Preparation method and application of quinazoline derivative containing chalcone

Abstract

The invention discloses a preparation method and application of a quinazoline derivative containing chalcone, belongs to the technical field of pharmaceutical chemistry, and particularly discloses the quinazoline derivative containing chalcone, a preparation method of the quinazoline derivative, physiologically acceptable salt formed by inorganic or organic acid of the quinazoline derivative, a pharmaceutical composition containing the quinazoline derivative and the physiologically acceptable salt. The quinazoline derivative containing chalcone is formed by combining a chalcone structure with quinazoline, and a compound with higher biological activity or multiple action mechanisms can be designed. A chalcone unit is introduced into a framework of quinazoline, and the pharmacological activity of the quinazoline is screened, so that a better drug molecular structure is expected to be obtained, and particularly, the quinazoline has a better cell proliferation inhibition effect on human lung cancer cells A549 and human lung cancer drug-resistant cells H1975.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of a quinazoline derivative containing chalcone and its application as an anti-tumor drug. Background Art

[0002] Heterocycles have been widely used in the development of anti-cancer drugs, which interact with various targets and biological pathways involved in cancer progression. The quinazoline structure is a class of promising benzopyrimidine heterocyclic compounds with a wide range of biological and pharmacological activities. Therefore, quinazoline, as a partial structural unit of drug molecules, has been widely studied and used in the treatment of various diseases. In addition, the chalcone structure has been proven to be an important source of naturally occurring α,β-unsaturated ketones and has a variety of pharmacological activities, including anti-inflammatory, antibacterial, antimalarial, anti-Alzheimer's, and anti-cancer. The cytotoxic mechanism of action of chalcone derivatives has been proposed, including inhibition of angiogenesis, reversal of multidrug resistance, anti-proliferative activity, anti-mitotic effect, and induction of apoptosis in various cancer cell lines. Chalcone derivatives, as key units of compounds with various physiological activities, have inspired extensive interest among medicinal chemists.

[0003] Currently, the small molecule drugs targeting the tyrosine kinase receptor (EGFR) that have been marketed mainly include gefitinib, erlotinib, zolitinib, afatinib, etc. The use of EGFR inhibitors can lead to mutations in EGFR, thereby causing cancer cells to develop drug resistance. For example, when using the first-generation EGFR inhibitor, some patients have the EGFRT790M mutation, and then they can take the second-generation EGFR inhibitor. If the side effects of the second-generation EGFR inhibitor are relatively large, they can directly take the third-generation EGFR inhibitor. However, if the EGFRC797S mutation occurs after taking the third-generation inhibitor, they cannot continue to take the targeted drug for treatment. Moreover, for the brain metastasis phenomenon that occurs in non-small cell lung cancer, due to the presence of the blood-brain barrier, the activity of most small molecule tyrosine kinase inhibitors is affected and they cannot fully play their role, with a low inhibition rate. Summary of the Invention

[0004] The purpose of the present invention is to provide a quinazoline derivative containing chalcone or a pharmaceutically acceptable salt thereof, its preparation method and application, aiming to solve the problem that the activity of the inhibitors in the prior art is poor, resulting in a low inhibition rate of cancer cells.

[0005] To achieve the above purpose, the present invention adopts the following technical solutions: In the first aspect, a quinazoline derivative containing chalcone, and the structural formula of the derivative is as follows: Wherein, R 1Selected from mono-substituted hydrogen, fluorine, chlorine, bromine, methyl, methoxy, di-substituted methyl, di-substituted methyl and chlorine, di-substituted methoxy and chlorine, di-substituted fluorine and chlorine; R 2 Selected from meta-methyl, meta-methoxy, para-methyl, para-methoxy.

[0006] In a second aspect, a method for preparing a chalcone-containing quinazoline derivative, comprising: Step 1: Using 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-yl acetate 1 as a raw material, toluene as a solvent, triethylamine as an acid-binding agent, and phosphorus oxychloride as a chlorinating reagent. After the reaction is completed, a substituted aniline is added to the reaction solution, cooled to room temperature, the solvent is evaporated to dryness, isopropanol is added, stirred, filtered by suction, the filter cake is washed with isopropanol, and dried to obtain intermediate 3; Step 2: Then, methanol and ammonia water are sequentially added to intermediate 3. After the reaction is completed, methanol is removed by distillation under reduced pressure, filtered by suction, and dried to obtain intermediate 4; Step 3: At room temperature, compound 5, compound 6 and solvent ethanol are sequentially added to obtain a reaction solution, and then a 20% aqueous sodium hydroxide solution is slowly dropped into the reaction solution. After the reaction is completed, ethanol is removed by distillation under reduced pressure to obtain a yellow solid intermediate 7; Step 4: At room temperature, intermediate 7, dichloromethane and triethylamine are sequentially added, and then chloroacetyl chloride is slowly dropped in. After the reaction is completed, dichloromethane is removed by distillation under reduced pressure to obtain intermediate 8; Step 5: At room temperature, intermediate 4, intermediate 8, DMF and potassium carbonate are sequentially added. After the reaction is completed, deionized water is added to the reaction solution, stirred, filtered by suction, and the filter cake is dried in vacuo to obtain a pale yellow solid target product.

[0007] Furthermore, in step 1, the solvent, acid-binding agent and chlorinating reagent are sequentially added into a 100 mL single-necked flask, heated to 80 °C and reacted for 2 h, reacted for 3 h after adding aniline, and in the drying step, vacuum drying is carried out at 50 °C for 6 h. The aniline includes 4-chloro-2-methylaniline, 3-methoxyaniline, 4-methoxyaniline, 2,4-dimethylaniline, 2-fluoroaniline, 3-chloro-2-fluoroaniline.

[0008] Furthermore, in step 2, the reaction is carried out at room temperature for 4 h.

[0009] Furthermore, in step 3, the reaction solution is dropped into 20% sodium hydroxide at 5 °C, and after dropping, the reaction is carried out at room temperature for 4 h. Compound 5 includes 4-acetyl aniline, and compound 6 includes 3-methoxybenzaldehyde, 3-methylbenzaldehyde, 4-methoxybenzaldehyde.

[0010] Furthermore, in step 4, the reaction solution is slowly dropped into chloroacetyl chloride at 5 °C, and after dropping, the reaction is carried out at room temperature for 4 h.

[0011] Further, in the step 5, the reaction temperature is 80 °C, the reaction time is 2 h, the vacuum drying temperature is 60 °C for drying, and the drying time is 8 h.

[0012] In a third aspect, a medicinal salt is formed by using a quinazoline derivative containing chalcone or a pharmaceutically acceptable salt thereof and an acid. The applicable acids are: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, tartaric acid, salicylic acid, methanesulfonic acid, succinic acid, fumaric acid, butyric acid, lactic acid, citric acid, malic acid or maleic acid.

[0013] In a fourth aspect, an application of using a quinazoline derivative containing chalcone as a drug preparation is provided. The application is to use a quinazoline derivative containing chalcone or a pharmaceutically acceptable salt thereof and an acid to form a medicinal salt as an application in the preparation of a drug for treating diseases of the abnormal EGFR family.

[0014] In a fifth aspect, an application of using a quinazoline derivative containing chalcone or a pharmaceutically acceptable salt thereof and an acid to form a medicinal salt as an active ingredient of a pharmaceutical composition as an application in the preparation of an anti-tumor drug. The anti-tumor drug is used to prepare a pharmaceutical preparation for subcutaneous administration or oral administration. The anti-tumor drug has a cell proliferation inhibitory effect on human lung adenocarcinoma cells A549 and human lung cancer drug-resistant cells H1975.

[0015] The technical solution adopted by the present invention has the following beneficial effects: In the present invention, the chalcone structure is combined with quinazoline to form a quinazoline derivative containing chalcone, and compounds with stronger biological activity or multiple action mechanisms can be designed. By introducing a chalcone unit into the skeleton of quinazoline and screening its pharmacological activity, a better drug molecular structure is expected to be obtained. Through the analysis and comparison of the preclinical, clinical data, patents, etc. of Zorifertinib, it is determined as the positive control drug. Then, based on the reported compounds and biological activity test data, computer-aided means are used to purposefully design, synthesize and screen the structure, in order to find novel, highly specific and more active anti-tumor compounds.

[0016] Specifically, the inhibition rates of quinazoline derivatives I-d and I-h containing chalcone on human lung adenocarcinoma cells A549 are 84.96% and 76.55% respectively, both better than 62.14% of the positive control drug Zorifertinib. The inhibition rates of quinazoline derivatives I-d, I-f and I-h containing chalcone on human lung cancer drug-resistant cells H1975 are 55.25%, 82.22% and 58.99% respectively, all better than 49.60% of the positive control drug Zorifertinib. Among them, compounds I-a, I-c, I-d and I-f have growth inhibitory activity IC 50The values are 7.75 (nM / mL), 7.94, 2.96 (nM / mL), and 8.46 (nM / mL) respectively, all superior to 31.08 (nM / mL) of the positive control drug Zorifertinib; and the growth inhibitory activities IC of compounds I-c, I-d, I-f, and I-h against human lung cancer drug-resistant cell line H1975 50 The values are 8.73 (nM / mL), 23.5 (nM / mL), 7.88 (nM / mL), and 3.65 (nM / mL) respectively, all superior to 64.17 (nM / mL) of the positive control drug Zorifertinib. Therefore, the designed chalcone-containing quinazoline derivatives have better cell inhibitory activities and good application prospects.

[0017] Compared with Zorifertinib, the chalcone-containing quinazoline derivatives I-d and I-h provided by the present invention have good selectivity. The growth inhibitory activities IC of chalcone-containing quinazoline derivative I-d against human lung adenocarcinoma cell line A549 and human lung cancer drug-resistant cell line H1975 50 The values are 2.96 (nM / mL) and 23.5 (nM / mL) respectively; the growth inhibitory activities IC of chalcone-containing quinazoline derivative I-h against human lung adenocarcinoma cell line A549 and human lung cancer drug-resistant cell line H1975 50 The values are 37.47 (nM / mL) and 3.65 (nM / mL) respectively. It can be seen that the designed quinazoline derivatives have better selectivity. Compound I-d is beneficial to the inhibition of human lung adenocarcinoma cell line A549, and compound I-h is beneficial to the inhibition of human lung cancer drug-resistant cell line H1975. Some of the quinazoline derivatives provided by the present invention have good selectivity. Description of the Drawings

[0018] Figure 1 is the general structural formula of the chalcone-containing quinazoline derivatives in the present invention; Figure 2 is the roadmap for synthesizing the derivatives shown in the general structural formula of the chalcone-containing quinazoline derivatives in the present invention. Detailed Embodiments

[0020] To make the objectives, technical solutions and effects of the present invention clearer and more definite, the following further describes the present invention in detail with reference to the accompanying drawings and by way of examples. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the present invention.

[0021] The present invention provides a class of chalcone-containing quinazoline derivatives with good anti-drug resistance. The present invention provides a series of chalcone-containing quinazoline derivatives with strong inhibitory activities against lung cancer cell lines.

[0022] Based on the principles of drug structure-activity relationship theory, bioisosterism, pharmacokinetics and other drug design principles, combined with the structure-activity relationship of the quinazoline parent nucleus, using the quinazoline as the basic skeleton and the principle of fusion, the 4-position and 6-position of the quinazoline nucleus are structurally modified and transformed. Different substituted anilines are connected to its 4-position, and chalcone structures with different substituents are selected for modification at the 6-position. By utilizing the dual activity effects of quinazoline and chalcone, a synergistic effect is achieved, with the expectation of obtaining lead compounds with good specificity, high selectivity and low toxicity, and further obtaining targeted anti-tumor drugs with anti-drug resistance.

[0023] This invention relates to derivatives of general formula (I) or pharmaceutically acceptable salts thereof and their preparation methods, pharmaceutical preparations containing such pharmacologically effective derivatives and their applications.

[0024] As Figure 1 shown, quinazoline derivatives containing chalcone of general formula (Ⅰ) or pharmaceutically acceptable salts thereof: (Ⅰ) Wherein, R1 is selected from monosubstituted hydrogen, fluorine, chlorine, bromine, methyl, methoxy, disubstituted methyl, disubstituted methyl and chlorine, disubstituted methoxy and chlorine, disubstituted fluorine and chlorine; R2 is selected from meta-methyl, meta-methoxy, para-methyl, para-methoxy.

[0025] The quinazoline derivatives containing chalcone or pharmaceutically acceptable salts thereof are characterized in that: R1 is selected from monosubstituted hydrogen, fluorine, chlorine, bromine, methyl, methoxy, disubstituted methyl, disubstituted methyl and chlorine, disubstituted methoxy and chlorine, disubstituted fluorine and chlorine; R2 is selected from meta-methyl, meta-methoxy, para-methyl, para-methoxy.

[0026] The quinazoline derivatives containing chalcone or pharmaceutically acceptable salts thereof are characterized in that: the quinazoline derivatives containing chalcone or pharmaceutically acceptable salts thereof form medicinal salts with acids, and the applicable acids are: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, tartaric acid, salicylic acid, methanesulfonic acid, succinic acid, fumaric acid, butyric acid, lactic acid, citric acid, malic acid or maleic acid.

[0027] The application of any of the above compounds in the preparation of drugs for treating diseases of the abnormal EGFR family.

[0028] The application of any of the above compounds or salts, and pharmaceutical compositions containing any of the above compounds or salts as active ingredients in the preparation of anti-tumor drugs.

[0029] The application of any of the above compounds or salts, and pharmaceutical compositions containing any of the above compounds or salts as active ingredients, which are used for the preparation of pharmaceutical preparations for subcutaneous administration or oral administration.

[0030] The compounds or their pharmaceutically acceptable salts according to the present invention can be administered alone or in the form of a pharmaceutical composition. The pharmaceutical compositions of the present invention can be formulated into various suitable dosage forms according to the administration route. One or more physiologically acceptable carriers are used, including excipients and adjuvants, which facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate dosage form depends on the selected administration route and can be prepared according to the common knowledge well-known in the art.

[0031] The administration route can be oral, parenteral or topical administration, preferably oral and injection forms. Pharmaceutical preparations for oral administration include capsules, tablets, etc. The compounds of the present invention can also be formulated for parenteral administration, transdermal administration, transmucosal administration, or administered in the form of suppositories or implants. Those skilled in the art can understand that the compounds of the present invention can adopt a suitable drug delivery system (DDS) to obtain more favorable effects.

[0032] In vitro (CCK8 method) tests of the present invention show that quinazoline derivatives with the general formula (I) structure have strong inhibitory effects on human lung adenocarcinoma cells (A-549), human lung cancer drug-resistant cells (H1975), etc.

[0033] The following further illustrates the present invention with specific examples: Synthesize the quinazoline derivative containing chalcone shown in formula (I) as Figure 1 shown, where R 1 and R 2 are as defined above.

[0034] The roadmap for synthesizing the derivative shown in the general formula of the quinazoline derivative containing chalcone is as Figure 2 shown. Using 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-ol acetate 1 as the raw material, toluene as the solvent, triethylamine as the acid-binding agent, and phosphorus oxychloride as the chlorinating reagent. After the reaction is completed, add the substituted aniline to the reaction solution, cool to room temperature, evaporate the solvent, add isopropanol, stir, filter, and wash the filter cake with isopropanol to obtain intermediate 3; then add methanol and ammonia water to intermediate 3 in sequence. After the reaction is completed, evaporate methanol under reduced pressure, filter, and dry to obtain intermediate 4. At room temperature, add compound 5, compound 6, and solvent ethanol in sequence, and then slowly drop 20% sodium hydroxide aqueous solution. After the reaction is completed, evaporate ethanol under reduced pressure to obtain a yellow solid intermediate 7. At room temperature, add compound 7, dichloromethane, and triethylamine in sequence, and then slowly drop chloroacetyl chloride. After the reaction is completed, evaporate dichloromethane under reduced pressure to obtain a pale yellow solid intermediate 8. At room temperature, add compound 4, compound 8, DMF, and potassium carbonate in sequence. After the reaction is completed, add deionized water to the reaction solution, stir, filter, and vacuum dry the filter cake to obtain the target product (I).

[0035] Example 1 (E)-2-((4-((4-Chloro-2-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-(4-(3-(3-methoxyphenyl)acryloyl)phenyl)acetamide I-a 3,4-Dihydro-7-methoxy-4-oxoquinazoline-6-yl acetate 1 (1.00 g, 4.27 mmol), triethylamine (0.73 g, 7.26 mmol), toluene (20 mL), and phosphorus oxychloride (1.64 g, 10.67 mmol) were successively added into a 100 mL single-necked flask. The temperature was raised to 80 °C and the reaction was carried out for 2 h. 4-Chloro-2-methylaniline (0.48 g, 4.35 mmol) was added, and the reaction was continued for 3 h. Isopropanol was added, stirred, filtered by suction, and the filter cake was washed with isopropanol and dried in vacuo at 50 °C for 6 h to obtain intermediate 3.

[0036] Methanol (15 ml) and ammonia water (0.50 g, 17.50 mmol) were successively added to intermediate 3, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the temperature was lowered to room temperature, methanol was removed by distillation under reduced pressure, filtered by suction, and after drying, yellow solid powder intermediate 4-((4-chloro-2-methylphenyl)amino)-7-methoxyquinazolin-6-ol was obtained. Yield: 90.0%. m.p.: 123.1 - 125.3 °C. 1 H NMR(400 MHz, DMSO- d 6 ) δ 9.37 (s, 1H), 8.43(s, 1H), 7.89 - 7.70 (m, 3H), 7.36 (t, J = 7.6 Hz, 2H), 7.20 (s,1H), 7.07 (t, J = 7.2 Hz, 1H), 3.98 (s, 3H).

[0037] At room temperature, 4-acetylphenylamine (5) (1.00 g, 3.70 mmol), 3-methoxybenzaldehyde (6) (0.88 g, 3.70 mmol), and ethanol (15 ml) were successively added. The reaction solution was placed at 5 °C, and an aqueous solution of 20% sodium hydroxide (0.29 g, 7.40 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was allowed to react at room temperature for 4 h. After the reaction was completed, ethanol was removed by distillation under reduced pressure to obtain intermediate (2E)-1-(4-aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (7) (0.81 g) with a yield of 93%.

[0038] At room temperature, intermediate 7 (1.00 g, 4.21 mmol), dichloromethane (10 ml) and triethylamine (0.51 g, 5.06 mmol) were added successively. The reaction solution was placed at 5 °C, and chloroacetyl chloride (1.43 g, 12.64 mmol) was slowly added. After the addition was completed, the reaction solution was allowed to react at room temperature for 4 h. After the reaction was completed, dichloromethane was removed by distillation under reduced pressure to obtain intermediate (E)-2-chloro-N-(4-(3-(3-methoxyphenyl)acryloyl)phenyl)acetamide (8) (0.75 g), with a yield of 59%. m.p.: 125.7 - 128.5 °C. 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.84 –7.68(m, 3H), 7.51 (d, J = 5.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.16 (s,1H), 6.98 (d, J = 8.2 Hz, 1H), 4.23 (s, 2H), 3.86 (s, 3H).

[0039] At room temperature, intermediate 4-((4-chloro-2-methylphenyl)amino)-7-methoxyquinazolin-6-ol (0.50 g, 1.69 mmol), intermediate (2E)-1-(4-aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (0.50 g, 1.69 mmol), DMF (10 ml) and potassium carbonate (0.47 g, 3.39 mmol) were added successively. The reaction solution was heated to 80 °C and reacted for 2 h. After the reaction was completed, 30 ml of deionized water was added to the reaction solution, stirred, and filtered by suction. It was dried in vacuo at 60 °C for 8 h to obtain (E)-2-((4-((4-chloro-2-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-(4-(3-(3-methoxyphenyl)acryloyl)phenyl)acetamide (I-a) 0.35 g, with a yield of 36%. m.p: 149.5 - 152.1 °C. 1 H NMR(300 MHz, CDCl 3) δ 8.93 (s, 1H), 8.60 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.85– 7.67 (m, 3H), 7.49 – 7.43 (m, 1H), 7.33 (d, J = 6.9 Hz, 3H), 7.16 (s, 2H),7.06 – 6.91 (m, 3H), 4.78 (s, 2H), 4.10 (s, 3H), 3.87 (s, 3H), 2.28 (s, 3H).

[0040] Example 2 Synthesis of (E)-2-((7-methoxy-4-((3-methoxyphenyl)amino)quinazolin-6-yl)oxy)-N-(4-(3-(m-tolyl)acryloyl)phenyl)acetamide I-b Prepared by the same method as in Example 1, replacing 3-methoxybenzaldehyde with 3-methylbenzaldehyde and 4-chloro-2-methylaniline with 3-methoxyaniline, 0.45 g of the target compound (I-b) was synthesized, yield: 48%. m.p: 118.4 - 121.7 °C. 1 H NMR (300 MHz, CDCl 3 ) δ 8.90 (d, J = 7.3 Hz, 1H), 8.69 (s, 1H), 8.04(d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.53(s, 1H), 7.47– 7.39 (m, 4H), 7.32 (d, J = 4.6 Hz, 2H), 7.29 (s, 1H), 7.22 (s,1H), 6.71 (dd, J = 8.0, 1.9 Hz, 1H), 4.78 (s, 2H), 4.09(s, 3H), 3.82 (d, J =1.1 Hz, 3H), 2.40 (s, 3H).

[0041] Example 3 Synthesis of (E)-2-((7-methoxy-4-((4-methoxyphenyl)amino)quinazolin-6-yl)oxy)-N-(4-(3-(3-methoxyphenyl)acryloyl)phenyl)acetamide I-c Prepared by the same method as in Example 1, replacing 4-chloro-2-methylaniline with 4-methoxyaniline. 0.49 g of the target compound (I-c) was synthesized, yield: 51%. m.p: 140.3 - 143.7 °C. 1 H NMR (300 MHz, CDCl 3 ) δ 8.94(s, 1H), 8.62 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.80 – 7.68 (m, 3H), 7.58 –7.44 (m, 4H), 7.41 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H),7.23 (d, J = 7.7 Hz,1H), 7.14 (s, 1H), 6.91 (d, J = 8.6 Hz, 2H), 4.75 (s, 2H), 4.07 (s, 3H), 3.86(s, 3H), 3.80 (s, 3H).

[0042] Example 4 Synthesis of (E)-2-((4-((2,4-dimethylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-(4-(3-(3-methoxyphenyl)acryloyl)phenyl)acetamide I-d Prepared by the same method as in Example 1, replacing 4-chloro-2-methylaniline with 2,4-dimethylaniline. 0.29 g of the target compound (I-d) was synthesized, yield: 32%. m.p: 132.5 - 135.6 °C. 1 H NMR (300 MHz, DMSO- d 6 ) δ10.49 (s, 1H), 9.27 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.5 Hz, 2H), 7.91 (d,J = 9.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.49 – 7.31 (m, 3H), 7.21 (s, 1H),7.18 – 7.06 (m, 3H), 7.02 (d, J = 8.4 Hz, 2H), 4.92 (s, 2H),3.96 (d, J = 4.0Hz, 3H), 3.82 (d, J = 1.2 Hz, 3H), 2.29 (s, 3H), 2.09 (s, 3H).

[0043] Example 5 Synthesis of (E)-2-((4-((2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-(4-(3-(3-methoxyphenyl)acryloyl)phenyl)acetamide I-e Prepared by the same method as in Example 1, replacing 4-chloro-2-methylaniline with 2-fluoroaniline, 0.38 g of the target compound (I-e) was synthesized, yield: 47%. m.p: 158.9 - 160.3 °C. 1 H NMR (300 MHz, DMSO- d 6 ) δ 10.51(s, 1H), 9.47 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.91 (d, J =7.6 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.69 (d, J =5.6 Hz, 1H), 7.53 – 7.46(m, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 7.4, 4.8 Hz, 2H), 7.26 (d, J= 8.0 Hz,3H), 7.02 (d, J = 8.1 Hz, 1H), 4.94 (s, 2H), 3.98 (s, 3H), 3.82 (s,3H).

[0044] Example 6 (E)-2-((7-methoxy-4-((4-methoxyphenyl)amino)quinazolin-6-yl)oxy)-N-(4-(3-(m-tolyl)acryloyl)phenyl)acetamide I-f Prepared by the same method as in Example 1, replacing 3-methoxybenzaldehyde with 3-methylbenzaldehyde and 4-chloro-2-methylaniline with 4-methoxyaniline, 0.47 g of the target compound (I-f) was synthesized, yield 78%. m.p: 132.5 - 135.7 °C. 11H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 8.62 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.82 – 7.67 (m, 4H), 7.54 – 7.44 (m, 4H), 7.29 (d, J = 3.5 Hz, 2H), 7.23 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 4.75 (s, 2H), 4.06 (s, 3H), 3.79 (s, 3H), 2.40 (s, 3H).

[0045] Example 7 (E)-2-((4-((2,4-dimethylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-(4-(3-(m-tolyl)acryloyl)phenyl)acetamide I-g Prepared by the same method as in Example 1, replacing 3-methoxybenzaldehyde with 3-methylbenzaldehyde and 4-chloro-2-methylaniline with 2,4-dimethylaniline, 0.49 g of the target compound (I-g) was synthesized, yield: 52%. m.p: 138.7 - 141.7 °C. 1 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 8.59 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.84 – 7.73 (m, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.42 (dd, J = 9.9, 9.8 Hz, 3H), 7.31 (d, J = 4.8 Hz, 2H), 7.16 – 7.02 (m, 3H), 4.71 (s, 2H), 4.08 (s, 3H), 2.59 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H).

[0046] Example 8 (E)-2-((7-methoxy-4-phenylaminoquinazolin-6-yl)oxy)-N-(4-(3-(3-methoxyphenyl)acryloyl)phenyl)acetamide I-h Prepared by the same method as in Example 1, replacing 4-chloro-2-methylaniline with aniline, 0.67 g of the target compound (I-h) was synthesized, yield: 69%. m.p: 127.4 - 130.9 °C. 1 H NMR (300 MHz, CDCl3) δ 8.93 (s,1H),8.68 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.78 (s, 1H), 7.73 (s, 2H), 7.70(s, 2H), 7.68 (s, 1H), 7.50 (s, 1H), 7.45 (s, 2H), 7.37 (s, 2H), 7.16 (d, J =8.4Hz, 2H), 7.01 – 6.92 (m, 1H), 4.76 (s, 2H), 4.07 (s, 3H), 3.86 (s, 3H). Example 9 (E)-2-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-(4-(3-(4-)methoxyphenyl)acryloyl)phenyl)acetamide I-i Prepared by the same method as in Example 1, replacing 3-methoxybenzaldehyde with 4-methoxybenzaldehyde and 4-chloro-2-methylaniline with 3-chloro-2-fluoroaniline, 0.33 g of the target compound (I-i) was synthesized, yield 41%. m.p: 118.4 - 121.9 °C. 1 H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H),8.73 (s, 1H), 8.47 (t, J= 8.3 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.79 –7.70 (m, 3H),7.61 (d, J = 8.6 Hz, 1H), 7.45 (s, 2H), 7.37 (s, 1H), 7.32 (d, J= 4.1 Hz, 1H), 7.25 – 7.09 (m, 4H), 6.95 (d, J = 8.7 Hz, 1H),4.82 (d, J = 2.8Hz, 3H), 4.11 (d, J = 2.5 Hz, 3H), 3.87 (s, 2H). Example 10 The tablet preparation method is as follows: Prescription Dosage per Tablet I-a 25 mg Microcrystalline Cellulose 25 mg Starch 30 mg Polyvinylpyrrolidone 10 mg Sodium Carboxymethyl Starch 15 mg Magnesium Stearate qs Process: Pass the active ingredient and excipients through a 100-mesh sieve respectively. Weigh the prescription amounts of the active pharmaceutical ingredient and excipients (half of the sodium carboxymethyl starch), mix them thoroughly, add an appropriate amount of aqueous polyvinylpyrrolidone solution to make a soft mass, pass through a 24-mesh sieve, prepare wet granules and dry them in an oven at 50 °C for about 2 hours. Mix the remaining sodium carboxymethyl starch and magnesium stearate evenly with the granules, size the granules, determine the content of the intermediate, and press tablets with a shallow punch of φ8 mm.

[0047] Example 11 Preparation of Injection I-a 25 mg Sodium Dihydrogen Phosphate 5 mg Citric Acid 10 mg Water for Injection 50 mL Process: Take 50 mL of water for injection, weigh the prescription amounts of citric acid and sodium dihydrogen phosphate, stir to dissolve, add the sample and stir to dissolve, adjust the pH value to 5.0 with 0.1 mol / L hydrochloric acid or sodium hydroxide, add 0.1% activated carbon and adsorb for 30 minutes. Filter through a 0.22 μm filter precisely. Fill into each ampoule with 5 mL, and sterilize at 105 °C for 30 minutes to obtain the injection.

[0048] Example 12 In Vitro Antitumor Activity Test of Compound I (1) Materials Cell Lines: Human Lung Adenocarcinoma Cells (A549), Human Lung Cancer Drug-Resistant Cells (H1975).

[0049] Reagents: CCK8 Instruments: Laminar Flow Hood, Suzhou Purification Equipment Factory; CO 2 Incubator, Thermo Company, Model: HERACell150; Inverted Microscope, Carl Zeiss Company, Model: Axiovert 200; Enzyme-Linked Immunosorbent Assay Detector, TECAN Company, Model: Sunrise.

[0050] (2) Methods Cell Culture: One day before detection, inoculate A549 cells at 1000 cells per well in a 96-well cell culture plate, inoculate H1975 cells at 2000 cells per well in a 96-well cell culture plate, inoculate 80 µL of cell suspension per well, place the cell culture plate at 37 °C, 5% CO2 Incubate in an incubator overnight.

[0051] Detection by CCK8 method: Take out the cell plate from the incubator. According to the compound layout diagram, add 20 μL / well of the prepared compound working solution to the cell plate. The cell plate is placed in an incubator at 37 °C with 5% CO 2 Incubate in an incubator for 72 hours in the dark. After the incubation is completed, add CCK8 to the cells, 10 μL / well, and place them in an incubator at 37 °C with 5% CO 2 Incubate in the incubator for 1 hour. Measure the absorbance at a wavelength of 450 nm on an Envision, calculate the inhibition rate, and calculate the IC of the test derivative by the Bliss method 50 value. The test results are shown in Table 1 and Table 2.

[0052] Inhibition rate (%) = (OD S - OD NC ) / (OD STSP -OD NC ) × 100% OD S : Absorbance value of the sample well (test compound) OD NC : Absorbance value of the negative well (cells + medium + DMSO) OD STSP : Absorbance value of the STSP well (cells + medium + 10 μM STSP) (3) Results Table 1 Inhibition rate (%) of cells cultured in vitro Table 2 IC of some derivatives for in vitro cell culture 50 (nM / mL) The above are the specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention can easily think of changes or substitutions, which should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A quinazoline derivative containing chalcone, characterized in that The structural formula of the derivative is as follows: Among them, R1 is selected from monosubstituted hydrogen, fluorine, chlorine, bromine, methyl, methoxy, disubstituted methyl, disubstituted methyl and chlorine, disubstituted methoxy and chlorine, disubstituted fluorine and chlorine; R2 is selected from m-methyl, m-methoxy, p-methyl, p-methoxy.

2. A method for preparing a chalcone-containing quinazoline derivative as claimed in claim 1, characterized in that: include: Step 1, using 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-ol acetate 1 as raw material, toluene as solvent, triethylamine as acid binding agent, phosphorus oxychloride as chlorination agent, after the reaction, adding substituted aniline to the reaction solution, cooling to room temperature, evaporating the solvent, adding isopropanol, stirring, filtering, washing the filter cake with isopropanol, and drying to obtain intermediate 3; Step 2, then adding methanol and ammonia water to the intermediate 3 in sequence, after the reaction, distilling off the methanol under reduced pressure, filtering, and drying to obtain the intermediate 4; Step 3: At room temperature, compound 5, compound 6 and solvent ethanol are added in sequence to obtain a reaction solution, and then a 20% sodium hydroxide aqueous solution is slowly added dropwise to the reaction solution. After the reaction is completed, ethanol is evaporated under reduced pressure to obtain intermediate 7; Step 4: At room temperature, add intermediate 7, dichloromethane and triethylamine in sequence, and then slowly drop chloroacetyl chloride. After the reaction is completed, dichloromethane is evaporated under reduced pressure to obtain intermediate 8; Step 5: At room temperature, add intermediate 4, intermediate 8, DMF and potassium carbonate in sequence. After the reaction, add deionized water to the reaction solution, stir, filter, and vacuum dry the filter cake to obtain the target product.

3. The method for preparing a quinazoline derivative containing chalcone according to claim 2, characterized in that: In the step 1, the solvent, the acid binding agent and the chlorination agent are added into a 100 mL single-mouth bottle in sequence, the temperature is raised to 80° C. and the reaction is carried out for 2 h, and aniline is added and the reaction is carried out for 3 h, and the drying step is vacuum dried at 50° C. for 6 h, and the aniline includes 4-chloro-2-methylaniline, 3-methoxyaniline, 4-methoxyaniline, 2,4-dimethylaniline, 2-fluoroaniline, and 3-chloro-2-fluoroaniline.

4. The method for preparing a quinazoline derivative containing chalcone according to claim 2, characterized in that: In the step 2, the reaction was carried out at room temperature for 4 hours.

5. The method for preparing a quinazoline derivative containing chalcone according to claim 2, characterized in that: In the step 3, the reaction solution is placed at 5° C. and 20% sodium hydroxide is added dropwise, and after the addition is completed, the solution is placed at room temperature to react for 4 hours, and compound 5 includes 4-acetylaniline, and compound 6 includes 3-methoxybenzaldehyde, 3-methylbenzaldehyde, and 4-methoxybenzaldehyde.

6. The method for preparing a quinazoline derivative containing chalcone according to claim 2, characterized in that: In the step 4, the reaction solution is placed at 5° C. and chloroacetyl chloride is slowly added dropwise, and after the addition is completed, the reaction solution is placed at room temperature for 4 hours.

7. The method for preparing a quinazoline derivative containing chalcone according to claim 2, characterized in that: In step 5, the reaction temperature is 80° C., the reaction time is 2 h, the vacuum drying temperature is 60° C., and the drying time is 8 h.

8. A pharmaceutically acceptable salt, formed by combining the chalcone-containing quinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 with an acid, wherein: Suitable acids are: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, tartaric acid, salicylic acid, methanesulfonic acid, succinic acid, fumaric acid, succinic acid, lactic acid, citric acid, malic acid or maleic acid.

9. A use of the chalcone-containing quinazoline derivative according to any one of claims 1 or 8 for preparing a medicine, characterized in that: The invention discloses an application of a quinazoline derivative containing chalcone or a pharmaceutically acceptable salt thereof and an acid to form a pharmaceutical salt for preparing a drug for treating abnormal EGFR family diseases.

10. Use of a pharmaceutical composition using the chalcone-containing quinazoline derivative according to any one of claims 1 or 8 or a pharmaceutically acceptable salt thereof and an acid to form a pharmaceutically acceptable salt as an active ingredient for preparing an anti-tumor drug, characterized in that: The anti-tumor drug is used to prepare a subcutaneous or oral drug preparation. The anti-tumor drug has a cell proliferation inhibitory effect on human lung adenocarcinoma cell A549 and human lung cancer resistant cell H1975.

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