KR20230159803A - Quinoline-based histone deacetylase inhibitory compounds, method for preparing the same, and pharmaceutical composition comprising the same as the active ingredient - Google Patents

Abstract

The present invention relates to a quinoline derivative, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient for the prevention or treatment of cancer, autoimmune disease, fibrosis, and neurodegenerative disease. The compound represented by Formula 1 described herein It selectively inhibits HDAC6 and HDAC8 and shows excellent effects, so it is expected to be useful for cancer, autoimmune diseases, fibrosis, and degenerative nerve diseases.

Description

Quinoline-based histone deacetylase inhibitory compound, method for preparing the same, and pharmaceutical composition comprising the same as an active ingredient {Quinoline-based histone deacetylase inhibitory compounds, method for preparing the same, and pharmaceutical composition comprising the same as the active ingredient}

The present invention relates to a quinoline derivative, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient for the prevention or treatment of cancer, autoimmune disease, fibrosis, and neurodegenerative disease.

Histone deacetylase (HDAC) is an enzyme that regulates the balance of acetylation and deacetylation of histone and non-histone proteins by promoting the hydrolysis of the ε-amide bond of lysine residues, contributing to gene expression and differentiation, It plays an important role in maintaining cellular homeostasis. HDAC is classified into four classes: Class I (HDAC1,2,3,8), Class II (HDAC4,5,6,7,9,10) and Class IV (HDAC11) are dependent on zinc ions, and Class III ( SIRT1-7) is dependent on NAD.

HDAC is overexpressed in various cancers and plays a key role in cancer formation, progression, and metastasis by participating in cell proliferation, differentiation, apoptosis, and cancer cell invasion. In addition, HDAC is an important regulator of the immune response, mainly regulating the innate immune response through the Toll-like receptor (TLR) signaling system and the interferon (IFN) signaling system, and the acquired immune response via the T cell receptor (TCR) signaling system. Regulates immune response. Therefore, HDAC is an important drug target for the development of anti-cancer and anti-inflammatory drugs, and research and development are being actively conducted.

Currently, a number of HDAC inhibitors have been reported for anticancer purposes and are in clinical development. To date, five types of HDAC inhibitors (Vorinostat, Belinostat, Panobinostat, Romidepsin, and Pracinostat) have been developed and used as treatments for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). However, all approved drugs currently in clinical use are non-selective inhibitors, and numerous side effects have been reported, including fatigue, nausea, vomiting, and cardiac toxicity. It is reported that this is largely due to a lack of HDAC isozyme selectivity, and the development of a selective inhibitor to solve this problem is required.

HDAC6 and HDAC8 act as key factors in various carcinomas, inflammation, and immune responses, and the development of their selective inhibitors is attracting attention as an important approach to developing selective treatments for diseases with reduced side effects. In particular, HDAC6 and HDAC8 are overexpressed in certain carcinomas, including ovarian cancer, breast cancer, and uterine cancer, and promote cancer metastasis by increasing microtubule dynamics and causing cell invasion and metastasis. In addition, HDAC6 is mainly involved in the innate immune response and HDAC8 is mainly involved in the innate or adaptive immune response, so HDAC6 and HDAC8 inhibitors can be used to develop treatments for various inflammatory diseases. When cancer cells are treated with HDAC inhibitors, the expression of PD-L1 increases, increasing the sensitivity of immunotherapy agents and increasing the efficacy of anticancer immunotherapy agents, making it an appropriate anticancer agent for combination therapy. In addition, HDAC6 is overexpressed in Alzheimer's disease patients and animal models, and a close relationship with Parkinson's disease has been reported. When treated with an HDAC6 inhibitor in an animal model of Alzheimer's disease, amyloid plaques and neurofibrillary tangles, which are typical pathological characteristics of Alzheimer's disease, were improved. As such, HDAC6 is known to play an important role in various diseases such as cancer, autoimmune diseases, fibrosis, and neurodegenerative disorders (Santo et al., Blood 2012 119: 2579-258; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).

Accordingly, the inventors of the present invention developed a novel HDAC inhibitor with improved efficacy and selectivity for the purpose of developing treatments for various neurodegenerative diseases including cancer, autoimmune disease, fibrosis, Alzheimer's disease, and Parkinson's disease, and the present invention It was discovered that the novel HDAC inhibitor specifically targets HDAC6 and HDAC8, exhibits the desired level of drug efficacy, and is excellent for preventing or treating cancer, autoimmune diseases, fibrosis, and neurodegenerative diseases. The invention was completed.

The purpose of the present invention is to provide a novel quinoline derivative that selectively inhibits HDAC6 and HDAC8.

Another object of the present invention is to provide a method for producing a novel quinoline derivative that selectively inhibits HDAC6 and HDAC8.

Another object of the present invention is to provide a novel pharmaceutical composition for preventing or treating cancer, autoimmune diseases, fibrosis, and neurodegenerative diseases.

Another object of the present invention is to provide a novel health functional food composition for preventing or improving cancer, autoimmune diseases, fibrosis, and neurodegenerative diseases.

In order to achieve the above purpose,

The present invention provides a compound represented by the following formula (1), a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

X is hydrogen or halogen;

Y is -CH=CH- or -CH ₂ CH ₂ -;

R is hydrogen, unsubstituted or substituted C6-C10 aryl or 5-10 membered heteroaryl,

Here, the substituted C6-C10 aryl and 5-10 membered heteroaryl are halogen, unsubstituted or substituted C1-C10 alkyl or C1-C10 alkoxy,

At this time, the substituted C1-C10 alkyl and C1-C10 alkoxy are substituted with one or more selected from the group consisting of halogen, C3-C10 cycloalkyl, and C6-C10 aryl.

In another aspect, the present invention is as shown in Scheme 1 below,

Provided is a method for producing a compound represented by Formula 1, which includes the step of reacting a compound represented by Formula 2 to produce a compound represented by Formula 1.

[Scheme 1]

In Scheme 1 above,

X, Y and R are as defined in Formula 1 above.

In another aspect, the present invention provides a method for preventing cancer, autoimmune disease, fibrosis, and neurodegenerative disease containing the compound represented by Formula 1, its solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. Alternatively, a pharmaceutical composition for treatment is provided.

In another aspect, the present invention provides a method for preventing cancer, autoimmune disease, fibrosis, and neurodegenerative disease containing the compound represented by Formula 1, its solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. Alternatively, a health functional food composition for improvement is provided.

The compound represented by Formula 1 described herein exhibits selective and excellent inhibitory activity against HDAC6 and HDAC8, and is expected to be useful for cancer, autoimmune diseases, fibrosis, and neurodegenerative diseases.

Hereinafter, the present invention will be described in detail.

Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Additionally, the embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the relevant technical field.

Furthermore, “including” a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless specifically stated to the contrary.

The terms “alkylene”, “alkenyl” or “alkyl” include straight or branched chain saturated hydrocarbon moieties, unless otherwise specified. For example, “C1-6alkyl” means alkyl with a skeleton of 1 to 6 carbons. Specifically, C1-6alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, It may include hexyl, etc.

The term “cycloalkyl,” unless otherwise specified, includes carbocyclic groups containing carbon atoms. For example, “C3-C8 cycloalkyl” means cycloalkyl with a skeleton of 3 to 8 carbons. Specifically, C3-C8 cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "heteroaryl", unless otherwise specified, refers to an aromatic ring having one or more aromatic rings containing 1, 2 or 3 ring heteroatoms selected from N, O or S or an aromatic ring of 2 or 3 fused rings. May contain radicals.

One embodiment of the present invention,

Provided is a compound represented by the following formula (1), a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

X is hydrogen or halogen;

Y is -CH=CH- or -CH ₂ CH ₂ -;

R is hydrogen, unsubstituted or substituted C6-C10 aryl or 5-10 membered heteroaryl,

Here, the substituted C6-C10 aryl and 5-10 membered heteroaryl are halogen, unsubstituted or substituted C1-C10 alkyl or C1-C10 alkoxy,

At this time, the substituted C1-C10 alkyl and C1-C10 alkoxy are substituted with one or more selected from the group consisting of halogen, C3-C10 cycloalkyl, and C6-C10 aryl.

Another embodiment of the present invention is,

In Formula 1,

X is hydrogen or halogen;

Y is -CH=CH- or -CH ₂ CH ₂ -;

R is hydrogen, unsubstituted or substituted C6 aryl or 5-6 membered heteroaryl,

Here, the substituted C6aryl and 5-6 membered heteroaryl are halogen, unsubstituted or substituted C1-C5alkyl or C1-C5alkoxy;

In this case, the substituted C1-C5 alkyl and C1-C5 alkoxy are compounds substituted with one or more selected from the group consisting of halogen, C3-C6 cycloalkyl, and C6 aryl, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable compound thereof. Available salts are provided.

Another embodiment of the present invention is,

In Formula 1,

X is hydrogen or F;

Y is -CH=CH- or -CH ₂ CH ₂ -;

R is hydrogen, unsubstituted or substituted phenyl, pyridinyl or thiophenyl,

wherein the substituted phenyl, pyridinyl and thiophenyl are Cl, unsubstituted or substituted methyl, ethyl, methoxy or ethoxy;

At this time, the substituted methyl, ethyl, methoxy and ethoxy provide a compound substituted with one or more selected from the group consisting of F, cyclopropyl and phenyl, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof. do.

Another embodiment of the present invention is,

In Formula 1,

X is hydrogen or F;

Y is -CH=CH- or -CH ₂ CH ₂ -;

R is hydrogen, , , , , , , , , , , , , , , , , or A phosphorus compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is provided.

Another embodiment of the present invention is,

In Formula 1,

The compound represented by Formula 1 provides a compound selected from the group of compounds below, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

<1> N -hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propenamide;

<2> N -hydroxy-3-(2-phenylquinolin-4-yl)propenamide;

<3> N -hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propanamide;

<4> N -hydroxy-3-(2-phenylquinolin-4-yl)propanamide;

<5> N -Hydroxy-3-(2-(3-chlorophenyl)quinolin-4-yl)propanamide;

<6> N -Hydroxy-3-(2-(3-methoxyphenyl)quinolin-4-yl)propanamide;

<7> N -Hydroxy-3-(2-(3-ethoxyphenyl)quinolin-4-yl)propanamide;

<8> N -Hydroxy-3-(2-(3-trifluoromethylphenyl)quinolin-4-yl)propanamide;

<9> N -Hydroxy-3-(2-(3-cyclopropylmethoxyphenyl)quinolin-4-yl)propanamide;

<10> N -Hydroxy-3-(2-(4-chlorophenyl)quinolin-4-yl)propanamide;

<11> N -Hydroxy-3-(2-(4-methoxyphenyl)quinolin-4-yl)propanamide;

<12> N -Hydroxy-3-(2-(4-ethoxyphenyl)quinolin-4-yl)propanamide;

<13> N -Hydroxy-3-(2-(4-trifluoromethylphenyl)quinolin-4-yl)propanamide;

<14> N -Hydroxy-3-(2-(4-cyclopropylmethoxyphenyl)quinolin-4-yl)propanamide;

<15> N -Hydroxy-3-(2-( m -tolyl)quinolin-4-yl)propanamide;

<16> N -Hydroxy-3-(2-(3-trifluoromethoxyphenyl)quinolin-4-yl)propanamide;

<17> N -Hydroxy-3-(2-(3-phenoxyphenyl)quinolin-4-yl)propanamide;

<18> N -Hydroxy-3-(2-( p -tolyl)quinolin-4-yl)propanamide;

<19> N -Hydroxy-3-(2-(4-trifluoromethoxyphenyl)quinolin-4-yl)propanamide;

<20> N -Hydroxy-3-(2-(thiophen-3-yl)quinolin-4-yl)propanamide;

<21> 3-(7-fluoro-2-phenylquinolin-4-yl) -N -hydroxypropanamide;

<22> 3-(7-fluoro-2-(4-methoxyphenyl)quinolin-4-yl) -N -hydroxypropanamide;

<23> 3-(7-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- N -hydroxypropanamide

<24> 3-(7-fluoro-2-(p-tolyl)quinolin-4-yl)- N -hydroxypropanamide

<25> 3-(6-fluoro-2-phenylquinolin-4-yl) -N -hydroxy-propanamide

<26> 3-(6-fluoro-2-(4-methoxyphenyl)quinolin-4-yl) -N -hydroxypropanamide;

<27> 3-(6-fluoro-2-(3-methoxyphenyl)quinolin-4-yl) -N -hydroxypropanamide;

<28> 3-(6-fluoro-2-( p -tolyl)quinolin-4-yl) -N -hydroxypropanamide; and

<29> 3-(2-(4-chlorophenyl)-6-fluoroquinolin-4-yl))- N -hydroxypropanamide.

Another embodiment of the present invention is,

As shown in Scheme 1 below,

Provided is a method for producing a compound represented by Formula 1, which includes the step of reacting a compound represented by Formula 2 to produce a compound represented by Formula 1.

[Scheme 1]

In Scheme 1 above,

X, Y and R are as defined in Formula 1 above.

Another embodiment of the present invention is,

A pharmaceutical composition for the prevention or treatment of cancer, autoimmune disease, fibrosis, and neurodegenerative disease, containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

The above cancers include pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, and acute lymphocytic leukemia. , basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, and ampullary carcinoma of Vater. , bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinonasal cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney Cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, Gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, Spinal cord cancer, acoustic neurula, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyomas, laryngeal cancer, pleural cancer, It may be one or more types selected from the group consisting of blood cancer and thymic cancer.

The autoimmune diseases include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplant rejection. , graft-versus-host disease (GVHD), lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary tract. It may be one or more types selected from the group consisting of sexual cirrhosis, allergic conjunctivitis, and atopic dermatitis.

The fibrosis includes pulmonary fibrosis, idiopathic pulmonary fibrosis, irradiation-induced lung damage or pulmonary fibrosis, pulmonary edema, cystic fibrosis, liver fibrosis, endomyocardial fibrosis, myocardial infarction, atrial fibrosis, glial scar, renal fibrosis, and bone marrow. It may be one or more types selected from the group consisting of fibrosis, articular fibrosis, fatty fibrosis, skin fibrosis, nerve fibrosis, and muscle fibrosis.

The neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Wilson disease, neurodegeneration due to traumatic brain injury, neurodegeneration due to spinal cord injury, neurodegeneration due to stroke, and amyotrophic lateral cord injury. It may be one or more types selected from the group consisting of cirrhosis, human immunodeficiency virus dementia, Huntington's disease, multiple sclerosis, cerebral amyloid angiopathy, and tauopathy.

Another embodiment of the present invention is,

Provided is a pharmaceutical composition for preventing or treating diseases caused by hyperactivation of HDAC6 or HDAC8, containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the term "containing as an active ingredient" means containing in a dosage range that brings about the effect of preventing, improving, or treating cancer, and the dosage range may vary depending on the severity and formulation, and application. The number of times may vary depending on the age, weight, and constitution of the subject.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.

In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is determined by the type and severity of the individual, age, It can be determined based on factors including gender, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts of 0.001 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg/kg, or 0.1 mg/kg to 1 mg/kg are included. The upper quantitative limit of the pharmaceutical composition of the present invention can be selected and implemented by a person skilled in the art within an appropriate range.

The pharmaceutical composition according to the present invention may contain an effective amount of the compound represented by Formula 1 alone or may include one or more pharmaceutically acceptable carriers, excipients, or diluents.

The pharmaceutically acceptable carrier, excipient, or diluent refers to a substance that is physiologically acceptable and does not typically cause gastrointestinal upset, allergic reactions such as dizziness, or similar reactions when administered to humans. Examples of the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Examples include, but are not limited to, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.

A pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you do it.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form. It can be manufactured with The composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.

In the present invention, the term "prevention" refers to the administration, ingestion, or application of the pharmaceutical composition or health functional food composition of the present invention to an individual who is not suffering from cancer, autoimmune disease, fibrosis, or neurodegenerative disease, thereby preventing cancer, It means preventing symptoms of cancer from occurring in advance by suppressing or blocking the symptoms of autoimmune disease, fibrosis, and degenerative nerve disease.

In the present invention, the term "treatment" refers to the treatment of cancer, autoimmune disease, fibrosis or neurodegenerative disease as a result of administering the pharmaceutical composition of the present invention to an individual suffering from cancer, autoimmune disease, fibrosis or neurodegenerative disease. It includes complete cure of symptoms as well as partial cure, improvement, and relief of cancer symptoms.

Furthermore, the compound represented by Formula 1 can be used not only in the form of its pharmaceutically acceptable salt, but also in the form of solvates, hydrates, etc. that can be prepared therefrom.

The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain more than 1 equivalent of water, preferably 1 to 5 equivalents of water. Such hydrates can be prepared by crystallizing the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

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

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedio acids. Non-toxic organic acids such as ate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol Includes nitrate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

The acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

In addition, a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, its solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or used as an additive to other therapeutic agents in use. It can be used in combination with , and the effect can be enhanced by combined administration.

One embodiment of the present invention,

A health functional food composition for preventing or improving cancer, autoimmune disease, fibrosis, and neurodegenerative disease, containing the compound represented by Formula 1, its solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. provides.

In the present invention, the term "improvement" means administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to an individual suffering from cancer, autoimmune disease, fibrosis, or neurodegenerative disease. It is meant to include alleviating or relieving the symptoms of inflammatory or degenerative neurological diseases.

The term “health functional food” refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with the Health Functional Food Act, and the term “functional” refers to food that is useful for the structure and function of the human body. It means ingestion for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects. The health functional food or health supplement food of the present invention obtained in this way is very useful because it can be consumed on a daily basis.

There are no particular restrictions on the type of food, and it includes all health functional foods in the conventional sense.

* Matters mentioned in the pharmaceutical composition and health functional food composition of the present invention apply equally unless they contradict each other.

Another embodiment of the present invention is,

Prevention of cancer, autoimmune disease, fibrosis, and neurodegenerative disease, including the step of administering a compound represented by Formula 1 described herein, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to a subject in need. Provides treatment methods.

Another embodiment of the present invention is,

A compound represented by Formula 1 described herein, a solvate thereof, a hydrate thereof, or a pharmaceutical thereof for use in the manufacture of a medicament for use in the prevention or treatment of cancer, autoimmune disease, fibrosis, and neurodegenerative disease. Provides an acceptable use of salt.

For the above method or use, the detailed description of the pharmaceutical composition described above may be applied.

Hereinafter, the present invention will be described in detail through production examples, examples and experimental examples.

However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Preparation Examples, Examples and Experimental Examples.

<Manufacturing example>

Most reagents and solvents were purchased from Sigma-Aldrich Chemicals and used without further purification. Unless otherwise specified, all anhydrous solvents were distilled under nitrogen gas. Ethyl alcohol, dichloroethane and triethylamine were distilled from calcium hydride under nitrogen gas. Column chromatography was performed using silica gel 60 (230-400 mesh, Merck). Thin layer chromatography (TLC) was performed using Kieselgel 60 F254 plates (Merck). Infrared (IR) spectra were measured with a JASCO FT/IR 430 spectrophotometer. NMR spectra were measured on a Bruker 500 spectrometer ( ¹ H 500 MHz and ¹³ C 125 MHz). Chemical shifts are expressed in parts per million (ppm, δ) relative to the internal standard, tetramethylsilane. ¹ H-NMR data includes chemical shifts, multiplicities (s, singlet, d, doublet, t, triplet, q, quartet, m, multiplet and/or multiple resonance), proton number and coupling constant ( Hz) are displayed in order.

<Preparation Example 1> Preparation of meta- or para-substituted acetophenone

[Scheme 2]

CS ₂ CO ₃ (1.0 equivalent) was added to a solution of (meta or para)-hydroxyacetophenone (1.0 equivalent) in DMF (0.5M). After stirring for 15 minutes, bromoethane or (bromethyl)cyclopropane (2.0 equiv) was added and the reaction mixture was stirred at room temperature for 3-6 hours. The reaction mixture was diluted with water at 0°C and extracted three times with ethyl acetate. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc) to obtain the desired compound.

Illustratively, meta-hydroxyacetophenone and bromoethane were reacted using the preparation method of Preparation Example 1 to obtain 1-(3-ethoxyphenyl)ethanone as a yellow oil with a yield of 63%.

R _f = 0.66 ( n -Hexane/EtOAc = 2:1), ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.53 - 7.51 (m, 1H), 7.49 - 7.46 (m, 1H), 7.37- 7.34 (m , 1H), 7.10 (ddd, J = 8.2, 2.6, 0.7 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 197.33, 158.79, 138.07, 129.17, 120.50, 119.46, 112.74, 63.21, 26.24, 14.35.

<Preparation Example 2> Pfitzinger reaction

[Scheme 3]

To a suspension of indoline-2,3-dione (1.0 equiv) in 33% potassium hydroxide (KOH) solution was slowly added various substituted acetophenones (1.2 equiv) in ethanol (0.5 M). The resulting reaction mixture was heated to 80° C. for 8-24 hours and checked by TLC. The solvent was concentrated in vacuo and the residue was dissolved in water, extracted three times with diethyl ether, and the aqueous layer was acidified to pH 2 with hydrochloride. The resulting precipitate was filtered, dried, and recrystallized with ethanol to obtain a series of 2-arylquinoline-4-carboxylic acid hydrochlorides (Preparation Examples 2-1 to 2-12).

Illustratively, indoline-2,3-dione and 1-(pyridin-4-yl)ethan-1-one were reacted using the preparation method of Preparation Example 2 to produce 2-pyridin-4-yl as a dark red solid. -Quinoline-4-carboxylic acid hydrochloride was obtained in 45.0% yield.

R _f = 0.23 (EtOAc/MeOH= 5:1), ¹ H NMR (500 MHz, DMSO) δ 14.14 (s, 1H), 8.82 -8.82 (m, 2H), 8.68 (d, J =8.4, 1H) , 8.58 (s, 1H), 8.34 -8.33 (m, 2H), 8.24 (d, J =8.4, 1H), 7.94 -7.91 (m, 1H), 7.81 -7.78 (m, 1H); ¹³ C NMR (125 MHz, DMSO) δ 167.37, 153.49, 150.30, 148.30, 138.15, 130.56, 130.01, 128.67, 125.44, 124.09, 119.09.

<Preparation Example 3> Esterification reaction

[Scheme 4]

A mixture of 2-substituted quinoline-4-carboxylic acid hydrochloride (1.0 equiv) and thionyl chloride (2.0 equiv) in anhydrous dichloromethane (0.5 M) was heated at 80°C for 2-4 hours. Excess SOCl ₂ and dichloromethane were removed under reduced pressure to obtain the corresponding acid chloride intermediate. Then, the acid chloride intermediate was dissolved in anhydrous ethanol (0.5M) and triethylamine (1.0 equivalent) was added at room temperature for 0.5-2 hours. The reaction mixture was diluted with dichloromethane and washed with aqueous NaHCO ₃ solution and finally with brine solution. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane/EtOAc) to obtain the desired compound.

Illustratively, 2-pyridin-4-yl-quinoline-4-carboxylic acid hydrochloride obtained in Preparation Example 2-1 was reacted with the preparation method of Preparation Example 3 to produce ethyl 2-pyridin-4-yl as a pale yellow solid. Quinoline-4-carboxylate was obtained in 90.0% yield.

R _f = 0.41 ( n -hexane/EtOAc = 1:1), ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.81 -8.80 (m, 2H), 8.78 (d, J = 8.5 Hz, 1H), 8.40 ( s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.10 -8.09 (m, 2H), 7.81 (ddd, J = 8.5, 7.0, 1.3 Hz, 1H), 7.68 (ddd, J = 8.5, 7.0, 1.3 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.52 (t, J = 7.1 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 166.02, 153.84, 150.57, 149.21, 145.73, 136.52, 130.52, 130.25, 128.66, 125.49, 124.68, 121.40, 119.5 5, 62.08, 14.30.

<Preparation Example 4> Reduction reaction

[Scheme 5]

NaBH ₄ (3.0 equivalent) was added to a solution of ethyl 2-substituted quinoline-4-carboxylate (1.0 equivalent) prepared in Preparation Examples 3-1 to 3-13 in THF/EtOH (0.5M). was added little by little with constant stirring. The reaction mixture was stirred at room temperature for 1-5 hours and quenched with water. The aqueous layer was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous MgSO ₄ and evaporated under reduced pressure to obtain the compound.

Illustratively, ethyl 2-pyridin-4-ylquinoline-4-carboxylate obtained in Preparation Example 3-1 was reacted with the preparation method of Preparation Example 4 to produce (2-pyridin-4-yl-quinoline) as a white solid. -4-day) Methanol was obtained in 93.7% yield.

R _f = 0.10 ( n -hexane/EtOAc = 1:1), ¹ H NMR (500 MHz, MeOD) δ 8.55 - 8.65 (m, 2H), 8.02 - 7.98 (m, 4H), 7.87 (d, J = 8.3 Hz, 1H), 7.67 -7.64 (m, 1H), 7.50 -7.48 (m, 1H), 5.09 (s, 2H); ¹³ C NMR (125 MHz, MeOD) δ 154.88, 150.55, 150.24, 148.82, 148.56, 130.93, 128.36, 126.67, 124.00, 123.10, 116.40, 61.52.

<Preparation Example 5> Oxidation reaction

[Scheme 6]

Manganese dioxide (10.0 equivalents) was added with stirring to DMF (0.3M) in which 2-substituted quinolin-4-yl methanol (1.0 equivalents) prepared in Preparation Examples 4-1 to 4-13 was dissolved, producing The reaction mixture was heated to 100°C for 4-10 hours. It was then cooled to room temperature, filtered through a pad of Celite, and rinsed with EtOAc or DCM. The filtrate was concentrated in vacuo and purified by flash column chromatography (n-hexane/EtOAc) to obtain the desired compound.

Illustratively, (2-pyridin-4-yl-quinolin-4-yl)methanol obtained in Preparation Example 4-1 was reacted with the preparation method of Preparation Example 5 to produce 2-(pyridin-4-yl) as a pale yellow solid. ) Quinoline-4-carbaldehyde was obtained in 79.2% yield.

R _f = 0.29 (CHCl ₃ /MeOH = 30:1), ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.61 (s, 1H), 8.98 (dd, J = 8.5, 0.7 Hz, 1H), 8.82 -8.81 (d, J = 5.4 Hz, 2H), 8.29 - 8.27(m, 2H), 8.11 (dd, J = 5.4 Hz, 2H), 7.86 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.75 ( ddd, J = 8.5, 6.9, 1.3 Hz, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 192.30, 154.44, 150.62, 149.35, 145.31, 137.86, 130.70, 130.49, 129.84, 124.06, 123.55, 122.78, 121.2 7.

<Preparation Example 6> Preparation of 2-chloroquinoline-4-carbaldehyde

<Preparation Example 6-1> Preparation of 1-acetyl-1H-indole-2,3-dione

[Scheme 7]

A mixture of indoline-2,3-dione (10 g, 67.96 mmol), acetic anhydride (50 mL) and sulfuric acid (0.1 mL) was heated under reflux for 3 hours. The resulting solution was then cooled to room temperature, and the solid formed was collected by filtration, washed with a small amount of diethyl ether, dried, and suspended in 30 mL of water. The precipitated solid was filtered, washed with ice water, and dried to obtain 1-acetyl-1H-indole-2,3-dione as an orange solid in 92.9% yield.

R _f = 0.45 ( n -hexane/EtOAc = 2:1), ^1H NMR (500 MHz, DMSO) δ 8.28 (d, J = 8.2 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.39 - 7.37 (m, 1H), 2.60 (s, 3H); ¹³ C NMR (125 MHz, DMSO) δ 180.67, 170.31, 158.73, 148.40, 138.24, 126.00, 124.87, 120.35, 117.67, 26.48.

<Preparation Example 6-2> Preparation of 2-oxo-1,2-dihydroquinoline-4-carboxylic acid hydrochloride

[Scheme 8]

1-Acetyl-1H-indole-2,3-dione 12 (4.2g, 55.51mmol) prepared in Preparation Example 6-1 was added to an aqueous solution (74mL) of NaOH (2.2g, 22.20mmol), and the reaction mixture was Heated under reflux for 1 hour. The resulting mixture was cooled and acidified to pH 2 with hydrochloride salt. The precipitate was collected by filtration, washed with acetone and ice water, and dried to obtain 2-oxo-1,2-dihydroquinoline-4-carboxylic acid hydrochloride as a pale yellow solid in 94% yield.

R _f = 0.08 (CHCl ₃ /MeOH = 3:1), ¹ H NMR (500 MHz, DMSO) δ 14.09 (s, 1H), 12.03 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H) , 7.56 - 7.53 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.24 - 7.20 (m, 1H), 6.82 (s, 1H); ¹³ C NMR (125 MHz, DMSO) δ 166.89, 161.10, 139.39, 130.76, 126.21, 122.93, 122.13, 115.86, 115.69.

<Preparation Example 6-3> Preparation of 2-chloroquinoline-4-carboxylic acid

[Scheme 9]

A mixture of 2-oxo-1,2-dihydroquinoline-4-carboxylic acid hydrochloride (2.1 g, 11.10 mmol) prepared in Preparation Example 6-2 was dissolved in phosphorus chloride (15 mL) and refluxed for 3 hours. The resulting mixture was cooled and suspended in 30 mL of ice water. The precipitate was collected by filtration, washed with dichloromethane and ice water, and then dried to give 2-chloroquinoline-4-carboxylic acid as a dark red solid in 90.9% yield. R _f = 0.30 (CHCl ₃ /MeOH = 3:1), ^1H NMR (500 MHz, DMSO) δ 14.16 (s, 1H), 8.65 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.92 - 7.89 (m, 1H), 7.77 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H); ¹³ C NMR (125 MHz, DMSO) δ 166.17, 149.44, 148.09, 140.10, 131.25, 128.54, 128.48, 125.75, 123.42, 122.83.

<Preparation Example 6-4> Preparation of ethyl 2-chloroquinoline-4-carboxylate

[Scheme 10]

By reacting 2-chloroquinoline-4-carboxylic acid obtained in Preparation Example 6-3 with the preparation method of Preparation Example 3, ethyl 2-chloroquinoline-4-carboxylate as a pale yellow solid was obtained in 99.5% yield.

R _f = 0.53 ( n -hexane/EtOAc = 10:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.73 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H) , 7.89 (s, 1H), 7.78 (ddd, J = 8.6, 6.9, 1.3 Hz, 1H), 7.65 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H) ), 1.48 (t, J = 7.1 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 164.84, 150.06, 148.82, 138.06, 130.80, 129.04, 128.27, 125.67, 123.92, 123.64, 62.22, 14.19.

<Preparation Example 6-5> Preparation of (2-chloroquinolin-4-yl)methanol

[Scheme 11]

By reacting ethyl 2-chloroquinoline-4-carboxylate obtained in Preparation Example 6-4 using the preparation method of Preparation Example 4, (2-chloroquinolin-4-yl)methanol as a pale yellow solid was obtained in 90.4% yield. .

R _f = 0.43 ( n -hexane/EtOAc = 3:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.05 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H) , 7.74 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.62 - 7.53 (m, 2H), 5.22 (d, J = 3.3 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 151.11, 149.35, 147.68, 130.38, 129.29, 127.02, 124.36, 122.69, 119.19, 61.25.

<Preparation Example 6-6> Preparation of 2-chloroquinoline-4-carbaldehyde

[Scheme 12]

By reacting (2-chloroquinolin-4-yl)methanol obtained in Preparation Example 6-5 with the preparation method of Preparation Example 5, 2-chloroquinoline-4-carbaldehyde as a pale yellow solid was obtained in 66.8% yield.

R _f = 0.59 ( n -hexane/EtOAc = 3:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 10.44 (s, 1H), 8.92 (dd, J = 8.5, 0.8 Hz, 1H), 8.10 ( d, J = 8.4 Hz, 1H), 7.82 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.76 (s, 1H), 7.72 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 191.14, 150.69, 149.20, 139.50, 131.33, 129.48, 129.11, 127.33, 124.52, 122.79.

<Production Example 7> Suzuki coupling reaction

[Scheme 13]

Benzene / prepared by dissolving 2-chloroquinoline-4-carbaldehyde (1.0 equivalent), arylboronic acid or heteroarylboronic acid (1.0 equivalent), and Pd(PPh ₃ )4 (0.05 equivalent) prepared in Preparation Example 6-6. The ethanol (0.5M) mixture and 1M aqueous sodium carbonate solution (0.2M) were stirred, refluxed under nitrogen gas, and heated for 6-28 hours. After cooling, the reaction mixture was poured into water and the crude product was extracted three times with ethyl acetate. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc) to obtain the desired compound.

Illustratively, m-tolylboronic acid was reacted using the preparation method of Preparation Example 7 to obtain 2-m-tolyl-quinoline-4-carbaldehyde as a white solid with a yield of 68.5%.

R _f = 0.49 ( n -hexane/EtOAc = 6:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 10.52 (s, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.80 - 7.77 (m, 1H), 7.67 - 7.64 (m, 1H) ), 7.44 -7.41 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 2.48 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 192.96, 157.42, 149.30, 138.72, 138.29, 137.52, 130.75, 130.22, 130.14, 128.88, 128.73, 127.97, 124.4 8, 124.14, 124.11, 122.76, 21.53.

<Preparation Example 8> Wittig reaction

[Scheme 14]

The reaction mixture containing 2-substituted quinoline-4-carbaldehyde (1.1 equivalent) and ethyl (triphenylphosphoranylidene) acetate (1.1 equivalent) prepared in Preparation Example 5 and Preparation Example 7 was mixed with toluene (0.5 M). ) and then heated at 100°C for 4-8 hours. After completion of the reaction, the reaction mixture was poured into water, and the crude product was extracted three times with ethyl acetate. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc) to obtain the desired compound.

Illustratively, 2-(pyridin-4-yl)quinoline-4-carbaldehyde obtained in Preparation Example 5-1 was reacted with the preparation method of Preparation Example 8 to produce 3-(2-pyridin-4-yl) as a white solid. -Quinolin-4-yl)acrylic acid ethyl ester was obtained in 74.1% yield.

R _f = 0.37 ( n -hexane/EtOAc = 1:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.80 (s, 2H), 8.44 (d, J = 15.9 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 5.8 Hz, 2H), 8.01 (s, 1H), 7.81 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.65 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 6.73 (d, J = 15.9 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 165.83, 154.21, 150.54, 148.73, 146.16, 141.30, 139.07, 130.69, 130.33, 127.84, 125.57, 125.13, 123.2 2, 121.48, 115.57, 61.10, 14.27.

<Preparation Example 9> Hydrolysis reaction

[Scheme 15]

2N NaOH (0.2M) was added to a solution of 2-substituted quinolin-4-yl-acrylic acid ethyl ester (1.0 equivalent) prepared in Preparation Example 8-1 and Preparation Example 8-2 in EtOH (0.5M). was added and the reaction mixture was stirred at room temperature for 1-2 hours. The solvent was concentrated in vacuo and the residue was dissolved in water, which was extracted three times with diethyl ether and the aqueous layer was acidified to pH 4 with 1N hydrochloride solution. The resulting precipitate was filtered, dried, and recrystallized from ethanol to obtain the desired compound.

Illustratively, 3-(2-pyridin-4-yl-quinolin-4-yl)acrylic acid ethyl ester obtained in Preparation Example 8-1 was reacted with the preparation method of Preparation Example 9 to produce 3-(2-) as a white solid. Pyridin-4-yl-quinolin-4-yl)acrylic acid hydrochloride was obtained in 61.5% yield.

R _f = 0.13 ( n -hexane/EtOAc = 1:2), ¹ H NMR (500 MHz, DMSO) δ 9.00 - 8.99 (m, 2H), 8.76 -8.75 (m, 2H), 8.73 (s, 1H) , 8.40 (d, J = 15.8 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.95 - 7.92 (m, 1H), 7.81 - 7.79 ( m, 1H), 7.17 (d, J = 15.8 Hz, 1H); ¹³ C NMR (125 MHz, DMSO) δ 167.48, 165.43, 148.54, 137.84, 132.00, 131.92, 131.22, 130.64, 129.97, 129.29, 129.03, 127.50, 125.91, 124.06, 116.80.

<Preparation Example 10> Hydrogenation reaction

[Scheme 16]

2-Substituted quinolin-4-yl acrylic acid ethyl ester (1.0 equivalent) prepared in Preparation Example 8-1 to Preparation Example 8-19 was dissolved in MeOH/THF (0.3M), stirred, and palladium on carbon (10 % by weight) was added and the reaction mixture was stirred at room temperature for 4-6 hours. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and rinsed with EtOAc or DCM. The filtrate was concentrated in vacuo and purified by flash column chromatography (n-hexane/EtOAc) to obtain the desired compound.

For example, 3-(2-pyridin-4-yl-quinolin-4-yl)acrylic acid ethyl ester obtained in Preparation Example 8-1 was reacted with the preparation method of Preparation Example 10 to produce 3-(2-) as a yellow solid. Pyridin-4-yl-quinolin-4-yl)propionic acid ethyl ester was obtained in 92.8% yield.

R _f = 0.41 ( n -hexane/EtOAc = 1:1), ^1H NMR (500 MHz, CDCl ₃ ) δ = 8.77 (d, J =5.3, 2H), 8.21 (d, J =8.4, 1H), 8.07 - 8.04 (m, 3H), 7.78 - 7.74 (m, 2H), 7.63 - 7.59 (m, 1H), 4.16 (q, J =7.1, 2H), 3.50 (t, J =7.7, 2H), 2.84 (t, J =7.7, 2H), 1.24 (t, J =7.1, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 172.21, 154.14, 150.42, 148.40, 147.56, 146.58, 130.85, 129.76, 127.20, 126.74, 123.02, 121.51, 118.0 5, 60.77, 34.20, 27.37, 14.14.

<Preparation Example 11> Hydrolysis reaction

[Scheme 17]

Using the preparation method of Preparation Example 9, the result was obtained by reacting 2-substituted quinolin-4-yl-acrylic acid ethyl ester prepared in Preparation Examples 10-1 to 10-19.

Illustratively, 3-(2-pyridin-4-yl-quinolin-4-yl)propionic acid ethyl ester obtained in Preparation Example 10-1 was reacted with the preparation method of Preparation Example 9 to produce 3-(2) as a pale yellow solid. -Pyridin-4-yl-quinolin-4-yl)propionic acid hydrochloride was obtained in 41.0% yield.

R _f = 0.12 ( n -hexane/EtOAc = 1:4), ¹ H NMR (500 MHz, MeOD) δ 8.72 (d, J = 5.9 Hz, 2H), 8.22 - 8.17 (m, 4H), 8.01 (s) , 1H), 7.82 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.69 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 3.55 (t, J = 7.7 Hz, 2H), 2.90 ( t, J = 7.7 Hz, 2H); ¹³ C NMR (125 MHz, DMSO) δ 173.46, 151.40, 149.25, 147.58, 145.37, 130.40, 130.34, 128.15, 127.06, 123.95, 123.25, 118.70, 33.68,2 6.72.

<Preparation Example 12> Preparation of 2-chloro-7-fluoroquinoline-4-carbaldehyde

<Preparation Example 12-1> Preparation of 7-fluoro-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid

[Scheme 18]

A mixture of 6-fluoroindoline-2,3-dione (3.0 g, 18.17 mmol), malonic acid (5.7 g, 54.50 mmol) and acetic acid (36 mL) was heated under reflux for 12 hours. The resulting solution was then cooled to room temperature and the solid formed was collected by filtration. It was then washed with a small amount of diethyl ether or methanol, dried, and suspended in 30 mL of water. The precipitated solid was filtered, washed with ice water, and dried to obtain 7-fluoro-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid as a light red solid in 79.0% yield.

R _f = 0.40 ( n -hexane/EtOAc/Acetic acid = 1:1:0.1), ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.96 (s, 1H), 12.11 (s, 1H), 8.27 - 8.24 (m, 1H), 7.13 - 7.09 (m, 2H), 6.83 (s, 1H); ¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 166.75, 163.04, 161.34, 141.19, 141.03, 129.13, 122.63, 113.01, 110.48, 101.57.

<Preparation Example 12-2> Preparation of 2-chloro-7-fluoroquinoline-4-carboxylic acid ethyl ester

[Scheme 19]

By the preparation method of Preparation Example 3, 7-fluoro-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid prepared in Preparation Example 12-1 was reacted to produce 2-chloroquine as a pale yellow solid. -7-Fluoroquinoline-4-carboxylic acid ethyl ester was obtained in 54.7% yield.

R _f = 0.36 ( n -hexane/EtOAc = 10:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.77 (dd, J = 9.4, 6.1 Hz, 1H), 7.83 (s, 1H), 7.65 ( dd, J = 9.5, 2.7 Hz, 1H), 7.40 (ddd, J = 9.4, 8.0, 2.7 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H) ); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 164.68, 162.66, 151.61, 150.21, 137.93, 128.30, 123.16, 121.13, 118.75, 113.08, 62.52, 14.31.

<Preparation Example 12-3> Preparation of (2-chloro-7-fluoroquinolin-4-yl)methanol

[Scheme 20]

By the preparation method of Preparation Example 4, 2-chloro-7-fluoroquinoline-4-carboxylic acid ethyl ester prepared in Preparation Example 12-2 was reacted to produce (2-chloro-7-fluoroquinoline) as a white solid. -4-day) Methanol was obtained in 87.0% yield.

R _f = 0.36 ( n -hexane/EtOAc = 10:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.77 (dd, J = 9.4, 6.1 Hz, 1H), 7.83 (s, 1H), 7.65 ( dd, J = 9.5, 2.7 Hz, 1H), 7.40 (ddd, J = 9.4, 8.0, 2.7 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H) ); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 164.68, 162.66, 151.61, 150.21, 137.93, 128.30, 123.16, 121.13, 118.75, 113.08, 62.52, 14.31.

<Preparation Example 12-4> Preparation of 2-chloro-7-fluoroquinoline-4-carbaldehyde

[Scheme 21]

By the preparation method of Preparation Example 5, (2-chloro-7-fluoroquinolin-4-yl)methanol prepared in Preparation Example 12-3 was reacted to produce 2-chloro-7-fluoroquinoline- as a pale yellow solid. 4-Carbaldehyde was obtained in 40.0% yield.

* R _f = 0.35 (n-hexane/EtOAc = 5:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 10.38 (s, 1H), 9.02 (dd, J = 9.4, 6.0 Hz, 1H), 7.77 - 7.74 (m, 2H), 7.52 (ddd, J = 9.4, 8.0, 2.7 Hz, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 191.1, 164.9, 162.8, 152.1, 150.5, 139.4, 127.2, 127.1, 119.7, 113.2.

<Production Example 13> Suzuki coupling reaction

[Scheme 22]

It was prepared by the preparation method of Preparation Example 7, illustratively, by reacting 2-chloro-7-fluoroquinoline-4-carbaldehyde prepared in Preparation Example 12-4 with phenylboronic acid to give 7-fluorocarbon as a yellow solid. Ro-2-phenylquinoline-4-carbaldehyde was obtained in 72.9% yield.

R _f = 0.38 ( n -hexane/EtOAc = 5:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 10.52 (s, 1H), 9.06 (dd, J = 9.3, 6.2 Hz, 1H), 8.26 - 8.20 (m, 3H), 7.89 (dd, J = 9.9, 2.7 Hz, 1H), 7.62 - 7.51 (m, 3H), 7.48 (ddd, J = 9.3, 8.1, 2.7 Hz, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 193.06, 164.51, 158.63, 150.85, 150.75, 137.92, 130.37, 129.16, 127.49, 126.80, 124.05, 119.69, 119.1 1, 113.89.

<Preparation Example 14> Wittig reaction

[Scheme 23]

It was prepared by the preparation method of Preparation Example 8, and illustratively reacted with 7-fluoro-2-phenylquinoline-4-carbaldehyde prepared in Preparation Example 13 to produce 3-(7-fluoro-2-) as a white solid. Phenylquinolin-4-yl)acrylic acid ethyl ester was obtained in 91.6% yield.

R _f = 0.44 ( n -hexane/EtOAc = 5:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J = 15.9 Hz, 1H), 8.19 - 8.08 (m, 3H), 7.95 ( s, 1H), 7.82 (dd, J = 10.0, 2.6 Hz, 1H), 7.57 - 7.47 (m, 3H), 7.37 (ddd, J = 9.2, 8.0, 2.7 Hz, 1H), 6.71 (d, J = 15.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 166.05, 164.45, 158.38, 150.16, 141.01, 139.38, 139.00, 129.98, 129.08, 127.64, 125.47, 125.21, 122.1 2, 117.34, 115.66, 114.07, 61.26, 14.44.

<Preparation Example 15> Hydrogenation reaction

[Scheme 24]

It was prepared by the preparation method of Preparation Example 10, and illustratively reacted with 3-(7-fluoro-2-phenylquinolin-4-yl)acrylic acid ethyl ester prepared in Preparation Example 14 to produce 3-(of colorless oil). 7-Fluoro-2-phenylquinolin-4-yl)propionic acid ethyl ester was obtained in 86.3% yield.

R _f = 0.32 ( n -hexane/EtOAc = 5:1), ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.13 (dd, J = 7.2 Hz, 2H), 8.03 (dd, J = 9.1, 6.0 Hz, 1H), 7.81 (dd, J = 10.2, 2.6 Hz, 1H), 7.72 (s, 1H), 7.57 - 7.43 (m, 3H), 7.37 - 7.30 (m, 1H), 4.16 (q, J = 7.1 Hz) , 2H), 3.47 (t, J = 7.8 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 172.45, 163.20, 158.41, 149.86, 147.20, 139.44, 129.73, 129.00, 127.68, 125.28, 123.35, 118.10, 116.6 9, 114.19, 60.99, 34.46, 27.64, 14.33.

<Preparation Example 16> Hydrolysis reaction

[Scheme 25]

It was prepared by the preparation method of Preparation Example 9, and illustratively reacted with 3-(7-fluoro-2-phenylquinolin-4-yl)propionic acid ethyl ester prepared in Preparation Example 15 to produce 3-(as a white solid). 7-Fluoro-2-phenylquinolin-4-yl)propionic acid hydrochloride was obtained in 93.6% yield.

R _f = 0.44 ( n -hexane/EtOAc/Acetic acid = 1:4:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.57 (dd, J = 9.4, 5.4 Hz, 1H), 8.19 (s, 1H ), 8.09 - 7.95 (m, 4H), 7.80 - 7.61 (m, 5H), 3.64 (t, J = 7.3 Hz, 2H), 2.89 (t, J = 7.3 Hz, 2H).

<Preparation Example 17> Preparation of 2-chloro-6-fluoroquinoline-4-carbaldehyde

<Preparation Example 17-1> Preparation of 6-fluoro-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid

[Scheme 26]

A mixture of 5-fluoroindoline-2,3-dione (3.0 g, 18.17 mmol), malonic acid (5.7 g, 54.50 mmol) and acetic acid (36 mL) was heated under reflux for 12 hours. The resulting solution was then cooled to room temperature and the solid formed was collected by filtration. It was then washed with a small amount of diethyl ether or methanol, dried, and suspended in 30 mL of water. The precipitated solid was filtered, washed with ice water, and dried to obtain 6-fluoro-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid as a light red solid with a yield of 60.7%.

R _f = 0.12 (CHCl ₃ /MeOH = 3:1), ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.61 (s, 1H), 8.12 (dd, J = 11.0, 2.8 Hz, 1H), 7.36 - 7.18 (m, 2H), 6.47 (s, 1H).

<Preparation Example 17-2> Preparation of 2-chloro-6-fluoroquinoline-4-carboxylic acid ethyl ester

[Scheme 27]

By the preparation method of Preparation Example 3, 6-fluoro-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid prepared in Preparation Example 17-1 was reacted to produce 2-chloroquine as a pale yellow solid. -6-Fluoroquinoline-4-carboxylic acid ethyl ester was obtained in 80.4% yield.

R _f = 0.53 ( n -hexane/EtOAc = 4:1), ^1H NMR (500 MHz, CDCl ₃ ) 8.49 (dd, J = 10.5, 2.8 Hz, 1H), 8.06 (dd, J = 9.2, 5.5 Hz) , 1H), 7.96 (s, 1H), 7.55 (ddd, J = 9.2, 7.8, 2.8 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H) ; ¹³ C NMR (125 MHz, CDCl ₃ ) δ 164.42, 161.55, 149.42, 145.99, 137.00, 131.43, 125.05, 124.71, 121.04, 109.97, 62.38, 14.18.

<Preparation Example 17-3> Preparation of (2-chloro-6-fluoroquinolin-4-yl)methanol

[Scheme 28]

By the preparation method of Preparation Example 4, 2-chloro-6-fluoroquinoline-4-carboxylic acid ethyl ester prepared in Preparation Example 17-2 was reacted to produce (2-chloro-6-fluoroquinoline) as a white solid. -4-day) Methanol was obtained in 70.2% yield.

R _f = 0.24 ( n -hexane/EtOAc = 4:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 7.97 (dd, J = 9.2, 5.5 Hz, 1H), 7.69 (dd, J = 9.8, 2.8 Hz, 1H), 7.61 (s, 1H), 7.61 - 7.57 (m, 1H), 5.05 (s, 2H); ¹³ C NMR (125 MHz, MeOD) δ 162.98, 161.01, 152.85, 151.60, 145.70, 132.00, 126.84, 121.45, 120.77, 108.51, 61.21.

<Preparation Example 17-4> Preparation of 2-chloro-6-fluoroquinoline-4-carbaldehyde

[Scheme 29]

By the preparation method of Preparation Example 5, (2-chloro-6-fluoroquinolin-4-yl)methanol prepared in Preparation Example 17-3 was reacted to produce 2-chloro-6-fluoroquinoline- as a pale yellow solid. 4-Carbaldehyde was obtained in 54.0% yield.

R _f = 0.65 ( n -hexane/EtOAc = 2:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 10.36 (s, 1H), 8.68 (dd, J = 10.5, 2.8 Hz, 1H), 8.11 ( dd, J = 9.3, 5.5 Hz, 1H), 7.82 (s, 1H), 7.61 (ddd, J = 9.3, 7.8, 2.8 Hz, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 190.96, 162.52, 149.91, 146.29, 138.91, 131.38, 128.85, 123.50, 121.51, 109.18.

<Production Example 18> Suzuki coupling reaction

[Scheme 30]

It was prepared by the preparation method of Preparation Example 7, illustratively, by reacting 2-chloro-6-fluoroquinoline-4-carbaldehyde prepared in Preparation Example 17-4 with phenylboronic acid to give 6-fluoroquine as a yellow solid. Ro-2-(4-methoxyphenyl)quinoline-4-carbaldehyde was obtained in 78.4% yield.

R _f = 0.37 ( n -hexane/EtOAc = 4:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 10.41 (s, 1H), 8.64 (dd, J = 10.3, 2.8 Hz, 1H), 8.19 - 8.07 (m, 4H), 7.55 - 7.47 (m, 1H), 7.04 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 192.84, 162.05, 161.33, 156.12, 146.51, 137.04, 132.17, 130.53, 128.59, 125.08, 122.99, 120.28, 114.4 1, 108.59, 55.39.

<Preparation Example 19> Wittig reaction

[Scheme 31]

It was prepared by the preparation method of Preparation Example 8, and illustratively reacted with 6-fluoro-2-(4-methoxyphenyl)quinoline-4-carbaldehyde prepared in Preparation Example 18 to produce 3-[6 as a white solid. -Fluoro-2-(4-methoxyphenyl)quinolin-4-yl]acrylic acid ethyl ester was obtained in 82.9% yield.

R _f = 0.39 ( n -hexane/EtOAc = 4:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.26 (d, J = 15.8 Hz, 1H), 8.18 - 8.14 (m, 1H), 8.10 ( d, J = 8.9 Hz, 2H), 7.94 (s, 1H), 7.69 (dd, J = 9.8, 2.8 Hz, 1H), 7.49 (ddd, J = 9.2, 8.1, 2.8 Hz, 1H), 7.04 (d , J = 8.9 Hz, 2H), 6.68 (d, J = 15.8 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H) ); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 165.89, 160.99, 160.53, 155.97, 145.88, 140.02, 139.61, 132.61, 131.41, 128.64, 125.35, 124.71, 119.9 2, 116.28, 114.27, 106.92, 61.06, 55.36, 14.27.

<Preparation Example 20> Hydrogenation reaction

[Scheme 32]

It was prepared by the preparation method of Preparation Example 10, illustratively by reacting 3-[6-fluoro-2-(4-methoxyphenyl)quinolin-4-yl]acrylic acid ethyl ester prepared in Preparation Example 19. 3-[6-Fluoro-2-(4-methoxyphenyl)quinolin-4-yl]propionic acid ethyl ester as a colorless oil was obtained in 66.3% yield.

R _f = 0.38 ( n -hexane/EtOAc = 4:1), ^1H NMR (500 MHz, CDCl ₃ ) δ 8.13 (dd, J = 9.2, 5.6 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.69 (s, 2H), 7.57 (dd, J = 9.9, 2.7 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 2.7 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.36 (t, J = 7.7 Hz, 2H), 2.79 ((t, J = 7.7 Hz, 2H) , 1.23 (t, J = 7.1 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 172.25, 160.75, 155.96, 146.04, 145.43, 132.58, 131.74, 128.64, 126.48, 119.2 5, 118.59, 116.04, 114.13, 106.63, 60.76, 55.28, 33.89, 27.32, 14.11.

<Preparation Example 21> Hydrolysis reaction

[Scheme 33]

It was prepared by the preparation method of Preparation Example 9, illustratively by reacting 3-[6-fluoro-2-(3-methoxyphenyl)quinolin-4-yl]propionic acid ethyl ester prepared in Preparation Example 20. 3-[6-Fluoro-2-(3-methoxyphenyl)quinolin-4-yl]propionic acid hydrochloride as a white solid was obtained in 38.2% yield.

R _f = 0.12 ( n -hexane/EtOAc/Acetic acid = 1:2:0.1), ^1H NMR (500 MHz, MeOD) δ 8.16 (dd, J = 9.2, 5.5 Hz, 1H), 7.89 (s, 1H ), 7.87 (d, J = 2.7 Hz, 1H), 7.69 - 7.68 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.47 - 7.73 (m, 1H), 7.06 (dd, J = 8.2, 1.9 Hz, 1H), 3.91 (s, 3H), 3.46 (t, J = 7.4 Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H); ¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 167.90, 159.87, 159.75, 155.16, 147.80, 144.90, 140.03, 132.68, 129.92, 126.91, 119.56, 119.55, 119 .06, 115.27, 112.42, 107.57, 55.27, 32.23, 27.15 .

<Example 1> N -Hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propenamide

[Scheme 1]

3-(2-pyridin-4-yl-quinolin-4-yl)acrylic acid hydrochloride (1.0 equivalent), hydroxyamine hydrochloride (1.0 equivalent), BOP reagent (1.0 equivalent) and N prepared in Preparation Example 9-1. A solution of N-diisopropylethylamine (DIPEA, 3.0 equivalents) in DMSO (0.5M) was stirred at room temperature or 60°C for 6-12 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was recrystallized from dichloromethane or ethyl diether to give a pale yellow solid in 61.5% yield.

R _f = 0.10 ( n -hexane/EtOAc = 1:4), ^1H NMR (500 MHz, MeOD) δ 8.74 (d, J = 6.1 Hz, 2H), 8.42 (d, J = 15.8 Hz, 1H), 8.32 - 8.28 (m, 4H), 8.22 (d, J = 7.0 Hz, 1H), 7.89 - 7.86 (m, 1H), 7.75 - 7.72 (m, 1H), 6.86 (d, J = 15.8 Hz, 1H) ;

<Example 2> N -Hydroxy-3-(2-phenylquinolin-4-yl)propenamide

3-(2-phenylquinolin-4-yl)acrylic acid hydrochloride obtained in Preparation Example 9-2 was reacted with the preparation method of Example 1 to obtain a white solid result with a yield of 15.6%.

R _f = 0.13 (EtOAc/MeOH = 10:1), ^1H NMR (500 MHz, MeOD) δ 8.47 (d, J = 8.5 Hz, 1H), 8.37 - 8.34 (m, 2H), 8.27 (d, J = 8.5 Hz, 1H), 8.07 -8.05 (m, 3H), 7.90 - 7.87 (m, 1H), 7.69 - 7.63 (m, 3H), 6.99 (d, J = 15.8 Hz, 1H); ¹³ C NMR (125 MHz, DMSO) δ 61.39, 155.16, 144.79, 135.84, 131.72, 131.58, 130.85, 129.03, 128.92, 128.70, 128.19, 128.03, 126.98, 124.82, 124.11, 116.72.

<Example 3> N -Hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propanamide

3-(2-pyridin-4-yl-quinolin-4-yl)propionic acid hydrochloride obtained in Preparation Example 11-1 was reacted using the preparation method of Example 1 to obtain a white solid product with a yield of 41.0%.

R _f = 0.28 (CHCl ₃ /MeOH/Acetic acid = 15:1:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.72 (d, J = 4.9 Hz, 2H), 8.25 (d, J = 7.9 Hz) , 1H), 8.22 - 8.21 (m, 2H), 8.18 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.82 - 7.80 (m, 1H), 7.71 - 7.68 (m, 1H), 3.55 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 177.27, 155.24, 150.80, 150.59, 149.59, 148.96, 131.25, 131.21, 128.67, 128.35, 124.78, 123.44, 119.76, 36.49, 28.93.

<Example 4> N -Hydroxy-3-(2-phenylquinolin-4-yl)propanamide

3-(2-phenylquinolin-4-yl)propionic acid hydrochloride obtained in Preparation Example 11-2 was reacted with the preparation method of Example 1 to obtain a white solid result with a yield of 31.1%.

R _f = 0.11 (CHCl ₃ /MeOH/Acetic acid = 20:1:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.21 (d, J = 8.2 Hz, 1H), 8.14 - 8.09 (m, 3H) , 7.86 (s, 1H), 7.79 -7.76 (m, 1H), 7.65-7.62 (m, 1H), 7.56 -7.54 (m, 2H), 7.51 -7.49 (m, 1H), 3.52 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H).; ¹³ C NMR (125 MHz, MeOD) δ 171.35, 159.02, 149.43, 140.81, 130.92, 130.59, 130.49, 129.87, 128.88, 127.78, 127.51, 124.66, 120.60, 34.04, 28.84.

<Example 5> N -Hydroxy-3-(2-(3-chlorophenyl)quinolin-4-yl)propanamide

3-[2-(3-chlorophenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-3 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 11%.

R _f = 0.36 (EtOAc/Acetic acid = 100:1), ¹ H NMR (500 MHz, MeOD) δ 8.19 (d, J = 8.3 Hz, 1H), 8.17 - 8.16 (m, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.05 - 8.03 (m, 1H), 7.85 (s, 1H), 7.77 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.66 - 7.62 (m, 1H), 7.54 - 7.48 (m, 2H), 3.51 (t, J = 7.5 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 171.31, 157.10, 149.83, 149.45, 142.73, 135.94, 131.39, 131.03, 130.78, 130.42, 128.70, 128.08, 127.71, 127.10, 124.66, 120.21, 34.03, 28.85.

<Example 6> N -Hydroxy-3-(2-(3-methoxyphenyl)quinolin-4-yl)propanamide

3-[2-(3-methoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-4 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 50.4%.

R _f = 0.37 (CHCl ₃ /MeOH/Acetic acid = 20:1:0.1), ¹ H NMR (500 MHz, DMSO) δ 10.48 (s, 1H), 8.78 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.96 (s, 1H), 7.83 - 7.76 (m, 3H), 7.64 - 7.61 (m, 1H), 7.49 - 7.45 (m, 1H) ), 7.08 (dd, J = 8.3, 2.0 Hz, 1H), 3.88 (s, 3H), 3.40 (t, J = 7.5 Hz, 2H), 2.51 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, DMSO) δ 167.94, 159.71, 155.51, 147.96, 147.65, 140.27, 129.92, 129.86, 129.55, 126.46, 126.05, 123.65, 119.59, 118.29, 115.21, 112.43, 55.24, 32.35, 27.09.

<Example 7> N -Hydroxy-3-(2-(3-ethoxyphenyl)quinolin-4-yl)propanamide

3-[2-(3-Ethoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-5 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 34.5%.

R _f = 0.10 ( n -hexane/EtOAc = 1:1), ^1H NMR (500 MHz, MeOD) δ 8.22 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.80 - 7.77 (m, 1H), 7.68 - 7.64 (m, 3H), 7.47 - 7.44 (m, 1H), 7.07 (dd, J = 8.0, 2.0 Hz, 1H), 4.19 ( q, J = 7.0 Hz, 2H), 3.53 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, DMSO) δ 167.98, 159.03, 155.54, 147.99, 147.68, 140.25, 129.96, 129.91, 129.60, 126.50, 126.09, 123.71, 119.50, 118.34, 115.57, 113.04, 63.19, 32.41, 27.14, 14.75.

<Example 8> N -Hydroxy-3-(2-(3-trifluoromethylphenyl)quinolin-4-yl)propanamide

3-[2-(3-trifluoromethylphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-6 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 12.8%.

R _f = 0.36 (EtOAc/Acetic acid = 100:1), ¹ H NMR (500 MHz, DMSO) δ 10.49 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 8.57 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H) , 7.82 - 7.79 (m, 2H), 7.68 - 7.65 (m, 1H), 3.42 (t, J = 7.6 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H); ¹³ C NMR (125 MHz, DMSO) δ 167.92, 153.99, 148.65, 147.65, 139.70, 131.12, 130.02, 129.83, 129.68, 129.58, 126.91, 126.25, 126.03, 123.77, 123.52, 123.18, 118.27, 32.53, 27.24.

<Example 9> N -Hydroxy-3-(2-(3-cyclopropylmethoxyphenyl)quinolin-4-yl)propanamide

By reacting 3-[2-(3-cyclopropylmethoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-7 using the preparation method of Example 1, a pale yellow solid result was obtained in 17.7% yield. .

R _f = 0.36 ( n -hexane/EtOAc/Acetic acid = 1:4:0.1), ^1H NMR (500 MHz, MeOD) δ 8.22 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.80 - 7.78 (m, 1H), 7.68 - 7.64 (m, 3H), 7.47 - 7.44 (m, 1H), 7.07 (dd, J = 8.2, 2.0 Hz, 1H), 3.98 (d, J = 6.9 Hz, 2H), 3.54 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 1.37 - 1.29 (m, 1H), 0.69 - 0.65 (m, 2H), 0.43 - 0.41 (m, 2H); ¹³ C NMR (125 MHz, MeOD) δ 171.35, 161.03, 158.88, 149.61, 149.33, 142.14, 130.96, 130.91, 130.44, 127.82, 127.58, 124.67, 121.19, 120.70, 117.10, 114.73, 73.91, 34.00, 28.82, 11.27, 3.56.

<Example 10> N -Hydroxy-3-(2-(4-chlorophenyl)quinolin-4-yl)propanamide

3-[2-(4-chlorophenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-8 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 22%.

R _f = 0.40 (EtOAc/Acetic acid = 100:1), ¹ H NMR (500 MHz, MeOD) δ 8.17 (d, J = 8.3 Hz, 1H), 8.10 - 8.08 (m, 3H), 7.81 (s, 1H), 7.77 - 7.74 (m, 1H), 7.63 - 7.60 (m, 1H), 7.52 (d, J = 8.5 Hz, 2H), 3.49 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 171.32, 157.46, 149.72, 149.40, 139.33, 136.75, 131.03, 130.61, 130.33, 129.98, 127.96, 127.54, 124.67, 120.18, 34.01, 28.85.

<Example 11> N -Hydroxy-3-(2-(4-methoxyphenyl)quinolin-4-yl)propanamide

3-[2-(4-methoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-9 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 64.4%.

R _f = 0.13 ( n -hexane/EtOAc = 1:2), ^1H NMR (500 MHz, MeOD) δ 8.27 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H), 7.87 - 7.84 (m, 1H), 7.72 - 7.69 (m, 1H), 7.15 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 3.57 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H); ¹³ C NMR (125 MHz, DMSO) δ 167.98, 160.57, 155.40, 147.70, 131.18, 129.69, 129.46, 128.63, 126.00, 125.68, 123.63, 117.68, 114.17, 55.30, 32.41, 27.17.

<Example 12> N -Hydroxy-3-(2-(4-ethoxyphenyl)quinolin-4-yl)propanamide

By reacting 3-[2-(4-ethoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-10 using the preparation method of Example 1, a white solid result was obtained with a yield of 31.1%.

R _f = 0.11 (CHCl ₃ /MeOH/AcOH = 20:1:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.15 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.79 (s, 1H), 7.75 -7.72 (m, 1H), 7.60 -7.57 (m, 1H), 7.06 (d, J = 8.5 Hz, 2H) ), 4.12 (q, J = 7.0 Hz, 2H), 3.48 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.4 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, MeOD) δ 161.89, 158.70, 149.40, 132.99, 130.80, 130.24, 127.36, 127.20, 124.60, 120.19, 115.74, 64.66, 34.04, 2 8.86, 15.13.

<Example 13> N -Hydroxy-3-(2-(4-trifluoromethylphenyl)quinolin-4-yl)propanamide

3-[2-(4-trifluoromethylphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-11 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 19.1%.

R _f = 0.40 (EtOAc/Acetic acid = 100:1), ¹ H NMR (500 MHz, MeOD) ¹ H NMR (500 MHz, MeOD) δ 8.34 (d, J = 8.1 Hz, 2H), 8.23 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.80 - 7.78 (m, 1H), 7.69 - 7.65 (m, 1H), 3.54 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, DMSO) δ 167.89, 154.15, 148.57, 147.68, 142.56, 130.05, 129.87, 127.94, 127.01, 126.29, 126.23, 125.71, 123.78, 118.42, 32.43, 27.21.

<Example 14> N -Hydroxy-3-(2-(4-cyclopropylmethoxyphenyl)quinolin-4-yl)propanamide

By reacting 3-[2-(4-cyclopropylmethoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-12 using the preparation method of Example 1, a pale yellow solid result was obtained with a yield of 13.8%. .

R _f = 0.36 ( n -hexane/EtOAc/Acetic acid = 1:4:0.1), ^1H NMR (500 MHz, DMSO) δ 10.48 (s, 1H), 8.78 (s, 1H), 8.21 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.91 (s, 1H), 7.78 - 7.73 (m, 1H), 7.60 - 7.57 (m, 1H), 7.08 (d, J = 8.5 Hz, 2H), 3.91 (d, J = 6.9 Hz, 2H), 3.37 (t, J = 7.5 Hz, 2H), 2.49 (t, J = 7.5 Hz) , 2H), 1.26 - 1.25 (m, 1H), 0.61 - 0.58 (m, 2H), 0.36 - 0.35 (m, 2H); ¹³ C NMR (125 MHz, DMSO) δ 167.96, 159.96, 155.38, 147.76, 147.64, 130.97, 129.66, 129.41, 128.56, 125.94, 125.64, 123.59, 117.61, 114.63, 72.14, 32.39, 27.14, 10.12, 3.10.

<Example 15> N -Hydroxy-3-(2-( m -Tolyl)quinoline-4-yl)propanamide

3-(2-m-tolyl-quinolin-4-yl)propionic acid hydrochloride obtained in Preparation Example 11-13 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 33.6%.

R _f = 0.25 (CHCl ₃ /MeOH/Acetic acid = 15:1:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.21 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz) , 1H), 7.94 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.78 (dd, J = 8.0, 7.5 Hz, 1H), 7.64 (dd, J = 8.0, 7.5 Hz, 1H), 7.46 - 7.43 (m, 1H), 7.34 (d, J = 7.6 Hz, 1H), 3.53 (t , J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.49 (s, 3H); ¹³ C NMR (125 MHz, MeOD) δ 171.35, 159.22, 149.54, 149.39, 140.78, 139.70, 131.27, 130.89, 130.41, 129.79, 129.48, 127.72, 126.06, 124.65, 120.72, 34.04, 28.84, 21.55.

<Example 16> N -Hydroxy-3-(2-(3-trifluoromethoxyphenyl)quinolin-4-yl)propanamide

3-[2-(3-trifluoromethoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-14 was reacted with the preparation method of Example 1 to obtain a white solid result with a yield of 33.5%.

R _f = 0.20 (CHCl ₃ /MeOH/Acetic acid = 15:1:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.21 (d, J = 8.3 Hz, 1H), 8.15 - 8.13 (m, 2H) , 8.09 (s, 1H), 7.89 (s, 1H), 7.81 - 7.76 (m, 1H), 7.67 - 7.63 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 3.52 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 156.77, 151.11, 149.89, 149.49, 143.07, 131.58, 131.07, 130.91, 128.15, 127.77, 127.43, 124.68, 122.83, 121.24, 120.15, 40.43, 28.88.

<Example 17> N -Hydroxy-3-(2-(3-phenoxyphenyl)quinolin-4-yl)propanamide

3-[2-(3-phenoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Examples 11-15 was reacted using the preparation method of Example 1 to obtain a pale yellow solid product with a yield of 29%.

R _f = 0.33 ( n -hexane/EtOAc = 1:4), ^1H NMR (500 MHz, MeOD) δ 8.19 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.85 - 7.84 (m, 2H), 7.80 - 7.79 (m, 1H), 7.78 - 7.75 (m, 1H), 7.65 - 7.62 (m, 1H), 7.54 - 7.51 (m, 1H), 7.41 - 7.37 (m , 2H), 7.16 - 7.06 (m, 4H), 3.51 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 171.33, 159.28, 158.64, 158.06, 149.72, 149.38, 142.76, 131.34, 131.01, 130.61, 127.94, 127.62, 124.6 7, 124.60, 123.83, 120.84, 120.50, 119.94, 119.21, 34.06 , 28.88.

<Example 18> N -Hydroxy-3-(2-( p -Tolyl)quinoline-4-yl)propanamide

3-(2-p-tolyl-quinolin-4-yl)propionic acid hydrochloride obtained in Preparation Examples 11-16 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 56%.

R _f = 0.28 (CHCl ₃ /MeOH/Acetic acid = 15:1:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.17 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz) , 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.82 (s, 1H), 7.76 - 7.73 (m, 1H), 7.62 - 7.59 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 3.50 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H); ¹³ C NMR (125 MHz, MeOD) δ 171.35, 159.02, 149.46, 149.40, 140.93, 137.97, 130.85, 130.52, 130.36, 128.80, 127.59, 127.40, 124.62, 120.46, 34.03, 28.84, 21.32.

<Example 19> N -Hydroxy-3-(2-(4-trifluoromethoxyphenyl)quinolin-4-yl)propanamide

3-[2-(4-trifluoromethoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 11-17 was reacted with the preparation method of Example 1 to obtain a white solid product with a yield of 55%.

R _f = 0.23 (CHCl ₃ /MeOH/Acetic acid = 15:1:0.1), ¹ H NMR (500 MHz, DMSO) δ 10.49 (s, 1H), 8.78 (s, 1H), 8.38 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.00 (s, 1H), 7.81 - 7.78 (m, 1H), 7.67 - 7.65 ( m, 1H), 7.55 (d, J = 8.8 Hz, 2H), 3.41 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, DMSO) δ 168.41, 154.83, 149.79, 148.82, 148.16, 138.44, 130.41, 130.21, 129.68, 127.18, 126.53, 124.20, 121.65, 118.63, 32.88, 27.66.

<Example 20> N -Hydroxy-3-(2-(thiophen-3-yl)quinolin-4-yl)propanamide

3-(2-thiophen-3-yl-quinolin-4-yl)propionic acid hydrochloride obtained in Preparation Examples 11-18 was reacted with the preparation method of Example 1 to obtain a yellow solid result with a yield of 34.5%.

R _f = 0.13 (CHCl ₃ /MeOH/Acetic acid = 15:1:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.21 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 8.4 Hz) , 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 7.85 (s, 1H), 7.78 - 7.75 (m, 1H), 7.64 - 7.59 (m, 1H), 7.58 (dd, J = 5.0, 2.8 Hz, 1H), 3.51 (t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 171.35, 154.79, 149.37, 143.38, 130.91, 130.21, 127.90, 127.55, 127.45, 126.46, 124.65, 120.52, 118.40, 33.98, 28.76.

<Example 21> 3-(7-fluoro-2-phenylquinolin-4-yl)- N -Hydroxypropanamide

By reacting 3-(7-fluoro-2-phenylquinolin-4-yl)propionic acid hydrochloride obtained in Preparation Example 16-1 using the preparation method of Example 1, a white solid result was obtained with a yield of 32.1%.

R _f = 0.33 ( n -hexane/EtOAc/Acetic acid = 1:4:0.1), ^1H NMR (500 MHz, MeOD) δ 8.26 (dd, J = 9.1, 6.0 Hz, 1H), 8.12 (d, J = 7.1 Hz, 2H), 7.84 (s, 1H), 7.75 (dd, J = 10.3, 2.4 Hz, 1H), 7.59 - 7.41 (m, 4H), 3.51 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.4 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 171.22, 160.16, 159.17, 149.90, 147.64, 140.43, 130.86, 129.92, 128.88, 127.42, 124.66, 120.01, 117.63, 113.75, 34.04, 28.92.

<Example 22> 3-(7-fluoro-2-(4-methoxyphenyl)quinolin-4-yl)- N -Hydroxypropanamide

3-[7-Fluoro-2-(4-methoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 16-2 was reacted with the preparation method of Example 1 to obtain a pale yellow solid with a concentration of 3.5%. obtained by yield.

R _f = 0.23 ( n -hexane/EtOAc/Acetic acid = 1:4:0.1), ^1H NMR (500 MHz, MeOD) δ 8.23 (dd, J = 9.2, 6.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.80 (s, 1H), 7.71 (dd, J = 10.3, 2.6 Hz, 1H), 7.47 - 7.37 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.89 (s, 2H), 3.49 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H).

<Example 23> 3-(7-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- N -Hydroxypropanamide

3-[7-Fluoro-2-(3-methoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 16-3 was reacted with the preparation method of Example 1 to obtain a pale yellow solid with a concentration of 16.1%. obtained by yield.

R _f = 0.21 ( n -hexane/EtOAc/Acetic acid = 1:4:0.1), ^1H NMR (500 MHz, MeOD) δ 8.27 (dd, J = 9.2, 6.0 Hz, 1H), 7.84 (s, 1H ), 7.76 (dd, J = 10.3, 2.6 Hz, 1H), 7.68 (dd, J = 11.4, 5.0 Hz, 2H), 7.49 - 7.43 (m, 2H), 7.08 (dd, J = 8.1, 2.1 Hz, 1H), 3.92 (s, 3H), 3.51 (t, J = 7.5 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 169.87, 169.64, 160.27, 158.58, 140.43, 129.56, 126.02, 119.83, 118.67, 116.36, 116.16, 115.23, 112.68, 112.34, 54.49, 41.08, 27.47

<Example 24> 3-(7-fluoro-2-( p -Tolyl)quinoline-4-yl)- N -Hydroxypropanamide

By reacting 3-[7-fluoro-2-(p-tolyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 16-4 using the preparation method of Example 1, a pale yellow solid result was obtained with a yield of 30.6%. got it

R _f = 0.40 (ChCl ₃ /MeOH = 15:1), ^1H NMR (500 MHz, MeOD)δ 8.25 (dd, J = 9.2, 6.0 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H) , 7.82 (s, 1H), 7.73 (dd, J = 10.3, 2.5 Hz, 1H), 7.44 (td, J = 9.0, 2.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 3.50 ( t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.44 (s, 3H); ¹³ C NMR (125 MHz, MeOD) δ 169.79, 164.34, 162.36, 158.59, 148.86, 140.07, 135.85, 129.21, 127.46, 126.07, 123.19, 118.53, 116.15, 111.95, 32.62, 27.54, 19.95

<Example 25> 3-(6-fluoro-2-phenylquinolin-4-yl)- N -Hydroxypropanamide

By reacting 3-[6-fluoro-2-(phenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 21-3 using the preparation method of Example 1, a pale yellow solid result was obtained with a yield of 83.1%.

R _f = 0.59 (ChCl ₃ /MeOH = 7:1), ^1H NMR (500 MHz, MeOD) δ 8.16 (dd, J = 9.2, 5.5 Hz, 1H), 8.11 (d, J = 7.2 Hz, 2H) , 7.93 - 7.84 (m, 2H), 7.62 - 7.56 (m, 1H), 7.54 (t, J = 7.3 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 3.46 (t, J = 7.5) Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 169.83, 159.66, 156.98, 147.66, 145.20, 139.13, 131.87, 129.22, 128.48, 127.33, 126.98, 119.74, 119.33, 106.92, 32.38, 27.44

<Example 26> 3-(6-fluoro-2-(4-methoxyphenyl)quinolin-4-yl)- N -Hydroxypropanamide

3-[6-Fluoro-2-(4-methoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 21-1 was reacted with the preparation method of Example 1 to obtain a pale yellow solid with a concentration of 3.5%. obtained by yield.

R _f = 0.14 ( n -hexane/EtOAc/Acetic acid = 1:2:0.1), ¹ H NMR (500 MHz, MeOD) δ 8.55 (s, 1H), 8.11 - 8.06 (m, 3H), 7.91 - 7.85 (m, 2H), 7.54 (td, J = 10, 2.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.40 (t, J = 7.7 Hz, 2H) , 2.64 (t, J = 7.7 Hz, 2H), 1.89 (s, 1H).

<Example 27> 3-(6-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- N -Hydroxypropanamide

3-[6-Fluoro-2-(3-methoxyphenyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 21-2 was reacted with the preparation method of Example 1 to obtain a pale yellow solid with a concentration of 38.2%. obtained by yield.

R _f = 0.12 ( n -hexane/EtOAc/Acetic acid = 1:2:0.1), ^1H NMR (500 MHz, MeOD) δ 8.16 (dd, J = 9.2, 5.5 Hz, 1H), 7.89 (s, 1H ), 7.87 (d, J = 2.7 Hz, 1H), 7.69 - 7.68 (m, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.47 - 7.73 (m, 1H), 7.06 (dd, J = 8.2, 1.9 Hz, 1H), 3.91 (s, 3H), 3.46 (t, J = 7.4 Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H); ¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 167.90, 159.87, 159.75, 155.16, 147.80, 144.90, 140.03, 132.68, 129.92, 126.91, 119.56, 119.55, 119 .06, 115.27, 112.42, 107.57, 55.27, 32.23, 27.15 .

<Example 28> 3-(6-fluoro-2-( p -Tolyl)quinoline-4-yl)- N -Hydroxypropanamide

By reacting 3-[6-fluoro-2-(p-tolyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 21-4 using the preparation method of Example 1, a pale yellow solid result was obtained with a yield of 67.9%. got it

R _f = 0.54 ( n -hexane/EtOAc = 3:1), ^1H NMR (500 MHz, MeOD) δ 8.14 (dd, J = 9.2, 5.5 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H ), 7.88 - 7.84 (m, 2H), 7.60 - 7.55 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 3.45 (t, J = 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H); ¹³ C NMR (125 MHz, MeOD) δ 169.80, 159.63, 156.87, 147.92,139.82, 135.92, 131.34, 129.20, 127.34, 119.74, 119.60, 119.37, 107.12, 106.93, 32.35, 27.48, 19.93

<Example 29> 3-[2-(4-chlorophenyl)-6-fluoroquinolin-4-yl)]- N -Hydroxypropanamide

3-[2-(4-chlorophenyl)-6-fluoro-quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 21-5 was reacted with the preparation method of Example 1 to obtain a pale red solid with a concentration of 28.8%. obtained by yield.

R _f = 0.28 (ChCl ₃ /MeOH = 15:1), ¹ H NMR (500 MHz, MeOD) δ 8.17 - 8.11 (m, 3H), 7.89 (s, 1H), 7.87 (dd, J = 10.1, 2.7 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.54 (d, J = 8.6 Hz, 2H), 3.46 (t, J = 7.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H); ¹³ C NMR (125 MHz, MeOD) δ 169.81, 159.76, 155.43, 147.78, 145.24, 137.73, 135.38, 132.07, 128.77, 128.59, 127.02, 119.54, 119.31, 106.93, 32.38, 27.45.

The compound structures and compound names of Examples 1 to 29 are shown in Table 1 below.

SPA Example compound structure Compound name 3431 One N -Hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propenamide 3409 2 N -Hydroxy-3-(2-phenylquinolin-4-yl)propenamide
3430 3 N -Hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propanamide 3408 4 N -Hydroxy-3-(2-phenylquinolin-4-yl)propanamide 3432 5 N -Hydroxy-3-[2-(3-chlorophenyl)quinolin-4-yl]propanamide 3434 6 N -Hydroxy-3-[2-(3-methoxyphenyl)quinolin-4-yl]propanamide 3438 7 N -Hydroxy-3-[2-(3-ethoxyphenyl)quinolin-4-yl]propanamide 3433 8 N -Hydroxy-3-[2-(3-trifluoromethylphenyl)quinolin-4-yl]propanamide 3453 9 N -Hydroxy-3-[2-(3-cyclopropylmethoxyphenyl)quinolin-4-yl]propanamide 3435 10 N -Hydroxy-3-[2-(4-chlorophenyl)quinolin-4-yl]propanamide 3437 11 N -Hydroxy-3-[2-(4-methoxyphenyl)quinolin-4-yl]propanamide 3439 12 N -Hydroxy-3-[2-(4-ethoxyphenyl)quinolin-4-yl]propanamide 3436 13 N -Hydroxy-3-[2-(4-trifluoromethylphenyl)quinolin-4-yl]propanamide 3454 14 N -Hydroxy-3-[2-(4-cyclopropylmethoxyphenyl)quinolin-4-yl]propanamide 3451 15 N -Hydroxy-3-[2-( m -tolyl)quinolin-4-yl]propanamide 3455 16 N -Hydroxy-3-[2-(3-trifluoromethoxyphenyl)quinolin-4-yl]propanamide 3462 17 N -Hydroxy-3-[2-(3-phenoxyphenyl)quinolin-4-yl]propanamide 3452 18 N -Hydroxy-3-[2-( p -tolyl)quinolin-4-yl]propanamide 3456 19 N -Hydroxy-3-[2-(4-trifluoromethoxyphenyl)quinolin-4-yl]propanamide 3460 20 N -Hydroxy-3-[2-(thiophen-3-yl)quinolin-4-yl]propanamide 3471 21 3-(7-fluoro-2-phenylquinolin-4-yl)- N -hydroxypropanamide 3472 22 3-[7-fluoro-2-(4-methoxyphenyl)quinolin-4-yl]- N -hydroxypropanamide 3473 23 3-(7-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- N -hydroxypropanamide 3474 24 3-(7-fluoro-2-( p -tolyl)quinolin-4-yl)- N -hydroxypropanamide 3481 25 3-(6-fluoro-2-phenylquinolin-4-yl)- N -hydroxypropanamide 3482 26 3-(6-fluoro-2-(4-methoxyphenyl)quinolin-4-yl)- N -hydroxypropanamide 3483 27 3-(6-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- N -hydroxypropanamide 3484 28 3-(6-fluoro-2-( p -tolyl)quinolin-4-yl)- N -hydroxypropanamide 3485 29 3-[2-(4-chlorophenyl)-6-fluoroquinolin-4-yl)]- N -hydroxypropanamide

<Experimental Example 1> Evaluation of HDAC inhibitory activity

To evaluate the inhibitory activity of the new compound of the present invention against histone deacetylation (HDAC) enzyme, the following experiment was performed.

1.1 Experimental method

Enzyme inhibition assessments were performed at Reaction Biology Corporation, Malvern, PA. The activity of all 11 HDACs was evaluated using acetylated AMC-labeled peptide substrates. The substrate RHK-K(Ac)-AMC was used for the evaluation of all Class I and IIb HDACs (i.e., HDAC1, HDAC2, HDAC3, HDAC6, HDAC10, and HDAC11). Activity against Class IIa HDACs (i.e., HDAC4, HDAC5, HDAC7, and HDAC9) was assessed using acetyl-Lys(trifluoroacetyl)-AMC. In the case of HDAC8, it was evaluated using RHKAcK(Ac)-AMC. All evaluations were performed using previously published methods for fluorescent substrate and developer combinations (Chem Biol. 2003; 10:61-68). HDAC enzyme was incubated in assessment buffer (50mM Tris-HCl, pH 8.0, 137mM NaCl, 2.7mM KCl, 1mM MgCl2, and 1mg/mL bovine serum albumin). Then, the substrate was added to start the reaction. After the reaction was completed, a developer was added to decompose the diacetylated substrate and EnVision Multilabel Plate Reader (PerkinElmer, Santa Clara, California, USA). Fluorescence generated by excitation (Ex) at 360 nM and emission (Em) at 460 nM was detected. The example compounds were dissolved in DMSO and tested in minimum 10-volume IC ₅₀ mode with 3-fold serial dilutions starting at 10 μM. Trichostatin A, an HDAC control compound, was also tested at 10-dose IC ₅₀ starting at 10 μM and serially diluted 3 times. HDAC inhibitory activity data were expressed as the percentage of HDAC activity remaining in the experimental samples compared to the reaction setup containing only vehicle (dimethyl sulfoxide).

1-2. Assessment of HDAC1, HDAC6 and HDAC8 inhibitory activity

The results of evaluating the inhibitory activities of substituents Y and R corresponding to Examples 1 to 29 in Formula 1 and HDAC1, HDAC6, and HDAC8 are shown in Table 2 below.

SPA Example X Y R IC ₅₀ (nM) ^a % inhibition ^b HDAC6 HDAC8 HDAC1 HDAC6 HDAC8 3431 One H -CH=CH- 2574 1750 N.D. N.D. N.D. 3409 2 H -CH=CH- 533 299 N.D. N.D. N.D. 3430 3 H -CH ₂ CH ₂ - N.A. N.A. N.D. N.D. N.D. 3408 4 H -CH ₂ CH ₂ - 427.1 58.7 51.0 98.6 101.7 3432 5 H -CH ₂ CH ₂ - 279.1 193 82.2 99.3 100.9 3434 6 H -CH ₂ CH ₂ - 131.2 82.7 83.3 100.1 101.0 3438 7 H -CH ₂ CH ₂ - 81.8 139 91.1 100.0 98.8 3433 8 H -CH ₂ CH ₂ - 267.3 722.2 84.3 100.4 104.6 3453 9 H -CH ₂ CH ₂ - 90 234 N.D. N.D. N.D. 3435 10 H -CH ₂ CH ₂ - 590.3 188.1 76.8 99.4 104.7 3437 11 H -CH ₂ CH ₂ - 153.9 48.4 61.7 80.2 86.0 3439 12 H -CH ₂ CH ₂ - 87.6 112 57.4 51.6 87.2 3436 13 H -CH ₂ CH ₂ - 637.5 223 84.1 99.5 106.1 3454 14 H -CH ₂ CH ₂ - 115 247 N.D. N.D. N.D. 3451 15 H -CH ₂ CH ₂ - 64 194 N.D. N.D. N.D. 3455 16 H -CH ₂ CH ₂ - 510 2000 N.D. N.D. N.D. 3462 17 H -CH ₂ CH ₂ - 75.6 810 N.D. N.D. N.D. 3452 18 H -CH ₂ CH ₂ - 63 72 N.D. N.D. N.D. 3456 19 H -CH ₂ CH ₂ - 537 470 N.D. N.D. N.D. 3460 20 H -CH ₂ CH ₂ - 1000 906 N.D. N.D. N.D. 3471 21 7F -CH ₂ CH ₂ - 497 156 N.D. N.D. N.D. 3472 22 7F -CH ₂ CH ₂ - >10000 uM >10000 uM N.D. N.D. N.D. 3473 23 7F -CH ₂ CH ₂ - 420.9 339.7 N.D. N.D. N.D. 3474 24 7F -CH ₂ CH ₂ - 359.9 117.6 N.D. N.D. N.D. 3481 25 6F -CH ₂ CH ₂ - 506.4 799.9 N.D. N.D. N.D. 3482 26 6F -CH ₂ CH ₂ - 56.8 1094 N.D. N.D. N.D. 3483 27 6F -CH ₂ CH ₂ - 48.21 937.4 N.D. N.D. N.D. 3484 28 6F -CH ₂ CH ₂ - 58.35 805.7 N.D. N.D. N.D. 3485 29 6F -CH ₂ CH ₂ - 771.2 932.9 N.D. N.D. N.D.

^aIC₅₀was calculated using GraphPad Prism version 4.0. ^bThe rate of HDAC inhibition was measured compared to the negative control (DMSO) at 20 μM. Measurements represent the average of two separate experiments.

Results showing no activity at 20 μM are indicated as NA.

Results that were not measured were expressed as ND.

1-3. Evaluation of HDAC 1 to HDAC 11 inhibitory activity

The HDAC 1 to HDAC 11 inhibitory activity results of the compounds of Examples 4, 11, and 18 are shown in Table 3 below. As a result, it was confirmed that there was selective inhibitory activity on HDAC 6 and HDAC 8.

SPA Example HDAC % Inhibition at 20 μM ^a One 2 3 4 5 6 7 8 9 10 11 3408 4 67.4 44.5 48.9 13.1 33.6 98.4 17.5 97.1 14.6 38.3 46.6 3437 11 57.1 39.1 63.4 9.9 5.0 41.3 11.8 94.0 NA ^b N D ^c 60.1 3452 18 84.5 70.7 78.3 12.0 23.6 97.3 26.6 100 NA ^b N D ^c 75.8

^a HDAC inhibition ratio was measured compared to negative control (DMSO) at 20 μM. Measurements represent the average of two separate experiments. ^b Results showing no activity at 20 μM are expressed as NA.

^c Results not measured are expressed as ND.

<Experimental Example 2> Evaluation of proliferation inhibition ability for triple negative breast cancer cell lines

To evaluate the proliferation inhibitory activity of the new compound according to the present invention on triple negative breast cancer cell lines, the following experiment was performed.

2-1. Cell lines and cell culture

Human breast cancer cell lines BT-20 and MDA-MB-231 were purchased from the Korea Cell Line Bank (Seoul, Korea), and Roswell Park Memorial Institute medium-1640 (RPMI-1640) medium containing 10% fetal bovine serum (FBS) was used. and cultured in an incubator at 37°C and 5% CO ₂ . RPMI-1640 and FBS were purchased from Gibco Life Technologies. The medium of cells in culture was replaced with new medium once every 2-3 days.

2-2. Measurement of cell viability (CCK-8 Assay)

BT-20, MDA-MB-231 cells were dispensed into 96-well plates with 100 μL of _medium at 70% confluency (each 1.2 After culturing in the incubator for 24 hours, each well was treated with the test substance at a concentration of 0.1, 0.4, 1.6, 6.3, 25.0, 100 μM or 0.2, 0.8, 4.0, 20.0, 100, 500 μM and incubated for 72 hours. After incubation, WST-8 solution (abcam) was dispensed into each well at a concentration of 10 μL/well, cultured in an incubator for 4 hours, and absorbance was measured at 460 nm using a Variskan Lux multimode microplate reader (ThermoFisher Scientific).

SPA Example G.I. ₅₀ (μM) ^a BT-20 MDA-MB-231 3431 One 338.6 0.158 3430 3 567.7 0.515 3408-Free 4-Free 43.09 164.8 3408-HCl 4-HCl 50.16 136.7 3432 5 47.49 243.3 3434 6 49.94 83.12 3438 7 21.35 168.4 3433 8 45.55 249.2 3453 9 2.573 39.6 3435 10 353.5 174.0 3437 11 10.91 0.581 3439 12 19.51 174.9 3436 13 49.52 141.8 3454 14 15.47 4.355 3451 15 1.878 159.2 3455 16 17.11 17.51 3452 18 2.848 31.16 3456 19 3.349 100.3 3460 20 20.13 81.54

^a GI ₅₀ was calculated using GraphPad Prism version 5.0.

Claims (13)

A compound represented by the following formula (1), a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
X is hydrogen or halogen;
Y is -CH=CH- or -CH ₂ CH ₂ -;
R is hydrogen, unsubstituted or substituted C6-C10 aryl or 5-10 membered heteroaryl,
Here, the substituted C6-C10 aryl and 5-10 membered heteroaryl are halogen, unsubstituted or substituted C1-C10 alkyl or C1-C10 alkoxy,
At this time, the substituted C1-C10 alkyl and C1-C10 alkoxy are substituted with one or more selected from the group consisting of halogen, C3-C10 cycloalkyl, and C6-C10 aryl. According to paragraph 1,
X is hydrogen or halogen;
Y is -CH=CH- or -CH ₂ CH ₂ -;
R is hydrogen, unsubstituted or substituted C6 aryl or 5-6 membered heteroaryl,
Here, the substituted C6aryl and 5-6 membered heteroaryl are halogen, unsubstituted or substituted C1-C5alkyl or C1-C5alkoxy;
In this case, the substituted C1-C5 alkyl and C1-C5 alkoxy are compounds substituted with one or more selected from the group consisting of halogen, C3-C6 cycloalkyl, and C6 aryl, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable compound thereof. Possible salt. According to paragraph 1,
X is hydrogen or F;
Y is -CH=CH- or -CH ₂ CH ₂ -;
R is hydrogen, unsubstituted or substituted phenyl, pyridinyl or thiophenyl,
wherein the substituted phenyl, pyridinyl and thiophenyl are Cl, unsubstituted or substituted methyl, ethyl, methoxy or ethoxy;
At this time, the substituted methyl, ethyl, methoxy and ethoxy are compounds substituted with one or more selected from the group consisting of F, cyclopropyl and phenyl, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof. According to paragraph 1,
X is hydrogen or F;
Y is -CH=CH- or -CH ₂ CH ₂ -;
R is hydrogen, , , , , , , , , , , , , , , , , or A phosphorus compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. According to paragraph 1,
The compound represented by Formula 1 is any one selected from the following compound group, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
<1> N -hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propenamide;
<2> N -hydroxy-3-(2-phenylquinolin-4-yl)propenamide;
<3> N -hydroxy-3-(2-(pyridin-4-yl)quinolin-4-yl)propanamide;
<4> N -hydroxy-3-(2-phenylquinolin-4-yl)propanamide;
<5> N -Hydroxy-3-(2-(3-chlorophenyl)quinolin-4-yl)propanamide;
<6> N -Hydroxy-3-(2-(3-methoxyphenyl)quinolin-4-yl)propanamide;
<7> N -Hydroxy-3-(2-(3-ethoxyphenyl)quinolin-4-yl)propanamide;
<8> N -Hydroxy-3-(2-(3-trifluoromethylphenyl)quinolin-4-yl)propanamide;
<9> N -Hydroxy-3-(2-(3-cyclopropylmethoxyphenyl)quinolin-4-yl)propanamide;
<10> N -Hydroxy-3-(2-(4-chlorophenyl)quinolin-4-yl)propanamide;
<11> N -Hydroxy-3-(2-(4-methoxyphenyl)quinolin-4-yl)propanamide;
<12> N -Hydroxy-3-(2-(4-ethoxyphenyl)quinolin-4-yl)propanamide;
<13> N -Hydroxy-3-(2-(4-trifluoromethylphenyl)quinolin-4-yl)propanamide;
<14> N -Hydroxy-3-(2-(4-cyclopropylmethoxyphenyl)quinolin-4-yl)propanamide;
<15> N -Hydroxy-3-(2-( m -tolyl)quinolin-4-yl)propanamide;
<16> N -Hydroxy-3-(2-(3-trifluoromethoxyphenyl)quinolin-4-yl)propanamide;
<17> N -Hydroxy-3-(2-(3-phenoxyphenyl)quinolin-4-yl)propanamide;
<18> N -Hydroxy-3-(2-( p -tolyl)quinolin-4-yl)propanamide;
<19> N -Hydroxy-3-(2-(4-trifluoromethoxyphenyl)quinolin-4-yl)propanamide;
<20> N -Hydroxy-3-(2-(thiophen-3-yl)quinolin-4-yl)propanamide;
<21> 3-(7-fluoro-2-phenylquinolin-4-yl) -N -hydroxypropanamide;
<22> 3-(7-fluoro-2-(4-methoxyphenyl)quinolin-4-yl) -N -hydroxypropanamide;
<23> 3-(7-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- N -hydroxypropanamide
<24> 3-(7-fluoro-2-(p-tolyl)quinolin-4-yl)- N -hydroxypropanamide
<25> 3-(6-fluoro-2-phenylquinolin-4-yl) -N -hydroxy-propanamide
<26> 3-(6-fluoro-2-(4-methoxyphenyl)quinolin-4-yl) -N -hydroxypropanamide;
<27> 3-(6-fluoro-2-(3-methoxyphenyl)quinolin-4-yl) -N -hydroxypropanamide;
<28> 3-(6-fluoro-2-( p -tolyl)quinolin-4-yl) -N -hydroxypropanamide; and
<29> 3-(2-(4-chlorophenyl)-6-fluoroquinolin-4-yl))- N -hydroxypropanamide. As shown in Scheme 1 below,
Method for producing a compound represented by Formula 1, comprising the step of reacting a compound represented by Formula 2 to produce a compound represented by Formula 1:
[Scheme 1]

In Scheme 1 above,
X, Y and R are as defined in Formula 1 of Clause 1. A pharmaceutical product for the prevention or treatment of cancer, autoimmune disease, fibrosis, and neurodegenerative disease, containing the compound represented by Formula 1 of claim 1, its solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. Composition. A pharmaceutical composition for preventing or treating diseases caused by hyperactivation of HDAC6 or HDAC8, containing the compound represented by Formula 1 of claim 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In clause 7,
The above cancers include pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, and acute lymphocytic leukemia. , basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, and ampullary carcinoma of Vater. , bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinonasal cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney Cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, Gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, Spinal cord cancer, acoustic neurula, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyomas, laryngeal cancer, pleural cancer, A pharmaceutical composition, which is at least one selected from the group consisting of hematological cancer, and thymic cancer. In clause 7,
The autoimmune diseases include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplant rejection. , graft-versus-host disease (GVHD), lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary tract. A pharmaceutical composition that is at least one selected from the group consisting of cirrhosis, allergic conjunctivitis, and atopic dermatitis. In clause 7,
The fibrosis includes pulmonary fibrosis, idiopathic pulmonary fibrosis, irradiation-induced lung damage or pulmonary fibrosis, pulmonary edema, cystic fibrosis, liver fibrosis, endomyocardial fibrosis, myocardial infarction, atrial fibrosis, glial scar, renal fibrosis, and bone marrow. A pharmaceutical composition, which is at least one selected from the group consisting of fibrosis, articular fibrosis, fatty fibrosis, skin fibrosis, nerve fibrosis and muscle fibrosis. In clause 7,
The neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Wilson disease, neurodegeneration due to traumatic brain injury, neurodegeneration due to spinal cord injury, neurodegeneration due to stroke, and amyotrophic lateral cord injury. A pharmaceutical composition, which is at least one selected from the group consisting of sclerosis, human immunodeficiency virus dementia, Huntington's disease, multiple sclerosis, cerebral amyloid angiopathy, and tauopathy. Health function for preventing or improving cancer, autoimmune disease, fibrosis, and neurodegenerative disease, containing the compound represented by Formula 1 of Paragraph 1, its solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. Food composition.