A quinazoline compound and application thereof

Abstract

The application belongs to the technical field of chemical medicine raw materials, and particularly relates to a quinazoline compound and application thereof, a structure of the compound is shown as formula I. It is verified through experiments that the compound provided in the application has good in-vitro anti-tumor activity, and lays a foundation for further development of anti-tumor drugs. Formula I.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical raw material technology, specifically relating to a quinazoline compound and its application. Background Technology

[0002] Malignant tumors, as heterogeneous diseases characterized by uncontrolled cell proliferation, are one of the leading causes of morbidity and mortality worldwide. In recent years, the incidence of cancer worldwide has shown a continuous upward trend. Various factors that cause malignant tumors include: chemical carcinogenesis, viral infection, epigenetic changes, and somatic mutations.

[0003] Triple-negative breast cancer has a high incidence rate worldwide. In recent years, the incidence rate has been on the rise, particularly in urban areas.

[0004] Currently, the main treatment methods for triple-negative breast cancer include four types: surgery, radiotherapy, immunotherapy, and chemotherapy. Among these treatments, chemotherapy plays a crucial role in tumor treatment. It utilizes anti-tumor drugs to inhibit the proliferation of tumor cells, thereby shrinking and destroying tumor tissue. While surgical treatment has made significant progress in early-stage breast cancer, the survival rate for advanced breast cancer has not improved much, and surgery often requires chemotherapy as an adjunct to improve survival rates. Therefore, the development of new drugs is becoming increasingly important.

[0005] This invention designs and synthesizes a series of novel quinazoline compounds in order to explore their potential as anti-tumor drugs. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a quinazoline compound with good in vitro antitumor activity.

[0007] To solve the above problems, the technical solution adopted by the present invention is as follows:

[0008] Technical Topic 1

[0009] A quinazoline compound, its pharmaceutically acceptable salt, or its stereoisomer, the key being that its structure is shown in Formula I:

[0010]

[0011] Formula I

[0012] Where L is selected from —O—, —NH— or —CONH—;

[0013] M is either N or C;

[0014] R1 is , , , , -OH or ;

[0015] n1 is selected from 0, 1, 2, 3, 4 or 5;

[0016] n2 is selected from 0, 1, 2, 3, 4 or 5;

[0017] n3 is selected from 0, 1, 2, 3, 4 or 5;

[0018] n4 is selected from 0, 1, 2, 3, 4 or 5;

[0019] Ring A1 is a 5-6 membered heteroaryl or Ra-substituted aryl containing 1-3 N atoms;

[0020] A2 is an aryl group substituted with Ra.

[0021] Ra is a monosubstituted or polysubstituted group, independently selected from H or halogen;

[0022] R5 is -OH or -NR x R y ;

[0023] R x R y Independently selected from H or C1-C5 alkyl groups;

[0024] R2 is H, a halogen, a C1-C5 alkyl group, or a C1-C5 alkyl group substituted with 1-3 halogens.

[0025] R3 is H, halogen, C2-C5 alkenyl or C2-C5 alkynyl;

[0026] R4 is selected from C1-C5 alkyl groups. , , , or .

[0027] As a further improvement of the present invention, the C1-C5 alkyl group is selected from -CH3, -CH2CH3, -CH(CH3)2, -(CH2)2CH3, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -(CH2)4CH3, -CH(CH3)(CH2)2CH3, -CH(CH2CH3)2, -CH2C(CH2)3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2 or -(CH2)2CH(CH3)2;

[0028] The halogen is selected from F, Cl, Br or I;

[0029] The 5-6 membered heteroaryl group containing 1-3 N is selected from pyrrole, pyridine, pyrimidine or pyrazine;

[0030] The 1-3 halogen-substituted C1-C5 alkyl groups are selected from —CF3, —CH2CF3, —(CH2)2CF3

[0031] —(CH2)3CF3 or —(CH2)4CF3;

[0032] C2-C5 alkenyl groups are selected from vinyl, isopropenyl, n-propenyl, n-butenyl, isobutenyl, sec-butenyl, n-pentenyl, or isopentenyl.

[0033] The C2-C5 ynyl groups are selected from ethynyl, propynyl, butynyl, or penynyl.

[0034] As a further improvement to the present invention, L is selected from... —O—, —NH— or —CONH—;

[0035] M is either N or C;

[0036] R1 is , , , , -OH or ;

[0037] n1, n2, n3, n4 are selected from 0 or 1;

[0038] Ring A1 is a 5-6 membered heteroaryl group or Ra-substituted benzene ring containing 1-3 N atoms;

[0039] Ring A2 is a Ra-substituted benzene ring

[0040] Ra is a monosubstituted or polysubstituted group, independently selected from H or F;

[0041] R5 is -OH or -NR x R y ;

[0042] R x R y Independently selected from H or C1-C5 alkyl groups;

[0043] R2 is H, halogen, methyl, or trifluoromethyl;

[0044] R3 is H, halogen, or acetylene group;

[0045] R4 is selected from methyl, , , , or .

[0046] As a further improvement to the present invention, the structure of ring A1 is selected from the following: , , , or ;

[0047] The structure of ring A2 is selected from the following: , , or .

[0048] As a further improvement of the present invention, the compound is selected from the following structures:

[0049] 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-6-yl)-N-(4-(hydroxycarbamoyl)benzyl)-2H-1,2,3-triazol-4-carboxamide;

[0050] (S,E)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-N-(4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)-2H-1,2,3-triazol-4-carboxamide;

[0051] 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)-N-(4-(hydroxycarbamoyl)benzyl)-2H-1,2,3-triazol-4-carboxamide;

[0052] (E)-N-(4-(3-((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)-2H-1,2,3-triazol-4-carboxamide;

[0053] (R,E)-N-(4-(3-((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide;

[0054] N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide;

[0055] N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide;

[0056] 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-N-hydroxy-2H-1,2,3-triazol-4-carboxamide;

[0057] (S)-N-(2-aminophenyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide;

[0058] N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)amino)methyl)benzamide;

[0059] N-(2-aminophenyl)-5-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)amino)methyl)pyrazine-2-carboxamide;

[0060] (R)-N-(2-aminophenyl)-4-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)amino)-2-oxoethyl)benzamide;

[0061] (R,E)-3-(4-(((4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)amino)methyl)phenyl)-N-hydroxyacrylamide;

[0062] 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethylbenzoylhydrazine;

[0063] 5-N-(2-aminophenyl)-6-(((4-(((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxy)methyl)nicotinamide;

[0064] 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-2,5-difluorobenzoylhydrazine;

[0065] 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-2-fluorobenzoylhydrazine;

[0066] 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-3-fluorobenzoylhydrazine;

[0067] N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-2,5-difluorobenzamide;

[0068] N-(2-aminophenyl)-4-(((4-((3-ethynylphenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide;

[0069] N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-3-fluorobenzamide;

[0070] N-(2-aminophenyl)-4-(((7-methoxy-4-((4-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)oxymethyl)benzamide;

[0071] N-(2-aminophenyl)-4-(((4-((3-ethynyl-4-methylphenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide;

[0072] N-(2-aminophenyl)-4-(((4-((3-bromophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide.

[0073] Technical Theme Two

[0074] A composition comprising a quinazoline compound as described in Technical Subject 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0075] As a further improvement of the present invention, the composition further includes one or more pharmaceutically acceptable carriers or excipients.

[0076] Technical Theme 3

[0077] The use of a quinazoline compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described in Technical Subject 1, in the preparation of an antitumor drug.

[0078] As a further improvement of the present invention, the tumor is breast cancer.

[0079] The beneficial effects of adopting the above technical solution are as follows:

[0080] This invention provides a novel quinazoline compound. Preliminary experiments have verified that the quinazoline compound provided in this application has anti-breast cancer activity at the cellular level, laying the foundation for the development of anti-breast cancer drugs. Detailed Implementation

[0081] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described clearly and completely below in conjunction with specific embodiments.

[0082] In this invention, the term "pharmaceutical acceptable" means that a substance or composition, when exposed to mammals, will not produce unreasonable toxicity, irritation, allergic reactions, or other adverse side effects.

[0083] In this invention, the term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of this invention. These salts not only retain the pharmacological activity of the compounds but also possess favorable pharmaceutical properties, such as enhanced solubility, stability, or bioavailability. These salts include, but are not limited to, organic acid salts such as acetates, citrates, fumarates, maleates, oxalates, malates, citrates, succinates, tartrates, lactates, camphor sulfonates, benzene sulfonates, p-toluene sulfonates, methanesulfonates, trifluoroacetates, trifluoromethanesulfonates, etc.; and inorganic acid salts such as hydrohalides, sulfates, phosphates, nitrates, etc. Furthermore, the active pharmaceutical ingredient can also form salts with amino acids such as glutamic acid or aspartic acid, i.e., glutamate or aspartate.

[0084] As used herein, “pharmaceutically acceptable carriers or excipients” include: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will understand that some pharmaceutically acceptable excipients may be used for more than one function and for alternative functions, depending on the amount of said excipient present in the formulation and what other ingredients are present in the formulation. For example, when used orally, it can be formulated into oral preparations such as tablets, capsules, granules, and pills, containing fillers (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium aluminum metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (e.g., gelatin, polyvinylpyrrolidone, and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose and polyvinylpyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, cetyl, boric acid, sodium benzoate, and leucine), stabilizers (e.g., methylparaben, propylparaben, etc.), and flavoring agents (e.g., commonly used sweeteners, acidulants, and flavorings, etc.). When used parenterally, the drug can be formulated as an injection, comprising a sterile powder for injection and a solvent for injection. The carrier or excipient used may contain sterile water, Ringer's solution, and isotonic sodium chloride solution. Suitable adjuvants such as antioxidants, buffers, and antibacterial agents may also be added depending on the properties of the drug. When used for rectal administration, the drug can be formulated as suppositories, etc. When used for pulmonary administration, the drug can be formulated as an inhaler or spray, etc. Many resources are available to those skilled in the art describing pharmaceutically acceptable excipients and which can be used to select suitable pharmaceutically acceptable excipients, such as the Remington Pharmacy Encyclopedia, the Chinese Pharmaceutical Yearbook, and Pharmaceutics.

[0085] In this invention, the compounds and their stereoisomers described are all within the scope of protection, including but not limited to enantiomers, diastereomers, and cis-trans isomers. Therefore, the compounds protected by this invention include not only all possible single stereoisomers, but also their optically active mixtures and racemates. Furthermore, those skilled in the art will understand that different stereoisomers may exhibit significant differences in biological activity, pharmacodynamics, and toxicity; therefore, selecting specific stereoisomers or combinations thereof may optimize therapeutic effects. Stereoisomers can be obtained by known chemical or physical methods, such as chiral catalysis, chiral synthesis, or chiral resolution by chromatographic or chemical methods. This invention also includes stereoisomers obtained by these methods and their pharmaceutically acceptable salts.

[0086] The correspondence between compound codes and compound names is shown in Table 1: Table 1

[0087] Example 1: Synthesis of 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-6-yl)-N-(4-(hydroxycarbamoyl)benzyl)-2H-1,2,3-triazol-4-carboxamide (11a)

[0088]

[0089] Step 1: Synthesis of Compound 2

[0090] Compound 1 (20.00 g, 66.34 mmol) and thionyl chloride (40 mL) were mixed, and DMF (0.5 mL) was added. The mixture was refluxed. After the reaction was completed by TLC [dichloromethane / methanol = 5 / 1 (v / v)], heating was stopped, the reaction solution was cooled to room temperature, and thionyl chloride was removed by vacuum distillation. Dichloromethane (10 mL) was added, and the mixture was stirred to disperse the solid. The dichloromethane was then removed by vacuum distillation. This process was repeated three times to remove residual thionyl chloride, yielding compound 2, a white solid of 20.08 g, with a yield of 98.0%.

[0091] Step 2: Synthesis of Compound 3

[0092] Compound 2 (20.00 g, 87.88 mmol), 3-chloro-4-fluoroaniline (15.31 g, 105.16 mmol), and acetonitrile (200 mL) were mixed and stirred under reflux. After the reaction was complete as detected by TLC [dichloromethane / methanol = 25 / 1 (v / v)], the reaction solution was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, collected, and dried to give target compound 3, a yellow solid of 22.10 g, yield 81.2%.

[0093] Step 3: Synthesis of compound 4a

[0094] Compound 3 (19.50 g, 63.26 mmol), (tetrahydro-2H-pyran-4-yl)methanol (11.28 g, 97.25 mmol), potassium tert-butoxide (21.00 g, 187.15 mmol), and DMSO (200 mL) were mixed and stirred at room temperature. After the reaction was complete as determined by TLC [dichloromethane / methanol = 15 / 1 (v / v)], water (400 mL) was added to the reaction mixture, and the mixture was stirred until a solid precipitated. The solid was filtered, collected, and dried to give the target compound 4a as a yellow solid, yielding 9.70 g (42.1%).

[0095] Step 4: Synthesis of compound 5a

[0096] Compound 4a (9.00 g, 24.70 mmol), iron powder (5.50 g, 98.21 mmol), ethanol (120 mL), water (120.0 mL), and acetic acid (15 mL) were mixed and refluxed. After the reaction was completed by TLC [dichloromethane / methanol = 15 / 1 (v / v)], the mixture was extracted with ethyl acetate (150 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give the target compound 5a as a yellow solid, 7.90 g, yield 95.6%.

[0097] Step 5: Synthesis of compound 6a

[0098] Compound 5a (1.87 g, 3.53 mmol) was dissolved in 20 mL of water and 3.7 mL of concentrated hydrochloric acid. The mixture was cooled to 0 °C and a solution of sodium nitrite (0.87 g, 12.7 mmol) in 10 mL of water was added dropwise. After stirring for 5 minutes, the solution was added dropwise to a solution of ethyl-(2E)-3-(dimethylamino)acrylate (2.0 mL, 14 mmol) and potassium acetate (1.87 g, 19.0 mmol), 30 mL of ethanol, and the mixture was kept at 0 °C. The mixture was stirred at room temperature for one hour, then diluted with ethyl acetate, washed twice with water, and once with brine. The organic phase was dried over sodium sulfate, filtered, and evaporated to give compound 6a (3.20 g, 83% yield).

[0099] Step 6: Synthesis of compound 7a

[0100] Compound 6a (3.20 g, 10.6 mmol), hydroxylamine hydrochloride (881 mg, 12.7 mmol), and potassium acetate (2.59 g, 26.4 mmol) were dissolved in 46 mL of ethanol and stirred at 80°C for 30 min. The reaction mixture was diluted with ethyl acetate, washed twice with water, and then once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dried under vacuum to give compound 7a (3.17 g, 82% yield).

[0101] Step 7: Synthesis of compound 8a

[0102] 7a (3.17 g, 8.66 mmol) was stirred in 44 mL of acetic anhydride for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. The mixture was purified by silica gel chromatography to give 8a (1.96 g, 83% yield).

[0103] Step 8: Synthesis of compound 9a

[0104] Dissolve 8a (0.5 g, 1.03 mmol) in ethanol (15 mL), then add 10% sodium hydroxide solution (15 mL), stir at room temperature for 2 hours, adjust pH with 1M hydrochloric acid to weakly acidic, a light yellow solid precipitates, filter and collect filter cake, dry to obtain light yellow solid 9a (0.35 g, yield 74%).

[0105] Step 9: Synthesis of compound 10a

[0106] 9a (0.3 g, 0.65 mmol) was dissolved in 25 mL of DMF, methyl 4-(aminomethyl)benzoate (0.2 g, 1.21 mmol) was added, followed by HBTU (0.40 g, 1.05 mmol) and DMAP (0.24 g, 1.96 mmol). The mixture was stirred at room temperature for 4 hours. A yellow solid precipitated upon the addition of water. The solid was filtered and the filter cake was dried to give compound 10a (0.19 g, 51% yield).

[0107] Step 10: Synthesis of compound 11a

[0108] Potassium hydroxide (5.61 g, 100 mmol) was dissolved in 14 mL of methanol, and hydroxylamine hydrochloride (4.67 g, 67 mmol) was dissolved in 24.0 mL of methanol. The methanol solution of potassium hydroxide was added to the methanol solution of hydroxylamine hydrochloride at 0 °C, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The above filtrate (25.0 mL) was added to compound 10a, and the reaction was allowed to proceed at room temperature. After the reaction was complete as detected by TLC [dichloromethane / methanol = 15 / 1 (v / v)], dilute hydrochloric acid was added to adjust the pH to approximately 7. A large amount of solid precipitated out. The solid was filtered, the filter cake was collected, and dried to obtain the target compound 11a, a dark brown solid of 0.26 g, with a yield of 29.3%. 1 H NMR (600 MHz, DMSO-d6) δ 9.29 (t, J = 6.2 Hz, 1H), 9.01 (s, 1H), 8.95 (s, 1H), 8.59 (s,1H), 8.06 (d, J = 9.4 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.58 – 7.52 (m, 1H), 7.38 (d, J = 8.3 Hz, 2H), 4.52 (d, J = 6.2 Hz, 1H), 4.31 (s, 1H), 4.15 (d, J= 6.2 Hz, 2H), 3.81 (d, J = 28.9 Hz, 2H), 3.26 (t, J = 10.7 Hz, 2H), 2.89 (d,J = 14.7 Hz, 1H), 2.68 (d, J = 6.3 Hz, 1H), 2.40 (d, J = 14.7 Hz, 1H), 2.23(d, J = 18.0 Hz, 1H), 1.93 (t, J = 4.5 Hz, 1H), 1.79 (d, J = 18.1 Hz, 1H), 1.55 (d, J = 10.7 Hz, 1H), 1.34 – 1.21 (m, 3H).

[0109] HRMS: [M +H] + calcd for C 31 H 29 ClFN8O5, 647.1928, found 647.1924

[0110] Example 2: Synthesis of (S,E)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-N-(4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)-2H-1,2,3-triazol-4-carboxamide (11b)

[0111]

[0112] Prepared using the method described in Example 1, the difference being that (tetrahydro-2H-pyran-4-yl)methanol in step 3 was replaced with an equimolar amount of (S)-tetrahydrofuran-3-ol and methyl 4-(aminomethyl)benzoate in step 9 was replaced with an equimolar amount of methyl(E)-3-(4-(aminomethyl)phenyl)acrylate, yielding a white solid with a yield of 36.1%. 1 H NMR (600MHz, DMSO-d6) δ 9.29 (s, 1H), 8.99 (s, 1H), 8.91 (s, 1H), 8.58 (s, 1H), 8.09(d, J = 9.4 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 3.81 (d, J = 7.9 Hz, 2H), 3.26 (t, J = 10.7 Hz, 2H), 2.87 (d, J = 14.7 Hz, 1H), 2.38 (d, J = 14.7 Hz, 1H), 1.93 (t, J = 4.5Hz, 1H), 1.79 (d, J = 18.1 Hz, 1H), 1.57 – 1.53 (m, 2H), 1.27 (d, J = 7.4 Hz,2H).

[0113] HRMS: [M +H] + calcd for C 31 H 27ClFN8O5, 645.1771, found 645.1761.

[0114] Example 3: Synthesis of 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)-N-(4-(hydroxycarbamoyl)benzyl)-2H-1,2,3-triazol-4-carboxamide (11c)

[0115]

[0116] Prepared using the method described in Example 1, the difference being that (tetrahydro-2H-pyran-4-yl)methanol in step 3 was replaced with an equimolar amount of (tetrahydrofuran-2-yl)methanol, yielding a white solid with a yield of 35.1%. 1 H NMR (600 MHz, DMSO-d6) δ 11.48 (s, 1H), 11.18 (s, 1H), 8.99 (d, J = 20.5 Hz, 2H), 8.52 (s, 1H), 8.05 (d, J = 4.4 Hz, 1H), 7.77 – 7.65 (m, 1H), 7.60 – 7.52 (m, 2H), 4.32 –4.24 (m, 1H), 4.20 (t, J = 8.6 Hz, 1H), 3.71 – 3.59 (m, 3H), 3.49 – 3.43 (m,1H), 2.90 (d, J = 14.7 Hz, 1H), 2.67 (t, J = 10.7 Hz, 1H), 2.41 (d, J = 14.7Hz, 1H), 2.24 (d, J = 18.0 Hz, 1H), 1.94 (t, J = 5.0 Hz, 2H), 1.80 (d, J =18.1 Hz, 1H), 1.64 (dd, J = 12.8, 6.5 Hz, 1H), 1.35 – 1.25 (m, 3H).

[0117] HRMS: [M +H] + calcd for C 30 H 27 ClFN8O5, 633.1771, found 633.1704.

[0118] Example 4: Synthesis of (E)-N-(4-(3-((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)-2H-1,2,3-triazol-4-carboxamide (11d)

[0119]

[0120] Prepared using the method described in Example 1, the difference being that (tetrahydro-2H-pyran-4-yl)methanol in step 3 of Example 1 was replaced with an equimolar amount of sodium methoxide, and methyl 4-(aminomethyl)benzoate in step 9 was replaced with an equimolar amount of methyl(E)-3-(4-(aminomethyl)phenyl)acrylate, yielding 9d white solid with a yield of 36.1%. 9d (1.2 g, 2.11 mmol) was dissolved in ethanol, and an equal volume of 10% NaOH solution was added. The mixture was stirred at room temperature for 2 hours, the pH was adjusted to neutral, and the mixture was filtered to obtain 10d pale yellow solid (1.0 g, yield 86.2%).

[0121] Dissolve 10d (1.0 g, 1.87 mmol) in 15 mL of DMF, add o-phenylenediamine (0.21 g, 1.87 mmol), HBTU (0.85 g, 2.24 mmol) and DMAP (0.27 g, 2.24 mmol), stir at room temperature for 4 hours, add water and filter to obtain 11d yellow solid (1.0 g, yield 83.3%). 1 H NMR (600 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.39 (s, 1H), 9.34 (t, J = 6.2 Hz, 1H), 8.86 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.19 (dd,J = 6.9, 2.7 Hz, 1H), 7.81 (dt, J = 7.4, 3.2 Hz, 1H), 7.59 (d, J = 7.9 Hz,2H), 7.56 – 7.49 (m, 2H), 7.45 (t, J = 9.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 2H),7.33 (d, J = 7.8 Hz, 1H), 6.94 – 6.84 (m, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.58(t, J = 7.6 Hz, 1H), 4.51 (d, J = 6.2 Hz, 2H), 3.98 (s, 3H), 1.23 (d, J = 2.2Hz, 2H).

[0122] HRMS: [M +H] + calcd for C 34 H 28 ClFN9O3, 664.1982, found 664.1975.

[0123] Example 5: Synthesis of (R,E)-N-(4-(3-((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide (11e)

[0124]

[0125] Prepared using the method described in Example 4, the difference being that only the (tetrahydro-2H-pyran-4-yl)methanol in step 3 of Example 1 was replaced with an equimolar amount of (S)-tetrahydrofuran-3-ol, yielding a grayish-white solid with a yield of 26.1%. 1 H NMR (600MHz, DMSO-d6) δ 10.02 – 9.88 (m, 2H), 9.39 (s, 1H), 9.31 (t, J = 6.2 Hz, 1H), 8.90 (d, J = 13.0 Hz, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.19 (dd, J = 6.7, 3.0Hz, 1H), 7.81 (dd, J = 6.6, 2.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.53 (d, J= 4.5 Hz, 1H), 7.51 (s, 1H), 7.45 (t, J = 9.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 6.5 Hz, 1H), 6.95 – 6.87 (m, 1H), 6.75 (d, J = 6.5 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 5.39 (s, 1H), 4.95 (s, 2H), 4.52 (d, J = 6.3 Hz,2H), 3.95 (dd, J = 10.4, 4.9 Hz, 1H), 3.83 – 3.67 (m, 4H), 2.37 – 2.17 (m,1H), 2.01 – 1.90 (m, 1H).

[0126] HRMS: [M +H] + calcd for C 37 H 32 ClFN9O4, 720.2244, found 720.2232.

[0127] Example 6: Synthesis of N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide (11f)

[0128]

[0129] Prepared using the method described in Example 4, the difference being that only the (tetrahydro-2H-pyran-4-yl)methanol in step 3 of Example 1 is replaced with an equimolar amount of (tetrahydrofuran-2-yl)methanol, yielding a grayish-white solid with a yield of 36.4%. 1 H NMR (600MHz, DMSO-d6) δ 10.12 (s, 1H), 9.69 (s, 1H), 9.41 (t, J = 6.3 Hz, 1H), 9.02(s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.24 (d, J = 4.2 Hz, 1H), 7.97 (d, J =8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J = 4.6 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.01 – 6.94 (m, 1H), 6.79 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 4.56 (d, J = 6.2 Hz, 2H), 4.27 – 4.19 (m, 1H), 4.19– 4.12 (m, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.67 (t, J = 7.9 Hz, 1H), 3.62 (q,J = 6.8 Hz, 2H), 3.49 – 3.43 (m, 2H), 1.99 (s, 1H), 1.91 (s, 1H), 1.69 – 1.60(m, 1H), 1.23 (s, 1H), 1.18 (t, J = 7.1 Hz, 1H).

[0130] HRMS: [M +H] + calcd for C 36 H 32 ClFN9O4, 708.2244, found 708.2241.

[0131] Example 7: Synthesis of N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide (11 g)

[0132]

[0133] Prepared using the method described in Example 4, the difference being that only the (tetrahydro-2H-pyran-4-yl)methanol in step 3 of Example 1 is replaced with an equimolar amount of (tetrahydro-2H-pyran-3-yl)methanol, yielding a grayish-white solid with a yield of 33.4%. 1 H NMR(600 MHz, DMSO-d6)δ9.96 (s, 1H), 9.63 (s, 1H), 9.37 (t, J = 6.2 Hz, 1H), 8.90(s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.20 (d, J = 4.2 Hz, 1H), 7.95 (d, J =7.9 Hz, 2H), 7.81 (d, J = 4.7 Hz, 1H), 7.49 (s, 1H), 7.45 (s, 3H), 7.17 (d, J=7.8 Hz, 1H), 7.00–6.95 (m, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 7.5Hz, 1H), 4.88 (s, 2H), 4.56 (d, J = 6.2 Hz, 3H), 4.15 (d, J = 15.1 Hz, 1H), 4.12–4.03 (m, 1H), 3.77–3.67 (m, 2H), 3.27 –3.21 (m, 1H), 3.19–3.11 (m, 1H),1.91 (s, 1H), 1.73 (d, J = 8.7 Hz, 1H), 1.53 (s, 1H), 1.46 (s, 1H), 1.31 (d,J = 9.1 Hz, 1H), 1.23 (s, 1H).

[0134] HRMS: [M +H] + calcd for C37 H 34 ClFN9O4, 722.2401, found 722.2354.

[0135] Example 8: Synthesis of 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-N-hydroxy-2H-1,2,3-triazol-4-carboxamide (11 h)

[0136]

[0137] Prepared using the method described in Example 1, the difference being that only the (tetrahydro-2H-pyran-4-yl)methanol in step 3 of Example 1 is replaced with an equimolar amount of (S)-tetrahydrofuran-3-ol, and steps 8 and 9 are skipped, yielding a grayish-white solid with a yield of 23.9%. 1 H NMR (600 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.97 (s, 1H), 9.29 (s, 1H), 8.85 (s, 1H), 8.69 (s, 1H), 8.47 (s, 1H), 8.19 (dd, J = 6.9, 2.6 Hz, 1H),7.85 – 7.75 (m, 1H), 7.54 – 7.36 (m, 2H), 5.37 (t, J = 5.4 Hz, 1H), 3.94 (dd,J = 10.5, 4.5 Hz, 1H), 3.77 – 3.66 (m, 3H), 2.32 – 2.18 (m, 1H), 1.99 – 1.83 (m, 1H).

[0138] HRMS: [M+H]+calcd for C 21 H 17 ClFN7O4,486.1088, found 486.1083.

[0139] Example 9: Synthesis of (S)-N-(2-aminophenyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide (11i)

[0140]

[0141] Prepared using the method described in Example 4, the difference being that only the (tetrahydro-2H-pyran-4-yl)methanol in step 3 of Example 1 is replaced with an equimolar amount of (S)-tetrahydrofuran-3-ol, and steps 8 and 9 are skipped, yielding a grayish-white solid with a yield of 42.1%. 1 H NMR (600 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.91 (s, 1H), 8.90 (s, 1H), 8.69 (s, 1H), 8.64 (s, 1H), 8.19 (dd, J = 6.9, 2.7 Hz, 1H), 7.81 (ddd, J =9.1, 4.3, 2.6 Hz, 1H), 7.52 (s, 1H), 7.45 (t, J = 9.1 Hz, 1H), 7.24 (dd, J =7.8, 1.5 Hz, 1H), 7.03 – 6.96 (m, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.62 (t, J =6.8 Hz, 1H), 5.44 – 5.33 (m, 1H), 4.95 (s, 2H), 3.95 (dd, J = 10.5, 4.6 Hz,1H), 3.87 – 3.72 (m, 3H), 2.30 (td, J = 14.2, 8.2 Hz, 1H), 1.98 (dt, J =12.5, 5.6 Hz, 1H).

[0142] HRMS: [M +H] + calcd for C 27 H 23 ClFN8O3, 561.1608, found 561.1533.

[0143] Example 10: Synthesis of N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)amino)methyl)benzamide (11j)

[0144]

[0145] Step 1: Synthesis of Compound 2

[0146] Compound 1 (30.00 g, 99.36 mmol) was mixed with thionyl chloride (1 mL), and DMF (0.5 mL) was added. The mixture was refluxed. After the reaction was completed by TLC [dichloromethane / methanol = 5 / 1 (v / v)], heating was stopped, the reaction solution was cooled to room temperature, and thionyl chloride was removed by vacuum distillation. Dichloromethane (10 mL) was added, and the mixture was stirred to disperse the solid. The dichloromethane was then removed by vacuum distillation. This process was repeated three times to remove residual thionyl chloride, yielding compound 2, a white solid of 30.12 g, with a yield of 98.0%.

[0147] Step 2: Synthesis of Compound 3

[0148] Compound 2 (20.00 g, 87.88 mmol), 3-chloro-4-fluoroaniline (15.31 g, 105.16 mmol), and acetonitrile (200 mL) were mixed and stirred under reflux. After the reaction was complete as detected by TLC [dichloromethane / methanol = 25 / 1 (v / v)], the reaction solution was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, collected, and dried to give target compound 3, a yellow solid of 22.10 g, yield 81.2%.

[0149] Step 3: Synthesis of compound 4j

[0150] Compound 3 (19.50 g, 63.26 mmol), sodium methoxide (5.2 g, 97.25 mmol), potassium tert-butoxide (21.00 g, 187.15 mmol), and DMSO (200 mL) were mixed and stirred at room temperature. After the reaction was complete as detected by TLC [dichloromethane / methanol = 15 / 1 (v / v)], water (400 mL) was added to the reaction mixture, and the mixture was stirred, resulting in the precipitation of a solid. The solid was filtered, collected, and dried to give the target compound 4j, a yellow solid, in a yield of 9.70 g (42.1%).

[0151] Step 4: Synthesis of compound 5j

[0152] Compound 4j (8.54 g, 24.70 mmol), iron powder (5.50 g, 98.21 mmol), ethanol (120 mL), water (120.0 mL), and acetic acid (15 mL) were mixed and refluxed. After the reaction was completed by TLC [dichloromethane / methanol = 15 / 1 (v / v)], the mixture was extracted with ethyl acetate (150 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give the target compound 5j, a yellow solid, 7.90 g, yield 85.6%.

[0153] Step 5: Synthesis of compound 6j

[0154] Compound 5j (7.9 g, 24.79 mmol), potassium carbonate (5.13 g, 37.19 mmol), methyl 4-(bromomethyl)benzoate (5.7 g, 24.79 mmol), and acetone were refluxed in the solvent. After the reaction was completed by TLC [dichloromethane / methanol = 15 / 1 (v / v)], the mixture was extracted with ethyl acetate (150 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give the target compound 6j, a yellow solid, 7.80 g, yield 67.6%.

[0155] Step 6: Synthesis of compound 7j

[0156] Dissolve 6j (1.1g, 2.09mmol) in ethanol, add an equal volume of 10% NaOH solution, stir at room temperature for 2 hours, adjust the pH to neutral, and filter to obtain 7j (1.0g, yield 86.2%), a light yellow solid.

[0157] Step 7: Synthesis of compound 11j

[0158] Dissolve 7j (1.0g, 1.87mmol) in 15 mL of DMF, add o-phenylenediamine (0.21g, 1.87mmol), HBTU (0.85g, 2.24mmol) and DMAP (0.27g, 2.24mmol), stir at room temperature for 4 hours, add water and filter to obtain 11j yellow solid (1.0g, yield 83.3%). 1 H NMR (600 MHz, DMSO-d6) δ 9.67 (d, J = 13.3 Hz, 2H), 8.55 (s, 1H), 8.14 (dd, J = 6.8, 2.7 Hz, 1H), 8.04 (d, J = 7.3 Hz, 3H), 7.81(ddd, J = 9.1, 4.3, 2.6 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.47 (t, J = 9.1Hz, 1H), 7.26 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.98 (td, J = 7.6, 1.6 Hz,1H), 6.79 (dd, J = 8.0, 1.5 Hz, 1H), 6.60 (td, J = 7.5, 1.5 Hz, 1H), 5.34 (s,2H), 3.96 (s, 3H), 2.89 (s, 1H), 2.73 (s, 1H), 1.23 (s, 1H).HRMS: [M +H]+calcd for C 29 H25 ClFN6O2, 543.1706, found 543.1691.

[0159] Example 11: Synthesis of N-(2-aminophenyl)-5-(((4-(((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)amino)methyl)pyrazine-2-carboxamide (11k)

[0160]

[0161] Prepared using the method described in Example 10, the difference being that only the methyl 4-(bromomethyl)benzoate in step 5 is replaced with an equimolar amount of methyl 5-(bromomethyl)pyrazine-2-carboxylic acid, yielding a grayish-white solid with a yield of 66.8%. 1 H NMR (600 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.60 (s, 1H), 9.31 (d, J = 1.4 Hz, 1H), 9.01 (d, J = 1.4 Hz, 1H), 8.54 (s, 1H), 8.16 – 8.03 (m, 2H), 7.80 (d, J = 2.1Hz, 1H), 7.48 – 7.36 (m, 2H), 7.29 (s, 1H), 7.06 – 6.96 (m, 1H), 6.82 (d, J =9.4 Hz, 1H), 6.65 (t, J = 6.8 Hz, 1H), 5.56 (s, 2H), 4.00 (s, 3H), 3.18 (s,1H), 1.24 (d, J = 19.1 Hz, 2H).

[0162] HRMS: [M +H] + calcd for C 27 H 23 ClFN8O2, 545.1611, found 545.1481.

[0163] Example 12: Synthesis of (R)-N-(2-aminophenyl)-4-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)amino)-2-oxoethyl)benzamide (11l)

[0164]

[0165] Prepared using the method described in Example 10, the difference being that only the sodium methoxide in step 3 is replaced with an equimolar amount of (S)-tetrahydrofuran-3-ol, and the methyl 4-(bromomethyl)benzoate in step 5 is replaced with an equimolar amount of 2-(4-(methoxycarbonyl)phenyl)acetic acid, yielding a grayish-white solid with a yield of 56.3%.

[0166] 1H NMR (600 MHz, DMSO-d6) δ 9.62 (d, J = 52.6 Hz, 2H), 9.12 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.58 (s, 2H), 7.51 (s,2H), 7.23 (s, 1H), 7.13 (d, J = 7.7 Hz, 2H), 6.96 (d, J = 7.4 Hz, 2H), 6.77(d, J = 4.7 Hz, 2H), 6.58 (s, 1H), 5.93 (s, 2H), 4.66 (s, 2H), 3.99 (s, 2H),2.89 (s, 2H), 2.73 (s, 2H).

[0167] HRMS: [M +H] + calcd for C 33 H 29 ClFN6O4, 627.1917, found 627.1884.

[0168] Example 13: (R,E)-3-(4-(((4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)amino)methyl)phenyl)-N-hydroxyacrylamide (11m)

[0169]

[0170] Prepared using the method described in Example 10, the difference being that only the sodium methoxide in step 3 is replaced with an equimolar amount of (S)-tetrahydrofuran-3-ol, and the methyl 4-(bromomethyl)benzoate in step 5 is replaced with an equimolar amount of methyl (E)-4-(3-methoxy-3-oxoprop-1-en-1-yl)benzoate, yielding a yellow solid with a yield of 47.9%.

[0171] 1H NMR (500 MHz, Chloroform-d) δ 9.52 (d, J = 4.8 Hz, 1H), 8.61 (s,1H), 8.51 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 7.91 – 7.86 (m, 2H), 7.69–7.63(m, 2H), 7.56–7.49 (m, 2H), 7.29 (m, 2H), 7.25 (s, 1H), 7.17 – 7.10 (m, 1H), 6.72 (d, J = 15.0 Hz, 1H), 5.89 (t, J = 8.2 Hz, 1H), 4.44 (m, 2H), 4.23 (p, J= 7.0 Hz, 1H), 3.94 (dd, J = 12.6, 6.9 Hz, 1H), 3.87 (dd, J = 12.2, 7.0 Hz, 1H), 3.84 – 3.72 (m, 2H), 2.29 – 2.13 (m, 2H).

[0172] HRMS: [M +H] + calcd for C 28 H 26 ClFN5O4, 550.1652, found 550.1624.

[0173] Example 14: Synthesis of 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethylbenzoylhydrazine (11n)

[0174] Step 1: Synthesis of compound 2n

[0175] Compound 1n (7.8 g, 24.79 mmol), potassium carbonate (5.13 g, 37.19 mmol), methyl 4-(bromomethyl)benzoate (5.7 g, 24.79 mmol), and acetone were refluxed in the solvent. After the reaction was completed by TLC [dichloromethane / methanol = 15 / 1 (v / v)], the mixture was extracted with ethyl acetate (150 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give the target compound 2n as a yellow solid, 7.50 g, yield 65.6%.

[0176] Step 2: Synthesis of compound 3n

[0177] Dissolve 2n (1.0 g, 2.09 mmol) in ethanol, add an equal volume of 10% NaOH solution, stir at room temperature for 2 hours, adjust the pH to neutral, and filter to obtain a light yellow solid 3n (1.0 g, yield 75.2%).

[0178] Step 3: Synthesis of compound 11n

[0179] Dissolve 3n (1.0 g, 1.87 mmol) in 15 mL of DMF, add ethylhydrazine (0.11 g, 1.87 mmol), HBTU (0.85 g, 2.24 mmol) and DMAP (0.27 g, 2.24 mmol), stir at room temperature for 4 hours, add water and filter to obtain 11n yellow solid (0.9 g, yield 63.9%). 1 H NMR (600 MHz, DMSO-d6) δ 10.06 (d, J = 6.3 Hz, 1H),9.64 (s, 1H), 8.52 (s, 1H), 8.15 (dd, J = 6.8, 2.7 Hz, 1H), 8.02 (s, 1H),7.89 (d, J = 8.2 Hz, 2H), 7.85 – 7.79 (m, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.46(d, J = 9.1 Hz, 1H), 7.24 (s, 1H), 5.29 (s, 2H), 5.09 (d, J = 6.1 Hz, 1H),3.95 (s, 3H), 2.86 – 2.79 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H).

[0180] HRMS: [M +H] + calcd for C 25 H 24 ClFN5O3, 496.1546, found 496.1515.

[0181] Example 15: Synthesis of N-(2-aminophenyl)-6-(((4-(((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxy)methyl)nicotinamide (11o)

[0182]

[0183] Prepared using the method described in Example 10, the difference being that only methyl 4-(bromomethyl)benzoate in step 5 is replaced with an equimolar amount of methyl bromomethylnicotinate, yielding a grayish-white solid with a yield of 76.1%. 1H NMR (600 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.62 (s, 1H), 9.18 (d, J = 2.3 Hz, 1H), 8.54 (s,1H), 8.43 (d, J = 10.4 Hz, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 9.1 Hz, 1H), 7.29 (s, 1H), 7.19 (s,1H), 6.99 (t, J = 8.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 5.45 (s, 2H), 4.00 (s, 2H), 1.24 (d, J = 18.7 Hz, 3H).

[0184] HRMS: [M +H] + calcd for C 28 H 23 ClFN6O3,545.1499, found 545.1484.

[0185] Example 16: Synthesis of 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-2,5-difluorobenzoylhydrazine (11p)

[0186]

[0187] Prepared by the method described in Example 15, except that methyl 4-(bromomethyl)benzoate in step 1 was replaced with an equimolar amount of methyl 4-(bromomethyl)-2,5-difluorobenzoate, yielding a white solid with a yield of 45.2%. 1H NMR (600MHz, DMSO-d6) δ 9.90 (s, 1H), 9.60 (s, 1H), 8.53 (s, 1H), 8.14 (d, J = 4.2Hz, 1H), 8.02 (s, 1H), 7.82 – 7.78 (m, 1H), 7.61 (dd, J = 9.7, 5.6 Hz, 1H),7.50 (dd, J = 9.4, 5.4 Hz, 1H), 7.45 (t, J = 9.1 Hz, 1H), 7.25 (s, 1H), 5.30(s, 2H), 5.17 (s, 1H), 3.95 (s, 3H), 2.83 (d, J = 11.0 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H).

[0188] HRMS: [M +H] + calcd for C 25 H 22 ClF3N5O3, 532.1358, found 532.1326.

[0189] Example 17: Synthesis of 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-2-fluorobenzoylhydrazine (11q)

[0190]

[0191] Prepared by the method described in Example 15, except that methyl 4-(bromomethyl)benzoate in step 1 was replaced with an equimolar amount of methyl 4-(bromomethyl)-2-fluorobenzoate, yielding a white solid with a yield of 44.2%. 1H NMR (600 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.58 (s, 1H), 8.52 (s, 1H), 8.14 (d, J = 4.1 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.47(s, 1H), 7.45 (d, J = 4.1 Hz, 1H), 7.43 (s, 2H), 7.25 (s, 1H), 5.29 (s, 2H),5.15 (s, 1H), 3.95 (s, 3H), 2.83 (q, J = 7.1 Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H).

[0192] HRMS: [M+H] + calcd for C 25 H 23 ClF2N5O3, 514.1452, found 514.1424

[0193] Example 18: Synthesis of 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-3-fluorobenzoylhydrazine (11r)

[0194]

[0195] Prepared using the method described in Example 15, the difference being that methyl 4-(bromomethyl)benzoate in step 1 was replaced with an equimolar amount of methyl 4-(bromomethyl)-3-fluorobenzoate, yielding a white solid with a yield of 54.7%. 1 H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.61 (s, 1H), 8.53 (s, 1H), 8.14 (d, J = 4.1 Hz,1H), 8.04 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.76 (s, 2H), 7.72 (d, J = 10.6Hz, 1H), 7.46 (t, J = 9.1 Hz, 1H), 7.25 (s, 1H), 5.34 (s, 2H), 5.14 (s, 1H),3.94 (s, 3H), 2.83 (q, J = 7.1 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H).

[0196] HRMS: [M +H] + calcd for C 25 H 23 ClF2N5O3, 514.1452, found 514.1423.

[0197] Example 19: Synthesis of N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-2,5-difluorobenzamide (11s)

[0198]

[0199] Prepared by the method described in Example 15, the difference being that methyl 4-(bromomethyl)benzoate in step 1 was replaced with an equimolar amount of methyl 4-(bromomethyl)-2,5-difluorobenzoate, and ethyl hydrazine in step 3 was replaced with an equimolar amount of o-phenylenediamine to obtain a white solid with a yield of 55.1%. 1 H NMR (600 MHz, DMSO-d6)δ9.67 (s, 1H), 9.60 (s, 1H), 8.54 (s, 1H), 8.15 (d, J = 4.2 Hz, 1H), 8.05 (s, 1H), 7.84–7.79 (m,1H), 7.74 (dd, J = 9.4, 5.5 Hz, 1H), 7.67 (dd, J = 9.8, 5.5 Hz, 1H), 7.47 (t,J = 9.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.27 (s, 1H), 7.01–6.95 (m, 1H),6.79 (d, J = 9.3 Hz, 1H), 6.61 (t, J = 7.0 Hz, 1H), 5.35 (s, 2H), 4.98 (s,2H), 3.97 (s, 3H).

[0200] HRMS: [M +H] + calcd for C 29 H 22 ClF3N5O3, 580.1358, found 580.1324.

[0201] Example 20: Synthesis of N-(2-aminophenyl)-4-(((4-((3-ethynylphenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide (11t)

[0202]

[0203] Step 1: Synthesis of 2t

[0204] A mixture of 1 t (2.5 g, 2.55 mmol) and pyridine (4 mL) was dissolved in acetic anhydride (20 mL). The solution was stirred at 100°C for 6 hours. Cold water (200 mL) was added to the solution to precipitate the product. Stirring was continued for 20 minutes. The solution was cooled to room temperature. The solid was filtered and washed with water. A mixture of a quinazolone derivative (2.6 g, 2.55 mmol) and DMF (75 μL) was dissolved in SOCl2 (15 mL). The solution was stirred at 90°C for 2 hours. The solution was cooled to room temperature. The solution was concentrated, dragged three times by DCM, and then 2 t (2.3 g, yield 89.22%) of gray solid was obtained.

[0205] Step 2: Synthesis of 3t

[0206] Compound 2t (2.30 g, 2.18 mmol), 3-ethynylaniline (1.30 g, 1.16 mmol), and acetonitrile (20 mL) were mixed and stirred under reflux. After the reaction was complete as detected by TLC [dichloromethane / methanol = 25 / 1 (v / v)], the reaction solution was cooled to room temperature, filtered, the filter cake was washed with acetonitrile, collected, and dried to give the target compound 3t, 2.10 g of yellow solid, yield 83.2%.

[0207] Step 3: Synthesis of 4t

[0208] Dissolve 3t (2.1g, 1.99mmol) in ethanol, add an equal volume of 10% NaOH solution, stir at room temperature for 2 hours, adjust the pH to neutral, and filter to obtain 4t (1.7g, yield 86.2%) of light yellow solid.

[0209] The subsequent synthesis was carried out in accordance with steps 5, 6 and 7 of Example 10, yielding a pale yellow solid (1.1 g, yield 67.1%). 1H NMR (600 MHz, DMSO-d6)δ9.70 (s, 1H), 9.56 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 8.11–8.00 (m, 3H), 7.91 (d, J = 5.9 Hz, 1H), 7.69 (d, J = 8.1Hz, 2H), 7.37 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 7.26 (s, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.98 (t, J = 6.9 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H),6.61 (t, J = 7.5 Hz, 1H), 5.35 (s, 3H), 3.96 (s, 3H), 3.15 (s, 2H).HRMS: [M +H]+ calcd for C 31 H 26 N5O3, 516.2030, found 516.2007.

[0210] Example 21: Synthesis of N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-3-fluorobenzamide (11u)

[0211]

[0212] Prepared by the method described in Example 20, the difference being that 3-ethynylaniline in step 2 was replaced with an equimolar amount of 3-chloro-4-fluoroaniline, and methyl 4-(bromomethyl)benzoate in step 5 was replaced with an equimolar amount of methyl 4-(bromomethyl)-3-fluorobenzoate, yielding a white solid with a yield of 59.2%. 1H NMR (600 MHz, DMSO-d6)δ9.58 (s, 2H),8.53 (s, 1H), 8.15 (d, J = 4.2 Hz, 1H), 8.02 (s, 1H), 7.94 (d, J = 8.6 Hz,1H), 7.82 (t, J = 7.3 Hz, 2H), 7.51 (dd, J = 14.7, 9.4 Hz, 2H), 7.46 (t, J =9.0 Hz, 2H), 7.32 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 6.97 (t, J = 7.6 Hz,1H), 6.78 (d, J = 8.1 Hz, 1H), 6.61 (t, J = 7.5 Hz, 1H), 5.33 (s, 2H), 3.97 (s, 3H).

[0213] HRMS: [M +H] + calcd for C 29 H 23 ClF2N5O3, 562.1452, found 562.1421.

[0214] Example 22: Synthesis of N-(2-aminophenyl)-4-(((7-methoxy-4-((4-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)oxymethyl)benzamide (11v)

[0215]

[0216] Prepared using the method described in Example 20, the difference being that 3-ethynylaniline in step 2 was replaced with an equimolar amount of 4-trifluoromethylaniline, yielding a white solid with a yield of 49.5%. 1H NMR (600 MHz, DMSO-d6)δ9.81 (s,1H), 9.70 (s, 1H), 8.60 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 7.9Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.29 (s, 1H), 7.19 (d, J = 7.8 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.61 (t, J = 7.5 Hz, 1H), 5.37 (s, 2H), 3.97 (s, 3H).

[0217] HRMS: [M +H] + calcd for C 30 H 25 F3N5O3, 560.1904, found 560.1891.

[0218] Example 23: Synthesis of N-(2-aminophenyl)-4-(((4-((3-ethynyl-4-methylphenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide (11w)

[0219]

[0220] Prepared using the method described in Example 20, the difference being that 3-ethynylaniline in step 2 was replaced with an equimolar amount of 3-ethynyl-4-methylaniline, yielding a white solid with a yield of 49.5%. 1H NMR (600 MHz, DMSO-d6)δ9.69(s, 1H), 9.48 (s, 1H), 8.51 (s, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.95 (d, J =2.4 Hz, 1H), 7.80 (d, J = 10.7 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.31 (d, J= 8.4 Hz, 1H), 7.24 (s, 1H), 7.19 (d, J = 9.2 Hz, 1H), 7.01–6.95 (m, 1H), 6.79 (d, J = 6.6 Hz, 1H), 6.60 (t, J = 8.3 Hz, 1H), 5.34 (s, 2H), 4.39 (s,1H), 3.95 (s, 3H), 2.38 (s, 3H), 1.98 (s, 1H), 1.21 (s, 1H), 1.17 (t, J = 7.1Hz, 1H).

[0221] HRMS: [M +H] + calcd for C 32 H 28 N5O3, 530.2187, found 530.2172.

[0222] Example 24: Synthesis of N-(2-aminophenyl)-4-(((4-((3-bromophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide (11x)

[0223]

[0224] Prepared using the method described in Example 20, the difference being that 3-ethynylaniline in step 2 was replaced with an equimolar amount of 3-bromoaniline, yielding a white solid with a yield of 55.5%. 1H NMR (600 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.64 (s, 1H), 8.86 (s, 1H), 8.81 (s, 1H), 8.19 (d, J = 8.1 Hz, 2H), 7.94 (s,1H), 7.86 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 6.6 Hz,1H), 7.53 (d, J = 6.5 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 7.2 Hz,2H), 7.37 – 7.30 (m, 1H), 5.52 (s, 2H), 4.28 (s, 1H), 4.00 (s, 3H), 3.20 (d,J = 40.9 Hz, 1H), 2.88 (s, 1H).

[0225] HRMS: [M +H] + calcd for C 29 H 25 BrN5O3,570.1135, found 570.1108.

[0226] Example 25 Screening experiment for in vitro antitumor proliferation inhibitory activity

[0227] In this embodiment, the CCK-8 assay was used as the detection method for this experiment. This method is based on the fact that WST-8 (2-(2-methoxy-4-nitrobenzene)-3-(4-nitrobenzene)-5-(2,4-disulfonylbenzene)-2H-tetrazole monosodium salt) dye can be reduced by dehydrogenases in mitochondria to an orange-yellow water-soluble formazan dye. The amount of formazan produced is directly proportional to the number of live cells, and the intensity of the solution color has a linear relationship with the number of cells. Therefore, the number of live cells can be compared by comparing the intensity of the solution color.

[0228] Specific experimental procedure:

[0229] 1) Select human breast cancer MDA-MB-453 cell line in the logarithmic growth phase and with good cell condition for the experiment. Remove the original culture medium in the culture flask and wash three times with 2 mL PBS.

[0230] 2) Add 1 mL of trypsin for digestion. After most cells have detached, add 2 mL of complete culture medium (DMEM (Thermo Fisher, batch number: 6125218) + 10% FBS) to stop the digestion. Gently pipette to allow all cells to detach completely and disperse into single cells.

[0231] 3) Transfer the cell suspension to a centrifuge tube, centrifuge at 1000 r / min for 5 min, discard the supernatant, add 1 mL of complete culture medium, mix well by pipetting, and adjust the cell density to obtain a cell density of 5 × 10⁻⁶. 4 Cell suspension of cells / mL.

[0232] 4) Seed cells into 96-well plates, adding 100 μL of cell suspension to each well. Place the 96-well plates in a cell culture incubator for 24 h.

[0233] 5) Discard the original culture medium and add 100 μL of culture medium solution containing different concentrations (10, 2, 0.4, 0.08, 0.016, 0.003 μM) of the compound. Continue to incubate in the incubator for 72 h.

[0234] 6) Add 10 μL of CCK-8 solution to each well, incubate for 1.5 h, and use a microplate reader to measure the OD value of each well at a wavelength of 450 nm.

[0235] 7) Process the data according to the following calculation formula:

[0236]

[0237] The compound's half-maximal inhibitory concentration (IC50) against tumor cells 50 The values ​​were obtained using GraphPad Prism9 software.

[0238] Experimental results:

[0239] IC50 assay of compounds in compounds 11a-11x against MDA-MB-453 cells 50 The test results are shown in Table 2:

[0240] Table 2

[0241]

[0242] The results showed that the compound provided in this application has a certain anti-tumor effect, which is superior to the control drug gefitinib, proving that the compound provided in this application has the potential to prepare anti-tumor drugs.

[0243] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A quinazoline compound, its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, Its structure is shown in Equation I: ; Formula I Where L is selected from —O—, —NH— or —CONH—; M is either N or C; R1 is , , , , -OH or ; n1, n2, n3, n4 are selected from 0, 1, 2, 3, 4 or 5; Ring A1 is a 5-6 membered heteroaryl or Ra-substituted aryl containing 1-3 N atoms; Ring A2 is an aryl group substituted with Ra; Ra is a monosubstituted or polysubstituted group, independently selected from H or halogen; R5 is -OH or -NR x R y ; R x R y Independently selected from H or C1-C5 alkyl groups; R2 is H, halogen, C1-C5 alkyl, or C1-C5 alkyl with 1-3 halogen substituted. R3 is H, halogen, C2-C5 alkenyl or C2-C5 alkynyl; R4 is selected from C1-C5 alkyl groups. , , , or .

2. The quinazoline compound, its pharmaceutically acceptable salt, or its stereoisomer according to claim 1, characterized in that, The C1-C5 alkyl group is selected from —CH3, —CH2CH3, —CH(CH3)2, —(CH2)2CH3, —(CH2)3CH3, —CH2CH(CH3)2, —C(CH3)3, —CH(CH3)CH2CH3, —(CH2)4CH3, —CH(CH3)(CH2)2CH3, —CH(CH2CH3)2, —CH2C(CH2)3, —CH2CH(CH3)CH2CH3, —C(CH3)2CH2CH3, —CH(CH3)CH(CH3)2 or —(CH2)2CH(CH3)2; The halogen is selected from F, Cl, Br or I; The 5-6 membered heteroaryl group containing 1-3 N is selected from pyrrole, pyridine, pyrimidine or pyrazine; The 1-3 halogen-substituted C1-C5 alkyl groups are selected from —CF3, —CH2CF3, —(CH2)2CF3, —(CH2)3CF3 or —(CH2)4CF3; C2-C5 alkenyl groups are selected from vinyl, isopropenyl, n-propenyl, n-butenyl, isobutenyl, sec-butenyl, n-pentenyl, or isopentenyl. The C2-C5 ynyl groups are selected from ethynyl, propynyl, butynyl, or penynyl.

3. The quinazoline compound, its pharmaceutically acceptable salt, or its stereoisomer according to claim 1, characterized in that, L is selected from —O—, —NH— or —CONH—; M is either N or C; R1 is , , , , -OH or ; n1, n2, n3, n4 are selected from 0 or 1; Ring A1 is a 5-6 membered heteroaryl group or Ra-substituted benzene ring containing 1-3 N atoms; Ring A2 is a Ra-substituted benzene ring Ra is a monosubstituted or polysubstituted group, independently selected from H or F; R5 is -OH or -NR x R y ; R x R y Independently selected from H or C1-C5 alkyl groups; R2 is H, halogen, methyl, or trifluoromethyl; R3 is H, halogen, or acetylene group; R4 is selected from methyl, , , , or .

4. The quinazoline compound, its pharmaceutically acceptable salt, or its stereoisomer according to claim 1, characterized in that, The structure of ring A1 is selected from the following: , , , or ; The structure of ring A2 is selected from the following: , , or .

5. The quinazoline compound, its pharmaceutically acceptable salt, or its stereoisomer according to claim 1, characterized in that, The compound is selected from the following structures: 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-6-yl)-N-(4-(hydroxycarbamoyl)benzyl)-2H-1,2,3-triazol-4-carboxamide; (S,E)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-N-(4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)-2H-1,2,3-triazol-4-carboxamide; 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)-N-(4-(hydroxycarbamoyl)benzyl)-2H-1,2,3-triazol-4-carboxamide; (E)-N-(4-(3-((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)-2H-1,2,3-triazol-4-carboxamide; (R,E)-N-(4-(3-((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide; N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide; N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydro-2H-pyran-3-yl)methoxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide; 2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-N-hydroxy-2H-1,2,3-triazol-4-carboxamide; (S)-N-(2-aminophenyl)-2-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-2-yl)oxy)quinazolin-6-yl)-2H-1,2,3-triazol-4-carboxamide; N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)amino)methyl)benzamide; N-(2-aminophenyl)-6-(((4-(((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)amino)methyl)nicotinamide; N-(2-aminophenyl)-5-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)amino)methyl)pyrazine-2-carboxamide; (R)-N-(2-aminophenyl)-4-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)amino)-2-oxoethyl)benzamide; (R,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzamide; 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethylbenzoylhydrazine; 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-2,5-difluorobenzoylhydrazine; 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-2-fluorobenzoylhydrazine; 4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-N'-ethyl-3-fluorobenzoylhydrazine; N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-2,5-difluorobenzamide; N-(2-aminophenyl)-4-(((4-((3-ethynylphenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide; N-(2-aminophenyl)-4-(((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)-3-fluorobenzamide; N-(2-aminophenyl)-4-(((7-methoxy-4-((4-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)oxymethyl)benzamide; N-(2-aminophenyl)-4-(((4-((3-ethynyl-4-methylphenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide; N-(2-aminophenyl)-4-(((4-((3-bromophenyl)amino)-7-methoxyquinazoline-6-yl)oxymethyl)benzamide.

6. A composition comprising a quinazoline compound as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

7. The pharmaceutical composition according to claim 6, characterized in that, It also includes one or more pharmaceutically acceptable carriers or excipients.

8. The use of a quinazoline compound as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of an antitumor drug.

9. The application according to claim 8, characterized in that... The tumor is breast cancer.

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