KR100519010B1 - 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 and R ₂ are each independently aryl or heteroaryl unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl and nitro, wherein The heteroaryl includes one or more nitrogen or oxygen in the ring.

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 chromaffin. 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 conducted (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 and R ₂ are each independently aryl or heteroaryl unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl and nitro, wherein The heteroaryl includes one or more nitrogen or oxygen in the ring.

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

Preferred benzhydroxyamide derivatives of formula 1 according to the present invention

4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (3-benzyloxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (quinolin-6-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (anthracene-1-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

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

4- [3- (naphthalen-1-yl oxy) -2- (4-t-butylphenylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (4-methoxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (3,4-dimethoxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (1H-benzimidazol-2-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (naphthalen-1-yl oxy) -2- (1H-pyrazol-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (9H-carbazol-2-yl oxy) -2-phenylcarbamoyl-propenyl] -N-hydroxybenzamide,

4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-4-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (9H-carbazol-2-yl oxy) -2- (naphthalen-1-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (9H-carbazol-2-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide,

4- [3- (biphenyl-4-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide,

4- [3- (dibenzofuran-2-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide, and

4- [3- (isoquinolin-3-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide is mentioned.

Compound of Formula 1 according to the present invention is prepared according to the synthetic route represented by Scheme 1.

Wherein R ₁ and R ₂ are as defined above,

X is a hydroxy protecting group,

Y is a C _1-4 alkyl group.

In Scheme 1, 4- (methoxycarbonyl) benzaldehyde (2) is substituted with alkyl acrylate (e.g. ethyl acrylate, iso) in the presence of 1,4-diazabicyclo [2,2,2] octane (DABCO). Butyl acrylate, t-butyl acrylate) for 5 days to prepare hydroxy compound (3), and then react with phosphorus tribromide (PBr ₃ ) to convert to bromo compound (4), which is then Aryl ether (5) is prepared by reaction with aryl alcohol (R ₁ OH) in an acetone solvent in the presence of potassium carbonate. It is converted to organic acid (6) by ester hydrolysis with an inorganic acid or organic acid (eg hydrochloric acid, sulfuric acid, trifluoroacetic acid (TFA)) in a dichloromethane solvent. This is acylated with arylamine (R ₂ NH ₂ ) to prepare arylamide (7). Hydrolyzing arylamide (7) with an inorganic salt (e.g. lithium hydroxide) in a water soluble alcohol or tetrahydrofuran solvent to produce an organic acid (8), which is then protected hydroxylamine (e.g. t-butyldimethyl Acylation with silyloxyamine to prepare formula (9), which is reacted with an organic acid (eg trifluoroacetic acid (TFA)) in a dichloromethane solvent to give a hydroxy protecting group (eg t-butyldimethylsilyl group) The desired compound of formula 1 is prepared by removing. At this time, the acylation reaction is effectively carried out using an acylating agent such as N-methanesulfonyloxy-6-trifluoro benzotriazole (FMS) in an aprotic solvent such as dimethylformamide.

The compound of formula (2) used in 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.

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, in addition to the active ingredients, diluents (e.g., lactose, dextrose, water, 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 t-butyl-3-hydroxy-2-methylene-3- (4-methoxycarbonylphenyl) propane (Compound (3))

4- (methoxycarbonyl) benzaldehyde (3.3 g, 20 mmol) and t-butylacrylate (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 ethyl 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 = 1/19). This gave 4.1 g (73%) of the title compound as a white solid.

MP 70 ° C .; ¹ H NMR (200 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), 7.82 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 292 (M ⁺ ), 278, 239, 220, 187, 124, 118, 102.

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

T-Butyl-3-hydroxy-2-methylene-3- (4-methoxycarbonylphenyl) propane (994 mg, 3.4 mmol) synthesized in Preparation Example 1 was dissolved in ethyl ether (10 ml), and 0 ° C. After cooling down, phosphorus tribromide (0.35 ml, 3.74 mmol) was added slowly and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was cooled to -10 ° C, ice water was added, extracted with ethyl ether, washed with brine, dried (MgSO ₄ ), filtered, and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluent: ethyl acetate). / Normal hexane = 1/9) to give 831 mg (71%) of the title compound as a light green solid.

MP 78 ° C .; 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.

Example 1 4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide (Compound (1))

Step (1-1): 4- [3- (naphthalen-1-yl oxy) -2-t-butoxycarbonylpropenyl] benzoic acid methyl ester (Compound (5))

4- (3-bromo-2-t-butoxycarbonylpropenyl) benzoic acid methyl ester (355 mg, 1.00 mmol) synthesized in Preparation Example 2 was dissolved in acetone (5 ml), and then potassium carbonate. (207 mg, 1.50 mmol) and 1-naphthalenol (144 mg 1.00 mmol) were added and boiled for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure at room temperature, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / normal hexane = 1/9) to obtain 441 mg (100%) 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).

Step (1-2): 4- [3- (naphthalen-1-yl oxy) -2-carboxypropenyl] benzoic acid methyl ester (Compound (6))

4- [3- (naphthalen-1-yloxy) -2-t-butoxycarbonylpropenyl] benzoic acid methyl ester (372 mg, 0.89 mmol) in dichloromethane After dissolving in (12 ml), trifluoroacetic acid (0.90 ml, 1.00 mmol) was added slowly at 0 ° C. and reacted at room temperature for 30 minutes. When the reaction was completed, the solvent was removed under reduced pressure at room temperature, and the remaining residue was purified by adding extra dichloroethane to give 315 mg (98%) of the title compound as a brown solid.

Step (1-3): 4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] benzoic acid methyl ester (Compound (7))

4- [3- (naphthalen-1-yloxy) -2-carboxypropenyl] benzoic acid methyl ester (150 mg, 0.414 mmol) was dissolved in dimethylformamide (2 ml) and cooled to 0 ° C., followed by triethylamine (87 μl, 0.621 mmol) and N-methanesulfonyloxy-6-trifluoro benzotriazole (140 mg, 0.497 mmol) were added and stirred at 0 ° C. for 30 minutes, followed by aniline (46 μl, 0.497 mmol) Was added slowly and stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was cooled to room temperature, ice-water was added, extracted with ethyl acetate, washed with 1N hydrochloric acid solution, sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, the solvent was removed under reduced pressure, and the remaining residue was purified by silica gel column chromatography. Purification (eluent: ethyl acetate / normal hexane = 1/4) gave 171 mg (91%) of the title compound as a pale yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.90 (S, 3H, OCH ₃ ), 5.10 (S, 2H, CH ₂ ), 6.83 (d, 1H J = 6.9 Hz, ArH), 7.10 (m, 1H, ArH), 7.26-7.82 (m, 10H, ArH), 7.88 (m, 1H, ArH), 8.05 (m, 3H, ArH), 8.34 (m, 1H, ArH).

Step (1-4): 4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] benzoic acid (compound (8))

4- [3- (naphthalen-1-yloxy) -2-phenylcarbamoylpropenyl] benzoic acid methyl ester (148 mg, 0.338 mmol) was dissolved in 30% aqueous ethanol solution (2 ml), followed by dihydrate lithium hydroxide (71 mg, 1.692 mmol) and tetrahydrofuran (2 ml) were added and stirred at room temperature for 10 minutes and at 50 ° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, ice-water was added, the solvent was removed under reduced pressure, cooled to 5 ° C, acidified with 2N hydrochloric acid solution (pH 2), filtered, dried over anhydrous magnesium sulfate, and 125 mg of the target compound as a white solid ( 87%).

Step (1-5): 4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] -N-t-butyldimethylsilyloxybenzamide (Compound (9))

4- [3- (naphthalen-1-yloxy) -2-phenylcarbamoylpropenyl] benzoic acid (100 mg, 0.236 mmol) was dissolved in dimethylformamide (1.5 ml) and cooled to 0 ° C., followed by triethylamine (49 μL, 0.354 mmol) and N-methanesulfonyloxy-6-trifluoro benzotriazole (80 mg, 0.283 mmol) were added and stirred at 0 ° C. for 20 minutes, followed by Nt-butyldimethylsilyloxyamine (52 mg, 0.354 mmol) was added and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, added with ice water, extracted with ethyl acetate, washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the remaining residue was purified by silica gel column chromatography to give a yellow solid as target compound 96 mg (74%) was obtained.

Step (1-6): 4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide (Compound (1))

4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] -N-t-butyldimethylsilyloxybenzamide (96 mg, 0.174 mmol) in dichloromethane After dissolving in (4 ml), trifluoroacetic acid (0.2 ml 1.00 mmol) was added slowly at 0 ° C. and reacted at room temperature for 30 minutes. After the reaction was completed, the solvent was removed under reduced pressure at room temperature, and the remaining residue was purified by silica gel column chromatography to obtain 48 mg (44%) of the title compound as a brown solid.

Example 2: 4- [3- (naphthalen-1-yl oxy) -2- (3-benzyloxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide

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

Example (1-3) of Example 1 using 4- [3- (naphthalen-1-yloxy) -2-carboxy propenyl] benzoic acid methyl ester prepared in step (1-2) of Example 1; In the same manner, 229 mg (98%) of the title compound were obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.91 (S, 3H, OCH ₃ ), 4.99 (S, 2H, CH ₂ ), 5.09 (S, 2H, CH ₂ ), 6.73 (m, 1H, ArH), 6.83 (d, 1H J = 6.92 Hz, ArH), 6.99 (m, 1H, ArH), 7.14-7.58 (m, 12H, ArH), 7.89 (m, 1H, ArH), 8.05 (m, 3H, ArH) , 8.35 (m, 1H, ArH), 8.58 (S, 1H, ArH).

Step (2-2): 4- [3- (naphthalen-1-yl oxy) -2- (3-benzyloxy-phenylcarbamoyl) propenyl] benzoic acid

Target compound in the same manner as in Step (1-4) of Example 1 using 4- [3- (naphthalen-1-yloxy) -2- (3-benzyloxyphenylcarbamoyl) propenyl] benzoic acid methylester 100 mg (51%) was obtained.

Step (2-3): 4- [3- (naphthalen-1-yl oxy) -2- (3-benzyloxyphenylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

In the same manner as in Example (1-5), 98 mg (83%) of the target compound were synthesized.

Step (2-4): 4- [3- (naphthalen-1-yl oxy) -2- (3-benzyloxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide

31 mg (40%) of the target compound were synthesized in the same manner as in Example (1-6).

MS (EI, 70 eV) m / z 544 (M < + >), 467, 399, 323, 255, 202.

Example 3: 4- [3- (naphthalen-1-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (3-1): 4- [3- (naphthalen-1-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] benzoic acid methyl ester

Example (1-3) of Example 1 using 4- [3- (naphthalen-1-yloxy) -2-carboxypropenyl] benzoic acid methyl ester prepared in step (1-2) of Example 1; In the same manner, 130 mg (33%) of the title compound were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.90 (s, 3H, OCH ₃ ), 5.01 (s, 2H, PhCH ₂ ), 6.89 (d, 2H, J = 7.0 Hz, ArH), 7.51 (m, 5H , ArH), 7.59 (d, 2H, J = 8.4 Hz, ArH), 7.84 (d, 1H, J = 7.8 Hz, ArH), 8.01 (d, 2H, J = 8.4 Hz, ArH), 8.15 (s, 1H, CH), 8.26 (d, 1H, J = 8.4 Hz, ArH).

Step (3-2): 4- [3- (naphthalen-1-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] benzoic acid

105 mg (23%) of the title compound were obtained by the same method as Step (1-4) of Example 1.

Step (3-3): 4- [3- (naphthalen-1-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.2 (S, 9H), 0.8 (S, 6H), 5.05 (S, 2H, CH ₂ ), 7.03-7.16 (m, 3H, ArH), 7.40-7.48 (m, 5H, ArH), 7.60 (m, 2H, ArH), 7.71-7.82 (m, 6H, ArH); MS (LC, 70 eV) m / z 553 (M + l), 439, 425, 142, 139, 102, 101.

Step (3-4): 4- [3- (naphthalen-1-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide

The desired compound (94%) was synthesized in the same manner as in Step (1-6) of Example 1.

¹ H NMR (300 MHz, dmso-d ₆ ) δ5.05 (S, 2H, CH ₂ ), 6.95-7.10 (m, 3H, ArH), 7.36-7.48 (m, 5H, ArH), 7.59 (m, 2H, ArH), 7.71-7.85 (m, 6H, ArH); MS (LC, 70 eV) m / z 440 (M ⁺¹ ), 425, 142, 139, 102, 101.

Example 4: 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (4-1): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] benzoic acid methyl ester

Example (1-3) of Example 1 using 4- [3- (naphthalen-1-yloxy) -2-carboxypropenyl] benzoic acid methyl ester prepared in step (1-2) of Example 1; In the same manner, 436 mg (98%) of the target compound were synthesized.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.88 (S, 3H, OCH ₃ ), 5.14 (S, 2H, CH ₂ ), 6.88 (d, 1H J = 6.9 Hz, ArH), 7.12 (d, 1H J = 6.7 Hz, ArH), 7.17 to 7.57 (m, 11H, ArH), 7.88 (d, 2H J = 8.0 Hz, ArH), 8.14 (d, 1H J = 8.9 Hz, ArH), 8.80 (d, 1H J = 7.2 Hz, ArH); MS (EI, 70 eV) m / z 488 (M < + >), 345, 301, 186, 185, 170, 146.

Step (4-2): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] benzoic acid

The desired compound (95%) was synthesized in the same manner as in Step (1-4) of Example 1.

MS (EI, 70 eV) m / z 462 (M < + >), 393, 327, 309, 227, 176, 138, 128.

Step (4-3): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

380 mg (78%) of the target compound were synthesized in the same manner as in Step (1-5) of Example 1.

Step (4-4): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide

122 mg (62%) of the target compound were synthesized in the same manner as in Example (1-6).

Example 5: 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-6-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (5-1): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-6-ylcarbamoyl) propenyl] benzoic acid methyl ester

Example (1-3) of Example 1 using 4- [2-carboxy-3- (naphthalen-1-yl oxy) propenyl] benzoic acid methyl ester prepared in step (1-2) of Example 1; In the same manner, the target compound (81%) was synthesized.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.88 (S, 3H, OCH ₃ ), 5.17 (S, 2H, CH ₂ ), 6.93 (d, 1H J = 7.1 Hz, ArH), 7.15 (d, 1H J = 6.8 Hz, ArH), 7.29-7.07 (m, 11H, ArH), 7.92 (d, 2H J = 8.2 Hz, ArH), 8.16 (d, 1H J = 9.4 Hz, ArH), 8.85 (d, 1H J = 7.4 Hz, ArH); MS (EI, 70 eV) m / z 488 (M < + >), 344, 296, 204, 181, 172, 143.

Step (5-2): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-6-ylcarbamoyl) propenyl] benzoic acid

The target compound (83%) was synthesized in the same manner as in Step (1-4) of Example 1.

MS (EI, 70 eV) m / z 462 (M < + >), 391, 326, 309, 249, 168, 136, 121.

Step (5-3): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-6-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.2 (S, 9H), 0.8 (S, 6H), 5.15 (S, 2H, CH ₂ ), 6.91 (d, 1H, J = 7.1 Hz, CH), 7.15 (d, 1H, J = 7.1 Hz, ArH), 7.24-7.60 (m, 11H, ArH), 7.8-7.9 (d, 2H, J = 8.4 Hz, ArH), 8.1-8.2 (d, 1H, J = 9.0 Hz, ArH), 8.80-8.82 (d, 1H, J = 7.2 Hz, ArH); MS (LC, 70 eV) m / z 603 (M < + >), 489, 476, 465, 441, 413, 391, 377, 301, 279, 204, 149.

Step (5-4): 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-6-ylcarbamoyl) propenyl] -N-hydroxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-6) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ5.15 (S, 2H, CH ₂ ), 6.91 (d, 1H J = 7.1 Hz, CH), 7.13 (d, 1H J = 7.2 Hz, ArH), 7.25- 7.58 (m, 11H, ArH), 7.81-7.90 (d, 2H J = 8.2 Hz, ArH), 8.0-8.2 (d, 1H, J = 6.8 Hz, ArH), 8.69-8.75 (d, 1H, J = 7.2 Hz, ArH); MS (LC, 70 eV) m / z 490 (M + l), 475, 464, 440, 413, 391, 377, 301, 279, 204, 149.

Example 6: 4- [3- (naphthalen-1-yl oxy) -2- (anthracene-1-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (6-1): 4- [3- (naphthalen-1-yl oxy) -2- (anthracene-1-ylcarbamoyl) propenyl] benzoic acid methyl ester

Example (1-3) of Example 1 using 4- [3- (naphthalen-1-yloxy) -2-carboxypropenyl] benzoic acid methyl ester prepared in step (1-2) of Example 1; In the same manner 355 mg (98%) of the title compound were synthesized.

Step (6-2): 4- [3- (naphthalen-1-yl oxy) -2- (anthracene-1-ylcarbamoyl) propenyl] benzoic acid

82 mg (17%) of the target compound were synthesized in the same manner as in Example (1-4).

Step (6-3): 4- [3- (naphthalen-1-yl oxy) -2- (anthracene-1-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The target compound (95%) was obtained by the same method as the step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.2 (S, 9H), 0.8 (S, 6H), 5.04 (S, 2H, CH ₂ ), 7.05-7.09 (m, 3H, ArH), 7.40-7.49 (m, 5H, ArH), 7.62-7.69 (m, 5H, ArH), 7.70-7.90 (m, 8H, ArH); MS (LC, 70 eV) m / z 652 (M < + >), 538, 440, 412, 312, 297, 245, 222, 194, 145, 102.

Step (6-4): 4- [3- (naphthalen-1-yl oxy) -2- (anthracene-1-ylcarbamoyl) propenyl] -N-hydroxybenzamide

The target compound (95%) was obtained by the same method as the step (1-6) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ5.04 (S, 2H, CH ₂ ), 7.01-7.04 (m, 3H, ArH), 7.35-7.41 (m, 5H, ArH), 7.52-7.64 (m, 5H, ArH), 7.69-7.88 (m, 8H, ArH); MS (LC, 70 eV) m / z 539 (M + l), 440, 412, 312, 297, 245, 222, 194, 145, 101.

Example 7: 4- [2- (naphthalen-1-yloxymethyl) -3-oxo-3- (3,4-dihydro-1H-isoquinolin-2-yl) propenyl] -N-hydroxy Benzamide

Step (7-1): 4- [2- (naphthalene-6-ylcarbamoyl) -3-oxo-3- (3,4-dihydro-1H-isoquinolin-2-yl) propenyl] benzoic acid methyl ester

Example (1-3) of Example 1 using 4- [3- (naphthalen-1-yloxy) -2-carboxypropenyl] benzoic acid methyl ester prepared in step (1-2) of Example 1; In the same manner, the target compound (80%) was synthesized.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.81 (d, 1H J = 6.9 Hz), 3.29 (d, 1H J = 7.9 Hz), 3.86 (S, 3H, OCH ₃ ), 4.22 (S, 1H), 4.82 (S, 2H, CH ₂ ), 6.64 (d, 1H J = 6.9 Hz, ArH), 7.02 (m, 4H, ArH), 7.23-7.48 (m, 7H, ArH), 7.66 (d, 1H J = 7.2 Hz, Ar), 7.92 (d, 2H J = 7.9 Hz, Ar), 8.17 (d, 1H J = 7.3 Hz, Ar); MS (EI, 70 eV) m / z 477 (M < + >), 345, 334, 303, 202, 134, 132.

Step (7-2): 4- [2- (naphthalen-1-yloxymethyl) -3-oxo-3- (3,4-dihydro-1H-isoquinolin-2-yl) propenyl] benzoic acid

The desired compound (96%) was synthesized in the same manner as in Step (1-4) of Example 1.

Mass (EI, 70 eV) m / z 463 (M +), 397, 331, 321, 216, 189, 148, 132.

Step (7-3): 4- [2- (naphthalen-1-yloxymethyl) -3-oxo-3- (3,4-dihydro-1H-isoquinolin-2-yl) propenyl] -Nt -Butyldimethylsilyloxybenzamide

The target compound (95%) was obtained by the same method as the step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.2 (S, 9H), 0.8 (S, 6H), 2.81-2.82 (d, 1H, J = 6.4 Hz), 3.27-3.29 (d, 1H, J = 7.8 Hz), 4.20 (S, 1H), 4.78 (S, 2H, CH ₂ ), 6.63-6.65 (d, 1H, J = 6.8 Hz, ArH), 6.91-7.22 (m, 4H, ArH), 7.25- 7.52 (m, 7H, ArH), 7.65-7.68 (d, 1H, J = 7.6 Hz, ArH), 7.92-7.94 (d, 2H, J = 7.8 Hz, ArH), 8.17-8.20 (d, 1H, J = 7.4 Hz, ArH); MS (LC, 70 eV) m / z 592 (M < + >), 464, 440, 204, 156, 142, 139, 116.

Step (7-4): 4- [2- (naphthalen-1-yloxymethyl) -3-oxo-3- (3,4-dihydro-1H-isoquinolin-2-yl) propenyl] -N Hydroxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-6) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ2.81-2.82 (d, 1H, J = 6.6 Hz), 3.25-3.27 (d, 1H, J = 7.6 Hz), 4.18 (S, 1H), 4.60 (S , 2H, CH ₂ ), 6.70-6.75 (d, 1H, J = 6.8 Hz, ArH), 6.91-7.21 (m, 4H, ArH), 7.23-7.42 (m, 7H, ArH), 7.67-7.68 (d , 1H, J = 7.6 Hz, ArH), 7.92-7.94 (d, 2H, J = 7.8 Hz, ArH), 8.17-8.20 (d, 1H, J = 7.6 Hz, ArH); MS (LC, 70 eV) m / z 479 (M + l), 464, 335, 320, 245, 204, 189.

Example 8: 4- [3- (naphthalen-1-yl oxy) -2- (4-t-butylphenylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (8-1): 4- [3- (naphthalen-1-yl oxy) -2- (4-t-butyl-phenylcarbamoyl) propenyl] benzoic acid methyl ester

Example (1-3) of Example 1 using 4- [3- (naphthalen-1-yloxy) -2-carboxypropenyl] benzoic acid methyl ester prepared in step (1-2) of Example 1; In the same manner, the target compound (77%) was synthesized.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 (S, 9H), 3.90 (S, 3H, OCH ₃ ), 5.08 (S, 2H, CH ₂ ), 6.83 (d, 1H J = 7.4 Hz), 7.18 ~ 7.36 (m, 6H, ArH), 7.41 (d, 2H J = 8.2 Hz), 7.56 (d, 2H J = 8.2 Hz), 7.98 (d, 2H J = 8.6 Hz), 8.27 (d, 1H J = 7.4 Hz); MS (EI, 70 eV) m / z 493 (M < + >), 350, 345, 326, 295, 200, 190, 150.

Step (8-2): 4- [3- (naphthalen-1-yl oxy) -2- (4-t-butyl-phenylcarbamoyl) propenyl] benzoic acid

The desired compound (89%) was synthesized in the same manner as in Step (1-4) of Example 1.

MS (EI, 70 eV) m / z 479 (M < + >), 428, 382, 336, 280, 214, 190, 150, 116.

Step (8-3): 4- [3- (naphthalen-1-yl oxy) -2- (4-t-butyl-phenylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-5) of Example 1.

Step (8-4): 4- [3- (naphthalen-1-yl oxy) -2- (4-t-butyl-phenylcarbamoyl) propenyl] -N-hydroxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-6) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.31 (S, 9H), 5.09 (S, 2H, CH ₂ ), 6.80-6.82 (d, 1H, J = 6.8 Hz), 7.18-7.24 (m, 6H , ArH), 7.40-7.42 (d, 2H, J = 7.4Hz, ArH), 7.48-7.49 (d, 2H, J = 7.2Hz, ArH), 7.88-7.92 (d, 2H, J = 8.0Hz, ArH ), 8.24-8.26 (d, 1H, J = 7.4 Hz, ArH); MS (LC, 70 eV) m / z 495 (M + 1), 480, 458, 443, 419, 399, 397, 391, 351, 309, 295, 279, 204, 149, 130, 113

Example 9: 4- [3- (naphthalen-1-yl oxy) -2- (4-methoxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (9-1): 4- [3- (naphthalen-1-yl oxy) -2- (4-methoxy-phenylcarbamoyl) propenyl] -benzoic acid methyl ester

Example 1 step (1-3) using 4- [3- (naphthalen-1-yl oxy) -2-carboxy-propenyl] -benzoic acid methylester prepared in step (1-2) of example 1 The desired compound (95%) was synthesized in the same manner as).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.84 (S, 3H. OCH ₃ ), 3.92 (S, 3H, OCH ₃ ), 5.11 (S, 2H, PhCH ₂ ), 6.85 (m, 2H ArH), 7.48 (m, 10H, ArH), 7.88 (d, 1H J = 9.2 Hz), 8.02 (s, 1H), 8.06 (d, 2H J = 8.2 Hz), 8.36 (s, 1H); MS (EI, 70 eV) m / z 467 (M < + >), 344, 285, 257, 231, 202, 181, 152, 123, 108, 80, 53.

Step (9-2): 4- [3- (naphthalen-1-yl oxy) -2- (4-methoxy-phenylcarbamoyl) propenyl] -benzoic acid

The desired compound (95%) was synthesized in the same manner as in Step (1-4) of Example 1.

Step (9-3): 4- [3- (naphthalen-1-yl oxy) -2- (4-methoxy-phenylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.2 (S, 9H), 0.8 (S, 6H), 3.92 (S, 3H, OCH ₃ ), 5.03 (S, 2H, CH ₂ ), 7.05-7.18 ( m, 3H, ArH), 7.34-7.42 (m, 5H, ArH), 7.61-7.63 (d, 2H, J = 7.2 Hz, ArH), 7.73-7.78 (m, 6H, ArH); MS (LC, 70 eV) m / z 582 (M < + >), 440, 351, 269, 204, 187, 179, 116, 101.

Step (9-4): 4- [3- (naphthalen-1-yl oxy) -2- (4-methoxy-phenylcarbamoyl) propenyl] -N-hydroxybenzamide

The desired compound (94%) was synthesized in the same manner as in Step (1-6) of Example 1.

¹ H NMR (300 MHz, dmso-d ₆ ) δ3.92 (S, 3H, OCH ₃ ), 5.03 (S, 2H, CH ₂ ), 7.10-7.21 (m, 3H, ArH), 7.38-7.48 (m , 5H, ArH), 7.60-7.62 (d, 2H, J = 7.2 Hz, ArH), 7.75-7.82 (m, 6H, ArH); MS (LC, 70 eV) m / z 469 (M + l), 440, 351, 269, 187, 116, 101.

Example 10 4- [3- (naphthalen-1-yl oxy) -2- (3,4-dimethoxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (10-1): 4- [3- (naphthalen-1-yl oxy) -2- (3,4-dimethoxy-phenylcarbamoyl) -propenyl] -benzoic acid methyl ester

Example 1 step (1-3) using 4- [3- (naphthalen-1-yl oxy) -2-carboxypropenyl] -benzoic acid methylester prepared in step (1-2) of example 1 In the same manner as the target compound (87%) was synthesized.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.80 (S, 3H. OCH ₃ ), 3.85 (S, 3H. OCH ₃ ), 3.93 (S, 3H, OCH ₃ ), 5.13 (S, 2H, PhCH ₂ ) , 6.77 (d, 2H, J = 8.1 Hz, ArH), 6.85 (d, 2H, J = 7.5 Hz, ArH), 6.92 (d, 2H, J = 2.4 Hz, ArH), 7.29 (d, 2H J = 6.0 Hz, ArH), 7.40 (t, 1H J = 8.1 Hz, ArH), 7.48 (d, 2H J = 8.1 Hz, ArH), 7.57 (m, 7H, ArH), 7.89 (d, 1H J = 9.3 Hz , ArH), 8.07 (t, 4H, J = 8.1 Hz, ArH, CH).

Step (10-2): 4- [3- (naphthalen-1-yl oxy) -2- (3,4-dimethoxy-phenylcarbamoyl) propenyl] -benzoic acid

The desired compound (93%) was synthesized in the same manner as in Step (1-4) of Example 1.

Step (10-3): 4- [3- (naphthalen-1-yl oxy) -2- (3,4-dimethoxy-phenylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.2 (S, 9H), 0.8 (S, 6H), 3.94 (S, 6H, OCH ₃ ), 5.09 (S, 2H, CH ₂ ), 7.05-7.22 ( t, 3H, J = 7.8 Hz, 6.0 Hz, ArH), 7.28-7.38 (m, 5H, ArH), 7.58-7.60 (d, 2H, J = 7.8 Hz, ArH), 7.75-7.82 (m, 6H, ArH); MS (LC, 70 eV) m / z 612 (M < + >), 484, 462, 441, 363, 301, 295, 269, 187, 142, 116, 105, 102.

Step (10-4): 4- [3- (naphthalen-1-yl oxy) -2- (3,4-dimethoxy-phenylcarbamoyl) propenyl] -N-hydroxybenzamide

The desired compound (94%) was synthesized in the same manner as in Step (1-6) of Example 1.

¹ H NMR (300 MHz, dmso-d ₆ ) δ 3.94 (S, 6H, OCH ₃ ), 5.09 (S, 2H, CH ₂ ), 7.05-7.22 (t, 3H, J = 7.8 Hz, 6.0 Hz, ArH), 7.28-7.38 (m, 5H, ArH), 7.58-7.60 (d, 2H, J = 7.8 Hz, ArH), 7.75-7.82 (m, 6H, ArH); MS (LC, 70 eV) m / z 499 (M + l), 484, 462, 440, 351, 301, 269, 187, 142, 116, 105, 101.

Example 11 4- [3- (naphthalen-1-yl oxy) -2- (1H-benzimidazol-2-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (11-1): 4- [3- (naphthalen-1-yl oxy) -2- (1H-benzimidazol-2-ylcarbamoyl) -propenyl] -benzoic acid methyl ester

Example 1 step (1-3) using 4- [3- (naphthalen-1-yl oxy) -2-carboxy-propenyl] -benzoic acid methylester prepared in step (1-2) of example 1 The desired compound (36%) was synthesized in the same manner as).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.86 (S, 3H. OCH ₃ ), 4.99 (S, 2H, PhCH ₂ ), 6.86 (d, 1H, J = 7.4 Hz, ArH), 7.48 (m, 7H, ArH), 8.06 (d, 2H J = 8.6 Hz, ArH), 8.12 (S, 1H, CH).

Step (11-2): 4- [3- (naphthalen-1-yl oxy) -2- (1H-benzimidazol-2-ylcarbamoyl) propenyl] -benzoic acid

The desired compound (78%) was synthesized in the same manner as in Step (1-4) of Example 1.

Step (11-3): 4- [3- (naphthalen-1-yl oxy) -2- (1H-benzimidazol-2-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.2 (S, 9H), 0.8 (S, 6H), 5.01 (S, 2H, CH ₂ ), 7.05-7.13 (t, 3H, J = 8.4 Hz, 6.4 Hz, ArH), 7.36-7.42 (d, 5H, J = 7.2 Hz, ArH), 7.58-7.64 (m, 2H, ArH), 7.74-7.80 (m, 6H, ArH); MS (LC, 70 eV) m / z 592 (M < + >), 478, 440, 401, 308, 295, 241, 197, 174, 160, 146, 138, 119, 94, 75.

Step (11-4): 4- [3- (naphthalen-1-yl oxy) -2- (1H-benzimidazol-2-ylcarbamoyl) propenyl] -N-hydroxybenzamide

The target compound (95%) was obtained by the same method as the step (1-6) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ5.02 (S, 2H, CH ₂ ), 7.02-7.11 (t, 3H, J = 8.4 Hz, 6.4 Hz, ArH), 7.34-7.38 (d, 5H, J = 7.2 Hz, ArH), 7.60-7.64 (m, 2H, ArH), 7.76-7.80 (m, 6H, ArH); MS (LC, 70 eV) m / z 479 (M + l), 440, 401, 308, 295, 241, 197, 174, 160, 146, 138, 119, 94, 75.

Example 12 4- [3- (naphthalen-1-yl oxy) -2- (1H-pyrazol-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (12-1): 4- [3- (naphthalen-1-yl oxy) -2- (1H-pyrazol-3-ylcarbamoyl) propenyl] -benzoic acid methyl ester

Example 1 step (1-3) using 4- [3- (naphthalen-1-yl oxy) -2-carboxypropenyl] -benzoic acid methylester prepared in step (1-2) of example 1 In the same manner as the target compound (64%) was synthesized.

¹ H NMR (200 MHz, acetone-d ₆ ) δ 3.88 (S, 3H. OCH ₃ ), 5.18 (S, 2H, PhCH ₂ ), 5.93 (d, 1H, J = 2.8 Hz, ArH), 6.79 ( de, 1H J = 1.0, 7.4 Hz, ArH), 7.48 (m, 5H, ArH), 7.56 (d, 2H, J = 8.8 Hz, ArH), 7.79 (S, 2H, ArH, CH), 8.06 (d , 2H, J = 8.8 Hz, ArH), 8.13 (d, 1H, J = 1.0 Hz, ArH).

Step (12-2): 4- [3- (naphthalen-1-yl oxy) -2- (1H-pyrazol-3-ylcarbamoyl) propenyl] -benzoic acid

124 mg (73%) of the title compound was synthesized in the same manner as in Example (1-4).

Step (12-3): 4- [3- (naphthalen-1-yl oxy) -2- (1H-pyrazol-3-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-5) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ0.2 (S, 9H), 0.8 (S, 6H), 5.04 (S, 2H, CH ₂ ), 6.98-7.11 (d, 3H, J = 6.8 Hz, ArH ), 7.22-7.34 (m, 3H, ArH), 7.55-7.61 (m, 2H, ArH), 7.80-7.82 (m, 6H, ArH); MS (LC, 70 eV) m / z 542 (M < + >), 428, 413, 400, 391, 386, 364, 331, 279, 204, 149, 145.

Step (12-4): 4- [3- (naphthalen-1-yl oxy) -2- (1H-pyrazol-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide

The desired compound (95%) was synthesized in the same manner as in Step (1-6) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ5.04 (S, 2H, CH ₂ ), 7.02-7.10 (d, 3H, J = 6.8 Hz, ArH), 7.28-7.36 (m, 3H, ArH), 7.58 -7.65 (m, 2H, ArH), 7.82-7.85 (m, 6H, ArH); MS (LC, 70 eV) m / z 428 (M < + >), 414, 405, 399, 386, 364, 331, 279, 204, 149, 145.

Example 13: 4- [3- (9H-carbazol-2-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide

Step (13-1): 4- [3- (9H-carbazol-2-yl oxy) -2-t-butoxycarbonyl-propenyl] -benzoic acid methyl ester

4- (3-Bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester synthesized in Preparation Example 2 was used, and 2-carbazole was used instead of 1-naphthalenol. 244 mg (100%) of the title compound was synthesized in the same manner as in step (1-1).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.53 (S, 9H, OCH ₃ ), 3.90 (S, 3H, CH ₂ ), 4.86 (S, 2H, CH ₂ ), 6.90 (d, 1H J = 8.5 Hz, ArH), 6.95 (d, 1H J = 11.5 Hz, ArH), 7.29 (m, 2H, ArH), 7.35 (m, 3H, ArH), 7.57 (d, 1H J = 8.3 Hz, ArH), 7.98 (m, 1H, ArH).

Step (13-2): 4- [3- (9H-carbazol-2-yl oxy) -2-carboxy-propenyl] -benzoic acid methylester

204 mg (100%) of the target compound were synthesized in the same manner as in Step (1-2) of Example 1.

Step (13-3): 4- [3- (9H-carbazol-2-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid methyl ester

212 mg (89%) of the target compound were synthesized in the same manner as in Step (1-3) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.91 (S, 2H, OCH ₃ ), 4.99 (S, 2H, CH ₂ ), 6.90 (m, 2H, ArH), 7.29 (m, 8H, ArH), 7.60 (m, 2H, ArH), 8.00 (m, 6H, ArH).

Step (13-4): 4- [3- (9H-carbazol-2-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid

146 mg (80%) of the title compound was synthesized in the same manner as in Example (1-4).

Step (13-5): 4- [3- (9H-carbazol-2-yl oxy) -2-phenylcarbamoylpropenyl] -N-t-butyldimethylsilyloxybenzamide

127 mg (76%) of the target compound were synthesized in the same manner as in Step (1-5) of Example 1.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.24 (S, 6H, OCH ₃ ), 1.00 (S, 3H, OCH ₃ ), 4.96 (d, 2H J = 3.83 Hz, CH ₂ ), 6.91 (m, 1H , ArH), 7.17 (m, 1H, ArH), 7.40 (m, 7H, ArH), 7.64 (m, 3H, ArH), 7.92 (m, 4H, ArH), 8.13 (m, 3H, ArH).

Step (13-6): 4- [3- (9H-carbazol-2-yl oxy) -2-phenylcarbamoyl-propenyl] -N-hydroxy-benzamide

48 mg (44%) of the target compound were synthesized in the same manner as in Example (1-6).

Example 14 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (14-1): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -benzoic acid methyl ester

Example 1 step (1) using 4- [3- (9H-carbazol-2-yl oxy) -2-carboxypropenyl] -benzoic acid methylester prepared in step (13-2) of Example 13 The desired compound was synthesized in the same manner as in -3).

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.91 (S, 3H, OCH ₃ ), 5.12 (S, 2H, CH ₂ ), 6.82 (m, 1H, ArH), 7.22 to 7.58 (m, 6H, ArH) , 7.88 (m, 1H, ArH), 8.02-8.14 (m, 5H, ArH), 8.31 (m, 2H, ArH), 8.52 (m, 1H, ArH).

Step (14-2): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -benzoic acid

In the same manner as in Example (1-4), 76 mg of the target compound (crude product) was synthesized.

Step (14-3): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

20 mg of the target compound was synthesized in the same manner as in Example (1-5).

Step (14-4): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide

20 mg of the target compound was synthesized in the same manner as in Step (1-6) of Example 1.

Example 15 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-4-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (15-1): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-4-ylcarbamoyl) propenyl] -benzoic acid methyl ester

Example 1 step (1) using 4- [3- (9H-carbazol-2-yl oxy) -2-carboxypropenyl] -benzoic acid methylester prepared in step (13-2) of Example 13 241 mg of crude product was synthesized in the same manner as in −3).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.95 (S, 3H, OCH ₃ ), 4.86 (S, 2H, CH ₂ ), 6.82 (m, 2H, ArH), 6.91-7.83 (m, 8H, ArH ), 8.04 (m, 1H, ArH).

Step (15-2): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-4-ylcarbamoyl) propenyl] -benzoic acid

74 mg of the target compound was synthesized in the same manner as in Example (1-4).

Step (15-3): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-4-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

20 mg of the target compound was synthesized in the same manner as in Example (1-5).

Step (15-4): 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-4-ylcarbamoyl) propenyl] -N-hydroxybenzamide

20 mg of the target compound was synthesized in the same manner as in Example (1-6).

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.92 (S, 2H, CH ₂ ), 6.85 (m, 1H, ArH), 7.00 (m, 3H, ArH), 7.30 to 8.02 (m, 12H, ArH).

Example 16: 4- [3- (9H-carbazol-2-yl oxy) -2- (naphthalen-1-ylcarbamoyl) propenyl] -N-hydroxy-benzamide

Step (16-1): 4- [3- (9H-carbazol-2-yl oxy) -2- (naphthalen-1-ylcarbamoyl) propenyl] -benzoic acid methyl ester

Example 1 step (1) using 4- [3- (9H-carbazol-2-yl oxy) -2-carboxypropenyl] -benzoic acid methylester prepared in step (13-2) of Example 13 455 mg of the target compound was synthesized in the same manner as in −3).

¹ H NMR (200 MHz, CD ₃ OD) δ 3.95 (S, 3H, OCH ₃ ), 4.89 (S, 2H, CH ₂ ), 6.92 (m, 1H, ArH), 7.12 (m, 2H, ArH), 7.24-7.58 (m, 5H, ArH), 7.70 (m, 2H, ArH), 7.82-6.29 (m, 8H, ArH).

Step (16-2): 4- [3- (9H-carbazol-2-yl oxy) -2- (naphthalen-1-ylcarbamoyl) propenyl] -benzoic acid

109 mg of the target compound were synthesized in the same manner as in Step (1-4) of Example 1.

Step (16-3): 4- [3- (9H-carbazol-2-yl oxy) -2- (naphthalen-1-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

54 mg of the target compound was synthesized in the same manner as in Example (1-5).

Step (16-4): 4- [3- (9H-carbazol-2-yl oxy) -2- (naphthalen-1-ylcarbamoyl) propenyl] -N-hydroxybenzamide

34 mg of the target compound was synthesized in the same manner as in Example (1-6).

Example 17 4- [3- (9H-carbazol-2-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide

Step (17-1): 4- [3- (9H-carbazol-2-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -benzoic acid methyl ester

Example 1 step (1) using 4- [3- (9H-carbazol-2-yl oxy) -2-carboxypropenyl] -benzoic acid methylester prepared in step (13-2) of Example 13 280 mg of the target compound was synthesized in the same manner as in -3).

¹ H NMR (200 MHz, CDCl ₃ ) δ3.92 (S, 2H, OCH ₃ ), 5.09 (S, 2H, CH ₂ ), 7.09 ~ 7.62 (m, 11H, ArH), 8.05 (m, 6H, ArH ), 8.89 (m, 1 H, ArH).

Step (17-2): 4- [3- (9H-carbazol-2-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -benzoic acid

226 mg of the target compound was synthesized in the same manner as in Step (1-4) of Example 1.

Step (17-3): 4- [3- (9H-carbazol-2-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-t-butyldimethylsilyloxybenzamide

132 mg of the target compound were synthesized in the same manner as in Step (1-5) of Example 1.

Step (17-4): 4- [3- (9H-carbazol-2-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide

116 mg of the target compound was synthesized in the same manner as in Step (1-6) of Example 1.

Example 18 4- [3- (biphenyl-4-yloxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide

Step (18-1): 4- [3- (biphenyl-4-yl oxy) -2-t-butoxycarbonylpropenyl] -benzoic acid methyl ester

Example using 4- (3-bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester synthesized in Preparation Example 2 and using biphenyl-4-ol instead of 1-naphthalenol The target compound (56%) was obtained by the same method as Step (1-1) in 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.45 (s, 9H), 3.79 (s, 3H), 4.80 (s, 2H), 6.89 (d, 1H, J = 6.8 Hz), 7.34 (m, 1H ), 7.64 (d, 2H, J = 7.8 Hz), 7.83 (d, 2H, J = 7.8 Hz), 7.92 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 444 (M < + >), 405, 347, 321, 259, 205, 169, 121.

Step (18-2): 4- (3-biphenyl-4-yl-2-carboxypropenyl) -benzoic acid methyl ester

In the same manner as in step (1-2) of Example 1, the target compound of the white solid was synthesized and used directly in the subsequent reaction.

Step (18-3): 4- [3- (biphenyl-4-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid methyl ester

In the same manner as in Step (1-3) of Example 1, the target compound (68%) was obtained as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ3.82 (s, 3H), 4.80 (s, 2H), 7.22 (m, 3H), 7.47 (d, 2H, J = 7.6 Hz), 7.78 (d, 2H , J = 7.6 Hz), 7.89 (d, 2H, J = 8.2 Hz); MS (EI, 70 eV) m / z 463 (M < + >), 452, 412, 367, 311, 289, 226, 210, 124.

Step (18-4): 4- [3- (biphenyl-4-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid

The desired compound (98%) as a white solid was synthesized in the same manner as in step (1-4) of Example 1.

Step (18-5): 4- [3- (biphenyl-4-yl oxy) -2-phenylcarbamoylpropenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound (98%) was synthesized in the same manner as in Step (1-5) of Example 1.

Step (18-6): 4- [3- (biphenyl-4-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide

The desired compound (40%) was synthesized in the same manner as in Step (1-6) of Example 1.

Example 19 4- [3- (dibenzofuran-2-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide

Step (19-1): 4- [3- (dibenzofuran-2-yl oxy) -2-t-butoxycarbonylpropenyl] -benzoic acid methyl ester

4- (3-bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester synthesized in Production Example 2 was used, and dibenzofuran-2-ol was used instead of 1-naphthalenol. The target compound (70%) was obtained by the same method as Step (1-1) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.49 (s, 9H), 3.88 (s, 3H), 4.80 (s, 2H), 6.87 (d, 1H, J = 6.6 Hz), 7.06 (s, 1H ), 7.34 (m, 3H), 7.85 (d, 2H, J = 7.6 Hz), 7.90 (d, 2H, J = 8.0 Hz); MS (EI, 70 eV) m / z 458 (M < + >), 452, 427, 394, 341, 279, 239, 210, 129.

Step (19-2): 4- [3- (dibenzofuran-2-yl oxy) -2-carboxypropenyl] -benzoic acid methyl ester

Synthesis was carried out in the same manner as in Step (1-2) of Example 1 and immediately used in the subsequent reaction.

Step (19-3): 4- [3- (dibenzofuran-2-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid methyl ester

The target compound (84%) was synthesized in the same manner as in Step (1-3) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.76 (s, 3H), 4.82 (s, 2H), 6.49 (s, 1H), 7.30 (m, 7H), 7.72 (d, 2H, J = 7.4 Hz ), 7.94 (d, 2H, J = 8.2 Hz); MS (EI, 70 eV) m / z 477 (M < + >), 435, 396, 367, 311, 294, 239, 217, 116.

Step (19-4): 4- [3- (dibenzofuran-2-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid

The desired compound (89%) was synthesized in the same manner as in Step (1-4) of Example 1.

MS (EI, 70 eV) m / z 463 (M < + >), 431, 395, 367, 313, 266, 223, 198. 124.

Step (19-5): 4- [3- (dibenzofuran-2-yl oxy) -2-phenylcarbamoyl-propenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound was synthesized in the same manner as in Step (1-5) of Example 1.

Step (19-6): 4- [3- (dibenzofuran-2-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide

The desired compound was synthesized in the same manner as in Step (1-6) of Example 1.

Example 20 4- [3- (isoquinolin-3-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide

Step (20-1): 4- [3- (isoquinolin-3-yl oxy) -2-t-butoxycarbonylpropenyl] -benzoic acid methyl ester

Example using 4- (3-bromo-2-t-butoxycarbonylpropenyl) -benzoic acid methyl ester synthesized in Preparation Example 2 and isoquinolin-3-ol instead of 1-naphthalenol The target compound (48%) was obtained by the same method as Step (1-1) in 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ1.43 (s, 9H), 3.84 (s, 3H), 4.79 (s, 2H), 7.09 (s, 1H), 7.61 (m, 2H), 7.87 (d , 2H, J = 7.6 Hz), 8.88 (s, 1H); MS (EI, 70 eV) m / z 435 (M < + >), 413, 367, 331, 289, 268, 235, 210, 109.

Step (20-2): 4- [3- (isoquinolin-3-yl oxy) -2-carboxypropenyl] -benzoic acid methyl ester

In the same manner as in Example (1-2), the target compound was synthesized and used directly in the subsequent reaction.

Step (20-3): 4- [3- (isoquinolin-3-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid methyl ester

The desired compound (71%) was synthesized in the same manner as in Step (1-3) of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.89 (s, 3H), 4.81 (s, 2H), 6.52 (s, 1H), 7.01 (s, 1H), 7.48 (m, 5H), 7.68 (d , 2H, J = 7.6 Hz), 7.88 (d, 2H, J = 7.8 Hz), 8.77 (s, 1H); MS (EI, 70 eV) m / z 438 (M < + >), 381, 376, 331, 289, 267, 235, 181, 116.

Step (20-4): 4- [3- (isoquinolin-3-yl oxy) -2-phenylcarbamoylpropenyl] -benzoic acid

The desired compound (80%) was synthesized in the same manner as in Step (1-4) of Example 1.

MS (EI, 70 eV) m / z 424 (M < + >), 412, 372, 311, 280, 226, 210, 163, 114.

Step (20-5): 4- [3- (isoquinolin-3-yl oxy) -2-phenylcarbamoylpropenyl] -N-t-butyldimethylsilyloxybenzamide

The desired compound was synthesized in the same manner as in Step (1-5) of Example 1.

Step (20-6): 4- [3- (isoquinolin-3-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide

The desired compound was synthesized in the same manner as in Step (1-6) of Example 1.

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 the DAC reacts with the 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 steps, A, B, and C. ).

HDAC Inhibitory Activity (IC ₅₀ ) Test Results compound Active degree compound Active degree Example 1 A Example 12 B Example 2 B Example 13 A Example 3 A Example 14 B Example 4 B Example 15 B Example 9 A Example 16 B Example 10 A Example 19 B Example 11 B SAHA B

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 (4)

Benzhydroxyamide derivatives of the general formula Formula 1 Where R ₁ and R ₂ are each independently aryl or heteroaryl unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl and nitro, wherein The heteroaryl includes one or more nitrogen or oxygen in the ring. The method of claim 1, 4- [3- (naphthalen-1-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (3-benzyloxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (quinolin-6-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (anthracene-1-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [2- (naphthalen-1-yloxymethyl) -3-oxo-3- (3,4-dihydro-1H-isoquinolin-2-yl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (4-t-butylphenylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (4-methoxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (3,4-dimethoxyphenylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (1H-benzimidazol-2-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (naphthalen-1-yl oxy) -2- (1H-pyrazol-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (9H-carbazol-2-yl oxy) -2-phenylcarbamoyl-propenyl] -N-hydroxybenzamide, 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-3-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (9H-carbazol-2-yl oxy) -2- (pyridin-4-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (9H-carbazol-2-yl oxy) -2- (naphthalen-1-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (9H-carbazol-2-yl oxy) -2- (quinolin-8-ylcarbamoyl) propenyl] -N-hydroxybenzamide, 4- [3- (biphenyl-4-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide, 4- [3- (dibenzofuran-2-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide, and 4- [3- (isoquinolin-3-yl oxy) -2-phenylcarbamoylpropenyl] -N-hydroxybenzamide Benzhydroxyamide derivatives, characterized in that selected from the group consisting of. A) reacting a compound of formula 2 with an alkylacrylate to prepare a compound of formula 3, B) reacting it with phosphorus tribromide to produce the compound of formula 4, C) reacting it with aryl alcohol (R ₁ OH) to prepare a compound of formula 5, D) ester hydrolysis reaction with an inorganic or organic acid to prepare a compound of formula 6, E) an acylation reaction with arylamine (R ₂ NH ₂ ) to prepare a compound of formula (7), F) hydrolyzing it with an inorganic salt to prepare a compound of formula 8, G) acylation with a protected hydroxylamine to prepare a compound of formula 9, H) reacting it with an organic acid to remove the hydroxy protecting group, Process for preparing benzhydroxyamide derivative of formula 1: Formula 1 Wherein R ₁ and R ₂ are as defined in claim 1, X is a hydroxy protecting group, Y is a C _1-4 alkyl group. An anticancer composition comprising as an active ingredient a benzhydroxyamide derivative of formula 1 and a pharmaceutically acceptable carrier.