Thiazole class of histone deacetylase inhibitors and methods of making and using the same

Abstract

The present application relates to the field of pharmaceutical chemistry, and discloses a kind of thiazole structure containing hydroxamic acid compound and its derivative, and its application as new type histone deacetylase inhibitor, its structure is as shown in the following: the present application also discloses the application of the compound or its pharmaceutical composition in the preparation and treatment of various malignant tumor growth, metastasis and recurrence and other diseases caused by histone acetylation disorder.The compound of the present application can inhibit the growth and metastasis of various malignant tumors, and has the potential effect of relieving the malignant degree of tumor metastasis patients.

Description

Technical Field

[0001] This invention relates to a histone deacetylase inhibitor, and more particularly to a method for synthesizing and using a class of isohydroxamic acid compounds containing a tetrathiazole structure. Background Technology

[0002] Cancer, also known as malignant tumor, is a disease that seriously threatens life and health. Cancer is characterized by abnormal cell differentiation and proliferation, uncontrolled growth, invasiveness, and metastasis. Cancer treatment has always been an unsolved problem in clinical medicine. Many traditional anti-tumor drugs lack selectivity for tumor cells and have serious adverse reactions on normal cells or tissues. Therefore, the development of targeted anti-tumor drugs has become one of the hottest research directions in anti-tumor drug research in recent years.

[0003] Studies have found a close relationship between tumorigenesis and the imbalance of acetylation and deacetylation of lysine residues at the N-terminus of nucleosome core histones. In vivo, this dynamic balance is maintained by HAT and HDAC. Histone acetyltransferases (HATs) catalyze the attachment of N-terminal lysine residues of histones to acetyl groups on acetyl-CoA, reducing the electronegativity of histones and thus weakening the interaction between DNA and histones, facilitating DNA transcription. Histone deacetylases (HDACs) act inversely to histone acetyltransferases, catalyzing the weakening of the bond between N-terminal lysine residues of histones and acetyl groups, achieving deacetylation, thereby increasing the interaction between histones and DNA, inhibiting transcription, and hindering the expression of related genes. High expression of HDACs has been found in many cancers, making them a popular target in anticancer drug research.

[0004] Histone deacetylase inhibitors (HDACis) inhibit tumor development through multiple mechanisms, such as inhibiting tumor cell invasion and migration, inhibiting angiogenesis, regulating gene expression, and promoting apoptosis. Analysis of the specific molecular docking process in the recognition of HDACis and HDACs reveals that these inhibitors all possess the same pharmacodynamic group, consisting of three parts: (1) a specific zinc ion-binding group (ZBG) for chelating with zinc ions at the bottom of the HDAC pocket structure; (2) a surface recognition group (CAP) that interacts with amino acid residues on the HDAC surface; and (3) a hydrophobic linker chain connecting the zinc ion-binding group and the surface recognition group. Modifications to the CAP region can not only enhance the activity of the compounds but also improve their selectivity.

[0005] Based on the classic hydroxamic acid structural framework, this invention introduces a benzothiazole structure to synthesize a series of small molecule organic compounds. Experiments have shown that the compounds of this invention have inhibitory effects on various malignant tumor cells and have the potential to inhibit the malignant development of tumors. Summary of the Invention

[0006] This invention provides a class of isohydroxamic acid compounds containing a thiazole structure, wherein the isohydroxamic acid skeleton is supplemented with a benzothiazole structure; this invention also provides the application of this compound as a histone deacetylase inhibitor, which can prevent and treat various malignant tumors by inhibiting the histone deacetylase pathway; finally, this invention also provides a method for preparing this compound.

[0007] A class of isohydroxamic acid compounds containing a thiazole structure, with the structural formula shown in formula (I): In formula (I), R1 is independently selected from the following groups: -H, -CH3, -OCH3, -F, -Cl, Br.

[0008] A class of isohydroxamic acid compounds containing a thiazole structure, with the structural formula shown in formula (II): In formula (II), R2 is independently selected from the following groups: -H, -CH3, -OCH3, -F, -Cl, Br.

[0009] The compound according to claim 1, preferably, is characterized in that the C chain is a straight chain of 5 carbon atoms, R1 is hydrogen, and the structural formula is shown in formula (III): In formula (III), R3 is independently selected from the following groups: .

[0010] The compound according to claim 1, 2 or 3 is characterized in that it comprises: an acid addition salt formed with an acid, said acid being hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, salicylic acid, tartaric acid, methanesulfonic acid, citric acid, lactic acid, p-toluenesulfonic acid, succinic acid, maleic acid, or pyruvic acid.

[0011] A class of isohydroxamic acid compounds containing a thiazole structure and their derivatives are used as drugs for the prevention and treatment of cancer, including hematologic malignancies and various solid tumors.

[0012] A class of isohydroxamic acid compounds containing a thiazole structure and their derivatives, as histone deacetylase inhibitors, can be used in drugs that inhibit the proliferation, growth, migration, and invasion of tumor cells; the tumor cells include breast cancer cells, lung cancer cells, liver cancer cells, colon cancer cells, gastric cancer cells, epidermal cancer cells, pancreatic cancer cells, prostate cancer cells, ovarian cancer cells, leukemia cells, kidney cancer cells, bladder cancer cells, and oral cancer cells.

[0013] A class of isohydroxamic acid compounds containing a thiazole structure and their derivatives, as histone deacetylase inhibitors, can be used in drugs for treating metastatic and recurrent malignant tumors, including breast cancer, lung cancer, liver cancer, colon cancer, prostate cancer, stomach cancer, skin cancer, pancreatic cancer, leukemia, ovarian cancer, bladder cancer, kidney cancer, and oral cancer.

[0014] A class of isohydroxamic acid compounds containing a thiazole structure and their derivatives, as histone deacetylase inhibitors, can be used in antitumor therapy drugs for antitumor treatment after chemotherapy failure due to induced acquired resistance.

[0015] The drugs described above may be used alone or in combination with other drugs.

[0016] A method for preparing a class of isohydroxamic acid compounds containing a thiazole structure includes the following steps: Compound 1 reacts with bromoacetonitrile to generate compound 2. Compound 2 is then reacted with dimethylformamide, dioxane, toluene, benzene, or tetrahydrofuran solvent upon heating to generate compound 4. Compound 4 is then esterified in a suitable solvent such as dichloromethane, methanol, ethanol, dimethyl sulfoxide, or toluene to generate the target compound 5. Compound 5 reacts with ammonium sulfide under heating conditions to generate compound 6. Compound 6 clads with various benzene-substituted 2-chloroacetophenones to generate compound 8. Compound 8 reacts with hydroxylamine hydrochloride under alkaline conditions upon heating to generate compound 9. After the reaction is complete, the mixture is extracted, washed successively with water and saturated brine, dried, and the solvent is removed under low temperature and reduced pressure. The final product is obtained by column chromatography.

[0017] A method for preparing a class of isohydroxamic acid compounds containing a thiazole structure includes the following steps: Compound 1 reacts with ammonium sulfide under heating conditions to give compound 2. Compound 2 reacts with 1,3-dichloroacetone to form compound 4. Compound 4 reacts with p-methoxyaniline to give compound 6. Compound 6 is heated in dimethylformamide, dioxane, toluene, benzene, or tetrahydrofuran to give compound 8. Compound 8 is esterified in a suitable solvent such as dichloromethane, methanol, ethanol, dimethyl sulfoxide, or toluene to give target compound 9. Compound 9 reacts with hydroxylamine hydrochloride under alkaline conditions to give compound 10. After the reaction is complete, the product is extracted, washed successively with water and saturated brine, dried, and the solvent is removed under low temperature and reduced pressure. The final product is obtained by column chromatography.

[0018] A method for preparing a class of isohydroxamic acid compounds containing a thiazole structure includes the following steps: Compound 1 is hydrolyzed by boron tribromide in dichloromethane, methanol, ethanol, dimethyl sulfoxide or toluene to generate compound 2. Compound 2 is reacted with different brominated derivatives in dimethylformamide, dioxane, toluene, benzene or tetrahydrofuran to generate compound 3. Compound 3 reacts with hydroxylamine hydrochloride under alkaline conditions to generate target compound 4. After the reaction is complete, the mixture is quenched with ice water, extracted, washed successively with water and saturated brine, dried, and the solvent is removed under low temperature and reduced pressure. The final product is obtained by column chromatography.

[0019] Beneficial effects.

[0020] 1. The compounds of this invention can inhibit the growth of various malignant tumors and have the potential to alleviate the malignant development of cancer.

[0021] 2. Studies have shown that both thiazole compounds and hydroxamic acid compounds have significant antitumor effects. Therefore, this invention combines the thiazole structure as the CAP region with the hydroxamic acid structure to synthesize a novel class of histone deacetylase inhibitors, laying the foundation for subsequent drug development studies of the compounds.

[0022] 3. The compound HR-471C of this invention exhibits significantly better inhibition of HDAC1 enzyme than the control compound SAHA. The compound of this invention also shows a significant inhibitory effect on tumor proliferation. Attached Figure Description

[0023] Figure 1-3 The figure shown is a graph illustrating the inhibition rate of the compounds of this invention on the proliferation of different tumor cells.

[0024] Figure 4-13 The figure shows the IC50 of the compound of the present invention in different tumor cells. 50 Result image. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to the specific embodiments and accompanying drawings. The scope of protection of the present invention is not limited to the following embodiments. All variations that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention and are protected by the appended claims.

[0026] 1 ¹H-NMR was performed using a Bruker AVANCE Ⅲ HD 600 MHz NMR spectrometer; MS was performed using an Agilent 6440 Triple Quad LC / MS instrument, ESI mode unless otherwise specified; all solvents were redistilled before use, and all anhydrous solvents were obtained by drying according to standard methods; unless otherwise specified, all reactions were carried out under argon protection and monitored by TLC, and post-processing included washing with saturated brine and drying with anhydrous magnesium sulfate; unless otherwise specified, the products were purified by silica gel (200-30 mesh) column chromatography; the silica gel used included 200-300 mesh and GF. 254 Produced by Qingdao Hailang Silica Gel Desiccant Co., Ltd.

[0027] Example 1-1, Compound N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-453A).

[0028] Dissolve p-anisidine (4320 mg, 35 mmol) in 8 ml of N,N-dimethylformamide, add K2CO3 (4920 mg, 35 mmol) and bromoacetonitrile (1.68 ml, 23.3 mmol), stir at room temperature for 6 hours, add hydrochloric acid aqueous solution to adjust to acidity, extract, separate and purify to obtain brown solid intermediate 2 (3120 mg, 82.5%).

[0029] Intermediate 2 (3120 mg, 19.23 mmol) and pimelic anhydride (3280 mg, 23.08 mmol) were dissolved in 15 ml of 1,4-dioxane, heated under reflux at 110 °C for more than 4 hours, extracted and evaporated to dryness to obtain intermediate 4 (4340 mg, 74.1%).

[0030] Intermediate 4 was dissolved in methanol (40 ml), and 3-4 drops of thionyl chloride were added dropwise. The reaction system was heated to reflux. After 5 hours, excess solvent was removed under reduced pressure to obtain crude product 5, which was used directly in the next reaction step.

[0031] Intermediate 5 (1418 mg, 4.46 mmol) was dissolved in 15 mL of pyridine solution, and ammonium sulfide (1215 μL, 17.48 mmol) and triethylamine (1253 μL, 8.92 mmol) were added. The reaction was heated and stirred at 50 °C for 5 hours. The solvent was removed under reduced pressure, and the solution was passed through a silica gel column to obtain target intermediate 6 (1152 mg, 73.4%).

[0032] Intermediate 6 (1152 mg, 3.27 mmol) and 2-chloroacetophenone (3.93 mmol) were dissolved in ethanol and stirred under reflux at 80 °C for 4 hours. The solvent was evaporated and the mixture was passed through a silica gel column in an ethyl acetate / petroleum ether system to obtain intermediate 8 (828 mg, 56%).

[0033] Hydroxylamine hydrochloride (6350 mg, 91.5 mmol) was dissolved in 20 ml methanol, and KOH (5130 mg, 91.5 mmol) was slowly added. The solution was heated to 40 °C and stirred for 30 minutes. The reaction system was then cooled in an ice bath, filtered, and intermediate 8 was dissolved in the filtrate. KOH (513 mg, 9.15 mmol) was then added to the solution, and the reaction was stirred at room temperature for 3 hours. After evaporation and extraction, the solution was purified by silica gel column chromatography in a methanol / dichloromethane system to obtain the target compound HR-453A (635 mg, 76.8%).

[0034] 1 H NMR (600 MHz, DMSO- d 6) δ 10.32 (br s, 1H), 8.66 (br s, 1H), 8.04(s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.41 (dd, J = 7.2, 7.2 Hz, 2H), 7.32 (dd, J = 7.2, 7.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H), 5.10 (s, 2H), 3.74 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.89 (t, J= 7.8 Hz,2H), 1.50 – 1.45 (m, 2H), 1.42 – 1.37 (m, 2H), 1.17 – 1.12 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.34, 169.00, 167.21, 158.60, 153.45, 134.75, 133.99, 129.21, 128.79, 127.99, 125.93, 114.93 ,114.76, 55.32, 50.71, 33.10, 32.13, 28.16, 24.93, 24.58.

[0035] Examples 1-2, Compounds N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 4-(4-(o-tolyl)thiazolyl-2-yl)methyl)heptanidamide (HR-467B).

[0036] Replace compound 7 with 2-chloro-1-(2-methylphenyl)ethyl ketone. 1 H NMR (600 MHz, DMSO- d 6) δ 11.96(br s, 1H), 7.69 (br s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.26 – 7.22 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 5.08 (s, 2H), 3.75 (s,3H), 2.33 (s, 3H), 2.13 (t, J = 7.2 Hz, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.50 –1.45 (m, 2H), 1.41 – 1.36 (m, 2H), 1.19 – 1.14 (m, 2H). 13 C NMR (150 MHz, DMSO-d 6) δ 174.39, 172.24, 165.67, 158.60, 153.75, 135.53, 134.74, 134.15, 130.79, 129.48, 129.21, 127.94 ,125.86, 117.81, 114.73, 55.34, 50.48, 33.52, 33.08, 28.10, 24.57, 24.27, 20.90.

[0037] Examples 1-3 N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 4-(4-(m-tolyl)thiazolyl-2-yl)methyl)heptanidamide (HR-467C).

[0038] Replace compound 7 with 2-chloro-1-(3-methylphenyl)ethyl ketone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30(br s, 1H), 8.64 (br s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 7.8, 7.8 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 7.13 (d, J =7.2 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 2.34 (s,3H), 2.06 (t, J = 7.8 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.50 – 1.45 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.12 (m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.34, 168.97, 167.09, 158.60, 153.55, 137.90, 134.72, 133.92, 129.22, 128.68, 128.63, 126.51 ,123.10, 114.76, 55.32, 50.69, 33.10, 32.12, 28.15, 24.91, 24.58, 21.08.

[0039] Examples 1-4 N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 4-(p-tolyl)thiazolyl-2-yl)methyl)heptanidamide (HR-467A).

[0040] Replace compound 7 with 2-chloro-1-(4-methylphenyl)ethyl ketone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31(br s, 1H), 8.65 (br s, 1H), 7.96 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.24 –7.21 (m, 4H), 6.96 (d, J = 8.4 Hz, 2H), 5.08 (s, 2H), 3.75 (s, 3H), 2.31 (s,3H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.33, 168.99, 167.06, 158.60, 153.54, 137.33, 134.76, 131.35, 129.35, 129.22, 125.86, 114.76 ,114.02, 55.33, 50.71, 33.10, 32.12, 28.15, 24.92, 24.58, 20.82.

[0041] Examples 1-5 N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 1-((4-(4-methoxyphenyl)thiazolyl-2-yl)methyl)heptanidamide (HR-483A).

[0042] Replace compound 7 with 2-chloro-4-methoxyacetophenone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (brs, 1H), 8.65 (br s, 1H), 7.87 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.23 (d, J =9.0 Hz, 2H), 6.97 (d, J = 2.4 Hz, 2H), 6.96 (d, J = 2.4 Hz, 2H), 5.08 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz,2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.32, 168.99, 166.97, 159.10, 158.60, 153.37, 134.78, 129.23, 127.29, 126.86, 114.76, 114.14 ,112.82, 55.33, 55.18, 50.69, 33.10, 32.13, 28.15, 24.92, 24.59.

[0043] Examples 1-6 N 1 -((4-(2-fluorophenyl)thiazolyl-2-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-471B).

[0044] Replace compound 7 with 2-chloro-1-(2-fluorophenyl)ethyl ketone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (brs, 1H), 8.66 (brs, 1H), 8.02 (dd, J = 7.2,7.2 Hz, 1H), 7.92 (s, 1H), 7.40 -7.36 (m, 1H), 7.33 – 7.26 (m, 2H), 7.23 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0Hz, 2H), 5.10 (s, 2H), 3.75 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J =7.2 Hz, 2H), 1.50 – 1.45 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.41, 169.02, 166.75, 160.20, 158.64, 158.55, 146.97 (d, J= 2.3 Hz), 134.76 , 129.76 (d, J = 8.6 Hz), 129.59 (d, J = 3.0 Hz), 129.21, 124.87, 124.85, 121.63 (d, J = 11.6 Hz), 119.25 (d, J = 13.5 Hz), 116.19 (d, J = 22.1 Hz), 114.80, 55.34, 50.68, 33.11, 32.14, 28.16, 24.94, 24.59.

[0045] Examples 1-7 N 1 -((4-(3-fluorophenyl)thiazolyl-2-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-471C).

[0046] Replace compound 7 with 2-chloro-1-(3-fluorophenyl)ethyl ketone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.34 (brs, 1H), 8.69 (br s, 1H), 8.14 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.66 (d, J =10.2 Hz, 1H), 7.48 – 7.43 (m, 1H), 7.22 (d, J = 9.0 Hz, 2H), 7.16 – 7.13 (m,1H), 6.96 (d, J = 9.0 Hz, 2H), 5.08 (s, 2H), 3.74 (s, 3H), 2.05 (t, J = 7.2Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.48 – 1.43 (m, 2H), 1.40 – 1.35 (m, 2H), 1.16 – 1.10 (m, 2H).

[0047] 13 C NMR (150 MHz, DMSO- d 6) δ 172.65, 169.29, 167.68, 163.52, 161.91, 158.77, 152.24 (d, J = 3.0 Hz), 136.43 (d, J = 8.3 Hz), 134.84, 131.07 (d, J = 8.4 Hz), 129.35 , 122.14 (d, J = 2.6 Hz), 116.53, 114.94, 114.81, 112.59 (d, J = 22.8 Hz), 55.49, 50.84, 33.23, 32.25, 28.26, 25.04, 24.71.

[0048] Examples 1-8 N 1 -((4-(4-fluorophenyl)thiazolyl-2-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-471A).

[0049] Replace compound 7 with 2-chloro-1-(4-fluorophenyl)ethyl ketone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30 (brs, 1H), 8.64 (br s, 1H), 8.03 (s, 1H), 7.93 (dd, J = 7.2, 7.2 Hz, 2H), 7.26 –7.22 (m, 4H), 6.97 (d, J = 8.4 Hz, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.34, 168.98, 167.36, 161.05, 158.60, 152.40, 134.74, 130.61, 129.21, 127.98 (d, J = 8.2 Hz), 115.73, 115.59, 114.77, 55.33, 50.67, 33.09, 32.12, 28.14, 24.91, 24.57.

[0050] Examples 1-9 N 1 -((4-(2-chlorophenyl)thiazo-2-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-488B).

[0051] Replace compound 7 with 2,2'-dichloroacetophenone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30 (br s,1H), 8.64 (br s, 1H), 8.03 (s, 1H), 7.78 (dd, J = 4.8, 4.8 Hz, 1H), 7.54 (dd, J = 4.8, 4.8 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.23 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 5.09 (s, 2H), 3.76 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.88(t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11(m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.32, 168.97, 166.11, 158.61, 149.98, 134.72, 132.76, 131.39, 130.93, 130.34, 129.55, 129.22 ,127.38, 119.78, 114.76, 55.34, 50.50, 33.10, 32.12, 28.15, 24.91, 24.57.

[0052] Examples 1-10 N 1 -((4-(3-chlorophenyl)thiazo-2-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-488C).

[0053] Replace compound 7 with 2,3'-dichloroacetophenone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s,1H), 8.65 (br s, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 7.8, 7.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 9.0Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 2.06 (t, J =7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.44, 169.05, 167.61, 158.65, 151.83, 136.00, 134.73, 133.67, 130.78, 129.23, 127.79, 125.56 ,124.52, 116.53, 114.81, 55.36, 50.70, 33.12, 32.15, 28.18, 24.94, 24.60.

[0054] Examples 1-11 N 1 -((4-(4-chlorophenyl)thiazo-2-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-488A).

[0055] Replace compound 7 with 2,4'-dichloroacetophenone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30 (br s,1H), 8.64 (br s, 1H), 8.12 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.61 (d, J =8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.09 (s,2H), 3.75 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 –1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.35, 168.96, 167.53, 158.60, 152.21, 134.71, 133.18, 131.73, 129.20, 127.94, 121.09, 115.80 ,114.77, 55.32, 50.67, 33.08, 32.11, 28.13, 24.90, 24.55.

[0056] Examples 1-12 N 1 -((4-(4-bromophenyl)thiazo-2-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-532A).

[0057] Replace compound 7 with 2'-chloro-4-bromoacetophenone. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s,1H), 8.65 (br s, 1H), 8.11 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.47 (d, J =9.0 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 5.09 (s,2H), 3.75 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 –1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.36, 168.99, 167.52, 158.61, 152.17, 134.72, 132.85, 132.48, 129.21, 128.83, 127.65, 115.72 ,114.78, 55.33, 50.69, 33.09, 32.13, 28.14, 24.91, 24.57.

[0058] Example 2-1 N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 1-((2-phenylthiazo-4-yl)methyl)heptanediamide (HR-453).

[0059] Benzonitrile (2062 mg, 20 mmol) was dissolved in 10 mL of solution, and ammonium sulfide (1500 μL, 22 mmol) and triethylamine (3097 μL, 22 mmol) were added. The reaction was heated and stirred at 50 °C for 5 hours. The solvent was removed under reduced pressure, and the solution was passed through a silica gel column to obtain the target intermediate 10 (2257 mg, 82.3%).

[0060] Intermediate 10 was dissolved in 30 ml of ethanol solution with 1,3-dichloropropanone (3134 mg, 24.69 mmol), and the mixture was stirred and refluxed at 80 °C for 4 hours. The solvent was evaporated, and the mixture was passed through a silica gel column in an ethyl acetate / petroleum ether system to obtain intermediate 12 (2579 mg, 74.77%).

[0061] Dissolve p-anisidine (2269 mg, 10.95 mmol) in 20 ml of N,N-dimethylformamide, add K2CO3 (1513 mg, 10.95 mmol), stir at room temperature for 30 minutes, then add intermediate 12. The reaction system is stirred at room temperature for 6 hours, then hydrochloric acid aqueous solution is added to adjust to acidity, and the mixture is extracted, separated and purified to obtain brown solid intermediate 13 (3017 mg, 82.8%).

[0062] Intermediate 13 (10.18 mmol) and pimelic anhydride (2171 mg, 15.27 mmol) were dissolved in 20 ml of 1,4-dioxane, heated under reflux at 110 °C for more than 4 hours, extracted and evaporated to dryness to obtain intermediate 14 (3122 mg, 70.1%).

[0063] Intermediate 14 was dissolved in methanol (30 ml), and 3-4 drops of thionyl chloride were added dropwise. The reaction system was heated to reflux. After 5 hours, excess solvent was removed under reduced pressure to obtain crude product 15, which was used directly in the next reaction step.

[0064] Hydroxylamine hydrochloride (680 mg, 125 mmol) was dissolved in 20 mL of methanol, and KOH (7010 mg, 125 mmol) was slowly added. The solution was heated to 40 °C and stirred for 30 minutes. The reaction system was then cooled in an ice bath, filtered, and intermediate 14 was dissolved in the filtrate. KOH (701 mg, 912.5 mmol) was then added to the solution, and the reaction was stirred at room temperature for 3 hours. After evaporation and extraction, the solution was purified by silica gel column chromatography in a methanol / dichloromethane system to obtain the target compound HR-453 (871 mg, 76.9%).

[0065] 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s, 1H), 8.65 (br s, 1H), 7.88(d, J = 7.8 Hz, 2H), 7.50 – 7.46 (m, 4H), 7.23 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.92 (s, 2H), 3.74 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88(t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.15 – 1.10(m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.94, 169.06, 166.71, 158.36, 153.76, 135.15, 133.04, 130.23, 129.43, 129.27, 126.04, 116.66 ,114.55, 55.30, 48.89, 33.32, 32.16, 28.22, 24.96, 24.65.

[0066] Example 2-2 N 1-hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 2-((2-(o-tolyl)thiazolyl-4-yl)methyl)heptanamide (HR-467D).

[0067] Replace compound 9 with 2-methylbenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30 (br s,1H), 8.65 (br s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.37 – 7.34 (m,2H), 7.30 (dd, J = 7.2, 7.2 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.93 (d, J =8.4 Hz, 2H), 4.93 (s, 2H), 3.74 (s, 3H), 2.48 (s, 3H), 2.03 (t, J = 7.2 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.48 – 1.43 (m, 2H), 1.40 – 1.35 (m, 2H), 1.14– 1.09 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.83, 169.03, 166.43, 158.35, 153.07, 135.78, 135.15, 132.35, 131.57, 129.51, 129.45, 129.39 ,126.38, 117.20, 114.54, 55.29, 48.80, 33.33, 32.14, 28.23, 24.95, 24.65, 21.18.

[0068] Examples 2-3 N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N7 Preparation of 2-((2-(m-tolyl)thiazolyl-4-yl)methyl)heptanidamide (HR-467E).

[0069] Replace compound 9 with 3-methylbenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s,1H), 8.65 (br s, 1H), 7.69 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.36 (dd, J = 7.8, 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.92 (s, 2H), 3.74 (s, 3H), 2.36 (s, 3H), 2.04(t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 –1.36 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.92, 169.03, 166.83, 158.35, 153.66, 138.60, 135.12, 133.00, 130.87, 129.42, 129.15, 126.43 ,123.26, 116.50, 114.53, 55.28, 48.86, 33.31, 32.15, 28.22, 24.95, 24.64, 20.90.

[0070] Examples 2-4 N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7Preparation of 2-(p-tolyl)thiazolyl-4-yl)methyl)heptanidamide (HR-467).

[0071] Replace compound 9 with 4-methylbenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30 (br s,1H), 8.65 (br s, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.41 (s, 1H), 7.29 (d, J =7.8 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.91 (s,2H), 3.74 (s, 3H), 2.34 (s, 3H), 2.04 (t, J = 7.4 Hz, 2H), 1.88 (t, J = 7.4Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.91, 169.04, 166.82, 158.34, 153.57, 140.02, 135.15, 130.48, 129.77, 129.42, 125.97, 116.04 ,114.53, 55.29, 48.90, 33.31, 32.15, 28.21, 24.95, 24.63, 20.95.

[0072] Examples 2-5 N 1 -hydroxy- N 7 -(4-Methoxyphenyl)- N 7 Preparation of 2-((2-(4-methoxyphenyl)thiazolyl-4-yl)methyl)heptanidamide (HR-483).

[0073] Replace compound 9 with 4-methoxybenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 11.96 (br s,1H), 7.81 (d, J = 8.4 Hz, 2H), 7.35 (br s, 1H), 7.23 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.90 (s, 2H), 3.81 (s,3H), 3.74 (s, 3H), 2.13 (t, J = 7.2 Hz, 2H), 2.04 (t, J = 7.2 Hz, 2H), 1.49 –1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 174.41, 171.86, 166.60, 160.80, 158.33, 153.42, 135.19, 129.39, 127.57, 125.91, 115.40, 114.54 ,114.49, 55.37, 55.26, 48.89, 33.50, 33.25, 28.14, 24.62, 24.26.

[0074] Examples 2-6 N 1 -((2-(2-fluorophenyl)thiazo-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-471D).

[0075] Replace compound 9 with 2-fluorobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (br s, 1H),8.70 (br s, 1H), 8.12 (dd,J = 7.9,7.9 Hz, 1H), 7.58 (s, 1H), 7.53 – 7.50 (m,1H), 7.41 – 7.34 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 4.95 (s, 2H), 3.72 (s, 3H), 2.03 (t, J = 7.2 Hz, 2H), 1.87 (t, J = 7.2 Hz,2H), 1.48 – 1.43 (m, 2H), 1.40 – 1.34 (m, 2H), 1.14 – 1.09 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.33, 169.42, 160.19, 159.14 (d, J =5.4 Hz), 158.55, 152.98, 135.27, 131.99 (d, J = 8.4 Hz), 129.59, 128.46, 125.45 (d, J = 3.2 Hz), 120.70 (d, J = 11.4 Hz), 118.28 (d, J = 8.1 Hz), 116.64 (d, J = 21.6 Hz), 114.74, 55.48, 49.00, 33.47, 32.31, 28.35, 25.10, 24.81.

[0076] Examples 2-7 N 1 -((2-(3-fluorophenyl)thiazolyl-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-471E).

[0077] Replace compound 9 with 3-fluorobenzonitrile. 1 H NMR (600 MHz, DMSO-d 6) δ 10.34 (br s, 1H), 8.69 (br s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.54 –7.51 (m, 1H), 7.51 (s, 1H), 7.32 – 7.28 (m, 1H), 7.22 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.92 (s, 2H), 3.73 (s, 3H), 2.03 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.48 – 1.43 (m, 2H), 1.40 – 1.35 (m, 2H), 1.14– 1.09 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.17 , 169.27 , 165.29 (d, J = 3.2 Hz),163.38, 161.75, 158.48, 153.99, 135.27 (d, J = 8.1 Hz), 135.19, 131.59 (d, J = 8.7 Hz), 129.52, 122.41 (d, J = 2.7 Hz), 117.63, 117.07 (d, J =21.0 Hz), 114.66, 112.53 (d, J = 23.4 Hz), 55.40, 48.93, 33.41, 32.25, 28.31, 25.05, 24.74.

[0078] Examples 2-8 N 1 -((2-(4-fluorophenyl)thiazolyl-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-471).

[0079] Replace compound 9 with 4-fluorobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30 (br s, 1H), 8.65 (br s, 1H), 7.93 (dd, J = 7.2, 7.2 Hz, 2H), 7.46 (s, 1H), 7.32 (dd, J =8.4, 8.4 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.92(s, 2H), 3.74 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.89, 169.02, 165.52, 163.95, 162.31, 158.34, 153.74, 135.12, 129.71 (d, J = 3.0 Hz), 129.41, 128.34, 128.28, 116.75, 116.33, 116.19, 114.53, 55.27, 48.82, 33.29, 32.14, 28.20, 24.94 , 24.62.

[0080] Examples 2-9 N 1 -((2-(2-chlorophenyl)thiazo-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-488D).

[0081] Replace compound 9 with 2-chlorobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.32 (br s, 1H), 8.66 (br s, 1H), 8.11 – 8.08 (m, 1H), 7.64 (s, 1H), 7.63 – 7.61 (m, 1H), 7.49– 7.46 (m, 2H), 7.23 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.96 (s,2H), 3.73 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 –1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.95, 169.07, 161.91, 158.38, 152.67, 135.13, 131.20, 131.09, 130.77, 130.67, 130.63, 129.45 ,127.76, 118.66, 114.56, 55.30, 48.79, 33.33, 32.16, 28.24, 24.97, 24.65.

[0082] Examples 2-10 N 1 -((2-(3-chlorophenyl)thiazo-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-488E).

[0083] Replace compound 9 with 3-chlorobenzonitrile. 1 H NMR (600 MHz, DMSO- d6) δ 10.31 (br s, 1H), 8.66 (br s, 1H), 7.88 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.55 – 7.50 (m, 3H), 7.22 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.93 (s, 2H), 3.73 (s,3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.99, 169.08, 164.91, 158.39, 153.97, 135.10, 134.90, 133.99, 131.26, 129.92, 129.45, 125.34 ,124.82, 117.67, 114.56, 55.31, 48.79, 33.32, 32.17, 28.24, 24.97, 24.66.

[0084] Example 2-11 N 1 -((2-(4-chlorophenyl)thiazolyl-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-488).

[0085] Replace compound 9 with 4-chlorobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s, 1H),8.65 (br s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.54 (d, J= 9.0 Hz, 2H), 7.50 (s,1H), 7.23 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.92 (s, 2H), 3.74(s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 – 1.44 (m,2H), 1.41 – 1.36 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.90 , 169.02 , 165.33 , 158.35 ,153.92 , 135.10 , 134.70 , 131.85 , 129.40 , 129.29 , 127.70 , 117.18 ,114.54, 55.28, 48.81, 33.29, 32.15, 28.20, 24.94, 24.62.

[0086] Examples 2-12 N 1 -((2-(2-bromophenyl)thiazo-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-532D).

[0087] Replace compound 9 with 2-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (br s, 1H), 8.70 (br s, 1H), 7.92 – 7.90 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.50 (dd, J = 7.2, 7.2 Hz, 1H), 7.40 (dd, J = 7.8 Hz, 1H), 7.21 (d, J= 8.4Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 4.94 (s, 2H), 3.73 (s, 3H), 2.02 (t, J =7.2 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.47 – 1.42 (m, 2H), 1.39 – 1.34 (m, 2H), 1.13 – 1.08 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.19 , 169.33 , 163.79 , 158.52 ,152.78 , 135.17 , 134.16 , 133.55 , 131.55 , 131.47 , 129.60 , 128.30 ,120.85, 118.79, 114.70, 55.44, 48.85, 33.46, 32.27, 28.33, 25.07, 24.77.

[0088] Examples 2-13 N 1 -((2-(3-bromophenyl)thiazo-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-532E).

[0089] Replace compound 9 with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.34 (br s, 1H), 8.69 (br s, 1H), 8.00 (dd, J = 1.8, 1.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.44 (dd, J = 7.8, 7.8 Hz, 1H), 7.20(d, J = 9.0Hz, 2H), 6.92 (d,J = 8.4 Hz, 2H), 4.92 (s, 2H), 3.73 (s, 3H), 2.03 (t, J = 7.2 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.48 – 1.43 (m, 2H), 1.40 – 1.35 (m, 2H), 1.15 – 1.09 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.24, 169.34, 164.97, 158.52, 154.04, 135.19, 135.17, 132.96, 131.67, 129.57, 128.28, 125.33 ,122.58, 117.81, 114.68, 55.44, 48.89, 33.44, 32.28, 28.33, 25.07, 24.77.

[0090] Examples 2-14 N 1 -((2-(4-bromophenyl)thiazo-4-yl)methyl)- N 7 -hydroxy- N 1 Preparation of 1-(4-methoxyphenyl)heptanediamide (HR-532).

[0091] Replace compound 9 with 4-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s, 1H),8.65 (br s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.50 (s,1H), 7.22 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 4.92 (s, 2H), 3.74(s, 3H), 2.03 (t, J = 7.2 Hz, 2H), 1.88 (t,J = 7.2 Hz, 2H), 1.48 – 1.43 (m,2H), 1.40 – 1.35 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 171.92, 169.04, 165.44, 158.35, 153.95, 135.10, 132.20 (d, J = 4.9 Hz), 129.41, 127.92, 123.46, 117.21, 114.55, 55.29, 48.82, 33.30, 32.15, 28.21, 24.95, 24.62.

[0092] Example 3-1 N 1 -(4-ethoxyphenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-467F).

[0093] Compound 8 (452.5 mg, 1 mmol) was dissolved in 10 mL of dichloromethane. Boron tribromide (2 mL, 4 mmol) was slowly added under ice bath conditions. The reaction was carried out at 0 °C for 30 minutes, then stirred at room temperature for 6 hours. Methanol was added to inactivate the compound, the solvent was evaporated under reduced pressure, and the solution was passed through a silica gel column to obtain the target intermediate 16 (399.2 mg, 92.3%).

[0094] Intermediate 16 was dissolved in 8 ml of DMF solvent, and then K2CO3 (188.4 mg, 1.36 mmol) was added at room temperature. After stirring at room temperature for 30 minutes, bromoethane (148 mg, 1.36 mmol) was added. The reaction system was stirred at 45 °C for 8 hours. The mixture was extracted with EtOAc and separated by silica gel column chromatography to obtain intermediate 17 (252 mg, 60.3%).

[0095] Hydroxylamine hydrochloride (1870 mg, 27 mmol) was dissolved in 10 ml methanol, and KOH (1520 mg, 27 mmol) was slowly added. The solution was heated to 40 °C and stirred for 30 minutes. The reaction system was then cooled in an ice bath, filtered, and intermediate 17 was dissolved in the filtrate. KOH (514 mg, 2.7 mmol) was then added to the solution, and the reaction was stirred at room temperature for 3 hours. After evaporation and extraction, the solution was purified by silica gel column chromatography in a methanol / dichloromethane system to obtain the target compound HR-467F (149 mg, 59.8%).

[0096] 1 H NMR (600 MHz, DMSO- d 6) δ 10.33 (br s, 1H), 8.67 (br s, 1H), 8.03(s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.41 (dd, J = 7.2, 7.2 Hz, 2H), 7.32 (dd, J = 7.2, 7.2 Hz, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 5.08(s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 2.05 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2Hz, 2H), 1.49 – 1.44 (m, 2H), 1.40 – 1.35 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H),1.16 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.50, 169.16, 167.32, 158.01, 153.53, 134.67, 134.05, 129.29, 128.90, 128.11, 126.01, 115.25 ,115.02, 63.40, 50.78, 33.17, 32.20, 28.22, 24.99, 24.66, 14.69.

[0097] Example 3-2 N 1 -(4-(allyloxy)phenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-479).

[0098] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s,1H), 8.67 (br s, 1H), 8.04 (s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.41 (dd, J =7.8, 7.8 Hz, 2H), 7.32 (dd, J = 7.2, 7.2 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.05 – 5.99 (m, 1H), 5.39 (d, J = 17.4 Hz, 1H), 5.25 (d, J = 10.2 Hz, 1H), 5.09 (s, 2H), 4.56 (d, J = 5.4 Hz, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.50 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.17 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d6) δ 172.50, 169.05, 167.31, 157.64, 153.54, 134.93, 134.06, 133.54, 129.30, 128.91, 128.12, 126.01 ,117.85, 115.55, 115.03, 68.48, 50.77, 33.19, 32.27, 28.26, 25.06, 24.68.

[0099] Example 3-3 N 1 -hydroxy- N 7 -((4-phenylthiazo-2-yl)methyl)- N 7 Preparation of 1-(4-propoxyphenyl)heptanediamide (HR-481).

[0100] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (s,1H), 8.69 (s, 1H), 8.01 (s, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.41 (dd, J = 7.8, 7.8 Hz, 2H), 7.31 (dd, J = 7.2, 7.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.94(d, J = 9.0 Hz, 2H), 5.08 (s, 2H), 3.89 (t, J = 6.6 Hz, 2H), 2.05 (t, J = 7.2Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.72 – 1.66 (m, 2H), 1.49 – 1.43 (m, 2H), 1.40 – 1.35 (m, 2H), 1.16 – 1.10 (m, 2H), 0.94 (t, J = 7.2 Hz, 2H). 13 C NMR (150 MHz, DMSO-d 6) δ 172.63, 169.30, 167.40, 158.24, 153.60, 134.72, 134.10, 129.36, 128.98, 128.20, 126.07, 115.35 ,115.07, 114.93, 69.33, 55.48, 50.86, 33.24, 32.26, 28.27, 25.05, 24.73, 22.14, 10.55.

[0101] Examples 3-4 N 1 -(4-(allyloxymethoxy)phenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-493).

[0102] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.34 (br s,1H), 8.68 (br s, 1H), 8.01 (s, 1H), 7.89 – 7.85 (m, 2H), 7.41 (dd, J = 6.6, 6.6 Hz, 2H), 7.31 (dd, J = 6.6, 6.6 Hz, 1H), 7.19 (d, J = 3.0 Hz, 2H), 6.93(d, J = 3.0 Hz, 2H), 5.07 (s, 2H), 3.78 (d, J = 6.0 Hz, 2H), 2.05 (t, J = 7.2Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.48 – 1.43 (m, 2H), 1.39 – 1.34 (m, 2H), 1.22 – 1.16 (m, 2H), 1.14 – 1.09 (m, 2H), 0.56 – 0.52 (m, 2H), 0.30 – 0.27(m, 2H). 13C NMR (150 MHz, DMSO- d 6) δ 172.63, 169.30, 167.40, 158.17, 153.60, 134.70, 134.10, 129.34, 128.99, 128.20, 126.07, 115.38 ,115.09, 72.43, 50.86, 33.23, 32.26, 28.27, 25.05, 24.74, 10.23, 3.27.

[0103] Examples 3-5 N 1 -(4-Butoxyphenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-495).

[0104] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.35 (br s,1H), 8.69 (br s, 1H), 8.01 (s, 1H), 7.87 (d, J = 7.0 Hz, 2H), 7.41 (t, J =7.8 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 9.0 Hz, 2H), 6.94 (d, J =9.0 Hz, 2H), 5.08 (s, 2H), 3.93 (t, J = 6.6 Hz, 2H), 2.05 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.68 – 1.63 (m, 2H), 1.48 – 1.43 (m, 2H), 1.41 – 1.35 (m, 2H), 1.15 – 1.10 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, DMSO- d 6) δ 172.64, 169.32, 167.41, 158.26, 153.62, 134.73, 134.11, 129.35, 128.99, 128.21, 126.08, 115.36 ,115.08 , 67.55 , 50.87 , 33.25 , 32.27 , 30.85 , 28.28 , 25.06 , 24.74 ,18.88 , 13.85 .

[0105] Examples 3-6 N 1 -hydroxy- N 7 -(4-Isobutoxyphenyl)- N 7 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-495A).

[0106] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s,1H), 8.65 (br s, 1H), 8.04 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.41 (t, J =7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.95 (d, J =8.4 Hz, 2H), 5.09 (s, 2H), 3.72 (d, J = 6.6 Hz, 2H), 2.06 (t, J = 7.2 Hz,2H), 2.01 – 1.96 (m, 1H), 1.88 (t, J = 7.2 Hz, 2H), 1.50 – 1.45 (m, 2H), 1.42 – 1.37 (m, 2H), 1.18 – 1.11 (m, 2H). 0.95 (d, J = 6.6 Hz, 6H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.34, 169.00, 167.22, 158.16, 153.45, 134.63, 134.00, 129.20, 128.79, 128.00, 125.93, 115.24 ,114.93, 73.91, 50.71, 33.10, 32.13, 28.16, 27.69, 24.93, 24.59, 19.03.

[0107] Examples 3-7 N 1 -hydroxy- N 7 -(4-(2-methoxyethoxy)phenyl)- N 7 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-497).

[0108] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.33 (br s,1H), 8.68 (br s, 1H), 8.02 (s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.41 (t, J =7.8 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.97 (d, J =9.0 Hz, 2H), 5.09 (s, 2H), 4.07 (t, J = 9.0 Hz, 2H), 3.63 (t, J = 9.0 Hz,2H), 3.28 (s, 3H), 2.05 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.49 –1.44 (m, 2H), 1.40 – 1.35 (m, 2H), 1.15 – 1.10 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.54, 169.22, 167.33, 157.98, 153.57, 134.89, 134.07, 129.35, 128.94, 128.15, 126.03, 115.35 ,115.04, 70.40, 67.22, 58.27, 50.79, 33.21, 32.23, 28.24, 25.01, 24.69.

[0109] Examples 3-8 N 1 -hydroxy- N 7 -(4-(3-methoxypropoxy)phenyl)- N 7 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-511).

[0110] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.32 (br s,1H), 8.66 (br s, 1H), 8.03 (s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.41 (t, J =7.8 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.95 (d, J =9.0 Hz, 2H), 5.09 (s, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.44 (s, 2H), 3.22 (s,3H), 2.06 (t, J = 7.2 Hz, 2H), 1.92 (t, J = 6.0 Hz, 2H), 1.88 (t, J = 7.2 Hz,2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.34, 169.00, 167.21, 157.97, 153.45, 134.72, 134.00, 129.23, 128.79, 128.00, 125.93, 115.22 ,114.93, 68.43, 64.80, 57.95, 50.70, 48.62, 33.10, 32.13, 28.90, 28.16, 24.93, 24.59.

[0111] Examples 3-9 N 1 -(4-(2-ethoxyethoxy)phenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-511B).

[0112] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.32 (br s,1H), 8.66 (br s, 1H), 8.03 (s, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.41 (t, J =7.8 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.97 (d, J =8.4 Hz, 2H), 5.09 (s, 2H), 4.07 (t, J = 4.8 Hz, 2H), 3.67 (t, J = 4.8 Hz,2H), 3.49 – 3.45 (m, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J= 7.2 Hz, 2H),1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H), 1.10 (t, J =7.2 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.43, 169.09, 167.25, 157.94, 153.51, 134.83, 134.03, 129.28, 128.86, 128.07, 125.98, 115.31 ,114.99, 68.32, 67.43, 65.73, 50.73, 33.15, 32.18, 28.20, 24.97, 24.64, 15.14.

[0113] Examples 3-10 N 1 -(4-(benzyloxy)phenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-529).

[0114] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.32 (br s,1H), 8.66 (br s, 1H), 8.04 (s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.44 – 7.37 (m,6H), 7.32 (t, J = 7.2 Hz, 2H), 7.24 (d, J = 10.2 Hz, 2H), 7.05 (d, J = 9.0Hz, 2H), 5.09 (d, J = 8.4 Hz, 4H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J= 7.2Hz, 2H), 1.50 – 1.45 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.38, 169.06, 167.24, 157.80, 153.48, 136.77, 134.96, 134.01, 129.28, 128.83, 128.50, 128.04 ,128.00 , 127.91 , 125.96 , 115.59 , 114.98 , 69.54 , 50.72 , 33.15 , 32.16 ,28.18 , 24.95 , 24.61 .

[0115] Examples 3-11 N 1 -(4-(cyclohexylmethoxy)phenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-535).

[0116] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s,1H), 8.65 (br s, 1H), 8.03 (s, 1H), 7.88 (d, J = 6.6 Hz, 2H), 7.41 (t, J =7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 9.0 Hz, 2H), 6.94 (d, J =9.0 Hz, 2H), 5.09 (s, 2H), 3.75 (d, J = 6.6 Hz, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J= 7.2 Hz, 2H), 1.78 – 1.76 (m, 2H), 1.71 – 1.67 (m, 3H), 1.64 – 1.61 (m, 1H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.26 – 1.17 (m,3H), 1.16 – 1.11 (m, 2H), 1.04 – 0.98 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.38, 169.03, 167.25, 158.23, 153.47, 134.61, 134.01, 129.20, 128.81, 128.02, 125.95, 115.22 ,114.94, 72.94, 50.74, 37.08, 33.11, 32.15, 29.24, 28.17, 26.05, 25.28, 24.95, 24.61.

[0117] Examples 3-12 N 1 -hydroxy- N 7 -(4-((4-methylbenzyl)oxy)phenyl)- N 7 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-543).

[0118] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (br s,1H), 8.65 (br s, 1H), 8.04 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.41 (dd, J =6.6, 6.6 Hz, 2H), 7.32 (d, J = 13.2 Hz, 3H), 7.23 (d, J = 6.6 Hz, 2H), 7.18(d, J = 6.0 Hz, 2H), 7.03 (d, J= 6.6 Hz, 2H), 5.09 (s, 2H), 5.03 (s, 2H), 2.29 (s, 3H), 2.06 (t, J = 6.6 Hz, 2H), 1.88 (t, J = 6.6 Hz, 2H), 1.50 – 1.44(m, 2H), 1.41 – 1.36 (m, 2H), 1.17 – 1.12 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.34, 169.02, 167.22, 157.81, 153.46, 137.22, 134.88, 134.00, 133.72, 129.23, 129.01, 128.80 ,128.01, 127.96, 125.94, 115.56, 114.94, 69.41, 50.70, 33.12, 32.14, 28.16, 24.93, 24.59, 20.80.

[0119] Examples 3-13 N 1 -(4-((4-fluorobenzyl)oxy)phenyl)- N 7 -hydroxy- N 1 Preparation of 1-((4-phenylthiazo-2-yl)methyl)heptanediamide (HR-548).

[0120] Replace bromoethane in the route with 3-bromobenzonitrile. 1 H NMR (600 MHz, DMSO- d 6) δ 10.33 (br s,1H), 8.67 (br s, 1H), 8.03 (s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.49 (d, J =3.0 Hz, 2H), 7.41 (dd, J = 7.8 Hz, 2H), 7.32 (dd, J = 7.2, 7.2 Hz, 1H), 7.24(d, J= 8.4 Hz, 2H), 7.20 (dd, J = 9.0, 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H),5.09 (s, 2H), 5.06 (s, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz,2H), 1.49 – 1.44 (m, 2H), 1.41 – 1.36 (m, 2H), 1.16 – 1.11 (m, 2H). 13 C NMR (150 MHz, DMSO- d 6) δ 172.43, 169.13, 167.26, 161.89 (d, J =243.6 Hz), 157.74, 153.51, 135.04, 134.04, 133.04 (d, J = 3.0 Hz), 130.24(d, J = 8.4 Hz), 129.33, 128.88, 128.09, 125.99, 115.63, 115.35 (d, J =21.4 Hz), 115.02, 68.84, 50.75, 33.18, 32.18, 28.20, 24.97, 24.64.

[0121] Example 4: The inhibitory effect of the compound of the present invention on HDAC1 enzyme activity at the molecular level.

[0122] Using Ac-Lys-Tyr-Lys(Ac)-AMC as a substrate, enzyme activity was detected in 96-well or 384-well flat-bottom microplates using a fluorescence detection method. After deacetylation of the substrate Ac-Lys-Tyr-Lys(Ac)-AMC with HDAC1, the product AMC obtained by trypsin hydrolysis was detectable under 355nm excitation and 460nm emission light using a fluorescence detector. The initial reaction rate was calculated by detecting changes in the fluorescence signal over time. The results are shown in Table 1, indicating that the compounds of this invention generally exhibit better inhibitory effects on HDAC1 enzyme activity than SAHA.

[0123] Table 1. HDAC1 inhibition by the compounds of this invention. Example 5: The compound of the present invention has a significant inhibitory effect on the proliferation of tumor cells.

[0124] Cell viability was determined using the CCK8 assay.

[0125] Tumor cells at 5x10 3 Cells were seeded at a density of [number] cells / well in 96-well plates and cultured for 24 hours. Then, SAHA diluted to 2.5 μmol / L and the compound of this invention were added sequentially. The control group received an equal volume of DMSO. Each group had three replicates. After culturing for 48 or 72 hours, cells were fixed, stained with CCK8, and the OD values ​​were measured at 450 nm using a microplate reader. The effect of the drug on cell viability was statistically analyzed.

[0126] The compounds of this invention exhibit a very significant inhibitory effect on the proliferation of lung adenocarcinoma PC9 cells and lung cancer A549 and H1975 cells at a concentration of 2.5 μmol / L. (See attached image.) Figure 1-3 Compared with the control group, HR-532, HR-453A, HR-467, HR467A, HR-471, HR483A, and HR488B showed significant inhibitory activity, and the IC50 values ​​of these seven compounds were further determined. 50 .

[0127] CCK8 method for IC testing 50 .

[0128] Tumor cell suspension was seeded at 100 μL per well (approximately 5000 cells) into 96-well plates and cultured at 37°C for 24 h. Then, serially diluted SAHA and the compound of this invention were added sequentially, while the control group received an equal volume of DMSO. Each group had three replicates. After culturing for another 48 h, cells were fixed, stained with CCK8, and the OD values ​​were measured at 450 nm using a microplate reader. The IC50 of the drug of this invention in different tumor cell types was statistically analyzed. 50 .

[0129] The IC50 of the compounds of this invention in PC9 lung adenocarcinoma cells, A549 lung cancer cells, and H1975 lung cancer cells 50 Significantly superior to the control compound SAHA, see Figure 4 5. In A549 and H1975 cells, HR-532, HR-488B, and HR-453A showed better results, and further parallel experiments were conducted on these three compounds.

[0130] The compounds of this invention exhibit significant inhibitory effects on the proliferation of lung cancer A549, H1299, colorectal cancer HCT116, and breast cancer MCF-7 cells, and are superior to the control compound SAHA. (See [link to relevant documentation]). Figure 6-13Compounds HR-532, HR488B, and HR-453A showed IC50 values ​​in A549 cells. 50 Compared to SAHA, the levels were 2.13-fold, 2.85-fold, and 2.01-fold lower, respectively, and the IC50 in H1299 cells was significantly lower. 50 Compared to SAHA, they are 2.50 times, 1.51 times, and 2.74 times lower, respectively.

Claims

1. A class of isohydroxamic acid compounds containing a thiazole structure, characterized in that, The structural formula is shown in equation (I): In formula (I), R1 is independently selected from the following groups: -H, -OCH3, -F, -Cl, Br.

2. A class of isohydroxamic acid compounds containing a thiazole structure, characterized in that, The structural formula is shown in formula (II): In formula (II), R2 is independently selected from the following groups: -H, -OCH3, -F, -Cl, Br.

3. A class of isohydroxamic acid compounds containing a thiazole structure, characterized in that, The structural formula is shown in equation (III): In formula (III), R3 is independently selected from the following groups: 。 4. The salt of the compound according to claim 1, 2 or 3, characterized in that, An acid addition salt is formed by the compound and an acid, wherein the acid is hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, salicylic acid, tartaric acid, methanesulfonic acid, citric acid, lactic acid, p-toluenesulfonic acid, succinic acid, maleic acid, or pyruvic acid.

5. The use of the compound according to any one of claims 1-4 in the preparation of a medicament for treating cancer, characterized in that, The compound inhibits tumor cell proliferation and induces cell differentiation and apoptosis by inhibiting the histone deacetylase pathway.

6. The use of the compound according to any one of claims 1-4 in the preparation of a medicament for the prevention and treatment of hematological malignancies and solid tumors, characterized in that... The compound exerts its antitumor effect by inhibiting HDAC.

7. A method for preparing the compound according to claim 1, characterized in that, R1 = -H, -OCH3, -F, -Cl, -Br, including the following steps: Compound 1 reacts with bromoacetonitrile to generate compound 2. Compound 2 is heated in solvent A to generate compound 4. Compound 4 is esterified in solvent B to generate target compound 5. Compound 5 reacts with ammonium sulfide in solvent A to generate compound 6. Compound 6 clads with various benzene-substituted 2-chloroacetophenones to generate compound 8. Compound 8 is heated in solvent B under alkaline conditions to generate compound 9. After the reaction is complete, the mixture is extracted, washed successively with water and saturated brine, dried, and the solvent is removed under low temperature and reduced pressure. The final product is obtained by column chromatography. Solvent A is dimethylformamide, dioxane, pyridine, or tetrahydrofuran; Solvent B is dichloromethane, methanol, ethanol, dimethyl sulfoxide, or toluene; The extractant is ethyl acetate, dichloromethane, or diethyl ether.

8. A method for preparing the compound according to claim 2, characterized in that, R2 = -H, -OCH3, -F, -Cl, -Br, including the following steps: Compound 1 was reacted with ammonium sulfide in solvent C to give compound 2. Compound 2 was clad with 1,3-dichloroacetone to generate compound 4. Compound 4 was reacted with p-methoxyaniline to generate compound 6. Compound 6 was heated in solvent C to give compound 8. Compound 8 was esterified in solvent D to generate target compound 9. Compound 9 was heated in solvent D under alkaline conditions to generate compound 10. After the reaction was completed, the product was extracted, washed successively with water and saturated brine, dried, and the solvent was removed under low temperature and reduced pressure. The final product was obtained by column chromatography. The solvent C is dimethylformamide, dioxane, pyridine, or tetrahydrofuran; The solvent D is dichloromethane, methanol, ethanol, dimethyl sulfoxide, or toluene; The extractant is ethyl acetate, dichloromethane, or diethyl ether.

9. A method for preparing the compound according to claim 3, characterized in that... The R3 is derived from the following independent groups: Includes the following steps: Compound 1 was hydrolyzed by boron tribromide in solvent E to generate compound 2. Compound 2 reacted with different brominated derivatives to generate compound 3. Compound 3 reacted with hydroxylamine hydrochloride in solvent E to generate target compound 4. After the reaction was completed, the mixture was quenched with ice water, extracted, washed successively with water and saturated brine, dried, and the solvent was removed under low temperature and reduced pressure. The final product was obtained by column chromatography. The solvent E is dimethylformamide, dioxane, toluene, benzene, or tetrahydrofuran; The solvent F is dichloromethane, methanol, ethanol, dimethyl sulfoxide, or toluene; The extractant is ethyl acetate, dichloromethane, or diethyl ether.

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