Quinazoline compound and application thereof

Abstract

The invention relates to the technical field of medicines, and particularly discloses a quinazoline compound and application thereof. The quinazoline compound has a structure as shown in a formula (I), the compound or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutical composition containing the compound can effectively inhibit TNF-alpha induced apoptosis, and in tumor cell proliferation inhibitory activity research, the compound has a good application prospect. The compound has a relatively strong inhibition effect on MCF-7 cells, HepG2 cells, MIAPaCa-2 cells, PANC-1 cells and A375 cells, so that the proliferation of tumor cells can be inhibited; the compound can be used for preparing tumor prevention or treatment drugs, and has the prospect of being developed into novel antitumor drugs.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, in particular to a quinazoline compound and use thereof. Background Art

[0002] Cancer is a serious threat to human health. Currently, chemotherapy is one of the mainstays of cancer treatment, but it faces safety concerns and the development of long-term drug resistance, which can lead to chemotherapy failure. Quinazoline derivatives possess potent biological activities, including anti-inflammatory, antibacterial, and anticancer properties. Therefore, it is highly desirable to develop novel quinazoline compounds and explore their biological efficacy. Summary of the Invention

[0003] The purpose of the present invention is to provide a quinazoline compound and its use in response to the above-mentioned deficiencies in the prior art.

[0004] The first object of the present invention is to provide a compound of formula (I)

[0005]

[0006] or its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts, wherein:

[0007] R1 is selected from

[0008]

[0009] R2 selection

[0010] R3 is selected from wherein R5, R6, and R7 are selected from hydrogen bonds and halogen elements;

[0011] R8 is selected from methyl, propyl, isopropyl;

[0012] R4 is selected from

[0013] Furthermore, the compound has a structure shown in formula (II):

[0014]

[0015] Furthermore, the compound has a structure represented by formula (III):

[0016]

[0017] Furthermore, the compound has a structure represented by formula (IV):

[0018]

[0019] Furthermore, the compound has a structure represented by general formula (V):

[0020]

[0021] The second object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts; and a pharmaceutically acceptable excipient.

[0022] In a preferred embodiment of the present invention, the dosage form of the pharmaceutical composition is an oral dosage form or an injection, and the oral dosage form includes tablets, capsules, films, and granules.

[0023] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0024] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0025] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection ((such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0026] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0027] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0028] The pharmaceutical composition of the present invention can be used to prevent and / or treat pain. When using the pharmaceutical preparation of the present invention, other pain treatment agents such as fluoxetine, opioid analgesics, non-opioid analgesics, etc. can also be used simultaneously.

[0029] The pharmaceutical compositions of the present invention contain a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable carrier or excipient. Such carriers include (but are not limited to) one or more of saline, buffer, glucose, water, glycerol, ethanol, and powders. The pharmaceutical formulation should be compatible with the route of administration.

[0030] The pharmaceutical compositions of the present invention can be prepared in the form of injections, for example, using physiological saline or an aqueous solution containing glucose and other adjuvants by conventional methods. Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets, and capsules are preferably manufactured under sterile conditions. The pharmaceutical compositions of the present invention can also be prepared in the form of powders for aerosol inhalation.

[0031] The active ingredient is administered in a therapeutically effective amount, for example, about 1 μg / kg body weight to about 50 mg / kg body weight per day; preferably, about 5 μg / kg body weight to about 10 mg / kg body weight; and more preferably, about 10 μg / kg body weight to about 5 mg / kg body weight. In addition, the compounds of the present invention may also be used in conjunction with other therapeutic agents.

[0032] The pharmaceutical composition of the present invention can be administered to a desired subject (such as a human or non-human mammal) in a conventional manner. Representative administration methods include (but are not limited to): oral administration, injection, aerosol inhalation, and the like.

[0033] When using a pharmaceutical composition, a safe and effective amount of the drug is administered to a mammal, wherein the safe and effective amount is generally at least about 10 μg / kg body weight and, in most cases, does not exceed about 50 mg / kg body weight. Preferably, the dose is about 10 μg / kg body weight to about 20 mg / kg body weight. Of course, the specific dose will also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.

[0034] As used herein, the term "effective amount" refers to an amount of a compound that, when administered, will alleviate to some extent one or more symptoms of the condition being treated. Specifically, as used herein, an "effective amount" of a compound refers to an amount sufficient to inhibit tumor cell proliferation.

[0035] The dosing regimen can be adjusted to provide the optimum desired response. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values can vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the

[0036] As used herein, "treatment" refers to improving or otherwise altering in any manner the symptoms or pathology of a patient's condition, disorder, or disease. As described herein, "improving the symptoms of a particular disease by use of a particular compound or pharmaceutical composition" refers to any decrease, whether permanent or temporary, lasting or transient, that can be attributed to or associated with the use of that composition.

[0037] As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) who have a disease (e.g., a disease described herein) or normal individuals. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, farm animals, and / or laboratory animals (e.g., sheep, dog, cat, cow, pig, etc.).

[0038] In some embodiments, the pharmaceutical composition of the present application can further comprise one or more additional therapeutic or prophylactic agents.

[0039] A third object of the present application is to provide use of the above-mentioned compound or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a TNF-α inhibitor.

[0040] A fourth object of the present application is to provide use of the above-mentioned compound or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of an antitumor drug.

[0041] Further, the antitumor drug includes any one of an anti-breast cancer drug, an anti-liver cancer drug, or an anti-human melanoma drug.

[0042] Further, the only effective component of the antitumor drug is a compound of the structure shown in formula (II).

[0043] Compared with the prior art, the present application has the following beneficial effects:

[0044] The compound provided by the application has structural originality, can effectively inhibit TNF-alpha induced cell apoptosis, has strong inhibitory effect on MCF-7 cells, HepG2 cells, MIAPaCa-2 cells, PANC-1 cells and A375 cells in the study of tumor cell proliferation inhibition activity, thereby being capable of inhibiting the proliferation of tumor cells; and can be used for preparing a tumor prevention or treatment drug, and has the prospect of developing into a new type of anti-tumor drug. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 Anti-TNF-alpha induced L929 cell apoptosis results comparison chart. DETAILED DESCRIPTION

[0046] In order to more clearly and clearly explain the technical solutions and beneficial effects of the application, the application will be described in detail below in combination with the drawings and examples. It should be clear that the described reference drawings are only part of the embodiments of the application, and are only used to explain the application, and cannot be understood as a limitation on the application. Unless otherwise specified, the equipment and reagents used in the application are commonly purchased products in the technical field.

[0047] Example 1

[0048]

[0049] Step one: 7-methoxy-4-oxo-3,4-dihydroquinazoline-6-ol acetate (2.13 mmol) was added to a round-bottom flask containing a mixed solution of DIPEA (0.5 mL) and toluene (5 mL), 1 mL of POCl3 was slowly added, nitrogen was introduced for protection and the reaction was stirred at 75°C for 3 hours. 3,4-Dichloro-2-fluoroaniline (2.13 mmol) was dissolved in 2 mL of toluene and slowly added to the round-bottom flask, nitrogen was introduced for protection and the reaction was stirred at 75°C for 2 hours. The reaction was detected by thin layer chromatography. After the reaction was completed, the solution was cooled to room temperature, the reaction liquid was reduced pressure filtered, and the solid was washed with toluene several times. The solid was added to 30 mL of isopropanol and stirred at room temperature for 3 hours. The reaction liquid was filtered and the solid was washed with isopropanol several times and dried. The obtained solid was compound-M-1. 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 7.79-7.52 (m, 3H), 4.03 (s, 3H), 2.40 (s, 3H).

[0050]

[0051] Step 2: Dissolve Compound M-1 (0.63 mmol) in methanol and add it to a round-bottom flask. Add 1 mL of aqueous ammonia dropwise to the flask under an ice bath. Allow to react for 1 hour. Thin-layer chromatography confirmed the reaction was complete. The reaction solution was filtered and the solid was washed several times with a 1:1 ratio of methanol to water. The solid was dried and further structural identification confirmed that the resulting solid was Compound M-2. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.35 (s, 1H), 7.67 (s, 1H), 7.64-7.50 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

[0052]

[0053] Step 3: Compound M-2 (0.705 mmol), tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (0.824 mmol), and anhydrous potassium carbonate (2.22 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF. Under the condition of accessing a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 90 ° C. for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain compound M-3.1H NMR(400MHz,DMSO-d6)δ9.67(d,J=15.2Hz,1H),8.43-8.32(m,1H),7.91(d, J=34.8Hz,1H),7.71-7.45(m,2H),7.24(s,1H),4.71(tt,J=7.5,3.5Hz,1H) ,3.97(d,J=15.8Hz,3H),3.70(ddd,J=13.4,6.6,4.0Hz,2H),3.26(s,2H),2 .05-1.95(m,2H),1.64(dtd,J=12.4,8.1,3.8Hz,2H),1.42(d,J=3.2Hz,9H).

[0054]

[0055] Step 4: Compound M-3 was dissolved in 1 mL of acetone, and 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was determined to be complete by thin-layer chromatography. The solvent was removed by rotary evaporation, and the resulting solid was washed with acetone and dried to obtain compound M-4. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.81 (s, 1H), 8.72 (s, 1H), 7.72-7.48 (m, 2H), 7.35 (s, 1H), 5.03 (s, 2H), 4.02 (s, 3H), 3.25 (d, J = 36.8 Hz, 4H), 2.28 (d, J = 12.7 Hz, 2H), 2.03-1.83 (m, 2H).

[0056]

[0057] Step 5: Compound M-4 (0.57 mmol), N-Boc-L-phenylalanine (0.85 mmol), and HBTU (0.85 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF. DIPEA (2.57 mmol) was added dropwise. Under the condition of accessing a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C for 5 hours of stirring reaction. The reaction was complete by thin layer chromatography. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporator to obtain a crude product. Compound M-5 was purified by automatic column chromatography. 1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.41(s,1H),7.86(s,1H),7.65-7.55(m,2H),7. 27(dd,J=5.7,2.3Hz,4H),7.26-7.14(m,3H),4.69(dq,J=33.4,8.6,7.8Hz,2H),3.96( d,J=5.1Hz,3H),3.89-3.61(m,2H),3.55-3.40(m,1H),3.32-3.25(m,1H),2.97-2.72( m,2H),2.00(s,1H),1.90(d,J=20.0Hz,1H),1.73-1.52(m,2H),1.33(d,J=2.9Hz,9H).

[0058] Step 6: Dissolve compound-M-5 in 1 mL of acetone, slowly add 0.5 mL of 6 M hydrochloric acid solution, and stir at room temperature for 3 hours. The reaction is complete when detected by thin layer chromatography. The solvent is removed by rotary evaporator, and the resulting solid is washed with acetone and dried to obtain compound-1. 1H NMR (400 MHz, DMSO-d6) δ8.90-8.60 (m, 2H), 8.30 (s, 2H), 7.76-7.49 (m, 2H), 7.44-7.16 (m, 5H), 5.10-4.85 (m, 1H), 4.68 (s, 1H), 3.93 (t, J = 12.1 Hz, 1H), 3.47 (s, 1H), 3.45 (s ,1H),3.42(d,J=7.0Hz,2H),3.35(d,J=6.7Hz,2H),3.27(s,1H),3.09(dt,J=12.6,6.0 Hz,1H),2.95(ddd,J=12.9,8.3,4.2Hz,1H),2.11-1.85(m,2H),1.68-1.40(m,2H).13C NMR(101MHz,Methanol-d4)δ157.30,154.57,173.00(d,J=6.8Hz),156.60,152.59,152.0 7,147.18,146.64,137.17,136.99,129.80,129.21,128.30,126.59,125.85,124.79,120. 62,120.43,108.98,106.37,105.43,73.13(d,J=53.8Hz),56.96,55.32,51.38,42.02(d,J =38.2Hz),38.62(d,J=40.5Hz),30.22,29.60(d,J=24.7Hz).ESI-MS: (m / z)584.1636[M+H] + , calculated(m / z)584.1631[M+H] + .

[0059] Example 2

[0060]

[0061] The synthesis steps of compound-2 are the same as those in Example 1. NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.39(s,1H),7.86(s,1H),7.60(d,J=5.4 Hz,2H),7.32–7.20(m,5H),7.18(ddd,J=8.6,4.7,2.4Hz,1H),4.75(p,J=3.8Hz ,1H),3.95(s,3H),3.85(dd,J=18.4,10.5Hz,1H),3.72(d,J=14.1Hz,1H),2.9 1-2.79(m,2H),2.75-2.63(m,2H),2.00-1.90(m,2H),1.64(s,1H),1.32-1.21( m,1H).13CNMR(101MHz,MeOD)δ171.87,157.97,157.59,156.78,152.69,152. 32,147.36,146.74,140.89,140.89,130.08,128.14,128.13,126.10,125.89, 124.87,124.83,120.70,120.51,108.98,106.35,106.35,105.54,73.46,55.2 8,42.50,38.44,34.21,31.43,30.54,29.83ppm.ESI-MS: (m / z)569.1525[M+H] + , calculated(m / z)569.1522[M+H] + .

[0062] Example 3

[0063]

[0064] Step 1: 4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-6-hydroxyquinazoline (0.705mmol), 4-(p-toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (0.824mmol) and anhydrous potassium carbonate (2.22mmol) were added sequentially to a dry round-bottom flask, and 2mL of anhydrous DMF was used as the solvent. Under the condition of accessing a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 90°C for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added twice to the reaction solution. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain a light yellow solid product compound-M-6.1H NMR (400MHz, DMSO-d6) δ9.50 (s, 1H), 8.52 (s, 1H), 8.14 (dd, J = 6.9, 2.6Hz, 1H), 7.92 (s, 1H),7.82(ddd,J=9.1,4.3,2.7Hz,1H),7.43(t,J=9.1Hz,1H),7.23(s,1H),4.76(dp,J=7 .8,3.6Hz,1H),3.96(s,3H),3.72(ddd,J=13.5,7.1,4.0Hz,2H),3.32(ddd,J=12.9,8.4, 3.6Hz, 2H), 2.02 (q, J=5.6, 3.9Hz, 3H), 1.70 (dtd, J=12.3, 7.9, 3.9Hz, 2H), 1.44 (s, 9H).

[0065] Step 2: Dissolve Compound M-6 (0.602 mmol) in 1 mL of anhydrous acetone. Slowly add 0.5 mL of 6 M hydrochloric acid solution dropwise in an ice bath. Remove the ice bath and stir at 25°C for 3 hours. After confirming the completion of the reaction by TLC monitoring, remove the solvent under reduced pressure using a rotary evaporator at 44°C to obtain crude Compound 3. The crude product was washed with cold acetone (3×5 mL) and dried in a vacuum oven at 50°C to obtain the target product, compound 3, as white crystals. 1H NMR (400 MHz, DMSO-d6) δ8.78 (s, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 8.01 (dd, J=6.8, 2.6 Hz, 1H), 7.70 (dq, J=7.0, 2.6, 2.2 Hz, 1H), 7.54 (t, J=9.0 Hz, 1H), 7.33 (s, 1H), 4.00 (s, 3H), 3.28 (s, 2H), 3.15 (s, 2H), 2.18 (s, 2H). 13C NMR(101MHz,MeOD)δ158.81,158.57,155.00,148.47,135.72,133.53,126.84,124.90,120.37,116.33,11 6.11,107.35,106.92,99.63,70.85,56.18,48.32,40.92,34.03,26.99ppm.ESI-MS: (m / z)403.1338[M+H] + , calculated(m / z)403.1337[M+H] + .

[0066] Example 4

[0067]

[0068] Compound 3 (0.57 mmol), N-Boc-L-phenylalanine (0.85 mmol) and HBTU (0.85 mmol) were placed in a round-bottom flask, 2 mL of DMF was added for dissolution, and then DIPEA (2.57 mmol) was slowly added dropwise. Under the condition of connecting a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer at a heating temperature of 25° C. for stirring reaction for 5 hours. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain the target product Compound M-7. NMR (400MHz, DMSO-d6) δ9.86 (s, 1H), 8.56 (s, 1H), 8.12 (dd, J = 6.9, 2.6Hz, 1H), 8.07-7.93 (m, 1H), 7.8 0(ddd,J=9.0,4.3,2.6Hz,1H),7.46(t,J=9.1Hz,1H),7.27(d,J=6.1Hz,4H),7.25-7.15(m,3H),4.89-4 .74(m,1H),4.64(q,J=7.7Hz,1H),3.96(d,J=5.1Hz,3H),3.75(d,J=9.8Hz,1H),3.57-3.40(m,3H),2. 91(dd,J=13.5,6.3Hz,1H),2.81(dd,J=13.5,8.1Hz,1H),1.91(s,2H),1.72-1.52(m,2H),1.33(s,9H).

[0069]

[0070] Compound M-7 (0.52 mmol) was dissolved in 1 mL of anhydrous acetone. 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise in an ice bath. After removing the ice bath, the reaction was stirred at 25°C for 3 hours. After confirming the completion of the reaction by TLC monitoring, the solvent was removed by rotary evaporation at 44°C under reduced pressure to obtain crude compound 4. The crude product was washed with cold acetone (3×5 mL) and dried in a vacuum oven at 50°C for 6 hours to obtain the target product, compound 4, as white crystals. 1H NMR (400 MHz, Methanol-d4) δ8.72 (s, 1H), 8.18 (d, J = 14.9 Hz, 1H), 7.97 (ddd, J = 6.4, 3.7, 2.6 Hz, 1H), 7.87-7.62 (m, 1H), 7.57-7.17 (m, 7H), 4.76 (s, 1H), 4.09 (d, J = 19.3 Hz, 3H), 3.94-3.52 (m, 3H), 3.24-3.03 (m, 3H), 2.83 (s, 1H). 13C NMR (101MHz, MeOD) δ166.70,158.69,158.57,148.73,148.20,135.39,134.03,133.53,129.44,128.79,127.71,127.64,126.80,124.87,120. 33,116.35,116.08,107.31,106.16,106.03,99.45,73.20,56.15,50.6 9,42.32,38.95,37.63,30.02,29.32ppm.ESI-MS:(m / z)550.2023[M+H] + , calculated(m / z)550.2021[M+H] + .

[0071] Example 5

[0072]

[0073] Compound-3 (0.57 mmol), phenylpropionic acid (0.85 mmol) and HBTU (0.85 mmol) were placed in a round-bottom flask, 2 mL of DMF was added for dissolution, and then DIPEA (2.57 mmol) was slowly added dropwise. Under the condition of connecting a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 25° C. for stirring reaction for 5 hours. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain the target product Compound-5. NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 8.50 (s, 1H), 8.11 (dd, J = 6.8, 2.6Hz, 1H), 7.92 (s, 1H), 7. 78(ddd,J=9.1,4.3,2.7Hz,1H),7.46(t,J=9.1Hz,1H),7.31-7.21(m,5H),7.20-7.15(m,1H),4. 77(dt,J=7.6,3.8Hz,1H),3.94(s,3H),3.89-3.67(m,2H),3.40(dt,J=8.8,4.4Hz,2H),2.83(dd ,J=8.5,6.8Hz,2H),2.67(dd,J=8.4,6.5Hz,2H),1.97(d,J=18.3Hz,3H),1.72-1.57(m,2H).13C NMR (101MHz, DMSO) δ170.31,156.64,156.21,154.95,153.41,152.54,147.82,146.76,141.94,137.22,128.87,128.69,126.30,124.19,123.0 1,119.37,117.09,116.88,109.26,108.33,106.92,74.07,56.48,42.4 6,38.68,34.39,31.35,31.20,30.53ppm.ESI-MS:(m / z)535.1915[M+H] + , calculated(m / z)535.1912[M+H] + .

[0074] Example 6

[0075]

[0076] Dissolve 4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (0.63 mmol) in 2 mL of methanol in a round-bottom flask. Place the flask in an ice bath and slowly add 1 mL of aqueous ammonia dropwise. Stir and react for 1 hour. Thin-layer chromatography confirmed the reaction was complete. The solution was filtered through a funnel and the solid was washed with methanol (methanol:water = 1:1). After drying in a dry oven, compound M-8 was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.34 (s, 1H), 7.65 (s, 1H), 7.54-7.42 (m, 2H), 7.29-7.19 (m, 2H), 3.97 (s, 3H).

[0077]

[0078] Step 2: Compound M-8 (0.705 mmol), tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (0.824 mmol), and anhydrous potassium carbonate (2.22 mmol) were added to a round-bottom flask and dissolved in 2 mL of DMF. Under the condition of connecting to a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 90°C for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporator to obtain 273 mg of compound M-9 (yield: 78%). 1HNMR(400MHz,DMSO-d6)δ9.61(s,1H),8.41(s,1H),7.90(s,1H),7.62-7.43(m,2H),7.36-7.18(m,2H),4.73(tt,J=7.8,3.6Hz, 1H),3.72(ddd,J=13.4,6.7,4.0Hz,2H),3.34-3.14(m,2H),2.06-1.97(m,2H),1.67(dtd,J=12.5,8.1,3.8Hz,2H),1.43(s,9H).

[0079]

[0080] Step 3: Dissolve compound-M-9 in 1 mL of acetone, slowly add 0.5 mL of trifluoroacetic acid, and stir at room temperature for 3 hours. The reaction is complete after thin layer chromatography. After concentration under reduced pressure, the precipitated solid is washed with acetone to obtain compound-6. NMR (400MHz, DMSO-d6) δ8.86(d,J=5.8Hz,2H),8.77(s,1H),8.11(dd,J=6.8,2.6Hz,1H),7.85(ddd,J=9.0,4.4,2.6Hz,1H),7.54(t,J=9. 1Hz,1H),7.34(s,1H),5.14(dt,J=8.7,4.6Hz,1H),4.01(s,3H),3.29(s,2H),3.22(s,2H),2.27(d,J=13.3Hz,2H),2.01-1.83(m,2H).13C NMR(101MHz,MeOD)δ159.82,158.79,154.64,152.14,148.57,135.91,129.63,127.04,125.70,124.58,12 1.34,107.07,106.67,99.65,70.90,56.94,56.27,40.93,26.96,16.97ppm.ESI-MS: (m / z)403.1339[M+H] + , calculated(m / z)403.1337[M+H] + .

[0081] Example 7

[0082]

[0083] Step 1: Compound 6 (0.57 mmol), N-Boc-L-phenylalanine (0.85 mmol), and HBTU (0.85 mmol) were added to a round-bottom flask and dissolved in 2 mL of DMF, followed by dropwise addition of DIPEA (2.57 mmol). Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C. and stirred for 5 hours. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and the compound was extracted with EA as the organic phase. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain the crude product compound M-10.

[0084]

[0085] Step two: dissolve compound-M-10 crude in 1 mL acetone, slowly add 0.5 mL 6M hydrochloric acid solution, stir at room temperature for 3 hours, TLC detection reaction complete, concentrated under reduced pressure, precipitate solid washed with acetone to obtain compound-7.1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 8.17 (d, J = 14.9 Hz, 1H), 7.95 (ddd, J = 6.4, 3.7, 2.6 Hz, 1H), 7.70 (dtd, J = 9.0, 3.9, 2.6 Hz, 1H), 7.44 - 7.22 (m, 7H), 4.79 - 4.68 (m, 1H), 4.08 (d, J = 19.3 Hz, 3H), 3.91 - 3.74 (m, 1H), 3.72 - 3.55 (m, 2H), 3.17 - 3.07 (m, 2H), 1.98 (t, J = 15.0 Hz, 2H), 1.86 - 1.64 (m, 2H), 1.50 - 1.15 (m, 2H).13C NMR (101 MHz, MeOD) δ 166.72, 159.78, 158.87, 158.83, 152.13, 148.90, 148.42, 148.39, 135.75, 134.04, 129.64, 129.45, 128.80, 127.71, 127.66, 126.95, 124.62, 107.10, 105.80, 99.51, 99.48, 73.20, 56.16, 50.71, 42.26, 38.88, 37.40, 29.30, 16.95 ppm. ESI-MS: (m / z) 550.2025 [M+H] + , calculated (m / z) 550.2021 [M+H] + .

[0086] Example 8

[0087]

[0088] Compound-6 (0.57 mmol), phenylpropionic acid (0.85 mmol), and HBTU (0.85 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF, followed by dropwise addition of DIPEA (2.57 mmol). The mixture was purged with nitrogen and stirred at 25° C. for 12 hours. The reaction was complete as determined by thin-layer chromatography. Water was added twice to the reaction solution, and after solids precipitated, the solution was placed in a separatory funnel and extracted with EA. The organic phases were combined, washed three times with saturated sodium bicarbonate and saturated brine, and then dehydrated with anhydrous sodium sulfate and the solvent was removed by rotary evaporation to obtain the product, compound-8. NMR (400MHz, Methanol-d4) δ8.36(s,1H),7.78(s,1H),7.54(ddd,J=8.3,6.8,1.6Hz,1H),7.38(ddd,J=8.2, 6.6,1.6Hz,1H),7.30-7.14(m,7H),4.73(dt,J=6.9,3.5Hz,1H),4.00(s,3H),3.85(ddt,J=13.7,9.4,4.7Hz, 1H), 3.74 (ddd, J=12.2, 8.0, 3.6Hz, 1H), 3.64-3.53 (m, 1H), 3.42 (ddd, J=13.6, 7.3, 3.7Hz, 1H), 2.93 (t, J=7. 5Hz,2H),2.72(dd,J=8.0,6.6Hz,2H),2.03-1.91(m,1H),1.79(ddtd,J=34.3,13.4,7.8,6.5,3.7Hz,3H).13C NMR(101MHz,MeOD)δ171.87,157.83,156.79,154.28,152.57,151.80,147.36,146.25,140.89,128.14,128.13,127.53,126.35,125.89,124.3 1,124.26,121.33,121.16,108.93,106.11,105.65,73.47,55.30,42.5 2,38.45,34.21,31.43,30.53,29.83ppm.ESI-MS:(m / z)535.1914[M+H] + , calculated(m / z)535.1912[M+H] + .

[0089] Example 9

[0090]

[0091] Step 1: 6-acetoxy-4-chloro-7-methoxyquinazoline (0.393 mmol), N-methylpiperazine (0.593 mmol), and anhydrous potassium carbonate (1.197 mmol) were added to a round-bottom flask containing 3 mL of isopropanol, and nitrogen was introduced. The mixture was condensed and refluxed at 100° C. and stirred for 6 h. The reaction was detected by thin layer chromatography. After the reaction was complete, the reaction solution was removed from the solvent by a rotary evaporator to obtain a pale yellow solid crude product, which was purified by an automatic column machine to obtain a pure product. Further structural identification confirmed that the solid was compound-M-11.1H NMR (400MHz, Methanol-d4) δ8.51(d,J=1.4Hz,1H),7.28(d,J=3.9Hz,1H),7.21(d,J=5.2Hz,1 H), 4.04 (d, J = 4.9Hz, 3H), 3.82 (t, J = 4.7Hz, 4H), 3.05 (q, J = 5.1Hz, 4H), 2.66 (d, J = 3.8Hz, 3H).

[0092]

[0093] Step 2: Compound M-11 (0.364 mmol), tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (0.547 mmol), and anhydrous potassium carbonate (1.14 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF. Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 90 ° C for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporator to obtain a crude product. Compound M-12 was purified by automatic column chromatography. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 4.68 (tt, J = 7.2, 3.6 Hz, 1H), 3.99 (s, 3H), 3.74 (dt, J = 16.0, 4.2 Hz, 6H), 3.39 (ddd, J = 17.5, 8.1, 4.3 Hz, 2H), 2.75 (t, J = 4.9 Hz, 4H), 2.44 (s, 3H), 1.99 (ddq, J = 15.0, 7.3, 3.6 Hz, 2H), 1.78 (dtd, J = 13.8, 7.5, 3.8 Hz, 2H), 1.48 (s, 9H).

[0094]

[0095] Step 3: Compound M-12 was dissolved in 1 mL of acetone, and 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise. The reaction was stirred at room temperature for 3 hours. The reaction was detected to be complete by thin layer chromatography. The solvent was removed by rotary evaporation to obtain light yellow crystals. The crystals were washed with acetone solution and dried to obtain compound 9. NMR (400MHz, Methanol-d4) δ8.50(s,1H),7.35(s,1H),7.23(s,1H),4.74(dt,J=6.3,3.2Hz,1H),4.00(s,3H),3.76(t,J=5.0Hz,4H ),3.40(ddd,J=12.6,8.9,3.5Hz,2H),3.23-3.08(m,3H),2.67(t,J=4.9Hz,4H),2.39(s,3H),2.27-2.12(m,2H),2.11-1.93(m,2H).

[0096] Example 10

[0097]

[0098] Step 1: Same as Example 9. Compound M-13 was synthesized: 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.25 (s, 1H), 7.17 (s, 1H), 4.01 (s, 3H), 3.75-3.59 (m, 4H), 2.84-2.68 (m, 5H), 1.13 (d, J = 6.5 Hz, 6H).

[0099]

[0100] Step 2: Compound M-13 (0.364 mmol), tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (0.547 mmol), and anhydrous potassium carbonate (1.14 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF. Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 90 ° C for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporator to obtain a crude product. Compound M-14 was purified by automatic column chromatography. 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 4.56-4.37 (m, 1H), 3.92 (s, 3H), 3.79-3.61 (m, 4H), 3.26 (ddd, J = 12.7, 7.8, 3.6 Hz, 2H), 3.05-2.54 (m, 5H), 1.96-1.86 (m, 2H), 1.76 (dtd, J = 12.1, 7.7, 3.8 Hz, 2H), 1.41 (s, 9H), 1.24-1.14 (m, 6H).

[0101]

[0102] Step 3: Compound M-14 was dissolved in 1 mL of acetone, and 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise. The reaction was stirred at room temperature for 3 hours. The reaction was detected to be complete by thin layer chromatography. The solvent was removed by rotary evaporation to obtain light yellow crystals. The crystals were washed with acetone solution and dried to obtain compound 10. NMR (400MHz, Methanol-d4) δ8.77(s,1H),7.66(s,1H),7.35(d,J=22.4Hz,1H),5.07(s,1H),4.17(dd,J=19.2,8.9Hz,2H),4.08(d,J =10.5Hz,3H),3.85-3.62(m,4H),3.61-3.38(m,5H),3.36(d,J=6.5Hz,2H),2.38-2.25(m,2H),2.22-2.10(m,2H),1.51-1.42(m,6H).

[0103] Example 11

[0104]

[0105] Step 1: Same as Example 9. Compound-M-15: 1H NMR (400 MHz, Methanol-d4) δ 8.41 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 3.93 (s, 3H), 3.74 (t, J = 4.8 Hz, 4H), 3.10 (t, J = 5.1 Hz, 4H), 1.23 (s, 9H).

[0106]

[0107] Step 2: Compound M-15 (0.364 mmol), tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (0.547 mmol), and anhydrous potassium carbonate (1.14 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF. Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 90 ° C for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporator to obtain a crude product. Compound M-16 was purified by automatic column chromatography. 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 4.66 (tt, J = 7.1, 3.5 Hz, 1H), 3.98 (s, 3H), 3.74 (h, J = 4.4, 3.7 Hz, 6H), 3.38 (ddd, J = 14.5, 6.4, 2.7 Hz, 2H), 2.90-2.80 (m, 4H), 1.99 (ddt, J = 14.2, 7.7, 3.7 Hz, 2H), 1.86-1.73 (m, 2H), 1.47 (s, 9H), 1.17 (s, 9H).

[0108]

[0109] Step 3: Compound M-16 was dissolved in 1 mL of acetone, and 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise. The reaction was stirred at room temperature for 3 hours. The reaction was detected to be complete by thin layer chromatography. The solvent was removed by rotary evaporation to obtain light yellow crystals. The crystals were washed with acetone solution and dried to obtain compound 11. NMR (400MHz, Methanol-d4) δ8.47(s,1H),7.28(s,1H),7.18(s,1H),4.56(tt,J=8.0,3.7Hz,1H),3.99(s,3H),3.77-3.67(m,4 H),3.14(ddd,J=12.9,6.2,3.9Hz,2H),2.85-2.67(m,6H),2.11-1.99(m,2H),1.77(dtd,J=12.7,8.6,3.8Hz,2H),1.15(s,9H).

[0110] Example 12

[0111]

[0112] Step 1: Compound 9 (0.28 mmol), N-Boc-glycine (0.42 mmol), and HBTU (0.42 mmol) were added to a round-bottom flask and dissolved in 2 mL of DMF, followed by dropwise addition of DIPEA (1.26 mmol). Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C. for 5 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain a crude product. Compound M-17 was purified by automatic column chromatography. 1H NMR (400 MHz, Methanol-d4) δ8.54 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.17 (d, J = 3.1 Hz, 1H), 4.82 (dp, J = 7.4, 3.5 Hz, 1H), 4.09 (qd, J = 7.1, 1.5 Hz, 2H), 4.01-3.97 (m, 3H), 3.96 (d, J = 5.9 Hz, 2H), 3.94 -3.67(m,6H),3.62-3.53(m,1H),3.53-3.43(m,1H),2.84(s,3H),2.01(s,4H),1.91-1.72(m,2H),1.44(d,J=2.1Hz,9H).

[0113]

[0114] Step 2: Dissolve compound M-17 in 1 mL of acetone, slowly add 0.5 mL of 6 M hydrochloric acid solution, and stir the reaction at room temperature for 3 hours. The reaction is complete by thin layer chromatography. The solvent is removed by rotary evaporation to obtain a white solid crude product, which is further purified by automatic column chromatography. After further structural identification, the solid is confirmed to be compound 12. 1 H NMR(400MHz,Methanol-d4)δ8.61(s,1H),7.39(s,1H),7.28(s,1H),4.91(dq,J =6.8,3.3Hz,1H),4.01(s,8H),3.86(ddd,J=12.5,8.1,3.8Hz,1H),3.73(ddd,J =14.6,7.9,3.9Hz,2H),3.54-3.48(m,1H),3.45(t,J=5.1Hz,4H),3.35(s,1H), 2.93(s,3H),2.16-2.00(m,2H),1.91(ddtd,J=24.3,13.6,6.9,4.0Hz,2H).13C NMR(101MHz,MeOD)δ164.09,163.14,157.17,151.35,146.93,110.44,107.67,105.33,73.19,56.93,5 5.51,52.67,42.48,41.21,39.70,38.68,35.62,30.14,29.55,17.00ppm.ESI-MS: (m / z)437.2274[M+H] + , calculated(m / z)437.2277[M+H] + .

[0115] Example 13

[0116]

[0117] Step one: Compound-10 (0.28 mmol), N-Boc-glycine (0.42 mmol), HBTU (0.42 mmol) were added to a round bottom flask dissolved in 2 mL DMF, then DIPEA (1.26 mmol) was added dropwise, and the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 25°C under the condition of nitrogen protection device, and stirred for 5 hours. TLC plate detection showed that the reaction was complete. Water was added to the reaction solution, and the solution was placed in a separatory funnel to extract the compound with EA as the organic phase. The organic phase was combined and washed with saturated sodium bicarbonate, saturated brine three times, then dehydrated over anhydrous sodium sulfate, and the solvent was removed by rotary evaporator to obtain the crude product. Compound-M-18 was obtained by purification with an automatic column machine. 1H NMR (400 MHz, Methanol-d4) δ 8.54 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.17 (d, J = 3.1 Hz, 1H), 4.82 (dp, J = 7.4, 3.5 Hz, 1H), 4.09 (qd, J = 7.1, 1.5 Hz, 2H), 4.01-3.97 (m, 3H), 3.96 (d, J = 5.9 Hz, 2H), 3.94-3.67 (m, 6H), 3.62-3.53 (m, 1H), 3.53-3.43 (m, 1H), 2.84 (s, 3H), 2.01 (s, 4H), 1.91-1.72 (m, 2H), 1.44 (d, J = 2.1 Hz, 9H).

[0118]

[0119] Step two: Compound-M-18 was dissolved in 1 mL of acetone, and 0.5 mL of 6M hydrochloric acid solution was slowly added dropwise. The reaction was stirred at room temperature for 3 hours, and TLC detection showed that the reaction was complete. The solvent was removed by rotary evaporator to obtain a white solid crude product, which was further purified by automatic column machine to obtain a solid. Further structural identification confirmed that the solid was compound-13. 1 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.34 (s, 1H), 7.22 (s, 1H), 5.89-5.65 (m, 1H), 3.99 (s, 3H), 3.87 (dd, J = 19.5, 10.2 Hz, 2H), 3.76 (t, J = 5.0 Hz, 4H), 3.71-3.62 (m, 2H), 3.61-3.58 (m, 2H), 2.76 (t, J = 5.0 Hz, 5H), 2.03 (d, J = 4.5 Hz, 2H), 1.95-1.80 (m, 2H), 1.13 (d, J = 6.5 Hz, 6H). 13C NMR(101MHz,MeOD)δ163.56,156.58,152.38,148.61,146.06,110.74,109.10,106.44,101.87,73.74,55.25,54.6 7,49.29,48.37,48.09,47.88,47.66,47.45,40.87,38.67,30.33,29.75,17.27ppm.ESI-MS: (m / z)465.2586[M+H] + , calculated(m / z)465.2590[M+H] + .

[0120] Example 14

[0121]

[0122] Step 1: Compound 11 (0.28 mmol), N-Boc-glycine (0.42 mmol), and HBTU (0.42 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF, followed by dropwise addition of DIPEA (1.26 mmol). Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C for 5 hours of stirring reaction. The reaction was complete by thin layer chromatography. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporator to obtain a crude product. The pure product was purified by automatic column chromatography, and the solid was confirmed to be compound-M-19 by further structural identification. 1 H NMR (400MHz, Methanol-d4) δ8.56(s,1H),7.38(s,1H),7.26(s,1H),4.81(dq,J=6.8,3.4Hz,1H),4.01(s,3H),3.96(s,2H),3.93-3 .72(m,6H),3.60(q,J=7.0Hz,2H),3.50(s,1H),3.25(s,3H),2.03(d,J=14.2Hz,3H),1.95-1.77(m,2H),1.46(s,9H),1.34(s,9H).

[0123]

[0124] Step 2: Dissolve compound M-19 in 1 mL of acetone, slowly add 0.5 mL of 6 M hydrochloric acid solution, and stir the reaction at room temperature for 3 hours. The reaction is complete by thin layer chromatography. The solvent is removed by rotary evaporation to obtain a white solid crude product, which is further purified by automatic column chromatography. After further structural identification, the solid is confirmed to be compound 14. 1 H NMR (400MHz, Methanol-d4) δ8.54(s,1H),7.39(s,1H),7.25(s,1H),4.85-4.82(m,1H),4.00(s,3H),3.96-3.81(m,7H),3.72(ddt,J=11.8,8.8,3 .8Hz,2H),3.47(ddd,J=13.8,7.1,4.0Hz,1H),3.15(t,J=4.9Hz,4H),2.13-1.98(m,2H),1.91(dddd,J=21.2,13.5,6.7,3.1Hz,2H),1.31(s,9H). 13 C NMR(101MHz,MeOD)δ164.90,163.25,156.75,152.33,148.67,146.35,110.83,108.77,106.54,73.49,5 8.81,56.94,55.34,45.62,41.12,39.90,38.69,30.22,29.61,23.95.ppm.ESI-MS: (m / z)479.2740[M+H] + , calculated(m / z)479.2747[M+H] + .

[0125] Example 15

[0126]

[0127] Step 1: 6-Acetoxy-4-chloro-7-methoxyquinazoline (0.393 mmol) and anhydrous potassium carbonate (1.197 mmol) were added to a round-bottom flask containing 2 mL of isopropanol. Piperidine (0.593 mmol) was then added dropwise. The flask was stirred at 100°C under nitrogen for 6 hours. The reaction was monitored by thin-layer chromatography. After the reaction was complete, the flask was allowed to stand at room temperature. The solution was cooled to room temperature and filtered to obtain Compound M-20. 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 7.24 (s, 1H), 7.14 (s, 1H), 4.01 (s, 3H), 3.62 (t, J = 4.8 Hz, 4H), 1.85-1.74 (m, 6H).

[0128]

[0129] Step 2: Compound M-20 (0.364 mmol), tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (0.547 mmol), and anhydrous potassium carbonate (1.14 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF. Under the condition of accessing a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 90 ° C. for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration through anhydrous sodium sulfate, the mixture was dried by rotary evaporation. The solvent was removed by rotary evaporation to obtain crude compound M-30, which was then purified using an automatic column chromatography apparatus to obtain compound M-21. 1H NMR (400 MHz, Methanol-d4) δ 8.41 (s, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 4.61 (tt, J = 7.3, 3.5 Hz, 1H), 3.97 (s, 3H), 3.81-3.71 (m, 2H), 3.60 (t, J = 4.4 Hz, 4H), 3.41-3.33 (m, 2H), 2.07-1.92 (m, 2H), 1.83-1.65 (m, 8H), 1.47 (s, 9H).

[0130]

[0131] Step 3: Dissolve compound M-21 in a round-bottom flask with 1 mL of acetone, slowly add 0.5 mL of 6 M hydrochloric acid solution into the flask, place the flask at room temperature and stir to react for 3 hours. After the reaction is complete by thin-layer chromatography, the reaction solution is concentrated under reduced pressure on a rotary evaporator to remove the solvent, and then the precipitated solid is washed with acetone. Finally, the product is dried in a drying oven to obtain compound 15. 1 HNMR(400MHz,Methanol-d4)δ8.55(s,1H),7.42(d,J=109.4Hz,2H),4.87(s,1H),4.19(s ,4H),4.08(s,3H),3.47(d,J=10.8Hz,2H),3.29(s,2H),2.35-2.06(m,4H),1.87(s,6H).

[0132] Example 16

[0133]

[0134] Step 1: Compound-15 (0.28 mmol), N-Boc-L-phenylalanine (0.42 mmol), and HBTU (0.42 mmol) were added to a round-bottom flask and dissolved in 2 mL of DMF, followed by dropwise addition of DIPEA (1.26 mmol). Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C. and stirred for 5 hours. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and the compound was extracted with EA as the organic phase. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain the product compound-M-22. 1 H NMR (400MHz, Methanol-d4) δ8.43(d,J=1.8Hz,1H),7.35-7.04(m,7H),4.81(d,J=15.2Hz,1H),4.66-4.46(m,1H),3.97(d ,J=10.7Hz,3H),3.80-3.40(m,8H),2.94(dtdd,J=17.6,13.0,9.0,3.6Hz,2H),2.02-1.62(m,10H),1.40(d,J=3.0Hz,9H).

[0135]

[0136] Step 2: Dissolve compound M-22 in a round-bottom flask with 1 mL of acetone, slowly add 0.5 mL of 6 M hydrochloric acid solution into the flask, place the flask at room temperature and stir for 3 hours. After the reaction is complete by thin-layer chromatography, the reaction solution is concentrated under reduced pressure on a rotary evaporator to remove the solvent, and the precipitated solid is washed with acetone. Finally, the product is dried in a drying oven to obtain compound 16. 1HNMR (400 MHz, Methanol-d4) δ8.33 (d, J = 1.6 Hz, 1H), 7.29-7.04 (m, 7H), 4.52-4.24 (m, 2H), 3.87 (d, J = 13.1 Hz, 3H), 3.73-3.59 (m, 1H), 3.59 -3.41(m,6H),3.25(s,1H),2.99-2.80(m,2H),1.69(d,J=4.5Hz,8H),1.26-1.17(m,1H),1.11(dt,J=23.3,5.9Hz,1H).13C NMR(101MHz,MeOD)δ165.48,158.03,157.90,153.94,149.91,147.27,137.47,130.95,130.87,130.10,128.62,112.28,111.10,110.60 ,107.85,74.71,58.53,56.82,52.77,52.26,43.65,41.88,40.22,31.38,31.16,27.30,25.93,18.56ppm.ESI-MS: (m / z)490.2820[M+H] + , calculated(m / z)490.2818[M+H] + .

[0137] Example 17

[0138]

[0139] Step 1: Compound 15 (0.28 mmol), N-Boc-Lg glycine (0.42 mmol), and HBTU (0.42 mmol) were added to a round-bottom flask and dissolved in 2 mL of DMF, followed by dropwise addition of DIPEA (1.26 mmol). Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C. for 5 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and the compound was extracted with EA as the organic phase. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain the product compound-M-23. 1H NMR(400MHz, Methanol-d4)δ8.43(s,1H),7.26(s,1H),7.15(s,1H),4.71(tt,J=6.9,3.4Hz,1H),3.98(s,3H),3.97-3.94 (m,2H),3.67-3.55(m,5H),3.52-3.42(m,1H),2.05(dddd,J=26.2,12.4,7.5,3.2Hz,2H),1.94-1.74(m,8H),1.46(s,9H).

[0140]

[0141] Step 2: Compound M-23 was dissolved in 1 mL of acetone in a round-bottom flask. 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise to the flask. The flask was placed at room temperature and stirred for 3 hours. After the reaction was complete by thin-layer chromatography, the reaction solution was concentrated under reduced pressure on a rotary evaporator to remove the solvent. The precipitated solid was then washed with acetone and the product was dried in a drying oven to obtain compound 17. 1HNMR (400 MHz, Methanol-d4) δ8 .44(s,1H),7.31(s,1H),7.19(s,1H),4.73(dt,J=6.7,3.4Hz,1H),3.99(s,3H),3.97-3.84(m,3 H),3.68(q,J=6.7,4.9Hz,6H),3.51-3.41(m,1H),1.96-1.86(m,2H),1.79(d,J=2.7Hz,6H).13C NMR(101MHz,MeOD)δ163.71,156.51,151.97,147.69,145.79,110.38,109.44,105.86,73.54,56.94,5 5.32,50.66,41.19,39.78,38.73,30.21,29.62,25.71,24.29,16.98ppm.ESI-MS:(m / z)400.2350[M+H] + , calculated(m / z)400.2349[M+H] + .

[0142] Example 18

[0143]

[0144] Step 1: Add 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-ol acetate (0.427 mmol) to a round-bottom flask containing 3 mL of methanol. Add 1 mL of aqueous ammonia dropwise in an ice bath and stir for one hour. The reaction was complete as determined by thin-layer chromatography. The solution was filtered, and the solid was washed with methanol and water to obtain Compound M-24. Compound M-23: 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.39 (s, 1H), 7.10 (s, 1H), 3.91 (s, 3H).

[0145]

[0146] Step 2: Compound M-24 (0.260 mmol), tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (0.325 mmol), and anhydrous potassium carbonate (0.782 mmol) were added to a round-bottom flask and dissolved in 2 mL of DMF. Under the condition of accessing a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 90° C. for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain compound M-25. 1H NMR(400MHz,Chloroform-d)δ11.92(s,1H),7.98(s,1H),7.58(s,1H),7.11(s,1H),4.58(tt,J=7.5,3.6Hz,1H),3.92(s,3H),3.83-3 .67(m,2H),3.25(ddd,J=13.5,8.3,3.6Hz,2H),1.95(ddd,J=13.8,7.1,3.3Hz,2H),1.77(dtd,J=12.3,8.0,3.8Hz,2H),1.40(s,9H).

[0147]

[0148] Step 3: Compound M-25 was dissolved in 1 mL of acetone, and 0.5 mL of trifluoroacetic acid was slowly added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was confirmed to be complete by thin-layer chromatography. The mixture was concentrated under reduced pressure and the precipitated solid was washed with acetone to obtain compound M-26. 1H NMR (400 MHz, Methanol-d4) δ 9.03 (s, 1H), 7.69 (s, 1H), 7.16 (s, 1H), 3.96 (s, 3H), 3.34 (ddd, J = 12.9, 9.2, 3.8 Hz, 2H), 3.20-3.13 (m, 2H), 2.15 (ddt, J = 13.1, 7.8, 3.6 Hz, 2H), 2.01 (dtd, J = 14.0, 6.4, 3.8 Hz, 2H).

[0149]

[0150] Step 4: Compound M-26 (0.28 mmol), N-Boc-L-phenylalanine (0.42 mmol), and HBTU (0.42 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF, followed by dropwise addition of DIPEA (1.26 mmol). Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C. for 5 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and the compound was extracted with EA as the organic phase. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain the product compound M-27. 1H NMR(400MHz,Chloroform-d)δ8.04(d,J=1.8Hz,1H),7.59(d,J=20.0Hz,1H),7.34 -7.13(m,6H),5.66(dd,J=8.7,5.3Hz,1H),4.90(td,J=8.6,6.2Hz,1H),4.59(ddd, J=41.6,7.0,3.8Hz,1H),3.98(d,J=17.0Hz,3H),3.82-3.52(m,3H),3.38(tdd,J=1 3.6,7.5,3.9Hz,1H),3.12-2.95(m,2H),2.15-1.64(m,4H),1.41(d,J=6.5Hz,9H).

[0151]

[0152] Step 5: Compound M-27 was dissolved in 1 mL of acetone, and 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was detected to be complete by thin layer chromatography. After concentration under reduced pressure, the precipitated solid was washed with acetone to obtain compound 18. 1H NMR (400 MHz, Methanol-d4) δ7.99 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.32 (td, J = 7.6, 7.1, 2.0 Hz, 2H), 7.29-7.26 (m, 1H), 7.23 (dt, J = 7.9, 1.7 Hz, 2H), 7.13 (d, J = 5.2 Hz, 1H), 4.62-4.47 (m, 1H), 4.23 (ddd, J = 8 .4,6.3,2.2Hz,1H),3.96(d,J=14.4Hz,3H),3.86-3.45(m,3H),3.11(ddd,J=13.7,7.3,4.5Hz,1H),2.99- 2.85(m,2H),2.02-1.87(m,1H),1.77(dq,J=10.5,5.9,5.2Hz,2H),1.62(ddq,J=13.5,6.4,3.3Hz,1H).13C NMR(101MHz,MeOD)δ168.04,167.11,143.80,134.69,134.58,129.36,128.70,127.48,115.41,109.98,109. 63,107.66,72.87,55.40,50.85,48.31,42.01,38.73,38.42,29.89,29.48ppm.ESI-MS: (m / z)445.1852[M+H] + , calculated(m / z)445.1852[M+H] + .

[0153] Example 19

[0154]

[0155] Step 1: Compound M-26 (0.28 mmol), N-Boc-L-phenylalanine (0.42 mmol), and HBTU (0.42 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF, followed by dropwise addition of DIPEA (1.26 mmol). Under the condition of access to a nitrogen protection device, the reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C. for 5 hours of stirring reaction. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and the compound was extracted with EA as the organic phase. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain the product compound M-28. 1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.65(s,1H),7.19(s,1H),5.79-5.59(m,1H),4.75(tt,J=6.8,3.4Hz,1H),4.04(dd,J=8.4,4.5Hz,1H),3.9 9(s,3H),3.85(ddd,J=12.6,8.1,4.0Hz,1H),3.71(ddd,J=12.8,6.8,3.5H z,2H),3.40(ddd,J=14.0,6.8,3.9Hz,1H),2.09-1.88(m,4H),1.47(s,9H).

[0156]

[0157] Step 2: Compound M-28 was dissolved in 1 mL of acetone, and 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was detected to be complete by thin layer chromatography. After concentration under reduced pressure, the precipitated solid was washed with acetone to obtain compound 19. NMR (400MHz, Methanol-d4) δ8.02(s,1H),7.64(s,1H),7.15(s,1H),4.74(tt,J=7.1,3.4Hz,1H),3.97(s,3H),3.90(ddd,J=12.4,7. 9,3.9Hz,1H),3.69(s,3H),3.65-3.54(m,1H),3.48-3.37(m,1H),2.04(dddt,J=21.6,14.0,7.6,3.6Hz,2H),1.91-1.75(m,2H).13C NMR(101MHz,MeOD)δ168.50,161.43,156.88,146.83,145.23,143.85,115.43,109.59,10 7.59,73.40,55.37,41.04,40.83,38.77,30.30,29.77ppm.ESI-MS: (m / z)335.1383[M+H] + ,calculated(m / z)335.1382[M+H] + .

[0158] Example 20

[0159]

[0160] Step 1: Compound M-24 (0.28 mmol), N-Boc-glycine (0.42 mmol), HOBT (0.42 mmol), and EDCI (0.42 mmol) were added to a round-bottom flask with 2 mL of DMF. Under the condition of accessing a nitrogen protection device, the reaction bottle was placed in a constant temperature magnetic stirrer with a heating temperature of 25 ° C. and stirred for 5 hours. The reaction was complete by thin layer chromatography spot plate detection. Water was added to the reaction solution twice. After the solid precipitated, the solution was placed in a separatory funnel and EA was used as the organic phase to extract the compound. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain compound M-29. 1H NMR (400MHz, Methanol-d4) δ8.09(d,J=3.2Hz,1H),7.87(s,1H),7.25(s,1H),4.12(s,2H),3.96(s,3H),3.35(s,4H),1.47(s,9H).

[0161]

[0162] Step 3: Compound M-29 was dissolved in 1 mL of acetone, and 0.5 mL of 6 M hydrochloric acid solution was slowly added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was detected to be complete by thin-layer chromatography. After concentration under reduced pressure, the precipitated solid was washed with acetone to obtain compound 20. 1H NMR (400 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.08 (s, 1H), 7.37 (s, 1H), 4.28 (s, 2H), 4.07 (d, J = 8.1 Hz, 3H). 13C NMR(101MHz,MeOD)δ149.05,147.32,146.36,132.99,119.67,115.08,110.01,106.22,101.04,55.86,39.43ppm.ESI-MS: (m / z)250.0827[M+H] + , calculated(m / z)250.0828[M+H] + .

[0163] Example 21

[0164]

[0165] 2-Chloroquinazoline-4-amine (0.279 mmol) and anhydrous potassium carbonate (0.418 mmol) were added to a round-bottom flask and dissolved with 2 mL of DMF. Benzylamine (0.418 mmol) was then added dropwise to the reaction solution. Under nitrogen protection, the reaction flask was placed in a constant temperature magnetic stirrer at 120° C. for 12 hours of stirring reaction. The reaction was complete by thin layer chromatography (TLC) plate detection. Secondary water was added to the reaction solution. After solid precipitation, the solution was placed in a separatory funnel and the compound was extracted with EA as the organic phase. The organic phases were combined and washed three times with saturated sodium bicarbonate and saturated brine. After dehydration with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain a crude product. The compound 21 was purified by automatic column chromatography. 1HNMR (400 MHz, Methanol-d4) δ 7.86 (td, J = 8.6, 1.3 Hz, 1H), 7.52 (ddt, J = 8.2, 7.1, 1.2 Hz, 1H), 7.40 (ddd, J = 17.3, 8.1, 1.2 Hz, 1H), 7.33 (d, J = 7.2 Hz, 2H), 7.30–7.20 (m, 2H), 7.20–7.13 (m, 1H), 7.07 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 4.64 (s, 2H). 13C NMR(101MHz,MeOD)δ163.11,159.75,151.50,140.05,132.98,131.53,128.03,127.25,126.98,126.49,123.60,122.97,120.98,110.60,44.57ppm ESI-MS:(m / z)251.1302[M+H] + , calculated(m / z)250.1297[M+H] + .

[0166] Example 22

[0167]

[0168] Into a round bottom flask, 2-chloroquinazolin-4-amine (0.279 mmol), anhydrous potassium carbonate (0.418 mmol) were added and dissolved in 2 mL of DMF, then 2-methoxybenzylamine (0.418 mmol) was added dropwise into the reaction solution. The reaction flask was placed in a constant temperature magnetic stirrer with a heating temperature of 120°C under the protection of nitrogen gas, and stirred for 12 hours. TLC plate detection showed that the reaction was complete. Water was added to the reaction solution, and the solution was placed in a separatory funnel to extract the compound with EA as the organic phase. The organic phase was combined and washed with saturated sodium bicarbonate, saturated brine three times, and then anhydrous sodium sulfate was added to remove water, and then the solvent was removed by a rotary evaporator to obtain a crude product. The automatic column machine was used for purification to obtain a pure product, and further structure identification confirmed that the solid was compound-22. 1 HNMR (400 MHz, Methanol-d4) δ 7.92 (dd, J = 8.2, 1.4 Hz, 1H), 7.61 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 7.5, 1.7 Hz, 1H), 7.22 (dtd, J = 16.4, 7.4, 1.4 Hz, 2H), 6.96 (dd, J = 8.3, 1.1 Hz, 1H), 6.89 (td, J = 7.4, 1.1 Hz, 1H), 4.65 (s, 2H), 3.88 (s, 3H). 13 C NMR (101 MHz, MeOD) δ 157.47, 133.76, 128.19, 126.71, 123.44, 122.06, 120.05, 109.91, 54.41, 40.19 Pppm. ESI-MS: (m / z) 281.1407 [M+H] + , calculated (m / z) 281.1402 [M+H] +

[0169] Example 23

[0170] Detection of the inhibitory activity of the compound on tumor cell proliferation.

[0171] MCF-7 cells, HepG2 cells, MIAPaCa-2 cells and PANC-1 cells were cultured in vitro respectively. They were divided into control group and drug administration group. Nine drug concentrations (0 μM, 1 μM, 2 μM, 4 μM, 8 μM, 16 μM, 32 μM, 64 μM, 128 μM) were set for each compound, and three repeated holes were set in each group. After the drug was incubated with the cells for 48 h, the XTT method was used to detect the cell survival rate.

[0172] The experimental results are shown in Table 1. Table 1 shows the range of inhibitory activity of the compounds of the present invention against various tumor cell lines, with IC 50 (μM) values ​​are shown.

[0173] Study on the anti-apoptosis of compounds

[0174] L929 cells were cultured in vitro and divided into a control group, a positive control group, and a compound-treated group. The compound was administered at a concentration of 1 μM, with triplicate wells set up in each group. After incubation of the drug with the cells for 1 hour, TNF-α was added to each group and incubated for 4 hours. Cell viability was then assessed by XTT assay.

[0175] The experimental results are as follows Figure 1 The results showed that compounds 1, 3 and 4 could inhibit TNF-α-induced cell apoptosis, and the anti-apoptotic effects of compounds 1, 3 and 4 were better than those of the positive control drug pocitinib.

[0176] Table 1. Antitumor activity of compounds.

[0177]

[0178] "+++", <5μM; "++", 5-25μM; "+", 25-50μM; "-", >50μM

[0179] Any matters not mentioned above shall be subject to the existing technology.

[0180] Although some specific embodiments of the present invention have been described in detail through examples, those skilled in the art should understand that the above examples are for illustration only and are not intended to limit the scope of the present invention. Those skilled in the art of the present invention may make various modifications or additions to the described specific embodiments or replace them in similar ways, but they will not deviate from the direction of the present invention or exceed the scope defined by the appended claims. Those skilled in the art should understand that any modifications, equivalent replacements, improvements, etc. made to the above embodiments based on the technical essence of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound of formula (I) or its tautomers, stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts, wherein: R1 is selected from R2 selection R3 is selected from wherein R5, R6, and R7 are selected from hydrogen bonds and halogen elements; R8 is selected from methyl, propyl, and isopropyl; R4 is selected from 2. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has the structure shown in formula (II):

3. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has a structure shown in formula (III):

4. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has a structure shown in formula (IV):

5. The compound according to claim 1 or its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein: The compound has a structure shown in formula (V):

6. A pharmaceutical composition, characterized in that The invention comprises a compound according to any one of claims 1 to 5 or a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

7. Use of the compound according to any one of claims 2 to 5 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 6 in the preparation of a TNF-α inhibitor.

8. Use of the compound according to any one of claims 1 to 5 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 6 in the preparation of an anti-tumor drug.

9. The use according to claim 8, characterized in that The anti-tumor drug includes any one of an anti-breast cancer drug, an anti-liver cancer drug or an anti-human melanoma drug.

10. The use according to claim 8, characterized in that The only active ingredient of the anti-tumor drug is the compound according to claim 2.

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