KR20050036366A - Benzhydroxyamide derivatives having inhibitory activity against histone deacetylase and preparation thereof - Google Patents

Abstract

The present invention relates to a benzhydroxyamide derivative of formula 1, a method for preparing the same, and an anticancer composition containing the same, wherein the benzhydroxyamide derivative of the present invention effectively inhibits the enzymatic activity of histone deacetylase to proliferate tumor cells. Can be suppressed.

Where

R ₁ is C ₃ -C ₈ cycloalkyl, aryl unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, amide and sulfone Or heteroaryl; Or C ₃ -C ₈ cycloalkyl substituted with aryl or heteroaryl, optionally substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro or amide; The heteroaryl includes one or more nitrogen, sulfur or oxygen in the ring;

Q is vinyl, ethyl, 2-propenyl or 2-propyl.

Description

Benzhydroxyamide derivatives having a histone deacetylase inhibitory activity and a preparation method thereof {BENZHYDROXYAMIDE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND PREPARATION THEREOF}

The present invention relates to a novel benzhydroxyamide derivative, a preparation method thereof, and an anticancer composition containing the same, which effectively inhibit the enzymatic activity of histone deacetylase.

Histone deacetylases (HDACs) are known as target proteins for cancer therapeutics and are enzymes involved in important cellular activities such as cell proliferation, cell growth cycle regulation, differentiation, and cancer formation in the body. This enzyme is functionally responsible for removing the acetyl group in the -amino group of the lysine tail on the N-terminal side of the histone.

Histone, which acts as a substrate of HDAC, is a basic protein that binds to DNA in the nucleus of eukaryotic cells, and reversible acetylation occurs at the amino group of the lysine residue at a specific position in each molecule of histone. The acetylation of histones is thought to be involved in the regulation of gene expression along with nonhistone proteins because they are related to the formation of higher order structures of chromatin and the cell division cycle.

Eukaryotic DNA is compressed and stored in a narrow nucleus space, wound twice in a basic protein called a histone, an octamer (H2A, H2B, H3, H4). In order to use this compressed DNA as genetic information, it must be decompressed again. To this end, it has been anticipated that cells have a mechanism to modify and control the structure of chromatin. Chromatin remodeling factors (SWI / SNF, RSC, NURF, NRD, etc.) that modify the structure to facilitate access to transcription factors and DNA, and histone acetyltransferases that regulate the acetylation state of histones ( HATs) and histone deacetylases (HDACs) have been found to be important regulators. In particular, by neutralizing the positive charges of the lysine residues (four for H4) present at the amino terminus of the histones by acetylation (inducing transcriptional activation) or by inducing charges again by deacetylation (inducing transcription inhibition). Induction of equilibrium is known to regulate the on / off of gene expression switches at the transcription level.

To date, 17 human genes encoding HDAC have been identified, and 17 (HDAC1-10 & SIRT1-7) are classified into three classes according to their characteristics (Nature Reviews 2002 1, 287). HDAC1 and 2 belonging to the first group (HDAC1, 2, 3 and 8), the most studied among them, form complexes with nucleosome remodeling deacetylase (NuRD) or transcription repressor (SIN3) Indirectly, it forms complexes with several transcription factors through the nuclear-receptor corepressor (NCOR) and the silencing mediator for retinoid and thyroid-hormome receptors (SMOR) (Curr. Opin. Genet. Dev 2001 11, 162). Group 2 HDACs (HDAC4, 5, 6, 7, 9 and 10) are known to be expressed in both the cytoplasm and the nucleus compared to the first group mainly expressed in the nucleus. Group 2 HDACs are expressed in NuRD or SIN3. It is known to bind to a transcription factor such as myocyte enhancer factor 2 (MEF2) without forming a complex with it (Cell Biol 2001 79, 337). Group 3 HDAC (SIRT1-7) has an amino acid sequence similar to that of Sir2, a yeast transcription inhibitor, and studies in higher animals have not been actively conducted.

Since HDAC is involved in important cellular activities such as cell proliferation, cell growth cycle regulation, differentiation, and cancer formation, HDAC is highly expressed under poor environmental conditions such as hypoxia, low glucose, and cell carcinogenesis, thereby inhibiting the expression of cell proliferation inhibitors. Recently, it has been shown to play a role in promoting the role of a key regulator in the regulation of cancer and differentiation of cells. In other words, while the high acetylation state of chromatin inhibits cell proliferation and promotes differentiation, HDAC will play a crucial role in inducing proliferation through deacetylation of histones. This fact is supported as a result of inhibition of cell proliferation and angiogenesis when treated with HDAC inhibitors.

The association between abnormalities in HDAC activity and cancer production is best observed in acute promyelocytic leukemia (APL) (Oncogene 2001 20, 7204; Oncogene 2001 20, 7186). Retinoic acid receptor (RAR) and RXR complexes bind to retinoic acid response elements (RAREs). In the absence of ligand, NCOR and SMART react with SIN3 / HDAC to inhibit transcription. If a ligand is added, the HDAC complex is released from RARa-RXR and activates transcription. In APL, fusion proteins including RARa and promyelocytic-leukaemia protein (PML) complexes or RARa and promyelocytic zinc finger (PLZF) complexes are formed by chromosomal translocation. After these strange complexes bind to RAREs, they react with HDAC with a high affinity and not to retinoids, thereby inhibiting the expression of genes regulated by RAR. Other fusion proteins produced by chromosomal translocation in APL include NPM (nucleophosmin) -PARa and STAT5b (signal trasnsducer and activator of transcription) -RARa (Oncogene 2001 20, 7186). Both complexes have a strong affinity for SMRT corepressors and allow them to react with HDACs in RAREs. Therefore, it has been found that the regulation of abnormal histone deacetylation is one of the major causes of acute leukemia.

Therefore, improper transcription inhibition and abnormality in chromatin structure of oncoprotein caused by abnormal regulation of HDAC activity affect normal cell differentiation and induce 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 in the development of new anticancer drugs, and the inhibitor of HDAC is very likely to be developed as a breakthrough anticancer agent that inhibits the proliferation of cancer cells.

The first compound used as an inhibitor of HDACs is n-butyrate, which is still used in the treatment of colorectal cancer, as well as in biochemical and molecular biology experiments as an enzyme inhibitor of HDACs. However, the effective concentration of n-butyrate is high in mM (milimolar), which affects other enzymes, cytoskeleton, and cell membranes in the cell. Development was required. In 1988, M. Yoshida and Professor B. Teruhiko of the University of Tokyo, Japan, induce differentiation of Friend murine erythroleukemia (MEL) at the nM (nanomolar) level and promote the proliferation of animal cells in G1 and G2. Trichostatin A (TSA) was found to be an inhibitor of GI activity and its target molecule was HDAC. The HDAC inhibitors known to date are mainly composed of trichostatin A (TSA) -based compounds and trapoxin A (TPA), among which FR901288 and N-acetyldinaline (CI 994) are used in animal experiments. Has shown widespread anticancer activity, and clinical trials are underway at NCI. The structures of substances known to be inhibitors of HDAC so far are as follows.

For the development of new HDAC inhibitors, analysis of the tertiary structure of HDAC is essential. Recently, a tertiary structural analysis of HDAC1 like protein (HDLP) of Aquifex aeolicus , which has high homology with human HDAC1, has been performed (Nature 1999 401, 188). The complex structural analysis of TSA and A. aeolicus HDLP reveals the molecular mechanism of the tertiary structure of HDAC and the enzymatic reaction modality.

In the meantime, researches on anticancer drugs have been mainly conducted in three fields, cell signaling inhibition, cell cycle regulation, and angiogenesis inhibition. Recently, however, the study of anticancer drugs using chromatin remodeling has begun, and it is in the early stage of the study. Recently, treatment with HDAC inhibitors (eg, SAHA, apicidin) inhibits the proliferation of cancer cells and induces differentiation. The study of HDAC inhibitors is being actively conducted with the publication of the research results (Cancer research 2001 61, 8492; Cancer research 2000 60, 6068).

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

Another object of the present invention is to provide an anticancer composition containing the benzhydroxyamide derivative as an active ingredient.

In order to achieve the above object, the present invention provides a benzhydroxyamide derivative of the general formula (1):

Formula 1

Where

R ₁ is C ₃ -C ₈ cycloalkyl, aryl unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, amide and sulfone Or heteroaryl; Or C ₃ -C ₈ cycloalkyl substituted with aryl or heteroaryl, optionally substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro or amide; The heteroaryl includes one or more nitrogen, sulfur or oxygen in the ring;

Q is vinyl, ethyl, 2-propenyl or 2-propyl.

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

According to an embodiment of the present invention, the heteroaryl substituent containing nitrogen, sulfur or oxygen in the ring in the definition for the R ₁ substituent of Formula 1 is pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1 , 2,4-triazole, isoxazole, oxazole, isothiazole, thiazolidine, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,2, Can be selected from the group consisting of 5-thiodiazole, 1,2,3-thiodiazole, 1,3,4-oxadiazole, 1,3,4-thiodiazole, pyridine, pyrimidine and triazine have.

Preferred benzhydroxyamide derivatives of formula 1 according to the present invention

4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide,

4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] -N-hydroxybenzamide,

4- [2- (4-dimethylamino-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide,

4- [2- (4-cyano-phenylcarbamoyl) -vinyl] -N-hydro-benzamide,

4- [2- (4-t-butyl-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide,

4- [2- (1H - benzimidazol-2-ylcarbamoyl) -vinyl] -N-hydroxybenzamide,

4- [2- (3,4-dimethoxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide,

4- [2- (4-phenoxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide,

4- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxo-propenyl] -N-hydroxybenzamide,

4- [2- (quinolin-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide,

4- [2- (5-hydro-naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide,

4- [2- (3-benzyloxyphenylcarbamoyl) -ethyl] -N-hydroxybenzamide,

4- [2- (naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide,

4- [2- (4-t-butyl-phenylcarbamoyl) -ethyl] -N-hydroxybenzamide,

4- [2- (4-dimethylamino-phenylcarbamoyl) -ethyl] -N-hydroxybenzamide,

4- (2-phenylcarbamoyl-ethyl) -N-hydroxybenzamide,

4- [2- (pyridin-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide,

4- (2-phenylcarbamoyl-propyl) -N-hydroxybenzamide,

4- [2- (4-methoxy-phenylcarbamoyl) -propyl] -N-hydroxybenzamide,

4- [2- (3-benzyloxyphenylcarbamoyl) -propyl] -N-hydroxybenzamide,

4- [2- (3,4-dimethoxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide and

4- [2- (3-benzyloxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide is mentioned.

In the compound of Formula 1 according to the present invention, the compound having substituent Q of vinyl or ethyl may be prepared by the following reaction steps:

A) reacting a compound of formula 3 with malonic acid ester in the presence of an organic base to prepare a compound of formula 4,

B) Hydrogenation of a compound of Formula 4 under a palladium catalyst to prepare a compound of Formula 5, followed by acylation with arylamine (R ₁ -NH ₂ ), where R ₁ is as defined in Formula 1 To prepare a compound of formula 6 (Q = ethyl) or acylation of the compound of formula 4 with arylamine (R ₁ -NH ₂ ) immediately to prepare a compound of formula 6 (Q = vinyl),

C) converting the compound of formula 6 to an organic acid of formula 7 by treating with an inorganic salt (eg, sodium hydroxide, lithium hydroxide),

D) A benzhydroxyamide derivative of Formula 1 is prepared by acylation of a compound of Formula 7 with a protected hydroxyamine (eg, hydroxy amine protected with t-butylsilyl, benzyl, etc.) and then deprotected. do.

Wherein R ₁ and Q are as defined in formula (1).

Specifically, the synthesis route of the compound in which the substituent Q of Formula 1 is vinyl or ethyl is given as Reaction Scheme 1 below.

In Scheme 1, 4-formyl-benzoic acid methyl ester (3) was added to malonic acid in the presence of an organic base such as piperidine, and then stirred at 60 ° C. to 100 ° C. for 2 hours to obtain vinyl-benzoic acid methyl ester (4). 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride in the presence of N-hydroxy-6-trifluoro benzotriazole (FOBT) in an aprotic solvent such as dimethylformamide Acylation reactions using (EDC.HCl) give arylcarbamoylvinyl benzoic acid ester (6). In addition, compound (4) was hydrogenated in the presence of 10% palladium / carbon in an alcohol solvent to prepare ethylbenzoic acid methyl ester (5), followed by N-hydroxy-6-trifluoro in an aprotic solvent such as dimethylformamide. When acylation was carried out using 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) in the presence of benzotriazole (FOBT), arylcarbamoylethyl benzoic acid ester (6) Are manufactured. It is converted to an organic acid (7) by treatment with an inorganic salt such as lithium hydroxide in an aqueous alcohol solvent. The organic acid (7) is subjected to an acylation reaction with a hydroxyamine protected with a t-butyldimethylsilyl group, such as t-butyldimethylsilyloxyamine, and then the t-butyldimethylsilyl group is removed in the presence of an acid or protected with benzyloxyamine hydrochloride. Compounds of formula (I) wherein substituent Q is vinyl or ethyl can be prepared by acylation with hydroxyamine and then removing the benzyl group in an alcohol solvent by hydrogenation in the presence of 10% palladium / carbon.

In addition, in the compound of Formula 1, the compound whose substituent is Q is 2-propenyl or 2-propyl may be prepared through the following reaction steps:

A) reacting a compound of formula 8 with t-butylacrylate to prepare a hydroxy compound of formula 9,

B) reacting a compound of formula 9 with acetylchloride or acetic anhydride to prepare a compound of formula 10,

C) it is converted to a compound of formula 11 by hydrogenation with an organometallic hydride,

D) Hydrogenation of a compound of Formula 11 under a palladium catalyst, followed by hydrolysis to prepare a compound of Formula 12, and then acylation with arylamine (R ₁ -NH ₂ ) to yield a compound of Formula 13 (Q = 2-propyl). Preparing a compound or reacting with an arylamine (R ₁ -NH ₂ ) by hydrolysis of the compound of formula 11 to prepare a compound of formula 13 (Q = 2-propenyl),

E) converting the compound of formula 13 to an organic acid of formula 14 by treatment with an inorganic salt (e.g., sodium or lithium hydroxide),

F) This is acylated with a protected hydroxyamine (eg, a hydroxyamine protected with t-butylsilyl, benzyl, etc.) and then deprotected to prepare a benzhydroxyamide derivative of formula (1).

Wherein R ₁ is as defined in formula (1).

Specific examples of the compound synthesis route in which the substituent is Q is 2-propenyl or 2-propyl in the compound of Formula 1 are shown in Scheme 2 below.

In Scheme 2, 4- (methoxycarbonyl) benzaldehyde (8) is reacted with t-butylacrylate for 5 days in the presence of 1,4-diazabicyclo [2,2,2] octane for a hydroxy compound (9) is prepared, followed by reaction with acetylchloride in the presence of pyridine to give the acetoxy compound (10), which is converted to compound (11) by reaction with sodium borohydride in the presence of ethylchloroformate. This was hydrolyzed with trifluoroacetic acid to prepare 2-propenyl benzoic acid methyl ester (12), or compound (11) was hydrogenated in the presence of 10% palladium / carbon in an alcohol solvent and hydrolyzed with trifluoroacetic acid. 2-Benzobenzoic acid methyl ester (12) is prepared and then subjected to an acylation reaction in an aprotic solvent such as dimethylformamide to prepare benzoic acid ester (13). The acylation reaction is effectively used an acylating agent such as N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS) in an aprotic solvent such as dimethylformamide. It is converted to organic acid (14) by treatment with an inorganic salt such as lithium hydroxide in a water soluble alcohol solvent and tetrahydrofuran. The organic acid (14) is subjected to an acylation reaction with a hydroxyamine protected with a t-butyldimethylsilyl group such as t-butyldimethylsilyloxyamine, and then the t-butyldimethylsilyl group is removed in the presence of an acid or protected with benzyloxyamine hydrochloride. Compounds of formula (I) wherein substituent Q is 2-propenyl or 2-propyl can be prepared by subjecting hydroxyamine to an acylation reaction and then removing the benzyl group in an alcohol solvent by hydrogenation in the presence of 10% palladium / carbon.

In Schemes 1 and 2, the compounds of Formulas 3 and 8 used in the preparation of the compound of Formula 1 can be easily prepared by conventional methods, and commercially available ones can be purchased and used if necessary.

The benzhydroxyamide derivative of the formula (1) prepared as described above effectively inhibits the enzymatic activity of histone deacetylase to selectively induce terminal differentiation of tumor cells, thereby inhibiting the proliferation of these tumor cells.

Accordingly, the present invention provides an anticancer composition comprising the compound of formula 1 of the active ingredient and a pharmaceutically acceptable carrier. 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 Disintegrants or boiling mixtures such as sodium salts and / or absorbents, colorants, flavors, and sweeteners. The formulations may be prepared by conventional mixing, granulating or coating methods. Also representative of parenteral formulations 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 the control of osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulating Or according to a coating method.

As an active ingredient, the compound of formula 1 may be divided or divided once a day 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. Administration can be via oral or parenteral routes.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1 4- (2-carboxyvinyl) benzoic acid methyl ester

4-formylbenzoic acid methyl ester (500 mg, 3.046 mmol) and malonic acid (800 mg, 7.688 mmol) were dissolved in pyridine (2.5 ml), piperidine (0.25 ml) was added, followed by stirring at 60 ° C. for 1 hour and then at 100 ° C. Stir for 2 hours. After the reaction was completed, the resulting solid was acidified with 4N hydrochloric acid solution (pH = 3), the resulting solid was filtered, washed with water, the obtained solid was dissolved in a small amount of methanol, and water was added thereto, followed by stirring at 0 ° C. for 30 minutes. The resulting solid was filtered again, washed with water and dried to afford 520 mg (83%) of the title compound as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 3.87 (s, 3H), 6.67 (d, 1H, J = 16.1 Hz), 7.65 (d, 1H, J = 16.1 Hz), 7.84 (d, 2H , J = 8.1 Hz), 7.98 (d, 2H, J = 8.3 Hz), 12.35 (bs, 1H); MS (EI, 70 eV, m / z) 206 (M ⁺ ), 191, 175, 147, 102, 91, 75, 65.

Preparation Example 2 4- (2-carboxyethyl) benzoic acid methyl ester

Dissolve 4- (2-carboxyvinyl) benzoic acid methyl ester (2.1 g, 10.18 mmol) in methanol (40 ml) and tetrahydrofuran (40 ml), add 10% palladium / carbon (400 mg), and add 50 psi hydrogen gas. After stirring for 6 hours under air flow, filtration and concentration under reduced pressure gave 1.92 g (91%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.54 (d, 2H, J = 7.3 Hz), 2.87 (d, 2H, J = 7.3 Hz), 3.81 (s, 3H), 7.35 (d, 2H, J = 8.5 Hz), 7.84 (d, 2H, J = 8.2 Hz).

Preparation Example 3 t-Butyl 3-hydroxy-2-methylene-3- [4- (methoxycarbonyl) phenyl] propanoate

4- (methoxycarbonyl) benzaldehyde (3.3 g, 20 mmol) and t-butyl acrylate (3.5 ml, 24 mmol) and 1,4-diazabicyclo [2,2,2] octane (449 mg, 4 mmol) was stirred in a closed vessel at room temperature for 5 days. 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 and concentrated by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/1). Purification gave 4.2 g (73%) of the title compound as a white solid.

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, 2 H, 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; mp 70 ^o C.

Preparation Example 4 4- (1-acetoxy-2-t-butoxycarbonylallyl) benzoic acid methyl ester

t-butyl 3-hydroxy-2-methylene-3- [4- (methoxycarbonyl) phenyl] propanoate (305 mg, 1.04 mmol) and pyridine (0.20 ml, 2.50 mmol) were dried with anhydrous methylene chloride (3 ml) and acetylchloride (0.149 ml, 2.08 mmol) were slowly added at 0 ^° C. and stirred at room temperature for 10 minutes. After completion of the reaction, the 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 and concentrated by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/1). Purified with to give 337 mg (97%) of the title compound as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.37 (s, 9H), 2.11 (s, 3H), 3.91 (s, 3H), 5.76 (s, 1H), 6.34 (s, 1H), 6.68 (s, 1H), 7.44 (d, 2H, J = 8.4 Hz), 8.01 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 334 (M < + >), 325, 297, 283, 255, 241, 202, 179, 162, 135, 111; mp 59 ^o C.

Preparation Example 5 4- (2-t-butoxycarbonylpropenyl) benzoic acid methyl ester

Sodium borohydride (78 mg) in a solution of 4- (1-acetoxy-2-t-butoxycarbonylallyl) benzoic acid methyl ester (350 mg, 1.04 mmol) in anhydrous t-butyl alcohol (10 ml) , 2.08 mmol) was slowly added and stirred at room temperature for 3 hours. After the reaction is complete, t-butyl alcohol is removed by distillation under reduced pressure. Pour ice water, extract with diethyl ether and wash with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/1) to give 230 mg (73%) of the title compound as a white oil. Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 2.12 (s, 3H), 3.82 (s, 3H), 7.68 (s, 1H), 7.83 (d, 2H, J = 8.0 Hz) , 7.90 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 276 (M < + >), 269, 255, 241, 233, 219, 202, 179, 166, 135.

Preparation Example 6 4- (2-carboxy-propenyl) benzoic acid methyl ester

To a solution of 4- (2-t-butoxycarbonyl-propenyl) benzoic acid methyl ester (670 mg, 2.43 mmol) in methylene chloride (30 ml) was slowly added trifluoroacetic acid (3.0 ml) at 0 ^o C. After stirring at room temperature for 15 hours. After distillation under reduced pressure to remove the solvent, the title compound was obtained as a pale yellow solid.

Preparation Example 7 4- (2-t-butoxycarbonyl-propyl) benzoic acid methyl ester

To a solution of 4- (2-t-butoxycarbonyl-propenyl) benzoic acid methyl ester (100 mg, 0.36 mmol) in methanol (3 ml) was added 10% palladium / carbon (20 mg) and then under hydrogen conditions. Stir at room temperature for 10 hours. After the reaction was terminated by filtration to remove the palladium / carbon and the filtered solution was distilled under reduced pressure to give the target compound of a light green solid (98 mg, 98%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.19 (s, 3H), 1.45 (s, 9H), 2.68 (m, 2H), 3.85 (s, 3H), 7.10 (d, 2H, J = 8.4 Hz) , 7.90 (d, 2H, J = 8.6 Hz); MS (EI, 70 eV) m / z 278 (M ⁺ ), 272, 268, 242, 221, 202, 186, 174, 135.

Preparation Example 8 4- (2-carboxy-propyl) benzoic acid methyl ester

The target compound was synthesized in the same manner as in Preparation Example 6, using 4- (2-t-butoxycarbonyl-propyl) benzoic acid methyl ester as a starting material.

Example 1 4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 1-1: 4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl] benzoic acid methyl ester

4- (2-carboxy-vinyl) benzoic acid methyl ester (206 mg, 1 mmol) synthesized in Preparation Example 1 was dissolved in dimethylformamide (3 ml), cooled to 0 ° C., and cooled to N-hydroxy-6-trifluoro. 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) (249 mg, 1.3 mmol) was added sequentially in the presence of benzotriazole (FOBT) (203 mg, 1 mmol) and 3 -Benzyloxy-phenylamine (190 mg, 0.95 mmol) was added thereto, stirred at 0 ° C. for 10 minutes, and then gradually heated up to 30 minutes at room temperature. Upon completion of the reaction, the mixture was diluted with ethyl acetate and the organic layer was washed with 1N hydrochloric acid solution and sodium bicarbonate, washed with brine again, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/1) to obtain 356 mg (92%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ), δ 3.93 (s, 3H), 5.07 (S, 2H), 6.63 (d, 1H, J = 15.3 Hz), 6.65 (bs, 1H), 7.12 (bs, 1H) , 7.35 (m, 6H), 7.53 (d, 2H, J = 8.4 Hz), 7.67 (s, 1H), 7.76 (d, 1H, J = 15.3 Hz), 8.01 (d, 2H, J = 8.4 Hz) ; MS (EI, 70 eV, m / z) 388 (M ⁺¹ ), 296, 238, 199, 189, 91, 76.

Step 1-2: 4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl-benzoic acid

4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl] benzoic acid methyl ester (320 mg, 0.829 mmol) was dissolved in 30% aqueous ethanol solution (2 ml) and tetrahydrofuran (2 ml), followed by lithium hydroxide (348 mg). , 8.29 mmol) was added and stirred at 50 ° C. for 2 hours. After concentration under reduced pressure, the residue was dissolved in water, washed with dichloromethane, and the water layer was acidified (pH = 3). The resulting solid was filtered and dried to yield 256 mg (83%) of the title compound.

Step 1-3: 4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide

4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl] benzoic acid (240 mg, 0.643 mmol) was dissolved in dimethylformamide (2 ml), cooled to 0 ° C. and N-hydroxy-6-trifluoro benzo 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) (160 mg, 0.836 mmol), t-butyldimethylsilyl in the presence of triazole (FOBT) (131 mg, 0.643 mmol) Oxyamine (143 mg, 0.965 mmol) was added and stirred at room temperature for 30 minutes. Water and ethyl acetate were added, the organic layer was taken, washed with sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1) to obtain the title compound. 75 mg (30%) of compound was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 5.09 (s, 2H), 6.75 (s, 1H), 6.89 (d, 1H, J = 15.0 Hz), 7.44 (m, 8H), 7.71 (m , 5H), 9.12 (s, 1H), 10.28 (s, 1H), 11.30 (s, 1H); MS (EI, 70 eV, m / z) 388, 372, 344, 253, 234, 146, 118, 91, 65.

Example 2: 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 2-1: 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 175 mg (70%) of the target compound were obtained by the same method as Step 1-1 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 3.89 (s, 3H), 7.31 (d, 1H, J = 15.3 Hz), 7.59 (m, 3H), 7.70 (d, 1H, J = 15.9 Hz ), 7.80 (m, 3H), 7.96 (m, 2H), 8.05 (d, 2H, J = 8.1 Hz), 8.16 (d, 1H, J = 6.9 Hz), 10.24 (s, 1H); MS (EI, 70 eV, m / z) 332 (M ⁺ ), 189, 143, 130, 115, 102, 89, 77, 59.

Step 2-2: 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] benzoic acid

116 mg (76%) of the title compound were obtained in the same manner as in Step 1-2 of Example 1.

¹ H NMR (300MHz, DMSO-d ₆ ), δ 7.26 (d, 1H, J = 13.6 Hz), 7.58 (m, 3H), 7.80 (m, 4H), 8.16 (d, 1H, J = 9.0 Hz) , 10.23 (s, 1 H); MS (EI, 70 eV, m / z) 318 (M ⁺ ), 175, 143, 115, 103, 91, 77.

Step 2-3: 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] -N-hydroxybenzamide

25 mg (23%) of the title compound were obtained in the same manner as in Step 1-3 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.23 (d, 1H, J = 13.8 Hz), 7.75 (m, 1H), 8.15 (d, 1H, J = 6.3 Hz), 9.12 (s, 1H ), 10.21 (s, 1 H), 11.32 (s, 1 H); MS (EI, 70 eV, m / z) 333 (M ⁺ ), 316, 288, 146, 118, 91, 77.

Example 3: 4- [2- (4-dimethylamino-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 3-1: 4- [2- (4-dimethylamino-phenylcarbamoyl) -vinyl] benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 275 mg (98%) of the title compound was obtained by the same method as Step 1-1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ , δ) 2.94 (s, 6H), 3.93 (s, 3H), 6.64 (d, 1H, J = 15.3 Hz), 6.73 (d, 2H, J = 8.9 Hz), 7.49 (d, 2H, J = 8.9 Hz), 7.58 (d, 2H, J = 8.2 Hz), 7.76 (d, 1H, J = 15.8 Hz), 8.04 (d, 2H, J = 8.2 Hz); MS (EI, 70 eV, m / z) 325 (M ⁺ ), 135, 119, 102, 93, 76, 59.

Step 3-2: 4- [2- (4-Dimethylamino-phenylcarbamoyl) -vinyl] benzoic acid

193 mg (78%) of the title compound were obtained in the same manner as in Step 1-2 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.87 (s, 6H), 6.73 (d, 2H, J = 9.0 Hz), 6.91 (d, 1H, J = 15.9 Hz) 7.53 (d, 2H, J = 7.5 Hz), 7.57 (d, 1H, J = 14.1 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.99 (d, 2H, J = 8.4 Hz), 10.03 (s, 1H); MS (EI, 70 eV, m / z) 311 (M ⁺¹ ), 135, 119, 108, 93, 77, 65.

Step 3-3: 4- [2- (4-Dimethylamino-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide

50 mg (28%) of the title compound were obtained by the same method as Steps 1-3 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.87 (s, 6H), 6.72 (d, 2H, J = 8.7 Hz), 6.90 (d, 1H, J = 15.6 Hz) 7.56 (m, 3H) , 7.67 (d, 2H, J = 8.1 Hz), 7.81 (d, 2H, J = 8.1 Hz), 9.12 (s, 1H), 10.06 (s, 1H), 11.31 (s, 1H); MS (EI, 70 eV, m / z) 325, 281, 146, 136, 122, 108, 91.

Example 4: 4- [2- (4-cyano-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 4-1: 4- [2- (4-cyano-phenylcarbamoyl) -vinyl] benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 299 mg (100%) of the title compound was obtained by the same method as Step 1-1 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 4.08 (s, 3H), 6.88 (d, 1H, J = 16.2 Hz), 7.87 (d, 1H, J = 16.2 Hz), 7.93 (d, 1H , J = 9.0 Hz), 8.07 (m, 3H), 8.21 (m, 2H), 8.45 (m, 2H); MS (EI, 70 eV, m / z) 307 (M ⁺ ), 189, 175, 145, 130, 102, 91, 76, 59.

Step 4-2: 4- [2- (4-cyano-phenylcarbamoyl) -vinyl] benzoic acid

128 mg (48%) of the title compound were obtained in the same manner as in Step 1-2 of Example 1.

MS (EI, 70 eV, m / z) 293 (M ⁺ ), 175, 147, 131, 103, 77.

Step 4-3: 4- [2- (4-cyano-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide

4.5 mg (10%) of the title compound was obtained by the same method as Steps 1-3 of Example 1.

Example 5: 4- [2- (4-t-butylphenylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 5-1: 4- [2- (4-t-butylphenylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 250 mg (93%) of the target compound were obtained by the same method as Step 1-1 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 1.27 (s, 9H), 3.88 (s, 3H), 6.97 (d, 1H, J = 15.6 Hz), 7.36 (d, 2H, J = 8.4 Hz ), 7.65 (m, 3H), 7.76 (d, 2H, J = 8.1 Hz), 8.02 (d, 2H, J = 8.1 Hz), 10.24 (s, 1H); MS (EI, 70 eV, m / z) 338 (M ⁺ ), 322, 306, 189, 149, 134, 102, 91, 59.

Step 5-2: 4- [2- (4-t-Butylphenylcarbamoyl) -vinyl] -benzoic acid

187 mg (85%) of the title compound was obtained in the same manner as in the step 1-2 of Example 1.

¹ H NMR (300MHz, DMSO-d ₆ ), δ 1.27 (s, 9H), 6.91 (d, 1H, J = 16.1 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.62 (m, 3H) , 7.72 (d, 2H, J = 7.8 Hz), 7.99 (d, 2H, J = 8.1 Hz), 10.23 (s, 1H); MS (EI, 70 eV, m / z) 324 (M ⁺ ), 308, 175, 149, 134, 103, 77.

Step 5-3: 4- [2- (4-t-butylphenylcarbamoyl) -vinyl] -N-hydroxybenzamide

40 mg (43%) of the target compound were obtained by the same method as Steps 1-3 of Example 1.

Example 6: 4- [2- (1H - benzimidazol-2-ylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 6-1: 4- [2- (1H - benzimidazol-2-ylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 300 mg (100%) of the title compound was obtained by the same method as in Step 1-1 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 3.93 (s, 3H), 6.73 (d, 1H, J = 16.0 Hz), 7.16 (m, 2H), 7.53 (m, 2H), 7.68 (d , 1H, J = 16.1 Hz), 7.85 (m, 3H), 8.06 (m, 3H); MS (EI, 70 eV, m / z) 322 (M ⁺ ), 293, 189, 145, 133, 115, 102, 91, 76, 59.

Step 6-2: 4- [2- (1H - benzimidazol-2-ylcarbamoyl) -vinyl] -benzoic acid

152 mg (59%) of the title compound were obtained in the same manner as in Step 1-2 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 6.67 (d, 1H, J = 15.3 Hz), 7.11 (m, 2H), 7.48 (m, 2H), 7.64 (d, 1H, J = 16.2 Hz ), 7.79 (m, 3H), 8.00 (m, 3H), 12.41 (bs, 1H); MS (EI, 70 eV, m / z) 308 (M ⁺ ), 279, 186, 175, 133, 103, 90, 77.

Step 6-3: 4- [2- (1H - benzimidazol-2-ylcarbamoyl) -vinyl] -N-hydroxybenzamide

4 mg (8%) of the title compound were obtained in the same manner as in Step 1-3 of Example 1.

Example 7: 4- [2- (3,4-dimethoxyphenylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 7-1: 4- [2- (3,4-dimethoxyphenylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxyvinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 339 mg (99%) of the title compound was obtained by the same method as Step 1-1 of Example 1.

Step 7-2: 4- [2- (3,4-Dimethoxy-phenylcarbamoyl) -vinyl] -benzoic acid

202 mg (85%) of the title compound was synthesized in the same manner as in Example 1-2.

Step 7-3: 4- [2- (3,4-dimethoxyphenylcarbamoyl) -vinyl] -N-hydroxy benzamide

130 mg (65%) of the title compound was synthesized in the same manner as in Example 1-3.

¹ H NMR (200 MHz, DMSO-d ₆ ), δ 3.72 (s, 6H), 6.88 (d, 1H, J = 9.0 Hz), 7.28 (d, 2H, J = 7.6 Hz), 7.54 (m, 4H ), 7.83 (d, 2H, J = 9.0 Hz).

Example 8: 4- [2- (4-phenoxyphenylcarbamoyl) -vinyl] -N-hydroxybenzamide

Step 8-1: 4- [2- (4-phenoxyphenylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 341 mg (91%) of the title compound was obtained by the same method as Step 1-1 of Example 1.

Step 8-2: 4- [2- (4-phenoxyphenylcarbamoyl) -vinyl] -benzoic acid

202 mg (84%) of the title compound was synthesized in the same manner as in Example 1-2.

Step 8-3: 4- [2- (4-phenoxyphenylcarbamoyl) -vinyl] -N-hydroxybenzamide

108 mg (54%) of the target compound were synthesized in the same manner as in Example 1-3.

¹ H NMR (200 MHz, DMSO-d ₆ ), δ 3.72 (s, 6H), 6.88 (d, 1H, J = 9.0 Hz), 7.28 (d, 2H, J = 7.6 Hz), 7.54 (m, 4H ), 7.83 (d, 2H, J = 9.0 Hz).

Example 9: 4- [3- (3,4-Dihydro-1H-isoquinolin-2-yl) -3-oxo-propenyl] -N-hydroxybenzamide

Step 9-1: 4- [3- (3,4-Dihydro-1 H-isoquinolin-2-yl) -3-oxo-propenyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

Step 9-2: 4- [3- (3,4-Dihydro-1 H-isoquinolin-2-yl) -3-oxo-propenyl] -benzoic acid

The desired compound was synthesized in the same manner as in Step 1-2 of Example 1.

Step 9-3: 4- [3- (3,4-Dihydro-1 H-isoquinolin-2-yl) -3-oxo-propenyl] -N-benzyloxybenzamide

4- [3- (3,4-Dihydro-1H-isoquinolin-2-yl) -3-oxo-propenyl] -benzoic acid (240 mg, 0.781 mmol) was dissolved in diaminoformamide (2 ml) and 0 ° C. After cooling with triethylamine (327 μl, 2.343 mmol) and N-methanesulfonyloxy-6-trifluoro benzotriazole (264 mg, 0.937 mmol), the mixture was stirred at 0 ° C. for 20 minutes and benzyloxyamine hydrochloride ( 187 mg, 1.172 mmol) was added thereto, followed by stirring at 0 ° C. for 10 minutes and at room temperature for 30 minutes. Water and ethyl acetate were added, the organic layer was taken, washed with sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (146 mg (45). %) Was obtained.

¹ H NMR (300MHz, DMSO-d ₆ ), δ 2.83 (m, 2H), 3.85 (m, 2H), 4.94 (s, 2H), 7.20 (m, 4H), 7.48 (m, 7H), 7.83 ( dd, 4H, J = 8.4 Hz); MS (EI, 70 eV, m / z) 413 (M ⁺¹ ), 306, 290, 175, 132, 117, 103, 91, 77.

Step 9-4: 4- [3- (3,4-Dihydro-1 H-isoquinolin-2-yl) -3-oxo-propenyl] -N-hydroxybenzamide.

4- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxo-propenyl] -N-benzyloxybenzamide (134 mg, 0.325 mmol) in methanol (3 ml) Was dissolved in 10% palladium / carbon (27 mg) and stirred for 16 hours in the presence of hydrogen gas. The residue was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 9/1) to obtain 44 mg (42%) of the title compound.

Example 10 4- [2- (quinolin-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

Step 10-1: 4- [2- (Quinoline-3-ylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

Step 10-2: 4- [2- (Quinoline-3-ylcarbamoyl) -vinyl] -benzoic acid

132 mg (77%) of the title compound was obtained in the same manner as in Example 1-2.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.04 (d, 1H, J = 15.6 Hz), 7.74 (m, 5H), 8.02 (d, 4H, J = 8.1 Hz), 8.90 (s, 1H) , 9.10 (s, 1 H), 10.96 (s, 1 H); MS (EI, 70 eV, m / z) 319 (M ⁺ ), 175, 144, 116, 103, 89, 77, 63.

Step 10-3: 4- [2- (Quinoline-3-ylcarbamoyl) -vinyl] -N-benzyloxybenzamide

12 mg (15%) of the title compound were obtained by the same method as Step 9-3 of Example 9.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 5.01 (s, 2H), 7.04 (d, 1H, J = 15.6 Hz), 7.38 (m, 5H), 7.74 (m, 5H), 8.02 (d , 4H, J = 8.1 Hz), 8.90 (s, 1H), 9.10 (s, 1H), 10.96 (s, 1H), 11.78 (s, 1H); MS (EI, 70 eV, m / z) 424 (M ⁺ ), 317, 170, 144, 115, 106, 91, 77.

Step 10-4: 4- [2- (Quinoline-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

5 mg (71%) of the title compound were obtained in the same manner as in Step 9-4 of Example 9.

Example 11 4- [2- (5-hydro-naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

Step 11-1: 4- [2- (5-hydro-naphthalen-1-ylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 220 mg (79%) of the title compound was obtained by the same method as Step 1-1 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 3.88 (s, 3H), 6.92 (d, 1H, J = 7.5 Hz), 7.40 (m, 3H), 7.71 (m, 8H), 10.09 (s , 1H), 10.21 (s, 1H); MS (EI, 70 eV, m / z) 375 (M ⁺ ), 189, 159, 145, 130, 115, 102, 91, 77.

Step 11-2: 4- [2- (5-hydro-naphthalen-1-ylcarbamoyl) -vinyl] -benzoic acid

158 mg (92%) of the title compound was obtained in the same manner as in Step 1-2 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 6.92 (d, 2H, J = 7.2 Hz), 7.42 (m, 3H), 7.59 (d, 1H, J = 8.7 Hz), 7.68 (d, 1H , J = 15.6 Hz), 7.78 (d, 2H, J = 8.1 Hz), 7.90 (d, 1H, J = 7.5 Hz), 8.02 (d, 3H, J = 7.8 Hz), 10.09 (s, 1H), 10.20 (s, 1 H), 13.06 (s, 1 H); MS (EI, 70 eV, m / z) 334 (M ⁺¹ ), 198, 175, 159, 131, 103, 77, 65.

Step 11-3: 4- [2- (5-hydro-naphthalen-1-ylcarbamoyl) -vinyl] -N-benzyloxybenzamide

24 mg (30%) of the title compound were obtained by the same method as Step 9-3 of Example 9.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 4.95 (s, 2H), 6.92 (d, 1H, J = 7.5 Hz), 7.42 (m, 8H), 7.81 (m, 7H), 7.99 (d , 1H, J = 8.4 Hz), 10.07 (s, 1H), 10.22 (s, 1H), 11.86 (s, 1H); MS (EI, 70 eV, m / z) 439 (M ⁺ ), 330, 197, 159, 108, 77.

Step 11-4: 4- [2- (5-hydro-naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

In the same manner as in Example 9-4 of Example 9, 4 mg (15%) of the title compound were obtained.

Example 12 4- [2- (3-benzyloxyphenylcarbamoyl) -ethyl] -N-hydroxybenzamide

Step 12-1: 4- [2- (3-benzyloxyphenylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxyvinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, 245 mg (47%) of the title compound was obtained by the same method as Step 1-1 of Example 1.

¹ H NMR (200 MHz, CDCl ₃ ), δ 2.64 (t, 2H, J = 7.5 Hz), 3.07 (t, 2H, J = 7.5 Hz), 3.88 (s, 3H), 5.02 (s, 2H), 6.70 (d, 1H, J = 2.0 Hz), 6.74 (d, 1H, J = 2.0 Hz), 7.37 (m, 9H), 7.93 (d, 2H, J = 8.1 Hz).

Step 12-2: 4- [2- (3-benzyloxyphenylcarbamoyl) -vinyl] -benzoic acid

189 mg (98%) of the title compound was obtained in the same manner as in the step 1-2 of Example 1.

¹ H NMR (200 MHz, DMSO ₆ ), δ 2.62 (t, 2H, J = 7.5 Hz), 2.96 (t, 2H, J = 7.5 Hz), 5.02 (s, 2H), 6.63 (d, 1H, J = 7.7 Hz), 7.10 (m, 2H), 7.35 (m, 8H), 7.84 (d, 2H, J = 8.1 Hz), 9.84 (s, 2H, NH).

Step 12-3: 4- [2- (3-benzyloxyphenylcarbamoyl) -ethyl] -N-benzyloxybenzamide

35 mg (25%) of the title compound was obtained by the same method as Step 9-3 of Example 9.

¹ H NMR (200 MHz, Acetone-d ₆ ), δ 0.22 (s, 2H), 1.00 (s, 3H), 2.725 (t, 2H, J = 7.6 Hz), 3.04 (t, 2H, J = 7.5 Hz ), 5.09 (s, 2H), 6.72 (d, 1H, J = 7.3 Hz), 7.16 (m, 2H), 7.42 (m, 8H), 7.73 (m, 2H).

Step 12-4: 4- [2- (3-benzyloxyphenylcarbamoyl) -ethyl] -N-hydroxybenzamide

14 mg (64%) of the target compound were obtained by the same method as Step 9-4 of Example 9.

¹ H NMR (200 MHz, DMSO ₆ ), δ 2.65 (t, 2H, J = 7.6 Hz), 2.94 (t, 2H, J = 7.5 Hz), 5.05 (s, 2H), 6.68 (d, 1H, J = 7.3 Hz), 7.14 (m, 2H), 7.36 (m, 7H), 7.67 (m, 3H), 8.97 (s, 1H, NH), 9.90 (s, 1H, NH), 11.13 (s, 1H, OH).

Example 13: 4- [2- (naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

Step 13-1: 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-vinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

Step 13-2: 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] -benzoic acid

The desired compound was synthesized in the same manner as in Step 1-2 of Example 1.

Step 13-3: 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] -N-benzyloxybenzamide

71 mg (41%) of the target compound were obtained by the same method as Step 9-3 of Example 9.

MS (EI, 70 eV, m / z) 423 (M ⁺¹ ), 372, 316, 230, 174, 143, 131, 115, 77.

Step 13-4: 4- [2- (naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

22 mg (43%) of the title compound were obtained in the same manner as in Step 9-4 of Example 9.

Example 14 4- [2- (4-t-butylphenylcarbamoyl) -ethyl] -N-hydroxybenzamide

Step 14-1: 4- [2- (4-t-butylphenylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxyvinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

Step 14-2: 4- [2- (4-t-butylphenylcarbamoyl) -vinyl] -benzoic acid

The desired compound was synthesized in the same manner as in Step 1-2 of Example 1.

Step 14-3: 4- [2- (4-t-butylphenylcarbamoyl) -vinyl] -N-benzyloxybenzamide

The desired compound was synthesized in the same manner as in Step 9-3 of Example 9.

Step 14-4: 4- [2- (4-t-butylphenylcarbamoyl) -ethyl] -N-hydroxybenzamide

18 mg (59%) of the title compound were obtained in the same manner as in Step 9-4 of Example 9.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 1.25 (s, 9H), 2.62 (t, 2H, J = 7.7 Hz), 2.95 (t, 2H, J = 7.2 Hz), 7.30 (t, 4H, J = 6.9 Hz), 7.47 (d, 2H, J = 8.6 Hz), 7.78 (d, 2H, J = 8.1 Hz), 7.88 (s, 1H), 9.83 (s, 1H).

Example 15 4- [2- (4-Dimethylamino-phenylcarbamoyl) -ethyl] -N-hydroxybenzamide

Step 15-1: 4- [2- (4-dimethylaminophenylcarbamoyl) -vinyl] -benzoic acid methyl ester

Using the 4- (2-carboxyvinyl) -benzoic acid methyl ester prepared in Preparation Example 1 as a starting material, the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

Step 15-2: 4- [2- (4-Dimethylaminophenylcarbamoyl) -vinyl] -benzoic acid

The desired compound was synthesized in the same manner as in Step 1-2 of Example 1.

Step 15-3: 4- [2- (4-dimethylaminophenylcarbamoyl) vinyl] -N-benzyloxybenzamide

The desired compound was synthesized in the same manner as in Step 9-3 of Example 9.

Step 15-4: 4- [2- (4-Dimethylaminophenylcarbamoyl) -ethyl] -N-hydroxybenzamide

In the same manner as in Example 9-4 of Example 9, 10 mg (44%) of the title compound were obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.69 (t, 2H, J = 7.5 Hz), 2.78 (t, 2H, J = 7.7 Hz), 2.88 (s, 6H), 6.70 (m, 4H ), 7.51 (m, 4H), 7.78 (s, 1H), 8.53 (s, 1H).

Example 16: 4- (2-phenylcarbamoyl-ethyl) -N-hydroxybenzamide

Step 16-1: 4- (2-phenylcarbamoyl-ethyl) -benzoic acid methyl ester

4- (2-carboxyethyl) -benzoic acid methyl ester prepared in Preparation Example 2 was reacted with aniline in the same manner as in Step 1-1 of Example 1 to obtain 278 mg (98%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.66 (t, 2H, J = 7.8 Hz), 2.99 (t, 2H, J = 7.5 Hz), 3.83 (s, 3H), 7.02 (t, 1H, J = 7.3 Hz), 7.28 (t, 2H, J = 7.6 Hz), 7.41 (d, 2H, J = 8.1 Hz), 7.56 (d, 2H, J = 7.6 Hz), 7.89 (d, 2H, J = 8.2 Hz), 9.92 (s, 1 H); MS (EI, 70 eV, m / z) 284 (M ⁺ ), 252, 149, 131, 93, 77.

Step 16-2: 4- (2-phenylcarbamoyl-ethyl) -benzoic acid

In the same manner as in Example 1-2, 188 mg (76%) of the title compound was obtained, and used for the next reaction.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.66 (t, 2H, J = 7.5 Hz), 2.98 (t, 2H, J = 7.3 Hz), 7.01 (t, 1H, J = 7.2 Hz), 7.28 (t, 2H, J = 7.7 Hz), 7.38 (d, 2H, J = 8.1 Hz), 7.56 (d, 2H, J = 8.0 Hz), 7.87 (d, 1H, J = 8.1 Hz), 9.92 (s , 1H); MS (EI, 70 eV, m / z) 270 (M ⁺¹ ), 149, 135, 107, 93, 77, 65.

Step 16-3: 4- (2-phenylcarbamoyl-ethyl) -N-benzyloxybenzamide

38 mg (28%) of the title compound were obtained by the same method as Step 9-3 of Example 9.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.64 (t, 2H, J = 7.5 Hz), 2.96 (t, 2H, J = 7.2 Hz), 4.91 (s, 2H), 7.03 (t, 1H , J = 6.9 Hz), 7.37 (m, 9H), 7.56 (d, 2H, J = 8.4 Hz), 7.67 (d, 2H, J = 7.8 Hz), 9.91 (s, 1H), 11.69 (s, 1H ); MS (EI, 70 eV, m / z) 375 (M ⁺ ), 342, 268, 252, 148, 131, 105, 93, 77, 65.

Step 16-4: 4- (2-phenylcarbamoyl-ethyl) -N-hydroxybenzamide

10 mg (46%) of the title compound were obtained by the same method as Step 9-4 of Example 9.

Example 17 4- [2- (pyridin-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

Step 17-1: 4- [2- (pyridin-3-ylcarbamoyl) -ethyl] -benzoic acid methyl ester

Using the 4- (2-carboxy-ethyl) -benzoic acid methyl ester prepared in Preparation Example 2 as a starting material, 246 mg (87%) of the title compound was obtained by the same method as Step 1-1 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.70 (t, 2H, J = 7.8 Hz), 3.00 (t, 2H, J = 7.2 Hz), 3.83 (s, 3H), 7.33 (m, 1H ), 7.41 (d, 2H, J = 8.1 Hz), 7.89 (d, 2H, J = 8.1 Hz), 8.01 (d, 1H, J = 8.4 Hz), 8.24 (s, 1H), 8.70 (s, 1H ), 10.16 (s, 1 H); MS (EI, 70 eV, m / z) 285 (M ⁺¹ ), 253, 163, 149, 131, 103, 94, 77, 59.

Step 17-2: 4- [2- (pyridin-3-ylcarbamoyl) -ethyl] -benzoic acid

127 mg (58%) of the title compound were obtained in the same manner as in Example 1-2.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.70 (t, 2H, J = 7.8 Hz), 3.00 (t, 2H, J = 7.5 Hz), 7.35 (m, 3H), 7.86 (m, 2H ), 8.01 (s, 1H), 8.24 (s, 1H), 8.70 (s, 1H), 10.16 (s, 1H), 12.68 (bs, 1H); MS (EI, 70 eV, m / z) 271 (M ⁺¹ ), 226, 149, 135, 107, 94, 77.

Step 17-3: 4- [2- (pyridin-3-ylcarbamoyl) -ethyl] -N-benzyloxybenzamide

168 mg (98%) of the title compound was obtained by the same method as Step 9-3 of Example 9.

¹ H NMR (300MHz, DMSO-d ₆ ), δ 2.79 (t, 2H, J = 7.8 Hz), 3.07 (t, 2H, J = 7.2 Hz), 5.02 (s, 2H), 7.50 (m, 8H) , 7.77 (d, 2H, J = 7.8 Hz), 8.11 (d, 1H, J = 8.4 Hz), 8.34 (d, 1H, J = 4.8 Hz), 8.81 (s, 1H), 10.26 (s, 1H) , 11.81 (s, 1 H); MS (EI, 70 eV, m / z) 376 (M ⁺¹ ), 269, 253, 226, 176, 148, 134, 121, 94.

Step 17-4: 4- [2- (pyridin-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide

In the same manner as in Example 9-4 of Example 9, 27 mg (25%) of the title compound were obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ), δ 2.69 (t, 2H, J = 7.5 Hz), 2.96 (t, 2H, J = 7.7 Hz), 7.28 (m, 3H), 7.67 (d, 2H , J = 7.5 Hz), 8.02 (d, 1H, J = 7.2 Hz), 8.24 (d, 1H, J = 4.2 Hz), 8.71 (s, 1H), 10.22 (s, 1H).

Example 18 4- (2-phenylcarbamoyl-propyl) -N-hydroxybenzamide

Step 18-1: 4- (2-phenylcarbamoyl-propenyl) -benzoic acid methyl ester

Using the 4- (2-carboxy-propenyl) -benzoic acid methyl ester synthesized in Preparation Example 6 as a starting material, 78% of the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.92 (s, 3H), 3.82 (s, 3H), 6.70 (s, 1H), 7.53 (d, 2H, J = 8.0 Hz), 7.82 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 295 (M < + >), 279, 219, 187, 172, 142, 115.

Step 18-2: 4- (2-phenylcarbamoyl-propenyl) -benzoic acid

In the same manner as in Example 1-2, the desired compound was synthesized and used directly in the next reaction.

MS (EI, 70 eV) m / z 281 (M < + >), 234, 218, 207, 192, 178, 168, 154, 143, 127, 106.

Step 18-3: 4- (2-phenylcarbamoyl-propenyl) -N-benzyloxybenzamide

The desired compound (96%) was synthesized in the same manner as in Step 9-3 of Example 9.

Step 18-4: 4- (2-phenylcarbamoyl-propyl) -N-hydroxybenzamide

The desired compound was synthesized in the same manner as in Step 9-4 of Example 9.

¹ H NMR (300 MHz, acetone-d ₆ ) δ 3.8 (S, 3H), 4.9 (s, 2H), 6.9-7.0 (s, 1H), 7.23-7.25 (t, J = 7.8 Hz, 6.0 Hz, 3H), 7.35 (s, 1H), 7.4-7.5 (m, 5H), 7.6-7.7 (t, J = 7.6 Hz, 3H), 7.9-8.0 (d, J = 7.2 Hz, 2H); MS (EI, 70 eV) m / z 386 (M ⁺ ), 374, 234, 218, 207, 192, 178, 168, 154, 143, 127, 106.

Example 19 4- [2- (4-methoxyphenylcarbamoyl) -propyl] -N-hydroxybenzamide

Step 19-1: 4- [2- (4-methoxyphenylcarbamoyl) -propyl] -benzoic acid methyl ester

100% of the target compound was synthesized in the same manner as in Step 1-1 of Example 1, using 4- (2-carboxypropyl) -benzoic acid methyl ester synthesized in Preparation Example 8 as a starting material.

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 1.23-1.25 (d, 3H, J = 7.6 Hz), 2.76-2.89 (m, 2H), 3.01-3.04 (q, 1H, J = 7.4 Hz, 7.6 Hz), 3.76 (s, 3H), 3.88 (s, 3H), 6.82-6.86 (d, 2H, J = 7.8 Hz), 7.29-7.36 (dd, 4H, J = 7.6 Hz, 7.6 Hz), 7.91- 7.94 (d, 2H, J = 7.8 Hz); MS (LC, 70 eV) m / z 328 (M + l), 283.

Step 19-2: 4- [2- (4-methoxyphenylcarbamoyl) -propyl] -benzoic acid

30% of the target compound was obtained in the same manner as in Example 1-2 of Example 1.

MS (LC, 70 eV) m / z 314 (M + l), 297, 281, 239, 163, 142, 123, 116.

Step 19-3: 4- [2- (4-methoxyphenylcarbamoyl) -propyl] -N-hydroxybenzamide

The desired compound was synthesized in the same manner as in Step 1-3 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.23-1.27 (d, 3H, J = 7.2 Hz), 2.75-2.82 (m, 2H), 3.02-3.06 (q, 1H, J = 7.6 Hz, 7.6 Hz), 3.78 (s, 3H), 6.84-6.88 (d, 2H, J = 8.2 Hz), 7.32-7.38 (dd, 4H, J = 7.6 Hz, 7.6 Hz), 7.89-7.91 (d, 2H, J = 8.4 Hz); MS (LC, 70 eV) m / z 327 (M < -1 >), 298, 202, 203.

Example 20 4- [2- (3-benzyloxyphenylcarbamoyl) -propyl] -N-hydroxybenzamide

Step 20-1: 4- [2- (3-benzyloxyphenylcarbamoyl) -propyl] -benzoic acid methyl ester

Using the 4- (2-carboxypropyl) -benzoic acid methyl ester synthesized in Preparation Example 8 as a starting material, 85% of the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.12 (s, 3H), 2.44 (m, 2H), 3.85 (s, 3H), 5.05 (s, 2H), 6.76 (d, 2H, J = 8.0 Hz) , 7.06 (d, 1H, J = 7.4 Hz), 7.86 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 403 (M < + >), 392, 377, 329, 302, 278, 250, 219, 124.

Step 20-2: 4- [2- (3-benzyloxyphenylcarbamoyl) -propyl] -benzoic acid

78% of the target compound was obtained in the same manner as in Step 1-2 of Example 1.

MS (EI, 70 eV) m / z 389 (M < + >), 388, 329, 301, 277, 276, 219, 116.

Step 20-3: 4- [2- (3-benzyloxyphenylcarbamoyl) -propyl] -N-hydroxy benzamide

94% of the title compound was obtained in the same manner as in Step 1-3 of Example 1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.21 (s, 3H), 2.41-2.42 (m, 2H), 5.05 (s, 2H), 6.76-6.80 (d, 2H, J = 7.6 Hz), 7.04-7.08 (m, 6H), 7.82-7.84 (m, 5H); MS (LC, 70 eV) m / z 405 (M + l), 390, 296, 295, 278, 204, 103, 102.

Example 21 4- [2- (3,4-dimethoxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide

Step 21-1: 4- [2- (3,4-Dimethoxyphenylcarbamoyl) -propenyl] -benzoic acid methyl ester

Using the 4- (2-carboxypropenyl) -benzoic acid methyl ester synthesized in Preparation Example 6 as a starting material, 80% of the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.92 (s, 3H), 3.82 (s, 3H), 3.87 (s, 6H), 6.70 (s, 1H), 7.53 (s, 3H), 7.82 (d, 2H, J = 8.0 Hz), 7.85 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 355 (M < + >), 276, 246, 232, 218, 204, 194, 152.

Step 21-2: 4- [2- (3,4-Dimethoxy-phenylcarbamoyl) -propenyl] -benzoic acid

80% of the target compound was synthesized in the same manner as in Example 1-2.

MS (EI, 70 eV) m / z 341 (M < + >), 318, 301, 279, 217, 162, 124.

Step 21-3: 4- [2- (3,4-Dimethoxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide

95% of the target compound was synthesized in the same manner as in Example 1-3.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.23 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H), 6.80 (s, 1H), 7.04-7.08 (d, 2H, J = 8.4 Hz), 7.28-7.34 (t, 3H, J = 7.4 Hz, 7.4 Hz), 7.84-7.89 (d, 2H, J = 8.4 Hz); MS (LC, 70 eV) m / z 357 (M + l), 342, 204, 103, 102.

Example 22: 4- [2- (3-benzyloxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide

Step 22-1: 4- [2- (3-benzyloxyphenylcarbamoyl) -propenyl] -benzoic acid methyl ester

Using the 4- (2-carboxypropenyl) -benzoic acid methyl ester synthesized in Preparation Example 6 as a starting material, 64% of the target compound was synthesized in the same manner as in Step 1-1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.92 (s, 3H), 3.82 (s, 3H), 5.05 (s, 2H), 6.76 (d, 2H, J = 8.0 Hz), 7.15 (s, 1H) , 7.69 (d, 1H, J = 7.4 Hz), 7.79 (d, 2H, J = 8.0 Hz), 7.83 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 401 (M < + >), 391, 377, 322, 301, 229, 152, 125.

Step 22-2: 4- [2- (3-benzyloxyphenylcarbamoyl) -propenyl] -benzoic acid

100% of the target compound was synthesized in the same manner as in Example 1-2.

MS (LC, 70 eV) m / z 388 (M + l), 324, 323, 204, 203, 160, 159, 146, 103, 102.

Step 22-3: 4- [2- (3-benzyloxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide

The desired compound was synthesized in the same manner as in Step 1-3 of Example 1.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 1.24 (s, 3H), 5.05 (s, 2H), 6.72 (s, 1H), 6.78-6.80 (d, 2H, J = 7.2 Hz), 7.04-7.08 (m, 6H), 7.80-7.84 (m, 5H); MS (LC, 70 eV) m / z 403 (M + l), 402, 388, 324, 204, 203, 159, 103, 102.

Test Example

Analysis of HDAC activity was performed based on the BioOMOL Quantizyme ™ Assay System. The analysis consists of two steps. The first step is an enzyme reaction step in which HDAC reacts with a substrate. In this step, the inhibition of HDAC enzyme activity was measured by adding an HDAC inhibitor. To prepare the reaction mixture, 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, and 5 μL of 250 μM Fluor de LysTM substrate was added. At this time, 2.5 μL of inhibitor of the desired concentration was added. HeLa cell nucleus extract (nuclear extract) is used as the HDAC enzyme source. 0.5 μL of HeLa nucleus extract (10 μM) was added so that the final concentration was 100 nM, and the enzyme reaction was performed for 1 hour.

Subsequently, as a detection step, 2 μM tricostatin A was added to a 50 uL Fluor de Lys ™ Developer (Developer) and reacted for 15 minutes at room temperature. Deacetylase of the substrate was detected by the developer to form a fluorophore. The fluoropores were detected with a fluorometric plate reader, which was excited at 355 nm light and emitted at 460 nm. 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.

The degree of HDAC inhibitory activity of the compounds prepared in Example was divided into three stages of A, B, and C. ).

HDAC Inhibitory Activity (IC ₅₀ ) Test Results compound Active degree compound Active degree SAHA A Example 12 A Example 1 A Example 13 B Example 2 B Example 14 C Example 3 B Example 15 C Example 4 B Example 16 B Example 5 B Example 17 B Example 6 C Example 18 B Example 7 B Example 19 B Example 8 B Example 20 A Example 9 A Example 21 B Example 10 A Example 22 B Example 11 A

From Table 1, it can be seen that the benzhydroxyamide derivative according to the present invention shows excellent HDAC inhibitory activity.

Benzhydroxyamide derivatives of the present invention effectively inhibit the enzymatic activity of histone deacetylase to selectively induce terminal differentiation of tumor cells, thereby inhibiting the proliferation of these tumor cells, and thus can be usefully used as anticancer agents.

Claims (8)

Benzhydroxyamide derivatives of the general formula Formula 1 Where R ₁ is C ₃ -C ₈ cycloalkyl, aryl unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, amide and sulfone Or heteroaryl; Or C ₃ -C ₈ cycloalkyl substituted with aryl or heteroaryl, optionally substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro or amide; The heteroaryl includes one or more nitrogen, sulfur or oxygen in the ring; Q is vinyl, ethyl, 2-propenyl or 2-propyl. The method of claim 1, Heteroaryl substituents containing nitrogen, sulfur or oxygen in the ring include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, isoxazole, oxazole, isothia Sol, thiazolidine, thiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,2,5-thiodiazole, 1,2,3-thiodiazole, 1 A benzhydroxyamide derivative, characterized in that it is selected from the group consisting of 3,4-oxadiazole, 1,3,4-thiodiazole, pyridine, pyrimidine and triazine. The method of claim 1, 4- [2- (3-benzyloxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide, 4- [2- (naphthalen-1-ylcarbamoyl) -vinyl] -N-hydroxybenzamide, 4- [2- (4-dimethylamino-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide, 4- [2- (4-cyano-phenylcarbamoyl) -vinyl] -N-hydro-benzamide, 4- [2- (4-t-butyl-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide, 4- [2- (1H - benzimidazol-2-ylcarbamoyl) -vinyl] -N-hydroxybenzamide, 4- [2- (3,4-dimethoxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide, 4- [2- (4-phenoxy-phenylcarbamoyl) -vinyl] -N-hydroxybenzamide, 4- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxo-propenyl] -N-hydroxybenzamide, 4- [2- (quinolin-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide, 4- [2- (5-hydro-naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide, 4- [2- (3-benzyloxyphenylcarbamoyl) -ethyl] -N-hydroxybenzamide, 4- [2- (naphthalen-1-ylcarbamoyl) -ethyl] -N-hydroxybenzamide, 4- [2- (4-t-butyl-phenylcarbamoyl) -ethyl] -N-hydroxybenzamide, 4- [2- (4-dimethylamino-phenylcarbamoyl) -ethyl] -N-hydroxybenzamide, 4- (2-phenylcarbamoyl-ethyl) -N-hydroxybenzamide, 4- [2- (pyridin-3-ylcarbamoyl) -ethyl] -N-hydroxybenzamide, 4- (2-phenylcarbamoyl-propyl) -N-hydroxybenzamide, 4- [2- (4-methoxy-phenylcarbamoyl) -propyl] -N-hydroxybenzamide, 4- [2- (3-benzyloxyphenylcarbamoyl) -propyl] -N-hydroxybenzamide, 4- [2- (3,4-dimethoxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide and 4- [2- (3-benzyloxyphenylcarbamoyl) -propenyl] -N-hydroxybenzamide Benzhydroxyamide derivatives, characterized in that selected from the group consisting of. A) reacting a compound of formula 3 with malonic acid ester in the presence of an organic base to prepare a compound of formula 4, B) hydrogenation of a compound of Formula 4 under a palladium catalyst to prepare a compound of Formula 5, and then acylation with an arylamine (R ₁ -NH ₂ ) to prepare a compound of Formula 6 (Q = ethyl) To acylate the compound of Formula 4 directly with arylamine to produce a compound of Formula 6 (Q = vinyl), C) treating the compound of formula 6 with an inorganic salt to convert it to an organic acid of formula 7, D) A process for preparing the benzhydroxyamide derivative of formula 1 according to claim 1 comprising acylation of a compound of formula 7 with a protected hydroxyamine followed by deprotection: Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Formula 1 Wherein R ₁ is as defined in claim 1 and Q is vinyl or ethyl. The method of claim 1, A) reacting a compound of formula 8 with t-butylacrylate to prepare a hydroxy compound of formula 9, B) reacting a compound of formula 9 with acetylchloride or acetic anhydride to prepare a compound of formula 10, C) it is converted to a compound of formula 11 by hydrogenation with an organometallic hydride, D) Hydrogenation of a compound of Formula 11 under a palladium catalyst followed by hydrolysis to prepare a compound of Formula 12, followed by an acylation reaction with arylamine (R ₁ -NH ₂ ) to formula 13 (Q = 2-propyl) To prepare a compound of Formula 11 or by reacting with a arylamine (R ₁ -NH ₂ ) by hydrolysis of the compound of formula 11 to prepare a compound of formula 13 (Q = 2-propenyl), E) treating the compound of formula 13 with an inorganic salt to convert it to an organic acid of formula 14, F) A process for preparing the benzhydroxyamide derivative of formula 1 according to claim 1 comprising acylation with a protected hydroxyamine followed by deprotection: Formula 8 Formula 9 Formula 10 Formula 11 Formula 12 Formula 13 Formula 14 Formula 1 Wherein R ₁ is as defined in claim 1 and Q is 2-propenyl or 2-propyl. The method of claim 4 or 5, wherein the inorganic salt is sodium hydroxide or lithium hydroxide. 6. Process according to claim 4 or 5, characterized in that the protected hydroxyamine is hydroxyamine protected with t-butylsilyl or benzyl. An anticancer composition comprising as an active ingredient a benzhydroxyamide derivative of formula 1 and a pharmaceutically acceptable carrier.