A triazine-thiazolidinone compound and its preparation method and application

Abstract

The present invention belongs to the field of medicinal chemistry and relates to a triazine-thiazolidinone compound and its preparation method and application. Its structural formula is wherein R1 is any one of alkyl, pyranyl, indolyl, phenyl or thienyl. Its pharmaceutically acceptable salt is the acid salt of the compound, and the acid is any one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, citric acid, lactic acid, pyruvic acid, tartaric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, salicylic acid or phenylacetic acid. The triazine-thiazolidinone compound skeleton provided by the present invention is novel, has a good inhibitory effect on glucose transporter 1 (GLUT1), and its inhibitory effect in HT29 cells is much better than that of positive control compound BAY-876, with good potential for further development as an anti-tumor drug.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to a triazine-thiazolidinone compound and a preparation method and application thereof. Background Art

[0002] Glucose is the main energy source in mammals, providing energy to the body through oxidative metabolism. Glucose is hydrophilic in nature and cannot penetrate the lipid bilayer of the cell membrane. It requires specific membrane carrier proteins to transport it into the cell, the so-called glucose transporters. There are two different types of glucose transporters in the human body, namely SGLTs (sodium-dependent glucose transporters) and GLUTs (facilitatory glucose transporters). Studies have found that in order to grow, proliferate and metastasize rapidly, tumor cells must express a large number of GLUTs to increase glucose uptake to provide sufficient energy. Therefore, GLUTs are overexpressed in many tumors, including brain cancer, breast cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, etc.

[0003] There are 14 GLUTs (GLUT1-GLUT14). GLUT1 is the most intensively studied of these 14 subtypes. It is widely distributed on the surface of most cells and is often overexpressed in malignant tumor cells, increasing their glucose uptake and providing sufficient raw materials for tumor growth. Studies have shown that GLUT1 is closely associated with tumor proliferation, invasion, and metastasis. It can serve as a diagnostic marker for early malignant lesions and has become a popular new target for tumor treatment in recent years.

[0004] There are currently two common methods for testing the inhibition rate of compounds on GLUT1. One is to add glucose after incubating the compound with tumor cells, and then measure the amount of ATP produced by the tumor cells to calculate the glucose consumption, thereby indirectly obtaining the inhibitory activity data of the compound on GLUT1; the other is to directly incubate the compound with tumor cells and add glucose analogs, and then obtain the direct inhibition of the compound on GLUT1 by measuring the cell uptake of glucose analogs. The first method is more sensitive by detecting the amount of ATP; the second method is more direct and can better reflect the actual inhibition of the compound on GLUT1 in tumor cells, but its sensitivity is lower than the first method. The results obtained by the two methods (IC 50 ) values ​​often differ greatly, so a certain compound is generally selected as a positive control compound and compared with the same method to evaluate the inhibitory activity of the compound on GLUT1.

[0005] Currently, a variety of synthetic GLUT1 inhibitors such as WZB117, BAY-876, Glutor, PUG-1, etc. have been reported (as shown below). These compounds have been shown to be extremely valuable for tumor suppression in various types of cancer cells and animal model experiments. Bayer uses the ATP detection method to characterize the inhibitory activity of compounds on GLUT1. The IC of BAY-876 on GLUT1 inhibition is 50 The activity reaches 2 nM, which is the best among the inhibitors reported so far.

[0006]

[0007] However, it's important to note that as an emerging anti-tumor target in recent years, the number of reported inhibitors and scaffold types remains relatively limited, hindering the development of anti-tumor drugs targeting GLUT1. Currently, no compounds targeting this target have been approved for marketing or are in clinical development. Bayer's BAY-876 is currently in preclinical development.

[0008] Therefore, the research and development of GLUT1 inhibitors that are different from those reported and have novel structures and better inhibitory activity has important significance and application value for the development of anti-tumor drugs. Summary of the Invention

[0009] The present invention aims to provide a novel class of previously unreported compounds containing a triazine-thiazolidinone structure. Another objective is to provide methods for their preparation and their use as anti-tumor agents for inhibiting glucose transporter 1. This class of GLUT1 inhibitors containing a triazine-thiazolidinone structure exhibits significantly enhanced GLUT1 inhibitory activity, generally significantly outperforming Bayer's BAY-876, and has great potential for development as anti-tumor drugs.

[0010] In order to achieve the above object, the technical solution of the present invention is achieved as follows:

[0011] A triazine-thiazolidinone compound, the triazine-thiazolidinone compound has a structural formula as shown in formula (I) Wherein R1 is any one of alkyl, pyranyl, indolyl, phenyl or thienyl.

[0012] The alkyl group in R1 is a substituted or optionally substituted chain saturated hydrocarbon group or a cyclic saturated hydrocarbon group; the pyranyl group is a tetrahydropyranyl group; the indolyl group is a substituted indolyl group or an isoindolyl group; the thienyl group is a thiophene-2-methyl group; and the phenyl group is an unsubstituted phenyl group or a 4-aminophenyl group.

[0013] The alkyl group in R1 is any one of propyl, diethyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-aminoethyl or 3-aminopropyl; the pyranyl is tetrahydropyranyl; the indolyl is octahydroisoindolyl or dihydroindolyl; the thienyl is thiophene-2-methyl; and the phenyl is unsubstituted phenyl or 4-aminophenyl.

[0014] The triazine-thiazolidinone compound has the structure shown below:

[0015]

[0016] A pharmaceutically acceptable salt of a triazine-thiazolidinone compound, comprising a pharmaceutically acceptable salt of the triazine-thiazolidinone compound, wherein the salt is any one of hydrochloride, hydrobromide, sulfate, phosphate, borate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, benzenesulfonate, citrate, lactate, pyruvate, tartrate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, salicylate or phenylacetate.

[0017] The preparation method of the triazine-thiazolidinone compound comprises the following steps:

[0018]

[0019] (1) The amine raw material containing R1 is dissolved in solvent A and reacted with bromoacetyl bromide under the action of an alkaline substance to prepare intermediate 17; wherein the structural formula of intermediate 17 is

[0020] (2) After the intermediate 17 and the raw material 18 are dissolved in solvent B, they are heated under reflux reaction under the action of an alkaline substance to obtain a triazine-thiazolidinone compound, wherein the structural formula of the triazine-thiazolidinone compound is Wherein R1 is any one of alkyl, pyranyl, indolyl, phenyl or thienyl.

[0021] The structural formula of the amine raw material containing R1 in step (1) is R1 is any one of alkyl, pyranyl, indolyl, phenyl or thienyl; the structural formula of bromoacetyl bromide is Solvent A is any one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dichloromethane, chloroform or dioxane; the alkaline substance is any one or more of triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide; the molar ratio of the amine raw material containing R1 to bromoacetyl bromide and the alkaline substance in step (1) is 1:(1-1.2):(1.1-1.4); the reaction temperature is -10°C to room temperature, and the reaction time is 1-2h.

[0022] The structural formula of the raw material 18 in step (2) is The molar ratio of raw material 18 to intermediate 17 and alkaline substance is 1:(1.1-1.2):(1.2-1.4); solvent B is any one or more of tetrahydrofuran, acetonitrile, and dioxane; and the heating reflux time is 1-2 h.

[0023] If the amine raw material containing R1 used in step (1) contains a tert-butyloxycarbonyl protecting group (abbreviated as Boc), an acidic substance is required to remove the tert-butyloxycarbonyl protecting group in step (2). The acidic substance is one of trifluoroacetic acid, hydrogen chloride gas, and hydrogen chloride solution. After the tert-butyloxycarbonyl protecting group is removed by acid, the resulting product is a salt corresponding to the acid used. The resulting salt can be used directly, or can be further neutralized with a base to form a neutral compound for use, or can be further subjected to a salt-forming reaction with other types of acids, all of which will not affect the skeleton structure and use effect of the triazine-thiazolidinone compound of the present invention.

[0024] In the present invention, the total yield of the two-step reaction is 46-80%.

[0025] The preparation method of raw material 18 in step (2) is:

[0026]

[0027] (a) Dissolving cyanuric acid and cyclopentylamine in solvent 1, and reacting to obtain intermediate 19; wherein the structural formula of intermediate 19 is

[0028] (b) Dissolving intermediate 19 with 4-hydroxyaniline and a base in solvent 1 and reacting to obtain intermediate 20; wherein the structural formula of intermediate 20 is

[0029] (c) Dissolving intermediate 20 and hydrazine hydrate in solvent II, heating under reflux to react, to obtain intermediate 21; wherein the structural formula of intermediate 21 is

[0030] (d) Dissolving intermediate 21 and (biscarboxymethyl) trithiocarbonate in solvent II and reacting to obtain intermediate 22; wherein the structural formula of intermediate 22 is

[0031] (e) adding intermediate 22, thiophene-3-carboxaldehyde, and catalyst I to glacial acetic acid for reaction to obtain raw material 18; wherein the structural formula of raw material 18 is

[0032] In the step (a), the solvent I is any one or more of tetrahydrofuran, acetonitrile, acetone, methanol or ethanol; the molar ratio of melamine to cyclopentylamine is 1:(0.8-1.2); the reaction temperature is 0-40° C., and the reaction time is 1-3 h.

[0033] In step (b), the base is any one or more of triethylamine, potassium carbonate or sodium carbonate; the molar ratio of intermediate 19, 4-hydroxyaniline and base is 1:(0.9-1.1):(1.1-1.2); the solvent I is any one or more of tetrahydrofuran, acetonitrile, acetone, methanol or ethanol; the reaction temperature is 0-40° C., and the reaction time is 4-8 h.

[0034] In the step (c), the molar ratio of the intermediate 20 to hydrazine hydrate is 1:(2-6); the solvent II is any one or more of methanol, ethanol or 1,4-dioxane; and the heating reflux reaction time is 2-6 hours.

[0035] In step (d), the molar ratio of intermediate 21 to (dicarboxymethyl) trithiocarbonate is 1:(0.8-1.2); the reaction temperature is 80-100° C., and the reaction time is 4-6 hours; and the solvent II is any one or more of methanol, ethanol, or 1,4-dioxane.

[0036] In the step (e), the catalyst I is any one or more of ammonium acetate, sodium acetate, acetic acid, 2,2,6,6-tetramethylpiperidine, cesium carbonate, sodium carbonate, potassium iodide, potassium carbonate, potassium hydrogen sulfate, ethanolamine or sodium bicarbonate; the molar ratio of the intermediate 22 to thiophene-3-carboxaldehyde and the catalyst I is 1:(0.8-1.2):(1.1-1.3), the reaction temperature is 80-120° C., and the reaction time is 4-8 h.

[0037] Finally, the present invention provides the use of triazine-thiazolidinone compounds or pharmaceutically acceptable salts thereof in glucose transporter inhibition and anti-tumor activity, which is embodied in:

[0038] Triazine-thiazolidinone compounds are used as active ingredient drugs to exert anti-tumor effects by inhibiting glucose transporter 1.

[0039] A pharmaceutically acceptable salt of a triazine-thiazolidinone compound is used as an active ingredient drug, and the drug exerts an anti-tumor effect by inhibiting glucose transporter 1.

[0040] Compounds of formula (I) were tested for cellular glucose transport inhibition activity using general methods. Fifteen of the 16 compounds demonstrated superior inhibition at 100 μM compared to the positive control compound BAY-876. Compound 12 achieved an inhibition rate of 83.66% at 100 μM, significantly exceeding the 49.36% observed for the positive control compound BAY-876. This demonstrates that compounds of formula (I) possess excellent activity and value in glucose transporter inhibition and anti-tumor activity, providing new compound entities and research directions for the development of anti-tumor drugs targeting GLUT1.

[0041] The present invention has the following beneficial effects:

[0042] The triazine-thiazolidinone compounds provided by the present invention have a novel skeleton and exhibit excellent inhibitory effects on glucose transporter 1 (GLUT1). Their inhibitory effects in HT29 cells are far superior to those of the positive control compound BAY-876, suggesting promising potential for further development as anti-tumor drugs. Test results indicate that the triazine-thiazolidinone compounds exhibit excellent GLUT1 inhibitory activity. In human colorectal cancer cells HT29, the prepared triazine-thiazolidinone compounds exhibited significantly higher inhibition rates at a concentration of 100 μM than the positive control compound BAY-876. Sixteen compounds exhibited inhibition rates ranging from 56.52% to 83.66% at 100 μM, with compound 12 achieving an inhibition rate of 83.66% at 100 μM, significantly exceeding the 49.36% observed for the positive control compound BAY-876. Therefore, the triazine-thiazolidinone compounds of the present invention exhibit excellent inhibitory activity against GLUT1 and possess promising potential for development as anti-tumor drugs. DETAILED DESCRIPTION

[0043] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] The structures of the compounds involved in the present invention were determined by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The nuclear magnetic resonance instrument used was a Swedish Bruker DPX-400 superconducting nuclear magnetic resonance instrument, with tetramethylsilane (TMS) as the internal standard; the high-resolution mass spectrometer used was a Waters-Micromass Q-Tof mass spectrometer. The 16 compounds are all new compounds, and their structures were determined by melting point, 1 H NMR, 13 It was confirmed by modern spectroscopic methods such as C NMR and HRMS.

[0045] Example 1

[0046] A method for preparing a triazine-thiazolidinone compound (Compound 1) comprises the following steps:

[0047]

[0048] (1) Preparation of intermediate 19

[0049] The raw material, cyanuric chloride (20 g, 1.0 eq.), was added to a 250 mL eggplant-shaped flask and dissolved in 50 mL of acetone. The mixture was stirred in an ice bath and cooled to 0°C. A mixture of cyclopentylamine (9.63 mL, 0.9 eq.) and 50 mL of acetone was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, the mixture was stirred at room temperature for 2 h and monitored by TLC (PE:EA = 15:1). After completion of the reaction, the solvent was evaporated under reduced pressure and then dissolved in ethyl acetate and washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 25:1) to obtain intermediate 19.

[0050] Colorless oily liquid, yield 78%. 1 HNMR (300MHz, DMSO-d6) δ9.21 (d, J = 7.5Hz, 1H), 4.16 (m, 1H), 1.87 (m, 2H), 1.75–1.59 (m, 2H), 1.60–1.43 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ169.27,168.23,164.46,52.44,32.16,31.64,23.32,22.97.

[0051] (2) Preparation of Intermediate 20

[0052] The intermediate 19 obtained in step (1) was added to a 250 mL eggplant-shaped flask along with 4-hydroxyaniline (10 g, 1.0 eq.) and triethylamine (6.56 g, 1.1 eq.). The mixture was dissolved in 50 mL of tetrahydrofuran and placed in an ice bath with stirring. The mixture was cooled to 0°C. After the addition was complete, the mixture was stirred at 10°C for 8 h. The reaction was monitored by TLC (PE:EA = 1:1). After the reaction was completed, the solvent was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified and concentrated by column chromatography using PE:EA = 2:1 to obtain the intermediate 20.

[0053] White solid, yield 80%, melting point 119.8-120.7℃. 1H NMR(400MHz, DMSO-d6)δ9.66m,1H),9.16(s,1H),7.99(m,1H),7.39(m,2H),6.69(m,2H),4.14(m,1H),2.00–1.30(m,8H). 13 CNMR(101MHz,DMSO-d6)δ167.41,164.93,163.21,153.17,130.39,121.76,114.93,114.88,51.82,32.03,31.94,23.47,23.32.

[0054] (3) Preparation of Intermediate 21

[0055]

[0056] Intermediate 20 (5 g, 1.0 eq.) and hydrazine hydrate (1.57 g, 3.0 eq.) were added to a 100 mL eggplant-shaped flask and dissolved in 50 mL of anhydrous ethanol. The mixture was refluxed at 78°C for 4 h. The reaction was monitored by TLC (PE:EA = 1:10). After completion, the solvent was evaporated under reduced pressure. 100 mL of distilled water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product (Intermediate 21), which was directly carried on to the next step without further purification.

[0057] (4) Preparation of intermediate 22

[0058]

[0059] Intermediate 21 (2 g, 1.0 eq.) and bis(carboxymethyl)trithiocarbonate (1.35 g, 0.9 eq.) were placed in a 100 mL thick-walled eggplant-shaped flask. 50 mL of 1,4-dioxane was added and the mixture was heated under reflux at 100°C for 6 h. The reaction was monitored by TLC (PE:EA = 1:2). After completion, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was then dried and purified by column chromatography using PE:EA = 1:1, resulting in intermediate 22.

[0060] Yellow solid, yield 80%, melting point 144.4-146.1℃. 1 HNMR (300MHz, DMSO-d6) δ9.07–8.65(m,2H),7.53–7.20(m,2H),7.06(s,1H),6.64(m,2H),4.26(m,3H),1.90–1.36(m,8H). 13C NMR (101MHz, DMSO-d6) δ200.78,171.03,170.41,168.03,164.32,115.02,114.77,51.64,40.58,32.17,32.03,23.29.

[0061] (5) Preparation of raw material 18

[0062]

[0063] Compound 22 (0.25 g, 1 eq.), thiophene-3-imidazolecarboxaldehyde (1.1 eq.), and sodium acetate (0.059 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of glacial acetic acid was added for dissolution and then heated under reflux at 100°C for 8 h. The reaction was monitored by TLC (PE:EA = 1:3). After completion of the reaction, most of the glacial acetic acid was evaporated under reduced pressure, and the remaining glacial acetic acid was neutralized by adding saturated sodium bicarbonate solution. The mixture was then extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried, purified by column chromatography with PE:EA = 1:2.5, and concentrated to obtain raw material 18.

[0064] Raw material 18: (Z)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-5-(thiophen-3-ylmethylene)-2-thioxothiazolin-4-one, yellow solid, yield 60%, melting point 170.1-174.4°C. 1 H NMR (400MHz, DMSO-d6) δ9.08–8.68 (m, 2H), 8.23 ​​(d, J = 8.5Hz, 1H), 7.98 (s, 1H), 7. 82(m,1H),7.54–7.00(m,4H),6.70–6.29(m,2H),4.20(m,1H),1.91–1.24(m,8H). 13 C NMR(101MHz,DMSO-d6)δ191.02,165.04,164.50,164.15,164.02,163.71,135.02,133.50,131.49,128 .95,128.21,127.85,118.05,114.76,114.49,51.53,32.22,32.05,23.31,23.01.HR-MS(ESI):Calcd.C 22 H 21 N7O2S3,[M+H] + m / z:512.0992,found:512.0988.

[0065] (6) Preparation of Intermediate 17a

[0066]

[0067] n-Propylamine (0.5 g, 1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane, the mixture was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford product 17a, which was directly carried on to the next step without further separation or purification.

[0068] (7) Preparation of Compound 1

[0069]

[0070] The starting material 18 (0.3 g, 1.0 eq.), intermediate 17a (0.127 g, 1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. The mixture was dissolved in 15 mL of acetonitrile and heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After completion of the reaction, the acetonitrile was evaporated under reduced pressure to dryness, then dissolved in ethyl acetate and washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then purified by column chromatography using PE:EA = 1:1 to obtain compound 1.

[0071] Compound 1: (Z)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazine-2-yl)aminophenoxy)-N-propylacetamide, yellow solid, yield 70%, melting point 157.6-159.4°C. 1 H NMR(400MHz, DMSO-d6)δ9.31–8.79(m,2H),8.29(d,J=9.2Hz,1H),8.18–7.94(m,2H),7.83(m,1H),7.57–7.10(m,4H),6.6 5(d,J=8.3Hz,1H),6.37(t,J=9.1Hz,1H),4.55(m,1H),4.43–4.07(m,2H),3.11(m,2H),1.96–1.19(m,10H),0.84(m,3H). 13CNMR(101MHz,DMSO-d6)δ190.45,167.33,165.13,164.27,163.66,163.54,134.93,133.97,131.17,129.10,128.74,127.80,120 .84,114.74,114.42,52.57,51.87,40.34,32.17,32.07,31.97,23.56,23.23,22.83,22.33,22.17,11.28.HR-MS(ESI):Calcd.C 27 H 30 N8O3S3,[M+H] + m / z:611.1676,found:611.1681.

[0072] Example 2

[0073] A method for preparing a triazine-thiazolidinone compound (Compound 2), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that n-propylamine in step (6) is replaced by N,N-diethylamine, and the product of step (6) is used in step (7), and the steps are as follows:

[0074] (6) Preparation of Intermediate 17b

[0075] N,N-diethylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out into the next step without further separation or purification.

[0076] (7) Preparation of Compound 2

[0077] The raw material 18 (0.3 g, 1 eq.), intermediate 17b (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was dissolved and heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure to dryness, and then ethyl acetate was added to dissolve it. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 2.

[0078] Compound 2: (Z)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazoline-3-yl)amino)-1,3,5-triazine-2-yl)aminophenoxy)-N,N-diethylacetamide, yellow solid, yield 65%, melting point 158.8-160.1°C. 1 H NMR(400MHz, DMSO-d6)δ9.05(m,2H),8.24(d,J=7.3Hz,1H),7.96–7.92(m,1H),7.82(m,1H),7.52–7.16(m,4H),6.69(d,J=8.6Hz,1H),6 .37(m,1H),4.92(m,1H),4.54(m,1H),4.31–4.20(m,1H),3.49(m,2H),3.27–3.12(m,2H),1.52(m,8H),1.18(m,3H),1.01–0.94(m,3H). 13 C NMR(101MHz,DMSO-d6)δ189.36,165.09,164.13,163.80,163.41,134.93,133.54,131.11,129.02,127.81,1 17.61,114.80,114.43,51.82,41.46,32.30,32.06,23.34,22.88,14.26,14.12,12.47.HR-MS(ESI):Calcd.C 28 H 32 N8O3S3,[M+H] + m / z:625.1832,found:625.1830.

[0079] Example 3

[0080] A method for preparing a triazine-thiazolidinone compound (Compound 3), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that tert-butylamine is used instead of n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0081] (6) Preparation of Intermediate 17c

[0082] Tert-butylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C thermostatic bath and cooled for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out into the next step without further separation or purification.

[0083] (7) Preparation of Compound 3

[0084] The raw material 18 (0.3 g, 1 eq.), intermediate 17c (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure to dryness, then dissolved in ethyl acetate and washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 3.

[0085] Compound 3: (Z)-N-(tert-Butyl)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)acetamide, yellow solid, yield 72%, melting point 153.3-155.1°C. 1 H NMR(400MHz,DMSO-d6)δ9.22(m,1H),8.28(m,1H),8.04(s,1H),7.88–7.75(m,2H),7.55–7 .16(m,4H),6.65(m,2H),4.44–4.33(m,1H),4.20(m,2H),1.89–1.36(m,8H),1.29(s,9H). 13 C NMR(101MHz,DMSO-d6)δ190.46,166.93,166.93,164.99,163.85,152.71,134.93,134.02,129.09,128.85,127.8 1,118.29,117.70,114.90,114.56,52.69,52.03,50.28,32.00,31.46,28.34,23.44,22.83.HR-MS(ESI):Calcd.C28 H 32 N8O3S3,[M+H] + m / z:625.1832,found:625.1840.

[0086] Example 4

[0087] A method for preparing a triazine-thiazolidinone compound (Compound 4), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that n-cyclopropylamine is used instead of n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0088] (6) Preparation of Intermediate 17d

[0089] N-cyclopropylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of dichloromethane was added to dissolve the mixture and placed in a -10°C constant temperature bath for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, stirring was continued for 0.5 h. The reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out in the next step without further separation or purification.

[0090] (7) Preparation of Compound 4

[0091] The raw material 18 (0.3 g, 1 eq.), intermediate 17d (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 4.

[0092] Compound 4: (Z)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolidin-3-yl)amino)-1,3,5-triazin-2-yl)aminophenoxy)-N-cyclopropylacetamide, yellow solid, yield 68%, melting point 183.0-184.2°C. 1H NMR(400MHz, DMSO-d6)δ9.25–8.77(m,2H),8.28(d,J=7.8Hz,1H),8.04(s,2H),7.87–7.78(m,1H),7.55–7.14(m,4H),6 .66(d,J=8.7Hz,1H),6.37(m,1H),4.53(m,1H),4.22(m,2H),2.66(s,1H),1.97–1.27(m,8H),0.66(m,2H),0.40(m,2H). 13 C NMR(101MHz,DMSO-d6)δ190.39,168.65,165.05,164.32,164.01,163.70,163.57,152.55,135.46,134.95,133.95,131.15,129.09,128.81,1 27.80,122.15,121.66,121.13,120.92,117.77,114.79,114.48,52.59,52.02,32.03,23.59,23.28,22.84,22.25,5.74.HR-MS(ESI):Calcd.C 27 H 28 N8O3S3,[M+H] + m / z:609.1519,found:609.1521.

[0093] Example 5

[0094] A method for preparing a triazine-thiazolidinone compound (Compound 5), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that 1-methylcyclopropylamine is used instead of n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0095] (6) Preparation of intermediate 17e

[0096] 1-Methylcyclopropylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of dichloromethane was added to dissolve the mixture and placed in a -10°C constant temperature bath for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, stirring was continued for 0.5 h. The reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out in the next step without further separation or purification.

[0097] (7) Preparation of Compound 5

[0098] The raw material 18 (0.3 g, 1 eq.), intermediate 17e (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure to dryness, and then ethyl acetate was added to dissolve it. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 5.

[0099] Compound 5: (Z)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)-N-(1-methylcyclopropyl)acetamide, yellow solid, yield 70%, melting point 181.6-182.7°C. 1 HNMR(400MHz, DMSO-d6)δ9.22(m,1H),8.27(d,J=6.5Hz,1H),8.20(s,1H),8.04(s,1H),7.81(s,1H),7.53–7.31(m,4H),7.19(m,1 H),6.66(d,J=7.9Hz,1H),6.38(m,1H),4.48(m,1H),4.24–4.12(m,2H),1.88(m,2H),1.59(m,6H),1.28(s,3H),0.63–0.53(m,4H). 13 C NMR(101MHz,DMSO-d6)δ190.39,167.45,164.66,163.94,153.30,134.92,134.00,129.10,128.82,127.79,1 17.68,114.91,114.54,52.72,52.05,32.00,31.47,28.41,23.48,22.36,13.62,13.33.HR-MS(ESI):Calcd.C 28 H 30 N8O3S3,[M+H] + m / z:623.1676,found:6231674.

[0100] Example 6

[0101] A method for preparing a triazine-thiazolidinone compound (Compound 6), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that cyclobutylamine is used to replace n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0102] (6) Preparation of intermediate 17f

[0103] Cyclobutylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out in the next step without further separation or purification.

[0104] (7) Preparation of Compound 6

[0105] The raw material 18 (0.3 g, 1 eq.), intermediate 17f (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 6.

[0106] Compound 6: (Z)-N-cyclobutyl-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)acetamide, yellow solid, yield 75%, melting point 163.5-164.7°C. 1 H NMR(400MHz, DMSO-d6)δ9.22(m,1H),8.29(d,J=8.0Hz,1H),8.06(s,1H),7.86–7.80(m,1H),7.54–7.18(m,5H) ,6.66(d,J=8.6Hz,1H),6.37(m,1H),4.52(m,1H),4.22(m,3H),2.19(m,2H),1.87(m,2H),1.70–1.41(m,10H). 13C NMR (101MHz, DMSO-d6) δ190.54,166.34,165.27,163.98,153.11,134.95,134.02,129.10,128.83,127.81,116. 72,114.87,114.54,52.72,52.14,43.89,32.03,31.86,30.30,23.54,22.83,14.74,14.71.HR-MS(ESI):Calcd.C 28 H 30 N8O3S3,[M+H] + m / z:623.1676,found:623.1686.

[0107] Example 7

[0108] A method for preparing a triazine-thiazolidinone compound (Compound 7), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that cyclopentylamine is used to replace n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0109] (6) Preparation of intermediate 17g

[0110] Cyclopentylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out into the next step without further separation or purification.

[0111] (7) Preparation of Compound 7

[0112] The raw material 18 (0.3 g, 1 eq.), the intermediate 17 g (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added and dissolved, and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 7.

[0113] Compound 7: (Z)-N-cyclopentyl-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)acetamide, yellow solid, yield 74%, melting point 167.6-169.5°C. 1 H NMR(400MHz, DMSO-d6)δ9.12(m,1H),8.28(d,J=9.8Hz,1H),8.04(s,1H),7.86–7.79(m,1H),7.54–7.19(m,5H ),6.65(d,J=8.3Hz,1H),6.38(m,1H),4.51(m,1H),4.31–4.11(m,2H),3.68–3.61(m,1H),1.85–1.38(m,16H). 13 C NMR(101MHz,DMSO-d6)δ190.78,166.82,164.96,164.26,163.69,152.51,152.37,134.96,133.98,131.09,129.10,1 28.77,127.80,114.77,114.50,52.59,51.86,50.40,32.42,32.16,32.00,23.56,23.23,22.85.HR-MS(ESI):Calcd.C 29 H 32 N8O3S3,[M+H] + m / z:637.1832,found:637.1830.

[0114] Example 8

[0115] A method for preparing a triazine-thiazolidinone compound (Compound 8), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that cyclohexylamine is used to replace n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0116] (6) Preparation of intermediate 17h

[0117] Cyclohexylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out into the next step without further separation or purification.

[0118] (7) Preparation of Compound 8

[0119] The raw material 18 (0.3 g, 1 eq.), intermediate 17h (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added and dissolved, and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 8.

[0120] Compound 8: (Z)-N-cyclohexyl-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)acetamide, yellow solid, yield 69%, melting point 172.9-174.4°C. 1 H NMR(400MHz, DMSO-d6)δ9.11(m,2H),8.28(d,J=7.7Hz,1H),8.04(s,1H),7.94(m,1H),7.86–7.79(m,1H),7.56–7 .05(m,4H),6.65(d,J=8.3Hz,1H),6.37(m,1H),4.53(m,1H),4.23(m,2H),3.69–3.57(m,1H),1.91–1.21(m,18H). 13C NMR(101MHz,DMSO-d6)δ190.47,166.45,165.00,164.30,163.69,134.96,133.94,131.16,129.09,128.76,1 27.80,114.73,114.49,51.88,47.27,32.20,32.02,25.14,24.00,23.56,23.29,22.84.HR-MS(ESI):Calcd.C 30 H 34 N8O3S3,[M+Na] + m / z:673.1808,found:673.1818.

[0121] Example 9

[0122] A method for preparing a triazine-thiazolidinone compound (Compound 9), wherein steps (1), (2), (3), (4), and (5) are the same as those in Example 1, except that tetrahydropyranamine is used to replace n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0123] (6) Preparation of intermediate 17i

[0124] Tetrahydropyranylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out in the next step without further separation or purification.

[0125] (7) Preparation of Compound 9

[0126] The raw material 18 (0.3 g, 1 eq.), intermediate 17i (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure to dryness, then dissolved in ethyl acetate and washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 9.

[0127] Compound 9: (Z)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide, yellow solid, yield 65%, melting point 175.7-177.0℃. 1 H NMR (400MHz, DMSO-d6) δ9.12(m,2H),8.29(d,J=9.9Hz,1H),8.05(s,1H),7.84(d,J=3.0Hz,1H),7.56–7.16(m,5 H),6.65(d,J=8.3Hz,1H),6.36(m,1H),4.56(m,1H),4.34–4.10(m,2H),3.90–3.71(m,4H),1.89–1.31(m,12H). 13 C NMR (101MHz, DMSO-d6) δ191.47,166.77,164.99,164.27,163.67,134.95,134.03,131.17,131.10,129.11,128.83,127.82,122.08,120. 85,118.24,117.72,114.74,114.44,65.33,52.59,51.86,44.70,32.19,32.07,31.99,31.47,23.56,23.23,22.83.HR-MS(ESI):Calcd.C 29 H 32 N8O4S3,[M+Na] + m / z:675.1601,found:675.1614.

[0128] Example 10

[0129] A method for preparing a triazine-thiazolidinone compound (Compound 10), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that octahydroisoindole is used to replace n-propylamine in step (6), and the product of step (6) is used in step (7), and the steps are as follows:

[0130] (6) Preparation of Intermediate 17j

[0131] Octahydroisoindole (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane, the mixture was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried on to the next step without further separation or purification.

[0132] (7) Preparation of Compound 10

[0133] The raw material 18 (0.3 g, 1 eq.), intermediate 17j (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 10.

[0134] Compound 10: (Z)-3-((4-(cyclopentylamino)-6-(4-(2-(octahydro-2H-isoindol-2-yl)-2-oxoethoxy)phenyl)amino)-1,3,5-triazin-2-yl)amino)-5-(thiophen-3-ylmethylene)-2-sulfoxythiazoline-4-one, yellow solid, yield 60%, melting point 205.1-207.2°C. 1 H NMR(400MHz, DMSO-d6)δ9.15–8.76(m,2H),8.24(d,J=11.7Hz,1H),7.98–7.93(m,1H),7.82(m,1H),7.52–7.01(m,4H),6.68(m,1H),6.36( m,1H),4.96–4.41(m,2H),4.26(m,1H),3.73–3.46(m,2H),3.25–3.11(m,2H),2.26(m,1H),2.11(m,1H),1.90(m,2H),1.74–1.25(m,14H). 13C NMR(101MHz,DMSO-d6)δ189.83,165.04,164.38,163.78,163.49,134.94,133.54,131.30,131.17,129.01,128.15,127.80,120.80,117.64,11 4.72,114.41,52.53,51.86,49.67,36.94,35.23,32.11,31.98,31.53,25.39,25.11,23.49,23.24,22.89,22.50,22.13.HR-MS(ESI):Calcd.C 32 H 36 N8O3S3,[M+H] + m / z:677.2145,found:677.2156.

[0135] Example 11

[0136] A method for preparing a triazine-thiazolidinone compound (Compound 11), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that aniline is used instead of n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0137] (6) Preparation of intermediate 17k

[0138] Aniline (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried on to the next step without further separation or purification.

[0139] (7) Preparation of Compound 11

[0140] The raw material 18 (0.3 g, 1 eq.), intermediate 17k (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure to dryness, and then ethyl acetate was added for dissolution. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 11.

[0141] Compound 11: (Z)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)-N-phenylacetamide, yellow solid, yield 70%, melting point 166.0-167.3°C. 1 H NMR (400MHz, DMSO-d6) δ10.19–10.01(m,1H),9.25–8.78(m,2H),8.31(m,1H),8.11(s,1H),7.83(m,1H),7.63(m,2H),7.53(m,1H ),7.34(m,5H),7.08(m,1H),6.63(d,J=8.4Hz,1H),6.38(s,1H),4.72(m,1H),4.46(m,1H),4.30–4.05(m,1H),1.89–1.35(m,8H). 13 C NMR(101MHz,DMSO-d6)δ191.25,165.64,164.89,164.21,163.67,138.28,134.95,134.18,131.04,129.16,128.95,128.87 ,127.84,123.67,118.71,118.47,117.71,114.77,114.46,52.62,51.67,32.00,31.69,23.29,22.88.HR-MS(ESI):Calcd.C 30 H 28 N8O3S3,[M+H] + m / z:645.1519,found:645.1520.

[0142] Example 12

[0143] A method for preparing a triazine-thiazolidinone compound (Compound 12), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that thiophene-2-methylamine is used to replace n-propylamine in step (6), and the product of step (6) is used in step (7). The steps are as follows:

[0144] (6) Preparation of Intermediate 171

[0145] Thiophene-2-methylamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out into the next step without further separation or purification.

[0146] (7) Preparation of Compound 12

[0147] The raw material 18 (0.3 g, 1 eq.), intermediate 171 (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 12.

[0148] Compound 12: (Z)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazine-2-yl)aminoamino)phenoxy)-N-(thiophen-2-ylmethyl)acetamide, yellow solid, yield 75%, melting point 159.6-160.8°C. 1H NMR(400MHz,DMSO-d6)δ9.21–8.78(m,2H),8.61–8.41(m,1H),8.25m,1H),8.02–7.96(m,1H),7.86–7.78(m,1H ),7.53–7.10(m,6H),7.06–6.86(m,2H),6.67(m,1H),6.47–6.31(m,1H),4.74–4.06(m,4H),1.92–1.37(m,8H). 13 C NMR(101MHz,DMSO-d6)δ190.64,167.41,164.83,164.31,164.09,163.66 ,141.52,141.42,135.01,134.93,133.90,129.12,128.94,128.70,128.2 9,127.84,126.64,125.51,125.12,117.81,114.80,114.48,53.21,52.2 5,37.28,32.17,31.99,31.52,23.58,23.30,22.84.HR-MS(ESI):Calcd.C 29 H 28 N8O3S4,[M+H] + m / z:665.1240,found:665.1249.

[0149] Example 13

[0150] A method for preparing a triazine-thiazolidinone compound (Compound 13), wherein steps (1), (2), (3), (4), and (5) are the same as those in Example 1, except that n-propylamine in step (6) is replaced by dihydroindole, and the product of step (6) is used in step (7). The steps are as follows:

[0151] (6) Preparation of intermediate 17m

[0152] Indoline (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 10 mL of dichloromethane was placed in a -10°C constant temperature bath and placed on ice for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after complete addition, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out into the next step without further separation or purification.

[0153] (7) Preparation of Compound 13

[0154] The raw material 18 (0.3 g, 1 eq.), intermediate 17m (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was then washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:1 to obtain compound 13.

[0155] Compound 13: (Z)-3-(4-(cyclopentylamino)-6-((4-(2-(indolin-1-yl)-2-oxoethoxy)phenyl)amino)-1,3,5-triazin-2-yl)amino)-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-4-one, yellow solid, yield 60%, melting point 186.6-187.7°C. 1 H NMR(400MHz, DMSO-d6)δ9.08(m,2H),8.23(d,J=8.7Hz,1H),8.04–7.93(m,2H),7.85–7.78(m,1H),7.52–7.10(m,6 H),7.01(m,1H),6.73–6.32(m,2H),4.94(m,1H),4.75(m,1H),4.35–4.06(m,3H),3.18(m,2H),1.89–1.29(m,8H). 13 C NMR(101MHz,DMSO-d6)δ189.95,164.58,164.04,163.50,142.68,135.00 ,134.94,133.62,131.78,131.27,131.06,129.02,128.32,127.82,126.9 6,126.96,124.81,123.54,120.87,117.64,115.98,114.71,114.43,52.5 7,51.62,47.25,32.19,31.48,27.58,23.24,22.89.HR-MS(ESI):Calcd.C 32 H 30 N8O3S3,[M+H] + m / z:671.1676,found:671.1689.

[0156] Example 14

[0157] A method for preparing a triazine-thiazolidinone compound (Compound 14), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 1, except that n-propylamine in step (6) is replaced by N-BOC-p-phenylenediamine, the product of step (6) is used in step (7), and after the reaction is completed, the solvent is evaporated, 4 mL of 4 M hydrogen chloride ethyl acetate solution is added, the mixture is stirred at room temperature for 12 h, filtered, and dried to obtain the hydrochloride of Compound 14, the steps being as follows:

[0158] (6) Preparation of intermediate 17n

[0159] N-BOC-p-phenylenediamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of dichloromethane was added to dissolve the mixture and placed in a -10°C constant temperature bath for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. Stirring was continued for 0.5 h after the addition was complete, and the reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out in the next reaction without further separation or purification.

[0160] (7) Preparation of Compound 14

[0161] The raw material 18 (0.3 g, 1 eq.), the intermediate 17n (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was dissolved and heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA=1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and dried. After dissolving an appropriate amount of ethyl acetate, 4 mL of 4 M hydrogen chloride ethyl acetate solution was added. The mixture was stirred at room temperature for 12 h, filtered, and dried to obtain the hydrochloride of compound 14 (the hydrochloride of compound 14 obtained at this time can be used directly), or neutralized with alkali to obtain compound 14.

[0162] Hydrochloride of compound 14: (Z)-N-(4-aminophenyl)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfanyloxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)acetamide hydrochloride, yellow solid, yield 92%, melting point 192.8-194.6°C. 1H NMR (400MHz, DMSO-d6) δ10.65–9.92(m,3H),8.32(d,J=9.2Hz,1H),8.08(s,1H),7.86(m,1H),7.75(d,J=8.3Hz ,2H),7.57–7.15(m,5H),6.67(m,1H),6.46(m,1H),4.78(m,1H),4.58(m,1H),4.16(m,1H),1.97–1.25(m,8H). 13 C NMR(101MHz,DMSO-d6)δ189.75,165.03,163.83,163.60,163.18,138.35,138.09,134.75,129.16,127.72,126 .46,124.34,123.88,119.78,117.44,115.08,114.67,52.19,31.81,31.30,23.16,22.79.HR-MS(ESI):Calcd.C 30 H 30 ClN9O3S3,[M+Na] + m / z:718.1214,found:718.1231.

[0163] Example 15

[0164] A method for preparing a triazine-thiazolidinone compound (Compound 15), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 14, except that n-propylamine in step (6) is replaced by N-BOC-ethylenediamine. The steps are as follows:

[0165] (6) Preparation of intermediate 17o

[0166] N-BOC-ethylenediamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of dichloromethane was added to dissolve the mixture and placed in a -10°C constant temperature bath for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, stirring was continued for 0.5 h. The reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out in the next step without further separation or purification.

[0167] (7) Preparation of Compound 15

[0168] The raw material 18 (0.3 g, 1 eq.), intermediate 17o (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped bottle. 15 mL of acetonitrile was dissolved and heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA=1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and dried. After dissolving an appropriate amount of ethyl acetate, 4 mL of 4 M hydrogen chloride ethyl acetate solution was added. The mixture was stirred at room temperature for 12 h, filtered, and dried to obtain the hydrochloride of compound 15 (the hydrochloride of compound 15 obtained at this time can be used directly), or neutralized with alkali to obtain compound 15.

[0169] Hydrochloride of compound 15: (Z)-N-(2-aminoethyl)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfanyloxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)acetamide hydrochloride, yellow solid, yield 89%, melting point 197.0-199.0°C. 1 H NMR(400MHz, DMSO-d6)δ8.66–8.45(m,1H),8.31(d,J=10.1Hz,2H),8.15(m,3H),8.04(s,1H),7.84(m,1H),7.55–7.27(m,2H), 7.20(m,1H),6.75(d,J=8.4Hz,1H),6.42(m,1H),4.71(m,1H),4.40–4.20(m,2H),3.37(m,2H),2.88(m,2H),2.01–1.12(m,8H). 13 C NMR(101MHz,DMSO-d6)δ166.54,134.80,134.28,129.24,127.79,114.77,52.35,42 .67,38.11,36.70,36.37,31.99,31.35,23.46,23.28,22.83.HR-MS(ESI):Calcd.C 26 H 30 ClN9O3S3,[M+Na] + m / z:670.1214,found:670.1215.

[0170] Example 16

[0171] A method for preparing a triazine-thiazolidinone compound (Compound 16), wherein steps (1) (2) (3) (4) (5) are the same as those in Example 14, except that n-propylamine in step (6) is replaced by N-BOC-propylenediamine. The steps are as follows:

[0172] (6) Preparation of intermediate 17p

[0173] N-BOC-propylenediamine (1 eq.) and triethylamine (1.03 g, 1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of dichloromethane was added to dissolve the mixture and placed in a -10°C constant temperature bath for 0.5 h. A mixture of bromoacetyl bromide (1.88 g, 1.1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, stirring was continued for 0.5 h. The reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out in the next reaction without further separation or purification.

[0174] (7) Preparation of Compound 16

[0175] The raw material 18 (0.3 g, 1.0 eq.), intermediate 17p (1.2 eq.), and potassium carbonate (0.106 g, 1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was added for dissolution and then heated under reflux at 80°C for 1.5 h. The reaction was monitored by TLC (PE:EA=1:2). After the reaction was completed, the acetonitrile was evaporated under reduced pressure and dried. After dissolving in an appropriate amount of ethyl acetate, 4 mL of 4 M hydrogen chloride ethyl acetate solution was added. The mixture was stirred at room temperature for 12 h, filtered, and dried to obtain the hydrochloride of compound 16 (the hydrochloride of compound 16 obtained at this time can be used directly), or neutralized with alkali to obtain compound 16.

[0176] Hydrochloride of compound 16: (Z)-N-(3-aminopropyl)-2-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfanyloxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenoxy)acetamide hydrochloride, yellow solid, yield 90%, melting point 178.2-180.1°C. 1 H NMR (400MHz, DMSO-d6) δ8.34–7.92(m,5H),7.89–7.79(m,1H),7.59–7.10(m,3H),6.84–6.68(m,1H),6.43(m,1H ),5.01–4.89(m,1H),4.67–4.56(m,2H),4.46–4.19(m,2H),3.22(m,2H),2.93–2.67(m,2H),1.99–1.28(m,8H). 13CNMR(101MHz,DMSO-d6)δ134.83,129.25,127.82,115.25,114.76,52.34,36.42,35.94,31.93,31.36,27.00,23.50,23.27,22.85.HR-MS(ESI):Calcd.C 27 H 32 ClN9O3S3,[M+H] + m / z:662.1552,found:662.1566.

[0177] Example 17

[0178] A method for preparing a triazine-thiazolidinone compound (Compound 1) comprises the following steps:

[0179] (1) Preparation of intermediate 19

[0180] The raw material, cyanuric chloride (20 g, 1.0 eq.), was added to a 250 mL eggplant-shaped flask and dissolved in 50 mL of acetonitrile. The mixture was stirred in an ice bath and cooled to 0°C. A mixture of cyclopentylamine (8.56 mL, 0.8 eq.) and 50 mL of acetone was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, the mixture was stirred at 5°C for 2.8 h and monitored by TLC (PE:EA = 15:1). After completion of the reaction, the solvent was evaporated under reduced pressure and then dissolved in ethyl acetate and washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 25:1) to obtain intermediate 19 (a colorless oily liquid).

[0181] (2) Preparation of Intermediate 20

[0182] The intermediate 19 obtained in step (1) was added to a 250 mL eggplant-shaped flask with 4-hydroxyaniline (9 g, 0.9 eq.) and potassium carbonate (1.05 eq.). 50 mL of ethanol was added to dissolve the mixture. The mixture was placed in an ice bath with stirring and cooled to 0°C. After the addition was complete, the mixture was stirred at 10°C for 8 h. The reaction was monitored by TLC (PE:EA = 1:1). After the reaction was completed, the solvent was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified and concentrated by column chromatography using PE:EA = 2:1 to obtain the intermediate 20 (white solid).

[0183] (3) Preparation of Intermediate 21

[0184] Intermediate 20 (5 g, 1.0 eq.) and hydrazine hydrate (3.14 g, 6.0 eq.) were added to a 100 mL eggplant-shaped flask and dissolved in 50 mL of anhydrous methanol. The mixture was refluxed at 78°C for 2 h. The reaction was monitored by TLC (PE:EA = 1:10). After completion, the solvent was evaporated under reduced pressure and dried. 100 mL of distilled water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product (Intermediate 21), which was directly carried on to the next step without further purification.

[0185] (4) Preparation of intermediate 22

[0186] Intermediate 21 (2 g, 1.0 eq.) and bis(carboxymethyl)trithiocarbonate (1.8 g, 1.2 eq.) were placed in a 100 mL thick-walled eggplant-shaped flask. 50 mL of 1,4-dioxane was added and the mixture was heated under reflux at 80°C for 4 h. The reaction was monitored by TLC (PE:EA = 1:2). After completion, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was then dried and purified by column chromatography using PE:EA = 1:1, yielding Intermediate 22 (yellow solid).

[0187] (5) Preparation of raw material 18

[0188] Compound 22 (0.25 g, 1 eq.), thiophene-3-imidazolecarboxaldehyde (0.8 eq.), and ethanolamine (1.3 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of glacial acetic acid was added for dissolution, followed by heating under reflux at 120°C for 4 h. The reaction was monitored by TLC (PE:EA = 1:3). After completion of the reaction, most of the glacial acetic acid was evaporated under reduced pressure, and the remaining glacial acetic acid was neutralized by adding saturated sodium bicarbonate solution. The mixture was then extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried, purified by column chromatography with PE:EA = 1:2.5, and concentrated to obtain raw material 18 (yellow solid).

[0189] (6) Preparation of Intermediate 17a

[0190] The compounds n-propylamine (0.5 g, 1 eq.) and N,N-diisopropylethylamine (1.4 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of tetrahydrofuran was added for dissolution and then placed in a 0°C constant temperature bath for 0.5 h. A mixture of bromoacetyl bromide (1.2 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, stirring was continued for 1 h. The reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried on to the next step without further separation or purification.

[0191] (7) Preparation of Compound 1

[0192] Raw material 18 (0.3 g, 1 eq.), intermediate 17a (1.1 eq.), and potassium hydroxide (1.2 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 15 mL of acetonitrile was dissolved and heated under reflux at 80°C for 2 h. The reaction was monitored by TLC (PE:EA = 1:2). After completion of the reaction, the acetonitrile was evaporated under reduced pressure to dryness, then dissolved in ethyl acetate and washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried, purified, and concentrated by column chromatography using PE:EA = 1:1 to afford compound 1 (yellow solid).

[0193] Example 18

[0194] A method for preparing a triazine-thiazolidinone compound (Compound 1) comprises the following steps:

[0195] (1) Preparation of intermediate 19

[0196] The raw material, cyanuric chloride (20 g, 1.0 eq.), was added to a 250 mL eggplant-shaped flask and dissolved in 50 mL of methanol. The mixture was stirred in an ice bath and cooled to 0°C. A mixture of cyclopentylamine (14.45 mL, 1.2 eq.) and 50 mL of acetone was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, the mixture was stirred at 40°C for 2 h and monitored by TLC (PE:EA = 15:1). After completion of the reaction, the solvent was evaporated under reduced pressure and then dissolved in ethyl acetate and washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 25:1) to obtain intermediate 19.

[0197] Colorless oily liquid, yield 78%. 1 HNMR (300MHz, DMSO-d6) δ9.21 (d, J = 7.5Hz, 1H), 4.16 (m, 1H), 1.87 (m, 2H), 1.75–1.59 (m, 2H), 1.60–1.43 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ169.27,168.23,164.46,52.44,32.16,31.64,23.32,22.97.

[0198] (2) Preparation of Intermediate 20

[0199] The intermediate 19 obtained in step (1) was added to a 250 mL eggplant-shaped flask along with 4-hydroxyaniline (11 g, 1.1 eq.) and triethylamine (7.16 g, 1.2 eq.). 50 mL of acetone was added to dissolve the mixture. The mixture was placed in an ice bath with stirring and cooled to 0°C. After the addition was complete, the mixture was stirred at 40°C for 4 h. The reaction was monitored by TLC (PE:EA = 1:1). After the reaction was completed, the solvent was evaporated under reduced pressure and then dissolved in ethyl acetate. The mixture was washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified and concentrated by column chromatography using PE:EA = 2:1 to obtain the intermediate 20.

[0200] (3) Preparation of Intermediate 21

[0201] Intermediate 20 (5 g, 1.0 eq.) and hydrazine hydrate (1.05 g, 2.0 eq.) were added to a 100 mL eggplant-shaped flask, and 50 mL of 1,4-dioxane was added for dissolution. The mixture was refluxed at 78°C for 6 h. The reaction was monitored by TLC (PE:EA = 1:10). After completion, the solvent was evaporated under reduced pressure and dried. 100 mL of distilled water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product (Intermediate 21), which was directly carried on to the next step without further purification.

[0202] (4) Preparation of intermediate 22

[0203] Intermediate 21 (2 g, 1.0 eq.) and bis(carboxymethyl)trithiocarbonate (1.2 g, 0.8 eq.) were placed in a 100 mL thick-walled eggplant-shaped flask. 50 mL of 1,4-dioxane was added and the mixture was heated under reflux at 100°C for 5 h. The reaction was monitored by TLC (PE:EA = 1:2). After completion, the reaction was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was then dried, purified, and concentrated by column chromatography using PE:EA = 1:1 to obtain Intermediate 22.

[0204] (5) Preparation of raw material 18

[0205] Compound 22 (0.25 g, 1 eq.), thiophene-3-imidazolecarboxaldehyde) (1.2 eq.), and cesium carbonate (1.1 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of glacial acetic acid was added and dissolved, followed by heating under reflux at 80°C for 8 h. The reaction was monitored by TLC (PE:EA = 1:3). After completion of the reaction, most of the glacial acetic acid was evaporated under reduced pressure, and then saturated sodium bicarbonate solution was added to neutralize the remaining glacial acetic acid. The mixture was then extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried, purified by column chromatography with PE:EA = 1:2.5, and concentrated to obtain raw material 18 (yellow solid).

[0206] (6) Preparation of Intermediate 17a

[0207] The compound n-propylamine (0.5 g, 1 eq.) and sodium hydroxide (1.03 g, 1.1 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. 10 mL of chloroform was dissolved and placed in a room temperature water bath for 1 hour. A mixture of bromoacetyl bromide (1 eq.) and 10 mL of dichloromethane was then slowly added dropwise using a constant pressure dropping funnel. After complete addition, stirring was continued for 1 hour. The reaction was monitored by TLC (PE:EA = 2:1). After completion of the reaction, the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was directly carried out to the next step without further separation or purification.

[0208] (7) Preparation of Compound 1

[0209] Raw material 18 (0.3 g, 1 eq.), intermediate 7a (1.15 eq.), and sodium hydroxide (1.4 eq.) were weighed and added to a 50 mL thick-walled eggplant-shaped flask. Dissolved in 15 mL of tetrahydrofuran, the mixture was heated under reflux at 80°C for 1 h and monitored by TLC (PE:EA = 1:2). After completion of the reaction, acetonitrile was evaporated under reduced pressure to dryness, then dissolved in ethyl acetate and washed three times with brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then sautéed and purified by column chromatography using PE:EA = 1:1 to afford compound 1 (yellow solid).

[0210] The pharmaceutically acceptable salt of the triazine-thiazolidinone compound described in the present invention is an acid addition salt formed by the compound and an acid, and the acid addition salt is any one of hydrochloride, hydrobromide, sulfate, phosphate, borate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, benzenesulfonate, citrate, lactate, pyruvate, tartrate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, salicylate or phenylacetate.

[0211] Application Example 1

[0212] The glucose transporter 1 inhibitory activity test in HT29 cells was performed as follows:

[0213] 1. Experimental methods:

[0214] The samples were synthesized compounds 1 to 16; sample stock solution: 4 to 5 mg of sample was weighed and placed in a 1.5 mL EP tube, and 100% DMSO was added to prepare 10 mM compound stock solution. Human colorectal cancer cells HT29 were plated at 2.0 × 10 5The cells were seeded in a 96-well plate with opaque walls. After 12 hours of normal culture, the original culture medium was replaced with a sugar-free culture medium. After 2 hours of glucose starvation, the cells were treated with a compound at a concentration of 100 μM for 30 minutes, and then 20 μM 2-NBDG was added and incubated for 30 minutes (2-NBDG is a fluorescent analog of glucose). The fluorescence intensity of the cells was detected using the FL module of a microplate reader at absorption and emission wavelengths of 488 nm and 542 nm, respectively, to evaluate the effect of the compound on glucose uptake in cancer cells.

[0215]

[0216] 2. The experimental results are shown in the following table:

[0217] Table 1. Activity data of compounds 1-16 against GLUT1 small molecule inhibitors in HT29 cells

[0218]

[0219] aPositive control compound

[0220] The triazine-thiazolidinone compounds provided by the present invention have a novel skeleton and exhibit a strong inhibitory effect on glucose transporter 1 (GLUT1). Their inhibitory effect in HT29 cells is far superior to that of the positive control compound BAY-876, suggesting great potential for further development as anti-tumor drugs. Test results demonstrate that the triazine-thiazolidinone compounds prepared by the present invention exhibit excellent glucose transporter 1 inhibitory activity. In human colorectal cancer cells HT29, the prepared triazine-thiazolidinone compounds exhibited significantly higher inhibition rates at a concentration of 100 μM than the positive control compound BAY-876. The inhibition rates of the 16 compounds at 100 μM ranged from 56.52% to 83.66%, with compound 12 in particular achieving an inhibition rate of 83.66% at 100 μM, significantly exceeding the 49.36% of the positive control compound BAY-876. Conclusion: The compound of formula (I) of the present invention has a novel structure, has excellent inhibitory activity against glucose transporter 1 (GLUT1), and has excellent potential for development as an anti-tumor drug. It provides an excellent compound entity and research direction for the development of anti-tumor drugs targeting GLUT1 and has good application prospects.

[0221] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A triazine-thiazolidinone compound, characterized in that: The triazine-thiazolidinone compound has the structural formula shown in formula (I): wherein R1 is any one of propyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-aminoethyl, 3-aminopropyl, pyranyl, tetrahydropyranyl, indolyl or thienyl.

2. A triazine-thiazolidinone compound, characterized in that: Having any of the following structural formulas:

3. A pharmaceutically acceptable salt of a triazine-thiazolidinone compound, characterized in that: A pharmaceutically acceptable salt of the triazine-thiazolidinone compound according to any one of claims 1 or 2, wherein the salt is any one of hydrochloride, hydrobromide, sulfate, phosphate, borate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, benzenesulfonate, citrate, lactate, pyruvate, tartrate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, salicylate or phenylacetate.

4. The method for preparing the triazine-thiazolidinone compound according to claim 1, characterized in that: Here are the steps: (1) The amine raw material containing R1 is dissolved in solvent A and reacted with bromoacetyl bromide under the action of an alkaline substance to prepare intermediate 17; wherein the structural formula of intermediate 17 is (2) After the intermediate 17 and the raw material 18 are dissolved in solvent B, they are heated under reflux reaction under the action of an alkaline substance to obtain a triazine-thiazolidinone compound, wherein the structural formula of the raw material 18 is The structural formula of triazine-thiazolidinone compounds is R1 is as described in claim 1.

5. The method for preparing a triazine-thiazolidinone compound according to claim 4, wherein: The structural formula of the amine raw material containing R1 in step (1) is R1 as claimed in claim 1; The structural formula of bromoacetyl bromide is Solvent A is any one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dichloromethane, chloroform or dioxane; the alkaline substance is any one or more of triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide; In step (1), the molar ratio of the amine raw material containing R1 to bromoacetyl bromide and the alkaline substance is 1:(1-1.2):(1.1-1.4); the reaction temperature is -10°C to room temperature, and the reaction time is 1-2 hours; In step (2), the molar ratio of the raw material 18 to the intermediate 17 and the alkaline substance is 1:(1.1-1.2):(1.2-1.4); the solvent B is any one or more of tetrahydrofuran, acetonitrile, and dioxane; and the heating reflux time is 1-2 h.

6. The method for preparing a triazine-thiazolidinone compound according to claim 4, wherein: The preparation method of raw material 18 in step (2) is: (a) Dissolving cyanuric acid and cyclopentylamine in solvent 1, and reacting to obtain intermediate 19; wherein the structural formula of intermediate 19 is (b) Dissolving intermediate 19 with 4-hydroxyaniline and a base in solvent 1 and reacting to obtain intermediate 20; wherein the structural formula of intermediate 20 is (c) Dissolving intermediate 20 and hydrazine hydrate in solvent II, heating under reflux to react, to obtain intermediate 21; wherein the structural formula of intermediate 21 is (d) Dissolving intermediate 21 and (biscarboxymethyl) trithiocarbonate in solvent II and reacting to obtain intermediate 22; wherein the structural formula of intermediate 22 is (e) adding intermediate 22, thiophene-3-carboxaldehyde, and catalyst I to glacial acetic acid for reaction to obtain raw material 18; wherein the structural formula of raw material 18 is 7. The method for preparing a triazine-thiazolidinone compound according to claim 6, wherein: In step (a), the solvent I is any one or more of tetrahydrofuran, acetonitrile, acetone, methanol or ethanol; the molar ratio of trichlorocyanurate to cyclopentylamine is 1:(0.8-1.2); the reaction temperature is 0-40° C., and the reaction time is 1-3 h; In step (b), the base is any one or more of triethylamine, potassium carbonate or sodium carbonate; the molar ratio of intermediate 19, 4-hydroxyaniline and base is 1:(0.9-1.1):(1.1-1.2); solvent I is any one or more of tetrahydrofuran, acetonitrile, acetone, methanol or ethanol; the reaction temperature is 0-40° C., and the reaction time is 4-8 h; In step (c), the molar ratio of intermediate 20 to hydrazine hydrate is 1:(2-6); solvent II is any one or more of methanol, ethanol or 1,4-dioxane; and the heating reflux reaction time is 2-6 hours; In step (d), the molar ratio of intermediate 21 to (biscarboxymethyl) trithiocarbonate is 1:(0.8-1.2); the reaction temperature is 80-100° C., and the reaction time is 4-6 h; the solvent II is any one or more of methanol, ethanol, or 1,4-dioxane; In step (e), catalyst I is any one or more of ammonium acetate, sodium acetate, acetic acid, 2,2,6,6-tetramethylpiperidine, cesium carbonate, sodium carbonate, potassium iodide, potassium carbonate, potassium hydrogen sulfate, ethanolamine or sodium bicarbonate; the molar ratio of intermediate 22, thiophene-3-carboxaldehyde and catalyst I is 1:(0.8-1.2):(1.1-1.3); the reaction temperature is 80-120° C., and the reaction time is 4-8 h.

Images