CN106986895A - Quinazoline ditosylate salt Mutiple Targets antitumoral compounds and its preparation method and application - Google Patents

Abstract

The present invention provides a kind of quinazoline class multi-target anti-tumor compound as shown in chemical formula (I) and preparation method thereof, especially relate to EGFR, HER-2 and DNA multi-target anti-tumor compound, also provide its preparation method and Application in antitumor drugs. Studies have shown that the compound of the present invention has significant antitumor activity, and its metabolic stability has been significantly improved compared with the reference substance EMB-3.

Description

Quinazoline multi-target anti-tumor compound and its preparation method and application

technical field

The invention belongs to the field of medicinal chemistry, and relates to EGFR, HER-2 and DNA multi-target anti-tumor compound and its preparation method, as well as its application in treating tumors.

Background technique

The occurrence and development of tumors is a complex biological process involving multiple factors and multiple genes. Treatment methods with a single drug and a single target often have problems such as poor efficacy, severe side effects, and drug resistance. At present, a combination of drugs with different mechanisms of action is often used in clinical treatment to overcome the above-mentioned problems. According to this clinical experience, scientists have designed and synthesized many small molecule drugs with multi-target mechanism of action, and pharmacological experiments have proved that this idea is feasible.

EGFR small-molecule inhibitors are anti-tumor drugs that have been on the market in recent years, and have remarkable therapeutic effects. However, in clinical applications, since these drugs all act on the ATP binding site, mutations will continue to occur during use, resulting in drug resistance , reducing the efficacy of the drug. Moreover, many cells express both EGFR and HER-2 receptors, which significantly reduces the therapeutic effect of EGFR inhibitors. This requires the design of new inhibitors that can act on both EGFR and HER-2 and are effective on mutant receptors.

Cyclophosphamide is a DNA alkylating agent antitumor drug that has been used for many years, but its severe side effects limit its clinical application. Although some scientists have combined EGFR small molecule inhibitors and DNA alkylating agents to design a series of dual-target drug molecules, the antitumor activity of these compounds is mediocre.

According to the concept of multi-target drug design and the research basis of cyclophosphamide quaternary ammonium salt derivatives in our experimental group for many years, the parent structure of the EGFR/HER-2 inhibitor is combined with phosphoryl mustard through a suitable linker arm , designed and synthesized a class of 4-arylaminoquinazoline phosphoramide mustard inhibitors of EMB-3. This compound has both EGFR/HER-2 receptor inhibitory activity and DNA alkylation effect, and no Obvious toxic and side effects, but in vivo experiments prove that its metabolism is fast and its half-life in vivo is short. In order to improve the metabolic stability of these compounds, we designed and synthesized a series of ring-structured EGFR/HER-2/DNA damage multi-target compounds based on the principle of skeleton transition, hoping to improve the stability of these compounds in vivo. Increase the anti-tumor activity of the drug and reduce the dose of the drug.

Contents of the invention

The present invention provides a ring-shaped EGFR/HER-2/DNA damage multi-target compound, which has a structure as shown in chemical formula (I):

Wherein, R is selected from hydrogen, lower alkoxy _; preferably from hydrogen, methoxy or ethoxy.

R ₂ is selected from substituted or unsubstituted phenyl, the substituted phenyl means that phenyl is substituted by one or more halogen, C1-C4 alkynyl, lower alkyl, lower alkoxy or arylalkoxy ; preferably selected from 3-bromo, 3-chloro-4-fluoro, 3-ethynyl or 3-chloro-4-(3-fluorobenzyloxy), 3-trifluoromethyl, 3-benzyloxy.

R ₃ is selected from hydrogen, cyano; preferably from hydrogen.

A is O or NH;

Defined in the present invention:

The "lower alkyl" can be C1-C6 alkyl or substituted alkyl, for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, Tert-butyl group, cyclobutyl group, etc., when it is a substituted alkyl group, the substituent may be, for example, halogen or substituted phenyl group.

The "lower alkoxy" can be C1-C6 alkoxy or substituted alkoxy, for example, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutyl Oxygen, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, etc. In the case of substituted alkoxy, the substituents may be, for example, halogen or substituted benzene Base etc.

The "arylalkoxy" can be, for example, benzyloxy or lower substituted benzyloxy, and the lower substituent can be one or more halogens, amino or C1-C4 alkane on the benzene ring group, C1-C4 alkoxy group, etc.

The "halogen" is chlorine, fluorine or bromine.

Compounds of the present invention may include, but are not limited to, the following preferred compounds, the structures of which are shown in the table below:

The present invention also provides the preparation method of the multi-target compound shown in chemical formula (I):

Wherein, when A is O and R ₁ is hydrogen, and R ₂ and R ₃ are as defined in the aforementioned chemical formula (I), the synthetic route 1 of the compound is as follows:

Synthetic route one:

Reagent conditions and reactions: a) Et ₃ N, react at room temperature; b) HCONH ₂ , 160°C; c) Ac ₂ O, 100°C; d) SOCl ₂ , reflux;

e) Substituted aniline, i-PrOH, Et ₃ N, reflux; f) NH ₃ OH, CH ₃ OH, reaction at room temperature; g) 3, DIAD, PPh ₃ , CH ₂ Cl ₂ .

Phosphoryl mustard dichloride reacts with 3-amino-1,2-dihydroxypropane to give 2-(bis(2-chloroethyl)amino)-5-hydroxymethyl-1,3,2-oxazaphosphorine Cyclopentane-2-oxide.

5-Hydroxy-2-aminobenzoic acid and formamide are closed at high temperature to obtain 4,6-dihydroxyquinazoline; then 6-OH is selectively acetylated to obtain 6-acetoxy-4-hydroxyquinazoline, Then react with thionyl chloride to become 6-acetoxy-4-chloroquinazoline, directly react with substituted aniline to obtain 4-substituted anilino-6-acetoxyquinazoline without purification, and then react in ammonia/methanol system In deacetylation, 4-substituted anilino-6-hydroxyquinazoline is obtained; finally, under the conditions of triphenylphosphine and diisopropyl azodicarboxylate, with 2-(bis(2-chloroethyl)amino) -5-Hydroxymethyl-1,3,2-oxazaphospholane-2-oxide reacts to obtain some compounds represented by formula (I).

Wherein, when A is O and R ₁ is methoxy, and R ₂ and R ₃ are as defined in the aforementioned chemical formula (I), the second synthetic route of the compound is as follows:

Synthetic route two:

Reagents and reaction conditions: a) SOCl ₂ , DMF (cat.), reflux; b) NH ₄ OH, Methanol, reaction at room temperature; c) 3, PPh ₃ , DTAD, DCM, reaction at room temperature; d) substituted aniline, DMF, 90°C

7-Methoxyl-4-hydroxyquinazolin-6-ol acetate was refluxed in thionyl chloride to give 7-methoxyl-4-chloroquinazolin-6-ol acetate, without purification in In the ammonia/methanol system, deacetylation obtains 6-hydroxyl-7-methoxy-4-chloroquinazoline; 2-Chloroethyl) amino)-5-hydroxymethyl-1,3,2-oxazaphospholane-2-oxide reacts to obtain 2-bis(2-chloroethyl)amino-5-( 4-chloro-7-methoxyl group) quinazoline methyl ether-1,3,2-oxazaphospholane-2-oxide compound; Finally obtain partial formula (I ) compounds shown.

Wherein, when A is NH and R ₁ is hydrogen, and R ₂ and R ₃ are as defined in the aforementioned chemical formula (I), the synthetic route 3 of the compound is as follows:

Synthetic route three:

Reagents and reaction conditions: a) HCONH ₂ , 160°C; b) SOCl ₂ , DMF; c) CH ₃ OH, NH ₄ OH, substituted aniline, reaction at room temperature;

d) (NH ₂ CH ₂ ) ₂ CHOH, Cul, t-BuONa, DMF, reflux; e) Cl ₂ PON(CH ₂ CH ₂ Cl) ₂ , Et ₃ N, i-PrOH, 80 °C

After 2-amino-5-iodobenzoic acid is added with excess formamide, the ring closure at high temperature obtains 6-iodo-4-hydroxyquinazoline, and then refluxes with thionyl chloride to obtain 4-chloro-6-iodoquinazoline, and then Directly react with substituted aniline without purification to obtain 6-iodo-4-arylaminoquinazoline intermediate. Then under argon protection, using DMF as a solvent, the Ullmann reaction catalyzed by CuI reacts with 2-hydroxyl-1,3-diaminopropane to obtain the intermediate 1-amino-3-((4-substituted anilinoquinazoline ) 6-amino) propanediol, and finally cyclized with phosphoryl mustard to obtain the compound shown in the partial formula (I).

The present invention also provides the anti-tumor application of the multi-target compound represented by the chemical formula (I), and studies have shown that it has significant anti-tumor activity.

detailed description

Below in conjunction with specific embodiment the present invention is described in further detail, and the embodiment that gives is only to illustrate the present invention, but not in order to limit the scope of the present invention.

Example 1: Preparation of 2-bis(2-chloroethyl)amino-5-(6-(4-(3-bromoanilino)quinazoline)oxy)methyl-1,3,2-oxazaphosphorus Heterocyclopentane-2-oxide (Code: 10a1)

1. Synthesis of 2-(bis(2-chloroethyl)amino)-5-hydroxymethyl-1,3,2-oxazaphospholane-2-oxide (3)

3-Amino-1,2-propanediol (5.54 g, 60.8 mmol) was dissolved in 100 mL of isopropanol, and phosphoryl mustard dichloride (15.7 g, 60.8 mmol) and triethylamine (12.3 g, 121.6 mmol) were added , stirred at room temperature for 24 hours. After the reaction, filter with suction, evaporate the filtrate to dryness and extract three times with ethyl acetate and water (150mL×3), combine the organic layers and wash with saturated sodium chloride solution three times, add anhydrous sodium sulfate to dry, concentrate, and flash column separation (dichloromethane:methanol=40:1), 9.08g milky white solid was obtained, the yield was 54%. Mp: 98°C.

¹ H NMR (400MHz, CDCl ₃ )δ4.53(m,1H),3.84(d,1H),3.63(m,6H),3.44(m,6H),3.32(d,1H)

¹³ C NMR (101MHz, CDCl ₃ ) δ78.71, 63.56, 49.09, 43.07, 42.24.

³¹ P NMR (162MHz, CDCl ₃ ) δ30.37.

2. Synthesis of 4,6-dihydroxyquinazoline (5)

5-Hydroxy-2-aminobenzoic acid (45.00g, 150mmol) was added to 200mL formamide, reacted at 150°C for 1h, a lot of solids were produced. After cooling, add water for suction filtration, and dry to obtain 21.25 g of light brown metallic luster scale-like solid with a yield of 86%. Mp>300℃

¹ H NMR (400MHz,DMSO)δ12.02(s,1H),10.05(s,1H),7.90(s,1H),7.61–7.49(m,1H), 7.42(s,1H),7.25(d ,J＝7.8Hz,1H).

¹³ C NMR (101MHz, DMSO) δ161.04, 156.58, 142.66, 142.37, 129.29, 124.12, 109.19.

3. Synthesis of 4-hydroxyl-6-acetoxyquinazoline (6)

Add 4,6-dihydroxyquinazoline (23.50g, 145mmol) and 30mL pyridine to 220mL acetic anhydride, and react at 100°C for 2h. After cooling, it was poured into crushed ice, and a large amount of solid was precipitated, filtered with suction, and dried to obtain 30.00 g of a light brown solid, with a yield of 84%. Mp:130-132℃

4. Synthesis of 4-(3-bromoanilino)-6-acetoxyquinazoline (8)

Compound 6-acetoxy-4-hydroxyquinazoline (15.00g, 60mmol) and DMF (10mL) were added to 80mL thionyl chloride, and refluxed for 5h. The thionyl chloride was distilled off under reduced pressure, and the residual thionyl chloride was removed by rotary evaporation with ethyl acetate (100 mL×3) to obtain a yellow solid. Add 100 mL of isopropanol, 3-bromoaniline (12.00 g, 70 mmol) and triethylamine (9.00 g, 90 mmol), and reflux at 80° C. for 6 h. Cool, filter with suction, wash with isopropanol, water and ether successively, and dry to obtain light yellow solid, 15.30 g, yield 71%. Mp:238-239℃

¹ H NMR(300MHz,DMSO-d ₆ ):δ2.40(s,3H),7.44-7.54(m,2H),7.78(d,J＝7.5Hz,1H), 7.93-8.09(m,3H) ,8.67(s,1H),8.99(s,1H),11.39(s,1H).

5. Synthesis of 4-(3-bromoanilino)-6-hydroxyquinazoline (9)

Add 4-(3-bromoanilino)-6-acetoxyquinazoline (15.00 g, 40 mmol) and concentrated ammonia water 50 mL into 150 mL methanol, and react overnight at room temperature. Concentrate, add water, filter with suction, and dry to obtain 12.10 g of a yellow-brown solid with a yield of 95%. Mp>300°C.

¹ H NMR (400MHz,DMSO)δ10.10(s,1H),9.58(s,1H),8.51(s,1H),8.27(s,1H),7.93(d,J=7.7Hz,1H), 7.79(s, 1H), 7.70(d, J=8.9Hz, 1H), 7.45(d, J=8.6Hz, 1H), 7.33(t, J=7.9Hz, 1H), 7.26(d, J=7.6 Hz,1H).

6. Synthesis of 2-bis(2-chloroethyl)amino-5-(6-(4-(3-bromoanilino)quinazoline)oxy)methyl-1,3,2-oxazaphosphine Pentane-2-oxide (Code: 10a1)

2-(bis(2-chloroethyl)amino)-5-hydroxymethyl-1,3,2-oxazaphospholane-2-oxide (1.00g, 3.6mmol) and triphenylphosphine (1.04g, 4mmol) was suspended in 6mL of dichloromethane and stirred at 0°C. DIAD was slowly added dropwise, the solution was light yellow and clear, and reacted at 0°C for 1 h. Add 4-(3-bromoanilino)-6-hydroxyquinazoline (0.40 g, 1 mmol) and react overnight, the solution turns from yellow-green turbidity to brown clarification. After the reaction, the system was extracted with dichloromethane and water, concentrated after standing with anhydrous sodium sulfate, and flashed (dichloromethane:methanol=60:1) to obtain 372 mg of light yellow foamy solid with a yield of 18%. Mp: 84-87°C.

¹ H NMR (400MHz, CDCl ₃ )δ9.57(s,1H),8.62(s,1H),8.15(s,1H),7.97(m,2H),7.67(m,2H),7.30(s, 1H),7.20(s,2H),4.87(s,1H),4.66–4.50(m,1H),4.19(m,1H),3.85–3.54(m,6H), 3.39(m,5H).

¹³ C NMR (101MHz, CDCl ₃ ) δ157.55, 157.10, 152.38, 144.21, 140.62, 129.95, 128.38, 126.72, 125.49, 124.69, 122.15, 120.58, 115.83, 103.59, 71.24, 481 , 43.74 (d, J=9 Hz), 42.13.

³¹ P NMR (162MHz, CDCl ₃ ) δ29.25.

HRMS(ESI ⁺ )m/z calcd for C ₂₁ H ₂₄ BrC ₁₂ N ₅ O ₃ P(M+H) ⁺ 574.01717,found 574.01751.

Example 2: Preparation of 2-bis(2-chloroethyl)amino-5-(6-(4-(3'-chloro-4'-(3"-fluorobenzyloxy)anilino)quinazoline) O)methyl-1,3,2-oxazaphospholane-2-oxide (Code: 10a2)

1. Synthesis of 6-hydroxyl-7-methoxy-4-chloroquinazoline (13)

7-Methoxy-4-hydroxyquinazolin-6-ol acetate (4.68g, 20mmol) and DMF (0.4mL) were added to 25mL of thionyl chloride and refluxed for 5 hours. The thionyl chloride was evaporated under reduced pressure, and then the residual thionyl chloride was removed by rotary evaporation with chloroform (10mL×3) and toluene (10mL×2) to obtain 7-methoxy-4-chloroquinazoline-6- alcohol acetate. Without purification, it was added to a solution of concentrated ammonia (35mL) in methanol (70mL), stirred at room temperature for 3 hours, filtered with suction, and the filter cake was washed with ether to obtain 6-hydroxy-7-methoxy-4-chloroquinazoline , 3.61 g of pale white solid, yield 84.6%.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.75(s,1H),8.79(s,1H),7.39(s,1H),7.37(s,1H),4.01(s,3H).

¹³ C NMR (101MHz, DMSO-d ₆ ) δ157.64, 157.03, 151.78, 150.34, 148.24, 119.37, 107.43, 105.73, 56.84.

2. Synthesis of 2-bis(2-chloroethyl)amino-5-(6-(4-chloro-7-methoxyquinazoline)oxy)methyl-1,3,2-oxazaphosphine Pentane-2-oxide (14)

6-Hydroxy-7-methoxy-4-chloroquinazoline (211mg, 1.0mmol), 2-(bis(2-chloroethyl)amino)-5-hydroxymethyl-1,3,2-oxo Nitrophospholane-2-oxide (333mg, 1.2mmol) and triphenylphosphine (341mg, 1.3mmol) were added into anhydrous dichloromethane (15mL) under the protection of argon. Slowly add DTAD (300mg, 1.3mmol) dropwise under stirring at room temperature, and then stir at room temperature for 12 hours after dropping for a few minutes. Ethyl acetate:methanol=40:40:1) to obtain 397 mg of white solid with a yield of 84.5%.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.86(s, 1H), 7.42(s, 2H), 5.12(d, J=16.0Hz, 1H), 4.88(m, 1H), 4.33(d, J＝5.3Hz, 2H), 4.02(s, 3H), 3.70(m, 4H), 3.51(m, 1H), 3.33(dd, J＝13.0, 4.9Hz, 4H)

¹³ C NMR (101MHz, DMSO-d ₆ ) δ158.53, 157.08, 152.79, 150.52, 149.10, 118.89, 107.54, 104.14, 75.78, 70.97, 57.06, 48.70, 43.55, 42.89.

3. Synthesis of 2-bis(2-chloroethyl)amino-5-(6-(4-(3'-chloro-4'-(3"-fluorobenzyloxy)anilino)quinazoline)oxy) Methyl-1,3,2-oxazaphospholane-2-oxide (Code: 10a2)

2-bis(2-chloroethyl)amino-5-(4-chloro-7-methoxy)quinazoline methyl ether-1,3,2-oxazaphospholane-2-oxidation (170mg, 0.362mmol), 3-chloro-4-(3-fluorobenzyloxy)aniline (109mg, 0.434mmol) were added to DMF (5mL), stirred at 100°C for 10 hours, cooled after the reaction, and added acetic acid Ethyl ester (10 mL), suction filtered, and the filter cake was washed with a large amount of ethyl acetate. After the filtrate was evaporated to dryness, the sample was mixed directly, and separated by flash column (dichloromethane:ethyl acetate=1:1→dichloromethane:ethyl acetate:methanol=40:40:1) to obtain 42mg of yellow solid, yield 16.9% , Mp:108-110℃

¹ H NMR (400MHz, DMSO-d ₆ )δ9.53(s, 1H), 8.46(s, 1H), 7.99(d, J=2.5Hz, 1H), 7.93(s, 1H), 7.74(d, J＝9.0Hz, 1H), 7.47(dd, J＝12.0, 4.3Hz, 1H), 7.35–7.15(m, 5H), 5.24(s, 3H), 4.90(d, J＝5.8Hz, 1H), 4.32(d,J=44.4Hz,2H),3.94(s,3H),3.68(d,J=6.9Hz,4H),3.55(d,J=13.4Hz,1H),3.37(s,1H), 3.31(s,1H),3.25(s,1H),3.03(s,1H).

¹³ C NMR(101MHz,DMSO-d ₆ )δ164.71,163.89,161.49,156.82,154.78,153.54,149.83, 148.20,147.57,140.25,134.19,131.03,130.97,124.17,123.79,122.33,121.59,115.24,115.04, 114.90 ,114.61,114.39,109.15,108.03,76.03,71.25,70.01,56.38,48.66,46.20,42.86.

³¹ P NMR (162MHz, DMSO-d ₆ ) δ29.92.

HRMS: m/z calcd. for C ₂₉ H ₃₁ Cl ₃ FN ₅ O ₅ P[M+H] ⁺ 684.110693; found 684.11057.

Example 3: Preparation of 2-bis(2-chloroethyl)amino-5-(6-(4-(3-chloro-4-fluoroanilino)quinazoline)oxy)methyl-1,3,2 - Oxazaphospholane-2-oxide (Code: 10a3)

The synthesis method is the same as compound 10a2. Pale yellow solid, denoted as 10a3, yield 22.6%, Mp: 112-114°C

¹ H NMR (400MHz, CDCl ₃ ) δ9.37(s,1H),8.64(s,1H),8.18(s,1H),8.12(d,J＝6.7Hz,1H), 7.96–7.85(m, 1H),7.21(s,1H),7.10(t,J=8.9Hz,1H),4.97(dt,J=17.1,8.7Hz,1H),4.72(dd,J=13.2,9.4Hz,1H), 4.32(dd, J＝13.3, 2.4Hz, 1H), 4.00(s, 3H), 3.73(dd, J＝17.2, 8.7Hz, 1H), 3.58(t, J＝6.5Hz, 4H), 3.40(d ,J=43.0Hz,5H),3.19(d,J=15.9Hz,1H).

¹³ C NMR (101MHz, CDCl ₃ ) δ157.00, 154.85, 153.79–153.59(m), 152.91, 148.52, 136.60, 123.26(d, J=1.7Hz), 121.07(d, J=4.1Hz), 120.43(d, J=18.3Hz), 116.25, 116.03, 109.45, 107.28, 106.01(s), 77.31, (d, J=21.1Hz), 72.34, 56.21, 48.74(d, J=5.1Hz), 43.32(d, J= 9.6Hz), 42.01.

³¹ P NMR (162MHz, CDCl ₃ ) δ29.93.

HRMS: m/z calcd. for C ₂₂ H ₂₅ Cl ₃ FN ₅ O ₄ P[M+H] ⁺ 578.068829; found 578.06898.

Example 4: Preparation of 2-bis(2-chloroethyl)amino-5-(6-(4-(3-bromoanilino)quinazoline)oxy)methyl-1,3,2-oxazaphosphorus Heterocyclopentane-2-oxide (Code: 10a4)

The synthesis method is the same as compound 10a2. Pale yellow solid, denoted as 10a4, yield 7.5%, Mp: 117-119°C

¹ H NMR (400MHz, CDCl ₃ )δ9.30(s,1H),8.63(s,1H),8.16(s,1H),8.11(s,1H),7.99(d,J＝7.4Hz,1H) ,7.19(dd,J＝13.6,5.5Hz,3H),4.91(s,1H),4.71–4.56(m,1H),4.25(d,J＝12.9Hz, 1H),3.95(s,3H), 3.65(dd,J=17.2,8.7Hz,1H),3.60–3.51(m,4H),3.43(d,J=12.3Hz,4H), 3.36(s,2H).

¹³ C NMR(101MHz,CDCl ₃ )δ156.96,154.74,153.74,148.38,147.53,141.35,129.95, 125.99,124.01,122.17,119.89,109.59,107.47,105.81,77.26,72.14,56.17,48.72(d,J＝5.1 Hz), 43.38(d, J＝9.5Hz), 42.16.

³¹ P NMR (162MHz, CDCl ₃ ) δ29.01.

HRMS: m/z calcd. for C ₂₂ H ₂₆ BrCl ₂ N ₅ O ₄ P[M+H] ⁺ 604.027735; found 604.02691.

Example 5: Preparation of 2-bis(2-chloroethyl)amino-5-(6-(4-(3-ethynylanilino)quinazoline)oxy)methyl-1,3,2-oxazone Phospholane-2-oxide (Code: 10a5)

The synthesis method is the same as compound 10a2. Yellow-brown solid, recorded as 10a5, yield 19.9%, Mp: 113-115°C

¹ H NMR (400MHz, CDCl ₃ ) δ9.30(s, 1H), 8.64(s, 1H), 8.16(s, 1H), 8.06(d, J=6.2Hz, 2H), 7.30(t, J= 8.2Hz, 1H), 7.19(d, J=7.1Hz, 2H), 4.93(dt, J=16.2, 8.0Hz, 1H), 4.67(dd, J=13.0, 9.2Hz, 1H), 4.26(d, J＝13.0Hz, 1H), 3.97(s, 3H), 3.67(q, J＝8.8Hz, 1H), 3.56(t, J＝5.8Hz, 4H), 3.50–3.27(m, 6H), 3.06( s, 1H).

¹³ C NMR(101MHz,CDCl ₃ )δ157.08,154.60,154.00,148.30,147.75,140.00,128.74, 126.91,124.69,122.27,122.06,109.67,107.65,105.83,83.89,77.32,76.90,72.24,56.19,48.75(d , J＝5.1Hz), 43.34(d, J＝9.5Hz), 42.24.

³¹ P NMR (162MHz, CDCl ₃ ) δ28.87.

HRMS: m/z calcd. for C ₂₄ H ₂₇ Cl ₂ N ₅ O ₄ P[M+H] ⁺ 550.117223; found 550.11609.

Example 6: Preparation of intermediate 6-iodo-4-(haloanilino)quinazoline (number: 17b-17g);

1. Synthesis of 6-iodo-4-(3-bromoanilino)quinazoline (17b)

Add 6-iodo-4-hydroxyquinazoline (2.72g, 10mmol) and DMF (0.2mL) to 24mL thionyl chloride, and reflux for 5h. The thionyl chloride was evaporated under reduced pressure, and the residual thionyl chloride was removed by rotary evaporation with ethyl acetate (100 mL×3), to obtain 4-chloro-6-iodoquinazoline as a yellow solid. Add 20mL of isopropanol, 3-bromoaniline (2.06g, 12mmol) and triethylamine (1.00g, 10mmol), and reflux at 80°C for 6h. Cool, filter with suction, add diethyl ether to the filtrate to continue to precipitate solids, wash the obtained solids with a large amount of water, filter with suction again, and dry to obtain 3.61 g of light yellow solids, with a yield of 84.6%, Mp: 197-199°C.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.90(s, 1H), 9.22(s, 1H), 8.84(s, 1H), 8.23(dd, J=8.2, 3.4Hz, 1H), 8.13( s,1H),7.85(dd,J=8.2,3.4Hz,1H),7.64(d,J=8.7Hz,1H),7.40(t,J=9.0Hz,1H).

¹³ C NMR (101MHz, DMSO-d ₆ ) δ157.84, 152.05, 143.47, 141.3, 138.94, 132.65, 130.52, 128.31, 126.16, 123.9, 122.6, 121.12, 115.6, 93.69.

Example 7: Preparation of 6-iodo-4-(3-chloro-4-fluoroanilino)quinazoline (17c)

The synthesis method is the same as compound 17b. White solid, denoted as 17c, yellow solid, yield 95.1%, Mp: 162–165°C.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.77(s,1H),9.15(s,1H),8.80(s,1H),8.22(d,J＝8.7Hz,1H),8.15(dd, J=6.7,2.3Hz,1H),7.84(dd,J=8.2,3.4Hz,1H),7.64(d,J=8.7Hz,1H),7.49(t,J=9.0Hz,1H).

¹³ C NMR (101MHz, DMSO-d ₆ )δ156.18, 154.52, 152.11, 150.02, 147.86, 143.16, 137.78(d, J＝2.9Hz), 129.2, 124.3, 123.24, 122.17(d, J＝6.6Hz), 119.14 (d, J=18.3Hz), 117.01 (d, J=7.4 Hz), 116.76, 101.28.

Example 8: Preparation of 6-iodo-4-(3-ethynylamino)quinazoline (code: 17d)

The synthesis method is the same as compound 17b. Pale yellow solid, denoted as 17d, yield 80.0%, Mp: 185-186°C.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.90(s,1H),9.01(s,1H),8.67(s,1H),8.24–8.02(m,2H), 7.95(d,J＝8.0 Hz,1H),7.58(d,J=8.7Hz,1H),7.43(t,J=7.9Hz,1H),7.26(d,J=7.5Hz,1H), 4.21(s,1H).

¹³ C NMR (101MHz, DMSO-d ₆ ) δ156.85, 155.17, 149.30, 141.90, 139.76, 131.92, 130.28, 129.40, 127.39, 125.41, 123.14, 122.28, 117.37, 92.15, 83.081.8

Example 9: Preparation of 6-iodo-4-(3'-chloro-4'-(3"-fluorobenzyloxy)anilino)quinazoline (code: 17e)

The synthesis method is the same as compound 17b. Milky white powder, denoted as 17e, yield 93.0%, Mp: 221–224°C.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.84(s,1H),8.95(s,1H),8.62(s,1H),8.10(d,J＝8.6Hz,1H),8.05(s, 1H),7.77(d,J=8.8Hz,1H),7.56(d,J=8.7Hz,1H),7.48(dd,J=13.9,7.8Hz,1H), 7.38–7.24(m,3H), 7.19(t,J=8.5Hz,1H),5.26(s,2H).

¹³ C NMR (101MHz, DMSO-d ₆ ) δ163.65, 161.23, 156.53, 155.03, 149.98, 148.97, 141.52, 139.87(d, J＝7.7Hz), 133.23, 131.59, 130.77(d, J＝8.0Hz), 130.01 ,124.16,123.53,122.30,121.30,117.05,114.92(d,J=20.8Hz),114.42(d,J=13.6Hz),114.14,91.74,69.63.

Example 10: Preparation of 6-iodo-4-(3-trifluoromethylanilino)quinazoline (code: 17f)

The synthesis method is the same as compound 17b. Light gray solid, denoted as 17f, yield 78.2%, Mp: 149-151°C.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 9.42(s, 1H), 9.01(s, 1H), 8.39(dd, J=8.7, 1.6Hz, 1H), 8.20( s,1H),8.13(d,J=8.2Hz,1H),7.80(d,J=8.7Hz,1H),7.78–7.64(m,2H).

¹³ C NMR (101MHz, DMSO-d ₆ ) δ158.50, 151.46, 144.14, 139.23, 137.70, 132.98, 129.98, 129.53, 129.21, 128.13, 125.27, 122.73 (d, J＝8.2Hz), 122.379 (d, J. =9Hz), 115.39, 94.23.

Example 11: Preparation of 6-iodo-4-(3'-benzyloxy)anilinoquinazoline (code: 17g)

The synthesis method is the same as compound 17b. Light yellow solid, recorded as 17g, yield 89.7%, Mp: 175-176°C.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.02(s,1H),8.65(s,1H),8.20–8.04(m,1H),7.71(s,1H),7.58(d,J＝8.7 Hz,1H),7.53–7.39(m,5H),7.36(d,J=7.2Hz,1H),7.32(t,J=8.1Hz,1H),6.82 (dd,J=8.1,1.8Hz,1H ),5.14(s,2H).

¹³ C NMR(101MHz,DMSO-d ₆ )δ158.89,156.77,155.21,149.34,141.84,140.47,137.51, 131.85,130.21,129.70,128.91,128.30,128.14,117.44,115.03,110.48,109.38,92.02,69.74.

Example 12: Preparation of 2-(bis(2-chloroethyl))amino-5-(6-(4-(3-bromoanilino)quinazoline)amino)methyl-1,3,2-oxo Azaphospholane-2-oxide (Code: 10b)

6-iodo-4-(3-bromoaniline) quinazoline (5mmol, 2.13g), 2-hydroxy-1,3-propanediamine (10mmol, 0.92g) and sodium tert-butoxide (5mmol, 0.48g ) and catalyst CuI (4%, 0.04 g) were added into a dry three-necked flask, protected by argon, and injected with 12 mL of DMF. 80 ° C constant temperature reflux reaction for 4h. After filtering, 50 mL of distilled water was added, and the filtrate was extracted three times with ethyl acetate, 50 mL each time. The combined filtrates were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude yellow-brown oily liquid was obtained, which was directly used in the next reaction without separation. The crude yellow-brown oily liquid obtained in the previous step, triethylamine (0.36 mL, 5 mmol) was added to 10 mL of isopropanol and stirred for 1 min. Phosphoryl mustard (1.30 g, 5 mmol) was added to the system, and stirred at room temperature for 12 h. Add 50 mL of distilled water, and extract 3 times with ethyl acetate, 50 mL each time. The filtrates were combined, dried, and separated by silica gel column chromatography (dichloromethane:methanol=50:1→20:1). Obtained 0.170 g of bright yellow foamy solid, 11.8% overall yield over two steps, Mp: 85-87°C.

¹ H NMR (400MHz, CDCl ₃ )δ9.57(s,1H),8.62(s,1H),8.15(s,1H),7.97(m,2H),7.67(m,2H),7.30(s, 1H),7.20(s,2H),4.87(m,1H),457(m,1H),4.17(m,1H),3.41-3.59(m,6H), 3.32-3.37(m,5H).

¹³ C NMR (101MHz, CDCl ₃ ) δ157.55, 157.10, 152.38, 144.21, 140.62, 129.95, 128.38, 126.72, 125.49, 124.69, 122.15, 120.58, 115.83, 103.59, 48.727, 43.2, 48.

³¹ P NMR (162MHz, CDCl ₃ ) δ29.25.

HRMS(ESI+)m/z calcd for C ₂₁ H ₂₅ BrCl ₂ N ₆ O ₂ P(M+H) ⁺ 573.03316,found 573.03318.

Example 13: Preparation of 2-(bis(2-chloroethyl))amino-5-(6-(4-(3-chloro-4-fluoroanilino)quinazoline)amino)methyl-1,3 ,2-Oxazaphospholane-2-oxide (Code: 10c)

The synthesis method is the same as compound 10b. Yellow foamy solid, denoted as 10c, yield 8.67%, Mp: 112-117°C.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.88(s, 1H), 8.44(s, 1H), 8.24(dd, J=6.8, 2.5Hz, 1H), 7.96(ddd, J=8.9, 4.2 ,2.8Hz,1H),7.57(d,J=9.0Hz,1H),7.48(d,J=2.0Hz,1H),7.43(t,J=9.1Hz,1H),7.35(dd,J=9.0 ,2.1Hz,1H),6.65(t,J＝6.0Hz,1H),4.67(dt,J＝8.7,6.1Hz,1H), 3.71–3.61(m,4H),3.55(dd,J＝14.0, 7.0Hz, 2H), 3.48–3.41(m, 1H), 3.38–3.29(m, 4H), 3.24 (d, J=10.9Hz, 2H).

¹³ C NMR (101MHz, DMSO-d ₆ ) δ156.07, 154.34, 149.13, 147.75, 141.06, 136.85, 127.28, 124.30, 123.21, 122.12, 118.76(d, J＝18.4Hz), 116.52, 116.24(d,1J Hz), 97.11, 77.68, 54.86, 48.17, 44.46 (d, J=9.4Hz), 42.28.

³¹ P NMR (162MHz, CDCl ₃ ) δ29.21.

HRMS(ESI+)m/z calcd for C ₂₁ H ₂₃ Cl ₃ FN ₆ O ₂ P(M+H) ⁺ 547.03316,found 547.02883.

Example 14: Preparation of 2-(bis(2-chloroethyl))amino-5-(6-(4-(3-ethynylanilino)quinazoline)amino)methyl-1,3,2-oxo Azaphospholane-2-oxide (Code: 10d)

The synthesis method is the same as compound 10b. Pale yellow foamy solid, denoted as 10d, yield 11.43%, Mp: 93–97°C.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.48(s,1H),8.51(s,1H),8.09(s,1H),7.99(d,J＝8.0Hz,1H),7.58(s, 2H), 7.28(dd, J＝9.1, 6.6Hz, 1H), 7.19(d, J＝7.5Hz, 1H), 7.05(d, J＝8.3Hz, 1H), 4.85(s, 1H), 4.63– 4.46(m,1H),3.63(d,J=10.8Hz,2H),3.51(dd,J=14.5,7.9Hz,5H),3.36 (dd,J=11.9,6.2Hz,2H),3.30–3.15 (m,4H),3.08(s,1H)

¹³ C NMR (101MHz, DMSO-d ₆ ) δ157.08, 150.69, 146.89, 142.58, 139.77, 130.94, 128.77 (d, J＝11.5Hz), 127.91, 127.23, 125.18, 123.80, 122.59, 122.239, 119.6 ,79.48,49.41, 48.82,44.46(d,J＝9.5Hz),42.26.

³¹ P NMR (162MHz, CDCl ₃ ) δ29.34.

HRMS(ESI+)m/z calcd for C ₂₃ H ₂₆ Cl ₂ N ₆ O ₂ P(M+H) ⁺ 519.12264,found 519.12247

Example 15: Preparation of 2-(bis(2-chloroethyl))amino-5-(6-(4-(3'-chloro-4'-(3"-fluorobenzyloxy)anilino)quinazole Phyloline)amino)methyl-1,3,2-oxazaphospholane-2-oxide (Code: 10e)

The synthesis method is the same as compound 10b. Pale yellow foamy solid. Denoted as 10e, the yield is 14.9%, Mp: 125–130°C.

¹ H NMR (400MHz, CDCl ₃ ) δ9.29(s, 1H), 8.41(s, 1H), 7.93(d, J=2.4Hz, 1H), 7.71(dd, J=8.9, 2.4Hz, 1H) ,7.27–7.19(m,1H),7.14–7.08(m,2H),6.97–6.87(m,2H),6.81(d,J＝9.0Hz, 1H),4.99(s,2H),4.63(s ,1H),4.57–4.41(m,1H),3.62–3.47(m,3H),3.43(t,J＝6.6Hz,4H), 3.34–3.07(m,6H).

¹³ C NMR (101MHz, CDCl ₃ ) δ164.18, 161.73, 157.04, 151.09, 150.05, 146.74, 143.05, 139.31 (d, J＝7.4Hz), 134.10, 130.14 (d, J＝8.1Hz), 128.24, 123.895, 122 ,122.54(d,J=2.9Hz),121.46,116.76,114.80(d,J=21.1Hz),114.47,113.98(d,J=22.2Hz),99.28,79.50,70.46,62.50,49.54,48.80(d , J=4.9Hz), 44.41, 42.14, 30.11.

³¹ P NMR (162MHz, CDCl ₃ ) δ29.66.

HRMS(ESI+)m/z calcd for C ₂₈ H ₃₀ Cl ₃ N ₆ O ₃ P(M+H) ⁺ 653.11611,found 653.11449.

Example 16: Preparation of 2-bis(2-chloroethyl)amino-5-(6-(4-(3'-trifluoromethylphenylamino)quinazoline)amino)methyl-1,3,2-oxo Azaphospholane-2-oxide (Code: 10f)

The synthesis method is the same as compound 10b. Pale yellow foamy solid. Denoted as 10f, yield 14.9%, Mp: 95–97°C.

¹ H NMR (400MHz, CDCl ₃ )δ9.42(s,1H),8.50(s,1H),7.74(s,1H),7.54(s,2H),7.50–7.37 (m,4H),7.37– 7.26(m,4H),7.24–7.19(m,1H),6.99(d,J＝7.0Hz,1H),6.69(d,J＝7.3Hz,1H), 5.02(s,2H),4.76(s ,1H),4.43(s,1H),3.76(d,J=14.0Hz,1H),3.52(s,2H),3.44(s,4H),3.30(s,4H),3.22(d,J= 14.6Hz, 2H), 3.15–2.99(m, 3H).

¹³ C NMR (101MHz, CDCl ₃ ) δ148.4, 128.99, 125.66, 124.97, 120.38, 119.01, 98.86, 79.45, 48.94, 48.81(d, J=5.0Hz), 44.71(d, J=9.6Hz), 42.07.

HRMS(ESI+)m/z calcd for C ₂₂ H ₂₅ Cl ₂ N ₆ O ₂ P(M+H) ⁺ 563.11611,found 563.11449.

Example 17: Preparation of 2-(bis(2-chloroethyl))amino-5-(6-(4-(3'-benzyloxy)anilinoquinazoline)amino)methyl-1,3, 2-Oxazaphospholane-2-oxide (Code: 10g)

The synthesis method is the same as compound 10b. Pale yellow foamy solid. Recorded as 10 g, yield 15.9%, Mp: 89–92°C.

¹ H NMR (400MHz, CDCl ₃ )δ9.42(s,1H),8.50(s,1H),7.74(s,4H),7.54(s,5H),7.50–7.37(m,4H),7.31( m,4H),7.24–7.18(m,1H),6.99(d,J=7.0Hz,1H),6.69(d,J=7.3Hz,1H),5.02(s,2H),4.76(s,1H ),4.43(s,1H),3.76(d,J＝14.0Hz,1H),3.52(s,2H),3.44(s,4H),3.30(s,4H), 3.22(d,J＝14.6Hz ,2H),3.18–2.98(m,3H)

¹³ C NMR (101MHz, CDCl ₃ ) δ161.56, 158.07, 155.99, 152.61, 149.51, 145.47, 138.99, 135.79, 128.50, 127.52, 126.98, 126.59, 122.38, 115.54 (d, J＝4.408.2)7 , 98.14, 69.04, 47.34, 41.12, 35.48, 28.67.

³¹ P NMR (162MHz, CDCl ₃ ) δ28.87

HRMS(ESI+)m/z calcd for C ₂₈ H ₃₂ Cl ₂ N ₆ O ₃ P(M+H) ⁺ 601.16451,found 601.16485.

Embodiment 18: Antitumor activity test of the compound of the present invention

Experimental Example 1: Effects on the proliferation of SKBr-3, MDA-MB-468, Calu-3 and H522 cells

Culture human breast cancer cells SKBr-3, MDA-MB-468, and lung cancer cells H522 and Calu-3 in vitro. After the cells grow to the logarithmic growth phase, collect the cells, centrifuge at 1000rpm for 5min, discard the supernatant, suspend with an appropriate amount of medium, and adjust The cell concentration was 3.5-4.5×10 ⁴ /ml. The cell suspension was inoculated into a 96-well cell culture plate, 100 μl per well, placed in a cell culture incubator (37°C, 5% CO ₂ ) for 24 hours, and 100 μl of the drug diluted in the cell culture medium was added to each well of the drug group. Three replicate wells were set up for drugs, and the negative control group was medium containing 0.5% DMSO. After culturing in an incubator for 72 hours, 20 μl of 5 mg/ml MTT was added to each well, and placed at 37° C. for 3 hours. Add 150 μl DMSO to each well, shake on a shaker at 37° C. for 5 minutes, and detect the absorbance (OD) at 492 nm. _IC50 values were calculated using Prism Graphpad 5.0 statistical software.

Some compounds shown in chemical formula (I) have good antitumor activity to above-mentioned four tumor cell lines, and its _IC50 value result is shown in Table 1:

Table 1. IC ₅₀ values of compounds against four tumor cell lines (unit: μM)

Experimental Example 2: Binding experiment to EGFR and HER-2 receptors

In order to confirm that the compounds have an inhibitory effect on EFGR and HER-2 receptors, some compounds represented by the chemical formula (I) were selected as probes, and receptor binding experiments were carried out. As shown in table 2:

Table 2. IC ₅₀ values of compounds against EGFR and HER-2 (unit: nM)

Kinase 10a2 10a3 10a4 10a5 10e EMB-3 Staurosporine EGFR 4.61 0.26 0.27 0.24 18.38 7.4 33.00 HER-2 0.94 29.49 11.82 111.95 2.35 82 44.42

Embodiment 19: In vivo metabolic stability test of the compound of the present invention

The drug metabolism of compounds 10b and 10e in SD rats is shown in Table 3:

Table 3 compound cjb-11 and cjb-41 SD rat in vivo drug metabolism test

compound Method of administration t _1/2 (hr) AUClast(hr*ng/mL) AUCInf(hr*ng/mL) CL(mL/min/kg) 10b IV 1.17±0.06 761±91 765±92 22.0±2.7 10e IV 1.49±0.02 959±177 969±177 17.6±3.6 EMB-3 IV 0.52±0.023 659±84 661±85 75.7±8.5

After transforming the tether of EMB-3 into a ring structure and maintaining the carbon chain length of 3 carbon atoms in the tether, the half-lives of compounds 10b and 10e reached 1.17 hours and 1.49 hours, respectively, which are the half-lives of EMB-3 2.25 times and 2.87 times of that, proving that its metabolic stability has been significantly improved.

Claims (8)

1. A class of multi-target antitumor compounds, the compound has a structure as shown in chemical formula (I): Wherein, R is selected from hydrogen, lower alkoxy _; R is selected from substituted or unsubstituted phenyl, the substituted phenyl means that phenyl is substituted by one or more halogen, C1 _- C4 alkynyl, lower alkyl, lower alkoxy or arylalkoxy ; R ₃ is selected from hydrogen, cyano; A is O or NH. 2. The compound according to claim 1, wherein the lower alkyl group is a C1-C6 alkyl group or a substituted alkyl group, and the substituted alkyl group can be, for example, a halogen or a substituted phenyl group and the like. 3. The compound according to claim 1, wherein the lower alkoxy group is a C1-C6 alkoxy group or a substituted alkoxy group, and the substituted alkoxy group can be, for example, a halogen or a substituted phenyl group and the like. 4. The compound according to claim 1, wherein arylalkoxy is benzyloxy or lower substituted benzyloxy, and said lower substituent refers to one or more halogens located on the benzene ring, Amino or 1-3 carbon alkyl, alkoxy, etc. 5. The compound of claim 1, wherein halogen is chlorine, fluorine or bromine. 6. The compound according to claim ₁ , wherein R is selected from hydrogen, methoxy or ethoxy; R is selected from ₃ -bromo, 3-chloro-4-fluoro, 3-ethynyl or 3-chloro -4-(3-fluorobenzyloxy), 3-trifluoromethyl, 3-benzyloxy; R ₃ is selected from hydrogen. 7. The preparation method of the compound described in any one of claims 1-6, the method comprising the steps of: Wherein, when A is O and R ₁ is hydrogen, and R ₂ and R ₃ are as defined in the aforementioned chemical formula (I), the synthetic route 1 of the compound is as follows: Synthetic route one: Reagent conditions and reactions: a) Et ₃ N, react at room temperature; b) HCONH ₂ , 160°C; c) Ac ₂ O, 100°C; d) SOCl ₂ , reflux; e) Substituted aniline, i-PrOH, Et ₃ N, reflux; f) NH ₃ OH, CH ₃ OH, reaction at room temperature; g) 3, DIAD, PPh ₃ , CH ₂ Cl ₂ . Phosphoryl mustard dichloride reacts with 3-amino-1,2-dihydroxypropane to give 2-(bis(2-chloroethyl)amino)-5-hydroxymethyl-1,3,2-oxazaphosphorine Cyclopentane-2-oxide. 5-Hydroxy-2-aminobenzoic acid and formamide are closed at high temperature to obtain 4,6-dihydroxyquinazoline; then 6-OH is selectively acetylated to obtain 6-acetoxy-4-hydroxyquinazoline, Then react with thionyl chloride to become 6-acetoxy-4-chloroquinazoline, directly react with substituted aniline without purification to obtain 4-substituted anilino-6-acetoxyquinazoline, and then react in ammonia/methanol system In deacetylation, 4-substituted anilino-6-hydroxyquinazoline is obtained; finally, under the conditions of triphenylphosphine and diisopropyl azodicarboxylate, with 2-(bis(2-chloroethyl)amino) -5-Hydroxymethyl-1,3,2-oxazaphospholane-2-oxide reacts to obtain some compounds represented by formula (I). Wherein, when A is O and R ₁ is methoxy, and R ₂ and R ₃ are as defined in the aforementioned chemical formula (I), the second synthetic route of the compound is as follows: Synthetic route two: Reagents and reaction conditions: a) SOCl ₂ , DMF (cat.), reflux; b) NH ₄ OH, Methanol, reaction at room temperature; c) 3, PPh ₃ , DTAD, DCM, reaction at room temperature; d) substituted aniline, DMF, 90°C 7-Methoxyl-4-hydroxyquinazolin-6-ol acetate was refluxed in thionyl chloride to give 7-methoxyl-4-chloroquinazolin-6-ol acetate, without purification in In ammonia/methanol system, deacetylation obtains 6-hydroxyl-7-methoxy-4-chloroquinazoline; then under triphenylphosphine, di-tert-butyl azodicarboxylate conditions, with 2-( 2-Chloroethyl) amino)-5-hydroxymethyl-1,3,2-oxazaphospholane-2-oxide reacts to obtain 2-bis(2-chloroethyl)amino-5-( 4-chloro-7-methoxyl group) quinazoline methyl ether-1,3,2-oxazaphospholane-2-oxide compound; Finally obtain partial formula (I ) compounds shown. Wherein, when A is NH and R ₁ is hydrogen, and R ₂ and R ₃ are as defined in the aforementioned chemical formula (I), the synthetic route 3 of the compound is as follows: Synthetic route three: Reagents and reaction conditions: a) HCONH ₂ , 160°C; b) SOCl ₂ , DMF; c) CH ₃ OH, NH ₄ OH, substituted aniline, reaction at room temperature; d) (NH ₂ CH ₂ ) ₂ CHOH, Cul, t-BuONa, DMF, reflux; e) Cl ₂ PON(CH ₂ CH ₂ Cl) ₂ , Et ₃ N, i-PrOH, 80°C. After 2-amino-5-iodobenzoic acid is added with excess formamide, the ring closure at high temperature obtains 6-iodo-4-hydroxyquinazoline, and then refluxes with thionyl chloride to obtain 4-chloro-6-iodoquinazoline, and then Directly react with substituted aniline without purification to obtain 6-iodo-4-arylaminoquinazoline intermediate. Then under the protection of argon, using DMF as a solvent, the Ullmann reaction catalyzed by CuI reacts with 2-hydroxyl-1,3-diaminopropane to obtain the intermediate 1-amino-3-((4-substituted anilinoquinazoline ) 6-amino) propanediol, and finally cyclized with phosphoryl mustard to obtain the compound shown in the partial formula (I). 8. Use of the compound according to any one of claims 1-6 or the compound prepared according to the preparation method of claim 7 in the preparation of antitumor drugs.