Phenylthiazolamine-based PI4KIIIβ inhibitor, preparation method therefor, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention is a phenylthiazolamine-based PI4KIIIβ inhibitor. The inhibitor is a substituted phenylthiazoleamine-based compound represented by general formula V, or a stereoisomer, hydrate, or pharmaceutically acceptable salt thereof. The inhibitor has the characteristic of effectively inhibiting a PI3K / Akt / mTOR signaling pathway of PI4KIII β, and has efficient and excellent PI4KIII β enzyme inhibitory activity, low costs, high efficacy, low toxicity, and a high yield of an intermediate product during synthesis, reducing resource waste, thus facilitating cost reduction; and the inhibitor has a small dosage requirement and significant activity when applied to anti-tumor drugs.

Description

A phenylthiazolamine PI4KIIIβ inhibitor, preparation method, pharmaceutical composition and application thereof Technical Field

[0001] The present invention relates to a phenylthiazolamine PI4KIIIβ inhibitor, and also relates to a preparation method, a pharmaceutical composition and application of the inhibitor, belonging to the field of medical technology. Background Art

[0002] Traditional treatments for malignant tumors primarily include surgery, chemotherapy, and radiotherapy. While surgery is a preferred approach, it is not ideal for prolonging life without other adjuvant therapies. Chemotherapy can lead to drug resistance and side effects, most commonly bone marrow suppression and intestinal dysfunction. Radiotherapy is a localized treatment that can inhibit tumor growth but can also affect and damage surrounding tissues. Molecularly targeted therapy has become a new approach to cancer treatment due to its high specificity and low toxicity.

[0003] The lipid phosphatidylinositol is an essential regulator of numerous cellular processes, including signaling, membrane trafficking, and cytokinesis. Phosphatidylinositol is produced by phosphorylation of the inositol ring of phosphatidylinositol. Phosphatidylinositol can be phosphorylated and dephosphorylated by a diverse set of enzymes, resulting in a total of seven different mono- and multiply-phosphorylated phosphatidylinositols. The lipid species phosphatidylinositol 4-phosphate (PI4P) is produced by the action of phosphatidylinositol 4-kinases (PI4Ks). PI4P is the primary biosynthetic pathway for the multiply-phosphorylated signaling lipids phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate (PIP3). In mammals, there are four distinct PI4K enzymes: two type II enzymes (PI4KIIα and PI4KIIβ) and two type III enzymes (PI4KIIIα and PI4KIIIβ).

[0004] PI4KIIIβ is a peripheral membrane protein primarily localized to the Golgi apparatus and the trans-Golgi network (TGN). It plays a key role, along with Rab GTPases, in mediating lipid transport, cytokinesis, maintaining lysosomal identity, and regulating membrane trafficking. Dysregulation of PI4KIIIβ has also been implicated in cancer. PI4KIIIβ is frequently amplified and oncogenically activated in tumors, and its expression can inhibit cancer cell apoptosis. Loss of the PI4KIIIβ isoform induces apoptosis in cancer cells. Although PI4KIIIβ has been identified as a novel cancer driver, few studies have investigated specific PI4KIIIβ inhibitors for cancer therapy. To date, several small-molecule PI4KIIIβ inhibitors have been identified as potent antiviral drug candidates in preclinical studies. Numerous studies have demonstrated the medicinal potential of PI4KIIIβ inhibitors, but considerably less attention has been paid to exploring PI4KIIIβ inhibitors as chemotherapeutic agents for cancer treatment. Therefore, developing a new class of PI4KIIIβ inhibitors and exploring their application in cancer therapy is a significant and valuable endeavor.

[0005] Summary of the Invention

[0006] Purpose of the invention: The purpose of the present invention is to provide a highly active phenylthiazolamine PI4KIIIβ inhibitor, and also provide a preparation method, pharmaceutical composition and application of the above inhibitor.

[0007] The phenylthiazolamine PI4KIIIβ inhibitor of the present invention is a substituted phenylthiazolamine compound represented by general formula V, or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof: Among them, A is

[0008] R1 is a substituent on the phenyl ring selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy or C1-C6 alkoxy C1-C6 alkyl; R2 is R3 or R4 is C1-C6 alkyl, C1-C6 alkyl containing one or more substituents, C1-C6 alkoxy, C1-C6 alkoxy containing one or more substituents, C1-C6 alkylacyl, C1-C6 alkylsulfonyl, C3-C6 heterocyclyl, or C3-C6 heterocyclyl containing one or more substituents;

[0009] X is a sulfone group or a carbonyl group.

[0010] Preferably, the inhibitor is a compound represented by formula I or II: Wherein, R1, R2, R4 and X are as defined above; R3 is Preferably, in the inhibitor of formula V, the hydrogen attached to carbon is replaced by deuterium, an isotope of hydrogen.

[0011] 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.

[0012] Preferably, a pharmaceutically acceptable salt refers to a salt form in which a basic group in the parent compound is converted; wherein the pharmaceutically acceptable salt is an inorganic or organic acid salt of a basic group, more preferably an amine or amino group; the basic group in the parent compound reacts with 1 to 4 equivalents of an acid in a solvent system.

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

[0014] Preferably, the compounds and pharmaceutically acceptable salts of the present invention also include solvate or hydrate forms.

[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 R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers.

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

[0017] (1) tert-Butyl (2-(5-(2-acetylamino-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethyl)carbamate;

[0018] (2) N-(5-(4-chloro-3-(N-(2-hydroxy-2-methylpropyl)aminosulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide;

[0019] (3) N-(2-(2-acetylamino-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethylpropionamide;

[0020] (4) methyl (2-(2-acetylamino-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethylcarbamate;

[0021] tert-Butyl (5)(2-((5-(2-acetylamino-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonamido)ethyl)carbamate;

[0022] (6) N-(5-(4-chloro-3-(N-(3-hydroxy-4-methylphenyl)aminosulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide;

[0023] (7) N-(5-(3-(N-(2,4-difluorophenyl)aminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)acetamide;

[0024] (8) tert-Butyl (5-(2-propionamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate;

[0025] (9) tert-Butyl (5-(2-butyramido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate;

[0026] (10) tert-Butyl (5-(2-pentanamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate;

[0027] (11) tert-Butyl (5-(2-hexanoylamino-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate;

[0028] (12) tert-Butyl (5-(2-heptylamino-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate;

[0029] (13) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(3-propylureido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate;

[0030] (14) tert-butyl (2-(5-(2-(3-butylureido)-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethyl)carbamate;

[0031] (15) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(3-methylbutanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate;

[0032] (16) tert-Butyl (5-(2-isobutyramido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate;

[0033] (17) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)ethylcarbamate;

[0034] (18) tert-Butyl (5-(2-(3,3-dimethylbutanamido)-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate;

[0035] (19) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(4-methylpentanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate;

[0036] (20) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(5-methylhexanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate

[0037] (21) tert-Butyl (2-(5-(2-(cyclohexanecarboxamido)-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonamido)ethylcarbamate;

[0038] (22) tert-Butyl (2-(2-chloro-5-(4-methyl-2-(3-methylbutanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate;

[0039] (23) tert-Butyl (2-chloro-5-(2-(3,3-dimethylbutanamido)-4-methylthiazol-5-yl)phenylsulfonamido)ethylcarbamate;

[0040] (24) tert-Butyl (2-chloro-5-(4-methyl-2-pentanamido-5-yl)phenylsulfonamido)ethylcarbamate;

[0041] (25) tert-Butyl (2-chloro-5-(2-hexanoylamino-4-methylthiazol-5-yl)phenylsulfonamido)ethylcarbamate;

[0042] (26) tert-Butyl (2-(5-(2-(3-acetamidopropionamido)-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonamido)ethylcarbamate;

[0043] (27) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(6-oxoheptamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate;

[0044] (28) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(6-oxohexanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate;

[0045] (29) tert-Butyl (R)-(1-((5-(2-hexanoylamino-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonyl)piperidin-3-yl)carbamate;

[0046] (30) tert-Butyl (S)-(1-((5-(2-hexamethyleneimino-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonyl)pyrrolidin-3-yl)carbamate;

[0047] (31) tert-Butyl 4-((2-hexanoyl-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)piperidine-1-carboxylate;

[0048] (32) N-(5-(3-(2-(3,3-dimethylbutanamide)ethylaminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0049] (33) N-(5-(3-(2-hydroxy-2-methylpropyl)aminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-ylhexanamide;

[0050] (34) N-(5-(3-(N-(2-Phenyloylethyl)aminosulfonyl))-4-methoxyphenyl)-4-methylthiazol-2-ylhexanamide;

[0051] (35) N-(5-(3-(((4-fluorophenyl)-12-nitrogenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0052] (36) N-(5-(3-(((4-chlorophenyl)-12-nitrophenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0053] (37) N-(5-(3-(((4-fluorobenzyl)-12-nitro-1-yl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0054] (38) N-(5-(3-(((3-fluorobenzyl)-12-nitro-1-yl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0055] (39) N-(5-(3-(((2-fluorobenzyl)-12-nitro-1-yl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0056] (40) N-(4-(3-(((2,4-difluorobenzyl)-12-nitroanilide)sulfonyl)-4-methoxyphenyl)-5-methylthiazol-2-yl)hexanamide;

[0057] (41) N-(5-(3-(((3,4-difluorobenzyl)-12-nitroaniline)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0058] (42) N-(5-(3-(((3-chloro-4-fluorobenzyl)-12-nitro-1-yl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0059] (43) N-(5-(3-(((4-fluoro-3-(trifluoromethyl)benzyl)-12-nitroylidene)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0060] (44) N-(5-(4-methoxy-3-(((3,4,5-trifluorobenzyl)-12-nitroanilide)sulfonyl)phenyl)-4-methylthiazol-2-yl)hexanamide;

[0061] (45) N-(5-(3-(((4-fluorophenethyl)-12-nitroaniline)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide;

[0062] (46) tert-Butyl (2-(2-hexanoylamino-4-methylthiazol-5-yl)-2-methoxybenzamido)ethylcarbamate;

[0063] (47) N-(4-(3-(((2,4-difluorobenzyl)-12-nitroylidene)sulfonyl)-4-methoxyphenyl)-5-methylthiazol-2-yl)hexanamide.

[0064] The preparation method of the above-mentioned inhibitor is as follows: using 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone as raw materials 1a, 1b, raw materials 1a, 1b and chlorosulfonic acid undergo a substitution reaction at the 3rd position of the benzene ring to obtain intermediates 2a, 2b; based on intermediates 2a, 2b, an R2 group is introduced through a Hinsberg reaction to obtain intermediates 3a-3g; intermediates 3a-3g undergo an α-bromination reaction with phenyltrimethylammonium tribromide to obtain intermediates 4a-4g; intermediates 4a-4g undergo a condensation reaction with N-acetylthiourea to obtain target compounds 5a-5g. The synthetic route is as follows: Methods for preparing the above-mentioned inhibitors also include, according to the preparation method of target compounds 5a-5g, using intermediates 4d and 4e as raw materials, simultaneously reacting thiourea with various acyl chlorides to introduce an R3 group to obtain intermediate N-substituted thiourea as another type of raw material; condensing the two to obtain target compounds 7a-7r; or using intermediate 4e as a raw material, reacting it with thiourea to obtain intermediate 8; and then reacting intermediate 8 with 3-acetylaminopropionyl chloride, 6-carbonylheptanoyl chloride, and 5-carbonylhexanoyl chloride to obtain target compounds 9a-9c. The synthetic routes are as follows: Alternatively, according to the preparation method of target compounds 5a-5g, compounds 4h-4x are obtained as raw materials, and condensed with N-hexanoylthiourea to obtain target compounds 10a-10q. The synthetic route is as follows: The preparation method of the above-mentioned inhibitor also includes using compound 8 as a raw material, undergoing a two-step reaction to obtain intermediate 9; intermediate 9 is heated to reflux in acetic acid to undergo a reduction reaction with iron powder to obtain intermediate 10; intermediate 10 is hydrolyzed under acidic conditions to obtain intermediate 11; intermediate 11 is reacted with tert-butyl (2-aminoethyl)carbamate to obtain intermediate 12, and the target compound 46 is obtained through a two-step reaction. The synthetic route is as follows: Alternatively, 4′-methoxypropiophenone 14 is used as the starting material, and the target compound 47 is obtained through four steps of reaction. The synthetic route is as follows:

[0065] The present invention also discloses a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, adjuvant or carrier, and the above-mentioned phenylthiazolamine PI4KIIIβ inhibitor.

[0066] Use of the above-mentioned phenylthiazolamine PI4KIIIβ inhibitor or pharmaceutical composition in the preparation of a drug for preventing, treating or assisting in the treatment of proliferative diseases, metabolic diseases, nervous system diseases or tuberous sclerosis caused by overactivation of PI4KIIIβ kinase.

[0067] Preferably, the proliferative disease comprises colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain cancer, cervical cancer, cancer of the CNS, malignant glioma, myeloproliferative disease, blood cancer or lymphoma.

[0068] Use of the above-mentioned phenylthiazolamine PI4KIIIβ inhibitor or pharmaceutical composition in the preparation of a drug for inhibiting cancer cell growth.

[0069] Principle of the Invention: Due to the weak inhibitory activity and insufficient anti-tumor effects of PIK4KIIIβ, PIK-93 was selected as a lead compound for further structural modification. The basic skeleton structure was determined to be phenylthiazolamine, and through the screening of substituent groups, a highly effective inhibitory effect was achieved.

[0070] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) It has the characteristics of effectively inhibiting the PI3K / Akt / mTOR signaling pathway of PI4KIIIβ and has high efficiency and excellent PI4KIIIβ enzyme inhibitory activity; (2) It has low cost, good efficacy, low toxicity, and a high yield of intermediate products in the synthesis process, which reduces resource waste and is conducive to reducing costs; (3) It has significant anti-tumor activity and a small dosage. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] FIG1 shows the results of in vivo anti-tumor efficacy and toxicity studies of Examples 11 and 27, wherein FIGA is a curve showing changes in mouse tumor volume, FIGB is a curve showing growth of body weight, and FIGC is a representative image of mouse tumor tissue;

[0072] FIG2 shows the results of in vivo anti-tumor efficacy and toxicity studies of Example 40, wherein FIGA is a curve showing changes in mouse tumor volume, FIGB is a curve showing growth of body weight, and FIGC is a representative image of mouse tumor tissue;

[0073] Figure 3 is a stained image of histopathological sections of tumor-bearing mice. DETAILED DESCRIPTION

[0074] The technical solution of the present invention will be further described below in conjunction with the embodiments and drawings.

[0075] 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 indicated. 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 in degrees Celsius unless otherwise indicated.

[0076] In the examples described below, the chromatographic column used was a silica gel column. Silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Co., Ltd. Nuclear magnetic resonance spectra were performed using CDCl₃ or DMSO-d₆ as solvents (in ppm), with TMS (0 ppm) as the reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0077] The low-resolution mass spectrometry (MS) data in the examples described below were analyzed using an Agilent 6120 series LC-MS equipped with a G1329B autosampler and a G4212B detector using a G1311B quaternary pump and a G1316A column oven. An ESI source was used for the LC-MS spectrometer.

[0078] In the examples described below, for ease of description, some raw materials will be described by their abbreviations, which are compared with their full names as follows: DCM is CH2Cl2, i.e. dichloromethane; CDCl3 is 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-d6 is hexadeuterated dimethyl sulfoxide; THF is tetrahydrofuran; NaCl is sodium chloride; Na2SO4 is sodium sulfate; CDI is N,N-carbonyldiimidazole.

[0079] Example 1

[0080] The synthesis of tert-butyl (2-(5-(2-acetylamino-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethyl)carbamate is as follows:

[0081] Step 1: Synthesis of 2-chloro-5-(2-oxopropyl)benzenesulfonyl chloride:

[0082] 10 mL of ClSO₃H₃ (132 mmol, 11.0 eq.) was added to a 25 mL eggplant-shaped reaction flask and pre-cooled in an ice bath for 30 min. 2.02 g (12.0 mmol) of 4-chlorophenylacetone was slowly added dropwise to the ClSO₃H₃. The reaction was allowed to react at room temperature for approximately 6 h, until complete consumption of starting material 1a was observed by TLC. The reaction solution was slowly added dropwise onto ice to quench unreacted ClSO₃H₃. The aqueous solution was then extracted with ethyl acetate (3 x 100 mL). The organic phase was collected, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product, which was purified by silica gel column chromatography (PE:EA = 4:1-2:1). The product was obtained as a white solid in a 60% yield. 1 H NMR (300MHz, Chloroform-d) δ7.95 (d, J=2.1Hz, 1H), 7.63 (d, J=8.2Hz, 1H), 7.50 (dd, J=8.2, 2.1Hz, 1H), 3.86 (s, 2H), 2.30 (s, 3H).

[0083] Step 2: Synthesis of tert-butyl (2-(2-chloro-5-(2-oxopropyl)phenylsulfonamido)ethyl)carbamate:

[0084] 5 mmol of 2-chloro-5-(2-oxopropyl)benzenesulfonyl chloride was dissolved in 20 mL of dichloromethane. 7.5 mmol of tert-butyl (2-aminoethyl)carbamate (1.5 eq.) and 1.01 g of triethylamine (2.0 eq.) were added to the reaction mixture. The mixture was stirred at room temperature for 12 hours until the 2-chloro-5-(2-oxopropyl)benzenesulfonyl chloride was completely consumed. After the reaction, the product was purified by column chromatography (PE:EA = 1:1). The resulting product was a white solid in a yield of 78%. 1 H NMR (400MHz, DMSO-d6) δ7.85 (t, J=5.9Hz, 1H), 7.78 (d, J=2.1Hz, 1H), 7.60 (d, J=8.1Hz, 1H), 7.43 (dd, J=8.2, 2.2Hz , 1H), 6.78 (t, J=5.8Hz, 1H), 3.95 (s, 2H), 3.02-2.93 (m, 2H), 2.84 (dt, J=8.2, 6.0Hz, 2H), 2.18 (s, 3H), 1.35 (s, 9H); 13 C NMR (101MHz, DMSO-d6) δ205.63, 155.97, 137.78, 135.79, 135.40, 132.09, 131.92, 129.09, 78.30, 48.54, 42.60, 30.21, 28.64.

[0085] Step 3: Synthesis of tert-butyl (5-(1-bromo-2-oxopropyl)-2-chlorophenylsulfonamido)ethyl)carbamate:

[0086] Weigh 1 mmol of tert-butyl (2-(2-chloro-5-(2-oxopropyl)phenylsulfonamido)ethyl)carbamate and dissolve it in 5 mL of tetrahydrofuran. Place the mixture in an eggplant-shaped flask. Slowly add 1.1 mmol of phenyltrimethylammonium tribromide in 10 mL of tetrahydrofuran to the reaction mixture while cooling it in an ice bath. Remove the ice bath and allow the mixture to react at room temperature for 0.5 h until the reactants are completely consumed. Purify the mixture (PE:EA = 1:1) to obtain the brominated product as a pale yellow oil in a 60% yield. 1 H NMR (300MHz, Chloroform-d) δ8.11 (d, J=2.3Hz, 1H), 7.66 (dd, J=8.3, 2.3Hz, 1H), 7.57 (d, J=8.3Hz, 1H), 5.7 2(s, 1H), 5.42(s, 1H), 4.87(s, 1H), 3.28(q, J=5.7Hz, 2H), 3.08(q, J=5.8Hz, 2H), 2.44(s, 3H), 1.46(s, 9H).

[0087] Step 4: Synthesis of tert-butyl (2-(5-(2-acetylamino-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethyl)carbamate, the structural formula is as follows:

[0088] First, prepare N-acetylthiourea. Weigh 10 mmol of thiourea and dissolve it in 30 mL of anhydrous toluene solution and place it in a 100 mL eggplant-shaped flask. Weigh 15 mmol of acetyl chloride and dissolve it in 2 mL of anhydrous toluene and slowly add it dropwise to the reactor. Heat the reaction to 110°C and reflux for 5 hours. After the reaction is completed, cool the reaction solution to room temperature and concentrate the reaction solution. Column chromatography (PE:EA=8:1) is used to obtain white solid N-acetylthiourea with a yield of 71% ( 1 H NMR (400 MHz, Chloroform-d) δ 9.88 (s, 1H), 8.99 (s, 1H), 7.14 (s, 1H), 2.19 (s, 3H). 1 mmol of intermediate 4d was weighed into a 25 mL eggplant flask, 10 mL of acetone solution was added, and 1 mmol of N-acetylthiourea (1.0 eq.) was added to the reaction solution. The temperature was raised to 60°C and refluxed for 1 h. TLC monitoring was performed until the intermediate 4a was completely consumed (DCM:MeOH = 25:1). The product was concentrated in vacuo and purified by column chromatography. The product was a white solid in a 60% yield. 1 H NMR (400MHz, DMSO-d6) δ12.25 (s, 1H), 8.04 (t, J = 5.7Hz, 1H), 7.93 (t, J = 1.3Hz, 1H), 7.72 (d, J = 1.3Hz, 2H) , 6.77 (t, J=5.6Hz, 1H), 2.97 (q, J=6.4Hz, 2H), 2.93-2.80 (m, 2H), 2.37 (s, 3H), 2.15 (s, 3H), 1.33 (s, 9H); 13 C NMR (101MHz, DMSO-d6) δ175.44, 156.03, 155.52, 143.80, 138.28, 133.23, 132.53, 131.84 ,129.39,128.96,121.44,77.86,42.22,42.21,28.19,19.09,16.13.ESI—HRMScalcdforC 19 H 25 ClN4O5S2m / z[M+H] + 489.1028, found [M+H] + 489.1032.

[0089] Example 2

[0090] N-(5-(4-chloro-3-(N-(2-hydroxy-2-methylpropyl)aminosulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide, the structural formula is as follows:

[0091] The fragment (2-aminoethyl) tert-butyl carbamate in step 2 of Example 1 was replaced with 1-amino-2-methyl-2-propanol. The other steps and operations were the same as those in Example 1; the product was a white solid. Yield: 25% 1 H NMR (400MHz, DMSO-d6) δ12.24 (s, 1H), 7.94 (s, 1H), 7.77 (t, J=6.3Hz, 1H), 7.72-7.6 8(m, 2H), 4.45(s, 1H), 2.83(d, J=6.2Hz, 2H), 2.37(s, 3H), 2.16(s, 3H), 1.05(s, 6H); 13 C NMR (101MHz, DMSO-d6) δ166.42, 145.50, 138.51, 132.58, 132.11, 132.03, 128.42, 127.28, 114.92, 68.87, 53.89, 27.03, 16.48.ESI-HRMScalcdforC 16 H 20 ClN3O4S2m / z[M+H] + 418.0657, found [M+H] + 418.0663.

[0092] Example 3

[0093] N-(2-(2-acetylamino-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethyl propionamide, the structural formula is as follows:

[0094] The fragment (2-aminoethyl) tert-butyl carbamate in step 2 of Example 1 was replaced with N-(2-aminoethyl) propionamide. Other steps and operations were the same as in Example 1; white solid, yield: 30%. 1 H NMR (400MHz, DMSO-d6) δ7.93 (s, 1H), 7.76 (t, J = 5.7Hz, 1H), 7.71-7.69 (m, 2H), 3.09 (q, J = 6.4Hz, 2 H), 2.92 (t,, J=6.7Hz, 2H), 2.37 (s, 3H), 2.15 (s, 3H), 2.00 (q,, J=7.5Hz, 2H), 0.93 (td, J=7.6, 3H); 13C NMR (101MHz, DMSO-d6) δ173.13, 168.66, 155.88, 143.79, 138.26, 133.20, 132.48.131.8 0, 129.34, 128.92, 121.34, 42.07, 38.62, 28.39, 22.48, 16.16, 9.74.ESI—HRMScalcdforC 17 H 21 ClN4O4S2m / z[M+H] + 445.0766, found [M+H] + 445.0762.

[0095] Example 4

[0096] (2-(2-acetylamino-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0097] The fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 of Example 1 was replaced with (2-aminoethyl)carbamic acid methyl ester. Other steps and operations were the same as those in Example 1. The product was a white solid with a yield of 29%. 1 H NMR (400MHz, DMSO-d6) δ12.24 (s, 1H), 8.06 (t, J = 5.8Hz, 1H), 7.93 (s, 1H), 7.71 (d, J = 1.3Hz, 2H), 7.07 (t, J=5.7Hz, 1H), 3.46 (s, 3H), 3.03 (q, J=6.4Hz, 2H), 2.93 (q, J=6.4Hz, 2H), 2.37 (s, 3H), 2.15 (s, 3H); 13 C NMR (101MHz, DMSO-d6) δ168.66, 156.65, 155.90, 143.79, 138.28, 133.17, 132.47, 131 .80, 129.33, 128.94, 121.38, 51.35, 42.12, 40.33, 22.48, 16.16.ESI—HRMScalcdforC 16 H 19 ClN4O5S2m / z[M+H] + 447.0558, found [M+H] + 447.0556.

[0098] Example 5

[0099] Tert-butyl (2-((5-(2-acetylamino-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonamido)ethyl)carbamate, the structural formula is as follows:

[0100] The raw material in step 1 of Example 1 was replaced by 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the other steps and operations were the same as those in Example 1; the product was a white solid, with a yield of 28%. 1 H NMR (400MHz, DMSO-d6) δ12.14 (s, 1H), 7.71 (d, J = 2.4Hz, 1H), 7.68 (dd, J = 8.6, 2.4Hz, 1H), 7.38 (t, J = 5.9Hz, 1H), 7.31 (d, J = 8.6H z, 1H), 6.74 (t, J = 5.8Hz, 1H), 3.94 (s, 3H), 2.95 (q, J = 6.5Hz, 2H), 2.82 (q, J = 6.5Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.34 (s, 9H); 13 C NMR (101MHz, DMSO-d6) δ168.41, 155.46, 155.30, 155.01, 142.06, 134.26, 128.89, 128. 17, 124.02, 122.27, 113.62, 77.80, 56.37, 42.38, 42.36, 28.19, 22.46, 15.85; ESI-HRMS calcd for C 20 H 28 N4O6S2m / z[M+H] + 485.1523, found [M+H] + 485.1519.

[0101] Example 6

[0102] N-(5-(4-chloro-3-(N-(3-hydroxy-4-methylphenyl)aminosulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide, the structural formula is as follows:

[0103] The fragment (2-aminoethyl) tert-butyl carbamate in step 2 of Example 1 was replaced with 5-amino-2-methylphenol, and the other steps and operations were the same as in Example 1; the product was a white solid, with a yield of 25%. 1H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 9.89 (s, 1H), 9.72 (s, 1H), 7.84 (dd, J = 10.3, 2.1Hz, 1H), 7.73-7 .61 (m, 2H), 7.25 (s, 1H), 6.72 (s, 1H), 5.75 (d, J = 1.6Hz, 1H), 2.22 (d, J = 4.8Hz, 3H), 2.18-2.09 (m, 6H); 13 C NMR (101MHz, DMSO-d6) δ168.58, 155.90, 150.55, 143.61, 138.06, 135.64, 133.50, 132.38, 131.30, 129.72, 129.51, 128.46, 122.67, 121.26, 117.71, 111.63, 22.44, 21.99, 15.78; ESI-HRMScalcdforC 19 H 18 ClN3O4S2m / z[M+H] + 452.0500, found [M+H] + 452.0511.

[0104] Example 7

[0105] N-(5-(3-(N-(2,4-difluorophenyl)aminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)acetamide, the structural formula is as follows:

[0106] The raw materials in step 1 of Example 1 were replaced by 1-(4-chlorophenyl)-2-propanone and 1-(4-methoxyphenyl)-2-propanone, and the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced by 2,4-difluoroaniline. Other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 39%. 1 H NMR (400MHz, DMSO-d6) δ12.12 (d, J = 5.6Hz, 1H), 9.89 (s, 1H), 7.81-7.53 (m, 2H), 7.37-7.16(m, 3H), 7.11-6.87(m, 1H), 3.90(d, J=22.1Hz, 4H), 2.25-2.10(m, 6H); 13C NMR (101MHz, DMSO) δ168.40, 155.64, 155.01, 142.09, 134.86, 129.78, 129.08, 128.91, 128.86, 128.80, 128.77, 1 27.48, 123.76, 122.01, 113.61, 111.63.111.58, 104.70, 104.41, 104.17, 56.26, 22.43, 14.22; ESI-HRMScalcdfor C 19 H 17 F2N3O4S2m / z[M+H] + 454.0701, found [M+H] + 454.0709.

[0107] Example 8

[0108] Tert-butyl (5-(2-propionamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0109] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with propionyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 32%. 1 H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.67 (dd, J = 8.5, 2.4Hz, 1H), 7.38 (t, J = 5.9Hz, 1H), 7.31 (d, J = 8.7Hz, 1H), 6.75 (t, J=5.7Hz, 1H), 3.94 (s, 3H), 2.96 (q, J=6.5Hz, 2H), 2.83 (q, J=6.6Hz, 2H), 2.43 (q, J=7.5Hz, 2H), 2.32 (s, 3H), 1.34 (s, 9H), 1.09 (t, J=7.6Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ172.07, 155.46, 155.30, 155.06, 142.07, 134.25, 128.90, 128. 20, 124.06, 122.22, 113.63, 77.80, 56.37, 42.39, 28.23, 28.19, 15.84, 9.18; ESI-HRMS calcd for C 21 H 30 N4O6S2m / z[M+H]+ 499.1680, found [M+H] + 499.1671.

[0110] Example 9

[0111] Tert-butyl (5-(2-butyramido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0112] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with butyryl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 34%. 1 H NMR (400MHz, DMSO-d6) δ12.11 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.6 , 2.4Hz, 1H), 7.37 (t, J=6.9, 6.4Hz, 1H), 7.31 (d, J=8.6Hz, 1H), 6.74 (t, J=5.6 Hz, 1H), 3.94 (s, 3H), 2.96 (q, J=6.5Hz, 2H), 2.88-2.76 (m, 2H), 2.40 (t, J=7. 3Hz, 2H), 2.32 (s, 3H), 1.66-1.57 (m, 2H), 1.34 (s, 9H), 0.89 (t, J=7.4Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.24, 155.47, 155.31, 154.99, 142.07, 134.26, 128.93, 128.20, 124.06, 122.26, 113.62, 77.80, 56.37, 42.39, 36.78, 28.18, 18.23, 15.82, 13.50; ESI-HRMS calcd for C 22 H 32 N4O6S2m / z[M+H] + 513.1836, found [M+H] + 513.1841.

[0113] Example 10

[0114] Tert-butyl (5-(2-pentanamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0115] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone and 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with valeryl chloride. The other steps and operations were the same as in Example 1; the product was a white solid with a yield of 35%. 1 H NMR (300MHz, DMSO-d6) δ12.12 (s, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.68 (dd, J = 8.5, 2.4Hz, 1H), 7.46 (t, J = 5.9Hz, 2H), 7.31 (d, J = 8.7Hz, 1H), 3.94 (s, 3H), 3 .15-3.03(m, 2H), 2.83(q, J=6.6Hz, 2H), 2.42(t, J=7.4Hz, 2H), 2.32(s, 3H) , 1.63-1.53 ​​(m, 2H), 1.36-1.24 (m, 2H), 1.04 (s, 9H), 0.88 (t, J=7.3Hz, 3H); 13 C NMR (101MHz, DMSO) δ171.42, 155.50, 155.33, 155.02, 142.10, 134.29, 128.94, 128.23, 124.08, 122.29, 113.66, 77.83 ,56.40, 42.41, 40.17, 39.96, 39.75, 39.54, 39.33, 39.12, 38.92, 34.88, 28.20, 24.45, 21.85, 15.83, 13.85; ESI-HRMS calcd for C 23 H 34 N4O6S2m / z[M+H] + 527.1993, found [M+H] + 527.1995.

[0116] Example 11

[0117] Tert-butyl (5-(2-hexaneamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0118] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 34%. 1H NMR (300MHz, DMSO-d6) δ12.11 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.5, 2 .4Hz, 1H), 7.38 (t, J=5.8Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 6.74 (t, J=5.5Hz, 1H), 3.94 (s, 3H), 3.03-2.90 (m, 2H), 2.90-2.76 (m, 2H), 2.41 (t, J=7.3Hz, 2H), 2.31 (s, 3H), 1.64-1.54 (m, 2H), 1.34 (s, 9H), 1.29-1.22 (m, 4H), 0.88-0.84 (m, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.40, 155.48, 155.31, 155.00, 142.08, 134.27, 128.92, 128.21, 124.06, 122.27, 113.64, 77.81, 56.38, 42.39, 34.86, 30.72, 28.18, 24.43, 21.83, 15.81, 13.83; ESI-HRMS calcd for C 24 H 36 N4O6S2m / z[M+H] + 541.2149, found [M+H] + 541.2147.

[0119] Example 12

[0120] Tert-butyl (5-(2-heptylamino-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0121] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with heptanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 35%. 1H NMR(400 MHz, DMSO-d6) δ12.11 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.6, 2.4Hz, 1 H), 7.38 (t, J=5.8Hz, 1H), 7.31 (d, J=8.6Hz, 1H), 6.74 (t, J=5.7Hz, 1H), 3.94 ( s, 3H), 2.95 (q, J=6.5Hz, 2H), 2.86-2.77 (m, 2H), 2.41 (t, J=7.4Hz, 2H), 2.32 ( s, 3H), 1.62-1.55 (m, 2H), 1.34 (s, 9H), 1.30-1.26 (m, 6H), 0.87-0.84 (m, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.36, 155.45, 155.29, 154.98, 142.06, 134.24, 128.91, 128.20, 124.04, 122.25, 113.62, 77.78, 56.35, 42.37, 34.88, 30.93, 28.17, 24.68, 21.95, 15.80, 13.91.; ESI-HRMS calcd for C 25 H 38 N4O6S2m / z[M+H] + 555.2306, found [M+H] + 555.2310.

[0122] Example 13

[0123] Tert-butyl (2-(2-methoxy-5-(4-methyl-2-(3-propylureido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0124] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with propylcarbamoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 36%. 1H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 7.68 (d, J=2.4Hz, 1H), 7.63 (dd, J=8.6, 2.4Hz, 1H), 7.39 (t, J=5.9Hz, 1H), 7.29 (d, J=8.7Hz, 1H), 6.76 (t, J=5.7Hz, 1H), 6.57 (t, J=5.9Hz, 1H), 3.93 (s, 3H), 3.08 (q, J=6.6Hz, 2H), 2.95 (q, J=6.5Hz, 2H), 2.81 (q, J=6.6Hz, 2H), 2.26 (s, 3H), 1.49-1.40 (m, 2H), 1.33 (s, 9H), 0.86 (t, J=7.4Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ156.83, 155.50, 155.05, 152.76, 141.76, 134.00, 128.72, 128.09, 124 .51, 120.77, 113.60, 77.85, 65.01, 56.37, 50.02, 42.41, 28.81, 28.22, 15.96, 15.24; ESI-HRMS calcd for C 22 H 33 N5O6S2m / z[M+H] + 528.1945, found [M+H] + 528.1940.

[0125] Example 14

[0126] Tert-butyl (2-(5-(2-(3-butylureido)-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethyl)carbamate, the structural formula is as follows:

[0127] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with butylcarbamoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 42%. 1H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.63 (dd, J = 8.6, 2.4Hz, 1H ), 7.36 (t, J = 5.8Hz, 1H), 7.29 (d, J = 8.7Hz, 1H), 6.74 (t, J = 5.7Hz, 1H), 6.56-6.53 (m, 1H ), 3.93 (s, 3H), 3.12 (q, J = 6.5Hz, 2H), 2.95 (q, J = 6.5Hz, 2H), 2.82 (q, J = 6.5Hz, 2H), 2.2 6 (s, 3H), 1.46-1.39 (m, 2H), 1.34 (s, 9H), 1.29 (t, J=7.5Hz, 2H), 0.89 (t, J=7.3Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ164.06, 155.50, 155.08, 153.83, 141.81, 134.05, 128.73, 128.10, 124 .45, 113.60, 77.85, 65.01, 56.37, 42.41, 41.05, 28.22, 22.82, 15.93, 15.24, 11.30; ESI-HRMS calcd for C 23 H 35 N5O6S2m / z[M+H] + 542.2102, found [M+H] + 542.2105.

[0128] Example 15

[0129] Tert-butyl (2-(2-methoxy-5-(4-methyl-2-(3-methylbutanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0130] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 3-methylbutyryl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 40%. 1H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.68 (dd, J= 8.6, 2.4Hz, 1H), 7.37 (t, J = 5.8Hz, 1H), 7.31 (d, J = 8.7Hz, 1H), 6.73 (t, J = 5.7Hz, 1H), 3.94 (s, 3H), 2.96 (q, J = 6 .5Hz, 2H), 2.83 (q, J = 6.3Hz, 2H), 2.31 (d, J = 7.7Hz, 5H), 2.11-2.03 (m, 1H), 1.34 (s, 9H), 0.92 (d, J = 6.7Hz, 6H); 13 C NMR (75MHz, DMSO-d6) δ170.76, 155.49, 155.34, 154.95, 142.11, 134.31, 128.98, 128.19, 124. 07, 122.31, 113.64, 77.83, 59.81.56.39, 43.94, 42.41, 28.20, 25.59, 22.19, 15.83; ESI-HRMS calcd for C 23 H 34 N4O6S2m / z[M+H] + 527.1993, found [M+H] + 527.2001.

[0131] Example 16

[0132] Tert-butyl (5-(2-isobutyramido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0133] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 2-methylpropanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 26%. 1H NMR (400MHz, DMSO-d6) δ12.11 (s, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.67 (dd, J = 8.6, 2.4Hz, 1H), 7.39 (t, J = 5.9Hz, 1H), 7.31 (d, J = 8.7Hz, 1H), 6.75 (t ; 13 C NMR (101MHz, DMSO-d6) δ175.22, 155.47, 155.32, 155.15, 142.09, 134.29, 128.93, 128.23, 124 .06, 122.35, 113.64, 77.80, 56.38, 42.40, 39.82, 33.82, 28.19, 19.11, 15.80; ESI-HRMScalcd for C 22 H 32 N4O6S2m / z[M+H] + 513.1836, found [M+H] + 513.1839.

[0134] Example 17

[0135] Tert-butyl (2-(2-methoxy-5-(4-methyl-2-pivalamidothiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0136] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 2,2-dimethylpropionyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 30%. 1 H NMR (300MHz, DMSO-d6) δ11.85 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.5, 2.4Hz, 1H), 7.40 (t, J=5.9Hz, 1H), 7.32 (d, J=8. 6Hz, 1H), 6.76 (t, J=5.6Hz, 1H), 3.94 (s, 3H), 3.05-2.90 (m, 2H), 2.83 (q, J=6.8Hz, 2H), 2.33 (s, 3H), 1.34 (s, 9H), 1.24 (s, 9H); 13C NMR (101MHz, DMSO) δ176.70, 155.79, 155.48, 155.32, 141.99, 134.28, 128.95, 128.26 , 124.11, 122.42, 113.64, 77.81, 56.37, 42.43, 38.77, 28.18, 26.60, 15.71; ESI-HRMS calcd for C 23 H 34 N4O6S2m / z[M+H] + 527.1993, found [M+H] + 527.2000.

[0137] Example 18

[0138] Tert-butyl (5-(2-(3,3-dimethylbutanamide)-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0139] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 3,3-dimethylbutyryl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 40%. 1 H NMR (400MHz, DMSO-d6) δ12.05 (s, 1H), 7.73 (d, J = 2.4Hz, 1H), 7.68 (dd, J = 8.6, 2.4Hz, 1H), 7.36 (t, J = 5.8Hz, 1H), 7.31 (d, J = 8.6Hz, 1H), 6.73 (t, J=5.7Hz, 1H), 3.94 (s, 3H), 2.95 (q, J=6.5Hz, 2H), 2.89-2.77 (m, 2H), 2.32 (d, J=2.6Hz, 5H), 1.34 (s, 9H), 1.00 (s, 9H); 13 C NMR (101MHz, DMSO-d6) δ174.22, 155.45, 155.29, 155.10, 142.05, 134.25, 128.90, 128.22, 124.07, 122.27, 113.62, 77.78, 56.35, 43.33, 42.38, 28.76, 28.17, 25.03, 15.78; ESI-HRMS calcd for C 24 H 36 N4O6S2m / z[M+H] + 541.2149, found [M+H]+ 541.2152.

[0140] Example 19

[0141] Tert-butyl (2-(2-methoxy-5-(4-methyl-2-(4-methylpentanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0142] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 4-methylvaleryl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 34%. 1 H NMR (400MHz, DMSO-d6) δ12.14 (s, 1H), 7.71 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.6, 2.4Hz, 1H), 7.40 (t, J=5.9Hz, 1H), 7.31 (d, J=8.6Hz, 1H), 6.76 (t, J=5.7Hz , 1H), 3.94 (s, 3H), 2.95 (q, J=6.5Hz, 2H), 2.86-2.75 (m, 2H), 2.43 (t, J=7.3 Hz, 2H), 2.31 (s, 3H), 1.53-1.47 (m, 3H), 1.33 (s, 9H), 0.87 (d, J=6.2Hz, 6H); 13 C NMR (101MHz, DMSO) δ169.96, 155.44, 155.29, 154.81, 142.05, 134.24, 128.93, 128.18, 12 4.05, 122.26, 113.60, 77.77, 56.35, 47.91, 42.37, 30.98, 29.44, 28.16, 15.79; ESI-HRMS calcd for C 24 H 36 N4O6S2m / z[M+H] + 541.2149, found [M+H] + 541.2143.

[0143] Example 20

[0144] Tert-butyl (2-(2-methoxy-5-(4-methyl-2-(5-methylhexanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0145] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 5-methylhexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 34%. 1 H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.67 (dt, J = 8.7, 2.1 Hz, 1 H), 7.37 (t, J=5.8Hz, 1H), 7.31 (dd, J=8.7, 1.8Hz, 1H), 6.73 (t, J=5.8Hz, 1H), 3.94 (s, 3H), 2.96 (q, J=6.6Hz, 2H), 2.83 (q, J=6.6Hz, 2H), 2.45-2.36 (m, 2H), 2.32 (d, J=1.7Hz , 3H), 1.67-1.46 (m, 3H), 1.34 (s, 9H), 1.21-1.11 (m, 2H), 0.86 (dd, J=6.7, 1.9Hz, 6H); 13 C NMR (101MHz, DMSO-d6) δ171.37, 155.47, 155.31, 155.00, 142.07, 134.26, 128.93, 128.20, 124.06 , 122.27, 113.62, 77.80, 56.37, 42.39, 37.81, 35.11, 28.18, 27.25, 22.66, 22.42, 15.82; ESI-HRMS calcd for C 25 H 38 N4O6S2m / z[M+H] + 555.2306, found [M+H] + 555.2307.

[0146] Example 21

[0147] Tert-butyl (2-(5-(2-(cyclohexanecarboxamido)-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0148] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with cyclohexanecarbonyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 45%. 1H NMR (400MHz, DMSO-d6) δ12.06 (s, 1H), 7.71 (d, J = 2.4Hz, 1H), 7.66 (dd, J = 8.6, 2.4H z, 1H), 7.38 (t, J = 5.9Hz, 1H), 7.31 (d, J = 8.7Hz, 1H), 6.74 (t, J = 5.8Hz, 1H), 3.94 (s , 3H), 2.95 (q, J = 6.5Hz, 2H), 2.82 (q, J = 6.5Hz, 2H), 2.45 (dt, J = 11.4, 3.5Hz, 1H), 2 .31(s, 3H), 1.82-1.72(m, 4H), 1.45-1.38(m, 2H), 1.34(s, 9H), 1.29-1.15(m, 4H); 13 C NMR (101MHz, DMSO-d6) δ174.26, 155.48, 155.32, 155.12, 142.08, 134.29, 128.92, 128.21, 124.08 , 122.29, 113.65, 77.82, 56.39, 43.36, 42.40, 39.82, 28.79, 28.20, 25.29, 25.06, 15.82; ESI-HRMS calcd for C 25 H 36 N4O6S2m / z[M+H] + 553.2149, found [M+H] + 553.2153.

[0149] Example 22

[0150] Tert-butyl (2-(2-chloro-5-(4-methyl-2-(3-methylbutanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0151] The acetyl chloride in step 4 of Example 1 was replaced with 3-methylbutyryl chloride, and the other steps and operations were the same as those of Example 1; a white solid was obtained, with a yield of 35%. 1 H NMR (300MHz, DMSO-d6) δ12.23 (s, 1H), 8.05 (t, J = 5.6Hz, 1H), 7.97-7.91 (m, 1H), 7.72 (t, J = 1.4Hz, 2H), 6.79 (t, J = 5.5 Hz, 1H), 2.97 (dd, J = 12.2, 6.6Hz, 2H), 2.91 (d, J = 6.7Hz, 2H), 2.38 (s, 3H), 1.34 (s, 8H), 1.16 (dd, J = 18.6, 7.0Hz, 8H); 13C NMR (101MHz, DMSO-d6) δ175.85, 156.46, 155.94, 144.22, 138.72, 133.64, 132.94, 132.27, 129 .82, 129.38, 121.86, 78.28, 60.22, 42.65, 34.28, 28.62, 21.23, 19.52, 16.55, 14.55; ESI-HRMS calcd for C 22 H 31 N4O5S2m / z[M+H] + 531.1497, found [M+H] + 531.1495.

[0152] Example 23

[0153] Tert-butyl (2-chloro-5-(2-(3,3-dimethylbutanamide)-4-methylthiazol-5-yl)phenylsulfonamido)ethylcarbamate, the structural formula is as follows:

[0154] The acetyl chloride in step 4 of Example 1 was replaced with 3,3-dimethylbutyryl chloride, and the other steps and operations were the same as those of Example 1; a white solid was obtained, with a yield of 35%. 1 H NMR (300MHz, DMSO-d6) δ12.19 (s, 1H), 8.04 (t, J = 5.7Hz.1H), 7.94 (t, J = 1.3Hz, 1H), 7.72 (d, J = 1.3Hz , 2H), 6.78 (t, J=5.6Hz, 1H), 2.98-2.88 (m, 4H), 2.37 (s, 3H), 2.33 (s, 2H), 1.33 (s, 9H), 1.00 (s, 9H); 13 C NMR (101MHz, DMSO-d6) δ170.17, 155.67, 155.48, 143.75, 138.21, 133.18, 132.45, 131.82, 129.40, 128.90, 121. 34, 77.81, 47.90, 42.17, 40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89, 31.01, 29.43, 28.16, 16.09; ESI-HRMS calcd for C 23 H 33 ClN4O6S2m / z[M+H] + 545.1654, found [M+H] + 545.1660.

[0155] Example 24

[0156] Tert-butyl (2-chloro-5-(4-methyl-2-pentanamido-5-yl)phenylsulfonamido)ethylcarbamate, having the following structural formula:

[0157] The acetyl chloride in step 4 of Example 1 was replaced with valeryl chloride, and the other steps and operations were the same as those in Example 1; a white solid was obtained, with a yield of 35%. 1 H NMR (400MHz, DMSO-d6) δ12.22 (s, 1H), 8.03 (t, J = 5.6Hz, 1H), 7.93 (s, 1H), 7.73-7.69 (m, 2H), 6.77 (t, J = 5.6Hz, 1H), 2.98 (q, J = 6.5Hz, 2H) ; 13 C NMR (101MHz, DMSO-d6) δ171.59, 155.87, 155.50, 143.77, 138.25, 133.19, 132.48, 131.82, 129.39, 128.92, 121.34, 77.84, 42.20, 34.61, 28.17, 26.81, 21.67, 16.11, 13.65; ESI-HRMS calcd for C 22 H 31 ClN4O5S2m / z[M+H] + 531.1497, found [M+H] + 531.1498.

[0158] Example 25

[0159] Tert-butyl (2-chloro-5-(2-hexanoylamino-4-methylthiazol-5-yl)phenylsulfonamido)ethylcarbamate, having the following structural formula:

[0160] The acetyl chloride in step 4 of Example 1 was replaced with hexanoyl chloride, and the other steps and operations were the same as those of Example 1; a white solid was obtained, with a yield of 36%. 1H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.71 (d, J = 1.8Hz, 2H), 6.85-6.65 (m, 1H), 2.98 (q, J = 6.5Hz, 2H), 2 .91 (q, J=6.6Hz, 2H), 2.43 (t, J=7.4Hz, 2H), 2.37 (s, 3H), 1.64-1.56 (m, 2H), 1.33 (s, 9H), 1.30-1.24 (m, 4H), 0.86 (t, J=6.8Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.56, 155.84, 155.47, 143.74, 138.24, 133.16, 132.46, 131.81, 129.37 , 128.90, 121.32, 77.81, 42.18, 39.87, 34.84, 30.69, 28.15, 24.37, 21.80, 16.10, 13.81; ESI-HRMS calcd for C 23 H 33 ClN4O5S2m / z[M+H] + 545.1654, found [M+H] + 545.1645.

[0161] Example 26

[0162] Tert-butyl (2-(5-(2-(3-acetamidopropionamido)-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0163] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 3-acetamidopropionyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 30%. 1H NMR (300MHz, DMSO-d6) δ12.17 (s, 1H), 7.99 (t, J = 5.7Hz, 1H), 7.72 (d, J = 2.4Hz, 1 H), 7.68 (dd, J=8.5, 2.4Hz, 1H), 7.39 (t, J=5.8Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 6. 83-6.67 (m, 1H), 3.94 (s, 3H), 3.31 (t, J=6.2Hz, 2H), 2.95 (q, J=6.5Hz, 2H), 2.82 (q, J=6.4Hz, 2H), 2.59 (t, J=6.7Hz, 2H), 2.32 (s, 3H), 1.78 (s, 3H), 1.34 (s, 9H); 13 C NMR (101MHz, DMSO-d6) δ169.72, 169.36, 155.50, 155.36, 154.91, 142.14, 134.33, 128.97, 128.20, 124.02, 122.36, 113.68, 77.86, 56.42, 42.40, 39.83, 35.16, 34.66, 28.22, 22.60, 15.88; ESI-HRMS calcd for C 23 H 33 N5O7S2m / z[M+H] + 556.1894, found [M+H] + 556.1896.

[0164] Example 27

[0165] Tert-butyl (2-(2-methoxy-5-(4-methyl-2-(6-oxoheptamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0166] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 6-carbonylheptanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 35%. 1H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.5, 2.4H z, 1H), 7.36 (t, J = 5.8Hz, 1H), 7.31 (d, J = 8.6Hz, 1H), 6.73 (t, J = 5.7Hz, 1H), 3.94 (s, 3H), 2.96 (q, J=6.5Hz, 2H), 2.89-2.77 (m, 2H), 2.43 (dt, J=13.9, 7.3Hz, 4H), 2.32 (s, 3H), 2.07 (s, 3H), 1.63-1.41 (m, 4H), 1.34 (s, 9H); 13 C NMR (101MHz, DMSO-d6) δ208.42, 171.28, 155.53, 155.36, 155.00, 142.13, 134.32, 128.96, 128.22, 124.07 , 122.33, 113.67, 77.88, 56.41, 42.43, 42.36, 39.84, 34.77, 29.76, 28.21, 24.29, 22.71, 15.84; ESI-HRMS calcd for C 25 H 36 N4O7S2m / z[M+H] + 569.2098, found [M+H] + 569.2103.

[0167] Example 28

[0168] Tert-butyl (2-(2-methoxy-5-(4-methyl-2-(6-oxohexanamido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate, having the following structural formula:

[0169] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, and the acetyl chloride in step 4 was replaced with 5-carbonylhexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 35%. 1H NMR (400MHz, DMSO-d6) δ12.11 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.6, 2. 4Hz, 1H), 7.36 (t, J=5.9Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 6.73 (t, J=5.7Hz, 1H), 3.9 4(s, 3H), 2.96 (q, J=6.5Hz, 2H), 2.83 (q, J=6.6Hz, 2H), 2.46 (t, J=3.6Hz, 2H), 2.4 2(t, J=7.3Hz, 2H), 2.32(s, 3H), 2.08(s, 3H), 1.77(p, J=7.4Hz, 2H), 1.34(s, 9H); 13 C NMR (101MHz, DMSO-d6) δ208.03, 171.04, 155.50, 155.34, 154.98, 142.10, 134.28, 128.96, 128.23, 124.07, 122.32, 113.65, 77.84, 56.39, 41.86, 41.81, 34.01, 29.75, 28.20, 18.80, 15.83; ESI-HRMS calcd for C 24 H 34 N4O7S2m / z[M+H] + 555.1942, found [M+H] + 555.1946.

[0170] Example 29

[0171] (R)-tert-Butyl(1-((5-(2-hexaneamido-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonyl)piperidin-3-yl)carbamate, having the following structural formula:

[0172] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with (R)-piperidin-3-ylcarbamic acid tert-butyl ester, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. Other steps and operations were the same as in Example 1; the product was a white solid with a yield of 18%. 1H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 7.73 (d, J = 2.3Hz, 1H), 7.69 (dd, J = 8.6, 2.5H z, 1H), 7.33 (d, J = 8.6Hz, 1H), 6.83 (d, J = 7.7Hz, 1H), 3.93 (s, 3H), 3.55 (dd, J = 63.9, 12.2Hz, 2H), 2.59 (t, J = 11.5Hz, 1H), 2.41 (t, J = 7.4Hz, 2H), 2.31 (s, 3H), 1.76-1.6 8(m, 2H), 1.63-1.56(m, 2H), 1.37(s, 9H), 1.29-1.17(m, 8H), 0.86(t, J=6.8Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.43, 155.65, 155.06, 154.87, 142.17, 134.71, 130.23, 126.27, 124.24, 122.14, 113. 99, 77.96, 56.34, 50.00, 46.74, 45.50, 34.87, 30.74, 29.42, 28.23, 24.45, 23.70, 21.86, 15.83, 13.86; ESI-HRMS calcd for C 27 H 40 N4O6S2m / z[M+H] + 581.2462, found [M+H] + 581.2471.

[0173] Example 30

[0174] (S)-tert-Butyl(1-((5-(2-hexamethyleneimino-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonyl)pyrrolidin-3-yl)carbamate, structural formula is as follows:

[0175] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 20%. 1H NMR (300MHz, DMSO-d6) δ12.11 (s, 1H), 7.76 (d, J=2.4Hz, 1H), 7.69 (dd, J=8.6, 2 .4Hz, 1H), 7.34 (d, J=8.7Hz, 1H), 7.11 (d, J=6.5Hz, 1H), 3.95 (s, 3H), 3.55-3.3 8(m, 2H), 3.25(q, J=7.9Hz, 1H), 2.41(t, J=7.4Hz, 2H), 2.32(s, 3H), 2.06-1.66 (m, 2H), 1.65-1.53 ​​(m, 2H), 1.35 (s, 9H), 1.34-1.20 (m, 6H), 0.89-0.82 (m, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.39, 155.59, 155.21, 155.02, 142.11, 134.55, 130.65, 126.31, 124.17, 122.18, 113.83 , 78.02, 56.36, 52.49, 49.98, 45.99, 34.85, 30.73, 30.56, 28.17, 24.43, 21.85, 15.82, 13.84; ESI-HRMScalcdforC 26 H 38 N4O6S2m / z[M+H] + 567.2306, found [M+H] + 567.2313.

[0176] Example 31

[0177] tert-Butyl 4-((2-hexaneamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)piperidine-1-carboxylate, the structural formula is as follows:

[0178] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 40%. 1H NMR (300MHz, DMSO-d6) δ 12.11 (s, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.67 (dd, J = 8.5, 2.4Hz, 1H), 7.47 (t, J = 6.0Hz, 1H), 7.30 (d, J = 8.6Hz, 1H), 3.92 (s, 3H), 3. 87 (t, J=13.1Hz, 2H), 2.69 (t, J=6.3Hz, 2H), 2.41 (t, J=7.3Hz, 2H), 2.31 (s, 3H), 1.64-1.49(m, 5H), 1.36(s, 9H), 1.28-1.14(m, 6H), 0.96-0.83(m, 5H); 13 C NMR (101MHz, DMSO-d6) δ171.46, 155.37, 155.02, 153.88, 142.07, 134.17, 129.00, 128.61, 124.03, 122.3 4, 113.61, 78.52, 59.82, 56.35, 47.98, 35.82, 34.89, 30.75, 28.12, 24.46, 21.86, 15.83, 13.86; ESI-HRMS calcd for C 28 H 42 N4O6S2m / z[M+H] + 595.2619, found [M+H] + 595.2624.

[0179] Example 32

[0180] N-(5-(3-(2-(3,3-dimethylbutanamide)ethylaminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0181] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with N-(2-aminoethyl)-3,3-dimethylbutanamide, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 30%. 1H NMR (300MHz, DMSO-d6) δ12.11 (s, 1H), 7.84-7.59 (m, 3H), 7.42 (t, J=5.9Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 3.93 (s, 3H), 3.37 (s, 3H), 3.07 (t, J=6. 6Hz, 2H), 2.84 (q, J=6.7Hz, 2H), 2.41 (t, J=7.4Hz, 2H), 2.31 (s, 3H), 1.88 (s, 2H), 1.59 (t, J=7.2Hz, 2H), 1.32-1.21 (m, 4H), 0.97-0.83 (m, 9H); 13 C NMR (101MHz, DMSO-d6) δ171.39, 171.06, 155.33, 155.02, 142.07, 134.25, 128.94, 128.23, 124.09, 122.26, 113 .64, 56.38, 48.83, 42.40, 38.46, 34.87, 30.73, 30.29, 29.64, 24.44, 21.84, 15.81, 13.82; ESI-HRMScalcdforC 25 H 38 N4O5S2m / z[M+H] + 539.2356, found[M+H] + 539.2358.

[0182] Example 33

[0183] N-(5-(3-(2-hydroxy-2-methylpropyl)aminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-ylhexanamide, the structural formula is as follows:

[0184] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 1-amino-2-methyl-2-propanol, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 31%. 1H NMR (400MHz, DMSO-d6) δ12.12 (s, 1H), 7.72 (d, J = 2.4Hz, 1H), 7.68 (dd, J = 8.6, 2.4Hz, 1H), 7.32 (d, J = 8.7Hz, 1H), 6.96 (t, J = 6.4Hz, 1H), 3.94 (s, 3H), 2.70 (d, J = 6.4Hz, 2H), 2.41 (t, J = 7.4Hz.2H), 2.32 (s, 3H), 1.59 (p, J = 7.4Hz, 2H), 1.32-1.23 (m, 4H), 1.06 (s, 6H), 0.92-0.81 (m, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.37, 155.23, 154.97, 142.04, 134.12, 128.94, 128.23, 124.05, 122 .25, 113.60, 68.74.56.39, 53.89, 34.84, 30.71, 27.06, 24.40, 21.81, 15.81, 13.81; ESI-HRMS calcd for C 21 H 30 N3O5S2m / z[M+H] + 470.1778, found [M+H] + 470.1785.

[0185] Example 34

[0186] N-(5-(3-(N-(2-pyrolylethyl)aminosulfonyl))-4-methoxyphenyl)-4-methylthiazol-2-ylhexanamide, the structural formula is as follows:

[0187] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with N-(2-aminoethyl)morpholine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 20%. 1H NMR (400MHz, DMSO-d6) δ12.12 (s, 1H), 7.73 (d, J=2.3Hz, 1H), 7.68 (dd, J=8.6, 2.4Hz, 1H), 7.32 (d, J=8.7Hz, 1H), 7.16-7.04 (m, 1H), 3.96 ( s, 3H), 3.45 (t, J=4.7Hz, 4H), 2.96 (q, J=6.3Hz, 2H), 2.42 (t, J=7.4Hz, 2H), 2.32 (s, 3H), 2.28-2.19 (m, 6H), 1.79-1.73 (m, 2H), 1.37-1.17 (m, 4H), 0.90-0.85 (m, 3H); 13 C NMR (101MHz, DMSO) δ155.35, 154.96, 136.08, 134.65, 130.56, 129.14, 126.96, 126.53, 113.86, 112.90, 63.17, 56.35, 55.51, 51.35, 47.92, 36.94, 30.70, 24.40, 21.80, 15.85, 13.82.ESI-HRMS calcd for C 23 H 34 N4O5S2m / z[M+H] + 511.2043, found [M+H] + 511.2044.

[0188] Example 35

[0189] N-(5-(3-(((4-fluorophenyl)-12-nitrogenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0190] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 4-fluoroaniline, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 55%. 1H NMR (300MHz, DMSO-d6) δ12.10 (s, 1H), 10.10 (s, 1H), 7.71-7.67 (m, 1H), 7.65-7.59 (m, 1H), 7.24 (dd, J=9.1, 3.3Hz, 1H), 7.15-7.01 (m, 4H), 3.91 (d, J=2.0Hz, 3H), 2.46-2.35 (m, 2H), 2.22 (q, J=2.7, 1.9Hz, 3H), 1.57 (d, J=7.4Hz, 2H), 1.30-1.19 (m, 4H), 0.88-0.82 (m, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.47, 160.10 (d, J = 241.4Hz), 155.43, 155.05, 142.21, 134.97, 134.01, 129.75, 126.46, 124.04 , 122.19 (d, J=8.1Hz), 122.00, 115.91 (d, J=23.2Hz), 113.70, 56.42, 34.87, 30.75, 24.46, 21.87, 15.72, 13.87; ESI-HRMS calcd for C 23 H 25 FN3O4S2m / z[M+H] + 492.1422, found [M+H] + 492.1420.

[0191] Example 36

[0192] N-(5-(3-(((4-chlorophenyl)-12-nitrophenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0193] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 4-chloroaniline, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 49%. 1H NMR (300MHz.DMSO-d6) δ12.11 (s, 1H), 10.32 (s, 1H), 7.74 (d, J = 2.4Hz, 1H), 7.63 (dd, J = 8.6, 2.4Hz, 1H), 7.29-7.22 (m, 3H), 7.15 -7.10 (m, 2H), 3.89 (s, 3H), 2.40 (t, J = 7.4Hz, 2H), 2.24 (s, 3H), 1.58 (p, J = 7.3Hz, 2H), 1.37-1.12 (m, 4H), 0.84 (t, J = 6.8Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.45, 155.43, 155.09, 142.25, 136.83, 135.06, 129.79, 129.03, 127.86, 1 26.45, 124.12, 121.98, 121.06, 113.77, 56.44, 34.88, 30.75, 24.45, 21.86, 15.72, 13.85; ESI-HRMS calcd for C 23 H 25 ClN3O4S2m / z[M+H] + 508.1126, found [M+H] + 508.1133.

[0194] Example 37

[0195] N-(5-(3-(((4-fluorobenzyl)-12-nitrogenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0196] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 4-fluorobenzylamine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 54%. 1H NMR (300MHz, DMSO-d6) δ12.11 (s, 1H), 7.96 (t, J = 6.4Hz, 1H), 7.64-7.52 (m, 2H), 7.23-7.09 (m, 3H), 6.96 (dd, J = 10.1, 7.7Hz, 2H), 4.08 ( d, J=6.4Hz, 2H), 3.85 (s, 3H), 2.41 (t, J=7.4Hz, 2H), 2.29 (s, 3H), 1.65-1.54 (m, 2H), 1.26 (dd, J=6.4, 2.9Hz, 4H), 0.86 (t, J=6.7Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.41, 162.40 (d, J=244.4Hz), 155.11, 155.00, 141.96, 134.01, 133.71, 133.68, 129.71 (d, J=8.1Hz ), 128.84, 123.78, 122.38, 114.68 (d, J=21.2Hz), 113.18, 56.15, 45.63, 34.88, 30.74, 24.45, 21.85, 15.72, 13.85; ESI-HRMS calcd for C 24 H 28 FN3O4S2m / z[M+H] + 506.1578, found [M+H] + 506.1581.

[0197] Example 38

[0198] N-(5-(3-(((3-fluorobenzyl)-12-nitrogenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0199] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 3-fluorobenzylamine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 48%. 1H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 8.03 (t, J = 6.5Hz, 1H), 7.62 (d, J = 2.4H z, 1H), 7.54 (dd, J = 8.6, 2.4Hz, 1H), 7.21-7.16 (m, 1H), 7.11 (d, J = 8.8Hz, 1H) , 7.00-6.91(m, 3H), 4.12(d,J=6.5Hz, 2H), 3.85(s, 3H), 2.41(t,J=7.4Hz, 2H ), 2.28 (s, 3H), 1.62-1.56 (m, 2H), 1.38-1.16 (m, 4H), 0.85 (d, J=7.1Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.43, 163.11 (d, J=244.4Hz), 155.15, 155.02, 142.0 0, 140.54 (d, J = 7.1Hz), 134.17, 129.89 (d, J = 9.1Hz), 128.86 (d, J = 10.1Hz), 12 3.81, 123.66 (d, J=3.0Hz), 122.38, 114.34, 114.12, 113.82 (d, J=21.2Hz), 113 .15, 56.15, 45.77, 34.89, 30.77, 24.48, 21.89, 15.74, 14.02, 13.89; ESI-HRMS calcd for C 24 H 28 FN3O4S2m / z[M+H] + 506.1578, found [M+H] + 506.1584.

[0200] Example 39

[0201] N-(5-(3-(((2-fluorobenzyl)-12-nitrogenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0202] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 2-fluorobenzylamine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 42%. 1H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 7.93 (t, J=6.4Hz, 1H), 7.63 (d, J=2.4Hz, 1H ), 7.56-7.49(m, 1H), 7.32(td, J=7.6, 1.8Hz, 1H), 7.22-7.13(m, 1H), 7.09-6.97(m , 2H), 6.93-6.89 (m, 1H), 4.12 (dd, J=28.1, 6.3Hz, 2H), 3.82 (s, 3H), 2.41 (t, J=7.4 Hz, 2H), 2.29 (s, 3H), 1.60 (p, J = 7.4Hz, 2H), 1.36-1.21 (m, 4H), 0.90-0.81 (m, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.41, 160.78 (d, J=245.4Hz), 155.09, 155.02, 141.94, 134.14, 130.37 (d, J=3.0Hz), 129.69 (d, J=132.3Hz), 129.33 (d, J=8.1Hz), 128.88, 124.29 (d, J=15.2Hz), 123.97 (d, J=3.0Hz), 123.72, 122.40, 114.79 (d, J=21.2Hz), 113.04, 56.06, 55.90 (d, J=788.8Hz), 34.88, 30.76, 24.47, 21.88, 15.71, 13.87; ESI-HRMS calcd for C 24 H 28 FN3O4S2m / z[M+H] + 506.1578, found [M+H] + 506.1575.

[0203] Example 40

[0204] N-(4-(3-(((2,4-difluorobenzyl)-12-nitro-)sulfonyl)-4-methoxyphenyl)-5-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0205] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 2,4-difluorobenzylamine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 52%. 1H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 7.92 (t, J = 6.4Hz, 1H), 7.60 (d, J = 2.4Hz, 1 H), 7.54 (dd, J=8.6, 2.4Hz, 1H), 7.35 (td, J=8.7, 8.3, 6.6Hz, 1H), 7.07 (d, J=8.7H z, 1H), 6.96-6.84 (m, 2H), 4.13 (d, J=6.4Hz, 2H), 3.83 (s, 3H), 2.42 (t, J=7.4Hz, 2 H), 2.30 (s, 3H), 1.60 (p, J=7.4Hz, 2H), 1.32-1.25 (m, 4H), 0.87 (t, J=6.9Hz, 3H); 13 C NMR (101MHz, DMSO) δ171.35, 162.73 (dd, J=189.9, 12.1Hz), 160.28 (dd, J=192.9, 1 1.1Hz), 154.98, 141.93, 134.04, 131.70 (dd, J=15.2, 5.1Hz), 128.79, 128.35, 123. 73, 122.32, 120.67 (d, J = 4.0Hz), 120.54 (m), 112.97, 111.09 (dd, J = 18.2, 2.0Hz), 103.03 (t, J=51.5Hz), 56.04, 34.84, 30.72, 24.42, 21.82, 15.65, 13.82.; ESI-HRMS calcd for C 24 H 27 F2N3O4S2m / z[M+H] + 524.1484, found [M+H] + 524.1489.

[0206] Example 41

[0207] N-(5-(3-(((3,4-difluorobenzyl)-12-nitro-1-yl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0208] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 3,4-difluorobenzylamine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 54%. 1H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 8.00 (t, J=6.5Hz, 1H), 7.60 (d, J=2.4Hz, 1H), 7.55 (dd, J=8.6, 2.4Hz, 1H), 7.20-7.09 (m, 3H), 7.04-6.96 (m, 1H), 4.10 (d, J=6.5Hz, 2H), 3.86 (s, 3H), 2.41 (t, J=7.4Hz, 2H), 2.29 (s, 2 H), 1.63-1.56 (m, 2H), 1.27 (dt, J=10.3, 4.9, 4H), 0.87 (t, J=6.9Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.36, 155.02, 154.99, 141.96, 135.32 (dd, J=4.0, 3.0Hz), 134.05, 129.65, 128.82, 128.74, 124.50 (dd, J=3.0, 3.0 Hz), 123.80, 122.29, 116.86 (d, J = 17.2Hz), 116.62 (d, J = 17.2Hz), 113.03, 56.12, 45.27, 34.85, 30.72, 24.42, 21.83, 15.65, 13.82; ESI-HRMS calcd for C 24 H 27 F2N3O4S2m / z[M+H] + 524.1484, found [M+H] + 524.1480.

[0209] Example 42

[0210] N-(5-(3-(((3-chloro-4-fluorobenzyl)-12-nitro-)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0211] The raw material in step 1 of Example 1 was changed from 1-(4-chlorophenyl)-2-propanone to 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was changed to 3-chloro-4-fluorobenzylamine, and the acetyl chloride in step 4 was changed to hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid, yield: 50% 。 1H NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 8.00 (t, J=6.6Hz, 1H), 7.61-7.50 (m, 2H), 7.31 (d, J=7.3Hz, 1H), 7.15 (d, J=7.3Hz, 2H), 7.10 (d, J=8.6 Hz, 1H), 4.11 (d, J=6.5Hz, 2H), 3.86 (s, 3H), 2.41 (t, J=7.3Hz, 2H), 2.29 (s, 3H), 1.63-1.56 (m, 2H), 1.32-1.25 (m, 4H), 0.86 (t, J=6.8Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.35, 157.31 (d, J=247.4Hz), 154.97, 154.94, 1 41.94, 135.29 (d, J=3.0Hz), 134.03, 129.66, 128.766, 128.70, 128.41 (d, J=7.1Hz), 123.84, 122.29, 118.86 (d, J=17.2Hz), 116.23 (d, J=20.2Hz), 1 12.96, 56.11, 45.14, 34.85, 30.72, 24.42, 21.82, 15.71, 13.82; ESI-HRMS calcd for C 24 H 27 ClFN3O4S2m / z[M+H] + 540.1188, found [M+H] + 540.1182.

[0212] Example 43

[0213] N-(5-(3-(((4-fluoro-3-(trifluoromethyl)benzyl)-12-nitro-1-yl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0214] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 3-chloro-4-(trifluoromethyl)benzylamine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. Other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 44%. 1H NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 8.05 (t, J = 6.5Hz, 1H), 7.58 (d, J = 2.4Hz, 1H), 7.56-7.50 (m, 3H), 7.32-7.24 (m, 1H), 7.08 (d, J = 8.7Hz, 1H), 4.19 (d, J=6.5Hz, 2H), 3.83 (s, 3H), 2.41 (t, J=7.4Hz, 2H), 2.28 (s, 3H), 1.60 (p, J=7.4Hz, 2H), 1.36-1.18 (m, 4H), 0.87 (t, J=6.9Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.44, 156.56 (d, J=194.9Hz), 155.03, 154.90, 142 .00, 134.65 (d, J = 54.5Hz), 134.61 (d, J = 5.0Hz), 130.20 (d, J = 49.5Hz), 128.7 4, 128.67, 127.92, 126.60, 126.27 (m), 123.90, 122.29, 116.68 (d, J = 20.2Hz ), 113.00, 56.06, 45.15, 34.90, 30.79, 24.50, 21.91, 15.75, 13.90; ESI-HRMS calcd for C 25 H 27 F4N3O4S2m / z[M+H] + 574.1452, found [M+H] + 574.1444.

[0215] Example 44

[0216] N-(5-(4-methoxy-3-(((3,4,5-trifluorobenzyl)-12-nitrogenyl)sulfonyl)phenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0217] The raw material in step 1 of Example 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 3,4,5-trifluorobenzylamine, and the acetyl chloride in step 4 was replaced with hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 31%. 1H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 8.06 (t, J=6.6Hz, 1H), 7.60 (d, J=2.3Hz, 1H), 7.57 (dd, J=8.5, 2.4Hz, 1H), 7.14 (d, J=8.7Hz, 1H), 7.09 (dd, J=8. 9, 6.7Hz, 2H), 4.12 (d, J=6.6Hz, 2H), 3.87 (s, 3H), 2.41 (t, J=7.4Hz, 2H), 2. 28 (s, 3H), 1.60 (p, J = 7.2Hz, 2H), 1.33-1.23 (m, 4H), 0.87 (t, J = 6.8Hz, 3H); 13 C NMR (101MHz, DMSO-d6) δ171.37, 155.04, 154.99, 154.72, 141.98. 135.49, 134.15, 130. 23, 128.87, 128.66, 127.85, 126.62, 123.87, 122.22, 112.96 (d, J=72.7Hz), 112.03 (m), 56.14 (d, J=22.2Hz), 47.94, 45.10, 45.00, 34.85, 30.72, 24.43, 21.83, 15.59, 13.82; ESI-HRMS calcd for C 24 H 26 F3N3O4S2m / z[M+H] + 542.1390, found [M+H] + 542.1395.

[0218] Example 45

[0219] N-(5-(3-(((4-fluorophenethyl)-12-nitrogenyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0220] The raw material in step 1 of Example 1 was changed from 1-(4-chlorophenyl)-2-propanone to 1-(4-methoxyphenyl)-2-propanone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was changed to 4-fluorophenethylamine, and the acetyl chloride in step 4 was changed to hexanoyl chloride. The other steps and operations were the same as those in Example 1; the product was a white solid with a yield of 32%. 1H NMR (400MHz, DMSO-d6) δ12.12 (s, 1H), 7.70 (d, J=2.4Hz, 1H), 7.65 (dd, J=8.6, 2.4Hz, 1 H), 7.43 (t, J=5.8Hz, 1H), 7.26 (d, J=8.7Hz, 1H), 7.17-7.13 (m, 2H), 7.06-7.01 (m, 2H), 3.89 (s, 3H), 3.06 (q, J=6.8Hz, 2H), 2.68 (t, J=7.1Hz, 2H), 2.41 (t, J=7.4Hz, 2H), 2.31 (s, 3H), 1.59 (p, J=7.2Hz, 2H), 1.27 (td, J=8.5, 7.4, 5.0Hz, 4H), 0.86 (t, J=6.8Hz, 3H); 13 CNMR (101MHz, DMSO-d6) δ171.54, 162.12 (d, J=242.4Hz), 155.38, 155.07, 142.11, 135.00 (d, J=3.0Hz), 134.22, 130.55, 130.47, 128.93 ( d, J=53.5Hz),, 124.05, 122.40, 115.10 (d, J=20.2Hz), 113.65, 56.36, 44.20, 34.94, 34.49, 30.81, 24.53, 21.93, 15.87, 13.92; ESI-HRMS calcd for C 25 H 30 FN3O4S2m / z[M+H] + 520.1735, found [M+H] + 520.1735.

[0221] Example 46

[0222] Tert-butyl (2-(2-hexaneamido-4-methylthiazol-5-yl)-2-methoxybenzamido)ethylcarbamate:

[0223] Step 1: Synthesis of 2-methoxy-5-(2-oxopropyl)benzoic acid:

[0224] The raw materials (10 mmol) of methyl 5-formyl-2-methoxybenzoate and butylamine (2.0 eq.) were dissolved in toluene and refluxed for 3 h. After distillation to dryness under reduced pressure, the mixture was dissolved in 10 mL of acetic acid. 1.14 mL of nitroethane (1.5 eq.) was slowly added to the reaction solution, and the mixture was heated to 100°C for 3 h. After the reaction, the reaction solution was cooled to room temperature and slowly poured into 40 mL of ice-water solution (stirred vigorously throughout the process), and the mixture was extracted with ethyl acetate solution (2×40 mL). The organic phase was collected and washed with water (2×40 mL), 10% sodium bicarbonate solution (2×30 mL) and brine in sequence, dried over anhydrous magnesium sulfate, and purified by column chromatography (PE:EA=2:1) ​​to obtain (Z)-2-methoxy-5-(2-nitropropen-1-yl)benzoic acid methyl ester with a yield of 80%. 100 mmol of iron powder was added to a reaction bottle with 22 mL of acetic acid, and the solution of (Z)-2- A solution of methyl methoxy-5-(2-nitropropen-1-yl)benzoate (8 mmol) in 12 mL of acetic acid was slowly added dropwise to the above reactor. After reflux for 2 h, the reaction solution was cooled to room temperature, the iron powder was filtered, 30 mL of water was added to the filtrate, and the mixture was extracted with ethyl acetate solution (3×40 mL). The organic phase was collected and washed with water (2×30 mL), 10% sodium bicarbonate solution (2×30 mL) and brine (30 mL) in sequence, dried over anhydrous magnesium sulfate, and purified by column chromatography (PE:EA=1:1) to give methyl 2-methoxy-5-(2-oxopropyl)benzoate in a yield of 90%. 2 mmol of methyl 2-methoxy-5-(2-oxopropyl)benzoate was weighed and subjected to acid hydrolysis to obtain 2-methoxy-5-(2-oxopropyl)benzoic acid as a white solid, with a yield of 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-d6) 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). Step 2: Synthesis of tert-butyl (2-(2-hexaneamido-4-methylthiazol-5-yl)-2-methoxybenzamido)ethylcarbamate, the structural formula is as follows:

[0225] 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 tert-butyl (2-aminoethyl)carbamate was added to the reaction solution and reacted at room temperature. The reaction was completed and purified to give tert-butyl (2-(2-methoxy-5-(2-oxopropyl)benzamido)ethyl)carbamate. Subsequently, steps 3 and 4 of Example 1 were followed to give tert-butyl (2-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamido)ethylcarbamate as a white solid in a 40% yield. 1 H NMR (400MHz, DMSO-d6) δ12.12 (s, 1H), 7.73 (d, J = 2.3Hz, 1H), 7.68 (dd, J = 8. 6, 2.4Hz, 1H), 7.32 (d, J = 8.7Hz, 1H), 7.16-7.04 (m, 1H), 3.96 (s, 3H), 3.45 ( t, J=4.7Hz, 4H), 2.96 (q, J=6.3Hz, 2H), 2.42 (t, J=7.4Hz, 2H), 2.32 (s, 3H), 2.28-2.19(m, 6H), 1.79-1.73(m, 2H), 1.37-1.17(m, 4H), 0.90-0.85(m, 3H); 13 C NMR (101MHz, DMSO) δ155.35, 154.96, 136.08, 134.65, 130.56, 129.14, 126.96, 126.53, 113.86, 112.90, 63.17, 56.35, 55.51, 51.35, 47.92, 36.94, 30.70, 24.40, 21.80, 15.85, 13.82.ESI-HRMS calcd for C 23 H 34 N4O5S2m / z[M+H] + 511.2043, found [M+H] + 511.2044.

[0226] Example 47

[0227] N-(4-(3-(((2,4-difluorobenzyl)-12-nitro-)sulfonyl)-4-methoxyphenyl)-5-methylthiazol-2-yl)hexanamide, the structural formula is as follows:

[0228] The preparation method was similar to that of Example 1, except that the starting material in step 1 was replaced with 1-(4-chlorophenyl)-2-propanone or 4′-methoxypropiophenone, the fragment (2-aminoethyl)carbamic acid tert-butyl ester in step 2 was replaced with 2,4-difluorobenzylamine, and acetyl chloride in step 4 was replaced with hexanoyl chloride. Other steps and operations were the same as those of Example 1. The product was a white solid with a yield of 51%. 1 H NMR (300MHz, DMSO-d6) δ12.08 (s, 1H), 8.01 (d, J = 2.3Hz, 1H), 7.84 (d, J = 6.4Hz, 1H), 7.75 (dd, J=8.7, 2.3Hz, 1H), 7.39-7.31 (m, 1H), 7.09 (d, J=8.7Hz, 1H), 6.97 -6.89(m, 2H), 4.09(d, J=6.3Hz, 2H), 3.84(s, 3H), 2.45(s, 3H), 2.4(0(t, J=7.4 Hz, 2H), 1.64-1.56 (m, 2H), 1.26 (td, J=6.4, 6.0, 3.0Hz, 4H), 0.89-0.84 (m, 3H); 13 C NMR (101MHz, DMSO) δ171.33, 162.77 (d, J = 204.0Hz), 160.17 (d, J = 177.8Hz), 1 54.88, 154.01, 142.26, 132.99, 131.58 (d, J=6.1Hz), 128.78, 127.96, 126.88, 120.88 (dd, J=15.2, 3.0Hz), 120.26, 112.27, 111.08 (dd, J=18.2, 3.0Hz), 103. 12(t, J=52.5Hz), 55.98, 34.81, 30.74, 24.43, 21.82, 13.82, 11.77.; ESI-HRMS calcd for C 24 H 27 F2N3O4S2m / z[M+H] + 524.1484, found [M+H] + 524.1491.

[0229] PI4KIII β kinase inhibition experiment was performed on the inhibitor of the present invention: ADP-Glo ​​Luminescent Kinase Assay method was used for testing. The reagents used in the kinase reaction were as follows: HEPES (50mM) pH 7.5 with NaCl (100mM), EGTA (1.0mM), MgCl2 (3.0mM), DTT (2.0mM) and CHAPS (0.03%). During the reaction, 50μM PIP2 and 25μM ATP were added to each 10mL of test compound (0.05nM-1.0μM) at different concentrations. The reaction system was incubated at room temperature for 1h, and then 10μL of the reagent ADP-Glo ​​was added to terminate the enzyme reaction. Data were collected using Envision software, and Graphpad Prism 5 was used to analyze and fit the IC of the compound. 50 value.

[0230] Table 1 PI4KIII β enzyme inhibitory activity (IC 50 , nM)

[0231] As shown in Table 1, the compounds of the present invention exhibit nanomolar inhibitory activity against PI4KIII β kinase, and some compounds are significantly superior to the positive control PIK-93. In particular, Examples 10, 11, 12, 14, 20, 21, 24, 27, and 33 exhibit significantly superior inhibitory activity against PI4KIII β kinase compared to the positive control PIK-93. This demonstrates that the compounds of the present invention are highly effective PI4KIII β inhibitors.

[0232] Anti-proliferative activity experiments on tumor cell lines were conducted using the inhibitors of the present invention:

[0233] The CCK 8 method was used to evaluate the inhibitory activity of the compounds on cell proliferation, and the half-maximal inhibitory concentration (IC) was determined by single-concentration activity screening and multiple-concentration determination. 50 The assay principle is as follows: Cytotoxicity (CCK 8 assay): The CCK 8 reagent contains WST-8, which is reduced by mitochondrial dehydrogenases to a highly water-soluble yellow formazan product (formazan) under the action of the electron carrier 1-methoxy-5-methylphenazine methylsulfate (1-methoxy PMS). The amount of formazan produced is proportional to the number of viable cells.

[0234] The experimental method is as follows:

[0235] (1) Cell inoculation: Prepare cells into a single cell suspension using culture medium containing 10% fetal bovine serum, and inoculate 90 μL of 5×10 cells per well of a 96-well plate. 4 / mL of adherent cells and 9×10 4 / mL suspension cells were pre-cultured at 5% CO2 and 37°C for 24h.

[0236] (2) Add the sample solution to be tested: add 10 μL of sample solution to each well. Set one concentration for each sample in the initial activity screening, and set up 3 replicate wells; IC 50 Eight concentrations (including 0) were measured, with three replicates for each concentration. The cells were then incubated in an incubator for 48 hours. The experiment consisted of a blank group (Blank), a control group (Control), and a drug group (Drug).

[0237] (3) Color development: Aspirate the old culture medium and drug solution from adherent cells (add 10 μL CCK 8 stock solution directly to suspended cells), add 100 μL CCK 8 solution diluted tenfold to each well, and continue to culture at 37°C, 5% CO2 for 14 h (operation, real-time observation).

[0238] (4) Detection: Measure the absorbance at 450 nm using an enzyme-labeled instrument and record the raw data results.

[0239] (5) The original data were normalized using Excel software, and the cell proliferation inhibition rate was calculated by the OD value of each well (formula = (OD Control OD Drug ) / (OD Control OD Blank )×100%), statistical inhibition rate. IC 50 Calculated by GraphPad Prism 8.

[0240] Table 2 Tumor cell line proliferation inhibitory activity (IC 50 , μM)

[0241] As shown in Table 2, the compounds of the present invention exhibit micromolar-level antiproliferative activity against various tumor strains. In particular, most of the example compounds exhibited high sensitivity against the human small cell lung cancer cell line H446 and the human colon cancer cell line HT29. Among them, 12 compounds, including Example 9, exhibited nanomolar inhibitory activity against multiple cell lines listed in Table 3, significantly outperforming the positive control PIK-93. Furthermore, Example 11 exhibited nanomolar inhibitory activity against six of the eight cell lines listed in Table 3, with inhibitory activities of 38 nM and 49 nM against the H446 and HT29 cell lines, respectively, significantly outperforming the positive control PIK-93. This suggests that the compounds of the examples of the present invention have potential clinical applications in the treatment of these tumors.

[0242] PI4KIII β pharmacokinetic experiments were performed on the inhibitors of the present invention:

[0243] Weigh the test sample into a sterile vial and add 250 μL of DMSO, followed by 10 μL of methanesulfonic acid. Dissolve the sample, then add 4.78 mL of 5% glucose injection. Mix by sonication and vortexing to create a 2 mg / mL test sample solution. This solution is used for oral administration. Separately, take 0.5 mL of the 2 mg / mL test sample solution, add 4.5 mL of 5% glucose injection, vortex and mix to create a 0.2 mg / mL test sample solution for intravenous administration.

[0244] Twenty SD rats were divided into four groups. Due to the instability of the structures of Examples 11 and 27 under acidic conditions, Examples 11 and 27 were injected via the tail vein (5 mg / kg), while Example 40 was administered via tail vein injection (5 mg / kg) and oral gavage (50 mg / kg), respectively. Blood samples (approximately 0.25 mL) were collected from the retroorbital venous plexus at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h after administration in the intravenous injection group; and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration in the oral gavage group. The concentrations of Examples 11, 27, and 40 in the plasma samples of SD rats were determined by LC-MS / MS, and the pharmacokinetic parameters were calculated using WinNolin software. The results are shown in Table 3.

[0245] The results are shown in Table 3. Examples 11, 27 and 40 of the present invention are well metabolized in rats, with good absorption and exposure, and Example 40 has a high bioavailability.

[0246] Table 3 Pharmacokinetic parameter records

[0247] Experiments were conducted on the anti-tumor efficacy and toxicity of the PI4KIII β inhibitor of the present invention:

[0248] The drugs used were those in Examples 11, 27, and 40. The cell line was the human small cell lung cancer cell line H446, cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum. The test animals were SPF-grade male BALB / c nude mice, five per group. The drug dosages were as shown in Table 4.

[0249] Table 4 Drug dosage configuration

[0250] Drug preparation method:

[0251] Example 11 (20 mg / kg): 4 mg of the test compound powder was weighed and dissolved in 2 mL of normal saline to prepare a drug concentration of 2 mg / mL, which was administered orally or by injection at a volume of 0.2 mL / 20 g.

[0252] Example 11 (30 mg / kg): 6 mg of the test compound powder was weighed and dissolved in 2 mL of normal saline to a concentration of 3 mg / mL. The drug was administered orally or by injection at a volume of 0.2 mL / 20 g.

[0253] Example 27 (30 mg / kg): 6 mg of the test compound powder was weighed and dissolved in 2 mL of normal saline to a concentration of 3 mg / mL. The drug was administered orally or by injection at a volume of 0.2 mL / 20 g.

[0254] Example 40 (75 mg / kg): 15 mg of the test compound powder was weighed and dissolved in 2 mL of normal saline to a concentration of 7.5 mg / mL. The drug was administered orally by gavage at a volume of 0.2 mL / 20 g.

[0255] Example 40 (150 mg / kg): 30 mg of the test compound powder was weighed and dissolved in 2 mL of normal saline to a concentration of 15 mg / mL. The drug was administered orally by gavage at a volume of 0.2 mL / 20 g.

[0256] Experimental Methods: A human lung cancer xenograft model was established in nude mice by inoculating the human small cell lung cancer cell line H446 subcutaneously in the axilla of 1,000 nude mice. H446 cells in the logarithmic growth phase were taken and inoculated subcutaneously in the right axilla of 50 nude mice under sterile conditions. The cell inoculation volume was 5×10 6 Use a vernier caliper to measure the diameter of the transplanted tumor. When the tumor grows to 80 mm 3 42 tumor-bearing nude mice with good growth and uniform tumor size were selected and randomly divided into 7 groups, each with 6 mice, namely model group 1, low-dose group of Example 11 (20 mg / kg), high-dose group of Example 11 (30 mg / kg), group of Example 27 (30 mg / kg), model group 2, low-dose group of Example 40 (75 mg / kg), and high-dose group of Example 40 (150 mg / kg). The test drug of the low-dose and high-dose groups of Example 11 and Example 27 was administered by injection, and the low-dose and high-dose groups of Example 40 were administered by gavage, with administration every two days. Model groups 1 and 2 were given an equal volume of vehicle as a control. The anti-tumor effect of the test substance was dynamically observed by measuring tumor diameter. The tumor diameter was measured every other day, and the nude mice were weighed at the same time as the tumor diameter was measured. On the 27th day, the mice were sacrificed, and the tumor masses were surgically removed and fixed with 10% formaldehyde and stored in liquid nitrogen for later use.

[0257] Experimental results showed that Example 11 exhibited effective antitumor activity at 20 mg / kg, with a tumor growth inhibition rate (TGI) of 25.7% and a relative tumor growth rate (T / C) of 72.3% compared to the model group. When the dose was increased to 30 mg / kg, the tumor growth inhibition effect was even greater (TGI = 37.1%, T / C = 60.2%), significantly exceeding that of Example 27 (TGI = 30.2% and T / C = 66.8%). Furthermore, Example 40 demonstrated even more significant antitumor efficacy at an oral dose of 150 mg / kg, with a TGI of 42.2% and a T / C of 52.1%. (Figures 1-3 show the results of in vivo anti-tumor efficacy and toxicity studies of PI4KIII β inhibitors. Figures 1 and 2 contain growth curves of mouse tumor volume and body weight and representative images of mouse tumor tissues; Figure 3 shows pathological sections of major tissues obtained from mice bearing lung tumors; organs were stained with hematoxylin and eosin (H&E) and representative images were captured). Combined with the above figures, it can be seen that the test drugs prepared in Examples 11 and 40 have a significant inhibitory effect on the growth of human lung cancer H446 xenograft tumors in nude mice.

[0258] The phenylthiazolamine PI4KIII β inhibitor of the present invention effectively inhibits the proliferation of various solid tumors and blood tumor cells by PI4KIII β, has high sensitivity to small cell lung cancer and colon cancer, and has anti-tumor efficacy, and can be potentially used in the clinical treatment of these diseases.

Claims

1. A phenylthiazolamine-based PI4KIIIβ inhibitor, characterized in that, The inhibitor is a substituted phenylthiazolamine compound represented by General Formula V, or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof: Among them, A is R1 is a substituent on the benzene ring selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy or C1-C6 alkoxy C1-C6 alkyl; R2 is R3 or R4 is 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; X is sulfonyl or carbonyl.

2. The inhibitor according to claim 1, wherein The inhibitor is a compound represented by General Formula I or II: wherein, the definitions of R1, R2, R4 and X are the same as those described in Claim 1; R3 is 3. The inhibitor according to claim 1, wherein In the inhibitor of General Formula V, the hydrogen connected to carbon is replaced by the isotope deuterium of hydrogen.

4. The inhibitor according to any one of claims 1 to 3, characterized in that, The inhibitor is one of the following: (1) tert-Butyl (2-(5-(2-acetamido-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethyl)carbamate; (2) N-(5-(4-Chloro-3-(N-(2-hydroxy-2-methylpropyl)aminosulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide; (3) N-(2-(2-Acetamido-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethyl propionamide; (4) Methyl (2-(2-acetamido-4-methylthiazol-5-yl)-2-chlorophenylsulfonamido)ethylcarbamate; (5) tert-Butyl (2-((5-(2-acetamido-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonamido)ethyl)carbamate; (6) N-(5-(4-Chloro-3-(N-(3-hydroxy-4-methylphenyl)aminosulfonyl)phenyl)-4-methylthiazol-2-yl)acetamide; (7) N-(5-(3-(N-(2,4-Difluorophenyl)aminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)acetamide; (8) tert-Butyl (5-(2-propionamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate; (9) tert-Butyl (5-(2-butyramido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate; (10) tert-Butyl (5-(2-valeramido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate; (11) tert-Butyl (5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate; (12) tert-Butyl (5-(2-heptanamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethylcarbamate; (13) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(3-propylureido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate; (14) tert-Butyl (2-(5-(2-(3-butylureido)-4-methylthiazol-5-yl)-2-methoxyphenylsulfonamido)ethyl)carbamate; (15) tert-Butyl (2-(2-methoxy-5-(4-methyl-2-(3-methylbutyramido)thiazol-5-yl)phenyl)sulfonamido)ethylcarbamate; (16)tert-Butyl ((5-(2-isobutyrylamino-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfamoyl)ethylcarbamate; (17)tert-Butyl ((2-(2-methoxy-5-(4-methyl-2-pivaloylaminothiazol-5-yl)phenyl)sulfamoyl)ethylcarbamate; (18)tert-Butyl ((5-(2-(3,3-dimethylbutyramido)-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfamoyl)ethylcarbamate; (19)tert-Butyl ((2-(2-methoxy-5-(4-methyl-2-(4-methylpentanamido)thiazol-5-yl)phenyl)sulfamoyl)ethylcarbamate; (20)tert-Butyl ((2-(2-methoxy-5-(4-methyl-2-(5-methylhexanamido)thiazol-5-yl)phenyl)sulfamoyl)ethylcarbamate (21)tert-Butyl ((2-(5-(2-(cyclohexanecarboxamido)-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfamoyl)ethylcarbamate; (22)tert-Butyl ((2-(2-chloro-5-(4-methyl-2-(3-methylbutyramido)thiazol-5-yl)phenyl)sulfamoyl)ethylcarbamate; (23)tert-Butyl ((2-chloro-5-(2-(3,3-dimethylbutyramido)-4-methylthiazol-5-yl)phenylsulfamoyl)ethylcarbamate; (24)tert-Butyl ((2-chloro-5-(4-methyl-2-pentanamido-5-yl)phenylsulfamoyl)ethylcarbamate; (25)tert-Butyl ((2-chloro-5-(2-hexanamido-4-methylthiazol-5-yl)phenylsulfamoyl)ethylcarbamate; (26)tert-Butyl ((2-(5-(2-(3-acetamidopropanamido)-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfamoyl)ethylcarbamate; (27)(2-(2-methoxy-5-(4-methyl-2-(6-oxoheptanamido)thiazol-5-yl)phenyl)sulfamoyl) tert-Butyl ethylcarbamate; (28)tert-Butyl ((2-(2-methoxy-5-(4-methyl-2-(6-oxohexanamido)thiazol-5-yl)phenyl)sulfamoyl)ethylcarbamate; (29)(R)-(tert-Butyl (1-((5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonyl)piperidin-3-yl)carbamate; (30)(S)-(tert-Butyl (1-((5-(2-hexanamido-4-methylthiazol-5-yl)-2-methoxyphenyl)sulfonyl)pyrrolidin-3-yl)carbamate; (31)tert-Butyl 4-((2-hexanamido-4-methylthiazol-5-yl)-2-methoxyphenylsulfamoyl)piperidine-1-carboxylate; (32)N-(5-(3-(2-(3,3-dimethylbutyramido)ethylsulfamoyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (33) N-(5-(3-(2-Hydroxy-2-methylpropyl)aminosulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-ylhexanamide; (34) N-(5-(3-(N-(2-Quinolinylethyl)aminosulfonyl))-4-methoxyphenyl)-4-methylthiazol-2-ylhexanamide; (35) N-(5-(3-(((4-Fluorophenyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (36) N-(5-(3-(((4-Chlorophenyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (37) N-(5-(3-(((4-Fluorobenzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (38) N-(5-(3-(((3-Fluorobenzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (39) N-(5-(3-(((2-Fluorobenzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (40) N-(4-(3-(((2,4-Difluorobenzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-5-methylthiazol-2-yl)hexanamide; (41) N-(5-(3-(((3,4-Difluorobenzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (42) N-(5-(3-(((3-Chloro-4-fluorobenzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (43) N-(5-(3-(((4-Fluoro-3-(trifluoromethyl)benzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (44) N-(5-(4-Methoxy-3-(((3,4,5-trifluorobenzyl)-l2-azanyl)sulfonyl)phenyl)-4-methylthiazol-2-yl)hexanamide; (45) N-(5-(3-(((4-Fluorophenethyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-4-methylthiazol-2-yl)hexanamide; (46) tert-Butyl (2-(2-Hexanamido-4-methylthiazol-5-yl)-2-methoxybenzamido)ethylcarbamate; (47) N-(4-(3-(((2,4-Difluorobenzyl)-l2-azanyl)sulfonyl)-4-methoxyphenyl)-5-methylthiazol-2-yl)hexanamide.

5. A method for preparing the inhibitor according to claim 1, characterized in that, Using 1-(4-chlorophenyl)-2-propanone or 1-(4-methoxyphenyl)-2-propanone as raw materials 1a and 1b, the raw materials 1a and 1b undergo a substitution reaction with chlorosulfonic acid at the 3-position of the benzene ring to obtain intermediates 2a and 2b; on the basis of intermediates 2a and 2b, the R2 group is introduced through the Hinsberg reaction to obtain intermediates 3a - 3g; intermediates 3a - 3g undergo an α-bromination reaction with phenyltrimethylammonium tribromide to obtain intermediates 4a - 4g; intermediates 4a - 4g undergo a condensation reaction with N-acetylthiourea to obtain the target compounds 5a - 5g. The synthetic route is as follows:

6. The manufacturing method according to claim 5, characterized in that, According to the preparation method of target compounds 5a - 5g, using intermediates 4d and 4e as raw materials, and simultaneously introducing the R3 group by the substitution reaction of thiourea with various acyl chlorides to obtain intermediate N - substituted thiourea as another type of raw material; the two are subjected to a condensation reaction to obtain target compounds 7a - 7r; or using intermediate 4e as a raw material, reacting with thiourea to obtain intermediate 8; intermediate 8 respectively undergoes substitution reactions with 3 - acetamidopropanoyl chloride, 6 - oxoheptanoyl chloride, and 5 - oxohexanoyl chloride to obtain target compounds 9a - 9c. The synthetic routes are as follows: Or according to the preparation method of target compounds 5a - 5g, obtaining compounds 4h - 4x as raw materials, reacting with N - hexanoylthiourea to undergo a condensation reaction to obtain target compounds 10a - 10q. The synthetic routes are as follows:

7. The manufacturing method according to claim 6, wherein Using compound 8 as the raw material, intermediate 9 was obtained through two-step reactions; intermediate 9 was subjected to a reduction reaction with iron powder by heating under reflux in acetic acid to obtain intermediate 10; intermediate 10 underwent a hydrolysis reaction under acidic conditions to obtain intermediate 11; intermediate 11 reacted with tert-butyl (2-aminoethyl)carbamate to obtain intermediate 12, and the target compound 46 was obtained through two-step reactions. The synthetic route is as follows: Or using 4'-methoxypropiophenone 14 as the raw material, the target compound 47 was obtained through four-step reactions. The synthetic route is as follows:

8. A pharmaceutical composition, characterized in that, The composition comprises at least one pharmaceutically acceptable excipient, adjuvant or carrier, and the phenylthiazolamine PI4KIIIβ inhibitor according to any one of claims 1 to 3.

9. Use of the phenylthiazolamine PI4KIIIβ inhibitor according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of a drug for preventing, treating or adjuvantly treating proliferative diseases, metabolic diseases, nervous system diseases or tuberous sclerosis caused by overactivation of PI4KIIIβ kinase.

10. Use of the phenylthiazolamine PI4KIIIβ inhibitor according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of a drug for inhibiting the growth of cancer cells.

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