CN115108999B

CN115108999B - Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application

Info

Publication number: CN115108999B
Application number: CN202210554025.0A
Authority: CN
Inventors: 李沙; 蒋杰; 祁健斌; 王书胜; 满江红
Original assignee: Jinan University
Current assignee: Jinan University
Priority date: 2019-07-26
Filing date: 2019-07-26
Publication date: 2023-11-03
Anticipated expiration: 2039-07-26
Also published as: CN112300082B; CN112300082A; CN114920704B; CN114920704A; WO2021017996A1; CN115108999A

Abstract

The application discloses a phenylpiperazine quinazoline compound or pharmaceutically acceptable salt thereof, a preparation method and application thereof. The phenylpiperazine quinazoline compounds or pharmaceutically acceptable salts thereof have the following structures of general formulas (I), (II) and (III). The synthesis method of the compounds provided by the application is easy to realize, has low cost, and can generate anti-tumor effect from EGFR kinase inhibition and integrin alpha v beta 3 receptor inhibition double targets. In-vitro and in-vivo experimental researches show that the compound has anti-tumor activity in vitro and in vivo, wherein the in-vivo anti-tumor activity of the compound QJJ-12 is similar to that of clinical gefitinib. The compounds can also inhibit the activity of EGFR kinase or EGFR T790M/L858R double mutant kinase, inhibit the horizontal migration capacity of HUVEC cells, and can compete with an alpha v beta 3 antibody for binding with an integrin alpha v beta 3 receptor on the surface of the HUVEC cells. (I) (II) (III).

Description

Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application

The application is a divisional application of an application patent application 201910680663.5 of 2019, 7, 26 days.

Technical Field

The invention belongs to the field of medicines, and in particular relates to a phenylpiperazine quinazoline compound or pharmaceutically acceptable salt thereof, a preparation method and application thereof.

Background

Cancer is a serious disease severely threatening human health and social development, cancer cells are abnormally divided, hyperproliferative differentiated, and invading metastasis to normal cellular tissues of the human body, and is a heavy burden on both individuals and society. Ten cancers before cancer onset in China are lung cancer, gastric cancer, colorectal cancer, liver cancer, esophageal cancer, female breast cancer, pancreatic cancer, lymphoma, bladder cancer and thyroid cancer, which account for 76.39% of all cancer onset, and ten cancers before cancer death in China are lung cancer, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, breast cancer, leukemia, brain tumor and lymphoma, which account for 84.27% of all cancer deaths. Therefore, the development of novel, low-toxicity, high-efficiency and specific anticancer drugs is still an important direction of current drug research.

EGFR is one of the most studied molecular targets in the field of cancer at present, and is expressed or overexpressed on the surface of many tumor cells. EGFR is an expression product of the proto-oncogene Cerb, and the EGFR family includes ERBB1 (HER 1), ERBB2 (Neu/HER 2), ERBB3 (HER 3), and ERBB4 (HER 4). ERBB receptors are expressed in different cells, such as epithelial cells, mesenchymal cells and neurons. ERBB1 (HER 1) is involved in proliferation of regenerative epithelial cells. ERBB2 (Neu/HER 2) plays an important role in heart development and embryos lacking ERBB2 die due to abnormal development of ventricular trabeculae. ERBB3 (HER 3) lacks intrinsic activity and so far lacks reports on ERBB3 (HER 3) homodimerization, activation of ERBB3 (HER 3) being dependent on binding to a ligand or heterodimerization with other ERBB receptors. Homologous or heterodimerization of ERBB4 (HER 4) plays an important regulatory role in metabolism of pulmonary surfactant phosphorylation and in lung cell proliferation, affecting tumor proliferation, differentiation, survival, transformation, and apoptosis. After EGFR is phosphorylated by itself, intracellular signaling is started, downstream cascade reaction occurs, and the main signaling channels are PI3K/Akt pathway, ras/MARK pathway, STAT pathway and the like.

Quinazoline compounds are effective EGFR inhibitors and are widely paid attention. For this feature, antitumor drugs targeting EGFR kinase inhibitors such as Gefitinib (Gefitinib), imatinib, erlotinib (Erlotinib), icotinib (Icotinib), sorafenib, sunitinib, and lapatinib have been developed. However, the tenib drugs act on a single target, only symptoms can be relieved, and the disease cannot be thoroughly radically cured, and more importantly, the single-target antitumor drugs are easy to generate drug resistance, so that the development of novel multi-target drugs has very important significance.

The integrin receptor family is a heterodimeric transmembrane glycoprotein consisting of an extracellular region, a transmembrane region and an intracellular region, and members of this family have been found to include 18 alpha subunits and 8 beta subunits, which, in various combinations, form 24 different integrin molecules. Wherein, the integrin alpha v beta 3 receptor is highly expressed on the surface of neovascular endothelial cell membrane of various malignant tumor cells and tissues thereof, but is little or not expressed in normal tissues. The phenylpiperazine derivatives (publication No. CN 201110146835) for inhibiting tumor metastasis and tumor angiogenesis disclose the use of phenylpiperazine and its derivatives for inhibiting tumor growth and angiogenesis with integrin αvβ3 as target.

The integrin alpha v beta 3 receptor is involved in the processes of tumor adhesion, metastasis, survival proliferation, drug resistance and the like, and has particularly obvious effect in the case of being in a new blood vessel. The integrin family is widely expressed on tissues, however, integrin αvβ3 is most abundantly expressed in vascular endothelial cell remodeling and pathological tissues. Vascular growth factors such as fibroblast growth factor-2%growth factor-2, FGF-2), TNF- α and interleukin-8 (IL-8) stimulate the expression of integrin αvα03 receptor in endothelial cells. Integrin α1vα23 receptor and enzymatically activated MMP-2 aggregate in nascent blood vessels, resulting in cell-mediated collagen degradation and recombination of the ECM. Thus, binding of integrin α3vα43 receptor to fibronectin, fibrinogen or osteopontin promotes the induction of endothelial cell migration. Most integrins, including integrins expressed in endothelial cells, have an "on" and an "off" state. The extracellular domain of integrin α5vα63 receptor is bent and folded, hiding the RGD binding region and preventing binding to the ligand. In contrast, integrin α7vα83, which binds to RGD, has a straightened extracellular region. Although the cytoplasmic tail of integrins is smaller than the extracellular region, it plays a critical role in the signal pathway of integrins, and separation of the cytoplasmic tail and torsion all affect integrin activation. In the course of cancer development, integrin α9vβ3, β1vβ05, β35β21, β56β44, α4β61 and αvβ6 receptors are most involved in tumor development. In the development of breast cancer, overexpression of integrin αvβ3 receptors is associated with bone metastases, which react with osteopontin production to cause tumor growth and invasion. In the development of glioblastoma, integrin αvβ3 receptors are overexpressed on the invasive edges of tumors, and the expression levels of fibrin are also increased, which is related to tumor cell motility An increase in resistance to apoptosis. In the occurrence of pancreatic cancer, overexpression of integrin αvβ3 receptors is associated with excessive activation of MMP-2 and metastasis of lymph nodes. In the occurrence of prostate cancer, integrin αvβ3 receptor overexpression leads to the occurrence of bone metastases as integrin is linked to the adhesive metastasis of laminin, fibronectin and osteopontin.

Currently, more and more researchers consider that molecular targeted drugs are too simplistic for traditional cancers, and targeted attack on a target is not ideal for inhibiting the progression of tumors with complex conditions, such as prostate and colon cancers. Current research suggests that the signal pathways produced by tumors are crossed, resulting in the appearance of this phenomenon. Signaling pathways for EGFR and integrin are also cross-linked, for which dual-target small molecule drugs are expected to be designed to better treat cancer.

The traditional signaling pathways for EGFR are as described above for Ras/Raf/MEK/ERK/MAPK and PI3K/PDK1/Akt, while the downstream signaling pathways for integrins are mainly FAK/paxillin and p130cas. The association of these two signal paths is the most popular research hotspot at present. The EGFR and integrin pathways are very tightly linked to tumor cell invasion and proliferation, and it is difficult to block tumor cell proliferation, metastasis and invasion by a single target. It is reported that in pancreatic cancer, EGFR interacts with integrin αvβ5, resulting in invasion and proliferation of cancer cells. After EGFR is stimulated to activate, more than ERK and PKB are activated, as well as FAK, paxillin and p130cas downstream of integrin. Thus, controlling the progression of cancer, starting from one target of EGFR or integrin alone, blocks much less than the same time as blocking both signaling pathways or their crossing points.

Disclosure of Invention

The primary aim of the invention is to overcome the defects and shortcomings of the prior art and provide a phenylpiperazine quinazoline compound or pharmaceutically acceptable salt thereof. In an effort to obtain novel structural classes of compounds that inhibit both EGFR and integrin αvβ3 receptor activity.

The invention also aims to provide a preparation method of the phenylpiperazine quinazoline compound or pharmaceutically acceptable salt thereof.

It is still another object of the present invention to provide the use of the phenylpiperazine quinazoline compounds or pharmaceutically acceptable salts thereof for treating cancers or diseases associated with EGFR and integrin αvβ3.

The aim of the invention is achieved by the following technical scheme: a phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof, specifically having the structure of the following general formulas (I), (II), (III):

wherein R is a substituted or unsubstituted, straight, branched or cyclic hydrocarbyl carbon chain of up to 10 carbon atoms (preferably 1-8, more preferably 1-4) with or without heteroatoms, a substituted or unsubstituted monocyclic aryl, heteroaryl;

the substituted or unsubstituted monocyclic aryl, heteroaryl is preferably phenyl, p-methylphenyl, p-nitrophenyl, p-fluorophenyl, p-bromophenyl, o-methoxyphenyl, benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl, m-nitrobenzenesulfonyl, benzyl or m-chlorobenzyl.

Preferably, the phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof is selected from, but not limited to, one of the following compounds (QJJ-1 to QJJ-28):

the preparation method of the phenylpiperazine quinazoline compound or the pharmaceutically acceptable salt thereof comprises the following steps:

morpholine is taken as an initial raw material, and is dissolved in toluene together with 1-bromo-3-chloropropane to undergo substitution reaction to obtain 4- (3-chloropropyl) morpholine (3 a); in the environment of formic acid and sodium formate, using isovanillin (3-hydroxy-4-methoxybenzaldehyde) as a raw material, and preparing an intermediate compound 3-hydroxy-4-methoxybenzonitrile (5 a) by reacting with hydroxylamine hydrochloride; then, 4- (3-chloropropyl) morpholine and 3-hydroxy-4-methoxyl benzonitrile undergo etherification reaction to generate 4-methoxy-3- (3-morpholinopropoxy) benzonitrile (6 a); then, nitrifying to obtain a nitrified compound (7 a); then indium trichloride is used as a catalyst, a quinazolinone compound (8 a) is obtained through cyclization in a microwave reaction instrument, and finally the quinazolinone compound is reacted with oxalyl chloride to obtain a chloroquinazoline compound (9 a); the chloro quinazoline compound reacts with substituted benzenesulfonyl piperazine, substituted phenylpiperazine and substituted benzyl piperazine compound respectively to obtain compounds QJJ-1 to QJJ-12;

Triethylene glycol (3 c) which takes triethylene glycol as a starting material and is dissolved with p-toluenesulfonyl chloride (TsCl) in THF (tetrahydrofuran) to carry out substitution reaction to obtain the hydroxy-substituted p-toluenesulfonyl; 3, 4-dihydroxybenzonitrile (5 c) is prepared by reacting 3, 4-dihydroxybenzaldehyde with hydroxylamine hydrochloride in formic acid and sodium formate environment; dissolving triglycol with hydroxy substituted by p-toluenesulfonyl and 3, 4-dihydroxybenzonitrile in tetrahydrofuran, and cyclizing with sodium hydroxide and lithium hydroxide to obtain crown ether benzonitrile (6 c); then performing nitration reaction to obtain a nitro compound (7 c), then using indium trichloride as a catalyst, performing reaction in a microwave reactor to obtain a quinazolinone compound (8 c), and using oxalyl chloride as a chlorinating agent and chloroform as a solvent to obtain an intermediate chloroquinazoline compound (9 c); finally, reacting the chloroquinazoline compound with a substituted benzenesulfonyl piperazine, a substituted phenylpiperazine and a substituted benzylpiperazine compound to obtain a compound QJJ-13-QJJ-18;

taking ethylene glycol monomethyl ether as a starting material, and carrying out nucleophilic substitution reaction on the ethylene glycol monomethyl ether and p-toluenesulfonyl chloride in tetrahydrofuran to obtain 2-methoxyethyl-4-methylbenzenesulfonate (3 d); 2-methoxyethyl-4-methylbenzenesulfonate and 3, 4-dihydroxybenzaldehyde are substituted in acetonitrile under the protection of nitrogen to generate 3, 4-di- (2-methoxyethoxy) benzaldehyde (4 d); reducing the aldehyde group of 3, 4-di- (2-methoxyethoxy) benzaldehyde by hydroxylamine hydrochloride to obtain 3, 4-di- (2-methoxyethoxy) benzonitrile (5 d); 3, 4-di- (2-methoxyethoxy) benzonitrile reacts with concentrated nitric acid at low temperature, and 4, 5-di- (2-methoxyethoxy) -2-nitrobenzonitrile (6 d) is obtained through nitration; 4, 5-bis- (2-methoxyethoxy) -2-nitrobenzonitrile is subjected to microwave cyclization (Niementowski cyclization) with indium trichloride in formamide to obtain 6, 7-bis- (2-methoxyethoxy) -3H-4-quinazolinone (7 d); the 6, 7-di- (2-methoxyethoxy) -3H-4-quinazolinone is chlorinated by oxalyl chloride to obtain 4-chloro-6, 7-di- (2-methoxyethoxy) quinazoline (8 d); the 4-chloro-6, 7-di- (2-methoxyethoxy) quinazoline reacts with substituted benzenesulfonyl piperazine, substituted phenylpiperazine and substituted benzyl piperazine compounds respectively to obtain compounds QJJ-19-QJJ-28.

The preparation method of the phenylpiperazine quinazoline compound or the pharmaceutically acceptable salt thereof more preferably comprises the following steps:

(1) Dissolving morpholine and 1-bromo-3-chloropropane in toluene, heating to 65-85 ℃ for reflux reaction for 2.5-6.5 h, cooling to room temperature after the reaction is finished, filtering, extracting with HCl solution to remove toluene, adjusting pH to strong alkalinity, separating an oil layer from a water layer, extracting with diethyl ether, and evaporating diethyl ether to obtain 4- (3-chloropropyl) morpholine (3 a); uniformly mixing isovanillin (3-hydroxy-4-methoxybenzaldehyde), hydroxylamine hydrochloride, formic acid and sodium formate, heating to 100 ℃ for reflux reaction for 5-7.5 hours, adding saturated saline after the reaction is finished, filtering, washing with water, and drying to obtain an intermediate compound 3-hydroxy-4-methoxybenzonitrile (5 a); uniformly mixing 4- (3-chloropropyl) morpholine, 3-hydroxy-4-methoxybenzonitrile, potassium carbonate, potassium iodide and acetonitrile, heating to 75-85 ℃ for reflux reaction for 3-7 h to obtain 4-methoxy-3- (3-morpholinopropoxy) benzonitrile (6 a); dissolving 4-methoxy-3- (3-morpholinopropoxy) benzonitrile with glacial acetic acid, adding the dissolved 4-methoxy-3- (3-morpholinopropoxy) benzonitrile into nitric acid solution at 0 ℃, keeping the temperature of 0 ℃ for reaction for 2-5 h, heating to 40-50 ℃ for reflux for 3-6 h, adding ice water for washing after the reaction is finished, separating out solids, filtering, washing with normal hexane, and drying to obtain a nitrated compound 7a (4-methoxy-5- (3-morpholinopropoxy) -2-nitrobenzonitrile); dissolving the nitrated compound 7a into formamide, and adding trichlorination Indium is used as a catalyst, and is subjected to microwave reaction for 40-70 minutes at the temperature of 100-120 ℃ and the condition of 400W, dichloromethane is used for extraction, and anhydrous Na is used ₂ SO ₄ Drying, filtering and concentrating, and separating by a silica gel column to obtain a quinazolinone compound 8a (7-methoxy-6- (3-morpholinopropoxy) quinazolin-4 (3H) -one); adding quinazolinone compound 8a and N, N-dimethylformamide into chloroform, then adding oxalyl chloride, heating to 60-70 ℃ to react for 1.5-3 hours, and then adding saturated sodium bicarbonate solution until the pH value is observed to be 10.0; ethyl acetate extraction, organic layer with anhydrous Na ₂ SO ₄ Drying, filtering and concentrating, and separating by a silica gel column to obtain a chloroquinazoline compound 9a (4-chloro-7-methoxy-6- (3-morpholinylpropoxy) quinazoline); adding chloroquinazoline compound 9a and substituent into N, N-dimethylformamide, adding triethylamine as catalyst, microwave reacting for 15-30 min at 100-130 deg.C and 100W, adding saturated saline, extracting with ethyl acetate, and using anhydrous Na for ethyl acetate layer ₂ SO ₄ Drying, filtering and concentrating, separating by a silica gel column to obtain compounds QJJ-1 to QJJ-12; wherein the substituent is a substituted benzenesulfonyl piperazine, a substituted phenylpiperazine and a substituted benzylpiperazine compound;

(2) Evenly mixing triethylene glycol, tetrahydrofuran, sodium hydroxide and water, then adding tetrahydrofuran-dissolved p-toluenesulfonyl chloride (TsCl) under ice bath, continuing to react for 2.5-4 hours under ice bath, evaporating out tetrahydrofuran after finishing, cooling, filtering, and washing with methanol, ethanol and ice water in sequence to obtain the triethylene glycol (3 c) with hydroxy substituted by p-toluenesulfonyl; uniformly mixing 3, 4-dihydroxybenzaldehyde, hydroxylamine hydrochloride, sodium formate and formic acid, heating to 100 ℃ for reflux reaction for 5-7.5 hours, adding saturated saline water after the reaction is finished, filtering, washing with water, and drying to obtain 3, 4-dihydroxybenzonitrile (5 c); uniformly mixing 3, 4-dihydroxybenzonitrile, tetrahydrofuran, sodium hydroxide, lithium hydroxide and water, reacting for 1h at 60-75 ℃ under the protection of nitrogen, then adding triethylene glycol with hydroxy substituted by p-toluenesulfonyl dissolved in tetrahydrofuran, continuously reacting for 60-80 h, evaporating tetrahydrofuran after the reaction is finished, extracting the residual part with dichloromethane, and evaporating the solvent to obtain crown ether benzonitrile (6 c); crown ether benzylDissolving nitrile in glacial acetic acid, adding the solution into nitric acid solution at 0 ℃, keeping the temperature of 0 ℃ for reaction for 2-5 hours, heating to 40-50 ℃ for reflux for 3-6 hours, adding ice water for washing after the reaction is finished, separating out solid, filtering, washing with n-hexane, and drying to obtain a nitrated compound 7c (12-cyano-13-nitro-2, 3,5,6,8, 9-hexahydrobenzo [ b ] ][1,4,7,10]Tetraoxacyclododecane); dissolving the nitrated compound 7c into formamide, adding indium trichloride as a catalyst, carrying out microwave reaction for 40-70 minutes at 100-120 ℃ and 400W, extracting with dichloromethane, and obtaining anhydrous Na ₂ SO ₄ Drying, filtering, concentrating, and separating with silica gel column to obtain quinazolinone 8c (7,8,10,11,13,14-hexahydro- [1,4,7, 10)]Tetraoxycyclododecano [2,3-g]Quinazolin-4 (3H) -one); adding quinazolinone compound 8c and N, N-dimethylformamide into chloroform, then adding oxalyl chloride, heating to 60-70 ℃ to react for 1.5-3 hours, and then adding saturated sodium bicarbonate solution until the pH value is observed to be 10.0; ethyl acetate extraction, organic layer with anhydrous Na ₂ SO ₄ Drying, filtering and concentrating, separating with silica gel column to obtain intermediate chloroquinazoline compound 9c (4-chloro-7,8,10,11,13,14-hexahydro- [1,4,7, 10)]Tetraoxycyclododecano [2,3-g]Quinazoline); adding chloroquinazoline compound 9c and substituent into N, N-dimethylformamide, adding triethylamine as catalyst, microwave reacting at 100-130 deg.C and 100W for 15-30 min, adding saturated saline, extracting with ethyl acetate, and using anhydrous Na for ethyl acetate layer ₂ SO ₄ Drying, filtering and concentrating, separating by a silica gel column to obtain compounds QJJ-13 to QJJ-18; wherein the substituent is a substituted benzenesulfonyl piperazine, a substituted phenylpiperazine and a substituted benzylpiperazine compound;

(3) Adding ethylene glycol monomethyl ether into a mixed solution of THF (tetrahydrofuran) and water, carrying out ice bath treatment for 1-3 hours, adding THF-dissolved p-toluenesulfonyl chloride, continuing ice bath for 3-6 hours, then spin-drying the THF, washing with saturated saline water, extracting with dichloromethane, and adding anhydrous Na into an organic layer ₂ SO ₄ Drying, concentrating under reduced pressure, separating by silica gel column chromatography, and vacuum drying to obtain 2-methoxyethyl-4-methylbenzenesulfonate (3 d); 2-methoxyethyl-4-methylbenzenesulfonate,3, 4-dihydroxybenzaldehyde, acetonitrile and potassium carbonate are uniformly mixed, vacuumized and N ₂ Protecting, reacting at 70-85 ℃ for 30-45 h, filtering, taking filtrate, spin-drying acetonitrile, washing with saturated saline water, extracting with ethyl acetate, adding anhydrous Na into an organic layer ₂ SO ₄ Drying, concentrating under reduced pressure, and separating by silica gel column chromatography to obtain 3, 4-di- (2-methoxyethoxy) benzaldehyde (4 d); adding sodium formate and 3, 4-di- (2-methoxyethoxy) benzaldehyde into formic acid, heating to 75-85 ℃, adding hydroxylamine hydrochloride, reacting for 4-7 h, cooling to room temperature, adding cold saturated saline water to precipitate solid, filtering, recrystallizing with ethyl acetate, and drying to obtain 3, 4-di- (2-methoxyethoxy) benzonitrile (5 d); dissolving 3, 4-di- (2-methoxyethoxy) benzonitrile with glacial acetic acid, adding the dissolved 3, 4-di- (2-methoxyethoxy) benzonitrile into nitric acid solution at 0 ℃, keeping the temperature of 0 ℃ for reaction for 2-5 h, heating to 40-50 ℃ for reflux for 3-6 h, adding ice water for washing after the reaction is finished, separating out solids, filtering, washing with n-hexane, and drying to obtain 4, 5-di- (2-methoxyethoxy) -2-nitrobenzonitrile (6 d); dissolving 4, 5-bis- (2-methoxyethoxy) -2-nitrobenzonitrile into formamide, then adding indium trichloride (Niementowski cyclization) as a catalyst, carrying out microwave reaction for 40-70 minutes at the temperature of 100-120 ℃ and the pressure of 400W, filtering after the reaction is finished, washing filtrate with saturated saline water, extracting with ethyl acetate, concentrating an organic layer under reduced pressure, and recrystallizing with ethyl acetate to obtain 6, 7-bis- (2-methoxyethoxy) -3H-4-quinazolinone (7 d); dissolving 6, 7-di- (2-methoxyethoxy) -3H-4-quinazolinone in chloroform, adding N, N-dimethylformamide, dropwise adding oxalyl chloride, refluxing at 60-70deg.C for 1.5-3H, washing with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, adding anhydrous Na into the organic layer ₂ SO ₄ Drying, concentrating under reduced pressure, separating by silica gel column chromatography, and vacuum drying to obtain 4-chloro-6, 7-di- (2-methoxyethoxy) quinazoline (8 d); adding 4-chloro-6, 7-di- (2-methoxyethoxy) quinazoline and a substituent into N, N-dimethylformamide, adding triethylamine as a catalyst, carrying out microwave reaction for 15-30 minutes at 100-130 ℃ and 300W, adding saturated brine, extracting with ethyl acetate, and using anhydrous Na for an ethyl acetate layer ₂ SO ₄ Drying, filtering and concentrating, separating by silica gel column to obtain compounds QJJ-19-QJJ-28; wherein the substituent is a substituted benzenesulfonyl piperazine, a substituted phenylpiperazine and a substituted benzylpiperazine compound.

The volume ratio of morpholine to 1-bromo-3-chloropropane in step (1) is preferably 1:1.15.

The mass ratio of isovanillin to hydroxylamine hydrochloride described in step (1) is preferably 1:1.1.

The mass ratio of 4- (3-chloropropyl) morpholine to 3-hydroxy-4-methoxybenzonitrile in step (1) is preferably 5.25:4.

The concentration of the nitric acid solution described in steps (1), (2) and (3) is preferably 65% by mass.

The molar ratio of chloroquinazoline compound to substituent described in step (1) is preferably 1:1.

The substituted benzenesulfonyl piperazine in the steps (1), (2) and (3) is synthesized by taking substituted benzenesulfonyl chloride and piperazine as raw materials; preferably benzenesulfonyl piperazine (1- (phenylsulfonyl) piperazine), p-toluenesulfonyl piperazine (1-tosyl piperazine), p-methoxybenzenesulfonyl piperazine (1- ((4-methoxyphenylphenyl) piperazine), or m-nitrobenzenesulfonyl piperazine (1- ((3-nitrophenyl) piperazine).

The substituted phenylpiperazine described in steps (1), (2) and (3) is preferably phenylpiperazine (1-phenylpiperazine), p-methylphenyl piperazine (1- (4-methylphenyl) piperazine), p-nitrophenylpiperazine (1- (4-nitrophenyl) piperazine), p-fluorophenyl piperazine (1- (4-fluorophenyl) piperazine), p-bromophenyl piperazine (1- (4-bromophenyl) piperazine), or o-methoxyphenylpiperazine (1- (2-methoxyphenyl) piperazine.

The substituted benzylpiperazine compound described in steps (1), (2) and (3) is preferably benzylpiperazine (1-benzylpiperazine) or m-chlorobenzyl piperazine (1- (3-chlorobenzyl) piperazine).

The molar ratio of triethylene glycol to p-toluenesulfonyl chloride described in step (2) is preferably 6.7:12.

The mass ratio of the 3, 4-dihydroxybenzaldehyde to the hydroxylamine hydrochloride in the step (2) is 13.8:16.7.

The mass ratio of the triglycol of the p-toluenesulfonyl substituted hydroxyl group and the 3, 4-dihydroxybenzonitrile in the step (2) is preferably 3.73:1.

The molar ratio of the crown ether benzonitrile to the nitric acid solution in the step (2) is 1:10.

The molar ratio of the quinazolinone compound to oxalyl chloride in the step (2) is 0.3:0.86.

The molar ratio of chloroquinazoline compound to substituent described in step (2) is preferably 1:1.

The mol ratio of the ethylene glycol monomethyl ether to the p-toluenesulfonyl chloride in the step (3) is 1:1.05

The molar ratio of the 2-methoxyethyl-4-methylbenzenesulfonate to the 3, 4-dihydroxybenzaldehyde in the step (3) is 2:1.

The molar ratio of 3, 4-di- (2-methoxyethoxy) benzaldehyde to hydroxylamine hydrochloride in the step (3) is 1:2.4.

The molar ratio of 4-chloro-6, 7-di- (2-methoxyethoxy) quinazoline to substituents described in step (3) is preferably 1:2.

The phenylpiperazine quinazoline compounds and the pharmaceutically acceptable salts thereof can be used for preparing antitumor drugs, and can be used as auxiliary drugs in tumor chemotherapy drugs and surgical treatment or combined with other medicaments for treating various cancers.

The tumor is a tumor including, but not limited to, non-small cell lung cancer, breast cancer, cervical cancer, brain tumor, pancreatic cancer, liver cancer, colorectal cancer, medullary thyroid cancer, glioma, neuroblastoma, renal tumor (kidney cancer), lung cancer, pancreatic cancer, astrocytoma, bladder cancer, ovarian cancer, head and neck cancer, cervical cancer, thymus cancer, gastric cancer, ovarian cancer and prostate cancer; preferably non-small cell lung cancer, lung adenocarcinoma or cervical cancer.

The phenylpiperazine quinazoline compound and the pharmaceutically acceptable salt thereof can inhibit the activity of EGFR kinase or EGFR T790M/L858R double mutant kinase, inhibit the horizontal migration capacity of HUVEC cells, and can compete with an alpha v beta 3 antibody for binding with an integrin alpha v beta 3 receptor on the surface of the HUVEC cells.

The kinase is EGFR kinase or EGFR T790M/L858R double mutant kinase.

The term "hydrocarbyl" as used herein refers to a hydrocarbyl carbon chain of up to 10 carbon atoms, unsubstituted or substituted, straight, branched or cyclic, or a hydrocarbyl group containing at least one heteroatom (e.g., nitrogen, oxygen or sulfur) in the chain. Non-limiting examples of straight-chain hydrocarbon groups include saturated hydrocarbon groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl, unsaturated hydrocarbon groups containing substituents such as olefinic, acetylenic, carbonyl, cyano, and the like, and hydrocarbon groups containing heteroatoms such as-CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ and-CH ₂ CH ₂ SCH ₃ Etc. Non-limiting examples of branched hydrocarbon groups containing no or hetero atoms include, for example, isopropyl, sec-butyl, isobutyl, tert-butyl, neopentyl, -CH ₂ CH(OCH ₃ )CH ₃ 、-CH ₂ CH(N(CH ₃ ) ₂ )CH ₃ and-CH ₂ CH(SCH ₃ )CH ₃ . Non-limiting examples of cyclic hydrocarbon radicals ("cyclic hydrocarbon radicals") containing no or heteroatoms include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, six-membered rings containing O, N, S, for example, -CH (CH) ₂ CH ₂ ) ₂ O、-CH(CH ₂ CH ₂ ) ₂ NCH ₃ and-CH (CH) ₂ CH ₂ ) ₂ S, etc. and the corresponding five membered heterocyclic ring, etc. The hydrocarbyl group may be substituted with one or more substituents, non-limiting examples of which include-N (CH) ₃ ) ₂ 、F、Cl、Br、I、-OCH ₃ 、-CO ₂ CH ₃ -CN, -OH, aryl and heteroaryl.

The term "aryl" as used herein refers to unsubstituted or substituted aromatic compounds, carbocyclic groups, and heteroaryl groups. Aryl is either a monocyclic or polycyclic fused compound. Aryl groups may be substituted with one or more substituents, non-limiting examples of which aresub-inclusion-N (CH) ₃ ) ₂ 、F、Cl、Br、I、-OCH ₃ 、-CO ₂ CH ₃ -CN, -OH, aryl and heteroaryl.

Heteroaryl refers to substituted or unsubstituted monocyclic or polycyclic groups containing at least one heteroatom, such as nitrogen, oxygen, and sulfur, within the ring. Exemplary heterocyclic groups include, for example, one or more nitrogen atoms such as tetrazolyl, pyrrolyl, pyridinyl (e.g., 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, etc.), pyridazinyl, indolyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, etc.), imidazolyl, isoquinolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridonyl; typical heterocyclic groups containing one oxygen atom include 2-furyl, 3-furyl or benzofuryl; typical sulfur heteroatom groups include thienyl, benzothienyl; typical mixed heteroatom groups include furazanyl, oxazolyl, isoxazolyl, thiazolyl, and phenothiazinyl. The heterocyclic group can be substituted with one or more substituents including-O-alkyl, -NH-alkyl, -N- (alkyl) ₂ -NHC (O) -alkyl, F, cl, br, I, -OH, -OCF ₃ 、-CO ₂ -alkyl, -CN, aryl and polyaryl.

The term "pharmaceutically acceptable" as used herein means having no unacceptable toxicity in a compound such as a salt or excipient. Pharmaceutically acceptable salts include inorganic anions such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, hydrogen phosphate, and the like. The organic anions include acetate, propionate, cinnamate, benzoate, citrate, lactate, gluconate, fumarate, tartrate, succinate, and the like. The invention relates to hydrocarbyl, aryl, heteroaryl, nitrate, halogenated and sulfonyl derivatives of a phenylpiperazine quinazoline compound, which can be administered to a patient in the form of a pharmaceutically acceptable salt or pharmaceutical complex. A complex may be mixed with a suitable carrier or excipient to form a pharmaceutical composition to ensure that an effective therapeutic agent is achieved. By "therapeutically effective amount" is meant that amount of the compound or derivative thereof which is required to achieve a therapeutic effect.

Compared with the prior art, the invention has the following advantages:

(1) The compounds provided by the invention have novel structures and easy realization of synthesis methods. In-vitro antitumor activity experiments show that the antitumor activity of the compounds is similar to that of clinical erlotinib. The compound and the pharmaceutically acceptable salt thereof can be used for preparing antitumor drugs, medicaments for treating non-small cell lung cancer, breast cancer, liver cancer and cervical cancer, and auxiliary medicaments for tumor chemotherapy medicaments and surgical treatment.

(2) The preparation process of the phenylpiperazine quinazoline compound is simple, raw materials are easy to obtain, the cost is low, and the preparation process is economical and effective.

Drawings

FIG. 1 is a scheme showing the synthesis of compounds 1a to 1d (in the figure, a represents piperazine, triethylamine, methylene chloride, ice bath reaction, reaction time 3h, and return to room temperature after completion of the reaction).

FIG. 2 is a scheme showing the synthesis of compound QJJ-1 to QJJ-12 (A represents morpholine, toluene, 65 to 85 ℃,2.5 to 6.5 hours; B represents hydroxylamine hydrochloride, sodium formate, formic acid, 100 ℃,5 to 7.5 hours; C represents potassium carbonate, potassium iodide, acetonitrile, 75 to 85 ℃,3 to 7 hours; D represents 65% nitric acid, glacial acetic acid, 0 ℃,2 to 5 hours, 40 to 50 ℃,3 to 6 hours; E represents formamide, indium trichloride, microwaves 400w,100 to 120 ℃,40 to 70 minutes; F represents oxalyl chloride, N, N-dimethylformamide, chloroform, 60 to 70 ℃,1.5 to 3 hours; G represents each substituted phenylpiperazine, triethylamine, N, N-dimethylformamide, microwaves 100w,100 to 130 ℃,15 to 30 minutes; H represents 1b/1c/1d/1a, triethylamine, N, N-dimethylformamide, microwaves 100w,100 to 130 ℃ I represents each substituted benzyl chloride, N, N-dimethylformamide, 100w,100 to 30 minutes; N-dimethylformamide, 100w,100 to 30 minutes).

FIG. 3 is a synthetic scheme for compounds QJJ-13-QJJ-18 (wherein A represents p-toluenesulfonyl chloride, tetrahydrofuran, sodium hydroxide, water, ice bath, 2.5-4 h; B represents hydroxylamine hydrochloride, sodium formate, formic acid, 100deg.C, 5-7.5 h; C represents tetrahydrofuran, sodium hydroxide, lithium hydroxide, water, N) ₂ Protecting at 60-75 deg.c for 60-80 hr; d represents 65% nitric acid, glacial acetic acid, 0 ℃, 2-5 h, 40-50 ℃ and 3-6 h; e represents formamide, indium trichloride, 400w of microwave, 100-120 ℃ and 40-70 minutes; f represents oxalyl chloride, N, N-dimethylformamide, chloroform, at 60-70 ℃ for 1.5-3 h; g represents each substituted phenylpiperazine, triethylamine, N, N-dimethylformamide, 100w of microwaves, 100-130 ℃ and 15-30 min; h represents 1a/1d, triethylamine, N, N-dimethylformamide, the microwave is 100w, the temperature is 100-130 ℃ and the time is 15-30 min; i represents each substituted benzyl piperazine, triethylamine, N, N-dimethylformamide, the microwave is 100w, the temperature is 100-130 ℃, and the time is 15-30 min.

FIG. 4 is a synthetic scheme for compounds QJJ-19-QJJ-28 (wherein A represents p-toluenesulfonyl chloride, tetrahydrofuran, sodium hydroxide, water, ice bath, 4-9 h, B represents 3, 4-dihydroxybenzaldehyde, potassium carbonate, acetonitrile, N) ₂ Protecting at 70-85 ℃; c represents hydroxylamine hydrochloride, sodium formate, formic acid, 75-85 ℃ and 4-7 h; d represents 65% nitric acid, glacial acetic acid, 0 ℃, 2-5 h, 40-50 ℃ and 3-6 h; e represents formamide, indium trichloride, 400w of microwave, 100-120 ℃ and 40-70 minutes; f represents oxalyl chloride, N, N-dimethylformamide, chloroform, at 60-70 ℃ for 1.5-3 h; g represents 1a/1b/1c/1d, N-dimethylformamide, triethylamine, microwave 300w, 100-130 ℃ for 15-30 min; h represents each substituted phenylpiperazine, N, N-dimethylformamide, triethylamine, microwaves 300w, 100-130 ℃ and 15-30 min; i represents each substituted benzyl piperazine, N, N-dimethylformamide, triethylamine, microwave 300w, 100-130 ℃ for 15-30 min).

FIG. 5 is a microscopic image (10X 10) of the inhibition of HUVEC human umbilical vein endothelial cell migration by compounds QJJ-28.

FIG. 6 is a flow cytometry detection of QJJ-12 binding to integrin αvβ3 receptor.

FIG. 7 is a flow cytometry detection of QJJ-28 binding to integrin αvβ3 receptor.

Fig. 8 is a graph showing the body weight change of each group of nude mice in the experiment.

Fig. 9 is a graph of change in body weight of nude mice before and after dosing throughout the experiment (< 0.05, <0.01, <0.001 versus pre-dosing group).

Fig. 10 is a tumor tissue diagram of each group of nude mice in the experiment.

Fig. 11 is a graph of tumor growth in nude mice of each group of experiments (< 0.05, <0.01, <0.001, <0.05, #p <0.01, #p <0.001, < Gefitinib,) versus Ctrl group.

Fig. 12 is a graph showing tumor growth inhibition rates (#p <0.05, #p <0.01, #p <0.001 versus Gefitinib group) of nude mice of each group.

Detailed Description

The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. The test methods for specific experimental conditions are not noted in the examples below, and are generally performed under conventional experimental conditions or under experimental conditions recommended by the manufacturer. The reagents and starting materials used in the present invention are commercially available unless otherwise specified.

Example 1: synthesis of Compound 1- (phenylsulfanyl) piperazine (1 a)

Anhydrous piperazine (3.24 g,37.7 mmol), triethylamine (2.10 g,20.7 mmol) were weighed out and dissolved in anhydrous dichloromethane (100 mL) and ice-bathed. After 30min, diluted benzenesulfonyl chloride (4.0 g,22.6 mmol) in dry dichloromethane (20 mL) was added dropwise and the reaction was continued for 3h in ice bath. TLC (thin layer chromatography) detection reaction, after the reaction is complete, the dichloromethane is dried, saturated saline water is washed, ethyl acetate is extracted, the organic layer is added with anhydrous sodium sulfate for drying, and then reduced pressure concentration is carried out, silica gel column chromatography separation (eluent: petroleum ether: ethyl acetate=1:2 (volume ratio), then 1% (v/v) triethylamine is added), TLC tracking collection is carried out, and vacuum drying is carried out, thus obtaining white solid 1a (yield 62%) (FIG. 1).

ESI-MS:[M+H] ⁺ m/z 227.3。 ¹ H NMR(300MHz,CDCl ₃ )δ:7.71–7.63(m,2H),7.57–7.42(m,3H),2.94–2.86(m,4H),2.85–2.78(m,4H),1.70(s,1H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:135.32,132.84,129.02,127.69,46.82,45.20。

Example 2: synthesis of Compound 1-tosylpiperazin (1 b)

Specific synthetic methods of compound 1b can be referred to the synthetic procedure of compound 1 a. P-toluenesulfonyl chloride (4.0 g,21.0 mmol) was substituted for benzenesulfonyl chloride in example 1 to give 1b (60% yield) as a white solid (FIG. 1).

ESI-MS:[M+H] ⁺ m/z 241.3。 ¹ H NMR(300MHz,CDCl ₃ )δ7.61(t,J＝9.4Hz,2H),7.37–7.27(m,2H),2.98(t,J＝22.3Hz,8H),2.43(s,3H),1.77(s,1H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ143.63,132.27,129.60,127.77,46.85,45.21,21.47。

Example 3: synthesis of Compound 1- ((4-methoxyphenyl) sulfophenyl) piperazine (1 c)

Specific synthetic methods of compound 1c can be referred to the synthetic procedure of compound 1 a. P-methoxybenzenesulfonyl chloride (4.0 g,19.4 mmol) was substituted for the benzenesulfonyl chloride of example 1 to give 1c (79% yield) as a pale yellow solid (FIG. 1).

ESI-MS:[M+H] ⁺ m/z 257.1。 ¹ H NMR(300MHz,CDCl ₃ )δ:7.59–7.46(m,2H),6.91–6.82(m,2H),3.72(s,3H),2.76(d,J＝4.8Hz,8H),1.96–1.72(m,1H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:162.98,129.76,126.71,114.15,55.61,46.78,45.09。

Example 4: synthesis of Compound 1- ((3-nitrophenyl) sulfoyl) piperazine (1 d)

Specific synthetic methods of compound 1d can be referred to the synthetic procedure of compound 1 a. M-nitrobenzenesulfonyl chloride (4.0 g,18.2 mmol) was substituted for the benzenesulfonyl chloride of example 1 to afford 1d (65% yield) as a yellow solid (FIG. 1).

ESI-MS:[M+H] ⁺ m/z 272.3,[M+Na] ⁺ m/z 284.3。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.57(dt,J＝10.2,1.9Hz,1H),8.47(ddd,J＝8.2,2.2,1.0Hz,1H),8.15–8.03(m,1H),7.84–7.74(m,1H),3.14–3.03(m,4H),3.02–2.92(m,4H),2.19–1.84(m,1H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:148.37,138.15,133.19,130.53,127.30,122.76,46.83,45.23。

Example 5: synthesis of Compound 4- (3-chloropropyl) morph (3 a)

Morpholine (30 ml), 1-bromo-3 chloropropane (34.4 ml), toluene (90 ml) were added sequentially to a round bottom flask, heated to 80 ℃, refluxed for 6h, cooled to room temperature after completion, filtered to give a filtrate, extracted with 3mol/L HCl solution, toluene removed, then pH adjusted to strong basicity with 10mol/L NaOH solution, oil-water layer separation, diethyl ether extraction, and diethyl ether evaporation to give colorless liquid 3a (fig. 2).

ESI-MS:m/z 164.1([M+H] ⁺ )。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:3.75(s,2H),3.55(s,4H),2.44(s,2H),2.33(s,4H),2.03(s,2H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:67.08,53.71,53.07,41.28,29.15。

Example 6: synthesis of 3-hydroxy-4-methoxybenzonitrile (5 a) compound

2g of isovanillin, 2.2g of hydroxylamine hydrochloride, 1.7g of sodium formate and 11ml of formic acid are sequentially added into a round-bottom flask, the mixture is heated to 100 ℃ and refluxed for 6 hours, 10ml of saturated saline is added into the reaction solution after the completion of the refluxing, the mixture is stirred and filtered, and a filter cake is washed with water (20 ml multiplied by 3) and dried to obtain gray powder 5a (figure 2).

ESI-MS:m/z 150.1([M+H] ⁺ )。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:7.66(s,1H),7.53(s,1H),6.94(s,1H),5.56(s,1H),3.86(s,3H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:153.91,147.34,125.90,118.82,117.41,113.77,104.59,56.83。

Example 7: synthesis of 4-methoxy-3- (3-morpholinopropoxy) benzonitrile (6 a) compound

3a 0.525g,5a 0.4g, 0.75g of potassium carbonate, 0.023g of potassium iodide and 2.2ml of acetonitrile are added to a round-bottomed flask in sequence. Stirring for dissolving, heating to 82 ℃, refluxing for 3-4 h, cooling to room temperature after the completion, filtering to obtain filtrate, evaporating acetonitrile to obtain crude product, and separating with silica gel column (petroleum ether: ethyl acetate=1:1, volume ratio) to obtain colorless liquid 6a (figure 2).

ESI-MS:m/z 277.1([M+H] ⁺ )。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:7.59–7.27(m,3H),7.11(d,J＝8.1Hz,1H),4.13–3.95(m,2H),3.84(s,3H),3.64–3.48(m,4H),2.38(dd,J＝13.5,6.1Hz,6H),1.87(p,J＝6.5Hz,2H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:153.25,148.17,126.46,119.44,116.10,112.68,102.72,67.23,66.18,55.84,54.84,53.46,26.00。

Example 8: synthesis of 4-methoxy-5- (3-morpholinopropoxy) -2-nitrobenzonitrile (7 a)

1.7ml of 65% nitric acid by mass is added into a round bottom flask, the mixture is cooled to 0 ℃, 6a 0.66g dissolved by 5ml of glacial acetic acid is slowly added, the mixture is kept at 0 ℃ for 4 hours, then the mixture is heated to 50 ℃ and refluxed for 4 hours, ice water is added into the reaction solution after the completion of the reaction to wash, yellow solid is separated out, the mixture is filtered, washed by normal hexane and dried, and yellow solid 7a (yield 49.3%) is obtained (FIG. 2).

ESI-MS:m/z 322.1([M+H] ⁺ )。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:7.88(d,J＝3.5Hz,1H),7.70(d,J＝9.4Hz,1H),4.36–4.12(m,2H),4.06–3.91(m,3H),3.66–3.48(m,4H),2.48(s,2H),2.33(s,4H),1.83(s,2H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:154.41,151.95,151.86,117.76,117.08,111.45,104.54,67.91,67.08,56.83,53.07,52.49,28.13.

Example 9: synthesis of the Compound 7-methoxy-6- (3-morpholinopropoxy) quinazolin-4 (3H) -one (8 a)

7a (1.56 mmol,0.5 g) was added to a flask containing 20ml of formamide, which was completely dissolved by stirring, and indium trichloride (1.56 mmol,0.35 g) was added as a catalyst. The reaction was carried out in a microwave reactor (110 ℃, 400W) and terminated after 60 minutes. A small amount of water was added to the mixture, and extracted with dichloromethane. The dichloromethane layer was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave a residue which was purified by silica gel column (ethyl acetate: triethylamine=100:1, volume ratio) to give compound 8a (white solid, yield 30.2%) (fig. 2).

ESI-MS:m/z 319.3([M+H] ⁺ )。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:12.08(s,1H),7.98(s,1H),7.43(s,1H),7.13(s,1H),4.10(t,J＝6.4Hz,2H),3.90(s,3H),3.60(dd,J＝17.0,12.6Hz,4H),2.41(dd,J＝16.6,9.6Hz,6H),1.92(p,J＝6.6Hz,2H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:160.59,154.91,148.17,145.24,144.17,115.43,108.39,106.05,67.22,66.66,56.40,55.18,53.82,26.15。

Example 10: synthesis of Compound 4- (3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) propyl) morph (9 a)

8a (3 mmol,1 g) and N, N-dimethylformamide (0.22 ml) were added to a flask containing 30ml of chloroform, and when it was completely dissolved, oxalyl chloride (7.5 mmol,0.67 ml) was slowly added, and the reaction was terminated after heating to 61℃for 2 hours. Saturated sodium bicarbonate solution was added until a pH of 10.0 was observed. The mixture was extracted with ethyl acetate. Anhydrous Na for organic layer ₂ SO ₄ Drying, filtration and concentration gave a residue which was purified by silica gel column (petroleum ether: ethyl acetate=1:1, volume ratio) to give compound 9a (white solid, yield 60.0%).

ESI-MS:m/z 320.3([M+H] ⁺ )。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.86(s,1H),7.38(s,1H),7.32(s,1H),4.27(t,J＝6.5Hz,2H),4.05(s,3H),3.78–3.66(m,4H),2.59(t,J＝7.1Hz,2H),2.55–2.44(m,4H),2.13(p,J＝6.7Hz,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:158.92,156.87,152.55,150.90,148.57,119.43,107.02,103.01,67.54,66.96,56.54,55.31,53.74,25.94。

Example 11: synthesis of Compound 4- (3- ((7-methoxy-4- (4-phenylpiperazine-1-yl) quinazolin-6-yl) oxy) propyl) morph (QJJ-1)

Compound 9a (0.3 mmol) and 1-phenylpiperazine (0.3 mmol) were added to a flask containing 20ml of DMF (N, N-dimethylformamide), and triethylamine was added as a catalyst. The reaction was carried out in a microwave reactor, the reaction conditions (120 ℃ C., 100W) were set, and the reaction was terminated after 20 minutes. A small amount of saturated brine was added to the mixture, and extracted with ethyl acetate. Anhydrous Na for ethyl acetate layer ₂ SO ₄ Drying, filtration and concentration gave a residue which was purified by silica gel column (ethyl acetate: petroleum ether=1:1, volume ratio) to give compound QJJ-1 as a pale yellow solid in 85% yield, m.p.119.6 ℃ -120.5 ℃ (fig. 2).

ESI-HRMS m/z:464.2656[M+H] ⁺ ,calcd for C ₂₆ H ₃₃ N ₅ O ₃ 464.2654。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.69(s,1H),7.29(dd,J＝7.2,1.3Hz,2H),7.25(s,1H),7.17(s,1H),6.99(d,J＝7.9Hz,2H),6.90(t,J＝7.3Hz,1H),4.21–4.11(m,2H),3.99(s,3H),3.79(dd,J＝13.1,8.0Hz,4H),3.75–3.66(m,4H),3.45–3.35(m,4H),2.58(t,J＝7.2Hz,2H),2.53–2.43(m,4H),2.09(dq,J＝12.8,6.4Hz,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.93,154.54,152.87,150.89,148.85,148.18,128.81,119.73,115.73,111.05,109.67,107.71,104.33,67.21,66.55,56.16,55.14,53.48,49.72,49.14,25.99。

Example 12: synthesis of the Compound 4- (3- ((7-methoxy-4- (4- (p-tolyl) piperazin-1-yl) quinazolin-6-yl) oxy) propyl) morph (QJJ-2)

Synthesis of Compound QJJ-2 (FIG. 2) Synthesis of Compound QJJ-1 of example 11. 1- (4-methylphenyl) piperazine (0.3 mmol) was reacted with compound 9a to give compound QJJ-2 instead of 1-phenylpiperazine of example 11. Pale yellow solid, yield 82%, m.p.122.0 ℃ -124.8 ℃.

ESI-HRMS m/z:478.2813[M+H] ⁺ ,calcd for C ₂₇ H ₃₅ N ₅ O ₃ 478.2811。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.70(s,1H),7.25(s,1H),7.17(s,1H),7.12(d,J＝8.3Hz,2H),6.92(d,J＝8.5Hz,2H),4.18(t,J＝6.4Hz,2H),4.00(s,3H),3.88–3.66(m,8H),3.44–3.28(m,4H),2.59(t,J＝7.2Hz,2H),2.51(d,J＝4.1Hz,4H),2.30(s,3H),2.17–2.05(m,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.81,154.79,153.04,148.98,147.90,129.78,116.51,111.53,107.43,104.23,67.23,66.97,56.04,55.15,53.42,49.78,26.15,20.29。

Example 13: synthesis of the Compound 4- (3- ((7-methoxy-4- (4- (4-nitrophenyl) piperazin-1-yl) quinazolin-6-yl) oxy) propyl) morph (QJJ-3)

Synthesis of Compound QJJ-3 (FIG. 2) Synthesis of Compound QJJ-1 in example 11. 1- (4-Nitrophenyl) piperazine (0.3 mmol) was reacted with compound 9a to give compound QJJ-3 instead of 1-phenylpiperazine of example 11. Yellow solid, yield 89%, m.p.90.2 ℃ -91.4 ℃.

ESI-HRMS m/z:509.2507[M+H] ⁺ ,calcd for C ₂₆ H ₃₂ N ₆ O ₅ 509.2511。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.69(s,1H),8.18–8.10(m,1H),7.27(s,1H),7.17(s,1H),6.91–6.83(m,1H),4.18(t,J＝6.4Hz,1H),4.01(s,1H),3.87(dd,J＝6.3,3.9Hz,2H),3.75–3.69(m,2H),3.66(dd,J＝6.2,3.9Hz,2H),2.59(t,J＝7.2Hz,1H),2.53–2.45(m,2H),2.16–2.07(m,1H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.42,155.16,154.66,152.82,149.14,148.23,138.75,125.96,112.65,111.29,107.66,104.05,67.40,66.93,56.21,55.42,53.72,48.96,46.65,26.12。

Example 14: synthesis of Compound 4- (3- ((4- (4- (4-fluorophenyl) piperazin-1-yl) -7-methoxyquinazolin-6-yl) oxy) propyl) morph (QJJ-4)

Synthesis of Compound QJJ-4 (FIG. 2) Synthesis of Compound QJJ-1 in example 11. 1- (4-fluorophenyl) piperazine (0.3 mmol) in place of the 1-phenylpiperazine in example 11 was reacted with the compound 9a to obtain the compound QJJ-4. White solid, yield 82%, m.p.131.7 ℃ -133.2 ℃.

ESI-HRMS m/z:482.2562[M+H] ⁺ ,calcd for C ₂₆ H ₃₂ FN ₅ O ₃ 482.2581。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.70(s,1H),7.26(s,1H),7.17(s,1H),7.08–6.88(m,4H),4.18(t,J＝6.1Hz,2H),4.01(s,3H),3.81(s,4H),3.72(s,4H),3.33(s,4H),2.59(t,J＝7.0Hz,2H),2.49(s,4H),2.17–2.05(m,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.80,155.03,153.04,149.17,148.10,147.74,118.13,118.03,115.83,115.53,111.55,107.67,104.33,67.39,66.98,56.17,55.43,53.75,50.16,49.77,26.19。

Example 15: synthesis of Compound 4- (3- ((4- (4- (4-bromobenzyl) piperazin-1-yl) -7-methoxyquinazolin-6-yl) oxy) propyl) morph (QJJ-5)

Synthesis of Compound QJJ-5 (FIG. 2) Synthesis of Compound QJJ-1 in example 11. 1- (4-bromophenyl) piperazine (0.3 mmol) was reacted with compound 9a to give compound QJJ-5 instead of 1-phenylpiperazine in example 11. Pale yellow solid, yield 85%, m.p.145.5 ℃ -147.2 ℃.

ESI-HRMS m/z:542.1761[M+H] ⁺ ,calcd for C ₂₆ H ₃₂ BrN ₅ O ₃ 542.1783。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.70(s,1H),7.44–7.34(m,1H),7.26(s,1H),7.16(s,1H),6.90–6.82(m,2H),4.18(t,J＝6.4Hz,2H),4.01(s,3H),3.84–3.69(m,8H),3.42–3.33(m,4H),2.61(t,J＝7.2Hz,2H),2.55–2.49(m,4H),2.18–2.06(m,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.73,155.01,152.94,150.06,149.07,148.11,131.97,117.74,112.31,111.50,107.57,104.18,67.34,66.94,56.18,55.42,53.72,49.53,48.88,26.15。

Example 16: synthesis of the Compound 4- (3- ((7-methoxy-4- (4- (2-methoxyphenyl) piperazin-1-yl) quinazolin-6-yl) oxy) propyl) morph (QJJ-6)

Synthesis of Compound QJJ-6 (FIG. 2) Synthesis of Compound QJJ-1 in example 11. 1- (2-methoxyphenyl) piperazine (0.3 mmol) was reacted with compound 9a to give compound QJJ-6 instead of 1-phenylpiperazine in example 11. Pale yellow solid, yield 83%, m.p.87.9 ℃ -88.7 ℃.

ESI-HRMS m/z:494.2762[M+H] ⁺ ,calcd for C ₂₇ H ₃₅ N ₅ O ₄ 494.2768。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.69(s,1H),7.25(s,1H),7.18(s,1H),7.09–6.90(m,4H),4.16(q,J＝6.1Hz,2H),4.01(s,3H),3.91(s,3H),3.87(dd,J＝5.5,4.0Hz,4H),3.74–3.69(m,4H),3.35–3.23(m,4H),2.58(t,J＝7.2Hz,2H),2.53–2.44(m,4H),2.15–2.02(m,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.78,154.86,153.09,152.27,149.12,147.85,140.88,123.38,121.09,118.34,111.41,107.59,104.58,67.36,66.98,56.16,55.45,53.75,50.63,49.98,26.18。

Example 17: synthesis of Compound 4- (3- ((7-methoxy-4- (4-tosylpiperaziin-1-yl) quinazolin-6-yl) oxy) propyl) morph (QJJ-7)

Synthesis of Compound QJJ-7 (FIG. 2) Synthesis of Compound QJJ-1 in example 11. Compound 1b (0.3 mmol) was reacted with compound 9a to give compound QJJ-7 instead of 1-phenylpiperazine in example 11. Brown solid, yield 81%, m.p.164.4 ℃ -167.7 ℃.

ESI-HRMS m/z:542.2432[M+H] ⁺ ,calcd for C ₂₇ H ₃₅ N ₅ O ₅ S 542.2428。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.47(s,1H),7.75(s,1H),7.63(s,2H),7.43(s,2H),7.37(s,1H),4.03(s,2H),3.84(d,J＝15.0Hz,7H),3.54(s,4H),3.04(s,4H),2.45(d,J＝25.0Hz,5H),2.32(s,4H),1.83(s,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:156.55,152.80,149.95,143.56,141.08,135.58,129.69,127.53,112.87,110.65,109.09,67.91,67.08,56.83,53.07,52.49,48.73,45.75,28.13,21.15。

Example 18: synthesis of the Compound 4- (3- ((7-methoxy-4- (4- ((4-methoxyphenyl) sulfophenyl) piperazin-1-yl) quinazolin-6-yl) oxy) propyl) morpholine (QJJ-8)

Synthesis of Compound QJJ-8 (FIG. 2) Synthesis of Compound QJJ-1 in example 11. Compound 1c (0.3 mmol) was reacted with compound 9a to give compound QJJ-8 instead of 1-phenylpiperazine in example 11. Brown solid, 86% yield, m.p.141.8-143.4 ℃.

ESI-HRMS m/z:558.2381[M+H] ⁺ ,calcd for C ₂₇ H ₃₅ N ₅ O ₆ S 558.2368。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.49(s,1H),7.88(s,1H),7.78–7.61(m,2H),7.40(s,1H),7.18–6.93(m,2H),4.04(t,J＝15.0Hz,2H),3.91–3.71(m,10H),3.55(t,J＝9.4Hz,4H),3.05(t,J＝10.2Hz,4H),2.48(t,J＝11.0Hz,2H),2.33(t,J＝9.4Hz,4H),1.83(tt,J＝14.9,11.0Hz,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.15,154.97,152.66,149.20,148.21,129.87,127.04,114.39,111.08,107.62,104.03,67.41,66.94,56.16,55.63,55.29,53.73,48.96,45.56,26.14。

Example 19: synthesis of the Compound 4- (3- ((7-methoxy-4- (4- ((3-nitrophenyl) sulfonyl) piperazin-1-yl) quinazolin-6-yl) oxy) propyl) morpholine (QJJ-9)

Synthesis of Compound QJJ-9 (FIG. 2) was conducted in the same manner as in Synthesis of Compound QJJ-1 of example 11. Compound 1d (0.3 mmol) was reacted with compound 9a to give compound QJJ-9 instead of 1-phenylpiperazine in example 11. Yellow solid, yield 79%, m.p.191.5 ℃ -194.0 ℃.

ESI-HRMS m/z:573.2126[M+H] ⁺ ,calcd for C ₂₆ H ₃₂ N ₆ O ₇ S 573.2119。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.54(dt,J＝15.0,3.1Hz,1H),8.49(s,1H),8.43(t,J＝3.0Hz,1H),8.22(dt,J＝15.0,3.1Hz,1H),7.97(t,J＝15.0Hz,1H),7.79(s,1H),7.69(s,1H),4.04(t,J＝15.2Hz,2H),3.85(dd,J＝18.6,7.5Hz,7H),3.55(t,J＝9.4Hz,4H),3.05(t,J＝11.0Hz,4H),2.48(t,J＝15.0Hz,2H),2.33(t,J＝9.4Hz,4H),1.95–1.70(m,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:162.93,155.13,152.53,149.31,148.32,138.17,133.16,130.65,127.59,122.42,111.04,107.59,103.65,67.35,66.94,56.11,55.38,53.73,48.93,45.47,26.13。

Example 20: synthesis of the Compound 4- (3- ((7-methoxy-4- (4- (phenylsulfanyl) piperazin-1-yl) quinazolin-6-yl) oxy) propyl) morph (QJJ-10)

Synthesis of Compound QJJ-10 (FIG. 2) Synthesis of Compound QJJ-1 in example 11. Compound 1a (0.3 mmol) was reacted with compound 9a to give compound QJJ-10 instead of 1-phenylpiperazine in example 11. Tan solid, yield 79%, m.p.159.1 ℃ -160.6 ℃.

ESI-HRMS m/z:528.2275[M+H] ⁺ ,calcd for C ₂₆ H ₃₃ N ₅ O ₅ S 528.2272。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.49(s,1H),8.07–7.77(m,3H),7.70–7.57(m,3H),7.38(s,1H),4.04(t,J＝15.0Hz,2H),3.85(dd,J＝17.9,7.6Hz,7H),3.55(t,J＝9.3Hz,4H),3.05(t,J＝10.2Hz,4H),2.48(t,J＝11.0Hz,2H),2.33(t,J＝9.4Hz,4H),1.83(tt,J＝14.9,11.0Hz,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.04,155.27,152.79,149.17,148.13,135.80,133.09,132.78,129.07,128.94,127.73,111.07,107.74,103.91,67.48,66.95,56.18,55.38,53.61,48.93,46.83,45.55,45.29,26.13。

Example 21: synthesis of Compound 4- (3- ((4- (4-benzoylpiperazine-1-yl) -7-methoxyquinazolin-6-yl) oxy) propyl) morpholine (QJJ-11)

Synthesis of Compound QJJ-11 (FIG. 2) Synthesis of Compound QJJ-1 of example 11. 1-Benzylpiperazine (0.3 mmol) was reacted with compound 9a instead of 1-phenylpiperazine in example 11 to obtain compound QJJ-11. Pale yellow oily, yield 87%.

ESI-HRMS m/z:478.2813[M+H] ⁺ ,calcd for C ₂₇ H ₃₅ N ₅ O ₃ 478.2808。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.49(s,1H),7.97(s,1H),7.79(s,1H),7.33–7.13(m,5H),4.04(t,J＝15.0Hz,2H),3.87(dd,J＝22.7,12.6Hz,7H),3.66(s,2H),3.55(t,J＝9.4Hz,4H),2.62(t,J＝10.2Hz,4H),2.48(t,J＝11.0Hz,2H),2.33(t,J＝9.4Hz,4H),1.83(tt,J＝14.9,11.0Hz,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.23,154.91,152.57,148.86,147.88,137.51,129.16,128.15,127.44,111.03,107.71,104.65,67.36,66.96,63.10,56.10,55.46,53.73,52.95,49.68,26.12。

Example 22: synthesis of Compound 4- (3- ((4- (4- (3-chlorobenzoyl) piperazin-1-yl) -7-methoxyquinazolin-6-yl) oxy) propyl) morph (QJJ-12)

Synthesis of Compound QJJ-12 (FIG. 2) Synthesis of Compound QJJ-1 of example 11. 1- (3-chlorobenzyl) piperazine (0.3 mmol) was reacted with compound 9a to give compound QJJ-12 instead of 1-phenylpiperazine of example 11. Pale yellow oil, 76% yield.

ESI-HRMS m/z:512.2423[M+H] ⁺ ,calcd for C ₂₇ H ₃₄ ClN ₅ O ₃ 512.2418。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.49(s,1H),7.85(s,1H),7.48–7.30(m,4H),7.25–7.13(m,1H),4.04(t,J＝15.0Hz,2H),3.87(dd,J＝22.9,12.5Hz,7H),3.66(s,2H),3.55(t,J＝9.4Hz,4H),2.62(t,J＝10.4Hz,4H),2.48(t,J＝11.0Hz,2H),2.33(t,J＝9.4Hz,4H),1.83(tt,J＝14.9,11.0Hz,2H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.22,154.51,152.86,149.23,147.49,139.85,133.80,129.60,129.00,127.41,127.14,111.26,107.45,104.55,67.34,66.95,62.40,56.12,55.38,53.71,52.90,49.64,26.13。

Example 23: synthesis of the Compound (ethane-1, 2-diylbis) bis (ethane-2, 1-diyl) bis (4-methylpbenzenesulfonate) (3 c)

Triethylene glycol (0.9 mL,6.7 mmol), tetrahydrofuran (1.5 mL), water (4 mL) and sodium hydroxide (0.76 g) are sequentially added into a round-bottom flask, 2.2mL of tetrahydrofuran-dissolved p-toluenesulfonyl chloride (2.39 g,12 mmol) is slowly added dropwise under ice bath, the reaction is continued for 3h under ice bath after the dropwise addition, tetrahydrofuran is distilled off after the dropwise addition, the mixture is cooled, white solid is separated out, suction filtration and washing with methanol, ethanol and ice water are sequentially carried out, and white solid 3c (figure 3) is obtained after drying.

ESI-MS:m/z 459.2[M+H] ⁺ 。 ¹ H NMR(300MHz,CDCl ₃ )δ:2.46(s,6H),3.54(s,4H),3.66(t,4H),4.15(t,4H),7.35(d,4H),7.80(d,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:144.9,132.9,129.9,128.0,70.7,69.2,68.7,21.7。

Example 24: synthesis of 3,4-dihydroxybenzonitrile (5 c) compound

13.8g of 3, 4-dihydroxybenzaldehyde, 16.7g of hydroxylamine hydrochloride, 13.6g of sodium formate and 50ml of formic acid are sequentially added into a round-bottom flask, the mixture is heated to 100 ℃ and refluxed for 6 hours, saturated saline is added into the reaction solution after the completion of the refluxing, the mixture is stirred and filtered, and a filter cake is washed with water and dried to obtain gray powder 5c (figure 3).

ESI-MS:m/z 136.1[M+H] ⁺ 。 ¹ H NMR(300MHz,CDCl ₃ )δ:7.49(s,1H),7.36(s,1H),6.79(s,1H),3.05(s,1H),2.93(s,1H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:153.08,146.56,125.51,118.82,117.67,116.22,101.67。

Example 25: synthesis of 2,3,5,6,8, 9-hexahydroxyboot [ b ] [1,4,7,10] tetraoxyacylodecene-12-carbonidazole (6 c)

To a round bottom flask, 5c 10g, 200mL of tetrahydrofuran, 40mL of water, 2.8g of sodium hydroxide, 8.8g of lithium hydroxide and nitrogen were added in this order, and the mixture was reacted at 70℃for 1 hour. After 1h, 70mL of tetrahydrofuran-dissolved 3c (37.3 g) was added dropwise to the reaction system, and the reaction was continued for 72h. After the reaction was completed, tetrahydrofuran was distilled off, the residual portion was extracted with methylene chloride, and the solvent was evaporated to dryness to give a black viscous oil. The crude product was separated on a silica gel column (petroleum ether: ethyl acetate=4:1, volume ratio) to give a white solid 6c (fig. 3).

ESI-MS:m/z 250.3[M+H] ⁺ 。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:7.56(d,J＝2.0Hz,1H),7.46(dd,J＝8.4,2.0Hz,1H),7.21(d,J＝8.4Hz,1H),4.23–4.13(m,4H),3.75–3.63(m,4H),3.58(s,4H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:155.29,150.54,128.20,122.64,119.32,117.93,104.19,72.73,70.99,70.69,70.36,69.11,68.92。

Example 26: synthesis of Compound 13-nitro-2,3,5,6,8, 9-hexahydrobenzob 1,4,7,10 tetraoxyacylodecene-12-carbonidazole (7 c)

To a round bottom flask was added 65% by mass nitric acid (38 mmol,2.7 ml), cooled to 0 ℃, 6c (3.8 mmol,0.95 g) dissolved in 5ml glacial acetic acid was slowly added, kept at 0 ℃ for 4h, then heated to 50 ℃ and refluxed for 4h, after the completion of which the reaction solution was washed with ice water, yellow solid was precipitated, filtered, washed with n-hexane, and dried to give yellow solid 7c (yellow solid, yield 51%) (fig. 3).

ESI-MS:m/z 295.3[M+H] ⁺ 。 ¹ H NMR(300MHz,CDCl ₃ )δ:7.90(s,1H),7.37(s,1H),4.35(dd,J＝8.4,4.3Hz,4H),3.98–3.80(m,4H),3.73(s,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:155.40,154.12,143.24,122.72,115.05,114.60,101.98,94.33,72.56,72.47,70.85,70.84,69.20,69.17。

Example 27: synthesis of Compound 7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxyacidiodecno [2,3-g ] quinazolin-4 (3H) -one (8 c)

7c (0.68 mmol,0.2 g) was added to a flask containing 20ml formamide, which was completely dissolved with stirring, and indium trichloride (0.68 mmol,0.15 g) was added as a catalyst. The reaction was carried out in a microwave reactor (110 ℃, 400W) and terminated after 60 minutes. A small amount of water was added to the mixture, and extracted with dichloromethane. The dichloromethane layer was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave a residue which was purified by column on silica gel (ethyl acetate: triethylamine 100:1, volume ratio) to give compound 8c (white solid, yield 25.6%) (fig. 3).

ESI-MS:m/z 293.3[M+H] ⁺ 。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:12.07(s,1H),7.99(d,J＝2.7Hz,1H),7.62(s,1H),7.22(s,1H),4.28–4.16(m,4H),3.81–3.66(m,4H),3.62(s,4H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:160.44,156.84,150.03,146.23,144.69,117.10,113.76,113.08,73.20,71.00,70.92,70.51,69.23,68.93。

Example 28: synthesis of 4-chloro-7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxyacetodecilo [2,3-g ] quinazoline (9 c)

8c (0.3 mmol,0.1 g) and N, N-dimethylformamide (0.024 ml) were added to a flask containing 30ml of chloroform when it was completeUpon complete dissolution, oxalyl chloride (0.86 mmol,0.073 ml) was slowly added, heated to 61℃and the reaction was stopped after 2 hours. Saturated sodium bicarbonate solution was added until a pH of 10.0 was observed. The mixture was extracted with ethyl acetate. Anhydrous Na for organic layer ₂ SO ₄ Drying, filtration and concentration gave a residue which was purified by silica gel column (petroleum ether: ethyl acetate=1:1, volume ratio) to give compound 9c (white solid, yield 65.0%) (fig. 3).

ESI-MS:m/z 311.7[M+H] ⁺ 。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.88(s,1H),7.67(s,1H),7.41(s,1H),4.47–4.28(m,4H),4.03–3.85(m,4H),3.80(s,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:159.83,158.57,152.93,152.55,149.56,120.01,111.94,111.27,73.74,71.53,71.01,70.89,69.63,69.18。

Example 29: synthesis of the Compound 4- (4- (4-fluorophenyl) piperazin-1-yl) -7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxa-cyclopodecino [2,3-g ] quinazoline (QJJ-13)

Synthesis of Compound QJJ-13 (FIG. 3) was conducted in the same manner as in Synthesis of Compound QJJ-1 of example 11. Namely, compound 9c (0.3 mmol) was substituted for 9a of example 11 and 1- (4-fluorophenyl) piperazine (0.3 mmol) was synthesized as compound QJJ-13. Pale yellow solid, yield 83%, m.p.161.2 ℃ -165.2 ℃.

ESI-HRMS m/z:455.2089[M+H] ⁺ ,calcd for C ₂₄ H ₂₇ FN ₄ O ₄ 455.2092。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.49(s,1H),8.03(s,1H),7.81(s,1H),6.99–6.83(m,2H),6.78–6.63(m,2H),4.34–4.22(m,4H),3.88(dt,J＝13.6,9.3Hz,4H),3.70(s,4H),3.65–3.47(m,8H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.96,156.41,153.51,150.21,149.19,147.70,118.19,118.09,115.83,115.53,113.46,111.88,111.13,74.12,71.69,70.82,69.92,69.77,69.32,50.23,49.76。

Example 30: synthesis of the Compound 4- (4- (4-nitrophenyl) piperazin-1-yl) -7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxa-cyclopodecino [2,3-g ] quinazoline (QJJ-14)

Synthesis of Compound QJJ-14 (FIG. 3) was conducted in the same manner as in Synthesis of Compound QJJ-1 of example 11. Namely, compound 9c (0.3 mmol) was substituted for 9a of example 11 and 1- (4-nitrophenyl) piperazine (0.3 mmol) to synthesize compound QJJ-14. Yellow solid, yield 81%, m.p.146.2 ℃ -146.8 ℃.

ESI-HRMS m/z:482.2034[M+H] ⁺ ,calcd for C ₂₄ H ₂₇ N ₅ O ₆ 482.2042。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.49(s,1H),8.04(s,2H),7.84(d,J＝15.9Hz,2H),7.01(s,2H),4.28(d,J＝10.2Hz,4H),3.93(s,2H),3.85(s,2H),3.65(s,4H),3.55(d,J＝15.0Hz,8H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.58,156.42,154.56,153.47,150.16,149.36,138.72,125.87,113.26,112.50,111.83,111.14,74.08,71.66,70.71,69.92,69.75,69.19,48.93,46.65。

Example 31: synthesis of the Compound 4- (4- (phenylsulfanyl) piperazin-1-yl) -7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxa-cyclopodecino [2,3-g ] quinazoline (QJJ-15)

Synthesis of Compound QJJ-15 (FIG. 3) was conducted in the same manner as in Synthesis of Compound QJJ-1 of example 11. Namely, compound 9c (0.3 mmol) was substituted for 9a of example 11 and 1a (0.3 mmol) was synthesized as compound QJJ-15. Pale yellow solid, 76% yield, m.p.162.1 ℃ -163.9 ℃.

ESI-HRMS m/z:501.1802[M+H] ⁺ ,calcd for C ₂₄ H ₂₈ N ₄ O ₆ S 501.1807。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.60(s,1H),7.78(dd,J＝9.5,7.9Hz,2H),7.70–7.51(m,3H),7.31–7.24(m,2H),4.33–4.19(m,4H),4.03–3.91(m,2H),3.90–3.69(m,10H),3.29–3.13(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:156.28,152.73,151.20,141.08,137.97,134.30,129.96,128.95,112.87,110.50,109.36,70.17,68.31,48.73,45.75。

Example 32: synthesis of the Compound 4- (4- ((3-nitrophenyl) sulfophenyl) piperazin-1-yl) -7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxyacylodeceno [2,3-g ] quinazoline (QJJ-16)

Synthesis of Compound QJJ-16 (FIG. 3) was conducted in the same manner as in Synthesis of Compound QJJ-1 of example 11. Namely, compound 9c (0.3 mmol) was substituted for 9a of example 11 and 1d (0.3 mmol) was synthesized as compound QJJ-16. Yellow solid, 75% yield, m.p.141.6 ℃ -147.5 ℃.

ESI-HRMS m/z:546.1653[M+H] ⁺ ,calcd for C ₂₄ H ₂₇ N ₅ O ₈ S 546.1659。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.58–8.50(m,1H),8.49(s,1H),8.43(t,J＝3.0Hz,1H),8.22(dt,J＝15.0,3.1Hz,1H),8.02–7.92(m,2H),7.85(s,1H),4.35–4.23(m,4H),3.96–3.79(m,8H),3.67(s,4H),3.05(t,J＝10.2Hz,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.43,156.81,153.42,150.21,149.47,148.41,137.96,133.06,130.65,127.62,122.65,113.05,111.69,110.93,74.08,71.73,70.63,69.81,69.65,69.19,48.95,45.67。

Example 33: synthesis of the Compound 4- (4-benzoylpiperazine-1-yl) -7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxyacetyclo-docino [2,3-g ] quinazoline (QJJ-17)

Synthesis of Compound QJJ-17 (FIG. 3) was conducted in the same manner as in Synthesis of Compound QJJ-1 of example 11. Namely, compound 9c (0.3 mmol) was substituted for 9a of example 11 and 1-benzylpiperazine (0.3 mmol) was synthesized as compound QJJ-17. Pale yellow oil, 86% yield.

ESI-HRMS m/z:451.2340[M+H] ⁺ ,calcd for C ₂₅ H ₃₀ N ₄ O ₄ 451.2353。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:8.49(s,1H),8.00(s,1H),7.85(s,1H),7.24(t,J＝17.5Hz,5H),4.30(d,J＝16.8Hz,4H),3.88(t,J＝25.1Hz,8H),3.67(d,J＝9.9Hz,6H),2.62(s,4H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:163.46,156.28,153.33,149.73,149.17,138.49,129.23,128.69,127.24,112.59,111.75,111.04,73.76,71.07,70.72,70.54,69.32,68.75,62.36,52.92,49.49。

Example 34: synthesis of the Compound 4- (4- (3-chlorobenzoyl) piperazin-1-yl) -7,8,10,11,13,14-hexahydro- [1,4,7,10] tetraoxyacylodeceno [2,3-g ] quinazoline (QJJ-18)

Synthesis of Compound QJJ-18 (FIG. 3) was conducted in the same manner as in Synthesis of Compound QJJ-1 of example 11. Namely, compound 9c (0.3 mmol) was substituted for 9a of example 11 and 1- (3-chlorobenzyl) piperazine (0.3 mmol) to synthesize compound QJJ-18. Pale yellow oil, 85% yield.

ESI-HRMS m/z:485.1950[M+H] ⁺ ,calcd for C ₂₅ H ₂₉ ClN ₄ O ₄ 485.1981。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.65(s,1H),7.39(d,J＝4.8Hz,2H),7.31–7.23(m,4H),4.34–4.20(m,4H),4.02–3.93(m,2H),3.86(dd,J＝4.6,3.1Hz,2H),3.81(s,4H),3.76–3.66(m,4H),3.57(s,2H),2.73–2.56(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.86,156.17,153.45,149.98,148.85,140.06,134.26,129.55,129.07,127.39,127.14,113.62,111.79,110.91,74.11,71.70,70.81,69.91,69.71,69.34,62.41,52.94,49.63。

Example 35: synthesis of 2-methoxymyl-4-methyzenesulfonate (3 d)

NaOH (14.4 g,0.36 mol), ethylene glycol monomethyl ether (22.8 g,0.3 mol) was weighed out and dissolved in a mixture of THF (tetrahydrofuran) (90 mL) and water (180 mL), and the mixture was ice-bath treated. After 2 hours, p-toluenesulfonyl chloride (59.9 g,0.315 mol) was dissolved in THF (150 mL) and the above system was added dropwise and the ice bath was continued for 4 hours. After the completion of the TLC detection reaction, THF was dried, saturated brine was washed with water, dichloromethane was extracted, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate=9:1, volume ratio), collected by TLC trace, and dried in vacuo to give compound 3d (yield 47%) (fig. 4).

ESI-MS:[M+H] ⁺ m/z 231.0,[M+NH ₄ ] ⁺ m/z 248.3。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:7.79(d,J＝8.3Hz,2H),7.48(d,J＝8.0Hz,2H),4.16–4.08(m,2H),3.55–3.44(m,2H),3.18(s,3H),2.41(s,3H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:145.37,132.85,130.57,128.06,70.17,69.71,58.37,21.50。

Example 36: synthesis of 3,4-bis (2-methoxyyethoxy) benzaldehyde (4 d) compound

3, 4-dihydroxybenzaldehyde (6.9 g,0.05 mol) was weighed, dissolved in acetonitrile (300 mL), potassium carbonate (13.8 g,0.1 mol), compound 3d (23.1 g,0.1 mol) was added, and vacuum was applied, N ₂ Protection, reaction at 84℃for 36h. After the TLC detection reaction is complete, the solution is filtered by suction, and the filtrate is taken and the acetonitrile is dried by spin. Saturated brine is washed with water, extracted with ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate=4:1, volume ratio). TLC trace collection Drying in vacuo afforded compound 4d (80.3% yield) as an orange oil (fig. 4).

ESI-MS:[M+H] ⁺ m/z 255.3,[M+Na] ⁺ m/z 277.3。 ¹ H NMR(300MHz,CDCl ₃ )δ:9.79(s,1H),7.40(dt,J＝8.2,2.6,1.8Hz,2H),6.96(d,J＝8.0Hz,1H),4.23–4.13(m,4H),3.76(dt,J＝6.2,3.8Hz,4H),3.41(s,6H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:190.90,154.35,149.16,130.20,126.75,112.43,111.70,70.76,70.66,68.57,68.55,59.27,59.19。

Example 37: synthesis of 3,4-bis (2-methoxythoxy) benzonitrile (5 d) compound

Sodium formate (2.68 g,39.9 mmol) was weighed and dissolved in formic acid (1.63 g,35.4 mmol), compound 4d (5.0 g,19.69 mmol) was added, after heating to 85℃hydroxylamine hydrochloride (3.3 g,47.2 mmol) was added, and after reacting for 5h, cooling to room temperature. The reaction solution was poured into cold saturated brine, stirred, a large amount of white solid was precipitated, the crude product was obtained by filtration, ethyl acetate was recrystallized, and dried to obtain compound 5d (yield 75.5%) as a white solid (fig. 4).

ESI-MS:[M+H] ⁺ m/z 252.3,[M+NH ₄ ] ⁺ m/z 269.3。 ¹ H NMR(300MHz,CDCl ₃ )δ:7.27(dd,J＝8.4,2.0Hz,1H),7.15(d,J＝1.9Hz,1H),6.93(dd,J＝8.4,2.7Hz,1H),4.25–4.13(m,4H),3.79(dt,J＝4.3,3.1Hz,4H),3.45(d,J＝0.9Hz,6H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:152.93,148.90,126.83,119.16,117.05,113.51,104.17,70.80,70.69,69.05,68.62,59.29,59.25。

Example 38: synthesis of the Compound 4,5-bis (2-methoxyythoxy) -2-nitrobenzonitrile (6 d)

Weighing 65% nitric acid (10.5 mL), placing in a low-temperature reactor, and pre-cooling at 0deg.C for 30min. After compound 5d (3.7 g,14.8 mmol) was dissolved in glacial acetic acid (8.0 mL), the above system was added dropwise and the reaction was continued at 0 ℃. After 4h, the temperature was raised to 50℃and the reaction was continued. After 4h, 30mL of ice water was added for washing, filtration, washing of the filter cake with ice water, washing with n-hexane, and drying to give compound 6d (yield 50%) as a yellow solid (fig. 4).

ESI-MS:[M+H] ⁺ m/z 297.3。 ¹ H NMR(300MHz,CDCl ₃ )δ:7.87(s,1H),7.29(s,1H),4.31(td,J＝6.2,4.6Hz,4H),3.88–3.79(m,4H),3.47(s,6H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:153.16,151.90,142.69,117.32,115.55,109.62,100.85,70.51,70.45,69.61,69.42,59.38。

Example 39: synthesis of 6,7-bis (2-methoxyyethoxy) quinazolin-4 (3H) -one (7 d)

Compound 6d (0.4 g,1.35 mmol) was weighed, indium trichloride (0.3 g,1.35 mmol) was dissolved in formamide (20 mL), and the reaction was carried out for 1h with a microwave reactor set at 110℃and 400w power. After completion of the reaction, the filtrate was filtered, washed with saturated brine, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure, followed by recrystallization from a small amount of ethyl acetate to give compound 7d (yield 50%) as a white solid (fig. 4).

ESI-MS:[M+H] ⁺ m/z 295.3,[M+Na] ⁺ m/z 317.3。 ¹ H NMR(300MHz,CDCl ₃ )δ:12.17(s,1H),8.04(s,1H),7.51(s,1H),7.09(s,1H),4.36–4.14(m,4H),3.83(s,4H),3.45(d,J＝0.7Hz,6H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:162.39,154.74,148.62,145.33,142.76,115.65,109.06,106.47,70.63,70.48,68.50,68.43,59.27,59.23。

Example 40: synthesis of 4-chloro-6,7-bis (2-methoxyxanthoxy) quinazoline (8 d)

Compound 7d (0.13 g,0.44 mmol) was weighed out and dissolved in chloroform (20 mL) and N, N-dimethylformamide (0.03 g,0.38 mmol) was added. Oxalyl chloride (0.14 g,1.1 mmol) was added dropwise and refluxed at 61℃for 2h. After the completion of the TLC detection reaction, the reaction was washed with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate=1:1, volume ratio). TLC was collected by tracing and dried in vacuo to give compound 8d (94% yield) as a white solid (fig. 4).

ESI-MS:[M+H] ⁺ m/z 313.3。 ¹ H NMR(300MHz,d ₆ -DMSO)δ:8.48(s,1H),7.47(s,1H),7.26(s,1H),4.24(ddd,J＝9.3,5.3,3.7Hz,4H),3.74(ddd,J＝9.1,8.0,4.6Hz,4H),3.35(dd,J＝5.8,2.2Hz,6H)。 ¹³ C NMR(75MHz,d ₆ -DMSO)δ:159.40,154.75,148.92,146.05,139.75,115.35,107.24,106.06,70.55,70.39,68.85,68.73,58.81,58.76。

Example 41: synthesis of the Compound 6,7-bis (2-methoxythoxy) -4- (4- (phenylsulfanyl) piperazin-1-yl) quinazoline (QJJ-19)

Compound 8d (0.1 g,0.32 mmol) was weighed, dissolved in N, N-dimethylformamide (20 mL), and compound 1a (0.15 g,0.64 mmol) and triethylamine (0.1 mL) were added to carry out a microwave reaction for 20min, the microwave reactor set to a parameter temperature of 120℃and a power of 300w. After the reaction, the mixture was washed with saturated brine, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1 (volume ratio), followed by addition of 1% (v/v) triethylamine). TLC was collected by tracing and dried under vacuum to give compound QJJ-19 (yield 50%), m.p. 89.9-90.4 ℃ (FIG. 4) as a white solid.

ESI-MS:[M+H] ⁺ m/z 503.2。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.54(s,1H),7.78–7.72(m,2H),7.61–7.48(m,3H),7.16(s,1H),7.06(s,1H),4.26–4.14(m,4H),3.78(ddd,J＝6.2,4.6,3.3Hz,4H),3.73–3.66(m,4H),3.40(d,J＝6.4Hz,6H),3.21–3.13(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.26,154.51,152.80,149.26,148.24,135.56,133.11,129.24,127.69,111.28,108.49,105.81,71.11,70.38,69.22,68.25,59.27,59.22,48.97,45.66。ESI-HRMS m/z:503.1961[M+H] ⁺ ,calcd for C ₂₄ H ₃₀ N ₄ O ₆ S 503.1959。

Example 42: synthesis of the Compound 6,7-bis (2-methoxythoxy) -4- (4-tosylpiperazin-1-yl) quinazoline (QJJ-20)

Specific synthetic methods for compounds QJJ-20 can be found in the synthetic procedure for compounds QJJ-19 of example 41. Compound 1b (0.15 g,0.64 mmol) was weighed to replace compound 1a and to give compound QJJ-20 (62% yield) as an oil (fig. 4).

ESI-MS:[M+H] ⁺ m/z 517.2。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.56(s,1H),7.72–7.65(m,2H),7.17(s,1H),7.08(s,1H),7.01–6.98(m,1H),6.98–6.95(m,1H),4.21(ddd,J＝12.8,5.4,3.9Hz,4H),3.87–3.75(m,7H),3.75–3.67(m,4H),3.42(d,J＝4.7Hz,6H),3.19–3.12(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.25,154.50,152.81,149.25,148.20,143.98,132.44,129.86,127.76,111.24,108.46,105.87,71.11,70.38,69.22,68.25,59.28,59.24,48.95,45.67,21.55。ESI-HRMS m/z:517.2124[M+H] ⁺ ,calcd for C ₂₅ H ₃₂ N ₄ O ₆ S 517.2115。

Example 43: synthesis of 6,7-bis (2-methoxyxanthoxy) -4- (4- ((4-methoxyphenyl) sulfoxyl) piperazin-1-yl) quinazoline (QJJ-21)

Specific synthetic methods for compounds QJJ-21 can be found in the synthetic procedure for compounds QJJ-19 of example 41. Compound 1c (0.16 g,0.64 mmol) was weighed to replace compound 1a to give compound QJJ-21 (65% yield) as an oil (fig. 4).

ESI-MS:[M+H] ⁺ m/z 533.5。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.56(s,1H),7.76–7.61(m,2H),7.17(s,1H),7.08(s,1H),7.02–6.94(m,2H),4.21(ddd,J＝12.8,5.4,3.9Hz,4H),3.89–3.75(m,7H),3.74–3.67(m,4H),3.42(d,J＝4.7Hz,6H),3.22–3.06(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.28,163.20,154.53,152.86,149.32,148.22,129.87,126.99,114.39,111.28,108.54,105.96,71.14,70.41,69.28,68.27,59.31,59.26,55.63,48.95,45.68。ESI-HRMS m/z:533.2089[M+H] ⁺ ,calcd for C ₂₅ H ₃₂ N ₄ O ₇ S 533.2064。

Example 44: synthesis of the Compound 6,7-bis (2-methoxyyethoxy) -4- (4- ((3-nitrophenyl) sulfoyl) piperazin-1-yl) quinazoline (QJJ-22)

Specific synthetic methods for compounds QJJ-22 can be found in the synthetic procedure for compounds QJJ-19 of example 41. Compound 1d (0.17 g,0.64 mmol) was weighed to replace compound 1a to give compound QJJ-22 (yield 64%) as an orange-yellow solid, m.p.155.8-156.2 ℃ (FIG. 4).

ESI-MS:[M+H] ⁺ m/z 548.2。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.60(d,J＝8.6Hz,2H),8.48(d,J＝8.1Hz,1H),8.12(d,J＝7.7Hz,1H),7.80(t,J＝8.0Hz,1H),7.21(s,1H),7.09(s,1H),4.31–4.17(m,4H),3.88–3.71(m,8H),3.45(d,J＝5.1Hz,6H),3.34–3.22(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ163.17,154.62,152.79,149.29,148.43,148.39,138.15,133.15,130.78,127.60,122.73,111.30,108.51,105.61,71.15,70.40,69.24,68.31,59.33,59.27,48.94,45.62。ESI-HRMS m/z:548.1809[M+H] ⁺ ,calcd for C ₂₄ H ₂₉ N ₅ O ₈ S 548.1810。

Example 45: the specific synthetic method of compound 6,7-bis (2-methoxyxanthoxy) -4- (4-phenylpiperazine-1-yl) quinazoline (QJJ-23) can be found in the synthetic procedure of compound QJJ-19 of example 41. Compound 1-phenylpiperazine (0.1 g,0.64 mmol) was weighed to replace compound 1a, yielding compound QJJ-23 (yield 55%) (fig. 4).

ESI-MS:[M+H] ⁺ m/z 439.1。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.69(s,1H),7.38–7.23(m,4H),7.00(d,J＝7.9Hz,2H),6.91(t,J＝7.3Hz,1H),4.35–4.22(m,4H),3.93–3.75(m,8H),3.48(s,6H),3.45–3.36(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.82,154.41,153.08,151.08,149.15,148.11,129.24,120.22,116.24,111.55,108.52,106.08,71.11,70.48,69.13,68.31,59.39,59.32,49.70,49.19。ESI-HRMS m/z:439.2344[M+H] ⁺ ,calcd for C ₂₄ H ₃₀ N ₄ O ₄ 439.2340。

Example 46: synthesis of the Compound 4- (4- (4-fluorophenyl) piperazin-1-yl) -6,7-bis (2-methoxythoxy) quinazoline (QJJ-24)

Specific synthetic methods for compounds QJJ-24 can be found in the synthetic procedure for compounds QJJ-19 of example 41. Compound 1- (4-fluorophenyl) piperazine (0.12 g,0.64 mmol) was weighed to replace compound 1a, yielding compound QJJ-24 (50% yield) (fig. 4).

ESI-MS:[M+H] ⁺ m/z 457.5。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.68(s,1H),7.27(s,1H),7.25(s,1H),7.07–6.90(m,4H),4.37–4.19(m,4H),3.93–3.70(m,8H),3.48(s,6H),3.37–3.26(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.81,154.43,153.05,149.15,148.13,147.77,147.74,118.16,118.05,115.80,115.51,111.55,108.51,106.02,71.10,70.47,69.11,68.31,59.38,59.30,50.20,49.72。ESI-HRMS m/z:457.2245[M+H] ⁺ ,calcd for C ₂₄ H ₂₉ FN ₄ O ₄ 457.2246。

Example 47: synthesis of the Compound 6,7-bis (2-methoxyythoxy) -4- (4- (2-methoxyphenyl) piperazin-1-yl) quinazoline (QJJ-25)

Specific synthetic methods for compounds QJJ-25 can be found in the synthetic procedure for compounds QJJ-19 of example 41. Compound 1- (2-methoxyphenyl) piperazine (0.13 g,0.64 mmol) was weighed to replace compound 1a to give compound QJJ-25 (59% yield) (FIG. 4).

ESI-MS:[M+H] ⁺ m/z 469.4。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.65(s,1H),7.26(t,J＝7.3Hz,2H),7.11–6.81(m,4H),4.32–4.17(m,4H),3.93–3.78(m,11H),3.45(s,6H),3.25(s,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.72,154.26,153.05,152.24,149.07,147.88,140.86,123.36,121.05,118.34,111.37,108.40,106.20,71.05,70.46,69.04,68.25,59.33,59.27,55.43,50.63,49.91。ESI-HRMS m/z:469.2446[M+H] ⁺ ,calcd for C ₂₅ H ₃₂ N ₄ O ₅ 469.2445。

Example 48: synthesis of the Compound 6,7-bis (2-methoxyyethoxy) -4- (4- (4-nitrophenyl) piperazin-1-yl) quinazoline (QJJ-26)

Specific synthetic methods for compounds QJJ-26 can be found in the synthetic procedure for compounds QJJ-19 of example 41. Compound 1- (4-nitrophenyl) piperazine (0.13 g,0.64 mmol) was weighed to replace compound 1a to give compound QJJ-26 (59% yield), m.p.140.4-141.9 ℃ (FIG. 4) as an orange yellow solid.

ESI-MS:[M+H] ⁺ m/z 484.4。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.65(d,J＝4.7Hz,1H),8.16–8.01(m,2H),7.30–7.20(m,2H),6.91–6.77(m,2H),4.32–4.19(m,4H),3.91–3.76(m,8H),3.62(dd,J＝6.2,3.9Hz,4H),3.45(d,J＝1.0Hz,6H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.39,154.60,154.50,152.93,149.22,148.23,138.66,125.91,112.58,111.37,108.53,105.78,71.09,70.44,69.16,68.32,59.36,59.28,48.87,46.61。ESI-HRMS m/z:484.2186[M+H] ⁺ ,calcd for C ₂₄ H ₂₉ N ₅ O ₆ 484.2191。

Example 49: the specific synthetic method for compound 4- (4-benzoylpiperazine-1-yl) -6,7-bis (2-methoxyxanthoxy) quinazoline (QJJ-27) can be found in the synthetic procedure of compound QJJ-19 of example 41. Compound 1-benzylpiperazine (0.12 g,0.64 mmol) was weighed to replace compound 1a to give oily compound QJJ-27 (62% yield) (FIG. 4).

ESI-MS:[M+H] ⁺ m/z 453.5。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.63(s,1H),7.38–7.25(m,5H),7.20(d,J＝3.1Hz,2H),4.24(ddd,J＝14.0,5.4,4.0Hz,4H),3.83(dd,J＝9.6,5.0Hz,4H),3.71–3.63(m,4H),3.59(s,2H),3.46(s,6H),2.69–2.61(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.75,154.19,153.12,149.15,147.80,137.75,129.17,128.32,127.23,111.42,108.47,106.24,71.01,70.46,69.01,68.21,63.07,59.33,59.27,52.97,49.66。ESI-HRMS m/z:453.2493[M+H] ⁺ ,calcd for C ₂₅ H ₃₂ N ₄ O ₄ 453.2496。

Example 50: synthesis of the Compound 4- (4- (3-chlorobenzoyl) piperazin-1-yl) -6,7-bis (2-methoxyxanthoxy) quinazoline (QJJ-28)

Specific synthetic methods for compounds QJJ-28 can be found in the synthetic procedures for compounds QJJ-19 of example 41. Compound 1- (3-chlorobenzyl) piperazine (0.12 g,0.64 mmol) was weighed to replace compound 1a to give compound QJJ-28 (65% yield) as an oil (fig. 4).

ESI-MS:[M+H] ⁺ m/z 487.3。 ¹ H NMR(300MHz,CDCl ₃ )δ:8.64(s,1H),7.28(s,1H),7.24(dt,J＝11.6,3.8Hz,5H),4.26(ddd,J＝13.9,5.4,4.1Hz,4H),3.84(dd,J＝9.5,5.5Hz,4H),3.72–3.63(m,4H),3.56(s,2H),3.48–3.44(m,6H),2.68–2.61(m,4H)。 ¹³ C NMR(75MHz,CDCl ₃ )δ:163.74,154.26,153.09,149.15,147.87,140.08,134.24,129.60,129.03,127.41,127.16,111.43,108.48,106.25,71.04,70.47,69.07,68.25,62.40,59.35,59.29,52.95,49.64。ESI-HRMS m/z:487.2108[M+H] ⁺ ,calcd for C ₂₅ H ₃₁ ClN ₄ O ₄ 487.2107。

Example 51: experiment of anticancer cell proliferation activity of phenylpiperazine quinazoline compounds

The cells selected in this example were cervical cancer Hela cell line, human lung adenocarcinoma H1299 cell line, human lung adenocarcinoma A549 cell line (Shanghai China academy of sciences cell bank), and were cultured in RPMI 1640 medium (Gibco) containing 1% (w/v) of diabody (penicillin and streptomycin) and 10% (v/v) of FBS (fetal bovine serum) serum, and the MTT method was used to detect cell proliferation and apoptosis. The test method is briefly described as follows:

(1) Experimental samples: compounds QJJ-1 to QJJ-28 and positive control Erlotinib (Erlotinib).

(2) Dispensing: the concentrated solutions of the above compounds (mother liquor concentration: 200 mmol/L) were diluted with medium to a desired series of concentrations, respectively, for IC of the compounds against each tumor cell ₅₀ (half inhibition concentration) measurement.

(3) Seed plate: taking the desired cells in logarithmic growth phase at 5×10 ³ Density of wells/wells were seeded in 96-well plates with 100. Mu.L of each well and the edge wells filled with 100. Mu.L of sterile PBS, cells were placed in 37℃with 5% CO ₂ Is cultured overnight in a constant temperature incubator.

(4) Adding the medicine: after 24 hours, the original medium in the 96-well plate was carefully aspirated off, and a blank group and a dosing group were set. 100 mu L of non-drug-containing culture medium is added into a blank group, 100 mu L of drug-containing culture medium is added into an experimental group, 6 compound holes are arranged at each concentration, and the mixture is placed at 37 ℃ and 5% CO ₂ The culture was continued for 72 hours in a constant temperature incubator.

(5) Adding MTT: after 72h of incubation, a further 15. Mu.L MTT solution (0.5%) was added to each well and the incubator was incubated for a further 4h.

(6) DMSO dissolution: after 4h, the supernatant was blotted dry, taking care not to destroy the bottom cells, and 150 μl DMSO (dimethyl sulfoxide) was added to each well and shaken for 10min to allow formazan to dissolve well.

(7)IC ₅₀ Is determined by: the absorbance was measured at 570nm wavelength using a multifunctional microplate reader, and the cell growth inhibition (%) was calculated: growth inhibition = 1-drug group a570nm value/control group a570nm value; drawing curve, calculating IC ₅₀ 。

IC of compound QJJ-1-QJJ-28 and erlotinib on three cancer cell lines ₅₀ The results of the value measurement are shown in Table 1. The result shows that the phenylpiperazine quinazoline compounds QJJ-1 to QJJ-28 prepared by the invention all have different degrees on the growth of three tumor cells to be examined Inhibition, some compounds such as QJJ-12, QJJ-18, QJJ-28 showed better in vitro anticancer activity.

Compounds QJJ-1 to QJJ-28 of Table 1 and IC of erlotinib against three cancer cells ₅₀ Value of

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Example 52: EGFR wild type (EGFR wt) and EGFR T790M/L858R double mutant kinase inhibition assay

(1) Experimental samples: QJJ-12, QJJ-18, QJJ-28, positive control Erlotinib (Erlotinib).

(2) Experiment kit: ADP-Glo using Promega corporation of America ^TM Kinase Assay kit, ADP-Glo ^TM Kinase Assay is a luminescence Assay kit for detecting ADP (adenosine diphosphate) formed in a Kinase reaction; ADP is converted to ATP (adenosine triphosphate) which is then converted to light by luciferase and the luminescent signal is positively correlated with kinase activity. The reaction components are prepared according to the instructions of the kit by using the corresponding components in the kit, and corresponding experimental operations are carried out to determine the influence of the compound to be tested on the kinase activity.

(3) Preparing reaction components:

(1) 38.8. Mu.L of ultrapure water, 160. Mu.L of 5X Reaction Buffer A, 0.4. Mu.L of DTT (100 mM) and 0.8. Mu.L of MnCl were taken ₂ (2.5 mM) in a 1.5ml centrifuge tube was prepared 200. Mu.L of 4X Reaction Buffer A + DTT + MnCl ₂ And (5) vibrating and mixing uniformly.

(2) mu.L of ultra Pure water (79.6. Mu.L) and 0.4. Mu.L of 10mM mu.Ltra-Pure ATP were mixed by shaking in a 1.5ml centrifuge tube to prepare 80. Mu.L of 50. Mu.M ATP.

(3) 62.5. Mu.L of 4× Reaction Buffer A +DTT+MnCl was taken ₂ 62.5. Mu.L of 50uM ATP, 125. Mu.L of Poly (Glu: tyr=4:1, w/w) peptide (1 mg/ml), and 250. Mu.L of 2.5 XATP/submount Mix were prepared in a 1.5ml centrifuge tube and shakenAnd (5) evenly mixing.

(4) Taking 146. Mu.L of ultrapure water and 50. Mu.L of 4× Reaction Buffer A +DTT+MnCl ₂ mu.L EGFR kinase (100 ng/. Mu.L; promega Corporation) was prepared in a 1.5ml centrifuge tube and mixed by pipetting 200. Mu.L EGFR kinase solution.

(5) mu.L of ultrapure water, 37.5. Mu.L of 4X Reaction Buffer A + DTT + MnCl were taken ₂ 7.5. Mu.L EGFR T790M/L858R kinase (100 ng/. Mu.L; promega Corporation) A150. Mu.L EGFR kinase solution was prepared in a 1.5ml centrifuge tube and was blow-mixed.

(6) Taking 15. Mu.L of ultrapure water, 5. Mu.L of 4X Reaction Buffer A +DTT+MnCl ₂ mu.L of 1 Xreaction Buffer was prepared in a 1.5ml centrifuge tube and used as a kinase-free control, and mixed by shaking.

(4) The compounds were subjected to gradient dilution: 299.5. Mu.L of ultrapure water, 80. Mu.L of 5X Reaction Buffer A, 0.2. Mu.L of DTT (100 mM), 0.3. Mu.L of MnCl were taken ₂ (2.5 mM) and 20. Mu.L of DMSO, 400. Mu.L of 1 Xreaction buffer+5% DMSO was prepared in a 1.5ml centrifuge tube, and mixed by shaking. 10. Mu.L of the above liquid was added to A2 to A24 of the following 384-well plates: the A1 well was not added. Taking 14. Mu.L of ultrapure water, 5. Mu.L of 4X Reaction Buffer A +DTT+MnCl ₂ And 1. Mu.L of compound (DMSO dissolved to 1 mM) in a 1.5ml centrifuge tube, 20. Mu.L of 50. Mu.M inhibitor (5% DMSO) was formulated. Mix well with shaking and transfer to A1 wells (final concentration in kinase reaction system will be 10 μm,1% dmso). 10 mu L of the solution is sucked out from the A1 hole and transferred to the A2 hole, and the solution is blown for 6 to 10 times and uniformly mixed (taking care that air bubbles are not blown out). The wells were serially diluted to A21 wells with concentrations of 10000nM,5000nM,2500nM … …, 0.04nM,0.02nM,0.01nM. No liquid is supplied to a22, a23 and a24 Kong Zhuaiyi.

(5) Kinase reaction: 2. Mu.L of the prepared kinase solution (steps (3) (4), (5)) was added to wells B1 to B23, and wells B24 were not added. mu.L of 1 Xreaction Buffer (B24 well) was added to the kinase-free wells. 1 mu L of the gradient diluted compound is added, the reaction plate is placed on a shaking table and evenly mixed for 1-2 min at 600rpm, and the mixture is incubated for 10min at room temperature. mu.L of 2.5 XATP/Substrate Mix (from ADP-Glo) was added to all wells ^TM Kinase Assay kit), the reaction plate is placed on a shaking table at 600rpm and mixed for 1-2 min, and incubated for 60min at room temperature.

(6) ADP-Glo reagent detects the generated ADP: the ADP-Glo Reagent was melted at room temperature, 5. Mu.L of ADP-Glo Reagent was added to all the reaction wells, and the reaction plate was placed on a shaker at 600rpm and mixed for 1-2 min. Incubating at room temperature for 40min, preparing Kinase Detection Reagent according to the instruction of the kit, transferring Kinase Detection Buffer into Kinase Detection Substrate bottle, and mixing by reversing for several times. 10 mu L Kinase Detection Reagent is added into all the reaction holes, and the reaction plate is placed on a shaking table at 600rpm and mixed for 1-2 min. Incubating at room temperature for at least 30min, reading the optical signal value by using a luminescence detector, and analyzing data.

The results show that the compounds QJJ-12, QJJ-18 and QJJ-28 can inhibit wild EGFR, and QJJ-12 has no very different from the positive drug erlotinib, and QJJ-12 and QJJ-28 have better inhibition activity on EGFR T790M/L858R double mutant kinase than erlotinib.

TABLE 2 Effect of test Compounds on EGFR wild type kinase and EGFR T790M/L858R double mutant kinase Activity

Example 53: cell scratch test

The experiment used HUVEC human umbilical vein endothelial cells (Qiao Xin boat biosciences, inc. in Shanghai) as subjects. Firstly, a mark pen is used for marking transverse lines uniformly by comparison with a ruler on the back of a 6-hole plate, and the transverse lines are transversely crossed through holes at least through 3 lines at intervals of about 0.5cm to 1 cm. About 5X 10 of each well ⁵ Individual cells, cells were placed in 37 ℃,5% co ₂ Is cultured in a constant temperature incubator. After 24 hours, the cells are fully paved with 90 percent, and compared with a ruler, the gun head is scratched as far as possible perpendicular to the back transverse line, and the gun head is perpendicular and can not incline. Washing cells with PBS for 3 times, removing the scraped cells, adding 2mL of serum-free medium into blank group, adding 2mL of QJJ-28 (10 ummol/L) serum-free medium into experimental group, placing into 37 ℃ and 5% CO ₂ Is cultured in a constant temperature incubator. Photographs were observed at 0,6, 12 and 24 hours, scratch widths were recorded and average per well calculated, and finally average scratch healing rate at each time point was calculated, repeating 3 And twice.

The result shows that the healing rate of the blank group at 6 hours is 19%, and the addition group is 11%; the healing rate of the white group in 12 hours is 23%, and the adding group is 12%; the 24-hour blank group had a healing rate of 35% and the dosing group had a healing rate of 13%. It can be seen that compounds QJJ-28 inhibited the ability of HUVEC to migrate at the cellular level, with a significant inhibition of cell migration rate (FIG. 5).

Example 54: integrin αvβ3 receptor binding assay

Competition inhibition assays were used to determine the binding of compounds QJJ-12, QJJ-28 to integrin αvβ3 receptor on HUVEC cells. HUVEC cells in logarithmic growth phase were taken at 5X 10 ⁵ Density of wells/density of wells was grown in 6-well plates and incubated overnight. The negative control group was directly added with serum-containing and drug-free medium, and the experimental group was added with serum-containing medium containing QJJ-12, QJJ-28 and 40. Mu. Mmol/L erlotinib at final concentrations of 0, 10, 20 and 40. Mu. Mol/L, respectively. After 24h of action, the negative control group was added FITC-labeled mouse IgG-1 (2. Mu.L/mL cell suspension, millipore), and the experimental group was added FITC-. Alpha.vβ3 (LM 609) (2. Mu.L/mL cell suspension, millipore). After incubation for 1h in the dark, the upflow cytometer detects that the excitation wavelength and the emission wavelength are 488 nm and 525nm respectively, and the positive cell rate of 10000 cells is calculated. Experiments were repeated 3 times.

Flow cytometry measurements showed that positive cell rates gradually increased with decreasing concentrations of compounds QJJ-12 and QJJ-28, indicating that compounds QJJ-12 and QJJ-28 were able to compete with the αvβ3 antibody for binding to integrin αvβ3 receptors on the cell surface of HUVEC (fig. 6, 7).

Example 55: in vivo anti-tumor Activity Studies

(1) Sucking out all culture media under aseptic operation of logarithmic growth phase A549 cells, repeatedly washing the cells for three times by using PBS (phosphate buffer solution), removing protein components in the residual culture media by digesting the A549 cells into cell suspension by using 0.25% pancreatin, putting all digested cells into a centrifuge tube for centrifugation (1000 r/min), dissolving the cells by using matrigel after centrifugation, and the solution ratio is as follows: matrigel: PBS=1:1, v/v, 100. Mu.L of diabody/2 ml, and the concentration was adjusted to 1.0X10 after counting ⁷ Cells/ml. Each nude mouse is subcutaneously injected with 0.2 ml tumor liquid under armpit, i.e. about 2.0X10 tumor cells are planted in each mouse ⁶ The cells establish a allograft tumor model. All nude mice were housed in laminar racks without Specific Pathogen (SPF). The sterilized water and feed are fed to animals for free intake, the high-temperature sterilized feed is replaced every three days, the cage and the drinking bottle are sterilized by ultraviolet rays every three days, and the sterilized distilled water is drunk, so that the operation strictly follows the sterile principle when the feeding supplies are replaced. The nude mice were observed daily for mental, respiratory, motor, and tumor growth.

When the tumor grows to about 100-200 mm ³ And then randomly grouped according to the following grouping condition. 25 nude mice successfully vaccinated with A549 tumor cells were randomly divided into 5 groups of 5 mice each, namely:

(1) PBS control group;

(2) QJJ-12 groups (0.034 mmol/kg; QJJ-12L);

(3) QJJ-12 groups (0.102 mmol/kg; QJJ-12M);

(4) QJJ-12 groups (0.306 mmol/kg; QJJ-12H);

(5) gefitinib group (Gefitinib, 0.102 mmol/kg).

(2) After each group is inoculated, the corresponding compound or PBS is respectively administrated to tail veins on days 3, 6, 9, 12, 15 and 18 (3-4 days apart), the weight and tumor volume of the mice are weighed daily, the growth state of the mice is observed, after 21 days of inoculation, the cervical vertebrae of the mice are broken, the tumor bodies are peeled off, and each tissue organ (including brain, heart, liver, spleen, lung and kidney) is taken, the tumor weight is weighed, and the tumor weight inhibition rate is calculated. The antitumor activity of each group was compared, and the antitumor effect of compound QJJ-12 in vivo was evaluated.

(1) Daily observation: after tumor cell inoculation and drug administration, observing the mental state, general conditions such as drinking water and death conditions of nude mice; the presence of infection at the transplanted site, and the time of occurrence of tumor or tumor mass were recorded in detail.

(2) Body weight of nude mice: the body weight of each nude mouse was weighed every 3 days, the data were recorded and the body weight change curve of each group of nude mice was plotted.

(3) Tumor measurement: every 3 days precision vernier cardThe ruler measures the size of the transplanted tumor, and calculates the Tumor Volume (TV) according to the following formula, tv=0.5×a×b ² (wherein a and b are length and width, respectively). Tumor volumes were calculated according to the formula and growth curves were plotted. The tumor mass was weighed at the end of the experiment, and the percent tumor inhibition was calculated for each group.

The body weight change curve of the nude mice after administration is shown in FIG. 8. From the figure, it can be seen that the blank group body weight after administration significantly increased, the compound QJJ-12 group had slightly increased body weight in the low dose group (QJJ-12L), the medium dose group (QJJ-12M) had no significant difference in body weight change, the high dose group (QJJ-12H) had slightly decreased body weight, and the positive drug gefitinib group had significantly decreased body weight from the second administration. The change in body weight of nude mice before and after administration of each group is compared to the whole experiment is shown in fig. 9. From the figure, the blank group and the compound QJJ-12 groups before and after the administration have obvious weight increase in the low-dose group, the medium-dose group and the high-dose group have slight weight decrease, the weight change has no obvious difference, and the positive drug gefitinib group has obvious weight decrease. According to the weight measurement result of the nude mice, the compound QJJ-12 has no significant influence on the weight of the nude mice in the experimental selected concentration range, and the positive drug gefitinib group can significantly reduce the weight of the nude mice in the experimental.

After the end of the administration, the tumor tissues of each group of nude mice were dissected and obtained as shown in fig. 10. In the whole administration experiment process, the tumor volume growth curve results are shown in fig. 11, the tumor volume of the blank group is the fastest, the inhibition effect on the tumor growth of the QJJ-12 low-dose group and the medium-dose group is weak, and the high-dose group and the positive drug gefitinib group can obviously inhibit the tumor volume growth.

As shown in the results of experiments on the tumor growth inhibition rate of the nude mice in each group, the inhibition rates of the low-dose group and the medium-dose group of QJJ-12 are 25.15 percent and 31.07 percent respectively, while the inhibition rates of the high-dose group and the positive drug gefitinib group are higher than 40 percent and are 57.55 percent and 52.46 percent respectively, so that the nude mice have good tumor growth inhibition effect.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. A phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof, selected from any one of compounds QJJ-19-QJJ-21, QJJ-23-QJJ-25, QJJ-28: 。

2. The process for the preparation of a phenylpiperazine quinazoline compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) Taking ethylene glycol monomethyl ether as a starting material, and carrying out nucleophilic substitution reaction on the ethylene glycol monomethyl ether and p-toluenesulfonyl chloride in tetrahydrofuran to obtain 2-methoxyethyl-4-methylbenzenesulfonate;

(2) 2-methoxyethyl-4-methylbenzenesulfonate and 3, 4-dihydroxybenzaldehyde are substituted in acetonitrile under the protection of nitrogen to generate 3, 4-di- (2-methoxyethoxy) benzaldehyde;

(3) Reducing the aldehyde group of 3, 4-di- (2-methoxyethoxy) benzaldehyde by hydroxylamine hydrochloride to obtain 3, 4-di- (2-methoxyethoxy) benzonitrile;

(4) 3, 4-di- (2-methoxyethoxy) benzonitrile reacts with concentrated nitric acid at low temperature, and 4, 5-di- (2-methoxyethoxy) -2-nitrobenzonitrile is obtained through nitration;

(5) 4, 5-di- (2-methoxyethoxy) -2-nitrobenzonitrile is cyclized with indium trichloride microwave Niementowski in formamide to obtain 6, 7-di- (2-methoxyethoxy) -3H-4-quinazolinone;

(6) After the 6, 7-di- (2-methoxyethoxy) -3H-4-quinazolinone is chlorinated by oxalyl chloride, 4-chloro-6, 7-di- (2-methoxyethoxy) quinazoline is obtained;

(7) 4-chloro-6, 7-di- (2-methoxyethoxy) quinazoline reacts with 1-benzenesulfonyl piperazine, 1-p-toluenesulfonyl piperazine, 1- (4-methoxybenzenesulfonyl) piperazine, 1-phenylpiperazine, 1- (4-fluorophenyl) piperazine, 1- (2-methoxyphenyl) piperazine and 1- (3-chlorobenzyl) piperazine respectively to obtain the compound.

3. The application of the phenylpiperazine quinazoline compound or the pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament, wherein the tumor is cervical cancer.

4. The application of the phenylpiperazine quinazoline compounds QJJ-20 or pharmaceutically acceptable salts thereof in preparing antitumor drugs, wherein the tumor is non-small cell lung cancer H1299.

5. The use of a phenylpiperazine quinazoline compound according to claim 1, QJJ-21, QJJ-23-QJJ-25, QJJ-28 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-tumor medicament, wherein the tumors are non-small cell lung cancer a549 and H1299.

6. Use of a phenylpiperazine quinazoline compound QJJ-28, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in the manufacture of a medicament for inhibiting EGFR kinase, an integrin αvβ3 receptor, or a medicament for inhibiting HUVEC cell migration.

7. The use of a phenylpiperazine quinazoline compound QJJ-28 or a pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for inhibiting EGFR T790M/L858R double mutant kinase.