Quinazoline stilbene derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to quinazoline stilbene derivatives as well as a preparation method, a composition and application thereof. The quinazoline stilbene derivative is synthesized by combining quinazoline with pharmacophores such as a styrene skeleton, and the quinazoline stilbene derivative structurally contains functional units such as a quinazoline functional unit and the pharmacophores such as the styrene skeleton, so that the compound is endowed with good anti-tumor activity. Researches show that the quinazoline stilbene derivative has a good anti-tumor effect including KRASG12C mutation non-small cell lung cancer, has the advantage of multi-target action, has an adjusting effect on Src kinase and related downstream signal channels of Statat, mTOR, Akt and PI3k, and is beneficial to reduction of tumor drug resistance. Compared with a complex structure modified compound, the quinazoline stilbene derivative disclosed by the invention is simple in structure and easy to prepare, and has a good application prospect.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to quinazoline stilbene derivatives and preparation methods, compositions and uses thereof. Background Art

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

[0003] Quinazoline and stilbene derivatives have multiple biological activities and are a low-toxicity drug scaffold that can be developed. Among various heterocyclic compounds, quinazoline scaffolds have been recognized as multifunctional pharmacophores for anticancer drugs. Quinazoline is one of the most active classes of nitrogen-containing heterocyclic compounds. As a privileged scaffold widely used in clinical anticancer drugs, the quinazoline block is an important structural component of several commercial anticancer prescription drugs approved by the US Food and Drug Administration, such as gefitinib and lapatinib. Patent documents such as WO2021083346A1, WO2023083269A1, and CN107226815A disclose a large number of anti-tumor drugs with quinazoline structures.

[0004] Compounds containing stilbene nuclei, represented by resveratrol, have good biological activity. Based on the stilbene skeleton, medicinal chemists have developed stilbene drugs with antiviral, anti-tumor, and anti-inflammatory functions by making different substitutions on the benzene ring or replacing the benzene ring with an aromatic heterocycle through a variety of drug design strategies. For example, the ligustrazine stilbene derivatives disclosed in patent document CN100586937C have anti-ischemic effects.

[0005] Although medicinal chemists have been working hard to find highly effective antitumor drugs from quinazoline and stilbene compounds, the molecular design and modification of quinazoline antitumor drugs have become increasingly complex, but effective structural combination studies with stilbene derivatives have not yet been conducted. The literature "Design, synthesis, and antitumor activity of novel quinazolinederivatives" (Molecules, 2017, 22 (10): 1624.) only introduced stilbene structures into specific positions of the 4-position substituents of 4, 6, and 7 trisubstituted quinazolines, and was still limited to the structural optimization of existing trisubstituted quinazolines. Summary of the invention

[0006] In view of this, the present invention aims to provide quinazoline stilbene derivatives and preparation methods, compositions and uses. The quinazoline stilbene derivatives of the present invention have good anti-tumor function. In order to achieve the above-mentioned invention object, the technical scheme of the present invention is as follows:

[0007] Quinazoline stilbene derivatives have a 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-piperidinylbenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl, and 3-indolyl.

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

[0012] S1: Under the action of sodium hydroxide, o-aminoacetophenone and aromatic aldehyde are subjected to a condensation reaction in an alcohol solvent to prepare o-aminochalcone represented by formula Ia;

[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-piperidinylbenzaldehyde, 2-pyridylcarboxaldehyde, 3-pyridylcarboxaldehyde, 4-pyridylcarboxaldehyde, and 3-indolylcarboxaldehyde;

[0015] S2: The o-aminochalcone represented by formula Ia is reacted in methanol under the action of ammonium acetate, cuprous chloride and tert-butyl peroxide to prepare the quinazoline stilbene derivative represented by 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°C-30°C, and the time is 5h-10h.

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

[0018] A pharmaceutical composition contains the aforementioned quinazoline stilbene derivative or its salt, and pharmaceutically acceptable excipients.

[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, Fruquintinib, 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 stilbene derivatives or their compositions in the preparation of anti-tumor drugs, such as anti-human myeloid leukemia drugs, anti-liver cancer drugs, anti-pancreatic cancer drugs, anti-lung cancer drugs, anti-breast cancer drugs, and anti-gastric cancer drugs.

[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] Beneficial effects of the present invention:

[0026] (1) The quinazoline stilbene derivatives of the present invention combine the pharmacophores of quinazoline and stilbene structures and have good anti-tumor effects, especially for KRAS G12C Mutant non-small cell lung cancer has a good inhibitory effect.

[0027] (2) The quinazoline stilbene derivatives of the present invention have the advantage of multi-target effects. In addition to having an inhibitory effect on KRAS mutant tumors, they have a significant regulatory effect on Src kinase and related downstream signaling pathways such as Stat, mTOR, Akt, PI3k, etc., which is beneficial to reducing tumor resistance.

[0028] (3) Compared with quinazoline compounds with complex structural modifications, the quinazoline stilbene derivatives of the present invention have simpler structures, are easier to prepare, and have good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The experimental results of Example 16 are as follows;

[0030] Figure 2 The experimental results of Example 17 are as follows;

[0031] Figure 3 The experimental results of Example 18 are as follows;

[0032] Figure 4 These are the experimental results of Example 19. DETAILED DESCRIPTION

[0033] The technical scheme and effects of the present invention are clearly described below with reference to the accompanying drawings through specific examples. The examples are only explanations and descriptions of the technical scheme of the present invention and are not to be regarded as limitations on the scope of protection of the present invention. The initial raw materials used in the preparation of the examples are all commercially available known compounds.

[0034] The quinazoline stilbene derivatives of the present invention have a 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-piperidinylbenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl.

[0037] In the present invention, the quinazoline stilbene derivative having the structure shown in Formula I can be synthesized using the following synthesis route:

[0038]

[0039] Specifically, the preparation method of the quinazoline stilbene derivative having the structure shown in Formula I comprises the following steps:

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

[0041]

[0042] The aromatic aldehydes correspond to the 2-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,5-dimethoxybenzene, 4-dimethylaminobenzene, 4-diethylaminobenzene, 4-piperidinylbenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl, and 3-indolyl substituents in formula I 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-pyridylcarboxaldehyde, 3-pyridylcarboxaldehyde, 4-pyridylcarboxaldehyde, and 3-indolylcarboxaldehyde.

[0043] S2: The o-aminochalcone represented by formula Ia is reacted in methanol under the action of ammonium acetate, cuprous chloride and tert-butyl peroxide to prepare the quinazoline stilbene derivative represented by formula I.

[0044] That is, the compound of formula I can be selected from compounds I-1 to I-13 of the following formulas:

[0045]

[0046] Example 1 Compound I-1: Synthesis of (E)-4-(2-methoxyphenylvinyl)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, add 15 mL of dry methanol, add 3.0 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 20 ° C and stir for 5 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 2-methoxy substituted o-amino chalcone (ESI-MS (M+H) + :254.2), the yield reached 90.0%.

[0048] Take 2.5g 2-methoxy substituted o-amino chalcone and 200mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 2.5g ammonium acetate and 2.5g tert-butyl peroxide, stir at 50°C for 5h to monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-1 (E)-4-(2-methoxyphenylvinyl)quinazoline, with a yield of 73.8%. ESI-MS (M+H) of compound I-1 + :262.3.

[0049] NMR data of 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 Compound I-2: Synthesis of (E)-4-(2,3-dimethoxyphenylvinyl)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, add dry 15 mL of methanol, add 2.3 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 30 ° C and stir for 7 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 2,3-dimethoxy substituted o-amino chalcone (ESI-MS (M+H) + :284.3), the yield reached 77.3%.

[0052] 2.5g of 2,3-dimethoxy-substituted o-aminochalcone and 210mg of cuprous chloride were added to a 50ml round-bottom flask, 20ml of methanol was added to dissolve, and 1.1g of ammonium acetate and 1.2g of tert-butyl peroxide were added. After stirring at 70°C for 7h, the reaction of the raw materials was monitored to be complete, and water was added to stop the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined and column chromatography was performed, and the mixture was eluted with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-2: (E)-4-(2,3-dimethoxyphenylvinyl)quinazoline, with a yield of 55.6%. ESI-MS [M+H]+ of compound I-2: 292.1.

[0053] NMR data of 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 Compound I-3: Synthesis of (E)-4-(2,4-dimethoxyphenylvinyl)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, add dry 15 mL of ethanol, add 1.6 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 25 ° C and stir for 7 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 2,4-dimethoxy substituted o-amino chalcone (ESI-MS (M+H) + :284.3), the yield reached 68.3%.

[0056] Take 2.5g 2,4-dimethoxy-substituted o-aminochalcone and 90mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.5g ammonium acetate and 1.8g tert-butyl peroxide, stir at 80°C for 5h to monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-3: (E)-4-(2,4-dimethoxyphenylvinyl)quinazoline, with a yield of 55.9%. ESI-MS (M+H) of compound I-3 + :292.1.

[0057] NMR data of 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 Compound I-4: Synthesis of (E)-4-(2,5-dimethoxyphenylvinyl)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, add dry 15 mL of methanol, add 1.0 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 20 ° C and stir for 8 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 2,5-dimethoxy substituted o-amino chalcone (ESI-MS (M+H) + :284.3), the yield reached 58.3%.

[0060] Take 2.5g 2,5-dimethoxy-substituted o-aminochalcone and 250mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 900mg ammonium acetate and 900mg tert-butyl peroxide, stir at 50°C for 9h to monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-4: (E)-4-(2,5-dimethoxyphenylvinyl)quinazoline, with a yield of 48.9%. ESI-MS (M+H) of compound I-4 + :292.1.

[0061] NMR data of 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 Compound I-5: Synthesis of (E)-4-(2,6-dimethoxyphenylvinyl)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, add 15 mL of dry methanol, add 2.2 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 20 ° C and stir for 10 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent, and obtain 2,6-dimethoxy-substituted o-aminochalcone (ESI-MS (M+H) + :284.3), the yield reached 71.1%.

[0064] Take 2.5g 2,6-dimethoxy-substituted o-aminochalcone and 85mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 2.5g ammonium acetate and 1.8g tert-butyl peroxide, stir at 50°C for 9h, monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-5: (E)-4-(2,6-dimethoxyphenylvinyl)quinazoline, with a yield of 52.3%. ESI-MS (M+H) of compound I-5 + :292.1.

[0065] NMR data of 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 Compound I-6: Synthesis of (E)-4-(3,5-dimethoxyphenylvinyl)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, add 15 mL of dry methanol, add 2.3 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 30 ° C and stir for 5 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent, and obtain 3,5-dimethoxy-substituted o-aminochalcone (ESI-MS (M+H) + :284.3), the yield reached 71.1%.

[0068] Take 2.5g 3,5-dimethoxy-substituted o-aminochalcone and 185mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.9g ammonium acetate and 2.0g tert-butyl peroxide, stir at 50°C for 9h, monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-6: (E)-4-(3,5-dimethoxyphenylvinyl)quinazoline, with a yield of 66.3%. ESI-MS (M+H) of compound I-6 + :292.1.

[0069] NMR data of 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 Compound I-7: Synthesis of (E)-4-(4-dimethylaminophenylvinyl)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, add dry 15 mL of methanol, add 2.5 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 20 ° C and stir for 10 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 4-dimethylamino-substituted o-amino chalcone (ESI-MS (M+H) + :267.2), the yield reached 51.1%.

[0072] Take 2.5g 4-dimethylamino-substituted o-aminochalcone and 215mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.1g ammonium acetate and 2.0g tert-butyl peroxide, stir at 50°C for 10h, monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-7: (E)-4-(4-dimethylaminophenylvinyl)quinazoline, with a yield of 36.3%. ESI-MS (M+H) of compound I-7 + :275.3.

[0073] NMR data of 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 Compound I-8: Synthesis of (E)-4-(4-diethylaminophenylvinyl)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, add dry 15 mL of methanol, add 1.5 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 20 ° C and stir for 10 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 4-diethylamino substituted o-amino chalcone (ESI-MS (M+H) + :295.2), the yield reached 61.1%.

[0076] Take 2.5g 4-diethylamino-substituted o-aminochalcone and 215mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.1g ammonium acetate and 2.0g tert-butyl peroxide, stir at 50°C for 10h, monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-8: (E)-4-(4-diethylaminophenylvinyl)quinazoline, with a yield of 56.3%. ESI-MS (M+H) of compound I-8: + :303.1.

[0077] NMR data of 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 Compound I-9: Synthesis of (E)-4-(4-piperidinylphenylvinyl)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, add 15 mL of dry methanol, add 3.0 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 20 ° C and stir for 5 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 4-piperidinyl substituted o-amino chalcone (ESI-MS (M+H) + :307.4), the yield reached 90.0%.

[0080] Take 2.5g 4-piperidinyl substituted o-amino chalcone and 200mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 2.0g ammonium acetate and 2.0g tert-butyl peroxide, stir at 50°C for 5h, monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-9: (E)-4-(4-piperidinylphenylvinyl)quinazoline, with a yield of 73.8%. ESI-MS (M+H) of compound I-9 + :315.1.

[0081] NMR data of 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 Compound I-10: Synthesis of (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, add dry 15 mL of ethanol, add 2.3 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 30 ° C and stir for 7 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 2-pyridine substituted o-amino chalcone (ESI-MS (M+H) + :225.1), the yield reached 77.3%.

[0084] Take 2.5g 2-pyridyl substituted o-amino chalcone and 210mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.1g ammonium acetate and 1.2g tert-butyl peroxide, stir at 70°C for 7h to monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-10: (E)-4-(2-pyridinylvinyl)quinazoline, with a yield of 55.6%. ESI-MS (M+H) of compound I-10 + :223.1.

[0085] NMR data of 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 Compound I-11: Synthesis of (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, add dry 15 mL of methanol, add 2.3 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 30 ° C and stir for 7 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent to obtain 3-pyridine substituted o-amino chalcone (ESI-MS (M+H) + :225.1), the yield reached 67.3%.

[0088] Take 2.5g 3-pyridyl substituted o-amino chalcone and 210mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.1g ammonium acetate and 1.2g tert-butyl peroxide, stir at 70°C for 7h to monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-11: (E)-4-(3-pyridylvinyl)quinazoline, with a yield of 59.6%. ESI-MS (M+H) of compound I-11 + :223.1.

[0089] NMR data of 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, add dry 15 mL of methanol, add 2.5 g of sodium hydroxide at 0 ° C in an ice bath, and then transfer to 30 ° C and stir for 7 hours. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluents, remove the organic solvent, and obtain 4-pyridine-substituted o-aminochalcone (ESI-MS (M+H) + :225.1), the yield reached 76.3%.

[0092] Take 2.5g 4-pyridyl substituted o-amino chalcone and 210mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.1g ammonium acetate and 1.2g tert-butyl peroxide, stir at 70°C for 7h to monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-12: (E)-4-(4-pyridinylvinyl)quinazoline, with a yield of 45.6%. ESI-MS (M+H) of compound I-12 is + :223.1.

[0093] NMR data of 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 Compound I-13: Synthesis of (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, add dry 15 mL of methanol, add 2.3 g of sodium hydroxide under an ice bath at 2°C, and stir at 30°C for 5 h. After the reaction is completed, pour the reaction solution into 50 mL of water, extract with dichloromethane (50 mL×3), combine the organic layer extracts, use 200-300 mesh silica gel for column chromatography, and elute with petroleum ether / acetone (v / v) 4:1 system, combine the eluates, remove the organic solvent to obtain 3-indolyl substituted o-amino chalcone (ESI-MS (M+H) + :263.1), the yield reached 71.1%.

[0096] Take 2.5g 3-indolyl substituted o-amino chalcone and 185mg cuprous chloride, add them to a 50ml round-bottom flask, add 20ml methanol to dissolve, then add 1.9g ammonium acetate and 2.0g tert-butyl peroxide, stir at 50°C for 9h, monitor the reaction of the raw materials, add water to stop the reaction, extract three times with dichloromethane, combine the organic phases and column chromatography, and elute with petroleum ether / ethyl acetate (v / v) 1:1 to obtain compound I-13: (E)-4-(3-indolylphenylvinyl)quinazoline, with a yield of 66.3%. ESI-MS (M+H) of compound I-13 + :271.1.

[0097] NMR data of 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: Sulforhodamine B (SRB) detection method.

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

[0101] Cells in the logarithmic growth phase were obtained and inoculated into 96-well plates at a density of 5 × 10 3 cells / well. After adhesion, different concentrations of quinazoline stilbene derivatives were added and cultured for 72 hours. The control group was added with an equal dilution of cell-grade DMSO (dimethyl sulfoxide). The absorbance value at 515nm was determined by the SRB method. The absorbance value (OD value) reflects cell viability, and the cell proliferation inhibition rate of the compound was calculated based on the OD value. SPSS11.0 software was used to calculate the IC value 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 anti-tumor activities of some compounds of the present invention are shown in Table 1.

[0104] Table 1 Antitumor activity of quinazoline stilbene derivatives

[0105]

[0106]

[0107] The results showed that some compounds I-1, I-2, I-4, I-5, I-6, I-10, I-11, I-12, and I-13 provided by the present invention had strong proliferation inhibition activity against human non-small cell lung cancer NCI-H358, with a half inhibitory concentration IC 50 The value was below 10 μM. The other compounds in Table 1 also had good inhibitory effects on non-small cell lung cancer NCI-H358.

[0108] Example 15 Test of the activity of quinazoline stilbene derivative I-4 against various tumor cell lines

[0109] Conventional MTT assay was used to determine the inhibitory activity of quinazoline stilbene derivative I-4 against various other tumor cell lines, including chronic myeloid leukemia cells K562, human hepatoma cell line Huh7, pancreatic cancer cell line PANC-1, human pancreatic ductal carcinoma 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 Anti-tumor cell line activity of quinazoline stilbene derivative I-4

[0111] Cell lines <![CDATA[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 show that the compound quinazoline stilbene derivative I-4 provided by the present invention has strong inhibitory activity against the activity of various tumor cell lines. In addition to the human non-small cell lung cancer NCI-H358 in Example 16, the half-inhibitory concentration IC of chronic myeloid leukemia cells K562, human liver cancer cell line Huh7, pancreatic cancer cell line PANC-1, human pancreatic ductal carcinoma cell line MIA-PaCa-2, non-small cell lung cancer cell line A549, and human small cell lung cancer cell line H466 is 50 Below 10 μM. IC for drug-resistant small cell lung cancer cell line H69AR 50 It can also reach 24μM.

[0113] Example 16 Quinazoline stilbene 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. The samples were then heated at different temperatures by Biometra-TOne PCR (Analytikjena, Germany), centrifuged at 20,000 × g for 20 minutes at 4°C, and the supernatant was collected and added to the loading buffer before boiling. An 8% SDS-PAGE gel was prepared, the samples were added and protein electrophoresis was performed. After the electrophoresis was completed, the bands were transferred to the NC membrane (nitrocellulose membrane). Blocked with fast blocking solution for 15 minutes, incubated with primary antibody at 4°C overnight. Washed 4 times with TBST, 5 minutes each time, incubated with secondary antibody at room temperature for 1 hour, and protein expression was detected by ECL luminescence. The protein level was analyzed by conventional Western blotting.

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

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

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

[0118] The test results are as attached Figure 2 , Figure 2 The middle curves are DMSO, Src 100nM, Src 200nM, and Src 400nM from bottom to top. The compound can bind to the Src protein with good affinity, and the binding constant (KD value) is 0.143μM. The results suggest that the quinazoline stilbene derivative I-4 may directly bind to the Src protein, thereby exerting an anti-tumor effect.

[0119] Example 18 Regulation of Src Downstream Signaling Pathway Molecules by Quinazoline Stilbene Derivative I-4

[0120] NCI-H358 cells in the logarithmic growth phase were plated at 3 × 10 5 Cells were seeded in 6-well plates. siRNA was transfected with LipofectamineTM3000 without serum for 6 hours, and then cultured in complete medium for another 48 hours. Cellular Src gene silencing is a conventional technique, which can be found in "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 of NCI-H358 cells in the NC group and si-Src group are as follows:

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

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

[0123] Collect NCI-H358 cells from the NC group and si-Src group, add loading buffer and lyse the cells in a 4°C refrigerator for 45 minutes, collect samples, boil samples for 15 minutes, and store them in a -20°C refrigerator. Prepare 8% SDS-PAGE gel, add samples and perform protein electrophoresis. After the electrophoresis is completed, transfer the bands to the NC membrane (nitrocellulose membrane). Block with fast blocking solution for 15 minutes, incubate the primary antibody at 4°C overnight. Wash with TBST 4 times, 5 minutes each time, incubate the secondary antibody at room temperature for 1 hour, and detect protein expression by ECL luminescence.

[0124] The experimental results are as attached Figure 3 , where 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 group without I-4 and with I-4 for 1 hour after silencing Src, respectively. A and B are protein bands and their grayscale analysis, and C and D are interference efficiency.

[0125] Quinazoline stilbene derivative I-4 can significantly reduce 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 Src downstream signaling molecules Stat3, PI3K, Akt, and mTOR molecules no longer decrease, once again proving that quinazoline stilbene derivative I-4 can exert anti-tumor effects by targeting Src protein.

[0126] Example 19 Quinazoline stilbene derivative I-4 inhibits KRAS in vivo G12C Growth of mutant NSCLC xenografts

[0127] SPF male BALB / C nude mice (weight 18-20 g) were adapted to feeding in the animal room for 7 days. NCI-H358 cells were digested with trypsin, washed twice with pre-cooled PBS by centrifugation and resuspended at 5×10 6 The cells were subcutaneously inoculated in the axilla of nude mice until the average tumor volume in the axilla of nude mice reached 100 mm 3 At the same time, the nude mice were divided into the control group (Ctrl): injection solvent (10% DMSO, 40% PEG300, 5% Tween80, 45% saline); 25mg / kg I-4 group; 50mg / kg I-4 group; 100mg / kg I-4 group; 5 mice in each group, each group was intraperitoneally injected once a day. There was no significant difference in tumor volume and body weight between the groups of nude mice before administration. The nude mice were weighed every day, and the long and short diameters of the tumor were measured with a vernier caliper every two days to calculate the tumor volume (tumor volume = long diameter × short diameter 2 ×0.5). On the 31st day after administration, the nude mice were killed, the tumor tissues were dissected, the tumor weight was weighed, and the tumor inhibition rate was calculated (formula: ).

[0128] The experimental results are as attached Figure 4 Compared with the Ctrl group, with the increase of the dose of quinazoline stilbene derivative I-4, the tumor inhibition rate reached 42.48%, 49.72% and 60.39% respectively. And the tumor volume of the I-4 administration group at each time point after administration was significantly lower than that of the Ctrl group. Quinazoline stilbene derivative I-4 effectively inhibited KRAS in vivo G12C Growth of mutant NSCLC tumors.

[0129] Gross observations during the experiment, autopsy and microscopic pathological observations after the animals were killed showed that compared with the Ctrl group, the animals in the quinazoline stilbene derivative I-4 groups had no obvious toxic reactions.

[0130] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A quinazoline stilbene derivative, characterized in that: It has the structure shown in Formula I: In formula I, Ar is an aromatic group; 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-piperidinylbenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl, and 3-indolyl.

2. The method for preparing the quinazoline stilbene derivatives according to claim 1, characterized in that: The following steps are involved: S1: Under the action of sodium hydroxide, o-aminoacetophenone and aromatic aldehyde are subjected to a condensation reaction in an alcohol solvent to prepare o-aminochalcone represented by formula Ia; 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-piperidinylbenzaldehyde, 2-pyridylcarboxaldehyde, 3-pyridylcarboxaldehyde, 4-pyridylcarboxaldehyde, and 3-indolylcarboxaldehyde; S2: The o-aminochalcone represented by formula Ia is reacted in methanol under the action of ammonium acetate, cuprous chloride and tert-butyl peroxide to prepare the quinazoline stilbene derivative represented by formula I.

3. The preparation method according to claim 2, characterized in that: In step S1, the weight ratio of o-aminoacetophenone to aromatic aldehyde is 3:(1-3.5); the weight ratio of sodium hydroxide to o-aminoacetophenone is 3:(1-3.5); the alcohol solvent is methanol or ethanol; the temperature of the condensation reaction is 20°C-30°C, and the time is 5h-10h.

4. The preparation method according to claim 2, characterized in that: In step S2, the weight ratio of the o-aminochalcone to ammonium acetate is 2.5:(1-3); the weight ratio of the o-aminochalcone to cuprous chloride is 2.5:(0.05-0.3); the weight ratio of the o-aminochalcone to tert-butyl peroxide is 2.5:(0.5-3); the temperature of the condensation reaction is 50° C. to 80° C., and the time is 5 h to 10 h.

5. A pharmaceutical composition, characterized in that Contains the quinazoline stilbene derivative or its salt as claimed in claim 1 or 2, and a pharmaceutically acceptable auxiliary material.

6. A pharmaceutical composition according to claim 5, characterized in that: 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, Fruquintinib, Ispinesib, Barasertib, Tandutinib, Sotrastaurin.

7. A pharmaceutical composition according to claim 5, characterized in that: The pharmaceutical composition is at least one of an oral preparation, an injection preparation, a transdermal absorption preparation, and an inhalation preparation.

8. Use of the quinazoline stilbene derivative according to claim 1, or the quinazoline stilbene derivative prepared by the preparation method according to any one of claims 2 to 4, or the composition according to any one of claims 5 to 7 in the preparation of antitumor drugs.

9. The use according to claim 8, characterized in that The tumor is KRAS G12C mutation-positive tumors.

10. The use according to claim 8, characterized in that The tumor is a tumor in which Src kinase is involved or mediated.

11. The use according to claim 8, characterized in that 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.

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