KR20230163602A - Pharmaceutical composition comprising bicycle derivative for use in preventing or treating cancer as an active ingredient - Google Patents

Abstract

The present invention relates to a bicycle derivative and a pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient. The bicycle derivative described herein has been confirmed to have ACC inhibitory activity, which is involved in the tumor proliferation and metastasis inhibition mechanism. It is expected to be useful in preventing or treating cancer.

Description

Pharmaceutical composition comprising bicycle derivative for use in preventing or treating cancer as an active ingredient}

The present invention relates to a bicycle derivative and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

Liver cancer ranks 6th in incidence in Korea and 2nd in mortality among all cancers. It is a cancer with a high incidence and mortality rate and rapid metastasis to the lungs and bones. In addition, 70% of liver cancer surgery patients have a high recurrence rate, with recurrence within 5 years, and the treatment prognosis for relapsed liver cancer is also poor. For this reason, there is a need for the development of drugs that can effectively induce death and inhibition of proliferation of liver cancer cells.

Cancer cells proliferate through metabolism. In addition to serving as energy storage, lipids also serve as building blocks for newly synthesized membranes. It has been proven through many recent studies that specific mutations occur in the lipid metabolism of cancer cells, and it has been reported that changes in the expression and activity of lipid metabolism enzymes occur due to the activation of oncogenic signals. This fact suggests that proteins involved in lipid metabolism can be used as excellent chemotherapy targets for cancer treatment.

Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in fatty acid synthesis. When Acetyl-CoA Carboxylase (ACC) is phosphorylated and inactivated in cancer cells, it inhibits lipid synthesis and beta- Energy metabolism is regulated by promoting oxidation (β-oxidation). This regulation of energy metabolism also affects the proliferation and metastasis of cancer cells (WANG, Chao, et al. Expert Review of Anticancer Therapy, 2015, 15.6: 667-676).

In particular, inhibiting cancer growth and progression by reducing fat synthesis within the liver by inactivating enzymes such as Acetyl-CoA Carboxylase (ACC) in the liver, the central organ of lipid metabolism, is being studied as a useful target for the development of new anti-metabolic treatments. there is.

Accordingly, the present inventors confirmed that the bicycle derivative of the present specification has an inhibitory activity on Acetyl-CoA Carboxylase (ACC), a rate-limiting enzyme in fatty acid synthesis involved in inhibiting the proliferation of cancer cells in human liver cancer cell lines, and completed the present invention. did.

The object of the present invention is to provide bicycle derivatives.

Another object of the present invention is to provide a novel pharmaceutical composition for preventing or treating cancer.

Another object of the present invention is to provide a novel health functional food composition for preventing or improving cancer.

In order to achieve the above purpose,

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

[Formula 1]

In Formula 1,

X is C or N;

Y is NR ⁶ or O,

R ⁶ is hydrogen or C1-C10 alkyl;

R ¹ , R ² and R ³ are each independently hydrogen, hydroxy or halogen;

R ⁴ is hydrogen or C1-C10 alkyl;

R ⁵ is hydrogen or oxo (=O);

A is unsubstituted or substituted C6-C10 aryl or 6-10 membered heteroaryl,

Here, the substituted C6-C10 aryl or 6-10 membered heteroaryl is substituted with one or more selected from the group consisting of C1-C10 alkyl, halogen, hydroxy, phenyl, carboxy, and C1-C10 alkyloxycarbonyl, Alternatively, two adjacent atoms are substituted to form a 5-6 atom heterocycle, where the 5-6 atom heterocycle is unsubstituted or substituted with oxo (=O).

In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

In another aspect, the present invention provides a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. provides.

The compound represented by Formula 1 described herein is expected to be useful in the prevention or treatment of cancer by confirming the ACC inhibitory activity involved in tumor proliferation and metastasis inhibition mechanisms.

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 hydrocarbon moieties, unless otherwise specified. For example, “C1-C5alkyl” means alkyl with a skeleton of 1 to 5 carbons. Specifically, C1-C5 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, etc. may include.

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 “heterocycle” includes fully saturated or partially unsaturated heterocycloalkyl and heteroaryl.

The term “heterocycloalkyl”, unless otherwise specified, includes monovalent saturated moieties consisting of 1 to 3 rings containing 1, 2, 3 or 4 heteroatoms selected from N, O or S. Two or three rings may contain bridged, fused or spiro heterocycloalkyls.

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 stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

X is C or N;

Y is NR ⁶ or O,

R ⁶ is hydrogen or C1-C10 alkyl;

R ¹ , R ² and R ³ are each independently hydrogen, hydroxy or halogen;

R ⁴ is hydrogen or C1-C10 alkyl;

R ⁵ is hydrogen or oxo (=O);

A is unsubstituted or substituted C6-C10 aryl or 6-10 membered heteroaryl,

Here, the substituted C6-C10 aryl or 6-10 membered heteroaryl is substituted with one or more selected from the group consisting of C1-C10 alkyl, halogen, hydroxy, phenyl, carboxy, and C1-C10 alkyloxycarbonyl, Alternatively, two adjacent atoms are substituted to form a 5-6 atom heterocycle, where the 5-6 atom heterocycle is unsubstituted or substituted with oxo (=O).

One embodiment of the present invention,

In Formula 1,

X is C or N;

Y is NR ⁶ or O,

R ⁶ is hydrogen or C1-C5 alkyl;

R ¹ , R ² and R ³ are each independently hydrogen, hydroxy or halogen;

R ⁴ is hydrogen or C1-C5 alkyl;

R ⁵ is hydrogen or oxo (=O);

A is unsubstituted or substituted C6-C10 aryl or 9-10 membered heteroaryl,

Here, the substituted C6-C10 aryl or 9-10 membered heteroaryl is substituted with one or more selected from the group consisting of C1-C5 alkyl, halogen, hydroxy, phenyl, carboxy, and C1-C5 alkyloxycarbonyl, or two adjacent atoms are substituted to form a 6-atom heterocycle, wherein the 6-atom heterocycle is unsubstituted or substituted with oxo (=O), a compound, a stereoisomer thereof, and a solvent thereof. It provides a cargo, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention,

In Formula 1,

X is C or N;

Y is NR ⁶ or O,

R ⁶ is hydrogen or C1-C2alkyl;

R ¹ and R ² are each independently hydrogen or halogen;

R ³ is hydroxy or halogen;

R ⁴ is hydrogen or C1-C2alkyl;

R ⁵ is hydrogen or oxo (=O);

A is unsubstituted or substituted C6-C10 aryl or 9-10 membered heteroaryl,

Here, the substituted C6-C10 aryl or 9-10 membered heteroaryl is substituted with one or more selected from the group consisting of C1-C2 alkyl, halogen, hydroxy, phenyl, carboxy, and C1-C2 alkyloxycarbonyl, or two adjacent atoms are substituted to form a 6-atom heterocycle, wherein the 6-atom heterocycle is substituted with oxo (=O), a compound, a stereoisomer thereof, a solvate thereof, and a hydrate thereof. Or a pharmaceutically acceptable salt thereof is provided.

One embodiment of the present invention,

In Formula 1,

X is C or N;

Y is NR ⁶ or O,

R ⁶ is hydrogen or methyl;

R ¹ is hydrogen, F or Cl;

R ² is hydrogen or Cl;

R ³ is hydroxy or Cl;

R ⁴ is hydrogen, methyl or ethyl;

R ⁵ is hydrogen or oxo (=O);

A is unsubstituted or substituted phenyl, naphthalene, indazole, quinoline, quinoxaline or tunazoline,

Here, the substituted phenyl, naphthalene, indazole, quinoline, quinoxaline or tunazoline is substituted with one or more selected from the group consisting of methyl, F, Cl, hydroxy, phenyl, carboxy and methyloxycarbonyl, or Compounds, stereoisomers thereof, and their Solvates, hydrates thereof, or pharmaceutically acceptable salts thereof are provided.

One embodiment of the present invention,

In Formula 1,

A is , , , , , , , , , , , or It provides a compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, which is characterized in that:

One embodiment of the present invention,

In Formula 1,

The compound represented by Formula 1 provides any one compound selected from the following compound group, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

<1> 2-(1-(benzylamino)ethyl)-4-chlorophenol;

<2> 4-chloro-2-(1-((3-chloro-4-fluorobenzyl)amino)ethyl)phenol;

<3> 2-(1-(([1,1'-biphenyl]-4-ylmethyl)amino)ethyl)-4-chlorophenol;

<4> 4-chloro-2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol;

<5> 4-(1-(benzyloxy)ethyl)-3,5-dichloropyridine;

<6> 4-(1-([1,1'-biphenyl]-4-ylmethoxy)ethyl)-3,5-dichloropyridine;

<7> Methyl 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoate;

<8> 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoic acid;

<9> N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-2-naphthamide;

<10> Methyl 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoate;

<11> 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoic acid;

<12> 4-fluoro-2-(1-((naphthalen-2-ylmethyl)amino)propyl)phenol;

<13> 4-chloro-2-(1-(((1-methyl-1H-indazol-6-yl)methyl)amino)ethyl)phenol;

<14> 5-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)quinazolin-2(1H)-one;

<15> 4-chloro-2-(1-(methyl(naphthalen-2-ylmethyl)amino)ethyl)phenol;

<16> N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-6-hydroxy-2-naphthamide;

<17> 3,5-dichloro-4-(1-(naphthalen-2-ylmethoxy)ethyl)pyridine;

<18> N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-3-carboxamide;

<19> 2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol;

<20> N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinazoline-6-carboxamide;

<21> N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-6-carboxamide;

<22> 4-chloro-2-(1-((quinoxalin-6-ylmethyl)amino)ethyl)phenol;

<23> 4-chloro-2-(1-((quinolin-6-ylmethyl)amino)ethyl)phenol;

<24> 4-chloro-2-(1-((quinolin-3-ylmethyl)amino)ethyl)phenol;

<25> 4-fluoro-2-(1-((quinolin-3-ylmethyl)amino)propyl)phenol; and

<26> N-(1-(5-fluoro-2-hydroxyphenyl)propyl)quinoline-3-carboxamide.

One embodiment of the present invention,

Provided is a pharmaceutical composition for preventing or treating cancer, containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

These cancers include lung cancer, non-small cell lung cancer (NSCL), bronchoalveolar cell lung cancer, ovarian cancer, colorectal cancer, melanoma, stomach cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, and uterine cancer. , rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophagus cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer It may be any one of cancer, multiple myeloma, chronic or acute leukemia, and preferably liver cancer.

One embodiment of the present invention,

Containing the compound represented by Formula 1 above, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,

A pharmaceutical composition for preventing or treating diseases caused by ACC hyperactivation is provided.

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 prevention of cancer symptoms in advance by suppressing or blocking the symptoms of cancer by administering, ingesting, or applying the pharmaceutical composition or health functional food of the present invention to an individual who is not suffering from cancer. This means preventing it from occurring.

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

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 isomers, solvates, hydrates, etc. that can be prepared therefrom.

The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include structural isomers such as tautomers and stereoisomers, and stereoisomers include R or S isomers (optical isomers, enantiomers) and geometric isomers (trans, cis) with an asymmetric carbon center. Everything is included. In the present invention, all stereoisomers of the compound represented by Formula 1 and mixtures thereof are also included within the scope of the present invention.

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, an isomer thereof, 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, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent, or It can be used in combination with other treatments in use, and the effect can be enhanced by combined administration.

One embodiment of the present invention,

Provided is a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the term “improvement” means reducing or alleviating cancer symptoms by administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to a cancer-stricken individual.

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 related to 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 of the present invention apply equally unless they contradict each other.

One embodiment of the present invention is a method for preventing cancer, comprising administering to a subject in need a compound represented by Formula 1 described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. Or provide a treatment method.

One embodiment of the present invention is a compound represented by Formula 1 described herein for use in the manufacture of a medicament for use in the prevention or treatment of cancer, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutical thereof. 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 examples and experimental examples.

However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following production examples, examples, and experimental examples.

<Conditions for analysis and purification>

1. HPLC analysis conditions (A)

Device name: Shimadzu

Column: YMC-pack pro C18, 150x4.6mm I.D., 5 μm, 40℃

Mobile phase: 5% -> 100% acetonitrile/H ₂ O + 0.1% trifluoroacetic acid,

Analysis time: 9 minutes, flow rate: 1ml/min

UV detector: 254nm

2. HPLC analysis conditions (B)

Device Name: Thermo Scientific Ultimate 3000RSLC

Column: Kinetex® 2.6 μM biphenyl 100Å, 100x2.1mm

Mobile phase: 5% -> 100% acetonitrile/H ₂ O + 0.1% trifluoroacetic acid,

Analysis time: 8 minutes, flow rate: 0.7ml/min

UV detector: 254nm

3. LC-MS analysis conditions

Device name: Shimadzu LCMS-2020

Column: ACE Excel2 C18, 75x2.1 mm

Mobile phase: Acetonitrile/H ₂ O + 0.1% trifluoroacetic acid

Flow rate: 1mL/min

UV detector: 254nm

4. MPLC purification conditions

Device name: CombiFlash®Rf+

UV detector: 254nm

5. Prep-HPLC purification conditions

Device name: Gilson GX-281, 321 pump, UV/VIS-155

Column: Luna® 10 μM C18 (2) 100 Å, 250x21.2 mm

Mobile phase: Acetonitrile/0.1% trifluoroacetic acid H ₂ O

Flow rate: 15mL/min

UV detector: 254nm

6. ^One H NMR analysis conditions

Device name: Bruker Avance (400 MHz)

<Example 1> Preparation of 2-(1-(benzylamino)ethyl)-4-chlorophenol

1-(5-Chloro-2-hydroxyphenyl)ethanone (170 mg, 1 mmol) was dissolved in 1,2-dichloroethane, then phenylmethanamine (0.142 ml, 1.3 mmol) and acetic acid (0.115 ml, 2 mmol) was added. After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (381 mg, 1.80 mmol) was added. Heat to 80 ^o C, heat and stir for 4 hours, cool the mixture to room temperature, and then add water to terminate the reaction. It was diluted with dichloromethane and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-10% ethyl acetate/hexane) to obtain 2-(1-(benzylamino)ethyl)-4-chlorophenol (100 mg, 38%, green liquid). Obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.35 - 7.25 (m, 5H), 7.09 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 3.94 (q, J = 6.8 Hz, 1H), 3.67 (d of d, J = 13.1 Hz, 16.4 Hz, 2H), 1.41 (d, J = 6.8 Hz, 3H).

<Example 2> Preparation of 4-chloro-2-(1-((3-chloro-4-fluorobenzyl)amino)ethyl)phenol

The target compound 4-chloro-2-(1-((3-chloro-4-fluorobenzyl)amino)ethyl)phenol was obtained in a similar manner to Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.3 (s, 1H), 7.31 (d of d, J = 1.5 Hz, 6.8 Hz, 1H), 7.15 - 7.07 (m, 3H), 6.94 (d, J = 2.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 3.92 (q, J = 6.8 Hz, 1H), 3.73 (d, J = 13.2 Hz, 1H), 3.62 (d, J = 13.2 Hz) , 1H), 1.46 (d, J = 6.7 Hz 3H).

<Example 3> Preparation of 2-(1-(([1,1'-biphenyl]-4-ylmethyl)amino)ethyl)-4-chlorophenol

The target compound 2-(1-(([1,1'-biphenyl]-4-ylmethyl)amino)ethyl)-4-chlorophenol was obtained in a similar manner to Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.6 (s, 1H), 7.59 - 7.57 (m, 6H), 7.46 - 7.42 (m, 2H), 7.37 - 7.33 (m, 2H), 7.12 (d of d , J = 2.6 Hz, 8.6 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 3.97 (q, J = 6.8 Hz, 1H), 3.84 (d, J = 12.8 Hz, 1H), 3.69 ( d, J = 12.8 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H); LCMS, m/z 338[M+H] ⁺

<Example 4> Preparation of 4-chloro-2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol

The target compound 4-chloro-2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol was obtained in a similar manner to Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.7 (s, 1H), 7.85 - 7.81 (m, 3H), 7.70 (s, 1H), 7.52 - 7.46 (m, 2H), 7.39 (d of d, J = 1.7 Hz, 8.4 Hz, 1H), 7.12 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H) , 4.01 - 3.95 (m, 2H), 3.80 (d, J = 13.0 Hz, 1H), 1.46 (d, J = 6.8 Hz, 3H); LCMS, m/z 311[M+H] ⁺

<Example 5> Preparation of 4-(1-(benzyloxy)ethyl)-3,5-dichloropyridine

Dissolve 1-(5-chloro-2-hydroxyphenyl)ethanone (170 mg, 1 mmol) in tetrahydrofuran, and then slowly add 60% sodium hydride (32 mg, 0.781 mmol) at 0 ^o C. did. After stirring for 20 minutes, benzyl bromide (0.093 mL, 0.781 mmol) was slowly added dropwise. After stirring at room temperature for 15 hours, the reaction is terminated by adding ammonium chloride aqueous solution. It was diluted with ethyl acetate and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-10% ethyl acetate/hexane), and 4-(1-(benzyloxy)ethyl)-3,5-dichloropyridine (100 mg, 68%, colorless liquid) was obtained. ) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 2H), 7.32 - 7.26 (m, 4H), 5.25 (q, J = 6.7 Hz, 1H), 4.42 (d, J = 11.4 Hz, 1H) , 4.30 (d, J = 11.4 Hz, 1H), 1.59 (d, J = 6.7 Hz, 3H); LCMS, m/z 283[M+H] ⁺

<Example 6> Preparation of 4-(1-([1,1'-biphenyl]-4-ylmethoxy)ethyl)-3,5-dichloropyridine

The target compound 4-(1-([1,1'-biphenyl]-4-ylmethoxy)ethyl)-3,5-dichloropyridine was obtained in a similar manner to Example 5.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 2H), 7.58 - 7.53 (m, 4H), 7.46 - 7.31 (m, 5H), 5.29 (q, J = 6.7 Hz, 1H), 4.45 ( d, J = 11.4 Hz, 1H), 4.34 (d, J = 11.4 Hz, 1H), 1.62 (d, J = 6.7 Hz, 3H); LCMS, m/z 359[M+H] ⁺

<Example 7> Preparation of methyl 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoate

The target compound methyl 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoate was obtained in a similar manner to Example 5.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (s, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 5.27 (q, J = 6.7 Hz) , 1H), 4.45 (d, J = 12.3 Hz, 1H), 4.30 (d, J = 12.3 Hz, 1H), 3.91 (s, 3H), 1.62 (d, J = 6.7 Hz, 3H); LCMS, m/z 341[M+H] ⁺

<Example 8> Preparation of 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoic acid

Compound 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoate (33 mg, 0.097 mmol) prepared in Example 7 was mixed with tetrahydrofuran/distilled water (0.5 mL: After dissolving in 0.5 mL), lithium hydroxide monohydrate (8.1 mg, 0.194 mmol) was added. After stirring at room temperature for 15 hours, the reaction is terminated by adding 1M hydrochloric acid aqueous solution until pH 3. It was diluted with ethyl acetate and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoic acid (21 mg, 66%, white solid). Obtained.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (s, 2H), 7.89 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 5.24 (q, J = 6.7 Hz, 1H), 4.46 - 4.38 (m, 2H), 1.55 (d, J = 6.7 Hz, 3H); LCMS, m/z 327[M+H] ⁺

<Example 9> Preparation of N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-2-naphthamide

Step 1: Preparation of 3-(4-morpholinophenyl)prop-2-yn-1-ol

1-(5-Chloro-2-methoxyphenyl)ethanamine (30 mg, 0.16 mmol) was dissolved in dichloromethane, followed by 2-naphthoic acid (28 mg, 0.16 mmol) and DCC (33 mg, 0.16 mmol). was added. After stirring at room temperature for 15 hours, the mixture was filtered through Celite and concentrated under reduced pressure. The obtained residue was diluted in dichloromethane and washed with supersaturated sodium bicarbonate and water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-(4-morpholinophenyl)prop-2-yn-1-ol (35 mg, 63%, white solid). .

Step 2: Preparation of N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-2-naphthamide

3-(4-morpholinophenyl)prop-2-yn-1-ol (16 mg, 0.04 mmol) prepared in step 1 was dissolved in dichloromethane, and then dissolved in 1M BBr3 (dichloromethane) at -78 ^o C. Methane mixed solution (0.094 mL, 0.09 mmol) was slowly added. Raise the temperature to room temperature and stir for 2 hours, then add supersaturated aqueous sodium bicarbonate solution to terminate the reaction. The mixture was diluted with dichloromethane and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by preparative HPLC (0.1% trifluoroacetic acid H ₂ O/acetonitrile). The obtained trifluoroacetate compound was neutralized with a supersaturated aqueous sodium bicarbonate solution to obtain N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-2-naphthamide (14 mg, 91%, white solid). Obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 7.92 - 7.85 (m, 3H), 7.75 (d of d, J = 1.7 Hz, 8.6 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.26 (d, J = 2.7 Hz, 1H), 7.14 (d of d, J = 2.7 Hz, 8.6 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 5.51 (p, J = 7.8 Hz, 1H), 1.76 (d, J = 7.1 Hz, 3H); LCMS, m/z 326[M+H] ⁺

<Example 10> Preparation of methyl 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoate

Step 1: Preparation of 2-(1-aminoethyl)-4-chlorophenol

1-(5-Chloro-2-hydroxyphenyl)ethanone (341 mg, 2 mmol) was directly dissolved in 7N ammonia (methanol mixed solution) (4 mL, 28 mmol) and stirred at room temperature for 15 hours. . The mixture was concentrated under reduced pressure to obtain the target compound, 4-chloro-2-(1-iminoethyl)phenol (330 mg, 97%, yellow solid).

The previously obtained 4-chloro-2-(1-iminoethyl)phenol (156 mg, 0.92 mmol) was dissolved in tetrahydrofuran, and then Ti(OiPr) ₄ (0.323 ml, 1.10 mmol) was added. After stirring at room temperature for 30 minutes, 1M BH3 (tetrahydrofuran mixed solution) (1.2 mL, 1.2 mmol) was slowly added dropwise over 5 minutes. After stirring for 1 hour, 1M HCl aqueous solution (3 mL) was slowly added and stirred for 1 hour. Then, supersaturated aqueous sodium bicarbonate solution (10 mL) was added and stirred for 30 minutes. The mixture was filtered through Celite, and the filtered residue was extracted with ethyl acetate. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 2-(1-aminoethyl)-4-chlorophenol (150 mg, 91%, yellow solid).

Step 2: Preparation of methyl 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoate

2-(1-Aminoethyl)-4-chlorophenol (43 mg, 0.25 mmol) was dissolved in dimethylformamide, and then methyl 4-(bromomethyl)benzoate (19 mg, 0.08 mmol) was added at room temperature. Then, stir for 5 minutes. Then, DIPEA (0.022 mL, 0.12 mmol) was added. After stirring at room temperature for 3 hours, the reaction was terminated by adding water, then diluted with ethyl acetate and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to produce methyl 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoate. (18 mg, 67%, white solid) was obtained.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.01 - 7.97 (m, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.10 - 7.05 (m, 2H), 6.72 (d, J = 8.5 Hz) , 1H), 3.96 (q, J = 6.7 Hz, 1H), 3.92 (s, 3H), 3.78 - 3.72 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H); LCMS, m/z 320[M+H] ⁺

<Example 11> Preparation of 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoic acid

The compound methyl 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoate (23 mg, 0.07 mmol) prepared in Example 10 was mixed with tetrahydrofuran/distilled water (0.5 mL: 0.5 mL), and then lithium hydroxide monohydrate (7.5 mg, 0.18 mmol) was added. After stirring at 40 ^o C for 15 hours, the reaction is terminated by adding 1M hydrochloric acid aqueous solution until pH 7. It was diluted with ethyl acetate and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography to obtain 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoic acid (17 mg, 77%, white solid). did.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.24 - 7.21 (m, 2H), 6.88 - 6.84 (m , 1H), 4.38 (q, J = 6.8 Hz, 1H), 3.98 (q, J = 13.4 Hz, 2H), 1.60 (d, J = 6.8 Hz, 3H); LCMS, m/z 306[M+H] ⁺

<Example 12> Preparation of 4-fluoro-2-(1-((naphthalen-2-ylmethyl)amino)propyl)phenol

The target compound 4-fluoro-2-(1-((naphthalen-2-ylmethyl)amino)propyl)phenol was obtained in a similar manner to Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (s, 1H), 7.84 - 7.80 (m, 3H), 7.69 (s, 1H), 7.52 - 7.44 (m, 2H), 7.39 (d of d, J = 1.6 Hz, 8.4 Hz, 1H), 6.91 - 6.86 (m, 1H), 6.67 (d of d, J = 3.0 Hz, 8.8 Hz, 1H), 3.99 (d, J = 13.1 Hz, 1H), 3.77 ( d, J = 13.1 Hz, 1H), 3.66 (t, J = 7.3 Hz, 1H), 1.90 - 1.68 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); LCMS, m/z 310[M+H] ⁺ 310

<Example 13> Preparation of 4-chloro-2-(1-(((1-methyl-1H-indazol-6-yl)methyl)amino)ethyl)phenol

The target compound 4-chloro-2-(1-(((1-methyl-1H-indazol-6-yl)methyl)amino)ethyl)phenol was obtained in a similar manner to Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.25 (app s. overlapped with solvent peak, 1H), 7.12 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 7.06 (d of d, J = 1.1 Hz, 8.6 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H) , 4.07 (s, 3H), 3.98 - 3.92 (m, 2H), 3.82 - 3.77 (m, 1H), 1.46 (d, J = 6.7 Hz, 3H); LCMS, m/z 316[M+H] ⁺

<Example 14> Preparation of 5-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)quinazolin-2(1H)-one

The target compound 5-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)quinazolin-2(1H)-one was obtained in a similar manner to Example 10.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (d, J = 8.2 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.51 (d of d, J = 1.4 Hz, 8.2 Hz, 1H), 7.10 - 7.07 (m, 2H), 6.75 - 6.71 (m, 1H), 4.00 (q, J = 6.7 Hz, 1H), 3.85 (s, 2H), 1.44 (d, J = 6.7 Hz) , 3H); LCMS, m/z 330[M+H] ⁺

<Example 15> Preparation of 4-chloro-2-(1-(methyl(naphthalen-2-ylmethyl)amino)ethyl)phenol

4-Chloro-2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol (31 mg, 0.09 mmol) was dissolved in tetrahydrofuran, then paraformaldehyde (12 mg, 0.39 mmol), Sodium triacetoxyborohydride (105 mg, 0.49 mmol) and acetic acid (0.034 mL, 0.59 mmol) were added. After stirring at 60 ^o C for 2 hours, the reaction was terminated by adding distilled water, then diluted with ethyl acetate and washed with water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane), and 4-chloro-2-(1-(methyl(naphthalen-2-ylmethyl)amino)ethyl)phenol (15 mg) , 46%, colorless sticky solid) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.9 (s, 1H), 7.84 - 7.80 (m, 3H), 7.70 (s, 1H), 7.49 - 7.41 (m, 3H), 7.14 (d of d, J = 2.5 Hz, 8.6 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 3.96 (q, J = 6.7 Hz, 1H), 3.82 - 3.72 (m, 2H), 2.20 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 326[M+H] ⁺

<Example 16> Preparation of N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-6-hydroxy-2-naphthamide

2-(1-Aminoethyl)-4-chlorophenol (85 mg, 0.49 mmol) was dissolved in acetonitrile, then 6-hydroxy-2-naphthoic acid (93 mg, 0.49 mmol) and triethylamine. (0.17 mL, 1.23 mmol) and PyBOP (258 mg, 0.49 mmol) were added. After stirring at room temperature for 15 hours, acetonitrile is removed by concentration under reduced pressure. The mixture was diluted with ethyl acetate, and the organic layer was washed with 1M HCl aqueous solution and water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane) to obtain N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-6-hydroxy-2-naphtha. Mead (42 mg, 24%, brown solid) was obtained.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 1.1 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.17 - 7.14 (m, 2H), 7.07 (d of d, J = 2.6 Hz, 8.6 Hz, 1H), 6.80 (d, J = 6.8 Hz, 1H), 5.48 (q, J = 7.1 Hz, 1H), 1.58 (d, J = 7.1 Hz, 3H); LCMS, m/z 342[M+H] ⁺

<Example 17> Preparation of 3,5-dichloro-4-(1-(naphthalen-2-ylmethoxy)ethyl)pyridine

The target compound 3,5-dichloro-4-(1-(naphthalen-2-ylmethoxy)ethyl)pyridine was obtained in a similar manner to Example 5.

^1H NMR (400MHz, CDCl3) δ 8.44 (s, 2H), 7.83 - 7.79 (m, 3H), 7.74 (s, 1H), 7.49 - 7.44 (m, 3H), 5.30 (q, J = 6.8 Hz) , 4.59 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H); LCMS, m/z 332[M+H] ⁺

<Example 18> Preparation of N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-3-carboxamide

2-(1-Aminoethyl)-4-chlorophenol (60 mg, 0.350 mmol) was dissolved in dimethylformamide, then quinoline-3-carboxylic acid (61 mg, 0.35 mmol) and EDCI (101 mg, 0.52 mmol) were dissolved in dimethylformamide. mmol), HOBt (64 mg, 0.42 mmol), and DIPEA (0.157 mL, 0.87 mmol). was added. After stirring at room temperature for 15 hours, the reaction was terminated by adding water, diluted with ethyl acetate, and the organic layer was washed with 1M aqueous HCl solution and water. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0~50% ethyl acetate/hexane), and N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-3-carboxamide (74) mg, 65%, white solid) was obtained.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 9.30 (d, J = 2.1 Hz, 1H), 9.08 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.14 - 8.08 (m, 2H), 7.90 - 7.85 (m, 1H), 7.73 - 7.69 (m, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.09 (d of d , J = 2.6 Hz, 8.6 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.45 (p, J = 7.4 Hz, 1H), 1.45 (d, J = 7.4 Hz, 3H); LCMS, m/z 327[M+H] ⁺

<Example 19> Preparation of 2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol

The target compound 2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol was obtained in a similar manner to Example 10.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 - 7.80 (m, 3H), 7.71 (s, 1H), 7.50 - 7.45 (m, 2H), 7.41 (d of d, J = 1.6 Hz, 8.4 Hz, 1H), 7.20 - 7.16 (m, 1H), 6.98 (d of d, J = 1.6 Hz, 7.4 Hz, 1H), 6.88 (d of d, J = 1.1 Hz, 8.4 Hz, 1H), 6.81 (d of t, J = 1.1 Hz, 7.4 Hz, 1H), 4.05 - 3.98 (m, 2H), 3.82 (d, J = 13.1 Hz, 1H), 1.95 (broad s, 1H), 1.47 (d, J = 6.8 Hz) , 3H); LCMS, m/z 278[M+H] ⁺

<Example 20> Preparation of N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinazoline-6-carboxamide

The target compound N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinazoline-6-carboxamide was obtained in a similar manner to Example 10.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 9.39 (s, 1H), 9.10 (d, J = 8.2 Hz, 1H), 8.73 (d, J = 1.8 Hz, 1H) , 8.46 (d of d, J = 2.0 Hz, 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.09 (d of d, J = 2.6 Hz, 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.45 (p, J = 7.2 Hz, 1H), 4.14 - 4.10 (m, 1H), 1.44 (d, J = 6.9 Hz) , 3H); LCMS, m/z 346[M ⁺ +H ₂ O]

<Example 21> Preparation of N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-6-carboxamide

The target compound N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-6-carboxamide was obtained in a similar manner to Example 18.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 8.99 (d of d, J = 1.7 Hz, 4.2 Hz, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.51 (d, J = 8.1 Hz, 1H), 8.21 (d of d, J = 2.0 Hz, 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.62 (d of d, J = 4.2 Hz) , 8.1 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.08 (d of d, J = 2.7 Hz, 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.44 ( p, J = 7.4 Hz, 1H), 4.14 - 4.10 (m, 1H), 1.44 (d, J = 7.4 Hz, 3H); LCMS, m/z 327[M+H] ⁺

<Example 22> Preparation of 4-chloro-2-(1-((quinoxalin-6-ylmethyl)amino)ethyl)phenol

The target compound 4-chloro-2-(1-((quinoxalin-6-ylmethyl)amino)ethyl)phenol was obtained in a similar manner to Example 10.

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.3 (s, 1H), 8.86 - 8.83 (m, 2H), 8.11 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.71 (d of d, J = 1.9 Hz, 8.7 Hz, 1H), 7.12 (d of d, J = 2.6 Hz, 8.7 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 4.06 - 3.92 (m, 3H) , 1.50 (d, J = 6.7 Hz, 3H); LCMS, m/z 315[M+H] ⁺

<Example 23> Preparation of 4-chloro-2-(1-((quinolin-6-ylmethyl)amino)ethyl)phenol

The target compound 4-chloro-2-(1-((quinolin-6-ylmethyl)amino)ethyl)phenol was obtained in a similar manner to Example 10.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92 (d of d, J = 1.6 Hz, 4.2 Hz, 1H), 8.11 (d of d, J = 8.6 Hz, 16.7 Hz, 2H), 7.69 (s, 1H) ), 7.63 (d of d, J = 1.6 Hz, 8.6 Hz, 1H), 7.42 (d of d, J = 4.2 Hz, 8.6 Hz, 1H), 7.12 (d of d, J = 2.5 Hz, 8.6 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.01 - 3.84 (m, 3H), 1.48 (d, J = 6.7 Hz, 3H); LCMS, m/z 313[M+H] ⁺

<Example 24> Preparation of 4-chloro-2-(1-((quinolin-3-ylmethyl)amino)ethyl)phenol

Quinoline-3-carbaldehyde (50 mg, 0.31 mmol) was dissolved in methanol, then 2-(1-aminoethyl)-4-chlorophenol (82 mg, 0.47 mmol) and sodium cyanoborohydride (60 mg, 0.95 mmol) was added slowly at 0 ^o C. After stirring for 30 minutes, distilled water was added dropwise to terminate the reaction, extracted with dichloromethane, and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane), and 4-chloro-2-(1-((quinolin-3-ylmethyl)amino)ethyl)phenol (28 mg, 28%, white sticky solid) was obtained.

^1H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 8.83 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.73 - 7,70 (m, 1H), 7.60 - 7,55 (m, 1H), 7.14 (dd, J = 8.6, 2.6 Hz, 1H) , 6.98 (d, J = 2.6 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.02 - 3.97(m, 2H), 3.88 (d, J = 13.4 Hz, 1H), 2.02 (s, 1H), 1.49 (d, J = 6.7 Hz, 3H); LCMS, m/z 313[M+H] ⁺

<Example 25> Preparation of 4-fluoro-2-(1-((quinolin-3-ylmethyl)amino)propyl)phenol

The target compound 4-fluoro-2-(1-((quinolin-3-ylmethyl)amino)propyl)phenol was obtained in a similar manner to Example 24.

^1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.82 (dd, J = 8.2, 0.9 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.59 - 7.55 (m, 1H), 6.93 - 6.86 (m, 1H), 6.80 (dd, J = 8.9, 4.8 Hz, 1H) , 6.69 (dd, J = 8.9, 3.0 Hz, 1H), 4.03 (d, J = 13.5 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H), 3.67 (q, J = 7.4 Hz, 1H) , 1.91 - 1.71 (m, 2H), 1.26 (t, J = 7.1 Hz, 1H), 0.89 (t, J = 7.4 Hz, 3H); LCMS, m/z 311[M+H] ⁺

<Example 26> Preparation of N-(1-(5-fluoro-2-hydroxyphenyl)propyl)quinoline-3-carboxamide

Quinoline-3-carboxylic acid (64 mg, 0.37 mmol) was dissolved in dimethylformamide, then 2-(1-aminopropyl)-4-fluorophenol (76 mg, 0.44 mmol) and EDCI (108) were dissolved in dimethylformamide. mg, 0.56 mmol), HOBt (68 mg, 0.44 mmol), and DIPEA (0.16 mL, 0.93 mmol) were added. After stirring for 6 hours, distilled water was added dropwise to terminate the reaction, extracted with ethyl acetate, and washed with salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane), and N-(1-(5-fluoro-2-hydroxyphenyl)propyl)quinoline-3-carboxamide ( 81 mg, 66%, white solid) was obtained.

^1H NMR (400 MHz, CDCl3) δ 9.23 (d, J = 2.2 Hz, 1H), 9.18 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 7.1, 7.1 Hz, 1H), 7.65 (dd, J = 7.5, 7.5 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6,97 - 6.85 (m, 3H), 5.22 (q, J = 7.4 Hz, 1H), 2.15 - 2.04 (m, 2H), 1.26 (t, J = 7.1 Hz, 1H), 1.08 (t, J = 7.4 Hz, 3H); LCMS, m/z 325[M+H] ⁺

The compound structures and compound names of Examples 1 to 26 are shown in Table 1 below.

Example compound structure Compound name One 2-(1-(benzylamino)ethyl)-4-chlorophenol 2 4-Chloro-2-(1-((3-chloro-4-fluorobenzyl)amino)ethyl)phenol 3 2-(1-(([1,1'-biphenyl]-4-ylmethyl)amino)ethyl)-4-chlorophenol 4 4-chloro-2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol 5 4-(1-(benzyloxy)ethyl)-3,5-dichloropyridine 6 4-(1-([1,1'-biphenyl]-4-ylmethoxy)ethyl)-3,5-dichloropyridine 7 Methyl 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoate 8 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoic acid 9 N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-2-naphthamide 10 Methyl 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoate 11 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoic acid 12 4-fluoro-2-(1-((naphthalen-2-ylmethyl)amino)propyl)phenol 13 4-chloro-2-(1-(((1-methyl-1H-indazol-6-yl)methyl)amino)ethyl)phenol 14 5-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)quinazolin-2(1H)-one 15 4-chloro-2-(1-(methyl(naphthalen-2-ylmethyl)amino)ethyl)phenol 16 N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-6-hydroxy-2-naphthamide 17 3,5-dichloro-4-(1-(naphthalen-2-ylmethoxy)ethyl)pyridine 18 N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-3-carboxamide 19 2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol 20 N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinazoline-6-carboxamide 21 N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-6-carboxamide 22 4-chloro-2-(1-((quinoxalin-6-ylmethyl)amino)ethyl)phenol 23 4-chloro-2-(1-((quinolin-6-ylmethyl)amino)ethyl)phenol 24 4-chloro-2-(1-((quinolin-3-ylmethyl)amino)ethyl)phenol 25 4-fluoro-2-(1-((quinolin-3-ylmethyl)amino)propyl)phenol 26 N-(1-(5-fluoro-2-hydroxyphenyl)propyl)quinoline-3-carboxamide

<Experimental Example 1> Evaluation of p-ACC activity and growth inhibition of cancer cells in Huh7 liver cancer cell line

1-1. Experiment method

Huh7 liver cancer cell line was obtained from ATCC and cultured in complete DMEM medium (Hyclone, UT, USA) containing 10% fetal bovine serum (FBS; HyClone, AUS) in an environment of 37°C, 5% CO ₂ and 100% humidity. . Cells were seeded in 6-well microtiter plates at a plating density of 200,000 cells/well, depending on the doubling time of the individual cell lines. After culturing for 24 hours before drug addition, the compound of the present invention was added to each well at a concentration of 10 μM, and a group treated with 0.1% DMSO was used as a control group, and the culture was incubated at 37°C for 1 hour. Acetyl-CoA Carboxylase (ACC) and phosphorylated ACC (p-ACC), which are rate-limiting enzymes in fatty acid synthesis, were tested to confirm the inhibitory activity of fatty acid synthase, which is involved in the inhibition of proliferation of liver cancer cells by treatment with the compound of the present invention. Protein expression levels were compared using Western blot method.

Whole cell lysates were supplemented with 150 mM sodium chloride, 1.0% IGEPAL CA-630 (NP-40), 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, in addition to 50 mM Tris-HCl. Homogenization was performed using RIPA buffer (pH 8.0) containing a mixture of protease inhibitors and phosphatase inhibitors. The BCA Protein Analysis Kit (Thermo Fisher, IL, USA) was used to quantify proteins. Proteins were resolved by SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membrane (Merck Millipore, MA, USA). Membranes were blocked in 5% BSA for 1 h at room temperature and incubated with the indicated antibodies overnight at 4 °C. Afterwards, the membrane was washed with TBS-T three times for 10 minutes each at room temperature, and then incubated with horseradish peroxidase-conjugated secondary antibody for 1 hour and 30 minutes at room temperature. After incubation, the membrane was washed with TBS-T for 1 hour at room temperature and confirmed using an enhanced chemiluminescence detection system (ECL). Immunoreactive protein band images were scanned and visual density was quantified using computer software (ImageJ software, version 1.37, Wayne Rasband, NIH, Bethesda, MD).

1-2. result

As shown in Table 2, when the compounds of the present invention were treated with the liver cancer cell Huh7 model, the degree of inhibition of the activity of Acetyl-CoA Carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis, was determined by the degree of phosphorylated protein expression of phosphorylated ACC (p-ACC). This was confirmed, and the fatty acid synthesis enzyme inhibitory ability was evaluated by quantifying this. The results of enzyme inhibition ability obtained by treating the compound of the present invention at a concentration of 10 μM were reported by calculating the expression change (fold change) compared to the control group. Here, the higher the number, the stronger the hit, and the group of compounds that meet the standard of expression change (fold change) of 10 times or more; A, the group of compounds that meet the standard of 4 times or more; B, the compound that satisfies the standard of 2 times or more Group: C, a group of compounds satisfying the criteria of 1.2 times or more; D, a group of compounds satisfying the criteria of less than 1.2 times; E were evaluated separately (A ≥ 10, B ≥ 4, C ≥ 2, D ≥ 1.2, E < 1.2). The compounds of the present invention, especially compound No. 26 shown above, exhibit strong inhibitory activity with an expression change value of more than 14 times.

It is known that disturbances in the lipid metabolism process are involved in the progression of various cancers, including liver cancer, which means that dysregulation in fat synthesis ultimately promotes the growth and progression of cancer. When the compounds of the present invention are treated with the liver cancer cell Huh7 model, they promote lipid synthesis during lipid metabolism and at the same time inactivate Acetyl-CoA Carboxylase (ACC), which inhibits oxidation of existing fat, thereby reducing fat synthesis within the liver and liver cancer. It appears to contribute to the inhibition of tumor proliferation and metastasis by regulating energy metabolism at the tumor level in cells.

Example p-ACC activity Example p-ACC activity Example p-ACC activity One E 10 E 19 D 2 E 11 E 20 D 3 E 12 E 21 C 4 E 13 E 22 C 5 E 14 E 23 C 6 E 15 D 24 E 7 E 16 C 25 C 8 E 17 D 26 A 9 E 18 E

<Experimental Example 2> Evaluation of p-AMPK activity and cancer size in a xenograft animal model transplanted with Huh7 liver cancer cell line

Huh-7 (human, hepatocarcinoma) cells were cultured in a 15cm dish using DMEM medium (10% FBS, 10% P/S) ^, then 4 /C mouse (Orient bio., Busan, Korea) was transplanted into the right hip. When the size of the tumor grew to more than 300 mm ³ after administration of the cancer cells, it was divided into two groups: the solvent control group (Control) and the test substance group (Example 18 compound of the present invention).

Example 18 Compound of the present invention (10 mg/kg, body weight) and solvent (5% NMP, 5% DMSO, 10% Cremophor EL, 30% PEG, 50% water) were administered intraperitoneally 15 times for a total of 3 weeks. After transplanting cancer cells, 2 times/week based on the start of administration, the tumor volume is calculated in the following manner {tumor volume (mm ³ ) = [( ^longer diameter of tumor) 2} was measured and shown in Table 3 below.

In addition, to confirm the mechanism of suppressing tumor formation caused by administration of the compound of Example 18 of the present invention in a xenograft animal model transplanted with the Huh7 liver cancer cell line, proteins were extracted from tumor tissue and used in experiments. In the same manner as verification in the cell model, the expression level of p-AMPK, which is involved in tumor proliferation and metastasis inhibition mechanisms, was measured and shown in Table 3 below.

Xenograft animal model ((Huh7, 10mpk, IP) p-AMPK activity (multiple) Cancer size reduction (%) control group One 0% Example 18 14.81 35.85/38.46

The cancer size reduction experiment of Example 18 was repeated twice, and as a result, it was confirmed that the cancer size was reduced by 35.85% and 38.46%.

Claims (11)

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

In Formula 1,
X is C or N;
Y is NR ⁶ or O,
R ⁶ is hydrogen or C1-C10 alkyl;
R ¹ , R ² and R ³ are each independently hydrogen, hydroxy or halogen;
R ⁴ is hydrogen or C1-C10 alkyl;
R ⁵ is hydrogen or oxo (=O);
A is unsubstituted or substituted C6-C10 aryl or 6-10 membered heteroaryl,
Here, the substituted C6-C10 aryl or 6-10 membered heteroaryl is substituted with one or more selected from the group consisting of C1-C10 alkyl, halogen, hydroxy, phenyl, carboxy, and C1-C10 alkyloxycarbonyl, Alternatively, two adjacent atoms are substituted to form a 5-6 atom heterocycle, where the 5-6 atom heterocycle is unsubstituted or substituted with oxo (=O).
According to paragraph 1,
X is C or N;
Y is NR ⁶ or O,
R ⁶ is hydrogen or C1-C5 alkyl;
R ¹ , R ² and R ³ are each independently hydrogen, hydroxy or halogen;
R ⁴ is hydrogen or C1-C5 alkyl;
R ⁵ is hydrogen or oxo (=O);
A is unsubstituted or substituted C6-C10 aryl or 9-10 membered heteroaryl,
Here, the substituted C6-C10 aryl or 9-10 membered heteroaryl is substituted with one or more selected from the group consisting of C1-C5 alkyl, halogen, hydroxy, phenyl, carboxy, and C1-C5 alkyloxycarbonyl, or two adjacent atoms are substituted to form a 6-atom heterocycle, wherein the 6-atom heterocycle is unsubstituted or substituted with oxo (=O), a compound, a stereoisomer thereof, and a solvent thereof. cargo, hydrate thereof, or pharmaceutically acceptable salt thereof.
According to paragraph 1,
X is C or N;
Y is NR ⁶ or O,
R ⁶ is hydrogen or C1-C2alkyl;
R ¹ and R ² are each independently hydrogen or halogen;
R ³ is hydroxy or halogen;
R ⁴ is hydrogen or C1-C2alkyl;
R ⁵ is hydrogen or oxo (=O);
A is unsubstituted or substituted C6-C10 aryl or 9-10 membered heteroaryl,
Here, the substituted C6-C10 aryl or 9-10 membered heteroaryl is substituted with one or more selected from the group consisting of C1-C2 alkyl, halogen, hydroxy, phenyl, carboxy, and C1-C2 alkyloxycarbonyl, or two adjacent atoms are substituted to form a 6-atom heterocycle, wherein the 6-atom heterocycle is substituted with oxo (=O), a compound, a stereoisomer thereof, a solvate thereof, and a hydrate thereof. Or a pharmaceutically acceptable salt thereof.
According to paragraph 1,
X is C or N;
Y is NR ⁶ or O,
R ⁶ is hydrogen or methyl;
R ¹ is hydrogen, F or Cl;
R ² is hydrogen or Cl;
R ³ is hydroxy or Cl;
R ⁴ is hydrogen, methyl or ethyl;
R ⁵ is hydrogen or oxo (=O);
A is unsubstituted or substituted phenyl, naphthalene, indazole, quinoline, quinoxaline or tunazoline,
Here, the substituted phenyl, naphthalene, indazole, quinoline, quinoxaline or tunazoline is substituted with one or more selected from the group consisting of methyl, F, Cl, hydroxy, phenyl, carboxy and methyloxycarbonyl, or Compounds, stereoisomers thereof, and their Solvate, hydrate thereof or pharmaceutically acceptable salt thereof.
According to paragraph 1,
A is , , , , , , , , , , , or A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that.
According to paragraph 1,
The compound represented by Formula 1 is any one compound selected from the following compound group, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
<1>2-(1-(benzylamino)ethyl)-4-chlorophenol;
<2>4-chloro-2-(1-((3-chloro-4-fluorobenzyl)amino)ethyl)phenol;
<3>2-(1-(([1,1'-biphenyl]-4-ylmethyl)amino)ethyl)-4-chlorophenol;
<4>4-chloro-2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol;
<5>4-(1-(benzyloxy)ethyl)-3,5-dichloropyridine;
<6>4-(1-([1,1'-biphenyl]-4-ylmethoxy)ethyl)-3,5-dichloropyridine;
<7> Methyl 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoate;
<8> 4-((1-(3,5-dichloropyridin-4-yl)ethoxy)methyl)benzoic acid;
<9>N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-2-naphthamide;
<10> Methyl 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoate;
<11> 4-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)benzoic acid;
<12>4-fluoro-2-(1-((naphthalen-2-ylmethyl)amino)propyl)phenol;
<13>4-chloro-2-(1-(((1-methyl-1H-indazol-6-yl)methyl)amino)ethyl)phenol;
<14>5-(((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)methyl)quinazolin-2(1H)-one;
<15>4-chloro-2-(1-(methyl(naphthalen-2-ylmethyl)amino)ethyl)phenol;
<16>N-(1-(5-chloro-2-hydroxyphenyl)ethyl)-6-hydroxy-2-naphthamide;
<17>3,5-dichloro-4-(1-(naphthalen-2-ylmethoxy)ethyl)pyridine;
<18>N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-3-carboxamide;
<19>2-(1-((naphthalen-2-ylmethyl)amino)ethyl)phenol;
<20>N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinazoline-6-carboxamide;
<21>N-(1-(5-chloro-2-hydroxyphenyl)ethyl)quinoline-6-carboxamide;
<22>4-chloro-2-(1-((quinoxalin-6-ylmethyl)amino)ethyl)phenol;
<23>4-chloro-2-(1-((quinolin-6-ylmethyl)amino)ethyl)phenol;
<24>4-chloro-2-(1-((quinolin-3-ylmethyl)amino)ethyl)phenol;
<25>4-fluoro-2-(1-((quinolin-3-ylmethyl)amino)propyl)phenol; and
<26> N-(1-(5-fluoro-2-hydroxyphenyl)propyl)quinoline-3-carboxamide.
A pharmaceutical composition for the prevention or treatment of cancer, containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
Containing the compound represented by the formula 1 of claim 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient,
Pharmaceutical composition for preventing or treating diseases caused by ACC hyperactivation.
In clause 7,
These cancers include lung cancer, non-small cell lung cancer (NSCL), bronchoalveolar cell lung cancer, ovarian cancer, colorectal cancer, melanoma, stomach cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, and uterine cancer. , rectal cancer, colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophagus cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer A pharmaceutical composition for preventing or treating cancer, which is any one of cancer, multiple myeloma, chronic or acute leukemia.
According to clause 9,
A pharmaceutical composition wherein the cancer is liver cancer. A health functional food composition for preventing or improving cancer containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.