A quinazoline derivative, and a preparation method and application thereof

Abstract

The application belongs to the technical field of medicine, and particularly relates to quinazoline derivatives, a preparation method, a composition and use. The application combines quinazoline and a pharmacophore such as a styrene skeleton to synthesize quinazoline derivatives. The structure contains a quinazoline functional unit and a pharmacophore such as a styrene skeleton, and endows the compound with good antitumor activity. Research shows that the quinazoline derivatives have good antitumor effect on KRAS G12C mutant non-small cell lung cancer, and have the advantages of multi-target action, regulation of Src kinase and related Stat, mTOR, Akt, PI3k downstream signal pathways, and reduction of tumor drug resistance. Compared with a compound with a complex structure, the quinazoline derivatives have a simple structure, are easy to prepare, and have a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and specifically relates to quinazoline derivatives, a preparation method, a composition and a use. BACKGROUND

[0002] Cancer, also known as malignant tumor, is caused by the uncontrolled over-proliferation of normal cells in the body. In recent years, the incidence of cancer has gradually increased. According to the Global Cancer Report 2020 of the World Health Organization, there were 19.29 million new cancer cases and 9.96 million cancer deaths worldwide.

[0003] Quinazoline and stilbene derivatives have various biological activities and are a low-toxicity drug scaffold that can be developed. Among various heterocyclic compounds, quinazoline scaffolds have been recognized as a multifunctional pharmacophore for anticancer drugs. Quinazoline is one of the most active categories of nitrogen-containing heterocyclic compounds. As a privileged scaffold widely used in clinical anticancer drugs, quinazoline blocks are important structural components of several commercial anticancer prescription drugs approved by the US Food and Drug Administration, such as gefitinib and lapatinib. A large number of antitumor drugs with quinazoline structure are disclosed in patent documents such as WO2021083346A1, WO2023083269A1 and CN107226815A.

[0004] Compounds containing stilbene parent nucleus, represented by resveratrol, have good biological activity. Based on the stilbene skeleton, medicinal chemists have developed stilbene drugs with functions such as antiviral, antitumor and anti-inflammatory by various drug design strategies, such as different substitutions on the benzene ring or replacement of the benzene ring with aromatic heterocycles. For example, the stilbene derivatives of tetramethylpyrazine disclosed in patent document CN100586937C have the effect of resisting ischemia.

[0005] Although medicinal chemists have been trying to find highly efficient antitumor drugs from quinazoline and stilbene compounds, the molecular design and modification of quinazoline antitumor drugs have become increasingly complex, and there has been no effective structural combination investigation with stilbene derivatives. The literature “Design, synthesis, and antitumor activity of novel quinazoline derivatives” (Molecules, 2017, 22(10): 1624.) only investigated the introduction of stilbene structure into the specific position of the 4-substituent of 4, 6, 7-trisubstituted quinazoline, which is still limited to the structural optimization of existing trisubstituted quinazoline. SUMMARY

[0006] In view of the above, the present application aims to provide quinazoline derivatives, preparation methods, compositions and uses. The quinazoline derivatives of the present application have good anti-tumor function. In order to achieve the above-mentioned application purposes, the technical solutions of the present application are as follows.

[0007] The quinazoline derivative has the structure shown in formula I:

[0008]

[0009] In formula I, Ar is an aromatic group.

[0010] Preferably, the aromatic group is selected from any one of 2-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,5-dimethoxybenzene, 4-dimethylaminobenzene, 4-diethylaminobenzene, 4-piperidylbenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl.

[0011] The preparation method of the aforementioned quinazoline derivative comprises the following steps:

[0012] S1: condensation reaction of o-aminoacetophenone and aromatic aldehyde in an alcohol solvent under the action of sodium hydroxide to prepare o-aminochalcone shown in formula I-a;

[0013]

[0014] The aromatic aldehyde is one of 2-methoxybenzaldehyde, 2,3-dimethoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 2,6-dimethoxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-diethylaminobenzaldehyde, 4-piperidylbenzaldehyde, 2-pyridylcarboxaldehyde, 3-pyridylcarboxaldehyde, 4-pyridylcarboxaldehyde, 3-indolylcarboxaldehyde;

[0015] S2: reaction of o-aminochalcone shown in formula I-a in methanol under the action of ammonium acetate, cuprous chloride and tert-butyl hydroperoxide to prepare the quinazoline derivative shown in formula I.

[0016] Preferably, in step S1, the weight ratio of o-aminoacetophenone to aromatic aldehyde is 3:(1-3.5), preferably 3:(1.5-3.2); the weight ratio of sodium hydroxide to o-aminoacetophenone is 3:(1-3.5), preferably 3:(1-3); the alcohol solvent is methanol or ethanol; the condensation reaction temperature is 20-30℃, and the reaction time is 5-10h.

[0017] Preferably, in step S2, the weight ratio of the o-aminochalcone to ammonium acetate is 2.5:(1-3), preferably 2.5:(1-2.5); the weight ratio of the o-aminochalcone to cuprous chloride is 2.5:(0.05-0.3), preferably 2.5:(0.08-0.25); the weight ratio of the o-aminochalcone to tert-butyl hydroperoxide is 2.5:(0.5-3), preferably 2.5:(0.9-2.5); the temperature of the condensation reaction is 50-80°C, and the time is 5-10h.

[0018] A pharmaceutical composition containing the aforementioned quinazoline derivative or salt thereof, and a pharmaceutically acceptable excipient.

[0019] Preferably, the pharmaceutical composition further contains at least one of the following drugs: gefitinib, erlotinib, icotinib, afatinib, dacomitinib, lapatinib, Dacomitinib, Vandetanib, Varlitinib, Verubulin, Avadomide\Tesevatinib, Epertinib, Allitinib, Sapitinib, Irbinitinib, Poziotinib, Canertinib, Simotinib, Selatinib, Saracatinib, Idelalisib, Raltitrexed, Plevitrexed, Cediranib, Furquatnib, Ispinesib, Barasertib, Tandutinib, Sotrastaurin.

[0020] Preferably, the pharmaceutical composition is at least one of an oral preparation, an injection preparation, a transdermal absorption preparation, and an inhalation preparation.

[0021] The use of the aforementioned quinazoline derivative or its composition in the preparation of an antitumor drug, such as an anti-human myeloid leukemia drug, an anti-liver cancer drug, an anti-pancreatic cancer drug, an anti-lung cancer drug, an anti-breast cancer drug, an anti-gastric cancer drug.

[0022] Preferably, the tumor is a KRAS mutation-positive tumor.

[0023] Preferably, the tumor is a tumor in which Src kinase is involved or mediated.

[0024] Preferably, the tumor is at least one of chronic myeloid leukemia cells, liver cancer, pancreatic cancer, pancreatic ductal carcinoma, non-small cell lung cancer, and small cell lung cancer.

[0025] Advantages of the present application:

[0026] (1) The quinazoline-stilbene derivative of the present application combines the pharmacophore of quinazoline and stilbene structure, has good anti-tumor effect, especially for KRAS G12C mutant non-small cell lung cancer has good inhibitory effect.

[0027] (2) The quinazoline-stilbene derivative of the present application has the advantage of multi-target effect, in addition to the inhibitory effect on KRAS mutant tumor, it has significant regulation effect on Src kinase and related Stat, mTOR, Akt, PI3k and other downstream signal pathways, which is beneficial to reduce tumor drug resistance.

[0028] (3) The quinazoline-stilbene derivative of the present application has a simpler structure than the quinazoline compound with complex structure modification, is easy to prepare, and has good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 is the experimental result of example 16;

[0030] Figure 2 is the experimental result of example 17;

[0031] Figure 3 is the experimental result of example 18;

[0032] Figure 4 is the experimental result of example 19. DETAILED DESCRIPTION

[0033] The technical solutions and effects of the present application will be clearly explained by specific examples in combination with the accompanying drawings. The examples are only an explanation and description of the technical solutions of the present application, and are not regarded as a limitation of the protection scope of the present application. The initial raw materials used in the examples are all known compounds available in the market.

[0034] The quinazoline-stilbene derivative of the present application has the structure shown in formula I:

[0035]

[0036] In formula I, Ar is an aromatic group; wherein the aromatic group is preferably 2-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,5-dimethoxybenzene, 4-dimethylaminobenzene, 4-diethylaminobenzene, 4-piperidylbenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl.

[0037] In the present application, the quinazoline-stilbene derivative having the structure shown in formula I can adopt the following synthesis route:

[0038]

[0039] Specifically, the preparation method of quinazoline zirconia derivatives having the structure shown in Formula I includes the following steps:

[0040] S1: Under the action of sodium hydroxide, o-aminoacetophenone and aromatic aldehyde undergo a condensation reaction in an alcohol solvent to prepare o-aminochalcone as shown in formula Ia;

[0041]

[0042] The aromatic aldehyde is, in sequence, 2-methoxybenzaldehyde, 2,3-dimethoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 2,6-dimethoxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-diethylaminobenzaldehyde, 4-piperidinylbenzaldehyde, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and 3-indolyl substituents corresponding to the following in Formula I: 2-methoxybenzaldehyde, 2,3-dimethoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 2,6-dimethoxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-diethylaminobenzaldehyde, 4-piperidinylbenzaldehyde, 2-pyridinylformaldehyde, 3-pyridinylformaldehyde, 4-pyridinylformaldehyde, and 3-indolylformaldehyde.

[0043] S2: The o-aminochalcone shown in Formula Ia is reacted in methanol with ammonium acetate, cuprous chloride and tert-butanol peroxide to prepare the quinazoline zirconia derivative shown in Formula I.

[0044] The compounds of formula I can be selected from compounds I-1 to I-13 of the following formulas:

[0045]

[0046] Example 1: Synthesis of Compound I-1: (E)-4-(2-methoxystyryl)quinazoline

[0047] Add 3.0 g of o-aminoacetophenone and 3.0 g of 2-methoxybenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. Add 3.0 g of sodium hydroxide in an ice bath at 0 °C, then transfer to 20 °C and stir for 5 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 2-methoxysubstituted o-aminochalcone (ESI-MS (M+H)). + (254.2), with a yield of 90.0%.

[0048] 2.5 g of 2-methoxy-substituted o-aminochalcone and 200 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 2.5 g of ammonium acetate and 2.5 g of tert-butanol peroxide. The mixture was stirred at 50 °C for 5 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 gave compound I-1(E)-4-(2-methoxystyryl)quinazoline, with a yield of 73.8%. ESI-MS (M+H) of compound I-1 was obtained. + :262.3.

[0049] NMR data for compound I-1: 1 H NMR (400MHz, CDCl3): δ9.28 (s, 1H), 8.54 (d, J = 15.8Hz, 1H), 8.22 (d, J = 8.8Hz, 1H), 8.03-7.93 (m, 2H), 7.80 (t, J = 7.6Hz, 1H), 7.67 (dd,J=1.4Hz,6.4Hz,1H),7.56(t,J=7.6Hz,1H),7.30(t,J=7.6Hz,1H),6.97(t,J=7.6Hz,1H),6.89(d,J=8.3Hz,1H),3.88(s,3H). 13 C NMR (100MHz, CDCl3) δ162.66,158.38,135.42,133.41,130.96,128.79,128.76 ,127.30,124.72,124.02,120.97,120.72,111.12,77.58,77.26,76.94,55.48.

[0050] Example 2: Synthesis of Compound I-2: (E)-4-(2,3-dimethoxystyryl)quinazoline

[0051] Add 3.0 g of o-aminoacetophenone and 2.7 g of 2,3-dimethoxybenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 2.3 g of sodium hydroxide in an ice bath at 0 °C, the mixture is stirred at 30 °C for 7 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 2,3-dimethoxysubstituted o-aminochalcone (ESI-MS (M+H)). + (284.3), with a yield of 77.3%.

[0052] 2.5 g of 2,3-dimethoxy-substituted o-aminochalcone and 210 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.1 g of ammonium acetate and 1.2 g of tert-butanol peroxide. The mixture was stirred at 70 °C for 7 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined and eluted with petroleum ether / ethyl acetate (v / v) 1:1 to give compound I-2: (E)-4-(2,3-dimethoxystyryl)quinazoline, with a yield of 55.6%. The ESI-MS [M+H]+ of compound I-2 was 292.1.

[0053] NMR data for compound I-2: 1 H NMR (400MHz, CDCl3): δ9.26(s,1H),8.51(d,J=15.8Hz,1H),8.30(d,J=8.8Hz,1H),8.02(d,J=8.2Hz,1H),7.95(d,J=15.8Hz,1 H),7.87(t,J=7.6Hz,1H),7.69-7.60(m,2H),6.57(dd,J=2.4Hz,8.6Hz,1H),6.51(d,J=2.4Hz,1H),3.95(s,3H),3.87(s,3H). 13 C NMR (100MHz, CDCl3) δ163.21,162.46,160.02,135.69,133.43,130.52,128.73,127.23,124.15,118.54,118.07,105.38,98.50,55.61,55.51.

[0054] Example 3: Synthesis of Compound I-3: (E)-4-(2,4-dimethoxystyryl)quinazoline

[0055] Add 3.0 g of o-aminoacetophenone and 2.6 g of 2,4-dimethoxybenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry ethanol. After adding 1.6 g of sodium hydroxide in an ice bath at 0 °C, the mixture is stirred at 25 °C for 7 h. After the reaction is complete, pour the reaction mixture into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 2,4-dimethoxysubstituted o-aminochalcone (ESI-MS (M+H)). + (284.3), with a yield of 68.3%.

[0056] 2.5 g of 2,4-dimethoxy-substituted o-aminochalcone and 90 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.5 g of ammonium acetate and 1.8 g of tert-butanol peroxide. The mixture was stirred at 80 °C for 5 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-3: (E)-4-(2,4-dimethoxystyryl)quinazoline, with a yield of 55.9%. ESI-MS (M+H) of compound I-3 was analyzed. + :292.1.

[0057] NMR data for compound I-3: 1 H NMR (400MHz, CDCl3): δ9.26(1H,s),8.51(1H,d,J=15.8Hz), 8.30(1H,d,J=8.8Hz), 8.02(1H,d,J=8.2Hz), 7.95(1H,d,J=15.8H z),7.87(1H,t,J=7.6Hz),7.69-7.60(2H,m),6.57(1H,dd,J=8.6Hz,2.4Hz),6.51(1H,d,J=2.4Hz),3.95(3H,s),3.87(3H,s). 13 C NMR (100MHz, CDCl3) δ163.21,162.46,160.02,135.69,133.43,130.52,128.73,127.23,124.15,118.54,118.07,105.38,98.50,55.61,55.51.

[0058] Example 4: Synthesis of Compound I-4: (E)-4-(2,5-dimethoxystyryl)quinazoline

[0059] Add 3.0 g of o-aminoacetophenone and 3.2 g of 2,5-dimethoxybenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 1.0 g of sodium hydroxide in an ice bath at 0 °C, the mixture is stirred at 20 °C for 8 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 2,5-dimethoxy-substituted o-aminochalcone (ESI-MS (M+H)). + (284.3), with a yield of 58.3%.

[0060] 2.5 g of 2,5-dimethoxy-substituted o-aminochalcone and 250 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 900 mg of ammonium acetate and 900 mg of tert-butanol peroxide. The mixture was stirred at 50 °C for 9 h, and the reaction was monitored until complete. The reaction was stopped by adding water. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 gave compound I-4: (E)-4-(2,5-dimethoxystyryl)quinazoline, with a yield of 48.9%. ESI-MS (M+H) of compound I-4 was analyzed. + :292.1.

[0061] NMR data for compound I-4: 1 H NMR (400MHz, CDCl3): δ9.28(1H,s),8.51(1H,d,J=15.8Hz),8.27(1H,d,J=8.8Hz),8.05-7.95(2H,m),7.86( 1H,t,J=7.6Hz),7.62(1H,t,J=7.6Hz),7.25(1H,d,J=2.4Hz),6.93-6.84(2H,m),3.89(3H,s),3.82(3H,s). 13 C NMR (100MHz, CDCl3) δ162.70,154.71,153.53,153.00,150.82,135.45,133.56,128. 72,127.42,125.39,124.06,123.07,121.37,116.17,113.85,112.30,56.09,55.82.

[0062] Example 5: Synthesis of Compound I-5: (E)-4-(2,6-dimethoxystyryl)quinazoline

[0063] Add 3.0 g of o-aminoacetophenone and 1.8 g of 2,6-dimethoxybenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 2.2 g of sodium hydroxide in an ice bath at 0 °C, the mixture is stirred at 20 °C for 10 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 2,6-dimethoxysubstituted o-aminochalcone (ESI-MS (M+H)). + (284.3), with a yield of 71.1%.

[0064] 2.5 g of 2,6-dimethoxy-substituted o-aminochalcone and 85 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 2.5 g of ammonium acetate and 1.8 g of tert-butanol peroxide. The mixture was stirred at 50 °C for 9 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-5: (E)-4-(2,6-dimethoxystyryl)quinazoline, with a yield of 52.3%. ESI-MS (M+H) of compound I-5 was analyzed. + :292.1.

[0065] NMR data for compound I-5: 1 H NMR (400MHz, CDCl3): δ9.29(1H,s),8.72(1H,d,J=15.8Hz), 8.45(1H,d,J=15.8Hz), 8.26(1H,d,J=8.8Hz), 8.00(1H, d,J=8.8Hz), 7.83(1H,t,J=7.6Hz), 7.59(1H,t,J=7.6Hz), 7.25(1H,t,J=7.6Hz), 6.59(2H,d,J=8.0Hz), 3.94(6H,s). 13 C NMR (100MHz, CDCl3) δ163.96,160.01,154.93,150.88,133.29,131.09,130.77,128.69,127.12,124.33,123.29,123.27,113.61,103.80,55.93.

[0066] Example 6: Synthesis of Compound I-6: (E)-4-(3,5-dimethoxystyryl)quinazoline

[0067] Add 3.0 g of o-aminoacetophenone and 1.5 g of 3,5-dimethoxybenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 2.3 g of sodium hydroxide in an ice bath at 0 °C, the mixture is transferred to 30 °C and stirred for 5 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 3,5-dimethoxysubstituted o-aminochalcone (ESI-MS (M+H)). + (284.3), with a yield of 71.1%.

[0068] 2.5 g of 3,5-dimethoxy-substituted o-aminochalcone and 185 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.9 g of ammonium acetate and 2.0 g of tert-butanol peroxide. The mixture was stirred at 50 °C for 9 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-6: (E)-4-(3,5-dimethoxystyryl)quinazoline, with a yield of 66.3%. ESI-MS (M+H) of compound I-6 was analyzed. + :292.1.

[0069] NMR data for compound I-6: 1 H NMR (400MHz, CDCl3): δ9.25(1H,s),8.21(1H,d,J=8.8Hz), 8.14(1H,d,J=15.6Hz), 7.99(1H,d,J=8.8Hz ),7.86-7.76(2H,m),7.59(1H,t,J=7.2Hz),6.81(2H,d,J=2.4Hz),6.47(1H,t,J=2.4Hz),3.81(6H,s). 13 C NMR (100MHz, CDCl3) δ161.79,160.98,154.67,151.00,139.73,137.61,133.54,128.92,127.43,123.82,122.93,120.72,106.01,101.86,55.38.

[0070] Example 7: Synthesis of Compound I-7: (E)-4-(4-dimethylaminostyryl)quinazoline

[0071] Add 3.0 g of o-aminoacetophenone and 2.7 g of 4-dimethylaminobenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 2.5 g of sodium hydroxide in an ice bath at 0 °C, the mixture is stirred at 20 °C for 10 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluents and remove the organic solvent to obtain 4-dimethylamino-substituted o-aminochalcone (ESI-MS (M+H)). + (267.2), yield reached 51.1%.

[0072] 2.5 g of 4-dimethylamino-substituted o-aminochalcone and 215 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.1 g of ammonium acetate and 2.0 g of tert-butanol peroxide. The mixture was stirred at 50 °C for 10 h, and the reaction was monitored until complete. The reaction was stopped by adding water. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-7: (E)-4-(4-dimethylaminostyryl)quinazoline, with a yield of 36.3%. ESI-MS (M+H) of compound I-7 was analyzed. + :275.3.

[0073] NMR data for compound I-7: 1 H NMR (400MHz, CDCl3): δ9.21 (1H, s), 8.34-8.25 (2H, m), 8.02 (1H, d, J = 8.8Hz), 7.87 (1H, t, J=7.2Hz),7.71(1H,d,J=15.6Hz),7.67-7.61(3H,m),6.74(2H,d,J=8.4Hz),3.06(6H,s).

[0074] Example 8: Synthesis of Compound I-8: (E)-4-(4-diethylaminostyryl)quinazoline

[0075] Add 3.0 g of o-aminoacetophenone and 2.1 g of 4-diethylaminobenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 1.5 g of sodium hydroxide in an ice bath at 0 °C, the mixture is transferred to 20 °C and stirred for 10 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 4-diethylamino-substituted o-aminochalcone (ESI-MS (M+H)). + (295.2), with a yield of 61.1%.

[0076] 2.5 g of 4-diethylamino-substituted o-aminochalcone and 215 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.1 g of ammonium acetate and 2.0 g of tert-butanol peroxide. The mixture was stirred at 50 °C for 10 h, and the reaction was monitored until complete. The reaction was stopped by adding water. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 gave compound I-8: (E)-4-(4-diethylaminostyryl)quinazoline, with a yield of 56.3%. ESI-MS (M+H) of compound I-8 was analyzed. + :303.1.

[0077] NMR data for compound I-8: 1 H NMR (400MHz, CDCl3): δ9.20 (1H, s), 8.30 (1H, d, J = 8.8Hz), 8.25 (1H, d, J = 15.6Hz), 7.99 (1H, d, J = 8.8Hz), 7.85 (1H, t, J = 7.2Hz), 7.67 (1H, d, J = 15.6Hz), 7.64-7.58 (3H, m), 6.70 (2H, d, J = 8.8Hz), 3.42 (4H, q, J = 7.2Hz), 1.21 (6H, t, J = 7.4Hz). 13 C NMR (100MHz, CDCl3) δ162.93,154.82,150.91,149.15,140.60,133.26,130.24, 128.80,127.01,124.04,122.94,122.90,114.17,111.39,111.37,44.53,12.67.

[0078] Example 9: Synthesis of Compound I-9: (E)-4-(4-piperidinylstyryl)quinazoline

[0079] Add 3.0 g of o-aminoacetophenone and 3.0 g of 4-piperidinylbenzaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. Add 3.0 g of sodium hydroxide in an ice bath at 0 °C, then transfer to 20 °C and stir for 5 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 4-piperidinyl-substituted o-aminochalcone (ESI-MS (M+H)). + (307.4), with a yield of 90.0%.

[0080] 2.5 g of 4-piperidinyl-substituted o-aminochalcone and 200 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 2.0 g of ammonium acetate and 2.0 g of tert-butanol peroxide. The mixture was stirred at 50 °C for 5 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-9: (E)-4-(4-piperidinylstyryl)quinazoline, with a yield of 73.8%. ESI-MS (M+H) of compound I-9 was performed. + :315.1.

[0081] NMR data for compound I-9: 1H NMR (400MHz, CDCl3): δ9.20 (1H, s), 8.29 (1H, d, J = 8.8Hz), 8.23 ​​(1H, d, J = 15.6Hz), 7.99 (1H, d, J = 8.8Hz), 7.65 (1H, t, J=7.2Hz), 7.72(1H,d,J=15.6Hz), 7.64-7.58(3H,m), 6.92(2H,d,J=8.8Hz), 3.29(4H,t,J=7.2Hz), 1.72-1.59(6H,m).

[0082] Example 10: Synthesis of Compound I-10: (E)-4-(2-pyridyl)quinazoline

[0083] Add 3.0 g of o-aminoacetophenone and 2.7 g of 2-pyridinecarboxaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry ethanol. Add 2.3 g of sodium hydroxide in an ice bath at 0 °C, then transfer to 30 °C and stir for 7 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 2-pyridine-substituted o-aminochalcone (ESI-MS (M+H)). + (225.1), with a yield of 77.3%.

[0084] 2.5 g of 2-pyridyl-substituted o-aminochalcone and 210 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.1 g of ammonium acetate and 1.2 g of tert-butanol peroxide. The mixture was stirred at 70 °C for 7 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-10: (E)-4-(2-pyridinylvinyl)quinazoline, in 55.6% yield. ESI-MS (M+H) of compound I-10 was performed. + :223.1.

[0085] NMR data for compound I-10: 1H NMR (400MHz, CDCl3): δ9.30 (1H, s), 8.70 (1H, d, J = 8.8Hz), 8.60 (1H, d, J = 15.6Hz), 8.45 (1H, d, J = 8.8Hz), 8.21 (1H, d, J = 15.6Hz), 8.03 (1H,d,J=9.6Hz),7.89(1H,td,J=7.8Hz,2.0Hz),7.66(1H,td,J=7.8Hz,2.0Hz),7.48(1H,d,J=7.4Hz),7.28(1H,dd,J=7.5Hz,4.8Hz). 13 C NMR (100MHz, CDCl3) δ161.77,154.78,153.75,151.22,150.02,137.80,137.10,133.84,128.93,127.72,125.36,124.77,124.41,123.91,123.43.

[0086] Example 11 Synthesis of Compound I-11: (E)-4-(3-pyridyl)quinazoline

[0087] Add 3.0 g of o-aminoacetophenone and 2.7 g of 3-pyridinecarboxaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. Add 2.3 g of sodium hydroxide in an ice bath at 0 °C, then transfer to 30 °C and stir for 7 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 3-pyridine-substituted o-aminochalcone (ESI-MS (M+H)). + (225.1), with a yield of 67.3%.

[0088] 2.5 g of 3-pyridyl-substituted o-aminochalcone and 210 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.1 g of ammonium acetate and 1.2 g of tert-butanol peroxide. The mixture was stirred at 70 °C for 7 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-11: (E)-4-(3-pyridinylvinyl)quinazoline, with a yield of 59.6%. ESI-MS (M+H) of compound I-11 was analyzed. + :223.1.

[0089] NMR data for compound I-11: 1H NMR (400MHz, CDCl3): δ9.27(1H,s),8.92(1H,s),8.59(1H,d,J=4.9Hz), 8.27(1H,d,J=8.8Hz), 8.22(1H,d,J=15.6Hz), 8.03(1H,d,J=8.8Hz), 8.0 0(1H,dt,J=7.8Hz,1.6Hz),7.96(1H,d,J=15.6Hz),7.88(1H,td,J=7.8Hz,2.0Hz),7.66(1H,td,J=7.8Hz,2.0Hz),7.36(1H,dd,J=7.5Hz,4.8Hz). 13 C NMR (100MHz, CDCl3) δ161.27,154.72,151.19,150.28,149.52,136.01,134.39,133.86,129.15,127.83,123.86,123.72,122.98,122.51.

[0090] Example 12 Synthesis of Compound I-12: (E)-4-(4-pyridyl)quinazoline

[0091] Add 3.0 g of o-aminoacetophenone and 2.7 g of 4-pyridinecarboxaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 2.5 g of sodium hydroxide in an ice bath at 0 °C, the mixture is transferred to 30 °C and stirred for 7 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluents and remove the organic solvent to obtain 4-pyridine-substituted o-aminochalcone (ESI-MS (M+H)). + (225.1), with a yield of 76.3%.

[0092] 2.5 g of 4-pyridyl-substituted o-aminochalcone and 210 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.1 g of ammonium acetate and 1.2 g of tert-butanol peroxide. The mixture was stirred at 70 °C for 7 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 gave compound I-12: (E)-4-(4-pyridinylvinyl)quinazoline, with a yield of 45.6%. ESI-MS (M+H) of compound I-12 was analyzed. + :223.1.

[0093] NMR data for compound I-12: 1H NMR (400MHz, CDCl3): δ9.35(1H,s),8.74(2H,s),8.33(1H,d,J=8.8Hz), 8.21(1H,d,J=15.6Hz), 8.13(1H,d,J=15.6Hz), 8.10(1H, d, J=8.8Hz), 8.00 (1H, dt, J=7.8Hz, 1.6Hz), 7.96 (1H, td, J=7.8Hz, 2.0Hz), 7.73 (1H, td, J=7.8Hz, 2.0Hz), 7.62 (2H, d, J=3.4Hz). 13 C NMR (100MHz, CDCl3) δ160.83,154.74,151.32,149.96,143.61,136.63,134.01,129.28,128.03,125.37,123.62,123.11.

[0094] Example 13 Synthesis of Compound I-13: (E)-4-(3-indolyl)quinazoline

[0095] Add 3.0 g of o-aminoacetophenone and 2.5 g of 3-indolecarboxaldehyde to a dry 50 mL three-necked round-bottom flask, then add 15 mL of dry methanol. After adding 2.3 g of sodium hydroxide in an ice bath at 2 °C, the mixture is stirred at 30 °C for 5 h. After the reaction is complete, pour the reaction solution into 50 mL of water and extract with dichloromethane (50 mL × 3). Combine the organic layer extracts and perform column chromatography using 200-300 mesh silica gel, eluting with a petroleum ether / acetone (v / v) 4:1 system. Combine the eluates and remove the organic solvent to obtain 3-indole-substituted o-aminochalcone (ESI-MS (M+H)). + (263.1), with a yield of 71.1%.

[0096] 2.5 g of 3-indolyl-substituted o-aminochalcone and 185 mg of cuprous chloride were added to a 50 mL round-bottom flask, dissolved in 20 mL of methanol, followed by the addition of 1.9 g of ammonium acetate and 2.0 g of tert-butanol peroxide. The mixture was stirred at 50 °C for 9 h, and the reaction was monitored until complete. Water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined for column chromatography. Elution with petroleum ether / ethyl acetate (v / v) 1:1 yielded compound I-13: (E)-4-(3-indolylstyryl)quinazoline, with a yield of 66.3%. ESI-MS (M+H) of compound I-13 was analyzed. + :271.1.

[0097] NMR data for compound I-13: 1H NMR (400MHz, DMSO-d6): δ13.67(1H,s),9.30(1H,s),8.74(1H,d,J=8.8Hz),8.59(1H,d,J=15.6Hz),8.43(1H,d,J=8.8Hz),8.38(1H, d,J=15.6Hz),8.08-8.00(2H,m),7.81(1H,td,J=7.8Hz,2.0Hz),7.67(1H,d,J=8.2Hz),7.50(1H,t,J=8.2Hz),7.35(1H,t,J=8.2Hz). 13 C NMR(100MHz,d6-DMSO)δ162.04,155.00,151.06,141.93,141.77,134.65,131.66, 128.73,128.38,127.14,125.41,122.78,122.41,121.67,121.47,121.20,111.30.

[0098] Example 14 Antitumor Activity Test

[0099] Experimental method: Sulfodamine B (SRB) detection method.

[0100] Cell line: Human non-small cell lung cancer NCI-H358 (a KRAS-based cell line) G12C (Mutation-positive lung cancer cells). Specifically, the glycine at position 12 of the KRAS protein is mutated to cysteine ​​(G12C).

[0101] Cells in the logarithmic growth phase were digested with trypsin and then seeded into 96-well plates at a density of 5 × 10⁶ cells / well. 3 Cells / well. After adhesion, cells were cultured for 72 h with different concentrations of quinazoline zirconia derivatives. The control group was treated with an equal-diluted cell-grade DMSO (dimethyl sulfoxide). Absorbance at 515 nm was measured using the SRB method. Absorbance (OD value) reflects cell viability, and the cell proliferation inhibition rate of the compound was calculated based on the OD value. The IC50 was calculated using SPSS 11.0 software based on the cell proliferation inhibition rate. 50 .

[0102] Proliferation inhibition rate % = [(OD 对照组 -OD I-4组 [(OD control group)] x 100%

[0103] The antitumor activities of some compounds of this invention are shown in Table 1.

[0104] Table 1. Antitumor activity of quinazoline derivatives

[0105]

[0106]

[0107] The results showed that some of the compounds I-1, I-2, I-4, I-5, I-6, I-10, I-11, I-12, and I-13 provided in this invention exhibited strong inhibitory activity against human non-small cell lung cancer NCI-H358, with an IC50 concentration of 1 / 3. 50 The values ​​were below 10 μM. Other compounds in Table 1 also showed good inhibitory effects on non-small cell lung cancer NCI-H358.

[0108] Example 15: Activity test of quinazoline zirconia derivative I-4 against multiple tumor cell lines

[0109] The inhibitory activity of quinazoline derivative I-4 against various other tumor cell lines was determined using the conventional MTT assay, including chronic myeloid leukemia cell line K562, human liver cancer cell line Huh7, pancreatic cancer cell line PANC-1, human pancreatic ductal carcinoma passageable cell line MIA-PaCa-2, non-small cell lung cancer cell line A549, human small cell lung cancer cell line H466, and drug-resistant small cell lung cancer cell line H69AR. The activity results are shown in Table 2.

[0110] Table 2. Activity of quinazoline zirconia derivative I-4 against various tumor cell lines.

[0111] Cell lines IC 50 (μM) K562 3.01 Huh7 3.537 PANC-1 6.532 MIA-PaCa-2 8.335 A549 8.454 H466 9.54 H69AR 24

[0112] The results showed that the quinazoline derivative I-4 provided by this invention exhibited strong inhibitory activity against various tumor cell lines. Except for human non-small cell lung cancer NCI-H358 in Example 16, it also showed significant inhibitory activity against chronic myeloid leukemia cells K562, human liver cancer cell line Huh7, pancreatic cancer cell line PANC-1, human pancreatic ductal carcinoma passageable cell line MIA-PaCa-2, non-small cell lung cancer cell line A549, and human small cell lung cancer cell line H466. 50 Below 10 μM. IC50 against the drug-resistant small cell lung cancer cell line H69AR. 50 It can also reach 24μM.

[0113] Example 16: Quinazoline zirconia derivative I-4 improves the thermal stability of Src protein

[0114] NCI-H358 cells were resuspended in PBS (phosphate-buffered saline) and then frozen and thawed three times with liquid nitrogen. Subsequently, the cells were incubated with DMSO or I-4 (8 μM) for 30 minutes. Samples were then heated at different temperatures using a Biometra-TOne PCR instrument (Analytikjena, Germany), and centrifuged at 20000×g for 20 minutes at 4°C. The supernatant was collected, and loading buffer was added before boiling. An 8% SDS-PAGE gel was prepared, and the sample was added for protein electrophoresis. After electrophoresis, the bands were transferred to an NC membrane (nitrocellulose membrane). The membrane was blocked with rapid blocking buffer for 15 minutes and incubated with primary antibody overnight at 4°C. Cells were washed four times with TBST for 5 minutes each time, incubated with secondary antibody at room temperature for 1 hour, and protein expression was detected by ECL luminescence. Protein levels were analyzed using standard Western blotting.

[0115] The experimental results are attached. Figure 1 Compound I-4 improved the thermal stability of the Src protein, suggesting that compound I-4 can bind to the Src protein.

[0116] Example 17: Src protein is one of the target proteins of quinazoline zirconia derivative I-4.

[0117] The binding of I-4 to the Src protein was analyzed using surface resonance (SPR) ion technology. I-4 was coupled to the Graft-to-PCL biochip surface using the SpotBot3 microarray control software in the SpotBot3 platform, and the compound on the chip surface was cross-linked with UV light for 15 minutes. The Src protein was diluted to 100 nM, 200 nM, and 400 nM with PBS and injected for detection. Buffer: 1×PBS; Regeneration solution: 0.125% SDS; Injection flow rate: 2 μL / s, injection time: 120 s; Dissociation flow rate: 2 μL / s, injection time: 200 s; Regeneration flow rate: 2 μL / s, regeneration time: 200 s. The obtained data were analyzed and fitted using the PLEEXERA SPR Data Analysis Module (DAM) software to obtain the binding kinetic constant (KD).

[0118] The test results are attached. Figure 2 , Figure 2 The curves, from bottom to top, represent DMSO, Src 100 nM, Src 200 nM, and Src 400 nM, respectively. The compound binds to the Src protein with good affinity, exhibiting a binding constant (KD value) of 0.143 μM. These results suggest that the quinazoline zirconia derivative I-4 may directly bind to the Src protein, thereby exerting its antitumor effect.

[0119] Example 18 Regulation of downstream Src signaling pathway molecules by quinazoline zirconia derivative I-4

[0120] NCI-H358 cells in logarithmic growth phase were harvested and distributed at a density of 3 × 10⁶ cells per well. 5 Cells were seeded in 6-well plates. After 6 hours of serum-free transfection with siRNA using Lipofectamine™ 3000, cells were cultured in complete medium for another 48 hours. Src gene silencing is a routine technique; see "Src promotes cutaneous wound healing by regulating MMP-2 through the ERK pathway" (International journal of molecular medicine, 2016, 37(3):639-648). The interference sequences for NCI-H358 cells in the NC and si-Src groups are as follows:

[0121] si-SrcRNA(5'-CGAGUGCCUUAUCCAAGAATT-3');

[0122] NC RNA(5'-UUCUCCGAACGUGUCACGUTT-3').

[0123] NCI-H358 cells from the NC and si-Src groups were collected. After lysing the cells at 4°C for 45 min with loading buffer, samples were collected, boiled for 15 min, and stored at -20°C. An 8% SDS-PAGE gel was prepared, and the samples were added for protein electrophoresis. After electrophoresis, the bands were transferred to an NC membrane (nitrocellulose membrane). The membrane was blocked with rapid blocking buffer for 15 min and incubated with primary antibody overnight at 4°C. The cells were washed four times with TBST for 5 min each time, incubated with secondary antibody at room temperature for 1 h, and protein expression was detected by ECL luminescence.

[0124] The experimental results are attached. Figure 3 NC / - and NC / + represent the negative control group without I-4 and with I-4 for 1 hour, respectively; Si-Src / - and Si-Src / + represent the silenced Src group without I-4 and with I-4 for 1 hour, respectively. Figures A and B show the protein bands and their grayscale analysis, while figures C and D show the interference efficiency.

[0125] The quinazoline tincture derivative I-4 significantly reduced the phosphorylation levels of Stat3, PI3K, Akt, and mTOR molecules, indicating that compound I-4 can inhibit the activation of common proliferation signaling pathway molecules. However, after silencing the Src gene, the phosphorylation levels of downstream Src signaling molecules Stat3, PI3K, Akt, and mTOR no longer decreased, further demonstrating that the quinazoline tincture derivative I-4 can exert its anti-tumor effect by targeting the Src protein.

[0126] Example 19: In vivo inhibition of KRAS by quinazoline zirconia derivative I-4 G12C Growth of mutant NSCLC xenograft tumors

[0127] SPF-grade male BALB / c nude mice (weighing 18–20 g) were acclimatized in the animal room for 7 days. NCI-H358 cells were digested with trypsin, washed twice with pre-cooled PBS by centrifugation, and resuspended. Cells were then cultured at 5 × 10⁻⁶ cells / mL. 6 Cells / mouse were subcutaneously injected into the axillae of nude mice until the average tumor volume in the axillae of the nude mice reached 100 mm. 3 Nude mice were divided into a control group (Ctrl): injected with solvent (10% DMSO, 40% PEG300, 5% Tween 80, 45% physiological saline); a 25 mg / kg I-4 group; a 50 mg / kg I-4 group; and a 100 mg / kg I-4 group; with 5 mice in each group. All groups received intraperitoneal injections once daily. There were no significant differences in tumor volume and body weight among the groups before drug administration. The mice were weighed daily, and the long and short diameters of the tumor were measured every two days using calipers to calculate the tumor volume (tumor volume = long diameter × short diameter). 2 ×0.5). Nude mice were sacrificed on day 31 after drug administration, tumor tissue was dissected, tumor weight was measured, and tumor inhibition rate was calculated (formula: ).

[0128] The experimental results are attached. Figure 4 Compared with the Ctrl group, the tumor inhibition rates of the quinazoline derivative I-4 increased to 42.48%, 49.72%, and 60.39%, respectively, with increasing doses. Furthermore, the tumor volume in the I-4 group was significantly lower than that in the Ctrl group at all time points after administration. The quinazoline derivative I-4 effectively inhibited KRAS in vivo. G12C Growth of mutant NSCLC tumors.

[0129] Gross observations during the experiment, as well as post-mortem examinations and microscopic pathological observations of the animals, showed that, compared with the Ctrl group, no significant toxic reactions were observed in any of the quinazoline derivative I-4 groups.

[0130] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A quinazoline zirconia derivative, characterized in that, It has the structure shown in Equation I: Equation I; In Formula I, Ar is 2,5-dimethoxybenzene.

2. A pharmaceutical composition, characterized in that, Contains the quinazoline derivatives or salts thereof as described in claim 1, and pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to claim 2, characterized in that, The pharmaceutical composition is at least one of the following: oral formulation, injectable formulation, transdermal absorption formulation, and inhalation formulation.

4. The use of the quinazoline derivative of claim 1 or the composition of claim 2 in the preparation of antitumor drugs, characterized in that, The tumor cells were non-small cell lung cancer A549.

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