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. The triazine-thiazolidinone compound structural formula is wherein R1 is any one of an alkyl, aryl or heteroaryl group, and R2 is an alkyl or aryl group; its pharmaceutically acceptable salt is an 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 provided by the present invention has a novel structure and has a good inhibitory effect on glucose transporter 1 (GLUT1). In HT29 cells, its inhibitory effect is better than that of the positive control compound BAY-876, and has a 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 an important substrate for most cellular metabolism. It provides energy in the form of ATP through anaerobic glycolysis and the tricarboxylic acid cycle. It is also used in the synthesis of triglycerides and provides intermediates for the synthesis of non-essential amino acids. Because glucose is a polar molecule, it requires specific transport proteins to cross the cell membrane. Therefore, almost all mammalian cells have one or more transport systems on their membranes to transport glucose into or out of the cell.

[0003] Mammalian cells absorb glucose from the extracellular fluid into the cell through two structurally related families of glucose transporters: SGLTs (sodium-dependent glucose transporters) and GLUTs (facilitatory glucose transporters). The transport of glucose by GLUTs is the rate-limiting step in glucose metabolism in the body. GLUTs mediate glucose transport by facilitated diffusion. Fourteen members of the human GLUTs family have been identified, with GLUT1 being the most intensively studied subtype within the family. GLUT1 is widely distributed in tissues including the blood-brain barrier, placental barrier, glomerular mesangial cells, and retina, where it works with other subtypes to meet the energy needs of different tissues. GLUT1 not only plays an important role in mediating glucose transport across membranes but is also involved in the development and progression of various diseases.

[0004] In the early 20th century, German biochemist Otto Warburg and others revealed that tumor cells generate energy for survival and proliferation through a glucose metabolism pathway distinct from that of normal cells. To maintain their rapid growth, proliferation, and metastasis, tumor cells must express large quantities of glucose transporters called GLUTs to meet their glucose uptake and metabolism needs. Clinical studies have shown that GLUT1 is abnormally highly expressed in various malignant tumor tissues, and its expression level can be used to predict tumor stage, grade, and prognosis. GLUT1 is closely associated with tumor proliferation, invasion, and metastasis. Inhibiting GLUT1 in cancer cells can inhibit cancer cell growth, invasion, and metastasis, and induce apoptosis. Therefore, the search for highly effective GLUT1 inhibitors is crucial for the development of anti-tumor drugs, and the development of drugs targeting GLUT1 has become a new hotspot in cancer treatment.

[0005] As an emerging anti-tumor drug target, GLUT1 inhibitor research is gaining increasing attention from international pharmaceutical companies and researchers. Currently, several natural products, such as quercetin, phloretin, and kaempferol, as well as synthetic GLUT1 inhibitors, such as WZB117, BAY-876, Glutor, and PUG-1, have been reported. These compounds have demonstrated significant tumor suppression potential in various cancer cell types and animal models.

[0006] There are currently two common methods for testing GLUT1 inhibition rates. 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 compound's inhibitory activity data on GLUT1; the other is to directly incubate the compound with tumor cells and add glucose analogs, and then obtain the compound's direct inhibition of GLUT1 by measuring the cell's 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 compound's true inhibition of 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.

[0007] Bayer uses the ATP detection method to characterize the inhibitory activity of compounds on GLUT1. The IC of BAY-876 developed by Bayer on GLUT1 inhibition is 50 The activity reaches 2 nM, which is the best among the inhibitors reported so far.

[0008] As an emerging anti-tumor target in recent years, the number of reported inhibitors and scaffold types remains relatively small, 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.

[0009] 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

[0010] The present invention aims to provide a novel class of compounds containing a triazine-thiazolidinone structure, which have not been previously reported. Another aim is to provide methods for their preparation and their use as anti-tumor agents for inhibiting glucose transporter 1. The triazine-thiazolidinone compounds provided by the present invention have novel structures and exhibit potent inhibitory effects on glucose transporter 1 (GLUT1). Their inhibitory effects in HT29 cells are superior to those of the positive control compound BAY-876, suggesting their potential for further development as anti-tumor agents.

[0011] In order to achieve the above object, the technical solution of the present invention is achieved as follows:

[0012] First, the present invention provides a triazine-thiazolidinone compound represented by formula (I) Wherein R1 is any one of alkyl, aryl or heteroaryl; R2 is alkyl or aryl.

[0013] Furthermore, the alkyl group in R1 is an unsubstituted or optionally substituted cyclic saturated hydrocarbon group; the aryl group is an unsubstituted or monosubstituted or disubstituted phenyl group at any position; and the heteroaryl group is any one of an unsubstituted or monosubstituted or disubstituted pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group or an imidazolyl group.

[0014] Furthermore, the alkyl group in R2 is an unsubstituted or optionally substituted straight-chain saturated alkyl group; the aryl group is an unsubstituted or monosubstituted or disubstituted phenyl group at any position.

[0015] Preferably, the alkyl group in R1 is a cyclohexyl group; the aryl group is an unsubstituted phenyl group or a phenyl group substituted by a cyano group at any position; the heteroaryl group is any one of pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl and imidazolyl groups which are unsubstituted or mono- or di-substituted by a methyl group, a chlorine group, a bromine group or a methoxy group at any position.

[0016] Preferably, the alkyl group in R2 is a propyl group; the aryl group is unsubstituted or substituted with a hydroxyl group, an amide group, or an N-amide group at any position.

[0017] Typical compounds of the triazine-thiazolidinone compounds of the present invention include but are not limited to the following compounds:

[0018]

[0019]

[0020] A pharmaceutically acceptable salt of a triazine-thiazolidinone compound is an acid addition salt formed by the triazine-thiazolidinone compound represented by formula (I) and an acid, wherein 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.

[0021] Secondly, the present invention provides a method for preparing the compound represented by formula (I). The method for preparing the compound represented by formula (I) can be described by the following route:

[0022]

[0023] (a) dissolving trichlorocyanurate and cyclopentylamine in solvent A, reacting, and then post-treating to obtain intermediate 38; wherein the structural formula of intermediate 38 is

[0024] (b) Dissolving the intermediate 38, the amine raw material 39 containing R2, and the base B in a solvent A, and reacting them. After the reaction is completed, the intermediate 40 is obtained by post-treatment. The structural formula of the intermediate 40 is

[0025] (c) Dissolving intermediate 40 and hydrazine hydrate in solvent C, heating under reflux, and performing post-treatment after the reaction to obtain intermediate 41; wherein the structural formula of intermediate 41 is

[0026] (d) Dissolving intermediate 41 and (biscarboxymethyl) trithiocarbonate in solvent C, reacting, and post-treating after the reaction to obtain intermediate 42; wherein the structural formula of intermediate 42 is

[0027] (e) adding the intermediate 42, the aldehyde 43 containing R1, and the catalyst D to glacial acetic acid for reaction, and performing post-treatment after the reaction to obtain a triazine-thiazolidinone compound, wherein the triazine-thiazolidinone compound has the structural formula: Wherein R1 is any one of alkyl, aryl or heteroaryl; R2 is alkyl or aryl.

[0028] In the step (a), solvent A 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.

[0029] In the step (b), R2 in the R2-containing amine raw material 39 is an alkyl group or an aryl group; the base B is any one or more of triethylamine, potassium carbonate or sodium carbonate; the molar ratio of the intermediate 38, the R2-containing amine raw material 39 and the base B is 1:(0.9-1.1):(1.1-1.2); the solvent A 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 hours.

[0030] In the step (c), the molar ratio of the intermediate 40 to hydrazine hydrate is 1:(2-6); the solvent C is any one or more of methanol, ethanol or 1,4-dioxane; and the heating reflux reaction time is 2-6 hours.

[0031] In the step (d), the molar ratio of the intermediate 41 to (dicarboxymethyl) trithiocarbonate is 1:(0.8-1.2); the reaction temperature is 80-100° C., and the reaction time is 4-6 hours.

[0032] In the step (e), R1 in the R1-containing aldehyde 43 is any one of an alkyl group, an aryl group, or a heteroaryl group; the catalyst D 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 42, the R1-containing aldehyde 43, and the catalyst D 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.

[0033] The total yield of the five-step reaction in the present invention is 25-70%.

[0034] Again, the present invention provides a pharmaceutically acceptable salt of the triazine-thiazolidinone compound, which is an acid addition salt formed by the triazine-thiazolidinone compound and the following acids: the acid is 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.

[0035] Finally, the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in glucose transporter inhibition and anti-tumor activity, which is embodied in:

[0036] A triazine-thiazolidinone compound or a pharmaceutically acceptable salt thereof is used as an active ingredient drug, and exerts an anti-tumor effect by inhibiting glucose transporter 1.

[0037] Compounds of formula (I) were tested for glucose transport inhibition at the cellular level using general methods. Nineteen of the compounds demonstrated superior inhibition rates at 100 μM compared to the positive control compound BAY-876. Compound 28 achieved an inhibition rate of 73.52% 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.

[0038] The present invention has the following beneficial effects:

[0039] The triazine-thiazolidinone compounds prepared by the present invention have novel structures and exhibit excellent inhibitory effects on glucose transporter 1 (GLUT1). Their inhibitory effects in HT29 cells were superior to those of the positive control compound BAY-876, demonstrating their potential for further development as anti-tumor drugs. Specifically, test results showed that the triazine-thiazolidinone compounds represented by formula (I) were tested for glucose transport inhibition activity at the cellular level according to a general method. Among them, 19 compounds exhibited inhibition rates superior to those of the positive control compound BAY-876 at 100 μM, with compound 28 achieving an inhibition rate of 73.52% at 100 μM, significantly superior to the 49.36% of the positive control compound BAY-876. This demonstrates that the compounds of formula (I) possess excellent activity and value in terms of glucose transporter inhibition and anti-tumor activity, providing new compound entities and research directions for the development of anti-tumor drugs targeting GLUT1. DETAILED DESCRIPTION

[0040] 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.

[0041] 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. All 37 compounds were 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.

[0042] Example 1

[0043] A method for preparing a triazine-thiazolidinone compound (Compound 1) comprises the following steps:

[0044]

[0045] (a) Preparation of Intermediate 38

[0046]

[0047] 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 with PE:EA = 25:1 to obtain intermediate 38.

[0048] Intermediate 38 was a colorless oily liquid with a yield of 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.

[0049] (b) Preparation of Intermediate 40

[0050] The synthesis method of intermediate 40 is the same. This example takes the preparation of intermediate 40a as an example:

[0051]

[0052] Intermediate 38 (1.0 eq.) obtained in step (a) was added to a 250 mL eggplant-shaped flask along with raw material 39a (p-aminophenol) (10 g, 1.0 eq.) and triethylamine (6.56 g, 1.1 eq.). Dissolved in 50 mL of tetrahydrofuran, the mixture was placed in an ice bath and stirred to cool to 0°C. After complete addition, the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC (PE:EA = 1:1). After completion of the reaction, 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 purified by column chromatography with PE:EA = 2:1 to obtain intermediate 40a.

[0053] Intermediate 40a was obtained as a white solid with a yield of 80% and a melting point of 119.8-120.7°C. 1 H 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 C NMR (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] (c) Preparation of Intermediate 41

[0055] The synthesis method of intermediate 41 is the same. This example takes the preparation of intermediate 41a as an example:

[0056]

[0057] Intermediate 40a (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 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, which was directly carried out to the next step without further purification.

[0058] (d) Preparation of Intermediate 42

[0059] The synthesis method of intermediate 42 is the same. This example takes the preparation of intermediate 42a as an example:

[0060]

[0061] Intermediate 41a (2 g, 1.0 eq.) and bis(carboxymethyl)trithiocarbonate (1.35 g, 0.9 eq.) were added to 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, yielding intermediate 42a.

[0062] Intermediate 42a was obtained as a yellow solid with a yield of 80% and a melting point of 144.4-146.1°C.1 H NMR (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). 13 C 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.

[0063] (e) Preparation of Compound 1

[0064]

[0065] Compound 42a (0.25 g, 1.0 eq.), the corresponding aldehyde 43a (4-imidazolecarboxaldehyde) (0.063 g, 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, followed by heating 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 acetic acid was neutralized by adding saturated sodium bicarbonate solution. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:2.5 to obtain compound 1.

[0066] Compound 1: (Z)-5-((1H-imidazol-5-yl)methylene)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-2-thioxothiazolin-4-one, yellow solid, yield 55%, melting point 237.5-238.7°C. 1 HNMR(400MHz,DMSO-d6)δ12.83(s,1H),9.85(s,1H),9.05–8.65(m,2H),8.02(d,J=10.8Hz,1H),7.9 3(s,1H),7.82–7.77(m,1H),7.55–6.93(m,3H),6.71–6.28(m,2H),4.20(m,1H),1.94–1.32(m,8H). 13C NMR(101MHz,DMSO-d6)δ195.71,165.19,164.21,138.74,135.96,131.59,126.15,125 .28,115.51,114.73,114.50,51.49,32.24,31.60,23.31,23.06.HR-MS(ESI):Calcd.C 21 H 21 N9O2S2,[M+H] + m / z:496.1333,found:496.1327.

[0067] Example 2

[0068] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that pyrrole-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 2 The characterization results are as follows:

[0069] Compound 2: (Z)-5-((1H-pyrrol-3-yl)methylene)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-2-sulfoxythiazoline-4-one, yellow solid, yield 53%, melting point 215.6-216.0°C. 1 HNMR(400MHz,DMSO-d6)δ11.82(s,1H),8.98(m,2H),7.87(d,J=6.7Hz,1H),7.60–7.55(m,1H),7.48 (m,2H),7.05(m,2H),6.68(d,J=8.4Hz,1H),6.43(d,J=11.4Hz,2H),4.20(m,1H),1.92–1.38(m,8H). 13 C NMR(101MHz,DMSO-d6)δ190.51,163.52,131.67,128.01,122.54,118.50,118.47, 114.83,110.53,108.16,52.30,32.04,31.43,23.26,23.00.HR-MS(ESI):Calcd.C 22 H 22 N8O2S2,[M+H] + m / z:495.1380,found:495.1384

[0070] Example 3

[0071] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that furan-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 3 The characterization results are as follows:

[0072] Compound 3: (Z)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-5-(furan-3-ylmethylene)-2-sulfoxythiazoline-4-one, yellow solid, yield 55%, melting point 182.1-183.7°C. 1 H NMR (400MHz, DMSO-d6) δ9.05–8.68(m,2H),8.41(d,J=6.6Hz,1H),7.96(d,J=9.5Hz,1H),7.87(s,1 H),7.53–7.03(m,3H),6.89(d,J=10.1Hz,1H),6.70–6.32(m,2H),4.24(m,1H),1.93–1.34(m,8H). 13 C NMR(101MHz,DMSO-d6)δ190.78,165.11,165.01,163.68,148.91,146.24,131.48,125.68,120.73, 118.40,118.34,114.75,114.49,108.97,51.55,32.22,32.05,23.31,23.00.HR-MS(ESI):Calcd.C 22 H 21 N7O3S2,[M+H] + m / z:496.1220,found:496.1215.

[0073] Example 4

[0074] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that thiophene-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 4 The characterization results are as follows:

[0075] Compound 4: (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 170.1-173.4°C. 1H 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.

[0076] Example 5

[0077] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that 4-bromothiophene-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 5 The characterization results are as follows:

[0078] Compound 5: (Z)-5-((4-bromothiophen-2-yl)methylene)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-2-sulfoxythiazoline-4-one, red solid, yield 65%, melting point 164.8-166.2°C. 1 HNMR(400MHz,DMSO-d6)δ9.06–8.69(m,2H),8.30–8.22(m,1H),8.18(d,J=4.5Hz,1H),7.8 3(d,J=4.9Hz,1H),7.56–6.97(m,3H),6.74–6.29(m,2H),4.20(m,1H),1.93–1.30(m,9H). 13CNMR(101MHz,DMSO-d6)δ190.78,165.11,165.01,163.68,148.91,146.24,131.48,125. 68,120.73,118.40,118.34,114.75,114.49,108.97,51.55,32.22,31.98,23.31,23.00. 13 C NMR(101MHz,DMSO-d6)δ190.78,165.11,165.01,163.68,148.91,146.24,131.48,125.68,120.73, 118.40,118.34,114.75,114.49,108.97,51.55,32.22,31.98,23.31,23.00.HR-MS(ESI):Calcd.C 22 H 20 BrN7O2S3,[M+H] + m / z:590.0097,found:590.0091.

[0079] Example 6

[0080] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that cyclohexylcarboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 6 The characterization results are as follows:

[0081] Compound 6: (Z)-5-(cyclohexylmethylene)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-2-thioxothiazolin-4-one, yellow solid, yield 72%, melting point 176.5-177.9°C. 1 H NMR(400MHz,DMSO-d6)δ8.94(m,2H),7.47(m,1H),7.19(m,1H),6.97(m,1H ),6.72–6.43(m,2H),4.30–4.08(m,1H),2.25(m,1H),1.94–1.10(m,17H). 13C NMR(101MHz,DMSO-d6)δ191.74,164.91,163.55,163.06,162.61,144.54,131.30,121.23,121.1 8,114.70,114.35,51.44,40.45,32.11,31.89,30.25,24.96,24.54,23.19.HR-MS(ESI):Calcd.C 24 H 29 N7O2S2,[M+H] + m / z:512.1897,found:512.1901.

[0082] Example 7

[0083] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that benzaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 7 The characterization results are as follows:

[0084] Compound 7: (Z)-5-benzylidene-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-2-sulfoxythiazolin-4-one, yellow solid, 70% yield, melting point 176.0-177.6°C. 1H NMR (400 MHz, DMSO-d6) δ 9.10–8.72 (m, 2H), 7.95 (m, 1H), 7.72 (t, J = 7.8 Hz, 2H), 7.65–7.07 (m, 6H), 6.72–6.31 (m, 2H), 4.27 (s, 1H), 1.86 (m, 2H), 1.77–1.36 (m, 6H). 13 C NMR(101MHz,DMSO-d6)δ191.21,165.03,164.68,163.93,163.68,134.30,132.79,131.47,131.23, 130.80,129.59,129.55,119.61,114.76,51.51,32.21,32.04,23.29,22.97.HR-MS(ESI):Calcd.C 24 H 23 N7O2S2,[M+H] + m / z:506.1428,found:506.1436.

[0085] Example 8

[0086] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that 2-nitrile benzaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 8 The characterization results are as follows:

[0087] Compound 8: (Z)-2-((3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-4-oxo-2-thioxothiazolin-5-ylidene)methyl)benzonitrile, orange solid, yield 68%, melting point 160.3-162.0°C. 1 HNMR(400MHz,DMSO-d6)δ9.09–8.70(m,2H),8.09(d,J=7.6Hz,1H),7.93(m,2H),7.83 –7.70(m,2H),7.54–7.03(m,3H),6.71–6.30(m,2H),4.20(m,1H),1.94–1.20(m,8H). 13 C NMR(101MHz,DMSO-d6)δ190.45,164.94,164.59,164.04,163.71,134.82,134.32,134.22,131.24,128.71,128 .02,127.91,124.73,116.81,114.79,114.46,113.47,51.58,32.21,32.05,23.31,23.02.HR-MS(ESI):Calcd.C 25 H 22 N8O2S2,[M+H] + m / z:531.1380,found:531.1374.

[0088] Example 9

[0089] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that pyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 9 The characterization results are as follows:

[0090] Compound 9: (Z)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-5-(pyridin-2-ylmethylene)-2-thioxothiazolin-4-one, orange solid, yield 65%, melting point 184.2-185.5°C. 1H NMR (300MHz, DMSO-d6) δ9.02(d,J=17.9Hz,1H),8.76(m,2H),7.97(m,3H),7.55–6.96(m,4H),6.72–6.20(m,2H),4.20(m,1H),1.95–1.32(m,8H). 13 C NMR(101MHz,DMSO-d6)δ197.60,165.03,164.72,164.30,164.16,151.24,149.51,137.73,129 .52,128.44,124.34,114.74,114.47,51.57,32.22,32.04,23.31,22.96.HR-MS(ESI):Calcd.C 23 H 22 N8O2S2,[M+H] + m / z:507.1380,found:507.1376.

[0091] Example 10

[0092] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that 3-methylpyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 10 The characterization results are as follows:

[0093] Compound 10: (Z)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-5-((3-methylpyridin-2-yl)methylene)-2-thioxothiazolin-4-one, yellow solid, yield 75%, melting point 177.7-179.2°C. 1 HNMR(400MHz,DMSO-d6)δ9.05–8.65(m,3H),7.89(s,1H),7.82(d,J=7.5Hz,1H),7 .53–6.99(m,4H),6.70–6.22(m,2H),4.26(m,1H),2.54(s,3H),1.95–1.27(m,8H). 13C NMR(101MHz,DMSO-d6)δ198.33,165.11,164.20,163.72,149.40,146.68,139.10,136.24,131.52,125 .85,124.97,124.30,114.75,114.47,51.56,32.23,32.04,23.31,22.99,17.66.HR-MS(ESI):Calcd.C 24 H 24 N8O2S2,[M+H] + m / z:521.1537,found:521.1535.

[0094] Example 11

[0095] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that 3-chloropyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 11 The characterization results are as follows:

[0096] Compound 11: (Z)-5-((3-chloropyridin-2-yl)methylene)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-2-thioxothiazolin-4-one, orange solid, yield 72%, melting point 203.2-204.7°C. 1 HNMR(300MHz,DMSO-d6)δ9.03(d,J=17.8Hz,1H),8.88–8.67(m,2H),8.17(m,1H),7.93 (s,1H),7.62–7.41(m,2H),7.21(m,2H),6.67(m,2H),4.25(m,1H),1.95–1.25(m,8H). 13 C NMR(101MHz,DMSO-d6)δ196.99,164.94,164.64,164.06,147.92,138.45,133.17,131.40,127.65,125 .67,123.01,122.70,114.82,114.74,114.44,51.58,32.21,31.98,23.31,22.94.HR-MS(ESI):Calcd.C 23 H 21 ClN8O2S2,[M+H] + m / z:541.0990,found:541.0986.

[0097] Example 12

[0098] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that 3-methoxypyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 12 The characterization results are as follows:

[0099] Compound 12: (Z)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-5-((3-methoxypyridin-4-yl)methylene)-2-sulfoxythiazoline-4-one, orange solid, yield 70%, melting point 155.3-156.6°C. 1 HNMR(400MHz,DMSO-d6)δ9.07–8.70(m,2H),8.41–8.32(m,1H),7.88(s,1H),7.53 –7.04(m,5H),6.67(m,2H),4.26(m,1H),3.91(d,J=4.7Hz,3H),1.93–1.32(m,8H). 13 C NMR(101MHz,DMSO-d6)δ190.53,165.08,164.40,164.37,164.09,163.69,148.30,142.60,131.34,131.02 ,124.63,116.30,114.75,111.48,53.57,53.52,51.55,32.21,32.04,23.30,23.00.HR-MS(ESI):Calcd.C 24 H 24 N8O3S2,[M+H] + m / z:537.1486,found:537.1484.

[0100] Example 13

[0101] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that 3-bromopyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 13 The characterization results are as follows:

[0102] Compound 13: (Z)-5-((3-bromopyridin-4-yl)methylene)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-2-sulfoxythiazoline-4-one, red solid, yield 73%, melting point 166.6-167.8°C. 1 HNMR(400MHz,DMSO-d6)δ9.06–8.80(m,3H),8.74(m,1H),7.82(s,1H),7.60(d, J=5.3Hz,1H),7.53–7.02(m,3H),6.67(m,2H),4.26(m,1H),1.90–1.25(m,8H). 13 C NMR(101MHz,DMSO-d6)δ190.21,165.05,164.57,163.73,163.49,152.64,149.50,139.57,131.40,131 .26,128.51,127.27,122.99,122.51,114.76,51.55,32.21,32.03,23.31,23.12.HR-MS(ESI):Calcd.C 23 H 21 BrN8O2S2,[M+H] + m / z:585.0485,found:585.0484.

[0103] Example 14

[0104] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (b), (c), and (d) are the same as those in Example 1, except that 3,5-dichloropyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 14 The characterization results are as follows:

[0105] Compound 14: (Z)-3-((4-(cyclopentylamino)-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-5-((3,5-dichloropyridin-4-yl)methylene)-2-thiothiazoline-4-one, orange solid, yield 67%, melting point 161.3-163.0°C. 1 HNMR(400MHz,DMSO-d6)δ9.03(m,2H),8.81(s,2H),7.91–7.83(m,1H),7.52– 7.35(m,2H),7.14(m,2H),6.70–6.46(m,2H),4.25(m,1H),1.93–1.44(m,8H). 13C NMR(101MHz,DMSO-d6)δ190.16,165.07,164.63,162.67,148.01,138.40,129.82,129 .66,126.68,114.78,114.56,52.14,32.23,32.15,23.54,23.30.HR-MS(ESI):Calcd.C 23 H 20 Cl2N8O2S2,[M+H] + m / z:575.0601,found:575.0594.

[0106] Example 15

[0107] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), (d), and (e) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b). The prepared compound 15 The characterization results are as follows:

[0108] Compound 15: (Z)-N-(4-((4-(5-((1H-imidazol-5-yl)methylene)-4-oxo-2-thioxanthiazolidin-3-yl)amino)-6-(cyclopentylamino)-1,3,5-triazin-2-yl)aminoamino)phenyl)acetamide, yellow solid, yield 50%, melting point 215.6-217.3°C. 1 HNMR(400MHz,DMSO-d6)δ12.83(s,1H),9.73(m,1H),9.20–8.86(m,1H),8.02(s,1H),7.9 1(s,1H),7.79(s,1H),7.67(m,1H),7.63–7.05(m,4H),4.21(m,1H),2.02–1.41(m,11H). 13 C NMR(101MHz,DMSO-d6)δ195.67,167.77,165.17,164.19,163.95,138.73,135.89,135.34,126.22 ,125.36,120.41,120.12,119.18,51.53,32.24,31.98,23.80,23.32,23.08.HR-MS(ESI):Calcd.C 23 H 24 N 10 O2S2,[M+H] + m / z:537.1598,found:537.1599.

[0109] Example 16

[0110] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and pyrrole-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 16 The characterization results are as follows:

[0111] Compound 16: (Z)-N-(4-((4-(5-((1H-pyrrol-3-yl)methylene)-4-oxo-2-thioxanthiazolidin-3-yl)amino)-6-(cyclopentylamino)-1,3,5-triazin-2-yl)aminoamino)phenyl)acetamide, yellow solid, yield 52%, melting point 172.4-173.8°C. 1 HNMR(400MHz,DMSO-d6)δ11.83(s,1H),9.88–9.65(m,1H),9.26(m,1H),7.87(s,1H),7.65(m,1H), 7.57(s,1H),7.43(m,4H),7.06(s,1H),6.42(s,1H),4.20(m,1H),2.02(s,3H),1.94–1.46(m,8H). 13 C NMR(101MHz,DMSO-d6)δ190.82,168.09,167.89,163.65,127.88,122.47,119.29 ,118.47,108.16,52.19,32.08,31.39,23.83,23.29,23.04.HR-MS(ESI):Calcd.C 24 H 25 N9O2S2,[M+H] + m / z:536.1646,found:536.1652.

[0112] Example 17

[0113] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and furan-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 17 The characterization results are as follows:

[0114] Compound 17: (Z)-N-(4-((4-(cyclopentylamino)-6-((5-(furan-3-ylmethylene)-4-oxo-2-sulfoxythiazolidin-3-yl)amino)-1,3,5-triazin-2-yl)aminophenyl)acetamide, yellow solid, yield 50%, melting point 182.1-183.7°C. 1 HNMR(400MHz,DMSO-d6)δ9.84(m,1H),9.31(s,1H),8.40(d,J=5.4Hz,1H),7.96(s,1H),7.87(d,J =5.2Hz,1H),7.65(m,1H),7.53–7.21(m,4H),6.88(s,1H),4.13(m,1H),1.99(m,5H),1.58(m,6H). 13 C NMR(101MHz,DMSO-d6)δ190.68,167.85,164.50,163.57,148.96,146.22,133.97,125.90,125.49,121.01,120 .71,120.67,120.39,119.92,119.10,108.97,51.77,32.18,31.51,23.81,23.32,23.01.HR-MS(ESI):Calcd.C 24 H 24 N8O3S2,[M+H] + m / z:537.1486,found:537.1482.

[0115] Example 18

[0116] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and 3,5-dichloropyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 18 The characterization results are as follows:

[0117] Compound 18: (Z)-N-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(thiophen-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminophenyl)acetamide, yellow solid, yield 57%, melting point 213.9-215.3°C. 1HNMR(400MHz,DMSO-d6)δ9.80(s,1H),9.14(m,1H),8.22(s,1H),8.00–7.93(m,1H),7.81(m ,1H),7.67(m,1H),7.47(m,2H),7.24(m,2H),4.21(m,1H),1.98(m,5H),1.75–1.41(m,6H). 13 CNMR(101MHz,DMSO-d6)δ190.91,167.86,164.43,163.94,134.99,134.96,133.53,128.93,128.41,12 7.84,120.46,119.94,119.11,117.82,51.75,32.19,31.54,23.81,23.32,23.02.HR-MS(ESI):Calcd.C 24 H 24 N8O2S3,[M+H] + m / z:553.1257,found:553.1253.

[0118] Example 19

[0119] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and 5-methylthiophene-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 19 The characterization results are as follows:

[0120] Compound 19: (Z)-N-(4-((4-(cyclopentylamino)-6-((5-((5-methylthiophen-2-yl)methylene)-4-oxo-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenyl)acetamide, orange solid, yield 62%, melting point 200.1-201.7°C. 1 HNMR(400MHz,DMSO-d6)δ9.80(s,1H),9.25–8.92(m,1H),8.16–8.09(m,1H),7.70–7.62(m,2H),7.50 –7.15(m,4H),7.08(s,1H),4.21(m,1H),2.60(d,J=5.7Hz,3H),2.03–1.84(m,5H),1.73–1.43(m,6H). 13C NMR(101MHz,DMSO-d6)δ190.24,167.80,164.95,164.14,163.73,150.73,137.28,135.05,128.31 ,127.76,120.21,119.14,51.59,32.21,31.97,23.80,23.32,23.01,15.74.HR-MS(ESI):Calcd.C 25 H 26 N8O2S3,[M+H] + m / z:567.1414,found:567.1418.

[0121] Example 20

[0122] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and pyridine-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 20 The characterization results are as follows:

[0123] Compound 20: (Z)-N-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(pyridin-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminophenyl)acetamide, yellow solid, yield 60%, melting point 185.8-187.7°C. 1 HNMR(400MHz, DMSO-d6)δ9.80(s,1H),9.16(m,1H),8.93(d,J=7.9Hz,1H),8.70(d,J=4.3Hz,1H),8.07(d,J= 8.1Hz,1H),7.99(d,J=10.5Hz,1H),7.71–7.59(m,2H),7.36(m,4H),4.21(m,1H),2.01(m,5H),1.61(m,6H). 13 C NMR(101MHz,DMSO-d6)δ190.63,167.80,165.06,164.94,163.77,151.77,150.99,136.77,135.25,133.60,131.01,128 .97,124.43,121.83,120.24,119.97,119.17,118.97,51.61,32.20,32.03,23.82,23.32,23.00.HR-MS(ESI):Calcd.C 25 H 25N9O2S2,[M+H] + m / z:548.1646,found:548.1652.

[0124] Example 21

[0125] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and 3-bromopyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 21 The characterization results are as follows:

[0126] Compound 21: (Z)-N-(4-((4-(5-((3-bromopyridin-4-yl)methylene)-4-oxo-2-sulfanylthiazolin-3-yl)amino)-6-(cyclopentylamino)-1,3,5-triazin-2-yl)aminoamino)phenyl)acetamide, red solid, yield 70%, melting point 192.1-193.5°C. 1 H NMR(400MHz,DMSO-d6)δ9.80(s,1H),9.25–9.05(m,1H),8.95(d,J=4.7Hz,1H),8.74(d,J=5.1 Hz,1H),7.80(m,1H),7.71–7.55(m,2H),7.52–7.12(m,4H),4.21(m,1H),2.05–1.22(m,11H). 13 C NMR(101MHz,DMSO-d6)δ190.19,167.80,164.98,164.55,163.69,152.55,149.48,139.60,133.82,128.77,123 .01,122.43,120.33,120.09,119.20,118.84,51.63,32.20,32.03,23.80,23.32,23.13.HR-MS(ESI):Calcd.C 25 H 24 BrN9O2S2,[M+H] + m / z:626.0751,found:626.0759.

[0127] Example 22

[0128] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and 3-chloropyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 22 The characterization results are as follows:

[0129] Compound 22: (Z)-N-(4-((4-(5-((3-chloropyridin-2-yl)methylene)-4-oxo-2-thioxothiazolin-3-yl)amino)-6-(cyclopentylamino)-1,3,5-triazin-2-yl)aminophenyl)acetamide, orange solid, yield 70%, melting point 203.3-204.5°C. 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 9.14 (m, 1H), 8.82 (s, 1H), 8.16 (d, J = 8.2Hz, 1H), 7.9 6–7.89(m,1H),7.67(t,J=8.7Hz,1H),7.60–7.05(m,5H),4.21(m,1H),2.04–1.20(m,11H). 13 C NMR(101MHz,DMSO-d6)δ196.99,167.77,165.24,165.06,164.04,147.85,138.40,135.09,133.73,133.49,133.20,127.64 ,125.63,123.13,120.48,120.20,120.02,119.16,119.03,51.80,32.21,31.98,23.71,23.33,22.96.HR-MS(ESI):Calcd.C 25 H 24 ClN9O2S2,[M+H] + m / z:582.1256,found:582.1258.

[0130] Example 23

[0131] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and 3-methylpyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 23 The characterization results are as follows:

[0132] Compound 23: (Z)-N-(4-((4-(cyclopentylamino)-6-((5-((3-methylpyridin-2-yl)methylene)-4-oxo-2-sulfanyloxathiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenyl)acetamide, orange solid, yield 67%, melting point 202.7-204.5°C. 1H NMR(400MHz, DMSO-d6)δ9.80(s,1H),9.23–8.87(m,1H),8.68(t,J=4.8Hz,1H),7.93–7.85(m,1H),7.81 (d,J=7.8Hz,1H),7.68(m,1H),7.55–7.00(m,5H),4.21(m,1H),2.58–2.52(m,3H),2.05–1.43(m,11H). 13 C NMR(101MHz,DMSO-d6)δ198.29,167.81,164.92,164.70,164.16,149.32,146.64,139.06,136.28,125.97,124.2 7,120.72,120.21,119.79,119.17,51.64,32.22,31.98,23.83,23.33,23.01,17.65,17.61.HR-MS(ESI):Calcd.C 26 H 27 N9O2S2,[M+H] + m / z:562.1802,found:562.1804.

[0133] Example 24

[0134] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that 4-aminoacetanilide is used instead of 4-hydroxyaniline in step (b), and 6-methoxypyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 24 The characterization results are as follows:

[0135] Compound 24: (Z)-N-(4-((4-(cyclopentylamino)-6-((5-((6-methoxypyridin-2-yl)methylene)-4-oxo-2-sulfanyloxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminoamino)phenyl)acetamide, orange solid, yield 70%, melting point 194.1-195.1°C. 1HNMR(400MHz,DMSO-d6)δ9.80(s,1H),9.23–8.88(m,1H),7.92–7.83(m,2H),7.68( m,1H),7.62–7.08(m,5H),6.97(d,J=8.4Hz,1H),4.09(m,4H),2.06–1.39(m,11H). 13 C NMR(101MHz,DMSO-d6)δ190.19,167.80,164.98,164.55,163.69,152.55,149.48,139.60,133.82,128.77,123 .01,122.43,120.33,120.09,119.20,118.84,51.63,32.20,32.03,23.80,23.32,23.13.HR-MS(ESI):Calcd.C 26 H 27 N9O3S2,[M+H] + m / z:578.1751,found:578.1758.

[0136] Example 25

[0137] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that N-BOC-p-phenylenediamine is used to replace 4-hydroxyaniline in step (b), and pyridine-3-carboxaldehyde is used to replace 4-imidazolecarboxaldehyde in step (e). The prepared compound 25 The characterization results are as follows:

[0138] Compound 25: tert-Butyl (Z)-(4-((4-(cyclopentylamino)-6-((4-oxo-5-(pyridin-3-ylmethylene)-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminophenyl)carbamate, red solid, yield 65%, melting point 200.2-202.8°C. 1 H NMR (400MHz, DMSO-d6) δ9.21–9.07(m,1H),8.94(s,1H),8.70(m,1H),8.11–8.05(m,1H),8. 00(s,1H),7.62(m,2H),7.35(m,4H),4.27(m,1H),3.57(s,3H),1.91(m,2H),1.43(m,15H). 13C NMR(101MHz,DMSO-d6)δ190.60,164.86,164.62,163.64,152.82,151.77,150.91,136.82,134.17,130.97,128.98,124.41,1 21.90,120.95,120.33,119.87,118.31,78.70,78.58,51.63,32.20,32.05,28.13,28.07,23.33,23.01.HR-MS(ESI):Calcd.C 28 H 31 N9O3S2,[M+H] + m / z:606.2064,found:606.2072.

[0139] Example 26

[0140] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that N-BOC-p-phenylenediamine is used instead of 4-hydroxyaniline in step (b), and 3-methylpyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 26 The characterization results are as follows:

[0141] Compound 26: tert-Butyl (Z)-(4-((4-(cyclopentylamino)-6-((5-((3-methylpyridin-2-yl)methylene)-4-oxo-2-sulfoxythiazolin-3-yl)amino)-1,3,5-triazin-2-yl)aminophenyl)carbamate, yellow solid, yield 70%, melting point 151.7-152.6°C. 1 H NMR (400MHz, DMSO-d6) δ9.20–8.99(m,2H),8.68(t,J=4.1Hz,1H),7.90(s,1H),7.81(m,1 H),7.62(m,1H),7.43–7.15(m,4H),4.22(m,1H),2.54(s,3H),1.91(m,2H),1.43(m,15H). 13 C NMR (101MHz, DMSO-d6) δ164.59,164.16,163.50,152.82,149.38,149.33,146.61,139.07,136.28,125.97,124. 94,124.28,118.26,78.73,78.57,51.69,32.19,31.97,28.13,28.07,23.32,22.99,17.63.HR-MS(ESI):Calcd.C29 H 33 N9O3S2,[M+H] + m / z:620.2221,found:620.2220.

[0142] Example 27

[0143] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that N-BOC-p-phenylenediamine is used instead of 4-hydroxyaniline in step (b), and 3-bromopyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 27 The characterization results are as follows:

[0144] Compound 27: tert-Butyl (Z)-(4-((4-(5-((3-bromopyridin-4-yl)methylene)-4-oxo-2-sulfanylthiazolin-3-yl)amino)-6-(cyclopentylamino)-1,3,5-triazin-2-yl)aminophenyl)carbamate, red solid, yield 75%, melting point 178.9-180.1°C. 1 H NMR(400MHz,DMSO-d6)δ9.20–9.08(m,1H),8.99–8.91(m,1H),8.74(d,J=5.1Hz,1H), 7.86–7.79(m,1H),7.60(m,2H),7.35(m,4H),4.21(m,1H),1.91(m,2H),1.44(m,15H). 13 C NMR(101MHz,DMSO-d6)δ190.60,164.86,164.62,163.64,152.82,151.77,150.91,136.82,134.17,130.97,128.98,1 24.41,121.90,120.37,118.31,78.70,78.58,51.63,32.20,31.98,28.13,28.07,23.33,23.01.HR-MS(ESI):Calcd.C 28 H 30 BrN9O3S2,[M+H] + m / z:684.1169,found:684.1172.

[0145] Example 28

[0146] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), (d), and (e) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b). The prepared compound 28 The characterization results are as follows:

[0147] Compound 28: (Z)-5-((1H-imidazol-5-yl)methylene)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-2-sulfoxythiazoline-4-one, yellow solid, yield 55%, melting point 202.2-203.6°C. 1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),9.88–9.20(m,1H),8.00(s,1H),7.90(s,1H),7.76(s,1H), 7.03–6.63(m,2H),4.18(m,1H),3.14(m,2H),1.91–1.22(m,10H),0.92–0.74(m,2H),0.56(m,1H). 13 CNMR(101MHz,DMSO-d6)δ195.78,165.21,164.68,164.27,138.67,135.94,125.99,125.61,125.16,1 24.95,115.56,51.38,41.78,32.26,32.01,23.23,23.01,22.48,22.25,11.41.HR-MS(ESI):Calcd.C 18 H 23 N9OS2,[M+H] + m / z:446.1540,found:446.1543.

[0148] Example 29

[0149] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and 1H-pyrazole-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 29 The characterization results are as follows:

[0150] Compound 29: (Z)-5-((1H-pyrazol-4-yl)methylene)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-2-thiothiazoline-4-one, yellow solid, yield 60%, melting point 193.3-195.0℃. 1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),9.82(m,1H),8.04(m,2H),7.88(s,1H),7.1 1–6.72(m,2H),4.18(m,1H),3.14(m,2H),1.90–1.21(m,10H),0.92–0.52(m,3H). 13 C NMR(101MHz,DMSO-d6)δ190.93,165.47,165.08,163.80,126.79,126.39,115.65,115.2 1,51.42,41.78,32.24,32.04,23.45,23.22,22.96,22.46,11.41.HR-MS(ESI):Calcd.C 18 H 23 N9OS2,[M+H] + m / z:446.1540,found:446.1543.

[0151] Example 30

[0152] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and 1H-pyrrole-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 30 The characterization results are as follows:

[0153] Compound 30: (Z)-5-((1H-pyrrol-3-yl)methylene)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-2-thiothiazoline-4-one, yellow solid, yield 50%, melting point 250.1-250.6°C. 1 H NMR(400MHz,DMSO-d6)δ11.78(s,1H),10.06–9.21(m,1H),7.84(s,1H),7.55(s,1H),7.0 0(m,3H),6.40(s,1H),4.17(m,1H),3.14(m,2H),1.91–1.22(m,10H),0.91–0.55(m,3H). 13C NMR(101MHz,DMSO-d6)δ191.31,165.43,165.08,164.05,130.71,130.36,127.39,122.27,118.50,1 11.40,108.11,51.44,41.79,32.25,31.61,23.44,23.23,23.00,22.46,11.40.HR-MS(ESI):Calcd.C 19 H 24 N8OS2,[M+H] + m / z:445.1587,found:445.1580.

[0154] Example 31

[0155] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and 3-methylthiophene-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 31 The characterization results are as follows:

[0156] Compound 31: (Z)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-5-((3-methylthiophen-2-yl)methylene)-2-sulfoxythiazoline-4-one, yellow solid, yield 65%, melting point 172.3-173.6°C. 1 H NMR (400MHz, DMSO-d6) δ9.73(m,1H),8.10(m,1H),7.98(d,J=5.3Hz,1H),7.22(d,J=4.7Hz,1 H),6.87(m,2H),4.17(m,1H),3.13(m,2H),2.45(d,J=5.8Hz,3H),1.58(m,10H),0.84(m,3H). 13 C NMR (101MHz, DMSO-d6) δ190.32,165.09,164.29,163.80,146.08,145.79,133.94,133.77,132.01,131.29,125. 01,124.58,115.90,51.40,41.78,32.25,32.02,23.46,23.24,22.93,22.47,14.18,11.41.HR-MS(ESI):Calcd.C 20 H 25 N7OS3,[M+H] +m / z:476.1356,found:476.1351.

[0157] Example 32

[0158] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and 5-methylthiophene-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 32 The characterization results are as follows:

[0159] Compound 32: (Z)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-5-((5-methylthiophen-2-yl)methylene)-2-sulfoxythiazoline-4-one, yellow solid, yield 68%, melting point 160.5-161.5°C. 1 H NMR(400MHz,DMSO-d6)δ10.09–9.38(m,1H),8.11(s,1H),7.65(s,1H),7.10–6.72(m ,3H),4.17(m,1H),3.14(m,2H),2.59(s,3H),1.91–1.16(m,10H),0.90–0.53(m,3H). 13 C NMR(101MHz,DMSO-d6)δ190.32,165.12,164.21,163.76,150.54,150.37,137.15,137.01,135.08,128.28,127.50, 127.11,115.13,51.41,41.78,32.25,31.99,23.45,23.24,22.95,22.47,22.24,15.68,11.40.HR-MS(ESI):Calcd.C 20 H 25 N7OS3,[M+H] + m / z:476.1356,found:476.1353.

[0160] Example 33

[0161] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and benzaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 33 The characterization results are as follows:

[0162] Compound 33: (Z)-5-benzylidene-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-2-sulfoxythiazolin-4-one, yellow solid, yield 70%, melting point 121.4-123.5°C. 1 H NMR(400MHz,DMSO-d6)δ9.98(m,1H),7.94(s,1H),7.70(d,J=7.3Hz,2H),7.58(m,3H) ,6.99(m,2H),4.18(m,1H),3.25–3.01(m,2H),1.88–1.19(m,10H),0.90–0.53(m,3H). 13 C NMR(101MHz,DMSO-d6)δ191.26,165.39,165.01,164.45,163.98,134.18,133.75,131.17,130.76,129.5 3,119.68,119.61,51.42,41.77,32.22,31.96,23.44,23.22,22.93,22.46,11.43.HR-MS(ESI):Calcd.C 21 H 25 N7OS2,[M+H] + m / z:456.1635,found:456.1645.

[0163] Example 34

[0164] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and pyridine-2-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 34 The characterization results are as follows:

[0165] Compound 34: (Z)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-5-(pyridin-2-ylmethylene)-2-thioxothiazolin-4-one, yellow solid, yield 60%, melting point 153.6-155.5°C. 1 HNMR(400MHz,DMSO-d6)δ9.66(m,1H),8.83(d,J=4.8Hz,1H),7.95(m,3H),7.48(s,1H) ,7.06–6.71(m,2H),4.18(m,1H),3.14(m,2H),1.90–1.27(m,10H),0.91–0.76(m,3H). 13C NMR(101MHz,DMSO-d6)δ197.63,165.13,164.66,164.21,151.27,149.46,137.69,129.38,129.00,128.39,128.29,1 24.44,124.37,124.24,51.41,41.78,32.25,32.02,23.44,23.23,22.91,22.46,22.24,11.40.HR-MS(ESI):Calcd.C 20 H 24 N8OS2,[M+H] + m / z:457.1587,found:457.1582.

[0166] Example 35

[0167] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and pyridine-3-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 35 The characterization results are as follows:

[0168] Compound 35: (Z)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-5-(pyridin-3-ylmethylene)-2-sulfanylthiazoline-4-one, yellow solid, yield 65%, melting point 217.9-218.8°C. 1 HNMR(400MHz,DMSO-d6)δ9.93(m,1H),8.92(s,1H),8.68(s,1H),8.05(d,J=8.2Hz,1H),7.97(s,1H) ,7.60(m,1H),7.13–6.74(m,2H),4.18(m,1H),3.14(m,2H),1.90–1.14(m,10H),0.91–0.51(m,3H). 13 C NMR (101MHz, DMSO-d6) δ190.68,165.08,164.17,163.72,151.86,151.05,136.64,136.54,130.81,130.34,128. 97,124.36,121.83,51.41,41.79,32.24,32.02,23.45,23.23,22.94,22.46,22.23,11.40.HR-MS(ESI):Calcd.C 20 H 24 N8OS2,[M+H]+ m / z:457.1587,found:457.1585.

[0169] Example 36

[0170] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and 2-bromopyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 36 The characterization results are as follows:

[0171] Compound 36: (Z)-5-((2-bromopyridin-4-yl)methylene)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-2-thiothiazoline-4-one, yellow solid, yield 80%, melting point 151.3-153.2°C. 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=5.2Hz,1H),7.93(s,1H),7.87(s,1H),7.62(d,J=5.3 Hz,1H),6.98(m,2H),4.25–4.06(m,1H),3.14(m,2H),1.88–1.28(m,10H),0.84(m,3H). 13 C NMR(101MHz,DMSO-d6)δ190.12,164.84,163.50,151.45,142.91,142.43,129.26,128.83,128.40,1 26.15,122.32,51.47,41.79,32.22,31.96,23.38,23.23,22.98,22.43,11.39.HR-MS(ESI):Calcd.C 20 H 23 BrN8OS2,[M+Na] + m / z:557.0512,found:557.0516.

[0172] Example 37

[0173] A method for preparing a triazine-thiazolidinone compound, wherein steps (a), (c), and (d) are the same as those in Example 1, except that propylamine is used instead of 4-hydroxyaniline in step (b), and 3-methoxypyridine-4-carboxaldehyde is used instead of 4-imidazolecarboxaldehyde in step (e). The prepared compound 37 The characterization results are as follows:

[0174] Compound 37: (Z)-3-((4-(cyclopentylamino)-6-(propylamino)-1,3,5-triazin-2-yl)amino)-5-((3-methoxypyridin-4-yl)methylene)-2-sulfoxythiazolin-4-one, yellow solid, yield 80%, 152.1-153.7°C. 1 H NMR(400MHz,DMSO-d6)δ9.75(m,1H),8.49(s,1H),8.43(s,1H),7.95(s,1H),7.59(s,1H),7.12–6 .75(m,2H),4.25–4.05(m,1H),3.91(s,3H),3.19(m,2H),1.91–1.21(m,10H),0.91–0.76(m,3H). 13 CNMR(101MHz,DMSO-d6)δ190.60,165.47,165.07,163.65,155.43,143.09,139.50,130.80,130.33,129.65,122.17,122 .09,120.54,55.83,55.77,51.42,41.78,32.24,32.05,23.45,23.24,22.97,22.46,22.24,11.40.HR-MS(ESI):Calcd.C 21 H 26 N8O2S2,[M+H] + m / z:487.1693,found:487.1688.

[0175] Example 38

[0176] A method for preparing a triazine-thiazolidinone compound (Compound 1) comprises the following steps:

[0177] (a) Preparation of Intermediate 38

[0178] 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 ethanol. 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 10°C for 3 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 using PE:EA = 25:1 to obtain intermediate 38 (a colorless oily liquid).

[0179] (b) Preparation of Intermediate 40

[0180] The synthesis method of intermediate 40 is the same. This example takes intermediate 40a as an example:

[0181] Intermediate 38 (1.0 eq.) obtained in step (a), starting material 39a (9 g, 0.9 eq.), and potassium carbonate (1.05 eq.) were 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. After complete addition, the mixture was stirred at 5°C for 8 h and monitored by TLC (PE:EA = 1:1). After completion of the reaction, 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 purified by column chromatography with PE:EA = 2:1 to obtain intermediate 40a (white solid).

[0182] (c) Preparation of Intermediate 41

[0183] The synthesis method of intermediate 41 is the same, and this embodiment takes intermediate 41a as an example:

[0184] Intermediate 40a (5 g, 1.0 eq.) and hydrazine hydrate (1.05 g, 2.0 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 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, which was directly carried to the next step without further purification.

[0185] (d) Preparation of Intermediate 42

[0186] The synthesis method of intermediate 42 is the same, and this embodiment takes intermediate 42a as an example:

[0187] Intermediate 41a (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, resulting in Intermediate 42a. The product was a yellow solid with an 80% yield and a melting point of 144.4-146.1°C. 1 H NMR (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.

[0188] (e) Preparation of Compound 1

[0189] Compound 42a (0.25 g, 1.0 eq.), the corresponding aldehyde 43a (4-imidazolecarboxaldehyde) (0.046 g, 0.8 eq.), and ammonium acetate (1.1 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 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 the remaining acetic acid was neutralized by adding saturated sodium bicarbonate solution. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was fried and purified by column chromatography with PE:EA = 1:2.5 to obtain compound 1.

[0190] Example 39

[0191] A method for preparing a triazine-thiazolidinone compound (Compound 1) comprises the following steps:

[0192] (a) Preparation of Intermediate 38

[0193] 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 1 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 using PE:EA = 25:1 to obtain intermediate 38 (a colorless oily liquid).

[0194] (b) Preparation of Intermediate 40

[0195] The synthesis method of intermediate 40 is the same. This example takes intermediate 40a as an example:

[0196] Intermediate 38 (1.0 eq.) obtained in step (a), raw material 39a (11 g, 1.1 eq.), and sodium carbonate (1.2 eq.) were 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. After complete addition, the mixture was stirred at 38°C for 4 h and monitored by TLC (PE:EA = 1:1). 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 with PE:EA = 2:1 to obtain intermediate 40a (white solid).

[0197] (c) Preparation of Intermediate 41

[0198] The synthesis method of intermediate 41 is the same, and this embodiment takes intermediate 41a as an example:

[0199] Intermediate 40a (5 g, 1.0 eq.) and hydrazine hydrate (3.14 g, 6.0 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 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, which was directly carried on to the next step without further purification.

[0200] (d) Preparation of Intermediate 42

[0201] The synthesis method of intermediate 42 is the same, and this embodiment takes intermediate 42a as an example:

[0202] Intermediate 41a (2 g, 1.0 eq.) and bis(carboxymethyl)trithiocarbonate (1.2 g, 0.8 eq.) were added to 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 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 with PE:EA = 1:1 to afford Intermediate 42a (yellow solid).

[0203] (e) Preparation of Compound 1

[0204] Compound 42a (0.25 g, 1 eq.), the corresponding aldehyde 43a (4-imidazolecarboxaldehyde) (0.069 g, 1.2 eq.), and acetic acid (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, and concentrated by column chromatography with PE:EA = 1:2.5 to obtain compound 1.

[0205] The pharmaceutically acceptable salts of the triazine-thiazolidinone compounds of the present invention are acid addition salts formed by the compounds with an acid, wherein 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.

[0206] Application Example 1

[0207] The glucose transporter 1 inhibitory activity test in HT29 cells was performed as follows:

[0208] 1. Experimental methods:

[0209] The samples were synthesized compounds 1 to 37; 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 5 The 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.

[0210]

[0211] 2. The experimental results are shown in the following table:

[0212] Table 1. Activity data of compounds 1-37 against GLUT1 small molecule inhibitors in HT29 cells

[0213]

[0214] a Positive control compound

[0215] Test results demonstrated that the compounds of formula (I) exhibited significant glucose transporter 1 inhibitory activity. In human colorectal cancer cell lines HT29, 19 compounds exhibited higher inhibition rates at 100 μM than the positive control compound BAY-876. Compound 28 achieved an inhibition rate of 73.52% at 100 μM, significantly exceeding the 49.36% of the positive control compound BAY-876. Conclusion: The compounds of formula (I) of the present invention possess novel mechanisms of action and exhibit significant inhibitory activity against glucose transporter 1 (GLUT1). These compounds have excellent potential for development as anti-tumor drugs, providing promising compound entities and research directions for the development of anti-tumor drugs targeting GLUT1 and possessing promising application prospects.

[0216] 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 cyclohexyl, phenyl which is unsubstituted or substituted by cyano at any position, any one of pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl or imidazolyl which is unsubstituted or monosubstituted or disubstituted by methyl, chlorine, bromine or methoxy at any position; R2 is propyl, phenyl which is unsubstituted or substituted by hydroxyl at any position.

2. A triazine-thiazolidinone compound, characterized in that: The structure is as follows:

3. A pharmaceutically acceptable salt of a triazine-thiazolidinone compound, characterized in that: The pharmaceutically acceptable salt is an acid addition salt formed by the triazine-thiazolidinone compound according to claim 1 and an acid, wherein 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.

4. The method for preparing the triazine-thiazolidinone compound according to claim 1, characterized in that: Here are the steps: (a) dissolving trichlorocyanurate and cyclopentylamine in solvent A, reacting, and then post-treating to obtain intermediate 38; wherein the structural formula of intermediate 38 is (b) Dissolving the intermediate 38, the amine raw material 39 containing R2, and the base B in a solvent A, and reacting them. After the reaction is completed, the intermediate 40 is obtained by post-treatment. The structural formula of the intermediate 40 is (c) Dissolving intermediate 40 and hydrazine hydrate in solvent C, heating under reflux, and performing post-treatment after the reaction to obtain intermediate 41; wherein the structural formula of intermediate 41 is (d) Dissolving intermediate 41 and (biscarboxymethyl) trithiocarbonate in solvent C, reacting, and post-treating after the reaction to obtain intermediate 42; wherein the structural formula of intermediate 42 is (e) adding the intermediate 42, the aldehyde 43 containing R1, and the catalyst D to glacial acetic acid for reaction, and performing post-treatment after the reaction to obtain a triazine-thiazolidinone compound, wherein the triazine-thiazolidinone compound has the structural formula: Wherein R1 is cyclohexyl, phenyl which is unsubstituted or substituted by cyano at any position, any one of pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl or imidazolyl which is unsubstituted or monosubstituted or disubstituted by methyl, chlorine, bromine or methoxy at any position; R2 is propyl, phenyl which is unsubstituted or substituted by hydroxyl at any position.

5. The method for preparing a triazine-thiazolidinone compound according to claim 4, wherein: In step (a), solvent A 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 B is any one or more of triethylamine, potassium carbonate or sodium carbonate; the molar ratio of the intermediate 38, the amine raw material 39 containing R2 and the base B is 1:(0.9-1.1):(1.1-1.2); the solvent A is any one or more of tetrahydrofuran, acetonitrile, acetone, methanol or ethanol; the reaction temperature is 0-40°C, and the reaction time is 4-8h.

6. The method for preparing a triazine-thiazolidinone compound according to claim 5, wherein: In step (c), the molar ratio of the intermediate 40 to hydrazine hydrate is 1:(2-6); the solvent C 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 41 to (biscarboxymethyl) trithiocarbonate is 1:(0.8-1.2); the reaction temperature is 80-100° C., and the reaction time is 4-6 h; In step (e), catalyst D 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 42, R1-containing aldehyde 43 and catalyst D 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.

7. Use of the triazine-thiazolidinone compound according to claim 1 or 2 in the preparation of a glucose transporter 1 inhibitor.

8. Use of the pharmaceutically acceptable salt of the triazine-thiazolidinone compound according to claim 1 or 2 in the preparation of a glucose transporter 1 inhibitor.

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