Hydroxamic acid HDAC11 subtype selective inhibitor as well as preparation method and application thereof

Abstract

The invention provides a hydroxamic acid HDAC11 subtype selective inhibitor as well as a preparation method and application thereof. The inhibitor provided by the invention has a structure as shown in the following structural general formula (I) and pharmaceutically acceptable salts, hydrates or solvates thereof. The HDAC11 subtype selective inhibitor provided by the invention has high-activity and high-selectivity HDAC11 inhibitory activity, and has stronger in-vivo and in-vitro anti-hepatocellular carcinoma activity, good anti-pancreatic cancer potential and good water solubility than a marketed drug Sorafenib (Sorafenib), and a representative compound has good oral pharmacokinetic properties and good patent medicine potential.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis and pharmaceutical application technology, and in particular to a selective inhibitor of isohydroxamic acid HDAC11 subtype, its preparation method and application. Background Technology

[0002] Zinc-dependent histone deacetylases (HDACs) are a family of proteins that regulate epigenetics and post-translational modifications. Eleven subtypes of human zinc-dependent HDACs have been identified, with HDAC11 being the most recently discovered. HDAC11 is distributed in both the cytoplasm and nucleus, playing complex physiological and pathological functions. Notably, recent studies have shown that HDAC11 possesses very strong de-acylation activity (see: Cao J. et al., Proc Natl Acad Sci USA. 2019, 116, 5487-5492; Kutil Z. et al., ACS Chem. Biol. 2018, 13, 685-693).

[0003] High expression of HDAC11 is closely associated with the occurrence, development, and poor prognosis of various cancers, including hepatocellular carcinoma, acute myeloid leukemia, myeloproliferative neoplasms, multiple myeloma, Hodgkin's lymphoma, non-small cell lung cancer, glioblastoma, pituitary adenoma, prostate cancer, ovarian cancer, and acute lymphoblastic leukemia (see: Liu S. et al., Biomed. Pharmacother. 2020, 131, 110607; Núñez-Álvarez Y. et al., FEBS J. 2022, 289, 2771-2792; Yang M. et al., J. Med. Chem. 2025, 68, 8124-8142). For example, HDAC11 is highly expressed in hepatocellular carcinoma tissues / cells and is closely associated with sorafenib resistance and poor patient prognosis; correspondingly, HDAC11 knockout / knockdown can effectively inhibit hepatocellular carcinoma growth and invasion / metastasis, reduce tumor stem cell stemness, and reduce sorafenib resistance (see: Bi L. et al., Cancer Res. 2021, 81, 2015-2028; Wang W. et al., Front. Cell Dev. Biol. 2020, 8, 724). As another example, HDAC11 is highly expressed in patients with acute myeloid leukemia (AML) and is closely associated with poor prognosis. More importantly, HDAC11 inhibitors have multiple anti-AML effects, including inhibiting proliferation, inducing cell cycle arrest, inducing apoptosis, promoting differentiation, and inducing ferroptosis. Therefore, HDAC11 is considered a potential cancer therapeutic target.

[0004] In addition, numerous studies have shown that selective HDAC11 inhibitors may also be used to treat metabolic diseases such as obesity, diabetes, and fatty liver disease associated with metabolic dysfunction; autoimmune diseases such as inflammation, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus; and tissue fibrosis such as idiopathic pulmonary fibrosis and renal fibrosis (see: Liu S. et al., Biomed. Pharmacother, 2020, 131, 110607; Núñez-Álvarez Y. et al., FEBS J. 2022, 289, 2771-2792; Zhang F. et al., Adv. Sci. 2025, 12,e2412903; Li Y. et al., Research, 2025, 8, 0953; Mao L. et al., Front. CellDev. Biol. 2020, 8, 235).

[0005] However, the number of HDAC11 subtype selective inhibitors reported so far (structure shown in the figure below) is small and activity studies are still in their early stages. Furthermore, the oral pharmacokinetic properties of most existing HDAC11 subtype selective inhibitors are poor or undisclosed, and their HDAC11 inhibitory activity, HDAC11 subtype selectivity, and water solubility need improvement (see: Yang M. et al. J. Med. Chem. 2025, 68, 8124-8142; Martin MW et al., Bioorg. Med. Chem. Lett. 2018, 28, 2143-2147; Bai P. et al. J. Med. Chem. 2023, 66, 16075-16090; Son SI et al., ACS Chem. Biol. 2019, 14, 1393-1397; Ho TT et al., ACS Chem. Biol. 2023, 18, 803-809; Son SI et al., ACS Chem. Biol.). 2020, 15, 2866-2871).

[0006] Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a hydroxamic acid HDAC11 subtype selective inhibitor, its preparation method, and its applications. The HDAC11 subtype selective inhibitor of this invention exhibits high activity and high selectivity of HDAC11 inhibition, stronger in vitro and in vivo anti-hepatocellular carcinoma activity than the marketed drug Sorafenib, good anti-pancreatic cancer potential, good water solubility, and representative compounds possess favorable oral pharmacokinetic properties, demonstrating good drug development potential.

[0008] The technical solution of the present invention is as follows:

[0009] 1. HDAC11 subtype selective inhibitors

[0010] Inhibitors having the structure shown in general formula (I) and their pharmaceutically acceptable salts, hydrates or solvates:

[0011]

[0012] in,

[0013] R1 is or ;

[0014] R2 is , , , , , , , , , , , , , , , , or .

[0015] Preferably, the inhibitor has one of the following structures, and a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0016]

[0017]

[0018] 2. Preparation method of HDAC11 subtype selective inhibitor

[0019] The preparation method of the inhibitor is selected from one of the following:

[0020] (a) Compound 1 reacts with p-toluenesulfonyl chloride to generate compound 2. Compound 2 reacts with carbon tetrabromide to generate compound 3. Compound 3 and compound 4 undergo a Sonogashira coupling reaction to generate compound 5. Compound 5 is deprotected to give compound 6. Compound 6 undergoes a substitution reaction with halogenated compound 7 to give compound 8. Compound 8 reacts with potassium hydroxylamine to give compounds M1-M14, N1-N14.

[0021] The reaction formula is as follows:

[0022]

[0023] In the reaction formulas for preparing compounds M1-M14 and N1-N14, the substituents R1 and R2 are the same as those in the corresponding compounds M1-M14 and N1-N14.

[0024] The reagents and conditions in the above reaction formula:

[0025] a. Reaction of p-toluenesulfonyl chloride, sodium hydride, and tetrahydrofuran at room temperature;

[0026] b. Carbon tetrabromide, lithium diisopropylamino, tetrahydrofuran, reaction at -78°C and room temperature;

[0027] c. Cuprous iodide, triethylamine, bis(triphenylphosphine)palladium dichloride, 1,4-dioxane, reaction at 70°C;

[0028] d. Tetrabutylammonium fluoride trihydrate, tetrahydrofuran, reaction at 60°C;

[0029] e. Sodium hydride, N,N-dimethylformamide, reaction at 0℃-80℃;

[0030] f. Potassium hydroxylamine, methanol, reaction at room temperature;

[0031] (ii) Compounds 9 and 12 react with p-toluenesulfonyl chloride to form p-toluenesulfonate esters, which then undergo a substitution reaction with compound 6 to give compounds 10 and 13, respectively. Compounds 10 and 13 react with potassium hydroxylamine to give compounds 11 and 14, respectively. Compounds 11 and 14 are deprotected from Boc under acidic conditions to give compounds M15, N15 and M16, N16, respectively.

[0032] The reaction formula is as follows:

[0033]

[0034] In the reaction formula for preparing compounds M15-M16, N15-N16, the substituent R1 is the same as the substituent R1 in the corresponding compounds M15-M16, N15-N16.

[0035] The reagents and conditions in the above reaction formula:

[0036] a. p-Toluenesulfonyl chloride, triethylamine, 4-dimethylaminopyridine, dichloromethane, reaction at room temperature; sodium hydride, N,N-dimethylformamide, reaction at 0℃-80℃;

[0037] b. Potassium hydroxylamine, methanol, reaction at room temperature;

[0038] c. Ethyl hydrochloride solution, ethyl acetate, reaction at room temperature;

[0039] (iii) Compound 6 undergoes a substitution reaction with tert-butyl bromoacetate to generate compound 15. Compound 15 is deprotected under acidic conditions to give compound 16. Compound 16 is condensed with compounds 17 and 19, respectively, to give compounds 18 and 20. Compounds 18 and 20 react with potassium hydroxylamine, respectively, to give target compounds M17, N17 and intermediate 21. Intermediate 21 is deBoc-treated under acidic conditions to give compounds M18 and N18.

[0040]

[0041] In the reaction formula, the substituent R1 is the same as the substituent R1 in the corresponding compounds M17-M18 and N17-N18.

[0042] The reagents and conditions in the above reaction formula:

[0043] a. tert-butyl bromoacetate, sodium hydride, N,N-dimethylformamide, reaction at 0°C to room temperature;

[0044] b. Trifluoroacetic acid, dichloromethane, reaction at room temperature;

[0045] cO-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU), N,N-diisopropylethylamine, N,N-dimethylformamide, reaction at room temperature;

[0046] d. Potassium hydroxylamine, methanol, reaction at room temperature;

[0047] e. Ethyl hydrochloride solution, ethyl acetate, reaction at room temperature;

[0048] 3. Application of HDAC11 subtype selective inhibitors

[0049] Application of HDAC11 subtype selective inhibitors in the preparation of drugs for the prevention or treatment of diseases associated with abnormal HDAC11 expression or activity.

[0050] The diseases associated with abnormal HDAC11 expression or activity are cancer, metabolic diseases, autoimmune diseases, or tissue fibrosis.

[0051] The cancers mentioned are liver cancer, pancreatic cancer, acute myeloid leukemia, myeloproliferative neoplasm, multiple myeloma, Hodgkin's lymphoma, non-small cell lung cancer, glioblastoma, pituitary adenoma, prostate cancer, ovarian cancer, or acute lymphoblastic leukemia.

[0052] The metabolic diseases mentioned are obesity, diabetes, or fatty liver disease associated with metabolic dysfunction.

[0053] The autoimmune diseases mentioned are inflammation, psoriasis, rheumatoid arthritis, or systemic lupus erythematosus.

[0054] The tissue fibrosis mentioned refers to pulmonary fibrosis, renal fibrosis, or liver fibrosis.

[0055] The beneficial effects of this invention are as follows:

[0056] Patent document CN 116924959 A provides a selective inhibitor of the HDAC11 subtype, but the compound in that patent also has moderate inhibitory activity against HDAC8, so its selectivity for HDAC11 is not ideal. Furthermore, the compound in patent document CN 116924959 A has poor water solubility and very low oral bioavailability, therefore, in vivo anticancer activity evaluation was not conducted. This invention solves the aforementioned technical problems.

[0057] The HDAC11 subtype selective inhibitors of the present invention have a novel structure and highly active and selective HDAC11 inhibitory activity. Compared with existing inhibitors, the inhibitors of the present invention have superior HDAC11 inhibitory activity, higher HDAC11 subtype selectivity, and better water solubility. Furthermore, the representative compounds have stronger in vitro and in vivo anti-hepatocellular carcinoma activity, good anti-pancreatic cancer potential, and good oral pharmacokinetic properties than the marketed drug Sorafenib, thus demonstrating good drug development potential.

[0058] The main structural difference between the compounds of this invention and those in patent document CN 116924959 A lies in the different substituents on the N atom of the indole. Related experimental results of this invention confirm that introducing suitable substituents onto the N atom of the indole can significantly improve the HDAC11 inhibitory activity, HDAC11 isotype selectivity, and water solubility of the compounds, and improve their oral pharmacokinetic properties. Furthermore, the representative compounds in patent document CN 116924959 A contain only one substituent on the terminal benzene or pyridine ring, while some representative compounds of this invention contain two trifluoromethyl substituents on the terminal benzene ring. The test results of this invention show that the compounds with two trifluoromethyl substituents on the terminal benzene ring exhibit superior anti-hepatocellular carcinoma cell proliferation activity compared to the corresponding compounds with only one trifluoromethyl substituent on the terminal benzene ring. Attached Figure Description

[0059] Figure 1 The results of flow cytometry analysis of reactive oxygen species (ROS) and lipid peroxidation levels in Huh7 cells treated with compounds M15 and M16 in Experiment Example 3;

[0060] Figure 2 The results of the pharmacokinetic (PK) study of compound M16 in ICR (CD-1) mice in Experiment Example 5;

[0061] Figure 3 The results show the in vivo anti-hepatocellular carcinoma activity of compounds M15 and M16 in mice in Experiment Example 6. Detailed Implementation

[0062] The present invention will be further described below with reference to embodiments, but is not limited thereto.

[0063] Meanwhile, unless otherwise specified, all reagents used in the embodiments are commercially available; and unless otherwise specified, the methods and equipment used can be based on existing technologies.

[0064] Example 1. Preparation of compounds M1-M14, N1-N14, taking compound M1 as an example.

[0065] Synthesis route:

[0066]

[0067] The specific synthesis method and steps are as follows:

[0068] Compound 2: Compound 1 (0.50 g, 2.85 mmol) was placed in a round-bottom flask and dissolved in 30 mL of THF. Then, a 60% NaH mineral oil dispersion (0.17 g, 4.28 mmol) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, TsCl (0.60 g, 3.14 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated, dissolved in 70 mL of EA, washed with 100 mL of water, and the organic phase was washed with saturated NaCl aqueous solution and dried over anhydrous magnesium sulfate. The filtrate was collected by suction filtration, concentrated, and purified by column chromatography to give 0.69 g of a white solid, with a yield of 74%. The NMR data of the product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 8.3 Hz, 1H), 8.01 (d, J = 3.7Hz, 1H), 7.89 (dd, J = 7.9, 4.0 Hz, 3H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 3.7 Hz, 1H), 3.88 (s, 3H), 2.31 (s, 3H). ESI-MS,m / z=330.4 [M+H] + .

[0069] Compound 3: LDA (1.2 mL, 2 M) was added to a THF solution (5 mL) of Compound 2 (660 mg, 2 mmol) at -78 °C. After 30 min, a THF solution (5 mL) of CBr4 (797 mg, 2.4 mmol) was added dropwise. The reaction was continued at this temperature for 30 min, then cooled to room temperature for another 30 min. After the reaction was complete, the solvent was evaporated, and the mixture was dissolved in 80 mL of EA. The solution was washed with 120 mL of water, and the organic phase was washed again with saturated NaCl aqueous solution and dried over anhydrous magnesium sulfate. The residue was then concentrated and subjected to column chromatography to give 130 mg of a white solid (Compound 3), with a yield of 16%. The NMR data of the product are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 7.6Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 8.1 Hz, 1H), 7.49 – 7.36 (m,3H), 3.87 (s, 3H), 2.33 (s, 3H).

[0070] Compound 5m: Compound 3 (0.78 g, 1.90 mmol), Pd(PPh3)2Cl2 (0.27 g, 0.38 mmol), and CuI (72 mg, 0.38 mmol) were placed in a double-necked flask and dissolved in 4 mL of 1,4-dioxane. The mixture was evacuated and purged with argon three times. During stirring, TEA (10 mL) was added using a disposable syringe, followed by a 1,4-dioxane solution (2 mL) of 3-(trifluoromethyl)phenylacetylene (4m, 0.42 g, 2.47 mmol). The mixture was stirred at 70 °C for 24 h. TLC monitoring was performed. After the reaction was complete, the solvent was evaporated to dryness, and the mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated NaCl aqueous solution and dried over anhydrous magnesium sulfate. The filtrate was collected by filtration, concentrated, and purified by column chromatography to give 0.5 g of a pale yellow oil (compound 5m), with a yield of 53%. The NMR data of the product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 7.1Hz, 3H), 7.88 (t, J = 9.9 Hz, 3H), 7.78 (t, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 3.89 (d, J = 8.9 Hz, 3H), 2.31 (s, 3H). ESI-MS, m / z=498.4 [M+H] + .

[0071] Compound 6m: Compound 5m (0.52 g, 1.05 mmol) was placed in a round-bottom flask, dissolved in 8 mL of THF, and then a 2 mL THF solution of tetrabutylammonium fluoride trihydrate (0.50 g, 1.58 mmol) was added. The mixture was refluxed and stirred overnight at 60 °C. After complete reaction by TLC, the solvent was evaporated, dissolved in 70 mL of EA, washed with 100 mL of water, and the aqueous phase was washed three more times with EA. The organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was collected by vacuum filtration. The filtrate was concentrated and column chromatography was performed to give 0.28 g of a pale yellow solid (compound 6m), with a yield of 78%. The NMR data of the product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 7.96 (s, 1H), 7.91 (d, J =7.8 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.72 (t, J =7.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.37 – 7.29 (m, 2H), 3.91 (s, 3H). ESI-MS, m / z=342.3 [MH] - .

[0072] Compound 8m-1: Compound 6m (0.10 g, 0.30 mmol) was dissolved in DMF (8 mL) at 0 °C. A 60% NaH mineral oil dispersion (18 mg, 0.45 mmol) was added in portions, and the mixture was stirred at 0 °C for 30 min. Then, 2-bromoethyl methyl ether (7-1, 63 mg, 0.45 mmol) was added, and the mixture was stirred at 80 °C. The reaction was monitored by TLC for 30 min until completion. After the reaction was complete, the mixture was cooled, and the reaction solution was quenched in a large volume of water. The mixture was extracted three times with EA, and the organic phases were combined. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 59 mg of a pale yellow solid (compound 8m-1), with a yield of 49%. The NMR data of the product are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.85 – 7.80 (m, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.43– 7.33 (m, 2H), 4.61 (t, J = 5.2 Hz, 2H), 3.92 (s, 3H), 3.73 (t, J = 5.3 Hz, 2H), 3.20 (s, 3H). ESI-MS, m / z=402.2 [M+H] + .

[0073] Target compound M1: 5.00 g (71.95 mmol) of hydroxylamine hydrochloride was weighed and added to 12 mL of anhydrous methanol, and stirred in an ice bath. 6.00 g (106.95 mmol) of potassium hydroxide was weighed and added to 20 mL of anhydrous methanol, and stirred in an ice bath until dissolved. Under ice bath conditions, the methanol solution of potassium hydroxide was added dropwise to the methanol solution of hydroxylamine hydrochloride, and stirring was continued in an ice bath for 1 h. The solution of potassium hydroxylamine in methanol was obtained by filtration. 8 m-1 of compound (0.10 g, 0.25 mmol) was added to a round-bottom flask, and freshly prepared methanol solution of potassium hydroxylamine (8 mL) was added. The mixture was stirred at room temperature. TLC monitoring showed that after the reaction was complete, the solvent was evaporated, 2 mL of water was added to dissolve the compound, and the pH was slowly adjusted to 7-8 with 1 M hydrochloric acid. A large amount of solid precipitated out, which was filtered and dried to obtain the crude product. Purification by preparative high-performance liquid chromatography yielded 66 mg of brown solid (target compound M1), with a yield of 66%. The NMR data of the product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.03 (s, 1H), 8.02 (s, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 8.7 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.35 – 7.22 (m, 2H), 4.58 (t, J = 5.0 Hz, 2H), 3.72(t, J = 5.1 Hz, 2H), 3.21 (s, 3H). ESI-MS, m / z=401.36 [MH] - .

[0074] The preparation methods of compounds M2-M14 and N1-N14 are similar to those of compound M1 (the difference is that the structure of substituent R1 in compound 4 and / or substituent R2 in compound 7 is replaced).

[0075] Example 2. Preparation of compounds M15 and N15, taking compound M15 as an example.

[0076] Synthesis route:

[0077]

[0078] The specific synthesis method and steps are as follows:

[0079] Compound 10m: TEA (0.26 g, 2.60 mmol) was slowly added to 10 mL of DCM containing 4-(2-hydroxyethyl)piperidin-1-carboxylic acid tert-butyl ester (9 g, 0.30 g, 1.30 mmol), followed by the addition of 4-dimethylaminopyridine (8 mg, 0.07 mmol) and p-toluenesulfonyl chloride (0.27 g, 1.43 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction mixture was poured into a large volume of water, extracted with DCM, and the organic phases were combined. The organic phases were washed with saturated NaCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 0.45 g of a white solid, which was directly used in the next step. Compound 6m (0.15 g, 0.44 mmol) was dissolved in DMF (8 mL) at 0 °C. A 60% NaH mineral oil dispersion (27 mg, 0.66 mmol) was added in portions, and the mixture was stirred at 0 °C for 30 min. Then, the previously prepared white solid (0.20 g, 0.53 mmol) was added, and the mixture was stirred at 80 °C. The reaction was monitored by TLC for 1 h until completion. After the reaction was complete, the mixture was cooled, and the reaction solution was quenched in a large volume of water. The aqueous phase was extracted three times with EA, and the organic phases were combined. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 0.24 g of a pale yellow oil (compound 10m), with a yield of 96%. The NMR data of the product are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.90 –7.81 (m, 3H), 7.74 (t, J = 7.8 Hz, 1H), 7.42 – 7.32 (m, 2H), 4.47 (t, J = 7.3Hz, 2H), 3.92 (s, 3H), 3.88 – 3.80 (m, 2H), 2.70 – 2.55 (m, 2H), 1.82 – 1.62(m, 4H), 1.52 – 1.45 (m, 1H), 1.35 (s, 9H), 1.11 – 0.97 (m, 2H). ESI-MS, m / z=577.2 [M+Na] + .

[0080] Compound 11m: Weigh 5.00 g (71.95 mmol) of hydroxylamine hydrochloride and add it to 12 mL of anhydrous methanol. Stir in an ice bath. Weigh 6.00 g (106.95 mmol) of potassium hydroxide and add it to 20 mL of anhydrous methanol. Stir in an ice bath until dissolved. Under ice bath conditions, add the methanol solution of potassium hydroxide dropwise to the methanol solution of hydroxylamine hydrochloride. Continue stirring in an ice bath for 1 h. Filter to obtain a methanol solution of potassium hydroxylamine. Place compound 10m (0.24 g, 0.42 mmol) in a round-bottom flask and add freshly prepared methanol solution of potassium hydroxylamine (20 mL). Stir at room temperature for 6 h. Monitor the reaction by TLC. After the reaction is complete, evaporate the solvent, add 2 mL of water to dissolve, and then slowly adjust the pH to 7-8 with 1 M hydrochloric acid. A large amount of solid precipitates out. Filter and dry to obtain 0.23 g of brown solid (compound 11m), yield 99%, which is directly used in the next step. ESI-MS, m / z=594.4 [M+K] + .

[0081] Target compound M15: Compound 11m (0.23 g, 0.41 mmol) was placed in a round-bottom flask and dissolved in 4 mL of EA. While stirring, 10 mL of saturated ethyl acetate solution of hydrogen chloride was added. The mixture was stirred at room temperature, and a solid precipitated. After the reaction was complete as monitored by TLC, the product was filtered and dried to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to give 62 mg of a brown solid (hydrochloride of target compound M15), with a yield of 31%. The NMR data of the product are as follows: 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.93 (s, 1H), 8.75 (s, 1H), 8.03 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.78 -7.63(m, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.26 (s, 1H), 4.45 (t, J = 7.1 Hz, 2H), 3.20 – 3.08 (m, 2H), 2.74 – 2.65 (m, 2H), 1.97 –1.83 (m, 2H), 1.70 (q, J = 7.0 Hz, 2H), 1.63 – 1.51 (m, 1H), 1.39 (q, J =10.8 Hz, 2H). ESI-MS, m / z=456.1 [M+H] + .

[0082] The preparation method of compound N15 is similar to that of compound M15 (the difference lies in the substitution of the structure of substituent R1 in compound 6).

[0083] Example 3. Preparation of compounds M16 and N16, taking compound N16 as an example.

[0084] Synthesis route:

[0085]

[0086] The specific synthesis method and steps are as follows:

[0087] Compound 13n: TEA (1.49 g, 14.76 mmol) was slowly added to 21 mL of DCM containing 12 (1.70 g, 7.38 mmol) of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (7.38 mmol), followed by the addition of 4-dimethylaminopyridine (18 mg, 0.15 mmol) and p-toluenesulfonyl chloride (1.55 g, 8.12 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the reaction mixture was poured into a large volume of water, extracted with DCM, washed with saturated NaCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1.33 g of a white solid, which was directly used in the next step. Compound 6n (0.40 g, 0.97 mmol) was dissolved in DMF (15 mL) at 0 °C. A 60% NaH mineral oil dispersion (58 mg, 1.46 mmol) was added in portions, and the mixture was stirred at 0 °C for 30 min. Then, the previously prepared white solid (0.41 g, 1.07 mmol) was added, and the mixture was stirred at 80 °C. The reaction was monitored by TLC for 1 h until completion. After the reaction was complete, the mixture was cooled, and the reaction solution was quenched in a large volume of water. The aqueous phase was extracted three times with EA, and the organic phases were combined. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 0.4 g of a yellow solid (compound 13n), with a yield of 66%. The NMR data of the product are as follows: 1 HNMR (400 MHz, DMSO-d6) δ 8.40 (s, 2H), 8.19 (s, 1H), 7.90 (d, J = 8.3 Hz,1H), 7.83 (d, J = 7.4 Hz, 1H), 7.44 (s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 4.60(t, J = 5.8 Hz, 2H), 3.92 (s, 3H), 3.17 (t, J = 5.0 Hz, 4H), 2.69 (t, J = 6.5Hz, 2H), 2.42 (t, J = 5.0 Hz, 4H), 1.33 (s, 9H). ESI-MS, m / z=624.4 [M+H] + .

[0088] Compound 14n: Weigh 5.00 g (71.95 mmol) of hydroxylamine hydrochloride and add it to 12 mL of anhydrous methanol. Stir in an ice bath. Weigh 6.00 g (106.95 mmol) of potassium hydroxide and add it to 20 mL of anhydrous methanol. Stir in an ice bath until dissolved. Under ice bath conditions, add the methanol solution of potassium hydroxide dropwise to the methanol solution of hydroxylamine hydrochloride. Continue stirring in an ice bath for 1 h. Filter to obtain a methanol solution of potassium hydroxylamine. Place compound 13n (0.38 g, 0.61 mmol) in a round-bottom flask and add freshly prepared methanol solution of potassium hydroxylamine (20 mL). Stir overnight at room temperature. Monitor by TLC. After the reaction is complete, evaporate the solvent, add 2 mL of water to dissolve, and then slowly adjust the pH to 7-8 with 1 M hydrochloric acid. A large amount of solid precipitates out. Filter and dry to obtain 0.34 g of yellow solid (compound 14n), yield 89%, which is used directly in the next step. ESI-MS, m / z=625.3 [M+H] + .

[0089] Target compound N16: Compound 14n (0.34 g, 0.54 mmol) was placed in a round-bottom flask and dissolved in 4 mL of EA. While stirring, 15 mL of saturated ethyl acetate solution of hydrogen chloride was added. The mixture was stirred overnight at room temperature, and a solid precipitated. After the reaction was complete as monitored by TLC, the product was filtered and dried to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to give 97 mg of a brown solid (hydrochloride of target compound N16), with a yield of 32%. The NMR data of the product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 11.14 (s, 1H), 9.69 (s,3H), 8.60 (s, 2H), 8.17 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 7.3Hz, 1H), 7.43 – 7.28 (m, 2H), 4.93 (s, 2H), 3.77 – 3.21 (m, 10H). ESI-MS, m / z=559.0 [M+Cl] - .

[0090] The preparation method of compound M16 is similar to that of compound N16 (the difference lies in the substitution of the structure of substituent R1 in compound 6).

[0091] Example 4. Preparation of compounds M17 and N17, taking compound M17 as an example.

[0092] Synthesis route:

[0093]

[0094] The specific synthesis method and steps are as follows:

[0095] Compound 15m: Compound 6m (0.19 g, 0.55 mmol) was placed in a round-bottom flask and dissolved in 6 mL of DMF. A 60% NaH mineral oil dispersion (44 mg, 1.10 mmol) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, tert-butyl bromoacetate (0.16 g, 0.83 mmol) was added, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was quenched in a large volume of water, extracted with EA, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and column chromatographically purified to give 0.24 g of a yellow solid (compound 15m), with a yield of 95%. The NMR data of the product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.90 – 7.82 (m, 3H), 7.73 (t, J = 7.9 Hz, 1H), 7.43 (s, 1H), 7.39 (t, J = 7.9Hz, 1H), 5.27 (s, 2H), 3.93 (s, 3H), 1.37 (s, 9H). ESI-MS, m / z=458.2 [M+H] + .

[0096] Compound 16m: Compound 15m (0.24 g, 0.52 mmol) was dissolved in 6 mL of DCM, and then TFA (5.93 g, 52.00 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was evaporated to give 0.24 g of dark red solid (compound 16m) in 100% yield, which was used directly in the next reaction. ESI-MS, m / z = 801.4 [2M-H] - .

[0097] Compound 18m: TBTU (0.29 g, 0.90 mmol) and DIPEA (0.12 g, 0.90 mmol) were added to an 8 mL DMF solution of compound 16m (0.24 g, 0.60 mmol) under ice bath conditions. The mixture was stirred for 30 min under ice bath conditions, followed by the addition of N-methylpiperazine (17, 90 mg, 0.90 mmol). The mixture was stirred at room temperature. TLC monitoring was performed. After 7 h of reaction, the reaction mixture was poured into a large volume of water and extracted three times with EA. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and column chromatographically purified to give 0.10 g of a pale yellow solid (compound 18m), with a yield of 34%. The NMR data of the product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.94 (d, J = 7.8 Hz,1H), 7.87 – 7.80 (m, 2H), 7.79 – 7.70 (m, 2H), 7.41 (s, 1H), 7.39 – 7.33 (m,1H), 5.48 (s, 2H), 3.93 (s, 3H), 3.88 – 3.71 (m, 2H), 3.57 – 3.46 (m, 2H), 3.03 – 2.60 (m, 4H), 2.50 (s, 3H). ESI-MS, m / z=484.5 [M+H] + .

[0098] Target compound M17: 5.00 g (71.95 mmol) of hydroxylamine hydrochloride was weighed and added to 12 mL of anhydrous methanol, stirred in an ice bath. 6.00 g (106.95 mmol) of potassium hydroxide was weighed and added to 20 mL of anhydrous methanol, stirred in an ice bath until dissolved. Under ice bath conditions, the methanol solution of potassium hydroxide was added dropwise to the methanol solution of hydroxylamine hydrochloride, and stirring continued for 1 h. The solution of potassium hydroxylamine in methanol was obtained by filtration. 0.11 g (0.23 mmol) of compound 18m was added to a round-bottom flask, and 10 mL of freshly prepared methanol solution of potassium hydroxylamine was added. The mixture was stirred at room temperature. TLC monitoring showed that after the reaction was complete, the solvent was evaporated, 2 mL of water was added to dissolve the compound, and the pH was slowly adjusted to 8-9 with 1 M hydrochloric acid. A large amount of solid precipitated out, which was filtered and dried to obtain the crude product. Purification by preparative high-performance liquid chromatography yielded 23 mg of brown solid (target compound M17), with a yield of 21%. The NMR data of the product are as follows: 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.08 (s, 1H), 7.98 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H),7.61 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.31 – 7.21 (m, 2H), 5.41(s, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.43 (t, J = 4.6 Hz, 2H), 2.38 (t, J = 4.8Hz, 2H), 2.20 (t, J = 5.0 Hz, 2H), 2.13 (s, 3H). ESI-MS, m / z=969.0 [2M+H] + .

[0099] The preparation method of compound N17 is similar to that of compound M17 (the difference lies in the substitution of the structure of substituent R1 in compound 6).

[0100] Example 5. Preparation of compounds M18 and N18, taking compound M18 as an example.

[0101] Synthesis route:

[0102]

[0103] The specific synthesis method and steps are as follows:

[0104] Compound 20m: TBTU (0.30 g, 0.93 mmol) and DIPEA (0.12 g, 0.93 mmol) were added to an 8 mL DMF solution of compound 16m (0.25 g, 0.62 mmol) under ice bath conditions. The mixture was stirred for 30 min under ice bath conditions, followed by the addition of N-Boc-piperazine (19 g, 0.17 g, 0.93 mmol) and stirring at room temperature. After 10 h of reaction, the reaction mixture was poured into a large volume of water and extracted three times with EA. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and column chromatographically purified to give 0.13 g of a pale yellow solid (compound 20m), with a yield of 37%. ESI-MS, m / z = 570.3 [M+H] + .

[0105] Compound 21m: Weigh 5.00 g (71.95 mmol) of hydroxylamine hydrochloride and add it to 12 mL of anhydrous methanol. Stir in an ice bath. Weigh 6.00 g (106.95 mmol) of potassium hydroxide and add it to 20 mL of anhydrous methanol. Stir in an ice bath until dissolved. Under ice bath conditions, add the methanol solution of potassium hydroxide dropwise to the methanol solution of hydroxylamine hydrochloride. Continue stirring in an ice bath for 1 h. Filter to obtain a methanol solution of potassium hydroxylamine. Add 0.12 g (0.21 mmol) of compound 20m to a round-bottom flask and add freshly prepared methanol solution of potassium hydroxylamine (12 mL). Stir at room temperature. Monitor the reaction by TLC. After the reaction is complete, evaporate the solvent, add 2 mL of water to dissolve, and then slowly adjust the pH to 8-9 with 1 M hydrochloric acid. A large amount of solid precipitates out. Filter and dry to obtain 0.11 g of brownish-yellow crude solid (compound 21m), yield 92%, which is directly used in the next step. ESI-MS, m / z=1163.4 [2M+Na] + .

[0106] Target compound M18: Compound 21m (0.11 g, 0.19 mmol) was dissolved in 2 mL of ethyl acetate, and 8 mL of ethyl hydrochloride solution was added. The mixture was stirred at room temperature for 7 h, and a solid precipitated out. The solid was filtered and dried to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to give 24 mg of a dark brown solid (hydrochloride of target compound M18), with a yield of 25%. The NMR data of the product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.56 – 8.74 (m, 3H), 8.01(s, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.7Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.33 – 7.18 (m,2H), 5.46 (s, 2H), 3.92 (s, 2H), 3.66 (s, 2H), 3.21 (s, 2H), 3.05 (s, 2H). ESI-MS, m / z = 469.3 [MH] - .

[0107] The preparation method of compound N18 is similar to that of compound M18 (the difference lies in the substitution of the structure of substituent R1 in compound 6).

[0108] Experimental Example 1. Evaluation of the in vitro HDAC inhibitory activity and subtype selectivity of the target compound.

[0109] This invention utilizes fluorescence analysis to determine the inhibitory activity of the target compound on HDAC11, HDAC1 and HDAC6, using the previously reported selective inhibitors of HDAC11, SIS17 and FT895, as positive controls.

[0110] The experimental results (Table 1) show that, similar to the results of the positive controls SIS17 and FT895, all the target compounds of the present invention have an inhibition rate of more than 50% against HDAC11 at a concentration of 0.5 μM, but an inhibition rate of less than 20% against HDAC1 and HDAC6. This preliminarily proves that the target compounds of the present invention have good selective inhibitory activity against HDAC11 subtypes.

[0111] Table 1. Results of in vitro HDAC11, HDAC1 and HDAC6 inhibition rate tests of the compounds

[0112]

[0113] Next, the target compounds were subjected to half-maximal inhibitory concentrations (IC50) of HDAC1, HDAC4, HDAC6, HDAC8, and HDAC11. 50 The results in Table 2 show that all tested compounds exhibit potent inhibitory activity against HDAC11, and the vast majority of compounds showed stronger HDAC11 inhibitory activity than the previously reported selective HDAC11 inhibitors SIS17 and FT895. Compound A1 (its structure is described in the background section of this patent specification) is an HDAC11 inhibitor previously reported by our research group (see: Patent Document CN 116924959 A). The results of head-to-head parallel tests with the compounds of this invention in Table 2 show that compound A1 also has moderate inhibitory activity against HDAC8 (IC50). 50 = 1.2μM), therefore the selectivity for HDAC11 is not ideal, while the compounds of this invention have IC values ​​for HDAC1, HDAC4, HDAC6 and HDAC8. 50 All of them are greater than 10 μM, thus exhibiting better HDAC11 subtype selectivity than compound A1; and some of the compounds of this invention have better HDAC11 inhibitory activity than compound A1.

[0114] Table 2. In vitro IC50 values ​​of compounds HDAC1, HDAC4, HDAC6, HDAC8 and HDAC11 50 Test Results

[0115]

[0116] Experimental Example 2. In vitro anti-proliferative experiment of the target compound on tumor cells

[0117] This invention conducted head-to-head parallel tests and compared the in vitro antiproliferative activity of representative compounds M15, M16, N15, N16 and the marketed drug Sorafenib against human hepatocellular carcinoma cell lines HepG2, Huh7, and MHCC97H. Table 3 shows that compounds M15, M16, N15, and N16 all exhibited potent antiproliferative activity against HepG2, Huh7, and MHCC97H cells, and the IC50 values ​​were significantly higher than those of other compounds. 50 The antiproliferative activity of compounds M15 and N15 against HepG2, Huh7, and MHCC97H cells was comparable to or even lower than that of Sorafenib. It is worth noting that compounds M16 showed significantly stronger antiproliferative activity against MHCC97H cells than Sorafenib, and compounds N16 also showed significantly stronger antiproliferative activity against Huh7 and MHCC97H cells than Sorafenib. Furthermore, it is noteworthy that compounds with two trifluoromethyl substituents on the terminal benzene ring exhibited superior antiproliferative activity against hepatocellular carcinoma cells compared to those with only one trifluoromethyl substituent. Specifically, compound N15 showed superior antiproliferative activity against hepatocellular carcinoma cells compared to compound M15, and compound N16 showed superior activity against compound M16. In addition, this invention evaluated the in vitro antiproliferative activity of compounds M15 and M16 against the human pancreatic cancer cell line Mia Paca2, and the results showed that compounds M15 and M16 also exhibited good in vitro antiproliferative activity against human pancreatic cancer cells Mia Paca2.

[0118] Table 3. Results of in vitro antiproliferative experiments on tumor cells by the compounds

[0119]

[0120] Experimental Example 3. Experiment on Target Compound Inducing Ferrocyte Fertility in Tumor Cells

[0121] Target compounds M15 and M16 were selected for ferroptosis induction experiments in tumor cells. The levels of reactive oxygen species (ROS) and lipid peroxidation in the human hepatocellular carcinoma line Huh7 treated with M15 and M16 were detected using the C11-BODIPY fluorescent probe and the DCFH-DA fluorescent probe, respectively, and quantitative analysis was performed using flow cytometry. The results showed that after 24 h of treatment with M15 (2.5 μM and 5 μM) and M16 (2.5 μM and 5 μM), the levels of lipid peroxidation and ROS in Huh7 cells increased in a dose-dependent manner. Figure 1 This strongly demonstrates the ferroptosis-inducing effect of HDAC11 selective inhibitors on hepatocellular carcinoma cells.

[0122] Experiment 4. Determination of the water solubility of the target compound

[0123] Table 4 shows the solubility test results in phosphate buffer at 25℃ and pH = 6.8. Compared with compounds A1 and A9, the water solubility of the target compounds of this invention was significantly improved. Specifically, the water solubility of compounds M11 (307.9 μg / mL) and M14 (322.4 μg / mL) was improved by more than 100 times, the water solubility of compound M16 (132.3 μg / mL) was improved by approximately 50 times, and the water solubility of M15 (27.7 μg / mL) was improved by more than 10 times. These results further demonstrate that this series of compounds overcomes the problem of poor water solubility of existing HDAC11 inhibitors represented by A1 and A9, exhibiting greater drug-like properties and warranting further research.

[0124] Table 4. Solubility of the compound in phosphate buffer at 25°C and pH 6.8

[0125]

[0126] Experimental Example 5. Oral Pharmacokinetics of the Target Compound in Mice

[0127] This invention conducted a pharmacokinetic (PK) study of the target compound M16 in ICR (CD-1) mice. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration of the target compound M16 intravenously (iv) or orally (po) at 50 mg / kg. The obtained concentration-time curves and pharmacokinetic parameters are shown below. Figure 2 As shown, the results indicate that the target compound M16 exhibits good pharmacokinetic properties in mice, with an oral bioavailability of 20.8%. In stark contrast to M16, compounds A1 and A9 were almost undetectable in mouse plasma after gavage administration, indicating very low oral bioavailability. Therefore, compound M16 demonstrates better druggability than A1 and A9.

[0128] Experimental Example 6. In vivo anti-hepatocellular carcinoma activity of the target compound in mice

[0129] This invention evaluated the in vivo antitumor effects of M15 and M16 using a C57BL / 6J mouse subcutaneously loaded mouse hepatocellular carcinoma Hepa1-6 model. Experimental results ( Figure 3The results showed that, compared with the blank control group, the tumor volume of mice orally administered compounds M15 and M16 was significantly reduced, and the tumors of some mice regressed (as shown by circles in the figure), indicating that compounds M15 and M16 have a potent in vivo antitumor effect when administered orally. It is also worth noting that, compared with the marketed drug Sorafenib (po, 50 mg / kg), the same oral dose of compound M15 (po, 50 mg / kg) showed stronger in vivo tumor-suppressing activity.

Claims

1. A hydroxamic acid HDAC11 isoform selective inhibitor, characterized in that, Inhibitors having the following structural general formula (I) and pharmaceutically acceptable salts, hydrates or solvates thereof: wherein, R1 is or ; R2 is , , , , , , , , , , , , , , , , or .

2. The hydroxamic acid HDAC11 isoform selective inhibitor of claim 1, wherein, The structure of the inhibitor is one of the following, and pharmaceutically acceptable salts, hydrates or solvates thereof: 。 3. The method for preparing the isohydroxamic acid HDAC11 subtype selective inhibitor as described in claim 2, characterized in that, selected from one of the following: (1) Compound 1 reacts with p-toluenesulfonyl chloride to form compound 2, compound 2 reacts with carbon tetrabromide to form compound 3, compound 3 reacts with compound 4 by Sonogashira coupling reaction to form compound 5, compound 5 is deprotected to form compound 6, compound 6 reacts with halide 7 to form compound 8, compound 8 reacts with potassium hydroxylamine to form compounds M1-M14, N1-N14; The reaction formula is as follows: In the reaction formula for preparing compounds M1-M14, N1-N14, the substituent group R1, R2 is the same as the substituent group R1, R2 in the corresponding compound M1-M14, N1-N14; (2) Compound 9 and 12 respectively react with p-toluenesulfonyl chloride to form p-toluenesulfonate, which reacts with compound 6 to form compound 10 and 13 respectively, compound 10 and 13 respectively react with potassium hydroxylamine to form compounds 11 and 14, and compounds 11 and 14 are deprotected under acidic conditions to form compounds M15, N15 and M16, N16 respectively; The reaction formula is as follows: In the reaction formula for preparing compounds M15-M16, N15-N16, the substituent group R1 is the same as the substituent group R1 in the corresponding compound M15-M16, N15-N16. (3) Compound 6 reacts with tert-butyl bromoacetate to form compound 15, compound 15 is deprotected under acidic conditions to form compound 16, compound 16 is condensed with compound 17 and 19 to form compounds 18 and 20 respectively, compound 18 and 20 respectively react with potassium hydroxylamine to form target compounds M17, N17 and intermediate 21; intermediate 21 is deprotected under acidic conditions to form compounds M18, N18; In the reaction formula, the substituent group R1 is the same as the substituent group R1 in the corresponding compound M17-M18, N17-N18.

4. The method for preparing the isohydroxamic acid HDAC11 subtype selective inhibitor according to claim 3, characterized in that, One or more of the following conditions: I. Reagents and conditions in the reaction formula for preparing compounds M1-M14, N1-N14: a. p-toluenesulfonyl chloride, sodium hydride, tetrahydrofuran, room temperature reaction; b. carbon tetrabromide, lithium diisopropylamide, tetrahydrofuran, -78℃ and room temperature reaction; c. cuprous iodide, triethylamine, bis(triphenylphosphine)palladium dichloride, 1,4-dioxane, 70℃ reaction; d. tetrabutylammonium fluoride trihydrate, tetrahydrofuran, 60℃ reaction; e. sodium hydride, N,N-dimethylformamide, 0℃-80℃ reaction; f. potassium hydroxylamine, methanol, room temperature reaction; II. Reagents and conditions in the reaction formula for preparing compounds M15, N15 and M16, N16: a. p-toluenesulfonyl chloride, triethylamine, 4-dimethylamino pyridine, dichloromethane, room temperature reaction; sodium hydride, N,N-dimethylformamide, 0℃-80℃ reaction; b. potassium hydroxylamine, methanol, room temperature reaction; c. hydrogen chloride ethyl acetate solution, ethyl acetate, room temperature reaction; III. Reagents and conditions in the reaction formula for preparing compounds M17, N17 and M18, N18: a. tert-butyl bromoacetate, sodium hydride, N,N-dimethylformamide, 0 °C- room temperature reaction; b. trifluoroacetic acid, dichloromethane, room temperature reaction; c. O-benzotriazol-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N,N- diisopropylethylamine, N,N-dimethylformamide, room temperature reaction; d. potassium hydroxylamine, methanol, room temperature reaction; e. hydrogen chloride ethyl acetate solution, ethyl acetate, room temperature reaction.

5. The HDAC11 subtype selective inhibitor of claim 1 or 2 for use in the preparation of a medicament for preventing or treating a disease associated with abnormal expression or activity of HDAC11.

6. Use according to claim 5, characterized in that, The disease associated with abnormal expression or activity of HDAC11 is cancer, metabolic disease, autoimmune disease or tissue fibrosis.

7. Use according to claim 5, characterized in that, The cancer is liver cancer, pancreatic cancer, acute myeloid leukemia, myeloproliferative neoplasm, multiple myeloma, Hodgkin lymphoma, non-small cell lung cancer, glioblastoma, pituitary tumor, prostate cancer, ovarian cancer or acute lymphoblastic leukemia.

8. Use according to claim 5, characterized in that, The metabolic disease is obesity, diabetes or metabolic dysfunction-related fatty liver disease.

9. Use according to claim 5, characterized in that, The autoimmune disease is inflammation, psoriasis, rheumatic arthritis, rheumatoid arthritis or systemic lupus erythematosus.

10. Use according to claim 5, characterized in that, The tissue fibrosis is pulmonary fibrosis, renal fibrosis or hepatic fibrosis.

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