A phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor, its preparation method, its pharmaceutical composition and its application

Abstract

The present invention relates to a phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor, a preparation method thereof, a pharmaceutical composition thereof and applications, belonging to the technical field of medicine. The present invention provides a phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor, which is a substituted phenylthiazolamine compound represented by general formula I, or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof. The beneficial effects of the present invention are as follows: (1) It has the characteristics of effectively inhibiting the PI3K / Akt / mTOR signaling pathway of PI4KIIIβ and has excellent dual-enzyme inhibitory activity against PI4KIIIβ / HDAC; (2) It has low cost, good curative effect, low toxicity, and high yield of intermediate products during the synthesis process, reducing resource waste and thus being conducive to cost reduction; (3) It has high anti-hepatitis C virus activity and a small dosage.

Description

Technical Field

[0001] The present invention relates to a phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor, a preparation method thereof, a pharmaceutical composition thereof and an application thereof, belonging to the technical field of medicine. Background Art

[0002] The high expression of phosphatidylinositol 4-kinases (PI4Ks) is closely related to a variety of diseases, including viral infections, cancers, malaria and neurodegenerative diseases, etc. Phosphatidylinositol (PI) is phosphorylated by PI4Ks to produce phosphatidylinositol 4-phosphate (PI4P), which also plays a key role in Golgi function, protein sorting and membrane trafficking, etc., and also plays an important role in the replication and amplification of exogenous pathogens (such as viruses) in the host. Therefore, the research on inhibitors of PI4Ks with broad-spectrum antiviral activity has become one of the hotspots in current medicinal chemistry research. Lipid phosphatidylinositol is an important regulator of numerous cellular processes, including signal transduction, membrane trafficking and cytokinesis. Phosphatidylinositol is produced by phosphorylation of the inositol ring of phosphatidylinositol. In mammals, there are four different PI4K enzymes: two type II enzymes (PI4KIIα and PI4KIIβ) and two type III enzymes (PI4KIIIα and PI4KIIIβ).

[0003] PI4KIIIβ is a peripheral membrane protein distributed on the Golgi apparatus and plasma membrane, playing a key role in mediating lipid transport and cell division. The PI4KIIIβ protein consists of 801 amino acid residues, including a helical domain, a lipid kinase domain, and three disordered regions that mediate binding to regulatory proteins. The N-terminus of PI4KIIIβ is mainly responsible for interacting with Golgi proteins (such as acyl-CoA-binding domain protein 3, ACBD3) and then recruiting them; its C-terminus contains an amphiphilic lipid-packing sensor motif responsible for viral signal sensing and transport. The replication of various viruses (including common polioviruses, coxsackieviruses, and hepatitis C viruses, etc.) in host cells depends on the viral replication site PI4KIIIβ and its catalytic product PI4P. Therefore, PI4KIIIβ is also a key factor in the replication of many viruses. Generally, it is manifested that viruses hijack PI4KIIIβ to form replication organelles (ROs) containing PI4P, thereby inducing the formation of replication structures of viral proteins on biological membranes. PI4K IIIβ also plays a crucial role in human genetic diseases. PI4KIIIβ affects the transcriptional activation of the target gene HES-related family bHLH transcription factor and YRPW motif 1 (hey1) by regulating bone morphogenetic protein type II receptor (BMPR2) and signal transduction proteins 1 / 5 / 9 (Smad1 / 5 / 9), ultimately affecting the development of the zebrafish vestibular organ. STING is a key signal transduction factor in the innate immune response. The activation of the cGAS-STING pathway triggers exogenous DNA, thereby regulating immune responses such as spontaneous anti-tumor and anti-DNA virus responses. ARMH3 is a key factor for STING activation. ARMH3 activates STING by recruiting PI4KIIIβ.

[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 classical hydroxamic acid inhibitor of HDAC, contains a sequence of three main elements that form a pharmacophore: a cap, a linker, and a zinc-binding group (ZBG). On the one hand, the linker binds to the ZBG and facilitates its penetration into the hydrophobic "tunnel" of the HDAC active site, where chelation of the catalytic zinc ion occurs at the bottom. On the other hand, the linker is associated with the cap structure, most commonly an aryl or heteroaryl radical, which additionally interacts with the protein substrate-binding cavity, affecting the strength and selectivity of inhibition. Recent proteomic studies have revealed extensive acetylation in mouse and human hepatocytes. Upregulation of HDAC activity caused by HCV infection has also been reported. In addition, polymorphisms of three HDAC enzymes (HDAC2, 3, and 5) have been shown to be independently associated with sustained virological response in chronic HCV. Many observations suggest that HDAC inhibitors have promise in blocking HCV replication, and recently, benzohydroxamic acid and the pan-HDAC inhibitor vorinostat (SAHA) have been reported as potential anti-HCV drugs.

[0005] According to the existing literature, simultaneous inhibition of PI4KIIIβ and HDAC can efficiently block HCV replication and limit drug resistance by improving the efficacy. Selective inhibitors of PI4KIIIβ and HDAC may have lower toxicity, and there is no literature report on PI4KIIIβ / HDAC dual-target inhibitors yet. Summary of the Invention

[0006] The object of the present invention is to address the deficiencies in the prior art and propose a phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor, its preparation method, a pharmaceutical composition containing the inhibitor, and its application, to improve the inhibitory activity.

[0007] The present invention first provides: a phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor, which is a substituted phenylthiazolamine compound represented by the 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, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkoxy, or C1-C6 alkoxy C1-C6 alkyl;

[0008] R5 and R6 are selected from C1-C6 alkyl, C1-C6 alkyl with one or more substituents, C1-C6 alkoxy, C1-C6 alkoxy with one or more substituents, C1-C6 alkyl acyl, C1-C6 alkyl sulfonyl, C3-C6 heterocyclic group, C3-C6 heterocyclic group with one or more substituents.

[0009] X is selected from sulfonyl or carbonyl;

[0010] Y is selected from C1-C6 alkylene, C1-C6 alkylene with 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 connected to carbon is replaced by the isotope deuterium of hydrogen.

[0011] More preferably, the alkyl is replaced by deuterated alkyl, the alkoxy is replaced by deuterated epoxy group, the benzene ring is replaced by deuterated benzene ring, and the aromatic ring is replaced by deuterated aromatic ring.

[0012] Preferably, the pharmaceutically acceptable salt means converting the basic group in the parent compound into a salt form; wherein, the pharmaceutically acceptable salt is a basic group, more preferably inorganic or organic acid salts of amine group or amino group; reacting the basic group in the parent compound with 1-4 equivalents of acid in a solvent system.

[0013] Preferably, the basic group of the compound in the present invention can form a salt with an acid, and the acid salt specifically includes salts formed with inorganic acids, especially hydrohalic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc.; salts formed with lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid; salts formed with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts formed with organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; salts formed with amino acids, such as aspartic acid or glutamic acid.

[0014] Preferably, the compounds and pharmaceutically acceptable salts of the present invention also include solvates or hydrates.

[0015] Preferably, the structural formula of the compound in the phenylthiazolamine PI4KIIIβ inhibitor of the present invention includes isomeric forms, such as enantiomers, diastereomers, geometric isomers or conformational isomers, specifically the R and S configurations containing asymmetric centers, the ( Z ) and ( E ) isomers of the double bond, and the conformational isomers of ( Z ) and ( E ).

[0016] Preferably, the inhibitor is one of the following:

[0017] (1)N-Hydroxy-3-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)propanamide;

[0018] (2)N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)butanamide;

[0019] (3)N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)pentanamide;

[0020] (4)N-Hydroxy-6-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)hexanamide;

[0021] (5)N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)heptanamide;

[0022] (6)N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide;

[0023] (7)N-Hydroxy-4-(2-((2-methoxy-5-(4-methyl-2-valoylaminothiazol-5-yl)phenyl)sulfamido)ethoxy)benzamide;

[0024] (8)N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-propionylaminothiazol-5-yl)phenyl)sulfamoyl)butanamide;

[0025] (9)N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-butanoylaminothiazol-5-yl)phenyl)sulfamoyl)butanamide;

[0026] (10)N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-isobutanoylaminothiazol-5-yl)phenyl)sulfamoyl)butanamide;

[0027] (11)N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-valoylaminothiazol-5-yl)phenyl)sulfamoyl)butanamide;

[0028] (12)N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-isovaloylaminothiazol-5-yl)phenyl)sulfamoyl)butanamide;

[0029] (13)N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-hexanoylaminothiazol-5-yl)phenyl)sulfamoyl)butanamide;

[0030] (14) N-Hydroxy-3-((2-methoxy-5-(4-methyl-2-valeramidothiazol-5-yl)phenyl)sulfamoyl)propanamide;

[0031] (15) N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-valeramidothiazol-5-yl)phenyl)sulfamoyl)pentanamide;

[0032] (16) N-Hydroxy-6-((2-methoxy-5-(4-methyl-2-valeramidothiazol-5-yl)phenyl)sulfamoyl)hexanamide;

[0033] (17) N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-valeramidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide;

[0034] (18) N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-acetamidothiazol-5-yl)phenyl)sulfamoyl)heptanamide;

[0035] (19) N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-propionamidothiazol-5-yl)phenyl)sulfamoyl)pentanamide;

[0036] (20) N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-butyramidothiazol-5-yl)phenyl)sulfamoyl)pentanamide;

[0037] (21) N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-butyramidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide;

[0038] (22) N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-isobutyramidothiazol-5-yl)phenyl)sulfamoyl)pentanamide;

[0039] (23) N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfamoyl)heptanamide;

[0040] (24) N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide;

[0041] (25) N-Hydroxy-3-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfamoyl)propanamide;

[0042] (26)N-Hydroxy-6-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfamoyl)hexanamide;

[0043] (27)N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfamoyl)heptanamide;

[0044] (28)N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide;

[0045] (29)N-(2-Amino-4-fluorophenyl)-4-(((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide;

[0046] (30)N-(7-(Hydroxyamino)-4-oxobutyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide;

[0047] (31)N-(7-(Hydroxyamino)-7-oxoheptyl)-5-(2-isobutanamido-4-methylthiazol-5-yl)-2-methoxybenzamide;

[0048] (32)N-(7-(Hydroxyamino)-7-oxoheptyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide;

[0049] (33)N-(4-(Hydroxyaminocarbonyl)benzyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide.

[0050] The preparation method of the above inhibitors is as follows: according to one of the preparation methods of the target compounds, using 4-methoxypropiophenone as raw material (1), raw material (1) undergoes a substitution reaction with chlorosulfonic acid at the 3rd position of the benzene ring to obtain intermediate (2); based on intermediate (2), an amino carboxylic acid methyl ester is introduced through a 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 undergoes a condensation reaction 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: .

[0051] The preparation method of the above inhibitor further includes, according to the preparation method of the target compound, using 4-methoxypropiophenone as raw material (1), and 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), through the Hinsberg reaction, methyl aminocarboxylate is introduced 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), and condenses with intermediate (4) to obtain intermediate (7); intermediate (7) undergoes an amide condensation with 4-fluoro-1,2-phenylenediamine to obtain the target compound (9). The preparation route is as follows: 。

[0052] The preparation method of the above inhibitor further includes, using methyl 5-formyl-2-methoxybenzoate as raw material (10), and obtaining intermediate (11) through two-step reactions; intermediate (11) undergoes a reduction reaction with iron powder by heating under reflux in acetic acid to obtain intermediate (12); intermediate (12) undergoes a hydrolysis reaction under acidic conditions to obtain intermediate (13); intermediate (13) is chlorinated with thionyl dichloride 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) condenses with N-substituted thiourea to obtain intermediate (17); intermediate (17) undergoes an amide condensation with hydroxylamine to obtain the target compound (18). The preparation route is as follows: 。

[0053] The present invention further provides a pharmaceutical composition, comprising at least one pharmaceutically acceptable excipient, adjuvant or carrier, and the above-mentioned phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor.

[0054] The present invention further provides the use of the phenylthiazolamine-based PI4KIIIβ / HDAC dual-target inhibitor or the pharmaceutical composition in the preparation of a drug for inhibiting the growth of hepatitis C virus, and simultaneously for preventing, treating or adjuvantly treating hepatitis C caused by HCV virus.

[0055] Since the inhibitory activity of the PI4KIIIβ target is not strong, the anti-hepatitis C virus effect is insufficient and there is no literature reporting a PI4KIIIβ / HDAC dual-target inhibitor, PIK-93 was selected as the lead compound for further structural modification. The present invention determines that phenylthiazolamine is used as the basic skeleton structure, and by screening substituents, the efficient inhibition of PI4KIIIβ and HDAC is achieved, thereby inhibiting the growth of HCV virus, and at the same time having less cytotoxicity, so it can potentially be used as a clinical therapeutic drug. Its beneficial effects are as follows: (1) It has the characteristics of effectively inhibiting the PI3K / Akt / mTOR signaling pathway of PI4KIIIβ and has excellent dual-enzyme inhibitory activity of PI4KIIIβ / HDAC; (2) It has low cost, good curative effect, low toxicity, and high yield of intermediate products in the synthesis process, reducing resource waste, and thus is beneficial to reducing costs; (3) It has high anti-hepatitis C virus activity and a small dosage. Detailed implementation manners

[0056] The technical solutions of the present invention will be further described below in conjunction with the embodiments.

[0057] The reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., J&K Scientific Ltd., Aladdin Reagent Co., Ltd., Beijing Coupling Technology Co., Ltd., etc., and were not further purified when used, unless otherwise indicated. General reagents were obtained from Xilong Chemical Co., Ltd., Nanjing Chemical Reagent Co., Ltd., Sinopharm Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Co., Ltd., etc. Unless otherwise indicated, all temperatures in the examples were in degrees Celsius.

[0058] In the following described embodiments, the chromatographic column used is a silica gel column, and the silica gel (200 - 300 mesh) was purchased from Qingdao Ocean Chemical Co., Ltd. Nuclear magnetic resonance spectra were recorded in Chloroform- d or DMSO- d 6 as the solvent (in ppm), with TMS (0 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0059] In the following-described embodiments, the low-resolution mass spectrometry (MS) data is applied to analysis through the G1329B autosampler and G4212B detector of an Agilent 6120 series LC-MS equipped with a G1311B quaternary pump and a G1316A column oven. The ESI source is applied to the LC-MS spectrometer.

[0060] In the following-described embodiments, for the convenience of description, some raw materials will be described by their abbreviations, and the corresponding full names are as follows: DCM is CH2Cl2, that is, dichloromethane; Chloroform- d and CDC13 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; DMSO- d 6 is hexadeuterated dimethyl sulfoxide; THF is tetrahydrofuran; NaCl is sodium chloride; Na2SO4 is sodium sulfate; CDI is N,N'-carbonyldiimidazole. Example 1

[0061] Synthesis of N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfamoyl)propanamide, the synthesis steps are as follows:

[0062] Step 1: Synthesis of 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride, structural formula: , Measure 10 mL of ClSO3H (132 mmol, 11.0 eq.) and add it to a 25 mL eggplant-shaped reaction flask, pre-cool it in an ice bath for 30 min, slowly add 2.02 g (12.0 mmol) of 4-methoxyphenylacetone dropwise to ClSO3H, react at room temperature for about 6 h, and monitor by TLC until all the raw materials are consumed. Slowly add the reaction solution dropwise to ice cubes to quench the unreacted ClSO3H, then extract the above aqueous solution with ethyl acetate solution (3x100 mL), collect the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (PE:EA = 4:1 - 2:1). Yellow solid, yield: 60%. 1 1H NMR (300 MHz, Chloroform- d ) δ 7.77 (s, 1H), 7.54 (d, J J = 2.3Hz, 1H), 7.52 (d, J J = 2.3 Hz, 1H), 3.77 (s, 4H), 2.26 (s, 5H).

[0063] Step 2: Synthesis of methyl 3-((2-methoxy-5-(2-oxopropyl)phenyl)sulfamoyl)propionate, structural formula: , Weigh 5 mmol of 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride and dissolve it in 20 mL of dichloromethane. Add 7.5 mmol of methyl 3-aminopropionate hydrochloride (1.5 eq.) and 1.52 g of triethylamine (3.0 eq.) to the reaction solution and stir at room temperature for 12 h until all of 2-methoxy-5-(2-oxopropyl)benzenesulfonyl chloride is consumed. After the reaction is completed, it is purified by flash column chromatography (PE:EA = 1:1). White solid, yield: 75%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.52 (dt, J J = 2.1, 1.0 Hz, 1H), 7.25 (ddt, J J = 8.4, 2.2, 1.1 Hz, 1H), 7.01– 6.93 (m, 2H), 3.82 (s, 3H), 3.78 (t, J J = 1.0 Hz, 2H), 3.64 (s, 3H), 3.15(q, J J = 6.3 Hz, 2H), 2.75 (t, J J = 6.2 Hz, 2H).

[0064] Step 3: Synthesis of methyl 3-((2-methoxy-5-(4-methyl-2-pentamido thiazol-5-yl)phenyl)sulfamoyl)propionate, structural formula: , Weigh 1 mmol of methyl 3-((2-methoxy-5-(2-oxopropyl)phenyl)sulfamoyl)propionate and dissolve it in 5 mL of tetrahydrofuran solution in a round-bottom flask. Under ice bath conditions, slowly add 10 mL of tetrahydrofuran solution containing 1.1 mmol of phenyltrimethylammonium tribromide to the above reaction solution. After the addition is completed, remove the ice bath and react at room temperature for 0.5 h until all the reactants are consumed. After purification (PE:EA = 1:1), the brominated product (methyl 3-((5-(1-bromoethyl)-2-methoxyphenyl)sulfamoyl)propionate) is obtained. Pale yellow oil, yield: 60%. ( 1 H NMR (300 MHz, Chloroform- d ) δ 7.95 – 7.91 (m, 1H), 7.45 – 7.39(m, 1H), 7.14 (d, J= 8.4 Hz, 1H), 7.06 (t, J = 6.7 Hz, 1H), 5.90 (d, J = 0.9Hz, 1H), 3.89 (s, 2H), 3.64 (s, 2H), 3.19 (q, J = 6.3 Hz, 2H), 2.66 (t, J =6.2 Hz, 2H)). After that, N-pivaloylthiourea was first prepared. 10 mmol of thiourea was dissolved in 30 mL of anhydrous toluene solution and placed in a 100 mL eggplant-shaped flask. 15 mmol of pivaloyl 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 the reaction solution was concentrated. The white solid N-pivaloylthiourea was obtained by column chromatography (PE:EA = 8:1), yield: 71% ( 1 H 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 eggplant-shaped flask, 10 mL of acetone solution was added, and then N-pivaloylthiourea (1.0 eq.) was added to the reaction solution. The temperature was raised to 60 °C and refluxed for 1 h. TLC was monitored until the intermediate was completely consumed (DCM:MeOH = 25:1), and then concentrated under vacuum and purified by column chromatography. White solid, yield: 60%. 1 H 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).

[0065] Step 4: Synthesis of N-Hydroxy-3-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)propanamide, with the structural formula as follows: , First, prepare 3-((2-methoxy-5-(4-methyl-2-pentanoylaminothiazol-5-yl)phenyl)sulfamoyl)propanoic acid. Weigh 5 mmol of methyl 3-((2-methoxy-5-(4-methyl-2-pentanoylaminothiazol-5-yl)phenyl)sulfamoyl)propionate and dissolve it in 10 mL of a mixed solution of methanol, tetrahydrofuran, and water (MeOH:THF:H2O = 2:2:1) in a 50 mL eggplant-shaped flask. Weigh 10 mmol of lithium hydroxide (2 eq.) and slowly add it dropwise to the reaction flask. Stir overnight at room temperature. After the reaction is completed, add the reaction solution to ice-salt water while it is still hot to precipitate a large amount of white solid. After drying, obtain the crude product of 3-((2-methoxy-5-(4-methyl-2-pentanoylaminothiazol-5-yl)phenyl)sulfamoyl)propanoic acid. Weigh 1 mmol of the crude product of 3-((2-methoxy-5-(4-methyl-2-pentanoylaminothiazol-5-yl)phenyl)sulfamoyl)propanoic acid and 1.5 mmol of PyBOP condensing agent (1.5 eq.) in a 25 mL reaction flask, add 6 mL of DMF solution, measure 590 µL of DIPEA (3.5 eq.) and add it to the reaction solution. Stir at room temperature for a few minutes, then add 0.14 g of hydroxylamine hydrochloride (2.0 eq.). React at room temperature for 6 h, monitor by TLC until all the intermediate is consumed (DCM:MeOH = 25:1), concentrate under vacuum, and purify by column chromatography. White solid, yield: 66%. 1 H NMR (300 MHz, DMSO- d 6) δ 11.23 (s, 2H), 10.49 (s,1H), 8.77 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.5, 2.4 Hz, 1H),7.33 (d, J = 8.7 Hz, 1H), 3.95 (s, 3H), 3.01 (t, J = 7.4 Hz, 2H), 2.34 (s,3H), 2.15 (t, J = 7.3 Hz, 2H), 1.24 (s, 9H). 13 C NMR (101 MHz, DMSO- d 6) δ177.18, 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

[0066] N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfamoyl)butanamide, with the structural formula as follows: , in Step 2 of Example 1, change methyl 3-aminopropionate hydrochloride to methyl 4-aminobutyrate hydrochloride, and other steps and operations are the same as in Example 1; white solid, yield: 35%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.85 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J J = 2.4 Hz, 1H), 7.67 (dd, J J = 8.6, 2.4 Hz, 1H), 7.43 (t, J J = 5.9 Hz, 1H), 7.32 (d, J J = 8.7 Hz, 1H), 3.94 (s, 3H), 2.80 (q, J J = 6.7 Hz, 2H), 2.34 (s, 3H), 1.95 (t, J J = 7.5 Hz, 2H), 1.60 (p, J J = 7.4 Hz, 2H), 1.24 (s, 9H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0067] N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)pentanamide, the structural formula is as follows: , change the fragment methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 5-aminovalerate hydrochloride, and other steps and operations are the same as in Example 1; white solid, yield: 36%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.85 (s, 1H), 10.32 (s, 1H), 8.68 (s,1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.40 (t, J =5.9 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 2.81 (q, J = 6.5 Hz,2H), 2.34 (s, 3H), 1.88 (t, J = 7.2 Hz, 2H), 1.52 – 1.31 (m, 4H), 1.24 (s,9H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0068] N-Hydroxy-6-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)hexanamide, the structural formula is as follows: , change the fragment methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 6-aminohexanoate hydrochloride, and other steps and operations are the same as in Example 1; white solid, yield: 39%.1 H NMR (300 MHz, DMSO- d 6) δ 11.84 (s, 1H), 10.33 (s, 1H), 8.67(s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.41 –7.27 (m, 2H), 3.94 (s, 3H), 2.80 (q, J = 6.5 Hz, 2H), 2.34 (s, 3H), 1.88 (t, J = 7.3 Hz, 2H), 1.38 (dp, J = 16.2, 7.4 Hz, 5H), 1.24 (s, 9H), 1.22 – 1.13(m, 1H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0069] N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)heptanamide, the structural formula is as follows: , in Step 2 of Example 1, change 3-aminopropionate methyl ester hydrochloride to 7-aminoheptanoate methyl ester hydrochloride, and other steps and operations are the same as in Example 1; white solid, yield: 38%. 1 H NMR (300 MHz, DMSO- d 6) δ 11.83 (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= 6.5 Hz, 2H), 2.34 (s, 3H), 1.89 (t, J = 7.3 Hz, 2H), 1.38 (dt, J =20.6, 6.9 Hz, 3H), 1.24 (s, 9H), 1.22 – 1.09 (m, 5H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0070] N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide, with the structural formula as follows: , replace methyl 3-aminopropionate hydrochloride in step 2 of Example 1 with methyl 4-aminomethylbenzoate hydrochloride, and the other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 H NMR (300 MHz, DMSO- d 6) δ 11.85 (s, 1H), 11.15(s, 1H), 9.00 (s, 1H), 8.04 (t, J = 6.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H),7.58 (t, J = 7.8 Hz, 3H), 7.26 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.7 Hz, 1H),4.14 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 2.32 (s, 3H), 1.25 (s, 9H). 13 C NMR(101 MHz, DMSO-d 6) 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

[0071] N-Hydroxy-4-(2-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfonamido)ethoxy)benzamide, with the structural formula as follows: , replace methyl 3-aminopropionate hydrochloride in step 2 of Example 1 with methyl 4-(2-aminoethoxy)benzoate hydrochloride, and the other steps and operations are the same as those in Example 1; white solid, yield: 49%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.83 (s, 1H), 11.05 (s, 1H), 8.92 - 8.87 (m, 1H), 7.76 (d, J J = 2.4 Hz, 1H), 7.71 - 7.60 (m, 4H), 7.26 (d, J J = 8.7 Hz, 1H), 6.87 - 6.80 (m, 2H), 4.00 (t, J J = 5.3 Hz, 2H), 3.90 (s, 3H), 3.27 (t, J J = 5.7 Hz, 2H), 2.33 (s, 3H), 1.25 (s, 9H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0072] N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-propionamidothiazol-5-yl)phenyl)sulfamoyl)butyramide, the structural formula is as follows: , change methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 4-aminobutyrate hydrochloride and pivaloyl chloride in step 3 to propionyl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 42%. 1 H NMR (300 MHz, DMSO- d 6) δ 11.03 (d, J J = 56.8 Hz, 2H), 9.82 (s, 1H), 8.85 (s, 1H), 7.72 (d, J J = 2.3 Hz, 1H), 7.66 (dd, J J = 8.6, 2.4 Hz, 1H), 7.30 (d, J J = 8.7 Hz, 1H), 3.93 (s, 3H), 2.80 (t, J J = 7.1 Hz, 2H), 2.42 (q, J J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.94 (t, J J = 7.5Hz, 2H), 1.59 (t, J J = 7.3 Hz, 2H), 1.09 (td, J J = 7.3, 2.6 Hz, 3H). 13 C NMR(101 MHz, DMSO- d 6) 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

[0073] N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-butyramidothiazol-5-yl)phenyl)sulfamoyl)butyramide, the structural formula is as follows: , change methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 4-aminobutyrate hydrochloride and pivaloyl chloride in step 3 to butyryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 44%.1 H NMR (300 MHz, DMSO- d 6) δ 12.09(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 = 8.7 Hz, 1H), 3.94 (s, 3H), 2.80 (q, J = 6.7 Hz, 2H),2.41 (t, J = 7.3 Hz, 2H), 2.33 (s, 3H), 1.95 (t, J = 7.4 Hz, 2H), 1.62 (qd, J = 7.3, 3.2 Hz, 4H), 0.90 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0074] N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-isobutyrylaminothiazol-5-yl)phenyl)sulfamoyl)butyramide, with the structural formula as follows: , replace methyl 3-aminopropionate hydrochloride in Step 2 of Example 1 with methyl 4-aminobutyrate hydrochloride and pivaloyl chloride in Step 3 with isobutyryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 H NMR (300 MHz, DMSO- d 6) 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 = 8.7 Hz, 1H), 3.94 (s, 3H), 2.76 (dt, J = 25.4, 7.0 Hz, 3H), 2.32 (s, 3H), 1.95 (t, J = 7.4 Hz, 2H), 1.59 (q, J = 7.2 Hz, 2H), 1.11 (dd, J = 7.0, 3.0 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0075] N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfamoyl)butyramide, the structural formula is as follows: , in step 2 of Example 1, change methyl 3-aminopropionate hydrochloride to methyl 4-aminobutyrate hydrochloride and pivaloyl chloride in step 3 to valeryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 43%. 1 H NMR (300 MHz, DMSO- d 6) δ 12.12 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.42 (t, J = 5.9 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H), 2.80 (q, J= 6.7 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.33(s, 3H), 1.95 (t, J = 7.4 Hz, 2H), 1.68 – 1.51 (m, 4H), 1.37 – 1.26 (m, 2H),0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0076] N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfamoyl)butyramide, the structural formula is as follows: , replace methyl 3-aminopropionate hydrochloride in step 2 of Example 1 with methyl 4-aminobutyrate hydrochloride and pivaloyl chloride in step 3 with isovaleryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.11 (s, 1H), 10.34 (s, 1H), 8.70 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.68(dd, J = 8.5, 2.4 Hz, 1H), 7.42 (t, J = 6.0 Hz, 1H), 7.31 (d, J = 8.7 Hz,1H), 3.94 (s, 3H), 2.80 (q, J = 6.8 Hz, 2H), 2.32 (d, J = 8.4 Hz, 5H), 2.08(m, J= 6.9 Hz, 1H), 1.95 (t, J = 7.4 Hz, 2H), 1.60 (m, J = 7.2 Hz, 2H), 0.92(d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0077] N-Hydroxy-4-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfamoyl)butyramide, with the structural formula as follows: , in Step 2 of Example 1, change 3-aminopropionate methyl ester hydrochloride to 4-aminobutyrate methyl ester hydrochloride and in Step 3, change pivaloyl chloride to hexanoyl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 46%. 1 H NMR (300 MHz, DMSO- d 6) δ 12.10 (s, 1H), 10.32 (s, 1H), 8.68 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.68(dd, J = 8.6, 2.4 Hz, 1H), 7.40 (t, J = 5.9 Hz, 1H), 7.31 (d, J = 8.6 Hz,1H), 3.94 (s, 3H), 2.80 (q, J = 6.7 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.33(s, 3H), 1.97 (d, J = 11.7 Hz, 2H), 1.60 (p, J = 7.2 Hz, 4H), 1.37 – 1.22 (m, J= 5.5 Hz, 4H), 0.87 (t, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0078] N-Hydroxy-3-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfamoyl)propanamide, with the structural formula as follows: ,

[0079] Replace the pivaloyl chloride in step 3 of Example 1 with valeryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 42%. 1 H NMR (300 MHz, DMSO- d 6) δ 12.14 (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 =6.8 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.33 (s, 3H), 2.14 (t, J = 7.4 Hz,2H), 1.58 (p, J = 7.4 Hz, 2H), 1.30 (m, J = 8.6, 7.9 Hz, 2H), 0.89 (t, J =7.3 Hz, 3H). 13 C NMR (101 MHz, 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

[0080] N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfamoyl)pentanamide, the structural formula is as follows: , change the fragment 3-aminopropionate methyl ester hydrochloride in step 2 of Example 1 to 5-aminovalerate methyl ester hydrochloride and pivaloyl chloride in step 3 to valeryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 40%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.10 (s, 1H), 10.31 (s, 1H), 8.66 (s, 1H), 7.73 (d, J J = 2.4 Hz, 1H), 7.67(dd, J J = 8.6, 2.4 Hz, 1H), 7.37 (t, J J = 5.9 Hz, 1H), 7.30 (d, J J = 8.7 Hz,1H), 3.94 (s, 3H), 2.80 (q, J J = 6.5 Hz, 2H), 2.43 (t, J J = 7.4 Hz, 2H), 2.32(s, 3H), 1.91 (dt, J J = 25.8, 7.3 Hz, 2H), 1.59 (p, J J = 7.5 Hz, 2H), 1.52 –1.36 (m, 2H), 1.39 – 1.20 (m, 4H), 0.87 (dt, J J = 12.6, 7.3 Hz, 3H). 13 C NMR(101 MHz, DMSO) δ171.85, 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

[0081] N-Hydroxy-6-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfamoyl)hexanamide, with the structural formula as follows: , change the fragment 3-aminopropionate methyl ester hydrochloride in step 2 of Example 1 to 6-aminohexanoate methyl ester hydrochloride and the pivaloyl chloride in step 3 to valeryl chloride, and the other steps and operations are the same as in Example 1; white solid, yield: 36%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.12 (s, 1H), 10.32 (s, 1H), 8.66 (s, 1H), 7.73 (d, J J = 2.4 Hz, 1H), 7.67(dd, J J = 8.6, 2.4 Hz, 1H), 7.39 – 7.27 (m, 2H), 3.94 (s, 3H), 2.79 (q, J J = 6.6 Hz, 2H), 2.43 (t, J J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.88 (t, J J = 7.4 Hz, 2H), 1.58 (p, J J = 7.5 Hz, 2H), 1.43 – 1.32 (m, 4H), 1.31 – 1.14 (m, 4H), 0.89(t, J J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ174.80, 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

[0082] N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide, with the structural formula as follows: , change the methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 4-aminomethylbenzoate hydrochloride and change the pivaloyl chloride in step 3 to valeryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 30%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.98 (s, 1H), 11.14 (s, 1H), 8.95 (s, 1H), 8.02 (s, 1H), 7.69 (d, J J = 2.3Hz, 1H), 7.58 (td, J J = 8.3, 2.1 Hz, 3H), 7.26 (d, J J = 8.1 Hz, 2H), 7.14 (d, J J = 8.7 Hz, 1H), 4.14 (s, 2H), 3.86 (s, 3H), 2.43 (t, J J = 7.4 Hz, 2H), 2.30 (s,3H), 1.59 (p, J J = 7.4 Hz, 2H), 1.38 – 1.24 (m, 2H), 0.89 (t, J J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ171.85, 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

[0083] N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-acetamidothiazol-5-yl)phenyl)sulfamoyl)heptanamide, the structural formula is as follows: , change the fragment 3-aminopropionate methyl ester hydrochloride in step 2 of Example 1 to 7-aminoheptanoate methyl ester hydrochloride and pivaloyl chloride in step 3 to acetyl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 50%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 8.8, 2.4 Hz, 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, 5.6 Hz, 2H), 2.53 (s, 3H), 2.33 (t, J = 7.5 Hz, 2H), 1.72 –1.58 (m, 5H), 1.41 (m, J = 3.7 Hz, 4H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0084] N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-propionamidothiazol-5-yl)phenyl)sulfamoyl)pentanamide, the structural formula is as follows: , change methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 5-aminovalerate hydrochloride and pivaloyl chloride in step 3 to propionyl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 44%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.95(s, 1H), 10.31 (s, 0H), 8.66 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (dd, J =8.6, 2.4 Hz, 1H), 7.37 (t, J = 6.0 Hz, 1H), 7.30 (dd, J = 8.7, 1.0 Hz, 1H),3.94 (d, J = 1.4 Hz, 3H), 2.81 (p, J = 6.3 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H),2.32 (s, 3H), 2.12 (t, J = 7.2 Hz, 1H), 1.94 – 1.83 (m, 1H), 1.62 (h, J = 7.4Hz, 2H), 1.48 (dt, J = 15.2, 7.7 Hz, 1H), 1.44 (s, 1H), 1.43 – 1.29 (m, 2H),0.90 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ172.54, 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

[0085] N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-butylamidothiazol-5-yl)phenyl)sulfamoyl)pentanamide, with the structural formula as follows: , change the fragment 3-aminopropionate methyl ester hydrochloride in step 2 of Example 1 to 5-aminovalerate methyl ester hydrochloride and change pivaloyl chloride in step 3 to butyryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 43%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.95 (s, 1H), 10.31 (s, 0H), 8.66 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.37 (t, J = 6.0 Hz, 1H), 7.30 (dd, J = 8.7, 1.0 Hz, 1H), 3.94 (d, J = 1.4 Hz, 3H), 2.81 (p, J = 6.3 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.12 (t, J = 7.2 Hz, 1H), 1.94 – 1.83 (m, 1H), 1.62 (h, J = 7.4Hz, 2H), 1.48 (dt, J = 15.2, 7.7 Hz, 1H), 1.44 (s, 1H), 1.43 – 1.29 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 1313C NMR (101 MHz, DMSO- d 6) 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

[0086] N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-butyramidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide, the structural formula is as follows: , in Step 2 of Example 1, change methyl 3-aminopropionate hydrochloride to methyl 4-aminomethylbenzoate hydrochloride and in Step 3, change pivaloyl chloride to butyryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 1H NMR (400 MHz, DMSO- d 6) δ 12.09 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.02 (t, J J = 6.4 Hz, 1H), 7.69 (d, J J = 2.4 Hz, 1H), 7.59 (ddd, J J = 9.9, 7.7, 2.0 Hz, 3H), 7.29 – 7.23 (m, 2H), 7.14 (d, J J = 8.7 Hz, 1H), 4.14 (d, J J = 6.2 Hz, 2H), 3.86 (s, 3H), 2.41 (t, J J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.63 (h, J J = 7.3 Hz, 2H), 0.91 (t, J J = 7.4 Hz, 3H). 13 13C NMR (101 MHz, DMSO- d 6) δ171.69, 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

[0087] N-Hydroxy-5-((2-methoxy-5-(4-methyl-2-isobutyramidothiazol-5-yl)phenyl)sulfamoyl)pentanamide, the structural formula is as follows: , in Step 2 of Example 1, change 3-aminopropionate methyl ester hydrochloride to 5-aminovalerate methyl ester hydrochloride, and in Step 3, change pivaloyl chloride to isobutyryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.08 (s, 1H), 10.31 (s, 1H), 8.66 (s, 1H), 7.73 (d, J J = 2.4 Hz, 1H), 7.67(dd, J J = 8.6, 2.4 Hz, 1H), 7.37 (t, J J = 5.8 Hz, 1H), 7.31 (d, J J = 8.7 Hz,1H), 3.94 (s, 3H), 2.81 (q, J J = 6.4 Hz, 2H), 2.73 (p, J J = 6.8 Hz, 1H), 2.33(s, 3H), 1.88 (t, J J = 7.3 Hz, 2H), 1.52 – 1.40 (m, 2H), 1.36 (q, J J = 7.2 Hz,2H), 1.12 (d, J J = 6.8 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ175.68, 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

[0088] N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfamoyl)heptanamide, the structural formula is as follows: , replace the fragment methyl 3-aminopropionate hydrochloride in step 2 of Example 1 with methyl 7-aminoheptanoate hydrochloride and replace pivaloyl chloride in step 3 with isovaleryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 H NMR (300 MHz, DMSO- d 6) δ 12.11 (s, 1H), 10.33 (s, 1H), 8.67 (s, 1H), 7.73 (d, J J = 2.4 Hz, 1H), 7.67(dd, J J = 8.6, 2.4 Hz, 1H), 7.42 – 7.26 (m, 2H), 3.94 (s, 3H), 2.80 (q, J J = 6.3 Hz, 2H), 2.75 – 2.65 (m, 1H), 2.32 (s, 3H), 1.99 (s, 1H), 1.89 (t, J J = 7.3 Hz, 2H), 1.39 (dq, J J = 21.2, 7.1 Hz, 3H), 1.26 – 1.14 (m, 5H), 1.12 (d, J J = 6.9 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ175.68, 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

[0089] N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide, with the structural formula as follows: , change the methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 4-aminomethylbenzoate hydrochloride and change the pivaloyl chloride in step 3 to isovaleryl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.08 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.03 (t, J J = 6.4 Hz, 1H), 7.69 (d, J J = 2.4 Hz, 1H), 7.61 (d, J J = 1.7 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.26 (d, J J = 8.3 Hz, 2H), 7.14 (d, J J = 8.7 Hz, 1H), 4.14 (d, J J = 5.7 Hz, 2H), 3.86 (s, 3H), 2.73 (p, J J = 6.8 Hz, 1H), 2.31 (s, 3H), 1.12 (d, J J = 6.8 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ175.67, 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

[0090] N-Hydroxy-3-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfamoyl)propanamide, with the structural formula as follows: , replace the pivaloyl chloride in step 3 of Example 1 with hexanoyl chloride, and the other steps and operations are the same as in Example 1; white solid, yield: 46%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.08 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.03 (t, J J = 6.4 Hz, 1H), 7.69 (d, J J = 2.4 Hz, 1H), 7.61 (d, J J = 1.7 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.26 (d, J J = 8.3 Hz, 2H), 7.14 (d, J J = 8.7 Hz, 1H), 4.14 (d, J J = 5.7 Hz, 2H), 3.86 (s, 3H), 2.73 (p, J J = 6.8 Hz, 1H), 2.31 (s, 3H), 1.12 (d, J J = 6.8 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0091] N-Hydroxy-6-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfonamido)hexanamide, the structural formula is as follows: , change the fragment methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 6-aminohexanoate hydrochloride and change pivaloyl chloride in step 3 to hexanoyl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 40%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.05 (s, 1H), 10.31 (s, 1H), 8.65 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67(dd, J = 8.6, 2.4 Hz, 1H), 7.38 – 7.27 (m, 2H), 3.94 (s, 3H), 2.80 (p, J =6.2 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.89 (t, J = 7.4 Hz,2H), 1.67 – 1.54 (m, 2H), 1.43 – 1.05 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H). 13 CNMR (75 MHz, DMSO- d 6) 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

[0092] N-Hydroxy-7-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfonamido)heptanamide, the structural formula is as follows: , change the fragment methyl 3-aminopropionate hydrochloride in step 2 of Example 1 to methyl 7-aminoheptanoate hydrochloride and change pivaloyl chloride in step 3 to hexanoyl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%.1 1H NMR (400 MHz, DMSO- d 6) δ 12.21 (s, 1H), 10.30 (s, 1H), 8.64 (s, 1H), 7.98 (s, 1H), 7.94 (d, J J =1.8 Hz, 1H), 7.71 (d, J J = 2.2 Hz, 2H), 2.89 (t, J J = 7.0 Hz, 2H), 2.44 (t, J J =7.4 Hz, 2H), 2.37 (s, 3H), 1.89 (t, J J = 7.4 Hz, 2H), 1.61 (p, J J = 7.3 Hz,2H), 1.45 – 1.32 (m, 4H), 1.32 – 1.08 (m, 6H), 0.87 (t, J J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, DMSO- d 6) 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

[0093] N-Hydroxy-4-(((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfamoyl)methyl)benzamide, the structural formula is as follows: , in step 2 of Example 1, change methyl 3-aminopropionate hydrochloride to methyl 4-aminomethylbenzoate hydrochloride and pivaloyl chloride in step 3 to hexanoyl chloride, and other steps and operations are the same as in Example 1; white solid, yield: 45%. 1 1H NMR (300 MHz,DMSO- d 6) δ 12.08 (s, 1H), 11.19 (s, 1H), 9.02 (s, 1H), 8.86 (t, J= 6.1 Hz, 1H), 7.79 – 7.68 (m, 3H), 7.56 (dd, J = 8.6, 2.5 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.7 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.60 (p, J = 7.4 Hz, 2H), 1.36 – 1.18 (m, 4H), 0.92 – 0.82 (m, 3H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0094] N-(2-Amino-4-fluorophenyl)-4-(((2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfonamido)methyl)benzamide, the structural formula is as follows: , replace methyl 3-aminopropionate hydrochloride in step 2 of Example 1 with methyl 4-aminomethylbenzoate hydrochloride, and replace hydroxylamine hydrochloride in step 4 with 4-fluoro-1,2-phenylenediamine, and other steps and operations are the same as in Example 1; white solid, yield: 28%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.45 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.98– 7.92 (m, 2H), 7.77 (dd, J = 7.9, 2.2 Hz, 1H), 7.67 (dd, J= 8.2, 5.0 Hz, 1H), 7.47 – 7.40 (m, 3H), 7.17 (d, J = 7.9 Hz, 1H), 6.86 – 6.75 (m, 2H), 4.84(s, 2H), 4.24 (dt, J = 7.2, 1.0 Hz, 2H), 3.90 (s, 3H), 1.14 (s, 9H). 13 C NMR(101 MHz, DMSO- d 6) 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

[0095] N-(7-(Hydroxyamino)-4-oxobutyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide:

[0096] Step 1: Synthesis of 2-methoxy-5-(2-oxopropyl)benzoic acid, with the structural formula as follows: , Dissolve 10 mmol of the raw material methyl 5-formyl-2-methoxybenzoate and butylamine (2.0 eq.) in toluene and reflux for 3 h. After distilling to dryness under reduced pressure, dissolve it in 10 mL of acetic acid. Slowly add 1.14 mL of nitroethane (1.5 eq.) to the reaction solution, and heat the mixture to 100 °C for 3 h. After the reaction is completed, cool the reaction solution to room temperature and slowly pour it into 40 mL of ice water solution (stir vigorously throughout the process). Extract the mixture with ethyl acetate solution (2 x 40 mL), collect the organic phase, and wash the organic phase with water (2 x 40 mL), 10% sodium bicarbonate solution (2 x 30 mL), and brine in sequence. Dry over anhydrous magnesium sulfate and purify by column chromatography (PE:EA = 2:1) to obtain ( Z) Methyl 2-methoxy-5-(2-nitroprop-1-en-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, a 12 mL acetic acid solution containing (Z)-methyl 2-methoxy-5-(2-nitroprop-1-en-1-yl)benzoate (8 mmol) was slowly added dropwise to the above reactor. After refluxing for 2 h, the reaction solution was cooled to room temperature, the 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), dried over anhydrous magnesium sulfate, and 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 obtain white solid 2-methoxy-5-(2-oxopropyl)benzoic acid, yield: 95% (using 1.0 mL of hydrochloric acid solution (a mixed solution of 1 mol / L and 4 mL of acetic acid) as the acid hydrolysis solution). 1 H NMR (400 MHz, DMSO- d 6) δ 12.58 (s, 1H), 7.46(d, J = 2.3 Hz, 1H), 7.30 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (d, J = 8.6 Hz,1H), 3.80 (s, 3H), 3.75 (s, 2H), 2.13 (s, 3H).

[0097] Step 2: Synthesis of methyl 4-(5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamido)butyrate, the structural formula is as follows: , 2-methoxy-5-(2-oxopropyl)benzoic acid (1 mmol) and CDI (1 mmol) 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 and purified, methyl 4-(2-methoxy-5-(2-oxopropyl)benzamido)butyrate was obtained; then according to Step 3 in Example 1, pivaloyl chloride in Step 3 was changed to hexanoyl chloride, and white solid methyl 4-(5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamido)butyrate could be obtained, yield: 60%. 1 H NMR (400 MHz, DMSO- d 6)δ 8.42 (d, J J = 2.2 Hz, 1H), 7.80 (t, J J = 5.0 Hz,1H), 7.69 (dd, J J = 8.0, 2.3 Hz, 1H), 7.07 (d, J J = 7.9 Hz, 1H), 3.93 (s, 2H),3.64 (s, 2H), 3.39 – 3.32 (m, 2H), 2.47 (s, 2H), 2.42 (t, J J = 8.0 Hz, 2H),2.31 (t, J J = 8.4 Hz, 2H), 1.88 (tt, J J = 8.4, 5.8 Hz, 2H), 1.67 – 1.57 (m,2H), 1.39 – 1.25 (m, 4H), 0.92 – 0.86 (m, 3H).

[0098] Step 3: Synthesis of N-(7-(hydroxyamino)-4-oxobutyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide, the structural formula is as follows: , according to Step 4 in Example 1, first prepare 4-(5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamidoyl)butyric acid. Weigh 5 mmol of methyl 4-(5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamidoyl)butyrate and dissolve it in a mixed solution of 10 mL of methanol, tetrahydrofuran, and water (MeOH:THF:H2O = 2:2:1) in a 50 mL eggplant-shaped flask. Weigh 10 mmol of lithium hydroxide (2 eq.) and slowly add it dropwise to the reaction flask. Stir at room temperature overnight. After the reaction is completed, add the reaction solution to ice-saline while it is hot to precipitate a large amount of white solid. After drying, obtain the crude product of 4-(5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamidoyl)butyric acid. Weigh 1 mmol of the crude product and 1.5 mmol of PyBOP condensing agent (1.5 eq.) in a 25 mL reaction flask, add 6 mL of DMF solution, measure 590 µL of DIPEA (3.5 eq.) and add it to the reaction solution. Stir at room temperature for a few minutes, then add 0.14 g of hydroxylamine hydrochloride (2.0 eq.). React 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 1H NMR (300 MHz,DMSO-d 6) δ 12.06 (s, 1H), 10.41 (s, 1H), 8.72 (s, 1H), 8.28 (t, J J = 5.7 Hz,1H), 7.72 (d, J J = 2.5 Hz, 1H), 7.53 (dd, J J = 8.6, 2.5 Hz, 1H), 7.21 (d, J J =8.7 Hz, 1H), 3.92 (s, 3H), 3.27 (q, J J = 6.6 Hz, 2H), 2.41 (t, J J = 7.4 Hz,2H), 2.32 (s, 3H), 2.02 (t, J J = 7.5 Hz, 2H), 1.74 (p, J J = 7.3 Hz, 2H), 1.60(p, J J = 7.5 Hz, 2H), 1.27 (td, J J = 6.4, 3.3 Hz, 4H), 0.92 – 0.82 (m, 3H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0099] N-(7-(Hydroxyamino)-7-oxoheptyl)-5-(2-isobutyramido-4-methylthiazol-5-yl)-2-methoxybenzamide, the structural formula is as follows: , in step 2 of Example 30, change methyl 3-aminopropionate hydrochloride to methyl 7-aminoheptanoate hydrochloride and change hexanoyl chloride in step 3 to isovaleryl chloride, and other steps and operations are the same as in Example 30. White solid, yield: 46%. 1 H NMR (400 MHz, DMSO- d 6) δ11.80 (s, 1H), 10.34 (s, 1H), 8.66 (s, 1H), 8.21 (t, J J = 5.7 Hz,1H), 7.71 (d, J J = 2.5 Hz, 1H), 7.52 (dd, J J = 8.6, 2.5 Hz, 1H), 7.21 (d, J J =8.7 Hz, 1H), 3.91 (s, 3H), 3.27 (dt, J J = 13.2, 6.8 Hz, 2H), 2.73 (p, J J = 6.9Hz, 1H), 2.32 (s, 3H), 2.04 – 1.91 (m, 2H), 1.50 (ddt, J J = 9.8, 7.3, 4.6 Hz,4H), 1.29 (dt, J J = 9.5, 6.2 Hz, 4H), 1.12 (d, J J = 6.9 Hz, 6H). 13 C NMR (101MHz, DMSO- d 6) 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

[0100] N-(7-(Hydroxyamino)-7-oxoheptyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide, the structural formula is as follows: , in step 2 of Example 30, change methyl 3-aminopropionate hydrochloride to methyl 7-aminoheptanoate hydrochloride, and other steps and operations are the same as in Example 30. White solid, yield: 40%. 1 H NMR (300 MHz, DMSO- d 6) δ 12.06 (s, 1H), 10.36(s, 1H), 8.69 (s, 1H), 8.22 (t, J= 5.7 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H),7.53 (dd, J = 8.6, 2.5 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.33– 3.19 (m, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.95 (t, J = 7.3 Hz,2H), 1.49 (d, J = 7.2 Hz, 4H), 1.31 – 1.21 (m, 10H), 0.92 – 0.80 (m, 3H). 13 C NMR (101 MHz, DMSO- d 6) 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

[0101] N-(4-(Hydroxycarbamoyl)benzyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide, the structural formula is as follows: , in Step 2 of Example 30, change methyl 3-aminopropionate hydrochloride to methyl 4-(aminomethyl)benzoate hydrochloride, and other steps and operations are the same as in Example 30. White solid, yield: 51%. 1 H NMR (300 MHz, DMSO- d 6) δ 12.08 (s, 1H), 11.19(s, 1H), 9.02 (s, 1H), 8.86 (t, J = 6.1 Hz, 1H), 7.79 – 7.68 (m, 3H), 7.56(dd, J = 8.6, 2.5 Hz, 1H), 7.40 (d, J= 8.2 Hz, 2H), 7.25 (d, J = 8.7 Hz,1H), 4.55 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H), 2.32(s, 3H), 1.60 (p, J = 7.4 Hz, 2H), 1.36 – 1.18 (m, 4H), 0.92 – 0.82 (m, 3H). 13 C NMR (101 MHz, DMSO- d 6) 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.

[0102] The beneficial effects and applications of the compounds represented by the general formula (I) of the present invention are illustrated by the following experiments.

[0103] The PI4KIIIβ kinase inhibition experiment was carried out for the inhibitor of the present invention:

[0104] Tested by the ADP-Glo Luminescent Kinase Assay method, the reagents used in 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 containing different concentrations of the test compound (0.05 nM - 1.0 μM). The reaction system was incubated at room temperature for 1 h, and then 10 μL of the reagent ADP-Glo was added to terminate the enzyme reaction. Data collection was performed using Envision software, and the IC 50 value of the compound was analyzed and fitted using Graphpad Prism 5.

[0105] Example PI4KIIIβ Example PI4KIIIβ Example PI4KIIIβ Example 1 42 Example 13 3.2 Example 26 29 Example 2 25 Example 15 6.1 Example 27 7.6 Example 3 47 Example 17 13 Example 28 24 Example 4 56 Example 18 75 Example 29 245 Example 5 64 Example 19 75 Example 30 17 Example 6 173 Example 20 18 Example 31 39 Example 7 154 Example 21 42 Example 32 14 Example 8 57 Example 22 44 Example 33 22 Example 9 14 Example 23 204 PIK93 17 Example 10 7.3 Example 24 81 PIK93-10 6.8 Example 11 2.3 Example 25 3.7 , as shown in Table 1, the compounds of the present invention have nanomolar-level inhibitory activity against the PI4KIIIβ kinase, and some compounds are significantly superior to the positive control PIK-93. In particular, the inhibitory activities of Examples 11, 13, and 25 against the PI4KIIIβ kinase are superior to the positive control PIK-93. This shows that the compounds of some embodiments of the present invention are highly efficient PI4KIIIβ inhibitors.

[0106] An HDAC1 kinase inhibition experiment was conducted on the inhibitor of the present invention:

[0107] Using the HDAC1 fluorescence detection kit (Cat#50051) from BPS company, the HDAC1 inhibitory activities of the compounds of the examples were tested by fluorescence labeling method (Fluorescence assay). The experimental steps are as follows: (1) Prepare 1x assay buffer (modified Tris buffer); (2) Dilution of the compound: Transfer the compound to the assay plate in 100% DMSO by Echo. The final fraction of DMSO is 1%; (3) Preparation of the enzyme solution: Prepare the enzyme solution in 1x detection buffer; (4) Preparation of the substrate solution: Add trypsin and Ac-peptide substrate to 1x detection buffer to make the substrate solution; (5) Transfer 15 μL of the enzyme solution to the detection plate, or transfer 15 μL of 1x detection buffer for the low control. Incubate at room temperature for 15 min. Add 10 μL of the substrate solution to each well to start the reaction; (6) Data collection was performed using Envision software, and the IC 50 value of the compound was analyzed and fitted using Graphpad Prism 5.

[0108] Example HDAC1 Example HDAC1 Example HDAC1 Example 1 809 Example 13 16 Example 26 5.4 Example 2 25 Example 15 114 Example 27 77 Example 3 119 Example 17 >1000 Example 28 478 Example 4 70 Example 18 58 Example 29 >2000 Example 5 53 Example 19 131 Example 30 26 Example 6 902 Example 20 240 Example 31 53 Example 7 640 Example 21 627 Example 32 218 Example 8 24 Example 22 136 Example 33 48 Example 9 20 Example 23 4.1 Vorinostat 17 Example 10 12 Example 24 462 Tucidinostat 122 Example 11 11 Example 25 463 , as shown in Table 2, some compounds of the present invention have nanomolar-level inhibitory activity against HDAC1, and some compounds are significantly superior to the positive control Vorinostat. In particular, the inhibitory activities of Examples 10, 11, 13, 23, and 26 against the HDAC1 kinase are superior to the positive control Vorinostat. This shows that the compounds of some embodiments of the present invention are highly efficient HDAC inhibitors.

[0109] Combining the experimental data in Table 1 and Table 2 and analyzing and comparing, it can be obtained that Example 11 has the best kinase inhibitory activities against both PI4KIIIβ and HDAC1, which are 2.3 nM and 1 nM respectively. For this, a kinase selectivity experiment was conducted on Example 11, and the experimental method was the same as above. The results of the inhibitory activities of the kinase subtypes of the examples are shown in Tables 3 and 4.

[0110] Example PI4KIIIβ PI3Kα PI3Kδ PI3Kγ hVPS34 Example 11 2.3 542 47.8 1091 >5000 ,

[0111] Example HDAC1 HDAC2 HDAC3 HDAC4 HDAC5 HDAC6 Example 11 11 17 20 >5000 >5000 23 Example HDAC7 HDAC8 HDAC9 HDAC10 HDAC11 Example 11 >5000 >1000 >5000 75 >5000 , Combining the experimental data in Table 3 and Table 4, it can be analyzed that Example 11 has the best inhibitory activity against PI4KIIIβ, with an IC50 value reaching 2.3 nM, and can also inhibit the activity of PI3Kδ, with an IC 50 value of 47.8 nM. At the same time, Example 11 is also a broad-spectrum HDAC inhibitor, with good inhibitory activity against HDAC1, 2, 3, 6, and 10, and the IC 50 values are 11, 17, 20, 23, and 75 nM respectively.

[0112] An anti-HCV virus activity test experiment was carried out on the inhibitor of the present invention. The experimental method is as follows:

[0113] (1) Sample treatment: The sample to be tested for activity was dissolved in DMSO and then filtered through a 0.22 μm

[0114] membrane filter to remove bacteria. The original drug concentration was 20 mg / mL.

[0115] (2) Cell culture: Take out the human hepatoma cell line Huh-7.5.1 cells frozen in liquid nitrogen, immerse them in a 37 °C water bath, and shake to melt them as soon as possible (aspirate the cell suspension in a centrifuge tube within 1 min, add 5 mL of culture medium, centrifuge at 1000 rpm for 5 min, and discard the supernatant. Then add about 3-4 mL of culture medium, mix well, and inoculate it into a 25 cm 2 culture flask, and place it in a CO2 incubator for culture. Change the culture medium the next day. Passage the cells every three days. Change the medium and observe the cells one day before the experiment to make the cells in the exponential growth phase in good condition.

[0116] (3) Virus culture: Add J6 / JFH1 virus solution to the Huh-7.5.1 cell culture flask in the exponential growth phase, incubate for 5-8 h, discard the supernatant, change to fresh medium, change the medium for the cells every two days, discard the medium after 6 days, then add about 15 mL of medium and culture until the 7th day, centrifuge at 3000 rpm / min for 10 min, collect the clarified culture fluid, and aliquot and store it at -80 °C.

[0117] (4)Detection method: MTT method. Take Huh-7.5.1 cells in the logarithmic growth phase, digest them with 0.25% trypsin, then centrifuge at 1000 rpm / min for 3 min, count the cells with a hemocytometer, adjust the cell concentration to 9×104 cells / mL, and seed them in 96-well plates (100 μL / well). Incubate the plates in a 37 °C, 5% CO2 incubator. After 5 h of cell attachment, add drugs diluted with DMSO in gradients. There are a total of 8 dilution gradients, and three replicate wells are set for each gradient. At the same time, set up blank controls (containing only medium), DMSO controls, cell controls, positive drug controls, and drug color controls to make the final volume of the medium 200 μL / well. Place the culture plates in a 37 °C, 5% CO2 incubator for culture. On the third day, add 20 μL of 5 mg / mL MTT solution to the experimental wells, incubate at 37 °C and 5% CO2 for 4 h, discard the supernatant, add 100 μL / well of DMSO, shake and dissolve for 10 min, and then measure the OD 490 value on an enzyme-linked immunosorbent assay (ELISA) reader. Calculate the IC 50 value of the drug using the software GraphPad Prism 5.0. (IC 50 : half maximal inhibitory concentration, which is the concentration required to inhibit cell growth by 50%). (HCV replication inhibition rate formula = (OD Control - ODDrug) / (OD Control - OD Blank)×100%).

[0118] Example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 <![CDATA[CC 50 (μM)]]> 61.74 8.38 64.33 120.1 49.31 77.04 38.44 <![CDATA[IC 50 (nM)]]> - 18.41 - 59.96 - 1267 6027 SI - 455.13 - 2003 - 60.81 6.38 Example Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 <![CDATA[CC 50 (μM)]]> 106.1 90.56 110.23 89.41 70.12 35.63 74.46 <![CDATA[IC 50 (nM)]]> 614.4 - 31634 537 3594 419.9 24530 SI 172.69 - 3.48 166.5 19.51 84.85 3.04 Example Example 15 Example 16 Example 30 Example 31 Example 32 Example 33 PIK93-10 <![CDATA[CC 50 (μM)]]> 123.5 31.94 5.32 112.9 1.74 0.37 42.63 <![CDATA[IC 50 (nM)]]> - - - 46.41 - 188.9 529.3 SI - - - 2432.67 - 1.96 80.54 , where CC 50 represents the half cytotoxic concentration of the cells, which is the drug concentration that causes 50% morphological changes in the cells. IC 50 represents the half maximal effective concentration, which is the drug concentration that reduces the virus infection rate by 50%. SI represents selectivity, which is equal to the ratio of CC 50 to IC 50 and is used to evaluate the therapeutic potential of the drug. The higher the SI value, the stronger the anti-HCV virus efficacy of the drug. "-" indicates that the initial screening at 10 μM has no inhibitory effect on HCV or the IC 50 value cannot be fitted.

[0119] As can be seen from Table 5, some embodiments of the present invention have a high level of inhibitory activity against HCV virus proliferation and low cytotoxicity. Among them, Example 2 has an inhibitory effect on HCV virus reaching 18.41 nM. In particular, the SI values of Examples 4 and 31 are greater than 2000, and the CC 50 value is greater than 100 μM, and the IC 50The value is below 60 nM, significantly better than the positive control PIK93-10. Thus, it can be seen that the compounds of some embodiments of the present invention can potentially be used in the clinical treatment of anti-HCV.

[0120] In addition to the above embodiments, the present invention can also have other embodiments. All technical solutions formed by equivalent replacement or equivalent transformation fall within the protection scope required by the present invention.

Claims

1. A phenylthiazolamide PI4KIIIβ / HDAC dual-target inhibitor, characterized in that: The inhibitor is one of the following, (2) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)butyramide; (4) N-hydroxy-6-((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)hexanamide; (6) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)methyl)benzamide; (7) N-hydroxy-4-(2-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfonylamino)ethoxy)benzamide; (8) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-propionamidothiazol-5-yl)phenyl)sulfonamido)butyramide; (10) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isobutyramidothiazol-5-yl)phenyl)sulfonamido)butyramide; (11) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfonamido)butanamide; (12) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfonamido)butyramide; (13) N-hydroxy-4-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfonamido)butyramide; (14) N-hydroxy-3-((2-methoxy-5-(4-methyl-2-pentanamidothiazol-5-yl)phenyl)sulfonamido)propanamide; (18) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-acetamidothiazol-5-yl)phenyl)sulfonamido)heptylamide; (19) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-propionamidothiazol-5-yl)phenyl)sulfonamido)pentanamide; (20) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-butyramidothiazol-5-yl)phenyl)sulfonamido)pentanamide; (21) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-butyrylthiazol-5-yl)phenyl)sulfonamido)methyl)benzamide; (22) N-hydroxy-5-((2-methoxy-5-(4-methyl-2-isobutyramidothiazol-5-yl)phenyl)sulfonamido)pentanamide; (23) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfonamido)heptylamide; (24) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-isovaleramidothiazol-5-yl)phenyl)sulfonamido)methyl)benzamide; (25) N-hydroxy-3-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfonamido)propionamide; (26) N-hydroxy-6-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfonamido)hexanamide; (27) N-hydroxy-7-((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfonamido)heptylamide; (28) N-hydroxy-4-(((2-methoxy-5-(4-methyl-2-hexanamidothiazol-5-yl)phenyl)sulfonamido)methyl)benzamide; (31) N-(7-(Hydroxyamino)-7-oxoheptyl)-5-(2-isobutyramido-4-methylthiazol-5-yl)-2-methoxybenzamide; (33) N-(4-(Hydroxycarbamoyl)benzyl)-5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamide.

2. The method for preparing the phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor according to claim 1, characterized in that: The target compound 8 was prepared according to the following steps: 4-methoxyphenylpropiotone was used as raw material 1, and raw material 1 was substituted with chlorosulfonic acid at the 3rd position of the benzene ring to obtain intermediate 2; on the basis of intermediate 2, aminocarboxylic acid methyl ester was introduced through Hinsberg reaction to obtain intermediate 3; intermediate 3 was α-brominated with phenyltrimethylammonium tribromide to obtain intermediate 4; thiourea 5 was reacted with acyl chloride to obtain N-substituted thiourea 6, which was condensed with intermediate 4 to obtain intermediate 7; intermediate 7 was amide condensed with hydroxylamine to obtain the target compound 8. The preparation route is as follows: The target compound 8 is the compound (2), (4), (6), (7), (8), (10)-(14), (18)-(28) according to claim 1, R 6、 Y is a substituent corresponding to the above compound.

3. The method for preparing the phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor according to claim 1, characterized in that: The target compound 18 is prepared according to the following steps. 5-formyl-2-methoxybenzoic acid methyl ester is used as raw material 10, and intermediate 11 is obtained through two-step reaction; intermediate 11 is heated to reflux in acetic acid and reacted with iron powder for reduction reaction to obtain intermediate 12; intermediate 12 is hydrolyzed under acidic conditions to obtain intermediate 13; intermediate 13 is chlorinated with dichloride to generate intermediate 14; intermediate 14 is reacted with aminocarboxylic acid methyl ester to obtain intermediate 15; intermediate 15 is reacted with phenyltrimethylammonium tribromide to obtain intermediate 16 by α-bromination reaction; intermediate 16 is reacted with N-substituted thiourea by condensation reaction to obtain intermediate 17; intermediate 17 is reacted with hydroxylamine by amide condensation to obtain target compound 18. The preparation route is as follows: The target compound 18 is the compound (31) or (33) according to claim 1, R 6、 Y is a substituent corresponding to the above compound.

4. A pharmaceutical composition, characterized in that: The composition comprises at least one pharmaceutically acceptable excipient, auxiliary agent or carrier, and the phenylthiazolamine PI4KIIIβ / HDAC dual-target inhibitor according to claim 1.

5. Use of the phenylthiazolamide PI4KIIIβ / HDAC dual-target inhibitor according to claim 1 or the pharmaceutical composition according to claim 4 in the preparation of a drug for inhibiting the growth of hepatitis C virus.

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