A thiazole-containing 2,4-diaminopyrimidine compound and its applications

Abstract

This invention relates to a 2,4-diaminopyrimidine compound containing thiazole, the chemical structure of which is shown in formula (I) below, wherein in formula (I), when R 2 When R is 4-methylpiperazin-1-yl, 1 The groups are methyl, N-isopropylformamido, N-n-propylformamido, and N-cyclopropylformamido; when R 2 When R is 4-methylpiperazine-1-ylsulfonyl, 1 The compound is N-(2-chloro-6-methylphenyl)formamido. The thiazole-containing 2,4-diaminopyrimidine compounds of this invention can inhibit cyclin-dependent kinases (CDKs), especially CDK9, and have significant effects in controlling the proliferation of liver cancer, colon cancer, ovarian cancer, or breast cancer cells, and can be used to prepare antitumor drugs.

Description

Technical Field

[0001] This invention relates to nitrogen-containing heterocyclic compounds, specifically pyrimidine compounds containing thiazoles, which can inhibit cyclin-dependent kinases (CDKs), have antitumor activity, and are suitable for the preparation of antitumor drugs. Background Technology

[0002] Cancer has become the leading cause of death worldwide and the second leading cause of death globally, with its incidence rate rising annually, posing a serious threat to human health. In recent years, increasing research has confirmed that the mechanisms of various fundamental life activities within malignant tumor cells, such as signal transduction, cell cycle regulation, and apoptosis induction, are being gradually elucidated. While currently used anti-tumor drugs have some efficacy, they still suffer from poor selectivity, significant toxic side effects, and, in particular, acquired drug resistance and poor prognosis, which are the biggest obstacles in cancer treatment. Therefore, finding highly effective, highly selective, and low-toxicity broad-spectrum anti-cancer drugs is currently the main direction of anti-cancer drug development.

[0003] Cyclin-dependent protein kinases (CDKs) are a class of serine / threonine protein kinases that play irreplaceable roles in multiple pathways, including cell cycle, transcription, DNA damage response, and neuronal function. Currently, more than 20 human CDK subtypes and approximately 30 cell cycle chaperone proteins (Cyclins) have been identified. These CDKs can be activated by chaperone proteins and exert different biological functions. Among them, CDK9 is an important member of the CDK family, involved in various cellular functions. Its complex with the cell cycle chaperone protein CyclinT participates in the formation of positive transcription elongation factor b (P-TEFb), playing a crucial role in transcriptional regulation. Therefore, inhibiting CDK9 can block the phosphorylation of the RNA Poly-IIC terminal region by P-TEFb, thereby inhibiting transcription and leading to tumor cell apoptosis. Furthermore, current research indicates that abnormal expression and function of CDK9 are closely related to tumorigenesis and development. Therefore, CDK9 has become an important drug target for cancer treatment. In recent years, domestic and international pharmaceutical companies have been researching the use of CDK9 inhibitors for cancer treatment, and a small number of small molecules have entered clinical trials, but no CDK9 inhibitors have yet been approved for marketing. Therefore, developing novel and highly effective CDK9 inhibitors is a cutting-edge field in targeted anti-tumor drug development, which is expected to benefit more patients in clinical practice and plays an important role in improving public health.

[0004] Chinese patent application CN107903256A discloses a class of CDK2 kinase inhibitors that can be used to treat cancers such as lung cancer, colon cancer, and cervical cancer. Compound Ii exhibits good efficacy in controlling tumor cell proliferation. To meet the broad clinical demand, this field still requires compounds with higher activity and better safety profiles. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a 2,4-diaminopyrimidine compound containing thiazole, which has a significant effect on controlling the proliferation of liver cancer, colon cancer, ovarian cancer or breast cancer cells.

[0006] The solution of the present invention to the above-mentioned technical problems is as follows:

[0007] This invention relates to a 2,4-diaminopyrimidine compound containing thiazole, the chemical structural formula of which is shown in formula (Ⅰ) below:

[0008]

[0009] In equation (Ⅰ), when R 2 When it is 4-methylpiperazin-1-yl, R 1 The groups are methyl, N-isopropylformamido, N-n-propylformamido, and N-cyclopropylformamido; when R 2 When R is 4-methylpiperazine-1-ylsulfonyl, 1 It is N-(2-chloro-6-methylphenyl)formamido.

[0010] The thiazole-containing 2,4-diaminopyrimidine compounds of this invention are compounds with the following structures, which are referred to as compounds 1 to 5 in sequence:

[0011]

[0012] The preparation method of the above-mentioned thiazole-containing 2,4-diaminopyrimidine compounds includes the following steps:

[0013] (1) The 5-substituted N-(2-chloropyrimidin-4-yl)thiazol-2-amine of formula IV was prepared by reacting 2,4-dichloropyrimidine (Formula II) and 5-substituted 2-aminothiazole (Formula III) according to the following formula (V):

[0014]

[0015] (2) A 2,4-diaminopyrimidine compound containing thiazole, as shown in formula (I), is prepared by reacting 5-oN-(2-chloropyrimidin-4-yl)thiazole-2-amine (as shown in formula (IV)) and 4-substituted aniline (as shown in formula (VI)) according to formula (VII):

[0016]

[0017] The 2,4-diaminopyrimidine compound containing thiazole described in this invention has the effect of inhibiting CDK9 activity and significantly controlling the proliferation of liver cancer, colon cancer, ovarian cancer or breast cancer cells, and can be used to prepare antitumor drugs; the antitumor drug is composed of the 2,4-diaminopyrimidine compound containing thiazole and medically acceptable excipients.

[0018] The present invention will be further described below with reference to specific embodiments. Attached Figure Description

[0019] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound 1, a 2,4-diaminopyrimidine compound from Example 1.

[0020] Figure 2 This is the carbon nuclear magnetic resonance spectrum of compound 1, a 2,4-diaminopyrimidine compound from Example 1.

[0021] Figure 3 This is a high-resolution mass spectrum of compound 1 of the 2,4-diaminopyrimidine class in Example 1.

[0022] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of compound 2,4-diaminopyrimidine in Example 2.

[0023] Figure 5 This is the carbon nuclear magnetic resonance spectrum of compound 2,4-diaminopyrimidine in Example 2.

[0024] Figure 6 This is the high-resolution mass spectrum of compound 2,4-diaminopyrimidine 2 in Example 2.

[0025] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of compound 3, a 2,4-diaminopyrimidine compound from Example 3.

[0026] Figure 8 This is the carbon nuclear magnetic resonance spectrum of compound 3, a 2,4-diaminopyrimidine compound from Example 3.

[0027] Figure 9 This is a high-resolution mass spectrum of compound 3, a 2,4-diaminopyrimidine compound from Example 3.

[0028] Figure 10 This is the hydrogen nuclear magnetic resonance spectrum of compound 4, a 2,4-diaminopyrimidine compound from Example 4.

[0029] Figure 11 This is the carbon nuclear magnetic resonance spectrum of compound 4, a 2,4-diaminopyrimidine compound from Example 4.

[0030] Figure 12 This is the high-resolution mass spectrum of compound 4, a 2,4-diaminopyrimidine compound from Example 4. Figure 13 This is the hydrogen nuclear magnetic resonance spectrum of compound 5, a 2,4-diaminopyrimidine compound from Example 5.

[0031] Figure 14 This is the carbon nuclear magnetic resonance spectrum of compound 5, a 2,4-diaminopyrimidine compound from Example 5.

[0032] Figure 15 This is a high-resolution mass spectrum of compound 5, a 2,4-diaminopyrimidine compound from Example 5.

[0033] Figure 16 Figure A shows the effects of 2,4-diaminopyrimidine compounds 1-5 on tumor volume and body weight in nude mice in Example 8; Figure B is a flowchart of the animal experiment design; Figure C is a graph showing the effects of compounds 1-5 on tumor volume in nude mice; and Figure D is a graph showing the effects of compounds 1-5 on body weight in nude mice. Detailed Implementation

[0034] Example 1 [Preparation of 2,4-diaminopyrimidine compounds containing thiazole]

[0035] (1) Dissolve 2.0 mmol of 2,4-dichloropyrimidine and 2.0 mmol of 2-amino-5-methylthiazolium in 10 mL of DMF, and add 2.0 mmol of NaOH. Stir the resulting mixture at room temperature for about 12 hours. Monitor the reaction by TLC. After the reaction is complete, pour the reaction solution into 50 mL of water, extract with ethyl acetate (50 mL × 3), allow to stand and separate the liquid. Wash the organic phase with saturated brine (50 mL × 3), dry with anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure. Purify the crude product by silica gel column chromatography (using ethyl acetate / petroleum ether as eluent) to obtain the intermediate N-(2-chloropyrimidin-4-yl)-5-methylthiazol-2-amine; the chemical reaction formula for this step is shown in chemical formula (V) in the invention description.

[0036] (2) Place 1.0 mmol of the intermediate obtained in step (1) and 1.0 mmol of 4-(4-methylpiperazin-1-yl)aniline in a 50 mL round-bottom flask, add 10 mL of ethylene glycol methyl ether, and slowly add 0.1 mL of concentrated hydrochloric acid. Then heat to 100 °C and stir for 10 hours. Monitor by TLC. After the reaction is complete, pour the reaction solution into 50 mL of 5% NaHCO3 solution, extract with ethyl acetate (50 mL × 3), allow to stand and separate, wash the organic phase with saturated brine (50 mL × 3), dry with anhydrous magnesium sulfate, filter, remove ethyl acetate under reduced pressure, and purify the crude product by neutral alumina column chromatography (using ethyl acetate / petroleum ether as eluent) to obtain a light brown solid N. 2 -(4-(4-methylpiperazin-1-yl)phenyl)-N 4-(5-methylthiazolyl-2-yl)pyrimidine-2,4-diamine; the chemical reaction formula for this step is shown in chemical formula (VII) in the invention description;

[0037] The obtained light brown solid was analyzed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry (see [link to data]). Figure 1-3 The identification was conducted, and the results were as follows: 1 H NMR(400MHz,DMSO-d6)δ:2.22(s,3H,CH3),2.30(s,3H,CH3),2.50(s,4H,2×CH2),3.08(s,4H,2×CH2),6.33(d,J=4.8Hz,1H,ArH),6. 89(d,J=8.0Hz,2H,ArH),7.05(s,1H,ArH),7.47(d,J=8.0Hz,2H,ArH),8.04(d,J=5.2Hz,1H,ArH),8.86(s,1H,NH),11.10(s,1H,NH). 13 C NMR(100MHz,DMSO-d6)δ:160.00,157.58,157.50,157.06,147.19,134.98,132.37,1 26.11,123.08,116.01,98.17,55.07,49.18,46.12,11.58.HRMS(ESI)m / z:calcdfor C 19 H 23 N7S(M+H + )382.1809 found 382.1804.

[0038] The above identification results indicate that the obtained light brown solid is N. 2 -(4-(4-methylpiperazin-1-yl)phenyl)-N 4 -(5-methylthiazo-2-yl)pyrimidine-2,4-diamine, its structural formula is The yield of the method described in this example is calculated to be 83.5%.

[0039] Example 2 [Preparation of 2,4-diaminopyrimidine compounds containing thiazole]

[0040] This embodiment provides a 2,4-diaminopyrimidine compound 2 containing thiazole, the synthesis method of which is basically the same as that in Example 1, the only difference being:

[0041] By replacing the 2-amino-5-methylthiazole in Example 1 with 2-amino-N-isopropylthiazole-5-carboxamide, thiazole-containing 2,4-diaminopyrimidine compounds were prepared. The yield of the method described in this example was calculated to be 78.0%.

[0042] See also Figure 4-6 The obtained 2,4-diaminopyrimidine compound 2 containing thiazole was tested, and the results are as follows:

[0043] 1 H NMR (400MHz, DMSO-d6) δ: 1.17 (d, J=6.4Hz, 6H, 2×CH3), 2.23 (s, 3H, CH3), 2.46 (s, 4H,2×CH2),3.09(s,4H,2×CH2),4.00-4.08(m,1H,CH),6.40(d,J=4.8Hz,1H,ArH) ,6.89(d,J=8.0Hz,2H,ArH),7.53(d,J=8.4Hz,2H,ArH),8.01(s,1H,ArH),8.06(d ,J=7.6Hz,1H,NH),8.12(d,J=5.6Hz,1H,ArH),9.06(s,1H,NH),11.52(s,1H,NH). 13 C NMR(100MHz,DMSO-d6)δ:161.58,160.63,159.79,157.48,157.42,147.02,139.50 ,132.28,128.41,122.35,116.12,98.71,55.12,49.20,46.18,41.29,22.82.HRMS m / z(ESI)calcdfor C 22 H 28 N8OS[M+H] + 453.2180, found 453.2189.

[0044] Example 3 [Preparation of 2,4-diaminopyrimidine compounds containing thiazole]

[0045] This embodiment provides a 2,4-diaminopyrimidine compound 3 containing thiazole, the synthesis method of which is basically the same as that in Example 1, the only difference being:

[0046] By replacing the 2-amino-5-methylthiazole in Example 1 with 2-amino-N-propylthiazole-5-carboxamide, a 2,4-diaminopyrimidine compound containing thiazole was prepared. The yield of the method described in this example was calculated to be 86.3%.

[0047] See also Figure 7-9 The obtained 2,4-diaminopyrimidine compound 3 containing thiazole was tested, and the results are as follows:

[0048] 1H NMR(400MHz,DMSO-d6)δ:0.69(t,J=7.2Hz,3H,CH3),1.28-1.37(m,2H,CH2),2.02(s,3 H,CH3),2.26(s,4H,2×CH2),2.89(s,4H,2×CH2),2.96-3.01(m,2H,CH2),6.20(d,J=5.6 Hz,1H,ArH),6.70(d,J=8.8Hz,2H,ArH),7.32(d,J=8.8Hz,2H,ArH),7.78(s,1H,ArH),7 .92(d,J=5.6Hz,1H,ArH),8.12(t,J=5.6Hz,1H,NH),8.85(s,1H,NH),11.36(s,1H,NH). 13 C NMR(100MHz,DMSO-d6)δ:161.58,161.45,159.78,157.51,157.40,147.06,139.46,13 2.19,128.17,122.45,116.14,98.71,55.06,49.14,46.12,41.13,22.91,11.83.HRMS m / z(ESI)calcd for C 22 H 28 N8OS[M+H] + 453.2180, found 453.2207.

[0049] Example 4 [Preparation of 2,4-diaminopyrimidine compounds containing thiazole]

[0050] This embodiment provides a 2,4-diaminopyrimidine compound 4 containing thiazole, the synthesis method of which is basically the same as that in Example 1, the only difference being:

[0051] By replacing the 2-amino-5-methylthiazole in Example 1 with 2-amino-N-cyclopropylthiazole-5-carboxamide, a 2,4-diaminopyrimidine compound containing thiazole was prepared. The yield of the method described in this example was calculated to be 77.2%.

[0052] See also Figure 10-12 The obtained 2,4-diaminopyrimidine compound 4 containing thiazole was tested, and the results are as follows:

[0053] 1H NMR(400MHz,DMSO-d6)δ:0.53-0.57(m,2H,CH2),0.68-0.72(m,2H,CH2),2.22(s,3H, CH3),2.46(s,4H,2×CH2),2.75-2.80(m,1H,CH),3.09(s,4H,2×CH2),6.40(d,J=5.2Hz ,1H,ArH),6.90(d,J=8.8Hz,2H,ArH),7.53(d,J=8.8Hz,2H,ArH),7.96(s,1H,ArH),8. 12(d,J=5.6Hz,1H,ArH),8.31(d,J=2.4Hz,1H,NH),9.07(s,1H,NH),11.55(s,1H,NH). 13 C NMR(100MHz,DMSO-d6)δ:162.64,161.69,159.77,157.50,157.40,147.04,139.7 7,132.28,127.94,122.34,116.12,98.73,55.13,49.21,46.18,23.11,6.23.HRMS m / z(ESI)calcd for C 22 H 26 N8OS[M+H] + 451.2023, found 451.2029.

[0054] Example 5 [Preparation of 2,4-diaminopyrimidine compounds containing thiazole]

[0055] This embodiment provides a 2,4-diaminopyrimidine compound 5 containing thiazole, the synthesis method of which is basically the same as that in Example 1, the only difference being:

[0056] By replacing 2-amino-5-methylthiazole in Example 1 with 2-amino-N-(2-chloro-6-methylphenyl)-5-carboxamide, and by replacing 4-(4-methylpiperazin-1-yl)aniline in Example 1 with 4-(4-methylpiperazin-1-yl)aniline, 2,4-diaminopyrimidine compounds containing thiazole were prepared. The yield of the method described in this example was calculated to be 73.0%.

[0057] See also Figure 13-15 The obtained 2,4-diaminopyrimidine compound 5 containing thiazole was tested, and the results are as follows:

[0058] 1H NMR(400MHz,DMSO-d6)δ:2.11(s,3H,CH3),2.27(s,3H,CH3),2.33(s,4H,2×CH2),2.86(s,4 H,2×CH2),6.65(d,J=5.6Hz,1H,ArH),7.29(d,J=7.6Hz,1H,ArH),7.31(d,J=6.4Hz,1H,ArH ),7.42(d,J=7.6Hz,1H,ArH),7.63(d,J=8.4Hz,2H,ArH),8.05(d,J=8.4Hz,2H,ArH),8.31( d,1H,ArH),8.33(s,J=4.0Hz,1H,ArH),9.97(s,1H,NH),10.01(s,1H,NH),11.93(s,1H,NH). 13 C NMR(100MHz,DMSO-d6)δ:162.14,160.05,158.77,157.59,157.54,145.06,141.10,139.21,133.87,132.83,129 .46,128.91,128.64,127.50,127.45,126.55,119.31,101.04,53.73,46.04,45.43,18.71.HRMS(ESI)m / z:calcd forC 26 H 27 ClN8O3S2(M+H + )599.1409 found 599.1403.

[0059] Example 6 (Study on antitumor activity)

[0060] The in vitro antitumor activity of the compounds described in this invention was verified using the following methods. The following results indicate that the compounds of this invention can be used to treat cancer, particularly solid tumors such as liver cancer, colon cancer, ovarian cancer, or breast cancer. The specific verification methods are as follows:

[0061] The in vitro antitumor activity of the thiazole-containing 2,4-diaminopyrimidine compounds prepared in Examples 1-5 was detected using the MTT assay. Cells in the logarithmic growth phase were collected, and the cell suspension concentration was adjusted to 3 × 10⁻⁶. 3 -4×10 3Cells were seeded at a density of 1 / mL in 96-well plates and incubated for 12-24 hours. After cell attachment, different concentrations of the drug were added, with six concentration gradients (0.1, 0.3, 1, 3, 10, and 30 μmol / L), and four replicates per concentration. The plates were incubated at 37°C with 5% CO2 and timed. 48 hours after drug addition, the 96-well plates were removed, and 20 μL of 5 mg / mL MTT solution was added to each well. The plates were then incubated at 37°C for another 4 hours. The supernatant was carefully aspirated, and 200 μL of DMSO was added to each well, followed by shaking for 10 minutes to dissolve any crystals. The absorbance (OD value) of each well was measured at 570 nm using an ELISA reader. Finally, the data were statistically analyzed, with OD value (570 nm) on the ordinate and treatment time on the abscissa to depict the inhibitory effect of the drug on cell growth. The inhibition rate was calculated using the following formula: Inhibition rate = (1 - OD value of drug-treated group / OD value of control group) × 100%. Calculate the half-inhibition index (IC) using GraphPad Prism software. 50 .

[0062] The verification results are shown in Table 1:

[0063] Table 1. Antitumor activity of the target compounds

[0064]

[0065] The positive control in Table 1 above is Palbociclib, a commercially available anti-tumor drug that targets CDK4 / 6. The control is compound N disclosed in the examples of patent application CN107903256A. 2 -(4-Methanesulfonylphenyl)-N 4 -(5-methyl-thiazolyl-2-yl)-2,4-diaminopyrimidine (Ii), its structural formula is

[0066] The above in vitro experimental results show that 2,4-diaminopyrimidine compounds containing thiazoles with the structure of formula (Ⅰ) have a strong inhibitory effect on four types of human tumor cells: HepG2, HT-29, A2780, and MCF-7. The effects are significantly better than the inhibitory activity of the positive control Palbociclib and the control drug Ii.

[0067] Example 7 (CDK9 enzyme inhibitory activity experiment)

[0068] (1) Preparation of the drug: Prepare a 10mM stock solution with DMSO, accelerate the dissolution by sonication, and then perform gradient dilution with DMSO and kinase buffer to ensure that the final concentration of DMSO is less than 1%.

[0069] (2) Composition of kinase reaction buffer: 40mM Tris, pH 7.4, 10mM MgCl2, 0.1mg / ml BSA, 1mM MTT, 10μM ATP;

[0070] (3) The detailed experimental steps are as follows: On a white microplate, add 1 μL of drug to each well, then add 10 μL of LCDK9 / Cyclin T1 enzyme and mix well, then add 5 μL of Histone H1 substrate, followed by 34 μL of analytical buffer, mix well, incubate at 30°C for 40 minutes, then add 50 μL of ATP detection solution, react at room temperature for 5 minutes, and immediately detect the chemiluminescence signal on the microplate reader. The enzyme activity is inversely proportional to the chemiluminescence value. Substitute the value into the following formula to calculate the percentage of activity:

[0071] %activity = {(Lu drug – Lu background) / (Lu enzyme – Lu background)} × 100%.

[0072] Table 2 below shows the in vitro enzymatic inhibition activity results of the compounds of the present invention.

[0073] Table 2. CDK9 enzyme activity of compound I

[0074]

[0075] The control drug in Table 2 (AZD5438) is an orally available CDK1 / 2 / 9 inhibitor that underwent a phase I clinical trial in patients with advanced solid malignancies in 2004 (NCT00088790).

[0076] The above in vitro experimental results show that most of the compounds of this invention can achieve an inhibition rate of over 90% against CDK9 at a concentration of 1 μM. Therefore, the kinase activity assay results indicate that this type of thiazole-containing 2,4-diaminopyrimidine compound has good in vitro CDK9 protein kinase inhibitory activity.

[0077] Example 8 (Animal Experiment)

[0078] Effects of 2,4-diaminopyrimidine compounds 1-5 on tumor growth of HepG2 cells (the most sensitive cells for in vitro antitumor activity) xenografts in nude mice: Six- to eight-week-old female BALB / c nude mice were acclimatized to their environment for approximately one week. HepG2 cells were digested with trypsin, centrifuged at 800 rpm for 5-10 min, washed once with 10 mL of fresh, FBS-free DMEM, and then counted. The concentration was adjusted to 1 × 10⁻⁶. 5 Cells / mL were injected subcutaneously into the right axilla of each nude mouse under aseptic conditions at a dose of 100 μL. The diameter of the xenograft tumor in the nude mice was measured using calipers. Tumors were allowed to grow to 100 mm in diameter. 3Drug administration was then initiated. Mice were randomly divided into 8 groups of 6 mice each: drug 1–5 (50 mg / kg), positive control Palbociclib (50 mg / kg), control (see Example 6) Ii (50 mg / kg), and a solvent blank control. After tumor grafting, mice were administered the drug via intraperitoneal injection once daily, with each mouse receiving 100 μL of the drug (drugs 1–5, Ii, and Palbociclib dissolved in 4% DMSO + 1% Tween 80 + 95% sterile PBS, respectively) or a solvent blank control (4% DMSO + 1% Tween 80 + 95% sterile PBS) for 7 consecutive days. After 7 days of administration, the nude mice were fed for another 13 days. During the experiment, the weight of the nude mice and the volume of the xenograft tumor were recorded every 4 days. Xenograft tumor volume = (length × width) 2 ) / 2. At the experimental endpoint, tumor tissue was collected, and the inhibition rate was calculated as follows: Inhibition rate = (tumor volume of blank control group - tumor volume of drug-treated group) / tumor volume of blank control group × 100%. Results showed that compared with the blank control group, the tumor volume of treatment groups 1-5 was significantly reduced, and their in vivo antitumor activity was superior to that of control drug Ii and positive control drug Palbociclib. Figure 11 (B in the text). The weight of nude mice was measured, and the results showed that compounds 1–5 had no significant effect on the weight of nude mice. Figure 16 (See Figure C in the diagram). These results indicate that 2,4-diaminopyrimidine compounds 1–5 possess good in vivo antitumor activity without significant toxic side effects.

Claims

1. A 2,4-diaminopyrimidine compound containing thiazole, the chemical structural formula of which is shown in formula (Ⅰ): （Ⅰ） In equation (Ⅰ), R 2 It is 4-methylpiperazin-1-yl, R 1 It is N-isopropylformamido, N-n-propylformamido, or N-cyclopropylformamido; R 2 It is 4-methylpiperazine-1-ylsulfonyl, R 1 It is N-(2-chloro-6-methylphenyl)formamido.

2. The use of the thiazole-containing 2,4-diaminopyrimidine compound of claim 1 in the preparation of antitumor drugs.

3. The application according to claim 2, characterized in that, The antitumor drug is composed of a thiazole-containing 2,4-diaminopyrimidine compound as described in claim 1 and medically acceptable excipients.

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