Application of quinazoline compound or pharmaceutically acceptable salt thereof in preparation of medicine for preventing or treating cancer

Abstract

The invention discloses application of a quinazoline compound or a pharmaceutically acceptable salt thereof to preparation of a medicine for preventing or treating cancers. The structure of the quinazoline compound is shown as a formula (IA-3), a formula (IA-4), a formula (IA-8) or a formula (IB-5). The quinazoline compound provided by the invention has a very good inhibition effect on human lung cancer cells; the preparation method of the compound is simple and convenient, easy to operate, low in production cost and suitable for industrial application, and raw materials are easy to obtain. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a quinazoline compound and its application, and particularly to the application of a quinazoline compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer. Background Art

[0002] Quinazoline compounds have many good biological activities and are widely used in the pharmaceutical field. In particular, some quinazoline derivatives with special structures have obvious antiviral, antibacterial, antitumor activities, etc. Some varieties of quinazoline compounds have been marketed as antitumor drugs. For example, Gefitinib and Erlotinib for treating lung cancer, and Lapatinib for treating breast cancer, which all belong to quinazoline compounds. The new quinazoline compounds and their biological activities are also commonly reported in the literature (see Y.-Y. Ke, H.-Y. Shiao, Y. C. Hsu, C.-Y. Chu, W.-C. Wang, Y.-C. Lee, W.-H. Lin, C.-H. Chen, J. T. A. Hsu, C.-W. Chang, C.-W. Lin, T.-K. Yeh, Y.-S. Chao, M. S. Coumar, H.-P. Hsieh, ChemMedChem 2013, 8, 136 - 148; A. Garofalo, A. Farce, S. Ravez, A. Lemoine, P. Six, P. Chavatte, L. Goossens, P. Depreux, J. Med. Chem. 2012, 55, 1189 - 1204). Of course, most quinazoline compounds do not have antitumor activity. Summary of the Invention

[0003] The object of the present invention is to provide the application of a quinazoline compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer. This kind of compound has a good inhibitory effect on human lung cancer cells at a certain dose; and the preparation method of this kind of compound is simple, easy to operate, the raw materials are easy to obtain, and the production cost is relatively low, which is suitable for industrial application.

[0004] To achieve the above object of the invention, the present invention adopts the following technical solutions:

[0005] The present invention provides the application of a quinazoline compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer, wherein the cancer is lung cancer, and the structure of the quinazoline compound is shown as formula (IA - 3), (IA - 4), (IA - 8) or (IB - 5):

[0006]

[0007] Preferably, the cancer preventive or therapeutic drug is a drug for preventing or treating human lung cancer cell A549.

[0008] Preferably, the quinazoline compound is compound (IA-4).

[0009] The term "pharmaceutically acceptable" as used in this application means that the compound is chemically and / or toxicologically compatible with the other components of the formulation and / or with humans or mammals for which it is used to prevent or treat a disease or disorder.

[0010] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic or organic acid addition salts of the compounds of the present invention. For example, see S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19. Among them, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, etc.; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, etc.

[0011] The present invention provides a method for preparing a quinazoline compound, the preparation method comprising: (1) adding the compound shown by formula (II) to organic solvent A, stirring to dissolve, and dropwise adding a mixed solution containing the compound shown by formula (ⅢA) or (ⅢB), catalyst B and organic solvent A under stirring at room temperature. After dropping, the reaction solution is heated to reflux state, and after stirring and reacting for 0.5 to 12 hours, the reaction solution is separated and purified to obtain the quinazoline compounds shown by formula (IA-3), (IA-4), (IA-8) or (IB-5);

[0012] The organic solvent A is one of the following: dichloromethane, ethanol, isopropanol or toluene;

[0013] The catalyst B is one of the following: triethylamine, 4-dimethylaminopyridine (DMAP), pyridine or sodium hydroxide;

[0014]

[0015] In formula (IIIA), R is defined in the same way as in formula (IA-3), (IA-4) or (IA-8); in formula (IIIB), R is defined in the same way as in formula (IB-5).

[0016] Furthermore, the molar ratio of the compound shown in formula (II), the compound shown in formula (IIIA) or (IIIB) to catalyst B is 1﹕0.8 - 1.2﹕0.1 - 1.

[0017] Furthermore, the amount of organic solvent A used is such that it can dissolve the compound shown in formula (II), the compound shown in formula (IIIA) or (IIIB), and catalyst B. Preferably, the total volume of organic solvent A used is 10 - 30 mL / mmol based on the amount of substance of the compound shown in formula (II). Among them, the volume of organic solvent A used to dissolve the compound shown in formula (II) is 4 - 10 mL / mmol based on the amount of substance of the compound shown in formula (II), and the volume of organic solvent A used to dissolve the compound shown in formula (IIIA) or (IIIB) and catalyst B is 6 - 20 mL / mmol based on the amount of substance of the compound shown in formula (II).

[0018] Furthermore, the reaction process is monitored by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 0.5 - 10:1) to determine the end point of the reaction. Generally, the reaction time is 0.5 - 12 hours.

[0019] Furthermore, the separation and purification in step (1) of the present invention adopts the following steps: after the reaction is completed, the solvent is evaporated, and the residue is subjected to column chromatography to obtain the quinazoline compound.

[0020] Even further, the specific operation steps of the column chromatography in step (1) of the present invention are as follows: Take the residue after evaporating the solvent in a single-neck flask, add organic solvent C to dissolve it to obtain a solution, then add 1 - 4 times the mass of the residue of column chromatography silica gel (preferably 300 - 400 mesh coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, evaporate the solvent to obtain a dry mixture of the residue and silica gel, load the mixture onto the column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 0.5 - 10:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 0.5 - 10:1), collect the eluate containing the quinazoline compound according to the TLC detection, and concentrate and dry the eluate to obtain the quinazoline compound; the organic solvent C is one of the following: petroleum ether, dichloromethane, chloroform or ethyl acetate; the amount of organic solvent C used is such that it can dissolve the residue.

[0021] Both organic solvents A and C in the present invention are organic solvents, which are named for the convenience of distinguishing the organic solvents used in different steps, and the letters themselves have no meaning.

[0022] The beneficial effects of the present invention are mainly reflected in: (1) The quinazoline compound (I) of the present invention has good anti-lung cancer activity and is expected to be applied to the preparation of drugs for preventing or treating lung cancer; (2) The preparation method of the quinazoline compound provided by the present invention is simple and easy to operate, the raw materials are easy to obtain, and the production cost is relatively low, which is suitable for practical use. Detailed implementation mode

[0023] The present invention will be further described in conjunction with specific embodiments. The following embodiments illustrate the present invention and do not limit the present invention in any way.

[0024] For those conditions not specified in the embodiments of the present invention, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. For reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained by conventional technical means or purchased commercially.

[0025] Compound (II) was prepared by referring to the methods in the literature (Journal of Medicinal Chemistry, 2022, 65(10), 7246 - 7261; Bioorganic Chemistry, 2021, 117, 105407).

[0026] The specific structure of compound (ⅢA) is as follows:

[0027]

[0028] The specific structure of compound (IA) is as follows:

[0029]

[0030] The specific structure of compound (ⅢB) is as follows:

[0031]

[0032] The specific structure of compound (IB) is as follows:

[0033]

[0034] Example 1: Preparation of compound (ⅢA-1)

[0035] 1.12 g (12.0 mmol) of aniline and 1.22 g (10.0 mmol) of DMAP were added to 30 mL of dichloromethane and stirred. Under the condition of 0 - 5 °C, 30 mL of a dichloromethane solution containing 1.64 g (10.0 mmol) of 4-nitrophenyl isocyanate was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 20 h, washed with water (25 mL × 3), the organic phase was separated, dried, filtered, the solvent was removed by vacuum evaporation, and the residue was recrystallized from ethanol to obtain 1-(4-nitrophenyl)-3-phenylurea with a yield of 71%.

[0036] 1.29 g (5.0 mmol) of 1-(4-nitrophenyl)-3-phenylurea was added to 30 mL of ethanol, and then 0.20 g of Pd / C (5%) was added. Under the condition of stirring at room temperature, hydrogen was introduced at atmospheric pressure for reaction. TLC detection (the developing agent was a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1) was carried out until the reaction was completed. After filtration, the solvent was removed by vacuum evaporation, and the residue was recrystallized from ethanol to obtain the product (ⅢA-1) with a yield of 83%.

[0037] Preparation of compounds (ⅢA-2) - (ⅢA-9): Aniline was replaced with the corresponding substituted aniline, and the corresponding compounds (ⅢA-2) - (ⅢA-9) were prepared by referring to the method of Example 1, which will not be elaborated here.

[0038] Example 2: Preparation of compound (ⅢB-1)

[0039] 1.29 g (12.0 mmol) of benzylamine and 1.22 g (10.0 mmol) of DMAP were added to 30 mL of dichloromethane and stirred. Under the condition of 0 - 5 °C, 30 mL of a dichloromethane solution containing 1.64 g (10.0 mmol) of 4-nitrophenyl isocyanate was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 22 h, washed with water (25 mL × 3), the organic phase was separated, dried, filtered, the solvent was removed by vacuum evaporation, and the residue was recrystallized from ethanol to obtain 1-(4-nitrophenyl)-3-benzylurea with a yield of 65%.

[0040] 1.36 g (5.0 mmol) of 1-(4-nitrophenyl)-3-benzylurea was added to 30 mL of ethanol, and then 0.20 g of Pd / C (5%) was added. Under the condition of stirring at room temperature, hydrogen was introduced at atmospheric pressure for reaction. TLC detection (the developing agent was a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1) was carried out until the reaction was completed. After filtration, the solvent was removed by vacuum evaporation, and the residue was recrystallized from ethanol to obtain the product (ⅢB-1) with a yield of 78%.

[0041] Preparation of compounds (ⅢB-2) - (ⅢB-5): Benzylamine was replaced with the corresponding substituted benzylamine, and the corresponding compounds (ⅢB-2) - (ⅢB-5) were prepared by referring to the method of Example 2, which will not be elaborated here.

[0042] Example 3: Preparation of Compound (ⅠA-1)

[0043] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (Ⅱ) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.455 g (2.0 mmol) of compound (ⅢA-1) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 12 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:2). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:2 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:2). Collect the eluate containing the compound shown in formula (ⅠA-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (ⅠA-1), with a yield of 63% (calculated based on the amount of substance of 2,4-dichloroquinazoline (Ⅱ)), and a melting point of 218 - 220 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.72 (s, 1H), 8.69 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.9 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H). 13 C NMR (125 MHz, DMSO-d6) δ 155.2, 154.6, 153.2, 152.5, 151.3, 137.1, 133.6, 132.3, 122.1, 119.4, 119.1, 119.0, 118.8, 118.4, 118.3, 116.9, 116.7.

[0044] Example 4: Preparation of Compound (ⅠA-1)

[0045] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 8 mL of toluene. Under magnetic stirring at room temperature, add dropwise a 12 mL toluene solution containing 0.545 g (2.4 mmol) of compound (IIIA-1) and 0.008 g (0.2 mmol) of sodium hydroxide. After the addition is complete, heat the reaction mixture to reflux in an oil bath and reflux for 0.5 h (monitor the reaction process by TLC, the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of dichloromethane solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution. After mixing evenly, evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1). Collect the eluate containing the compound shown in formula (IA-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IA-1), with a yield of 45% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and the melting point is 218 - 220 °C. 1 H NMR and 13 C NMR are the same as in Example 1.

[0046] Example 5: Preparation of Compound (IA-1)

[0047] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of ethanol. Under magnetic stirring at room temperature, dropwise add a 40 mL ethanol solution containing 0.364 g (1.6 mmol) of compound (IIIA-1) and 0.202 g (2.0 mmol) of triethylamine. After dropping, heat the reaction solution to reflux in an oil bath and reflux for 6 hours (monitor the reaction process by TLC, the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of chloroform solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IA-1), with a yield of 55% (calculated based on the amount of substance of compound (IIIA-1)), and the melting point is 218 - 220 °C. 1 1H NMR and 13 13C NMR are the same as in Example 1.

[0048] Example 6: Preparation of compound (IA-1)

[0049] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 10 mL of isopropanol. Under magnetic stirring at room temperature, add dropwise a 15 mL isopropanol solution containing 0.455 g (2.0 mmol) of compound (IIIA-1) and 0.079 g (1.0 mmol) of pyridine. After the addition, heat the reaction mixture to reflux in an oil bath and reflux for 4 hours (monitor the reaction process by TLC, the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of ethyl acetate solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1). Collect the eluate containing the compound shown in formula (IA-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, which is compound (IA-1), with a yield of 42% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 218 - 220 °C. 1 1H NMR and 13 13C NMR are the same as in Example 1.

[0050] Example 7: Preparation of Compound (IA-2)

[0051] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.511 g (2.0 mmol) of compound (IIIA-2) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 10 hours (monitor the reaction process by TLC, the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-2) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, namely compound (IA-2), with a yield of 61% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and the melting point is 232 - 234 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.11 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.12 (td, J = 9.3, 6.2 Hz, 1H), 7.96 (s, 1H), 7.88 - 7.84 (m, 1H), 7.71 (dd, J = 8.4, 1.2 Hz, 1H), 7.69 - 7.64 (m, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.33 - 7.29 (m, 1H), 7.27 - 7.24 (m, 1H), 7.07 (dd, J = 8.6, 2.9 Hz, 1H), 2.90 (s, 3H), 2.79 (s, 3H).

[0052] Example 8: Preparation of compound (IA-3)

[0053] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.515 g (2.0 mmol) of compound (IIIA-3) and 0.122 g (1.0 mmol) of DMAP. After the addition is complete, heat the reaction solution to reflux in an oil bath and reflux for 9 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, evaporate the solvent, and obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-3) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IA-3), with a yield of 68% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 265 - 267 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 7.86 - 7.82 (m, 1H), 7.69 (dd, J = 8.4, 1.2 Hz, 1H), 7.67 - 7.58 (m, 3H), 7.55 - 7.44 (m, 2H), 7.42 - 7.28 (m, 2H), 7.22 - 7.07 (m, 1H), 6.96 - 6.76 (m, 2H), 3.71 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 163.0, 159.6, 156.6, 154.6, 153.0, 150.8, 150.5, 141.0, 137.3, 133.0, 132.0, 124.1, 122.5, 120.1, 118.3, 114.2, 113.9, 55.4.

[0054] Example 9: Preparation of Compound (IA-4)

[0055] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.592 g (2.0 mmol) of compound (IIIA-4) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 10 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 7 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-4) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IA-4), with a yield of 51% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 188 - 189 °C. 1 H NMR(500MHz,DMSO-d6)δ10.18(s,1H),9.05(s,1H),8.89(s,1H),8.54 - 8.51(m,1H),7.96 - 7.81(m,2H),7.75 - 7.60(m,4H),7.52(dd,J=8.8,4.3Hz,3H),7.34(dd,J=8.8,2.5Hz,1H); 13 C NMR(125MHz,DMSO-d6)δ159.4,156.4,152.4,150.7,140.1,136.3,134.0,132.5,131.1,130.62,126.8,126.5,123.9,123.4,123.0,119.2,118.6,118.2,113.8.

[0056] Example 10: Preparation of compound (IA-5)

[0057] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.511 g (2.0 mmol) of compound (IIIA-5) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 8 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution. After mixing, evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-5) according to the TLC detection. Evaporate the solvent from the collected eluate and dry it to obtain a white solid product, namely compound (IA-5), with a yield of 67% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 204 - 206 °C. 1 H NMR(500MHz,DMSO-d6)δ10.15(s,1H),8.69(s,1H),8.54(d,J=7.3Hz,2H),7.95 - 7.78(m,2H),7.73 - 7.67(m,1H),7.65(s,1H),7.66 - 7.60(m,3H),7.51(d,J=7.4Hz,2H),7.50(d,J=7.4Hz,1H),2.24(s,6H); 13 C NMR(125MHz,DMSO-d6)δ159.6,156.6,152.7,150.9,139.8,137.9,137.0,134.1,132.2,127.1,127.0,126.7,124.1,123.6,118.4,116.1,113.9,21.3.

[0058] Example 11: Preparation of compound (IA-6)

[0059] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.526 g (2.0 mmol) of compound (IIIA-6) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 11 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-6) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IA-6), with a yield of 67% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 238 - 239 °C. 1 H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.90 (s, 1H), 8.79 (s, 1H), 8.36 (d, J = 6.4 Hz, 1H), 7.82 (dd, J = 6.7, 1.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 6.0 Hz, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.32 (td, J = 6.0, 3.8 Hz, 2H), 7.17 (td, J = 8.4, 1.7 Hz, 2H), 13 C NMR (125 MHz, DMSO-d6) δ 162.1, 159.2, 156.2, 152.2, 150.6, 140.7, 136.2, 133.8, 132.2, 126.8, 126.7, 126.6, 126.3, 123.8, 123.26, 118.1, 115.1, 113.6, 99.4.

[0060] Example 12: Preparation of compound (IA-7)

[0061] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.523 g (2.0 mmol) of compound (IIIA-7) and 0.122 g (1.0 mmol) of DMAP. After the addition, the reaction solution is heated to reflux in an oil bath and refluxed for 6 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). The solvent of the reaction solution is evaporated, and the residue is subjected to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution. After mixing evenly, evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-7) according to the TLC detection. The collected eluate is evaporated to remove the solvent and dried to obtain a white solid product, that is, compound (IA-7), with a yield of 59% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and the melting point is 198 - 199 °C. 1 H NMR(500MHz,DMSO-d6)δ10.81(s,1H),9.66(d,J=6.4Hz,1H),8.83(s,1H),8.77(s,1H),8.57(dd,J=8.2,2.4Hz,1H),7.85(d,J=8.2Hz,1H),7.66(d,J=8.9Hz,2H),7.56 - 7.53(m,2H),7.47 - 7.44(m,2H),7.31 - 7.27(m,2H),6.98(d,J=7.4Hz,1H). 13 C NMR(125MHz,DMSO-d6)δ155.2,154.6,154.4,152.4,141.3,135.2,133.6,133.1,132.3,130.3,124.0,122.1,121.3,118.8,117.5,116.5,100.2.

[0062] Example 13: Preparation of Compound (IA-8)

[0063] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.483 g (2.0 mmol) of compound (IIIA-8) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 5 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution. After mixing evenly, evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-8) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IA-8), with a yield of 55% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 182 - 184 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 8.52 (d, J = 7.9 Hz 1H), 7.89 - 7.85 (m, 1H), 7.70 (d, J = 7.5 Hz 1H), 7.65 (m, 3H), 7.53 - 7.50 (m, 2H), 7.32 (s, 1H), 7.25 (d, J = 8.35 Hz 1H), 7.18 (m, 1H), 6.80 (d, J = 7.35 Hz 1H), 2.29 (s, 3H).

[0064] Example 14: Preparation of Compound (IA-9)

[0065] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.515 g (2.0 mmol) of compound (IIIA-9) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction mixture to reflux in an oil bath and reflux for 9 hours (monitor the reaction process by TLC, and the developing solvent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution. After mixing evenly, evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing solvent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IA-9) according to the TLC detection. Evaporate the solvent from the collected eluate and dry it to obtain a white solid product, that is, compound (IA-9), with a yield of 51% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and the melting point is 228 - 230 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.72 (s, 2H), 8.55 (d, J = 8.3 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 8.4, 2.7 Hz, 3H), 7.51 (dd, J = 6.7, 2.2 Hz, 2H), 7.19 - 7.14 (m, 2H), 6.94 (dd, J = 8.1, 1.9 Hz, 1H), 6.56 (dd, J = 8.2, 2.2 Hz, 1H), 3.74 (s, 3H).

[0066] Example 15: Preparation of compound (IB-1)

[0067] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.483 g (2.0 mmol) of compound (IIIB-1) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction mixture to reflux in an oil bath and reflux for 12 hours (the reaction process is monitored by TLC, and the developing solvent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:2). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution. After mixing evenly, evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:2 as the eluent for elution. Monitor by TLC (the developing solvent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:2). Collect the eluate containing the compound shown in formula (IB-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IB-1), with a yield of 70% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 189 - 191 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 10.10 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.88 - 7.84 (m, 2H), 7.71 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 5.7 Hz, 3H), 7.64 - 7.61 (m, 2H), 7.16 - 6.12 (m, 2H), 6.74 (dd, J = 6.3, 2.8 Hz, 1H), 6.61 - 6.57 (m, 1H), 3.90 (s, 2H).

[0068] Example 16: Preparation of Compound (IB-1)

[0069] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 8 mL of toluene. Under magnetic stirring at room temperature, add dropwise a 12 mL toluene solution containing 0.579 g (2.4 mmol) of compound (IIIB-1) and 0.008 g (0.2 mmol) of sodium hydroxide. After the addition is complete, heat the reaction mixture to reflux in an oil bath and reflux for 0.5 hour (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of dichloromethane solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a dry mixture of the residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 10:1). Collect the eluate containing the compound shown in formula (IB-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry it to obtain a white solid product, that is, compound (IB-1), with a yield of 56% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 189 - 191 °C. 1 1H NMR is the same as in Example 1.

[0070] Example 17: Preparation of Compound (IB-1)

[0071] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of ethanol. Under magnetic stirring at room temperature, add dropwise a 40 mL ethanol solution containing 0.386 g (1.6 mmol) of compound (IIIB-1) and 0.202 g (2.0 mmol) of triethylamine. After the addition is complete, heat the reaction mixture to reflux in an oil bath and reflux for 6 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of chloroform solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a dry mixture of the residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IB-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry it to obtain a white solid product, that is, compound (IB-1), with a yield of 67% (calculated based on the amount of substance of compound (IIIB-1)), and a melting point of 189 - 191 °C.1 1H NMR was the same as that in Example 1.

[0072] Example 18: Preparation of Compound (IB-1)

[0073] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 10 mL of isopropanol. Under magnetic stirring at room temperature, add dropwise a 15 mL isopropanol solution containing 0.483 g (2.0 mmol) of Compound (IIIB-1) and 0.079 g (1.0 mmol) of pyridine. After the addition, heat the reaction mixture to reflux in an oil bath and reflux for 4 hours (the reaction process was monitored by TLC, and the developing agent was a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of ethyl acetate solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then, add 1.5 g of silica gel (300-400 mesh, large pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a dry mixture of the residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent for elution. Monitor by TLC (the developing agent was a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1). Collect the eluate containing the compound shown by formula (IB-1) according to the TLC detection. Evaporate the solvent from the collected eluate and dry it to obtain a white solid product, namely Compound (IB-1), with a yield of 54% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and the melting point was 189-191 °C. 1 1H NMR was the same as that in Example 1.

[0074] Example 19: Preparation of Compound (IB-2)

[0075] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, slowly add a 30 mL dichloromethane solution containing 0.687 g (2.0 mmol) of compound (IIIB-2) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction mixture to reflux in an oil bath and reflux for 11 hours (monitor the reaction process by TLC, the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction mixture, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, type zcx.II, macroporous column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a dry mixture of the residue and silica gel. Pack the mixture into a column, and use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IB-2) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, namely compound (IB-2), with a yield of 55% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and the melting point is 267 - 269 °C. 1 H NMR(500MHz,DMSO-d6)δ10.18(d,J=8.8Hz,2H),8.55(dd,J=8.4,1.3Hz,1H),7.89-7.85(m,1H),7.77-7.56(m,6H),7.39(d,J=8.8Hz,1H),7.07(d,J=6.8Hz,1H),6.85(dd,J=8.8,2.9Hz,1H),6.73(s,1H),3.99(s,2H); 13 C NMR(125MHz,DMSO-d6)δ168.4,159.6,156.5,151.0,147.9,135.8,134.2,133.7,132.1,127.0,126.7,123.8,123.6,119.6,116.5,116.0,113.9,111.3,46.8,35.9.

[0076] Example 20: Preparation of compound (IB-3)

[0077] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, dropwise add a 30 mL dichloromethane solution containing 0.551 g (2.0 mmol) of compound (IIIB-3) and 0.122 g (1.0 mmol) of DMAP. After dropping, heat the reaction solution to reflux in an oil bath and reflux for 10 hours (monitor the reaction process by TLC, the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it to obtain a solution. Then add 1.5 g of silica gel (300 - 400 mesh, thick pore (zcx.II) type column chromatography silica gel) to the solution, mix well, evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IB-3) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IB-3), with a yield of 67% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and the melting point is 271 - 273 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.53 (d, J = 7.3 Hz, 2H), 7.86 (m, 1H), 7.69 (dd, J = 8.4, 1.2 Hz, 1H), 7.62 (t, J = 6.3 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.48 - 7.40 (m, 2H), 7.40 - 7.34 (m, 2H), 7.33 - 7.21 (m, 2H), 6.13 (t, J = 5.7 Hz, 1H), 2.76 (t, J = 7.0 Hz, 2H); 13 C NMR (125 MHz, DMSO-d6) δ 159.6, 156.7, 155.4, 151.0, 138.8, 137.8, 134.1, 131.5, 130.9, 130.8, 128.4, 127.0, 126.6, 124.1, 123.5, 117.9, 113.9, 35.3.

[0078] Example 21: Preparation of compound (IB-4)

[0079] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.542 g (2.0 mmol) of compound (IIIB-4) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 8 hours (the reaction process was monitored by TLC, and the developing agent was a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 7 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution. Monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IB-4) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IB-4), with a yield of 62% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point > 300 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 10.06 (s, 1H), 8.59 - 8.49 (m, 1H), 7.88 (m, 1H), 7.79 - 7.54 (m, 6H), 7.00 (t, J = 8.4 Hz, 1H), 6.30 - 6.10 (m, 3H), 6.03 (t, J = 6.1 Hz, 1H), 3.87 (d, J = 6.1 Hz, 2H), 3.67 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 169.0, 160.2, 159.2, 156.2, 150.7, 149.5, 135.6, 133.8, 133.2, 129.5, 126.7, 126.4, 123.5, 123.2, 119.3, 113.6, 105.3, 101.9, 98.2, 54.5, 47.2.

[0080] Example 22: Preparation of compound (IB-5)

[0081] Dissolve 0.398 g (2.0 mmol) of 2,4-dichloroquinazoline (II) in 20 mL of dichloromethane. Under magnetic stirring at room temperature, add dropwise a 30 mL dichloromethane solution containing 0.511 g (2.0 mmol) of compound (IIIB-5) and 0.122 g (1.0 mmol) of DMAP. After the addition, heat the reaction solution to reflux in an oil bath and reflux for 10 hours (the reaction process is monitored by TLC, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Evaporate the solvent from the reaction solution, and subject the residue to column chromatography. That is, add 10 mL of petroleum ether solvent to the residue after evaporating the solvent to dissolve it, obtaining a solution. Then, add 1.5 g of silica gel (300 - 400 mesh, coarse pore (zcx.II) type column chromatography silica gel) to the solution, mix well, and evaporate the solvent to obtain a mixture of the dried residue and silica gel. Pack the mixture into a column, and then use a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent for elution, and monitor by TLC (the developing agent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1). Collect the eluate containing the compound shown in formula (IB-5) according to the TLC detection. Evaporate the solvent from the collected eluate and dry to obtain a white solid product, that is, compound (IB-5), with a yield of 48% (calculated based on the amount of substance of 2,4-dichloroquinazoline (II)), and a melting point of 269 - 271 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 10.03 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.10 (dd, J = 8.0, 1.3 Hz, 1H), 7.91 - 7.87 (m, 2H), 7.72 (s, 1H), 7.67 - 7.63 (m, 2H), 7.59 - 7.56 (m, 1H), 7.25 - 7.21 (m, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.52 - 6.31 (m, 3H), 3.87 (d, J = 5.9 Hz, 2H), 2.20 (s, 3H).

[0082] Example 23: In vitro anti-cancer activity test

[0083] The prepared compounds (IA-1) - (IA-9) were respectively subjected to bioactivity tests on human lung cancer cell line A-549, and among them, compound (IA-1) was prepared by the method of Example 3. The prepared compounds (IB-1) - (IB-5) were respectively subjected to bioactivity tests on human lung cancer cell line A-549, and among them, compound (IB-1) was prepared by the method of Example 15.

[0084] Test method: Tetrazolium salt reduction method (MTT method).

[0085] Cell line: human lung cancer cell line A-549. The cell line was purchased from the Cell Bank of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0086] The experimental steps are as follows:

[0087] (1) Cultivation of tumor cells

[0088] The cell passages used in the experiment were all within 5 passages. The consumables and reagents used for cell culture were all subjected to strict sterilization operations, and all experimental operations were carried out in a sterile operating table.

[0089] (a) Resuscitation of tumor cells

[0090] Before the experiment, put the items to be used, such as culture flasks, centrifuge tubes, pipettes, pipette tips, waste liquid buckets, etc., into the laminar flow hood, turn on the ultraviolet lamp for sterilization, and preheat the reagents used for cell culture in a 37°C water bath. After all preparations are ready, turn off the ultraviolet lamp and turn on the fluorescent lamp and ventilation fan of the laminar flow hood. Take out the cryopreserved tumor cells from the -80°C refrigerator, quickly thaw them by shaking in a 37°C water bath. Ensure that there is still a small amount of the cryopreservation solution in the cryopreservation tube that has not thawed, spray alcohol, and then put it into the laminar flow hood. Immediately transfer all the cells in the cryopreservation tube to a 15 mL centrifuge tube containing 1640 culture medium, and gently pipette and mix them. Place the centrifuge tube in a centrifuge and centrifuge at 1000 rpm for 5 min. Aspirate the supernatant in the laminar flow hood. Pipette 2 mL of 1640 culture medium into the centrifuge tube containing the cell pellet to make a cell suspension, and pipette and mix the cell suspension and transfer it to a vented culture flask with a bottom area of 25 cm 2 Then add 4 mL of 1640 culture medium, gently shake the culture flask to mix the cells, and place the culture flask in a 5% CO2, 37°C constant temperature incubator for cultivation.

[0091] (b) Subculture of tumor cells

[0092] When the cells are in good growth condition and cover 70% - 80% of the bottom of the culture flask, subculture can be carried out. All subculture operation steps are completed in the laminar flow hood. After finishing the preparatory work, subculture can begin. First, suck out the original culture medium in the culture flask with a pipette and inject it into the waste liquid bucket. Add 2 mL of PBS and wash it several times and then suck it out. Then add about 600 - 700 μL of trypsin (containing 0.02% EDTA, phenol red and 0.25% trypsin) to ensure that the bottom of the flask is completely covered by trypsin. Gently shake the culture flask and place it in a 37°C constant temperature incubator for 1 - 2 min. Observe the cell detachment under the microscope. If a small amount of cells still adhere to the wall, gently tap the wall of the flask with your fingertip until most of the cells can detach from the bottom of the flask. Add 2 mL of 1640 culture medium to terminate digestion, and then gently pipette the cells to blow them off the bottom of the flask. Transfer the cell suspension to a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 min. Suck out the supernatant, dilute and pipette it evenly with 1640 culture medium, and then evenly distribute it into 2 - 3 culture flasks and continue to culture in a 5% CO2, 37°C constant temperature incubator.

[0093] (c) Cryopreservation of tumor cells

[0094] Prepare the cell cryopreservation solution in advance according to the volume ratio of FBS (fetal bovine serum): DMSO = 9:1 and place it in the 4°C refrigerator for standby. All cryopreservation operation steps are completed in the laminar flow hood. After finishing the preparatory work, cryopreservation can begin. First, suck out the original culture medium in the culture flask, add 2 mL of PBS buffer and wash it several times and then pour it out. Then add about 600 - 700 μL of trypsin (containing 0.02% EDTA, phenol red and 0.25% trypsin), gently shake the culture flask to ensure that the trypsin can cover the bottom of the culture flask, place it in a 37°C constant temperature incubator for 1 - 2 min. Observe the cell detachment under the microscope. If a small amount of cells still adhere to the wall, gently tap the wall of the flask with your fingertip until most of the cells can detach from the bottom of the flask. Add 2 mL of 1640 culture medium to terminate digestion, and then gently pipette the cells to blow them off the bottom of the flask. Transfer the cell suspension to a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 min. Pour out the supernatant. Add 1 mL of the cryopreservation solution just taken out from the 4°C refrigerator and pipette it evenly to form a cell suspension, and transfer it into a cryopreservation tube. After marking the cell type, cell passage number and cryopreservation date, place it in 4°C for 30 min, then in -20°C for 1 hour, and then store it in a -80°C ultra-low temperature refrigerator.

[0095] (2) MTT assay method

[0096] (a) Cell counting: The tumor cells in good growth state in the culture flask were digested and centrifuged, then resuspended with 4 mL of 1640 culture medium. 10 μL of the cell suspension was taken to the cell counting chamber. After counting, the B16F10 cells were diluted to 5×10 4 cells / mL.

[0097] (b) Seeding: Take a 96-well plate. Add 100 μL of the diluted cell suspension to the experimental wells, add 100 μL of 1640 culture medium to the blank wells, and supplement 100 μL of PBS buffer around. Incubate in a CO2 constant temperature incubator.

[0098] (c) Preparation of compound dosing: Dilute the 10 μmol / mL compound prepared with DMSO and the positive control drug sorafenib to the specified concentrations of 40 μM, 20 μM, 10 μM, 5 μM, 2.5 μM, and 1.25 μM with 1640 culture medium, and perform drug addition using the medium replacement method. Discard the original culture medium, add 100 μL of 1640 culture medium containing the compound or the positive control drug to the experimental wells, add 100 μL of 1640 culture medium to the control group and blank wells. After drug addition, place the 96-well plate in a 5% CO2, 37 °C constant temperature incubator for continued culture.

[0099] (d) Adding MTT: After 48 hours, take out the 96-well plate and place it in the laminar flow hood. Add 10 μL of 5 mg / mL MTT solution to each well under light protection conditions, and then place it in a 5% CO2, 37 °C constant temperature incubator for continued culture.

[0100] (e) Detection: The 96-well plate with MTT added was taken out after incubating in the incubator for 3.5 - 4 h. Carefully aspirate the solution in each well, add 150 μL of DMSO to each well to dissolve the formed formazan, then place it on a plate shaker and shake for 20 min. Use an enzyme-linked immunosorbent assay (ELISA) reader to detect the absorbance value at 490 nm.

[0101] (f) Experimental data processing: Calculate the cell survival rate according to the following formula. The value of 50% cell survival rate is the IC 50 .

[0102] Cell survival rate (%) = [(As - Ab) / (Ac - Ab)] × 100%

[0103] As: Experimental wells (culture medium containing cells, MTT, toxic substance (i.e., compound (IA) or (IB)))

[0104] Ac: Control wells (culture medium containing cells, MTT, without toxic substance)

[0105] Ab: Blank wells (culture medium containing MTT, without cells and toxic substances).

[0106] The results of the tests are shown in Tables 1 and 2:

[0107] Table 1. Inhibitory effect of compound (IA) on cancer cell growth (IC 50 , μΜ)

[0108] Compound A549 IA-1 ≥40 IA-2 ≥40 IA-3 30.69±2.45 IA-4 10.02±1.09 IA-5 ≥40 IA-6 ≥40 IA-7 ≥40 IA-8 29.94±2.21 IA-9 ≥40 Sorafenib 12.8±0.32

[0109] Table 2. Inhibitory effect of compound (IB) on cancer cell growth (IC 50 , μΜ)

[0110]

[0111]

Claims

1. Use of a quinazoline compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer, characterized in that: The cancer described is lung cancer, and the structure of the quinazoline compound is as shown in formula (IA-3), (IA-4), (IA-8) or (IB-5):

2. The application according to claim 1, wherein: The cancer prevention or treatment drug is a drug for preventing or treating human lung cancer cell A549.

3. The application according to claim 1, wherein: The quinazoline compound described is compound (IA-4).

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