WO2023219456A1

WO2023219456A1 - Quinoline-based histone deacetylase inhibitory substances, preparation method therefor, and pharmaceutical composition including same as active ingredient

Info

Publication number: WO2023219456A1
Application number: PCT/KR2023/006467
Authority: WO
Inventors: 전라옥; 조혜원; 윤혜지; 신혜란; 전여송
Original assignee: 숙명여자대학교 산학협력단
Priority date: 2022-05-12
Filing date: 2023-05-12
Publication date: 2023-11-16

Abstract

The present invention relates to a quinoline derivative, a preparation method therefor, and a pharmaceutical composition including same as an active ingredient for the prevention or treatment of cancer, autoimmune diseases, fibrosis, and neurodegenerative diseases. The compound represented by Chemical Formula 1, described in the description, selectively inhibits HDAC6 and HDAC8 and exhibits excellent efficacy, and as such, the compound is expected to be advantageously used for preventing or treating cancer, autoimmune diseases, fibrosis, and neurodegenerative diseases.

Description

Quinoline-based histone deacetylase inhibitory active substance, method for producing the same, and pharmaceutical composition containing the same as an 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 being actively researched and developed as an important drug target for the development of anti-cancer and anti-inflammatory drugs.

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.

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.

<제조예 2> 피칭거 반응(Pfitzinger reaction)<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.

<제조예 3> 에스테르화 반응<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.

<제조예 4> 환원 반응<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.

<제조예 5> 산화 반응<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.

<제조예 6> 2-클로로퀴놀린-4-카브알데하이드의 제조<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.

<제조예 7> 스즈키 커플링 반응(Suzuki coupling reaction)<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.

<제조예 8> 위티그 반응(Wittig reaction)<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.

<제조예 9> 가수분해 반응(Hydrolysis reaction)<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.

<제조예 10> 수소화 반응(Hydrogenation reaction)<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.

<제조예 11> 가수분해 반응(Hydrolysis reaction)<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.

<제조예 12> 2-클로로-7-플루오로퀴놀린-4-카브알데하이드의 제조<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.

<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.

<제조예 13> 스즈키 커플링 반응(Suzuki coupling reaction)<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.

<제조예 14> 위티그 반응(Wittig reaction)<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.

<제조예 15> 수소화 반응(Hydrogenation reaction)<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.

<제조예 16> 가수분해 반응(Hydrolysis reaction)<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).

<제조예 17> 2-클로로-6-플루오로퀴놀린-4-카브알데하이드의 제조<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 in 60.7% yield.

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.

<제조예 18> 스즈키 커플링 반응(Suzuki coupling reaction)<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.

<제조예 19> 위티그 반응(Wittig reaction)<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.

<제조예 20> 수소화 반응(Hydrogenation reaction)<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.

<제조예 21> 가수분해 반응(Hydrolysis reaction)<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 .

<실시예 1> <Example 1> NN -하이드록시-3-(2-(피리딘-4-일)퀴놀린-4-일)프로펜아미드-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) ;

<실시예 2> <Example 2> NN -하이드록시-3-(2-페닐퀴놀린-4-일)프로펜아미드-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.

<실시예 3> <Example 3> NN -하이드록시-3-(2-(피리딘-4-일)퀴놀린-4-일)프로판아미드-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.

<실시예 4> <Example 4> NN -하이드록시-3-(2-페닐퀴놀린-4-일)프로판아미드-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.

<실시예 5> <Example 5> NN -하이드록시-3-(2-(3-클로로페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 6> <Example 6> NN -하이드록시-3-(2-(3-메톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 7> <Example 7> NN -하이드록시-3-(2-(3-에톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 8> <Example 8> NN -하이드록시-3-(2-(3-트리플루오로메틸페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 9> <Example 9> NN -하이드록시-3-(2-(3-사이클로프로필메톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 10> <Example 10> NN -하이드록시-3-(2-(4-클로로페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 11> <Example 11> NN -하이드록시-3-(2-(4-메톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 12> <Example 12> NN -하이드록시-3-(2-(4-에톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 13> <Example 13> NN -하이드록시-3-(2-(4-트리플루오로메틸페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 14> <Example 14> NN -하이드록시-3-(2-(4-사이클로프로필메톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 15> <Example 15> NN -하이드록시-3-(2-(-Hydroxy-3-(2-( mm -톨릴)퀴놀린-4-일)프로판아미드-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.

<실시예 16> <Example 16> NN -하이드록시-3-(2-(3-트리플루오로메톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 17> <Example 17> NN -하이드록시-3-(2-(3-페녹시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 18> <Example 18> NN -하이드록시-3-(2-(-Hydroxy-3-(2-( pp -톨릴)퀴놀린-4-일)프로판아미드-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.

<실시예 19> <Example 19> NN -하이드록시-3-(2-(4-트리플루오로메톡시페닐)퀴놀린-4-일)프로판아미드-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.

<실시예 20> <Example 20> NN -하이드록시-3-(2-(티오펜-3-일)퀴놀린-4-일)프로판아미드-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.

<실시예 21> 3-(7-플루오로-2-페닐퀴놀린-4-일)-<Example 21> 3-(7-fluoro-2-phenylquinolin-4-yl)- NN -하이드록시프로판아미드-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.

<실시예 22> 3-(7-플루오로-2-(4-메톡시페닐)퀴놀린-4-일)-<Example 22> 3-(7-fluoro-2-(4-methoxyphenyl)quinolin-4-yl)- NN -하이드록시프로판아미드-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).

<실시예 23> 3-(7-플루오로-2-(3-메톡시페닐)퀴놀린-4-일)-<Example 23> 3-(7-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- NN -하이드록시프로판아미드-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

<실시예 24> 3-(7-플루오로-2-(<Example 24> 3-(7-fluoro-2-( pp -톨릴)퀴놀린-4-일)--Tolyl)quinoline-4-yl)- NN -하이드록시프로판아미드-Hydroxypropanamide

By reacting 3-[7-fluoro-2-(p-tolyl)quinolin-4-yl]propionic acid hydrochloride obtained in Preparation Example 16-4 with 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

<실시예 25> 3-(6-플루오로-2-페닐퀴놀린-4-일)-<Example 25> 3-(6-fluoro-2-phenylquinolin-4-yl)- NN -하이드록시프로판아미드-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

<실시예 26> 3-(6-플루오로-2-(4-메톡시페닐)퀴놀린-4-일)-<Example 26> 3-(6-fluoro-2-(4-methoxyphenyl)quinolin-4-yl)- NN -하이드록시프로판아미드-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).

<실시예 27> 3-(6-플루오로-2-(3-메톡시페닐)퀴놀린-4-일)-<Example 27> 3-(6-fluoro-2-(3-methoxyphenyl)quinolin-4-yl)- NN -하이드록시프로판아미드-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.

<실시예 28> 3-(6-플루오로-2-(<Example 28> 3-(6-fluoro-2-( pp -톨릴)퀴놀린-4-일)--Tolyl)quinoline-4-yl)- NN -하이드록시프로판아미드-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

<실시예 29> 3-[2-(4-클로로페닐)-6-플루오로퀴놀린-4-일)]-<Example 29> 3-[2-(4-chlorophenyl)-6-fluoroquinolin-4-yl)]- NN -하이드록시프로판아미드-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.

<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 21 in Formula 1 and HDAC1, HDAC6, and HDAC8 are shown in Table 2 below.

^a IC ₅₀ was calculated using GraphPad Prism version 4.0.

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

^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.

<실험예 2> 삼중음성 유방암 세포주에 대한 증식 저해능 평가<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).

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

Claims

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, comprising 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.