KR102085758B1 - A novel compound for inhibiting histone acetyltransferase p300 and antifibrotic composition comprising the same - Google Patents

Abstract

The present invention relates to a novel compound which enables additional hydrogen bonding with a specific amino acid position of histone acetyltransferase (HAT) p300 through the structural analysis of the HAT p300. The novel compound of the present invention has an excellent inhibitory effect of HAT p300 activity, thereby being able to be very effectively used for preventing, alleviating or treating fibrosis, a disease associated with the activation of HAT p300.

Description

Novel compound for inhibiting histone acetyltransferase p300 and antifibrotic composition comprising the same}

The present invention is a novel compound for inhibiting histone acetyltransferase p300; An antifibrotic composition comprising said novel compound; And various uses thereof.

Tissues comprise a well-ordered cell population bound to the extracellular matrix and surrounded by a vascular network. Fibrosis or fibrosis is an abnormal accumulation of collagen matrix following injury or inflammation that changes the structure and function of various tissues. In the case of fibrosis, irrespective of the location of its occurrence, excessive accumulation of fibrous connective tissue, such as a collagen matrix, which replaces normal tissue, is the most etiological factor. Progressive fibrosis, which occurs in the kidneys, liver, fat, lungs, heart, bone or bone marrow, and skin, is a major cause of death or pain.

In particular, pulmonary fibrosis, a fibrosis occurring in the lung, refers to a disease in which chronic inflammatory cells infiltrate the alveolar walls of lung tissue and induce tissue fibrosis to cause severe structural variation of lung tissue. For some reason, once fibrosis progresses, the lung tissue hardens and the alveolar walls become thick, reducing the oxygen supply by the blood, which makes breathing difficult. Currently, there is no medical treatment to completely recover the fibrotic lung tissue, which is usually found early in fibrosis or except for lung transplantation, which usually causes symptoms and eventually leads to death after three to five years. .

Treatment methods for pulmonary fibrosis found early in the treatment include steroids such as steroids, azathioprine and cyclophosphamide, and antioxidants such as acetylcysteine. There is a treatment method and the treatment method through the growth factor administration such as cytokines (Cytokine), IFN-γ (Interferon-γ). Therapeutic methods using steroid drugs and antioxidants have been studied and reported continuously since 2000, but have not yet been proven to have obvious drug efficacy, resulting in systemic side effects or long-term side effects. It has been reported. Treatment with growth factor has been gaining a lot of attention recently, and it is a relatively fundamental approach using 'interferon' that inhibits the production of transforming growth factor-β (TGF-β), which is known as an important factor for pulmonary fibrosis. . Due to the approach of analyzing the causes of the onset of treatment, various forms of treatment, such as injection or aerosol, have been reported due to less side effects and superior efficacy compared to treatment with steroid-based drugs and antioxidants. However, since the exact cause of pulmonary fibrosis is not yet known, the efficacy of treatment with a single component such as interferon may be temporary, which may only be effective for some patients, requiring ongoing research and clinical trials.

According to this necessity, it is a mechanism that regulates the functions of numerous proteins including transcription factors that play a direct role in transcription, and affects phenomena such as expression of proteins by regulating lysine residues in the amino acids that make up the protein. Studies on components related to post-translational modification of proteins, such as acetylation of histone proteins, have been conducted. However, studies on substances having excellent effects have been insufficient.

One object of the present invention is to provide a novel compound capable of inhibiting histone acetyltransferase (HAT) p300.

Still another object of the present invention is to provide a composition for preventing, ameliorating or treating a disease associated with HAT p300, including a novel compound that inhibits HAT p300.

Still another object of the present invention is to provide a method for preventing, ameliorating or treating a disease associated with HAT p300 using the composition.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task not mentioned will be clearly understood by those skilled in the art from the following description.

In one embodiment of the present invention, there is provided a compound selected from the compound represented by the following formula (1), a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof:

[Formula 1]

In Chemical Formula 1,

m and n are each independently an integer from 1 to 4;

R ₁ is selected from the group consisting of a substituted or unsubstituted C ₃ ~ C ₄₀ cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C ₆ to C ₁₄ aryl group and a heteroaryl group having 5 to 14 nuclear atoms A substituent;

p is an integer from 1 to 3, q is an integer from 0 to 3, but p + q does not exceed 4;

R ₂ is halogen, and when there are a plurality of R ₂ , they are the same or different from each other;

r is an integer from 0 to 5;

R ₃ is a substituent selected from the group consisting of halogen, cyano group (-CN), C ₁ -C ₅ alkylcarbonyl group and carbamoyl group (-C (= O)-(NH ₂ )), wherein R ₃ is a plurality In the individual case they may be the same or different from one another.

As used herein, unless otherwise indicated, hydrogen is C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl, and heterocyclyl, hydroxy, oxo (= O), halo, cyano (-CN), nitro (-NO ₂ ),- C (O) R _a , -C (O) OR _a , -C (O) NR _b R _c , -C (NR _a ) NR _b R _c , -OR _a , -OC (O) R _a , -OC (O) OR _a , -OC (O) NR _b R _c , -OC (= NR _a ) NR _b R _c , -OS (O) R _a , -OS (O) ₂ R _a , -OS (O) NR _b R _c , -OS (O) ₂ NR _b R _c , -NR _b R _c , -NR _a C (O) R _d , -NR _a C (O) OR _d , -NR _a C (O) NR _b R _c , -NR _a C (= NR _d ) NR _b R _c , -NR _a S (O) R _d , -NR _a S (O) ₂ R _d , -NR _a S (O) NR _b R _c , -NR _a S (O) ₂ NR _b R _c , -SR _a , -S (O) R _a , -S (O) ₂ R _a , -S (O) NR _b R _c and -S (O) _It may be substituted with at least one selected from the group consisting of ₂ NR _b R _c , but is not limited thereto. Wherein R _a , R _b , R _c , and R _d are each independently (i) hydrogen; (Ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl, or heterocyclyl Or; (Iii) R _b and R _c may form a substituted heterocyclyl together with the N atom to which they are attached. Preferably the substitution is -C (O) OR _a , wherein R _a may be hydrogen or a C _1-6 alkyl group, more preferably a carboxyl group, but is not limited thereto.

The term "cycloalkyl group" of the present invention means, unless stated otherwise, a monovalent substituent derived from a monocyclic or polycyclic non-aromatic hydrocarbon having 3 to 40 carbon atoms. Examples of such cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantine, and the like.

The term “heterocycloalkyl group” of the present invention, unless stated otherwise, includes 1 to 3 heteroatoms selected from N, O, P, or S, and has 3 to 20 monovalent monovalent monocyclic monocyclic ring atoms. Cyclic system. One or more hydrogen atoms of the heterocycloalkyl group may be optionally substituted. Examples of the heterocycloalkyl group include, but are not limited to, pyrrolidine, pyrazolidine, imidazolidine, piperidine, or piperazine.

The term "aryl group" of the present invention refers to a mono- or poly-cyclic carbocyclic ring system having 6 to 14 carbon atoms having at least one aromatic ring fused or non-fused unless otherwise stated, and aryl Examples include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl and andracenyl, and the like.

The term “heteroaryl group” of the present invention, unless stated otherwise, is a 5-14 membered monocyclic or bicyclic containing at least one selected from O, N and S, for example, 1 to 4 heteroatoms. It means an aromatic group more than a click. Examples of monocyclic heteroaryls include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, benzo [d] oxazolyl, isoxazolyl, oxazolopyridinyl, pyrazolyl, triazolyl, thia Jolyl, benzo [d] thiazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, naphthooxazolyl and similar groups It is not limited to these. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso Quinolinyl, purinyl, furypyridinyl and similar groups, but are not limited thereto.

The term "halogen" in the present invention means fluorine, chlorine, bromine or iodine unless otherwise stated.

The term "alkyl" of the present invention means a straight or branched chain saturated monovalent hydrocarbon radical, which alkyl may be optionally substituted with one or more substituents described in the present invention. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t -Butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).

The "pharmaceutically acceptable salts" of the present invention are low in toxic to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts of pharmaceutically acceptable free acids and base compounds of formula (1).

Preferred salt forms of the compounds of the present invention include salts with inorganic or organic acids. At this time, the hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid may be used as the inorganic acid. Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used for the preparation of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclohexylamine and the like. Amino acids that can be used to prepare amino acid addition salts are natural amino acids such as alanine, glycine and the like. It will be apparent to those skilled in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.

The salts of the present invention can be prepared by conventional methods. For example, the compound of Formula 1 may be prepared by dissolving in a solvent which may be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallizing after adding a free acid or free base.

As the "optical isomer" of the present invention may have an asymmetric carbon center, as the R or S isomer or racemic compound, all the optical isomers and mixtures which the compound of the present invention can achieve are all included in the scope of the present invention.

In the present invention, the compound may be a compound represented by Formula 2:

[Formula 2]

In Chemical Formula 2,

Each of R ₁ , R ₂ and R ₃ are the same as defined in Formula 1 above.

In one preferred embodiment of the present invention, m and n may each independently be an integer of 1 or 2.

In a preferred embodiment of the present invention, R ₁ is a C ₃ ~ C ₄₀ cycloalkyl group, a heterocycloalkyl group of 5 to 7 nuclear atoms, a C ₆ ~ C ₁₄ aryl group and a heteroaryl group of 5 to 14 nuclear atoms It may be a substituent selected from the group consisting of, preferably a heterocycloalkyl group having 5 to 7 nuclear atoms containing 1 or 2 N atoms; C ₆ -C ₁₀ aryl group; And it may be any substituent selected from the group consisting of heteroaryl group having 5 to 10 nuclear atoms containing one or two S atoms, more preferably piperidinyl group, pyridinyl group, phenyl group or thiophenyl group Can be.

In a preferred embodiment of the invention, the substituent of R ₁ , preferably the C ₆ to C ₁₄ aryl groups of R ₁ may be unsubstituted or substituted with at least one — (COO (R ₄ )); R ₄ is hydrogen or a C ₁ -C ₄ alkyl group, preferably hydrogen; When there are a plurality of R ₄ , they may be the same or different from each other.

In one preferred embodiment of the present invention, p may be an integer of 1 or 2, preferably an integer of 1.

In one preferred embodiment of the present invention, q may be an integer of 0 or 1, preferably an integer of 1.

In one preferred embodiment of the present invention, r may be an integer of 1 or 2, preferably an integer of 1.

In one preferred embodiment of the present invention, R ₃ may be a halogen or cyano group.

In a preferred embodiment of the present invention, R ₃ may be a C ₁ ~ C ₅ alkylcarbonyl group or carbamoyl group (-C (= O)-(NH ₂ )).

In one preferred embodiment of the invention, m and n are each independently an integer of 1 or 2; R ₁ is a substituent selected from the group consisting of a substituted or unsubstituted heterocycloalkyl group having 5 to 7 nuclear atoms, a C ₆ to C ₁₄ aryl group and a heteroaryl group having 5 to 14 nuclear atoms; p is an integer of 1 or 2; q is an integer from 0 to 2; R ₂ is halogen; R ₃ may be a substituent selected from the group consisting of halogen, cyano group, C ₁ to C ₅ alkylcarbonyl group and carbamoyl group.

In one preferred embodiment of the invention, m and n are each independently an integer of 1 or 2; R ₁ is a heterocycloalkyl group having 5 to 7 nuclear atoms, a C ₆ to C ₈ aryl group or a heteroaryl group having 5 to 14 nuclear atoms; p is an integer of 1 or 2; q is an integer from 0 to 2; r is an integer of 1 or 2; R ₂ is halogen; R ₃ is a C ₁ to C ₅ alkylcarbonyl group or carbamoyl group (—C (═O) — (NH ₂ )); R ₁ may be unsubstituted or substituted with at least one — (COO (R ₄ )); R ₄ is hydrogen or a C ₁ to C ₄ alkyl group, and when there are a plurality of R ₄ , they may be the same or different from each other.

In one preferred embodiment of the invention, m and n are each independently an integer of 1 or 2; r is an integer of 1 or 2; R ₁ is a substituent selected from a heterocycloalkyl group having 5 to 7 nuclear atoms or a C ₆ to C ₈ aryl group; R ₂ is halogen; R ₃ is halogen or cyano group; The aryl group of R ₁ is substituted with-(COO (R ₄ )); R ₄ may be hydrogen or a C ₁ to C ₄ alkyl group.

The compound of the present invention may be at least one selected from the group consisting of the following compounds, but is not limited thereto:

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In a preferred embodiment of the present invention, the compound may be any one of the following compounds, but is not limited thereto:

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In another embodiment of the present invention, a compound for inhibiting histone acetyltransferase p300 represented by Chemical Formula 1 is provided.

In the inhibitory compound of the present invention, the compound, histone acetyltransferase p300 and the like are the same as described above in the compound and are omitted to avoid excessive complexity of the specification.

In another embodiment of the present invention, a composition for preventing, ameliorating or treating a histone acetyltransferase p300 related disease is provided.

The composition of the present invention is a pharmaceutical composition; Food compositions; Or as a cosmetic composition.

The composition of the present invention comprises a compound selected from the novel compounds represented by the formula (1) of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof as an active ingredient. Therefore, since the composition of the present invention includes a novel compound that effectively inhibits HAT p300 as an effective ingredient, it is possible to exert a prophylactic, improvement or therapeutic effect of a fibrosis patient with increased HAT p300.

In the above composition of the present invention, the compound corresponding to the active ingredient is omitted in order to avoid excessive complexity of the specification as described above in the compound.

The histone acetyltransferase p300-related diseases of the present invention are all diseases caused by excessively increasing the expression level of histone acetyltransferase or excessive activity thereof, compared to the normal control group without the disease. It may include.

The “fibrosis” of the present invention is a disease in which abnormal production, accumulation, and deposition of extracellular matrix by fibroblasts occurs, and abnormal accumulation of collagen matrix due to damage or inflammation that can change the structure and function of various tissues may occur. The organ may include fibrosis of all organs, preferably fibrosis developed in at least one organ selected from the group consisting of kidney, liver, lung, heart, bone or bone marrow and skin, but is not limited thereto. It is not. For the purpose of the present invention, the fibrosis is a phenomenon in which the expression of genes related to fibrosis, such as collagen, is promoted by TGF-β (Transforming Growth Factor-β) whose expression level is increased by the acetylase p300. It may be induced by, or due to the absence of enzymes that can recover the cells from damage that fibrosis can be induced, but is not limited thereto.

The fibrosis of the present invention is pulmonary fibrosis (Pulmonary fibrosis), myoma, myelofibrosis (Myelofibrosis), liver fibrosis (Liver fibrosis), heart fibrosis (Heart fibrosis), multiple sclerosis, kidney fibrosis (Kidney fibrosis), cystic fibrosis ( Cystic fibrosis), neutropenia, skeletal muscle fibrosis, sclerosis, dermatitis, mediastinal fibrosis and splenic fibrosis due to sickle cell anemia, and preferably pulmonary fibrosis However, it is not limited thereto.

The "pulmonary fibrosis" of the present invention means the development of scarred (fibrous) tissue due to the formation or development of fibrous connective tissue (fibrosis) in the lung. Specifically, pulmonary fibrosis is a chronic disease that causes swelling and scarring of alveoli and interstitial tissue of the lungs. Such scar tissue replaces healthy tissue and causes inflammation, and chronic inflammation can be identified as a precursor to fibrosis. Such damage to lung tissue can lead to stiffness of the lungs and make it difficult for the subject to self-breath.

Pulmonary fibrosis in the present invention is idiopathic Pulmonary Fibrosis, Nonspecific Interstitial Pneumonia, Acute Interstitial Pneumonia, Cryptogenic Organizing Pneumonia, Respiratory bronchiolitis Respiratory Bronchiolitisassociated Interstitial Lung, Desquamative Interstitial Pneumonia, Lymphoid Interstitial Pneumonia, Interstitial Pulmonary Fibrosis and Diffuse Pulmonary Fibrosis, preferably idiopathic pulmonary fibrosis It may be, but is not limited thereto.

The pulmonary fibrosis of the present invention is caused by a variety of causes, for example, microscopic damage to the lungs induced by inhalation of microparticles (asbestos, stone powder, metal dust, particles present in tobacco smoke, silica dust, etc.). can do. In addition, pulmonary fibrosis can occur due to the secondary effects of other diseases (such as autoimmune diseases, viral or bacterial infections, etc.), and can include cytotoxic agents (such as bleomycin, busulfan and methotrexate); Antibiotics (nitrofurantoin and sulfasalazine, etc.); Arrhythmia treatments (such as amiodarone and tocainide); Anti-inflammatory drugs (such as gold and penicylamine); It may be caused by certain drugs such as illegal drugs (drugs, cocaine and heroin, etc.), and the idiopathic pulmonary fibrosis may be caused by an unknown cause other than this cause.

The "prevention" of the present invention can be used without limitation as long as it is any action that can block, inhibit or delay the symptoms caused by fibrosis using the composition of the present invention.

The "treatment" of the present invention may be included without limitation as long as all the actions to improve or benefit the symptoms caused by fibrosis using the composition of the present invention.

The "improvement" of the present invention may be included without limitation as long as all the acts that improve or beneficially change the symptoms caused by fibrosis using the composition of the present invention.

The pharmaceutical compositions of the present invention are not limited to these, but are formulated in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, capsules, tablets, aqueous suspensions, respectively, according to conventional methods, for use. Can be. Preferably the pharmaceutical composition is for intratracheal or inhalation administration; Or may be formulated to be used as an injection, but is not limited thereto. If fibrosis occurs in a respiratory organ such as the lung for the purposes of the present invention, it is preferable that the active ingredient is formulated for inhalation administration so that the effective organ can be reached in a yield suitable for prophylaxis or treatment.

The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a suspending agent, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a coloring agent, a flavoring agent, etc. in the case of oral administration, and in the case of an injection, a buffer, a preservative, Pain-free agents, solubilizers, isotonic agents, stabilizers and the like can be used in combination, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used. The formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with the pharmaceutically acceptable carrier as described above. For example, in the case of oral administration, it may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms. have. And other solutions, suspensions, tablets, capsules, sustained release preparations and the like.

Examples of suitable carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may further be included.

The route of administration of the pharmaceutical composition of the present invention is not limited thereto, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal. Oral or parenteral release is preferred.

The parenteral of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.

The pharmaceutical composition of the present invention depends on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed. The dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, extent of disease, drug form, route of administration, and duration, and may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg / kg per day. Or 0.001 to 50 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.

When the food composition of the present invention is prepared in the form of a drink, there is no particular limitation other than including the food composition at the indicated ratio, and it may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general drinks. . Specifically, monosaccharides such as glucose, disaccharides such as fructose, sucrose, and the like, and common sugars such as polysaccharides, dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol It may include. The flavourant may be a natural flavourant (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.), synthetic flavors (saccharin, aspartame, etc.).

The food composition of the present invention is a variety of nutrients, vitamins, minerals (electrolytes), synthetic flavors, such as natural flavors, flavoring agents, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks may be further included.

The components included in the food composition of the present invention may be used independently or in combination. The ratio of the additive is not a key element of the present invention, but may be selected from 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

The cosmetic composition of the present invention is a lotion, nutrition lotion, nutrition essence, massage cream, beauty bath additives, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, sunscreen cream , Suntan cream, skin lotion, skin cream, sunscreen cosmetic, cleansing milk, depilatory cosmetics, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, bath Manufactured in the form of soap, water soap, beauty soap, shampoo, hand cleaner (hand cleaner), medical soap soap, cream soap, facial wash, systemic cleaner, scalp cleaner, hair rinse, cosmetic soap, gel for whitening teeth, toothpaste Can be. The composition of the present invention may further comprise a solvent or a suitable carrier, excipient or diluent commonly used in the preparation of the cosmetic composition.

The kind of the solvent that may be further added in the cosmetic composition of the present invention is not particularly limited, and for example, water, saline, DMSO, or a combination thereof may be used. Carriers, excipients or diluents also include purified water, oils, waxes, fatty acids, fatty acid alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols, and the like. Included, but not limited to. In addition, a whitening agent, a moisturizing agent, vitamins, sunscreens, perfumes, dyes, antibiotics, antibacterial agents, antifungal agents may be included as necessary.

Hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil, avocado oil may be used as the oil of the present invention, and waxes, beeswax, carnauba, candelilla, montan, ceresin, and liquid paraffin may be used as waxes. Lanolin may be used.

Stearic acid, linoleic acid, linolenic acid, oleic acid may be used as the fatty acid of the present invention, cetyl alcohol, octyl dodecanol, oleyl alcohol, pantenol, lanolin alcohol, stearyl alcohol, hexadecanol Isopropyl myristate, isopropyl palmitate, butyl stearate may be used as the fatty acid ester. As surfactants, cationic surfactants, anionic surfactants and nonionic surfactants known in the art can be used, and surfactants derived from natural products are preferred as much as possible. In addition, it may include a hygroscopic agent, a thickener, an antioxidant, and the like, which are widely known in the cosmetic field, and their types and amounts are known in the art.

Another embodiment of the present invention provides a method for preventing, ameliorating or treating a histone acetyltransferase p300 related disease comprising administering the composition of the present invention to a desired individual.

In the present invention, the general description of the histone acetyltransferase p300 related diseases, prevention, amelioration, treatment, compounds, compositions is the same as described earlier in this specification, and will be omitted to avoid excessive complexity of the specification.

In the present invention, the "individual" is a subject suspected of developing histone acetyltransferase p300 related disease, and the subject suspected of histone acetyltransferase p300 related disease is a rat including a human who may develop or develop the disease. Means mammals, including livestock, etc., but the subject can be treated with the fusion protein of the present invention or the composition comprising the same without limitation.

The method of the present invention may include administering the active ingredient in a pharmaceutically effective amount. Appropriate total daily usage may be determined by the treating physician within the scope of good medical judgment and may be administered once or in divided doses. However, for the purposes of the present invention, the specific therapeutically effective amount for a particular patient is determined by the specific composition, including the type and severity of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general state of health, It is desirable to apply differently depending on various factors and similar factors well known in the medical arts, including sex and diet, time of administration, route of administration and rate of composition, duration of treatment, drugs used with or concurrent with the specific composition.

The method of preventing or treating the immune checkpoint inhibitor resistant cancer of the present invention may be a combination therapy further comprising administering a compound or substance having therapeutic activity against one or more cancer diseases, but is not limited thereto.

It is to be understood that the "combination" of the present invention denotes simultaneous, separate or sequential administration. If the administration is sequential or separate, the interval of administration of the secondary components should be such that the beneficial effect of the combination is not lost.

The dosage of the fusion protein of the present invention may be about 0.0001 μg to 500 mg per kg of patient's body weight, but is not limited thereto.

The present invention relates to a novel compound that enables additional hydrogen bonding with a specific amino acid position of the HAT p300 through structural analysis of histone acetyltransferase (HAT) p300, and the novel compound of the present invention. Is remarkably excellent in inhibiting the activity of HAT p300 can be used very effectively in the prevention, improvement or treatment of fibrosis, a disease associated with the activation of HAT p300.

1 to 3 are histone acetyltransferase (HAT) protein p300 (histone acetyltransferase p300; FIG. 1) and GCN5 (histone acetyltransferase GCN5; FIG. 2) in idiopathic pulmonary fibrosis patient tissues ) And PCAF (P300 / CBP-associated factor; Figure 3) shows the results confirmed by immunohistochemical staining.
Figure 4 shows the results confirming the degree of inhibition of HAT activity of candidates 1 to 67 and HAT-24, HAT-26 and HAT-28, which are PCAF inhibitors according to an embodiment of the present invention.
Figure 5 shows the results confirming the degree of activity inhibition of the HAT of candidates 1 to 14 according to an embodiment of the present invention.
Figure 6 shows the HAT p300 domain and substrate inhibitor Lys-CoA molecular model using a molecular docking simulation according to an embodiment of the present invention.
Figure 7 shows the results of analyzing the major residues involved in the binding between the HAT p300 domain and the substrate inhibitor Lys-CoA molecule using a molecular docking simulation according to an embodiment of the present invention.
Figure 8 shows the results of analyzing the major residues involved in the binding between candidate 12 and the HAT p300 domain using a molecular docking simulation according to an embodiment of the present invention.
Figure 9 shows the results of confirming the degree of activity inhibition of histone acetyltransferase of Synthesis Examples 1 to 19 (A1 to A19) according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example

Example 1 Confirmation of Protein Expression Levels in Fibrotic Tissues

Tissues from patients with idiopathic pulmonary fibrosis or normal persons were fixed with 10% formalin, embedded in paraffin, and 7 μm thick sections were attached to the slides. Then, after deparaffinization of the fragments with xylene, ethanol was treated in the order of high concentration to low concentration, and then to p300 (histone acetyltransferase p300), GCN5 (histone acetyltransferase GCN5) and PCAF (P300 / CBP-associated factor). After performing immunostaining with a specific antibody, the expression level of each protein was measured using an optical microscope, and the results are shown in FIGS. 1 to 3.

As shown in Figures 1 to 3, among the histone acetyltransferase (hereinafter referred to as 'HAT') p300, GCN5 and PCAF, p300 is increased in the tissues of patients with idiopathic pulmonary fibrosis compared to tissues obtained from normal individuals It was confirmed that it was done.

The results indicate that fibrosis, such as idiopathic pulmonary fibrosis, is particularly effective in inhibiting p300 expression or its function because p300 is present at a higher level in histone acetyltransferase than in normal tissues. It can be seen that it can be treated.

Example 2 p300 activity inhibitor screening

[2-1] Primary Screening

Kits for measuring the activity of HAT after dilution to 100 μM using candidate substances 1 to 67, which are HAT inhibitors based on the PCAF structure, and HAT-24, HAT-26, and HAT-28 (Biovision, Cat no. K332, USA), according to the method provided by the manufacturer to determine the degree of inhibition of activity of the HAT against p300 (deactivation), and the results are shown in FIG. Here, C646 (HAT inhibitor) was treated as a positive control.

As shown in Figure 4, candidates 1 to 14 was inhibited by more than 80% of the activity of the HAT, candidates 15 to 67, HAT-25, HAT-26 and HAT-28 is 20% to the efficiency of inhibiting the activity of the HAT It was only 50%.

[2-2] Secondary Screening

In [2-1], candidate substances 1 to 14 having good suppression efficiency of HAT were diluted to concentrations of 0.5 μM, 1 μM, 10 μM, and 100 μM. Then, the degree of inhibition of HAT activity was confirmed in the same manner as in [2-1], and the results are shown in FIG. 5 and Table 1. FIG.

Candidate Substance One 2 3 4 5 6 7 8 9 10 11 12 13 14 IC ₅₀
(μM) 50.84 44.09 28.9 12.12 32.4 10.14 27.65 35.52 9.01 13.12 41.67 0.953 32.84 35.82

As shown in FIG. 5 and Table 1, IC ₅₀ of candidate 12 (HAT-12) was found to be 0.953 among candidates 1 to 14. Here, candidate substance 12 is represented by the following Chemical Formula 3.

[Formula 3]

Example 3 Structural Analysis of Candidate 12

Co-crystal structure of the HAT p300 domain and its substrate inhibitor Lys-CoA (pdb: 3biy) to obtain information on the structure-activity correlation of candidates through molecular docking simulation Was used to establish a molecular model. Finally, the result of re-docking Lys-CoA and co-crystal structure were compared to the molecular model thus constructed, and the degree of similar binding pattern was confirmed to evaluate the accuracy of the docking result (FIG. 6). The major residues involved in binding between HAT p300 domain and Lys-CoA were analyzed (FIG. 7) and molecular docking simulations with candidate 12 were performed (FIG. 8).

As shown in Figure 6, it was confirmed that the similarity between the predicted binding pattern of the HAT p300 domain-ligand (Lys-CoA) and the co-crystal structure.

As shown in FIG. 7, analysis of the major residues involved in the binding between Lys-CoA and the HAT p300 domain revealed hydrogen bonds of R1410, T1411, W1466, Y1467, L1398, S1400, I1457, W1436 and Y1397. Among them, the interaction with R1410, T1411, W1466, and Y1467 is important for drug inhibitory activity, especially W1466 was found to be important (Erin M. Bowers et al., Virtual Ligand Screening of the p300 / CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor, Chem Biol. 2010 May 28; 17 (5): 471-82.).

As shown in Figure 8, the analysis of the major residues involved in the binding between candidate 12 and the HAT p300 domain, the interaction with R1410, T1411, W1466 and Y1467 was not confirmed, but it will cause hydrogen bonding with L1398 and S1400 It was confirmed that it can.

The results can be predicted that L1398 and S1400 also play an important role in the drug inhibitory activity, it can be seen that the additional hydrogen bond with R1410, T1411, W1466 and Y1467 can further increase the HAT p300 inhibitory activity have.

According to the above results, Synthesis Examples 1 to 19 were prepared as follows to have the above characteristics in order to further increase the HAT p300 inhibitory activity.

[ Synthesis Example  1 to 19] Acetyl Transferase  Preparation of Novel Compounds for Inhibiting p300

Scheme 1

Synthesis Method 1 Compound 1 to 17

Substituted 4-hydroxybenzaldehyde (1 equiv) and correspondingly substituted benzyl chloride (1 equiv) and K ₂ CO ₃ (1 equiv) were incubated with DMF in a solvent at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, and the extract was washed with water, NaHCO ₃ and brine and then dried over MgSO ₄ . Thereafter, the solvent was completely removed through reduced pressure, and then silica gel chromatography was performed to obtain compounds 1 to 17 which are O-benzylated compounds (see Table 2).

compound R R ₁ R ₂ One 3-chlorophenyl OCH ₃ Cl 2 3-chlorophenyl OCH ₃ Br 3 3-chlorophenyl OCH ₃ I 4 3-ethoxycarbonylphenyl
(3-Ethoxycarbonylphenyl) OCH ₃ Cl 5 3-ethoxycarbonylphenyl OCH ₃ Br 6 3-ethoxycarbonylphenyl OCH ₃ I 7 3-cyanophenyl
(3-Cyanophenyl) OCH ₃ Cl 8 3-cyanophenyl OCH ₃ Br 9 3-cyanophenyl OCH ₃ I 10 3-Fluorophenyl OCH ₃ Cl 11 3-chlorophenyl OCH ₃ H 12 4-carbamoylphenyl OCH ₃ Cl 13 4- carbamoylphenyl OCH ₃ Br 14 4- carbamoylphenyl OCH ₃ I 15 3- carbamoylphenyl OCH ₃ Cl 16 3- carbamoylphenyl OCH ₃ Br 17 3- carbamoylphenyl OCH ₃ I

[Compound 1] 3- Chloro -4- (3- Chlorobenzyloxy ) -5- Methoxybenzaldehyde (3- Chloro -4- (3-chlorobenzyloxy) -5-methoxybenzaldehyde)

5-chlorovanillin (1.00 g, 5.36 mmol) and 3-chlorobenzyl chloride (0.70 g, 5.36 mmol) were used to give an ivory solid compound 1 (1.50 g, 96.5%).

R _f 0.54 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.95 (s, 3H), 5.13 (s, 2H), 7.30-7.32 (m, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.37-7.39 (m, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), 7.53-7.54 (m, 1 H), 9.86 (s, 1 H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.5, 74.3, 109.6, 125.9, 126.4, 128.5, 128.6, 129.4, 129.9, 132.9, 134.5, 138.7, 149.4, 154.5, 190.1 ppm.

[Compound 2] 3- Bromo -4- (3- Chlorobenzyloxy ) -5- Methoxybenzaldehyde (3- Bromo -4- (3-chlorobenzyloxy) -5-methoxybenzaldehyde)

5-bromovanillin (1.00 g, 4.33 mmol) and 3-chlorobenzyl chloride (0.58 g, 5.36 mmol) were used to give an ivory solid compound 2 (1.50 g, 96.5%).

R _f 0.65 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.94 (s, 3H), 5.12 (s, 2H), 7.30-7.32 (m, 2H), 7.38 (dd, J = 8.4, 1.2 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.54-7.56 (m, 1H), 7.66 (d, J = 2.0 Hz, 1H), 9.85 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.5, 74.2, 110.3, 118.5, 126.5, 128.6, 129.0, 129.9, 133.5, 134.5, 138.7, 150.4, 154.4, 190.0 ppm.

[Compound 3] 4-((3- Chlorobenzyl ) Oxy )-3 degrees-5- Methoxybenzaldehyde (4-((3-Chlorobenzyl) oxy) -3-iodo-5-methoxybenzaldehyde)

5-Idovanillin (1.00 g, 3.60 mmol) and 3-chlorobenzyl chloride (0.58 g, 5.36 mmol) were used to give an ivory-colored solid compound 1 (1.423 g, 98.1%).

R _f 0.67 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.94 (s, 3H), 5.10 (s, 2H), 7.31-7.33 (m, 2H), 7.41 (dd, J = 8.4, 1.2 Hz, 1H). 7.43 (d, J = 1.6 Hz, 1H), 7.57-7.58 (m, 1H), 7.87 (d, J = 1.6 Hz, 1H), 9.84 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.4, 74.0, 92.8, 111.2, 126.6, 128.7, 128.8, 129.9, 134.4, 134.5, 135.1, 138.7, 152.9, 153.2, 189.9 ppm.

[Compound 4] ethyl 3-((2- Chloro -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzoate  (Ethyl 3-((2-chloro-4-formyl-6-methoxyphenoxy) methyl) benzoate)

5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3- (chloromethyl) benzoate (1.06 g, 5.36 mmol) gave yellow solid Compound 4 (1.18 g, 63.1%).

R _f 0.39 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.41 (t, J = 7.2 Hz, 3H), 3.95 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.21 (s, 2H), 7.30 (ddd, J = 7.6, 1.2, 1.2 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 7.6, 7.6 Hz, 1H), 7.50 (d, J = 2.0 Hz , 1H), 8.02 (ddd, J = 7.6, 1.2, 1.2 Hz, 1H), 8.18 (dd, J = 1.2, 1.2 Hz, 1H), 9.85 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.6, 56.5, 61.3, 74.7, 109.6, 126.0, 128.7, 129.4, 129.6, 129.7, 130.9, 132.8, 132.9, 137.1, 149.5, 154.6, 166.6, 190.2 ppm.

[Compound 5] ethyl 3-((2- Bromo -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzoate  (Ethyl 3-((2-bromo-4-formyl-6-methoxyphenoxy) methyl) benzoate)

5-Bromovanillin (1.00 g, 4.33 mmol) and ethyl 3- (chloromethyl) benzoate (0.86 g, 4.33 mmol) were used to give a pale yellow solid Compound 5 (1.53 g, 90.1%).

R _f 0.35 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.41 (t, J = 7.2 Hz, 3H), 3.95 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.21 (s, 2H), 7.40 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 7.6, 7.6 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.75 (ddd, J = 7.6, 1.2, 1.2 Hz , 1H), 8.02 (ddd, J = 7.6, 1.2, 1.2 Hz, 1H), 8.19 (dd, J = 1.2, 1.2 Hz, 1H), 9.85 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.6, 56.5, 61.3, 74.6, 110.3, 118.6, 128.7, 129.0, 129.7, 130.9, 133.0, 133.4, 137.1, 150.6, 154.4, 166.6, 190.0 ppm.

Compound 6 Ethyl 3-((4- Formyl 2-ido-6- Methoxyphenoxy ) methyl ) Benzoate  (Ethyl 3-((4-formyl-2-iodo-6-methoxyphenoxy) methyl) benzoate)

5-Idovanillin (1.00 g, 3.60 mmol) and ethyl 3- (chloromethyl) benzoate (0.71 g, 3.60 mmol) were used to give a pale yellow solid Compound 6 (1.41 g, 88.8%).

R _f 0.39 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.41 (t, J = 7.2 Hz, 3H), 3.95 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.21 (s, 2H), 7.43 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 7.6, 7.6 Hz, 1H), 7.78 (ddd, J = 7.6, 1.2, 1.2 Hz, 1H), 7.86 (d, J = 1.6 Hz , 1H), 8.02 (ddd, J = 7.6, 1.2, 1.2 Hz, 1H), 8.22 (dd, J = 1.6, 1.6 Hz, 1H), 9.83 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 14.6, 56.3, 61.3, 74.4, 92.8, 111.2, 128.7, 129.7, 129.8, 130.9, 133.1, 134.3, 135.1, 137.1, 152.9, 153.2, 166.6, 189.9 ppm.

[Compound 7] 3-((2- Chloro -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzonitrile (3-((2-Chloro-4-formyl-6-methoxyphenoxy) methyl) benzonitrile)

5-chloro vanillin (1.00 g, 5.36 mmol) and ethyl 3- (bromomethyl) benzonitrile (1.05 g, 5.36 mmol) gave a white solid compound 7 (1.30 g, 80.5%).

R _f 0.25 ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.96 (s, 3H), 5.17 (s, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 7.6, 7.6 Hz, 1H ), 7.52 (d, J = 2.0 Hz, 1H), 7.64 (ddd, J = 7.6, 1.6, 1.6 Hz, 1H), 7.75 (ddd, J = 7.6, 1.6, 1.6 Hz, 1H), 7.84 (dd, J = 1.6, 1.2 Hz, 1 H), 9.87 (s, 1 H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.6, 73.8, 109.6, 112.8, 118.9, 126.0, 129.4, 129.5, 131.8, 132.1, 132.5, 133.1, 138.4, 149.1, 154.5, 190.1 ppm.

Compound 8 3-((2- Bromo -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzonitrile (3-((2-Bromo-4-formyl-6-methoxyphenoxy) methyl) benzonitrile)

5-Bromovanillin (1.00 g, 4.33 mmol) and ethyl 3- (bromomethyl) benzonitrile (0.85 g, 4.33 mmol) were used to give a white solid compound 8 (1.53 g, 83.8%).

R _f 0.24 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.95 (s, 3H), 5.16 (s, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.0, 7.6 Hz, 1H ), 7.64 (ddd, J = 7.6, 2.0 1.6 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.70 (ddd, J = 8.0, 1.6, 1.2 Hz, 1H), 7.86 (dd, J = 1.6, 1.6 Hz, 1H), 9.86 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.5, 73.6, 110.3, 112.8, 118.5, 118.9, 129.0, 129.5, 131.9, 132.1, 132.6, 133.7, 138.4, 150.1, 154.3, 189.9 ppm.

[Compound 9] 3-((4- Formyl 2-ido-6- Methoxyphenoxy ) methyl ) Benzonitrile (3-((4-Formyl-2-iodo-6-methoxyphenoxy) methyl) benzonitrile)

5-Idovanillin (1.00 g, 3.60 mmol) and ethyl 3- (bromomethyl) benzonitrile (0.71 g, 3.60 mmol) were used to give a white solid compound 9 (1.20 g, 84.4%).

R _f 0.27 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.95 (s, 3H), 5.15 (s, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.0, 7.6 Hz, 1H ), 7.65 (ddd, J = 7.6, 1.6, 1.2 Hz, 1H), 7.78 (ddd, J = 7.6, 1.6, 1.2 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 1.6, 1.2 Hz, 1 H), 9.85 (s, 1 H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.4, 73.4, 92.7, 111.3, 112.8, 118.9, 129.5, 132.0, 132.1, 132.7, 134.6, 135.0, 138.3, 152.5, 153.2, 189.8 ppm.

[Compound 10] 3- Chloro -4-((3- Fluorobenzyl ) Oxy ) -5- Methoxybenzaldehyde  (3-Chloro-4-((3-fluorobenzyl) oxy) -5-methoxybenzaldehyde)

5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3-fluorobenzyl chloride (0.78 g, 5.36 mmol) were used to give a white solid compound 10 (1.15 g, 72.8%).

R _f 0.58 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.95 (s, 3H), 5.15 (s, 2H), 7.00-7.05 (m, 1H), 7.24-7.28 (m, 2H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 9.85 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.5, 74.4, 109.7, 115.3, 115.5, 123.8, 126.0, 130.1, 132.9, 139.3, 149.5, 154.6, 161.8, 164.3, 190.2 ppm.

Compound 11 4-((3- Chlorobenzyl ) Oxy ) -3- Methoxybenzaldehyde  (4-((3-Chlorobenzyl) oxy) -3-methoxybenzaldehyde)

Vanillin (1.00 g, 6.57 mmol) and 3-methoxybenzyl chloride (1.03 g, 6.57 mmol) were used to give a yellow semisolid compound 11 (1.48 g, 99.6%).

R _f 0.45 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.95 (s, 3H), 5.19 (s, 2H), 6.95 (d, J = 8.4 Hz, 1H), 7.29-7.32 (m, 3H), 7.39 (dd , J = 8.0, 1.6 Hz, 1H), 7.43-7.44 (m, 2H), 9.84 (s, 1H); ¹³ C-NMR (CDCl ₃ , 100 MHz) 56.2, 70.2, 109.7, 112.6, 125.4, 126.6, 127.4, 128.6, 130.2, 130.7, 134.8, 138.3, 150.3, 153.4, 191.0 ppm.

[Compound 12] 4-((2- Chloro -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzamide  (4-((2-Chloro-4-formyl-6-methoxyphenoxy) methyl) benzamide)

5-chloro vanillin (0.18 g, 0.96 mmol) and 4- (chloromethyl) benzamide (0.16 g, 0.96 mmol) were used to give a white solid compound 12 (0.22 g, 73.2%).

R _f 0.25 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 3.88 (s, 3H), 5.12 (s, 2H), 7.29 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H ), 7.48 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 9.78 (s, 1H); ¹³ C-NMR (400 MHz, DMSO- d ₆ ) 55.2, 73.7, 109.5, 124.5, 127.2, 127.4, 128.3, 132.0, 133.2, 139.4, 148.4, 153.7, 168.4, 189.4 ppm.

Compound 13 4-((2- Bromo -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzamide  (4-((2-Bromo-4-formyl-6-methoxyphenoxy) methyl) benzamide)

5-Bromovanillin (0.18 g, 0.79 mmol) and 4- (chloromethyl) benzamide (0.13 g, 0.79 mmol) were used to give a white solid compound 13 (0.20 g, 73.2%).

R _f 0.16 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 3.88 (s, 3H), 5.11 (s, 2H), 7.34 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H ), 7.60 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 9.78 (s, 1H); ¹³ C-NMR (400 MHz, DMSO- d ₆ ) 55.7, 73.6, 100.1, 117.6, 127.2, 127.4, 127.5, 132.6, 133.2, 139.4, 149.5, 153.5, 168.4, 189.3 ppm.

Compound 14 4-((4- Formyl 2-ido-6- Methoxyphenoxy ) methyl ) Benzamide  (4-((4-Formyl-2-iodo-6-methoxyphenoxy) methyl) benzamide)

5-Idovanillin (0.26 g, 0.94 mmol) and 4- (chloromethyl) benzamide (0.16 g, 0.94 mmol) were used to give a white solid compound 14 (0.28 g, 72.4%).

R _f 0.10 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 3.87 (s, 3H), 5.10 (s, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H ), 7.79 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 9.76 (s, 1H); ¹³ C-NMR (400 MHz, DMSO- d ₆ ) 55.6, 73.4, 92.1, 111.0, 127.2, 127.6, 133.1, 133.5, 133.6, 139.4, 151.9, 152.3, 168.4, 189.1 ppm.

Compound 15 3-((2- Chloro -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzamide  (3-((2-Chloro-4-formyl-6-methoxyphenoxy) methyl) benzamide)

5-chlorovanillin (0.40 g, 2.14 mmol) and 3- (chloromethyl) benzamide (0.36 g, 2.14 mmol) were used to give a white solid compound 15 (0.32 g, 45.0%).

R _f 0.10 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.88 (s, 3H), 5.11 (s, 2H), 7.30 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 7.6, 7.6 Hz, 1H ), 7.44 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.77 (ddd, J = 7.6, 1.6, 1.2 Hz, 1H), 794 (dd, J = 1.6, 1.6 Hz, 1 H), 9.78 (s, 1 H); ¹³ C-NMR (400 MHz, DMSO- d ₆ ) 56.4, 74.1, 110.9, 124.1, 127.2, 127.6, 127.9, 128.2, 131.1, 132.6, 134.4, 136.6, 148.2, 154.0, 167.6, 191.1 ppm.

Compound 16 3-((2- Bromo -4- Formyl -6- Methoxyphenoxy ) methyl ) Benzamide  (3-((2-Bromo-4-formyl-6-methoxyphenoxy) methyl) benzamide)

5-Bromovanillin (0.18 g, 0.79 mmol) and 3- (chloromethyl) benzamide (0.13 g, 0.79 mmol) were used to give a white solid compound 16 (0.20 g, 73.2%).

R _f 0.16 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (DMSO- d ₆ , 400 MHz) δ 3.88 (s, 3H), 5.10 (s, 2H), 7.34 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.0, 8.0 Hz , 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.62 (ddd, J = 7.6, 1.2, 1.2 Hz 1H), 7.78 (ddd, J = 7.6, 1.2, 1.2 Hz 1H), 7.96 (dd, J = 1.2, 1.2 Hz, 1 H), 9.78 (s, 1 H); ¹³ C-NMR (400 MHz, DMSO- d ₆ ) 55.7, 73.8, 110.0, 117.7, 126.9, 127.2, 127.6, 127.9, 131.0, 132.6, 133.5, 136.3, 149.5, 153.6, 168.5, 189.3 ppm.

Compound 17 3-((4- Formyl 2-ido-6- Methoxyphenoxy ) methyl ) Benzamide  (3-((4-Formyl-2-iodo-6-methoxyphenoxy) methyl) benzamide)

5-Idovanillin (0.26 g, 0.94 mmol) and 3- (chloromethyl) benzamide (0.16 g, 0.94 mmol) were used to give a white solid compound 17 (0.28 g, 72.4%).

R _f 0.10 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (DMSO- d ₆ , 400 MHz) δ 3.88 (s, 3H), 5.09 (s, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.0, 8.0 Hz , 1H), 7.65 (ddd, J = 7.6, 1.6, 1.6 Hz 1H), 7.78 (ddd, J = 7.6, 1.2, 1.2, Hz 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.98 (dd , J = 1.6, 1.6 Hz, 1H), 9.76 (s, 1H); ¹³ C-NMR (400 MHz, DMSO- d ₆ ) 55.6, 73.6, 92.2, 111.0, 126.9, 127.3, 127.8, 131.1, 133.5, 113.6, 133.7, 136.2, 151.9, 152.4, 168.5, 189.1 ppm.

Synthesis Method 2 Synthesis Examples 1 to 19 (A1 to A19)

O-benzylated compound (1 equivalent) synthesized in Synthesis Method 1 above; 1 equivalent of 1- (2-aminoethyl) piperidine; 2- (2-aminoethyl) pyridine (2- (2-aminoethyl) pyridine); 2- (2-aminoethyl) thiophene (2- (2-aminoethyl) thiophene); Alternatively, (4-carboxyphenyl) methylamine ((4-carboxyphenyl) methylamime) was refluxed for 2 hours with ethanol as a solvent and then cooled at room temperature. Then, Synthesis Examples 1 to 19 corresponding to the imine compound were obtained by completely removing the solvent through reduced pressure (see Table 3).

Synthesis Example R R ₁ R ₂ R ₃ One 3-chlorophenyl OCH ₃ Br N-piperidinyl
(N-Piperidinyl) 2 3-chlorophenyl OCH ₃ I N-piperidinyl 3 3-ethoxycarbonylphenyl OCH ₃ Cl N-piperidinyl 4 3-ethoxycarbonylphenyl OCH ₃ Br N-piperidinyl 5 3-ethoxycarbonylphenyl OCH ₃ I N-piperidinyl 6 3-cyanophenyl OCH ₃ Cl N-piperidinyl 7 3-cyanophenyl OCH ₃ Br N-piperidinyl 8 3-cyanophenyl OCH ₃ I N-piperidinyl 9 3-fluorophenyl OCH ₃ Cl N-piperidinyl 10 3-chlorophenyl OCH ₃ Cl 2-thiophenyl
(2-thiophenyl) 11 3-chlorophenyl OCH ₃ Cl 2-pyridyl 12 3-chlorophenyl OCH ₃ H 2-thiophenyl 13 3-chlorophenyl OCH ₃ H 2-pyridyl 14 4-carbamoylphenyl OCH ₃ Cl N-piperidinyl 15 4-carbamoylphenyl OCH ₃ Br N-piperidinyl 16 4-carbamoylphenyl OCH ₃ I N-piperidinyl 17 3-carbamoylphenyl OCH ₃ Cl N-piperidinyl 18 3-carbamoylphenyl OCH ₃ Cl 2-thiophenyl 19 3-chlorophenyl OCH ₃ Cl 4-carboxyphenyl
(4-carboxyphenyl)

[ Synthesis Example  One] ( E ) -1- (3- Bromo -4-((3- Chlorobenzyl ) Oxy ) -5- Methoxyphenyl ) -N- (2- (pyridine-1-1.48yl) ethyl) methaneimine ((E) -1- (3- bromo -4-((3- chlorobenzyl ) oxy) -5-methoxyphenyl) -N- (2- (piperidin-1-1.48yl) ethyl) methanimine)

Synthesis Example 1 of brown syrup was obtained using compound 2 (208 mg, 0.59 mmol) and 1- (2-aminoethyl) piperidine (75 mg, 0.59 mmol) (260 mg, 95.4%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.48-1.51 (m, 2H), 1.67-1.72 (m, 4H), 2.61-2.63 (m, 4H), 2.77 (t, J = 7.2 Hz, 2H), 3.85 (t, J = 6.8 Hz. 2H), 3.92 (s, 3H), 5.03 (s, 2H), 7.29-7.32 (m, 2H), 7.33 (d, J = 1.6 Hz, 1H), 7.39 (ddd , J = 8.8, 1.6, 1.6 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H). 7.54-7.56 (m, 1 H), 8.19 (dd, J = 1.6, 1.2 Hz, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 23.9, 25.3, 54.4, 54.9, 56.4, 59.3, 74.1, 110.1, 118.2, 125.9, 126.5, 128.5, 128.7, 129.8, 133.5, 134.4, 139.1, 147.3, 154.1, 160.8 ppm.

[ Synthesis Example  2] ( E ) -1- (4-((3- Chlorobenzyl ) Oxy )-3 degrees-5- Methoxyphenyl ) -N- (2- (piperidin-1-yl) ethyl) Methaneimine  ((E) -1- (4-((3- Chlororobenzyl ) oxy) -3- iodo -5-methoxyphenyl) -N- (2- (piperidin-1-yl) ethyl) methanimine)

Synthesis Example 2 of brown syrup was obtained using compound 3 (205 mg, 0.51 mmol) and 1- (2-aminoethyl) piperidine (55 mg, 0.51 mmol) (260 mg, 99.6%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.48-1.51 (m, 2H), 1.65-1.70 (m, 4H), 2.57-2.61 (m, 4H), 2.75 (t, J = 7.2 Hz, 2H), 3.83 (t, J = 6.8 Hz. 2H), 3.91 (s, 3H), 5.01 (s, 2H), 7.30-7.32 (m, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7/41 -7.43 (m, 1H), 7.57-7.59 (m, 1H), 7.62 (d, J = 1.6 Hz, 1H), 8.17 (dd, J = 1.6, 1.6 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 23.9, 25.3, 54.4, 54.9, 56.3, 59.3, 73.9, 92.8. 111.2. 111.3, 126.6, 128.5, 128.8, 129.8, 131.7, 134.4, 139.1, 149.8, 153.0, 160.5 ppm.

[ Synthesis Example  3] ethyl ( E ) -3-((2- Chloro -6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imido) methyl) phenoxy) methyl) benzoate (Ethyl (E) -3-((2- chloro -6- methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzoate)

Synthesis Example 3 of yellow syrup was obtained using compound 4 (200 mg, 0.57 mmol) and 1- (2-aminoethyl) piperidine (73.5 mg, 0.57 mmol) (275 mg, quantitative).

R _f 0.18 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (t, J = 7.2 Hz, 3H), 1.44-1.48 (m, 2H), 1.59-1.63 (m, 4H), 2.50-2.53 (m, 4H), 2.67 (t, J = 7.2 Hz, 2H), 3.78 (t, J = 6.8 Hz. 2H), 3.92 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.12 (s, 2H), 7.24 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.40 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 7.44 (dd, J = 8.0, 8.0 Hz , 1H), 8.00 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H). 8.16 (br s, 1 H), 8.18 (dd, J = 2.0, 2.0 Hz, 1 H);

[ Synthesis Example  4] ethyl ( E ) -3-((2- Bromo -6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl ) Benzoate  (Ethyl (E) -3-((2- bromo -6- methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzoate)

Synthesis Example 4 of yellow syrup was obtained using compound 5 (200 mg, 0.51 mmol) and 1- (2-aminoethyl) piperidine (65.2 mg, 0.51 mmol) (252 mg, 98.2%).

R _f 0.18 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (t, J = 7.2 Hz, 3H), 1.44-1.48 (m, 2H), 1.59-1.65 (m, 4H), 2.52-2.54 (m, 4H), 2.68 (t, J = 7.2 Hz, 2H), 3.76 (t, J = 6.8 Hz. 2H), 3.92 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.11 (s, 2H), 7.34 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 8.0 Hz, 1H), 7.76 (ddd, J = 8.0, 1.2. 1.2 Hz , 1H), 8.01 (ddd, J = 8.0, 1.2. 1.2 Hz, 1H). 8.16 (br S, 1 H), 8.20 (dd, J = 1.2 1.2 Hz, 1 H);

[ Synthesis Example  5] ethyl ( E ) -3-((2-degree-6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl ) Benzoate  (Ethyl (E) -3-((2- iodo -6- methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzoate)

Synthesis Example 5 of yellow syrup was obtained (238 mg, 93.0%) using compound 6 (200 mg, 0.45 mmol) and 1- (2-aminoethyl) piperidine (58.3 mg, 0.45 mmol).

R _f 0.21 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (t, J = 7.2 Hz, 3H), 1.43-1.46 (m, 2H), 1.59-1.64 (m, 4H), 2.47-2.51 (m, 4H), 2.67 (t, J = 7.2 Hz, 2H), 3.77 (t, J = 6.8 Hz. 2H), 3.91 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.10 (s, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.0, 8.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.7 (ddd, J = 7.6, 1.6, 1.6 Hz , 1H), 8.01 (ddd, J = 7.6, 1.6, 1.6 Hz, 1H). 8.15 (br s, 1 H), 8.22 (dd, J = 1.2 1.2 Hz, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 14.6, 24.4, 26.0, 55.1, 56.3, 59.1. 59.8, 61.2, 74.2, 92.7, 110.2, 129.6, 129.5, 129.8, 130.8, 131.8, 133.1, 134.6, 137.4, 149.8, 153.0, 160.0, 166.7 ppm.

[ Synthesis Example  6] ( E ) -3-((2- Chloro -6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzonitrile (( E ) -3-((2- Chloro -6- methoxy -4-(((2- ( piperidin -1-yl) ethyl) imino) methyl) phenoxy) methyl) benzonitrile)

Synthesis Example 6 of yellow syrup was obtained using compound 7 (200 mg, 0.66 mmol) and 1- (2-aminoethyl) piperidine (85.0 mg, 0.66 mmol) (273 mg, quantitative).

R _f 0.15 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40-1.46 (m, 2H), 1.54-1.62 (m, 4H), 2.47-2.49 (m, 4H), 2.64 (t, J = 7.6 Hz, 2H), 3.76 (t, J = 7.6 Hz. 2H), 3.91 (s, 3H), 5.07 (s, 2H), 7.24 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.47 (dd, J = 8.0, 7.6 Hz, 1H), 7.60 (ddd, J = 7.6, 1.2, 1.2 Hz, 1H), 7.83 (br s, 1H), 8.18 (br s, 1 H);

[ Synthesis Example  7] ( E ) -3-((2- Bromo -6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzonitrile (( E ) -3-((2- Bromo -6- methoxy -4-(((2- ( piperidin -1-yl) ethyl) imino) methyl) phenoxy) methyl) benzonitrile)

 Synthesis Example 7 of a yellow syrup was obtained using compound 8 (200 mg, 0.58 mmol) and 1- (2-aminoethyl) piperidine (74.1 mg, 0.58 mmol) (265 mg, quantitative).

R _f 0.15 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.42-1.46 (m, 2H), 1.55-1.62 (m, 4H), 2.46-2.49 (m, 4H), 2.64 (t, J = 7.6 Hz, 2H), 3.74 (t, J = 7.6 Hz. 2H), 3.91 (s, 3H), 5.06 (s, 2H), 7.34 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 7.6 Hz, 1H), 7.61 (ddd, J = 7.6, 1.6, 1.2 Hz, 1H), 7.75 (ddd, J = 7.6, 2.0, 1.2 Hz, 1H), 7.85 (dd, J = 1.6, 1.2 Hz, 1 H), 8.16 (br s, 1 H);

[ Synthesis Example  8] ( E ) -3-((2-degree-6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzonitrile ((E) -3-((2- Iodo -6- methoxy -4-(((2- ( piperidin -1-yl) ethyl) imino) methyl) phenoxy) methyl) benzonitrile)

Synthesis Example 8 of yellow syrup was obtained using compound 9 (200 mg, 0.51 mmol) and 1- (2-aminoethyl) piperidine (65.2 mg, 0.51 mmol) (245 mg, 95.7%).

R _f 0.14 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.42-1.48 (m, 2H), 1.58-1.62 (m, 4H), 2.48-2.52 (m, 4H), 2.66 (t, J = 7.2 Hz, 2H), 3.77 (t, J = 7.2 Hz. 2H), 3.91 (s, 3H), 5.06 (s, 2H), 7.38 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 8.0, 7.6 Hz, 1H ), 7.61 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.88 (br s, 1H), 8.16 (br s , 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 24.4, 26.1, 55.1, 56.3, 59.1. 59.8, 73.3, 92.6, 110.9, 112.7, 119.0, 129.4, 131.8, 131.9, 132.0, 132.7, 134.9, 138.7, 149.3, 152.9, 159.9 ppm.

[ Synthesis Example  9] ( E ) -1- (3- Chloro -4-((3- Fluorobenzyl ) Oxy -5- Methoxyphenyl ) -N- (2- (piperidin-1-yl) ethyl) methaneimine (( E ) -1- (3- Chloro -4-((3- fluorobenzyl ) oxy) -5-methoxyphenyl) -N- (2- (piperidin-1-yl) ethyl) methanimine)

Synthesis Example 9 of yellow syrup was obtained using compound 10 (200 mg, 0.68 mmol) and 1- (2-aminoethyl) piperidine (87.0 mg, 0.68 mmol) (267 mg, 97.2%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.44-1.49 (m, 2H), 1.60-1.66 (m, 4H), 2.51-2.54 (m, 4H), 2.69 (t, J = 7.2 Hz, 2H), 3.80 (t, J = 7.2 Hz. 2H), 3.92 (s, 3H), 5.06 (s, 2H), 7.02 (dd, J = 7.6, 7.2 Hz, 1H), 7.25-7.33 (m, 5H), 8.18 (br s, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 24.2, 25.8, 55.0, 56.4, 58.8. 59.6, 74.2, 109.2, 115.3, 115.5, 123.1, 128.9, 130.8, 133.1, 139.7, 146.2, 154.6, 160.6, 161.8, 164.3 ppm.

[ Synthesis Example  10] ( E ) -1- (3- Chloro -4-((3- Chlorobenzyl ) Oxy ) -5- Methoxyphenyl ) -N- (2- (thiophen-2-yl) ethyl) methaneimine (( E ) -1- (3- Chloro -4-((3- chlorobenzyl ) oxy) -5-methoxyphenyl) -N- (2- (thiophen-2-yl) ethyl) methanimine)

Synthesis Example 10 of brown syrup was obtained (270 mg, quantitative) using compound 1 (200 mg, 0.64 mmol) and 2- (2-aminoethyl) thiophene (87.6 mg, 0.64 mmol).

R _f 0.68 (ethyl acetate: n-hexane = 1: 3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.24 (t, J = 7.2 Hz, 2H), 3.88 (t, J = 7.2 Hz. 2H), 3.93 (s, 3H), 5.05 (s, 2H), 6.83 -6.84 (m, 1H), 6.92 (dd, J = 6.0, 3.6 Hz, 1H), 7.14 (dd, J = 3.6, 1.6 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.29- 7.32 (m, 2 H), 7.34 (br s, 1 H), 7.36-7.39 (m, 1 H), 7.54-7.55 (m, 1 H), 8.07 (s, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 31.6, 56.5, 62.9, 74.2, 109.6, 123.9, 126.0, 126.4, 126.5, 127.0, 128.5, 128.6, 128.7, 128.9, 129.8, 132.9, 134.4, 138.8, 154.3, 154.6 , 160.3 ppm.

[ Synthesis Example  11] ( E ) -1- (3- Chloro -4-((3- Chlorobenzyl ) Oxy ) -5-methoxybenzyl) -N- (2- (pyridin-2-yl) ethyl) methanimine (( E ) -1- (3- Chloro -4-((3- chlorobenzyl ) oxy) -5-methoxyphenyl) -N- (2- (pyridin-2-yl) ethyl) methanimine)

Synthesis Example 11 of brown syrup was obtained using compound 1 (100 mg, 0.32 mmol) and 12- (2-aminoethyl) pyridine (40 mg, 0.32 mmol) (133 mg, quantitative).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 3.07 (t, J = 7.6 Hz, 2H), 3.88 (s, 3H), 3.93 (t, J = 7.6 Hz. 2H), 5.06 (s, 2H) , 7.20 (ddd, J = 7.2, 4.8, 1.2 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.41-7.43 (m, 3H), 7.54 (dd, J = 1.2, 1.2 Hz, 1H), 7.69 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 8.24 (s, 1H), 8.50 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H); ¹³ C-NMR (100 MHz, DMSO- d ₆ ) 56.2, 59.9, 73.3, 121.3, 121.4, 123.3, 126.7, 127.3, 127.8, 128.0, 130.2, 132.98, 132.9, 136.3, 139.3, 144.9, 149.0, 153.7, 159.3 , 159.5, ppm.

[ Synthesis Example  12] (E) -1- (4-((3- Chlororobenzyl ) oxy) -3- methoxyphenyl ) -N- (2- (thiophen-2-yl) ethyl) methanimine  ((E) -1- (4-((3- Chlororobenzyl ) oxy) -3-methoxyphenyl) -N- (2- (thiophen-2-yl) ethyl) methanimine)

Synthesis Example 12 of brown syrup was obtained (280 mg, quantitative) using compound 11 (200 mg, 0.72 mmol) and 2-2 (aminoethyl) thiophene (91.9 mg, 0.72 mmol).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.24 (t, J = 7.2 Hz, 2H), 3.86 (t, J = 7.2 Hz. 2H), 3.97 (s, 3H), 5.16 (s, 2H), 6.84 (dd, J = 2.4, 1.2 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.91 (dd, J = 5.2, 3.2 Hz, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (dd, J = 5.2, 1.2 Hz, 1H), 7.28-7.32 (m, 3H), 7.44 (dd, J = 1.6, 1.6 Hz, 1H), 7.52 (br s, 1H), 8.08 (s, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 31.8, 56.3, 62.9, 70.3, 109.6, 113.2, 123.1, 123.8, 125.3, 125.4, 126.9, 127.5, 128.4, 130.1, 130.3, 134.8, 139.0, 142.6, 150.2, 150.4 , 161.5 ppm.

[ Synthesis Example  13] ( E ) -1- (4-((3- Chlorobenzyl ) Oxy ) -3- Methoxyphenyl ) -N- (2- (pyridin-2-yl) ethyl) methaneimine (( E ) -1- (4-((3- Chlororobenzyl ) oxy) -3- methoxyphenyl ) -N- (2- (pyridin-2-yl) ethyl) methanimine)

Synthesis Example 13 of brown syrup was obtained using compound 11 (200 mg, 0.72 mmol) and 2- (2-aminoethyl) thiophene (88.3 mg, 0.72 mmol) (277 mg, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.18 (t, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.99 (t, J = 7.2 Hz. 2H), 5.14 (s, 2H), 6.83 (dd, J = 8.4 Hz, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (ddd, J = 8.8, 4.8, 1.2 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.27-7.321 (m, 3H), 7.41-7.44 (m, 2H), 7.57 (ddd, J = 8.0, 7.6, 2.0 Hz ,, 1H), 8.11 (br s, 1H), 8.55 (ddd, J = 4.8, 1.2, 1.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 40.0, 56.2, 61.2, 70.3, 109.5, 113.2, 121.5, 123.0, 123.9, 125.4, 127.5, 128.4, 130.1, 130.2, 134.8, 136.4, 139.0, 149.6, 150.1, 150.3 , 160.1, 161.4 ppm.

[ Synthesis Example  14] ( E ) -4-((2- Chloro -6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) Already Methyl) phenoxy) methyl) benzamide (( E ) -4-((2- Chloro -6- methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide)

Synthesis Example 14 of a pink solid was obtained using compound 12 (100 mg, 0.31 mmol) and 1- (2-aminoethyl) piperidine (40.1 mg, 0.31 mmol) (132 mg, 98.6%).

R _f 0.10 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.43-1.49 (m, 2H), 1.60-1.67 (m, 4H), 2.52-2.54 (m, 4H), 2.69 (t, J = 7.2 Hz, 2H), 3.77 (t, J = 6.8 Hz. 2H), 3.91 (s, 3H), 5.13 (s, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 8.17 (br s, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 22.3, 22.7, 29.9, 54.0, 56.5, 74.5, 109.7, 126.0, 128.4, 129.4, 132.9, 133.3, 140.9, 149.4, 154.6, 168.9 ppm.

[ Synthesis Example  15] ( E ) -4-((2- Bromo -6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide (( E ) -4-((2- Bromo -6- methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide)

Synthesis Example 15 of a pale yellow solid was obtained using compound 13 (100 mg, 0.27 mmol) and 1- (2-aminoethyl) piperidine (35.2 mg, 0.27 mmol) (123 mg, 97.3%).

R _f 0.06 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.47-1.52 (m, 2H), 1.63-1.69 (m, 4H), 2.51-2.54 (m, 4H), 2.72 (t, J = 7.2 Hz, 2H), 3.82 (t, J = 6.8 Hz. 2H), 3.91 (s, 3H), 5.13 (s, 2H), 7.34 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 8.18 (br s, 1H);

[ Synthesis Example  16] ( E ) -4-((2-degree-6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) Benzamide  (( E ) -4-((2- Iodo -6- methoxy -4-(((2- ( piperidin -1-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide)

Compound 14 (100 mg, 0.24 mmol) and 1- (2-aminoethyl) piperidine (31.2 mg, 0.24 mmol) gave a pale yellow solid Synthesis Example 16 (128 mg, quantitative).

R _f 0.08 (ethyl acetate: n-hexane = 1: 1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.47-1.53 (m, 2H), 1.64-1.67 (m, 4H), 2.56-2.60 (m, 4H), 2.74 (t, J = 6.8 Hz, 2H), 3.83 (t, J = 7.2 Hz. 2H), 3.91 (s, 3H), 5.11 (s, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 8.17 (br s, 1H);

[ Synthesis Example  17] ( E ) -3-((2- Chloro -6- Methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide (( E ) -3-((2- Chloro -6- methoxy -4-(((2- (piperidin-1-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide)

Compound 15 (100 mg, 0.31 mmol) and 1- (2-aminoethyl) piperidine (40 mg, 0.31 mmol) gave Brown Syrup Synthesis 17 (97 mg, 72.1%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.41-1.44 (m, 2H), 1.58-1.63 (m, 4H), 2.58-2.62 (m, 4H), 2.81 (t, J = 6.8 Hz, 2H), 3.86 (t, J = 6.8 Hz. 2H), 3.92 (s, 3H), 5.13 (s, 2H), 7.26 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 7.6, 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.79 (dd, J = 7.6, 1.6 Hz, 1H), 7.96 (br s, 1H), 8.19 ( br s, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 22.8, 23.4, 54.2, 54.8, 56.5, 58.9, 74.5, 109.7, 122.9, 126.0, 127.3, 127.4, 128.9, 129.0, 132.1, 132.9, 133.7, 149.4, 154.3, 169.2 ppm.

[ Synthesis Example  18] ( E ) -3-((2- Chloro -6- methoxy -4-(((2- ( thiophen -2-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide  (( E ) -3-((2- Chloro -6- methoxy -4-(((2- (thiophen-2-yl) ethyl) imino) methyl) phenoxy) methyl) benzamide)

Synthesis Example 18 of foamy semi-solid was obtained using compound 15 (100 mg, 0.31 mmol) and 2- (2-aminoethyl) thiophene (39.8 mg, 0.31 mmol) (93 mg, 69.3%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.24 (t, J = 6.8 Hz, 2H), 3.88 (t, J = 6.8 Hz. 2H), 3.94 (s, 3H), 5.14 (s, 2H), 6.83 (dd, J = 3.2, 1.2 Hz, 1H), 6.93 (dd, J = 5.2, 3.6 Hz, 1H), 7.14 (dd, J = 4.8, 1.2 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 8.0, 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1 H), 7.97 (br s, 1 H), 8.06 (s, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 30.8, 56.6, 60.6, 74.6, 109.7, 124.1, 125.6, 126.0, 127.3, 127.4, 127.5, 128.9, 129.4, 131.9, 132.0, 132.9, 133.7, 137.5, 149.4, 154.6 , 169.1 ppm.

[ Synthesis Example  19] ( E ) -4-(((3- Chloro -4-((3- Chlorobenzyl ) Oxy ) -5- Methoxybenzylidene ) Amino) methyl) benzoic Acid  (( E ) -4-(((3- Chloro -4-((3- chlorobenzyl ) oxy) -5-methoxybenzylidene) amino) methyl) benzoic acid)

White solid synthesis example 19 was prepared using compound 1 (200 mg, 0.64 mmol), 4- (aminomethyl) benzoic acid (39.8 mg, 0.31 mmol), and triethylamine (65 mg, 0.64 mmol). Obtained (40 mg, 14.0%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 3.85 (s, 3H), 4.77 (s, 2H), 4.96 (s, 2H), 7.22-7.26 (m, 2H), 7.27-7.28 (d, J = 8.0 Hz, 2H), 7.32 (m, 2H), 7.45-7.46 (m, 2H), 7.93 (d, J = 8.0 Hz, 2H), 8.22 (br s, 1H);

Example 4 Confirmation of the inhibition of HAT p300 of Synthesis Examples 1 to 19

After diluting Synthesis Examples 1 to 19 to 100 μM, the degree of activity inhibition of HAT p300 was confirmed in the same manner as in [2-1], and the results are shown in FIG. 9. Here, in place of Synthesis Examples 1 to 19 as a control, C646 and candidate substance 12 (HAT-12) were treated.

As shown in FIG. 9, the degree of inhibition of HAT p300 activity of Synthesis Examples 1 to 19 (A 1 to A 19) corresponded to 50% on average. In particular, the synthesis examples 6 to 8 showed a degree of inhibition of HAT p300 activity of 80%, which is almost similar to candidate 12 (HAT 12). Furthermore, in the case of Synthesis Example 19 (A 19), HAT p300 activity was suppressed by 90% or more.

Through the above results, the novel synthetic compound according to the present invention is improved to allow additional hydrogen bonding with R1410, T1411, W1466, and Y1467 of HAT p300, thereby more effectively inhibiting the activity of HAT p300, and thereby HAT p300 It can be seen that it can be used very effectively for the prevention, amelioration or treatment of a disease associated with.

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that such a specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereto. Therefore, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (12)

A compound selected from a compound represented by the following formula (2), a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate and a solvate thereof:
[Formula 2]

In Chemical Formula 2,
R ₁ is the following Chemical Formula 3 or a substituted phenyl group;
[Formula 3]

R ₂ is halogen;
R ₃ is halogen or cyano group (—CN);
When R ₁ is Chemical Formula 3, R ₃ is a cyano group (-CN),
When R ₁ is a substituted phenyl group, R ₃ is halogen,
The substituted phenyl group is substituted with-(COOH). delete delete delete The method of claim 1,
The compound is any one selected from the group consisting of:

,

,

,

. A compound for inhibiting histone acetyltransferase p300 selected from a compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof:
[Formula 2]

In Chemical Formula 2,
R ₁ is the following Chemical Formula 3 or a substituted phenyl group;
[Formula 3]

R ₂ is halogen;
R ₃ is halogen or cyano group (—CN);
When R ₁ is Chemical Formula 3, R ₃ is a cyano group (-CN),
When R ₁ is a substituted phenyl group, R ₃ is halogen,
The substituted phenyl group is substituted with-(COOH). A pharmaceutical composition for preventing or treating a histone acetyltransferase p300 related disease comprising a compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof as an active ingredient,
The histone acetyltransferase p300-related disease is fibrosis, the pharmaceutical composition for preventing or treating histone acetyltransferase p300-related diseases:
[Formula 2]

In Chemical Formula 2,
R ₁ is the following Chemical Formula 3 or a substituted phenyl group;
[Formula 3]

R ₂ is halogen;
R ₃ is halogen or cyano group (—CN);
When R ₁ is Chemical Formula 3, R ₃ is a cyano group (-CN),
When R ₁ is a substituted phenyl group, R ₃ is halogen,
The substituted phenyl group is substituted with-(COOH). delete The method of claim 7, wherein
The fibrosis includes pulmonary fibrosis, uterine fibroids, myelofibrosis, liver fibrosis, Liver fibrosis, heart fibrosis, multiple sclerosis, Kidney fibrosis, cystic fibrosis Pharmaceutical composition, which is at least one selected from the group consisting of spleen fibrosis caused by neutropenia, skeletal muscle fibrosis, skin sclerosis, dermatitis, mediastinal fibrosis and sickle cell anemia. The method of claim 9,
The pulmonary fibrosis includes Idiopathic Pulmonary Fibrosis, Nonspecific Interstitial Pneumonia, Acute Interstitial Pneumonia, Cryptogenic Organizing Pneumonia, Respiratory bronchiolitis At least one selected from the group consisting of Respiratory Bronchiolitisassociated Interstitial Lung, Desquamative Interstitial Pneumonia, Lymphoid Interstitial Pneumonia, Interstitial Pulmonary Fibrosis and Diffuse Pulmonary Fibrosis. Pharmaceutical composition. As a food composition for preventing or ameliorating a histone acetyltransferase p300 related disease comprising a compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof as an active ingredient,
The histone acetyltransferase p300-related disease is fibrosis, food composition for preventing or improving histone acetyltransferase p300-related diseases:
[Formula 2]

In Chemical Formula 2,
R ₁ is the following Chemical Formula 3 or a substituted phenyl group;
[Formula 3]

R ₂ is halogen;
R ₃ is halogen or cyano group (—CN);
When R ₁ is Chemical Formula 3, R ₃ is a cyano group (-CN),
When R ₁ is a substituted phenyl group, R ₃ is halogen,
The substituted phenyl group is substituted with-(COOH). A cosmetic composition for preventing or ameliorating a histone acetyltransferase p300 related disease comprising a compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof as an active ingredient,
The histone acetyltransferase p300-related disease is fibrosis, cosmetic composition for preventing or improving histone acetyltransferase p300-related diseases:
[Formula 2]

In Chemical Formula 2,
R ₁ is the following Chemical Formula 3 or a substituted phenyl group;
[Formula 3]

R ₂ is halogen;
R ₃ is halogen or cyano group (—CN);
When R ₁ is Chemical Formula 3, R ₃ is a cyano group (-CN),
When R ₁ is a substituted phenyl group, R ₃ is halogen,
The substituted phenyl group is substituted with-(COOH).

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