WO2021017996A1 - 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 - Google Patents

一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 Download PDF

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WO2021017996A1
WO2021017996A1 PCT/CN2020/103753 CN2020103753W WO2021017996A1 WO 2021017996 A1 WO2021017996 A1 WO 2021017996A1 CN 2020103753 W CN2020103753 W CN 2020103753W WO 2021017996 A1 WO2021017996 A1 WO 2021017996A1
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compound
qjj
substituted
reaction
piperazine
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李沙
蒋杰
祁健斌
王书胜
满江红
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暨南大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof, a preparation method and use thereof.
  • Cancer is a major disease that seriously threatens human health and social development. Cancer cells divide abnormally, excessively proliferate and differentiate, and invade and metastasize normal human cells and tissues, which are a heavy burden on individuals and society.
  • the top ten cancers in my country are lung cancer, gastric cancer, colorectal cancer, liver cancer, esophageal cancer, female breast cancer, pancreatic cancer, lymphoma, bladder cancer, and thyroid cancer, accounting for 76.39% of all cancers, and my country’s cancer deaths
  • Ten are lung cancer, liver cancer, stomach cancer, esophageal cancer, colorectal cancer, pancreatic cancer, breast cancer, leukemia, brain tumor and lymphoma, accounting for 84.27% of all cancer deaths. Therefore, the research and development of new, low-toxic, efficient and specific anti-cancer drugs is still the focus of current drug research.
  • EGFR is expressed or overexpressed on the surface of many tumor cells. EGFR is currently one of the most studied molecular targets in the cancer field. EGFR is the expression product of the proto-oncogene Cerb B.
  • the EGFR family includes ERBB1 (HER1), ERBB2 (Neu/HER2), ERBB3 (HER3) and ERBB4 (HER4).
  • ERBB receptors are expressed in different cells, such as epithelial cells, mesenchymal cells and neurons.
  • ERBB1 (HER1) is related to the proliferation of regenerated epithelial cells.
  • ERBB2 (Neu/HER2) plays an important role in the development of the heart. Embryos lacking ERBB2 will die due to abnormal development of ventricular trabeculae.
  • ERBB3 (HER3) lacks intrinsic activity, and so far there is no related report on homodimerization of ERBB3 (HER3).
  • the activation of ERBB3 (HER3) depends on the binding of ligands or heterodimerization with other ERBB receptors.
  • the homologous or heterodimerization of ERBB4 (HER4) plays an important regulatory role in the metabolism of lung surfactant phosphorylation and lung cell proliferation, and affects tumor proliferation, differentiation, survival, transformation and apoptosis. After EGFR undergoes its own phosphorylation, the intracellular signal pathway conduction starts, and the downstream cascade reaction occurs.
  • the main signal pathways include PI3K/Akt pathway, Ras/MARK pathway and STAT pathway.
  • Quinazoline compounds are a class of effective EGFR inhibitors and have received widespread attention.
  • Gefitinib, Imatinib, Erlotinib, Icotinib, Sorafenib, Sunitinib and Lapatin have been developed Anti-tumor drugs targeting EGFR kinase inhibitors such as Nissan.
  • these tinib drugs all act on a single target, and they can only relieve symptoms and cannot completely cure the disease. More importantly, single-target anti-tumor drugs are prone to drug resistance, so the development of new multi-targets Ordering medicine is very important.
  • the integrin receptor family is a heterodimeric transmembrane glycoprotein consisting of an extracellular region, a transmembrane region and an intracellular region. So far, it has been found that its family members include 18 ⁇ subunits and 8 ⁇ subunits. The combination form of can form 24 different integrin molecules. Among them, the integrin ⁇ v ⁇ 3 receptor is highly expressed on the surface of the neovascular endothelial cell membrane of a variety of malignant tumor cells and their tissues, but is rarely expressed or not expressed in normal tissues.
  • Phenylpiperazine derivatives (publication number CN201110146835) for inhibiting tumor metastasis and tumor blood vessel growth discloses the use of phenylpiperazine and its derivatives to target integrin ⁇ v ⁇ 3 to inhibit tumor growth and angiogenesis.
  • Integrin ⁇ v ⁇ 3 receptors are involved in tumor adhesion, metastasis, survival, proliferation, and drug resistance, especially in neovascularization.
  • the integrin family is widely expressed in tissues, however, integrin ⁇ v ⁇ 3 is most abundantly expressed in the reconstruction of vascular endothelial cells and in diseased tissues.
  • Vascular growth factors such as fibroblast growth factor-2 (FGF-2), TNF- ⁇ and interleukin-8 (IL-8) can stimulate integrin ⁇ v ⁇ 3 receptors in endothelial cells. expression.
  • FGF-2 fibroblast growth factor-2
  • TNF- ⁇ TNF- ⁇
  • IL-8 interleukin-8
  • Integrin ⁇ v ⁇ 3 receptor and enzymatically activated MMP-2 accumulate in new blood vessels, leading to cell-mediated collagen degradation and ECM reorganization.
  • integrin ⁇ v ⁇ 3 receptor to fibronectin, fibrinogen or osteopontin will promote the induction of endothelial cell migration.
  • the extracellular region of the integrin ⁇ v ⁇ 3 receptor bends and folds, hiding the RGD binding region and preventing the binding with the ligand.
  • the integrin ⁇ v ⁇ 3 that binds to RGD has a straightened extracellular domain. Although the cytoplasmic tail region of integrin is smaller than the extracellular region, it plays a vital role in the signaling pathway of integrin.
  • integrin ⁇ v ⁇ 3, ⁇ v ⁇ 5, ⁇ 5 ⁇ 1, ⁇ 6 ⁇ 4, ⁇ 4 ⁇ 1 and ⁇ v ⁇ 6 receptors are most related to the occurrence of tumors.
  • the overexpression of integrin ⁇ v ⁇ 3 receptor is related to bone metastasis, and it reacts with osteopontin to cause tumor growth and invasion.
  • the integrin ⁇ v ⁇ 3 receptor In the occurrence of malignant glioma, the integrin ⁇ v ⁇ 3 receptor is overexpressed on the aggressive edge of the tumor, and the expression level of fibrin will also increase, which is related to the increase of tumor cell motility and the improvement of the ability to resist apoptosis .
  • the overexpression of integrin ⁇ v ⁇ 3 receptor In the occurrence of pancreatic cancer, the overexpression of integrin ⁇ v ⁇ 3 receptor is related to the overactivation of MMP-2 and lymph node metastasis.
  • the overexpression of integrin ⁇ v ⁇ 3 receptor leads to the occurrence of bone metastasis.
  • EGFR The traditional signaling pathways of EGFR include Ras/Raf/MEK/ERK/MAPK and PI3K/PDK1/Akt as mentioned above, while the downstream signaling pathways of integrin are mainly FAK/paxillin and p130cas.
  • the correlation of these two signal pathways is currently the most popular research focus.
  • EGFR and integrin pathways are very closely related to tumor cell invasion and proliferation. It is very difficult to block tumor cell proliferation, metastasis and invasion through only one target. According to reports, in pancreatic cancer, EGFR and integrin ⁇ v ⁇ 5 interact with each other, causing cancer cells to invade and proliferate.
  • the primary purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and provide a phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof.
  • a phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof In order to obtain a new type of compound structure that inhibits both EGFR and integrin ⁇ v ⁇ 3 receptor activity.
  • Another object of the present invention is to provide a method for preparing the phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide the use of the phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof, which can act on cancers or diseases related to EGFR and integrin ⁇ v ⁇ 3.
  • a phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof specifically the structure of the general formula (I), (II), (III):
  • R is a substituted or unsubstituted, heteroatom or heteroatom-free linear, branched or cyclic hydrocarbon chain of up to 10 carbon atoms (preferably the number of carbon atoms is 1-8, more preferably 1-4), substituted or unsubstituted monocyclic aryl, heteroaryl;
  • the substituted or unsubstituted monocyclic aryl and heteroaryl groups are preferably phenyl, p-methylphenyl, p-nitrophenyl, p-fluorophenyl, p-bromophenyl, o-methoxyphenyl, Benzenesulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl, m-nitrobenzenesulfonyl, benzyl or m-chlorobenzyl.
  • the phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof is selected from but not limited to one of the following compounds (QJJ-1 ⁇ QJJ-28):
  • the preparation method of the phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof includes the following steps:
  • nucleophilic substitution reaction occurs with p-toluenesulfonyl chloride in tetrahydrofuran to obtain 2-methoxyethyl-4-methylbenzenesulfonate (3d); 2-Methoxyethyl-4-methylbenzenesulfonate and 3,4-dihydroxybenzaldehyde are substituted in acetonitrile under nitrogen protection to generate 3,4-bis-(2-methoxyethoxy) Benzaldehyde (4d); the aldehyde group of 3,4-bis-(2-methoxyethoxy)benzaldehyde is reduced by hydroxylamine hydrochloride to obtain 3,4-bis-(2-methoxyethoxy)benzonitrile ( 5d); 3,4-bis-(2-methoxyethoxy)benzonitrile reacts with concentrated nitric acid at low temperature to obtain 4,5-bis-(2-methoxyethoxy)-2-nitro
  • the preparation method of the phenylpiperazine quinazoline compound or a pharmaceutically acceptable salt thereof more preferably comprises the following steps:
  • nitrated compound 7a (4-methoxy-5-(3-morpholinpropoxy)-2-nitrobenzonitrile); the nitrated compound 7a was dissolved in the formaldehyde In the amide, indium trichloride is added as a catalyst, and the reaction is microwaved at 100-120°C and 400W for 40-70 minutes, extracted with dichloromethane, dried with anhydrous Na 2 SO 4 , filtered and concentrated, separated by silica gel column, The quinazolinone compound 8a (7-methoxy-6-(3-morpholinylpropoxy) quinazolin-4(3H)-one) is obtained; the quinazolinone compound 8a and N, N- Dimethylformamide was added to chloroform, then oxalyl chloride was added, heated to 60 ⁇ 70°C and reacted for 1.5 ⁇ 3 hours, then saturated
  • the ethyl acetate layer is dried with anhydrous Na 2 SO 4 , filtered and concentrated, and separated by silica gel column to obtain compounds QJJ-13 ⁇ QJJ-18; among them, the substituted benzenesulfonate Acid piperazine, substituted phenyl piperazine and substituted benzyl piperazine compounds;
  • the volume ratio of morpholine to 1-bromo-3-chloropropane described 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 and 3-hydroxy-4-methoxybenzonitrile described 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 the chloroquinazoline compound and the substituent in step (1) is preferably 1:1.
  • the substituted benzenesulfonyl piperazine described in steps (1), (2) and (3) is a substituted benzenesulfonyl piperazine synthesized with substituted benzenesulfonyl chloride and piperazine as raw materials; preferably benzenesulfonyl piperazine ( 1-(phenylsulfonyl)piperazine), 1-tosylpiperazin, p-methoxybenzenesulfonyl piperazine (1-((4-methoxyphenyl)sulfonyl)piperazine), or m-nitrobenzene Sulfonyl piperazine (1-((3-nitrophenyl)sulfonyl)piperazine).
  • benzenesulfonyl piperazine 1-(phenylsulfonyl)piperazine
  • 1-tosylpiperazin 1-tosylpiperazin
  • the substituted phenylpiperazine described in step (1), (2) and (3) is preferably phenylpiperazine (1-phenylpiperazine), p-methylphenylpiperazine (1-(4-methyl Phenyl) piperazine), p-nitrophenyl piperazine (1-(4-nitrophenyl) piperazine), p-fluorophenyl piperazine (1-(4-fluorophenyl) piperazine), P-bromophenylpiperazine (1-(4-bromophenyl)piperazine), or o-methoxyphenylpiperazine (1-(2-methoxyphenyl)piperazine).
  • the substituted benzylpiperazine compounds described in steps (1), (2) and (3) are preferably benzylpiperazine (1-benzylpiperazine) or m-chlorobenzylpiperazine (1-(3-chloro Benzyl) piperazine).
  • the molar ratio of triethylene glycol to p-toluenesulfonyl chloride in step (2) is preferably 6.7:12.
  • step (2) The mass ratio of 3,4-dihydroxybenzaldehyde to hydroxylamine hydrochloride in step (2) is 13.8:16.7.
  • the mass ratio of the p-toluenesulfonyl substituted hydroxyl triethylene glycol and 3,4-dihydroxybenzonitrile described in step (2) is preferably 3.73:1.
  • the molar ratio of the crown ether benzonitrile to the nitric acid solution in step (2) is 1:10.
  • the molar ratio of the quinazolinone compound to oxalyl chloride in step (2) is 0.3:0.86.
  • the molar ratio of the chloroquinazoline compound and the substituent in step (2) is preferably 1:1.
  • step (3) The molar ratio of ethylene glycol monomethyl ether and p-toluenesulfonyl chloride described in step (3) is 1:1.05
  • the molar ratio of 2-methoxyethyl-4-methylbenzenesulfonate to 3,4-dihydroxybenzaldehyde described in step (3) is 2:1.
  • step (3) The molar ratio of 3,4-bis-(2-methoxyethoxy)benzaldehyde to hydroxylamine hydrochloride in step (3) is 1:2.4.
  • the molar ratio of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline to the substituent in step (3) is preferably 1:2.
  • Anti-tumor drugs can be prepared, used as tumor chemotherapy drugs and auxiliary drugs in surgical treatment, or combined with other drugs for the treatment of various cancers.
  • the tumor includes, but is 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, kidney tumor (Kidney cancer), lung cancer, pancreatic cancer, astrocytoma, bladder cancer, ovarian cancer, head and neck cancer, cervical cancer, thymic cancer, gastric cancer, ovarian cancer and prostate cancer; preferably non-small cell lung cancer, lung adenocarcinoma or cervical cancer cancer.
  • the phenylpiperazine quinazoline compound or its pharmaceutically acceptable salt in the preparation of a drug for inhibiting kinase and a drug for inhibiting HUVEC cell migration can inhibit the activity of EGFR kinase or EGFR T790M/L858R double mutant kinase, inhibit the horizontal migration ability of HUVEC cells, and can compete with ⁇ v ⁇ 3 antibody to bind to the integrin ⁇ v ⁇ 3 receptor on the surface of HUVEC cells.
  • the kinase is EGFR kinase or EGFR T790M/L858R double mutant kinase.
  • hydrocarbyl refers to an unsubstituted or substituted linear, branched or cyclic hydrocarbon chain of up to 10 carbon atoms, or contains at least one heteroatom (such as nitrogen, Oxygen or sulfur) hydrocarbon group.
  • 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, as well as those containing ethylenic, acetylenic, Unsaturated hydrocarbon groups with substituents such as carbonyl and cyano groups also include heteroatom-containing hydrocarbon groups such as -CH 2 CH 2 OCH 3 , -CH 2 CH 2 N(CH 3 ) 2 and -CH 2 CH 2 SCH 3 .
  • Non-limiting examples of branched hydrocarbon groups containing no or heteroatoms include 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 groups containing no or heteroatoms include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and six-membered rings containing O, N, and S such as -CH(CH 2 CH 2 ) 2 O, -CH(CH 2 CH 2 ) 2 NCH 3 and -CH(CH 2 CH 2 ) 2 S and the corresponding five-membered heterocyclic ring.
  • the hydrocarbyl group may be substituted by one or more substituents.
  • Non-limiting examples of the above substituents include -N(CH 3 ) 2 , F, Cl, Br, I, -OCH 3 , -CO 2 CH 3 , -CN,- OH, aryl and heteroaryl.
  • aryl refers to unsubstituted or substituted aromatic compounds, carbocyclic groups and heteroaryl groups.
  • Aryl groups are either monocyclic or polycyclic fused compounds.
  • the aryl group may be substituted by one or more substituents.
  • substituents include -N(CH 3 ) 2 , F, Cl, Br, I, -OCH 3 , -CO 2 CH 3 , -CN, -OH, aryl and heteroaryl.
  • Heteroaryl refers to a substituted or unsubstituted monocyclic or polycyclic group, which includes at least one heteroatom such as nitrogen, oxygen and sulfur.
  • typical heterocyclic groups include one or more nitrogen atoms such as tetrazolyl, pyrrolyl, pyridyl (such as 4-pyridyl, 3-pyridyl, 2-pyridyl, etc.), pyridazinyl, Indolyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, etc.), imidazolyl, isoquinolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridonyl; typically containing one
  • the heterocyclic group of the oxygen atom includes 2-furyl, 3-furyl or benzofuranyl; typical sulfur heteroatom groups include thienyl and benzothienyl; typical mixed heteroatom groups include furacryl , Oxazolyl, is
  • the heterocyclic group can be substituted by one or more substituents, these substituents include -O-alkyl, -NH-alkyl, -N-(alkyl) 2 , -NHC(O)-alkyl, F, Cl, Br, I, -OH, -OCF 3 , -CO 2 -alkyl, -CN and aryl and polyaryl groups.
  • pharmaceutically acceptable refers to the absence of unacceptable toxicity in compounds such as salts or excipients.
  • Pharmaceutically acceptable salts include inorganic anions such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, hydrogen phosphate and the like.
  • Organic anions include acetate, propionate, cinnamate, besylate, citrate, lactate, gluconate, fumarate, tartrate, succinate and the like.
  • the present invention relates to hydrocarbyl, aryl, heteroaryl, nitrate, halogen, and sulfonyl derivatives of a class of phenylpiperazine quinazoline compounds, which can be in the form of a pharmaceutically acceptable salt or drug complex Administer the patient.
  • a certain complex can be mixed with appropriate carriers or excipients to form a pharmaceutical composition to ensure an effective therapeutic agent.
  • Effective therapeutic dose refers to the dose required for the compound and its derivatives to achieve therapeutic effects.
  • the present invention has the following advantages and beneficial effects:
  • the compounds provided by the present invention have novel structures and easy synthesis methods. In vitro anti-tumor activity experiments show that the anti-tumor activity of this class of compounds is similar to that of the clinical drug erlotinib.
  • Such compounds and their pharmaceutically acceptable salts can be used to prepare anti-tumor drugs, can be prepared to treat non-small cell lung cancer, breast cancer, liver cancer and cervical cancer, and can be prepared as tumor chemotherapy drugs and auxiliary drugs in surgical treatment.
  • Figure 1 is a synthetic route diagram of compounds 1a to 1d (a in the figure represents: piperazine, triethylamine, dichloromethane, reaction in an ice bath, the reaction time is 3h, and it returns to room temperature after the reaction is completed).
  • Figure 2 is a synthetic route diagram of compounds QJJ-1 ⁇ QJJ-12 (in the figure: A represents morpholine, toluene, 65 ⁇ 85°C, 2.5 ⁇ 6.5h; B represents hydroxylamine hydrochloride, sodium formate, formic acid, 100°C, 5 ⁇ 7.5h; C represents potassium carbonate, potassium iodide, acetonitrile, 75 ⁇ 85°C, 3 ⁇ 7h; D represents 65% nitric acid, glacial acetic acid, 0°C, 2 ⁇ 5h, 40 ⁇ 50°C, 3 ⁇ 6h; E represents formamide , Indium trichloride, microwave 400w, 100 ⁇ 120°C, 40 ⁇ 70 minutes; F means oxalyl chloride, N,N-dimethylformamide, chloroform, 60 ⁇ 70°C, 1.5 ⁇ 3h; G means each substituted benzene Piperazine, triethylamine, N,N-dimethylformamide, microwave 100w, 100 ⁇ 130°C, 15 ⁇ 30
  • Figure 3 is a synthetic route diagram of compounds QJJ-13 ⁇ QJJ-18 (in the figure: A represents p-toluenesulfonyl chloride, tetrahydrofuran, sodium hydroxide, water, ice bath, 2.5 ⁇ 4h; B represents hydroxylamine hydrochloride, sodium formate, Formic acid, 100°C, 5 ⁇ 7.5h; C means tetrahydrofuran, sodium hydroxide, lithium hydroxide, water, N 2 protection, 60 ⁇ 75°C, 60 ⁇ 80h; D means 65% nitric acid, glacial acetic acid, 0°C, 2 ⁇ 5h, 40 ⁇ 50°C, 3 ⁇ 6h; E means formamide, indium trichloride, microwave 400w, 100 ⁇ 120°C, 40 ⁇ 70 minutes; F means oxalyl chloride, N,N-dimethylformamide, Chloroform, 60 ⁇ 70°C, 1.5 ⁇ 3h; G means each substituted phenylpiperazine, trieth
  • Figure 4 is a synthetic route diagram of compounds QJJ-19 ⁇ QJJ-28 (in the figure: A represents p-toluenesulfonyl chloride, tetrahydrofuran, sodium hydroxide, water, ice bath, 4-9h; B represents 3,4-di Hydroxybenzaldehyde, potassium carbonate, acetonitrile, N 2 protection, 70 ⁇ 85°C; C means hydroxylamine hydrochloride, sodium formate, formic acid, 75 ⁇ 85°C, 4 ⁇ 7h; D means 65% nitric acid, glacial acetic acid, 0°C, 2 ⁇ 5h, 40 ⁇ 50°C, 3 ⁇ 6h; E means formamide, indium trichloride, microwave 400w, 100 ⁇ 120°C, 40 ⁇ 70 minutes; F means oxalyl chloride, N,N-dimethylformamide, chloroform , 60 ⁇ 70°C, 1.5 ⁇ 3h; G means 1a/1b/1c/1d, N,N-d
  • Figure 5 is a microscopic view of compound QJJ-28 inhibiting HUVEC human umbilical vein endothelial cell migration (10 ⁇ 10).
  • Figure 6 is the result of flow cytometry detection of QJJ-12 binding to integrin ⁇ v ⁇ 3 receptor.
  • Figure 7 is the result of flow cytometry detection of QJJ-28 binding to integrin ⁇ v ⁇ 3 receptor.
  • Figure 8 is a graph showing the weight change of nude mice in each group of the experiment.
  • Figure 9 is a graph showing changes in the body weight of nude mice before and after administration in the whole experiment (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 compared to the pre-administration group).
  • Figure 10 is a diagram of the tumor tissues of nude mice in each experimental group.
  • Figure 11 is a graph of tumor growth curves of nude mice in each group of the experiment (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 compared with Ctrl group; #p ⁇ 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001 compared with Gefitinib group).
  • Figure 12 shows the tumor growth inhibition rate of nude mice in each experimental group (#p ⁇ 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001 compared with Gefitinib group).
  • the present invention will be further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
  • the test methods that do not indicate specific experimental conditions in the following examples are usually in accordance with conventional experimental conditions or in accordance with experimental conditions recommended by the manufacturer.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the specific synthesis method of compound 1b can refer to the synthesis procedure of compound 1a. Substituting p-toluenesulfonyl chloride (4.0 g, 21.0 mmol) for the benzenesulfonyl chloride in Example 1, a white solid 1b (yield 60%) was obtained ( Figure 1).
  • the specific synthesis method of compound 1c can refer to the synthesis procedure of compound 1a. Substituting p-methoxybenzenesulfonyl chloride (4.0 g, 19.4 mmol) for the benzenesulfonyl chloride in Example 1, a light yellow solid 1c (yield 79%) was obtained ( Figure 1).
  • the specific synthesis method of compound 1d can refer to the synthesis procedure of compound 1a. Substituting m-nitrobenzenesulfonyl chloride (4.0 g, 18.2 mmol) for the benzenesulfonyl chloride in Example 1, a yellow solid 1d (yield 65%) was obtained ( Figure 1).
  • Example 18 Compound 4-(3-((7-methoxy-4-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-8 )Synthesis
  • Example 19 Compound 4-(3-((7-methoxy-4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-9 )Synthesis
  • Example 29 Compound 4-(4-(4-fluorophenyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2 ,3-g]quinazoline (QJJ-13) synthesis
  • Example 30 Compound 4-(4-(4-nitrophenyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2 ,3-g]quinazoline(QJJ-14) Synthesis
  • Example 31 Compound 4-(4-(phenylsulfonyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2,3 -g] quinazoline (QJJ-15) synthesis
  • Example 32 Compound 4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[ Synthesis of 2,3-g]quinazoline(QJJ-16)
  • Example 34 Compound 4-(4-(3-chlorobenzyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3 -g] quinazoline (QJJ-18) synthesis
  • the specific synthesis method of compound QJJ-20 can refer to the synthesis procedure of compound QJJ-19 in Example 41. Weigh compound 1b (0.15g, 0.64mmol) to replace compound 1a to obtain oily compound QJJ-20 (yield 62%) ( Figure 4).
  • the specific synthesis method of compound QJJ-21 can refer to the synthesis procedure of compound QJJ-19 in Example 41. Weigh compound 1c (0.16 g, 0.64 mmol) to replace compound 1a to obtain oily compound QJJ-21 (yield 65%) ( Figure 4).
  • the specific synthesis method of compound QJJ-22 can refer to the synthesis procedure of compound QJJ-19 in Example 41. Weigh compound 1d (0.17g, 0.64mmol) to replace compound 1a to obtain orange-yellow solid compound QJJ-22 (yield 64%), m.p. 155.8-156.2°C ( Figure 4).
  • the specific synthesis method of compound QJJ-23 can refer to the synthesis procedure of compound QJJ-19 in Example 41.
  • the compound 1-phenylpiperazine (0.1 g, 0.64 mmol) was weighed to replace compound 1a to obtain oily compound QJJ-23 (yield 55%) ( Figure 4).
  • the specific synthesis method of compound QJJ-24 can refer to the synthesis procedure of compound QJJ-19 in Example 41. Weigh compound 1-(4-fluorophenyl)piperazine (0.12 g, 0.64 mmol) to replace compound 1a to obtain oily compound QJJ-24 (yield 50%) ( Figure 4).
  • the specific synthesis method of compound QJJ-25 can refer to the synthesis procedure of compound QJJ-19 in Example 41.
  • the compound 1-(2-methoxyphenyl)piperazine (0.13 g, 0.64 mmol) was weighed to replace compound 1a to obtain oily compound QJJ-25 (yield 59%) ( Figure 4).
  • the specific synthesis method of compound QJJ-26 can refer to the synthesis procedure of compound QJJ-19 in Example 41. Weigh out compound 1-(4-nitrophenyl)piperazine (0.13g, 0.64mmol) to replace compound 1a to obtain orange-yellow solid compound QJJ-26 (yield 59%), mp 140.4-141.9°C ( Figure 4) .
  • the specific synthesis method of compound QJJ-27 can refer to the synthesis procedure of compound QJJ-19 in Example 41. Weigh compound 1-benzylpiperazine (0.12 g, 0.64 mmol) to replace compound 1a to obtain oily compound QJJ-27 (yield 62%) ( Figure 4).
  • the specific synthesis method of compound QJJ-28 can refer to the synthesis procedure of compound QJJ-19 in Example 41.
  • the compound 1-(3-chlorobenzyl)piperazine (0.12 g, 0.64 mmol) was weighed to replace compound 1a to obtain oily compound QJJ-28 (yield 65%) ( Figure 4).
  • Example 51 Experiment of anti-cancer cell proliferation activity of phenylpiperazine quinazoline compounds
  • the selected cells in this example are the cervical cancer Hela cell line, the human lung adenocarcinoma H1299 cell line, and the human lung adenocarcinoma A549 cell line (Shanghai Chinese Academy of Sciences Cell Bank), using 1% (w/v) double antibodies (penicillin and Streptomycin), 10% (v/v) FBS (fetal bovine serum) serum RPMI 1640 medium (Gibco) was used for cell culture, and the MTT method was used to detect cell proliferation and apoptosis.
  • the test method is briefly described as follows:
  • Seed plate Take the required cells in the logarithmic growth phase and plant them in a 96-well plate at a density of 5 ⁇ 10 3 /well, with 100 ⁇ L per well, fill the edge holes with 100 ⁇ L sterile PBS, and put the cells in 37 Cultivate overnight in a constant temperature incubator at °C and 5% CO 2 .
  • DMSO dissolution After 4 hours, blot the supernatant, taking care not to damage the bottom cells, add 150 ⁇ L of DMSO (dimethyl sulfoxide) to each well and shake for 10 minutes to fully dissolve the formazan.
  • Table 1 shows the IC 50 values of compounds QJJ-1 to QJJ-28 and erlotinib on three cancer cell lines. The results show that the phenylpiperazine quinazoline compounds QJJ-1 to QJJ-28 prepared by the present invention have different degrees of inhibitory effects on the growth of the three tumor cells investigated. Some compounds such as QJJ-12, QJJ- 18. QJJ-28 shows good anti-cancer activity in vitro.
  • Table 1 IC 50 values of compounds QJJ-1 ⁇ QJJ-28 and erlotinib on three cancer cells
  • Example 52 EGFR wild type (EGFR wt) and EGFR T790M/L858R double mutant kinase inhibition experiment
  • the ADP-Glo TM Kinase Assay is a luminescence detection kit for detecting the ADP (adenosine diphosphate) formed in the kinase reaction. ); ADP is converted into ATP (adenosine triphosphate), and then ATP is converted into light by luciferase. The luminescence signal is positively correlated with kinase activity. Prepare the reaction components using the corresponding components in the kit according to the instructions of the kit, and perform corresponding experimental operations to determine the effect of the test compound on the kinase activity.
  • Kinase reaction Add 2 ⁇ L of the prepared kinase solution (steps (3) 4, 5) to wells B1 to B23, and not to well B24. Add 2 ⁇ L of 1 ⁇ Reaction Buffer (well B24) to the well without kinase. Add 1 ⁇ L of the compound in gradient dilution, place the reaction plate on a shaker at 600 rpm and mix for 1 to 2 minutes, and incubate at room temperature for 10 minutes.
  • ADP-Glo reagent detection of the generated ADP melt ADP-Glo Reagent at room temperature, add 5 ⁇ L ADP-Glo Reagent to all reaction wells, and place the reaction plate on a shaker at 600 rpm and mix for 1 to 2 minutes. Incubate at room temperature for 40 minutes, prepare Kinase Detection Reagent according to the kit instructions, transfer Kinase Detection Buffer to Kinase Detection Substrate bottle, invert several times and mix. Add 10 ⁇ L Kinase Detection Reagent to all reaction wells, and place the reaction plate on a shaker at 600 rpm and mix for 1 to 2 minutes. Incubate at room temperature for at least 30 minutes, read the light signal value with a luminescence detector, and analyze the data.
  • This experiment uses HUVEC human umbilical vein endothelial cells (Shanghai Zhongqiao Xinzhou Biotechnology Co., Ltd.) as the research object.
  • Approximately 5 ⁇ 10 5 cells were added to each well, and the cells were cultured in a constant temperature incubator at 37°C and 5% CO 2 . After 24 hours, 90% of the cells are spread.
  • Use the pipette tip to compare with the ruler, and try to make the scratch perpendicular to the horizontal line behind the pipe.
  • the pipette tip should be vertical and not inclined.
  • the competition inhibition experiment was used to determine the binding of compounds QJJ-12 and QJJ-28 to the integrin ⁇ v ⁇ 3 receptor on HUVEC cells.
  • the HUVEC cells in the logarithmic growth phase were planted in a 6-well plate at a density of 5 ⁇ 10 5 /well and cultured overnight.
  • the negative control group was directly added with serum-containing medium without drugs, and the experimental group was added with the final concentrations of 0, 10, 20, 40 ⁇ mol/L containing QJJ-12, QJJ-28 and 40 ⁇ mmol/L containing erlotinib Serum medium.
  • the negative control group was added with FITC-labeled mouse IgG-1 (2 ⁇ L/mL cell suspension, Millipore), and the experimental group was added with FITC- ⁇ v ⁇ 3 (LM609) (2 ⁇ L/mL cell suspension, Millipore).
  • the flow cytometer detects that the excitation wavelength and emission wavelength are 488 and 525 nm, respectively, and the positive cell rate of 10,000 cells is calculated. The experiment was repeated three times.
  • Example 55 Study on anti-tumor activity in vivo
  • Each nude mouse was injected subcutaneously with 0.2 ml of tumor solution, that is, about 2.0 ⁇ 10 6 cells planted with tumor cells per mouse to establish an allograft tumor model. All nude mice were reared in a laminar flow rack under specific pathogen-free (SPF) conditions. Sterile treated water and feed are for free ingestion by animals, high temperature sterilized feed, litter is replaced every three days, cages and drinking bottles are sterilized by ultraviolet light every three days, drinking sterile distilled water, and strictly follow when changing feeding supplies Aseptic principle operation. Observe the nude mice's mentality, breathing, exercise and tumor growth daily.
  • SPPF pathogen-free
  • mice successfully inoculated with A549 tumor cells were randomly divided into 5 groups, 5 mice in each group, namely:
  • mice were given the corresponding compound or PBS on the 3rd, 6th, 9th, 12th, 15th and 18th days (interval of 3 to 4 days) after inoculation.
  • the mice were weighed daily and the tumor volume was measured. Observe the growth status of the mice. 21 days after the inoculation, the mice were cut off the cervical spine and sacrificed, the tumor was stripped, and various tissues and organs (including brain, heart, liver, spleen, lung, and kidney) were taken, and the tumor was weighed and calculated. Inhibition rate.
  • the anti-tumor activity of each group was compared to evaluate the anti-tumor effect of compound QJJ-12 in vivo.
  • the body weight change curve of nude mice after administration is shown in Figure 8. It can be seen from the figure that the weight of the blank group increased significantly after administration, the weight of the compound QJJ-12 group in the low-dose group (QJJ-12L) increased slightly, and the weight of the middle-dose group (QJJ-12M) had no significant difference. The weight of the high-dose group (QJJ-12H) decreased slightly, while the weight of the positive drug gefitinib group decreased significantly from the second administration.
  • the comparison of the changes in the body weight of nude mice before and after the administration of each group in the entire experiment is shown in FIG. 9.
  • the tumor tissues of nude mice in each group were dissected, as shown in Figure 10.
  • the results of the tumor volume growth curve are shown in Figure 11.
  • the tumor volume of the blank group has the fastest growth, the QJJ-12 low-dose group and the middle-dose group have weaker tumor growth inhibitory effects, while the high-dose group And the positive drug gefitinib group can significantly inhibit the growth of tumor volume.

Abstract

本发明公开了一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途。该苯基哌嗪喹唑啉类化合物或其药学上可接受的盐具体如下通式(I)、(II)、(III)的结构。本发明的提供的这些化合物合成方法容易实现，成本较低，可从EGFR激酶抑制与整合素αvβ3受体抑制双靶点产生抗肿瘤作用。体内外实验研究表明，该类化合物在体内外均具有抗肿瘤活性，其中化合物QJJ-12的体内抗肿瘤活性类似临床用药吉非替尼。该类化合物还可以抑制EGFR激酶或EGFR T790M/L858R双突变型激酶的活性，抑制HUVEC细胞的水平迁移能力，能够与αvβ3抗体竞争结合HUVEC细胞表面的整合素αvβ3受体。

Description

一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 技术领域
本发明属于医药领域，特别涉及一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途。
背景技术
癌症是严重威胁人类健康和社会发展的重大疾病，癌细胞***异常，过度增殖分化，并对人体正常细胞组织侵犯转移，对个人和社会都是沉重的负担。我国癌症发病前十位的是肺癌、胃癌、结直肠癌、肝癌、食管癌、女性乳腺癌、胰腺癌、淋巴瘤、膀胱癌以及甲状腺癌，占全部癌症发病的76.39％，而我国癌症死亡前十位的是肺癌、肝癌、胃癌、食管癌、结直肠癌、胰腺癌、乳腺癌、白血病、脑瘤以及淋巴瘤，占全部癌症死亡的84.27％。因此，研发新型、低毒高效并具有特异性的抗癌药物依然是目前药物研究的重点方向。
在许多肿瘤细胞的表面都有EGFR的表达或过度表达，EGFR是目前癌症领域研究最多的分子靶点之一。EGFR是原癌基因Cerb B的表达产物，EGFR家族包括ERBB1(HER1)、ERBB2(Neu/HER2)、ERBB3(HER3)和ERBB4(HER4)。ERBB受体表达在不同的细胞中，如上皮细胞，间叶细胞和神经元。ERBB1(HER1)与再生上皮细胞的增殖有关。ERBB2(Neu/HER2)在心脏的发育中起到重要作用，缺少ERBB2的胚胎会由于心室小梁的异常发育而死亡。ERBB3(HER3)缺少内在活性，至今也缺少ERBB3(HER3)同源二聚化的相关报道，ERBB3(HER3)的活化依赖于与配体的结合或者与其他ERBB受体的异源二聚化。ERBB4(HER4)的同源或异源二聚化在肺表面活性物质磷酸化的代谢以及肺细胞增殖中起重要调节作用，影响肿瘤的增殖、分化、存活、转化和凋亡。EGFR经过自身的磷酸化之后，胞内的信号通路传导启动，下游级联反应发生，主要的信号通路有PI3K/Akt途径、Ras/MARK途径以及STAT途径等。
喹唑啉类化合物是一类有效的EGFR抑制剂，受到了普遍的重视。针对这一特点，已经开发了吉非替尼(Gefitinib)、伊马替尼、埃罗替尼(Erlotinib)、埃克替尼(Icotinib)、索拉非尼、舒尼替尼和拉帕替尼等靶向EGFR激酶抑制剂的抗肿瘤药物。但是这些替尼类药物都是作用于单一的靶点，而且只能缓解症状并不能彻底的根治疾病，更重要的是，单一靶点抗肿瘤药物很容易产生耐药性，因此开发新型多靶点药物有着非常重要的意义。
Figure PCTCN2020103753-appb-000001
整合素受体家族是异源二聚体跨膜糖蛋白，由胞外区，跨膜区和胞内区组成，至今发现其家族成员包括18种α亚基和8种β亚基，按照不同的组合形式可形成24种不同的整合素分子。其中，整合素αvβ3受体在多种恶性肿瘤细胞及其组织的新生血管内皮细胞膜表面上高度表达，而在正常组织中少表达或不表达。用于抑制肿瘤转移和肿瘤血管生长的苯基哌嗪类衍生物(公开号CN201110146835)公开了苯基哌嗪及其衍生物以整合素αvβ3为靶点，抑制肿瘤生长以及血管新生的用途。
整合素αvβ3受体参与肿瘤的粘附、转移、生存增殖和耐药等过程，尤其实在新生血管中效果尤其明显。整合素家族广泛表达在组织上，然而，整合素αvβ3在血管内皮细胞的重建以及病态组织中表达最为丰富。血管生长因子如纤维母细胞生长因子-2(fibroblast growth factor-2,FGF-2)、TNF-α和白介素-8(interleukin-8,IL-8)能刺激整合素αvβ3受体在内皮细胞的表达。整合素αvβ3受体与酶解活化的MMP-2在新生的血管聚集，导致细胞介导的胶原蛋白降解以及ECM的重组。因此，整合素αvβ3受体与纤连蛋白、纤维蛋白原或者骨桥蛋白的结合会促进诱导内皮细胞的迁移。大多数整合素，包括表达在内皮细胞的整合素，都具有“开”和“关”的状态。整合素αvβ3受体胞外区弯曲折叠，把RGD结合区隐藏起来从而阻止与配体的结合。相反，与RGD结合的整合素αvβ3有着伸直的胞外区。虽然整合素胞质尾区比胞外区要小，但它对于整合素的信号通路发挥着至关重要的作用，胞质尾 区的分离，扭转都影响着整合素的活化。在癌症的发生过程中，整合素αvβ3、αvβ5、α5β1、α6β4、α4β1和αvβ6受体与肿瘤的发生最为相关。在乳腺癌的发生中，整合素αvβ3受体的过度表达与骨转移有关，它与骨桥蛋白产生反应引起肿瘤的生长和侵袭。在恶性胶质瘤的发生中，整合素αvβ3受体过度表达在肿瘤的侵袭性边缘上，而且纤维蛋白的表达水平也会增高，这关系到肿瘤细胞运动性的增加以及抵制凋亡能力的提高。在胰腺癌的发生中，整合素αvβ3受体的过度表达关系到MMP-2的过度活化以及***的转移。在***癌的发生中，由于整合素与层粘连蛋白、纤连蛋白和骨桥蛋白的粘附转移发生作用联系，整合素αvβ3受体过度表达导致骨转移的发生。
目前，越来越多的研究者认为，分子靶向药物对于传统癌症过于简单，靶向攻击一个靶点对于抑制情况复杂的肿瘤的进展疗效并不理想，如***癌和结肠癌。目前的研究认为，肿瘤产生的信号通路存在交叉现象，从而导致这一现象的出现。EGFR和整合素的信号通路也是互相交叉关联，针对于此，有望设计出双靶点小分子药物以更好地治疗癌症。
EGFR的传统信号通路如上所述有Ras/Raf/MEK/ERK/MAPK和PI3K/PDK1/Akt，而整合素的下游信号通路主要是FAK/paxillin和p130cas。这两条信号通路的关联是目前最为热门的研究热点。EGFR和整合素通路对于肿瘤细胞的侵袭以及增殖是十分紧密关联的，如果想单只通过一个靶点阻断肿瘤细胞的增殖、转移及侵袭是十分困难的。据报道，在胰腺癌中，EGFR与整合素αvβ5相互发生作用，致使癌细胞发生侵袭和增殖。EGFR受到刺激被激活后，活化的不止ERK和PKB，也有整合素下游的FAK，paxillin和p130cas。因此，控制癌症发展进程，单从EGFR或者整合素一个靶点入手阻断远不如同时阻断两者信号通路或者它们的交叉点。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足，提供一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐。以期获得同时抑制EGFR和整合素αvβ3受体活性的新化合物结构类型。
本发明的另一目的在于提供所述苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法。
本发明的再一目的在于提供所述苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的用途，可作用于与EGFR和整合素αvβ3相关的癌症或疾病。
本发明的目的通过下述技术方案实现：一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐，具体如下通式(I)、(II)、(III)的结构：
Figure PCTCN2020103753-appb-000002
其中，R为取代或未取代、有杂原子或无杂原子的直链、支链或环状的多至10个碳原子的烃基碳链(优选的碳原子数为1-8，更优选为1-4)，取代或未取代的单环芳基、杂芳基；
所述的取代或未取代的单环芳基、杂芳基优选为苯基、对甲基苯基、对硝基苯基、对氟苯基、对溴苯基、邻甲氧基苯基、苯磺酰基、对甲基苯磺酰基、对甲氧基苯磺酰基、间硝基苯磺酰基、苄基或间氯苄基。
优选的，所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐选自但不限于如下化合物之一(QJJ-1～QJJ-28)：
Figure PCTCN2020103753-appb-000003
Figure PCTCN2020103753-appb-000004
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法，包括以下步骤：
以吗啉为起始原料，将其与1-溴-3-氯丙烷溶于甲苯中，发生取代反应得到4-(3-氯丙基)吗啉(3a)；在甲酸和甲酸钠的环境中，以异香兰素(3-羟基-4-甲氧基苯甲醛)为原料，通过与盐酸羟胺反应制备中间体化合物3-羟基-4-甲氧基苯甲腈(5a)；然后4-(3-氯丙基)吗啉和3-羟基-4-甲氧基苯甲腈之间发生醚化反应生成4-甲氧基-3-(3- 吗啉丙氧基)苯甲腈(6a)；接着进行硝化，得到硝基化的化合物(7a)；再使用三氯化铟作为催化剂，在微波反应仪中环化得到喹唑啉酮化合物(8a)，最后与草酰氯反应得到氯代喹唑啉化合物(9a)；氯代喹唑啉化合物分别与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物进行反应，得到化合物QJJ-1～QJJ-12；
以三甘醇为起始原料，将其与对甲苯磺酰氯(TsCl)溶于THF(四氢呋喃)中，发生取代反应得对甲基苯磺酰取代羟基的三甘醇(3c)；在甲酸和甲酸钠环境中，以3,4-二羟基苯甲醛为原料，通过与盐酸羟胺反应制备3,4-二羟基苯甲腈(5c)；将对甲基苯磺酰取代羟基的三甘醇和3,4-二羟基苯甲腈溶解在四氢呋喃中，然后用氢氧化钠和氢氧化锂环化，得到冠醚苯甲腈(6c)；随后进行硝化反应，得到硝基化合物(7c)，接着使用三氯化铟作为催化剂，在微波反应仪中反应得到喹唑啉酮类化合物(8c)，再使用草酰氯作为氯化剂，氯仿作为溶剂，得到中间体氯代喹唑啉化合物(9c)；最后将氯代喹唑啉化合物与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物反应，得到化合物QJJ-13～QJJ-18；
以乙二醇单甲醚为起始原料，将其与对甲基苯磺酰氯在四氢呋喃中发生亲核取代反应得到2-甲氧基乙基-4-甲基苯磺酸酯(3d)；2-甲氧基乙基-4-甲基苯磺酸酯与3,4-二羟基苯甲醛在乙腈中，氮气保护下发生取代生成3,4-二-(2-甲氧乙氧基)苯甲醛(4d)；3,4-二-(2-甲氧乙氧基)苯甲醛的醛基经盐酸羟胺还原得到3,4-二-(2-甲氧乙氧基)苯甲腈(5d)；3,4-二-(2-甲氧乙氧基)苯甲腈低温下与浓硝酸反应，硝化得到4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈(6d)；4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈经过在甲酰胺中，与三氯化铟微波环合(Niementowski环合)得到6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮(7d)；6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮经草酰氯氯代后得到4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉(8d)；4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉分别与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物反应，得到化合物QJJ-19～QJJ-28。
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法，更优选包括以下步骤：
(1)将吗啉与1-溴-3-氯丙烷溶于甲苯中，加热至65～85℃回流反应2.5～6.5h，待反应结束后冷却至室温，过滤并用HCl溶液萃取去除甲苯，调pH至强碱性，油水层分离，再用***萃取，蒸去***，得到4-(3-氯丙基)吗啉(3a)；将异香兰素(3-羟基-4-甲氧基苯甲醛)、盐酸羟胺、甲酸和甲酸钠混合均匀，加热至100℃回流反应5～7.5h，待反应结束后加入饱和食盐水，过滤，水洗，干燥，得到中间体化合物3-羟基-4-甲氧基苯甲腈(5a)；将4-(3-氯丙基)吗啉、3-羟基-4-甲氧基苯甲腈、碳酸钾、碘化钾和乙腈混合均匀，加热至75～85℃回流反应3～7h，得到4-甲氧基-3-(3-吗啉丙氧基)苯甲腈(6a)；将4-甲氧基-3-(3-吗啉丙氧基)苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中，保持0℃反应2～5h，然后加热至40～50℃回流3～6h，待反应结束后加入冰水洗涤，析出固体，过滤，正己烷洗涤，干燥，得到硝基化的化合物7a(4-甲氧基-5-(3-吗啉丙氧基)-2-硝基苯甲腈)；将硝基化的化合物7a溶解到甲酰胺中，然后加入三氯化铟作为催化剂，在100～120℃，400W条件下微波反应40～70分钟，用二氯甲烷萃取，无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到喹唑啉酮化合物8a(7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉-4(3H)-酮)；将喹唑啉酮化合物8a和N，N-二甲基甲酰胺加入到氯仿中，然后加入草酰氯，加热至60～70℃反应1.5～3小时后，再加入饱和碳酸氢钠溶液直至观察到pH为10.0；乙酸乙酯萃取，有机层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到氯代喹唑啉化合物9a(4-氯-7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉)；将氯代喹唑啉化合物9a和取代物加入到N,N-二甲基甲酰胺中，加入三乙胺作为催化剂，在100～130℃，100W条件下微波反应15～30分钟，再加入饱和盐水，乙酸乙酯萃取，乙酸乙酯层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到化合物QJJ-1～QJJ-12；其中，取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物；
(2)将三甘醇、四氢呋喃、氢氧化钠和水混合均匀，然后在冰浴下加入四氢呋喃溶解的对甲基苯磺酰氯(TsCl)，在冰浴下继续反应2.5～4h，结束后蒸出四氢呋喃，冷却，抽滤，并依次用甲醇、乙醇和冰水洗涤，得到对甲基苯磺酰取代羟基的三甘醇(3c)；将3,4-二羟基苯甲醛、盐酸羟胺、甲酸钠和甲酸混合均匀，加热至100℃回流反应5～7.5h，结束后加入饱和食盐水，过滤，水洗，干燥，得到3,4-二羟基苯甲腈(5c)；将3,4-二羟基苯甲腈、四氢呋喃、氢氧化钠、氢氧化锂和水混合均匀，在氮气保护下，60～75℃反应1h，然后加入四氢呋喃溶解的对甲基苯磺酰取代羟基的三甘醇，继续反应60～80h，反应完毕后，蒸出四氢呋喃，残留部分用二氯甲烷萃取，蒸干溶剂，得到冠醚苯甲腈(6c)；将冠醚苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中，保持0℃反应2～5h，然后加热至40～50℃回流3～6h，待反应结束后加入冰水洗涤，析出固体，过滤，正己烷洗涤，干燥，得到硝基化的化合物7c(12-氰基-13-硝基-2,3,5,6,8,9-六氢苯并[b][1,4,7,10]四氧环十二烷)；将硝基化的化合物7c溶解到甲酰胺中，然后加入三氯化铟作为催化剂，在100～120℃，400W条件下微波反应40～70分钟，用二氯甲烷萃取，无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到喹唑啉酮类化合物8c(7,8,10,11,13,14-六氢-[1,4,7,10]四氧环十二烷并[2,3-g]喹唑啉-4(3H)-酮)；将喹唑啉酮类化合物8c和N，N-二甲基甲酰胺加入到氯仿中，然后加入草酰氯， 加热至60～70℃反应1.5～3小时后，再加入饱和碳酸氢钠溶液直至观察到pH为10.0；乙酸乙酯萃取，有机层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到中间体氯代喹唑啉化合物9c(4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧环十二烷并[2,3-g]喹唑啉)；将氯代喹唑啉化合物9c和取代物加入到N,N-二甲基甲酰胺中，加入三乙胺作为催化剂，在100～130℃，100W条件下微波反应15～30分钟，再加入饱和盐水，乙酸乙酯萃取，乙酸乙酯层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到化合物QJJ-13～QJJ-18；其中，取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物；
(3)将乙二醇单甲醚加入到THF(四氢呋喃)和水的混合液中，冰浴处理1～3小时后，加入THF溶解的对甲基苯磺酰氯，继续冰浴3～6小时，然后旋干THF，饱和食盐水水洗，二氯甲烷萃取，有机层加入无水Na 2SO 4干燥，减压浓缩，硅胶柱层析分离，真空干燥，得到2-甲氧基乙基-4-甲基苯磺酸酯(3d)；将2-甲氧基乙基-4-甲基苯磺酸酯、3,4-二羟基苯甲醛、乙腈和碳酸钾混合均匀，抽真空，N 2保护，70～85℃反应30～45h，抽滤，取滤液，旋干乙腈，用饱和食盐水水洗，乙酸乙酯萃取，有机层加入无水Na 2SO 4干燥，减压浓缩，硅胶柱层析分离，得到3,4-二-(2-甲氧乙氧基)苯甲醛(4d)；将甲酸钠和3,4-二-(2-甲氧乙氧基)苯甲醛加入到甲酸中，加热至75～85℃后加入盐酸羟胺，反应4～7h后，冷至至室温，加入冷的饱和食盐水析出固体，过滤，乙酸乙酯重结晶，干燥得3,4-二-(2-甲氧乙氧基)苯甲腈(5d)；将3,4-二-(2-甲氧乙氧基)苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中，保持0℃反应2～5h，然后加热至40～50℃回流3～6h，待反应结束后加入冰水洗涤，析出固体，过滤，正己烷洗涤，干燥，得到4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈(6d)；将4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈溶解到甲酰胺中，然后加入三氯化铟(Niementowski环合)作为催化剂，在100～120℃，400W条件下微波反应40～70分钟，反应结束后过滤，滤液用饱和食盐水水洗，乙酸乙酯萃取，有机层减压浓缩，再用乙酸乙酯重结晶，得到6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮(7d)；将6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮溶于氯仿，加入N,N-二甲基甲酰胺，滴加草酰氯，60～70℃回流1.5～3h，用饱和碳酸氢钠水溶液洗涤，乙酸乙酯萃取，有机层加入无水Na 2SO 4干燥，减压浓缩，硅胶柱层析分离，真空干燥，得到4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉(8d)；将4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉和取代物加入到N,N-二甲基甲酰胺中，加入三乙胺作为催化剂，在100～130℃，300W条件下微波反应15～30分钟，再加入饱和盐水，乙酸乙酯萃取，乙酸乙酯层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到化合物QJJ-19～QJJ-28；其中，取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物。
步骤(1)中所述的吗啉与1-溴-3-氯丙烷的体积比优选为1:1.15。
步骤(1)中所述的异香兰素与盐酸羟胺的质量比优选为1:1.1。
步骤(1)中所述的4-(3-氯丙基)吗啉和3-羟基-4-甲氧基苯甲腈的质量比优选为5.25:4。
步骤(1)、(2)和(3)中所述的硝酸溶液的浓度优选为质量百分比65％。
步骤(1)中所述的氯代喹唑啉化合物和取代物的摩尔比优选为1:1。
步骤(1)、(2)和(3)中所述的取代苯磺酰哌嗪是以取代苯磺酰氯与哌嗪为原料合成的取代苯磺酰哌嗪；优选为苯磺酰哌嗪(1-(phenylsulfonyl)piperazine)、对甲基苯磺酰哌嗪(1-tosylpiperazin)、对甲氧基苯磺酰哌嗪(1-((4-methoxyphenyl)sulfonyl)piperazine)、或间硝基苯磺酰哌嗪(1-((3-nitrophenyl)sulfonyl)piperazine)。
步骤(1)、(2)和(3)中所述的取代苯基哌嗪优选为苯基哌嗪(1-苯基哌嗪)、对甲基苯基哌嗪(1-(4-甲基苯基)哌嗪)、对硝基苯基哌嗪(1-(4-硝基苯基)哌嗪)、对氟苯基哌嗪(1-(4-氟苯基)哌嗪)、对溴苯基哌嗪(1-(4-溴苯基)哌嗪)、或邻甲氧基苯基哌嗪(1-(2-甲氧基苯基)哌嗪)。
步骤(1)、(2)和(3)中所述的取代苄基哌嗪化合物优选为苄基哌嗪(1-苄基哌嗪)或间氯苄基哌嗪(1-(3-氯苄基)哌嗪)。
步骤(2)中所述的三甘醇与对甲基苯磺酰氯的摩尔比优选为6.7:12。
步骤(2)中所述的3,4-二羟基苯甲醛与盐酸羟胺的质量比为13.8:16.7。
步骤(2)中所述的对甲基苯磺酰取代羟基的三甘醇和3,4-二羟基苯甲腈的质量比优选为3.73:1。
步骤(2)中所述的冠醚苯甲腈与硝酸溶液的摩尔比为1:10。
步骤(2)中所述的喹唑啉酮类化合物与草酰氯的摩尔比为0.3:0.86。
步骤(2)中所述的氯代喹唑啉化合物和取代物的摩尔比优选为1:1。
步骤(3)中所述的乙二醇单甲醚与对甲基苯磺酰氯的摩尔比为1:1.05
步骤(3)中所述的2-甲氧基乙基-4-甲基苯磺酸酯与3,4-二羟基苯甲醛的摩尔比为2:1。
步骤(3)中所述的3,4-二-(2-甲氧乙氧基)苯甲醛与盐酸羟胺的摩尔比为1:2.4。
步骤(3)中所述的4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉和取代物的摩尔比优选为1:2。
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用，本发明制备的苯基哌嗪喹唑啉类化合物以及其药学上可接受的盐可制备具有抗肿瘤的药物，作为肿瘤化疗药物和手术治疗中的辅助药物，或者与其它药剂组合用于各种癌症的治疗。
所述的肿瘤为包括且不局限于非小细胞肺癌、乳腺癌、***、脑瘤、胰腺癌、肝癌、结肠直肠癌、甲状腺髓样癌、神经胶质瘤、成神经细胞瘤、肾脏肿瘤(肾癌)、肺癌、胰腺癌、星细胞瘤、膀胱癌、卵巢癌、头颈癌、子***、胸腺癌、胃癌，卵巢癌和***癌；优选为非小细胞肺癌、肺腺癌或***。
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抑制激酶的药物、抑制HUVEC细胞迁移的药物中的应用，本发明制备的苯基哌嗪喹唑啉类化合物以及其药学上可接受的盐可以抑制EGFR激酶或EGFR T790M/L858R双突变型激酶的活性，抑制HUVEC细胞的水平迁移能力，能够与αvβ3抗体竞争结合HUVEC细胞表面的整合素αvβ3受体。
所述的激酶为EGFR激酶或EGFR T790M/L858R双突变型激酶。
本文所用的术语“烃基”是指未被取代的或被取代的直链、支链或环状的多至10个碳原子的烃基碳链，或在链上含有至少一个杂原子(例如氮、氧或硫)的烃基。直链烃基的非限定性例子包括如甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基等饱和烃基，也包括含有烯键、炔键、羰基、氰基等取代基的不饱和烃基，还包括含杂原子的烃基如-CH 2CH 2OCH 3、-CH 2CH 2N(CH 3) 2和-CH 2CH 2SCH 3等。不含或含杂原子的支链烃基的非限定性例子包括如异丙基、仲丁基、异丁基、叔丁基、新戊基、-CH 2CH(OCH 3)CH 3、-CH 2CH(N(CH 3) 2)CH 3和-CH 2CH(SCH 3)CH 3。不含或含杂原子的环状烃基(“环烃基”)的非限定性例子包括如环丙基、环丁基、环戊基和环己基等，含O、N、S的六元环如-CH(CH 2CH 2) 2O、-CH(CH 2CH 2) 2NCH 3和-CH(CH 2CH 2) 2S等及相应的五元杂环等。烃基可被一个或多个取代基取代，上述取代基的非限定性例子包括-N(CH 3) 2、F、Cl、Br、I、-OCH 3、-CO 2CH 3、-CN、-OH、芳基和杂芳基。
本文所用的术语“芳基”是指未被取代的或取代的芳香化合物、碳环基团和杂芳基。芳基或者是单环或者是多环稠合化合物。芳基可以被一个或多个取代基取代，取代基的非限制性的例子包括-N(CH 3) 2、F、Cl、Br、I、-OCH 3、-CO 2CH 3、-CN、-OH、芳基和杂芳基。
杂芳基涉及到取代的或非取代的单环或多环的基团，环内至少包括一个杂原子，如氮、氧以及硫。举例来说，典型的杂环基团包括一个或多个氮原子譬如四唑基、吡咯基、吡啶基(如4-吡啶基，3-吡啶基，2-吡啶基等)、哒嗪基、吲哚基、喹啉基(如2-喹啉基，3-喹啉基等)、咪唑基、异喹啉基，吡唑基、吡嗪基、嘧啶基、吡啶酮基；典型的含一个氧原子的杂环基团包括2-呋喃基，3-呋喃基或苯并呋喃基；典型的硫杂原子基团包括噻吩基、苯并噻吩基；典型的混合杂原子基团包括呋吖基、噁唑基、异噁唑基、噻唑基和吩噻噁基。杂环基团能被一个或多个取代基取代，这些取代基包括-O-烷基、-NH-烷基、-N-(烷基) 2、-NHC(O)-烷基、F、Cl、Br、I、-OH、-OCF 3、-CO 2-烷基、-CN以及芳基和多芳基。
本文使用的术语“药学上可接受的”指的是在化合物如盐或赋形剂中不具有不能接受的毒性。药学上可接受的盐包括无机阴离子，例如氯离子、溴离子、碘离子、硫酸根、亚硫酸根、硝酸根、亚硝酸根、磷酸根、磷酸氢根等。有机阴离子包括乙酸根、丙酸根、肉桂酸根、苯甲磺酸根、柠檬酸根、乳酸根、葡萄糖酸根、富马酸根、酒石酸根、琥珀酸根等。本发明涉及一类苯基哌嗪喹唑啉类化合物的烃基、芳基、杂芳基、硝酸酯基、卤代、磺酰基衍生物，可以一种药学可接受的盐或药物复合物的形式对病人给药。某个复合物可与适当载体或赋形剂混合形成药物组合物从而保证达到有效治疗剂。“有效治疗剂量”是指该种类化合物及其衍生物达到治疗效果所需的剂量。
与现有技术相比，本发明具有以下优点及有益效果：
(1)本发明提供的这些化合物，结构新颖、合成方法容易实现。体外抗肿瘤活性实验表明，该类化合物的抗肿瘤活性类似临床用药厄洛替尼。该类化合物以及其药学上可接受的盐可制备具有抗肿瘤的药物，可以制备治疗非小细胞肺癌、乳腺癌、肝癌和***药物，以及制备作为肿瘤化疗药物和手术治疗中的辅助药物。
(2)苯基哌嗪喹唑啉类化合物制备工艺简单，原料易得，成本较低，经济有效。
附图说明
图1是化合物1a～1d的合成路线图(图中a表示：哌嗪，三乙胺，二氯甲烷，冰浴反应，反应时间为3h，反应结束后恢复至室温)。
图2是化合物QJJ-1～QJJ-12的合成路线图(图中：A表示吗啉，甲苯，65～85℃，2.5～6.5h；B表示盐酸羟胺，甲酸钠，甲酸，100℃，5～7.5h；C表示碳酸钾，碘化钾，乙腈，75～85℃，3～7h；D表示65％硝酸，冰醋酸，0℃、2～5h，40～50℃、3～6h；E表示甲酰胺，三氯化铟，微波400w，100～120℃，40～70分钟；F表示草酰氯，N,N-二甲基甲酰胺，氯仿，60～70℃，1.5～3h；G表示各取代苯基哌嗪，三乙胺，N,N-二甲基甲酰胺，微波100w，100～130℃，15～30min；H表示1b/1c/1d/1a,三乙胺，N,N-二甲基甲酰胺，微波100w，100～130℃， 15～30min；I表示各取代苄基哌嗪，三乙胺，N,N-二甲基甲酰胺，微波100w，100～130℃，15～30min)。
图3是化合物QJJ-13～QJJ-18的合成路线图(图中：A表示对甲基苯磺酰氯，四氢呋喃，氢氧化钠，水，冰浴，2.5～4h；B表示盐酸羟胺，甲酸钠，甲酸，100℃，5～7.5h；C表示四氢呋喃，氢氧化钠，氢氧化锂，水，N 2保护，60～75℃，60～80h；D表示65％硝酸，冰醋酸，0℃、2～5h，40～50℃、3～6h；E表示甲酰胺，三氯化铟，微波400w，100～120℃，40～70分钟；F表示草酰氯，N,N-二甲基甲酰胺，氯仿，60～70℃，1.5～3h；G表示各取代苯基哌嗪，三乙胺，N,N-二甲基甲酰胺，微波100w，100～130℃，15～30min；H表示1a/1d,三乙胺，N,N-二甲基甲酰胺，微波100w，100～130℃，15～30min；I表示各取代苄基哌嗪，三乙胺，N,N-二甲基甲酰胺，微波100w，100～130℃，15～30min。
图4是化合物QJJ-19～QJJ-28的合成路线图(图中：A表示对甲基苯磺酰氯，四氢呋喃，氢氧化钠，水，冰浴，4～9h；B表示3,4-二羟基苯甲醛，碳酸钾，乙腈，N 2保护，70～85℃；C表示盐酸羟胺，甲酸钠，甲酸，75～85℃，4～7h；D表示65％硝酸，冰醋酸，0℃、2～5h，40～50℃、3～6h；E表示甲酰胺，三氯化铟，微波400w，100～120℃，40～70分钟；F表示草酰氯，N,N-二甲基甲酰胺，氯仿，60～70℃，1.5～3h；G表示1a/1b/1c/1d，N,N-二甲基甲酰胺，三乙胺，微波300w，100～130℃，15～30min；H表示各取代苯基哌嗪，N,N-二甲基甲酰胺，三乙胺，微波300w，100～130℃，15～30min；I表示各取代苄基哌嗪，N,N-二甲基甲酰胺，三乙胺，微波300w，100～130℃，15～30min)。
图5是化合物QJJ-28抑制HUVEC人脐静脉内皮细胞迁移镜下图(10×10)。
图6是流式细胞术对QJJ-12结合整合素αvβ3受体的检测结果。
图7是流式细胞术对QJJ-28结合整合素αvβ3受体的检测结果。
图8是实验各组裸鼠体重变化曲线图。
图9是整个实验给药前后裸鼠体重的变化图(*p<0.05，**p<0.01，***p<0.001对比于给药前组)。
图10是实验各组裸鼠肿瘤组织图。
图11是实验各组裸鼠肿瘤生长曲线图(*p<0.05，**p<0.01，***p<0.001与Ctrl组对比；#p<0.05，##p<0.01，###p<0.001与Gefitinib组对比)。
图12是实验各组裸鼠的肿瘤生长抑制率(#p<0.05，##p<0.01，###p<0.001与Gefitinib组对比)。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。下列实施例中未注明具体实验条件的试验方法，通常按照常规实验条件或按照制造厂所建议的实验条件。除非特别说明，本发明所用试剂和原材料均可通过市售获得。
实施例1：化合物1-(phenylsulfonyl)piperazine(1a)的合成
称取无水哌嗪(3.24g,37.7mmol)，三乙胺(2.10g,20.7mmol)，溶于无水二氯甲烷(100mL)中，冰浴。30min后，滴加稀释苯磺酰氯(4.0g,22.6mmol)的无水二氯甲烷(20mL)，冰浴下继续反应3h。TLC(薄层色谱)检测反应，反应完全后旋干二氯甲烷，饱和食盐水水洗，乙酸乙酯萃取，有机层加入无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱剂为：石油醚：乙酸乙酯＝1:2(体积比)，再加入1％(v/v)三乙胺)，TLC跟踪收集，真空干燥，得白色固体1a(产率62％)(图1)。
ESI-MS:[M+H] +m/z 227.3。 1H 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)。 13C NMR(75MHz,CDCl 3)δ:135.32,132.84,129.02,127.69,46.82,45.20。
实施例2：化合物1-tosylpiperazin(1b)的合成
化合物1b的具体合成方法可参照化合物1a的合成步骤。将对甲苯磺酰氯(4.0g,21.0mmol)替换实施例1中的苯磺酰氯，得白色固体1b(产率60％)(图1)。
ESI-MS:[M+H] +m/z 241.3。 1H 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)。 13C NMR(75MHz,CDCl 3)δ143.63,132.27,129.60,127.77,46.85,45.21,21.47。
实施例3：化合物1-((4-methoxyphenyl)sulfonyl)piperazine(1c)的合成
化合物1c的具体合成方法可参照化合物1a的合成步骤。将对甲氧基苯磺酰氯(4.0g,19.4mmol)替换实施例1中的苯磺酰氯，得淡黄色固体1c(产率79％)(图1)。
ESI-MS:[M+H] +m/z 257.1。 1H 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)。 13C NMR(75MHz,CDCl 3)δ:162.98,129.76,126.71,114.15,55.61, 46.78,45.09。
实施例4：化合物1-((3-nitrophenyl)sulfonyl)piperazine(1d)的合成
化合物1d的具体合成方法可参照化合物1a的合成步骤。将间硝基苯磺酰氯(4.0g，18.2mmol)替换实施例1中的苯磺酰氯，得黄色固体1d(产率65％)(图1)。
ESI-MS:[M+H] +m/z 272.3,[M+Na] +m/z 284.3。 1H 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)。 13C NMR(75MHz,CDCl 3)δ:148.37,138.15,133.19,130.53,127.30,122.76,46.83,45.23。
实施例5：化合物4-(3-chloropropyl)morpholine(3a)的合成
在圆底烧瓶中依次加入吗啉(30ml)，1-溴-3氯丙烷(34.4ml)，甲苯(90ml)，加热至80℃，回流6h，结束后冷却至室温，过滤得滤液，用3mol/L的HCl溶液萃取，除去甲苯，然后用10mol/L NaOH溶液调pH至强碱性，油水层分离，***萃取，蒸去***得无色液体3a(图2)。
ESI-MS:m/z 164.1([M+H] +)。 1H 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)。 13C NMR(75MHz,d 6-DMSO)δ:67.08,53.71,53.07,41.28,29.15。
实施例6：化合物3-hydroxy-4-methoxybenzonitrile(5a)的合成
在圆底烧瓶中依次加入异香兰素2g，盐酸羟胺2.2g，甲酸钠1.7g，甲酸11ml，加热至100℃回流6h，结束后在反应液中加入饱和食盐水10ml，搅拌过滤，滤饼水洗(20ml×3)，干燥，得灰色粉末5a(图2)。
ESI-MS:m/z 150.1([M+H] +)。 1H 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)。 13C NMR(75MHz,d 6-DMSO)δ:153.91,147.34,125.90,118.82,117.41,113.77,104.59,56.83。
实施例7：化合物4-methoxy-3-(3-morpholinopropoxy)benzonitrile(6a)的合成
在圆底烧瓶中依次加入3a 0.525g，5a 0.4g，碳酸钾0.75g，碘化钾0.023g，乙腈2.2ml。搅拌溶解，加热至82℃，回流3～4h，结束后冷却至室温，过滤得滤液，蒸去乙腈，得粗品用硅胶柱分离(石油醚:乙酸乙酯＝1:1，体积比)，得无色液体6a(图2)。
ESI-MS:m/z 277.1([M+H] +)。 1H 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)。 13C 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。
实施例8：化合物4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile(7a)的合成
在圆底烧瓶中加入质量分数65％的硝酸1.7ml，冷却至0℃，缓慢加入用5ml冰醋酸溶解的6a 0.66g,保持0℃4h，然后加热至50℃，回流4h，结束后反应液中加入冰水洗涤，析出黄色固体，过滤，正己烷洗涤，干燥，得黄色固体7a(产率49.3％)(图2)。
ESI-MS:m/z 322.1([M+H] +)。 1H 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)。 13C 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.
实施例9：化合物7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one(8a)的合成
将7a(1.56mmol，0.5g)加入到含有20ml甲酰胺的烧瓶中，搅拌使其完全溶解，加入三氯化铟(1.56mmol，0.35g)作为催化剂。反应在微波反应器中进行(110℃，400W)，反应60分钟后终止反应。向混合物中加入少量的水，并用二氯甲烷萃取。将二氯甲烷层用无水Na 2SO 4干燥，过滤并浓缩，得到残余物，将其通过硅胶柱(乙酸乙酯：三乙胺＝100:1，体积比)纯化，得到化合物8a(白色固体，产率30.2％)(图2)。
ESI-MS:m/z 319.3([M+H] +)。 1H 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)。 13C 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。
实施例10：化合物4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(9a)的合成
将8a(3mmol，1g)和N，N-二甲基甲酰胺(0.22ml)加入到含有30ml氯仿的烧瓶中，当其完全溶解时，缓慢加入草酰氯(7.5mmol，0.67ml)，加热至61℃，2小时后终止反应。加入饱和碳酸氢钠溶液直至观察到pH为10.0。混合物用乙酸乙酯萃取。有机层用无水Na 2SO 4干燥，过滤并浓缩，得到残余物，通过硅胶柱(石油醚：乙酸乙酯＝1：1，体积比)纯化，得到化合物9a(白色固体，产率60.0％)。
ESI-MS:m/z 320.3([M+H] +)。 1H 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)。 13C 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。
实施例11：化合物4-(3-((7-methoxy-4-(4-phenylpiperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-1)的合成
将化合物9a(0.3mmol)和1-苯基哌嗪(0.3mmol)加入到含有20ml DMF(N,N-二甲基甲酰胺)的烧瓶中，完全溶解，加入三乙胺作为催化剂。将反应在微波反应器中进行，设置反应条件(120℃，100W)，20分钟后终止反应。向混合物中加入少量饱和盐水，并用乙酸乙酯萃取。乙酸乙酯层用无水Na 2SO 4干燥，过滤并浓缩，得到残余物，通过硅胶柱(乙酸乙酯:石油醚＝1:1，体积比)纯化，得到化合物QJJ-1，淡黄色固体，产率85％，m.p.119.6℃-120.5℃(图2)。
ESI-HRMS m/z:464.2656[M+H] +,calcd for C 26H 33N 5O 3 464.2654。 1H 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)。 13C 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。
实施例12：化合物4-(3-((7-methoxy-4-(4-(p-tolyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-2)的合成
化合物QJJ-2(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-甲基苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-2。淡黄色固体，产率82％，m.p.122.0℃-124.8℃。
ESI-HRMS m/z:478.2813[M+H] +,calcd for C 27H 35N 5O 3 478.2811。 1H 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)。 13C 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。
实施例13：化合物4-(3-((7-methoxy-4-(4-(4-nitrophenyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-3)的合成
化合物QJJ-3(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-硝基苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-3。黄色固体，产率89％，m.p.90.2℃-91.4℃。
ESI-HRMS m/z:509.2507[M+H] +,calcd for C 26H 32N 6O 5 509.2511。 1H 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)。 13C 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。
实施例14：化合物4-(3-((4-(4-(4-fluorophenyl)piperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-4)的合成
化合物QJJ-4(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-氟苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-4。白色固体，产率82％，m.p.131.7℃-133.2℃。
ESI-HRMS m/z:482.2562[M+H] +,calcd for C 26H 32FN 5O 3 482.2581。 1H 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)。 13C 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。
实施例15：化合物4-(3-((4-(4-(4-bromophenyl)piperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-5)的合成
化合物QJJ-5(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-溴苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-5。淡黄色固体，产率85％，m.p.145.5℃-147.2℃。
ESI-HRMS m/z:542.1761[M+H] +,calcd for C 26H 32BrN 5O 3 542.1783。 1H 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)。 13C 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。
实施例16：化合物4-(3-((7-methoxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-6)的合成
化合物QJJ-6(图2)的合成同实施例11化合物QJJ-1的合成。将1-(2-甲氧基苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-6。淡黄色固体，产率83％，m.p.87.9℃-88.7℃。
ESI-HRMS m/z:494.2762[M+H] +,calcd for C 27H 35N 5O 4 494.2768。 1H 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)。 13C 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。
实施例17：化合物4-(3-((7-methoxy-4-(4-tosylpiperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-7)的合成
化合物QJJ-7(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1b(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-7。棕色固体，产率81％，m.p.164.4℃-167.7℃。
ESI-HRMS m/z:542.2432[M+H] +,calcd for C 27H 35N 5O 5S 542.2428。 1H 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)。 13C 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。
实施例18：化合物4-(3-((7-methoxy-4-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-8)的合成
化合物QJJ-8(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1c(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-8。棕色固体，产率86％，m.p.141.8-143.4℃。
ESI-HRMS m/z:558.2381[M+H] +,calcd for C 27H 35N 5O 6S 558.2368。 1H 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)。 13C 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。
实施例19：化合物4-(3-((7-methoxy-4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-9)的合成
化合物QJJ-9(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1d(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-9。黄色固体，产率79％，m.p.191.5℃-194.0℃。
ESI-HRMS m/z:573.2126[M+H] +,calcd for C 26H 32N 6O 7S 573.2119。 1H 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)。 13C 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。
实施例20：化合物4-(3-((7-methoxy-4-(4-(phenylsulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-10)的合成
化合物QJJ-10(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1a(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-10。棕褐色固体，产率79％，m.p.159.1℃-160.6℃。
ESI-HRMS m/z:528.2275[M+H] +,calcd for C 26H 33N 5O 5S 528.2272。 1H 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)。 13C 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。
实施例21：化合物4-(3-((4-(4-benzylpiperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-11)的合成
化合物QJJ-11(图2)的合成同实施例11化合物QJJ-1的合成。将1-苄基哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-11。淡黄色油状，产率87％。
ESI-HRMS m/z:478.2813[M+H] +,calcd for C 27H 35N 5O 3 478.2808。 1H 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)。 13C 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。
实施例22：化合物4-(3-((4-(4-(3-chlorobenzyl)piperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-12)的合成
化合物QJJ-12(图2)的合成同实施例11化合物QJJ-1的合成。将1-(3-氯苄基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪，与化合物9a反应得到化合物QJJ-12。淡黄色油状，产率76％。
ESI-HRMS m/z:512.2423[M+H] +,calcd for C 27H 34ClN 5O 3 512.2418。 1H 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)。 13C 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。
实施例23：化合物(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate)(3c)的合成
在圆底烧瓶中依次加入三甘醇(0.9mL，6.7mmol)，四氢呋喃1.5mL，水4mL，氢氧化钠0.76g，冰浴下缓慢滴加2.2mL四氢呋喃溶解的对甲基苯磺酰氯(2.39g,12mmol)，滴加完毕后冰浴下继续反应3h，结束后蒸出四氢呋喃，冷却，析出白色固体，抽滤并依次用甲醇、乙醇、冰水洗涤，干燥后得到白色固体3c(图3)。
ESI-MS:m/z 459.2[M+H] +。 1H 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)。 13C NMR(75MHz,CDCl 3)δ:144.9,132.9,129.9,128.0,70.7,69.2,68.7,21.7。
实施例24：化合物3,4-dihydroxybenzonitrile(5c)的合成
在圆底烧瓶中依次加入3,4-二羟基苯甲醛13.8g，盐酸羟胺16.7g，甲酸钠13.6g，甲酸50ml，加热至100℃回流6h，结束后在反应液中加入饱和食盐水，搅拌过滤，滤饼水洗，干燥，得灰色粉末5c(图3)。
ESI-MS:m/z 136.1[M+H] +。 1H 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)。 13C NMR(75MHz,CDCl 3)δ:153.08,146.56,125.51,118.82,117.67,116.22,101.67。
实施例25：化合物2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carbonitrile(6c)的合成
在圆底烧瓶中依次加入5c 10g，四氢呋喃200mL，水40mL，氢氧化钠2.8g，氢氧化锂8.8g，氮气保护，70℃反应1h。1h后将四氢呋喃70mL溶解的3c 37.3g滴加到反应体系中，继续反应72h。反应完毕后，蒸出四氢呋喃，残留部分用二氯甲烷萃取，蒸干溶剂，得到黑色粘稠油状物。粗品经硅胶柱分离(石油醚:乙酸乙酯＝4:1，体积比)，可得白色固体6c(图3)。
ESI-MS:m/z 250.3[M+H] +。 1H 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)。 13C 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。
实施例26：化合物13-nitro-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carbonitrile(7c)的合成
在圆底烧瓶中加入质量分数65％的硝酸(38mmol,2.7ml)，冷却至0℃，缓慢加入用5ml冰醋酸溶解的6c(3.8mmol,0.95g)，保持0℃4h，然后加热至50℃，回流4h，结束后反应液中加入冰水洗涤，析出黄色固体，过滤，正己烷洗涤，干燥，得黄色固体7c(黄色固体，产率51％)(图3)。
ESI-MS:m/z 295.3[M+H] +。 1H 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)。 13C 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。
实施例27：化合物7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4(3H)-one(8c)的合成
将7c(0.68mmol，0.2g)加入到含有20ml甲酰胺的烧瓶中，搅拌使其完全溶解，加入三氯化铟(0.68mmol,0.15g)作为催化剂。反应在微波反应器中进行(110℃，400W)，反应60分钟后终止反应。向混合物中加入少量的水，并用二氯甲烷萃取。将二氯甲烷层用无水Na 2SO 4干燥，过滤并浓缩，得到残余物，将其通过硅胶柱(乙酸乙酯：三乙胺100:1，体积比)纯化，得到化合物8c(白色固体，产率25.6％)(图3)。
ESI-MS:m/z 293.3[M+H] +。 1H 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)。 13C 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。
实施例28：化合物4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline(9c)的合成
将8c(0.3mmol，0.1g)和N，N-二甲基甲酰胺(0.024ml)加入到含有30ml氯仿的烧瓶中，当其完全溶解时，缓慢加入草酰氯(0.86mmol，0.073ml)，加热至61℃，2小时后终止反应。加入饱和碳酸氢钠溶液直至观察到pH为10.0。混合物用乙酸乙酯萃取。有机层用无水Na 2SO 4干燥，过滤并浓缩，得到残余物，通过硅胶柱(石油醚：乙酸乙酯＝1：1，体积比)纯化，得到化合物9c(白色固体，产率65.0％)(图3)。
ESI-MS:m/z 311.7[M+H] +。 1H 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)。 13C 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。
实施例29：化合物4-(4-(4-fluorophenyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2,3-g]quinazoline(QJJ-13)的合成
化合物QJJ-13(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a，与1-(4-氟苯基)哌嗪(0.3mmol)合成化合物QJJ-13。淡黄色固体，产率83％，m.p.161.2℃-165.2℃。
ESI-HRMS m/z:455.2089[M+H] +,calcd for C 24H 27FN 4O 4 455.2092。 1H 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)。 13C 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。
实施例30：化合物4-(4-(4-nitrophenyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2,3-g]quinazoline(QJJ-14)的合成
化合物QJJ-14(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a，与1-(4-硝基苯基)哌嗪(0.3mmol)合成化合物QJJ-14。黄色固体，产率81％，m.p.146.2℃-146.8℃。
ESI-HRMS m/z:482.2034[M+H] +,calcd for C 24H 27N 5O 6 482.2042。 1H 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)。 13C 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。
实施例31：化合物4-(4-(phenylsulfonyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2,3-g]quinazoline(QJJ-15)的合成
化合物QJJ-15(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a，与1a(0.3mmol)合成化合物QJJ-15。淡黄色固体，产率76％，m.p.162.1℃-163.9℃。
ESI-HRMS m/z:501.1802[M+H] +,calcd for C 24H 28N 4O 6S 501.1807。 1H 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)。 13C 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。
实施例32：化合物4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline(QJJ-16)的合成
化合物QJJ-16(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11 的9a，与1d(0.3mmol)合成化合物QJJ-16。黄色固体，产率75％，m.p.141.6℃-147.5℃。
ESI-HRMS m/z:546.1653[M+H] +,calcd for C 24H 27N 5O 8S 546.1659。 1H 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)。 13C 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。
实施例33：化合物4-(4-benzylpiperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclo-dodecino[2,3-g]quinazoline(QJJ-17)的合成
化合物QJJ-17(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a，与1-苄基哌嗪(0.3mmol)合成化合物QJJ-17。淡黄色油状，产率86％。
ESI-HRMS m/z:451.2340[M+H] +,calcd for C 25H 30N 4O 4 451.2353。 1H 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)。 13C 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。
实施例34：化合物4-(4-(3-chlorobenzyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline(QJJ-18)的合成
化合物QJJ-18(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a，与1-(3-氯苄基)哌嗪(0.3mmol)合成化合物QJJ-18。淡黄色油状，产率85％。
ESI-HRMS m/z:485.1950[M+H] +,calcd for C 25H 29ClN 4O 4 485.1981。 1H 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)。 13C 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。
实施例35：化合物2-methoxyethyl-4-methylbenzenesulfonate(3d)的合成
称取NaOH(14.4g,0.36mol)，乙二醇单甲醚(22.8g,0.3mol)，溶于THF(四氢呋喃)(90mL)和水(180mL)的混合液中，冰浴处理。2小时后，将对甲基苯磺酰氯(59.9g,0.315mol)溶于THF(150mL)，滴加入上述体系，继续冰浴4h。TLC检测反应完全后，旋干THF，饱和食盐水水洗，二氯甲烷萃取，有机层加入无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(石油醚：乙酸乙酯＝9:1，体积比)，TLC跟踪收集，真空干燥，得油状化合物3d(产率47％)(图4)。
ESI-MS:[M+H] +m/z 231.0,[M+NH 4] +m/z 248.3。 1H 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)。 13C NMR(75MHz,d 6-DMSO)δ:145.37,132.85,130.57,128.06,70.17,69.71,58.37,21.50。
实施例36：化合物3,4-bis(2-methoxyethoxy)benzaldehyde(4d)的合成
称取3,4-二羟基苯甲醛(6.9g,0.05mol)，溶于乙腈(300mL)，加入碳酸钾(13.8g,0.1mol)、化合物3d(23.1g,0.1mol)，抽真空，N 2保护，84℃反应36h。TLC检测反应完全后，抽滤，取滤液，旋干乙腈。饱和食盐水水洗，乙酸乙酯萃取，有机层加入无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(石油醚：乙酸乙酯＝4:1，体积比)。TLC跟踪收集，真空干燥，得橙色油状化合物4d(产率80.3％)(图4)。
ESI-MS:[M+H] +m/z 255.3,[M+Na] +m/z 277.3。 1H 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)。 13C 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。
实施例37：化合物3,4-bis(2-methoxyethoxy)benzonitrile(5d)的合成
称取甲酸钠(2.68g,39.9mmol)溶解于甲酸(1.63g,35.4mmol)中，加入化合物4d(5.0g,19.69mmol)，加热至85℃后加入盐酸羟胺(3.3g,47.2mmol)，反应5h后，冷至室温。将反应液倒入冷的饱和食盐水中，搅拌，析出大量白色固体，过滤得粗品，乙酸乙酯重结晶，干燥得白色固体化合物5d(产率75.5％)(图4)。
ESI-MS:[M+H] +m/z 252.3,[M+NH 4] +m/z 269.3。 1H 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)。 13C 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。
实施例38：化合物4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile(6d)的合成
称取质量分数65％的硝酸(10.5mL)，置于低温反应仪里，0℃预冷30min。将化合物5d(3.7g,14.8mmol)溶于冰醋酸(8.0mL)后，滴加入上述体系，0℃继续反应。4h后，升温至50℃继续反应。4h后，加入30mL冰水洗涤，过滤，滤饼用冰水洗涤、正己烷洗涤，干燥，得黄色固体化合物6d(产率50％)(图4)。
ESI-MS:[M+H] +m/z 297.3。 1H 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)。 13C 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。
实施例39：化合物6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one(7d)的合成
称取化合物6d(0.4g,1.35mmol)，三氯化铟(0.3g,1.35mmol)溶于甲酰胺(20mL)，进行微波反应1h，微波反应仪设置参数温度为110℃，功率为400w。反应结束后过滤，滤液用饱和食盐水水洗，乙酸乙酯萃取，有机层减压浓缩，再用少量乙酸乙酯重结晶，得白色固体化合物7d(产率50％)(图4)。
ESI-MS:[M+H] +m/z 295.3,[M+Na] +m/z 317.3。 1H 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)。 13C 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。
实施例40：化合物4-chloro-6,7-bis(2-methoxyethoxy)quinazoline(8d)的合成
称取化合物7d(0.13g,0.44mmol)溶于氯仿(20mL)，加入N,N-二甲基甲酰胺(0.03g,0.38mmol)。滴加草酰氯(0.14g,1.1mmol)，61℃回流2h。TLC检测反应完全后，用饱和碳酸氢钠水溶液洗涤，乙酸乙酯萃取，有机层加入无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(石油醚：乙酸乙酯＝1:1，体积比)。TLC跟踪收集，真空干燥，得白色固体化合物8d(产率94％)(图4)。
ESI-MS:[M+H] +m/z 313.3。 1H 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)。 13C 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。
实施例41：化合物6,7-bis(2-methoxyethoxy)-4-(4-(phenylsulfonyl)piperazin-1-yl)quinazoline(QJJ-19)的合成
称取化合物8d(0.1g,0.32mmol)，溶解于N,N-二甲基甲酰胺(20mL)，加入化合物1a(0.15g,0.64mmol)和三乙胺(0.1mL)，进行微波反应20min，微波反应仪设置参数温度为120℃，功率为300w。反应结束后用饱和食盐水水洗，乙酸乙酯萃取，有机层加入无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1:1(体积比)，再加入1％(v/v)三乙胺)。TLC跟踪收集，真空干燥，得白色固体化合物QJJ-19(产率50％)，m.p.89.9～90.4℃(图4)。
ESI-MS:[M+H] +m/z 503.2。 1H 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)。 13C 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 24H 30N 4O 6S 503.1959。
实施例42：化合物6,7-bis(2-methoxyethoxy)-4-(4-tosylpiperazin-1-yl)quinazoline(QJJ-20)的合成
化合物QJJ-20的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1b(0.15g,0.64mmol)替换化合物1a，得油状化合物QJJ-20(产率62％)(图4)。
ESI-MS:[M+H] +m/z 517.2。 1H 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)。 13C 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 25H 32N 4O 6S 517.2115。
实施例43：化合6,7-bis(2-methoxyethoxy)-4-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)quinazoline(QJJ-21)的合成
化合物QJJ-21的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1c(0.16g,0.64mmol)替换化合物1a，得油状化合物QJJ-21(产率65％)(图4)。
ESI-MS:[M+H] +m/z 533.5。 1H 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)。 13C 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 25H 32N 4O 7S 533.2064。
实施例44：化合物6,7-bis(2-methoxyethoxy)-4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)quinazoline(QJJ-22)的合成
化合物QJJ-22的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1d(0.17g,0.64mmol)替换化合物1a，得橙黄色固体化合物QJJ-22(产率64％)，m.p.155.8～156.2℃(图4)。
ESI-MS:[M+H] +m/z 548.2。 1H 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)。 13C 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 24H 29N 5O 8S 548.1810。
实施例45：化合物6,7-bis(2-methoxyethoxy)-4-(4-phenylpiperazin-1-yl)quinazoline(QJJ-23)的合成
化合物QJJ-23的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-苯基哌嗪(0.1g,0.64mmol)替换化合物1a，得油状化合物QJJ-23(产率55％)(图4)。
ESI-MS:[M+H] +m/z 439.1。 1H 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)。 13C 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 24H 30N 4O 4 439.2340。
实施例46：化合物4-(4-(4-fluorophenyl)piperazin-1-yl)-6,7-bis(2-methoxyethoxy)quinazoline(QJJ-24)的合成
化合物QJJ-24的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(4-氟苯基)哌嗪(0.12g,0.64mmol)替换化合物1a，得油状化合物QJJ-24(产率50％)(图4)。
ESI-MS:[M+H] +m/z 457.5。 1H 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)。 13C 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 24H 29FN 4O 4 457.2246。
实施例47：化合物6,7-bis(2-methoxyethoxy)-4-(4-(2-methoxyphenyl)piperazin-1-yl)quinazoline(QJJ-25)的合成
化合物QJJ-25的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(2-甲氧基苯基)哌嗪(0.13g,0.64mmol)替换化合物1a，得油状化合物QJJ-25(产率59％)(图4)。
ESI-MS:[M+H] +m/z 469.4。 1H 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)。 13C 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 25H 32N 4O 5 469.2445。
实施例48：化合物6,7-bis(2-methoxyethoxy)-4-(4-(4-nitrophenyl)piperazin-1-yl)quinazoline(QJJ-26)的合成
化合物QJJ-26的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(4-硝基苯基)哌嗪(0.13g,0.64mmol)替换化合物1a，得橙黄色固体化合物QJJ-26(产率59％)，m.p.140.4～141.9℃(图4)。
ESI-MS:[M+H] +m/z 484.4。 1H 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)。 13C 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 24H 29N 5O 6 484.2191。
实施例49：化合物4-(4-benzylpiperazin-1-yl)-6,7-bis(2-methoxyethoxy)quinazoline(QJJ-27)的合成
化合物QJJ-27的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-苄基哌嗪(0.12g,0.64mmol)替换化合物1a，得油状化合物QJJ-27(产率62％)(图4)。
ESI-MS:[M+H] +m/z 453.5。 1H 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)。 13C 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 25H 32N 4O 4 453.2496。
实施例50：化合物4-(4-(3-chlorobenzyl)piperazin-1-yl)-6,7-bis(2-methoxyethoxy)quinazoline(QJJ-28)的合成
化合物QJJ-28的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(3-氯苄基)哌嗪(0.12g,0.64mmol)替换化合物1a，得油状化合物QJJ-28(产率65％)(图4)。
ESI-MS:[M+H] +m/z 487.3。 1H 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)。 13C 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 25H 31ClN 4O 4 487.2107。
实施例51：苯基哌嗪喹唑啉类化合物抗癌细胞增殖活性实验
本实施例选用的细胞为***Hela细胞系，人肺腺癌H1299细胞系，人肺腺癌A549细胞系(上海中国科学院细胞库)，采用含1％(w/v)双抗(青霉素和链霉素)、10％(v/v)FBS(胎牛血清)血清的RPMI 1640培养基(Gibco)进行细胞培养，采用MTT法来检测细胞增殖及凋亡。试验方法简述如下：
(1)实验样品：化合物QJJ-1～QJJ-28及阳性对照厄洛替尼(Erlotinib)。
(2)配药：将上述化合物的浓溶液(母液浓度为200mmol/L)分别用培养基稀释到所需的一系列浓度，用于化合物对各肿瘤细胞的IC 50(半数抑制浓度)的测定。
(3)种板：取对数生长期的所需细胞，以5×10 3/孔的密度种植在96孔板中，每孔100μL，边缘孔用100μL无菌PBS填充，将细胞放入37℃，5％CO 2的恒温培养箱中培养过夜。
(4)加药：24h后，将96孔板中的原培养基小心吸掉，设置空白对照组和加药组。空白组加入不含药培养基100μL，实验组加入含药培养基100μL，每个浓度设置6个复孔，置于37℃，5％CO 2的恒温培养箱中继续培养72h。
(5)加入MTT：作用72h后每孔再加入15μL MTT溶液(0.5％)，恒温培养箱继续作用4h。
(6)DMSO溶解：4h后，将上清液吸干，小心不要破坏底部细胞，每孔加入150μL DMSO(二甲基亚砜)振摇10min，以使甲瓒充分溶解。
(7)IC 50的测定：用多功能酶标仪在570nm波长处测定吸光值，计算细胞生长抑制率(％)：生长抑制率＝1－药物组A570nm值/对照组A570nm值；绘制曲线，计算IC 50。
化合物QJJ-1～QJJ-28及厄洛替尼对三种癌细胞株的IC 50值测定结果如表1所示。结果显示，本发明制备的苯基哌嗪喹唑啉类化合物QJJ-1～QJJ-28均对所考察的三种肿瘤细胞的生长有不同程度的抑制作用，一些化合物如QJJ-12、QJJ-18、QJJ-28显示出较好的体外抗癌活性。
表1化合物QJJ-1～QJJ-28及厄洛替尼对三种癌细胞的IC 50值
Figure PCTCN2020103753-appb-000005
Figure PCTCN2020103753-appb-000006
实施例52：EGFR野生型(EGFR wt)以及EGFR T790M/L858R双突变型激酶抑制实验
(1)实验样品：QJJ-12、QJJ-18、QJJ-28，阳性对照厄洛替尼(Erlotinib)。
(2)实验试剂盒：采用美国promega公司的ADP-Glo TM Kinase Assay试剂盒，该ADP-Glo TM Kinase Assay是发光法检测试剂盒，用于检测激酶反应中所形成的ADP(二磷酸腺苷)；ADP被转化成ATP(三磷酸腺苷)，然后ATP再被萤光素酶转化成光，发光信号与激酶活性正相关。按照试剂盒说明使用试剂盒中相应的组分准备反应组分，并进行相应的实验操作，测定待测化合物对激酶活性的影响。
(3)准备反应组分：
①取38.8μL超纯水，160μL 5×Reaction Buffer A，0.4μL DTT(100mM)和0.8μL MnCl 2(2.5mM)，在1.5ml离心管中配制成200μL的4×Reaction Buffer A+DTT+MnCl 2，震荡混匀。
②取79.6μL超纯水，0.4μL 10mM ΜLtra-Pure ATP，在1.5ml离心管中配制80μL的50uM ATP，震荡混匀。
③取62.5μL 4×Reaction Buffer A+DTT+MnCl 2，62.5μL 50uM ATP，125μL Poly(Glu：Tyr＝4：1，w/w)peptide(1mg/ml)，在1.5ml离心管中配制250μL的2.5×ATP/Substrate Mix，震荡混匀。
④取146μL超纯水，50μL 4×Reaction Buffer A+DTT+MnCl 2，4μL EGFR激酶(100ng/μL；Promega Corporation)，在1.5ml离心管中配制200μL的EGFR激酶溶液，吹打混匀。
⑤取105μL超纯水，37.5μL 4×Reaction Buffer A+DTT+MnCl 2，7.5μL EGFR T790M/L858R激酶(100ng/μL；Promega Corporation)，在1.5ml离心管中配制150μL的EGFR激酶溶液，吹打混匀。
⑥取15μL超纯水，5μL 4×Reaction Buffer A+DTT+MnCl 2，在1.5ml离心管中配制20μL的1×Reaction Buffer用作无激酶的对照，震荡混匀。
(4)将化合物进行梯度稀释：取299.5μL超纯水，80μL 5×Reaction Buffer A，0.2μL DTT(100mM)，0.3μL MnCl 2(2.5mM)和20μL DMSO，在1.5ml离心管中配制400μL的1×Reaction Buffer+5％DMSO，震荡混匀。将10μL上述液体加入下面384孔板的A2～A24：A1孔不加。取14μL超纯水，5μL 4×Reaction Buffer A+DTT+MnCl 2和1μL化合物(DMSO溶解至1mM)，在1.5ml离心管中，配制20μL的50μM抑制剂(5％DMSO)。震荡混匀，转移到A1孔(在激酶反应体系中的终浓度将为10μM，1％DMSO)。从A1孔吸出10μL转移至A2孔，吹打6～10次混匀(注意不要吹出气泡)。依次稀释至A21孔，每孔浓度依次是10000nM,5000nM,2500nM……0.04nM,0.02nM,0.01nM。不要向A22、A23和A24孔转移液体。
(5)激酶反应：将配制好的激酶溶液(步骤(3)④、⑤)每孔2μL加入B1至B23孔，B24孔不加。向无激酶的孔中加入2μL的1×Reaction Buffer(B24孔)。加入1μL梯度稀释的化合物，将反应板放在摇床上600rpm混匀1～2min，室温孵育10min。向所有的反应孔中加入2μL的2.5×ATP/Substrate Mix(来源于ADP-Glo TM Kinase Assay试剂盒)，将反应板放在摇床上600rpm混匀1～2min，室温孵育60min。
(6)ADP-Glo试剂检测生成的ADP：在室温融化ADP-Glo Reagent，向所有的反应孔中加入5μL ADP-Glo Reagent，将反应板放在摇床上600rpm混匀1～2min。室温孵育40min，按试剂盒说明书配制Kinase Detection Reagent，将Kinase Detection Buffer转移到Kinase Detection Substrate瓶中，颠倒数次混匀。向所有的反应孔中加入10μL Kinase Detection Reagent，将反应板放在摇床上600rpm混匀1～2min。室温孵育至少30min，用发光检测仪读取光信号值，分析数据。
结果表明，化合物QJJ-12、QJJ-18和QJJ-28都能抑制野生型EGFR，且QJJ-12与阳性药厄洛替尼无甚差异，QJJ-12和QJJ-28对EGFR T790M/L858R双突变型激酶抑制活性优于厄洛替尼。
表2待测化合物对EGFR野生型激酶及EGFR T790M/L858R双突变型激酶活性的影响
Figure PCTCN2020103753-appb-000007
实施例53：细胞划痕试验
本项实验采用HUVEC人脐静脉内皮细胞(上海中乔新舟生物科技有限公司)作为研究对象。先用马克笔在6孔板背后，用直尺比着，均匀得划横线，大约每隔0.5cm至1cm一道，横穿过孔，每孔至少穿过3条线。每孔中加入约5×10 5个细胞，将细胞放入37℃，5％CO 2的恒温培养箱中培养。24h后细胞铺满90％，用枪头比着直尺，尽量垂直于背后的横线划痕，枪头要垂直，不能倾斜。用PBS洗细胞3次，去除划下的细胞，空白组加入无血清培养基2mL，实验组加入QJJ-28(10ummol/L)无血清培养基2mL，放入37℃，5％CO 2的恒温培养箱中培养。于0，6，12和24小时观察拍照，记录划痕宽度并计算每孔平均值，最后计算各时间点的平均划痕愈合率％，重复3次。
结果显示，6小时空白组愈合率为19％，加药组为11％；12小时空白组愈合率为23％，加药组为12％；24小时空白组愈合率为35％，加药组为13％。可以看出，化合物QJJ-28能抑制HUVEC细胞水平迁移能力，细胞迁移速度受到了明显的抑制(图5)。
实施例54：整合素αvβ3受体结合试验
采用竞争抑制实验测定化合物QJJ-12、QJJ-28与HUVEC细胞上整合素αvβ3受体的结合情况。取对数生长期的HUVEC细胞，以5×10 5/孔的密度种植在6孔板中，培养过夜。阴性对照组直接加入含血清不含药物的培养基，实验组分别加入终浓度为0、10、20、40μmol/L的含QJJ-12、QJJ-28以及40μmmol/L的含厄洛替尼的血清培养基。作用24h后，阴性对照组加入FITC标记小鼠IgG-1(2μL/mL细胞悬液，Millipore)，实验组加入FITC-αvβ3(LM609)(2μL/mL细胞悬液，Millipore)。避光孵育1h后，上流式细胞仪检测，激发波长和发射波长分别为488和525nm，计算10000个细胞的阳性细胞率。实验重复3次。
流式细胞仪检测结果显示，随着化合物QJJ-12和QJJ-28浓度的降低，阳性细胞率逐渐升高，表明化合物QJJ-12和QJJ-28能够与αvβ3抗体竞争结合HUVEC细胞表面的整合素αvβ3受体(图6、7)。
实施例55：体内抗肿瘤活性研究
(1)取对数生长期A549细胞无菌操作下吸出所有培养基，并用PBS反复对细胞进行三次洗涤，为避免细 胞脱落洗涤时尽量轻柔，以去除残余培养基中的蛋白成分，以0.25％胰酶对A549细胞进行消化成细胞悬液，然后将所有消化后的细胞放入离心管离心(1000r/min)，离心后用基质胶溶解，溶液比例为：基质胶：PBS＝1:1，v/v，100μL双抗/2ml，经计数后调整浓度为1.0×10 7细胞/毫升。每只裸鼠腋下皮下注射瘤液0.2毫升，即每鼠种植瘤细胞约为2.0×10 6细胞建立异体移植肿瘤模型。所有裸鼠在无特定病原体(SPF)条件下的层流架中饲养。经无菌处理的水和饲料供动物自由摄入，高温消毒的饲料，垫料每三天更换一次，笼具及饮水瓶每三天紫外线消毒一次，饮用无菌蒸馏水，更换饲养用品时严格遵循无菌原则操作。每日观察裸鼠精神、呼吸、运动以及肿瘤的生长情况。
待肿瘤生长至约100～200mm 3后按照下列分组情况随机分组。将25只接种A549肿瘤细胞成功的裸鼠随机分为5组，每组5只，即：
①PBS对照组；
②QJJ-12组(0.034mmol/kg；QJJ-12L)；
③QJJ-12组(0.102mmol/kg；QJJ-12M)；
④QJJ-12组(0.306mmol/kg；QJJ-12H)；
⑤吉非替尼组(Gefitinib，0.102mmol/kg)。
(2)各组接种后于第3、6、9、12、15、18天(间隔3～4天)分别尾静脉给予相应的化合物或PBS，每日称量小鼠体重，肿瘤体积，同时观察小鼠的生长状态，于接种21天后，将小鼠拉断颈椎处死，剥离瘤体，取各组织器官(包括脑，心，肝，脾，肺，肾)，称瘤重，计算瘤重抑制率。将各组的抗肿瘤活性进行比较，评价化合物QJJ-12体内抗肿瘤作用。
①日常观察：接种肿瘤细胞和给药后，观察裸鼠的精神状态，饮食饮水等一般状况及死亡情况；详细观察记录移植部位有无感染，肿瘤或肿块出现的时间。
②裸鼠体重：每3日称量每只裸鼠的体重，记录好数据并绘制每组裸鼠体重变化曲线。
③肿瘤测量：每3日用精密游标卡尺测量移植瘤大小，按以下公式计算肿瘤体积(tumor volume,TV)，计算公式为:TV＝0.5×a×b 2(其中a、b分别表示长、宽)。根据公式计算肿瘤体积并绘制生长曲线。实验结束时称瘤质量，计算各组的抑瘤率％。
给药后裸鼠体重变化曲线如图8所示。从图中可以看出给药后空白组体重明显上升，化合物QJJ-12组在低剂量组(QJJ-12L)的体重略有上升，中剂量组(QJJ-12M)体重变化无显著性差异，高剂量组(QJJ-12H)体重略有下降，而阳性药吉非替尼组从第二次给药开始体重下降明显。对比整个实验各组给药前后裸鼠体重的变化如图9所示。从图中可以看出给药前后空白组和化合物QJJ-12组在低剂量组体重上升明显，中剂量组和高剂量组体重略有下降，体重变化无显著性差异，而阳性药吉非替尼组体重下降明显。根据裸鼠体重测量结果，可知在实验选取的浓度范围内，化合物QJJ-12对实验裸鼠体重无显著性影响，而阳性药吉非替尼组使实验裸鼠体重显著下降。
给药结束后，解剖得到各组裸鼠肿瘤组织，如图10所示。在整个给药实验过程中，肿瘤体积生长曲线结果如图11所示，空白组肿瘤体积增长最快，QJJ-12低剂量组和中剂量组对肿瘤的增长抑制作用较弱，而高剂量组和阳性药吉非替尼组均能显著性抑制肿瘤体积的增长。
实验各组裸鼠的肿瘤生长抑制率结果如图12所示，可知QJJ-12低剂量组和中剂量组抑制率分别为25.15％、31.07％，而高剂量组和阳性药吉非替尼组抑制率均高于40％，分别为57.55％、52.46％，显示出良好的肿瘤生长抑制作用。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐，其特征在于，具体如下通式(I)、(II)、(III)的结构：
    Figure PCTCN2020103753-appb-100001
    其中，R为取代或未取代、有杂原子或无杂原子的直链、支链或环状的多至10个碳原子的烃基碳链，取代或未取代的单环芳基、杂芳基；
    所述的取代或未取代的单环芳基、杂芳基为苯基、对甲基苯基、对硝基苯基、对氟苯基、对溴苯基、邻甲氧基苯基、苯磺酰基、对甲基苯磺酰基、对甲氧基苯磺酰基、间硝基苯磺酰基、苄基或间氯苄基。
  2. 根据权利要求1所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐，其特征在于，所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐选自如下化合物之一：
    Figure PCTCN2020103753-appb-100002
    Figure PCTCN2020103753-appb-100003
  3. 权利要求1或2所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法，其特征在于：包括以下步骤：
    以吗啉为起始原料，将其与1-溴-3-氯丙烷溶于甲苯中，发生取代反应得到4-(3-氯丙基)吗啉；在甲酸和甲酸钠的环境中，以异香兰素(3-羟基-4-甲氧基苯甲醛)为原料，通过与盐酸羟胺反应制备中间体化合物3-羟基-4-甲氧基苯甲腈；然后4-(3-氯丙基)吗啉和3-羟基-4-甲氧基苯甲腈之间发生醚化反应生成4-甲氧基-3-(3-吗啉丙氧基)苯甲腈；接着进行硝化，得到硝基化的化合物；再使用三氯化铟作为催化剂，在微波反应仪中环化得到喹唑啉酮化合物，最后与草酰氯反应得到氯代喹唑啉化合物；氯代喹唑啉化合物分别与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物进行反应，得到化合物QJJ-1～QJJ-12；
    以三甘醇为起始原料，将其与对甲苯磺酰氯溶于四氢呋喃中，发生取代反应得对甲基苯磺酰取代羟基 的三甘醇；在甲酸和甲酸钠环境中，以3,4-二羟基苯甲醛为原料，通过与盐酸羟胺反应制备3,4-二羟基苯甲腈；将对甲基苯磺酰取代羟基的三甘醇和3,4-二羟基苯甲腈溶解在四氢呋喃中，然后用氢氧化钠和氢氧化锂环化，得到冠醚苯甲腈；随后进行硝化反应，得到硝基化合物，接着使用三氯化铟作为催化剂，在微波反应仪中反应得到喹唑啉酮类化合物，再使用草酰氯作为氯化剂，氯仿作为溶剂，得到中间体氯代喹唑啉化合物；最后将氯代喹唑啉化合物与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物反应，得到化合物QJJ-13～QJJ-18；
    以乙二醇单甲醚为起始原料，将其与对甲基苯磺酰氯在四氢呋喃中发生亲核取代反应得到2-甲氧基乙基-4-甲基苯磺酸酯；2-甲氧基乙基-4-甲基苯磺酸酯与3,4-二羟基苯甲醛在乙腈中，氮气保护下发生取代生成3,4-二-(2-甲氧乙氧基)苯甲醛；3,4-二-(2-甲氧乙氧基)苯甲醛的醛基经盐酸羟胺还原得到3,4-二-(2-甲氧乙氧基)苯甲腈；3,4-二-(2-甲氧乙氧基)苯甲腈低温下与浓硝酸反应，硝化得到4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈；4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈经过在甲酰胺中，与三氯化铟微波环合(Niementowski环合)得到6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮；6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮经草酰氯氯代后得到4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉；4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉分别与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物反应，得到化合物QJJ-19～QJJ-28。
  4. 根据权利要求3所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法，其特征在于：包括以下步骤：
    (1)将吗啉与1-溴-3-氯丙烷溶于甲苯中，加热至65～85℃回流反应2.5～6.5h，待反应结束后冷却至室温，过滤并用HCl溶液萃取去除甲苯，调pH至强碱性，油水层分离，再用***萃取，蒸去***，得到4-(3-氯丙基)吗啉；将异香兰素(3-羟基-4-甲氧基苯甲醛)、盐酸羟胺、甲酸和甲酸钠混合均匀，加热至100℃回流反应5～7.5h，待反应结束后加入饱和食盐水，过滤，水洗，干燥，得到中间体化合物3-羟基-4-甲氧基苯甲腈；将4-(3-氯丙基)吗啉、3-羟基-4-甲氧基苯甲腈、碳酸钾、碘化钾和乙腈混合均匀，加热至75～85℃回流反应3～7h，得到4-甲氧基-3-(3-吗啉丙氧基)苯甲腈；将4-甲氧基-3-(3-吗啉丙氧基)苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中，保持0℃反应2～5h，然后加热至40～50℃回流3～6h，待反应结束后加入冰水洗涤，析出固体，过滤，正己烷洗涤，干燥，得到硝基化的化合物7a；将硝基化的化合物7a溶解到甲酰胺中，然后加入三氯化铟作为催化剂，在100～120℃，400W条件下微波反应40～70分钟，用二氯甲烷萃取，无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到喹唑啉酮化合物8a；将喹唑啉酮化合物8a和N，N-二甲基甲酰胺加入到氯仿中，然后加入草酰氯，加热至60～70℃反应1.5～3小时后，再加入饱和碳酸氢钠溶液直至观察到pH为10.0；乙酸乙酯萃取，有机层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到氯代喹唑啉化合物9a；将氯代喹唑啉化合物和取代物9a加入到N,N-二甲基甲酰胺中，加入三乙胺作为催化剂，在100～130℃，100W条件下微波反应15～30分钟，再加入饱和盐水，乙酸乙酯萃取，乙酸乙酯层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到化合物QJJ-1～QJJ-12；其中，取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物；
    (2)将三甘醇、四氢呋喃、氢氧化钠和水混合均匀，然后在冰浴下加入四氢呋喃溶解的对甲基苯磺酰氯，在冰浴下继续反应2.5～4h，结束后蒸出四氢呋喃，冷却，抽滤，并依次用甲醇、乙醇和冰水洗涤，得到对甲基苯磺酰取代羟基的三甘醇；将3,4-二羟基苯甲醛、盐酸羟胺、甲酸钠和甲酸混合均匀，加热至100℃回流反应5～7.5h，结束后加入饱和食盐水，过滤，水洗，干燥，得到3,4-二羟基苯甲腈；将3,4-二羟基苯甲腈、四氢呋喃、氢氧化钠、氢氧化锂和水混合均匀，在氮气保护下，60～75℃反应1h，然后加入四氢呋喃溶解的对甲基苯磺酰取代羟基的三甘醇，继续反应60～80h，反应完毕后，蒸出四氢呋喃，残留部分用二氯甲烷萃取，蒸干溶剂，得到冠醚苯甲腈；将冠醚苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中，保持0℃反应2～5h，然后加热至40～50℃回流3～6h，待反应结束后加入冰水洗涤，析出固体，过滤，正己烷洗涤，干燥，得到硝基化的化合物7c；将硝基化的化合物7c溶解到甲酰胺中，然后加入三氯化铟作为催化剂，在100～120℃，400W条件下微波反应40～70分钟，用二氯甲烷萃取，无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到喹唑啉酮类化合物8c；将喹唑啉酮类化合物8c和N，N-二甲基甲酰胺加入到氯仿中，然后加入草酰氯，加热至60～70℃反应1.5～3小时后，再加入饱和碳酸氢钠溶液直至观察到pH为10.0；乙酸乙酯萃取，有机层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到中间体氯代喹唑啉化合物9c；将氯代喹唑啉化合物9c和取代物加入到N,N-二甲基甲酰胺中，加入三乙胺作为催化剂，在100～130℃，100W条件下微波反应15～30分钟，再加入饱和盐水，乙酸乙酯萃取，乙酸乙酯层用无水 Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到化合物QJJ-13～QJJ-18；其中，取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物；
    (3)将乙二醇单甲醚加入到四氢呋喃和水的混合液中，冰浴处理1～3小时后，加入THF溶解的对甲基苯磺酰氯，继续冰浴3～6小时，然后旋干THF，饱和食盐水水洗，二氯甲烷萃取，有机层加入无水Na 2SO 4干燥，减压浓缩，硅胶柱层析分离，真空干燥，得到2-甲氧基乙基-4-甲基苯磺酸酯；；将2-甲氧基乙基-4-甲基苯磺酸酯、3,4-二羟基苯甲醛、乙腈和碳酸钾混合均匀，抽真空，N 2保护，70～85℃反应30～45h，抽滤，取滤液，旋干乙腈，用饱和食盐水水洗，乙酸乙酯萃取，有机层加入无水Na 2SO 4干燥，减压浓缩，硅胶柱层析分离，得到3,4-二-(2-甲氧乙氧基)苯甲醛；将甲酸钠和3,4-二-(2-甲氧乙氧基)苯甲醛加入到甲酸中，加热至75～85℃后加入盐酸羟胺，反应4～7h后，冷至至室温，加入冷的饱和食盐水析出固体，过滤，乙酸乙酯重结晶，干燥3,4-二-(2-甲氧乙氧基)苯甲腈；将3,4-二-(2-甲氧乙氧基)苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中，保持0℃反应2～5h，然后加热至40～50℃回流3～6h，待反应结束后加入冰水洗涤，析出固体，过滤，正己烷洗涤，干燥，得到4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈；将4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈溶解到甲酰胺中，然后加入三氯化铟(Niementowski环合)作为催化剂，在100～120℃，400W条件下微波反应40～70分钟，反应结束后过滤，滤液用饱和食盐水水洗，乙酸乙酯萃取，有机层减压浓缩，再用乙酸乙酯重结晶，得到6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮；将6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮溶于氯仿，加入N,N-二甲基甲酰胺，滴加草酰氯，60～70℃回流1.5～3h，用饱和碳酸氢钠水溶液洗涤，乙酸乙酯萃取，有机层加入无水Na 2SO 4干燥，减压浓缩，硅胶柱层析分离，真空干燥，得到4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉；将4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉和取代物加入到N,N-二甲基甲酰胺中，加入三乙胺作为催化剂，在100～130℃，300W条件下微波反应15～30分钟，再加入饱和盐水，乙酸乙酯萃取，乙酸乙酯层用无水Na 2SO 4干燥，过滤并浓缩，硅胶柱分离，得到化合物QJJ-19～QJJ-28；其中，取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物。
  5. 根据权利要求3所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法，其特征在于：
    步骤(1)、(2)和(3)中所述的取代苯磺酰哌嗪为苯磺酰哌嗪、对甲基苯磺酰哌嗪、对甲氧基苯磺酰哌嗪、或间硝基苯磺酰哌嗪；
    步骤(1)、(2)和(3)中所述的取代苯基哌嗪为苯基哌嗪、对甲基苯基哌嗪、对硝基苯基哌嗪、对氟苯基哌嗪、对溴苯基哌嗪、或邻甲氧基苯基哌嗪；
    步骤(1)、(2)和(3)中所述的取代苄基哌嗪化合物为苄基哌嗪或间氯苄基哌嗪。
  6. 权利要求1或2所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用。
  7. 根据权利要求6所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用，其特征在于：
    所述的肿瘤为非小细胞肺癌、乳腺癌、***、脑瘤、胰腺癌、肝癌、结肠直肠癌、甲状腺髓样癌、神经胶质瘤、成神经细胞瘤、肾脏肿瘤、肺癌、胰腺癌、星细胞瘤、膀胱癌、卵巢癌、头颈癌、子***、胸腺癌、胃癌，卵巢癌，或***癌。
  8. 根据权利要求7所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用，其特征在于：
    所述的肿瘤为非小细胞肺癌、肺腺癌或***。
  9. 权利要求1或2所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抑制激酶的药物、抑制整合素受体的药物、或抑制HUVEC细胞迁移的药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于：所述的激酶为EGFR激酶或EGFR T790M/L858R双突变型激酶；所述整合素受体为整合素αvβ3受体。
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