Phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor, preparation method therefor, pharmaceutical composition thereof, and use thereof

Abstract

The present invention relates to a phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor, a preparation method therefor, a pharmaceutical composition thereof, and use thereof, and pertains to the technical field of medicines. The present invention provides a phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor that is a substituted phenylthiazolamine compound represented by general formula I or a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. The present invention has the following beneficial effects: (1) The inhibitor is characterized by effectively inhibiting the PI3K / Akt / mTOR signaling pathway of PI4KIIIβ and has efficient and excellent dual-enzyme inhibitory activity against PI4KIIIβ / HDAC. (2) The cost is low, the efficacy is good, and the toxicity is low. Moreover, the yield of intermediate products in the synthesis process is high, reducing the waste of resources and thus helping reduce the cost. (3) The inhibitor has relatively high anti-hepatitis C virus activity and is used in small doses.

Description

A phenylthiazolamine PI4KIII β / HDAC dual-target inhibitor, its preparation method, pharmaceutical composition, and applications. Technical Field

[0001] This invention relates to a phenylthiazolamine PI4KIII β / HDAC dual-target inhibitor, its preparation method, pharmaceutical composition, and application, belonging to the field of pharmaceutical technology. Background Technology

[0002] High expression of phosphatidylinositol 4-kinases (PI4Ks) is closely associated with a variety of diseases, including viral infections, cancer, malaria, and neurodegenerative diseases. Phosphatidylinositol (PI) is phosphorylated by PI4Ks to produce phosphatidylinositol 4-phosphate (PI4P), which plays a crucial role in Golgi apparatus function, protein sorting, and membrane transport. It also plays a significant role in the replication and amplification of exogenous pathogens (such as viruses) within the host. Therefore, research on broad-spectrum antiviral inhibitors of PI4Ks has become a hot topic in current medicinal chemistry research. Lipid phosphatidylinositol is an important regulator of numerous cellular processes, including signal transduction, membrane transport, and cytokinesis. Phosphatidylinositol is produced through phosphorylation of the inositol ring. In mammals, there are four different PI4K enzymes: two type II enzymes (PI4KII α and PI4KII β) and two type III enzymes (PI4KIII α and PI4KIII β).

[0003] PI4KIII β is a peripheral membrane protein distributed in the Golgi apparatus and plasma membrane, playing a crucial role in mediating lipid transport and cell division. The PI4KIII β protein consists of 801 amino acid residues, including a helical domain, a lipid kinase domain, and three disordered regions that mediate binding with regulatory proteins. The N-terminus of PI4KIII β is primarily responsible for interacting with and recruiting Golgi proteins (such as acyl-CoA binding domain protein 3, ACBD3); its C-terminus contains an amphiphilic lipid-accumulating sensor motif responsible for viral signal sensing and transport. Many viruses (including common polioviruses, Coxsackieviruses, and hepatitis C viruses) require the viral replication site PI4KIII β and its catalytic product PI4P for replication in host cells; therefore, PI4KIII β is also a key factor in the replication of many viruses. Generally, the virus hijacks PI4KIII β to form replication organelles (ROs) containing PI4P, thereby inducing viral proteins to form replication structures on the biomembrane. PI4KIII β also plays a crucial role in human genetic diseases. It regulates the transcriptional activation of target genes, such as HES-related family bHLH transcription factors and YRPW motif 1 (hey1), by modulating bone morphogenetic protein membrane type II receptor (BMPR2) and signal transduction proteins 1 / 5 / 9 (Smad1 / 5 / 9), ultimately affecting the development of the vestibular organ in zebrafish. STING is a key signal transduction factor in innate immune responses. Activation of the cGAS-STING pathway triggers exogenous DNA, thereby regulating spontaneous anti-tumor and anti-DNA virus immune responses. ARMH3 is a key factor in STING activation; ARMH3 activates STING by recruiting PI4KIII β.

[0004] Histone deacetylases (HDACs) are a class of epigenetic enzymes that catalyze the removal of acetyl groups from lysine residues of histones and other proteins, thereby regulating chromatin structure and transcriptional activity. Vorinostat (SAHA), a classic hydroxamic acid inhibitor of HDACs, contains sequences of three main elements forming the pharmacophore: a cap, a linker, and a zinc-binding group (ZBG). On one hand, the linker binds to the ZBG and facilitates its penetration into the hydrophobic “tunnel” at the HDAC active site, where it catalyzes the chelation of zinc ions at its base. On the other hand, the linker, associated with the cap-like structure, is most commonly an aryl or heteroaryl radical, which additionally interacts with the protein substrate-binding cavity, influencing the strength and selectivity of inhibition. Recent proteomics studies have revealed widespread acetylation in mouse and human hepatocytes. Upregulation of HDAC activity induced by HCV infection has also been reported. Furthermore, polymorphisms of the three HDAC enzymes (HDAC2, 3, and 5) have been shown to be independently associated with persistent virological responses to chronic HCV. Numerous observations have shown that HDAC inhibitors are promising in blocking HCV replication, and recently benzoxamic acid and the pan-HDAC inhibitor vorinostat (SAHA) have been reported as potential anti-HCV drugs.

[0005] Existing literature indicates that simultaneous inhibition of PI4KIII β and HDAC can effectively block HCV replication and limit drug resistance by improving efficacy. Selective inhibitors of PI4KIII β and HDAC may have lower toxicity. Currently, there are no reports on dual-target inhibitors of PI4KIII β / HDAC. Summary of the Invention

[0006] The purpose of this invention is to address the deficiencies of existing technologies by proposing a phenylthiazolamine PI4KIII β / HDAC dual-target inhibitor, its preparation method, a pharmaceutical composition containing the inhibitor, and its application, thereby improving inhibitory activity.

[0007] This invention first provides: a phenylthiazolamine PI4KIII β / HDAC dual-target inhibitor, which is a substituted phenylthiazolamine compound of general formula I, or its stereoisomer, hydrate, or pharmaceutically acceptable salt: Wherein, R1-R4 are substituents on the benzene ring selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C1 C6 alkyl, halo-C1 C6 alkyl, hydroxy-C1 C6 alkyl, C1 C6 alkoxy, halo-C1 C6 alkoxy, hydroxy-C1 C6 alkoxy, or C1 C6 alkoxy-C1 C6 alkyl; R5 and R6 are selected from C1 C6 alkyl, C1 C6 alkyl containing one or more substituents, C1 C6 alkoxy, C1 C6 alkoxy containing one or more substituents, C1 C6 alkyl acyl, C1 C6 alkyl sulfonyl, C3 C6 heterocyclic, and C3 C6 heterocyclic containing one or more substituents.

[0008] X is selected from sulfone or carbonyl; Y is selected from C1-C6 alkylene, C1-C6 alkylene containing one or more substituents, 4-substituted phenyl, 4-substituted benzyl, or 4-substituted phenoxyethyl, etc.; Z is selected from the following structures: Preferably, in the inhibitor of general formula I, the hydrogen bonded to carbon is replaced with the hydrogen isotope deuterium.

[0009] More preferably, 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.

[0010] Preferably, a pharmaceutically acceptable salt refers to the conversion of a basic group in a parent compound into a salt form; wherein, the pharmaceutically acceptable salt is a basic group, more preferably an inorganic or organic acid salt of an amino group or amino group; the reaction is carried out by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system.

[0011] Preferably, the basic group of the compound in this invention can form a salt with an acid. Specifically, the salt can be formed with inorganic acids, especially hydrohalic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc.; lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid; aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; or amino acids, such as aspartic acid or glutamic acid.

[0012] Preferably, the compounds and pharmaceutically acceptable salts of the present invention also include solvates or hydrates.

[0013] Preferably, the structural formula of the phenylthiazolamine PI4KIII β inhibitor of the present invention includes isomers, such as enantiomers, diastereomers, geometric isomers or conformational isomers, specifically R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers.

[0014] Preferably, the inhibitor is one of the following: (1) N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)propionamide; (2) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)butyramide; (3) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)pentanamide; (4) N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)hexamamide; (5) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)heptanamide; (6) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazolyl-5-yl)phenyl)sulfonamido)methyl)benzamide; (7) N-hydroxy-4-(2-((2-methoxy-5-(4-methyl-2-pentamidothiazolyl-5-yl)phenyl)sulfonamido)ethoxy)benzamide; (8) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-propamidothiazolyl-5-yl)phenyl)sulfonamido)butyramide; (9) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-butamidothiazolyl-5-yl)phenyl)sulfonamido)butyramide; (10) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isobutamidothiazolyl-5-yl)phenyl)sulfonamido)butyramide; (11) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)butyramide; (12) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isopentamidothiazo-5-yl)phenyl)sulfonamido)butyramide; (13) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)butyramide; (14) N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)propionamide; (15) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)pentamido)valvamide: (16) N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)hexamamide; (17) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide; (18) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-acetamidothiazo-5-yl)phenyl)sulfonamido)heptamide;(19) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-propamidothiazol-5-yl)phenyl)sulfonamido)pentanamide; (20) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-butamidothiazol-5-yl)phenyl)sulfonamido)pentanamide; (21) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-butamidothiazol-5-yl)phenyl)sulfonamido)methyl)benzamide; (22) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-isobutamidothiazol-5-yl)phenyl)sulfonamido)pentanamide; (23) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-isobutamidothiazol-5-yl)phenyl)sulfonamido)heptanamide; (24) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-isovalamidothiazolyl-5-yl)phenyl)sulfonamido)methyl)benzamide; (25) N-hydroxy-3-((2-methoxy-5-(4-methyl-2-hexamidothiazolyl-5-yl)phenyl)sulfonamido)propionamide; (26) N-hydroxy-6-((2-methoxy-5-(4-methyl-2-hexamidothiazolyl-5-yl)phenyl)sulfonamido)hexamidamide; (27) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-hexamidothiazolyl-5-yl)phenyl)sulfonamido)heptamide; (28) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-hexamidothiazolyl-5-yl)phenyl)sulfonamido)methyl)benzamide; (29) N-(2-amino-4-fluorophenyl)-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazol-5-yl)phenyl)sulfonamide)methyl)benzamide; (30) N-(7-(hydroxyamino)-4-oxobutyl)-5-(2-hexamido-4-methylthiazol-5-yl)-2-methoxybenzamide; (31) N-(7-(hydroxyamino)-7-oxoheptyl)-5-(2-isobutamido-4-methylthiazol-5-yl)-2-methoxybenzamide; (32) N-(7-(hydroxyamino)-7-oxoheptyl)-5-(2-hexamido-4-methylthiazol-5-yl)-2-methoxybenzamide; (33) N-(4-(hydroxycarbamoyl)benzyl)-5-(2-hexamido-4-methylthiazolyl-5-yl)-2-methoxybenzamide.

[0015] The above-mentioned inhibitor is prepared as follows: according to one of the preparation methods of the target compound, 4-methoxyphenylacetone is used as raw material (1). Raw material (1) undergoes a substitution reaction with chlorosulfonic acid at the 3-position of the benzene ring to obtain intermediate (2); based on intermediate (2), aminocarboxylic acid methyl ester is introduced through the Hinsberg reaction to obtain intermediate (3); intermediate (3) undergoes an α-bromination reaction with phenyltrimethylammonium tribromide to obtain intermediate (4); thiourea (5) reacts with various acyl chlorides to obtain N-substituted thiourea (6), which is then condensed with intermediate (4) to obtain intermediate (7); intermediate (7) undergoes an amide condensation reaction with hydroxylamine to obtain the target compound (8). The preparation route is as follows:

[0016] The preparation method of the above inhibitor also includes, according to the preparation method of the target compound, using 4-methoxyphenylacetone as raw material (1), the raw material (1) undergoes a substitution reaction with chlorosulfonic acid at the 3-position of the benzene ring to obtain intermediate (2); based on intermediate (2), an aminocarboxylic acid methyl ester is introduced through the Hinsberg reaction to obtain intermediate (3); intermediate (3) undergoes an α-bromination reaction with phenyltrimethylammonium tribromide to obtain intermediate (4); thiourea (5) reacts with various acyl chlorides to obtain N-substituted thiourea (6), which is then condensed with intermediate (4) to obtain intermediate (7); intermediate (7) undergoes an amide condensation reaction with 4-fluoro-1,2-phenylenediamine to obtain the target compound (9). The preparation route is as follows:

[0017] The preparation method of the above inhibitor also includes: using methyl 5-formyl-2-methoxybenzoate as raw material (10), intermediate (11) is obtained through a two-step reaction; intermediate (11) is heated under reflux in acetic acid and undergoes a reduction reaction with iron powder to obtain intermediate (12); intermediate (12) undergoes a hydrolysis reaction under acidic conditions to obtain intermediate (13); intermediate (13) is chlorinated with thionyl chloride to generate intermediate (14); intermediate (14) reacts with methyl aminocarboxylate to obtain intermediate (15); intermediate (15) undergoes an α-bromination reaction with phenyltrimethylammonium tribromide to obtain intermediate (16); intermediate (16) undergoes a condensation reaction with N-substituted thiourea to obtain intermediate (17); intermediate (17) undergoes an amide condensation reaction with hydroxylamine to obtain the target compound (18). The preparation route is as follows:

[0018] The present invention further provides a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, adjuvant or carrier, and the above-mentioned phenylthiazolamine PI4KIII β / HDAC dual-target inhibitor.

[0019] The present invention further provides the use of phenylthiazolamine PI4KIII β / HDAC dual-target inhibitors or pharmaceutical compositions in the preparation of drugs for inhibiting the growth of hepatitis C virus, and for the prevention, treatment or adjunctive treatment of hepatitis C caused by HCV virus.

[0020] Since the inhibitory activity of PI4KIII β is weak and its anti-hepatitis C virus effect is insufficient, and there are no reports of PI4KIII β / HDAC dual-target inhibitors, PIK-93 was selected as the lead compound for further structural modification. This invention determined that phenylthiazolamine is used as the basic skeleton structure, and by screening substituents, it can achieve efficient inhibition of PI4KIII β and HDAC, thereby inhibiting the growth of HCV virus, while having low cytotoxicity, thus potentially being used as a clinical therapeutic drug. Its beneficial effects are: (1) It has the characteristic of effectively inhibiting the PI3K / Akt / mTOR signaling pathway of PI4KIII β, and has highly efficient and excellent PI4KIII β / HDAC dual-enzyme inhibitory activity; (2) It is low in cost, has good efficacy, low toxicity, and the yield of intermediate products in the synthesis process is high, which reduces resource waste and thus helps to reduce costs; (3) It has high anti-hepatitis C virus activity and requires a small dosage. Detailed Implementation

[0021] The technical solution of the present invention will be further described below with reference to the embodiments.

[0022] Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Bailingwei Technology Co., Ltd., Aladdin Reagent Co., Ltd., and Beijing Coupling Technology Co., Ltd., and were used without further purification unless otherwise stated. Common reagents were purchased from Xilong Chemical Co., Ltd., Nanjing Chemical Reagent Co., Ltd., Sinopharm Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Co., Ltd. In the examples, all temperatures are set to Celsius unless otherwise stated.

[0023] In the examples described below, silica gel columns were used. The silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Co., Ltd. Nuclear magnetic resonance spectroscopy was performed using Chloroform-d or DMSO-d6 as solvents (in ppm), with TMS (0 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0024] In the embodiments described below, low-resolution mass spectrometry (MS) data were analyzed using an Agilent 6120 series LC-MS equipped with a G1329B autosampler and a G4212B detector, with an ESI source used in the LC-MS spectrometer.

[0025] For ease of description, some raw materials will be described using their abbreviations in the following examples. These abbreviations are explained in comparison with their full names as follows: DCM is CH2Cl2, i.e., dichloromethane; Chloroform-d and CDCl3 are deuterated chloroform; PE is petroleum ether; EtOAc and EA are both ethyl acetate; MeOH and CH3OH are both methanol; ClSO3H is chlorosulfonic acid; TEA and Et3N are triethylamine; DMSD-d6 is hexadeuterated dimethyl sulfoxide; THF is tetrahydrofuran; NaCl is sodium chloride; NaSO4 is sodium sulfate; CDI is N,N-carbonyldiimidazole. Example 1

[0026] The synthesis of N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)propionamide is as follows: Step 1: Synthesis of 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride, structural formula: 10 mL of ClSO3H (132 mmol, 11.0 eq.) was added to a 25 mL pear-shaped reaction flask and pre-cooled in an ice bath for 30 min. 2.02 g (12.0 mmol) of 4-methoxyphenylacetone was slowly added dropwise to the ClSO3H, and the reaction was allowed to proceed at room temperature for approximately 6 h. The reaction mixture was then spotted by TLC until all the starting material was consumed. The reaction solution was slowly added dropwise onto ice to quench any unreacted ClSO3H. The aqueous solution was then extracted with ethyl acetate (3 x 100 mL), and the organic phase was collected. The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 4:1–2:1). The product was a yellow solid, yield: 60%. 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 3.77 (s, 4H), 2.26 (s, 5H). Step 2: Synthesis of methyl 3-((2-methoxy-5-(2-oxopropyl)phenyl)sulfonamide)propionate, structural formula: 5 mmol of 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride was dissolved in 20 mL of dichloromethane. 7.5 mmol of methyl 3-aminopropionate hydrochloride (1.5 eq.) and 1.52 g of triethylamine (3.0 eq.) were added to the reaction solution and stirred at room temperature for 12 h until all the 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride was consumed. After the reaction was complete, the solution was purified by concentrated column chromatography (PE:EA = 1:1). The product was a white solid, yield: 75%. 1 ¹H NMR (400MHz, Chloroform-d) δ 7.52 (dt, J = 2.1, 1.0Hz, 1H), 7.25 (ddt, J = 8.4, 2.2, 1.1Hz, 1H), 7.01–6.93 (m, 2H), 3.82 (s, 3H), 3.78 (t, J = 1.0Hz, 2H), 3.64 (s, 3H), 3.15 (q, J = 6.3Hz, 2H), 2.75 (t, J = 6.2Hz, 2H). Step 3: Synthesis of methyl 3-((2-methoxy-5-(4-methyl-2-pentamidothiazolyl-5-yl)phenyl)sulfonamide)propionate, Structural formula: 1 mmol of methyl 3-((2-methoxy-5-(2-oxopropyl)phenyl)sulfonamido)propionate was dissolved in 5 mL of tetrahydrofuran solution and placed in a round-bottom flask. Under ice bath conditions, 10 mL of tetrahydrofuran solution containing 1.1 mmol of phenyltrimethylammonium tribromide was slowly added dropwise to the above reaction solution. After the addition was completed, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 0.5 h until all the reactants were consumed. The product was purified (PE:EA = 1:1) to obtain the brominated product (methyl 3-((5-(1-bromoethyl-2-methoxyphenyl)sulfonamido)propionate). It was a pale yellow oil, yield: 60%. 1 H NMR (300MHz, Chloroform-d) δ7.95-7.91 (m, 1H), 7.45-7.39 (m, 1H), 7.14 (d, J = 8.4Hz, 1H), 7.06 (t, J = 6. 7Hz, 1H), 5.90 (d, J = 0.9Hz, 1H), 3.89 (s, 2H), 3.64 (s, 2H), 3.19 (q, J = 6.3Hz, 2H), 2.66 (t, J = 6.2Hz, 2H)). Next, N-pentaylthiourea was prepared by dissolving 10 mmol of thiourea in 30 mL of anhydrous toluene solution and placing it in a 100 mL round-bottom flask. Then, 15 mmol of pentayl chloride was dissolved in 2 mL of anhydrous toluene and slowly added dropwise to the reactor. The reaction was heated to 110 °C and refluxed for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. The solution was then subjected to column chromatography (PE:EA = 8:1) to obtain a white solid N-pentaylthiourea, with a yield of 71%. 1¹H NMR (400 MHz, Chloroform-d) δ 9.84 (s, 1H), 8.87 (s, 2H), 1.34 (s, 9H)). 1 mmol of the intermediate was weighed into a 25 mL round-bottom flask, 10 mL of acetone solution was added, and then N-tervapotranilylthiourea (1.0 eq.) was added to the reaction solution. The mixture was heated to 60 °C and refluxed for 1 h. TLC monitoring continued until all the intermediate was consumed (DCM:MeOH = 25:1). The mixture was concentrated under vacuum and purified by column chromatography. A white solid was obtained; yield: 60%. 1 ¹H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 7.9, 2.2 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 7.00 (t, J = 6.7 Hz, 1H), 3.70 (s, 2H), 3.44 (s, 2H), 3.02 (q, J = 6.3 Hz, 2H), 2.62 (t, J = 6.2 Hz, 2H), 1.14 (s, 7H). Step 4: Synthesis of N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazolyl-5-yl)phenyl)sulfonamido)propionamide, with the following structural formula: First, 3-((2-methoxy-5-(4-methyl-2-pentamidothiazol-5-yl)phenyl)sulfonamide)propionic acid was prepared. 5 mmol of methyl 3-((2-methoxy-5-(4-methyl-2-pentamidothiazol-5-yl)phenyl)sulfonamide)propionic acid was dissolved in 10 mL of a mixed solution of methanol, tetrahydrofuran, and water (MeOH:THF:H2O = 2:2:1) and placed in a 50 mL round-bottom flask. 10 mmol of lithium hydroxide (2 eq.) was weighed and slowly added dropwise to the reaction flask. The mixture was left to stand overnight at room temperature. After the reaction was completed, the reaction solution was added to ice-salt water while still hot to precipitate a large amount of white solid. After drying, crude 3-((2-methoxy-5-(4-methyl-2-pentamidothiazol-5-yl)phenyl)sulfonamide)propionic acid was obtained. Weigh 1 mmol of crude 3-((2-methoxy-5-(4-methyl-2-pentamidothiazolyl-5-yl)phenyl)sulfonamide)propionic acid and 1.5 mmol of PyBOP condensing agent (1.5 eq.) into a 25 mL reaction flask, add 6 mL of DMF solution, and add 590 μL of DIPEA (3.5 eq.) to the reaction solution. After stirring at room temperature for a few minutes, add 0.14 g of hydroxylamine hydrochloride (2.0 eq.). After reacting at room temperature for 6 h, monitor with TLC until all intermediate is consumed (DCM:MeOH = 25:1). Concentrate under vacuum and purify by column chromatography. White solid, yield: 66%. 1H NMR (300MHz, DMSO-d6) δ11.23 (s, 2H), 10.49 (s, 1H), 8.77 (s, 1H), 7.74 (d, J = 2.3Hz, 1H), 7.69 (dd, J = 8.5, 2.4Hz, 1H), 7.33 (d, J = 8.7Hz, 1H), 3.95 (s, 3H), 3.01 (t, J = 7.4Hz, 2H), 2.34 (s, 3H), 2.15 (t, J = 7.3Hz, 2H), 1.24 (s, 9H). 13 C NMR (101MHz, DMSO-d6) δ 177.18, 167.27, 156.24, 155.77, 142.43, 134.76, 129.40, 128.44, 124.57, 122.82, 114.14, 56.87, 40.58, 40.37, 40.16, 39.96, 39.75, 39.54, 39.33, 39.22, 33.04, 27.05, 16.19. Example 2

[0027] N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentaventilamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula: The methyl 3-aminopropionic acid hydrochloride fragment in step 2 of Example 1 was replaced with methyl 4-aminobutyrate hydrochloride, and the other steps and operations were the same as in Example 1; white solid, yield: 35%. 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J = 2.4Hz, 1H), 7.67 (dd, J = 8.6, 2.4Hz, 1H), 7.43 (t, J = 5.9Hz, 1H), 7.32 (d, J = 8.7Hz, 1H), 3.94 (s, 3H), 2.80 (q, J = 6.7Hz, 2H), 2.34 (s, 3H), 1.95 (t, J = 7.5Hz, 2H), 1.60 (p, J = 7.4Hz, 2H), 1.24 (s, 9H). 13 C NMR (101MHz, DMSO-d6) δ 177.18, 169.08, 156.21, 155.79, 142.43, 134.63, 129.38, 128.87, 124.51, 122.87, 114.09, 56.79, 42.82, 40.59, 40.38, 40.17, 39.97, 39.76, 39.55, 39.34, 39.22, 30.02, 27.05, 25.92, 16.20. Example 3

[0028] N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pentapentamidothiazo-5-yl)phenyl)sulfonamido)pentanamide, with the following structural formula: The methyl 3-aminopropionic acid hydrochloride fragment in step 2 of Example 1 was replaced with methyl 5-aminovalerate hydrochloride, and the other steps and operations were the same as in Example 1; white solid, yield: 36%. 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 10.32 (s, 1H), 8.68 (s, 1H), 7.73 (d, J = 2.4Hz, 1H), 7.67 (dd, J = 8.6, 2.4Hz, 1H), 7.40 (t, J = 5.9H z, 1H), 7.31 (d, J = 8.8Hz, 1H), 3.94 (s, 3H), 2.81 (q, J = 6.5Hz, 2H), 2.34 (s, 3H), 1.88 (t, J = 7.2Hz, 2H), 1.52-1.31 (m, 4H), 1.24 (s, 9H). 13 C NMR (101MHz, DMSO-d6) δ 177.14, 169.32, 156.17, 155.80, 142.40, 134.56, 129.37, 129.02, 124.46, 122.91, 114.06, 56.76, 42.83, 40.59, 40.38, 40.17, 39.96, 39.75, 39.54, 39.33, 39.22, 32.25, 29.32, 27.05, 22.73, 16.18. Example 4

[0029] N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pentaventilamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide, with the following structural formula: The methyl 3-aminopropionic acid hydrochloride fragment in step 2 of Example 1 was replaced with methyl 6-aminohexanoate hydrochloride, and the other steps and operations were the same as in Example 1; white solid, yield: 39%. 1 H NMR (300MHz, DMSO-d6) δ11.84 (s, 1H), 10.33 (s, 1H), 8.67 (s, 1H), 7.73 (d, J = 2.3Hz, 1H), 7.67 (dd, J = 8.6, 2.4Hz, 1H), 7.41-7.27 (m, 2H) , 3.94 (s, 3H), 2.80 (q, J = 6.5Hz, 2H), 2.34 (s, 3H), 1.88 (t, J = 7.3Hz, 2H), 1.38 (dp, J = 16.2, 7.4Hz, 5H), 1.24 (s, 9H), 1.22-1.13 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 177.15, 169.44, 156.17, 155.81, 142.41, 134.58, 129.38, 129.03, 124.47, 122.91, 114.04, 56.77, 43.01, 40.59, 40.38, 40.17, 39.96, 39.75, 39.54, 39.34, 39.22, 32.63, 29.37, 27.04, 26.11, 25.20, 16.16. Example 5

[0030] N-hydroxy-7-((2-methoxy-5-(4-methyl-2-pentaventilamidothiazo-5-yl)phenyl)sulfonamido)heptamide, with the following structural formula: The methyl 3-aminopropionic acid hydrochloride fragment in step 2 of Example 1 was replaced with methyl 7-aminoheptanoate hydrochloride, and the other steps and operations were the same as in Example 1; white solid, yield: 38%. 1 H NMR (300MHz, DMSO-d6) δ11.83 (s, 1H), 10.32 (s, 1H), 8.66 (s, 1H), 7.76-7.62 (m, 2H), 7.41-7.27 (m, 2H), 3.94 (s, 3H), 2 .81(q, J=6.5Hz, 2H), 2.34(s, 3H), 1.89(t,J=7.3Hz, 2H), 1.38(dt,J=20.6, 6.9Hz, 3H), 1.24(s, 9H), 1.22-1.09(m, 5H). 13 C NMR (101MHz, DMSO-d6) δ 177.17, 169.51, 156.20, 155.81, 142.37, 134.56, 129.37, 129.11, 124.46, 122.90, 114.03, 56.76, 43.09, 40.59, 40.38, 40.17, 39.96, 39.75, 39.54, 39.33, 39.22, 32.63, 29.48, 28.64, 27.04, 26.20, 25.50, 16.15. Example 6

[0031] N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentaaminothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula: The methyl 3-aminopropionic acid hydrochloride fragment in step 2 of Example 1 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the other steps and operations were the same as in Example 1; white solid, yield: 45%. 1H NMR (300MHz, DMSO-d6) δ 11.85 (s, 1H), 11.15 (s, 1H), 9.00 (s, 1H), 8.04 (t, J = 6.4Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.58 (t, J =7.8Hz, 3H), 7.26 (d, J = 8.0Hz, 2H), 7.14 (d, J = 8.7Hz, 1H), 4.14 (d, J = 6.2Hz, 2H), 3.86 (s, 3H), 2.32 (s, 3H), 1.25 (s, 9H). 13 C NMR (101MHz, DMSO-d6) δ 178.88, 165.27, 161.15, 157.55, 149.05, 142.53, 131.81, 131.55, 130.58, 128.42-127.92 (m), 125.94, 114.21, 55.80, 47.71, 39.54, 27.57, 19.26. Example 7

[0032] N-hydroxy-4-(2-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonylamino)ethoxy)benzamide, with the following structural formula: The methyl 3-aminopropionic acid hydrochloride fragment in step 2 of Example 1 was replaced with methyl 4-(2-aminoethoxy)benzoate hydrochloride, and the other steps and operations were the same as in Example 1; white solid, yield: 49%. 1 H NMR (400MHz, DMSO-d6) δ11.83 (s, 1H), 11.05 (s, 1H), 8.92-8.87 (m, 1H), 7.76 (d, J = 2.4Hz, 1H), 7.71-7.60 (m, 4H), 7.26 ( d,J=8.7Hz, 1H), 6.87-6.80(m, 2H), 4.00(t,J=5.3Hz, 2H), 3.90(s, 3H), 3.27(t,J=5.7Hz, 2H), 2.33(s, 3H), 1.25(s, 9H). 13 C NMR (101MHz, DMSO-d6) δ 178.88, 164.94, 162.74, 161.15, 157.55, 149.05, 131.81, 130.58, 129.30, 128.14, 127.23, 126.16, 125.94, 115.25, 114.21, 66.73, 55.80, 43.44, 39.54, 27.57, 19.26. Example 8

[0033] N-hydroxy-4-((2-methoxy-5-(4-methyl-2-propamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula: In Example 1, the methyl 3-aminopropionate hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with propionyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 42%. 1 H NMR (300MHz, DMSO-d6) δ11.03 (d, J = 56.8Hz, 2H), 9.82 (s, 1H) , 8.85 (s, 1H), 7.72 (d, J = 2.3Hz, 1H), 7.66 (dd, J = 8.6, 2.4Hz, 1H), 7.30 (d, J = 8.7Hz, 1H), 3.93 (s, 3H), 2.80 (t, J = 7.1H z, 2H), 2.42 (q, J = 7.5Hz, 2H), 2.31 (s, 3H), 1.94 (t, J = 7.5Hz, 2H), 1.59 (t, J = 7.3Hz, 2H), 1.09 (td, J = 7.3, 2.6Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 173.58, 172.12, 161.10, 157.54, 149.05, 131.81, 130.58, 128.01, 127.66, 125.82, 114.21, 55.80, 42.78, 31.54, 28.65, 24.85, 19.26, 9.52. Example 9

[0034] N-hydroxy-4-((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with butyryl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 44%. 1 H NMR (300MHz, DMSO-d6) δ12.09 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.76-7.63 (m, 2H), 7.43 (t, J = 5.7Hz, 1H), 7.31 (d, J = 8.7Hz, 1H), 3.94 (s , 3H), 2.80 (q, J = 6.7Hz, 2H), 2.41 (t, J = 7.3Hz, 2H), 2.33 (s, 3H), 1.95 (t, J = 7.4Hz, 2H), 1.62 (qd, J = 7.3, 3.2Hz, 4H), 0.90 (t, J = 7.4Hz, 3H).13 C NMR (101MHz, DMSO-d6) δ 171.70, 169.09, 155.80, 155.41, 142.50, 134.60, 129.38, 128.86, 124.48, 122.73, 114.07, 56.79, 42.81, 40.60, 40.40, 40.19, 39.98, 39.77, 39.56, 39.35, 37.24, 30.02, 25.92, 18.68, 16.29, 13.95. Example 10

[0035] N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isobutyramamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with isobutyryl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 45%. 1 H NMR (300MHz, DMSO-d6) δ10.96 (s, 1H), 10.27 (s, 1H), 9.77 (s, 1H), 8.87 (s, 1H), 7.76-7.60 (m, 2H), 7.31 (d, J=8.7Hz, 1H), 3.94 (s, 3H), 2.76 (dt, J = 25.4, 7.0Hz, 3H), 2.32 (s, 3H), 1.95 (t, J = 7.4Hz, 2H), 1.59 (q, J = 7.2Hz, 2H), 1.11 (dd, J = 7.0, 3.0Hz, 6H). 13 C NMR (101MHz, DMSO-d6) δ 178.34, 172.12, 161.34, 157.54, 149.05, 131.81, 130.58, 128.01, 127.66, 125.94, 114.21, 55.80, 42.78, 35.73, 31.54, 24.85, 19.24, 19.21. Example 11

[0036] N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride. Other steps and operations were the same as in Example 1. White solid, yield 43%. 1H NMR (300MHz, DMSO-d6) δ12.12 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J=2. 4Hz, 1H), 7.68 (dd, J=8.5, 2.4Hz, 1H), 7.42 (t, J=5.9Hz.1H), 7.31 (d, J=8.7Hz, 1 H), -3.94 (s, 3H), 2.80 (q, J = 6.7Hz, 2H), 2.43 (t, J = 7.4Hz, 2H), 2.33 (s, 3H), 1.9 5(t,J=7.4Hz,2H), 1.68-1.51(m,4H), 1.37-1.26(m,2H), 0.89(t,J=7.3Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 171.70, 169.09, 155.80, 155.41, 142.50, 134.60, 129.38, 128.86, 124.48, 122.73, 114.07, 56.79, 42.81, 40.60, 40.40, 40.19, 39.98, 39.77, 39.56, 39.35, 37.24, 30.02, 25.92, 18.68, 16.29, 13.95. Example 12

[0037] N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isovaleramidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentovalyl chloride in step 3 was replaced with isovalyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 45%. 1 H NMR (400MHz, DMSO-d6) δ12.11 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J=2 .4Hz, 1H), 7.68 (dd, J=8.5, 2.4Hz, 1H), 7.42 (t, J=6.0Hz, 1H), 7.31 (d, J=8.7H z, 1H), 3.94 (s, 3H), 2.80 (q, J=6.8Hz, 2H), 2.32 (d, J=8.4Hz, 5H), 2.08 (m, J=6 .9Hz, 1H), 1.95(t,J=7.4Hz, 2H), 1.60(m,J=7.2Hz, 2H), 0.92(d,J=6.6Hz, 6H). 13C NMR (101MHz, DMSO-d6) δ 173.97, 172.12, 161.50, 157.54, 149.05, 131.81, 130.58, 128.01, 127.66, 125.82, 114.21, 55.80, 46.39, 42.78, 31.54, 25.22, 24.85, 22.53, 19.26 Example 13

[0038] N-hydroxy-4-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)butyramide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminobutyrate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 46%. 1 H NMR (300MHz, DMSO-d6) δ12.10 (s, 1H), 10.32 (s, 1H), 8.68 (s, 1H), 7.73 (d, J = 2.4Hz , 1H), 7.68 (dd, J = 8.6, 2.4Hz, 1H), 7.40 (t, J = 5.9Hz, 1H), 7.31 (d, J = 8.6Hz, 1H), 3.9 4 (s, 3H), 2.80 (q, J = 6.7Hz, 2H), 2.42 (t, J = 7.4Hz, 2H), 2.33 (s, 3H), 1.97 (d, J = 11. 7Hz, 2H), 1.60 (p, J=7.2Hz, 4H), 1.37-1.22 (m, J=5.5Hz, 4H), 0.87 (t, J=6.7Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 171.84, 169.08, 155.78, 155.42, 142.49, 134.60, 129.38, 128.83, 124.48, 122.72, 114.05, 56.77, 42.80, 35.30, 31.18, 30.01, 25.91, 24.88, 22.29, 16.29, 14.29. Example 14

[0039] N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)propionamide, with the following structural formula: In Example 1, pentanoyl chloride in step 3 was replaced with pentanoyl chloride, and other steps and operations were the same as in Example 1; white solid, yield: 42%. 1H NMR (300MHz, DMSO-d6) δ12.14 (s, 1H), 10.46 (s, 1H), 8.77 (s, 1H), 7.76-7.65 (m, 2H), 7.45-7.28 (m, 2H), 3.94 (s, 3H), 3.00 (q, J = 6.8Hz, 2H), 2.43(t,J=7.4Hz, 2H), 2.33(s, 3H), 2.14(t,J=7.4Hz, 2H), 1.58(p,J=7.4Hz, 2H), 1.30(m,J=8.6, 7.9Hz, 2H), 0.89(t,J=7.3Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 173.67, 169.83, 161.18, 157.55, 149.05, 131.81, 130.58, 128.10, 127.60, 125.82, 114.21, 55.80, 39.99, 36.01, 33.99, 26.86, 21.77, 19.26, 13.82. Example 15

[0040] N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)pentanamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 5-aminovalerate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride. Other steps and operations were the same as in Example 1: white solid, yield 40%. 1 H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 10.31 (s, 1H), 8.66 (s, 1H), 7.73 (d, J = 2.4Hz, 1H), 7.67(dd,J=8.6,2.4Hz,1H), 7.37(t,J=5.9Hz,1H), 7.30(d,J=8.7Hz.1H), 3.94(s,3H),2 .80(q,J=6.5Hz,2H),2.43(t,J=7.4Hz,2H),2.32(s,3H),1.91(dt,J=25.8,7.3Hz,2H),1 .59(p,J=7.5Hz,2H),1.52-1.36(m,2H),1.39-1.20(m,4H),0.87(dt,J=12.6,7.3Hz,3H). 13C NMR (101MHz, DMSO) δ 171.85, 169.32, 155.79, 155.42, 142.47, 134.54, 129.37, 128.98, 124.43, 122.75, 114.03, 56.76, 42.81, 40.58, 40.37, 40.21, 40.16, 39.95, 39.75, 39.54, 39.33, 35.05, 32.42, 32.24, 29.31, 27.72, 27.30, 22.73, 22.14, 16.28, 14.12. Example 16

[0041] N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 6-aminohexanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 36%. 1 H NMR (400MHz, DMSO-d6) δ12.12 (s, 1H), 10.32 (s, 1H), 8.66 (s, 1H), 7.73 (d, J=2 .4Hz, 1H), 7.67 (dd, J=8.6, 2.4Hz, 1H), 7.39-7.27 (m, 2H), 3.94 (s, 3H), 2.79 (q , J=6.6Hz, 2H), 2.43 (t, J=7.4Hz, 2H), 2.32 (s, 3H), 1.88 (t, J=7.4Hz, 2H), 1.58 (p,J=7.5Hz, 2H), 1.43-1.32(m, 4H), 1.31-1.14(m, 4H), 0.89(t,J=7.4Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 174.80, 173.67, 161.18, 157.54, 149.05, 131.81, 130.58, 128.01, 127.75, 125.82, 114.21, 55.80, 43.53, 36.01, 32.22, 29.51, 26.86, 26.07, 24.39, 21.77, 19.26, 13.82. Example 17

[0042] N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with pentanoyl chloride. Other steps and operations were the same as in Example 1: white solid, yield: 30%. 1 H NMR (400MHz, DMSO-d6) δ11.98 (s, 1H), 11.14 (s, 1H), 8.95 (s, 1H), 8.02 (s, 1 H), 7.69 (d, J=2.3Hz, 1H), 7.58 (td, J=8.3, 2.1Hz, 3H), 7.26 (d, J=8.1Hz, 2H ), 7.14 (d, J = 8.7Hz, 1H), 4.14 (s, 2H), 3.86 (s, 3H), 2.43 (t, J = 7.4Hz, 2H), 2 .30 (s, 3H), 1.59 (p, J = 7.4Hz, 2H), 1.38-1.24 (m, 2H), 0.89 (t, J = 7.3Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 171.85, 164.26, 155.62, 155.43, 142.46, 141.48, 134.57, 131.78, 129.32, 129.09, 127.84, 126.97, 124.28, 122.77, 113.74, 56.61, 46.36, 35.05, 27.30, 22.13, 16.20, 14.12. Example 18

[0043] N-hydroxy-7-((2-methoxy-5-(4-methyl-2-acetamidothiazo-5-yl)phenyl)sulfonamido)heptanoamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with acetyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 50%. 1 H NMR (400MHz, Chloroform-d) δ8.79 (d, J=2.4Hz, 1H), 8.17 (dd, J=8.8, 2.4Hz, 1H), 7.58 (t, J=5.5Hz, 1H), 7.28 (s, 0H), 7.12-6.97 (m, 1H ), 4.07 (s, 3H), 3.68 (s, 3H), 3.47 (td, J = 7.1, 5.6Hz, 2H), 2.53 (s, 3H), 2.33 (t, J = 7.5Hz, 2H), 1.72-1.58 (m, 5H), 1.41 (m, J = 3.7Hz, 4H). 13C NMR (101MHz, DMSO-d6) δ 171.75, 169.57, 164.96, 156.43, 155.21, 141.95, 132.26, 130.55, 124.76, 124.53, 123.51, 113.15, 56.55, 35.32, 31.19, 29.43, 26.65, 24.89, 22.28, 16.29, 14.28. Example 19

[0044] N-hydroxy-5-((2-methoxy-5-(4-methyl-2-propamidothiazo-5-yl)phenyl)sulfonamido)pentanamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 5-aminovalerate hydrochloride, and the pentanoyl chloride in step 3 was replaced with propionyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 44%. 1 H NMR (400MHz, DMSO-d6) δ11.95 (s, 1H), 10.31 (s, 0H), 8.66 (s, 1H), 7.73 (d, J = 2.4Hz, 1H), 7.67 (dd, J =8.6, 2.4Hz, 1H), 7.37 (t, J = 6.0Hz, 1H), 7.30 (dd, J = 8.7, 1.0Hz, 1H), 3.94 (d, J = 1.4Hz, 3H), 2.81 (p, J=6.3Hz, 2H), 2.41(t,J=7.3Hz, 2H), 2.32(s, 3H), 2.12(t,J=7.2Hz, 1H), 1.94-1.83(m, 1H), 1.62(h , J=7.4Hz, 2H), 1.48 (dt, J=15.2, 7.7Hz, 1H), 1.44 (s, 1H), 1.43-1.29 (m, 2H), 0.90 (t, J=7.4Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 172.54, 169.33, 155.79, 155.48, 142.46, 134.53, 129.35, 128.99, 124.44, 122.72, 114.03, 56.76, 42.81, 40.58, 40.37, 40.16, 39.95, 39.75, 39.54, 39.33, 32.24, 29.31, 28.68, 22.73, 16.30, 9.63. Example 20

[0045] N-hydroxy-5-((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)pentanamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 5-aminovalerate hydrochloride, and the pentanoyl chloride in step 3 was replaced with butyryl chloride. Other steps and operations were the same as in Example 1. White solid, yield 43%. 1 H NMR (400MHz, DMSO-d6) δ11.95 (s, 1H), 10.31 (s, 0H), 8.66 (s, 1H), 7.73 (d, J = 2.4Hz, 1H), 7.67 (dd, J =8.6, 2.4Hz, 1H), 7.37 (t, J = 6.0Hz, 1H), 7.30 (dd, J = 8.7, 1.0Hz, 1H), 3.94 (d, J = 1.4Hz, 3H), 2.81 (p, J=6.3Hz, 2H), 2.41(t, J=7.3Hz, 2H), 2.32(s, 3H), 2.12(t, J=7.2Hz, 1H), 1.94-1.83(m, 1H), 1.62(h ,J=7.4Hz.2H), 1.48(dt,J=15.2, 7.7Hz, 1H), 1.44(s, 1H), 1.43-1.29(m, 2H), 0.90(t,J=7.4Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 174.82, 171.70, 155.79, 155.40, 142.47, 134.55, 129.37, 129.02, 128.98, 124.43, 122.75, 114.02, 56.76, 42.76, 39.75, 39.54, 39.33, 37.23, 33.67, 29.09, 22.04, 18.68, 16.27, 14.02, 13.95. Example 21

[0046] N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with butyryl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 45%. 1H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.02 (t, J =6.4Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.59 (ddd, J = 9.9, 7.7, 2.0Hz, 3H), 7.29- 7.23 (m, 2H), 7.14 (d, J = 8.7Hz, 1H), 4.14 (d, J = 6.2Hz, 2H), 3.86 (s, 3H), 2.41 (t,J=7.3Hz, 2H), 2.31(s, 3H), 1.63(h,J=7.3Hz, 2H), 0.91(t,J=7.4Hz, 3H). 13 C NMR (101MHz, DMSO-d6) δ 171.69, 155.64, 155.42, 142.46, 141.50, 134.57, 131.79, 129.33, 129.13, 127.83, 126.99, 124.30, 122.78, 113.76, 56.62, 46.36, 37.24, 18.68, 16.21, 13.95. Example 22

[0047] N-hydroxy-5-((2-methoxy-5-(4-methyl-2-isobutyramamidothiazo-5-yl)phenyl)sulfonamido)pentanamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 5-aminovalerate hydrochloride, and the tervaponyl chloride in step 3 was replaced with isobutyryl chloride. Other steps and operations were the same as in Example 1. White solid, yield 45%. 1 H NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 10.31 (s, 1H), 8.66 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.6, 2.4Hz, 1H), 7.37 (t, J=5.8Hz, 1H), 7.31 (d, J=8.7Hz, 1H ), 3.94 (s, 3H), 2.81 (q, J = 6.4Hz, 2H), 2.73 (p, J = 6.8Hz, 1H), 2.33 (s, 3H), 1.88 ( t, J=7.3Hz, 2H), 1.52-1.40 (m, 2H), 1.36 (q, J=7.2Hz, 2H), 1.12 (d, J=6.8Hz, 6H). 13C NMR (101MHz, DMSO-d6) δ 175.68, 169.32, 155.81, 155.55, 142.48, 134.56, 129.36, 129.01, 124.43, 122.84, 114.05, 56.76, 42.82, 40.58, 40.38, 40.17, 39.96, 39.75, 39.54, 39.33, 34.26, 32.24, 29.31, 22.73, 19.55, 16.26. Example 23

[0048] N-hydroxy-7-((2-methoxy-5-(4-methyl-2-isovaleramidothiazo-5-yl)phenyl)sulfonamido)heptamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the pentovalyl chloride in step 3 was replaced with isovalyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 45%. 1 H NMR (300MHz, DMSO-d6) δ12.11 (s, 1H), 10.33 (s, 1H), 8.67 (s, 1H), 7.73 (d, J=2 .4Hz.1H), 7.67(dd, J=8.6, 2.4Hz, 1H), 7.42-7.26(m, 2H), 3.94(s, 3H), 2.80( q, J=6.3Hz, 2H), 2.75-2.65 (m, 1H), 2.32 (s, 3H), 1.99 (s, 1H), 1.89 (t, J=7.3H z, 2H), 1.39 (dq, J=21.2, 7.1Hz, 3H), 1.26-1.14 (m, 5H), 1.12 (d, J=6.9Hz, 6H). 13 C NMR (101MHz, DMSO-d6) δ 175.68, 169.51, 155.82, 155.56, 142.47, 134.55, 129.36, 129.10, 124.43, 122.83, 114.02, 60.23, 56.75, 43.08, 34.26, 32.63, 29.47, 28.63, 26.20, 25.50, 19.55, 16.23. Example 24

[0049] N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-isovaleramidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with isovaleryl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 45%. 1 H NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.03 (t, J = 6.4Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.61 (d, J = 1.7Hz, 1H), 7.62-7.53 ( m, 2H), 7.26 (d, J = 8.3Hz, 2H), 7.14 (d, J = 8.7Hz, 1H), 4.14 (d, J = 5.7Hz, 2H ), 3.86 (s, 3H), 2.73 (p, J = 6.8Hz.1H), 2.31 (s, 3H), 1.12 (d, J = 6.8Hz, 6H). 13 C NMR (101MHz, DMSO-d6) δ 175.67, 155.65, 155.57, 142.47, 141.48, 134.58, 131.79, 129.33, 129.15, 127.83, 126.98, 124.29, 122.86, 113.77, 56.62, 46.38, 34.26, 19.56, 16.18. Example 25

[0050] N-hydroxy-3-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)propionamide, with the following structural formula: In Example 1, pentanoyl chloride in step 3 was replaced with hexanoyl chloride, and other steps and operations were the same as in Example 1; white solid, yield: 46%. 1 H NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.03 (t, J = 6.4Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.61 (d, J = 1.7Hz, 1H), 7.62-7.53 ( m, 2H), 7.26 (d, J = 8.3Hz, 2H), 7.14 (d, J = 8.7Hz, 1H), 4.14 (d, J = 5.7Hz, 2H ), 3.86 (s, 3H), 2.73 (p, J = 6.8Hz, 1H), 2.31 (s, 3H), 1.12 (d, J = 6.8Hz, 6H). 13C NMR (101MHz, DMSO-d6) δ 175.67, 155.65, 155.57, 142.47, 141.48, 134.58, 131.79, 129.33, 129.15, 127.83, 126.98, 124.29, 122.86, 113.77, 56.62, 46.38, 34.26, 19.56, 16.18. Example 26

[0051] N-hydroxy-6-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 6-aminohexanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 40%. 1 H NMR (400MHz, DMSO-d6) δ12.05 (s, 1H), 10.31 (s, 1H), 8.65 (s, 1H), 7.73 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.6, 2.4Hz, 1H), 7.38-7.27 (m, 2H), 3.94 (s, 3 H), 2.80 (p, J=6.2Hz, 2H), 2.42 (t, J=7.4Hz, 2H), 2.32 (s, 3H), 1.89 (t, J= 7.4Hz, 2H), 1.67-1.54 (m, 2H), 1.43-1.05 (m, 10H), 0.87 (t,J=6.9Hz, 3H). 13 C NMR (75MHz, DMSO-d6) δ 171.85, 169.44, 155.80, 155.42, 142.46, 134.55, 129.38, 128.98, 124.44, 122.75, 114.00, 56.75, 42.99, 35.30, 32.63, 31.18, 29.35, 26.11, 25.19, 24.88, 22.29, 16.26, 14.29. Example 27

[0052] N-hydroxy-7-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)heptamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 45%. 1H NMR (400MHz, DMSO-d6) δ12.21 (s, 1H), 10.30 (s, 1H), 8.64 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 1.8Hz, 1H), 7.71 (d, J = 2.2Hz, 2H), 2.89 (t, J = 7.0Hz, 2H ), 2.44 (t, J=7.4Hz, 2H), 2.37 (s, 3H), 1.89 (t, J=7.4Hz, 2H), 1.61 (p, J= 7.3Hz, 2H), 1.45-1.32 (m, 4H), 1.32-1.08 (m, 6H), 0.87 (t, J=6.8Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 172.07, 169.50, 156.29, 144.17, 139.11, 133.51, 132.89, 132.22, 129.78, 129.44, 121.80, 42.98, 35.31, 32.62, 31.17, 29.53, 28.58, 26.12, 25.47, 24.84, 22.28, 16.54, 14.29. Example 28

[0053] N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide, with the following structural formula: In Example 1, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the pentanoyl chloride in step 3 was replaced with hexanoyl chloride. Other steps and operations were the same as in Example 1. White solid, yield: 45%. 1 H NMR (300MHz, DMSO-d6) δ12.08 (s, 1H), 11.19 (s, 1H), 9.02 (s, 1H), 8.86 (t, J=6 .1Hz, 1H), 7.79-7.68 (m, 3H), 7.56 (dd, J=8.6, 2.5Hz, 1H), 7.40 (d, J=8.2Hz, 2H ), 7.25 (d, J = 8.7Hz, 1H), 4.55 (d, J = 6.0Hz, 2H), 3.94 (s, 3H), 2.41 (t, J = 7.4Hz, 2H), 2.32(s, 3H), 1.60(p,J=7.4Hz, 2H), 1.36-1.18(m, 4H), 0.92-0.82(m, 3H). 13C NMR (101MHz, DMSO-d6) δ 171.75, 165.32, 156.59, 155.23, 143.41, 142.01, 132.59, 131.66, 130.66, 127.38, 127.36, 124.81, 124.02, 123.44, 113.21, 56.58, 42.90, 35.31, 31.19, 24.89, 22.29, 16.30, 14.30. Example 29

[0054] N-(2-amino-4-fluorophenyl)-4-(((2-methoxy-5-(4-methyl-2-pentaaminothiazo-5-yl)phenyl)sulfonamide)methyl)benzamide, with the following structural formula: The methyl 3-aminopropionic acid hydrochloride fragment in step 2 of Example 1 was replaced with methyl 4-aminomethylbenzoate hydrochloride, and the hydroxylamine hydrochloride in step 4 was replaced with 4-fluoro-1,2,-phenylenediamine. Other steps and operations were the same as in Example 1. White solid, yield: 28%. 1 H NMR (400MHz, DMSO-d6) δ9.45 (s, 1H), 8.14 (d, J = 2.2Hz, 1H), 7.98-7.92 (m, 2H), 7.77 (dd, J = 7.9, 2.2Hz, 1H), 7.67 (dd, J = 8.2, 5.0Hz, 1 H), 7.47-7.40 (m, 3H), 7.17 (d, J=7.9Hz, 1H), 6.86-6.75 (m, 2H), 4.84 (s, 2H), 4.24 (dt, J=7.2, 1.0Hz, 2H), 3.90 (s, 3H), 1.14 (s, 9H). 13 C NMR (101MHz, DMSO-d6) δ 178.88, 173.88, 161.15, 159.89, 157.87, 157.55, 149.05, 142.29, 142.01, 141.95, 132.73, 131.81, 130.58, 128.87, 128.27, 128.20, 128.14, 126.22, 126.20, 125.94, 122.86, 122.80, 114.21, 106.69, 106.53, 102.71, 102.55, 55.80, 47.71, 39.54, 27.57, 19.26. Example 30

[0055] N-(7-(hydroxyamino)-4-oxobutyl)-5-(2-hexamido-4-methylthiazo-5-yl)-2-methoxybenzamide: Step 1: Synthesis of 2-methoxy-5-(2-oxopropyl)benzoic acid, with the following structural formula: 10 mmol of methyl 5-formyl-2-methoxybenzoate and butylamine (2.0 e.) were dissolved in toluene and refluxed for 3 h. After being dried by vacuum distillation, the mixture was dissolved in 10 mL of acetic acid. 1.14 mL of nitroethane (1.5 e.) was slowly added to the reaction solution, and the mixture was heated to 100 °C and reacted for 3 h. After the reaction was complete, the reaction solution was cooled to room temperature and slowly poured into 40 mL of ice-water solution (with vigorous stirring throughout). The mixture was extracted with ethyl acetate solution (2 x 40 mL), and the organic phase was collected. The organic phase was washed successively with water (2 x 40 mL), 10% sodium bicarbonate solution (2 x 30 mL), and brine. After drying with anhydrous magnesium sulfate, the mixture was purified by column chromatography (PE:EA = 2:1) to give methyl (Z)-2-methoxy-5-(2-nitropropen-1-yl)benzoate, yield: 80%. 100 mmol of iron powder was added to a reaction flask containing 22 mL of acetic acid. Under nitrogen protection, the solution containing (Z)-2- A 12 mL acetic acid solution of methyl methoxy-5-(2-nitropropen-1-yl)benzoate (8 mmol) was slowly added dropwise to the reactor described above. After reflux for 2 h, the reaction solution was cooled to room temperature, iron powder was filtered off, 30 mL of water was added to the filtrate, and the mixture was extracted with ethyl acetate solution (3 x 40 mL). The organic phase was collected and washed successively with water (2 x 30 mL), 10% sodium bicarbonate solution (2 x 30 mL), and brine (30 mL). After drying with anhydrous magnesium sulfate, the solution was purified by column chromatography (PE:EA = 1:1) to obtain methyl 2-methoxy-5-(2-oxopropyl)benzoate, yield: 90%. 2 mmol of methyl 2-methoxy-5-(2-oxopropyl)benzoate was weighed and acid-hydrolyzed to give a white solid 2-methoxy-5-(2-oxopropyl)benzoic acid, yield: 95% (using 1.0 mL hydrochloric acid solution (a mixture of 1 mol / L and 4 mL acetic acid) as the acid hydrolysis solution). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.58 (s, ¹H), 7.46 (d, J = 2.3Hz, ¹H), 7.30 (dd, J = 8.5, 2.4Hz, ¹H), 7.07 (d, J = 8.6Hz, ¹H), 3.80 (s, ³H), 3.75 (s, 2H), 2.13 (s, ³H). Step 2: Synthesis of methyl 4-(5-(2-hexamido-4-methylthiazolyl-5-yl)-2-methoxybenzamido)butyrate, with the following structural formula: 1 mmol of 2-methoxy-5-(2-oxopropyl)benzoic acid and 1 mmol of CDI were dissolved in 10 mL of DCM solution and pre-reacted for 1 h. Then, 1.5 mmol of methyl 4-aminobutyrate was added to the reaction solution and reacted at room temperature. After the reaction was completed, the mixture was purified to obtain methyl 4-(2-methoxy-5-(2-oxopropyl)benzamido)butyrate. Then, following step 3 in Example 1, the pentanoyl chloride in step 3 was replaced with hexanoyl chloride to obtain methyl 4-(5-(2-hexamido-4-methylthiazolyl-5-yl)-2-methoxybenzamido)butyrate, a white solid, with a yield of 60%. 1 H NMR (400MHz, DMSO-d6) δ8.42 (d, J=2.2Hz, 1H), 7.80 (t, J=5.0Hz, 1H), 7.69 (dd , J=8.0, 2.3Hz, 1H), 7.07 (d, J=7.9Hz, 1H), 3.93 (s, 2H), 3.64 (s, 2H), 3.39-3. 32(m, 2H), 2.47(s, 2H), 2.42(t, J=8.0Hz, 2H), 2.31(t, J=8.4Hz, 2H), 1.88(tt , J=8.4, 5.8Hz, 2H), 1.67-1.57(m, 2H), 1.39-1.25(m, 4H), 0.92-0.86(m, 3H). Step 3: Synthesis of N-(7-(hydroxyamino)-4-oxobutyl)-5-(2-hexamido-4-methylthiazolyl-5-yl)-2-methoxybenzamide, with the following structural formula: According to step 4 in Example 1, 4-(5-(2-hexamido-4-methylthiazol-5-yl)-2-methoxybenzamido)butyric acid was first prepared. 5 mmol of methyl 4-(5-(2-hexamido-4-methylthiazol-5-yl)-2-methoxybenzamido)butyric acid was dissolved in 10 mL of a mixed solution of methanol, tetrahydrofuran, and water (MeOH:THF:H2O = 2:2:1) and placed in a 50 mL round-bottom flask. 10 mmol of lithium hydroxide (2 eq.) was weighed and slowly added dropwise to the reaction flask. The mixture was left at room temperature overnight. After the reaction was completed, the reaction solution was added to ice-salt water while hot to precipitate a large amount of white solid. After drying, crude 4-(5-(2-hexamido-4-methylthiazol-5-yl)-2-methoxybenzamido)butyric acid was obtained. Weigh 1 mmol of the crude product and 1.5 mmol of PyBOP condensing agent (1.5 eq.) into a 25 mL reaction flask, add 6 mL of DMF solution, and then add 590 μL of DIPEA (3.5 eq.) to the reaction solution. After stirring at room temperature for a few minutes, add 0.14 g of hydroxylamine hydrochloride (2.0 eq.). After reacting at room temperature for 4 h, monitor by TLC until all the intermediate is consumed (DCM:MeOH = 30:1). Concentrate under vacuum and purify by column chromatography. White solid, yield: 70%.1 H NMR (300MHz, DMSO-d6) δ12.06 (s, 1H), 10.41 (s, 1H), 8.72 (s, 1H), 8.28 (t, J = 5.7Hz, 1H) , 7.72 (d, J = 2.5Hz, 1H), 7.53 (dd, J = 8.6, 2.5Hz, 1H), 7.21 (d, J = 8.7Hz, 1H), 3.92 (s, 3H) , 3.27 (q, J=6.6Hz, 2H), 2.41 (t, J=7.4Hz, 2H), 2.32 (s, 3H), 2.02 (t, J=7.5Hz, 2H), 1.74 (p, J=7.3Hz, 2H), 1.60 (p, J=7.5Hz.2H), 1.27 (td, J=6.4, 3.3Hz, 4H), 0.92-0.82 (m, 3H). 13 C NMR (101MHz, DMSO-d6) δ 171.75, 169.32, 165.10, 156.46, 155.19, 141.96, 132.34, 130.58, 124.71, 124.38, 123.49, 113.11, 56.53, 35.30, 31.19, 30.43, 25.78, 24.89, 22.29, 16.29, 14.30. Example 31

[0056] N-(7-(hydroxyamino)-7-oxohepyl)-5-(2-isobutyramido-4-methylthiazo-5-yl)-2-methoxybenzamide, with the following structural formula: In Example 30, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride, and the hexanoyl chloride in step 3 was replaced with isovaleryl chloride. Other steps and operations were the same as in Example 30. White solid, yield: 46%. 1 H NMR (400MHz, DMSO-d6) δ11.80 (s, 1H), 10.34 (s, 1H), 8.66 (s, 1H), 8.21 (t, J=5.7Hz.1H ), 7.71 (d, J = 2.5Hz, 1H), 7.52 (dd, J = 8.6, 2.5Hz, 1H), 7.21 (d, J = 8.7Hz, 1H), 3.91 (s, 3H ), 3.27 (dt, J=13.2, 6.8Hz, 2H), 2.73 (p, J=6.9Hz, 1H), 2.32 (s, 3H), 2.04-1.91 (m, 2H) , 1.50 (ddt, J=9.8, 7.3, 4.6Hz, 4H), 1.29 (dt, J=9.5, 6.2Hz, 4H), 1.12 (dt, J=6.9Hz, 6H). 13C NMR (101MHz, DMSO-d6) δ 175.58, 169.57, 164.96, 156.43, 155.33, 141.96, 132.28, 130.54, 124.74, 124.52, 123.58, 113.15, 56.54, 34.26, 32.71, 29.43, 28.79, 26.65, 25.61, 19.91, 19.57, 16.27. Example 32

[0057] N-(7-(hydroxyamino)-7-oxohepyl)-5-(2-hexamido-4-methylthiazo-5-yl)-2-methoxybenzamide, with the following structural formula: In Example 30, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 7-aminoheptanoate hydrochloride; other steps and operations were the same as in Example 30. White solid, yield: 40%. 1 H NMR (300MHz, DMSO-d6) δ12.06 (s, 1H), 10.36 (s, 1H), 8.69 (s, 1H), 8.22 (t, J=5. 7Hz, 1H), 7.70 (d, J = 2.5Hz, 1H), 7.53 (dd, J = 8.6, 2.5Hz, 1H), 7.21 (d, J = 8.7Hz, 1H), 3.91 (s, 3H), 3.33-3.19 (m, 2H), 2.41 (t, J = 7.4Hz, 2H), 2.32 (s, 3H), 1.95 ( t, J=7.3Hz, 2H), 1.49 (d, J=7.2Hz, 4H), 1.31-1.21 (m, 10H), 0.92-0.80 (m, 3H). 13 C NMR (101MHz, DMSO-d6) δ 171.85, 169.51, 155.80, 155.41, 142.46, 134.53, 129.36, 129.06, 124.43, 122.75, 114.00, 56.75, 43.07, 35.30, 32.63, 31.18, 29.47, 28.64, 26.20, 25.50, 24.88, 22.29, 16.26, 14.30. Example 33

[0058] N-(4-(hydroxycarbamoyl)benzyl)-5-(2-hexanoyl-4-methylthiazolyl-5-yl)-2-methoxybenzamide, with the following structural formula: In Example 30, the methyl 3-aminopropionic acid hydrochloride fragment in step 2 was replaced with methyl 4-aminomethylbenzoate hydrochloride; other steps and operations were the same as in Example 30. White solid, yield: 51%. 1H NMR (300MHz, DMSO-d6) δ12.08 (s, 1H), 11.19 (s, 1H), 9.02 (s, 1H), 8.86 (t, J=6 .1Hz, 1H), 7.79-7.68 (m, 3H), 7.56 (dd, J=8.6, 2.5Hz, 1H), 7.40 (d, J=8.2Hz, 2H ), 7.25 (d, J = 8.7Hz, 1H), 4.55 (d, J = 6.0Hz, 2H), 3.94 (s, 3H), 2.41 (t, J = 7.4Hz, 2H), 2.32(s, 3H), 1.60(p, J=7.4Hz.2H), 1.36-1.18(m, 4H), 0.92-0.82(m, 3H). 13 C NMR (101MHz, DMSO-d6) δ 171.75, 165.32, 156.59, 155.23, 143.41, 142.01, 132.59, 131.66, 130.66, 127.38, 127.36, 124.81, 124.02, 123.44, 113.21, 56.58, 42.90, 35.31, 31.19, 24.89, 22.29, 16.30, 14.30. The beneficial effects and applications of the compounds represented by general formula (I) of the present invention are illustrated by the following experiments.

[0059] Inhibition experiments were conducted on the PI4KIIIβ kinase inhibitors of this invention. The ADP-Glo ​​Luminescent Kinase Assay was used. The reagents used for the kinase reaction were as follows: HEPES (50 mM) pH 7.5 with NaCl (100 mM), EGTA (1.0 mM), MgCl2 (3.0 mM), DTT (2.0 mM), and CHAPS (0.03%). During the reaction, 50 μM PIP2 and 25 μM ATP were added to each 10 mL of the test compound (0.05 nM–1.0 μM) at different concentrations. The reaction system was incubated at room temperature for 1 h, and then 10 μL of ADP-Glo ​​was added to terminate the enzyme reaction. Data were collected using Envision software, and the IC50 values ​​of the compounds were analyzed and fitted using Graphpad Prism 5. 50 value.

[0060] Table 1. PI4KIIIβ enzyme inhibitory activity (IC50) of the compounds in the examples. 50 (nM) As shown in Table 1, the compounds of the present invention exhibit nanomolar inhibitory activity against PI4KIIIβ kinase, and some compounds are significantly superior to the positive control PIK-93. In particular, the inhibitory activity of Examples 11, 13, and 25 against PI4KIIIβ kinase is superior to that of the positive control PIK-93. This demonstrates that some of the compounds in the examples of the present invention are highly effective PI4KIIIβ inhibitors.

[0061] HDAC1 kinase inhibition experiments were conducted on the inhibitors of this invention: The HDAC1 inhibitory activity of the compound in the examples was tested using the HDAC1 fluorescence assay kit (Cat#50051) from BPS Corporation. The experimental steps were as follows: (1) Preparation of 1x assay buffer (modified Tris buffer); (2) Dilution of the compound: The compound was transferred to the assay plate in 100% DMSO using Echo. The final fraction of DMSO was 1%; (3) Preparation of enzyme solution: The enzyme solution was prepared in 1x assay buffer; (4) Preparation of substrate solution: Trypsin and Ac peptide substrate were added to 1x assay buffer to prepare the substrate solution; (5) 15 μL of enzyme solution was transferred to the assay plate, or 15 μL of 1x assay buffer was transferred for the low control. The plate was incubated at room temperature for 15 min. 10 μL of substrate solution was added to each well to start the reaction; (6) Data collection was performed using Envision software, and the IC50 of the compound was analyzed and fitted using Graphpad Prism 5. 50 value.

[0062] Table 2. HDAC1 enzyme inhibitory activity (IC50) of the compounds in the examples. 50 (nM) As shown in Table 2, some compounds of the present invention exhibit nanomolar inhibitory activity against HDAC1, and some compounds are significantly superior to the positive control Vorinostat. In particular, the inhibitory activity of compounds 10, 11, 13, 23, and 26 against HDAC1 kinase is superior to that of the positive control Vorinostat. This demonstrates that some of the compounds in the embodiments of the present invention are highly effective HDAC inhibitors.

[0063] Based on the experimental data in Tables 1 and 2, the analysis and comparison show that Example 11 has the best kinase inhibitory activity against PI4KIIIβ and HDAC1, which are 2.3 nM and 1 nM, respectively. Kinase selectivity experiments were conducted on Example 11 using the same experimental methods as described above. The results of kinase subtype inhibitory activity of the example are shown in Tables 3 and 4.

[0064] Table 3. PI3Ks enzyme inhibitory activity (IC50) in Example 11 50 (nM) Table 4 HDAC of Example 11 s Enzyme inhibitory activity (IC50, nM) Based on the experimental data in Tables 3 and 4, analysis shows that Example 11 exhibits the best inhibitory activity against PI4KIIIβ, with an IC50 value reaching 2.3 nM. It also inhibits the activity of PI3Kδ, with an IC50 value of [missing value]. 50 The value was 47.8 nM. Meanwhile, Example 11 is also a broad-spectrum HDAC inhibitor, exhibiting good inhibitory activity against HDAC1, 2, 3, 6, and 10, with an IC50 value of 47.8 nM. 50 The values ​​are 11, 17, 20, 23, and 75 nM, respectively.

[0065] The anti-HCV virus activity test experiment of the inhibitor of the present invention was carried out. The experimental method is as follows: (1) Sample preparation: The sample to be tested was dissolved in DMSO and then filtered with a 0.22μm filter membrane for sterilization. The original drug concentration was 20mg / mL.

[0066] (2) Cell Culture: Human liver cancer cell line Huh-7.5.1, frozen in liquid nitrogen, was removed and immersed in a 37°C water bath. The cells were thawed quickly (within 1 minute) by shaking. The cell suspension was then transferred to a centrifuge tube, 5 mL of culture medium was added, and the tube was centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded. Approximately 3-4 mL of culture medium was added, mixed well, and the cells were seeded in a 25 cm² incubator. 2 Place the cells in a culture flask and incubate in a CO2 incubator. Change the culture medium the next day. Passage the cells every three days. Change the medium and observe the cells the day before the experiment to ensure they are in the exponential growth phase and in good condition.

[0067] (3) Virus culture: Add J6 / JFH1 virus solution to Huh-7.5.1 cell culture flasks with exponential growth phase, incubate for 5-8 hours, discard the supernatant, replace with fresh culture medium, change the medium every two days, discard the culture medium after 6 days, then add about 15 mL of culture medium and culture until the 7th day, centrifuge at 3000 rpm / min for 10 min, collect the clear culture medium, aliquot and store at -80℃.

[0068] (4) Detection method: MTT assay. Huh-7.5.1 cells in logarithmic growth phase were digested with 0.25% trypsin, centrifuged at 1000 rpm for 3 min, counted using a hemocytometer, and adjusted to a cell concentration of 9 × 10⁴ cells / mL. The cells were then seeded into 96-well plates (100 μL / well) and cultured at 37℃ in a 5% CO₂ incubator. After 5 h of adhesion, serially diluted DMSO was added, resulting in eight dilutions, with three replicates for each dilution. A blank control (containing only culture medium), DMSO control, cell control, positive drug control, and drug color control were also included, bringing the final culture medium volume to 200 μL / well. The culture plates were then placed in a 37℃ 5% CO₂ incubator for further culture. On the third day, add 20 μL of 5 mg / mL LMTT solution to each well and incubate at 37°C with 5% CO2 for 4 hours. Discard the supernatant, add 100 μL / well of DMSO, shake to dissolve for 10 min, and then measure the OD on a microplate reader. 490 The value was calculated using the software GraphPad Prism 5.0. 50 (IC 50 The half-maximal inhibitory concentration (MCC) is the concentration required to inhibit cell growth by 50%. (HCV replication inhibition rate formula = (OD Control OD Drug) / (OD Control OD Blank) × 100%). Table 5 shows the anti-HCV viral activity of compounds from some examples. CC 50 The half-maximal toxic concentration (IC50) indicates the concentration of a drug that causes 50% of the cells to undergo morphological changes. 50 The half-maximal effective concentration (MCC) represents the drug concentration that reduces the viral infection rate by 50%. SI stands for Selectivity, which is equal to CC. 50 With IC 50 The SI ratio is used to assess the therapeutic potential of a drug. A higher SI value indicates a stronger efficacy against HCV. A "-" indicates that 10 μM initial screening showed no inhibitory effect on HCV, or that the IC50 value could not be matched. 50 value.

[0069] As shown in Table 5, some embodiments of the present invention exhibit high levels of inhibitory activity against HCV virus and low cytotoxicity, with Example 2 achieving an inhibition level of 18.41 nM against HCV virus. In particular, Examples 4 and 31 have SI values ​​greater than 2000, and CC... 50 Value greater than 100μM, IC 50 The values ​​were below 60 nM, significantly superior to the positive control PIK93-10. Therefore, some of the compounds in the embodiments of this invention have the potential for clinical use in the treatment of HCV.

[0070] In addition to the above-described embodiments, the present invention may have other implementations. All technical solutions formed by equivalent substitution or equivalent transformation fall within the protection scope claimed by the present invention.

Claims

1. A phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor, characterized in that: The inhibitors are substituted phenylthiazole amine compounds of general formula I, or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof, wherein R1-R4 are substituents on the phenyl ring selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, hydroxy C1-C6 alkoxy or C1-C6 alkoxy C1-C6 alkyl; R5 and R6 are selected from C1 C6 alkyl, C1 C6 alkyl containing one or more substituents, C1 C6 alkoxy, C1 C6 alkoxy containing one or more substituents, C1 C6 alkyl acyl, C1 C6 alkyl sulfonyl, C3 C6 heterocyclic, and C3 C6 heterocyclic containing one or more substituents. X is selected from sulfone or carbonyl groups; Y is selected from C1-C6 alkylene, C1-C6 alkylene containing one or more substituents, 4-substituted phenyl, 4-substituted benzyl, or 4-substituted phenoxyethyl; Z is selected from the following structures, 2. The phenylthiazole amine PI4KIII β / HDAC dual-target inhibitor according to claim 1, characterized in that: In general formula I, the hydrogen atoms bonded to carbon are replaced with the hydrogen isotope deuterium.

3. The phenylthiazole amine PI4KIII β / HDAC dual-target inhibitor according to claim 1 or 2, characterized in that: The inhibitor is one of the following: N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)propionamide; N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)butyramide; N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)pentamidamide; N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide; N-hydroxy-7-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)heptamide; N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide; N-hydroxy-4-(2-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonylamino)ethoxy)benzamide; N-hydroxy-4-((2-methoxy-5-(4-methyl-2-propamidothiazo-5-yl)phenyl)sulfonamido)butyramide; N-hydroxy-4-((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)butyramide; N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isobutyramamidothiazo-5-yl)phenyl)sulfonamido)butyramide; N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)butyramide; N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isovalamidothiazo-5-yl)phenyl)sulfonamido)butyramide; N-hydroxy-4-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)butyramide; N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)propionamide; N-hydroxy-5-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)pentamido; N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)hexanoamide; N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide; N-hydroxy-7-((2-methoxy-5-(4-methyl-2-acetamidothiazo-5-yl)phenyl)sulfonamido)heptamide; N-hydroxy-5-((2-methoxy-5-(4-methyl-2-propamidothiazo-5-yl)phenyl)sulfonamido)pentanamide; N-hydroxy-5-((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)pentanamide; N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-butamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide; N-hydroxy-5-((2-methoxy-5-(4-methyl-2-isobutyramamidothiazo-5-yl)phenyl)sulfonamido)pentanamide; N-hydroxy-7-((2-methoxy-5-(4-methyl-2-isopentanothiazo-5-yl)phenyl)sulfonamido)heptamide: N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-isovaleramidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide; N-hydroxy-3-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)propionamide; N-hydroxy-6-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)hexamylamide; N-hydroxy-7-((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)heptamide; N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-hexamidothiazo-5-yl)phenyl)sulfonamido)methyl)benzamide; N-(2-amino-4-fluorophenyl)-4-(((2-methoxy-5-(4-methyl-2-pentamidothiazo-5-yl)phenyl)sulfonamide)methyl)benzamide; N-(7-(hydroxyamino)-4-oxobutyl)-5-(2-hexamido-4-methylthiazo-5-yl)-2-methoxybenzamide; N-(7-(hydroxyamino)-7-oxohepyl)-5-(2-isobutyramido-4-methylthiazo-5-yl)-2-methoxybenzamide; N-(7-(hydroxyamino)-7-oxohepyl)-5-(2-hexamido-4-methylthiazo-5-yl)-2-methoxybenzamide; N-(4-(hydroxycarbamoyl)benzyl)-5-(2-hexamido-4-methylthiazo-5-yl)-2-methoxybenzamide.

4. The preparation method of the phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor according to claim 3, characterized in that: The target compound (8) is prepared according to the following steps, taking 4-methoxypropiophenone as the raw material (1), the raw material (1) is subjected to substitution reaction at the 3rd position of the benzene ring with chlorosulfonic acid to obtain an intermediate (2); on the basis of the intermediate (2), an amino carboxylic acid methyl ester is introduced through Hinsberg reaction to obtain an intermediate (3); the intermediate (3) is subjected to α-bromination reaction with phenyltrimethylammonium tribromide to obtain an intermediate (4); an N-substituted thiourea (6) is obtained by reacting thiourea (5) with acyl chloride, and the intermediate (4) is subjected to condensation reaction to obtain an intermediate (7); the intermediate (7) is subjected to amide condensation with hydroxylamine to obtain the target compound (8), and the preparation route is as follows, 5. The method for preparing the phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor according to claim 3, characterized in that: The target compound (9) was prepared according to the following steps, using 4-methoxypropiophenone as the starting material (1), substitution reaction of the starting material (1) with chlorosulfonic acid at the 3rd position of the benzene ring to obtain intermediate (2); Hinsberg reaction based on intermediate (2) to introduce aminomethyl carboxylate to obtain intermediate (3); α-bromination of intermediate (3) with phenyltrimethylammonium tribromide to obtain intermediate (4); reaction of thiourea (5) with acyl chloride to obtain N-substituted thiourea (6), and condensation reaction with intermediate (4) to obtain intermediate (7); amide condensation of intermediate (7) with 4-fluoro-1,2-phenylenediamine to obtain the target compound (9), and the preparation route is as follows, 6. The method for preparing the phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor according to claim 3, characterized in that: The target compound (18) was prepared according to the following steps: methyl 5-formyl-2-methoxybenzoate was used as a raw material (10), and intermediate (11) was obtained through a two-step reaction; intermediate (11) was heated under reflux in acetic acid and reacted with iron powder to obtain intermediate (12); intermediate (12) was hydrolyzed under acidic conditions to obtain intermediate (13); intermediate (13) was chlorinated with thionyl chloride to generate intermediate (14); intermediate (14) was reacted with methyl aminocarboxylate to obtain intermediate (15); intermediate (15) was reacted with phenyltrimethylammonium tribromide in an α-bromination reaction to obtain intermediate (16); intermediate (16) was condensed with N-substituted thiourea to obtain intermediate (17); intermediate (17) was amide condensed with hydroxylamine to obtain target compound (18). The preparation route is as follows.

7. A pharmaceutical composition, characterized in that: The composition comprises at least one pharmaceutically acceptable excipient, adjuvant, or carrier, and a phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor as described in any one of claims 1-3.

8. The use of a phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor as described in any one of claims 1-3 or the pharmaceutical composition as described in claim 7 in the preparation of a medicament for inhibiting the growth of hepatitis C virus.

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