Histone deacetylase inhibitor and use

Abstract

A histone deacetylase inhibitor and the use, which belong to the field of medicinal chemistry. A structurally new and highly efficient HDAC inhibitor is obtained by introducing a succinimide fragment, which is as shown in formula (I) below. The beneficial effects thereof involve: having an excellent inhibitory activity on HDACs and also an excellent anti-tumor activity in vitro; and providing a new pathway for the application of the HDAC inhibitor in solid tumors and / or the treatment of diseases related to uncontrolled histone deacetylase activity.

Description

A histone deacetylase inhibitor and its use Technical Field

[0001] The present invention relates to a histone deacetylase inhibitor and application thereof, belonging to the technical field of chemistry. Background Art

[0002] Epigenetic abnormalities are closely associated with the development of numerous human diseases, primarily due to dysfunctional epigenetic proteins caused by genetic defects. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are a group of enzymes with opposing biological functions that dynamically regulate the deacetylation and acetylation of histones. In normal cells, HDACs and HATs maintain a dynamic equilibrium, playing a key role in normal gene expression. This dynamic equilibrium between HDACs and HATs is often disrupted by abnormally enhanced HDAC biological activity, leading to abnormal expression of genes involved in the cell cycle and apoptosis, as well as abnormalities in the corresponding signaling pathways. Studies have shown that abnormal HDAC expression is closely associated with the development and progression of a variety of diseases, including cancer, inflammation, and neurological disorders. Therefore, the development of HDAC inhibitors has attracted widespread interest in the field of drug discovery and development, and shows broad application prospects. To date, the U.S. Food and Drug Administration has approved four HDAC inhibitors—vorinostat, romidepsin, berinocetin, and panobinostat—as well as chidamide, approved by the China Food and Drug Administration. These inhibitors are primarily used to treat hematologic cancers such as cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. However, HDAC inhibitors face significant bottlenecks and challenges: currently marketed HDAC inhibitors have been successfully used primarily in the treatment of hematologic cancers, but their monotherapy efficacy against solid tumors, such as breast cancer, kidney cancer, prostate cancer, and head and neck cancer, is generally poor, limiting their widespread clinical use. Therefore, there is an urgent clinical need to develop novel, highly effective HDAC inhibitors to expand their application in solid tumors.

[0003] Summary of the Invention

[0004] The purpose of the present invention is to develop a new histone deacetylase inhibitor to address the shortcomings of existing HDAC inhibitor drugs in the treatment of solid tumors, aiming to provide more efficient and safe HDAC inhibitors and improve the therapeutic effect of HDAC inhibitors on solid tumors.

[0005] HDAC small molecule inhibitors are mainly composed of four parts: a zinc binding group (ZBG), a linker, a connecting unit (CU), and a cap group (Cap). The existing technology for the research of HDAC small molecule inhibitors mainly focuses on the zinc binding group and the connecting unit. The CU of most HDAC inhibitors is often only a simple sp2 hybrid group, such as an amide, a carbonyl group, etc. However, CU has a crucial influence on the molecular conformation and even the efficacy and pharmacokinetic properties. Therefore, the purpose of the present invention is to provide a new type of effective HDACs inhibitor and a pharmaceutically acceptable salt thereof. Based on this purpose, the present invention first provides the following compound, which has the following general formula:

[0006] Where X, Y, Z, M 1 、M 2 each independently represents a carbon or nitrogen atom,

[0007] When X, Y, Z, M 1 、M 2 When they are carbon atoms, they are each independently optionally replaced by R 2 Replacement, R 2 is hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

[0008] M 3 is carbon, which may be independently optionally replaced by R 4 、R 5 Replacement, R 4 、R 5 is hydrogen, deuterium, alkyl, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, methylene, aralkyl, diarylalkyl, aryl or Het;

[0009] Q 1 is selected from saturated or unsaturated straight or branched hydrocarbon groups with a length of 1 to 8 carbon atoms, aryl or Het;

[0010] R 1 Selected from hydroxyl, one or more R 3 Substituted 2-aminophenyl,

[0011] R 3 is hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, aryl or Het;

[0012] The alkyl group is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms;

[0013] Alkoxy is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted by oxygen;

[0014] Alkylamino is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted by an NH group;

[0015] Alkoxyalkyl is an alkoxy group as defined above attached to an alkyl group;

[0016] Alkenyl and alkynyl are straight-chain or branched unsaturated hydrocarbon groups containing double or triple bonds and having 1 to 6 carbon atoms;

[0017] Aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

[0018] Aralkyl and diarylalkyl are aryl groups as defined above linked to an alkyl group;

[0019] Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; or selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4] a bicyclic heterocycle selected from a dioxinyl or benzo[1,3]dioxolyl group; or a monocyclic saturated hydrocarbon group of 3-6 carbon atoms, a bicyclic saturated hydrocarbon group of 6-12 carbon atoms, wherein the carbon atoms on the ring are independently optionally substituted with 1-4 O, S, N or NH; each monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy;

[0020] Halogen is a substituent selected from fluorine, chlorine, bromine or iodine;

[0021] A haloalkyl group is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein one or more carbon atoms are substituted by one or more halogen atoms.

[0022] The present invention further selects the following compounds as HDACs inhibitors: wherein X, Y, Z, M 1 、M 2 Each independently represents a carbon or nitrogen atom. 1 、M 2 When they are carbon atoms, they are each independently optionally replaced by R 2 Replacement, R 2 is hydrogen, alkyl, cyano, halogen, haloalkyl, alkoxy, alkylthio, or alkoxyalkyl;

[0023] M 3 is carbon, which may be independently optionally replaced by R 4 、R 5 Replacement, R 4 、R 5 is hydrogen, deuterium, alkyl, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, methylene, aralkyl, diarylalkyl, aryl or Het;

[0024] Q 1 is selected from saturated or unsaturated straight or branched hydrocarbon groups and aromatic groups with a length of 1 to 8 carbon atoms;

[0025] R 1 Selected from hydroxyl, optionally replaced by one or more R 3 substituted 2-aminophenyl;

[0026] R 3 is hydrogen, alkyl, cyano, halogen, haloalkyl, aryl or Het.

[0027] The present invention further selects the following compounds as HDACs inhibitors: wherein X, Y, Z, M 1 、M 2 Each independently represents a carbon or nitrogen atom. 1 、M 2 When they are carbon atoms, they are each independently optionally replaced by R 2 Replacement, R 2 is hydrogen, alkyl, halogen, alkoxy;

[0028] M 3 is carbon, which may be independently optionally replaced by R 4 、R 5 Replacement, R 4 、R5 is hydrogen, deuterium, alkyl, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, methylene, aralkyl, diarylalkyl, aryl or Het;

[0029] Q 1 is selected from saturated or unsaturated straight or branched hydrocarbon groups or aromatic groups having a length of 3 to 8 carbon atoms;

[0030] R 1 Selected from hydroxyl, optionally replaced by one or more R 3 Substituted 2-aminophenyl,

[0031] R 3 is hydrogen, alkyl, cyano, halogen, haloalkyl, aryl or Het.

[0032] The present invention further selects the following compounds as HDACs inhibitors:

[0033] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxybutyramide (I-1),

[0034] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxypentanamide (I-2),

[0035] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyhexanamide (I-3),

[0036] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide (I-4),

[0037] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyoctanamide (I-5),

[0038] (E)-N-(2-amino-4-fluorophenyl)-4-(3-benzylidene-2,5-diketopyrrolidinyl)butanamide (I-6),

[0039] (E)-N-(2-amino-4-fluorophenyl)-5-(3-benzylidene-2,5-diketopyrrolidinyl)pentanamide (I-7),

[0040] (E)-N-(2-amino-4-fluorophenyl)-6-(3-benzylidene-2,5-diketopyrrolidinyl)hexanamide (I-8),

[0041] (E)-N-(2-amino-4-fluorophenyl)-7-(3-benzylidene-2,5-diketopyrrolidinyl)heptylamide (I-9),

[0042] 4-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)butanamide (I-10),

[0043] 5-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)pentanamide (I-11),

[0044] 6-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)hexanamide (I-12),

[0045] 7-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)heptylamide (I-13),

[0046] 8-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)octanamide (I-14),

[0047] (E)-7-(3-(4-isopropylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-15),

[0048] (E)-7-(3-(4-dimethylaminobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-16),

[0049] (E)-7-(3-(4-trifluoromethylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-17),

[0050] (E)-7-(3-(4-methylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-18),

[0051] (E)-7-(3-(2-methylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-19),

[0052] (E)-7-(3-(2-cyanobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-20),

[0053] (E)-7-(3-(2-methylenepyridine)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-21),

[0054] (E)-7-(3-(2-methylenenaphthyl)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-22),

[0055] (E)-7-(3-(2-methylenethienyl)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-23),

[0056] (E)-7-(3-(2-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-24),

[0057] (E)-7-(3-(3-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-25),

[0058] (E)-7-(3-(4-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-26),

[0059] (E)-7-(3-(3-bromobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-27),

[0060] (E)-7-(3-(3-fluorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-28),

[0061] (E)-7-(3-(3-iodobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-29),

[0062] (E)-7-(3-(3,4-dichlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-30),

[0063] (E)-7-(3-(2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-31),

[0064] (E)-7-(3-(3-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-32),

[0065] (E)-7-(3-(4-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-33),

[0066] (E)-7-(3-(3,4-dimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-34),

[0067] (E)-7-(3-(3,4,5-trimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-35),

[0068] (E)-7-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-36),

[0069] (E)-7-(3-(2-hydroxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-37),

[0070] (E)-7-(3-(2-ethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-38),

[0071] (E)-7-(3-(5-bromo-2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-39),

[0072] (E)-7-(3-(4-bromo-2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-40),

[0073] (E)-4-((3-benzylidene-2,5-diketopyrrolidinyl)methyl)-N-hydroxybenzamide (I-41).

[0074] The above compound was prepared by the following method:

[0075] The compounds of the present invention can be prepared according to the above or similar preparation methods, and corresponding raw materials can be selected according to the different substituents and the different positions of the substituents.

[0076] The present invention further provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the above compound or a pharmaceutically acceptable salt thereof is the active ingredient.

[0077] The present invention further provides the use of the above compounds in the preparation of medicaments for preventing or treating clinical conditions associated with HDACs. The HDAC-related diseases include lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin diseases, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin-dependent diabetes mellitus, and autoimmune diseases.

[0078] The present invention cyclizes the amide bond C—U to form a five-membered ring, resulting in a novel, highly effective HDAC inhibitor. This inhibitor exhibits excellent inhibitory activity against HDACs and in vitro anti-tumor activity, providing a new research avenue for the application of HDAC inhibitors in solid tumors. DETAILED DESCRIPTION

[0079] Example 1

[0080] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxybutyramide (I-1)

[0081] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0082] To a 100 mL round-bottom flask, maleimide (5 mmol, 485.35 mg), methanol (10 mL), triphenylphosphine (6 mmol, 1.57 g), and benzaldehyde (7.5 mmol, 795 mg) were added in sequence and stirred at reflux at 60°C for 8 h. After cooling to room temperature, a solid precipitated. The filter cake was filtered and dried to yield 750 mg of a white solid, in an 80.1% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.66-7.59 (m, 2H), 7.52-7.41 (m, 3H), 7.39 (t, J = 2.5 Hz, 1H), 3.66 (d, J = 2.5 Hz, 2H).

[0083] Step b: Synthesis of ethyl (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)butyrate

[0084] To a 100 mL round-bottom flask, (E)-3-benzylidenepyrrolidine-2,5-dione (749 mg, 4 mmol), DMF (10 mL), and potassium carbonate (829 mg, 6 mmol) were added sequentially. The mixture was stirred on ice for 30 min. After the reaction returned to room temperature, ethyl bromobutyrate (1.56 g, 8 mmol) was added and stirred at room temperature for 8 h. The mixture was extracted with water and ethyl acetate, and the organic layer was concentrated. The mixture was eluted by column chromatography using a 3:1 (volume ratio) mixture of petroleum ether and ethyl acetate to obtain 678 mg of a transparent liquid in a 56.2% yield. 1H NMR (300MHz, Chloroform-d) δ7.71-7.36 (m, 6H), 4.13 (q, J=7.1Hz, 2H), 3.70 (t, J=6.9Hz, 2H ), 3.57 (d, J=2.4Hz, 2H), 2.36 (t, J=7.4Hz, 2H), 1.99 (p, J=7.2Hz, 2H), 1.26 (t, J=7.1Hz, 3H).

[0085] Step c: Synthesis of (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxybutyramide

[0086] To a 50 mL round-bottom flask, ethyl (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)butyrate (600 mg, 1.99 mmol), 3 mL of glacial acetic acid, and 0.5 mL of concentrated hydrochloric acid were added. The reaction was stirred at 90° C. The reaction was monitored by TLC to be complete. The reaction solution was cooled and added to water. Solid precipitated, and the filter cake was filtered, collected, and dried.

[0087] Take a 50 mL round-bottom flask, add the dried filter cake, dissolve it with 5 mL of tetrahydrofuran, add 484 mg of N, N-carbonyldiimidazole and stir to react. After 1 hour, slowly add hydroxylamine hydrochloride (415 mg, 5.97 mmol) and stir to react for 12 hours. The reaction solution is concentrated and eluted by column chromatography with a mixed solvent of dichloromethane: methanol in a volume ratio of 25:1 as the eluent to obtain 63 mg of a slightly yellow solid with a yield of 11%. 1H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.71 (s, 1H), 7.69-7.62 (m, 2H), 7.48 (qt, J=6.9, 3.7Hz, 5H), 3.70 (d, J=2.4Hz, 2H), 3.50 (t, J=7.1Hz, 2H), 2.03-1.94 (m, 2H), 1.76 (p, J=7.5Hz, 2H).13C NMR (101MHz, DMSO-d6) δ174.78, 171.15, 168.83, 134.60, 132.37, 130.70, 130.27, 129.46, 125.80, 38.29, 34.20, 30.28, 24.05.

[0088] Example 2

[0089] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxypentanamide (I-2)

[0090] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0091] The operation and feeding are the same as those in step a of Example 1.

[0092] Step b: Synthesis of ethyl (E)-5-(3-benzylidene-2,5-dioxopyrrolidinyl)pentanoate

[0093] The target compound was synthesized using ethyl bromovalerate as raw material using a method similar to step b in Example 1.

[0094] Step c: Synthesis of (E)-5-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxypentanamide,

[0095] The target compound was synthesized using ethyl (E)-5-(3-benzylidene-2,5-dioxopyrrolidinyl)pentanoate in a manner similar to that described in Step c of Example 1. The product was a white solid in a 15.2% yield. H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.71 (s, 1H), 7.69-7.61 (m, 2H), 7.53-7.40 (m, 4H), 3.72 (d, J = 2.4 Hz, 2H), 3.48 (t, J = 6.2 Hz, 2H), 1.97 (t, J = 6.6 Hz, 2H), 1.58-1.48 (m, 2H), and 1.51-1.41 (m, 2H).

[0096] 13C NMR (101MHz, DMSO) δ 174.80, 171.16, 169.23, 134.59, 132.42, 130.71, 130.28, 129.45, 125.74, 38.29, 34.15, 32.28, 27.44, 23.00.

[0097] Example 3

[0098] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyhexanamide (I-3)

[0099] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0100] The operation and feeding are the same as those in step a of Example 1.

[0101] Step b: Synthesis of ethyl (E)-6-(3-benzylidene-2,5-dioxopyrrolidinyl)hexanoate

[0102] The target compound was synthesized using ethyl bromohexanoate as raw material using a method similar to step b in Example 1.

[0103] Step c: Synthesis of (E)-6-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyhexanamide,

[0104] The target compound was synthesized using ethyl (E)-6-(3-benzylidene-2,5-dioxopyrrolidinyl)hexanoate in a manner similar to that described in Step c of Example 1. The product was a yellow solid in an 18.2% yield. H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.69-7.62 (m, 2H), 7.56-7.40 (m, 4H), 3.72 (d, J = 2.4 Hz, 2H), 3.48 (t, J = 7.2 Hz, 2H), 1.94 (t, J = 7.4 Hz, 2H), 1.52 (dqd, J = 15.6, 7.7, 0.0 Hz, 4H), 1.31-1.17 (m, 2H).

[0105] 13C NMR (101MHz, DMSO) δ174.79, 171.15, 169.45, 134.58, 132.40, 130.70, 130.28, 129.45, 125.74, 38.43, 34.14, 32.52, 27.57, 26.33, 25.18.

[0106] Example 4

[0107] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide (I-4)

[0108] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0109] The operation and feeding are the same as those in step a of Example 1.

[0110] Step b: Synthesis of ethyl (E)-7-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate

[0111] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0112] Step c: Synthesis of (E)-7-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide,

[0113] The target compound was synthesized using ethyl ((E)-7-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate as starting material by a method similar to that in Step c of Example 1. The product was obtained as a white solid in a yield of 16.1%. H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.66 (s, 1H), 7.68-7.62 (m, 2H), 7.47 (qt, J = 6.9, 3.6 Hz, 4H), 3.71 (d, J = 2.4 Hz, 2H), 3.48 (t, J = 7.2 Hz, 2H), 1.94 (t, J = 7.4 Hz, 2H), 1.58-1.42 (m, 4H), 1.32-1.21 (m, 4H).

[0114] 13C NMR (101MHz, DMSO) δ174.78, 171.15, 169.53, 134.60, 132.38, 130.70, 130.26, 129.44, 125.76, 38.48, 34.14, 32.64, 28.63, 27.67, 26.44, 25.45.

[0115] Example 5

[0116] (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyoctanamide (I-5)

[0117] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0118] The operation and feeding are the same as those in step a of Example 1.

[0119] Step b: Synthesis of ethyl (E)-8-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate

[0120] The target compound was synthesized using ethyl bromooctanoate as raw material using a method similar to step b in Example 1.

[0121] Step c: Synthesis of (E)-8-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide,

[0122] The target compound was synthesized using ethyl (E)-8-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate in a manner similar to that described in Step c of Example 1. The product was a pale yellow solid in a 20.2% yield. H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.71-7.61 (m, 2H), 7.53-7.40 (m, 4H), 3.72 (d, J = 2.4 Hz, 2H), 3.48 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.56-1.43 (m, 4H), 1.31-1.19 (m, 6H).

[0123] 13C NMR (101MHz, DMSO) δ174.76, 171.15, 169.60, 134.58, 132.40, 130.68, 130.2 5, 129.43, 125.72, 38.50, 34.13, 32.71, 28.94, 28.78, 27.75, 26.65, 25.53.

[0124] Example 6

[0125] (E)-N-(2-amino-4-fluorophenyl)-4-(3-benzylidene-2,5-diketopyrrolidinyl)butanamide (I-6)

[0126] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0127] The operation and feeding are the same as those in step a of Example 1.

[0128] Step b: Synthesis of ethyl (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)butyrate

[0129] The target compound was synthesized using ethyl bromobutyrate as raw material in a manner similar to step b in Example 1.

[0130] Step c: Synthesis of (E)-N-(2-amino-4-fluorophenyl)-4-(3-benzylidene-2,5-diketopyrrolidinyl)butanamide,

[0131] The target compound was synthesized using ethyl (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)butanoate and 4-fluoro-o-phenylenediamine in a similar manner to step c in Example 1. The product was a white solid with a yield of 25.2%. 1HNMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 7.69-7.62 (m, 2H), 7.52-7.42 (m, 4H), 7.11-7.01 (m, 1H), 6.48 (dd, J=11.2, 2.9Hz, 1H), 6. 27 (td, J=8.6, 2.9Hz, 1H), 5.18 (s, 2H), 3.71 (d, J=2.4Hz, 2H), 3.57 (t, J=6.9Hz, 2H), 2.34 (t, J=7.5Hz, 2H), 1.88 (p, J=7.1Hz, 2H).

[0132] 13CNMR (101MHz, DMSO) δ174.88, 171.25, 171.11, 162.25, 159.88, 145.06, 144. 94, 134.58, 132.44, 130.70, 130.29, 129.47, 127.92, 127.82, 125.77, 119.76, 102.35, 102.13, 101.75, 101.50, 38.20, 34.22, 33.27, 23.78.

[0133] Example 7

[0134] (E)-N-(2-amino-4-fluorophenyl)-5-(3-benzylidene-2,5-diketopyrrolidinyl)pentanamide (I-7)

[0135] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0136] The operation and feeding are the same as those in step a of Example 1.

[0137] Step b: Synthesis of ethyl (E)-5-(3-benzylidene-2,5-dioxopyrrolidinyl)pentanoate

[0138] The target compound was synthesized using ethyl bromovalerate as raw material using a method similar to step b in Example 1.

[0139] Step c: Synthesis of (E)-N-(2-amino-4-fluorophenyl)-4-(3-benzylidene-2,5-diketopyrrolidinyl)butanamide,

[0140] The target compound was synthesized using ethyl ((E)-5-(3-benzylidene-2,5-dioxopyrrolidinyl)valerate and 4-fluoro-o-phenylenediamine in a similar manner to step c in Example 1. The product was a white solid with a yield of 36.8%. NMR (300MHz, DMSO-d6) δ9.03 (s, 1H), 7.72-7.59 (m, 2H), 7.55-7.37 (m, 4H), 7.09 (dd, J=8.7, 6.3Hz, 1H), 6.48 (dd, J=11.2, 2.9Hz, 1H ), 6.30 (td, J=8.5, 2.9Hz, 1H), 5.15 (s, 2H), 3.73 (d, J=2.3Hz, 2H), 3.53 (t, J=5.5Hz, 2H), 2.33 (t, J=6.9Hz, 2H), 1.65-1.50 (m, 4H).

[0141] 13CNMR (101MHz, DMSO) δ174.82, 171.53, 171.19, 162.13, 159.77, 144.78, 144.66, 134.59, 132.42, 130.70, 130.28, 1 29.45, 127.62, 127.52, 125.77, 119.95, 119.92, 102.43, 102.21, 101.89, 101.64, 38.37, 35.55, 34.17, 27.42, 22.97.

[0142] Example 8

[0143] (E)-N-(2-amino-4-fluorophenyl)-6-(3-benzylidene-2,5-diketopyrrolidinyl)hexanamide (I-8)

[0144] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0145] The operation and feeding are the same as those in step a of Example 1.

[0146] Step b: Synthesis of ethyl (E)-6-(3-benzylidene-2,5-dioxopyrrolidinyl)hexanoate

[0147] The target compound was synthesized using ethyl bromohexanoate as raw material using a method similar to step b in Example 1.

[0148] Step c: Synthesis of (E)-N-(2-amino-4-fluorophenyl)-6-(3-benzylidene-2,5-diketopyrrolidinyl)hexanamide,

[0149] The target compound was synthesized using ethyl ((E)-6-(3-benzylidene-2,5-dioxopyrrolidinyl)hexanoate and 4-fluoro-o-phenylenediamine in a similar manner to step c in Example 1. The product was a white solid with a yield of 36.8%. NMR (300MHz, DMSO-d6) δ9.03 (s, 1H), 7.72-7.59 (m, 2H), 7.55-7.37 (m, 4H), 7.09 (dd, J=8.7, 6.3Hz, 1H), 6.48 (dd, J=11.2, 2.9Hz, 1H ), 6.30 (td, J=8.5, 2.9Hz, 1H), 5.15 (s, 2H), 3.73 (d, J=2.3Hz, 2H), 3.53 (t, J=5.5Hz, 2H), 2.33 (t, J=6.9Hz, 2H), 1.65-1.50 (m, 4H).

[0150] 13CNMR (101MHz, DMSO) δ174.82, 171.53, 171.19, 162.13, 159.77, 144.78, 144.66, 134.59, 132.42, 130.70, 130.28, 1 29.45, 127.62, 127.52, 125.77, 119.95, 119.92, 102.43, 102.21, 101.89, 101.64, 38.37, 35.55, 34.17, 27.42, 22.97.

[0151] Example 9

[0152] (E)-N-(2-amino-4-fluorophenyl)-7-(3-benzylidene-2,5-diketopyrrolidinyl)heptylamide (I-9)

[0153] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0154] The operation and feeding are the same as those in step a of Example 1.

[0155] Step b: Synthesis of ethyl (E)-7-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate

[0156] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0157] Step c: Synthesis of (E)-N-(2-amino-4-fluorophenyl)-7-(3-benzylidene-2,5-diketopyrrolidinyl)heptylamide,

[0158] The target compound was synthesized using ethyl (E)-7-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate and 4-fluoro-o-phenylenediamine in a similar manner to step c in Example 1. The product was a white solid with a yield of 32.9%. 1H NMR (300MHz, DMSO-d6) δ9.02 (s, 1H), 7.73-7.59 (m, 2H), 7.53-7.37 (m, 4H), 7.09 (dd, J=8.7, 6.3Hz, 1H), 6.48 (dd, J=11.2, 2.9Hz, 1H), 6.29 (t d, J=8.6, 2.9Hz, 1H), 5.13 (s, 2H), 3.72 (d, J=2.4Hz, 2H), 3.50 (t, J=7.1Hz, 2H), 2.29 (t, J=7.4Hz, 2H), 1.67-1.47 (m, 4H), 1.40-1.23 (m, 4H).

[0159] 13C NMR (101MHz, DMSO) δ174.81, 171.82, 171.18, 162.39, 159.61, 144.77, 144.65, 134.60, 132.38, 130.70, 130.27, 129.4 5, 127.59, 127.49, 125.77, 120.04, 102.47, 102.24, 101.93, 101.68, 38.49, 36.03, 34.15, 28.75, 27.69, 26.52, 25.56.

[0160] Example 10

[0161] 4-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)butanamide (I-10)

[0162] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0163] The operation and feeding are the same as those in step a of Example 1.

[0164] Step b: Synthesis of ethyl (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)butyrate

[0165] The target compound was synthesized using ethyl bromobutyrate as raw material in a manner similar to step b in Example 1.

[0166] Step c: Synthesis of 4-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)butanamide,

[0167] The target compound was synthesized using ethyl (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)butanoate and (1S,2S)-2-aminocyclohexanol as starting materials using a method similar to that in Step c of Example 1. The product was a white solid in a 35.8% yield. 1H NMR (400MHz, DMSO-d6) δ7.68-7.63 (m, 2H), 7.59 (d, J=8.0Hz, 1H), 7.52-7.42 (m, 4H), 4.50 (d, J=4.8Hz, 1H), 3.70 (d, J=2.4Hz, 2H), 3 .51 (t, J=7.1Hz, 3H), 3.41 (m, 1H), 3.20 (m, 1H), 2.10 (t, J=7.0Hz, 2H), 1.76 (p, J=7.5Hz, 2H), 1.64-1.51 (m, 2H), 1.31-0.99 (m, 6H).

[0168] 13C NMR (101MHz, DMSO) δ174.80, 171.57, 171.18, 134.60, 132.38, 130.69, 130.27, 129. 47, 125.79, 71.73, 54.58, 38.32, 34.40, 34.20, 33.46, 31.42, 24.54, 24.19, 24.13.

[0169] Example 11

[0170] 5-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)pentanamide (I-11)

[0171] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0172] The operation and feeding are the same as those in step a of Example 1.

[0173] Step b: Synthesis of ethyl (E)-5-(3-benzylidene-2,5-dioxopyrrolidinyl)pentanoate

[0174] The target compound was synthesized using ethyl bromovalerate as raw material using a method similar to step b in Example 1.

[0175] Step c: Synthesis of 5-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)pentanamide,

[0176] The target compound was synthesized using ethyl (E)-5-(3-benzylidene-2,5-dioxopyrrolidinyl)pentanoate and (1S,2S)-2-aminocyclohexanol as starting materials in a manner similar to step c in Example 1. The product was a white solid with a yield of 40.6%. 1H NMR (400MHz, DMSO-d6) δ7.69-7.63 (m, 2H), 7.57 (d, J=7.8Hz, 1H), 7.51-7.42 (m, 4H), 4.50 (d, J=4.9Hz, 1H), 3.72 (d, J=2.5Hz, 2H), 3. 49 (t, J=6.5Hz, 2H), 3.42-3.36 (m, 1H), 3.20 (m, 1H), 2.09 (t, J=6.6Hz, 2H), 1.87-1.72 (m, 2H), 1.62-1.43 (m, 6H), 1.24-1.06 (m, 4H).

[0177] 13C NMR (101MHz, DMSO) δ174.78, 172.09, 171.15, 134.59, 132.41, 130.70, 130.27, 129.45, 125.76, 71.74, 54.54, 38.39, 35.50, 34.47, 34.15, 31.46, 27.43, 24.53, 24.20, 23.16.

[0178] Example 12

[0179] 6-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)hexanamide (I-12)

[0180] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0181] The operation and feeding are the same as those in step a of Example 1.

[0182] Step b: Synthesis of ethyl (E)-6-(3-benzylidene-2,5-dioxopyrrolidinyl)hexanoate

[0183] The target compound was synthesized using ethyl bromohexanoate as raw material using a method similar to step b in Example 1.

[0184] Step c: Synthesis of 6-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)hexanamide,

[0185] The target compound was synthesized using ethyl (E)-6-(3-benzylidene-2,5-dioxopyrrolidinyl)hexanoate and (1S,2S)-2-aminocyclohexanol as starting materials using a method similar to that in Step c of Example 1. The product was a white solid in a 38.5% yield. 1H NMR (400MHz, DMSO-d6) δ7.71-7.61 (m, 2H), 7.54 (d, J=7.8Hz, 1H), 7.52-7.41 (m, 4H), 4.48 (d, J=5.1Hz, 1H), 3.71 (d, J=2.4Hz, 2H), 3.48 (t, J=7.1Hz, 2H), 3.42-3.35 (m, 1H), 3.24-3.15 (m, 1H), 2.06 (t, J=7.4 Hz, 2H), 1.86-1.70 (m, 2H), 1.64-1.45 (m, 6H), 1.30-1.00 (m, 6H).

[0186] 13C NMR (101MHz, DMSO) δ174.75, 172.34, 171.13, 134.59, 132.39, 130.69, 130.26, 129.44, 125 .74, 71.81, 54.55, 38.47, 35.81, 34.51, 34.14, 31.46, 27.61, 26.35, 25.41, 24.54, 24.21.

[0187] Example 13

[0188] 7-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)heptylamide (I-13)

[0189] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0190] The operation and feeding are the same as those in step a of Example 1.

[0191] Step b: Synthesis of ethyl (E)-7-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate

[0192] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0193] Step c: Synthesis of 7-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)heptylamide,

[0194] The target compound was synthesized using ethyl (E)-7-(3-benzylidene-2,5-dioxopyrrolidinyl)heptanoate and (1S,2S)-2-aminocyclohexanol as starting materials in a manner similar to that in Step c of Example 1. The product was a white solid in a 48.1% yield. 1H NMR (400MHz, DMSO-d6) δ7.69-7.62 (m, 2H), 7.54 (d, J=7.8Hz, 1H), 7.51-7.42 (m, 4H), 4.48 (d, J=5.0Hz, 1H), 3.72 (d, J=2.4Hz, 2H), 3.48 (t, J=7.2 Hz, 2H), 3.42-3.35 (m, 1H), 3.25-3.15 (m, 1H), 2.05 (t, J=7.4Hz, 2H), 1.8 7-1.70(m, 2H), 1.64-1.40(m, 6H), 1.29-1.22(m, 4H), 1.22-1.07(m, 4H).

[0195] 13C NMR (101MHz, DMSO) δ174.79, 172.43, 171.16, 134.60, 132.37, 130.70, 130.26, 129.45, 125.78 ,71.78,54.53,38.51,35.94,34.52,34.14,31.47,28.70,27.70,26.53,25.68,24.54,24.20.

[0196] Example 14

[0197] 8-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)octanamide (I-14)

[0198] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0199] The operation and feeding are the same as those in step a of Example 1.

[0200] Step b: Synthesis of ethyl (E)-8-(3-benzylidene-2,5-dioxopyrrolidinyl)octanoate

[0201] The target compound was synthesized using ethyl bromooctanoate as raw material using a method similar to step b in Example 1.

[0202] Step c: Synthesis of 8-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)octanamide,

[0203] The target compound was synthesized using ethyl (E)-8-(3-benzylidene-2,5-dioxopyrrolidinyl)octanoate and (1S,2S)-2-aminocyclohexanol as starting materials in a manner similar to that in Step c of Example 1. The product was a white solid in a 36.2% yield. 1H NMR (400MHz, DMSO-d6) δ7.69-7.61 (m, 2H), 7.54 (d, J=7.8Hz, 1H), 7.51-7.43 (m, 4H), 4.49 (d, J=5.0Hz, 1H), 3.72 (d, J=2.4Hz, 2H), 3.48 ( t, J=7.2Hz, 2H), 3.42-3.35 (m, 1H), 3.24-3.15 (m, 1H), 2.05 (t, J=7.4Hz, 2H), 1.87-1.71 (m, 2H), 1.61-1.42 (m, 6H), 1.31-1.09 (m, 10H).

[0204] 13C NMR (101MHz, DMSO) δ174.77, 172.49, 171.15, 134.61, 132.38, 130.69, 130.25, 129.44, 125.77, 71 .79, 54.54, 38.51, 36.02, 34.50, 34.14, 31.46, 28.97, 28.84, 27.75, 26.66, 25.75, 24.54, 24.20.

[0205] Example 15

[0206] (E)-7-(3-(4-isopropylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-15)

[0207] Step a: Synthesis of (E)-3-(4-isopropylbenzylidene)pyrrolidine-2,5-dione

[0208] The target compound was synthesized using 4-isopropylbenzaldehyde as raw material using a method similar to step a in Example 1.

[0209] Step b: Synthesis of ethyl (E)-7-(3-(4-isopropylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0210] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0211] Step c: Synthesis of (E)-7-(3-(4-isopropylbenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0212] The target compound was synthesized using ethyl ((E)-7-(3-(4-isopropylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material by a method similar to that in step c of Example 1. The product was obtained as a white solid in a yield of 26.6%. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H). (t, J=2.2Hz, 1H), 7.36 (d, J=8.2Hz, 2H), 3.70 (d, J=2.4Hz, 2H), 3.47 (t, J=7.2Hz, 2H), 2 .94(hept, J=6.8Hz, 1H), 1.93(t, J=7.3Hz, 2H), 1.56-1.42(m, 4H), 1.28-1.20(m, 10H).

[0213] 13CNMR (1001MHz, DMSO) δ174.84, 171.25, 169.51, 150.98, 132.40, 132.29, 130.87 , 127.44, 124.69, 38.46, 34.14, 33.82, 32.64, 28.63, 27.68, 26.45, 25.45, 24.08.

[0214] Example 16

[0215] (E)-7-(3-(4-dimethylaminobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-16)

[0216] Step a: Synthesis of (E)-3-(4-dimethylaminobenzylidene)pyrrolidine-2,5-dione

[0217] The target compound was synthesized using 4-dimethylaminobenzaldehyde as raw material using a method similar to step a in Example 1.

[0218] Step b: Synthesis of ethyl (E)-7-(3-(4-dimethylaminobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0219] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0220] Step c: Synthesis of (E)-7-(3-(4-dimethylaminobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0221] The target compound was synthesized using ethyl ((E)-7-(3-(4-dimethylaminobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a yellow solid with a yield of 32.1%. 1H NMR (300MHz, DMSO-d6) δ10.35 (s, 1H), 8.68 (s, 1H), 7.46 (d, J = 8.5Hz, 2H), 7.35 (t, J = 2.0Hz, 1H), 6.76 (d, J = 8.4Hz, 2H), 3.61 (d, J=2.2Hz, 2H), 3.45 (t, J=7.1Hz, 2H), 2.99 (s, 6H), 1.93 (t, J=7.3Hz, 2H), 1.57-1.41 (m, 4H), 1.30-1.15 (m, 4H).

[0222] 13C NMR (101MHz, DMSO) δ174.98, 171.51, 169.53, 151.56, 133.35, 132.48, 121.9 5, 119.01, 112.34, 40.10, 38.29, 34.25, 32.65, 28.64, 27.77, 26.46, 25.46.

[0223] Example 17

[0224] (E)-7-(3-(4-trifluoromethylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-17)

[0225] Step a: Synthesis of (E)-3-(4-trifluoromethylbenzylidene)pyrrolidine-2,5-dione

[0226] The target compound was synthesized using 4-trifluoromethylbenzaldehyde as starting material using a method similar to step a in Example 1.

[0227] Step b: Synthesis of ethyl (E)-7-(3-(4-trifluoromethylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0228] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0229] Step c: Synthesis of (E)-7-(3-(4-trifluoromethylbenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0230] The target compound was synthesized using ethyl ((E)-7-(3-(4-trifluoromethylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate in a manner similar to that in Step c of Example 1. The product was a white solid in a yield of 15.8%. H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.55 (t, J = 2.3 Hz, 1H), 3.77 (d, J = 2.4 Hz, 2H), 3.49 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.59-1.43 (m, 4H), 1.29-1.22 (m, 4H).

[0231] 13C NMR (101MHz, DMSO) δ174.60, 170.84, 169.51, 138.61, 131.19, 130.53, 129.91, 129.59, 12 8.77, 126.16, 126.12, 125.83, 123.12, 38.58, 34.13, 32.63, 28.62, 27.62, 26.43, 25.44.

[0232] Example 18

[0233] (E)-7-(3-(4-methylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-18)

[0234] Step a: Synthesis of (E)-3-(4-methylbenzylidene)pyrrolidine-2,5-dione

[0235] The target compound was synthesized using 4-methylbenzaldehyde as raw material using a method similar to step a in Example 1.

[0236] Step b: Synthesis of ethyl (E)-7-(3-(4-methylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0237] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0238] Step c: Synthesis of (E)-7-(3-(4-methylbenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0239] The target compound was synthesized using ethyl ((E)-7-(3-(4-methylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 26.7%. NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 7.54 (d, J = 5.8Hz, 2H), 7.47-7.40 (m, 1H), 7.30 (d, J = 5.8Hz, 2H), 3 .69 (d, J=2.9Hz, 2H), 3.48 (t, J=6.0Hz, 2H), 2.36 (s, 3H), 1.94 (t, J=6.9Hz, 2H), 1.56-1.41 (m, 4H), 1.30-1.19 (m, 4H).

[0240] 13C NMR (101MHz, DMSO) δ174.82, 171.24, 169.52, 140.28, 132.42, 131.88, 130.7 3, 130.08, 124.62, 38.44, 34.16, 32.64, 28.62, 27.68, 26.43, 25.44, 21.48.

[0241] Example 19

[0242] (E)-7-(3-(2-methylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-19)

[0243] Step a: Synthesis of (E)-3-(2-methylbenzylidene)pyrrolidine-2,5-dione

[0244] The target compound was synthesized using 2-methylbenzaldehyde as raw material using a method similar to step a in Example 1.

[0245] Step b: Synthesis of ethyl (E)-7-(3-(2-methylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0246] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0247] Step c: Synthesis of (E)-7-(3-(2-methylbenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0248] The target compound was synthesized using ethyl ((E)-7-(3-(2-methylbenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 35.2%. 1H NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.68 (s, 1H), 7.64 (t, J=2.4Hz, 1H), 7.56 (d, J=7.1Hz, 1H), 7.36-7.25 (m, 3H), 3 .65 (d, J=2.4Hz, 2H), 3.48 (t, J=7.2Hz, 2H), 2.39 (s, 3H), 1.93 (t, J=7.4Hz, 2H), 1.58-1.44 (m, 4H), 1.29-1.20 (m, 4H).

[0249] 13C NMR (101MHz, DMSO) δ174.88, 171.07, 169.57, 138.63, 133.24, 131.10, 130.06, 129.81, 128.65, 126.81, 126.45, 38.47, 33.77, 32.64, 28.61, 27.66, 26.44, 25.43, 19.94.

[0250] Example 20

[0251] (E)-7-(3-(2-cyanobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-20)

[0252] Step a: Synthesis of (E)-3-(2-cyanobenzylidene)pyrrolidine-2,5-dione

[0253] The target compound was synthesized using 2-cyanobenzaldehyde as the starting material by a method similar to step a in Example 1.

[0254] Step b: Synthesis of ethyl (E)-7-(3-(2-cyanobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0255] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0256] Step c: Synthesis of (E)-7-(3-(2-cyanobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0257] The target compound was synthesized using ethyl ((E)-7-(3-(2-cyanobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 12.1%. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 7.99 (dd, J=7.8, 1.4Hz, 1H), 7.90 (d, J=7.9Hz, 1H), 7.82 (td, J=7.8, 1.4Hz, 1 H), 7.67-7.61 (m, 2H), 3.77 (d, J=2.5Hz, 2H), 3.50 (t, J=7.1Hz, 2H), 1.94 (t, J=7.4Hz, 2H), 1.60-1.44 (m, 4H), 130-1.22 (m, 4H).

[0258] 13C NMR (101MHz, DMSO) δ174.43, 170.56, 169.53, 136.91, 134.17, 134.16, 130.86, 130.5 9, 129.42, 126.63, 117.72, 113.25, 38.70, 34.04, 32.65, 28.62, 27.59, 26.44, 25.44.

[0259] Example 21

[0260] (E)-7-(3-(2-methylenepyridine)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-21)

[0261] Step a: Synthesis of (E)-3-(2-methylenepyridine)pyrrolidine-2,5-dione

[0262] The target compound was synthesized using 2-pyridinecarboxaldehyde as raw material using a method similar to step a in Example 1.

[0263] Step b: Synthesis of ethyl (E)-7-(3-(2-methylenepyridine)-2,5-dioxopyrrolidinyl)heptanoate

[0264] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0265] Step c: Synthesis of (E)-7-(3-(2-methylenepyridine)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0266] The target compound was synthesized using ethyl ((E)-7-(3-(2-methylenepyridine)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a yellow solid with a yield of 16.8%. NMR (300MHz, DMSO-d6) δ10.35 (s, 1H), 8.73 (d, J = 4.5Hz, 1H), 8.68 (s, 1H), 7.90 (td, J = 7.7, 1.8Hz, 1H), 7.76 (d, J = 7.7Hz, 1H), 7.48 (t, J = 2.2Hz, 1 H), 7.40 (ddd, J=7.5, 4.7, 1.3Hz, 1H), 3.78 (d, J=2.3Hz, 2H), 3.48 (t, J=7 .2Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.59-1.42 (m, 4H), 1.32-1.19 (1n, 4H).

[0267] 13C NMR (101MHz, DMSO) δ175.36, 171.10, 169.66, 153.68, 150.53, 137.58, 130.4 2, 129.55, 127.54, 124.19, 38.45, 35.37, 32.61, 28.58, 27.62, 26.40, 25.41.

[0268] Example 22

[0269] (E)-7-(3-(2-methylenenaphthyl)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-22)

[0270] Step a: Synthesis of (E)-3-(2-methylenenaphthyl)pyrrolidine-2,5-dione

[0271] The target compound was synthesized using 2-naphthaldehyde as raw material using a method similar to step a in Example 1.

[0272] Step b: Synthesis of ethyl (E)-7-(3-(2-methylenenaphthyl)-2,5-dioxopyrrolidinyl)heptanoate

[0273] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0274] Step c: Synthesis of (E)-7-(3-(2-methylenenaphthyl)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0275] The target compound was synthesized using ethyl ((E)-7-(3-(2-methylenenaphthyl)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 18.2%. NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 8.07-7.92 (m, 3H), 7.77 (dd, J=8.6, 1.8Hz, 1H), 7.63 (t, J=2 .4Hz, 1H), 7.61-7.55 (m, 2H), 3.85 (d, J=2.3Hz, 2H), 3.50 (t, J=7.2Hz, 2H), 1.94 (t, J=7.4Hz, 2H), 1.50 (m, 4H), 1.27 (m, 4H).

[0276] 13C NMR (101MHz, DMSO) δ174.88, 171.20, 169.56, 133.59, 133.33, 132.41, 132.20, 131.18, 129.11, 12 8.94, 128.05, 127.97, 127.23, 127.18, 126.05, 38.52, 34.29, 32.64, 28.62, 27.67, 26.45, 25.45.

[0277] Example 23

[0278] (E)-7-(3-(2-methylenethienyl)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-23)

[0279] Step a: Synthesis of (E)-3-(2-methylenethienyl)pyrrolidine-2,5-dione

[0280] The target compound was synthesized using 2-thiophenecarboxaldehyde as raw material by a method similar to step a in Example 1.

[0281] Step b: Synthesis of ethyl (E)-7-(3-(2-methylenethienyl)-2,5-dioxopyrrolidinyl)heptanoate

[0282] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0283] Step c: Synthesis of (E)-7-(3-(2-methylenethienyl)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0284] The target compound was synthesized using ethyl ((E)-7-(3-(2-methylenethienyl)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a yellow solid with a yield of 18.6%. 1H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.69 (s, 1H), 7.90 (d, J = 5.0Hz, 1H), 7.72 (t, J = 2.4Hz, 1H), 7.60 (d, J = 3.7Hz, 1H), 7.24 (t, J=4.3Hz, 1H), 3.52 (d, J=2.3Hz, 2H), 3.46 (t, J=7.2Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.58-1.42 (m, 4H), 1.29-1.18 (m, 4H).

[0285] 13C NMR (101MHz, DMSO) δ174.23, 170.77, 169.55, 138.65, 133.73, 132.12, 128.88, 125.49, 122.97, 38.52, 34.12, 32.63, 28.62, 27.69, 26.42, 25.45.

[0286] Example 24

[0287] (E)-7-(3-(2-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-24)

[0288] Step a: Synthesis of (E)-3-(2-chlorobenzylidene)pyrrolidine-2,5-dione

[0289] The target compound was synthesized using 2-chlorobenzaldehyde as raw material using a method similar to step a in Example 1.

[0290] Step b: Synthesis of ethyl (E)-7-(3-(2-chlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0291] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0292] Step c: Synthesis of (E)-7-(3-(2-chlorobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0293] The target compound was synthesized using ethyl ((E)-7-(3-(2-chlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a pale yellow solid with a yield of 10.2%. NMR (300MHz, DMSO-d6) δ10.34 (s, 1H), 8.67 (s, 1H), 7.80-7.73 (m, 1H), 7.71 (t, J=2.2Hz, 1H), 7.64-7.57 (m, 1H), 7.50- 7.41 (m, 2H), 3.71 (d, J=2.4Hz, 2H), 3.49 (t, J=7.1Hz, 2H), 1.94 (t, J=7.3Hz, 2H), 1.60-1.40 (m, 4H), 1.31-1.18 (m, 4H).

[0294] 13C NMR (101MHz, DMSO) δ174.63, 170.79, 169.55, 134.82, 132.19, 131.72, 130.45, 13 0.42, 128.77, 128.23, 127.33, 38.59, 33.68, 32.64, 28.61, 27.61, 26.43, 25.43.

[0295] Example 25

[0296] (E)-7-(3-(3-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-25)

[0297] Step a: Synthesis of (E)-3-(3-chlorobenzylidene)pyrrolidine-2,5-dione

[0298] The target compound was synthesized using 3-chlorobenzaldehyde as raw material by a method similar to step a in Example 1.

[0299] Step b: Synthesis of ethyl (E)-7-(3-(3-chlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0300] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0301] Step c: Synthesis of (E)-7-(3-(3-chlorobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0302] The target compound was synthesized using ethyl ((E)-7-(3-(3-chlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a pale yellow solid with a yield of 12.6%. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 7.72 (s, 1H), 7.65-7.60 (m, 1H), 7.50 (d, J=4.5Hz, 2H), 7.47 (t, J= 2.4Hz, 1H), 3.75 (d, J=2.4Hz, 2H), 3.48 (t, J=7.2Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.57-1.42 (m, 4H), 1.30-1.21 (m, 4H).

[0303] 13C NMR (101MHz, DMSO) δ174.67, 170.93, 169.59, 136.74, 134.14, 131.23, 130.83, 13 0.18, 129.93, 128.97, 127.49, 38.54, 34.00, 32.62, 28.59, 27.61, 26.41, 25.43.

[0304] Example 26

[0305] (E)-7-(3-(4-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-26)

[0306] Step a: Synthesis of (E)-3-(4-chlorobenzylidene)pyrrolidine-2,5-dione

[0307] The target compound was synthesized using 4-chlorobenzaldehyde as raw material using a method similar to step a in Example 1.

[0308] Step b: Synthesis of ethyl (E)-7-(3-(4-chlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0309] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0310] Step c: Synthesis of (E)-7-(3-(4-chlorobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0311] The target compound was synthesized using ethyl ((E)-7-(3-(4-chlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate in a manner similar to that in Step c of Example 1. The product was a yellow solid in a yield of 15.8%. H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 2.4 Hz, 1H), 3.71 (d, J = 2.4 Hz, 2H), 3.48 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.59-1.42 (m, 4H), 1.33-1.20 (m, 4H).

[0312] 13C NMR (101MHz, DMSO) δ174.67, 171.01, 169.55, 134.86, 133.53, 132.35, 131.01, 129.46, 126.59, 38.52, 34.07, 32.64, 28.61, 27.63, 26.42, 25.43.

[0313] Example 27

[0314] (E)-7-(3-(3-bromobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-27)

[0315] Step a: Synthesis of (E)-3-(3-bromobenzylidene)pyrrolidine-2,5-dione

[0316] The target compound was synthesized using 3-bromobenzaldehyde as starting material using a method similar to step a in Example 1.

[0317] Step b: Synthesis of ethyl (E)-7-(3-(3-bromobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0318] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0319] Step c: Synthesis of (E)-7-(3-(3-bromobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0320] The target compound was synthesized using ethyl ((E)-7-(3-(3-bromobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 26.2%. NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.70-7.60 (m, 2H), 7.46 (t, J=2.3Hz, 1H), 7.43 (d, J= 7.8Hz, 1H), 3.75 (d, J=2.4Hz, 2H), 3.48 (t, J=7.1Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.57-1.43 (m, 4H), 1.29-1.21 (m, 4H).

[0321] 13C NMR (101MHz, DMSO) δ174.67, 170.90, 169.52, 137.03, 133.11, 132.82, 131.47, 130.75, 129.27, 127.49, 122.71, 38.53, 34.00, 32.63, 28.61, 27.64, 26.43, 25.44.

[0322] Example 28

[0323] (E)-7-(3-(3-fluorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-28)

[0324] Step a: Synthesis of (E)-3-(3-fluorobenzylidene)pyrrolidine-2,5-dione

[0325] The target compound was synthesized using 3-fluorobenzaldehyde as starting material using a method similar to step a in Example 1.

[0326] Step b: Synthesis of ethyl (E)-7-(3-(3-fluorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0327] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0328] Step c: Synthesis of (E)-7-(3-(3-fluorobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0329] The target compound was synthesized using ethyl ((E)-7-(3-(3-fluorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate in a manner similar to that in Step c of Example 1. The product was a white solid in a yield of 29.6%. H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.59-7.44 (m, 4H), 7.34-7.22 (m, 1H), 3.75 (d, J = 2.4 Hz, 2H), 3.48 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.58-1.42 (m, 4H), 1.32-1.18 (m, 4H).

[0330] 13C NMR (101MHz, DMSO) δ174.69, 170.96, 169.52, 163.94, 161.51, 136.99, 136.91, 131.42, 131.34, 131.03, 12 7.35, 126.85, 126.82, 117.13, 117.06, 116.92, 116.84, 38.53, 34.02, 32.63, 28.62, 27.64, 26.43, 25.44.

[0331] Example 29

[0332] (E)-7-(3-(3-iodobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-29)

[0333] Step a: Synthesis of (E)-3-(3-iodobenzylidene)pyrrolidine-2,5-dione

[0334] The target compound was synthesized using 3-iodobenzaldehyde as raw material using a method similar to step a in Example 1.

[0335] Step b: Synthesis of ethyl (E)-7-(3-(3-iodobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0336] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0337] Step c: Synthesis of (E)-7-(3-(3-iodobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0338] The target compound was synthesized using ethyl ((E)-7-(3-(3-iodobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 18.6%. 1H NMR (300MHz, DMSO-d6) δ10.35 (s, 1H), 8.69 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 7.6Hz, 1H), 7.67 (d, J = 7.8Hz, 1H), 7.41 (t, J = 2.4Hz, 1H ), 7.27 (t, J=7.8Hz, 1H), 3.73 (d, J=2.4Hz, 2H), 3.47 (t, J=7.1Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.57-1.40 (m, 4H), 1.29-1.18 (m, 4H).

[0339] 13C NMR (101MHz, DMSO) δ174.68, 170.91, 169.52, 138.95, 138.67, 136.92, 131.41, 1 30.79, 129.55, 127.19, 95.92, 38.52, 33.98, 32.62, 28.61, 27.64, 26.42, 25.44.

[0340] Example 30

[0341] (E)-7-(3-(3,4-dichlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-30)

[0342] Step a: Synthesis of (E)-3-(3,4-dichlorobenzylidene)pyrrolidine-2,5-dione

[0343] The target compound was synthesized using 3,4-dichlorobenzaldehyde as raw material by a method similar to step a in Example 1.

[0344] Step b: Synthesis of ethyl (E)-7-(3-(3,4-dichlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0345] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0346] Step c: Synthesis of (E)-7-(3-(3,4-dichlorobenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0347] The target compound was synthesized using ethyl ((E)-7-(3-(3,4-dichlorobenzylidene)-2,5-dioxopyrrolidinyl)heptanoate in a manner similar to that of step c in Example 1. The product was a yellow solid in an 18.5% yield. H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.92 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 3.75 (s, 2H), 3.48 (t, J = 7.1 Hz, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.57-1.41 (m, 4H), 1.30-1.17 (m, 4H).

[0348] 13C NMR (101MHz, DMSO) δ174.56, 170.78, 169.51, 135.38, 132.63, 132.33, 132.19, 13 1.48, 130.26, 129.78, 128.08, 38.57, 33.94, 32.64, 28.62, 27.62, 26.43, 25.44.

[0349] Example 31

[0350] (E)-7-(3-(2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-31)

[0351] Step a: Synthesis of (E)-3-(2-methoxybenzylidene)pyrrolidine-2,5-dione

[0352] The target compound was synthesized using 2-methoxybenzaldehyde as raw material using a method similar to step a in Example 1.

[0353] Step b: Synthesis of ethyl (E)-7-(3-(2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0354] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0355] Step c: Synthesis of (E)-7-(3-(2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0356] The target compound was synthesized using ethyl ((E)-7-(3-(2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 19.3%. NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 7.77 (t, J=2.4Hz, 1H), 7.57 (dd, J=7.8, 1.6Hz, 1H), 7.44 (ddd, J=8.7, 7.3, 1.7Hz, 1H), 7.12 (dd, J=8. 4, 1.1Hz, 1H), 7.07-7.01 (m, 1H), 3.88 (s, 3H), 3.66 (d, J=2.4Hz, 2H), 3.47 (t , J=7.1Hz, 2H), 1.93 (t, J=7.4Hz, 2H), 1.56-1.42 (m, 4H), 1.29-1.20 (m, 4H).

[0357] 13C NMR (101MHz, DMSO) δ174.92, 171.26, 169.57, 158.48, 132.06, 129.58, 126.54, 125.2 5, 122.92, 121.16, 111.99, 56.18, 38.43, 33.95, 32.63, 28.61, 27.67, 26.43, 25.44.

[0358] Example 32

[0359] (E)-7-(3-(3-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-32)

[0360] Step a: Synthesis of (E)-3-(3-methoxybenzylidene)pyrrolidine-2,5-dione

[0361] The target compound was synthesized using 3-methoxybenzaldehyde as starting material using a method similar to step a in Example 1.

[0362] Step b: Synthesis of ethyl (E)-7-(3-(3-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0363] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0364] Step c: Synthesis of (E)-7-(3-(3-methoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0365] The target compound was synthesized using ethyl ((E)-7-(3-(3-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 10.3%. 1 H NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.68 (s, 1H), 7.45 (s, 1H), 7.39 (t, J = 8.0Hz, 1H), 7.22 (d, J = 7.8Hz, 1H), 7.19 (s, 1H), 7.02 (d, J=8.2Hz, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 3.48 (t, J=7.2Hz, 2H), 1.93 (t, J=7.4Hz, 2H), 1.61-1.41 (m, 4H), 1.32-1.20 (m, 4H).

[0366] 13C NMR (101MHz, DMSO) δ174.77, 171.12, 169.52, 159.94, 135.93, 132.39, 130.49, 126.0 1, 122.96, 116.23, 115.69, 55.67, 38.48, 34.08, 32.64, 28.62, 27.66, 26.43, 25.45.

[0367] Example 33

[0368] (E)-7-(3-(4-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-33)

[0369] Step a: Synthesis of (E)-3-(4-methoxybenzylidene)pyrrolidine-2,5-dione

[0370] The target compound was synthesized using 4-methoxybenzaldehyde as raw material using a method similar to step a in Example 1.

[0371] Step b: Synthesis of ethyl (E)-7-(3-(4-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0372] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0373] Step c: Synthesis of (E)-7-(3-(4-methoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0374] The target compound was synthesized using ethyl ((E)-7-(3-(4-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 12.5%. NMR, (400MHz, DMSO-d6) δ10.34 (s, 1H), 8.67 (s, 1H), 7.61 (d, J = 9.1Hz, 2H), 7.43 (t, J = 2.4Hz, 1H), 7.04 (d, J = 7.9Hz, 2H) , 3.82 (s, 3H), 3.66 (d, J = 2.1Hz, 2H), 3.46 (t, J = 7.2Hz, 2H), 1.93 (t, J = 7.3Hz, 2H), 1.53-1.43 (m, 4H), 1.26-1.22 (m, 4H).

[0375] 13C NMR (101MHz, DMSO) δ174.89, 171.35, 169.58, 160.98, 132.60, 132.32, 127.2 1, 122.77, 114.97, 55.82, 38.40, 34.08, 32.63, 28.61, 27.69, 26.43, 25.44.

[0376] Example 34

[0377] (E)-7-(3-(3,4-dimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-34)

[0378] Step a: Synthesis of (E)-3-(3,4-dimethoxybenzylidene)pyrrolidine-2,5-dione

[0379] The target compound was synthesized using 3,4-dimethoxybenzaldehyde as raw material using a method similar to step a in Example 1.

[0380] Step b: Synthesis of ethyl (E)-7-(3-(3,4-dimethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0381] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0382] Step c: Synthesis of (E)-7-(3-(3,4-dimethoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0383] The target compound was synthesized using ethyl ((E)-7-(3-(3,4-dimethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 21.5%. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 7.43 (t, J=2.3Hz, 1H), 7.23 (dd, J=8.4, 2.1Hz, 1H), 7.20 (d, J=2.0Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.73 (d, J=2.3Hz, 2H), 3.47 (t, J=7.1Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.54-1.43 (m, 4H), 1.28-1.22 (m, 4H).

[0384] 13C NMR (101MHz, DMSO) δ174.92, 171.32, 169.52, 150.82, 149.22, 132.76, 127.38, 124.63, 1 22.83, 113.58, 112.26, 56.06, 55.99, 38.41, 33.98, 32.64, 28.63, 27.70, 26.44, 25.46.

[0385] Example 35

[0386] (E)-7-(3-(3,4,5-trimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-35)

[0387] Step a: Synthesis of (E)-3-(3,4,5-trimethoxybenzylidene)pyrrolidine-2,5-dione

[0388] The target compound was synthesized using 3,4,5-trimethoxybenzaldehyde as raw material using a method similar to step a in Example 1.

[0389] Step b: Synthesis of ethyl (E)-7-(3-(3,4,5-trimethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0390] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0391] Step c: Synthesis of (E)-7-(3-(3,4,5-trimethoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0392] The target compound was synthesized using ethyl ((E)-7-(3-(3,4,5-trimethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate in a manner similar to that in Step c of Example 1. The product was a white solid in a yield of 19.7%. H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.43 (t, J = 2.4 Hz, 1H), 6.95 (s, 2H), 3.85 (s, 6H), 3.80 (d, J = 2.3 Hz, 2H), 3.71 (s, 3H), 3.48 (t, J = 7.1 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.59-1.43 (m, 4H), 1.31-1.20 (m, 4H).

[0393] 13C NMR (101MHz, DMSO) δ174.89, 171.18, 169.52, 153.46, 139.44, 132.76, 130.11, 1 24.57, 108.23, 600.59, 56.46, 38.46, 33.85, 32.63, 28.62, 27.67, 26.45, 25.46.

[0394] Example 36

[0395] (E)-7-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-36)

[0396] Step a: Synthesis of (E)-3-(4-hydroxy-3,5-dimethoxybenzylidene)pyrrolidine-2,5-dione

[0397] The target compound was synthesized using 4-hydroxy-3,5-dimethoxybenzaldehyde as raw material by a method similar to step a in Example 1.

[0398] Step b: Synthesis of ethyl (E)-7-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0399] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0400] Step c: Synthesis of (E)-7-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0401] The target compound was synthesized using ethyl ((E)-7-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate in a manner similar to that in Step c of Example 1. The product was a yellow solid in a yield of 13.1%. H NMR (400 MHz, DMSO-d6) δ 100.32 (s, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 7.39 (s, 1H), 6.91 (s, 2H), 3.82 (s, 6H), 3.75 (s, 2H), 3.48 (d, J = 7.2 Hz, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.52-1.44 (m, 4H), 1.27-1.21 (m, 4H).

[0402] 13C NMR (101MHz, DMSO) δ174.98, 171.35, 169.52, 148.46, 138.40, 133.48, 124.9 1, 122.02, 108.63, 56.51, 38.38, 33.93, 32.64, 28.62, 27.71, 26.45, 25.46.

[0403] Example 37

[0404] (E)-7-(3-(2-Hydroxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-37)

[0405] Step a: Synthesis of (E)-3-(2-hydroxybenzylidene)pyrrolidine-2,5-dione

[0406] The target compound was synthesized using 2-hydroxybenzaldehyde as raw material using a method similar to step a in Example 1.

[0407] Step b: Synthesis of ethyl (E)-7-(3-(2-hydroxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0408] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0409] Step c: Synthesis of (E)-7-(3-(2-hydroxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0410] The target compound was synthesized using ethyl ((E)-7-(3-(2-hydroxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 21.2%. NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 10.20 (s, 1H), 8.65 (s, 1H), 7.80 (t, J = 2.5Hz, 1H), 7.49 (d, J = 7.9Hz, 1H), 7.25 (t, J = 7.6Hz, 1H), 6.94 (d, J=8.1Hz, 1H), 6.88 (t, J=7.5Hz, 1H), 3.65 (d, J=2.7Hz, 2H), 3.47 (t, J=7.1Hz, 2H), 1.93 (t, J=7.3Hz, 2H), 1.62-1.42 (m, 4H), 1.34-1.18 (m, 4H).

[0411] 13C NMR (101MHz, DMSO) δ174.94, 171.38, 169.54, 157.51, 131.82, 129.56, 127.17, 12 3.88, 121.49, 119.87, 116.31, 38.41, 34.05, 32.64, 28.63, 27.70, 26.45, 25.45.

[0412] Example 38

[0413] (E)-7-(3-(2-ethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-38)

[0414] Step a: Synthesis of (E)-3-(2-ethoxybenzylidene)pyrrolidine-2,5-dione

[0415] The target compound was synthesized using 2-ethoxybenzaldehyde as raw material using a method similar to step a in Example 1.

[0416] Step b: Synthesis of ethyl (E)-7-(3-(2-ethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0417] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0418] Step c: Synthesis of (E)-7-(3-(2-ethoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0419] The target compound was synthesized from ethyl ((E)-7-(3-(2-ethoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate by a method similar to that in step c of Example 1. The product was a white solid in a yield of 12.5%. 1H NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.68 (s, 1H), 7.79 (t, J = 2.3 Hz, 1H), 7.57 (dd, J = 7.8, 1.6 Hz, 1H), 7.41 (ddd, J = 8.8, 7.4, 1.6 Hz, 1H), 7.10 (dd, J = 8.4, 1.0 Hz, 1H), 7.0 2(t, J=7.5Hz, 1H), 4.13 (q, J=6.9Hz, 2H), 3.66 (d, J=2.4Hz, 2H), 3.47 (t, J=7.1Hz, 2H ), 1.93 (t, J=7.3Hz, 2H), 1.55-1.44 (m, 4H), 1.38 (t, J=6.9Hz, 3H), 1.26-1.23 (m, 4H).

[0420] 13C NMR (75MHz, DMSO) δ174.89, 171.25, 169.52, 157.82, 131.99, 129.62, 126.64, 125.13, 12 3.03, 121.003, 112.81, 64.23, 38.43, 34.00, 32.63, 28.63, 27.68, 26.44, 25.44, 15.07.

[0421] Example 39

[0422] (E)-7-(3-(5-bromo-2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-39)

[0423] Step a: Synthesis of (E)-3-(5-bromo-2-methoxybenzylidene)pyrrolidine-2,5-dione

[0424] The target compound was synthesized using 5-bromo-2-methoxybenzaldehyde as starting material using a method similar to step a in Example 1.

[0425] Step b: Synthesis of ethyl (E)-7-(3-(5-bromo-2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0426] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0427] Step c: Synthesis of (E)-7-(3-(5-bromo-2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0428] The target compound was synthesized using ethyl ((E)-7-(3-(5-bromo-2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to step c in Example 1. The product was a white solid with a yield of 19.8%. NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 7.65 (t, J=2.4Hz, 1H), 7.50 (d, J=8.4Hz, 1H), 7.33 (d, J=1.9Hz, 1H), 7.23 (dd, J=8. 3, 1.9Hz, 1H), 3.90 (s, 3H), 3.63 (d, J=2.5Hz, 2H), 3.46 (t, J=7.2Hz, 2H), 1.93 (t, J=7.4Hz, 2H), 1.56-1.42 (m, 4H), 1.27-1.22 (m, 4H).

[0429] 13C NMR (101MHz, DMSO) δ174.72, 171.06, 169.52, 159.07, 130.97, 126.17, 125.42, 124.8 2, 124.10, 122.34, 115.37, 56.79, 38.48, 33.96, 32.64, 28.62, 27.65, 26.43, 25.44.

[0430] Example 40

[0431] (E)-7-(3-(4-bromo-2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-40)

[0432] Step a: Synthesis of (E)-3-(4-bromo-2-methoxybenzylidene)pyrrolidine-2,5-dione

[0433] The target compound was synthesized using 4-bromo-2-methoxybenzaldehyde as starting material using a method similar to step a in Example 1.

[0434] Step b: Synthesis of ethyl (E)-7-(3-(4-bromo-2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate

[0435] The target compound was synthesized using ethyl bromoheptanoate as raw material using a method similar to step b in Example 1.

[0436] Step c: Synthesis of (E)-7-(3-(4-bromo-2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide

[0437] The target compound was synthesized using ethyl ((E)-7-(3-(4-bromo-2-methoxybenzylidene)-2,5-dioxopyrrolidinyl)heptanoate as starting material using a method similar to that in step c of Example 1. The product was a white solid with a yield of 18.6%. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.65 (s, 1H), 7.67-7.63 (m, 2H), 7.60 (dd, J=8.8, 2.4Hz, 1H), 7.10 (d, J=8.9Hz, 1H) , 3.88 (s, 3H), 3.70 (d, J = 2.5Hz, 2H), 3.47 (t, J = 7.2Hz, 2H), 1.93 (t, J = 7.3Hz, 2H), 1.56-1.42 (m, 4H), 1.29-1.19 (m, 4H).

[0438] 13C NMR (101MHz, DMSO) δ174.70, 170.92, 169.52, 157.63, 134.22, 131.44, 127.04, 125.2 2, 125.12, 114.33, 112.73, 56.60, 38.50, 33.64, 32.64, 28.61, 27.64, 26.42, 25.44.

[0439] Example 41

[0440] (E)-4-((3-benzylidene-2,5-diketopyrrolidinyl)methyl)-N-hydroxybenzamide (I-41)

[0441] Step a: Synthesis of (E)-3-benzylidenepyrrolidine-2,5-dione

[0442] The operation and feeding are the same as those in step a of Example 1.

[0443] Step b: Synthesis of ethyl (E)-4-((3-benzylidene-2,5-diketopyrrolidinyl)methyl)benzoate

[0444] The target compound was synthesized using ethyl 4-bromomethylbenzoate as starting material using a method similar to step b in Example 1.

[0445] Step c: Synthesis of (E)-4-((3-benzylidene-2,5-diketopyrrolidinyl)methyl)-N-hydroxybenzamide

[0446] The target compound was synthesized using ethyl (E)-4-((3-benzylidene-2,5-diketopyrrolidinyl)methyl)benzoate in a manner similar to that described in Step c of Example 1. The product was a yellow solid in an 11.3% yield. H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.12 (s, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 7.0 Hz, 2H), 7.54-7.43 (m, 4H), 7.36 (d, J = 7.9 Hz, 2H), 4.74 (s, 2H), 3.82 (d, J = 2.3 Hz, 2H).

[0447] 13C NMR (101MHz, DMSO) δ174.67, 170.98, 164.41, 139.79, 134.50, 132.98, 132.38, 130.77, 130.41, 129.49, 127.84, 127.56, 125.62, 41.69, 34.34.

[0448] The compounds obtained in the above examples were subjected to pharmacological tests, and the results were as follows:

[0449] Determination of HDAC inhibitory activity of target compounds and results

[0450] The inhibitory activity of the synthesized compounds against HDAC1 was determined by fluorescence resonance energy transfer (FRET) and compared with a positive control drug to screen out compounds with better activity. HDAC1 was obtained by purification or direct purchase of a kit.

[0451] Specific methods:

[0452] Enzyme was added to the reaction wells, reaction buffer was added to the control wells, and samples dissolved in DMSO were added to the reaction wells. Incubation was performed using a non-contact nanoliter acoustic pipetting system (Ech-550; nanoliter). Fluorescent substrate was added to each reaction well and vortexed. The wells were sealed and incubated at 30°C for 1-2 hours. A color developer containing TMP26 was added to terminate the reaction and generate fluorescence. Fluorescence intensity was measured using an EnVision multi-label microplate reader (Perkin Elmer) (excitation: 490 nm, emission: 520 nm). Endpoint values ​​were read after color development reached stability. Percent inhibition (relative to the DMSO control group) was calculated using GraphPad Prism 4 software.

[0453] Results of the target compound's inhibitory activity against HDAC1:

[0454] (2) Determination of the in vitro antitumor activity of the target compound

[0455] The MTT method was used to determine the inhibitory effects of the compounds on human non-small cell lung cancer cell lines A549, NCI-H1650, human small cell lung cancer cell line H446, human prostate cancer cell lines DU145, PC-3, LNCAP, human colon cancer cell line HCT116, human breast cancer cell line MDA-MB-231, and MCF7 tumor cell lines.

[0456] Specific method: Collect cells in the exponential growth phase for viable cell counting. Adjust the concentration of the cell suspension with the corresponding culture medium of each cell. Add 100 μL of cell suspension to each well of a 96-well cell culture plate and culture in a 37°C, 5% CO2 box for 24 hours. Dissolve each test compound in DMSO to prepare a corresponding concentration stock solution. Then dilute with culture medium to 500-fold solution, and replicate in 4 wells. Add 100 μL of the corresponding 500-fold solution to each well of each cell line, and the final DMSO concentration is 0.1%. After 96 hours of drug treatment, add 10 μL of 5 mg / mL MTT in PBS solution to each well, place in a 37°C, 5% CO2 box for 4 hours, remove the culture medium from the 96-well plate, add 150 mL of DMSO to each well, and detect the absorbance on a microplate reader. Use GraphPad Prism 4 software to calculate the half-maximal inhibition rate (relative to the DMSO control group).

[0457] The in vitro antitumor activity (IC 50 )The results are as follows (unit: μM):

[0458] The above pharmacological test results indicate that the compounds of Formula I and their pharmaceutically acceptable salts of the present invention have excellent inhibitory activity against HDACs. Therefore, the compounds of Formula I and their pharmaceutically acceptable salts can be used to treat clinical conditions related to the above targets. Diseases related to HDACs may include, but are not limited to: lung cancer, melanoma, liver cancer, kidney cancer, leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, follicular thyroid cancer, gastrointestinal cancer, tumors of the central or peripheral nervous system (e.g., astrocytoma, neuroblastoma, glioma, or schwannoma), mesothelioma, type II or non-insulin-dependent diabetes mellitus, and autoimmune diseases.

[0459] In addition to the above embodiments, the present invention may also have other implementations. Any technical solution formed by equivalent replacement or equivalent transformation falls within the scope of protection required by the present invention.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, Where X, Y, Z, M 1 、M 2 each independently represents a carbon or nitrogen atom, When X, Y, Z, M 1 、M 2 When they are carbon atoms, they are each independently optionally replaced by R 2 Replacement, R 2 is hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het; M 3 is carbon, each independently optionally replaced by R 4 , R 5 Replacement, R 4 , R 5 is hydrogen, deuterium, alkyl, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, methylene, aralkyl, diarylalkyl, aryl or Het; Q 1 is selected from saturated or unsaturated straight or branched hydrocarbon groups with a length of 1 to 8 carbon atoms, aryl or Het; R 1 Selected from hydroxyl, one or more R 3 Substituted 2-aminophenyl, 2-hydroxycyclohexyl, R 3 is hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, aryl or Het; The alkyl group is a straight or branched saturated hydrocarbon group having 1 to 7 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms; Alkoxy is a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted by oxygen; Alkylamino is a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted by an NH atomic group; Alkoxyalkyl is an alkoxy group as defined above attached to an alkyl group; Alkenyl and alkynyl are straight-chain or branched unsaturated hydrocarbon groups with 1 to 6 carbon atoms and containing double or triple bonds; Aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each of which is independently selected from hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het; Aralkyl and diarylalkyl are aryl groups as defined above connected to an alkyl group; Het is a monocyclic heterocyclic ring selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or selected from quinolyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4] a bicyclic heterocycle selected from dioxinyl or benzo[1,3]dioxolyl; or a monocyclic saturated hydrocarbon group of 3-6 carbon atoms, a bicyclic saturated hydrocarbon group of 6-12 carbon atoms, wherein the carbon atoms on the ring are independently optionally substituted by 1-4 O, S, N or NH; each monocyclic or bicyclic ring is optionally substituted by 1, 2 or 3 substituents, each substituent is independently selected from halogen, haloalkyl, hydroxyl, alkyl or alkoxy; Halogen is a substituent selected from fluorine, chlorine, bromine or iodine; The haloalkyl group is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms connected to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein one or more carbon atoms are substituted by one or more halogen atoms.

2. The compound according to claim 1, characterized in that: Where X, Y, Z, M 1 、M 2 Each independently represents a carbon or nitrogen atom. 1 、M 2 When they are carbon atoms, they are each independently optionally replaced by R 2 Replacement, R 2 is hydrogen, alkyl, cyano, halogen, haloalkyl, alkoxy, alkylthio, alkoxyalkyl; M 3 is carbon, each independently optionally replaced by R 4 , R 5 Replacement, R 4 , R 5 is hydrogen, deuterium, alkyl, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, methylene, aralkyl, diarylalkyl, aryl or Het; Q 1 is selected from saturated or unsaturated straight or branched hydrocarbon groups or aromatic groups having a length of 1 to 8 carbon atoms; R 1 Selected from hydroxyl, optionally with one or more R 3 Substituted 2-aminophenyl; R 3 is hydrogen, alkyl, cyano, halogen, haloalkyl, aryl or Het.

3. The compound according to claim 1, characterized in that: Where X, Y, Z, M 1 、M 2 Each independently represents a carbon or nitrogen atom. 1 、M 2 When they are carbon atoms, they are each independently optionally replaced by R 2 Replacement, R 2 is hydrogen, alkyl, halogen, alkoxy; M 3 is carbon, each independently optionally replaced by R 4 , R 5 Replacement, R 4 , R 5 is hydrogen, deuterium, alkyl, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, methylene, aralkyl, diarylalkyl, aryl or Het; Q 1 is selected from saturated or unsaturated straight or branched hydrocarbon groups or aromatic groups having a length of 3 to 8 carbon atoms; R 1 Selected from hydroxyl, optionally with one or more R 3 Substituted 2-aminophenyl, R 3 is hydrogen, alkyl, cyano, halogen, haloalkyl, aryl or Het.

4. The compound according to claim 1, characterized in that: The compound is (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxybutyramide (I-1), (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxypentanamide (I-2), (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyhexanamide (I-3), (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyheptylamide (I-4), (E)-4-(3-benzylidene-2,5-dioxopyrrolidinyl)-N-hydroxyoctanamide (I-5), (E)-N-(2-amino-4-fluorophenyl)-4-(3-benzylidene-2,5-diketopyrrolidinyl)butyramide (I-6), (E)-N-(2-amino-4-fluorophenyl)-5-(3-benzylidene-2,5-diketopyrrolidinyl)pentanamide (I-7), (E)-N-(2-amino-4-fluorophenyl)-6-(3-benzylidene-2,5-diketopyrrolidinyl)hexanamide (I-8), (E)-N-(2-amino-4-fluorophenyl)-7-(3-benzylidene-2,5-diketopyrrolidinyl)heptylamide (I-9), 4-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)butanamide (I-10), 5-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)pentanamide (I-11), 6-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)hexanamide (I-12), 7-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)heptylamide (I-13), 8-(3-((E)-benzylidene)-2,5-diketopyrrolidinyl)-N-((1S,2S)-2-hydroxycyclohexyl)octanamide (I-14), (E)-7-(3-(4-isopropylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-15), (E)-7-(3-(4-dimethylaminobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-16), (E)-7-(3-(4-trifluoromethylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-17), (E)-7-(3-(4-methylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-18), (E)-7-(3-(2-methylbenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-19), (E)-7-(3-(2-cyanobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-20), (E)-7-(3-(2-methylenepyridine)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (Ⅰ-21), (E)-7-(3-(2-methylenenaphthyl)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (Ⅰ-22), (E)-7-(3-(2-methylenethienyl)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-23), (E)-7-(3-(2-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (Ⅰ-24) (E)-7-(3-(3-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-25), (E)-7-(3-(4-chlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-26), (E)-7-(3-(3-fluorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-28), (E)-7-(3-(3-iodobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-29), (E)-7-(3-(3,4-dichlorobenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-30), (E)-7-(3-(2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-31), (E)-7-(3-(3-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-32), (E)-7-(3-(4-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-33), (E)-7-(3-(3,4-dimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-34), (E)-7-(3-(3,4,5-trimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-35), (E)-7-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-36), (E)-7-(3-(2-hydroxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-37), (E)-7-(3-(2-ethoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-38), (E)-7-(3-(5-bromo-2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-39), (E)-7-(3-(4-bromo-2-methoxybenzylidene)-2,5-diketopyrrolidinyl)-N-hydroxyheptylamide (I-40), (E)-4-((3-Benzylidene-2,5-diketopyrrolidinyl)methyl)-N-hydroxybenzamide (I-41).

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein: The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof is an active ingredient.

6. Use of the compound according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating a clinical disorder associated with HDACs.

7. The use of the compound according to claim 6, characterized in that: Diseases associated with HDACs are lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin diseases, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin-dependent diabetes mellitus, and autoimmune diseases.

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