Diaminopyrimidine compounds containing a phenylmustard fragment, and methods of making and using the same

Abstract

The present application relates to the technical field of chemical medicine, in particular to a kind of diamino pyrimidine compound containing phenyl nitrogen mustard fragment and its preparation method and application.A kind of diamino pyrimidine compound containing phenyl nitrogen mustard fragment is provided in the present application, its structural formula is as shown in formula (I).The compound is a new compound newly synthesized.The diamino pyrimidine compound containing phenyl nitrogen mustard fragment is novel in structure, has strong inhibitory effect on tumor cells, and has good application prospect in the preparation of antitumor drugs.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, specifically to a diaminopyrimidine compound containing a phenylmustine fragment, its preparation method, and its application. Background Technology

[0002] With the combined effects of industrialization, population growth, environmental pollution, and chronic infections, the trend in cancer prevention and treatment is far from optimistic. According to data from the IARC (International Agency for Research on Cancer), approximately 19.9 million new cancer cases and 10 million cancer deaths were reported in 2020. By 2040, this number is projected to affect 29.5 million people, leading to 16.4 million deaths. Among these cancers, gliomas have the third-highest 5-year mortality rate among all cancers, after pancreatic and lung cancer. Despite significant advancements in science and technology, glioma remains an incurable disease, with a median survival (the time 50% of individuals survive) of approximately 18 months. Therefore, discovering new and effective treatment strategies for gliomas remains a challenging task.

[0003] Small molecule inhibitors are the most common treatment for gliomas because they target specific biomolecules or pathways that play an essential role in cancer progression. Some of these biotherapeutic targets include: epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGFR), tyrosine protein phosphatase (PTP), alkyl glycerol phosphosynthase (AGPS), mutant isocitrate dehydrogenase 1 / 2 (mIDH1 / 2), nicotinamide phosphoribosyltransferase (MNPRT), and FAK (focal adhesion kinase).

[0004] In addition, the interaction between anticancer drugs and DNA has always been a relatively active research area. Among them, alkylating agents are among the earliest discovered anticancer drugs, and nitrogen mustards, which are more common among alkylating agents, chlorambucil (CLB) belong to an earlier generation of anticancer agents. Similar to other drugs in this class, CLB exerts its drug effect by binding to DNA nucleotides at the N (7) and N (3) positions (such as guanine and adenine) to produce DNA cross-links.

[0005] Based on the above, it is necessary to continuously develop small molecule inhibitors with better activity in order to solve the current problems in the treatment of glioma. Summary of the Invention

[0006] In order to solve the above-mentioned technical problems in the prior art, the present invention provides a diaminopyrimidine compound containing a phenylmustine fragment, its preparation method and application.

[0007] A diaminopyrimidine compound containing a phenylmustine fragment has the following structural formula (Ⅰ):

[0008]

[0009] Equation (Ⅰ).

[0010] Furthermore, R1 is any one of -Cl, -Br, -CH3, -CF3, and -NO2.

[0011] Furthermore, R2 can be any of the following structures:

[0012] , , , .

[0013] Furthermore, R3 can be any of the following structures:

[0014] , .

[0015] The method for preparing the diaminopyrimidine compound containing the phenylmustine fragment includes the following steps:

[0016] 2,4-Dichloro-5-substituted pyrimidines were subjected to nucleophilic substitution reactions with 2-amino-N-methylbenzamide to obtain compounds with the structure shown in formula (II). The compounds with the structure shown in formula (II) were then subjected to a 1-2 step reaction with the derivatives with the structure shown in formula (III) to obtain compounds with the structure shown in formula (IV). Finally, the compounds with the structure shown in formula (IV) were subjected to a condensation reaction with the compounds with the structure shown in formula (V) to obtain diaminopyrimidine compounds containing phenylmustine fragments.

[0017] in

[0018] , , ,

[0019] Formula (II)

[0020]

[0021] Formula (III)

[0022]

[0023] Equation (Ⅳ)

[0024]

[0025] Formula (V).

[0026] The nucleophilic substitution reaction of 2,4-dichloro-5-substituted pyrimidine with 2-amino-N-methylbenzamide is preferably carried out under nitrogen or inert gas protection in a solvent environment. The solvent is selected from DMF, acetonitrile, methanol, or ethanol, preferably DMF. The reaction system for the nucleophilic substitution reaction also includes a base, selected from sodium hydride, sodium carbonate, potassium carbonate, or potassium bicarbonate, preferably sodium hydride. The temperature of the nucleophilic substitution reaction is 0~25℃, preferably 25℃. The reaction time is 4~12 h, preferably 8 h. The molar ratio of 2,4-dichloro-5-substituted pyrimidine to 2-amino-N-methylbenzamide and sodium hydride is 1:(1~2):(1~5), preferably 1:1.1:5. After the reaction is complete, the compound with the structure shown in formula (II) is preferably separated by vacuum filtration.

[0027] In the substitution reaction between the compound of formula (II) and the compound of formula (III) under acidic conditions, the substitution reaction is carried out in an organic solvent under the protection of nitrogen and / or an inert gas. The organic solvent is selected from DMF, trifluoroethanol, THF, or n-butanol, preferably trifluoroethanol. The reaction system of the substitution reaction also includes an acid, selected from HCl, AcOH, or trifluoroacetic acid, preferably trifluoroacetic acid. The temperature of the substitution reaction is 60℃~100℃, preferably 80℃. The time of the nucleophilic substitution reaction is 6 h~24 h, preferably 8 h. The molar ratio of the compound of formula (II), the compound of formula (III), and trifluoroacetic acid is 1:(1~2):(1~4), preferably 1:1.2:3. After the substitution reaction, the compound of formula (III) is preferably obtained by filtration.

[0028] Furthermore, the compound with the structure shown in formula (II) can also undergo a Buchwald reaction with the compound with the structure shown in formula (III) under basic conditions, followed by a substitution reaction at the 2-position pyrimidine ring. The substitution reaction is carried out in an organic solvent under the protection of nitrogen and / or an inert gas. The organic solvent is selected from DMF, trifluoroethanol, THF, 1,4-dioxane, or n-butanol, preferably 1,4-dioxane. The catalysts commonly used in the Buchwald reaction are selected from Pd2(dba)3 and pd(OAc)2, preferably pd(OAc)2. The ligands commonly used in the Buchwald reaction are selected from P(t-Bu)3, BINAP, P(o-tolyl)3, and Xantphos, preferably Xantphos. The reaction system also includes a base, selected from NaOH, Cs2CO3, and Ca2CO3, preferably Cs2CO3. The temperature of the substitution reaction is 60℃~100℃, preferably 100℃. The time of the nucleophilic substitution reaction is 6 h~24 h, preferably 12 h. h; the molar ratio of the compound with the structure shown in formula (II), the compound with the structure shown in formula (III), pd(OAc)2, Xantphos and Cs2CO3 is 1:(0.5~1.2):(1~4):(0.1~0.2):(1~2), preferably 1:0.8:0.1:1.5. After the substitution reaction, the intermediate product is preferably obtained by silica gel column chromatography. The intermediate product is then deprotected under acidic conditions by removing the boc protecting group. The reaction occurs in an acidic organic solvent, which is selected from hydrogen chloride-ethyl acetate solution, hydrogen chloride-ethanol solution and hydrogen chloride-cyclopentyl methyl ether solution, preferably hydrogen chloride-ethyl acetate solution. The reaction temperature is 0~40℃, preferably 25℃; the reaction time is 12h~24h, preferably 12h; the reaction ratio of the intermediate compound to the hydrogen chloride-ethyl acetate solution is 1mg:(1~2ml), preferably 1mg:(1ml). After the reaction was complete, the mixture was adjusted to neutral with saturated sodium bicarbonate solution and stirred for 0.5 h. The compound with the structure shown in formula (Ⅲ) was obtained preferentially by vacuum filtration.

[0029] In the condensation reaction of the compound with the structure shown in formula (IV) with the compound with the structure shown in formula (V) under alkaline conditions, the substitution reaction is carried out in an organic solvent, which is selected from anhydrous ethanol, anhydrous DCM, and anhydrous DMF, preferably anhydrous DCM; the condensing agent in the condensation reaction is selected from HATU and DCC, preferably DCC; the reaction system should also include a base, which is selected from DIEA, TEA, sodium hydroxide, and DMAP, preferably DMAP; the temperature of the condensation reaction is 0~40℃, preferably 25℃; the time of the nucleophilic substitution reaction is 1h~12h, preferably 5h; the molar ratio of the compound with the structure shown in formula (IV), the compound with the structure shown in formula (V), and DCC and DMAP is 1:(1~2):(1~2):(0.05~0.1), preferably 1:1.2:1.2:0.03. After the reaction is completed, the diaminopyrimidine compound containing the phenylmustine fragment is preferably separated by silica gel column chromatography.

[0030] The preferred method for preparing diaminopyrimidine compounds containing phenylmustine fragments is as follows:

[0031]

[0032]

[0033] Furthermore, R1 is any one of -Cl, -Br, -CH3, -CF3, and -NO2.

[0034] Furthermore, R2 can be any of the following structures:

[0035] , , , .

[0036] Furthermore, R3 can be any of the following structures:

[0037] , .

[0038] The diaminopyrimidine compounds containing phenylmustine fragments of this invention have novel structures and strong inhibitory effects on tumor cells, showing great application prospects in the preparation of anti-tumor drugs, especially in the preparation of drugs for treating glioma.

[0039] Compared with the prior art, the technical effects of this invention are reflected in:

[0040] This invention provides a novel diaminopyrimidine compound containing a phenylmustine fragment, the structural formula of which is shown in Formula (I). This compound is a newly synthesized novel compound. This diaminopyrimidine compound containing a phenylmustine fragment has a novel structure and exhibits strong inhibitory activity against tumor cells, showing great promise for application in the preparation of antitumor drugs. Detailed Implementation

[0041] The technical solution of the present invention will be further defined below with reference to specific embodiments, but the scope of protection is not limited to the description made.

[0042] Example 1: Synthesis of ethyl 4-(bis(2-hydroxyethyl)amino)benzoate 1

[0043]

[0044] Ethyl 4-aminobenzoate (8.25 g, 50 mmol) was reacted with ethylene oxide (30 mL), acetic acid, and aqueous solution (1:1, 70 mL) at room temperature under stirring and argon protection. After the reaction was completed by TLC monitoring, the solution was adjusted to neutral with 1 mol / L sodium hydroxide solution, extracted with EA, washed with saturated NaCl water, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography to obtain the corresponding product 1 (6.8 g), a white solid, mp: 75.8-76.1 ℃, yield 54%.

[0045] Characterization data of compound 1: 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.2 Hz, 2H), 6.64(d, J = 9.2 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.93 – 3.86 (m, 4H), 3.66 (t, J =4.8 Hz, 4H), 1.36 (t, J = 7.2 Hz, 3H).

[0046] Example 2 Synthesis of 4-(bis(2-chloroethyl)amino)benzoic acid 2

[0047]

[0048] Compound 1 (1.8 g, 7.89 mmol) was added to phosphorus oxychloride (5 mL) with stirring in an ice bath, and the mixture was heated to 100 °C for about 2 h until no gas was released. Then, 20 mL of concentrated hydrochloric acid was added and refluxed for 12 h. The mixture was left to stand at room temperature overnight, recrystallized from 50% ethanol solution, and filtered to obtain the corresponding product 2 (1.1 g), a white solid, mp: 178.5-179.2, yield 59%.

[0049] Characterization data of compound 2: 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 9.2 Hz, 2H), 6.69(d, J = 9.2 Hz, 2H), 3.83 (t, J = 7.2 Hz, 4H), 3.67 (t, J = 7.2Hz, 4H); 13 C NMR (100MHz, CDCl3) δ 171.8, 150.3, 132.6, 117.9, 110.9, 53.3, 40.1; ESI-HRMSC 11 H 13 Cl2NO2([M+H) + ): calcd 262.039611, found 262.0398.

[0050] Example 3: Synthesis of 2-((2,5-dichloropyrimidin-4-yl)amino)- N -Methylbenzamide 3a

[0051]

[0052] A mixture of 2,4,5-dichloropyrimidine (1100 mg, 6 mmol) and 2-amino-N-methylbenzamide (720 mg, 4.8 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (720 mg, 30 mmol) was added at 0 °C and the mixture was subjected to a nucleophilic substitution reaction overnight under argon protection. After the reaction was completed by TLC monitoring, H2O (30 mL) was added and the mixture was filtered to obtain the corresponding product 3a (800 mg), a yellow solid, mp: 182.7-182.5 °C, yield 45%.

[0053] Characterization data of compound 3a: 1 H NMR (400 MHz, DMSO- d 6) δ 12.20 (s, 1H), 8.86 (d,J =4.8 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 2.82 (d, J = 4.4 Hz, 3H).

[0054] Example 4: Synthesis of 2-((5-bromo-2-chloropyrimidin-4-yl)amino)- N -Methylbenzamide 3b

[0055]

[0056] A mixture of 5-bromo-2,4-dichloropyrimidine (2.28 g, 10 mmol) and 2-amino-N-methylbenzamide (1.65 g, 11 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (1.2 g, 50 mmol) was added at 0 °C and the mixture was subjected to a nucleophilic substitution reaction overnight under argon protection. After the reaction was completed by TLC monitoring, H2O (30 mL) was added, and the mixture was filtered to obtain the corresponding product 3b (1.35 g), a yellow solid, mp: 219.5–220.1 °C, yield 65%.

[0057] Characterization data of compound 3b: 1 H NMR (400 MHz, CDCl3) δ 11.50 (s, 1H), 8.65 (d, J =8.4 Hz, 1H), 8.32 (s, 1H), 7.60 – 7.51 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.13(t, J = 8.0 Hz, 1H), 6.30 (s, 1H), 3.04 (d, J = 4.8 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 169.1, 158.9, 157.9, 157.7, 138.6, 132.2, 128.6, 123.7, 122.0,121.6, 105.46, 26.8.

[0058] Example 5: Synthesis of 2-((2-chloro-5-methylpyrimidin-4-yl)amino)- N -Methylbenzamide 3c

[0059]

[0060] A mixture of 2,4-dichloro-5-methylpyrimidine (1.63 g, 10 mmol) and 2-amino-N-methylbenzamide (1.65 g, 11 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (1.2 g, 50 mmol) was added at 0 °C, and the mixture was subjected to a nucleophilic substitution reaction overnight under argon protection. After the reaction was completed by TLC monitoring, H₂O (30 mL) was added, and the mixture was filtered to give the corresponding product 3c (2.52 g), a yellow solid, mp: 241.7–242.3 °C, yield 91%.

[0061] Compound 3c characterization data: 1 H NMR (400 MHz, DMSO- d 6) δ 11.72 (s, 1H), 8.85 (s, 1H), 8.63 (d, J = 9.6 Hz, 1H), 8.16 (s, 1H), 7.80 (d, J = 6.4 Hz, 1H), 7.58 (t, J =8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 2.82 (d, J = 4.4 Hz, 3H), 2.19 (s, 3H); 13 CNMR (100 MHz, DMSO- d 6) δ 169.6 160.0, 157.1, 156.7, 140.0, 132.4, 128.6,122.7, 121.0, 120.7, 115.9, 26.8, 13.5.

[0062] Example 6 Synthesis of 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)- N -Methylbenzamide 3d

[0063]

[0064] A mixture of 2,4-dichloro-5-trifluoromethylpyrimidine (2.17 g, 10 mmol) and 2-amino-N-methylbenzamide (1.65 g, 11 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (1.2 g, 50 mmol) was added at 0 °C and the mixture was subjected to a nucleophilic substitution reaction overnight under argon protection. After the reaction was completed by TLC monitoring, H2O (30 mL) was added, and the product 3d (1.62 g) was obtained by filtration as a reddish-brown solid, mp: 181.2-181.8 °C, yield 49%.

[0065] 3D characterization data of compounds: 1 H NMR (400 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.87 (s,1H), 8.69 (s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.59 (t, J =8.8 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 169.1, 162.7, 157.3, 157.3, 156.9, 138.0, 132.1, 128.5, 124.4,122.8, 107.9, 107.6, 26.8.

[0066] Example 7 Synthesis of 2-((2-chloro-5-nitropyrimidin-4-yl)amino)- N -Methylbenzamide 3e

[0067]

[0068] A mixture of 2,4-dichloro-5-nitropyrimidine (2.91 g, 15 mmol) and 2-amino-N-methylbenzamide (2.48 g, 16.5 mmol) was stirred in DMF (10 mL) at room temperature. Then, sodium hydride (1.2 g, 50 mmol) was added at 0 °C, and the mixture was allowed to react overnight under argon protection for nucleophilic substitution. After the reaction was complete as monitored by TLC, H₂O (30 mL) was added, and the mixture was filtered to give the corresponding product 3e (1.95 g), a yellow solid, mp: 198.3–199.2 °C, yield 42%.

[0069] Characterization data of compound 3e: 1 H NMR (400 MHz, DMSO- d 6) δ 12.45 (s, 1H), 9.21 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.18 (dd, J = 8.4, 1.1 Hz, 1H), 7.71 (dd, J = 8.0,1.6 Hz, 1H), 7.64 – 7.52 (m, 1H), 7.33 (t, J = 8.4 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 168.5, 154.4, 150.5, 136.6, 131.0, 128.3,126.1, 125.0, 124.7, 120.0, 49.1, 26.7.

[0070] Example 8 Synthesis of 4-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 4a)

[0071]

[0072] Compound 3a (594 mg, 2 mmol), 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester (443 mg, 1.6 mmol), palladium acetate (44.8 mg, 0.2 mmol), Xantphos (231 mg, 0.4 mmol), and Cs₂CO₃ (978 mg, 3 mmol) were added to 1,4-dioxane (10 mL) with stirring. The flask was placed in an oil bath at 100 °C for 12 h under argon protection to carry out the substitution reaction. After cooling to room temperature, saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was slurried with EA and dried to give the corresponding product 4a (0.35 g). Yellow solid, mp: >250 °C, yield 33%.

[0073] Characterization data of compound 4a: 1 H NMR (400 MHz, DMSO- d6) δ 11.59 (s, 1H), 9.24 (s,1H), 8.77 – 8.72 (m, 2H), 8.17 (s, 1H), 7.53 – 7.43 (m, 3H), 7.13 (td, J = 7.6,1.2 Hz, 1H), 6.94 – 6.87 (m, 2H), 3.47 (t, J = 5.2 Hz, 4H), 3.03 (dd, J = 6.0, 4.0 Hz, 4H), 2.81 (d, J = 4.4 Hz, 3H), 1.43 (s, 9H); 13 C NMR (100 MHz, DMSO- d 6) δ169.4, 158.5, 155.4, 155.1, 154.3, 146.9, 139.9, 133.3, 131.9, 128.4, 122.3,121.8, 121.6, 120.9, 116.9, 104.8, 79.4, 49.8, 28.5, 26.8.; ESI-HRMSC 27 H 32 ClN7O3([M+H) + ):calcd 538.2328, found 538.2318

[0074] Example 9 Synthesis of 4-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 4b)

[0075]

[0076] Compound 3a (3.02 g, 10.2 mmol), 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 8.1 mmol), palladium acetate (0.23 g, 0.2 mmol), Xantphos (1.17 g, 2 mmol), and Cs₂CO₃ (4.97 g, 15.2 mmol) were added to 1,4-dioxane (10 mL) with stirring. The flask was placed in an oil bath at 100 °C for 12 h under argon protection to carry out the substitution reaction. After cooling to room temperature, saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was filtered, and the filter cake was slurried with EA and dried to give the corresponding product 4b (1.15 g). Yellow solid, mp: >250 °C, yield 20%.

[0077] Characterization data of compound 4a: 1 H NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 8.67 (dd, J =8.4, 1.2 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.56 – 7.38 (m, 2H), 7.31 (s, 1H), 7.08 (td, J = 7.6, 1.2 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.8, 2.4 Hz, 1H), 6.24 (d, J = 5.6 Hz, 1H), 3.87 (s, 3H), 3.64 – 3.57 (m,4H), 3.08 (t, J = 5.2 Hz, 4H), 3.03 (d, J = 4.8 Hz, 3H), 1.49 (s, 9H); 13 C NMR (100MHz, CDCl3) δ 169.6, 157.7, 155.8, 154.8, 149.4, 147.3, 139.7, 131.7, 126.6,122.8, 122.6, 122.2, 121.7, 120.7, 108.6, 106.3, 101.2, 79.9, 60.4, 55.7,50.7, 28.5, 26.935, 14.2.

[0078] Example 10 Synthesis of 4-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylic acid tert-butyl ester 4c

[0079]

[0080] Compound 3c (2.38 g, 8 mmol), tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylic acid (1.77 g, 6.4 mmol), palladium acetate (0.18 g, 0.8 mmol), Xantphos (0.956 g, 1.6 mmol), and Cs₂CO₃ (3.91 g, 12 mmol) were added to 1,4-dioxane (10 mL) under stirring. The flask was placed in an oil bath at 100 °C for 12 h under argon protection to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was stirred for 0.5 h, extracted three times with EA, washed three times with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography to obtain the corresponding product 4c (1.87 g), a white solid, mp: 240.4–241.3 °C, yield 44%.

[0081] Characterization data of compound 4c: 1 H NMR (400 MHz, CDCl3) δ 11.21 (s, 1H), 8.66 (d, J =8.4 Hz, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.59 (dd, J = 8.0, 4.0 Hz, 1H), 7.51 (dd, J = 8.4, 4.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.36 – 7.31 (m, 4H), 7.17 – 7.05(m, 4H), 3.00 (t, J = 4.4 Hz, 3H), 2.83 (d, J = 8.4 Hz, 2H), 2.69 – 2.56 (m, 2H), 1.83 (d, J = 8.4 Hz, 2H), 1.66 – 1.56 (m, 2H), 1.49 (d, J = 4.0 Hz, 9H), 1.26(td, J = 7.2, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.6, 157.8, 155.7, 154.9,154.3, 140.1, 139.5, 137.8, 131.4, 127.3, 126.9, 122.3, 122.1, 121.7, 120.3,106.5, 42.0, 33.3, 28.5, 26.8, 14.2; ESI-HRMS C 28 H 33 ClN6O3([M+H) + ):calcd537.2375, found 537.2381.

[0082] Example 11 Synthesis of 2-((5-chloro-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)- N -Methylbenzamide 5a

[0083]

[0084] Then quickly add 4 mL of ethyl hydrochloride (0.1 g of raw material corresponds to 1 mL of ethyl hydrochloride), stir at room temperature for 12 h, after the reaction is complete, add saturated sodium carbonate to adjust to neutral, stir for 0.5 h, filter, and obtain the corresponding product 3b (160 mg), a yellow solid, mp >250℃, yield 56%.

[0085] The characterization data of compound 5a are as follows:

[0086] 1 H NMR (400 MHz, DMSO- d 6) δ 11.59 (s, 1H), 9.21 (s, 1H), 8.75 (q, J =4.8 Hz, 2H), 8.16 (s, 1H), 7.74 (dd, J =8.0, 1.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 4H), 7.13 (t, J = 7.6 Hz, 1H), 6.91 – 6.84 (m, 2H), 3.03 (dd, J = 6.4, 3.6 Hz, 4H), 2.90 (t, J = 4.8 Hz, 4H), 2.81 (d, J = 4.4Hz, 4H); 13C NMR (100 MHz, DMSO- d 6)δ 169.4, 158.5, 155.4, 155.1, 150.4, 146.9, 139.9, 133.0, 131.9, 128.4,122.3, 121.7, 120.9, 116.5, 104.8, 49.1, 44.9, 26.8.

[0087] Example 12 Synthesis of 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)- N -Methylbenzamide 5b

[0088]

[0089] Then quickly add 12 mL of ethyl hydrochloride (0.1 g of raw material corresponds to 1 mL of ethyl hydrochloride), stir at room temperature for 12 h. After the reaction is complete, add saturated sodium carbonate to adjust to neutral, stir for 0.5 h, filter, and obtain the corresponding product 3c (0.8 g), a yellow solid, mp: 212.0-213.1 ℃, yield 84%.

[0090] Characterization data of compound 5b: 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.60 (s, 1H), 8.66 (d, J =6.0 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H), 7.71 (d, J =8.0 Hz, 1H), 7.41 (d, J = 8.8Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 6.4 Hz,1H), 3.76 (s, 3H), 3.15 – 3.00 (m, 4H), 2.90 – 2.75 (m, 7H); 13 C NMR (100 MHz, DMSO- d6) δ 169.4, 159.5, 155.4, 155.1, 153.2, 150.2, 140.1, 131.9, 128.9,128.3, 125.9, 121.9, 121.4, 120.6, 107.4, 104.5, 100.5, 55.9, 50.5, 46.2,26.8; ESI-HRMS C 23 H 26 ClN7O2([M+H) + ): calcd 468.1909, found 468.1907.

[0091] Example 13 Synthesis of 2-((5-chloro-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)- N -Methylbenzamide 5c

[0092]

[0093] Then quickly add 18 mL of ethyl hydrochloride (0.1 g of raw material corresponds to 1 mL of ethyl hydrochloride), stir at room temperature for 12 h. After the reaction is complete, add saturated sodium carbonate to adjust to neutral, stir for 0.5 h, filter, and obtain the corresponding product 3d (1.2 g), a brown solid, mp: 147.9-148.2 ℃, yield 82%.

[0094] Characterization data of compound 5c:

[0095] 1 H NMR (400 MHz, DMSO- d 6) δ 11.60 (s, 1H), 9.39 (s, 1H), 8.76 (t, J =7.6 Hz, 2H), 8.20 (s, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz,2H), 7.53 – 7.45 (m, 1H), 7.15 (t, J = 9.2 Hz, 3H), 3.20 – 3.08 (m, 2H), 2.81(d, J = 2.4 Hz, 3H), 2.78 – 2.67 (m, 2H), 2.65 – 2.57 (m, 1H), 1.83 – 1.71 (m,2H), 1.68 – 1.48 (m, 2H);13 C NMR (100 MHz, CDCl3) δ 174.1, 163.0, 160.2,159.8, 144.7, 144.6, 143.5, 136.7, 133.2, 131.7, 127.2, 126.6, 125.9, 125.2,110.1, 50.5, 37.4, 31.5; ESI-HRMS ESI-HRMS C 23 H 25 ClN6O ([M+H)) + ):calcd 437.1851,found 437.1852.

[0096] Example 14 Synthesis of 2-((5-chloro-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)- N -Methylbenzamide 6a

[0097]

[0098] Compound 3a (297 mg, 1 mmol) and trifluoroethanol (5 mL) were mixed with 2-(4-(4-(p-aminophenyl)piperazin-1-yl)ethane-1-ol (266 mg, 1.2 mmol) and trifluoroacetic acid (342 mg, 3 mmol) under stirring. The flask was placed in an oil bath at 80 °C for 12 h under argon protection to carry out the substitution reaction. The mixture was then cooled to room temperature, and saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was filtered, dried, and the product 3a (400 mg) was obtained as a pale yellow solid with mp >250 °C and a yield of 82%.

[0099] Characterization data of compound 6a:

[0100] 1 H NMR (400 MHz, CDCl3) δ 11.08 (s, 1H), 8.69 (t, J = 9.2 Hz, 1H), 8.08(s, 1H), 7.54 – 7.34 (m, 5H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 6.92 (dd, J = 9.2, 2.4 Hz, 3H), 6.30 (d, J = 5.2 Hz, 1H), 3.69 (t, J= 5.2 Hz, 2H), 3.23 – 3.16 (m,4H), 3.05 (t, J = 4.4 Hz, 4H), 2.75 – 2.68 (m, 3H), 2.64 (t, J = 5.2 Hz, 2H); 13 CNMR (100 MHz, CDCl3) δ 169.8, 158.2, 155.8, 154.5, 147.4, 139.7, 132.2,131.6, 126.9, 122.3, 122.1, 122.0, 121.5, 116.8, 106.2, 59.4, 57.9, 52.9,49.9, 26.9.

[0101] Example 15 Synthesis of 2-((5-bromo-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide 6b

[0102]

[0103] Compound 3b (0.42 g, 2 mmol) and trifluoroethanol (5 mL) were mixed with 2-(4-(4-(p-aminophenyl)piperazin-1-yl)ethane-1-ol (0.53 g, 2.4 mmol) and trifluoroacetic acid (0.342 g, 3 mmol) under stirring. The flask was placed in an oil bath at 80 °C for 12 h under argon protection to carry out the substitution reaction. After cooling to room temperature, saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was filtered, dried, and the corresponding product 6b (0.33 g) was given as a yellow solid, mp: 221.5-222.3 °C, yield 31%.

[0104] Characterization data of compound 6b:

[0105] 1 H NMR (400 MHz, DMSO- d 6) δ 11.35 (s, 1H), 9.19 (s, 1H), 8.72 (d, J =4.8 Hz, 1H), 8.22 (s, 1H), 7.75 – 7.69 (m, 1H), 7.45 (d, J = 9.2 Hz, 3H), 7.13(t, J = 7.6 Hz, 1H), 6.86 (d, J = 9.2 Hz, 2H), 4.43 (t,J = 5.6 Hz, 1H), 3.54 (q, J =6.0 Hz, 2H), 3.06 (t, J = 5.2 Hz, 4H), 2.81 (d, J = 4.4 Hz, 3H), 2.56 (t, J = 5.2Hz, 4H), 2.44 (t, J = 6.4 Hz, 2H); 13 C NMR (100 MHz, DMSO- d 6) δ 169.3, 158.9,158.0, 156.2 147.1, 139.8, 132.5, 131.8 128.4 122.3, 122.1, 121.8, 121.4,116.1, 60.8, 59.1, 53.7, 49.4, 47.1, 26.8.

[0106] Example 16 Synthesis of 2-((2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)- N -Methylbenzamide 6c

[0107]

[0108] Compound 3c (0.553 g, 2 mmol) and trifluoroethanol (5 mL) were mixed with 2-(4-(4-(p-aminophenyl)piperazin-1-yl)ethane-1-ol (0.53 g, 2.4 mmol) and trifluoroacetic acid (0.342 g, 3 mmol) under stirring. The flask was placed in an oil bath at 80 °C for 12 h under argon protection to carry out the substitution reaction. Then, the mixture was cooled to room temperature, and saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was filtered, dried, and the product 6c (0.674 g) was given as a yellow solid, mp: 183.3-184.2 °C, yield 73%.

[0109] Characterization data of compound 6c:

[0110] 1 H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 8.77 (d, J = 7.2 Hz, 1H), 7.89(s, 1H), 7.49 – 7.40 (m, 3H), 7.40 (d, J= 7.2 Hz, 1H), 7.05 – 6.96 (m, 1H), 6.90 (d, J = 9.2 Hz, 2H), 6.83 (s, 1H), 6.27 (d, J = 5.2 Hz, 1H), 3.67 (t, J = 5.2Hz, 2H), 3.24 – 3.13 (m, 4H), 3.01 (d, J = 4.8 Hz, 3H), 2.73 – 2.65 (m, 4H), 2.66 – 2.59 (m, 2H), 2.19 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.1, 159.1,158.7, 155.3, 147.0, 140.8, 133.0, 131.9, 126.6, 122.2, 121.7, 121.2, 120.5,117.0, 107.1, 59.4, 57.8, 53.0, 50.1, 26.9, 13.6.

[0111] Example 17 Synthesis of 2-((2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- N -Methylbenzamide 6d

[0112]

[0113] Compound 3d (0.661 g, 2 mmol) and trifluoroethanol (5 mL) were mixed with 2-(4-(4-(p-aminophenyl)piperazin-1-yl)ethane-1-ol (0.53 g, 2.4 mmol) and trifluoroacetic acid (0.342 g, 3 mmol) under stirring. The flask was placed in an oil bath at 80 °C for 12 h under argon protection to carry out the substitution reaction. The mixture was then cooled to room temperature, and saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was filtered, dried, and the product 6d (0.541 g) was given as a yellow solid, mp: 195.6–196.7 °C, yield 53%.

[0114] The 6d characterization data of the compound are as follows:

[0115] 1 H NMR (400 MHz, DMSO- d 6) δ 11.34 (s, 1H), 9.60 (s, 1H), 8.73 (d,J =4.8 Hz, 1H), 8.38 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.44 (s, 3H), 7.15 (t, J =7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.45 (s, 1H), 3.54 (q, J = 6.0 Hz, 2H), 3.08 (t, J = 4.8 Hz, 4H), 2.78 (d, J = 4.4 Hz, 3H), 2.58 (t, J = 4.8 Hz, 4H), 2.45(t, J = 6.4 Hz, 2H); 13 C NMR (100 MHz, DMSO- d 6) δ 169.3, 156.4, 148.3, 148.1,145.5, 136.8, 131.8, 128.3, 126.5, 123.8, 122.4, 116.0, 60.7, 59.0, 56.5,55.4, 53.6, 49.2, 49.1, 26.7, 19.0.

[0116] Example 18 Synthesis of 2-((2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-nitropyrimidine-4-yl)amino)- N -Methylbenzamide 6e

[0117]

[0118] Compound 3e (0.62 g, 2 mmol) and trifluoroethanol (5 mL) were added with stirring to 2-(4-(4-(p-aminophenyl)piperazin-1-yl)ethane-1-ol (0.53 g, 2.4 mmol) and trifluoroacetic acid (0.342 g, 3 mmol). The substitution reaction was carried out in an oil bath at 80 °C for 12 h under argon protection. The mixture was then cooled to room temperature, and saturated sodium bicarbonate (50 mL) was added to the reaction mixture. The mixture was filtered, dried, and the product 6e (0.315 g) was given as a red solid, mp: 223.3–224.5 °C, yield 32%.

[0119] The characterization data of compound 6e are as follows:

[0120] 1 H NMR (400 MHz, DMSO- d 6) δ 11.34 (s, 1H), 9.60 (s, 1H), 8.73 (d, J =4.8 Hz, 1H), 8.38 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.44 (s, 3H), 7.15 (t, J =7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.45 (s, 1H), 3.54 (q, J = 6.0 Hz, 2H), 3.08 (t, J = 4.8 Hz, 4H), 2.78 (d, J = 4.4 Hz, 3H), 2.58 (t, J = 4.8 Hz, 4H), 2.45(t, J = 6.4 Hz, 2H); 13 C NMR (100 MHz, DMSO- d 6) δ 169.3, 156.4, 148.3, 148.1,145.5, 136.8, 131.8, 128.3, 126.5, 123.8, 122.4, 116.0, 60.7, 59.0, 56.5,55.4, 53.6, 49.2, 49.1, 26.7, 19.0; ESI-HRMS C 25 H 28 F3N7O2([M+H + ]):calcd516.2329, found 516.2326.

[0121] Example 19 Synthesis of 2-((2-((4-(4-(-4-(4-(bis(2-chloroethyl)amino)phenyl)butyryl)piperazin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-N-methylbenzamide 7a)

[0122]

[0123] Add 5a (100 mg, 0.23 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (83 mg, 0.27 mmol), add DCC (56 mg, 0.27 mmol) dissolved in DCM (2 mL) dropwise, add DMAP (8 mg, 0.006 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 7a (60 mg), white solid, mp: >250°C, yield 36%.

[0124] The characterization data of compound 7a are as follows:

[0125] 1 H NMR (400 MHz, DMSO- d 6) δ 11.59 (s, 1H), 9.24 (s, 1H), 8.75 (s, 2H), 8.16 (s, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 3H), 7.17 –7.09 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.94 – 6.88 (m, 2H), 6.67 (d, J = 8.4 Hz, 2H), 3.70 (d, J = 2.8 Hz, 8H), 3.56 (d, J = 4.8 Hz, 4H), 3.03 (d, J = 6.0 Hz, 4H), 2.81 (d, J = 4.4 Hz, 3H), 2.35 (t, J = 7.6 Hz, 2H), 1.76 (p, J = 7.6 Hz, 2H), 1.32– 1.14 (m, 2H); 13 C NMR (100 MHz, DMSO- d6) δ 170.6 168.8, 157.2, 155.0, 153.7,146.24 143.6, 138.94 132.1, 130.9 130.0, 128.9, 125.9, 121.5, 121.3, 121.1,120.7, 111.4, 105.7, 52.8, 49.8, 49.4, 44.8, 40.8, 39.8, 33.4, 31.7, 26.2;ESI-HRMS ESI-HRMS C 38 H 45 Cl3N8O2([M+H) + ):calcd 723.2491, found 723.2485.

[0126] Example 20 Synthesis of 2-((2-((4-(4-(-4-(4-(bis(2-chloroethyl)amino)phenyl)butyryl)piperazin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)- N -Methylbenzamide 7b

[0127]

[0128] 4-(bis(2-chloroethyl)amino)benzoic acid (72 mg, 0.27 mmol) and anhydrous DCM (2 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at 0°C for 5 minutes, followed by the addition of anhydrous DMF (1 mL), EDCI (52 mg, 0.27 mmol), and DMAP (1.6 mg, 0.0078 mmol). The mixture was stirred at room temperature for 1 hour, and finally 5a (100 mg, 0.23 mmol) was added. The mixture was stirred at room temperature under Ar protection for approximately 5 hours. After the reaction was complete, water was added, and the mixture was extracted with DCM, washed with NaCl water, dried over anhydrous sodium sulfate, and evaporated to dryness. The product 7b (20 mg) was separated by silica gel column chromatography as a brown solid, mp: >250°C, yield 13%.

[0129] The characterization data of compound 7b are as follows:

[0130] 1H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H), 8.66 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.52 – 7.40 (m, 5H), 7.05 (t, J = 7.6 Hz, 1H), 6.96 – 6.87 (m,3H), 6.69 (d, J = 8.3 Hz, 2H), 6.36 – 6.31 (m, 1H), 4.10 – 3.55 (m, 12H),3.14 (s, 4H), 3.02 (d, J = 4.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.6,169.6, 158.0, 155.8, 154.4, 147.5, 147.1, 139.7, 132.8, 131.7, 129.8, 126.7,123.9, 122.3, 122.1, 121.9, 121.5, 117.5, 111.2, 106.5, 53.4, 50.6, 40.2,29.3, 26.9; ESI-HRMS C 33 H 35 Cl3N8O2([M+H) + ):calcd 681.2021, found 681.2003.

[0131] Example 21 Synthesis of 2-((2-((4-(4-(4-(4-(bis(2-chloroethyl)amino)phenyl)butyryl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)- N -Methylbenzamide 8a

[0132]

[0133] Add 5b (0.1 g, 0.23 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (0.084 g, 0.27 mmol), add DCC (0.056 g, 0.27 mmol) dissolved in DCM (2 mL), add DMAP (0.008 g, 0.006 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 8a (0.052 g), a brown solid, mp: 158.6-159.2 °C, yield 31%.

[0134] The characterization data of compound 8a are as follows:

[0135] 1 H NMR (400 MHz, CDCl3) δ 11.05 (s, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.13(d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.51 (dd, J = 8.0, 1.6 Hz, 1H), 7.45 (ddd, J = 8.8, 7.2, 1.6 Hz, 1H), 7.13 – 7.04 (m, 3H), 6.67 – 6.60 (m, 2H), 6.54 (d, J = 2.4Hz, 1H), 6.51 – 6.44 (m, 2H), 3.87 (s, 3H), 3.79 (t, J = 5.2 Hz, 2H), 3.75 – 3.66 (m, 4H), 3.66 – 3.55 (m, 6H), 3.09 (t, J = 5.2 Hz, 4H), 3.02(d, J = 4.8 Hz, 3H), 2.96 (s, 4H), 2.61 (t, J = 7.2 Hz, 2H), 2.42 – 2.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.4, 169.6, 162.6, 157.7, 155.8, 154.4, 149.4,146.9, 144.4, 139.6, 131.6, 130.8, 129.7, 126.8, 123.1, 122.1, 121.7, 120.7,112.2, 108.6, 106.3, 101.3, 55.7, 53.6, 45.6, 40.6, 36.5, 34.2, 32.5, 31.5,26.9; ESI-HRMS C 37 H 43 Cl3N8O3([M+Na) + ): calcd 755.2528, found 755.2561.

[0136] Example 22 Synthesis of 2-((2-((4-(4-(4-(bis(2-chloroethyl)amino)benzoyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-N-methylbenzamide 8b

[0137]

[0138] Add 5b (0.15 g, 0.34 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(bis(2-chloroethyl)amino)benzoic acid (0.1 g, 0.41 mmol), add DCC (0.085 g, 0.27 mmol) dissolved in DCM (2 mL), add DMAP (0.0012 g, 0.006 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 8b (0.016 g), a blue solid, mp: 218.7-219.8°C, yield 7%.

[0139] The NMR data for compound 8b are as follows:

[0140] 1 H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 8.67 (dd, J = 8.4, 1.2 Hz, 1H), 8.14 (d, J= 8.8 Hz, 1H), 8.08 (s, 1H), 7.52 – 7.38 (m, 4H), 7.33 (s, 1H), 7.08(td, J = 7.6, 1.2 Hz, 1H), 6.73 – 6.66 (m, 2H), 6.55 (d, J = 2.4 Hz, 1H), 6.49(dd, J = 8.8, 2.4 Hz, 1H), 6.25 (d, J = 5.2 Hz, 1H), 3.87 (s, 3H), 3.79 (t, J = 7.2Hz, 8H), 3.66 (t, J = 7.2 Hz, 4H), 3.15 (s, 4H), 3.03 (d, J = 4.8 Hz, 3H); 13 C NMR(100 MHz, CDCl3) δ 170.6, 169.6, 157.6, 155.8, 149.5, 147.5, 147.0, 139.6,131.7, 129.8, 126.7, 123.9, 122.9, 122.5, 122.2, 121.7, 120.7, 111.2, 108.7,106.3, 101.2, 55.7, 53.4, 50.9, 40.2, 33.9, 29.7, 26.9; ESI-HRMS ESI-HRMSC 34 H 37 Cl3N8O3([M+H) + ):calcd 711.2127, found 711.2126.

[0141] Example 23 Synthesis of 2-((2-((4-(1-(4-(4-(bis(2-chloroethyl)amino)phenyl)butyryl)piperidin-4-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)- N -Methylbenzamide 9a

[0142]

[0143] Add 5c (0.1 g, 0.22 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (0.084 g, 0.27 mmol), add DCC (0.085 g, 0.27 mmol) dissolved in DCM (2 mL) dropwise, add DMAP (0.008 g, 0.006 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 9a (0.140 g), a pink solid, mp: 158.6-159.2 °C, yield 85%.

[0144] The characterization data of compound 9a are as follows:

[0145] 1 H NMR (400 MHz, CDCl3) δ 11.11 (s, 1H), 8.56 (dd, J = 8.4, 1.2 Hz, 1H),7.96 (s, 1H), 7.50 (s, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (d, J = 8.4 Hz,2H), 7.35 – 7.26 (m, 1H), 7.05 – 6.93 (m, 5H), 6.69 (q, J = 4.8 Hz, 1H), 6.56 –6.50 (m, 2H), 3.86 – 3.73 (m, 1H), 3.64 – 3.48 (m, 8H), 2.91 (d, J = 4.8 Hz,3H), 2.78 (s, 1H), 2.67 – 2.44 (m, 4H), 2.33 – 2.19 (m, 2H), 1.90 – 1.79 (m,4H), 1.63 – 1.37 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.3, 169.6, 157.5,155.8, 153.7, 144.3, 139.7, 139.5, 137.7, 131.6, 130.9, 129.7, 126.9, 126.9,122.4, 122.4, 121.6, 120.5, 112.2, 106.7, 53.6, 46.3, 42.4, 42.2, 40.6, 34.3,32.7, 27.1, 26.9; ESI-HRMS C 37 H 42 Cl3N7O2([M+H) + ): calcd 722.2538, found722.2526.

[0146] Example 24 Synthesis of 2-((2-((4-(1-(4-(bis(2-chloroethyl)amino)benzoyl)piperidin-4-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)- N -Methylbenzamide 9b

[0147]

[0148] Add 5c (0.15 g, 0.34 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(bis(2-chloroethyl)amino)benzoic acid (0.11 g, 0.41 mmol), add DCC (0.085 g, 0.41 mmol) dissolved in DCM (2 mL), add DMAP (0.008 g, 0.006 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 9b (0.061 g), a yellow solid, mp: 198.1-199.0 °C, yield 26%.

[0149] The characterization data of compound 9b are as follows:

[0150] 1H NMR (400 MHz, CDCl3) δ 11.21 (s, 1H), 8.15 – 7.92 (m, 3H), 7.56 – 7.47 (m, 3H), 7.47 – 7.38 (m, 3H), 7.18 – 7.08 (m, 3H), 6.72 – 6.65 (m, 3H),3.86 – 3.73 (m, 6H), 3.71 – 3.61 (m, 6H), 3.03 (d, J = 4.8 Hz, 3H), 2.82 – 2.71(m, 1H), 1.92 (s, 2H), 1.74 – 1.67 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.6,169.5, 157.2, 155.9, 149.9, 147.3, 139.9, 139.3, 137.6, 132.4, 131.7, 129.6,126.9, 124.6, 122.6, 121.8, 120.7, 118.7, 111.2, 106.4, 53.4, 42.4, 40.2,40.1, 33.9, 26.9; ESI-HRMS C 34 H 36 Cl3N7O2([M+H) + ): calcd 680.2069, found680.2062.

[0151] Example 25 Synthesis of ethyl 2-(4-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-4-(4-(bis(2-chloroethyl)amino)phenyl)butyrate 10a)

[0152]

[0153] Add 6a (100 mg, 0.2 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (73 mg, 0.24 mmol), add DCC (49 mg, 0.24 mmol) dissolved in DCM (2 mL) dropwise, add DMAP (8 mg, 0.008 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 10a (30 mg), a yellow solid, mp: >250°C, yield 48%.

[0154] The characterization data of compound 10a are as follows:

[0155] 1 H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.08(s, 1H), 7.49 (dd, J = 7.6, 1.6 Hz, 1H), 7.45 – 7.39 (m, 3H), 7.13 – 7.03 (m,3H), 6.92 (d, J = 9.2 Hz, 3H), 6.67 – 6.60 (m, 2H), 6.25 (d, J = 5.2 Hz, 1H), 4.28 (t, J = 5.6 Hz, 2H), 3.87 – 3.50 (m, 8H), 3.18 (dd, J = 6.4, 3.6 Hz, 4H), 3.05 (d, J = 4.8 Hz, 3H), 2.72 (q, J = 5.2, 4.4 Hz, 6H), 2.59 (t, J = 7.6 Hz, 2H), 2.37 (t, J = 7.6 Hz, 2H), 1.94 (p, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, DMSO- d6) δ168.8, 164.9, 153.4, 151.0, 149.8, 142.7, 139.6, 134.9, 127.3, 127.0, 125.8,124.9, 121.9, 117.6, 117.4, 117.3, 116.7, 112.1, 107.4, 101.5, 56.8, 52.0,48.9, 48.8, 45.1, 35.8, 29.2, 28.9, 22.2, 22.0.

[0156] Example 26 Synthesis of 2-((2-((4-(4-(-4-(4-(bis(2-chloroethyl)amino)phenyl)butyryl)piperazin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-N-methylbenzamide 10b

[0157]

[0158] 4-(bis(2-chloroethyl)amino)benzoic acid (68 mg, 0.26 mmol) and anhydrous DCM (2 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at 0°C for 5 minutes, followed by the addition of anhydrous DMF (1 mL), EDCI (60 mg, 0.31 mmol), and DMAP (1.6 mg, 0.0078 mmol). The mixture was stirred at room temperature for 1 hour, and finally 6a (150 mg, 0.31 mmol) was added. The mixture was stirred at room temperature under Ar protection for approximately 5 hours. After the reaction was complete, water was added, and the mixture was extracted with DCM, washed with NaCl water, dried over anhydrous sodium sulfate, and evaporated to dryness. The product 10b (40 mg) was separated by silica gel column chromatography as a yellow solid, mp: >250°C, yield 32%.

[0159] The characterization data of compound 10b are as follows:

[0160] 1 H NMR (400 MHz, CDCl3) δ 11.07 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.06(s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.47 – 7.36 (m, 4H), 7.05 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 3H), 6.68 (d, J= 8.8 Hz, 2H), 6.24 – 6.20 (m, 1H), 4.48 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 7.2 Hz, 4H), 3.66 (t, J = 6.8 Hz, 4H), 3.49 (s, 2H), 3.19 (t, J = 5.2 Hz, 4H), 3.03 (d, J = 4.8 Hz, 3H), 2.88 – 2.69 (m, 4H); 13 C NMR(100 MHz, CDCl3) δ 169.6, 166.3, 158.14, 155.8, 154.4, 149.8, 147.5, 139.7,132.1, 131.9, 131.8, 126.6, 122.4, 122.2, 122.1, 121.4, 118.8, 116.9, 110.9,58.5, 53.3, 50.9, 49.8, 40.1, 26.9, 18.5.

[0161] Example 27 Synthesis of 2-(4-(4-((5-bromo-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl 4-(4-(bis(2-chloroethyl)amino)phenyl)butyrate 11a)

[0162]

[0163] Add 6b (0.13 g, 0.25 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (0.1 g, 0.3 mmol), add DCC (0.085 g, 0.27 mmol) dissolved in DCM (2 mL), add DMAP (0.008 g, 0.006 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 11a (0.023 g), a yellow solid, mp: >250°C, yield 11%.

[0164] The characterization data of compound 11a are as follows:

[0165] 1H NMR (400 MHz, CDCl3) δ 10.86 (s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.02(s, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 7.34 (d, J = 9.2 Hz,2H), 7.28 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 7.00 – 6.93 (m, 2H), 6.80 (d, J =9.2 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 6.26 (d, J = 4.8 Hz, 1H), 4.19 (t, J = 6.0Hz, 2H), 3.65 – 3.56 (m, 4H), 3.53 (t, J = 6.0 Hz, 4H), 3.12 – 3.05 (m, 4H),2.93 (d, J = 4.8 Hz, 3H), 2.68 – 2.60 (m, 6H), 2.49 (t, J = 7.6 Hz, 2H), 2.27 (t, J = 7.6 Hz, 2H), 1.90 – 1.78 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 175.8, 173.6,169.5, 158.4, 156.6, 156.6, 147.4, 144.4, 139.5, 132.1, 131.6 130.5, 129.7,126.7 122.7, 122.3, 122.1, 121.9, 116.8, 112.1, 94.6, 61.4, 56.7, 53.6, 53.3,49.7, 40.6 33.6, 26.9, 26.7; ESI-HRMS C 38 H 45 BrCl2N8O3([M+H + ]): calcd 811.2248,found 811.2248.

[0166] Example 28 Synthesis of 2-(4-(4-((5-methyl-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl 4-(4-(bis(2-chloroethyl)amino)phenyl)butyrate 12a)

[0167]

[0168] Add 6c (0.19 g, 0.41 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (0.15 g, 0.49 mmol), add dropwise DCC dissolved in DCM (2 mL), add DMAP (0.009 g, 0.0065 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 12a (0.048 g), a yellow solid, mp: >250°C, yield 16%.

[0169] The characterization data of compound 12a are as follows:

[0170] 1 H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.77 (d, J = 7.6 Hz, 1H), 7.87(s, 1H), 7.45 (d, J = 5.2 Hz, 2H), 7.42 (s, 1H), 7.41 – 7.33 (m, 1H), 7.11 (d, J = 10 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.96 (dd, J = 8.4, 7.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 4.8 Hz, 1H), 4.25 (t, J = 6.0Hz, 2H), 3.67 (t, J = 7.2 Hz, 4H), 3.64 – 3.55 (m, 4H), 3.17 – 3.10 (m, 4H), 2.97 (d,J = 4.8 Hz, 3H), 2.68 (q, J = 5.6, 5.1 Hz, 6H), 2.56 (t, J = 7.6 Hz, 2H), 2.34 (t, J = 7.6 Hz, 2H), 2.18 (s, 3H), 1.91 (p, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 173.6, 170.1, 159.1, 158.8, 155.4, 147.0, 144.4, 140.8, 133.0,131.8, 130.5, 129.7, 126.7, 122.1, 121.8, 121.2, 120.5, 117.0, 112.2, 107.0,61.6, 56.8, 53.6, 53.5, 50.0, 40.6, 34.0, 33.7, 26.8, 26.8, 13.6; ESI-HRMSC 39 H 48 C l2 N8O3([M+H + ]):calcd 747.3299, found 747.3299.

[0171] Example 29 Synthesis of 2-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl 4-(4-(bis(2-chloroethyl)amino)phenyl)butyrate 13a

[0172]

[0173] Add 6d (0.21 g, 0.41 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (0.15 g, 0.49 mmol), add dropwise DCC dissolved in DCM (2 mL), add DMAP (0.009 g, 0.0065 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 13a (0.025 g), a yellow solid, mp: >250°C, yield 8%.

[0174] The characterization data of compound 13a are as follows:

[0175] 1 H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.21(s, 1H), 7.34 (dd, J = 8.0, 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.0Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 9.2 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 6.25 (d, J = 5.0 Hz, 1H), 4.17 (t, J = 5.8 Hz, 2H), 3.64 – 3.55 (m, 4H), 3.55 – 3.47 (m, 4H), 3.11 – 3.02 (m, 4H), 2.86 (d, J = 4.8Hz, 3H), 2.61 (q, J = 5.6 Hz, 6H), 2.48 (t, J = 7.6 Hz, 2H), 2.26 (t, J = 7.6 Hz, 2H), 1.84 (q, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 173.6, 169.5, 161.1,157.0, 154.3, 149.4, 148.0, 144.4, 139.1, 131.3, 131.1, 130.6, 129.7, 129.7,126.8, 122.7, 122.6, 122.6, 116.6, 112.2, 106.6, 53.6, 53.4, 49.7, 49.0,40.5, 39.1, 34.0, 33.6, 25.6, 25.0; ESI-HRMS C 39 H 45Cl2F3N8O 3 ( [M+H + ]): calcd801.3017, found 801.3017.

[0176] Example 30 Synthesis of 2-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl 4-(bis(2-chloroethyl)amino)benzoate 13b

[0177]

[0178] Add 6d (0.16 g, 0.32 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add anhydrous DMF (1 mL), add 4-(bis(2-chloroethyl)amino)benzoic acid (0.1 g, 0.38 mmol), add DCC (0.066 g, 0.32 mmol) dissolved in DCM (2 mL), add DMAP (0.008 g, 0.006 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 13b (0.027 g), a green solid, mp: >250°C, yield 12%.

[0179] The characterization data of compound 13b are as follows:

[0180] 1 H NMR (400 MHz, CDCl3) δ 10.83 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.31(s, 1H), 7.98 – 7.91 (m, 2H), 7.45 (dd, J = 7.6, 1.6 Hz, 1H), 7.43 – 7.33 (m,3H), 7.12 – 7.03 (m, 2H), 6.92 – 6.85 (m, 2H), 6.71 – 6.65 (m, 2H), 6.17 (d, J = 5.2 Hz, 1H), 4.48 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 7.2Hz, 4H), 3.66 (t, J= 7.2Hz, 4H), 3.23 – 3.16 (m, 4H), 3.00 (d, J = 4.8 Hz, 3H), 2.86 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 5.2 Hz, 4H); 13 C NMR (100 MHz, CDCl3) δ 169.5, 166.4, 161.1, 156.9,155.8, 149.8, 147.9, 139.1, 131.9, 131.4, 131.0, 126.5, 123.8, 122.7, 122.7,122.6, 118.8, 116.7, 115.4, 110.9, 62.1, 56.8, 53.3, 49.7, 40.1, 33.9, 29.7,26.9; ESI-HRMS C 36 H 39 Cl2F3N8O3([M+H + ]):calcd 759.2547, found 759.2544.

[0181] Example 31 Synthesis of 2-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-nitropyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl 4-(4-(bis(2-chloroethyl)amino)phenyl)butyrate 14a)

[0182]

[0183] Add 6e (0.21 g, 0.41 mmol) and anhydrous DCM (2 mL) to a 50 mL round-bottom flask, stir at 0°C for 5 minutes, add 4-(4-(bis(2-chloroethyl)amino)phenyl)butyric acid (0.15 g, 0.49 mmol), add DCC (0.05 g, 0.245 mmol) dissolved in DCM (2 mL), add DMAP (0.009 g, 0.0065 mmol), and stir at room temperature for 5 hours. After the reaction is complete, add water, extract with DCM, wash with NaCl water, dry with anhydrous sodium sulfate, evaporate to dryness, and separate by silica gel column chromatography to obtain the corresponding product 14a (0.152 g), an orange-red solid, mp: >250°C, yield 46%.

[0184] The characterization data of compound 14a are as follows:

[0185] 11H NMR (400 MHz, CDCl3) δ 12.07 (s, 1H), 9.13 (s, 1H), 8.25 (d, J J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J J = 7.6 Hz, 1H), 7.39 (d, J J = 9.2 Hz, 3H), 7.24 – 7.15 (m, 1H), 7.07 (d, J J = 8.8 Hz, 2H), 6.83 (s, 2H), 6.61 (d, J J = 8.8 Hz, 2H), 6.04 (s, 1H), 4.27 (t, J J = 5.6 Hz, 2H), 3.73 – 3.65 (m, 4H), 3.65 – 3.56 (m, 4H), 3.22 – 3.15 (m, 4H), 2.99 (d, J J = 5.2 Hz, 3H), 2.71 (d, J J = 5.8 Hz, 6H), 2.57 (t, J J = 7.6 Hz, 2H), 2.35 (t, J J = 7.6 Hz, 2H), 1.92 (p, J J = 7.6 Hz, 2H); 13 13C NMR (100 MHz, CDCl3) δ 173.6, 168.6, 148.9, 148.5, 144.4, 136.6, 130.8, 130.5, 129.7, 126.7, 125.4, 124.6, 122.4, 116.4, 112.2, 61.4, 58.5, 56.7, 53.6, 53.3, 50.9, 49.3, 40.5, 34.0, 33.6, 26.9, 26.8, 25.6, Z5.0, 18.4; ESI-HRMS C 38 12 45 H + Cl2N9O5 ([M + H

[0186] Example 32

[0187] This embodiment tests the anti-glioma activity of the diaminopyrimidine compounds containing phenylmustine fragments prepared in Examples 19-31.

[0188] The MTT assay was used to test the IC50 of the compound against the glioma cell line (U87-MG cells). 50 U87-MG cells were seeded in 96-well plates. After cell adhesion, various concentrations of the test drug were added, along with a blank control and a negative control group. After co-culturing the cells and drugs for 72 h, the drug-containing medium was removed, and 10 μL of MTT solution (5 mg / mL, i.e., 0.5% MTT solution) was added to each well. Cells were cultured for another 4 h, and the absorbance at OD 570 nm (calibrated at 630 nm) of each well was measured directly on an ELISA reader. The IC50 value was then calculated. 50 Values. See Table 1 for the results. The results indicate that the diaminopyrimidine compounds containing the phenylmustine fragment of this invention have a good inhibitory effect on U87-MG cells.

[0189] Table 1. Test results of the diaminopyrimidine derivatives containing phenylmustine fragments prepared in Examples 19-31 on U87-MG cells.

[0190]

[0191]

[0192]

[0193] Finally, it should be noted that the above embodiments are merely representative examples of the present invention. Obviously, the technical solution of the present invention is not limited to the above embodiments, and many variations are possible. All variations that can be directly derived or conceived by those skilled in the art from the content disclosed in this invention should be considered within the scope of protection of this invention.

Claims

1. A diaminopyrimidine compound containing a phenylmustine fragment, characterized in that, It can be any of the following structures: 、 、 、 、 、 、 。 2. The use of the diaminopyrimidine compound containing the phenylmustine fragment as described in claim 1 in the preparation of anti-glioma drugs.

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