CN117800921B

CN117800921B - Imidazolidine diketone HDAC inhibitor, preparation method and application

Info

Publication number: CN117800921B
Application number: CN202410218988.2A
Authority: CN
Inventors: 周庆发; 姚圣法; 王恩源; 张玉飞; 贾硕磊
Original assignee: Nanjing Hongshun Pharmaceutical Technology Co ltd; China Pharmaceutical University
Current assignee: Nanjing Hongshun Pharmaceutical Technology Co ltd; China Pharmaceutical University
Priority date: 2024-02-28
Filing date: 2024-02-28
Publication date: 2024-06-11
Anticipated expiration: 2044-02-28
Also published as: CN117800921A

Abstract

The invention relates to an imidazolidine diketone HDAC inhibitor, a preparation method and application thereof, and belongs to the technical field of medicines. The invention provides an imidazolidinedione HDAC inhibitor, which is a substituted imidazolidinedione compound shown in a general formula V, or a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof; the inhibitor has high-efficiency excellent HDAC enzyme inhibition activity and also has excellent in-vitro anti-tumor activity, and provides a new way for the application of the HDAC inhibitor in tumors and/or the treatment of diseases related to uncontrolled histone deacetylase activity.

Description

Imidazolidine diketone HDAC inhibitor, preparation method and application

Technical Field

The invention relates to an imidazolidine diketone HDAC inhibitor, a preparation method and application thereof, and belongs to the technical field of medicines.

Background

Traditional methods of malignancy treatment mainly include surgical treatment, chemotherapy, and radiation therapy. Although surgical treatment is a better method, if other auxiliary treatments are not continued, the effect of prolonging the life of the patient is not ideal; the chemotherapy may have drug resistance, side effects of the drug, and frequent cases include suppression of bone marrow, suppression of intestinal functions, etc.; radiation therapy is a localized treatment that inhibits tumor growth, but on the other hand, affects and causes damage to surrounding tissue. Molecular targeting therapy is a novel method for treating cancers due to the characteristics of strong specificity, low toxicity and the like. In terms of chemotherapy, inhibition of histone deacetylase has been shown to have a considerable therapeutic effect on many cancers through a number of studies. Although the existing clinical candidate HDAC inhibitors have been studied for more than thirty years, the existing clinical candidate HDAC inhibitors still have the problems of poor pharmacokinetic properties, general drug effects, limited indications and the like, the combination advantages of HDAC targets are not fully exerted, and the marketed HDAC inhibitors have fewer varieties, so that the targets still have high research value and research space. Histone deacetylases (Histone deacetylase, HDAC) have been found in the 90 s of the last century to play an important role in post-translational modification of amino acid side chains of a variety of proteins, allowing proteins to exist in a variety of states and to have significantly altered biological properties. Because histone deacetylase is widely and highly expressed in various tumor cells, HDAC inhibitors can effectively target tumor cells without producing significant toxic effects, and at the same time, HDAC can slow down and reduce the process of obtaining drug resistance by tumor stem cells. Prostate cancer is the second most common male tumor worldwide (next to lung cancer), with common diseases occurring in adult males older than 50 years. Prostate cancer can often be cured when not metastasized, but metastasis occurs in about 25% of cases, and these patients often have no symptoms for months or even years in the early stages, making treatment and diagnosis more difficult, and can be treated by a method of depriving androgens initially, but the problem of drug resistance easily occurs, resulting in incurable diseases. There have been studies to begin to explore the assistance of HDAC inhibitors to prostate cancer patients. Firstly, over-expression of HDAC6 is associated with invasion and metastasis of tumor cells, whereas over-expression of HDAC is often observed in prostate cancer patients, and secondly HDAC exhibits high level inhibition in various tumor systems, a considerable number of academic studies have provided experimental basis for the treatment of prostate cancer with HDAC inhibitors, which can solve the drug resistance problem of many inhibitors, but not with HDAC inhibitors against prostate cancer.

Disclosure of Invention

Aiming at the defects existing in the prior art, the invention provides an imidazolidine diketone HDAC inhibitor, a preparation method and application.

The invention solves the technical problems through the following technical scheme: the imidazolidine diketone HDAC inhibitor is a substituted imidazolidine diketone compound shown in a general formula V, or a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof: Wherein W is selected from an oxygen atom or a sulfur atom; x, Y, Z, M ₁、M₂ each independently represents a carbon or nitrogen atom, and when X, Y, Z, M ₁、M₂ is a carbon atom, each independently is optionally substituted with R ₃, R ₃ may be hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, aryl, or Het;

q is selected from saturated or unsaturated linear or branched hydrocarbon groups of 1-9 carbon atoms in length, aryl or Het;

r ₁ is hydrogen, deuterium, alkyl, haloalkyl, hydroxy, mercapto, alkoxy, alkylamino, alkylthio, alkoxyalkyl, methylene, aralkyl, diarylalkyl, aryl, or Het;

R ₂ is selected from hydroxy, 2-aminophenyl optionally substituted with one or more R ₄;

R ₄ is hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, aryl, or Het;

alkyl is a straight or branched saturated hydrocarbon group having 1 to 9 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 which is a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms attached;

Alkoxy is a straight or branched saturated hydrocarbon radical having 1 to 9 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 9 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms which is a straight or branched saturated hydrocarbon group having 1 to 9 carbon atoms attached; wherein each carbon atom is optionally substituted with oxygen;

Alkylamino is a straight or branched saturated hydrocarbon radical having 1 to 9 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 which is a straight or branched saturated hydrocarbon group having 1 to 9 carbon atoms attached; wherein each carbon atom is optionally substituted with an NH radical;

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

alkenyl and alkynyl are straight-chain or branched unsaturated hydrocarbon groups containing double bonds or triple bonds and having 1 to 9 carbon atoms;

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

aralkyl, diarylalkyl are aryl groups as defined above attached to an alkyl group;

Het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxanyl or benzo [1,3] dioxolyl; or is selected from a monocyclic saturated hydrocarbon group of 3 to 6 carbon atoms, a bicyclic saturated hydrocarbon group of 6 to 12 carbon atoms, wherein the carbon atoms on the ring are independently optionally substituted with 1 to 4O, 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.

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

Haloalkyl is a straight or branched saturated hydrocarbon group having 1 to 9 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms linked to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms; wherein one or more carbon atoms are replaced by one or more halogen atoms.

Preferably, the present invention further selects the following compounds as imidazolidinedione HDAC inhibitors: wherein W is selected from an oxygen atom or a sulfur atom; x, Y, Z, M ₁、M₂ each independently represents a carbon or nitrogen atom, and when X, Y, Z, M ₁、M₂ is a carbon atom, each independently is optionally substituted with R ₃, R ₃ is hydrogen, alkyl, cyano, halogen, haloalkyl, alkoxy, alkylthio, alkoxyalkyl;

q is a saturated or unsaturated straight or branched hydrocarbon group selected from 1 to 9 carbon atoms in length, aryl;

R ₄ is hydrogen, alkyl, cyano, halogen, haloalkyl, aryl, or Het.

Preferably, the present invention further selects the following compounds as imidazolidinedione HDAC inhibitors: wherein W is selected from an oxygen atom or a sulfur atom; x, Y, Z, M ₁、M₂ each independently represents a carbon or nitrogen atom, and when X, Y, Z, M ₁、M₂ is a carbon atom, each independently is optionally substituted with R ₃, R ₃ is hydrogen, alkyl, halogen, alkoxy;

Q is a saturated or unsaturated straight or branched hydrocarbon radical selected from 3 to 9 carbon atoms in length, aryl;

R ₄ is hydrogen, alkyl, cyano, halogen, haloalkyl, aryl, or Het.

Preferably, in the inhibitor of formula V, the carbon-linked hydrogen is replaced with deuterium, an isotope of hydrogen.

It is further preferred that the alkyl group is replaced by a deuterated alkyl group, the alkoxy group is replaced by a deuterated epoxy group, the benzene ring is replaced by a deuterated benzene ring, and the aromatic ring is replaced by a deuterated aromatic ring.

Preferably, a pharmaceutically acceptable salt refers to the conversion of a basic group in the parent compound to a salt form; wherein the pharmaceutically acceptable salt is a basic group, and is further preferably an amino group or an inorganic or organic acid salt of an amino group; from the basic groups in the parent compound with 1 to 4 equivalents of acid in a solvent system.

Preferably, the basic groups of the compounds of the present invention may form salts with acids, in particular with inorganic acids, especially with hydrohalic acids (e.g. hydrochloric, hydrobromic, hydroiodic), nitric, sulfuric, phosphoric, carbonic acids and the like; salts of lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid; salts with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts with organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; salts with amino acids, such as aspartic acid or glutamic acid.

Preferably, the compounds and pharmaceutically acceptable salts of the present invention also include the forms of solvates or hydrates.

Preferably, the structural formula of the compounds in the imidazolidine-dione HDAC inhibitors of the present invention includes isomeric forms, such as enantiomers, diastereomers, geometric isomers or conformational isomers, in particular the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, (Z), (E) conformational isomers.

Preferably, the inhibitor is one of the following:

(1) (Z) -N-hydroxy-7- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) heptanamide;

(2) (Z) -N-hydroxy-8- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) octanamide;

(3) (Z) -N-hydroxy-6- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(4) (Z) -N-hydroxy-5- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) pentanamide;

(5) (Z) -N-hydroxy-7- (4- (4-bromo-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) heptanamide;

(6) (Z) -N-hydroxy-8- (4- (4-bromo-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) octanamide;

(7) (Z) -N-hydroxy-9- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) nonanamide;

(8) (Z) -N-hydroxy-10- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) decanoamide;

(9) (Z) -N-hydroxy-7- (4- (2-methoxybenzylidene) -3-methyl-2, 5-dioxoimidazolidin-1-yl) heptanamide;

(10) (Z) -N-hydroxy-7- (4- (4-bromo-2-methoxybenzylidene) -3-methyl-2, 5-dioxoimidazolidin-1-yl) heptanamide;

(11) (Z) -N-hydroxy-6- (4- (4-bromo-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(12) (Z) -N-hydroxy-6- (4- (3-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(13) (Z) -N-hydroxy-6- (4- (4-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(14) (Z) -N-hydroxy-6- (4- (2, 4-dimethoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(15) (Z) -N-hydroxy-6- (4- (4-fluoro-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(16) (Z) -N-hydroxy-6- (4- (4-chloro-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(17) (Z) -N-hydroxy-6- (4- (2-methoxy-4-methylbenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(18) (Z) -N-hydroxy-6- (4- (2-methoxy-4- (trifluoromethyl) benzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(19) (Z) -N-hydroxy-6- (2, 5-dioxo-4- (3, 4, 5-trimethoxybenzylidene) imidazolidin-1-yl) hexanamide;

(20) (Z) -N-hydroxy-6- (4- (naphthalen-1-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(21) (Z) -N-hydroxy-6- (4- (naphthalen-2-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(22) (Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-2-ylmethylene) imidazolidin-1-yl) hexanamide;

(23) (Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-3-ylmethylene) imidazolidin-1-yl) hexanamide;

(24) (Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-4-ylmethylene) imidazolidin-1-yl) hexanamide;

(25) (Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-6-ylmethylene) imidazolidin-1-yl) hexanamide;

(26) (Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-5-ylmethylene) imidazolidin-1-yl) hexanamide;

(27) (Z) -N-hydroxy-6- (4- (furan-2-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(28) (Z) -N-hydroxy-6- (2, 5-dioxo-4- (thiophen-2-ylmethylene) imidazolidin-1-yl) hexanamide;

(29) (Z) -N-hydroxy-6- (4- ((2, 3-dihydrobenzofuran-5-yl) methylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(30) (Z) -N-hydroxy-6- (4- (benzofuran-5-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(31) (Z) -N-hydroxy-6- (4- (benzo [ d ] [1,3] dioxol-5-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(32) (Z) -N-hydroxy-6- (4- ((2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) methylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide;

(33) (Z) -N- (2-amino-4-fluorophenyl) -4- ((2, 5-dioxo-4- (pyridin-3-ylmethylene) imidazolidin-1-yl) methyl) benzamide;

(34) (Z) -N- (2-amino-4-fluorophenyl) -4- ((3-methyl-2, 5-dioxo-4- (pyridin-3-ylmethylene) imidazolidin-1-yl) methyl) benzamide;

(35) (Z) -N-hydroxy-6- (2, 5-dioxo-4- ((4- (pyridin-4-yl) quinolin-6-yl) methylene) imidazolidin-1-yl) hexanamide.

The preparation method of the inhibitor comprises the steps of taking substituted formaldehyde (A) and hydantoin or substituted hydantoin (B) as raw materials, and carrying out Knoevenagel condensation reaction under the action of alanine to obtain an intermediate (C); nucleophilic substitution reaction is carried out between the intermediate (C) and bromocarboxylate to obtain a key intermediate (D); the intermediate (D) undergoes hydrolysis reaction under an acidic condition to obtain an intermediate (E); the intermediate (E) and hydroxylamine hydrochloride are subjected to condensation reaction to obtain target compounds (1-32), and the synthetic route is as follows:

。

The preparation method of the inhibitor is two, takes substituted formaldehyde (A) and hydantoin or substituted hydantoin (B) as raw materials, and takes Knoevenagel condensation reaction under the action of alanine to obtain an intermediate (C); nucleophilic substitution reaction is carried out between the intermediate (C) and bromocarboxylate to obtain a key intermediate (D); the intermediate (D) undergoes hydrolysis reaction under an acidic condition to obtain an intermediate (E); the intermediate (E) and 4-fluoro-1, 2-phenylenediamine are subjected to condensation reaction to obtain a target compound (1-32), and the synthetic route is as follows:

。

the preparation method of the inhibitor further comprises the steps of taking the compound (F) as a raw material, and carrying out Combes quinoline synthesis reaction with the cyclopropylester malonate to obtain an intermediate (G); the intermediate (G) and phosphorus tribromide undergo a bromination reaction in DMF to obtain an intermediate (H); performing Suzuki coupling reaction on the intermediate (H) and 4-pyridine boric acid to obtain an intermediate (I); the intermediate (I) and lithium aluminum hydride undergo a reduction reaction to obtain an intermediate (J); the intermediate (J) is selectively oxidized to obtain a key intermediate (K). The intermediate (K) is subjected to four-step reaction to obtain a target compound (35), and the synthetic route is as follows:

。

Use of an above-described imidazolidinedione HDAC inhibitor in the manufacture of a medicament for inhibiting the growth of cancer cells.

The invention selects the lead compound of vorinostat for further structural modification based on the characteristics of weak inhibiting activity of HDAC and insufficient anti-tumor effect. The imidazolidinedione is determined to be taken as a basic framework structure, and the substituent groups are screened, so that a high-efficiency inhibition effect is brought.

Compared with the prior art, the invention has the following remarkable advantages: (1) has a high-efficiency excellent HDAC enzyme inhibitory activity; (2) Low cost, good curative effect, low toxicity, high yield of intermediate products in the synthesis process, and reduced resource waste, thereby being beneficial to reducing the cost; and (3) the antitumor activity is remarkable, and the dosage is small.

Detailed Description

The technical scheme of the invention is further described below by referring to examples.

Reagents were purchased from commercial suppliers such as Anhui Zealand technologies, balanuginos, aba Ding Shiji, beijing coupling technologies, etc., and were not further purified unless otherwise indicated. General reagents are purchased from the chemical company of the chemical industry of the ridge, the chemical company of the Nanjing, the chemical company of the national medicine group, the ocean chemical company of the Qingdao, and the like. All temperatures in the examples are given in degrees celsius unless otherwise indicated. The chromatographic column in the examples described below uses a silica gel column, silica gel (200-300 mesh) available from Qingdao ocean chemical Co. Nuclear magnetic resonance spectroscopy was performed using CDCl ₃ or DMSO-d ₆ as solvent (in ppm)) and TMS (0 ppm) as a reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlet ), d (doublet, doublet), t (triplet, doublet), m (multiplet ), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).

The low resolution Mass Spectrometry (MS) data in the examples described below were analyzed by an Agilent 6120 series LC-MS G1329B autosampler and G4212B detector equipped with a G1311B quaternary pump and G1316A column oven, and the ESI source was applied to the LC-MS spectrometer.

For convenience of description, some of the raw materials will be described in terms of their abbreviations, which are fully described below: DCM is CH ₂Cl₂, i.e., dichloromethane; CDC1 ₃ is deuterated chloroform; PE is petroleum ether; etOAc and EA were both ethyl acetate; meOH and CH ₃ OH are both methanol; clSO ₃ H is chlorosulfonic acid; TEA and Et ₃ N are triethylamine; DMSO-d ₆ is hexadeuterated dimethyl sulfoxide; THF is tetrahydrofuran; naCl is sodium chloride; na ₂SO₄ is sodium sulfate; DIPEA is N, N-diisopropylethylamine, pyBOP is 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, pd (dppf) Cl ₂ is 1,1' -bis (diphenylphosphino) ferrocene palladium chloride, dichloromethane complex.

Example 1

The synthesis of (Z) -N-hydroxy-7- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) heptanamide comprises the following steps: step 1: the synthesis of (Z) -5- (2-methoxybenzylidene) imidazolidine-2, 4-dione has the following structural formula: 1.11 g of 2-methoxybenzaldehyde (10 mmol), 1.36 of g (11.0 mmol,1.1 eq.) of hydantoin and 1.07 of g (12.0 mmol,1.2 eq.) of beta-alanine were weighed out and dissolved in 25 mL of acetic acid and added to a 100 mL eggplant-shaped reaction flask for reflux reaction at 120℃overnight, and the plate was spotted by TLC until the starting material was completely consumed. The reaction solution was slowly added to ice water, a large amount of solids precipitated after stirring at room temperature, and the crude product was obtained by filtration and purified by silica gel column chromatography (PE: ea=1:1). Pale yellow solid, yield ：76 %.1H NMR (300 MHz, Chloroform-d) δ 9.62 (s, 1H), 9.05 (s, 1H), 7.67 (dd, J= 7.8, 1.6 Hz, 1H), 7.37 (td, J = 7.8, 1.5 Hz, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 7.00 (dd, J= 8.1, 1.3 Hz, 1H), 6.88 (s, 1H), 3.87 (s, 2H). step 2: the synthesis of (Z) -7- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) ethyl heptanoate has the following structural formula: 5 mmol (Z) -5- (2-methoxybenzylidene) imidazolidine-2, 4-dione was weighed, 10 mmol potassium carbonate (2.0. 2.0 eq.) was dissolved in 20mL DMF, the temperature was reduced to 0 ℃ and stirred for 30 min, 6 mmol ethyl 7-bromoheptanoate (1.2. 1.2 eq.) was slowly added dropwise, the temperature was raised to room temperature, and the reaction was 6-8 h. The end of the reaction was purified by column chromatography (PE: ea=5:1-2:1). White solid, yield ：52 %.¹H NMR (400 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.41 – 7.33 (m, 2H), 7.08 – 6.95 (m, 2H), 6.76 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.61 (dd, J = 8.0, 6.6 Hz, 2H), 2.30 (t, J = 7.5 Hz, 2H), 1.76 (s, 1H), 1.75 – 1.58 (m, 4H), 1.43 – 1.33 (m, J = 4.0, 3.5 Hz, 4H), 1.26 (t, J = 7.1 Hz, 4H).

Step 3: synthesis of (Z) -N-hydroxy-7- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) heptanamide, the structural formula is as follows:

Firstly, preparing (Z) -7- (4- (2-methoxybenzylidene) -2, 5-dioxo-imidazolidin-1-yl) heptanoic acid, namely, dissolving ethyl (Z) -7- (4- (2-methoxybenzylidene) -2, 5-dioxo-imidazolidin-1-yl) heptanoate of 5 mmol in an acetic acid solution of 10 mL, placing the ethyl (Z) -7- (4- (2-methoxybenzylidene) -2, 5-dioxo-imidazolidin-1-yl) heptanoic acid in a eggplant-shaped bottle of 50mL, measuring 1mL of concentrated hydrochloric acid, slowly dripping the concentrated hydrochloric acid into a reaction bottle, heating the reaction solution to 90 ℃, reacting 6 h, adding the reaction solution into brine ice while the reaction solution is hot to separate out a large amount of white solid, and drying to obtain a crude product of (Z) -7- (4- (2-methoxybenzylidene) -2, 5-dioxo-imidazolidin-1-yl) heptanoic acid. 1 mmol (Z) -7- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) heptanoic acid crude product and 1.5 mmol PyBOP condensing agent (1.5 eq.) were weighed into a 25 mL reaction flask, 6 mL DMF solution was added, 590 μL DIPEA (3.5 eq.) was added to the reaction solution, 0.14 g hydroxylamine hydrochloride (2.0 eq.) was added after stirring for several minutes at room temperature, after reaction at room temperature 6 h, TLC was monitored until the intermediate was completely consumed (DCM: meOH=25:1), concentrated in vacuo, and purified by column chromatography. White solid, yield ：53 %.¹H NMR (400 MHz, DMSO-d₆) δ10.60 (d, J= 3.5 Hz, 1H), 10.32 (d, J = 3.5 Hz, 1H), 8.52 (s, 1H), 7.66 (dd, J = 7.7, 1.6 Hz, 1H), 7.37 (td, J = 7.8, 1.6 Hz, 1H), 7.07 (td, J= 7.6, 1.2 Hz, 1H), 7.00 (dd, J = 8.0, 1.3 Hz, 1H), 6.86 (s, 1H), 3.87 (s, 2H), 3.72 (t, J = 6.6 Hz, 2H), 1.99 (t, J = 8.6 Hz, 2H), 1.62 (p, J = 6.7 Hz, 2H), 1.55 (ddd, J = 16.3, 8.5, 7.4 Hz, 2H), 1.41 – 1.28 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ174.79, 163.98, 158.56, 154.37, 132.25, 129.69, 127.13, 124.90, 123.38, 112.63, 110.42, 55.63, 37.80, 32.04, 28.24, 27.26, 26.86, 25.05.

Example 2

(Z) -N-hydroxy-8- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) octanamide having the structural formula: the procedure of example 1 was followed except that the ethyl 7-bromoheptanoate fragment of step 2 of example 1 was changed to ethyl 8-bromooctanoate; white solid, yield ：43 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (d, J = 3.5 Hz, 1H), 9.08 (d, J = 3.5 Hz, 1H), 8.52 (s, 1H), 7.62 (dd, J = 7.7, 1.6 Hz, 1H), 7.34 (td, J = 7.9, 7.3, 1.6 Hz, 1H), 7.09 – 6.95 (m, 2H), 6.74 (s, 1H), 3.85 (s, 3H), 3.46 (t, J = 7.1 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.51 (dp, J = 29.4, 7.2 Hz, 4H), 1.25 (h, J = 6.0 Hz, 6H); ¹³C NMR (101 MHz, DMSO-d₆) δ 174.80, 163.98, 158.56, 154.37, 132.25, 129.69, 127.13, 124.90, 123.38, 112.63, 110.42, 55.63, 37.80, 32.04, 28.81, 27.94, 27.26, 27.07, 25.05.

Example 3

(Z) -N-hydroxy-6- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that the ethyl 7-bromoheptanoate fragment of step 2 of example 1 was changed to ethyl 6-bromohexanoate; white solid, yield ：47 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (d, J = 3.5 Hz, 1H), 8.69 (d, J = 3.7 Hz, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.34 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.05 (dd, J = 8.4, 1.1 Hz, 1H), 6.98 (td, J = 7.4, 1.0 Hz, 1H), 6.73 (s, 1H), 3.84 (s, 3H), 3.44 (t, J = 7.1 Hz, 3H), 2.01 – 1.89 (m, 2H), 1.51 (dq, J = 15.1, 7.5 Hz, 4H), 1.30 – 1.13 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.72, 164.59, 157.59, 155.51, 130.87, 129.71, 126.96, 121.62, 121.08, 111.59, 104.57, 56.07, 38.28, 32.50, 27.81, 26.15, 24.61.

Example 4

(Z) -N-hydroxy-5- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) pentanamide having the structural formula: the procedure of example 1 was repeated except that the ethyl 7-bromoheptanoate fragment in step 2 of example 1 was changed to ethyl 5-bromopentanoate; white solid, yield ：48 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (d, J = 3.5 Hz, 1H), 9.08 (d, J = 3.5 Hz, 1H), 8.52 (s, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.35 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.06 (dd, J= 8.4, 1.0 Hz, 1H), 6.99 (td, J = 7.5, 1.0 Hz, 1H), 6.74 (s, 1H), 3.85 (s, 3H), 3.46 (t, J = 6.5 Hz, 2H), 1.98 (t, J = 6.2 Hz, 2H), 1.50 (ddt, J = 15.7, 12.1, 8.2 Hz, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.22, 164.78, 157.53, 155.60, 131.19, 129.64, 126.68, 121.34, 121.20, 111.63, 105.46, 56.02, 38.13, 32.13, 27.54, 22.82.

Example 5

(Z) -N-hydroxy-7- (4- (4-bromo-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) heptanamide having the structural formula: The procedure of example 1 was repeated except that the starting material 2-methoxybenzaldehyde in step1 of example 1 was changed to 4-bromo-2-methoxybenzaldehyde; white solid, yield ：38%.¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (d, J = 3.5 Hz, 1H), 10.32 (d, J = 3.5 Hz, 1H), 8.51 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 8.8, 2.2 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 6.85 (s, 1H), 3.88 (s, 2H), 3.72 (t, J = 6.6 Hz, 2H), 1.99 (t, J= 8.6 Hz, 2H), 1.62 (p, J = 6.7 Hz, 2H), 1.55 (ddd, J = 16.3, 8.5, 7.4 Hz, 2H), 1.41 – 1.28 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ 178.26, 162.10, 156.21, 152.45, 135.20, 124.25, 123.56, 123.21, 120.64, 112.11, 111.87, 56.07, 36.50, 32.64, 27.97, 27.02, 26.66, 25.14.

Example 6

(Z) -N-hydroxy-8- (4- (4-bromo-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) octanamide having the structural formula: the procedure of example 1 was followed except that the starting material 2-methoxybenzaldehyde in step 1 of example 1 was changed to 4-bromo-2-methoxybenzaldehyde, and the fragment 7-bromoheptanoic acid ethyl ester in step 2 was changed to ethyl 8-bromooctanoate; white solid, yield ：35%.¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (d, J= 3.5 Hz, 1H), 10.30 (d, J = 3.5 Hz, 1H), 8.53 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 8.8, 2.2 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 6.83 (s, 1H), 3.76 (s, 2H), 3.70 (t, J = 6.6 Hz, 2H), 2.01 (t, J = 8.6 Hz, 2H), 1.66 – 1.49 (m, 4H), 1.43 – 1.23 (m, 7H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.66, 164.44, 158.25, 155.49, 131.06, 127.61, 123.88, 123.25, 121.16, 114.92, 103.14, 56.67, 38.40, 32.68, 28.91, 28.69, 28.01, 26.52, 25.51.

Example 7

(Z) -N-hydroxy-9- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) nonanamide having the structural formula: the procedure of example 1 was followed except that the ethyl 7-bromoheptanoate fragment of step 2 of example 1 was changed to ethyl 9-bromononanoate; white solid, yield ：39%.¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (d, J = 3.5 Hz, 1H), 10.32 (d, J = 3.5 Hz, 1H), 8.66 (s, 1H), 7.60 (dd, J = 7.6, 1.6 Hz, 1H), 7.39 – 7.29 (m, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.73 (s, 1H), 3.84 (s, 3H), 3.45 (t, J = 7.1 Hz, 2H), 1.92 (t, J = 7.3 Hz, 2H), 1.55 (q, J = 7.0 Hz, 2H), 1.46 (p, J = 7.5, 7.0 Hz, 2H), 1.28 – 1.20 (m, 8H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.71, 164.55, 157.61, 155.50, 130.79, 129.74, 126.98, 121.68, 121.05, 111.59, 104.42, 56.08, 38.35, 32.68, 29.05, 28.96, 28.89, 28.01, 27.91, 26.58, 25.55.

Example 8

(Z) -N-hydroxy-10- (4- (2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) decanoamide having the structural formula: The procedure of example 1 was followed except that the ethyl 7-bromoheptanoate fragment of step 2 of example 1 was changed to ethyl 10-bromodecanoate; white solid, yield ：32%.¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (d, J = 3.5 Hz, 1H), 10.32 (d, J = 3.5 Hz, 1H), 8.66 (s, 1H), 7.60 (dd, J = 7.7, 1.6 Hz, 1H), 7.39 – 7.29 (m, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.73 (s, 1H), 3.84 (s, 3H), 3.45 (t, J = 7.1 Hz, 2H), 1.92 (t, J = 7.4 Hz, 2H), 1.50 (dp, J = 33.1, 7.0 Hz, 4H), 1.24 (d, J = 8.0 Hz, 10H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.64, 164.54, 157.62, 155.49, 130.76, 129.75, 127.00, 121.71, 121.04, 111.58, 104.35, 56.08, 38.35, 32.71, 29.27, 29.14, 29.01, 28.96, 28.01, 26.71, 25.57.

Example 9

(Z) -N-hydroxy-7- (4- (2-methoxybenzylidene) -3-methyl-2, 5-dioxoimidazolidin-1-yl) heptanamide having the structural formula: The procedure of example 1 was repeated except that the starting material hydantoin in step 1 of example 1 was changed to 1-methylhydantoin; white solid, yield ：34%.¹H NMR (400 MHz, DMSO-d₆) δ10.62 (d, J = 3.5 Hz, 1H), 10.32 (d, J = 3.5 Hz, 1H), .52 s, 1H), 7.71 (dd, J= 7.7, 1.6 Hz, 1H), 7.37 (td, J = 7.8, 1.6 Hz, 1H), 7.36 (s, 1H), 7.07 (td, J= 7.6, 1.2 Hz, 1H), 7.00 (dd, J = 8.1, 1.3 Hz, 1H), 3.87 (s, 2H), 3.72 (t, J= 6.7 Hz, 2H), 3.30 (s, 2H), 1.99 (t, J = 8.6 Hz, 2H), 1.66 – 1.50 (m, 4H), 1.41 – 1.28 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.54, 163.56, 161.67, 157.47, 131.35, 131.26, 130.75, 129.45, 121.50, 120.34, 111.34, 56.02, 38.90, 32.63, 30.09, 28.57, 27.96, 26.65, 25.43.

Example 10

(Z) -N-hydroxy-7- (4- (4-bromo-2-methoxybenzylidene) -3-methyl-2, 5-dioxoimidazolidin-1-yl) heptanamide having the structural formula:

The procedure of example 1 was followed except that the starting material hydantoin in step 1 of example 1 was changed to 1-methylhydantoin and 2-methoxybenzaldehyde was changed to 4-bromo-2-methoxybenzaldehyde; white solid, yield ：35 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (d, J = 3.3 Hz, 1H), 8.67 (d, J = 3.5 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.24 (s, 1H), 7.13 (dd, J = 9.0, 2.2 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 3.88 (s, 2H), 3.72 (t, J = 6.7 Hz, 2H), 3.30 (s, 2H), 1.99 (t, J = 8.6 Hz, 2H), 1.66 – 1.50 (m, 4H), 1.41 – 1.28 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.57, 163.47, 158.56, 153.56, 132.71, 130.04, 123.28, 123.05, 120.99, 114.72, 114.43, 56.60, 38.93, 32.63, 30.14, 28.56, 27.93, 26.67, 25.41.

Example 11

(Z) -N-hydroxy-6- (4- (4-bromo-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that 2-methoxybenzaldehyde used as the starting material in step 1 of example 1 was changed to 4-bromo-2-methoxybenzaldehyde and ethyl 7-bromoheptanoate used as the starting material in step 2 was changed to ethyl 6-bromohexanoate; white solid, yield ：40 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (d, J = 3.5 Hz, 1H), 8.76 (d, J = 3.5 Hz, 1H), 8.43 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.30 (dd, J = 9.0, 2.0 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 6.75 (s, 1H), 3.98 (s, 2H), 3.74 (t, J = 6.6 Hz, 2H), 2.10 (t, J = 8.6 Hz, 2H), 1.69 – 1.54 (m, 4H), 1.45 – 1.29 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.80, 165.71, 158.87, 155.31, 134.44, 127.54, 124.90, 124.46, 122.70, 118.04, 112.23, 57.17, 36.98, 33.77, 27.55, 26.54, 24.60.

Example 12

(Z) -N-hydroxy-6- (4- (3-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 3-methoxybenzaldehyde was used as the starting material, and ethyl 7-bromoheptanoate in step 2 was used as the 6-bromohexanoate; white solid, yield ：39 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.5 Hz, 1H), 8.79 (s, 1H), 7.26 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.15 (dt, J = 8.1, 2.5 Hz, 1H), 7.02 – 6.96 (m, 2H), 6.65 (s, 1H), 3.82 (s, 2H), 3.72 (t, J = 6.6 Hz, 2H), 1.99 (t, J = 8.6 Hz, 2H), 1.68 – 1.56 (m, 4H), 1.44 – 1.29 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.20, 160.57, 159.87, 155.68, 134.71, 130.75, 126.30, 124.62, 119.25, 118.51, 116.35, 52.27, 37.70, 36.52, 27.81, 26.68, 25.41.

Example 13

(Z) -N-hydroxy-6- (4- (4-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that the starting material 2-methoxybenzaldehyde in step 1 of example 1 was changed to 4-methoxybenzaldehyde and the fragment 7-bromoheptanoic acid ethyl ester in step 2 was changed to 6-bromohexanoic acid ethyl ester; white solid, yield ：38 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (d, J = 3.3 Hz, 1H), 9.20 (d, J = 3.5 Hz, 1H), 8.82 (s, 1H), 7.56 – 7.50 (m, 2H), 7.08 – 7.01 (m, 2H), 6.59 (s, 1H), 3.82 (s, 2H), 3.72 (t, J = 6.6 Hz, 2H), 1.99 (t, J = 8.6 Hz, 2H), 1.67 – 1.52 (m, 4H), 1.42 – 1.33 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.80, 168.10, 164.70, 150.38, 134.53, 129.69, 125.16, 119.05, 114.85, 56.32, 36.80, 31.22, 27.21, 26.48, 24.81.

Example 14

(Z) -N-hydroxy-6- (4- (2, 4-dimethoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 2, 4-dimethoxybenzaldehyde was used as the starting material, and ethyl 7-bromoheptanoate in step 2 was used as the 6-bromohexanoate; white solid, yield ：42 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (d, J = 3.5 Hz, 1H), 9.02 (d, J = 3.5 Hz, 1H), 8.56 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.63 – 6.56 (m, 2H), 3.88 (s, 2H), 3.82 (s, 2H), 3.72 (t, J = 6.6 Hz, 2H), 1.99 (t, J = 8.6 Hz, 2H), 1.64 – 1.50 (m, 4H), 1.47 – 1.32 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.57, 164.50, 160.87, 154.92, 152.61, 135.81, 129.45, 121.12, 115.45, 110.55, 100.21, 58.67, 53.12, 39.71, 33.55, 29.45, 26.53, 25.12.

Example 15

(Z) -N-hydroxy-6- (4- (4-fluoro-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: the procedure of example 1 was repeated except that 2-methoxybenzaldehyde used as the starting material in step 1 of example 1 was changed to 4-fluoro-2-methoxybenzaldehyde and ethyl 7-bromoheptanoate used as the starting material in step 2 was changed to ethyl 6-bromohexanoate; pale yellow solid, yield ：40 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (d, J = 3.5 Hz, 1H), 9.08 (d, J = 3.5 Hz, 1H), 8.51 (s, 1H), 7.52 (dd, J = 8.7, 5.0 Hz, 1H), 7.00 (ddd, J = 8.8, 8.1, 1.9 Hz, 1H), 6.81 – 6.76 (m, 2H), 3.77 (s, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.00 (t, J = 8.6 Hz, 2H), 1.64 – 1.50 (m, 4H), 1.39 – 1.29 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.40, 165.87, 164.98, 163.92, 160.22, 157.95, 153.67, 131.80, 131.21, 128.05, 122.61, 120.67, 113.06, 111.05, 109.97, 101.65, 101.42, 52.05, 38.51, 33.34, 28.05, 27.48, 25.21.

Example 16

(Z) -N-hydroxy-6- (4- (4-chloro-2-methoxybenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that 2-methoxybenzaldehyde used as the starting material in step 1 of example 1 was changed to 4-chloro-2-methoxybenzaldehyde and ethyl 7-bromoheptanoate used as the starting material in step 2 was changed to ethyl 6-bromohexanoate; white solid, yield ：36 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (d, J = 3.5 Hz, 1H), 9.08 (d, J = 3.5 Hz, 1H), 8.60 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.34 – 7.28 (m, 1H), 7.02 (d, J = 1.9 Hz, 1H), 6.82 (s, 1H), 3.98 (s, 2H), 3.70 (t, J = 6.6 Hz, 2H), 1.98 (t, J = 8.6 Hz, 2H), 1.64 – 1.50 (m, 4H), 1.41 – 1.30 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.50, 166.58, 160.54, 159.70, 136.08, 132.87, 128.71, 124.33, 120.71, 111.45, 110.12, 52.10, 38.70, 35.44, 29.02, 27.52, 25.21.

Example 17

(Z) -N-hydroxy-6- (4- (2-methoxy-4-methylbenzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 2-methoxy-4-methylbenzaldehyde was used as the starting material, and ethyl 7-bromoheptanoate in step 2 was used as the 6-bromohexanoate; white solid, yield ：41 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (d, J = 3.5 Hz, 1H), 8.86 (d, J = 3.5 Hz, 1H), 8.53 (s, 1H), 7.66 (dd, J = 7.7, 1.6 Hz, 1H), 7.31 (td, J = 7.8, 1.6 Hz, 1H), 7.09 (td, J = 7.6, 1.2 Hz, 1H), 7.00 (dd, J = 8.0, 1.3 Hz, 1H), 6.84 (s, 1H), 3.89 (s, 2H), 3.70 (t, J = 6.6 Hz, 2H), 1.97 (t, J = 8.6 Hz, 2H), 1.60 (p, J = 6.7 Hz, 2H), 1.52 (ddd, J= 16.3, 8.5, 7.4 Hz, 2H), 1.40 – 1.27 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ169.80, 160.98, 156.66, 152.37, 138.67, 124.59, 124.11, 122.41, 121.85, 112.05, 111.02, 54.50, 34.80, 31.22, 26.86, 26.42, 25.11, 22.78.

Example 18

(Z) -N-hydroxy-6- (4- (2-methoxy-4- (trifluoromethyl) benzylidene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 2-methoxy-4-trifluoromethylbenzaldehyde was used as the starting material, and ethyl 7-bromoheptanoate in step 2 was used as the 6-bromohexanoate; pale yellow solid, yield ：43 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (d, J = 3.5 Hz, 1H), 9.00 (d, J = 3.5 Hz, 1H), 8.52 (s, 1H), 7.60 (d, J = 1.5 Hz, 2H), 7.31 – 7.27 (m, 1H), 6.82 (s, 1H), 3.98 (s, 2H), 3.75 (t, J = 6.6 Hz, 2H), 2.02 (t, J = 8.6 Hz, 2H), 1.69 – 1.54 (m, 4H), 1.44 – 1.35 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.40, 163.98, 158.10, 158.08, 158.06, 158.05, 154.37, 132.84, 132.59, 132.33, 132.07, 129.17, 129.15, 129.14, 129.12, 127.11, 127.04, 124.89, 124.39, 122.75, 120.60, 120.52, 120.49, 120.46, 120.42, 112.07, 110.64, 110.61, 110.58, 110.55, 56.07, 37.80, 32.22, 27.01, 26.28, 25.11./>

Example 19

(Z) -N-hydroxy-6- (2, 5-dioxo-4- (3, 4, 5-trimethoxybenzylidene) imidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that 2-methoxybenzaldehyde used as the starting material in step 1 of example 1 was changed to 3,4, 5-trimethoxybenzaldehyde and ethyl 7-bromoheptanoate used as the starting material in step 2 was changed to ethyl 6-bromohexanoate; white solid, yield ：34 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (d, J= 3.3 Hz, 1H), 9.02 (d, J = 3.5 Hz, 1H), 8.72 (s, 1H), 7.23 (s, 1H), 6.84 (s, 2H), 3.86 (s, 5H), 3.90 (s, 2H), 3.72 (t, J = 6.6 Hz, 2H), 1.97 (t, J = 8.6 Hz, 2H), 1.75 – 1.64 (m, 4H), 1.48 – 1.37 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.10, 162.70, 155.28, 154.84, 142.12, 131.78, 126.24, 114.45, 109.54, 62.74, 57.42, 36.90, 33.81, 27.87, 27.22, 25.04.

Example 20

(Z) -N-hydroxy-6- (4- (naphthalen-1-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that the starting material 2-methoxybenzaldehyde in step 1 of example 1 was changed to 1-naphthaldehyde, and the fragment 7-ethyl bromoheptanoate in step 2 was changed to ethyl 6-bromohexanoate; pale yellow solid, yield ：37 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (d, J = 3.3 Hz, 1H), 9.10 (d, J = 3.5 Hz, 1H), 8.87 (s, 1H), 8.10 – 8.02 (m, 1H), 7.94 – 7.87 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.60 – 7.52 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 2.00 (t, J = 8.6 Hz, 2H), 1.70 – 1.55 (m, 4H), 1.45 – 1.36 (m, 2H).; ¹³C NMR (101 MHz, DMSO-d₆) δ 169.87, 161.15, 154.38, 133.08, 132.74, 132.36, 129.24, 128.34, 128.30, 128.25, 126.96, 126.74, 125.72, 124.74, 110.87, 37.80, 32.22, 28.01, 27.29, 25.31.

Example 21

(Z) -N-hydroxy-6- (4- (naphthalen-2-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 2-naphthaldehyde was used as the starting material and 7-bromoheptanoic acid ethyl ester in step 2 was changed to 6-bromohexanoic acid ethyl ester; pale yellow solid, yield ：35 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (d, J = 3.3 Hz, 1H), 9.02 (d, J = 3.5 Hz, 1H), 8.89 (s, 1H), 7.98 (dt, J = 6.8, 2.0 Hz, 1H), 7.87 (ddd, J = 5.7, 2.9, 1.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.58 – 7.49 (m, 3H), 6.52 (s, 1H), 3.78 (t, J = 6.6 Hz, 2H), 1.97 (t, J = 8.6 Hz, 2H), 1.69 – 1.53 (m, 4H), 1.41 – 1.30 (m, 2H).; ¹³C NMR (101 MHz, DMSO-d₆) δ 170.80, 166.09, 152.38, 135.52, 135.00, 132.05, 130.06, 129.11, 128.84, 128.28, 127.86, 127.74, 127.64, 118.25, 36.90, 34.35, 26.81, 26.08, 24.81.

Example 22

(Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-2-ylmethylene) imidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 2-quinolinecarboxaldehyde was used as the starting material, and ethyl 7-bromoheptanoate in step 2 was used as the 6-bromohexanoate; pale yellow solid, yield ：31 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (d, J = 3.3 Hz, 1H), 9.15 (d, J = 3.5 Hz, 1H), 8.74 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.09 – 7.99 (m, 1H), 7.95 – 7.88 (m, 1H), 7.75 – 7.69 (m, 2H), 7.58 (s, 1H), 7.51 (td, J = 7.9, 1.3 Hz, 1H), 3.78 (t, J = 6.6 Hz, 2H), 1.98 (t, J = 8.6 Hz, 2H), 1.70 – 1.54 (m, 4H), 1.46 – 1.32 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ169.89, 164.14, 154.31, 149.81, 147.93, 136.17, 129.80, 128.76, 128.56, 128.53, 126.98, 126.85, 122.01, 108.77, 37.80, 32.22, 28.01, 27.26, 26.86, 25.01.

Example 23

(Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-3-ylmethylene) imidazolidin-1-yl) hexanamide having the structural formula: the procedure of example 1 was followed except that the starting material 2-methoxybenzaldehyde in step 1 of example 1 was changed to 3-quinolinecarboxaldehyde, and the fragment 7-bromoheptanoic acid ethyl ester in step 2 was changed to 6-bromohexanoic acid ethyl ester; pale yellow solid, yield ：32 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (d, J = 3.3 Hz, 1H), 9.12 (d, J = 3.5 Hz, 1H), 8.92 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.38 (t, J = 1.9 Hz, 1H), 8.10 (dt, J = 8.2, 1.8 Hz, 1H), 8.02 (dd, J = 7.2, 1.3 Hz, 1H), 7.68 (td, J = 7.5, 1.3 Hz, 1H), 7.62 (td, J = 8.2, 1.4 Hz, 1H), 6.87 (s, 1H), 3.84 (t, J = 6.6 Hz, 2H), 2.00 (t, J = 8.6 Hz, 2H), 1.65 – 1.48 (m, 4H), 1.40 – 1.30 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 171.80, 166.12, 151.38, 148.02, 147.33, 132.67, 128.95, 128.65, 128.56, 128.43, 127.44, 126.81, 126.60, 113.70, 38.87, 33.54, 27.87, 27.27, 25.31.

Example 24

(Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-4-ylmethylene) imidazolidin-1-yl) hexanamide having the structural formula: the procedure of example 1 was followed except that the starting material 2-methoxybenzaldehyde in step 1 of example 1 was changed to 4-quinolinecarboxaldehyde, and the fragment 7-bromoheptanoic acid ethyl ester in step 2 was changed to 6-bromohexanoic acid ethyl ester; pale yellow solid, yield ：30 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (d, J = 3.3 Hz, 1H), 8.92 (d, J = 3.5 Hz, 1H), 8.70 (s, 1H), 8.71 (d, J = 4.9 Hz, 1H), 8.27 – 8.15 (m, 1H), 7.95 (dd, J = 8.2, 1.5 Hz, 1H), 7.61 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H), 7.52 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.40 (d, J = 4.9 Hz, 1H), 6.89 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 1.97 (t, J = 8.6 Hz, 2H), 1.60 – 1.45 (m, 4H), 1.40 – 1.29 (m, 2H).; ¹³C NMR (101 MHz, DMSO-d₆) δ 170.80, 162.16, 154.38, 148.08, 148.03, 136.58, 129.92, 129.80, 129.23, 127.88, 127.80, 124.29, 122.99, 111.37, 38.10, 34.55, 27.08, 26.84, 25.01.

Example 25

(Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-6-ylmethylene) imidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that the starting material 2-methoxybenzaldehyde in step 1 of example 1 was changed to 6-quinolinecarboxaldehyde, and the fragment 7-bromoheptanoic acid ethyl ester in step 2 was changed to 6-bromohexanoic acid ethyl ester; pale yellow solid, yield ：32 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (d, J = 3.3 Hz, 1H), 9.02 (d, J = 3.5 Hz, 1H), 8.95 (s, 1H), 8.89 (dd, J = 4.1, 1.7 Hz, 1H), 8.26 (dt, J = 8.4, 1.8 Hz, 1H), 8.15 – 8.09 (m, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 8.2, 2.2 Hz, 1H), 7.55 (dd, J = 8.2, 4.1 Hz, 1H), 6.65 (s, 1H), 3.70 (t, J = 6.6 Hz, 2H), 1.98 (t, J = 8.6 Hz, 2H), 1.69 – 1.52 (m, 4H), 1.41 – 1.30 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.24, 162.09, 155.38, 148.65, 145.76, 131.38, 130.17, 129.05, 128.37, 127.83, 127.28, 127.27, 122.01, 116.60, 39.40, 34.51, 26.98, 26.64, 25.54.

Example 26

(Z) -N-hydroxy-6- (2, 5-dioxo-4- (quinolin-5-ylmethylene) imidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that 2-methoxybenzaldehyde used as starting material in step 1 of example 1 was changed to 8-quinolinecarboxaldehyde, and ethyl 7-bromoheptanoate used as starting material in step 2 was changed to ethyl 6-bromohexanoate; pale yellow solid, yield ：30 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (d, J = 3.3 Hz, 1H), 9.13 (d, J = 3.5 Hz, 1H), 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.72 (s, 1H), 8.39 (dd, J = 7.6, 1.8 Hz, 1H), 8.01 (dd, J = 7.2, 1.3 Hz, 1H), 7.65 (dd, J = 8.3, 7.2 Hz, 1H), 7.57 – 7.45 (m, 1H), 7.43 (dd, J = 7.8, 4.1 Hz, 1H), 7.02 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 1.97 (t, J = 8.6 Hz, 2H), 1.66 – 1.50 (m, 4H), 1.45 – 1.31 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 171.01, 163.11, 152.12, 145.24, 144.53, 131.05, 130.12, 129.26, 129.03, 128.51, 128.44, 127.89, 123.40, 111.55, 37.80, 32.22, 27.01, 26.28, 24.41.

Example 27

(Z) -N-hydroxy-6- (4- (furan-2-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was followed except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 2-furaldehyde was used as the starting material, and ethyl 7-bromoheptanoate in step 2 was used as the 6-bromohexanoate; dark solid, yield ：31 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.66 (d, J = 3.3 Hz, 1H), 9.06 (d, J = 3.5 Hz, 1H), 8.75 (s, 1H), 7.89 (t, J = 1.5 Hz, 1H), 6.96 (dd, J= 5.0, 1.2 Hz, 1H), 6.76 (s, 1H), 6.58 (dd, J = 5.0, 1.7 Hz, 1H), 3.70 (t, J= 6.6 Hz, 2H), 1.99 (t, J = 8.6 Hz, 2H), 1.66 – 1.55 (m, 4H), 1.45 – 1.31 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 172.08, 160.34, 153.38, 151.83, 145.11, 127.00, 115.71, 111.59, 99.81, 37.80, 32.22, 27.01, 26.28, 25.14.

Example 28

(Z) -N-hydroxy-6- (2, 5-dioxo-4- (thiophen-2-ylmethylene) imidazolidin-1-yl) hexanamide: The procedure of example 1 was followed except that 2-methoxybenzaldehyde was used as the starting material in step 1 of example 1 and 2-thiophenecarboxaldehyde was used as the starting material, and ethyl 7-bromoheptanoate in step 2 was used as the 6-bromohexanoate; yellow solid, yield ：35 %.¹H NMR (400 MHz, DMSO-d₆) δ 10. 60 (d, J = 3.5 Hz, 1H), 9.02 (d, J = 3.5 Hz, 1H), 8.55 (s, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.35 (td, J = 7.8, 1.6 Hz, 1H), 7.02 (td, J = 7.6, 1.2 Hz, 1H), 6.98 (dd, J = 8.0, 1.3 Hz, 1H), 6.84 (s, 1H), 3.85 (s, 2H), 3.70 (t, J = 6.6 Hz, 2H), 1.92 (t, J = 8.6 Hz, 2H), 1.61 (p, J = 6.7 Hz, 2H), 1.54 (ddd, J = 16.3, 8.5, 7.4 Hz, 2H), 1.40 – 1.28 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.80, 162.50, 154.37, 137.94, 130.79, 128.83, 126.40, 124.32, 107.97, 37.80, 34.22, 26.51, 26.18, 25.51.

Example 29

(Z) -N-hydroxy-6- (4- ((2, 3-dihydrobenzofuran-5-yl) methylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide: the procedure of example 1 was repeated except that 2-methoxybenzaldehyde used as the starting material in step 1 of example 1 was changed to 2, 3-dihydrobenzofuran-5-carbaldehyde and ethyl 7-bromoheptanoate used as the starting material in step2 was changed to ethyl 6-bromohexanoate; white solid, yield ：28 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (d, J = 3.3 Hz, 1H), 9.08 (d, J = 3.5 Hz, 1H), 8.88 (s, 1H), 7.40 (dt, J = 2.4, 0.9 Hz, 1H), 7.39 (dd, J = 8.9, 2.3 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J = 8.9 Hz, 1H), 4.52 (ddd, J = 13.7, 5.1, 3.3 Hz, 2H), 3.75 (t, J = 6.6 Hz, 2H), 3.21 (ddd, J = 5.1, 3.3, 1.0 Hz, 1H), 3.15 (ddd, J = 5.1, 3.2, 1.0 Hz, 1H), 2.02 (t, J = 8.6 Hz, 2H), 1.70 – 1.56 (m, 4H), 1.41 – 1.32 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.22, 164.09, 160.24, 154.38, 130.17, 128.83, 127.44, 126.41, 125.77, 116.42, 110.54, 71.81, 38.78, 35.88, 29.73, 26.85, 26.28, 25.41.

Example 30

(Z) -N-hydroxy-6- (4- (benzofuran-5-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the formula: the procedure of example 1 was followed except that 2-methoxybenzaldehyde used as starting material in step 1 of example 1 was changed to 1-benzofuran-5-carbaldehyde and ethyl 7-bromoheptanoate used as starting material in step 2 was changed to ethyl 6-bromohexanoate; white solid, yield ：24 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (d, J = 3.3 Hz, 1H), 9.06 (d, J = 3.5 Hz, 1H), 8.86 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.96 – 7.88 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.4, 2.2 Hz, 1H), 6.81 (t, J = 1.8 Hz, 1H), 6.62 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 1.96 (t, J = 8.6 Hz, 2H), 1.60 – 1.45 (m, 4H), 1.40 – 1.32 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.95, 163.09, 155.98, 154.38, 145.74, 130.79, 128.96, 127.56, 125.84, 123.47, 117.25, 112.37, 106.95, 37.80, 35.85, 26.62, 26.22, 25.38.

Example 31

(Z) -N-hydroxy-6- (4- (benzo [ d ] [1,3] dioxol-5-ylmethylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that 2-methoxybenzaldehyde used as the starting material in step 1 of example 1 was changed to 3, 4-methylenedioxybenzaldehyde (piperonal), and ethyl 7-bromoheptanoate used in step 2 was changed to ethyl 6-bromohexanoate; white solid, yield ：40 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (d, J = 3.3 Hz, 1H), 9.01 (d, J = 3.5 Hz, 1H), 8.77 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.8, 2.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 6.00 (s, 2H), 3.75 (t, J = 6.6 Hz, 2H), 1.99 (t, J= 8.6 Hz, 2H), 1.69 – 1.50 (m, 4H), 1.41 – 1.32 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.12, 164.09, 154.38, 150.14, 147.86, 128.85, 125.62, 124.45, 115.35, 110.08, 109.64, 102.28, 37.80, 35.52, 26.70, 26.20, 25.52.

Example 32

(Z) -N-hydroxy-6- (4- ((2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) methylene) -2, 5-dioxoimidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that 2-methoxybenzaldehyde used as the starting material in step 1 of example 1 was changed to 2, 2-difluoro-1, 3-benzodioxole-5-carbaldehyde and ethyl 7-bromoheptanoate used in step 2 was changed to ethyl 6-bromohexanoate; pale yellow solid, yield ：33 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (d, J = 3.3 Hz, 1H), 9.11 (d, J = 3.5 Hz, 1H), 8.78 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.11 (dd, J = 8.0, 1.9 Hz, 1H), 6.66 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 1.99 (t, J= 8.6 Hz, 2H), 1.67 – 1.52 (m, 4H), 1.42 – 1.33 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.86, 164.09, 154.38, 143.72, 143.63, 143.55, 142.72, 142.63, 142.55, 134.27, 132.13, 129.98, 128.97, 125.62, 124.36, 115.49, 113.94, 113.93, 113.69, 38.80, 35.22, 26.77, 26.58, 25.01.

Example 33

(Z) -N- (2-amino-4-fluorophenyl) -4- ((2, 5-dioxo-4- (pyridin-3-ylmethylene) imidazolidin-1-yl) methyl) benzamide having the structural formula: other steps and operations of example 1 are the same, except that the starting material 2-methoxybenzaldehyde in step 1 of example 1 is changed to 3-pyridylaldehyde, the fragment 7-bromoheptanoic acid ethyl ester in step 2 is changed to methyl 4-bromomethylbenzoate, and the starting material hydroxylamine hydrochloride in step 4 is changed to 4-fluoro-1, 2-phenylenediamine; pale yellow solid, yield ：30 %.¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.89 (s, 1H), 8.73 – 8.69 (m, 1H), 8.53 (ddd, J = 3.9, 1.9, 1.1 Hz, 1H), 7.96 – 7.90 (m, 2H), 7.74 (dt, J = 7.7, 1.9 Hz, 1H), 7.67 (dd, J = 8.2, 5.0 Hz, 1H), 7.41 (dt, J = 8.4, 1.0 Hz, 2H), 7.33 (dd, J = 7.8, 3.8 Hz, 1H), 6.86 – 6.76 (m, 2H), 6.77 (s, 1H), 4.87 – 4.82 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ 173.88, 163.71, 159.89, 157.87, 153.97, 150.39, 149.90, 142.01, 141.95, 137.31, 134.82, 132.71, 130.72, 129.00, 128.44, 126.22, 126.20, 125.90, 123.64, 122.86, 122.80, 114.39, 106.69, 106.53, 102.71, 102.55, 39.76.

Example 34

(Z) -N- (2-amino-4-fluorophenyl) -4- ((3-methyl-2, 5-dioxo-4- (pyridin-3-ylmethylene) imidazolidin-1-yl) methyl) benzamide having the structural formula: Other steps and operations of example 1 were repeated except that 2-methoxybenzaldehyde was changed to 3-pyridylaldehyde, hydantoin was changed to 1-methylhydantoin, ethyl 7-bromoheptanoate was changed to methyl 4-bromomethylbenzoate, hydroxylamine hydrochloride was changed to 4-fluoro-1, 2-phenylenediamine, and the raw material in step 1 was changed to methyl 4-bromomethylbenzoate; pale yellow solid, yield ：31 %.¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.77 – 8.73 (m, 1H), 8.53 (ddd, J = 3.8, 1.9, 1.1 Hz, 1H), 7.96 – 7.90 (m, 2H), 7.82 (dt, J = 7.9, 1.9 Hz, 1H), 7.67 (dd, J = 8.2, 5.0 Hz, 1H), 7.41 (dt, J = 8.5, 1.0 Hz, 2H), 7.33 (dd, J = 7.8, 3.9 Hz, 1H), 7.00 (s, 1H), 6.83 (td, J = 8.1, 2.2 Hz, 1H), 6.78 (dd, J = 8.0, 2.3 Hz, 1H), 4.93 (t, J = 1.0 Hz, 2H), 4.84 (s, 2H), 3.30 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 173.88, 160.56, 159.89, 157.87, 154.94, 149.90, 149.87, 142.01, 141.95, 138.04, 134.62, 133.21, 132.71, 132.52, 129.00, 128.47, 126.22, 126.20, 123.63, 122.86, 122.80, 116.70, 106.69, 106.53, 102.71, 102.55, 41.30, 29.11./>

Example 35

The synthesis of (Z) -N-hydroxy-6- (2, 5-dioxo-4- ((4- (pyridin-4-yl) quinolin-6-yl) methylene) imidazolidin-1-yl) hexanamide is carried out as follows: step 1: synthesis of 4- (pyridin-4-yl) quinoline-6-carbaldehyde having the following structural formula:30 mmol isopropyl malonate (1.5 eq) is dissolved in 20 mL trimethyl orthoformate, added into a 100mL three-necked bottle, replaced by nitrogen, the reaction temperature is raised to 110 ℃, after reflux reaction is carried out for 2 h, 20 mmol raw material methyl 4-aminobenzoate is weighed and dissolved in 20 mL trimethyl orthoformate, carefully added into a reaction bottle, after continuous reaction for 2 h, cooled to room temperature, concentrated and evaporated to remove solvent, the compound is washed by methanol, filtered to obtain white solid, added with 40 mL diphenyl ether after drying, replaced by nitrogen, the reaction temperature is raised to 240 ℃, after cooling, 10-20 min, n-hexane 20 mL was added with continuous stirring, and the solid was filtered, washed with n-hexane, and dried to give Compound G (4-oxo-4, 4 a-dihydroquinoline-6-carboxylic acid methyl ester, yield: 78%) as a pale yellow solid. 3.3 mmol of Compound G was weighed out and dissolved in 10 mL DMF, 341. Mu.L of phosphorus tribromide (1.1. 1.1 eq.) was slowly added dropwise at room temperature and reacted under nitrogen protection at 1 h. After the reaction was completed, the reaction solution was slowly poured into 100mL ice water solution (stirring vigorously throughout), sodium acetate (neutralizing the reaction of phosphorus tribromide and water) was added, the mixture was extracted with ethyl acetate solution (3×60 mL), the organic phase was collected, washed with saturated brine (2×200 mL), dried over anhydrous magnesium sulfate, and purified by column chromatography (PE: ea=3:1) to give pale yellow compound H (4-bromoquinoline-6-carboxylic acid methyl ester, yield: 88%); compound H of 2 mmol, 4-pyridineboronic acid of 3 mmol, pd (dppf) Cl ₂ (5 mol%) of 0.1 mmol and potassium carbonate of 4 mmol were added to a reaction flask of 15 mL of 1, 4-dioxane and 3 mL water, the reaction solution was cooled to room temperature after reacting 2H at 80 ℃ under nitrogen atmosphere, and after filtering the solid, the column chromatography was purified (PE: ea=1:1) to give pale yellow compound I (methyl 4- (pyridin-4-yl) quinoline-6-carboxylate, yield: 90%). 1 mmol compound I was weighed and added to 4 mL anhydrous THF under nitrogen protection, 1.6 mL LiAlH ₄ THF solution (2.5 mol/L,4.0 eq.) was slowly added at 0deg.C, the reaction temperature was raised to room temperature, 0.16 g water was added after 2 h, the reaction was quenched, 0.16 g 10% NaOH aqueous solution, 0.48 g water was added sequentially after stirring 10 min, dried over anhydrous magnesium sulfate, the solid was filtered off, and concentrated to give a crude pale yellow compound J ((4- (pyridin-4-yl) quinolin-6-yl) methanol). 1 mmol crude compound J was dissolved in 10 mL DCM, DMP (dissolved in 10 mL DCM) of 1.2 mmol was slowly added dropwise at room temperature, the reaction was 5 h, the reaction solution was diluted by addition of 20 mL DCM, and then washed successively with saturated aqueous sodium carbonate (40 mL), saturated aqueous sodium thiosulfate (40 mL), saturated brine (2X 40 mL), dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM: meOH=20:1) to give pale yellow compound K (4- (pyridin-4-yl) quinoline-6-carbaldehyde, yield ：83 %）¹H NMR (400 MHz, Chloroform-d) δ8.71 – 8.64 (m, 3H), 8.52 (d, J = 4.8 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.03 (dd, J = 8.1, 2.2 Hz, 1H), 7.88 – 7.83 (m, 2H), 7.80 (d, J = 4.6 Hz, 1H).

Step 2: synthesis of (Z) -N-hydroxy-6- (2, 5-dioxo-4- ((4- (pyridin-4-yl) quinolin-6-yl) methylene) imidazolidin-1-yl) hexanamide having the structural formula: The procedure of example 1 was repeated except that the starting material 2-methoxybenzaldehyde in step 1 was changed to 4- (pyridin-4-yl) quinoline-6-carbaldehyde and the fragment 7-bromoheptanoic acid ethyl ester in step 2 was changed to ethyl 6-bromohexanoate ：40 %.¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (d, J = 3.3 Hz, 1H), 9.03 (d, J = 3.5 Hz, 1H), 8.84 (s, 1H), 8.69 – 8.64 (m, 2H), 8.48 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.88 – 7.83 (m, 2H), 7.75 (d, J = 4.7 Hz, 1H), 7.61 (dd, J = 8.2, 2.2 Hz, 1H), 6.68 (s, 1H), 3.72 (t, J = 6.6 Hz, 2H), 2.01 (t, J = 8.6 Hz, 2H), 1.68 – 1.53 (m, 4H), 1.41 – 1.30 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.53, 164.09, 154.38, 149.88, 149.55, 146.53, 141.95, 139.80, 132.11, 128.92, 128.87, 127.25, 126.96, 123.87, 122.06, 121.54, 115.90, 36.84, 35.10, 26.45, 26.51, 25.01.

HDAC kinase inhibition experiments were performed on the inhibitors of the invention:

The reagents used for the kinase reaction were as follows, tested using the ADP-Glo luminescence KINASE ASSAY method: HEPES (50 mM) pH 7.5 with NaCl (100 mM), EGTA (1.0 mM), mgCl ₂ (3.0 mM), DTT (2.0 mM) and CHAPS (0.03%). During the reaction, 50. Mu.M PIP2 and 25. Mu.M ATP were added to each 10mL containing different concentrations of the test compound (0.05 nM-1.0. Mu.M). The reaction system was incubated at room temperature for 1h and then 10. Mu.L of the reagent ADP-Glo was added to terminate the enzyme reaction. Data collection was performed using Envision software and compound IC ₅₀ values were analyzed and fitted using GRAPHPAD PRISM.

Table 1 HDAC1 enzyme inhibitory Activity of some of the example compounds (IC 50, nM)

Examples	Example 1	Example 2	Example 3	Example 4	Example 5
						HDAC1	8.6	13	2.8	76	6.4
Examples	Example 6	Example 7	Example 8	Example 9	Example 10
						HDAC1	7.8	25	68	16	6
Examples	Example 11	Example 12	Example 13	Example 14	Example 19
						HDAC1	0.57	1.7	1.0	1.2	1.2
Examples	Example 20	Example 21	Example 23	Example 31	Example 33
						HDAC1	3.6	2.4	2.0	5.9	180
Examples	Example 34	Vorinostat	Tucidinostat
						HDAC1	175	15.0	122.1

。

As shown in table 1, the compounds of the present invention have nanomolar inhibitory activity against HDAC1 and some of the compounds are significantly better than the positive control Vorinostat, especially example 11 has approximately 30 times the inhibitory activity against HDAC1 than the positive control Vorinostat. Thus, it is demonstrated that the compounds of the present embodiments are highly potent HDAC inhibitors.

Anti-proliferation activity experiments of tumor cell lines were performed against the inhibitors of the present invention:

The proliferation inhibitory activity of the compounds on cells was evaluated by CCK-8 method and the median inhibitory concentration IC ₅₀ was determined by single-concentration activity primary screening and multiple concentration. The detection principle is as follows: cytotoxicity (CCK-8 method) detection principle: the CCK-8 reagent contains WST-8, which is reduced into yellow formazan product (Formazan) with high water solubility by dehydrogenase in cell mitochondria under the action of electron carrier 1-Methoxy-5-methylphenazine dimethyl sulfate (1-Methoxy PMS). The amount of formazan produced is proportional to the number of living cells. The experimental method is as follows:

(1) Inoculating cells: cells were prepared as a single cell suspension in a culture medium containing 10% fetal bovine serum, and 90. Mu.L of 5X 10 ⁴/mL adherent cells and 9X 10 ⁴/mL suspension cells were inoculated per well in 96-well plates and pre-cultured at 5% CO ₂ at 37℃for 24 h.

(2) Adding a sample solution to be tested: adding 10 mu L of sample solution into each hole, setting 1 concentration of each sample by an active primary screen, and setting 3 compound holes; IC ₅₀ measures 8 concentrations (containing 0 concentration), each concentration has 3 complex wells; placing in an incubator for culturing 48 h. Experiments set up Blank (Blank), control and Drug.

(3) Color development: adherent cells were aspirated from the old medium and drug solution (10. Mu.L of CCK-8 stock solution was directly added to suspension cells), 100. Mu.L of CCK-8 solution was added ten times the dilution per well, and culture was continued at 37℃with 5% CO ₂ for 1-4 h (run, real time observation).

(4) And (3) detection: the absorbance at 450 nm was measured with a microplate reader and the raw data results were recorded.

(5) Raw data normalization was performed using Excel software, and cell proliferation inhibition was calculated by the initial screening through OD values per well (formula = (OD _Control-OD_Drug)/(OD_Control-OD_Blank) ×100%) and inhibition was counted. IC ₅₀ is calculated by GRAPHPAD PRISM.

TABLE 2 tumor cell line proliferation inhibiting Activity of some of the example compounds (IC 50, μM)

Examples	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7
								A549	5.81	9.70	7.94	6.82	5.03	7.60	-
DU145	0.69	1.45	0.26	>4	>4	1.65	>4
								Examples	Example 8	Example 9	Example 10	Example 11	Example 12	Example 13	Example 14
A549	-	4.43	5.13	2.36	9.74	1.49	2.02
								DU145	>4	2.26	3.53	<0.10	<0.10	<0.10	<0.10
Examples	Example 15	Example 16	Example 17	Example 18	Example 20	Example 21	Example 23
								A549	4.86	2.42	2.04	2.12	4.30	3.68	-
DU145	<0.10	<0.10	<0.10	<0.10	1.28	0.77	3.43
								Examples	Example 28	Example 29	Example 30	Vorinostat	Tucidinostat
A549	4.86	3.68	4.43	1.62	9.85
								DU145	1.04	<0.10	0.34	0.64	1.62

。

As can be seen from Table 2, the compounds of the present invention have a micromolar level of proliferation inhibitory activity against both tumor strains, and in particular the compounds of the examples have a higher sensitivity to human prostate cancer cell strain DU-145. Of these, 9 compounds of examples 11-18, 29, etc. all showed inhibitory activity on DU-145 of less than 100 nanomoles, which was significantly superior to the positive control Vorinostat. It follows that the compounds of the present embodiments may be potentially useful in the clinical treatment of the aforementioned neoplasms.

The imidazolidine diketone HDAC inhibitor has high sensitivity to prostate cancer and anti-tumor curative effect by inhibiting proliferation of solid tumor cells through high efficiency on HDAC, and can be potentially used for clinical treatment.

In addition to the implementations described above, other implementations of the invention are possible. All technical schemes formed by equivalent substitution or equivalent transformation fall within the protection scope of the invention.

Claims

1. An imidazolidinedione HDAC inhibitor, characterized in that: the inhibitor is one of the following,

2. The method of preparing an imidazolidine dione HDAC inhibitor according to claim 1, characterized in that: comprises the steps of taking substituted formaldehyde (A) and hydantoin or substituted hydantoin (B) as raw materials, and carrying out Knoevenagel condensation reaction under the action of beta-alanine to obtain an intermediate (C); nucleophilic substitution reaction is carried out between the intermediate (C) and bromocarboxylate to obtain a key intermediate (D); the intermediate (D) undergoes hydrolysis reaction under an acidic condition to obtain an intermediate (E); the intermediate (E) and hydroxylamine hydrochloride are subjected to condensation reaction to obtain target compounds (1-32), and the synthetic route is as follows:

。

3. The method of preparing an imidazolidine dione HDAC inhibitor according to claim 1, characterized in that: taking substituted formaldehyde (A) and hydantoin or substituted hydantoin (B) as raw materials, and carrying out Knoevenagel condensation reaction under the action of alanine to obtain an intermediate (C); nucleophilic substitution reaction is carried out between the intermediate (C) and bromocarboxylate to obtain a key intermediate (D); the intermediate (D) undergoes hydrolysis reaction under an acidic condition to obtain an intermediate (E); the intermediate (E) and 4-fluoro-1, 2-phenylenediamine are subjected to condensation reaction to obtain a target compound (33-34), and the synthetic route is as follows:

。

4. The method of preparing an imidazolidine dione HDAC inhibitor according to claim 1, characterized in that: taking a compound (F) as a raw material, and carrying out Combes quinoline synthesis reaction with isopropyl malonate to obtain an intermediate (G); the intermediate (G) and phosphorus tribromide undergo a bromination reaction in DMF to obtain an intermediate (H); performing Suzuki coupling reaction on the intermediate (H) and 4-pyridine boric acid to obtain an intermediate (I); the intermediate (I) and lithium aluminum hydride undergo a reduction reaction to obtain an intermediate (J); the intermediate (J) is selectively oxidized to obtain a key intermediate (K), and the intermediate (K) is subjected to four-step reaction to obtain a target compound (35), wherein the synthetic route is as follows:

。

5. A pharmaceutical composition comprising the imidazolidinedione HDAC inhibitor of any one of claims 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the imidazolidinedione HDAC inhibitor of any one of claims 1, or a pharmaceutically acceptable salt thereof, is an active ingredient.

6. Use of an imidazolidinedione HDAC inhibitor according to claim 1 in the manufacture of a medicament for the prevention or treatment of a clinical condition associated with HDACs.

7. The use of an imidazolidine dione HDAC inhibitor according to claim 6, characterized in that: the diseases related to HDACs are lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin disease, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gall bladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, noninsulin-dependent diabetes, autoimmune disease.