KR100718493B1 - Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives having inhibitory activity against histone deacetylase, method for the preparation thereof, and anticancer composition comprising the same - Google Patents

Abstract

The present invention relates to alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives of the following Chemical Formula 1 , a preparation method thereof, and a pharmaceutical composition for an anticancer agent comprising the same, wherein the alkylamino of the present invention Naphthalenyloxymethyl propenyl hydroxybenzamide derivatives can be effectively used to inhibit tumor cell proliferation by effectively inhibiting the enzymatic activity of histone deacetylase.

<Formula 1>

Where

R ₁ is hydrogen or methyl;

Each R ₂ is independently C _1-2 alkyl, hydroxyC _1-2 alkyl, haloC _1-2 alkyl, piperidinyl, morpholinyl, cyanomethyl, piperazinyl, diC _1-2 alkylamino C _1-3 alkyl, piperidinyl C _1-2 alkyl, C _1-2 alkyl and Dimorpholino Reno piperazino unsubstituted with at least one substituent selected from the group consisting of C _1-2 alkyl or substituted C _{1 - 2} alkyl Or;

R ₁ and R ₂ are connected to each other to form a morpholininyl, piperidinyl or piperazinyl ring with the nitrogen atom to which they are attached.

Description

Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives having histone deacetylase inhibitory activity, preparation method thereof, and pharmaceutical composition for anticancer agent using the same as an active ingredient TECHNICAL FIELD THE PREPARATION THEREOF, AND ANTICANCER COMPOSITION COMPRISING THE SAME}

The present invention relates to a novel alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative which effectively inhibits the enzymatic activity of histone deacetylase, a preparation method thereof and an anticancer pharmaceutical composition comprising the same as an active ingredient.

Histones are basic proteins that bind to the nucleus DNA of eukaryotic cells and undergo reversible acetylation of the amino groups of lysine residues at specific positions in each molecule of histones. The acetylation of histones is involved in the regulation of the expression of genetic information, which is related to the formation of higher structures of the chromatin or the cell division cycle, and histone acetyltransferases (HATs) and histone deacetylases (histone). deacetylase, HDACs). These enzymes neutralize the positive charges of lysine residues (four for H4) at the amino terminus of histones by acetylation to induce transcriptional activity, or deacetylate them to give charge again to inhibit transcription, thereby acetylating the levels of histones. Induction of equilibrium is known to regulate gene expression at the level of transcription.

HDAC has been shown to play a role in promoting cell proliferation by inhibiting the expression of cell proliferation inhibitors by being highly expressed in poor environmental conditions such as hypoxia, low glucose and cell carcinogenesis. It is recognized. In other words, if high acetylation of chromatin inhibits cell proliferation and promotes differentiation, HDAC plays a crucial role in inducing cell proliferation through deacetylation of histones. This is supported by the treatment of HDAC inhibitors as a result of inhibition of cell proliferation and angiogenesis.

Acute promyelocytic leukemia (APL) is one of the most important causes of the development of acute leukemia. Known (Lin RJ, et. Al. Oncogene 20: 7204, 2001; Zelent A, et. Al. Oncogene 20: 7186, 2001). Therefore, improper transcription inhibition and abnormality in chromatin structure of oncoproteins caused by abnormal regulation of HDAC activity affects normal cell differentiation, leading to cancer formation. Therefore, HDAC has become a very important research subject not only as an inhibitor of gene expression but also as a target molecule for the development of a new anticancer agent, and the HDAC inhibitor is very likely to be developed as a breakthrough anticancer agent that inhibits the proliferation of cancer cells.

In recent years, the development of anticancer drugs using chromatin remodeling has been started, and the development of anticancer drugs has been more active with the results of studies that treatment of HDAC inhibitors such as SAHA or apicidin inhibits the proliferation and differentiation of cancer cells. (Munster PN, et. Al. Cancer research 61: 8492, 2001; Han JW, et. Al. Cancer research 60: 6068, 2000).

The first compound used as an HDAC inhibitor is n-butyrate, which is currently used in the treatment of colorectal cancer as well as in biochemical and molecular biology experiments as an HDAC enzyme inhibitor. However, the effective concentration of n-butyrate is in the level of milimolar (mM), which is not suitable for the analysis of HDAC functions such as affecting other enzymes, cytoskeleton, and cell membranes in the cell. There is a need for the development of good HDAC inhibitors. In 1988, M. Yoshida and B. Teruhiko of the University of Tokyo, Japan, are active agents that induce the differentiation of Friend murine erythroleukemia (MEL) cells and inhibit the proliferation of animal cells. A (trichostatin A, TSA) was found and its intracellular target molecule was HDAC (Yoshida M, et. Al. Cancer Research 47: 3688, 1987; Yoshida M & Beppu T Exp. Cell Res. 177: 122, 1988; Yoshida M, et. Al. J of Biol. Chem. 265: 17174, 1990).

Therefore, the need for the discovery of HDAC inhibitor compounds considered to be anticancer drugs of the future is very increasing. Accordingly, the present inventors have diligently researched to find an HDAC inhibitor compound, and found that the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative effectively inhibits histone deacetylase activity and thus has a very strong cell proliferation inhibitory effect. The present invention has been completed by discovering and confirming that they can be usefully used for the treatment of cancer.

Accordingly, it is an object of the present invention to provide a novel alkylaminonaphthalenyloxymethyl propenyl hydroxybenzamide derivative and method for preparing the same, which effectively inhibit the proliferation of tumor cells by effectively inhibiting the enzymatic activity of histone deacetylase.

Another object of the present invention to provide a pharmaceutical composition for anticancer drugs containing the compound as an active ingredient.

Still another object of the present invention is to provide an enzyme activity inhibitor of histone deacetylase containing the compound as an active ingredient.

In order to achieve the above object, the present invention provides an alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of formula (I) and a pharmaceutically acceptable salt thereof:

<Formula 1>

Where

R ₁ is hydrogen or methyl;

Each R ₂ is independently C _1-2 alkyl, hydroxyC _1-2 alkyl, haloC _1-2 alkyl, piperidinyl, morpholinyl, cyanomethyl, piperazinyl, diC _1-2 alkylamino C _1-3 alkyl, piperidinyl C _1-2 alkyl, C _1-2 alkyl and Dimorpholino Reno piperazino unsubstituted with at least one substituent selected from the group consisting of C _1-2 alkyl or substituted C _{1 - 2} alkyl Or;

R ₁ and R ₂ are connected to each other to form a morpholininyl, piperidinyl or piperazinyl ring with the nitrogen atom to which they are attached.

In addition, the present invention provides a method for preparing alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of Chemical Formula 1 .

The present invention also provides a pharmaceutical composition for the anti-cancer agent for the alkyl amino naphthalene-yloxymethyl-propenyl-hydroxy-benzamide or a pharmaceutically acceptable salt thereof of formula (I) as an active ingredient.

Furthermore, the present invention provides an enzyme activity inhibitor of histone deacetylase of the alkylamino naphthalene yloxymethyl pro page carbonyl-hydroxy benzamide, or a pharmaceutically acceptable salt thereof of formula (I) as an active ingredient.

Hereinafter, the present invention will be described in more detail.

Preferred compounds of the alkylamino naphthaleneoxymethyl propenyl hydroxybenzamide derivatives of the general formula (1) according to the present invention

4-((Z) -3- (naphthalen-1-yloxy) -2-((piperidin-1-yl) methyl) prop-1-enyl) -N -hydroxybenzamide;

4-((Z) -2-((morpholinomethyl) -3- (naphthalen-1-yloxy) prop-1-enyl))- N -hydroxybenzamide;

4-((Z) -2-((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl))- N -hydroxybenzamide;

4-((Z) -3- (dimethylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

4-((Z) -3- ( N -methyl- N -hydroxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

4-((Z) -2- (3-hydroxyazetidin-1-yl) methyl) -2- (naphthalen-1-yloxy) prop-1-enyl) -N -hydroxybenzamide;

4-((Z) -3- ( N -methyl-1-methylpyrrolidin-3-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydr Oxybenzamide;

4-((Z) -3- ( N -methyl-1-cyanomethyl-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ;

4-((Z) -3- ( N- (2- (dimethylamino) ethyl) -N -methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N Hydroxybenzamide;

4-((Z) -3- ( N- (2- (diethylamino) ethyl) -N -methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N Hydroxybenzamide;

4-((Z) -3- (3- (diethylamino) pyrrolidin-1-yl) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide;

4-((Z) -3- (3- (dimethylamino) propyl) -N -methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide;

4-((Z) -3- (2- (dimethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

4-((Z) -3- (2- (diethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

4-((Z) -3- (2- (pyrrolidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide;

4-((Z) -3- (2- (piperidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide;

4-((Z) -3- (2-morpholinoethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide;

4 - ((Z) -3- ( 2- (4- methylpiperazin-l-yl) ethylamino) -2 - ((naphthalen-1-yloxy) methyl) prop-1-enyl) - N - Hydroxybenzamide;

4-((Z) -3- (3-dimethylamino) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; And

4 - ((Z) -3- ( 3- (4- methylpiperazin-l-yl) propylamino) -2 - ((naphthalen-1-yloxy) methyl) prop-1-enyl) - N - Hydroxybenzamide is mentioned as an example.

The compound of formula 1 according to the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, with preferred salts hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid , Malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methane Salts, such as a sulfonic acid, benzene sulfonic acid, and toluene sulfonic acid, are mentioned.

The present invention also provides a method for preparing the alkylamino naphthaleneoxymethyl propenyl hydroxybenzamide derivative of the formula (1 ).

In the compound of Formula 1 , when R ₁ is methyl, the preparation method of the present invention is

1) Performing Baylis Hillman reaction with alkyl acrylate of 4- (methoxycarbonyl) benzaldehyde ( Formula 2 ) in the presence of 1,4-diazabicyclo [2,2,2] octane (DABCO) Preparing 4- (2- t -butoxycarbonyl-1-hydroxy allyl) -benzoic acid methyl ester ( Formula 3 );

2) Reacting the compound of Formula 3 with phosphorus tribromide (PBr ₃ ) in an organic solvent to 4- (3-bromo-2- t -butoxycarbonyl-propenyl) -benzoic acid methyl ester ( Formula 4 ) Manufacturing step;

3) Reacting the compound of Formula 4 with 1-naphthol to 4- (3- (naphthalen-1-yloxy) -2-t-butoxycarbonyl-propenyl) -benzoic acid methyl ester ( Formula 5 ) Making a step;

4) Hydrolysis reaction of the compound of Formula 5 with trifluoroacetic acid (TFA) to prepare carboxypropenyl benzoate methyl ester, and then treated with ethylchloroformate (ECC) and reduced with sodium borohydride 4 -[2-hydroxymethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester ( Formula 6 );

5) After dissolving the compound of Chemical Formula 6 in a nonpolar solvent, triphenylphosphine (PPh ₃ ) and tetrabromomethane (CBr ₄ ) were added and brominated to give 4- [2-bromomethyl-3- (naphthalene- Preparing 1-yloxy) -propenyl] -benzoic acid methyl ester ( Formula 7 );

6) Reacting the compound of Formula 7 with secondary alkylamine (R ₁ R ₂ NH) to methyl-4-((Z) -3- ( N -R ₁ -N -R ₂ -amino) -2- ( Preparing (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate ( Formula 8 );

7) was hydrolyzed by the reaction of a compound of the formula (8) to the inorganic base treatment 4 - ((Z) -3- ( N -R 1 - N -R 2 - amino) -2 - ((naphthalen-1-yloxy ) Methyl) prop-1-enyl) benzoic acid ( Formula 9 ); And

8) The compound of formula 9 is acylated with trimethylsilyloxyamine (NH ₂ OSiMe ₃ ) by N -methanesulfonyloxy-6-trifluoro benzotriazole (FMS) treatment in an organic solvent and then water-soluble. Removing the trimethylsilyl group with an inorganic acid:

In the above formula , R ₁ is methyl, R ₂ is as defined in formula (I) .

The preparation method may be represented by the following Scheme 1 , which will be described below step by step.

In step 1), an aldehyde and an alkyl acrylate are reacted in the presence of DABCO by a Baileys Hillman reaction to produce an alkoxycarbonyl hydroxy allyl compound. As alkyl acrylate, ethyl acrylate, isobutyl acrylate and t -butyl acrylate are produced. And the like can be used.

The reaction of step 2) is preferably performed under ice cooling using ethyl ether, tetrahydrofuran, dichloromethane or dichloroethane as an organic solvent.

The reaction of step 3) is preferably carried out in the presence of an organic base or an inorganic base in an organic solvent. As the organic solvent, acetone, acetonitrile, dichloromethane or tetrahydrofuran may be used. As the amine, diisopropylethylamine or pyridine, and the inorganic base, potassium carbonate, sodium bicarbonate, sodium carbonate and the like can be used.

The reaction with ECC in step 4) is carried out under ice-cooling using a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, or chloroform, and the reduction reaction is sodium borohydride, sodium cyanobo as reducing agent. It is preferable to add low hydride lithium borohydride, lithium borohydride and the like while adding dropwise water.

In the bromination reaction of step 5), dichloromethane, chloroform, tetrahydrofuran, dichloroethane and the like may be used.

The amine reaction of step 6) is performed using an organic base or an inorganic base in a solvent. As a solvent, acetone, acetonitrile, dichloromethane or tetrahydrofuran may be used, and the organic base may be triethylamine, Diisopropylethylamine or pyridine or the like may be used as the inorganic base such as potassium carbonate, sodium bicarbonate or sodium carbonate.

The hydrolysis reaction of step 7) is carried out using an inorganic base in an aqueous alcohol solution or an aqueous tetrahydrofuran solution, which may be methanol, ethanol, isopropanol, n-butanol, t-butanol aqueous solution, or the like. As the inorganic base, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.

Examples of the organic solvent usable in step 8) include N, N -dimethylformamide, dimethylsulfoxide, tetrahydrofuran or dichloromethane, and the like, and water-soluble inorganic acids include hydrochloric acid, sulfuric acid, or phosphoric acid. The organic acid may be trifluoroacetic acid, acetic acid, citric acid, or the like.

In addition, in the compound of Formula 1 , when R ₁ is hydrogen, the preparation method of the present invention is

1) Reacting 4- [2-bromomethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester ( Formula 7 ) with primary alkylamine (R ₂ NH ₂ ) Preparing-((Z) -3- ( N -R ₂ -amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate ( Formula 10 );

2) The compound of formula 10 was dissolved in a non-polar solvent and protected with amine using t -butyl dicarbonate, t -butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalene Preparing -1-yloxy) methyl) allyl-R ₂ -carbamate ( 11 );

3) Hydrolyzing the Compound of Formula 11 with Inorganic Base to 4-((Z) -3- t -butoxycarbonyl (NR ₂ -amino) -2-((naphthalen-1-yloxy) methyl) prop Preparing p-1-enyl) benzoic acid ( 12 ); And

4) Acylation of the compound of Formula 12 with trimethylsilyloxyamine (NH ₂ OSiMe ₃ ) using N -methanesulfonyloxy-6-trifluoro benzotriazole (FMS) in an organic solvent Removing the trimethylsilyl group and the t -butoxycarbonyl group with an inorganic acid or an organic acid.

<Formula 7>

In the above formula , R ₁ is hydrogen, R ₂ is as defined in the formula (1) .

The preparation method may be represented by the following Scheme 2 , which will be described below step by step.

The reaction of step 1) is carried out using an organic base or an inorganic base in a solvent. As a solvent, acetone, acetonitrile, dichloromethane or tetrahydrofuran may be used, and as the organic base, triethylamine, dia As the inorganic base, isopropylethylamine or pyridine and the like can be used potassium carbonate, sodium bicarbonate or sodium carbonate.

Dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane or dichloroethane may be used as the nonpolar solvent in step 2), and triethylamine, diisopropylethylamine, or pyridine may be used as the organic base. Etc. may be used, and this reaction preferably uses 4-dimethylaminopyridine (DMAP) as a catalyst.

The hydrolysis reaction of step 3) is preferably carried out in an aqueous alcohol solution or an aqueous tetrahydrofuran solution, wherein the aqueous alcohol solution may be methanol, ethanol, isopropanol, N-butanol, t-butanol aqueous solution, or the like. As the preferred inorganic base, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.

In step 4), an organic solvent may include N, N -dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or dichloromethane, and the like, and as the water-soluble inorganic acid, hydrochloric acid, sulfuric acid, or phosphoric acid may be used. The organic acid may be trifluoroacetic acid, acetic acid, citric acid, or the like.

The compound of formula (2) used as a starting material for the preparation of the compound of formula (1 ) can be easily prepared by conventional methods, and if necessary, a commercially available one can be purchased and used.

Thus prepared alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of formula 1 of the present invention effectively inhibits the enzymatic activity of histone deacetylase to selectively induce terminal differentiation of tumor cells, thereby It can inhibit proliferation and ultimately cure cancer.

Therefore, the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of the general formula (1) of the present invention can be usefully used as an inhibitor of enzymatic activity of histone deacetylase.

The present invention also provides a pharmaceutical composition for an anticancer agent comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention may contain the compound of formula 1 as an active ingredient in an amount of 0.1 to 75% by weight, preferably 1 to 50% by weight, based on the total weight of the composition.

The pharmaceutical compositions of the invention can be formulated in a variety of oral or parenteral dosage forms. Formulations for oral administration include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, and granules. These formulations may contain diluents (e.g., lactose, dextrose, water, etc.) in addition to the active ingredients. Cross, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally starch, agar, alginic acid or its Disintegrating or boiling mixtures such as sodium salts and / or absorbents, colorants, flavoring agents, and sweetening agents. Also representative of formulations for parenteral administration are injectable formulations, preferably aqueous isotonic solutions or suspensions.

The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure and other therapeutically useful materials, and may be mixed, granulated or coated conventionally. It can be formulated according to the method.

As an active ingredient, the compound of formula 1 may be used orally or parenterally, once or daily, in an amount of 2.5 to 100 mg / kg body weight, preferably 5 to 60 mg / kg body weight, per day for mammals including humans. It can be administered via the route.

Hereinafter, the present invention will be described in more detail by the following Preparation Examples and Examples.

The following Preparation Examples and Examples are only for illustrating the present invention, but the scope of the present invention is not limited thereto.

Preparation Example 1: t -Butyl 3-hydroxy-2-methylene-3- [4- (methoxycarbonyl) phenyl] propanoate (compound of formula 3)

4- (methoxycarbonyl) benzaldehyde (3.3 g, 20 mM), t -butylacrylate (3.5 ml, 24 mM) and 1,4-diazabicyclo [2,2,2] octane (449 mg, 4 mM) was stirred for 5 days in a closed vessel at room temperature. The reaction mixture was extracted with diethyl ether, washed with 2N hydrochloric acid solution, water and sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, concentrated under reduced pressure, and purified by silica gel column chromatography to give 4.2 g of the title compound as a white solid (yield). 73%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (s, 9H), 3.28 (m, 1H), 3.91 (s, 3H), 5.53 (d, 1H, J = 5.2 Hz), 5.71 (s, 1H ), 6.27 (s, 1 H), 7.45 (d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz);

MS (EI, 70 eV) m / z 292 (M ⁺ ), 283, 255, 241, 227, 201, 189, 179, 150, 135;

Melting point: 70 ℃

Preparation Example 2 4- (3-Bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester (Compound 4)

T -Butyl-3-hydroxy-2-methylene-3- (4-methoxycarbonylphenyl) -propaneate (994 mg 3.4 mM) prepared in Preparation Example 1 was dissolved in ethyl ether (10 ml). After cooling to 0 ° C., phosphorus tribromide (0.35 mL 3.74 mM) was slowly added dropwise and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into iced water, extracted with ethyl ether, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The dried product was filtered, distilled under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to obtain 943 mg (yield 71%) of the title compound as a light green solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (S, 9H, OCH 3), 3.88 (S, 3H, OCH 3), 3.97 (S, 2H, CH 2), 7.41 (d, 2H J = 8.4 Hz, ArH ), 7.50 (s, 1 H), 7.91 (d, 2H, J = 8.4 Hz, ArH);

MS (EI, 70 eV) m / z 355 (M ⁺ ), 338, 296, 278, 259, 219, 187, 143, 115

Melting point: 78 ℃

Preparation Example 3 4- [2- t -Butoxycarbonyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (compound of formula 5)

4- (3-Bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester (355 mg, 1 mM) prepared in Preparation Example 2 was dissolved in acetone (5 ml), and potassium carbonate (207 mg, 1.50 mM) and 1-naphthalenol (144 mg, 1 mM) were added and heated to reflux for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered to remove the solvent, and the residue was purified by silica gel column chromatography to obtain 438 mg (yield 99%) of the title compound as a white solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.49 (S, 9H, CH 3), 3.89 (S, 3H, OCH 3), 4.96 (S, 2H, CH 2), 6.84 (d, 1H J = 7.33 Hz, ArH ), 7.53 (m, 5H, ArH), 7.89 (m, 1H, ArH), 8.01 (m, 3H, ArH), 8.24 (m, 3H, ArH)

Preparation Example 4 4- [2-hydroxymethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (compound of formula 6)

4- (2-carboxy-3- (naphthalen-1-yloxy) -propenyl) -benzoic acid methyl ester (2 g, 5.52 mM) prepared in Preparation Example 3 was dissolved in tetrahydrofuran (30 ml), Triethylamine (1.15 mL, 8.27 mM) and ethylchloroformate (0.792 mL, 8.279 mM) were slowly added dropwise at 0 ° C. and stirred for 1 hour. Sodium borohydride (1.462 mg, 38.64 mM) and distilled water (10 mL) were slowly added to the reaction mixture, followed by stirring at room temperature for 2.5 hours. The pH of the reaction mixture was adjusted to 2 using 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and filtered. The obtained residue was purified by silica gel column chromatography to obtain 1.58 mg (yield 82%) of the title compound as a white solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.89 (S, 3H, OCH 3), 4.55 (S, 2H, CH 2), 4.88 (S, 2H, CH 2), 6.71 (d, 1H J = 7.5 Hz, ArH ), 6.96 (S, 1H, CH), 7.28-7.54 (m, 6H, ArH), 7.83 (m, 1H, ArH), 8.03 (d, 2H J = 8.1 Hz, ArH), 8.30 (m, 1H, ArH)

Preparation Example 5 4- [2-Bromomethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (Compound of Formula 7)

4- [2-hydroxymethyl-3- (naphthalen-1-yloxy) -propenyl] -benzoic acid methyl ester (1.57 g, 4.52 mM) prepared in Preparation Example 4 was added to dichloromethane (15 ml). After dissolving, triphenylphosphine (1.78 g, 6.79 mM) was added, cooled to 0 ° C., then tetrabromomethane (2.25 g, 6.79 mM) was added and stirred for 6 hours. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1.36 g (yield 73%) of the title compound as a white solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ3.91 (S, 3H, OCH 3), 4.42 (S, 2H, CH 2), 4.98 (S, 2H, CH 2), 6.71 (d, 1H J = 7.5 Hz, ArH ), 7.05 (S, 1H, CH), 7.27-7.56 (m, 6H, ArH), 7.83 (m, 1H, ArH), 8.03 (d, 2H J = 8.1 Hz, ArH), 8.30 (m, 1H, ArH)

Preparation Example 6 methyl-4-((Z) -3- ( N -R _One - N -R ₂ -Amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (compound of formula 8)

(6-1) methyl-4-((Z) -3- (naphthalen-1-yloxy) -2-((piperidin-1-yl) methyl) prop-1-enyl) benzoate (8a )

Methyl-4-((E) -3-bromo-2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (411 mg) prepared in Preparation Example 5 in a 100 ml reaction flask. , 1 mM) was added and stirred in acetonitrile at 0 ° C. Triethylamine (0.21 ml, 1.5 mM, 1.5 equiv) and piperidine (0.15 ml, 1.5 mM, 1.5 equiv) were added thereto, and the mixture was reacted for 1 to 2 hours at room temperature at 0 ° C. After the reaction was completed, the solvent was distilled off under reduced pressure and the remaining filtrate was extracted with ethyl ester. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to obtain 341 mg (yield 82%) of the title compound.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.47 (m, 2H), 1.58 (m, 4H), 2.50 (m, 4H), 3.29 (s, 2H0, 3.89 (s, 3H), 4.82 (s, 2H), 6.75 (d, J = 7.4 Hz, 1H), 6.90 (s, 1H), 7.27-7.54 (m, 6H), 7.79 (m, 1H), 7.94 (d, J = 8.0 Hz, 2H), 8.24 (m, 1 H)

LC / MS (M + H): 416

(6-2) methyl-4-((Z) -2-((morpholinomethyl) -3- (naphthalen-1-yloxy) prop-1-enyl)) benzoate (8b)

Morpholin (0.13 mL) was used instead of piperidine to give 391 mg (yield 94%) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.55 (m, 4H), 3.32 (s, 2H), 3.72 (m, 4H), 3.89 (s, 3H), 4.83 (s, 2H), 6.74 (d , J = 7.2 Hz, 1H), 6.90 (s, 1H), 7.25-7.55 (m, 6H), 7.80 (m, 1H), 7.95 (d, J = 8.4 Hz, 2H), 8.23 (m, 1H)

LC / MS (M + H): 418

(6-3) Methyl-4-((Z) -2-((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl)) benzo 8 (8c)

N-methylpyrazine (0.07 mL) was used instead of piperidine to give 187 mg (yield 98%) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.28 (s, 3H), 2.46 (m, 4H), 2.58 (m, 4H), 3.31 (s, 2H), 3.89 (s, 3H), 4.81 (s , 2H), 6.74 (d, J = 7.4 Hz, 1H), 6.88 (s, 1H), 7.25-7.59 (m, 6H), 7.80 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H) , 8.25 (m, 1 H)

LC / MS (M + H): 445

(6-4) methyl-4-((Z) -3- (dimethylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (8d)

Dimethylamine hydrochloride (122 mg) was used instead of piperidine to give 303 mg (yield 81%) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.32 (s, 6H), 3.23 (s, 2H), 3.90 (s, 3H), 4.82 (s, 2H), 6.72 (d, J = 7.2Hz, 1H ), 6.87 (s, 1H), 7.26-7.55 (m, 6H), 7.79 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H), 8.25 (m, 1H)

LC / MS (M + H): 376

(6-5) methyl-4-((Z) -3- ( N -methyl- N -Hydroxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (8e)

N-methyl-N-hydroxyethylamine (0.12 ml) was used instead of piperidine to give 398 mg (yield 98%) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1). .

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.35 (s, 3H), 2.64 (t, J = 5.2 Hz, 2H), 3.37 (s, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.89 (s, 3H), 4.84 (s, 2H), 6.66 (d, J = 7.4 Hz, 1H). 6.87 (s, 1H), 7.30 (t, J = 7.8Hz, 1H), 7.32-7.52 (m, 5H), 7.79 (d, J = 6.6Hz, 1H), 7.97 (d, J = 8.4Hz, 2H ), 8.25 (d, J = 6.6 Hz, 1H)

LC / MS (M + H): 406

(6-6) methyl-4-((Z) -2- (3- t -Butyldimethylsilyloxyazetidin-1-yl) methyl) -2- (naphthalen-1-yloxy) prop-1-enyl) benzoate (8f)

Instead of piperidine, t -butyldimethylsilyloxyazetidine (140 mg) was used to obtain 398 mg (yield 98%) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ0.08 (s, 6H), 0.92 (s, 9H), 2.96 (t, J = 7.8Hz, 2H), 3.49 (s, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 4.50 (m, 1H), 4.79 (s, 2H), 6.70 (d, J = 7.8 Hz, 1H), 6.86 (s, 1H), 7.27-7.57 (m, 6H), 7.81 (m, 1H), 7.98 (d, J = 8.2 Hz 2H), 8.29 (m, 1H)

LC / MS (M + H): 518

(6-7) Methyl-4-((Z) -3- ( N -methyl-1-methylpyrrolidin-3-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1 -Enyl) benzoate (8 g)

404 mg (Yield) of the title compound as a pale yellow oil, in the same manner as in Preparation Example (6-1), using N -methyl-1-methylpyrrolidin-3-ylamine (0.17 ml) instead of piperidine. 91%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.97 (m, 1H), 2.10 (m, 1H), 2.27 (s, 3H), 2.34 (s, 3H), 2.67 (m, 2H), 3.04 (m , 1H), 3.17 (m, 1H), 3.29 (s, 2H), 3.52 (m, 1H), 3.89 (s, 1H), 4.82 (s, 2H), 6.73 (d, J = 7.4 Hz, 1H) , 6.86 (s, 1H), 7.24-7.54 (m, 6H), 7.78 (m, 1H), 7.96 (d, J = 8.6Hz, 2H), 8.23 (m, 1H)

LC / MS (M + H): 445

(6-8) methyl-4-((Z) -3- ( N -Methyl-1-cyanomethyl-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (8h)

380 mg (yield 95%) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1) using N -methyl-1-cyanomethyl-ylamine (105 mg) instead of piperidine. Got.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.46 (s, 3H), 3.45 (s, 2H), 3.63 (s, 2H), 3.89 (s, 3H), 4.79 (s, 2H), 6.70 (d , J = 7.4Hz, 1H), 6.95 (s, 1H), 7.26-7.58 (m, 6H), 7.80 (m, 1H), 7.97 (d, J = 8.2Hz, 2H), 8.23 (m, 1H)

LC / MS (M + H): 401

(6-9) Methyl-4-((Z) -3- (N- (2- (dimethylamino) ethyl) -N-methylamino) -2- (naphthalen-1-yloxy) methyl) prop -1-enyl) benzoate (8i)

160 mg of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1), using N- (2- (dimethylamino) ethyl) -N-methylamine (0.15 ml) instead of piperidine. (Yield 37%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.28 (s, 6H), 2.35 (s, 3H), 2.70 (t, J = 5.0 Hz, 2H), 2.77 (t, J = 5.2 Hz, 2H), 3.37 (s, 2H), 3.90 (s, 3H), 4.87 (s, 2H), 6.77 (d, J = 7.4Hz, 1H), 6.88 (s, 1H), 7.26-7.55 (m, 6H), 7.81 (m, 1H), 7.98 (d, J = 8.2 Hz, 2H), 8.24 (m, 1H)

LC / MS (M + H): 433

(6-10) methyl-4-((Z) -3- ( N -(2- (diethylamino) ethyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (8j)

387 mg of the title compound as a pale yellow oil, in the same manner as in Preparation Example (6-1), using N- (2- (diethylamino) ethyl) -N -methylamine (195 mg) instead of piperidine. (Yield 84%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.97 (t, J = 7.0 Hz, 6H), 2.35 (s, 3H), 2.49 (q, J = 7.2 Hz, 4H), 2.59 (s, 4H), 3.35 (s, 2H), 3.92 (s, 3H), 4.85 (s, 2H), 6.74 (d, J = 7.4Hz, 1H), 6.90 (s, 1H), 7.28-7.56 (m, 6H), 7.81 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 8.2 Hz, 2H), 8.28 (d, J = 9.0 Hz, 1H)

LC / MS (M + H): 461

(6-11) Methyl-4-((Z) -3- (3- (diethylamino) pyrrolidin-1-yl) -2- (naphthalen-1-yloxy) methyl) prop-1- Nyl) Benzoate (8k)

3- (diethylamino) pyrrolidine (213 mg) was used instead of piperidine to give 420 mg (yield 89%) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1). .

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.03 (t, J = 7.4 Hz, 6H), 1.79 (m, 1H), 2.05 (m, 1H), 2.59 (q, J = 7.0 Hz, 4H), 2.68 (m, 3H), 2.84 (t, J = 7.4 Hz, 1H), 3.36 (m, 1H), 3.40 (dd, J = 14.0, 13.8 Hz, 2H), 3.91 (s, 1H), 4.83 (s , 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.91 (s, 1H), 7.27-7.58 (m, 6H), 7.81 (m, 1H), 7.97 (d, J = 8.6 Hz, 2H) , 8.27 (m, 1 H)

LC / MS (M + H): 473

(6-12) Methyl-4-((Z) -3- (3- (dimethylamino) propyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (8 l)

376 mg (Yield 84) of the title compound as a pale yellow oil in the same manner as in Preparation Example (6-1) using 3- (dimethylamino) propyl) -N -methylamine (0.13 ml) instead of piperidine. %) Was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.70 (m, 2H), 2.06 (s, 6H), 2.26 (s, 3H), 2.36 (t, J = 6.4 Hz, 2H), 2.47 (t, J = 6.2 Hz, 2H), 3.29 (s, 2H), 3.88 (s, 3H), 4.79 (s, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.77 (s, 1H), 7.24-7.52 (m, 6H), 7.78 (m, 1H), 7.95 (d, J = 8.4 Hz, 2H), 8.24 (m, 1H)

LC / MS (M + H): 447

Preparation Example 7 4-((Z) -3- ( N -R _One - N -R ₂ -Amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (compound of formula 9)

(7-1) 4-((Z) -3- (naphthalen-1-yloxy) -2-((piperidin-1-yl) methyl) prop-1-enyl) benzoic acid (9a)

Methyl 4-((Z) -3- (naphthalen-1-yloxy) -2-((piperidin-1-yl) methyl) pro prepared in Preparation Example (6-1) in a 100 ml reaction vessel P-1-enyl) benzoate (341 mg, 0.82 mM) was dissolved in 4 ml of tetrahydrofuran and stirred. Lithium hydroxide. Monohydrate (104 mg, 2.49 mM, 3 equiv.) Was dissolved in 1 ml of water, and then stirred at room temperature for about 8 hours. After the reaction was completed, the water layer was washed with ethyl acetate and acidified (pH = 4) using 6N aqueous hydrochloric acid solution. The filtrate was distilled under reduced pressure and extracted with a mixture of chloroform and methanol (4: 1). The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The remaining residue was purified by silica gel column chromatography to obtain 198 mg (yield 60%) of the title compound as a pale yellow foam.

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.53 (m, 2H), 1.85 (m, 4H), 2.95 (m, 4H), 3.66 (s, 2H), 4.84 (s, 2H), 6.59 (d , J = 7.0Hz, 1H), 7.01 (s, 1H), 7.12 (m, 2H), 7.21 (d, J = 8.0Hz, 2H), 7.44 (m, 2H), 7.62 (m, 1H), 7.70 (d, J = 8.2 Hz, 2H), 8.20 (m, 1H)

LC / MS (M + H): 402

(7-2) 4-((Z) -2-((morpholinomethyl) -3- (naphthalen-1-yloxy) prop-1-enyl)) benzoic acid (9b)

Using the compound prepared in Preparation Example (6-2) as a starting material (391 mg), 277 mg (yield 69%) of the title compound in light yellow foamy form was obtained in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.56 (m, 4H), 3.32 (s, 2H), 3.72 (m, 4H), 4.82 (s, 2H), 6.73 (d, J = 7.4Hz, 1H ), 6.89 (s, 1H), 7.27-7.50 (m, 6H), 7.78 (m, 1H), 7.96 (d, J = 8.2 Hz, 2H), 8.22 (m, 1H)

LC / MS (M + H): 404

(7-3) 4-((Z) -2-((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl)) benzoic acid (9c )

Using the compound prepared in Preparation Example (6-3) as a starting material (199 mg), 144 mg (yield 76%) of the title compound in light yellow foamy form was obtained in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.50 (s, 3H), 2.77 (m, 8H), 3.75 (s, 2H), 4.81 (s, 2H), 6.67 (d, J = 7.2Hz, 1H ), 6.83 (s, 1H), 7.23-7.52 (m, 6H), 7.76 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H), 8.24 (m, 1H)

LC / MS (M + H): 417

(7-4) 4-((Z) -3- (dimethylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9d)

Using the compound prepared in Preparation Example (6-4) as a starting material (303 mg), 165 mg (yield 59%) of the title compound was obtained as a pale yellow foam, in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.59 (s, 6H), 3.57 (s, 2H), 4.86 (s, 2H), 6.64 (m, 1H), 6.97 (m, 3H), 7.22 (m , 2H), 7.42 (m, 2H), 7.55 (m, 1H), 7.65 (d, J = 8.2 Hz, 2H), 8.23 (m, 1H)

LC / MS (M + H): 362

(7-5) 4-((Z) -3- ( N -methyl- N -Hydroxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9e)

Using the compound prepared in Preparation Example (6-5) as a starting material (425 mg), 361 mg (yield 88%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.88 (s, 3H), 3.24 (t, J = 5.2 Hz, 2H), 3.89 (t, J = 5.2 Hz, 2H), 4.02 (s, 2H) , 5.00 (s, 2H), 6.79 (d, J = 7.8Hz, 1H), 7.23 (s, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.47 (m, 5H), 7.84 (m, 1H), 7.94 (d, J = 8.0 Hz, 2H), 8.24 (m, 1H)

LC / MS (M + H): 392

(7-6) 4-((Z) -2- (3-hydroxyazetidin-1-yl) methyl) -2- (naphthalen-1-yloxy) prop-1-enyl) benzoic acid (9f)

Using the compound prepared in Preparation Example (6-6) as a starting material (398 mg), 226 mg (yield 58%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.88 (s, 3H), 3.24 (t, J = 5.2 Hz, 2H), 3.89 (t, J = 5.2 Hz, 2H), 4.02 (s, 2H) , 5.00 (s, 2H), 6.79 (d, J = 7.8Hz, 1H), 7.23 (s, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.47 (m, 5H), 7.84 (m, 1H), 7.94 (d, J = 8.0 Hz, 2H), 8.24 (m, 1H),

LC / MS (M + H): 399

(7-7) 4-((Z) -3- ( N -methyl-1-methylpyrrolidin-3-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl Benzoic acid (9 g)

Using the compound prepared in Preparation Example (6-7) as a starting material (404 mg), 207 mg (yield 48%) of the title compound in light yellow foamy form was obtained in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.16 (m, 1H), 2.29 (m, 1H), 2.34 (s, 3H), 2.41 (s, 1H), 2.76 (m, 2H), 3.18 ( m, 1H), 3.32 (s, 2H), 3.64 (m, 1H), 4.98 (s, 2H), 6.87 (d, J = 7.0 Hz, 1H), 6.90 (s, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.52 (m, 5H), 7.80 (m, 1H), 7.98 (d, J = 8.2 Hz, 2H), 8.24 (m, 1H)

LC / MS (M + H): 431

(7-8) 4-((Z) -3- ( N -Methyl-1-cyanomethyl-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9h)

Using the compound prepared in Preparation Example (6-8) as a starting material (345 mg), 273 mg (yield 82%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.47 (s, 3H), 3.47 (s, 2H), 3.76 (s, 2H), 4.88 (s, 2H), 6.79 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.51 (m, 5H), 7.82 (m, 1H), 8.00 (d, J = 8.2Hz, 2H), 8.22 ( m, 1H)

LC / MS (M + H): 387

(7-9) 4-((Z) -3- ( N -(2- (dimethylamino) ethyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9i)

Using the compound obtained in Preparation Example (6-9) as a starting material (160 mg), 83 mg (yield 54%) of the title compound was obtained as a pale yellow foam, in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.29 (s, 3H), 2.65 (s, 6H), 2.81 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.8 Hz, 2H) , 3.30 (s, 2H), 4.90 (s, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.44 (m, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.79 (m, 1H), 8.26 (m, 1H)

LC / MS (M + H): 419

(7-10) 4-((Z) -3- ( N -(2- (diethylamino) ethyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9j)

Using the compound prepared in Preparation Example (6-10) as a starting material (481 mg), 415 mg (yield 89%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ1.01 (t, J = 7.0 Hz, 6H), 2.36 (s, 3H), 2.83 (t, J = 5.8 Hz, 2H), 3.00 (q, J = 7.4 Hz, 4H), 3.19 (t, J = 6.0 Hz, 2H), 3.45 (s, 2H), 4.88 (s, 2H), 6.77 (d, J = 6.8 Hz, 1H), 6.96 (s, 1H) , 7.26-7.56 (m, 6H), 7.83 (m, 1H), 7.89 (d, J = 8.2 Hz, 2H), 8.21 (m, 1H)

LC / MS (M + H): 447

(7-11) 4-((Z) -3- (3- (diethylamino) pyrrolidin-1-yl) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) Benzoic acid (9k)

Using the compound prepared in Preparation Example (6-11) as a starting material (505 mg), 359 mg (yield 78%) of the title compound in light yellow foamy form was obtained in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.10 (t, J = 7.6 Hz, 6H), 1.98 (m, 1H), 2.30 (m, 1H), 2.49 (m, 1H), 2.81 (m, 1H), 3.06 (q, J = 7.0 Hz, 4H), 3.14 (m, 2H), 3.50 (dd, J = 14.0 Hz, 13.8 Hz, 2H), 4.02 (m, 1H), 4.91 (s, 2H) , 6.86 (d, J = 7.0 Hz, 1H), 6.91 (s, 1H), 7.38 (t, J = 8.6 Hz, 1H), 7.49 (m, 5H), 7.83 (m, 1H), 7.97 (d, J = 8.2 Hz, 2H), 8.21 (m, 1H)

LC / MS (M + H): 459

(7-12) 4-((Z) -3- (3- (dimethylamino) propyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (9l)

Using the compound prepared in Preparation Example (6-12) as a starting material (376 mg), 258 mg (yield 71%) of the title compound in the form of a light yellow oil was obtained in the same manner as in Preparation Example (7-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ2.04 (m, 2H), 2.84 (s, 6H), 3.09 (s, 3H), 3.17 (t, J = 6.4 Hz, 2H), 3.44 (t, J = 6.0 Hz, 2H), 4.31 (s, 2H), 4.86 (s, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.85 (s, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.48 (m, 5H), 7.74 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H)

LC / MS (M + H): 433

Preparation Example 8: Methyl-4-((Z) -3- ( N -R ₂ -Amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (compound of formula 10)

(8-1) Methyl 4-((Z) -3- (2- (dimethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate ( 10a)

Methyl-4-((E) -3-bromo-2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (411 mg) prepared in Preparation Example 5 in a 100 ml reaction flask. , 1 mM) was dissolved in 5 ml of acetonitrile at 0 ° C. and stirred with triethylamine (0.21 ml, 1.5 mM, 1.5 equiv) and dimethylaminoethylamine (RNH ₂ ; 0.11 ml, 1.5 mM, 1.5 equiv) Was added and the mixture was allowed to react at room temperature at 0 ° C. for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the remaining filtrate was extracted with ethyl ester. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to obtain the title compound (276 mg, 66% yield) in light yellow oil form.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.84 (br, 1H), 2.26 (s, 6H), 2.49 (t, J = 6.2 Hz, 2H), 2.82 (t, J = 5.4 Hz, 2H), 3.68 (s, 2H), 3.92 (s, 3H), 4.87 (s, 2H), 6.71 (d, J = 7.4Hz, 1H), 6.92 (s, 1H), 7.25-7.57 (m, 6H), 7.84 (m, 1H), 7.98 (d, J = 8.2 Hz, 2H), 8.29 (m, 1H)

LC / MS (M + H): 419

(8-2) methyl 4-((Z) -3- (2- (diethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate ( 10b)

Instead of dimethylaminoethylamine, 364 mg (yield 82%) of the title compound as a pale yellow oil was obtained in the same manner as in Preparation Example (8-1), using 2- (diethylamino) ethylamine (0.21 ml). Got it.

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.00 (t, J = 6.8 Hz, 6H), 1.81 (br, 1H), 2.51 (q, J = 7.4 Hz, 4H), 2.60 (t, J = 5.6 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 3.66 (s, 2H), 3.89 (s, 3H), 6.69 (d, J = 7.4 Hz, 1H), 6.89 (s, 1H), 7.25-7.55 (m, 6H), 7.78 (m, 1H), 7.96 (d, J = 8.2 Hz, 2H), 8.25 (m, 1H)

LC / MS (M + H): 447

(8-3) Methyl 4-((Z) -3- (2- (pyrrolidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl ) Benzoate (10c)

349 mg of the title compound as a pale yellow oil in the same manner as in Preparation Example (8-1) using 2- (pyrrolidin-1-yl) ethylamine (207 mg) instead of dimethylaminoethylamine (yield) 79%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.76 (m, 4H), 2.54 (m, 4H), 2.68 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.6 Hz, 2H), 3.69 (s, 2H), 3.92 (s, 3H), 4.87 (s, 2H), 6.72 (d, J = 7.8Hz, 1H), 6.92 (s, 1H), 7.27-7.67 (m, 6H), 7.85 (m, 1H), 7.98 (d, J = 8.6 Hz, 2H), 8.32 (m, 1H)

LC / MS (M + H): 445

(8-4) Methyl 4-((Z) -3- (2- (piperidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl ) Benzoate (10d)

367 mg (yield) of the title compound as a pale yellow oil in the same manner as in Preparation Example (8-1), using 2- (piperidin-1-yl) ethylamine (0.21 ml) instead of dimethylaminoethylamine. 80%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.42 (m, 2H), 1.53 (m, 4H), 2.00 (br, 1H), 2.39 (m, 4H), 2.50 (t, J = 6.6 Hz, 2H ), 2.82 (t, J = 6.0 Hz, 2H), 3.66 (s, 2H), 3.90 (s, 3H), 4.85 (s, 2H), 6.69 (d, J = 7.4 Hz, 1H), 6.89 (s , 1H), 7.25-7.56 (m, 1H), 7.79 (m, 1H), 7.96 (d, J = 8.6 Hz, 2H), 8.26 (m, 1H)

LC / MS (M + H): 459

(8-5) Methyl 4-((Z) -3- (2-morpholinoethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (10e)

Using 2-morpholinoethylamine (0.20 mL) instead of dimethylaminoethylamine, 384 mg (yield 83%) of the title compound as a pale yellow oil was obtained in the same manner as in Preparation Example (8-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.95 (br, 1 H), 2.40 (m, 4 H), 2.54 (t, J = 5.8 Hz, 2H), 2.84 (t, J = 6.2 Hz, 2H), 3.54 (m, 4H), 3.70 (s, 2H), 3.89 (s, 3H), 4.86 (s, 2H), 6.70 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 7.26-7.54 (m, 6H), 7.79 (m, 1H), 7.96 (d, J = 8.4 Hz, 2H), 8.22 (m, 1H)

LC / MS (M + H): 461

(8-6) Methyl 4-((Z) -3- (2- (4-methylpiperazin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1 -Enyl) benzoate (10f)

139 mg (Yield) of the title compound as a pale yellow oil, in the same manner as in Preparation Example (8-1), using (4-methylpiperazin-1-yl) ethylamine (0.21 ml) instead of dimethylaminoethylamine. 29%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.01 (br, 1H), 2.21 (s, 3H), 2.34 (m, 4H), 2.46 (m, 4H), 2.52 (t, J = 6.2Hz, 2H ), 2.80 (t, J = 6.0 Hz, 2H), 3.66 (s, 2H), 3.89 (s, 3H), 4.84 (s, 2H), 6.69 (d, J = 7.4 Hz, 1H), 6.88 (s , 1H), 7.24-7.55 (m, 6H), 7.81 (m, 1H), 7.96 (d, J = 8.4 Hz, 2H), 8.25 (m, 1H)

LC / MS (M + H): 474

(8-7) Methyl 4-((Z) -3- (3-dimethylamino) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (10 g )

Using (3-dimethylamino) propylamine (0.19 mL) instead of dimethylaminoethylamine in the same manner as in Preparation Example (8-1), 271 mg (yield 63%) of the title compound in light yellow oil form. Got.

1 H-NMR (200 MHz, CDCl ₃ ) δ2.07 (m, 2H), 2.29 (s, 6H), 2.76 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 6.2 Hz, 2H), 3.86 (s, 2H), 3.91 (s, 3H), 4.90 (br, 1H), 4.96 (s, 2H), 6.76 (d, J = 7.8 Hz, 1H), 7.10 (s, 1H), 7.26-7.57 ( m, 6H), 7.84 (m, 1H), 7.99 (d, J = 8.2 Hz, 2H), 8.22 (m, 1H)

LC / MS (M + H): 433

(8-8) Methyl 4-((Z) -3- (3- (4-methylpiperazin-1-yl) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1 -Yl) benzoate (10 h)

237 mg (Yield) of the title compound as a pale yellow oil, in the same manner as in Preparation Example (8-1), using (4-methylpiperazin-1-yl) propylamine (0.20 ml) instead of dimethylaminoethylamine. 49%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.96 (m, 2H), 2.18 (s, 3H), 2.44 (m, 4H), 2.56 (m, 6H), 3.07 (t, J = 6.6 Hz, 2H ), 3.86 (s, 2H), 3.92 (s, 3H), 4.53 (br, 1H), 4.97 (s, 2H), 6.75 (d, J = 7.4 Hz, 1H), 7.11 (s, 1H), 7.27 -7.55 (m, 6H), 7.82 (m, 1H), 8.00 (d, J = 8.0 Hz, 2H), 8.20 (m, 1H)

LC / MS (M + H): 488

Preparation Example 9: t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl -R ₂ Carbamate (compound of formula 11)

(9-1) t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 2- (dimethylamino) ethylcarbamate (11a)

Methyl 4-((Z) -3- (2- (dimethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prepared in Preparation Example (8-1) in a 100 ml reaction flask prop-1-enyl) benzoate (329 ㎎, 0.79 mM) in a 0 ℃ with stirring and dissolved in dichloromethane 4 ㎖ triethylamine (0.13 ㎖, 0.95 mM, 1.2 eq.) and di t - butyl dicarbonate ((tBoc) ₂ O; 207 mg, 0.95 mM, 1.2 equiv) was added. A catalytic amount of 4-dimethylaminopyridine (DMAP; 5 mg, 0.05 equivalents) was added thereto, followed by reaction at 12 ° C. for 12 hours. Upon completion of the reaction, the reaction mixture was extracted with dichloromethane and the organic layer obtained was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography to obtain the title compound (302 mg, yield 73%) as a pale yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.34 (s, 9H), 2.23 (s, 6H), 2.48 (t, J = 6.2 Hz, 2H), 3.44 (t, J = 5.8 Hz, 2H), 3.88 (s, 3H), 4.29 (s, 2H), 4.74 (s, 2H), 6.67 (d, J = 7.4Hz, 1H), 6.73 (s, 1H), 7.23-7.54 (m, 6H), 7.82 (m, 1H), 7.95 (d, J = 8.2 Hz, 2H), 8.26 (m, 1H)

LC / MS (M + H): 519

(9-2) t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 2- (diethylamino) ethylcarbamate (11b)

Using the compound prepared in Preparation Example (8-2) as a starting material (339 mg), 285 mg (yield 68%) of the title compound in the form of a light yellow oil was obtained in the same manner as in Preparation Example (9-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.00 (t, J = 6.8 Hz, 6H), 1.35 (s, 9H), 2.51 (q, J = 7.6 Hz, 4H), 2.62 (t, J = 5.6 Hz, 2H), 3.39 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 4.30 (s, 2H), 4.74 (s, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 7.25-7.55 (m, 6H), 7.78 (m, 1H), 7.95 (d, J = 8.0Hz, 2H), 8.25 (m, 1H)

LC / MS (M + H): 547

(9-3) tert-butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 2- (pyrrolidin-1-yl Ethyl Carbamate (11c)

Using the compound prepared in Preparation Example (8-3) as a starting material (349 mg), 371 mg (yield 86%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (9-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.34 (s, 9H), 1.76 (m, 4H), 2.55 (m, 4H), 2.69 (m, 2H), 3.50 (t, J = 5.8Hz, 2H ), 3.89 (s, 3H), 4.30 (s, 2H), 4.74 (s, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 7.27-7.55 (m, 6H) , 7.79 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H), 8.26 (m, 1H)

LC / MS (M + H): 545

(9-4) t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 2- (piperidin-1-yl) ethylcarbamate (11d )

Using the compound prepared in Preparation Example (8-4) as a starting material (365 mg), 391 mg (yield 88%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (9-1).

¹ H-NMR (200MHz, CDCl ₃ ) δ1.33 (s, 9H), 1.41 (m, 2H), 1.52 (m, 4H), 2.38 (m, 4H), 2.49 (t, J = 6.4Hz, 2H ), 3.44 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 4.27 (s, 2H), 4.93 (s, 2H), 6.66 (d, J = 7.6 Hz, 1H), 6.72 (s , 1H), 7.24-7.52 (m, 6H), 7.78 (d, J = 6.4 Hz, 1H), 7.94 (d, J = 8.6 Hz, .2H), 8.24 (d, J = 9.0 Hz, 1H)

LC / MS (M + H): 559

(9-5) t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 2-morpholinoethylcarbamate (11e)

415 mg (yield 89%) of the title compound as a pale yellow oil was obtained in the same manner as in Preparation Example (9-1), using the compound prepared in Preparation Example (8-5) as the starting material (384 mg).

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.34 (s, 9H), 2.41 (m, 4H), 2.51 (t, J = 5.8 Hz, 2H), 3.44 (t, J = 6.2 Hz, 2H), 3.62 (m, 4H), 3.88 (s, 3H), 4.27 (s, 2H), 4.74 (s, 2H), 6.65 (d, J = 7.8 Hz, 1H), 6.73 (s, 1H), 7.26-7.50 (m, 6H), 7.78 (d, J = 6.4 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 8.23 (d, J = 7.2 Hz, 1H)

LC / MS (M + H): 561

(9-6) t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 2- (4-methylpiperazin-1-yl) ethylcarbamate (11f)

Using the compound prepared in Preparation Example (8-6) as a starting material (268 mg), 233 mg (yield 72%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (9-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ1.33 (s, 9H), 2.23 (s, 3H), 2.38 (m, 4H), 2.48 (m, 4H), 2.52 (t, J = 6.2Hz, 2H ), 3.42 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 4.27 (s, 2H), 4.73 (s, 2H), 6.64 (d, J = 7.6 Hz, 1H), 6.71 (s , 1H), 7.25-7.54 (m, 6H), 7.77 (m, 1H), 7.97 (d, J = 8.2 Hz, 2H), 8.23 (m, 1H)

LC / MS (M + H): 574

(9-7) t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 3- (dimethylamino) propylcarbamate (11 g)

Using the compound prepared in Preparation Example (8-7) as a starting material (271 mg), 164 mg (yield 49%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (9-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.35 (s, 9H), 1.95 (m, 2H), 2.23 (s, 6H), 2.31 (t, J = 7.0 Hz, 2H), 3.35 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 4.26 (s, 2H), 4.75 (s, 2H), 6.66 (d, J = 9.2 Hz, 1H), 6.71 (s, 1H), 7.25-7.52 (m, 6H), 7.79 (m, 1H), 7.95 (d, J = 8.2 Hz, 2H), 8.24 (m, 1H)

LC / MS (M + H): 533

(9-8) t -Butyl (Z) -3- (4- (methoxycarbonyl) phenyl) -2-((naphthalen-1-yloxy) methyl) allyl 3- (4-methylpiperazin-1-yl) propylcarbamate (11h)

Using the compound prepared in Preparation Example (8-8) as a starting material (237 mg), 165 mg (yield 49%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (9-1).

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.36 (s, 9H), 1.81 (m, 2H), 2.39 (s, 2H), 2.41 (t, J = 6.4 Hz, 2H), 2.64 (m, 8H ), 3.37 (t, J = 6.4 Hz, 2H), 3.91 (s, 3H), 4.26 (s, 2H), 4.77 (s, 2H), 6.65 (d, J = 7.4 Hz, 1H), 6.74 (s , 1H), 7.26-7.57 (m, 6H), 7.81 (m, 1H), 7.97 (d, J = 8.0 Hz, 2H), 8.25 (m, 1H)

LC / MS (M + H): 588

Preparation Example 10 4-((Z) -3- t Butoxycarbonyl ( N -R ₂ -Amino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (compound of formula 12)

(10-1) 4-((Z) -3- t Butoxycarbonyl (2- (dimethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (12a)

The compound (286 mg, 0.55 mM) prepared in Preparation Example (9-1) was dissolved in 4 ml of tetrahydrofuran and stirred in a 100 ml reaction vessel. Lithium hydroxide monohydrate (69 mg, 1.65 mM, 3 equivalents) was added thereto by dissolving in 1 ml of water, followed by stirring at room temperature for about 12 hours. After the reaction was completed, the water layer was washed with ethyl acetate and acidified (pH = 4) using 6N aqueous hydrochloric acid solution. The filtrate was distilled under reduced pressure and extracted with a mixture of chloroform and methanol (4: 1). The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The remaining residue was purified by silica gel column chromatography to obtain 224 mg (yield 80%) of the title compound as a pale yellow foam.

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.16 (s, 9H), 2.68 (s, 6H), 3.04 (t, J = 5.8 Hz, 2H), 3.40 (t, J = 5.4 Hz, 2H) , 4.31 (s, 2H), 4.82 (s, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 7.30 (t, J = 5.4 Hz, 1H), 7.52 (m, 5H), 7.73 (d, J = 8.2 Hz, 2H), 7.84 (m, 1H), 8.25 (m, 1H)

LC / MS (M + H): 505

(10-2) 4-((Z) -3-tert-butoxycarbonyl (2- (diethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1- Nyl) benzoic acid (12b)

Using the compound prepared in Preparation Example (9-2) as a starting material (251 mg), 201 mg (yield 83%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in Preparation Example (10-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.17 (s, 9H), 1.33 (t, J = 6.6 Hz, 6H), 3.04 (t, J = 6.6 Hz, 2H), 3.33 (q, J = 7.0 Hz, 4H), 3.42 (t, J = 6.0 Hz, 2H), 4.30 (s, 2H), 4.79 (s, 2H), 6.74 (d, J = 8.2 Hz, 1H), 6.84 (s, 1H) , 7.31 (t, J = 5.6 Hz, 1H), 7.50 (m, 5H), 7.70 (d, J = 8.2 Hz, 2H), 7.80 (m, 1H0, 8.23 (m, 1H)

LC / MS (M + H): 533

(10-3) 4-((Z) -3- t Butoxycarbonyl (2- (pyrrolidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoate (12c)

309 mg (yield 87%) of the title compound as a pale yellow foam was obtained in the same manner as in Preparation Example (10-1), using the starting material (364 mg) for the compound prepared in Preparation Example (9-3).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.17 (s, 9H), 2.02 (m, 4H), 3.69 (m, 6H), 3.74 (t, J = 5.8 Hz, 2H), 4.25 (s, 2H), 4.61 (s, 2H), 6.56 (d, J = 7.8 Hz, 1H), 6.73 (s, 2H), 6.97 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 8.2 Hz, 1H), 7.27-7.50 (m, 3H), 7.70 (d, J = 8.2 Hz, 2H), 7.73 (m, 1H), 8.26 (m, 1H)

LC / MS (M + H): 531

(10-4) 4-((Z) -3- t Butoxycarbonyl (2- (piperidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (12d)

Using the compound prepared in Preparation Example (9-4) as a starting material (368 mg), 341 mg (yield 98%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in Preparation Example (10-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.16 (s, 9H), 1.40 (m, 2H), 1.54 (m, 4H), 3.31 (m, 4H), 3.54 (m, 2H), 3.70 ( m, 2H), 4.19 (s, 2H), 4.80 (s, 2H), 6.59 (d, J = 7.4 Hz, 1H), 6.69 (s, 1H), 6.97 (s, J = 8.4 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.27-7.52 (m, 3H), 7.72 (d, J = 8.6 Hz, 2H), 7.75 (m, 1H), 8.23 (m, 1H)

LC / MS (M + H): 545

(10-5) 4-((Z) -3- t Butoxycarbonyl (2-morpholinoethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (12e)

Using the compound prepared in Preparation Example (9-5) as a starting material (415 mg), 388 mg (yield 96%) of the title compound in light yellow foamy form was obtained in the same manner as in Preparation Example (10-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.17 (s, 9H), 2.77 (m, 4H), 2.82 (t, J = 5.8 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H) , 3.83 (m, 4H), 4.25 (s, 2H), 4.59 (s, 2H), 6.59 (d, J = 7.4 Hz, 1H), 6.68 (s, 1H), 6.99 (m, 2H), 7.34 ( t, J = 7.8 Hz, 1H), 7.44 (m, 3H), 7.69 (d, J = 8.2 Hz, 1H), 7.76 (m, 1H), 8.30 (m, 1H)

LC / MS (M + H): 547

(10-6) 4-((Z) -3- t Butoxycarbonyl (2- (4-methylpiperazin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (12f)

Using the compound prepared in Preparation Example (9-6) as a starting material (227 mg), 167 mg (yield 75%) of the title compound was obtained as a pale yellow foam in the same manner as in Preparation Example (10-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.30 (s, 9H), 2.88 (s, 3H), 2.96 (m, 4H), 3.12 (m, 4H), 3.59 (m, 4H), 4.32 ( s, 2H), 4.81 (s, 2H), 6.78 (d, J = 7.4 Hz, 1H), 6.87 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.50 (m, 5H), 7.70 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 6.8 Hz, 1H), 8.24 (d, J = 6.4 Hz, 1H)

LC / MS (M + H): 560

(10-7) 4-((Z) -3- t Butoxycarbonyl (3-dimethylamino) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (12 g)

Using the compound prepared in Preparation Example (9-7) as a starting material (157 mg), 137 mg (yield 90%) of the title compound was obtained as a pale yellow oil, in the same manner as in Preparation Example (10-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.29 (s, 9H), 2.03 (m, 2H), 2.86 (s, 6H), 3.08 (t, J = 7.2 Hz, 2H), 3.44 (t, J = 6.4 Hz, 2H), 4.31 (S, 2H), 4.80 (s, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 7.31 (t, J = 5.2 Hz, 1H), 7.49 (m, 5H), 7.70 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 5.0 Hz, 1H), 8.23 (d, J = 5.0 Hz, 1H)

LC / MS (M + H): 519

(10-8) 4-((Z) -3- t Butoxycarbonyl (3- (4-methylpiperazin-1-yl) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) benzoic acid (12h)

Using the compound prepared in Preparation Example (9-8) as a starting material (237 mg), 144 mg (yield 63%) of the title compound was obtained as a pale yellow foam, in the same manner as in Preparation Example (10-1).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.17 (s, 9H), 2.04 (m, 2H), 2.70 (t, J = 6.6 Hz, 2H), 2.80 (s, 3H), 2.83 (t, J = 6.4 Hz, 2H), 3.26 (m, 4H), 3.33 (m, 4H), 4.14 (s, 2H), 4.84 (s, 2H), 6.79 (d, J = 7.8 Hz, 1H), 6.87 ( s, 1H), 7.32 (t, J = 5.2 Hz, 1H), 7.51 (m, 5H), 7.72 (d, J = 8.2 Hz, 2H), 7.84 (m, 1H), 8.24 (m, 1H)

LC / MS (M + H): 574

Example 1: 4-((Z) -3- (naphthalen-1-yloxy) -2-((piperidin-1-yl) methyl) prop-1-enyl)- N Hydroxybenzamide (1a)

Compound (9a; 190 mg, 0.47 mM) prepared in Preparation Example (7-1) was dissolved in 1 ml of N, N -dimethylformamide in a 50 ml reaction vessel and stirred with triethylamine (0.20 ml, 0.54 mM , 3 equivalents) and N -methanesulfonyloxy-6-trifluoro benzotriazole (FMS; 200 mg, 0.71 mM, 1.5 equivalents) were added at 0 ° C. and stirred for 30 minutes. After confirming that the acid was activated, trimethylsilyloxyamine (TMSONH ₂ ; 0.15 mL, 1.41 mM, 3 equivalents) was added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, ice water was added and extracted with a mixture of chloroform and methanol (4: 1). The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 57 mg (yield 30%) of the title compound as a yellow powder. .

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.44 (m, 2H), 1.56 (m, 4H), 2.52 (m, 4H), 3.26 (s, 2H), 4.75 (s, 2H), 6.76 (d , J = 7.2 Hz, 1H), 6.94 (s, 1H), 7.26-7.53 (m, 6H), 7.74 (d, J = 8.2 Hz, 2H), 8.00 (m, 1H), 8.21 (m, 1H)

LC / MS (M + H): 417

Example 2: 4-((Z) -2-((morpholinomethyl) -3- (naphthalen-1-yloxy) prop-1-enyl)) N Hydroxybenzamide (1b)

Using the compound prepared in Preparation Example (7-2) as a starting material (277 mg), 137 mg (yield 48%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.56 (m, 4H), 3.32 (s, 2H), 3.68 (m, 4H), 4.84 (s, 2H), 6.78 (d, J = 7.4Hz, 1H ), 6.93 (s, 1H), 7.24-7.54 (m, 6H), 7.75 (d, J = 8.2 Hz, 2H), 7.72 (m, 1H), 8.19 (m, 1H)

LC / MS (M + H): 419

Example 3: 4-((Z) -2-((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl))- N Hydroxybenzamide (1c)

Using the compound prepared in Preparation Example (7-3) as a starting material (140 mg), 29 mg (yield 21%) of the title compound was obtained as a pale yellow foam in the same manner as in Example 1.

¹ H-NMR (200 MHz, CDCl ₃ ) δ2.32 (s, 3H), 2.55 (m, 8H), 3.24 (s, 2H), 4.71 (s, 1H), 6.73 (d, J = 7.2Hz, 1H ), 6.78 (s, 1H), 7.26 (m, 3H), 7.42 (m, 3H), 7.64 (m, 1H), 7.75 (m, 1H), 8.01 (m, 1H), 8.21 (m, 1H)

LC / MS (M + H): 432

Example 4: 4-((Z) -3- (dimethylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1d)

Using the compound prepared in Preparation Example (7-4) as a starting material (165 mg), 173 mg (yield 42%) of the title compound in the form of a pale yellow foam was obtained in the same manner as in Example 1.

¹ H-NMR (200MHz, CD ₃ OD) δ2.35 (s, 6H), 3.31 (s, 2H), 4.83 (s, 2H), 6.71 (d, J = 7.2Hz, 1H), 6.90 (s, 1H), 7.28 (t, J = 8.2 Hz, 1H), 7.43 (m, 5H), 7.66 (d, J = 8.2 Hz, 2H), 7.76 (m, 1H), 8.19 (m, 1H)

LC / MS (M + H): 377

Example 5: 4-((Z) -3- ( N -methyl- N -Hydroxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1e)

Using the compound prepared in Preparation Example (7-5) as a starting material (361 mg), 96 mg (yield 26%) of the title compound was obtained as a pale yellow foam in the same manner as in Example 1.

¹ H-NMR (200MHz, CD ₃ OD) δ2.42 (s, 3H), 2.70 (t, J = 5.2Hz, 2H), 3.44 (s, 2H), 3.69 (t, J = 5.2Hz, 2H) , 4.88 (s, 2H), 6.79 (d, J = 7.4Hz, 1H), 6.99 (s, 1H), 7.33 (t, J = 7.8Hz, 1H), 7.48 (m, 5H), 7.69 (d, J = 8.0Hz, 2H), 7.80 (m, 1H), 8.20 (m, 1H)

LC / MS (M + H): 407

Example 6: 4-((Z) -2- (3-hydroxyazetidin-1-yl) methyl) -2- (naphthalen-1-yloxy) prop-1-enyl)- N Hydroxybenzamide (1f)

Using the compound prepared in Preparation Example (7-6) as a starting material (226 mg), 78 mg (yield 33%) of the title compound was obtained as a pale yellow foam in the same manner as in Example 1.

¹ H-NMR (200 MHz, CD ₃ OD) δ3.03 (t, J = 6.4 Hz, 2H), 3.49 (s, 2H), 3.74 (t, J = 6.2 Hz, 2H), 4.38 (m, 1H) , 4.81 (s, 2H), 6.72 (d, J = 7.2 Hz, 1H), 6.87 (s, 1H), 7.29 (t, J = 8.2 Hz, 1H), 7.42 (m, 5H), 7.66 (d, J = 8.2 Hz, 2H), 7.78 (m, 1H), 8.16 (m, 1H)

LC / MS (M + H): 405

Example 7: 4-((Z) -3- ( N -methyl-1-methylpyrrolidin-3-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) N -hydroxybenzamide (1 g)

Using the compound obtained in Preparation Example (7-7) as a starting material (207 mg), 89 mg (yield 42%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.15 (m, 1H), 2.28 (m, 1H), 2.35 (s, 3H), 2.44 (s, 3H), 2.70 (m, 2H), 3.15 ( m, 1H), 3.31 (s, 2H), 3.60 (m, 1H), 4.87 (s, 2H), 6.83 (d, J = 6.6 Hz, 1H), 6.94 (s, 1H), 7.50 (m, 6H ), 7.71 (m, 1H), 7.92 (d, J = 8.0 Hz, 2H), 8.25 (m, 1H)

LC / MS (M + H): 445

Example 8: 4-((Z) -3- ( N -Methyl-1-cyanomethyl-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1 h)

Using the compound prepared in Preparation Example (7-8) as a starting material (240 mg), 158 mg (yield 44%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.47 (s, 3H), 3.46 (s, 2H), 3.77 (s, 2H), 4.88 (s, 2H), 6.83 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 7.36 (t, J = 8.0Hz, 1H), 7.48 (m, 5H), 7.72 (d, J = 8.2Hz, 2H), 7.81 (m, 1H), 8.22 ( m, 1H)

LC / MS (M + H): 402

Example 9: 4-((Z) -3- ( N -(2- (dimethylamino) ethyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1i)

Using the compound prepared in Preparation Example (7-9) as a starting material (83 mg), 32 mg (yield 40%) of the title compound was obtained as a pale yellow foam, in the same manner as in Example 1.

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.23 (s, 6H), 2.34 (s, 3H), 2.62 (m, 4H), 3.34 (s, 2H), 4.88 (s, 2H), 6.78 ( d, J = 7.4 Hz, 1H, 6.94 (s, 1H), 7.36 (m, 3H), 7.47 (m, 5H), 7.70 (d, J = 13.0 Hz, 2H), 7.80 (m, 1H), 8.21 (m, 1 H)

LC / MS (M + H): 434

Example 10: 4-((Z) -3- ( N -(2- (diethylamino) ethyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1j)

Using the compound prepared in Example (7-10) as a starting material (459 mg), 116 mg (yield 25%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 1.

¹ H-NMR (200 MHz, CD ₃ OD) δ 0.93 (t, J = 7.0 Hz, 6H), 2.35 (s, 3H), 2.55 (q, J = 7.2 Hz, 4H), 2.68 (m, 4H) , 3.39 (s, 2H), 4.89 (s, 2H), 6.79 (d, J = 7.4Hz, 1H), 6.95 (s, 1H), 7.28-7.55 (m, 6H), 7.71 (d, J = 8.2 Hz, 2H), 7.84 (m, 1H), 8.23 (m, 1H)

LC / MS (M + H): 462

Example 11: 4-((Z) -3- (3- (diethylamino) pyrrolidin-1-yl) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl)- N -hydroxybenzamide (1k)

150 mg (yield 32%) of the title compound as a pale yellow oil was obtained in the same manner as in Example 1, using the compound prepared in Preparation Example (7-11) as a starting material (488 mg).

¹ H-NMR (200 MHz, CD ₃ OD) δ1.09 (t, J = 7.8 Hz, 6H), 1.96 (m, 1H), 2.26 (m, 1H), 2.47 (m, 1H), 2.78 (m, 1H), 3.02 (q, J = 7.0 Hz, 4H), 3.06 (m, 2H), 3.47 (dd, J = 14.0 Hz, 13.8 Hz, 2H), 3.96 (m, 1H), 4.92 (s, 2H) , 6.83 (d, J = 6.4 Hz, 1H), 6.97 (s, 1H), 7.50 (m, 6H), 7.70 (m, 1H), 7.90 (m, 2H), 8.21 (m, 1H)

LC / MS (M + H): 474

Example 12: 4-((Z) -3- (3- (dimethylamino) propyl)- N -Methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1 l)

Using the compound prepared in Preparation Example (7-12) as a starting material (258 mg), 67 mg (1 L, 25% yield) of the title compound was obtained as a light yellow oil, in the same manner as in Example 1.

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.27 (m, 2H), 2.84 (s, 6H), 3.08 (s, 3H), 3.19 (t, J = 6.4 Hz, 2H), 3.36 (t, J = 6.2 Hz, 2H), 4.25 (s, 2H), 5.03 (s, 2H), 6.82 (d, J = 7.4 Hz, 1H), 6.85 (s, 1H), 7.31 (m, 2H), 7.52 (m , 4H), 7.73 (d, J = 8.2 Hz, 2H), 7.83 (m, 1H), 8.23 (m, 1H)

LC / MS (M + H): 448

Example 13: 4-((Z) -3- (2- (dimethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1m)

Compound (12a; 224 mg, 0.44 mM) prepared in Preparation Example (10-1) was dissolved in 2 ml of N, N -dimethylformamide in a 50 ml reaction vessel and stirred with triethylamine (0.18 ml, 1.32 mM). , 3 equivalents) and N -methanesulfonyloxy-6-trifluoro benzotriazole (FMS; 186 mg, 0.66 mM, 1.5 equivalents) were added at 0 ° C. and stirred for 30 minutes. The acid was confirmed to be activated and trimethylsilyloxyamine (TMSONH ₂ ; 0.17 mL, 1.32 mM, 3 equiv) was added and stirred at room temperature for 12 hours. After the reaction was completed, ice water was added to the reaction mixture, and the mixture was extracted with a mixture of chloroform and methanol (4: 1). The organic layer obtained was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was dissolved in 15% trifluoroacetic acid (0.3 ml) / dichloromethane (1.7 ml) for 12 hours. Stirred. After the reaction was completed, the resultant was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 50 mg (yield 27%) of the title compound as a dark yellow foam.

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.98 (s, 6H), 3.67 (m, 4H), 4.18 (s, 2H), 4.91 (s, 2H), 6.79 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.33 (t, J = 5.4 Hz, 1H), 7.52 (m, 5H), 7.69 (d, J = 8.0 Hz, 2H), 7.80 (m, 1H), 8.24 ( m, 1H)

LC / MS (M + H): 420

Example 14: 4-((Z) -3- (2- (diethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1n)

Using the compound prepared in Preparation Example (10-2) as a starting material (310 mg), 88 mg (yield 35%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 13.

¹ H-NMR (200 MHz, CD ₃ OD) δ1.33 (t, J = 6.6 Hz, 6H), 3.33 (q, J = 7.0 Hz, 4H), 3.65 (m, 4H), 4.19 (s, 2H) , 4.98 (s, 2H), 6.79 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.47 (m, 5H), 7.69 (d, J = 8.0Hz, 2H), 7.80 (m, 1H), 8.30 (m, 1H)

LC / MS (M + H): 448

Example 15: 4-((Z) -3- (2- (pyrrolidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1o)

In the same manner as in Example 13, 105 mg (yield 62%) of the title compound was obtained as a starting material (200 mg), using the compound prepared in Preparation Example (10-3).

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.11 (m, 4H), 3.47 (m, 4H), 3.70 (m, 4H), 4.20 (s, 2H), 4.94 (s, 2H), 6.79 ( d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.31 (m, 1H), 7.32-7.52 (m, 5H), 7.67 (d, J = 8.2 Hz, 2H), 7.81 (m, 1H ), 8.24 (m, 1 H)

LC / MS (M + H): 446

Example 16: 4-((Z) -3- (2- (piperidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1p)

80 mg (yield 31%) of the title compound as a dark yellow oil was obtained in the same manner as in Example 13, using the compound prepared in Preparation Example (10-4) as a starting material (310 mg).

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.68 (m, 2H), 1.86 (m, 4H), 3.33 (m, 4H), 3.58 (t, J = 6.6 Hz, 2H), 3.71 (t, J = 6.2 Hz, 2H), 4.19 (s, 2H), 4.92 (s, 2H), 6.83 (d, J = 7.6 Hz, 1H), 7.28 (m, 2H), 7.27-7.53 (m, 4H), 7.68 (d, J = 8.2 Hz, 2H), 7.82 (m, 2H), 8.26 (m, 1H)

LC / MS (M + H): 460

Example 17: 4-((Z) -3- (2-morpholinoethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1q)

Using the compound prepared in Preparation Example (10-5) as a starting material (200 mg), 63 mg (yield 38%) of the title compound was obtained as a pale yellow foam, in the same manner as in Example 13.

¹ H-NMR (200 MHz, CD ₃ OD) δ2.44 (m, 4H), 2.64 (t, J = 5.8 Hz, 2H), 3.20 (t, J = 6.0 Hz, 2H), 3.45 (m, 4H) , 3.97 (s, 2H), 4.99 (s, 2H), 6.85 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.52 (m, 5H), 7.73 (d, J = 8.2 Hz, 2H), 7.84 (m, 1H), 8.23 (m, 1H)

LC / MS (M + H): 462

Example 18: 4-((Z) -3- (2- (4-methylpiperazin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl )- N Hydroxybenzamide (1r)

Using the compound obtained in Preparation Example (10-6) as a starting material (189 mg), 47 mg (yield 29%) of the title compound was obtained as a dark yellow foam, in the same manner as in Example 13.

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.42 (m, 2H), 2.60 (m, 2H), 2.67 (s, 3H), 2.79 (m, 2H), 3.00 (m, 2H), 3.31 ( m, 2H), 3.39 (m, 2H), 4.19 (s, 2H), 5.05 (s, 2H), 6.95 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.53 (m, 5H), 7.57 (d, J = 8.2 Hz, 2H), 7.87 (m, 1H), 8.24 (m, 1H)

LC / MS (M + H): 475

Example 19: 4-((Z) -3- (3-dimethylamino) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl)- N Hydroxybenzamide (1s)

Using the compound prepared in Preparation Example (10-7) as a starting material (111 mg), 36 mg (yield 24%) of the title compound was obtained as a pale yellow oil, in the same manner as in Example 13.

¹ H-NMR (200 MHz, CD ₃ OD) δ 2.37 (m, 2H), 3.15 (t, J = 7.0 Hz, 2H), 3.31 (s, 6H), 3.68 (t, J = 6.2 Hz, 2H) , 4.42 (s, 2H), 5.01 (s, 2H), 6.79 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.36 (t, J = 5.2 Hz, 1H), 7.48 (m, 5H), 7.74 (d, J = 8.2 Hz, 2H), 7.82 (m, 1H), 8.21 (m, 1H)

LC / MS (M + H): 434

Example 20: 4-((Z) -3- (3- (4-methylpiperazin-1-yl) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl )- N Hydroxybenzamide (1t)

16 mg (yield 27%) of the title compound as a pale yellow oil was obtained in the same manner as in Example 13, using the compound prepared in Preparation Example (10-8) as a starting material (65 mg).

¹ H-NMR (200MHz, CD ₃ OD) δ2.02 (m, 2H), 2.70 (t, J = 6.6Hz, 2H), 2.82 (s, 3H), 2.84 (t, J = 6.4Hz, 2H) , 3.26 (m, 4H), 3.34 (m, 4H), 4.14 (s, 2H), 5.02 (s, 2H), 6.85 (d, J = 7.4 Hz, 1H), 7.26 (s, 1H), 7.38 ( t, J = 8.2 Hz, 1H), 7.52 (m, 5H), 7.74 (d, J = 8.4 Hz, 2H), 7.85 (m, 1H), 8.23 (m, 1H)

LC / MS (M + H): 489

Test Example 1

HDAC activity assays were performed based on the Biomolar's Quantizyme ^™ assay system. The analysis consists of two steps. The first step is an enzyme reaction step in which the HDAC reacts with the substrate. In this step, an HDAC inhibitor was added to measure the degree of inhibition of HDAC enzyme activity. First, 42 μl of reaction buffer (25 mM Tris-HCl [pH 8.0], 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl ₂ ) was added to a 96-well plate to prepare a reaction mixture and 250 μM fluorescent label. 5 μl of lysine (Fluor de Lys ^™ ) substrate was added. At this time, 2.5 μl of the compounds of Examples 1 to 20 were added as 0.01, 0.1, 1, 10, and 100 μM concentrations as HDAC enzyme activity inhibitors, respectively. HeLa nuclear extract (nuclear extract) was used as the HDAC enzyme source, 0.5 μl of HeLa nuclear extract (10 μM) was added so that the final concentration was 100 nM and the enzyme reaction was performed for 1 hour. The second step was a detection step, in which 50 μl of fluorescent labeled lysine developer (Flour de Lys ^TM developer) was added 2 μM tricostatin A and reacted at room temperature for 15 minutes. Light excited from the fluorescent material at 355 nm and emitted at 460 nm was detected by a fluorometric plate reader. In this case, the higher the enzyme activity, the greater the fluorescence emitted at 460 nm, and the HDAC inhibitory effect was measured by comparing the fluorescence detected in the case with and without the HDAC inhibitor. At this time, SAHA (Biomol), which is known as an HDAC inhibitor, was used as a control at the same concentration.

The degree of HDAC inhibitory activity (IC ₅₀ ) of the representative compounds prepared in the Example is shown in Table 1 below.

From Table 1 , it was confirmed that the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative compounds of the formula (1) prepared according to the present invention showed similar or superior HDAC inhibitory activity to SAHA known as HDAC inhibitor.

Test Example 2

The cancer cell proliferation inhibitory effect of the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative compounds prepared in the above example was measured by SRB (Sulforhodamine B) analysis method. In this study, cervical cancer cells HeLa (Korea Cell Line Bank, KCLB 10002) and colorectal cancer cells, HCT116 (Korea Cell Line Bank, KCLB 10247) were used to measure cancer cell proliferation inhibitory effects.

First, the cells were separated by counting the number of cancer cells separated into single cells so that the number of cells was 1 × 10 ³ to 3 × 10 ³ cells per well of a 96-well plate. Cancer cells were cultured for 24 hours in a cell incubator maintained at 5% CO ₂ concentration and 37 ℃. When cancer cell culture was completed, test compounds were treated at concentrations of 0.2, 1, 5, 25, and 100 μM, and then cultured in a cell incubator for 48 hours. The inhibitory effect of cancer cells was measured by comparing the amount of protein in cancer cells treated with compound and the concentration of protein in cancer cells treated with compound after staining protein in cell substrate with SRB after cancer cell culture.

Specifically, after completion of the culture, the medium was removed and the cells were washed three times with PBS (pH 7.4). 50 μl / well of 50% TCA (Trichloroacetic acid) cooling solution was added thereto, and the cells were fixed at 4 ° C. for 1 hour. After cell fixation, the cells were washed 5 times with distilled water and dried in air.

50 [mu] l of 0.4% SRB solution prepared with 1% acetic acid was added to each well and stained for 1 hour at room temperature. After 1 hour, washed 5 times with 1% acetic acid and dried in air. 150 μl / well of 10 mM Tris-HCl (pH 10.5) was added thereto, and the absorbance was measured at 540 nm. When the test compounds were treated by concentration based on the absorbance of the cells not treated with the test compound, the degree of decreasing absorbance was measured and the concentration of the compound that inhibits the proliferation of cancer cells by 50% was determined as IC ₅₀ (μM), The results are shown in Table 2 below.

On the other hand, treatment of cancer cells with HDAC inhibitors inhibits histone deacetylation and increases the amount of acetylated histones. Thus, the increased acetyl-histone after treatment with the compound of the present invention. Western blotting was performed to determine the amount of.

First, cervical cancer cells HeLa cells were dispensed in a 6-well plate at a concentration of 1.5 × 10 ⁸ cells / well, and then cultured overnight in a cell incubator maintained at 5% CO ₂ concentration and 37 ° C. In order to screen for efficacy as HDAC inhibitors, each test compound and a control SAHA were added at a concentration of 10 μM, followed by culturing the cells in a 37 ° C., 5% CO ₂ cell incubator for 24 hours.

Cells cultured with the compound added were harvested and fractionation was performed to separate the nuclei from them. After inflating the cells in the stock solution, the cells were repeatedly frozen and thawed to destroy the cells, followed by centrifugation at 1,300 rpm for 5 minutes to separate only the nuclei. The resulting nuclei were lysed in lysis buffer (20 mM HEPES (pH7.9), 25% glycerol, 420 mM KCl, 1.5 mM MgCl ₂ , 0.2 mM EDTA) to obtain a protein extract. . In order to perform western blotting, the proteins were separated by size by SDS-PAGE and transferred to the membrane, and the subsequent procedure was performed according to a conventional western blotting method. Anti-acetyl histone H4 antibody (Upstate, USA) was used to measure the amount of acetylated histone H4. The efficacy of the compounds according to the invention as HDAC inhibitors was evaluated by comparing the amount of increased histone H4 upon treatment of SAHA and test compounds, the results are shown in Table 2 below.

From Table 2 , it can be seen that the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of Formula 1 according to the present invention shows very good HDAC inhibitory activity and cancer cell proliferation inhibitory effect in cancer cells.

As described above, the alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of Formula 1 of the present invention effectively inhibits the enzymatic activity of histone deacetylase to selectively induce terminal differentiation of tumor cells and inhibit proliferation. Therefore, it can be usefully used as an anticancer agent or inhibitor of enzymatic activity of histone deacetylase.

Claims (24)

Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative compound of Formula 1 <Formula 1>

Where R ₁ is hydrogen or methyl; Each R ₂ is independently one or more substituents selected from the group consisting of hydroxy, piperidinyl, morpholinyl, cyano, C _1-6 alkylpiperazinyl, diC _1-6 alkylamino, and pyrrolidinyl Substituted or unsubstituted C _1-6 alkyl, or pyrrolidinyl substituted with C _1-6 alkyl; R ₁ and R ₂ are connected to each other to form a morpholinyl, piperidinyl, diC _1-6 alkylaminopyrrolidine, hydroxyazetidine, or methylpiperazinyl ring with the nitrogen atom to which they are attached. The method of claim 1, A compound selected from the group consisting of: 4-((Z) -3- (naphthalen-1-yloxy) -2-((piperidin-1-yl) methyl) prop-1-enyl) -N -hydroxybenzamide; 4-((Z) -2-((morpholinomethyl) -3- (naphthalen-1-yloxy) prop-1-enyl))- N -hydroxybenzamide; 4-((Z) -2-((4-methylpiperazin-1-yl) methyl) -3- (naphthalen-1-yloxy) prop-1-enyl))- N -hydroxybenzamide; 4-((Z) -3- (dimethylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; 4-((Z) -3- ( N -methyl- N -hydroxyethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; 4-((Z) -2- (3-hydroxyazetidin-1-yl) methyl) -2- (naphthalen-1-yloxy) prop-1-enyl) -N -hydroxybenzamide; 4-((Z) -3- ( N -methyl-1-methylpyrrolidin-3-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydr Oxybenzamide; 4-((Z) -3- ( N -methyl-1-cyanomethyl-ylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide ; 4-((Z) -3- ( N- (2- (dimethylamino) ethyl) -N -methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N Hydroxybenzamide; 4-((Z) -3- ( N- (2- (diethylamino) ethyl) -N -methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N Hydroxybenzamide; 4-((Z) -3- (3- (diethylamino) pyrrolidin-1-yl) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide; 4-((Z) -3- (3- (dimethylamino) propyl) -N -methylamino) -2- (naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide; 4-((Z) -3- (2- (dimethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; 4-((Z) -3- (2- (diethylamino) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; 4-((Z) -3- (2- (pyrrolidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide; 4-((Z) -3- (2- (piperidin-1-yl) ethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxy Benzamide; 4-((Z) -3- (2-morpholinoethylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; 4 - ((Z) -3- ( 2- (4- methylpiperazin-l-yl) ethylamino) -2 - ((naphthalen-1-yloxy) methyl) prop-1-enyl) - N - Hydroxybenzamide; 4-((Z) -3- (3-dimethylamino) propylamino) -2-((naphthalen-1-yloxy) methyl) prop-1-enyl) -N -hydroxybenzamide; And 4 - ((Z) -3- ( 3- (4- methylpiperazin-l-yl) propylamino) -2 - ((naphthalen-1-yloxy) methyl) prop-1-enyl) - N - Hydroxybenzamide. 1) by carrying out the alkyl acrylate and Bailey Hillman (Baylis Hillman) reaction in the presence of 1,4-diamine ratio bicyclo [2,2,2] octane (DABCO) a compound of formula 2 to prepare a compound of formula (3) step; 2) preparing a compound of formula 4 to the compound of formula (III) to phosphorus tribromide (PBr ₃₎ reacting in an organic solvent; 3) reacting the compound of Formula 4 with 1-naphthol to convert the compound of Formula 5 ; 4) were then hydrolyzing the reaction with acetic acid (TFA) a compound of formula 5-trifluoromethyl prepare a carboxy-propenyl benzoic acid methyl ester, treatment with ethyl chloroformate (ECC), and reduced with sodium to view it hydride Formula 6 Preparing a compound of; 5) dissolving the compound of Formula 6 in a nonpolar solvent, and then adding triphenylphosphine (PPh ₃ ) and tetrabromomethane (CBr ₄ ) and bromination to prepare a compound of Formula 7 ; 6) reacting a compound of Formula 7 with a secondary alkylamine (R ₁ R ₂ NH) to produce a compound of Formula 8 ; 7) hydrolyzing the compound of Formula 8 by inorganic base treatment to prepare a compound of Formula 9 ; And 8) Acylating the compound of Formula 9 with trimethylsilyloxyamine (NH ₂ OSiMe ₃ ) by N -methanesulfonyloxy-6-trifluoro benzotriazole (FMS) treatment in an organic solvent A method for preparing a compound wherein R ₁ is methyl in an alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivative of Formula 1 , comprising the step of removing the trimethylsilyl group. <Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

<Formula 5>

<Formula 6>

<Formula 7>

<Formula 8>

<Formula 9>

Wherein R ₁ is methyl and R ₂ is as defined in claim 1. The method of claim 3, wherein In step 1), an aldehyde and an alkyl acrylate are reacted in the presence of 1,4-diazabicyclo [2,2,2] octane (DABCO) by a Baileys Hillman reaction to generate an alkoxycarbonyl hydroxy allyl compound. Manufacturing method. The method of claim 4, wherein The alkyl acrylate is selected from the group consisting of ethyl acrylate, isobutyl acrylate and t-butyl acrylate. The method of claim 3, wherein The reaction of step 2) is carried out under ice-cooling, and the organic solvent is selected from the group consisting of ethyl ether, tetrahydrofuran, dichloromethane and dichloroethane. The method of claim 3, wherein The reaction of step 3) is characterized in that using an organic base or an inorganic base in an organic solvent. The method of claim 7, wherein The organic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane and tetrahydrofuran, the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, the inorganic base is potassium carbonate, A process according to claim 1, wherein the method is selected from the group consisting of sodium bicarbonate and sodium carbonate. The method of claim 3, wherein The ethylchloroformate treatment in step 4) is carried out under ice-cooling using a solvent, and water is added dropwise upon reduction of sodium borohydride. The method of claim 9, And the solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, dichloromethane and chloroform. 4. A process according to claim 3, wherein the nonpolar solvent in step 5) is selected from the group consisting of dichloromethane, chloroform, tetrahydrofuran and dichloroethane. The method of claim 3, wherein The process of step 6) characterized in that the reaction is carried out using an organic base or an inorganic base in an organic solvent. The method of claim 12, The organic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane and tetrahydrofuran, the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, the inorganic base is potassium carbonate, A process according to claim 1, wherein the method is selected from the group consisting of sodium bicarbonate and sodium carbonate. The method of claim 3, wherein In step 8) the organic solvent is selected from the group consisting of N, N -dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane, and the water soluble inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid and phosphoric acid. And the organic acid is selected from the group consisting of trifluoroacetic acid, acetic acid and citric acid. 1) preparing a compound of formula 10 by reacting a compound of formula 7 with primary alkylamine (R ₂ NH ₂ ); 2) preparing a compound of formula 11 by dissolving the compound of formula 10 in a nonpolar solvent and protecting the amine with t -butyl dicarbonate; 3) hydrolyzing the compound of Formula 11 by inorganic base treatment to prepare a compound of Formula 12 ; And 4) Water-soluble inorganic acid after acylating the compound of Formula 12 with trimethylsilyloxyamine (NH ₂ OSiMe ₃ ) using N -methanesulfonyloxy-6-trifluoro benzotriazole (FMS) in an organic solvent or organic acids as trimethylsilyl gigwa t - butoxycarbonyl, comprising the step of removing the process for producing a compound, R ₁ is hydrogen, alkyl amino naphthalene-yloxymethyl-propenyl-hydroxy-benzamide derivatives of the formula (I). <Formula 7>

<Formula 10>

<Formula 11>

<Formula 12>

Wherein R ₂ is as defined in claim 1. The method of claim 15, The method of claim 1, wherein the reaction of step 1) is carried out using an organic base or an inorganic base in an organic solvent. The method of claim 16, The organic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane and tetrahydrofuran, the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, the inorganic base is potassium carbonate, A process according to claim 1, wherein the method is selected from the group consisting of sodium bicarbonate and sodium carbonate. The method of claim 15, The reaction of step 2) is carried out using an organic base and a catalyst in a nonpolar solvent. The method of claim 18, The nonpolar solvent is selected from the group consisting of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane and dichloroethane, and the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and pyridine And the catalyst is 4-dimethylaminopyridine (DMAP). The method of claim 15, The hydrolysis reaction of step 3) is carried out in an aqueous alcohol solution or tetrahydrofuran aqueous solution, characterized in that the inorganic base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide. The method of claim 20, The aqueous alcohol solution is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol and t-butanol aqueous solution. The method of claim 15, In step 4) the organic solvent is selected from the group consisting of N, N -dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane, the water soluble inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, The organic acid is selected from the group consisting of trifluoroacetic acid, acetic acid and citric acid. Claim 1 of the formula alkyl-amino-naphthalene-yloxymethyl-propenyl-hydroxy-benzamide derivatives or pharmaceutical composition for an anti-cancer agent for the pharmaceutically acceptable salt thereof as an active ingredient. delete