ring compound. The solvent used at this time may be a solvent commonly used in nucleophilic substitution reactions, such as acetone, tetrahydrofuran, or N,N-dimethylformamide. By carrying out the reaction at an appropriate temperature (e.g., 70°C) for an appropriate reaction time (e.g., about 6 hours), the compound of chemical formula I-2 can be obtained.

[0050] (2) The step of reducing the compound of chemical formula I-2 obtained above to produce the compound of chemical formula I-3 shown below. This step involves reducing the ketone of the compound of chemical formula I-2 obtained above using hydrazine and potassium hydroxide. The compound of chemical formula I-2 obtained above is dissolved in diethylene glycol, hydrazine is added, and then potassium hydroxide is gradually added at a high temperature (e.g., about 150°C) and the reaction is carried out for an appropriate reaction time (e.g., about 1 hour) to obtain the compound of chemical formula I-3.

[0051] (3) The step of reacting the compound of chemical formula I-3 obtained above with 4-anisoyl chloride to produce the compound of chemical formula I-4 shown below. This step is a Friedel-Crafts acylation reaction in which the benzofuran compound of chemical formula I-3 obtained above is reacted with 4-anisoyl chloride (4-methoxybenzoyl chloride) and a Lewis acid, tin tetrachloride (SnCl4), to obtain the compound of chemical formula I-4 shown below. The solvent used at this time can be a solvent that is normally used in Friedel-Crafts acylation reactions, such as dichloromethane or carbon disulfide.

[0052] (4) The step of removing the methyl methoxy from the compound of chemical formula I-4 obtained above to produce the compound of chemical formula I-5 below which has a hydroxy substituent. This step may be 1) a demethylation reaction using sodium ethanethiolate, or 2) a demethylation reaction using boron tribromide. The reaction using sodium ethanethiolate in 1) can be carried out mainly in N,N-dimethylformamide solvent, but is not limited to this. The second method, the demethylation reaction using boron tribromide in 2) can be carried out mainly in dichloromethane solvent, but is not limited to this.

[0053] (5) Steps to obtain the compound of chemical formula I below from the compound of chemical formula I-5 obtained above. This step involves the introduction of two bromogroups or iodine groups into the compound of chemical formula I-5 obtained above. 1) The reaction to introduce bromogroups is carried out by adding brometh or N-bromosuccinimide to the compound of chemical formula I-5 below. The solvent used at this time is a solvent commonly used in bromethionization reactions, such as dichloromethane or acetone. 2) The reaction to introduce iodine groups is obtained by reacting the compound of chemical formula I-5 below with iodine and silver nitrate. The solvent used at this time is mainly an alcohol solvent such as ethanol, but is not limited to this.

[0054] [ka]

[0055] In the aforementioned chemical formulas I, I-1, I-2, I-3, I-4, and I-5, R 1 , R 2 , R 3 , R a , R b , R c and R d This is the same as what was defined above.

[0056] The methods for producing the compound of chemical formula I of the present invention illustrate reaction formulas 1 to 24 in the examples, but these methods for producing reaction formulas 1 to 24 do not limit the method for producing the compound of chemical formula I according to the present invention. The methods for producing reaction formulas 1 to 24 are merely illustrative and it is obvious that they can be easily modified by an ordinary person depending on the specific substituted compound.

[0057] Furthermore, the present invention provides a pharmaceutical composition for inhibiting HSP47, comprising a benzofuranylhydroxyphenylmethanone derivative compound represented by the chemical formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0058] Furthermore, the present invention provides a method for preventing or treating related diseases for the purpose of suppressing HSP47, comprising administering to a patient a therapeutic dose of a benzofuranylhydroxyphenylmethanone derivative compound represented by the chemical formula I, or a pharmaceutically acceptable salt thereof.

[0059] Furthermore, the present invention provides applications for using a benzofuranylhydroxyphenylmethanone derivative compound represented by the chemical formula I, or a pharmaceutically acceptable salt thereof, for the purpose of inhibiting HSP47.

[0060] In one embodiment, the HSP47 inhibitor may be for the prevention or treatment of fibrosis that can be achieved by inhibiting HSP47. In this case, the fibrosis may be one or more selected from the group consisting of hepatic sclerosis, pulmonary fibrosis, keloids, hypertrophic scars, and renal fibrosis (glomerulosclerosis).

[0061] In one embodiment, the HSP47 inhibitor may be for the prevention or treatment of cancer that can be achieved by inhibiting HSP47. In this case, the cancer may be one or more selected from the group consisting of breast cancer, colorectal cancer, and cancer-related fibrosis.

[0062] In one embodiment, the HSP47 inhibitor may be used for the treatment of inflammatory diseases by suppressing the secretion of pro-inflammatory substances, which can be achieved by inhibiting HSP47. In this case, the inflammatory disease may be an autoinflammatory disease or autoimmune disease related to an increase in MCP-1.

[0063] In one example, the inflammatory disease is preferably one or more selected from the group consisting of liver cancer, prostate cancer, melanoma, ovarian cancer, neuroinflammatory diseases, arteriosclerosis, organ transplantation, dermatitis, atopic dermatitis, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, pancreatitis, gastritis, psoriasis, nephropathy, myasthenia gravis, Crohn's disease, inflammatory bowel disease, colitis, gout, ankylosing spondylitis, lupus, fibromyalgia, rheumatoid arthritis, osteoarthritis, osteoporosis, hepatitis, cystitis, nephritis, Sjögren's syndrome, and multiple sclerosis, but is not limited to these.

[0064] As a result of evaluating whether the compound of the present invention can inhibit HSP47 activity, the EC27 of HSP47 50 The compound was found to exhibit HSP47 inhibitory activity at concentrations of 15.89–104.5 μM or at a compound concentration of 100 μM. Involved in the ability to suppress fibrosis in tissue cells, the compound showed inhibitory activity against fibrosis in lung epithelial cells and hepatic stellate cells, and was shown to suppress fibrosis in skin fibroblasts. Furthermore, in an animal model of hepatic fibrosis induction, the compound was found to be involved in disease symptoms due to fibrosis, reducing the levels of serum hyaluronic acid, a biomarker for hepatic fibrosis, and reducing collagen deposition due to fibrosis by decreasing the content of 4-hydroxyproline in liver tissue. In addition, histologically, the compound was shown to suppress fibrosis in liver tissue and significantly reduce the area of ​​hepatic fibrosis.

[0065] As a result of evaluating whether the compound of the present invention can suppress MCP-1 secretion, 50 The concentration ranged from 1.374 to 17.14 μM. This was related to the ability to suppress MCP-1 secretion in tissue cells, and the compound was shown to suppress MCP-1 secretion from hepatic stellate cells.

[0066] In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable diluent or carrier.

[0067] Specifically, the pharmaceutical compositions of the present invention may contain pharmaceutically acceptable carriers, each of which can be formulated by conventional methods into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, as well as topical preparations, suppositories, and sterile injection solutions. The pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. They also contain fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other diluents or excipients. Solid oral preparations include tablets, pills, powders, granules, and capsules, and such solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or lactose, gelatin, and may contain lubricants such as magnesium stearate and talc. Liquid oral preparations include suspensions, internal solutions, emulsions, and syrups, and may contain water, diluents such as liquid paraffin, wetting agents, sweeteners, fragrances, and preservatives. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories, and non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Possible suppository bases include witepsol, macrogol, tween 61, cocoa butter, lauric acid butter, and glycerol gelatin.

[0068] The dosage of the compound of chemical formula I contained in the pharmaceutical composition of the present invention will vary depending on the patient's condition and weight, the severity of the disease, the drug form, the route of administration, and the duration of administration, but can be appropriately selected by a person of ordinary skill in the relevant field. For example, the compound of chemical formula I can be administered at a rate of 0.0001 to 1000 mg / kg per day, preferably 0.01 to 1000 mg / kg, and this administration can be done once a day or in several divided doses. Furthermore, the pharmaceutical composition of the present invention may contain the compound of chemical formula I at a weight percentage of 0.001 to 90% of the total weight of the composition.

[0069] The pharmaceutical compositions of the present invention can be administered to mammals such as rets, mice, livestock, and humans via various routes, for example, by injection orally, intraperitoneally, rectally or intravenously, intramuscularly, subcutaneously, intrauterine dura mater, or intracerebral (intracerebroventricular).

[0070] The pharmaceutical compositions of the present invention may contain pharmaceutically acceptable carriers or diluents, each of which can be formulated by conventional methods into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, as well as topical preparations, suppositories, and sterile injection solutions. The pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. They may also contain fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other diluents or excipients. Solid oral preparations include tablets, pills, powders, granules, and capsules, and such solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or lactose, gelatin, and may contain lubricants such as magnesium stearate and talc. Liquid oral preparations include suspensions, internal solutions, emulsions, and syrups, and may contain water, diluents such as liquid paraffin, wetting agents, sweeteners, fragrances, and preservatives. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories, and non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Possible suppository bases include witepsol, macrogol, tween 61, cocoa butter, lauric acid butter, and glycerol gelatin.

[0071] The pharmaceutical compositions of the present invention can be administered to mammals such as livestock and humans via various routes, for example, orally, cutaneously, subcutaneously, intramuscularly, intravenously, intraperitoneally, intrauterine dura mater or intracerebroventricular injection, or topically. Accordingly, the compositions of the present invention can be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions. For oral administration, carriers such as lactose and corn starch, and lubricants such as magnesium stearate may be added. For oral capsules, lactose and / or dried corn starch may be used as diluents. If an aqueous suspension for oral administration is required, the active ingredient may be combined with an emulsifier and / or suspending agent. If necessary, specific sweeteners and / or flavorings may be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is usually prepared and the pH of the solution needs to be appropriately adjusted and buffered. For intravenous administration, the total concentration of the solute needs to be adjusted so that the formulation isotonic. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline solution with a pH of 7.4. The solution can be introduced into the patient's intramuscular blood flow by local injection.

[0072] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration of administration, and can be appropriately adjusted according to the patient. For example, the active ingredient can be administered at a rate of 0.0001 to 1000 mg / kg per day, preferably 0.01 to 100 mg / kg, and this administration can be done once a day or in several divided doses. Furthermore, the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% of the total weight of the composition.

[0073] The present invention will be described in more detail below with reference to examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

[0074] Example 1. (4-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone

[0075] [ka]

[0076] Step A: In a reaction flask containing 2 g of 2-hydroxy-4-chlorobenzaldehyde, 1.5 equivalents of potassium carbonate, and 20 mL of anhydrous acetone, 1.2 equivalents of chloroacetone were added dropwise for 10 minutes, and the reaction solution was stirred under reflux for 3 hours. After the reaction was complete, the solid was removed by filtration, and the filtered liquid was dried over anhydrous magnesium sulfate, filtered, concentrated, and separated by column chromatography to obtain 2-acetylbenzofuran 1-1 (1.99 g, 78% yield).

[0077] Step B: Compound 1-1 (1.99 g, 0.011 mol) was mixed with 6 equivalents of 80% hydrazine (monohydrate) and 48 mL of diethylene glycol. The mixture was stirred at 150°C for 30 minutes, and then 3 equivalents of potassium hydroxide were gradually added dropwise over 10 minutes. The reaction solution was stirred under reflux for 3 hours, then cooled to room temperature. After dilution with 100 mL of water, the mixture was extracted with ethyl acetate (120 mL x 3). The ethyl acetate layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the target compound 1-2 (1.3 g, 72%).

[0078] Step C: Compound 1-2 (1.3 g, 0.0081 mol) was dissolved in anhydrous CS2 (20 vol) and cooled to 0°C. Then, 1.5 equivalents of 4-methoxybenzoyl chloride were added and the mixture was stirred for 5 minutes. 1.5 equivalents of tin(IV) chloride were gradually added dropwise to the reaction solution over 10 minutes, followed by stirring at 0°C for 2 hours, and then stirring at room temperature for 22 hours. After the reaction was complete, the reaction solution was diluted with 200 mL of water and extracted with dichloromethane (90 mL x 2). The extracted organic layer was sequentially washed with 50 mL of 1N hydrochloric acid solution, 50 mL of 1N sodium hydroxide aqueous solution, and 50 mL of brine. After drying with anhydrous sodium sulfate and filtering, the filtrate was concentrated and separated by column chromatography to obtain the target compound 1-3 (1.98 g, 83%).

[0079] Step D: Compound 1-3 (1.98 g, 0.0067 mol) was dissolved in N,N-dimethylformamide (20 mL), and 2.5 equivalents of sodium ethanethiolate (NaSEt) were added at room temperature. The reaction solution was stirred at 100 °C for 2 hours. After the reaction was complete, 100 mL of aqueous ammonium chloride solution was gradually added to dilute the solution. After extraction with dichloromethane (100 mL x 2), the extract was washed with 80 mL of brine, the organic layer was dried over anhydrous sodium sulfate and filtered, then concentrated and separated by column chromatography to obtain the target compound 1-4 (1.68 g, 89%).

[0080] Step E: Compounds 1-4 (100 mg, 0.35 mmol) were dissolved in 6 mL of glacial acetic acid and 2 mL of water. Then, 2.2 equivalents of bromine, diluted in 1.5 mL of glacial acetic acid and 0.5 mL of water, were added dropwise for 15 minutes, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was concentrated and separated by column chromatography to obtain the target compound (1.86 mg, 55% yield).

[0081] 1 H NMR (DMSO-d6,400MHz) δ 7.90(s,3H), 7.65(d,J=7.9Hz,1H), 7.40-7.26(m,2H), 2.75-2.58(m,2H), 1.17(t,J=7.5Hz,3H).

[0082] MS(ESI,m / z):Exact mass calculated[M+H] + :456.88;found:456.9.

[0083] Example 2. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methylbenzofuran-3-yl)methanone

[0084] [ka]

[0085] Steps A to E: Compound 2 was obtained by a method similar to steps A to E of Example 1.

[0086] 1 H NMR (DMSO-d6,400 MHz) δ 7.80(s,2H), 7.45(d,J=8.2Hz,1H), 7.33-6.99(m,2H), 2.71(d,J=7.4Hz,2H), 2.30(s,3H), 1.26-1.09(m,3H). MS(ESI,m / z):Exact mass calculated[M+H] + :436.93;found:437.1.

[0087] Example 3. (3,5-dibromo-4-hydroxyphenyl)(2,6-diethylbenzofuran-3-yl)methanone

[0088] [ka]

[0089] Steps A to E: Compound 3 was obtained by a method similar to steps A to E of Example 1.

[0090] 1 H NMR(DMSO-d6,400MHz) δ 7.88(s,2H), 7.46(s,1H), 7.26(d,J=8.1Hz,1H), 7.10(dd,J=8.0,1.4Hz,1H), 2.78-2.72(m,2H), 2.68(q,J=7.6Hz,2H), 1.23-1.17(m,6H).

[0091] Example 4. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-methylbenzofuran-3-yl)methanone

[0092] [ka]

[0093] Steps A to E: Compound 4 was obtained by a method similar to steps A to E of Example 1.

[0094] 1 H NMR (DMSO-d6,400MHz)7.97(s,2H), 7.19(dd,J=7.4,1.6Hz,1H), 7.14-7.05(m ,2H), 6.30(s,1H), 2.91(q,J=7.6Hz,2H), 2.54(s,3H), 1.36(t,J=7.5Hz,3H).

[0095] Example 5. (7-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone

[0096] [ka]

[0097] Steps A to E: Compound 5 was obtained by a method similar to that of Steps A and E of Example 1.

[0098] 1 H NMR(DMSO-d6,400MHz) δ 7.92(s,2H), 7.42(dd,J=7.8,0.9Hz,1H), 7.36(dd,J=7.9,1.0Hz,1H), 7.25(t,J=7.8Hz,1H), 2.78(q,J=7.5Hz,2H), 1.23(t,J=7.5Hz,3H).

[0099] Example 6. (7-bromo-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone

[0100] [ka]

[0101] Steps A to E: Compound 6 was obtained by a method similar to that of Steps A and E of Example 1.

[0102] 1 H NMR (DMSO-d6,400MHz) 7.90(s,2H), 7.62(d,J=8.7Hz,1H), 7.58(d,J=2.0Hz,1H), 7.47(dd,J=8.7,2.1Hz,1H), 2.73(q,J=7.5Hz, 2H), 1.21(t,J=7.5Hz,3H).

[0103] Example 7. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-fluorobenzofuran-3-yl) methanone

[0104] [ka]

[0105] Steps A to E: Compound 7 was obtained by a method similar to steps A to E of Example 1.

[0106] 1 H NMR (DMSO-d6,400MHz) δ 7.93(s,2H), 7.59(dd,J=7.0,6.2Hz,2H), 7.53-7.47(m, 1H),2.77(q,J=7.5Hz,2H), 1.22(t,J=7.4Hz, 3H).

[0107] Example 8. (2-ethyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0108] [ka]

[0109] Steps A to D: Compound 8-4 was obtained by a method similar to that of Steps A to D in Example 1.

[0110] Step E: Compound 8-4 (100 mg, 0.35 mmol) was dissolved in 3 mL of methanol, 2.5 equivalents of silver nitrate were added, followed by 2.5 equivalents of iodine, and the mixture was stirred at room temperature for 20 hours. After the reaction was complete, the solid was filtered, and the filtrate was concentrated and separated by column chromatography to obtain the target compound 8 (121 mg, 64% yield).

[0111] 1 H NMR (DMSO-d6,400MHz) δ 8.07(s,2H), 7.48(d,J=8.4Hz,1H), 7.26-7.19(m,1H), 7.12(dd,J=8.3,1.6Hz,1H), 2.71(q,J=7.6Hz, 2H),1.21(t,J=7.5Hz,3H).

[0112] Example 9. (5-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0113] [ka]

[0114] Steps A to E: Compound 9 was obtained by a method similar to that of Steps A and E of Example 8.

[0115] 1 H NMR (DMSO-d6,400MHz) δ 8.15(s,2H), 7.64(d,J=1.6Hz,1H), 7.43-7.35(m,2H), 2.83(dt,J=7.7,6.6Hz,2H), 1.34(td,J=7.5,1.9Hz,3H).

[0116] Example 10. (2-ethyl-6-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0117] [ka]

[0118] Steps A to E: Compound 10 was obtained by a method similar to steps A to E of Example 8.

[0119] 1 1H NMR (DMSO-d6, 400MHz) δ. Exact mass calculated [M+H] + :532.9;found:532.9.

[0120] Example 11. (6-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0121] [ka]

[0122] Steps A to E: Compound 11 was obtained by a method similar to steps A to E of Example 8.

[0123] 1 H NMR(DMSO-d6,400MHz) δ 8.07(s,2H), 7.95(d,J=1.6Hz,1H), 7.43(dd,J=8.4,1.7Hz,1H), 7.34(d,J=8.4Hz,1H), 2.73(q,J=7.5Hz,2H), 1.22(t,J=7.5Hz,3H).

[0124] Example 12. (6-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl) methanone

[0125] [ka]

[0126] Steps A to E: Compound 12 was obtained by a method similar to steps A to E of Example 8.

[0127] 1H NMR(DMSO-d6,400MHz) δ 8.15(s,2H), 7.50(d,J=1.8Hz,1H), 7.35(d,J=8.5Hz,1H), 7.22(dd,J=8.5,1.8Hz,1H), 2.86(q,J=7.6Hz,2H), 1.34(t,J=7.5Hz,3H).

[0128] Example 13. (2-ethyl-7-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0129] [ka]

[0130] Steps A to E: Compound 13 was obtained by a method similar to steps A to E of Example 8.

[0131] 1 H NMR(DMSO-d6,400MHz) δ 8.17(s,2H), 7.21(d,J=7.4Hz,1H), 7.15-7.05(m,2H), 6.16(s,1H),2.94-2.85(m,2H), 2.54(s,3H), 1.36(t,J=7.5Hz,3H).

[0132] Example 14. (7-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0133] [ka]

[0134] Steps A to E: Compound 14 was obtained by a method similar to steps A to E of Example 8.

[0135] 1 H NMR (DMSO-d6,400MHz) δ 8.15(s,2H), 7.77-6.99(m,3H), 3.21-2.69(m,2H), 0.85(d,J=10.1Hz,3H). Example 15. (7-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0136] [ka]

[0137] Steps A to E: Compound 15 was obtained by a method similar to steps A to E of Example 8.

[0138] 1 H NMR (DMSO-d6,400MHz) δ 8.15(s,2H), 7.45(d,J=8.3Hz,1H), 7.44-7.31(m,1H), 7.17-7.04(m,1H), 3.15-2.79(m,2H),1.60(m, 3H).

[0139] Example 16. Benzofuran-3-yl(3,5-dibromo-4-hydroxyphenyl)methanone

[0140] [ka]

[0141] Steps C to E: Compound 16 was obtained by a method similar to steps C to E of Example 8.

[0142] 1H NMR (DMSO-d6,400MHz) δ 8.15(s,2H), 7.45(d,J=8.3Hz,1H), 7.44-7.31(m,1H), 7.17-7.04(m,1H), 3.15-2.79(m,2H), 1.60(m, 3H).

[0143] Example 17. (6-bromo-2-methylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone

[0144] [ka]

[0145] Step F: 4-bromosalicyaldehyde (5 g, 32 mmol) was dissolved in 50 mL of anhydrous acetonitrile, 1.5 equivalents of potassium carbonate were added, and then 1.5 equivalents of methyl 2-bromopropionic acid were added dropwise for 10 minutes. The reaction solution was stirred at room temperature for 6 hours, and the resulting solid was filtered. The filtrate was concentrated, and then lithium hydroxide aqueous solution (1 N, 30 mL) and tetrahydrodofuran 30 mL were added and the mixture was stirred under reflux for 5 hours. After the reaction was complete, the mixture was neutralized with 1 N hydrochloric acid aqueous solution and extracted with ethyl acetate (3 × 150 mL). The extract was washed with 100 mL of water, dried over sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17-1 (3.50 g, 48% yield).

[0146] Step G: Compound 17-1 (3.5 g, 15.3 mmol) was mixed with 5 equivalents of sodium acetate, 40 mL of acetic anhydride, and 20 mL of glacial acetic acid, and stirred at 150°C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with 150 mL of water, and extracted with ethyl acetate (3 × 120 mL). The extract was sequentially washed with 100 mL of aqueous sodium bicarbonate solution and 100 mL of brine, dried with organic sulfuric acid, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the target compound 17-2 (1.77 g, 55% yield).

[0147] Step H: Compound 17-2 (1.77 g, 8.44 mol) was dissolved in 18 mL of anhydrous 1,4-dioxane, and 5 equivalents of 4 M hydrochloric acid 1,4-dioxane solution were added. The mixture was stirred under reflux for 16 hours. After the reaction was complete, the reaction mixture was gradually added to 200 mL of water and then extracted with ethyl acetate (100 mL x 3). The extract was washed with 150 mL of aqueous sodium bicarbonate solution, the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and separated by column chromatography to obtain the target compound 17-3 (1.16 g, 82% yield).

[0148] Step I: Compound 17-3 (1.16 g, 6.9 mmol) was dissolved in 18 mL of methanol and cooled to 0°C. Three equivalents of sodium borohydride were gradually added dropwise over 15 minutes. The reaction solution was stirred at room temperature for 2 hours, 20 mL of cold water was added, and the mixture was extracted with dichloromethane (100 mL x 2). The extract was sequentially washed with 50 mL of water and 50 mL of brine, dried over organic anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography to obtain the target compound 17-4 (0.918 g).

[0149] Step J: Compound 17-4 (0.918 g) was dissolved in 10 mL of 1,4-dioxane, then 5 equivalents of hydrochloric acid 1,4-dioxane solution were added and the mixture was stirred under reflux for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with 30 mL of water, and extracted with ethyl acetate (3 × 120 mL). The extract was washed with 20 mL of aqueous sodium bicarbonate solution, the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and separated by column chromatography to obtain the target compound 17-5 (0.641 g, 61% total yield in 2 steps).

[0150] Step K: Compound 17-5 (0.641 g, 4.2 mmol) was dissolved in 10 mL of anhydrous CS2, cooled to 0°C, and then 1.5 equivalents of 4-methoxybenzoyl chloride were added. 1.5 equivalents of tin(IV) chloride were added dropwise for 5 minutes. The reaction solution was stirred at room temperature for 24 hours, then diluted with 200 mL of cold water. The resulting solid was filtered, and the aqueous layer was extracted with dichloromethane (90 mL x 2). The extract was sequentially washed with 20 mL of 1 mol aqueous hydrochloric acid solution, 20 mL of 1 mol aqueous sodium hydroxide solution, and 30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography to obtain the target compound 17-6 (0.986 g, 78% yield).

[0151] Step L: Compound 17-6 (0.986 g, 3.2 mmol) was dissolved in 10 mL of anhydrous dichloromethane and cooled to -78°C. Boron tripromide (1 molar dichloromethane solution, 5 equivalents) was then added. The reaction solution was stirred at room temperature for 20 hours, then 10 mL of cold water was gradually added, and the mixture was extracted with dichloromethane (30 mL x 2). The extract was sequentially washed with 30 mL of water and 30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography to obtain the target compound 17-7 (0.856 g, 91% yield).

[0152] Step M: Using compound 17-7, the target compound 17 was obtained in a manner similar to step E of Example 25.

[0153] 1 H NMR (DMSO-d6,400MHz) 7.94(d,J=1.7Hz,1H), 7.89(s,2H), 7.43(dd,J=8.5,1.7Hz, 1H), 7.34(d,J=8.4Hz,1H), 2.44(s,3H).

[0154] Example 18. (5-bromo-2-methylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone

[0155] [ka]

[0156] Steps F to M: Compound 18 was obtained by a method similar to steps F to M of Example 17.

[0157] 1 H NMR (DMSO-d6,400MHz) 7.90(s,2H), 7.59(dd,J=6.8,5.4Hz,2H), 7.47(dd,J=8.7,2.0Hz,1H), 2.43(s,3H).

[0158] Example 19. (6-chloro-2-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone

[0159] [ka]

[0160] Steps F to L: Compound 19-7 was obtained by a method similar to steps F to L of Example 17.

[0161] Step M: Compound 19 was obtained using compound 19-7 in a manner similar to Step E of Example 8.

[0162] 1H NMR (DMSO-d6,400MHz) δ 8.07(s,2H), 7.94(d,J=1.7Hz,1H), 7.43(dd,J=8.3,1.7Hz,1H), 7.33(d,J=8.4Hz,1H), 2.43(s,3H).

[0163] Example 20. (3,5-dibromo-4-hydroxyphenyl)(2,5-diethylbenzofuran-3-yl)methanone

[0164] [ka]

[0165] Steps A to E: Compound 20 was obtained by a method similar to that of steps A and E in Example 1.

[0166] 1 H NMR(DMSO-d6,400MHz) δ 11.41(s,1H), 8.00-7.91(m,2H), 7.70(dt,J=8.4,2.8Hz,1H), 7.36(s,1H) ), 7.09(d,J=8.5Hz,1H), 2.76(dq,J=20.2,7.5Hz,4H), 1.24(t,J=7.5Hz, 3H), 1.14(t,J=7.5Hz,3H).

[0167] Example 21. (3,5-dibromo-4-hydroxyphenyl)(2,7-diethylbenzofuran-3-yl)methanone

[0168] [ka]

[0169] Steps A to E: Compound 21 was obtained by a method similar to that of Steps A and E of Example 1.

[0170] 1 H NMR(DMSO-d6,400MHz) δ 11.39(s,1H), 7.93(d,J=2.1Hz,1H), 7.67(dd,J=8.4,2.1Hz,1H), 7.47(d,J=8.3Hz,1H), 7.16(d,J=8.4H z,1H), 7.07(d,J=8.5Hz,1H), 3.01(q,J=7.6Hz,2H), 2.82(q,J=7.5Hz,2H), 1.26(td,J=7.5,5.9Hz,6H).

[0171] Example 22. (3,5-dibromo-4-hyde-roccypenyl)(2-ethyl-6-(trifluoromethyl)benzofuran-3-yl)methanone

[0172] [ka]

[0173] Steps A to E: Compound 22 was obtained by a method similar to steps A to E of Example 1.

[0174] 1 H NMR (DMSO-d6,400MHz) δ 8.16(s,1H), 7.98(s,2H), 7.69-7.62(m,2H), 2.85(q,J=7.5Hz,2H), 1.29(t,J=7.5Hz,3H).

[0175] Example 23. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-4-methylbenzofuran-3-yl)methanone

[0176] [ka]

[0177] Steps A to E: Compound 23 was obtained by a method similar to steps A to E of Example 1.

[0178] 1 H NMR(DMSO-d6,400MHz) δ 11.59(s,1H), 8.00(d,J=2.1Hz,1H), 7.69(dd,J=8.5,2.2Hz,1H), 7.56(d,J=8.7Hz,1H), 7.48(d ,J=8.7Hz,1H), 7.07(d,J=8.5Hz,1H), 2.62(q,J=7.5Hz,2H), 2.16(s,3H), 1.17(t,J=7.5Hz,3H).

[0179] Example 24. (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-4-fluorobenzofuran-3-yl)methanone

[0180] [ka]

[0181] Steps A to E: Compound 24 was obtained by a method similar to steps A to E of Example 1.

[0182] 1 H NMR(DMSO-d6,400MHz) δ 11.59(s,1H), 8.00(d,J=2.1Hz,1H), 7.69(dd,J=8.5,2.2Hz,1H), 7.56(d,J=8.7Hz,1H), 7.48(d ,J=8.7Hz,1H), 7.07(d,J=8.5Hz,1H), 2.62(q,J=7.5Hz,2H), 2.16(s,3H), 1.17(t,J=7.5Hz,3H).

[0183] <Example of experiment> 1. Evaluation of test substances (1) Activity evaluation of HSP47 Fibrils were formed by adding 180 μl of PBS (phosphate-buffered saline, pH 7.4) solution to 20 μl of collagen (collagen solution, UK) dissolved in an acidic solution, and then measuring the fibril activity at a wavelength of 340 nm. HSP47 activity was evaluated by the degree to which HSP47 protein (GenScript US) was suppressed by adding it at a concentration of 9.45 μg / ml. The degree of HSP47 inhibition was measured as a percentage or EC by adding the test substance at concentrations of 100 μM to 1 μM. 50 It was represented as follows.

[0184] (2) Sirius red assay Human liver cells (Liver stellate LX-2, Elabscience, CH), lung epithelial cells (A549), or cutaneous KEL FIB (ATCC, US) cells were cultured in 24-well tissue culture plates for 18 hours. After treatment with TGF-β 10 ng / ml, the cells were cultured with the test compound for 24 hours. The cells were washed with PBS, fixed with Bouin's solution, and then washed twice by distillation. The fixed cells were stained with Sirius Red over a 2-hour period, and morphological changes were observed. The cells were then washed with 0.01 N HCl solution, and Sirius Red bound to collagen was extracted with 0.1 N NaOH solution. The collagen production inhibitory efficacy of each compound was expressed as a percentage or EC2. 50 It was represented as follows.

[0185] (3) Suppression of MCP-1 (Monocyte Chemoattractant Protein-1) secretion LX-2 hepatic stellate cell lines were cultured in 24-well tissue culture plates for 18 hours, then treated with 10 ng / ml of TGF-β, and cultured with 30-1 μM of the test substance for 24 hours. MCP-1 protein secreted into the cell culture medium was quantified using ELISA reagent (RnD, USA). The MCP-1 quantification values ​​after each test substance treatment were analyzed using prism software (Graphpad, ver9.4, USA) for EC2. 50 The value was calculated.

[0186] (4) Statistical analysis The results of this experiment were analyzed using either parametric multiple comparison procedures or non-parametric multiple comparison procedures, assuming the normality of the data.

[0187] If the results of the parametric one-way ANOVA were significant, a post-hoc test was performed using Dunnett's multiple comparison test. If the results of the non-parametric Kruskal-Wallis' H-test were significant, a post-hoc test was performed using Dunn's multiple comparison test.

[0188] Statistical analysis was performed using Prism (GraphPad Software Inc., CA, USA), and a p-value of less than 0.05 was considered statistically significant.

[0189] 2.Results (1) Results of inhibiting the function of HSP47 protein Table 1 below shows the results of inhibiting the function of the HSP47 protein.

[0190] [Table 1]

[0191] (2) Results of suppression of hepatic stellate cell fibrosis with LX-2 Table 2 below shows the results of suppressing hepatic stellate cell fibrosis.

[0192] [Table 2]

[0193] (3) Results of suppression of fibrosis in A549 lung epithelial cells Table 3 below shows the results of suppressing fibrosis in lung epithelial cells.

[0194] [Table 3]

[0195] (4) Results of suppression of fibrosis in KEL FIB dermal fibroblasts Table 4 below shows the results of inhibiting fibrosis in skin fibroblasts.

[0196] [Table 4]

[0197] (5) Results of suppression of MCP-1 secretion by LX-2 hepatic stellate cells Table 5 below shows the effect of treatment with the test substance on suppressing MCP-1 secretion in LX-2 hepatic stellate cells.

[0198] [Table 5]

[0199] The above description of the present invention is illustrative, and a person with ordinary skill in the art to which the invention pertains will understand that it can be readily modified into other specific forms without altering the technical idea or essential features of the invention. Therefore, it should be understood that the above-described embodiments are illustrative and not limiting in all respects. For example, each component described as a single type can be implemented in a distributed manner, and similarly, components described in a distributed manner can be implemented in a combined manner.

[0200] The scope of this invention is defined by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and the concept of equivalents thereof shall be interpreted as being included within the scope of these claims.

Claims

1. A benzofuranylhydroxyphenylmethanone derivative compound represented by the following chemical formula I, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In the above formula, R １ and R ２ It is a halogen, R ３ C １ -C ３ It is alkyl, R ａ is hydrogen, C １ -C ３ Alkyl or halogen, R ｂ is hydrogen or C １ -C ３ alkyl. R ｃ is hydrogen, C １ -C ３ Alkyl or C １ -C ３ It is a haloalkyl, R ｄ is hydrogen, C １ -C ３ Alkyl or halogen: However, in the above formula, R ａ , R ｂ , R ｃ and R ｄ If R is hydrogen; １ and R ２ is iodine, and R ３ is ethyl, and R ａ , R ｃ and R ｄ is hydrogen and R ｂ Except when R1 is ethyl; when R1 and R2 are bromo, R3 is ethyl, Ra is fluoro, and Rb, Rc and Rd are hydrogen; and when R1 and R2 are iodine, R3 is ethyl, Ra is methyl, and Rb, Rc and Rd are hydrogen.

2. The aforementioned R １ and R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is bromo or iodine.

3. The aforementioned R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the substituent is selected from the group consisting of methyl and ethyl.

4. The aforementioned R ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the substituent is selected from the group consisting of hydrogen and chloro.

5. The aforementioned R ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the substituent is selected from the group consisting of hydrogen, methyl, and ethyl.

6. The aforementioned R ｃ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the substituent is selected from the group consisting of hydrogen, methyl, ethyl, and trifluoromethyl.

7. The aforementioned R ｄ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the substituent is selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, and bromo.

8. The benzofuranylhydroxyphenylmethanone derivative compound represented by the aforementioned chemical formula I, (4-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2,6-diethylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-methylbenzofuran-3-yl)methanone, (7-chloro-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (7-bromo-2-ethylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-fluorobenzofuran-3-yl)methanone, (2-ethyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (2-ethyl-6-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (2-ethyl-7-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (7-chloro-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (7-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2,5-diethylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2,7-diethylbenzofuran-3-yl)methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(trifluoromethyl)benzofuran-3-yl)methanone, and The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is any one compound selected from the group consisting of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-4-methylbenzofuran-3-yl)methanone.

9. (5-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (6-bromo-2-ethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone, (6-chloro-2-ethylbenzofuran-3-yl)(3,5-diiodo-4-hydroxyphenyl)methanone, Benzofuran-3-yl(3,5-dibromo-4-hydroxyphenyl)methanone, (6-bromo-2-methylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, (5-bromo-2-methylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone, Any one benzofuranylhydroxyphenylmethanone derivative compound selected from the group consisting of (6-chloro-2-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for inhibiting HSP47, comprising a benzofuranylhydroxyphenylmethanone derivative compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as an active ingredient.

11. A pharmaceutical composition for the prevention or treatment of fibrosis, comprising a benzofuranylhydroxyphenylmethanone derivative compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as an active ingredient.

12. The pharmaceutical composition for the prevention or treatment of fibrosis according to claim 11, characterized in that the fibrosis is one or more selected from the group consisting of liver sclerosis, pulmonary fibrosis, keloids, hypertrophic scars, and renal fibrosis (glomerulosclerosis).

13. A pharmaceutical composition for the prevention or treatment of cancer, comprising a benzofuranylhydroxyphenylmethanone derivative compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as an active ingredient.

14. The pharmaceutical composition for the prevention or treatment of cancer according to claim 13, characterized in that the cancer is one or more selected from the group consisting of breast cancer, colorectal cancer, and cancer-related fibrosis.

15. A pharmaceutical composition for the prevention or treatment of inflammatory diseases, comprising a benzofuranylhydroxyphenylmethanone derivative compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as an active ingredient.

16. The pharmaceutical composition for the prevention or treatment of an inflammatory disease according to claim 15, characterized in that the inflammatory disease is one or more selected from the group consisting of liver cancer, prostate cancer, ovarian cancer, neuroinflammatory disease, arteriosclerosis, organ transplantation, asthma, conjunctivitis, periodontitis, rhinitis, tonsillitis, pneumonia, gastric ulcer, pancreatitis, gastritis, nephropathy, inflammatory bowel disease, colitis, lupus, rheumatoid arthritis, osteoarthritis, hepatitis, nephritis, Sjögren's syndrome, and multiple sclerosis.

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