WO2023226323A1 - 一种喹唑啉衍生物及其制备方法和应用 - Google Patents
一种喹唑啉衍生物及其制备方法和应用 Download PDFInfo
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- WO2023226323A1 WO2023226323A1 PCT/CN2022/131932 CN2022131932W WO2023226323A1 WO 2023226323 A1 WO2023226323 A1 WO 2023226323A1 CN 2022131932 W CN2022131932 W CN 2022131932W WO 2023226323 A1 WO2023226323 A1 WO 2023226323A1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions
- the present invention relates to the technical field of chemical drugs, and in particular to a quinazoline derivative and its preparation method and application.
- Angiogenesis refers to the process of degrading the vascular matrix and basement membrane under the action of angiogenesis-related factors, promoting the proliferation and migration of endothelial cells, and causing the rearrangement of new endothelial cells, thereby forming a vascular network.
- Abnormal angiogenesis is often found in tumors, and hypoxia is the main factor that triggers abnormal tumor angiogenesis.
- hypoxia is the main factor that triggers abnormal tumor angiogenesis.
- hypoxia-inducible factor (PHD) decreases, which in turn blocks the degradation of its substrate hypoxia-inducible factor (HIF)-1 ⁇ .
- HIF-1 ⁇ translocates into the nucleus and interacts with its heterodimer.
- HIF-1 ⁇ binds to generate active HIF-1, and together with the hypoxia response element (HRE), promotes the expression of pro-angiogenic factors such as vascular endothelial growth factor A (VEGFA) and other genes, triggering endothelial cell proliferation. Promote angiogenesis within tumors. Therefore, VEGF is a key signaling molecule regulating angiogenesis.
- HRE hypoxia response element
- Vascular endothelial growth factor receptor is a typical tyrosine kinase receptor (RTK), with three main subtypes, including VEGFR1, VEGFR2 and VEGFR3.
- RTK tyrosine kinase receptor
- VEGFR inhibitors compete with adenine nucleoside triphosphate (ATP) to occupy the ATP binding pocket in the catalytic domain, thereby inhibiting signal transmission after the combination of VEGF and VEGFR, inhibiting tumor angiogenesis, and inhibiting tumor proliferation.
- ATP adenine nucleoside triphosphate
- VEGFR is weakly expressed in healthy tissues or cells, but highly expressed in colon cancer, breast cancer, cervical cancer, ovarian cancer, esophageal cancer, clear cell renal cell carcinoma, non-small cell lung cancer, and pancreatic cancer. Therefore, the development of VEGFR inhibitors can effectively inhibit the formation of tumor blood vessels and thus play an anti-tumor role. It is also targeted to tumors and has less impact on healthy tissues.
- the object of the present invention is to provide a quinazoline derivative and its preparation method and application.
- the quinazoline derivative can inhibit the high expression of VEGFR.
- the invention provides a quinazoline derivative having the structure shown in Formula I:
- n is a positive integer from 1 to 10;
- R is alkyl, substituted phenyl, unsubstituted phenyl, substituted heterocyclyl or unsubstituted heterocyclyl;
- X is halogen
- the substituent group in the substituted phenyl group is halogen, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, or aromatic group; the substituent group in the substituted phenyl group is The number is 1 or 2;
- the heteroatom in the heterocyclyl is one or more of N, O and S;
- the substituent group in the substituted heterocyclic group is an alkyl group
- X is F or Cl.
- the quinazoline derivative is:
- the present invention also provides a method for preparing the quinazoline derivative described in the above technical solution, which includes the following steps:
- R is an alkyl group, a substituted phenyl group, an unsubstituted phenyl group, a substituted heterocyclic group or an unsubstituted heterocyclic group.
- the preparation method of the compound having the structure shown in Formula VIII includes the following steps:
- R is alkyl, substituted phenyl, unsubstituted phenyl, substituted heterocyclyl or unsubstituted heterocyclyl.
- the temperature of the second condensation reaction is 60-80°C and the time is 4-6 hours.
- the present invention also provides the solvates and soluble salts of the quinazoline derivatives described in the above technical solutions or the quinazoline derivatives prepared by the preparation methods described in the above technical solutions.
- the present invention also provides the use of the quinazoline derivative described in the above technical solution or the solvate and its soluble salt of the quinazoline derivative described in the above technical solution in the preparation of drugs for treating and/or preventing cancer.
- the cancer is a malignant tumor with high VEGFR expression.
- the cancer is colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, bladder cancer, renal cancer or neuroblastoma cancer.
- the invention provides a quinazoline derivative having the structure shown in Formula I:
- n is a positive integer from 1 to 10;
- R is alkyl, substituted phenyl, unsubstituted phenyl, substituted heterocyclyl or unsubstituted heterocyclyl;
- X is halogen
- the quinazoline derivatives of the present invention have a quinazoline core similar to the adenosine structure of ATP.
- the introduction of structurally optimized heterocyclic substituents and aliphatic chain substituents at both ends of the core can further improve its effect on VEGFR targets. Point selectivity and inhibition.
- the kinase inhibitory activity of the quinazoline derivatives of the present invention on VEGFR1, VEGFR2 and VEGFR3 can reach low nanomolar concentrations, can inhibit the activity of VEGFR in a dose-dependent manner, and has been verified through in vivo anti-tumor experiments, showing effective inhibit the growth of colon cancer.
- the invention provides a quinazoline derivative having the structure shown in Formula I:
- n is a positive integer from 1 to 10;
- R is alkyl, substituted phenyl, unsubstituted phenyl, substituted heterocyclyl or unsubstituted heterocyclyl;
- X is halogen
- the substituent group in the substituted phenyl group is preferably halogen, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, or aromatic group; the substituted group in the substituted phenyl group is preferably The number of groups is 1 or 2;
- the heteroatom in the heterocyclic group of the substituted heterocyclyl or unsubstituted heterocyclyl is preferably one or more of N, O and S;
- the substituent group in the substituted heterocyclic group is preferably an alkyl group
- X is preferably F or Cl.
- the quinazoline derivative is preferably:
- the present invention also provides a method for preparing the quinazoline derivative described in the above technical solution, which includes the following steps:
- R is an alkyl group, a substituted phenyl group, an unsubstituted phenyl group, a substituted heterocyclic group or an unsubstituted heterocyclic group.
- the preparation method of the compound having the structure shown in Formula VIII preferably includes the following steps:
- R is alkyl, substituted phenyl, unsubstituted phenyl, substituted heterocyclyl or unsubstituted heterocyclyl.
- the preparation process of quinazoline derivatives with the structure shown in the formula I from the compound with the structure shown in the formula II is preferably as follows:
- a compound having a structure represented by formula II, a compound having a structure represented by formula III, pyridine and a first organic solvent are mixed to perform an amidation reaction of the compound having a structure represented by formula IV.
- the molar ratio of the compound having the structure represented by formula II, the compound having the structure represented by formula III and pyridine is preferably 1: (1.1-1.2): 3, more preferably, and most preferably 1: 1.2:3.
- the pyridine functions as a catalyst to promote the reaction and ensure that no other side reactions occur.
- the present invention does not have any special restrictions on the type and dosage of the first organic solvent.
- the type and dosage well known to those skilled in the art are adopted and ensured that compounds having the structure shown in Formula II and compounds having the structure shown in Formula III can be used. It can be fully dissolved with pyridine and amidation reaction can occur.
- the first organic solvent is N,N-dimethylformamide.
- the mixing preferably involves first mixing the compound having the structure represented by Formula II with the first organic solvent, then adding pyridine dropwise under conditions of ice bath and stirring, and then adding dropwise the compound having the structure represented by Formula III. compound of.
- the present invention does not have any special limitations on the stirring and dropping process, and it can be carried out by using processes well known to those skilled in the art.
- the amidation reaction is preferably carried out under ice bath conditions, and the amidation reaction time is preferably 0.8 to 1.5 h, more preferably 0.9 to 1.2 h, and most preferably 1 h.
- the present invention mixes the compound with the structure shown in Formula IV, R-NH 2 , N,N-diisopropylethylamine and the second organic solvent, and performs a reflux reaction.
- a compound having the structure shown in formula V is obtained.
- the molar ratio of the compound having the structure shown in Formula IV, R-NH 2 and N,N-diisopropylethylamine is preferably 1: (2 ⁇ 2.5): (3 ⁇ 4), More preferably, it is 1:2:3.
- the N,N-diisopropylethylamine is an organic base, which promotes the substitution reaction.
- the present invention does not have any special restrictions on the type and dosage of the second organic solvent.
- the type and dosage well known to those skilled in the art are adopted and ensure that the compound having the structure shown in Formula IV, R-NH 2 , N, N -Diisopropylethylamine can be fully dissolved and reflux reaction can occur.
- the second organic solvent is acetonitrile.
- the mixing preferably involves mixing the compound having the structure represented by Formula IV, R-NH 2 and the second organic solvent, and then adding N,N-diisopropylethylamine dropwise to the resulting solution.
- the temperature of the reflux reaction is preferably 55-75°C, more preferably 60-70°C, and most preferably 60°C; the time is preferably 1.8-3h, more preferably 1.9-2.5h, and most preferably 2h.
- the present invention mixes the compound with the structure represented by formula V, the compound with the structure represented by formula VI and the third organic solvent, and performs the second condensation reaction under alkaline conditions. , to obtain a compound with the structure shown in formula VII.
- the molar ratio of the compound having the structure represented by Formula V and the compound having the structure represented by Formula VI is preferably (1.2-1.5):1, more preferably 1.2:1.
- the alkaline condition is preferably achieved by adding potassium carbonate; the molar ratio of the compound having the structure shown in Formula V and potassium carbonate is preferably 1: (2.45-2.5), more preferably 2.21:5.52.
- the present invention does not have any special restrictions on the type and dosage of the third organic solvent.
- the type and dosage well known to those skilled in the art are adopted and ensured that the compound having the structure shown in Formula V and the compound having the structure shown in Formula VI can be used. It only needs to be fully dissolved and able to ensure that the condensation reaction occurs under alkaline conditions.
- the third organic solvent is N,N-dimethylformamide.
- the temperature of the second condensation reaction is preferably 60 to 80°C, more preferably 60 to 70°C, and most preferably 60°C; the time is preferably 5 to 7 hours, more preferably 6 to 7 hours, and most preferably is 6h.
- the present invention also preferably includes post-processing the obtained product system.
- the present invention mixes the compound having the structure represented by Formula VII, the palladium carbon catalyst and the fourth organic solvent, and then passes hydrogen gas to perform a deprotection reaction to obtain the compound having the structure represented by Formula VIII. compound showing the structure.
- the mass percentage of the palladium-carbon catalyst in the compound having the structure represented by Formula VII is preferably 10%.
- the present invention does not have any special restrictions on the type and dosage of the fourth organic solvent.
- the type and dosage well known to those skilled in the art are used to ensure that the compound having the structure shown in Formula VII and the palladium-carbon catalyst can be fully dissolved and It is enough to ensure that the deprotection reaction occurs.
- the fourth organic solvent is N,N-dimethylacetamide.
- the present invention does not have any special limitations on the mixing process, and it can be carried out using processes well known to those skilled in the art.
- the present invention preferably uses argon gas and hydrogen gas to replace the reaction environment gas in sequence.
- the number of replacements of argon gas is preferably 3 times; the number of replacements of hydrogen gas is preferably 3 times.
- the present invention does not have any special limitations on the process of introducing hydrogen gas, and it can be carried out by using processes well known to those skilled in the art.
- the temperature of the deprotection reaction is preferably room temperature; the time is preferably 2 to 3 hours, more preferably 2 to 2.5 hours, and most preferably 2 hours.
- the present invention also preferably includes post-processing the obtained product system.
- the present invention mixes the compound with the structure represented by formula VIII, potassium carbonate, the compound with the structure represented by formula IX and the fifth organic solvent, and performs the first condensation reaction to obtain The quinazoline derivatives.
- the molar ratio of the compound having the structure represented by formula VIII, potassium carbonate and the compound having the structure represented by formula IX is preferably (0.72 ⁇ 0.75):1.45:(0.798 ⁇ 0.89), more preferably 0.725 :1.45: (0.798 ⁇ 0.89), most preferably 0.725:1.45:0.798.
- the present invention does not have any special restrictions on the type and dosage of the fifth organic solvent.
- the type and dosage well known to those skilled in the art are adopted to ensure that the compound having the structure shown in formula VIII, potassium carbonate and formula IX can be used. It is sufficient that the compound of the structure shown is fully dissolved and the deprotection reaction can occur.
- the fifth organic solvent is N,N-dimethylformamide.
- the mixing preferably involves dissolving the compound having the structure represented by Formula VIII and potassium carbonate in the fifth organic solvent, and then injecting the compound having the structure represented by Formula IX into the resulting mixed solution.
- the temperature of the first condensation reaction is preferably 60 to 80°C, more preferably 60 to 70°C, and most preferably 70°C; the time is preferably 6 to 8 hours, more preferably 6 to 7 hours, and most preferably is 6h.
- the present invention also provides the use of the quinazoline derivatives and their solvates and pharmaceutically acceptable salts described in the above technical solution in the preparation of drugs for the treatment and/or prevention of cancer.
- the cancer is preferably a malignant tumor with high VEGFR expression.
- the cancer is preferably colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, bladder cancer, renal cancer or neuroblastic cancer.
- each compound in Examples 1 to 30 was determined by nuclear magnetic resonance (1H-NMR) and/or mass spectrometry (MS); the NMR measurement was carried out with a Bruker Advance (400MHz) nuclear magnetic resonance instrument, and the measurement solvent was deuterated chloroform. (CDCl 3 ), deuterated dimethyl sulfoxide (DMSO-d 6 ), and TMS as the internal standard; Waters UPLC-Mass Spectrometer was used for MS measurement. Column chromatography uses 200-300 mesh silica gel from Qingdao Ocean Chemical Plant;
- Compound 7b 1-(2-chloro-4-((7-hydroxy-6-methoxyquinazolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)urea (white solid, 58%);
- Compound 14a 1-(2-fluoro-4-((7-hydroxy-6-methoxyquinazolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)urea (white solid, 62%);
- Compound 12b 1-(2-fluoro-4-hydroxyphenyl)-3-phenylurea (white solid, 75%);
- Compound 13b 1-(4-((7-(benzyloxy)-6-methoxyquinazolin-4-yl)oxy)-2-fluorophenyl)-3-phenylurea (pink white solid, 74%);
- the HTRF KinEASE-TKkit method was used to measure VEGFR kinase activity: (1) Prepare 1X kinase reaction buffer: 1 times the volume of 5X kinase reaction buffer and 4 times the volume of water; 5mM MgCl 2 ; 1mM DTT; (2) 1mM MnCl 2 was used to perform a 3-fold gradient dilution of the compound with DMSO in the dilution plate, and the final starting concentration of the compound was 1 ⁇ M; (3) Dilute the compound in step (2) 40 times into 1X kinase reaction buffer on a shaker Shake for 20 minutes; (4) Use 1X enzyme reaction buffer to prepare 2X kinase, add 2 ⁇ L of kinase to each well of the reaction plate; (5) Add 1 ⁇ L of the compound diluted in the buffer to each well, and seal with a membrane Seal the plate, centrifuge at 1000g for 30 seconds, and leave it at room temperature for 10 minutes; (6) Use 1X enzyme reaction buffer to prepare 2.5
- the synthesized compounds show strong inhibitory effects on VEGFR1, VEGFR2 and VEGFR3; the inhibitory activity of most compounds on VEGFR1, VEGFR2 and VEGFR3 exceeds that of the positive drug regorafenib.
- the experimental process is as follows: collect tumor cells in good growth status, wash them twice with 1 ⁇ PBS, count the total number of cells with a cell counter, and dilute the cell solution to 1 ⁇ 10 7 cells/mL with 1XPBS.
- the amount of cells inoculated into each mouse was 1 ⁇ 10 6 , and 100 ⁇ L of cell suspension was inoculated into the axilla of the forelimb of the mouse.
- the mice are randomly divided into groups, with 8 mice in each group.
- the drug is administered orally by gavage every two days, 100mg/kg. After the administration, the mice were euthanized, the tumor weight and volume were measured, and the tumor inhibition rate was calculated; the test results are shown in Table 3:
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Abstract
本发明涉及化药技术领域，尤其涉及一种喹唑啉衍生物及其制备方法和应用。本发明提供的喹唑啉衍生物，具有式Ⅰ所示结构，本发明所述喹唑啉衍生物对VEGFR1、VEGFR2和VEGFR3的激酶抑制活性均能够达到低纳摩尔浓度，可以以剂量依赖性抑制VEGFR的活性，并通过体内抗肿瘤实验进行验证，表现出了有效的抑制结指肠癌的生长作用。
Description
本申请要求于2022年05月26日提交中国专利局、申请号为CN202210587104.1、发明名称为“一种喹唑啉衍生物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
本发明涉及化药技术领域，尤其涉及一种喹唑啉衍生物及其制备方法和应用。
血管生成是指在血管生成相关因子的作用下，通过降解血管基质和基底膜，促进内皮细胞增殖和迁移，并引起新的内皮细胞重新排列，进而形成血管网络的过程。在肿瘤中常发现血管生成异常，而缺氧是引发肿瘤血管生成异常的主要因素。在缺氧条件下，脯氨酸羟化酶(PHD)的羟基化活性下降，进而导致其底物缺氧诱导因子(HIF)-1α降解受阻，HIF-1α易位进入细胞核，并与其异二聚体对应物HIF-1β结合，生成活性的HIF-1，并与缺氧反应元件(HRE)一起促进促血管生成因子如血管内皮生长因子A(VEGFA)等基因的表达，引发内皮细胞增殖，促进肿瘤内部血管生成。因此，VEGF是调节血管生成的关键的信号分子。
血管内皮生长因子受体(VEGFR)属于典型的酪氨酸激酶受体(RTK)，主要有三种亚型，包括VEGFR1、VEGFR2和VEGFR3。当VEGF和VEGFR结合后，便会诱导VEGFR形成二聚体，使其胞内域的构像改变，暴露出内腺嘌呤核苷三磷酸的结合位点，进而使VEGFR的酪氨酸残基发生自身磷酸化，并将信号传递到下游，造成肿瘤血管新生，促进肿瘤的发展和迁移。而VEGFR抑制剂会与腺嘌呤核苷三磷酸(ATP)竞争而占据催化域中ATP的结合口袋，从而抑制VEGF和VEGFR结合之后的信号传递，抑制肿瘤血管新生，起到抑制肿瘤增殖的作用。
此外，研究发现VEGFR在健康的组织或细胞中弱表达，而在结肠癌、乳腺癌、宫颈癌、卵巢癌、食道癌、肾透明细胞癌、非小细胞肺癌和胰腺癌等中高表达。因此，开发VEGFR抑制剂可以有效抑制肿瘤血管的生成进而起到抗肿瘤的作用，并且对肿瘤具有靶向性，对健康组织影响较小。
发明内容
本发明的目的在于提供一种喹唑啉衍生物及其制备方法和应用，所述喹唑啉衍生物能够抑制VEGFR高表达。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种喹唑啉衍生物，具有式Ⅰ所示结构：
其中，n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基；
X为卤素。
优选的，所述取代的苯基中的取代基团为卤素、取代或未取代的烷基、取代或未取代的烷氧基、或芳香基；所述取代的苯基中的取代基团的个数为1或2；
所述取代的杂环基或未取代的杂环基中杂环基中的杂原子为N、O和S中的一种或几种；
所述取代的杂环基中的取代基团为烷基；
X为F或Cl。
优选的，所述喹唑啉衍生物为：
本发明还提供了上述技术方案所述喹唑啉衍生物的制备方法，包括以下步骤：
将具有式Ⅷ所示结构的化合物、碳酸钾、具有式Ⅸ所示结构的化合物和第五有机溶剂混合，进行第一缩合反应，得到所述喹唑啉衍生物；
式Ⅷ～式Ⅸ中，X为卤素；n为1～10的正整数；
式Ⅱ～式Ⅶ和R-NH
2中，R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
优选的，所述具有式Ⅷ所示结构的化合物的制备方法，包括以下步骤：
将具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物、吡啶和第一有机溶剂混合，进行酰胺化反应，所述具有式Ⅳ所示结构的化合物；
将具有式Ⅳ所示结构的化合物、R-NH
2、N,N-二异丙基乙胺和第二有机溶剂混合，进行回流反应，得到具有式Ⅴ所示结构的化合物；
将所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物和第三有机溶剂混合，在碱性条件下进行第二缩合反应，得到具有式Ⅶ所示结构的化合物；
将所述具有式Ⅶ所示结构的化合物、钯碳催化剂和第四有机溶剂混合后，通入氢气，进行脱保护反应，得到具有式Ⅷ所示结构的化合物；
式Ⅱ～式Ⅶ中，X为卤素；n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
优选的，所述第二缩合反应的温度为60～80℃，时间为4～6h。
本发明还提供了上述技术方案所述喹唑啉衍生物或上述技术方案所述的制备方法制备得到的喹唑啉衍生物的溶剂合物及其可溶性盐。
本发明还提供了上述技术方案所述喹唑啉衍生物或上述技术方案所述的喹唑啉衍生物的溶剂合物及其可溶性盐在制备治疗和/或预防癌症的药物中的应用。
优选的，所述癌症为VEGFR高表达的恶性肿瘤。
优选的，所述癌症为结直肠癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、肾癌或神经母细胞癌。
本发明提供了一种喹唑啉衍生物，具有式Ⅰ所示结构：
其中，n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基；
X为卤素。
本发明所述喹唑啉衍生物具有与ATP的腺苷结构类似的喹唑啉母核，母核两端引入经过结构优化的杂环取代基以及脂肪链取代基可以进一步提升了其对VEGFR靶点的选择性和抑制作用。本发明所述喹唑啉衍生物对VEGFR1、VEGFR2和VEGFR3的激酶抑制活性均能够达到低纳摩尔浓度，可以以剂量依赖性抑制VEGFR的活性，并通过体内抗肿瘤实验进行验证，表现出了有效的抑制结指肠癌生长的作用。
本发明提供了一种喹唑啉衍生物，具有式Ⅰ所示结构：
其中，n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基；
X为卤素。
在本发明中，所述取代的苯基中的取代基团优选为卤素、取代或未取代的烷基、取代或未取代的烷氧基、或芳香基；所述取代的苯基中的取代基团的个数为1或2；
所述取代的杂环基或未取代的杂环基中杂环基中的杂原子优选为N、O和S中的一种或几种；
所述取代的杂环基中的取代基团优选为烷基；
X优选为F或Cl。
在本发明中，所述喹唑啉衍生物优选为：
本发明还提供了上述技术方案所述喹唑啉衍生物的制备方法，包括以下步骤：
将具有式Ⅷ所示结构的化合物、碳酸钾、具有式Ⅸ所示结构的化合物和第五有机溶剂混合，进行第一缩合反应，得到所述喹唑啉衍生物；
式Ⅷ～式Ⅸ中，X为卤素；n为1～10的正整数；
式Ⅱ～式Ⅶ和R-NH
2中，R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
在本发明中，若无特殊说明，所有制备原料均为本领域技术人员熟知的市售产品。
在本发明中，所述具有式Ⅷ所示结构的化合物的制备方法，优选包括以下步骤：
将具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物、吡啶和第一有机溶剂混合，进行酰胺化反应， 所述具有式Ⅳ所示结构的化合物；
将具有式Ⅳ所示结构的化合物、R-NH
2、N,N-二异丙基乙胺和第二有机溶剂混合，进行回流反应，得到具有式Ⅴ所示结构的化合物；
将所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物和第三有机溶剂混合，在碱性条件下进行第二缩合反应，得到具有式Ⅶ所示结构的化合物；
将所述具有式Ⅶ所示结构的化合物、钯碳催化剂和第四有机溶剂混合后，通入氢气，进行脱保护反应，得到具有式Ⅷ所示结构的化合物；
式Ⅱ～式Ⅶ中，X为卤素；n为1～10的正整数；
R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。
在本发明中，由式Ⅱ所示结构的化合物制备式Ⅰ所示结构喹唑啉衍生物的制备流程优选为：
本发明将具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物、吡啶和第一有机溶剂混合，进行酰胺化反应，所述具有式Ⅳ所示结构的化合物。
在本发明中，所述具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物和吡啶的摩尔比优选为1：(1.1～1.2)：3，更优选为，最优选为1:1.2:3。
在本发明中，所述吡啶的作用是催化剂，促进反应的进行且保证不会有其他副反应的发生。
本发明对所述第一有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物和吡啶充分溶解并发生酰胺化反应即可。在本发明的实施例中，所述第一有机溶剂为N,N-二甲基甲酰胺。
在本发明中，所述混合优选为先将具有式Ⅱ所示结构的化合物与第一有机溶剂混合后，在冰浴和搅拌的条件下滴加吡啶后，再滴加具有式Ⅲ所示结构的化合物。本发明对所述搅拌和滴加的过程没有任何特殊的限定，采用本领域技术人员熟知的过程进行即可。
在本发明中，所述酰胺化反应优选在冰浴的条件下进行，所述酰胺化反应的时间优选为0.8～1.5h，更优选为0.9～1.2h，最优选为1h。
所述酰胺化反应完成后，本发明还优选包括对得到的产物体系进行后处理；所述后处理优选为在得到的产物体系中加入1M的盐酸水溶液搅拌1h，用饱和氯化钠溶液洗，乙酸乙酯萃取，将有机相浓缩，将残余物通过硅胶柱色谱层析法纯化(石油醚：乙酸乙酯＝6：1～1：1)。
所述具有式Ⅳ所示结构的化合物后，本发明将具有式Ⅳ所示结构的化合物、R-NH
2、N,N-二异丙基乙胺和第二有机溶剂混合，进行回流反应，得到具有式Ⅴ所示结构的化合物。
在本发明中，所述具有式Ⅳ所示结构的化合物、R-NH
2和N,N-二异丙基乙胺的摩尔比优选为1：(2～2.5)：(3～4)，更优选为1：2：3。
在本发明中，所述N,N-二异丙基乙胺为有机碱，促进取代反应的发生。
本发明对所述第二有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保 证能够使具有式Ⅳ所示结构的化合物、R-NH
2、N,N-二异丙基乙胺充分溶解并发生回流反应即可。在本发明的实施例中，所述第二有机溶剂为乙腈。
在本发明中，所述混合优选为将具有式Ⅳ所示结构的化合物、R-NH
2和第二有机溶剂混合后，在得到的溶液中滴加N,N-二异丙基乙胺。
在本发明中，所述回流反应的温度优选为55～75℃，更优选为60～70℃，最优选为60℃；时间优选为1.8～3h，更优选为1.9～2.5h，最优选为2h。
所述回流反应完成后，本发明还优选包括将得到的产物体系进行后处理；所述后处理优选包括：将得到的产物体系进行浓缩后，通过硅胶柱色谱法层析法纯化(二氯甲烷：甲醇＝60:1～40:1)。
得到具有式Ⅴ所示结构的化合物后，本发明将所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物和第三有机溶剂混合，在碱性条件下进行第二缩合反应，得到具有式Ⅶ所示结构的化合物。
在本发明中，所述具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物的摩尔比优选为(1.2～1.5)：1，更优选为1.2：1。
在本发明中，所述碱性条件优选通过添加碳酸钾实现；所述具有式Ⅴ所示结构的化合物和碳酸钾的摩尔比优选为1：(2.45～2.5)，更优选为2.21:5.52。
本发明对所述第三有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物充分溶解并能够保证在碱性条件下发生缩合反应即可。在本发明的实施例中，所述第三有机溶剂为N,N-二甲基甲酰胺。
在本发明中，所述第二缩合反应的温度优选为60～80℃，更优选为60～70℃，最优选为60℃；时间优选为5～7h，更优选为6～7h，最优选为6h。
所述第二缩合反应完成后，本发明还优选包括将得到的产物体系进行后处理，所述后处理优选包括将得到的产物体系用饱和氯化钠溶液洗涤后，用乙酸乙酯进行萃取，然后将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝80:1～60:1)纯化。
得到具有式Ⅶ所示结构的化合物后，本发明将所述具有式Ⅶ所示结构的化合物、钯碳催化剂和第四有机溶剂混合后，通入氢气，进行脱保护反应，得到具有式Ⅷ所示结构的化合物。
在本发明中，所述钯碳催化剂占具有式Ⅶ所示结构的化合物的质量百分含量优选为10％。
本发明对所述第四有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使所述具有式Ⅶ所示结构的化合物和钯碳催化剂充分溶解并能够保证发生脱保护反应即可。在本发明的实施例中，所述第四有机溶剂为N,N-二甲基乙酰胺。
本发明对所述混合的过程没有任何特殊的限定，采用本领域技术人员熟知的过程进行即可。
通入氢气之前，本发明优选依次采用氩气和氢气对反应环境气进行置换，所述氩气的置换的次数优选为3次；所述氢气的置换的次数优选为3次。
本发明对所述通入氢气的过程没有任何特殊的限定，采用本领域技术人员熟知的过程进行即可。
在本发明中，所述脱保护反应的温度优选为室温；时间优选为2～3h，更优选为2～2.5h，最优选为2h。
所述脱保护反应完成后，本发明还优选包括将得到的产物体系进行后处理，所述后处理优选包括在抽滤漏斗中加入硅藻土，滤掉所述产物体系中的钯碳催化剂后，将滤液用饱和氯化钠溶液进行洗涤，用乙酸乙酯进行萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝45:1～20:1)纯化。
得到具有式Ⅷ所示结构的化合物后，本发明将所述具有式Ⅷ所示结构的化合物、碳酸钾、具有式Ⅸ所示结构的化合物和第五有机溶剂混合，进行第一缩合反应，得到所述喹唑啉衍生物。
在本发明中，所述具有式Ⅷ所示结构的化合物、碳酸钾和具有式Ⅸ所示结构的化合物的摩尔比优选为(0.72～0.75):1.45:(0.798～0.89)，更优选为0.725:1.45:(0.798～0.89)，最优选为0.725:1.45:0.798。
本发明对所述第五有机溶剂的种类和用量没有任何特殊的限定，采用本领域技术人员熟知的种类和用量并保证能够使所述具有式Ⅷ所示结构的化合物、碳酸钾和具有式Ⅸ所示结构的化合物充分溶解并能够保证发生脱保护反应即可。在本发明的实施例中，所述第五有机溶剂为N,N-二甲基甲酰胺。
在本发明中，所述混合优选为将具有式Ⅷ所示结构的化合物和碳酸钾溶于第五有机溶剂中后，在得到的混合液中注射所述具有式Ⅸ所示结构的化合物。
在本发明中，所述第一缩合反应的温度优选为60～80℃，更优选为60～70℃，最优选为70℃；时间优选为6～8h，更优选为6～7h，最优选为6h。
所述第一缩合反应完成后，本发明还优选包括将得到的产物体系进行后处理；所述后处理优选包括：将得到的产物体系采用饱和氯化钠溶液进行洗涤，用乙酸乙酯进行萃取后，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝15：1-8:1)进行纯化。
本发明还提供了上述技术方案所述喹唑啉衍生物及其溶剂合物、可药用盐在制备治疗和/或预防癌症的药物中的应用。
在本发明中，所述癌症优选为VEGFR高表达的恶性肿瘤。
在本发明中，所述癌症优选为结直肠癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、肾癌或神经母细胞癌。
下面结合实施例对本发明提供的喹唑啉衍生物及其制备方法和应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
注：实施例1～30中各个化合物的结构均通过核磁共振(1H-NMR)和/或质谱(MS)来确定；NMR测定是用Bruker Advance(400MHz)核磁共振仪，测定溶剂为氘代氯仿(CDCl
3)、氘代二甲基亚砜(DMSO-d
6)，TMS为内标；MS测定用Waters UPLC-Mass Spectrometer。柱层析采用青岛海洋化工厂的200-300目硅胶；
实施例1
化合物3：(2-氯-4-羟基苯基)氨基甲酸苯酯的制备路线为：
将化合物1(10.0g，69.6mmol)溶于N,N-二甲基甲酰胺(140mL)中，冰浴下搅拌滴加吡啶(16.4g，208mmol)，接着缓慢滴加化合物2(13.1g，83.5mmol)，冰浴下反应1h。反应完成后，加入1M的盐酸水溶液(300mL)搅拌1h，用饱和氯化钠溶液(150mL)洗，乙酸乙酯(300mL)萃取，将有机相浓缩，将残余物通过硅胶柱色谱层析法纯化(石油醚：乙酸乙酯的体积比＝6：1～1：1)，得到化合物3(淡黄色固体，16.1g，88％)；
对化合物3进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.92(s,1H),9.47(s,1H),7.40(t,J＝7.7Hz,2H),7.32(d,J＝8.7Hz,1H),7.27-7.09(m,3H),6.77(dd,J＝8.7,2.7Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ156.8,153.5,151.3,129.8,126.2,125.7,122.3,116.3,115.1.HRMS(ESI)m/z calculated for C
13H
11ClNO
3
+[M+H]
+:264.0422,found:264.0423；
化合物4a：1-(2-氯-4-羟基苯基)-3-苯基脲的制备路线为：
制备过程：将化合物3(0.800g，3.04mmol)，苯胺(0.565g，6.08mmol)溶于乙腈(15mL)中，缓慢向溶液中滴加N,N-二异丙基乙胺(1.18g，9.12mmol)，反应回流2h。反应完成后，将混合物浓缩，并通过硅胶柱色谱法层析法纯化(二氯甲烷：甲醇＝60：1～40：1)，得到化合物4a(白色固体，0.653g，82％)。
对化合物4a进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.61(s,1H),9.11(s,1H),7.99(s,1H),7.74(d,J＝8.9Hz,1H),7.44(d,J＝8.0Hz,2H),7.27(t,J＝7.7Hz,2H),6.96(t,J＝7.3Hz,1H),6.85(d,J＝3.0Hz,1H),6.73(dd,J＝9.0,2.8Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.1,153.1,140.3,129.3,127.8,124.9,124.8,122.2,118.5,115.8,114.9.HRMS(ESI)m/z calculated for C
13H
12ClN
2O
2
+[M+H]
+:263.0581,found:263.0582；
化合物6a：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-苯基脲的制备路线为：
制备过程为：将化合物5(0.554g，1.84mmol)，化合物4a(0.578g，2.21mmol)，和K
2CO
3(0.761g，5.52mmol)溶于N,N-二甲基甲酰胺(10mL)中，于60℃下搅拌6h。待反应完毕后，用饱和氯化钠溶液(10mL)洗，乙酸乙酯(30mL)萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝80：1～60：1)纯化，得到化合物6a(粉白色固体，0.726g，75％)。
对化合物6a进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.44(s,1H),8.57(d,J＝1.8Hz,1H),8.40(s,1H),8.23(dd,J＝9.1,1.8Hz,1H),7.59-7.27(m,13H),7.00(td,J＝7.4,1.7Hz,1H),5.35(s,2H),3.98(d,J＝1.8Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.7,152.7,150.7,149.3,147.5,139.9,136.5,134.2,129.4,129.0,128.7,128.6,123.6,122.8,122.6,122.5,122.0,118.7,110.2,108.5,101.4,70.7,56.5.HRMS(ESI)m/z calculated for C
29H
24ClN
4O
4
+[M+H]
+:527.1480,found:527.1482；
化合物7a：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-苯基脲的制备路线为：
向三颈瓶中加入化合物6a(0.641g，1.22mmol)，10％钯碳(加约55％水湿润)(64mg)，然后加入N,N-二甲基乙酰胺(12mL)中，将反应装置用氩气置换三次，再用氢气置换三次，通入氢气室温反应2h。待反应完毕后，在抽滤漏斗中加入硅藻土，滤掉反应液中的钯碳，将反应液用饱和氯化钠溶液(15mL)洗，乙酸乙酯(30mL)萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝45：1～20：1)纯化，得到化合物7a(白色固体，0.345g，65％)；
对化合物7a进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.79(s,1H),9.44(s,1H),8.50(s,1H),8.40(s,1H),8.21(d,J＝9.0Hz,1H),7.54(d,J＝3.5Hz,2H),7.49(d,J＝8.0Hz,2H),7.37-7.26(m,3H),7.24(s,1H),7.00(t,J＝7.3Hz,1H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.7,152.5,150.4,149.4,147.56,139.9,134.1,129.4,123.5,122.8,122.6,122.6,122.0,118.7,110.1,109.4,101.6,56.5.HRMS(ESI)m/z calculated for C
22H
18ClN
4O
4
+[M+H]
+:437.1011,found:437.1013；
化合物9a 1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-苯基脲的制备路线：
制备过程：化合物7a(0.316g，0.725mmol)和K
2CO
3(0.202g，1.45mmol)溶于N,N-二甲基甲酰胺(7mL)中，接着向溶液中缓慢注射8(0.118g，0.798mmol)，于70℃下搅拌6h。待反应完毕后，用饱和氯化钠溶液(15mL)洗，乙酸乙酯(30mL)萃取，将有机相浓缩，用硅胶柱色谱层析法(二氯甲烷：甲醇＝15：1-8：1)纯化，得到化合物9a(白色固体，0.265g，67％)。
对化合物9a进行检测，其检测结果如下：M.p.209.8-210.3℃；IR(KBr):3306,3062,2954,2853,1649,1501,1233,1069,845,745,648cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.88(s,1H),8.60(dd,J＝15.4,2.1Hz,2H),8.22(dd,J＝9.0,2.1Hz,1H),7.54(ddd,J＝9.9,7.6,2.1Hz,4H),7.46-7.24(m,4H),7.14-6.89(m,1H),4.43-4.24(m,2H),3.99(d,J＝2.1Hz,3H),3.20(s,6H),2.25(p,J＝6.8Hz,2H),1.92(q,J＝8.0,4.4Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.9,152.8,150.5,149.3,147.4,140.1,134.3,129.3,123.5,123.1,122.7,122.5,121.9,118.6,110.2,107.9,101.3,66.9,56.6,53.5,51.8,25.9,23.3.HRMS(ESI)m/z calculated for C
29H
31ClN
5O
4
+[M+H]
+:548.2059,found:548.2060。
实施例2～30
参考实施例1的制备过程，区别仅在于调整R、X的种类，依次经过回流反应制备得到的4b～4z、12a～12c；经过第一缩合反应制备得到6b～6z、13a～13c；经过脱保护反应制备得到7b～7z、14a～14c；经过第二缩合反应制备得到9b～9z、15a～15c和17。
对应关系如表1所示：
表1实施例2～30中间产物和目标产物的对应关系
4b～4z、12a～12c、6b～6z、13a～13c、7b～7z、14a～14c、9b～9z、15a～15c和17的收率和结构表征：
化合物4b：1-(2-氯-4-羟基苯基)-3-(4-氟苯基)脲(白色固体，84％)；
对化合物4b进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.61(s,1H),9.13(s,1H),7.97(s,1H),7.71(d,J＝8.9Hz,1H),7.52-7.32(m,2H),7.11(t,J＝8.9Hz,2H),6.84(d,J＝2.7Hz,1H),6.72(dd,J＝8.9,2.7Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.2,153.2,136.6,127.8,125.1,124.9,120.2,120.1,115.9,115.7,114.9.
19F NMR(376MHz,DMSO-d
6)δ-121.59.HRMS(ESI)m/z calculated for C
13H
11ClFN
2O
2
+[M+H]
+:281.0487,found:281.0488；
化合物6b：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-氟苯基)脲(粉白色固体，80％)；
对化合物6b进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.49(s,1H),8.57(s,1H),8.38(s,1H),8.20(d,J＝9.0Hz,1H),7.60-7.48(m,7H),7.47-7.35(m,3H),7.30(dd,J＝9.0,2.7Hz,1H),7.20-7.08(m,2H),5.36(s,2H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.8,152.6,150.7,149.2,147.5,136.5,134.1,129.0,128.7,128.6,123.5,122.9,122.6,121.9,120.4,120.3,116.0,115.8,110.2,108.5,101.4,70.7,56.5.
19F NMR(376MHz,DMSO-d
6)δ-121.10.HRMS(ESI)m/z calculated for C
29H
23ClFN
4O
4
+[M+H]
+:545.1386,found:545.1387；
化合物7b：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，58％)；
对化合物7b进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.51(s,1H),8.49(s,1H),8.39(s,1H),8.19(d,J＝9.0Hz,1H),7.63-7.47(m,4H),7.29(dd,J＝9.0,2.7Hz,1H),7.24(s,1H),7.15(t,J＝8.7Hz,2H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.8,152.5,150.4,149.4,147.6,123.6,122.9,122.6,122.1,120.4,120.3,116.0,115.8,110.1,109.4,101.6,56.5.
19F NMR(376MHz,DMSO-d
6)δ-121.07.HRMS(ESI)m/z calculated for C
22H
17ClFN
4O
4
+[M+H]
+:455.0916,found:455.0918；
化合物9b：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，68％)；
对化合物9b进行检测，其检测结果如下：M.p.224.1-225.6℃；IR(KBr):3296,3055,2954,2803,1651,1374,1232,1045,815,785cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.01(s,1H),8.60(d,J＝15.1Hz,2H),8.19(d,J＝9.0Hz,1H),7.60-7.49(m,4H),7.41(s,1H),7.30(dd,J＝9.0,2.7Hz,1H),7.21-7.07(m,2H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.20(s,6H),2.24(q,J＝7.1,6.4Hz,2H),1.93(d,J＝6.8Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.9,152.7,150.6,149.3,147.5,136.5,134.2,123.5,123.2,122.8,121.9,120.25,120.2,115.9,115.7,110.2,108.0,101.3,66.9,56.6,53.5,51.8,25.9,23.3.
19F NMR(376MHz,DMSO-d
6)δ-121.07.HRMS(ESI)m/z calculated for C
29H
30ClFN
5O
4
+[M+H]
+:566.1964,found:566.1965；
化合物4c：1-(2-氯-4-羟基苯基)-3-(吡啶-4-基)脲(白色固体，83％)；
对化合物4c进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.69(d,J＝27.1Hz,2H),8.36(d,J＝5.6Hz,2H),8.26(s,1H),7.68(d,J＝8.9Hz,1H),7.57-7.36(m,2H),6.87(d,J＝2.7Hz,1H),6.74(dd,J＝8.8,2.8Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.8,152.8,150.2,147.4,127.1,125.8,125.7,115.9,115.0,112.6.HRMS(ESI)m/z calculated for C
12H
11ClN
3O
2
+[M+H]
+:264.0534,found:264.0535；
化合物6c：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(吡啶-4-基)脲(粉白色固体，72％)；
对化合物6c进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.80(s,1H),8.57(d,J＝2.2Hz,2H),8.44-8.35(m,2H),8.19(d,J＝9.0Hz,1H),7.61-7.56(m,2H),7.55-7.49(m,3H),7.49-7.36(m,5H),7.33(dd,J＝9.0,2.7Hz,1H),5.35(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.6,152.5,150.8,150.7,149.2,148.0,146.7,136.5,133.5,129.0,128.7,128.6,123.7,123.6,123.0,122.1,112.7,110.2,108.5,101.3,70.7,56.5.HRMS(ESI)m/z calculated for C
28H
23ClN
5O
4
+[M+H]
+:528.1433,found:528.1435；
化合物7c：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(吡啶-4-基)脲(白色固体，54％)；
对化合物7c进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.79(s,1H),9.78(s,1H),8.56(s,1H),8.50(s,1H),8.43-8.34(m,2H),8.17(d,J＝9.0Hz,1H),7.57(d,J＝2.7Hz,1H),7.54(s,1H),7.51-7.43(m,2H),7.32(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.1,155.1,152.5,150.8,150.4,149.4,148.2,146.7,133.5,123.7,123.2,122.1,112.7,110.1,109.4,101.6,56.4.HRMS(ESI)m/z calculated for C
21H
18ClN
5O
4
+[M+H]
+:438.0963,found:438.0965；
化合物9c：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(吡啶-4-基)脲(白色固体，69％)；
对化合物9c进行检测，其检测结果如下：M.p.210.3-211.2℃；IR(KBr):3302,3056,2954,5,1654,1507,1243,1066,845,787cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.58(d,J＝6.4Hz,1H),8.91(s,1H),8.58(s,1H),8.38(d,J＝5.5Hz,2H),8.15(d,J＝9.0Hz,1H),7.57(d,J＝4.5Hz,2H),7.49(d,J＝5.6Hz,2H),7.42(s,1H),7.32(dd,J＝9.0,2.7Hz,1H),4.32(t,J＝6.3Hz,2H),3.99(s,3H),3.33-2.94(m,6H),2.26(d,J＝8.2Hz,2H),1.93(s,4H).
13C NMR(100MHz,DMSO-d
6)δ155.2,152.7,150.8,150.6,149.3,148.0,146.9,133.6,123.9,123.7,123.4,121.9,112.7,110.1,108.0,101.4,66.8,56.6,53.5,51.7,23.26.HRMS(ESI)m/z calculated for C
28H
30ClN
6O
4
+[M+H]
+:549.2011,found:549.2013；
化合物4d：1-(2-氯-4-羟基苯基)-3-(对甲苯基)脲(白色固体，77％)；
对化合物4d进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.59(s,1H),9.00(s,1H),7.94(s,1H),7.74(d,J＝8.8Hz,1H),7.39-7.27(m,2H),7.12-6.98(m,2H),6.84(d,J＝2.8Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),2.23 (s,3H).
13C NMR(100MHz,DMSO-d
6)δ154.1,153.2,137.7,131.0,129.7,128.0,124.9,124.7,118.6,115.9,115.0,20.8.HRMS(ESI)m/z calculated for C
14H
14ClN
2O
2
+[M+H]
+:277.0743,found:277.0745；
化合物6d：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(对甲苯基)脲(粉白色固体，70％)；
对化合物6d进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.30(s,1H),8.56(d,J＝2.4Hz,1H),8.33(s,1H),8.23(d,J＝8.7Hz,1H),7.62-7.48(m,5H),7.48-7.34(m,5H),7.33-7.26(m,1H),7.11(d,J＝7.9Hz,2H),5.35(s,2H),3.98(s,3H),2.26(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.7,152.7,150.8,149.2,147.4,137.3,136.6,134.3,131.5,129.8,129.0,128.7,128.5,123.5,122.7,122.4,122.0,118.8,110.2,108.5,101.4,70.8,56.6,20.8.HRMS(ESI)m/z calculated for C
30H
26ClN
4O
4
+[M+H]
+:541.1637,found:541.1639；
化合物7d：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(对甲苯基)脲(白色固体，57％)；
对化合物7d进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.77(s,1H),9.30(s,1H),8.49(s,1H),8.32(s,1H),8.25-8.15(m,1H),7.57-7.51(m,2H),7.37(d,J＝8.3Hz,2H),7.28(dd,J＝9.1,2.7Hz,1H),7.23(s,1H),7.11(d,J＝8.2Hz,2H),3.98(s,3H),2.26(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,152.7,152.5,150.4,149.4,137.4,134.2,131.5,129.8,128.6,123.6,122.7,122.4,122.0,118.8,110.1,109.4,101.6,56.5,20.8.HRMS(ESI)m/z calculated for C
23H
20ClN
4O
4
+[M+H]
+:451.1167,found:451.1169；
化合物9d：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(对甲苯基)脲(白色固体，66％)；
对化合物9d进行检测，其检测结果如下：M.p.202.8-204.4℃；IR(KBr):3289,2950,2853,1710,1587,1270,1208,1145,840,667cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.66(s,1H),8.55(d,J＝26.4Hz,2H),8.21(d,J＝9.0Hz,1H),7.64-7.53(m,2H),7.49-7.37(m,3H),7.29(dd,J＝9.0,2.7Hz,1H),7.11(d,J＝8.1Hz,2H),4.32(t,J＝6.2Hz,2H),4.00(s,3H),3.30-2.89(m,6H),2.26(s,5H),1.94(d,J＝6.2Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.24,155.24,152.87,152.72,150.58,149.29,147.37,137.51,134.36,131.33,129.73,123.50,122.94,122.61,121.91,118.70,110.22,108.03,101.37,66.87,56.60,53.54,51.82,25.83,23.24,20.83.HRMS(ESI)m/z calculated for C
30H
33ClN
5O
4
+[M+H]
+:562.2216,found:562.2217；
化合物4e：1-(2-氯-4-羟基苯基)-3-(4-(三氟甲氧基)苯基)脲(白色固体，80％)；
对化合物4e进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.64(s,1H),9.30(s,1H),8.03(s,1H),7.71(d,J＝8.9Hz,1H),7.58-7.44(m,2H),7.35-7.25(m,2H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝8.9,2.8Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.4,153.0,143.0,139.6,127.6,125.2,122.2,119.6,115.9,115.0.
19F NMR(376MHz,DMSO-d
6)δ-57.10.HRMS(ESI)m/z calculated for C
14H
11ClF
3N
2O
3
+[M+H]
+:347.0404,found:347.0406；
化合物6e：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-(三氟甲氧基)苯基)脲(粉白色固体，73％)；
对化合物6e进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.62(s,1H),8.57(s,1H),8.43(s,1H),8.21(d,J＝9.0Hz,1H),7.60(d,J＝2.2Hz,1H),7.60-7.55(m,3H),7.55-7.49(m,3H),7.47-7.41(m,2H),7.41-7.23(m,4H),5.35(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.7,152.6,150.7,149.3,147.7,143.3,139.2,136.5,133.9,129.0,128.6,128.5,123.6,123.1,122.7,122.3,122.0,119.8,110.2,108.5,101.3,70.7,56.5.
19F NMR(376MHz,DMSO-d
6)δ-57.09.HRMS(ESI)m/z calculated for C
30H
23ClF
3N
4O
5
+[M+H]
+:611.1303,found:611.1305；
化合物7e：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲氧基)苯基)脲(白色固体，58％)；
对化合物7e进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.78(s,1H),9.60(s,1H),8.45(d,J＝30.9Hz,2H),8.20(d,J＝9.0Hz,1H),7.78-7.50(m,4H),7.31(dd,J＝9.2,7.1Hz,3H),7.23(s,1H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.1,155.1,152.7,152.5,150.4,149.4,147.7,143.3,139.2,133.8,123.6,123.1,122.7,122.3,122.1,119.8,110.1,109.4,101.6,56.4.
19F NMR(376MHz,DMSO-d
6)δ-57.08.HRMS(ESI)m/z calculated for C
23H
17ClF
3N
4O
5
+[M+H]
+:521.0834,found:521.0835；
化合物9e：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲氧基)苯基)脲(白色固体，72％)；
对化合物9e进行检测，其检测结果如下：M.p.239.5-241.5℃；IR(KBr):3291,2957,2854,1722,1537,1257,1207,1186,846,683cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.14(s,1H),8.62(d,J＝30.9Hz,2H),8.18(d,J＝9.0Hz,1H),7.70-7.50(m,4H),7.42(s,1H),7.37-7.23(m,3H),4.33(t,J＝6.2Hz,2H),3.99(s,3H),3.30(s,6H),2.27(p,J＝6.5Hz,2H),1.93(d,J＝15.2Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.8,152.7,150.6,149.3,147.6,143.2,139.4,134.0,123.6,123.4,122.9,122.3,121.9,119.7,110.2,108.0,101.3,66.8,56.6,53.4,51.7,25.6,23.2.
19F NMR(376MHz,DMSO-d
6)δ-57.07.HRMS(ESI)m/z calculated for C
30H
30ClF
3N
5O
5
+[M+H]
+:632.1882,found:632.1884；
化合物4f：1-(2-氯-4-羟基苯基)-3-(4-(三氟甲基)苯基)脲(白色固体，81％)；
对化合物4f进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.68(s,1H),9.51(s,1H),8.13(s,1H),7.71(d,J＝8.9Hz,1H),7.68-7.61(m,4H),6.86(d,J＝2.8Hz,1H),6.74(dd,J＝8.9,2.7Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.6,152.9,144.0,127.4,126.6,126.6,125.5,125.4,118.1,115.9,115.0,55.4.
19F NMR(376MHz,DMSO-d
6)δ-60.03.HRMS(ESI):m/z calculated for C
14H
11ClF
3N
2O
2
+[M+H]
+:331.0456,found:331.0457；
化合物6f：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-(三氟甲基)苯基)脲(粉白色固体，78％)；
对化合物6f进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.81(s,1H),8.57(s,1H),8.51(s,1H),8.21(d,J＝9.0Hz,1H),7.75-7.63(m,4H),7.62-7.56(m,2H),7.57-7.48(m,3H),7.48-7.42(m,2H),7.41-7.35(m,1H),7.33(dd,J＝9.0,2.7Hz,1H),5.35(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.6,152.6,150.7,149.2,147.8,143.6,136.5,133.7,129.0,128.7,128.6,126.7,126.7,123.6,123.3,122.9,122.1,118.4,110.2,108.5, 101.4,70.7,56.5.
19F NMR(376MHz,DMSO-d
6)δ-60.09.HRMS(ESI)m/z calculated for C
30H
23ClF
3N
4O
4
+[M+H]
+:595.1355,found:595.1356；
化合物7f：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲基)苯基)脲(白色固体，52％)；
对化合物7f进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.79(s,1H),9.80(s,1H),8.50(s,2H),8.20(d,J＝9.0Hz,1H),7.76-7.62(m,4H),7.61-7.52(m,2H),7.31(dd,J＝9.0,2.7Hz,1H),7.24(s,1H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.5,152.4,150.3,149.4,147.9,143.7,133.6,126.7,126.3,123.7,123.4,122.9,122.1,118.4,110.1,109.4,101.6,56.4.
19F NMR(376MHz,DMSO-d
6)δ-60.09.HRMS(ESI)m/z calculated for C
23H
17ClF
3N
4O
4
+[M+H]
+:505.0885,found:505.0886；
化合物9f：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-(三氟甲基)苯基)脲(白色固体，63％)；
对化合物9f进行检测，其检测结果如下：M.p.232.8-234.7℃；IR(KBr):3299,2950,2850,1722,1545,1276,1203,1167,845,687cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.40(s,1H),8.78(s,1H),8.59(s,1H),8.18(d,J＝9.0Hz,1H),7.72(d,J＝8.6Hz,2H),7.66(d,J＝8.7Hz,2H),7.61-7.56(m,2H),7.42(s,1H),7.32(dd,J＝9.0,2.7Hz,1H),4.32(t,J＝6.2Hz,2H),4.00(s,3H),3.28(t,J＝7.7Hz,6H),2.27(p,J＝6.5Hz,2H),2.01-1.90(m,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.8,152.7,150.6,149.3,147.9,143.9,133.9,126.7,126.6,123.7,123.6,123.2,122.0,118.2,110.2,108.0,101.4,66.8,56.6,53.5,51.7,25.6,23.2.
19F NMR(376MHz,DMSO-d
6)δ-60.03.HRMS(ESI)m/z calculated for C
30H
30ClF
3N
5O
4
+[M+H]
+:616.1933,found:616.1934；
化合物4g：1-(2-氯-4-羟基苯基)-3-(2-氟-5-甲基苯基)脲(白色固体，77％)；
对化合物4g进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.66(s,1H),8.97(d,J＝2.5Hz,1H),8.48(s,1H),7.98(dd,J＝7.9,2.2Hz,1H),7.72(d,J＝8.9Hz,1H),7.10(dd,J＝11.4,8.3Hz,1H),6.84(d,J＝2.7Hz,1H),6.78(ddd,J＝7.8,4.8,2.2Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),2.26(s,3H).
13C NMR(100MHz,DMSO-d
6)δ154.3,152.9,151.8,149.5,133.9,127.6,125.2,123.0,121.4,115.9,115.0,114.9,114.8,21.2.
19F NMR(376MHz,DMSO-d
6)δ-134.40.HRMS(ESI)m/z calculated for C
14H
13ClFN
2O
2
+[M+H]
+:295.0644,found:295.0646；
化合物6g：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(2-氟-5-甲基苯基)脲(粉白色固体，82％)；
对化合物6g进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.29(d,J＝2.4Hz,1H),8.86(s,1H),8.57(s,1H),8.21(d,J＝9.0Hz,1H),8.02(dd,J＝7.8,2.2Hz,1H),7.59-7.50(m,5H),7.44(dd,J＝8.4,6.4Hz,2H),7.38(t,J＝7.2Hz,1H),7.31(dd,J＝9.0,2.7Hz,1H),7.13(dd,J＝11.4,8.3Hz,1H),6.83(dq,J＝7.1,3.6,2.8Hz,1H),5.36(s,2H),3.99(s,3H),2.28(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.7,152.6,150.7,149.2,147.6,136.5,134.0,129.0,128.6,128.5,123.6,123.1,122.8,121.9,121.6,115.2,115.0,110.2,108.5,101.4,70.7,56.6,21.3.
19F NMR(376MHz,DMSO-d
6)δ-133.92.HRMS(ESI)m/z calculated for C
30H
25ClFN
4O
4
+[M+H]
+:559.1542,found:559.1544；
化合物7g：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2-氟-5-甲基苯基)脲(白色固体，49％)；
对化合物7g进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.81(s,1H),9.28(d,J＝2.4Hz,1H),8.86(s,1H),8.49(s,1H),8.20(d,J＝9.0Hz,1H),8.01(dd,J＝8.0,2.2Hz,1H),7.55(d,J＝3.1Hz,2H),7.29(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),7.13(dd,J＝11.4,8.3Hz,1H),6.83(ddd,J＝7.9,4.8,2.1Hz,1H),3.98(s,3H),2.28(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.6,152.5,150.4,149.4,147.7,134.0,127.4,127.3,123.6,123.1,122.8,122.0,121.6,115.2,115.0,110.1,109.4,101.6,56.5,21.2.
19F NMR(376MHz,DMSO-d
6)δ-133.93.HRMS(ESI)m/z calculated for C
23H
19ClFN
4O
4
+[M+H]
+:469.1073,found:469.1075；
化合物9g：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2-氟-5-甲基苯基))脲(白色固体，68％)；
对化合物9g进行检测，其检测结果如下：M.p.210.5-211.9℃；IR(KBr):3342,3056,2977,2654,1651,1374,1221,1087,845,756cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.39(d,J＝2.5Hz,1H),8.98(d,J＝3.0Hz,1H),8.58(s,1H),8.19(d,J＝9.0Hz,1H),7.99(dd,J＝7.8,2.2Hz,1H),7.73-7.51(m,2H),7.41(s,1H),7.31(dd,J＝9.0,2.7Hz,1H),7.13(dd,J＝11.3,8.3Hz,1H),6.83(ddd,J＝7.8,4.7,2.2Hz,1H),4.33(t,J＝6.3Hz,2H),3.99(s,3H),3.22(dt,J＝44.3,7.9Hz,6H),2.28(s,5H),1.95(s,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.7,150.5,149.2,147.7,134.0,133.9,127.3,127.2,123.6,123.3,123.1,121.9,121.8,115.2,115.0,110.2,108.0,101.3,66.8,56.6,53.4,51.6,25.5,23.2,21.2.
19F NMR(376MHz,DMSO-d
6)δ-133.49.HRMS(ESI)m/z calculated for C
30H
32ClFN
5O
4
+[M+H]
+:580.2121,found:580.2122；
化合物4h：1-(2-氯-4-羟基苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，76％)；
对化合物4h进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.57(s,1H),8.77(s,1H),7.89(s,1H),7.78-7.62(m,2H),7.37(d,J＝0.8Hz,1H),6.84(d,J＝2.7Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),4.42(hept,J＝6.7Hz,1H),1.38(d,J＝6.7Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ153.9,153.1,129.6,128.2,124.7,124.6,122.1,117.8,115.8,114.9,53.4,23.1.HRMS(ESI)m/z calculated for C
13H
16ClN
4O
2
+[M+H]
+:295.0956,found:295.0957；
化合物6h：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(粉白色固体，81％)。
对化合物6h进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.13(s,1H),8.56(s,1H),8.35-8.18(m,2H),7.81(d,J＝0.7Hz,1H),7.57(s,1H),7.53(h,J＝2.5,2.1Hz,3H),7.50(s,1H),7.48-7.41(m,3H),7.40-7.33(m,1H),7.28(dd,J＝9.0,2.7Hz,1H),5.35(s,2H),4.44(hept,J＝6.7Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.7,152.5,150.7,149.2,147.2,136.6,134.5,129.6,129.0,128.6,128.5,123.5,122.5,122.0,121.9,121.7,117.9,110.2,108.5,101.4,70.7,56.6,53.4,23.1.HRMS(ESI)m/z calculated for C
29H
28ClN
6O
4
+[M+H]
+:559.1855,found:559.1856；
化合物7h：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，59％)；
对化合物7h进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.10(s,1H),8.49(s,1H),8.31-8.18(m,2H),7.81(d,J＝0.8Hz,1H),7.58-7.49(m,2H),7.42(d,J＝0.8Hz,1H),7.30-7.16(m,2H),4.44(p,J＝6.6Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.6,152.5,150.4,149.4,147.3,134.4,129.7,123.5,122.5,122.0,121.9,121.7,118.0,110.1,109.4,101.6,56.5,53.4,23.1.HRMS(ESI)m/z calculated for C
22H
22ClN
6O
4
+[M+H]
+:469.1385found:469.1386；
化合物9h：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，62％)；
对化合物9h进行检测，其检测结果如下：M.p.162.8-163.5℃；IR(KBr):3302,2957,2853,2701,1701,1652,1418,1297,1136,1040,850,784cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.38(s,1H),8.57(s,1H),8.41(s,1H),8.23(d,J＝9.1Hz,1H),7.80(s,1H),7.57(s,1H),7.52(d,J＝2.7Hz,1H),7.41(d,J＝1.9Hz,2H),7.27(dd,J＝9.0,2.7Hz,1H),4.44(p,J＝6.7Hz,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.23(t,J＝7.0Hz,6H),2.25(t,J＝7.4Hz,2H),1.93(d,J＝6.1Hz,4H),1.40(d,J＝6.6Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.7,152.7,150.6,149.3,147.2,134.6,129.6,123.5,122.6,122.1,121.9,121.7,117.9,110.2,108.0,101.4,101.3,66.8,56.6,53.5,53.4,51.8,25.7,23.2,23.1.HRMS(ESI)m/z calculated for C
29H
35ClN
7O
4
+[M+H]
+:580.2433,found:580.2435；
化合物4i：1-(2-氯-4-羟基苯基)-3-(5-甲基异恶唑-3-基)脲(白色固体，84％)；
对化合物4i进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.86(s,1H),9.69(s,1H),8.38(s,1H),7.72(dd,J＝8.9,1.0Hz,1H),6.85(dd,J＝2.8,1.0Hz,1H),6.73(ddd,J＝8.9,2.8,1.0Hz,1H),6.45(s,1H),2.35(s,3H).
13C NMR(100MHz,DMSO-d
6)δ169.7,159.2,154.6,151.9,127.1,125.2,125.1,115.9,115.0,95.9,12.5.HRMS(ESI)m/z calculated for C
11H
11ClN
3O
3
+[M+H]
+:268.0483,found:268.0485；
化合物6i：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(5-甲基异恶唑-3-基)脲(粉白色固体，76％)；
对化合物6i进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.16(d,J＝2.0Hz,1H),8.76(s,1H),8.57(q,J＝2.3,1.9Hz,1H),8.21(dd,J＝9.0,2.1Hz,1H),7.61-7.56(m,2H),7.56-7.49(m,3H),7.49-7.42(m,2H),7.41-7.36(m,1H),7.33(dt,J＝9.0,2.4Hz,1H),6.52(s,1H),5.36(d,J＝1.9Hz,2H),3.99(d,J＝2.0Hz,3H),2.38(s,3H).
13C NMR(100MHz,DMSO-d
6)δ169.9,165.2,159.0,155.2,152.6,151.7,150.8,149.2,148.0,136.5,133.5,129.0,128.7,128.5,123.6,123.3,122.8,122.1,110.2,108.5,101.4,95.9,70.7,56.6,12.5.HRMS(ESI)m/z calculated for C
27H
23ClN
5O
5
+[M+H]
+:532.1382,found:532.1384；
化合物7i：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(5-甲基异恶唑-3-基)脲(白色固体，59％)。
对化合物7i进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.16(s,1H),8.76(s,1H),8.49(s,1H),8.19(d,J＝9.0Hz,1H),7.67-7.45(m,2H),7.31(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),6.51(d,J＝1.0Hz,1H),3.98(s,3H),2.38(s,3H).
13C NMR(100MHz,DMSO-d
6)δ169.9,165.1,159.0,155.1,152.5,151.7,150.4,149.4,148.1,133.5,123.7,123.3,122.8,122.1,110.1,109.4,101.6,95.9,56.5,12.6.HRMS(ESI)m/z calculated for C
20H
17ClN
5O
5
+[M+H]
+:442.0912,found:442.0913；
化合物9i：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(5-甲基异恶唑-3-基)脲(白色固体，67％)；
对化合物9i进行检测，其检测结果如下：M.p.162.7-163.9℃；IR(KBr):3304,2957,2853,2701,1732,1652,1418,1299,1136,1040,850,774cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.35(s,1H),8.96(s,1H),8.58(s,1H),8.17(d,J＝9.0Hz,1H),7.57(d,J＝2.9Hz,2H),7.41(s,1H),7.32(dd,J＝9.0,2.7Hz,1H),6.52(s,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.28-3.02(m,6H),2.38(s,3H),2.27(t,J＝7.4Hz,2H),1.95(s,4H).
13C NMR(100MHz,DMSO-d
6)δ169.8,165.2,159.0,155.2,152.7,151.9,150.6,149.3,148.0,133.6,123.6,123.1,122.0,110.2,108.0,101.3,96.0,66.8,56.6,53.4,51.7,25.623.2,12.6.HRMS(ESI)m/z calculated for C
27H
30ClN
6O
5
+[M+H]
+:553.1960,found:553.1962；
化合物4j：1-(2-氯-4-羟基苯基)-3-(1-甲基-1H-吲哚-5-基)脲(白色固体，85％)；
对化合物4j进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.57(s,1H),8.92(s,1H),7.91(s,1H),7.79(d,J＝8.9Hz,1H),7.70(d,J＝2.0Hz,1H),7.33(d,J＝8.7Hz,1H),7.26(d,J＝3.0Hz,1H),7.13(dd,J＝8.7,2.1Hz,1H),6.84(d,J＝2.7Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),6.34(dd,J＝3.0,0.8Hz,1H),3.75(s,3H).
13C NMR(100MHz,DMSO-d
6)δ153.7,153.5,133.3,132.2,130.5,128.6,128.3,124.6,124.3,115.8,114.9,114.8,110.3,110.1,100.4,32.9.HRMS(ESI)m/z calculated for C
16H
15ClN
3O
2
+[M+H]
+:316.0847,found:316.0849；
化合物6j：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-甲基-1H-吲哚-5-基)脲(粉白色固体，84％)；
对化合物6j进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.23(s,1H),8.57(s,1H),8.38-8.24(m,2H),7.75(s,1H),7.58-7.36(m,9H),7.30(dd,J＝8.1,2.9Hz,2H),7.18(d,J＝8.6Hz,1H),6.37(d,J＝3.0Hz,1H),5.35(s,2H),3.98(s,3H),3.77(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.3,155.2,153.0,152.7,150.7,149.2,147.1,136.5,134.6,133.5,131.8,130.6,129.0,128.7,128.6,128.6,123.5,122.4,122.2,121.9,114.9,110.6,110.2,110.2,108.5,101.4,100.5,70.7,56.6,32.9.HRMS(ESI)m/z calculated for C
32H
27ClN
5O
4
+[M+H]
+:580.1746,found:580.1748；
化合物7j：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吲哚-5-基)脲(白色固体，61％)；
对化合物7j进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.79(s,1H),9.22(s,1H),8.50(s,1H),8.39-8.17(m,2H),7.75(d,J＝2.1Hz,1H),7.60-7.47(m,2H),7.37(d,J＝8.7Hz,1H),7.33-7.26(m,2H),7.24(s,1H), 7.17(dd,J＝8.7,2.1Hz,1H),6.37(d,J＝3.0Hz,1H),3.99(s,3H),3.77(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,153.0,152.5,150.3,149.4,147.2,134.5,133.5,131.8,130.6,128.6,123.5,122.4,122.1,121.9,114.9,110.6,110.2110.1,109.4,101.6,100.5,56.6,32.9.HRMS(ESI)m/z calculated for C
25H
21ClN
5O
4
+[M+H]
+:490.1276,found:490.1277；
化合物9j：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吲哚-5-基)脲(白色固体，63％)；
对化合物9j进行检测，其检测结果如下：M.p.158.7-159.0℃；IR(KBr):3298,2955,2879,1742,1609,1539,1250,1232,1180,846,683cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.66(d,J＝13.4Hz,1H),8.58(s,1H),8.53(d,J＝5.5Hz,1H),8.26(d,J＝9.0Hz,1H),7.78(d,J＝1.7Hz,1H),7.60-7.50(m,2H),7.46-7.35(m,2H),7.29(dt,J＝5.2,2.5Hz,2H),7.22(dt,J＝8.8,1.7Hz,1H),6.36(d,J＝3.0Hz,1H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.77(s,3H),3.28-3.08(m,6H),2.28(p,J＝6.2Hz,2H),1.99-1.91(m,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,153.2,152.7,150.5,149.2,147.1,134.7,133.4,132.1,130.5,128.6,123.5,122.6,122.4,121.8,114.8,110.4,110.2,110.1,107.9,101.3,100.5,66.8,56.6,53.4,51.7,32.9,23.2.HRMS(ESI):m/z calculated for C
32H
34ClN
6O
4
+[M+H]
+:601.2324,found:601.2326.
化合物4k：1-(2-氯-4-羟基苯基)-3-(3-(三氟甲基)苯基)脲(白色固体，78％)；
对化合物4k进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.69(s,1H),9.49(s,1H),8.12(s,1H),8.03(s,1H),7.71(d,J＝8.9Hz,1H),7.65-7.42(m,2H),7.30(d,J＝7.2Hz,1H),6.86(d,J＝2.7Hz,1H),6.74(dd,J＝8.9,2.7Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.8,153.1,139.9,132.5,127.2,125.9,125.8,123.2,122.6,116.9,116.9,115.9,115.0.
19F NMR(376MHz,DMSO-d
6)δ-61.33.HRMS(ESI)m/z calculated for C
14H
11ClF
3N
2O
2
+[M+H]
+:331.0456,found:331.0457.
化合物6k：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(3-(三氟甲基)苯基)脲(粉白色固体，76％)。
对化合物6k进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.76(s,1H),8.57(s,1H),8.48(s,1H),8.21(d,J＝9.0Hz,1H),8.07(d,J＝2.4Hz,1H),7.61-7.50(m,7H),7.44(t,J＝7.1Hz,2H),7.41-7.30(m,3H),5.36(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.7,152.6,150.7,149.2,147.8,140.8,136.5,133.8,130.6,130.3,129.0,128.7,128.6,123.6,123.4,122.9,122.2,122.1,110.2,108.5,101.4,70.7,56.6.
19F NMR(376MHz,DMSO-d
6)δ-61.33.HRMS(ESI)m/z calculated for C
30H
23ClF
3N
4O
4
+[M+H]
+:595.1355,found:595.1356；
化合物7k：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲基)苯基)脲(白色固体，60％)；
对化合物7k进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.80(s,1H),9.76(s,1H),8.48(d,J＝10.1Hz,2H),8.19(d,J＝9.0Hz,1H),8.06(d,J＝2.4Hz,1H),7.74-7.52(m,4H),7.45-7.28(m,2H),7.23(s,1H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.8,152.5,150.4,149.4,147.9,140.8,133.7,130.6,123.6,123.5,123.0,122.3,122.1,118.9,110.1,109.4,101.6,56.5.
19F NMR(376MHz,DMSO-d
6)δ-61.33.HRMS(ESI)m/z calculated for C
23H
17ClF
3N
4O
4
+[M+H]
+:505.0885,found:505.0886；
化合物9k：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲基)苯基)脲(白色固体，61％)；
对化合物9k进行检测，其检测结果如下：M.p.230.5-231.2℃；IR(KBr):3298,2955,2879,1742,1539,1250,1232,1180,846,683cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.41(s,1H),8.75(s,1H),8.58(s,1H),8.18(d,J＝9.0Hz,1H),8.07(d,J＝2.2Hz,1H),7.67-7.61(m,1H),7.60-7.50(m,3H),7.40(s,1H),7.37-7.29(m,2H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.29(t,J＝7.7Hz,6H),2.27(p,J＝6.4Hz,2H),1.96(d,J＝6.0Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.9,152.7,150.5,149.2,147.8,141.0,133.9,130.5,123.6,123.6,123.2,122.1,121.9,114.4,114.3,110.2,108.0,101.3,66.8,56.6,53.5,40.6,40.4,40.2,39.7,39.5,39.3,25.6,23.2.
19F NMR(376MHz,DMSO-d
6)δ-61.31.HRMS(ESI)m/z calculated for C
30H
30ClF
3N
5O
4
+[M+H]
+:616.1933,found:616.1934；
化合物4l：1-(苯并呋喃-5-基)-3-(2-氯-4-羟基苯基)脲(白色固体，75％)；
对化合物4l进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.58(s,1H),9.11(s,1H),8.05-7.92(m,2H),7.83(d,J＝2.2Hz,1H),7.76(d,J＝8.9Hz,1H),7.49(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.2Hz,1H),6.91(dd,J＝2.2,1.0Hz,1H),6.85(d,J＝2.7Hz,1H),6.72(d,J＝2.8Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.0,153.4,150.6,146.9,135.6,128.0,128.0,124.9,124.7,116.6,115.9,115.0,111.6,110.7,107.3.HRMS(ESI)m/z calculated for C
15H
12ClN
2O
3
+[M+H]
+:303.0537,found:303.0538；
化合物6l：1-(苯并呋喃-5-基)-3-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)脲(粉白色固体，74％)；
对化合物6l进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.42(s,1H),8.57(s,1H),8.37(s,1H),8.26(d,J＝9.0Hz,1H),7.92(dd,J＝28.9,2.2Hz,2H),7.62-7.49(m,6H),7.48-7.37(m,3H),7.31(dt,J＝8.9,3.0Hz,2H),6.94(d,J＝2.1Hz,1H),5.36(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,153.0,152.7,150.8,149.2,147.4,147.0,136.6,135.2,134.3,129.0,128.7,128.5,128.0,123.5,122.7,122.4,122.0,116.8,111.8,111.0,110.2,108.5,107.4,101.4,70.8,56.6.HRMS(ESI)m/z calculated for C
31H
24ClN
4O
5
+[M+H]
+:567.1430,found:567.1430；
化合物7l：1-(苯并呋喃-5-基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，62％)；
对化合物7l进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.42(s,1H),8.50(s,1H),8.36(s,1H),8.24(d,J＝9.1Hz,1H),7.96(d,J＝2.2Hz,1H),7.88(d,J＝2.2Hz,1H),7.58-7.51(m,3H),7.36-7.26(m,2H),7.23(s,1H),6.94(d,J＝2.1Hz,1H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,153.0,152.5,150.8,150.4,149.4,147.5,147.0,135.3,134.2,128.0,123.6,122.7,122.4,122.0,116.8,111.8,111.0,110.1,109.3,107.4,101.6,56.5.HRMS m/z m/z calculated for C
24H
18ClN
4O
5
+[M+H]
+:477.0921,found:477.0922；
化合物9l：1-(苯并呋喃-5-基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)脲(白色固体，73％)。
对化合物9l进行检测，其检测结果如下：M.p.196.8-198.4℃；IR(KBr):3278,295,42838,1721,1587,1270,1208,1176,841,697cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.79(d,J＝11.8Hz,1H),8.65-8.48(m,2H),8.24(d,J＝9.0Hz,1H),7.93(dd,J＝24.3,2.2Hz,2H),7.55(dd,J＝12.5,9.6Hz,3H),7.41(s,1H),7.32(ddd,J＝11.9,9.0,2.4Hz,2H),6.94(d,J＝2.1Hz,1H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.17(s,6H),2.23(dq,J＝13.8,6.6,6.1Hz,2H),1.92(d,J＝6.4Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.3,155.3,153.1,152.7,150.7,150.6,149.3,147.3,147.0,135.4,134.4,128.0,123.5,122.9,122.6,121.9,116.7,111.7,110.8,110.2,108.0,107.4,101.3,66.9,56.6,53.6,51.9,23.3.HRMS(ESI)m/z calculated for C
31H
31ClN
5O
5
+[M+H]
+:588.2009,found:588.2009；
化合物4m：1-(4-溴-2-氟苯基)-3-(2-氯-4-羟基苯基)脲(白色固体，81％)；
对化合物4m进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.68(s,1H),9.14(d,J＝2.4Hz,1H),8.52(s,1H),8.14(t,J＝8.8Hz,1H),7.71(d,J＝8.9Hz,1H),7.57(dd,J＝11.0,2.3Hz,1H),7.34(dt,J＝8.9,1.6Hz,1H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝8.9,2.7Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.5,152.8,128.0,128.0,127.4,125.3,125.1,122.1,118.9,115.9,115.0,112.9,112.8.
19F NMR(376MHz,DMSO-d
6)δ-126.54.HRMS(ESI)m/z calculated for C
13H
10BrClFN
2O
2
+[M+H]
+:358.9588,found:358.9590；
化合物6m：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-溴-2-氟苯基)脲(粉白色固体，79％)；
对化合物6m进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.47(d,J＝2.5Hz,1H),8.92(s,1H),8.57(s,1H),8.23-8.13(m,2H),7.62-7.56(m,3H),7.52(s,2H),7.44(td,J＝7.8,7.4,1.9Hz,3H),7.39(dq,J＝5.8,1.8Hz,2H),7.32(dd,J＝9.0,2.7Hz,1H),5.36(s,2H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.8,152.7,150.8,149.2,147.9,142.6,136.6,136.6,133.8,129.0,128.7,128.5,123.7,123.3,123.0,122.2,122.0,119.0,115.8,113.3,110.2,108.5,101.4,70.8,56.6.
19F NMR(376MHz,DMSO-d
6)δ-126.02.HRMS(ESI)m/z calculated for C
29H
22BrClFN
4O
4
+[M+H]
+:623.0492,found:623.0494；
化合物7m：1-(4-溴-2-氟苯基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，56％)；
对化合物7m进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.79(s,1H),9.35(d,J＝2.5Hz,1H),8.87(s,1H),8.50(s,1H),8.20(dd,J＝8.7,2.9Hz,2H),7.55(d,J＝3.1Hz,2H),7.35-7.26(m,2H),7.25-7.18(m,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.7,152.7,152.5,150.3,149.4,147.8,133.9,127.7,125.0,123.7,123.3,123.1,122.9,122.0,121.3,115.5,110.1,109.4,101.6,56.5.
19F NMR(376MHz,DMSO-d
6)δ-126.02.HRMS(ESI)m/z calculated for C
22H
16BrClFN
4O
4
+[M+H]
+:533.0022,found:533.0022；
化合物9m：1-(4-溴-2-氟苯基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)脲(白色固体，66％)；
对化合物9m进行检测，其检测结果如下：M.p.167.3-168.7℃；IR(KBr):3320,3077,2965,2732,1657,1421,1287,1246,1016,955,786cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.40(d,J＝2.5Hz,1H),8.93(s,1H),8.58(s,1H),8.19(t,J＝7.9Hz,2H),7.58-7.56(m,2H),7.41(s,1H),7.29(ddd,J＝19.7,10.3,5.4Hz,2H),7.16(t,J＝7.8Hz,1H),4.30(d,J＝6.2Hz,2H),3.99(s,3H),3.19-3.09(m,6H),2.23(t,J＝7.3Hz,2H),1.91(s,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.3,152.7,150.6,149.3,147.7,134.0,127.8,127.7,125.0,123.6,123.3,123.0,122.0,121.4,110.2,108.0,101.3,66.9,56.6,55.4,53.6,51.9,49.1,23.3.
19F NMR(376MHz,DMSO-d
6)δ-126.02.HRMS(ESI)m/z calculated for C
29H
29BrClFN
5O
4
+[M+H]
+:644.1080,found:644.1081；
化合物4n：1-(4-氯-3-(三氟甲基)苯基)-3-(2-氯-4-羟苯基)脲(白色固体，80％)；
对化合物4n进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.72(s,1H),9.62(s,1H),8.16(s,1H),8.11(s,1H),7.66(d,J＝8.9Hz,1H),7.61(d,J＝1.5Hz,2H),6.86(d,J＝2.7Hz,1H),6.74(dd,J＝8.9,2.7Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.8,153.1,139.9,132.5,127.2,125.9,125.8,123.2,122.6,117.0,116.9,116.0,115.0.
19F NMR(376MHz,DMSO-d
6)δ-61.51.HRMS(ESI)m/z calculated for C
14H
10Cl
2F
3N
2O
2
+[M+H]
+:365.0072,found:365.0073；
化合物6n：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(4-氯-3-(三氟甲基)苯基)脲(粉白色固体，74％)；
对化合物6n进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.86(s,1H),8.57(s,1H),8.50(s,1H),8.22-8.06(m,2H),7.65(d,J＝1.7Hz,2H),7.61-7.56(m,2H),7.53(dd,J＝9.8,2.8Hz,3H),7.49-7.41(m,2H),7.41-7.28(m,2H),5.36(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.7,150.8,149.2,148.0,139.5,136.5,133.6,132.7,129.0,128.7,128.6,123.7,123.4,123.2,122.1,117.1,110.2,108.5,101.3,70.7,56.6.
19F NMR(376MHz,DMSO-d
6)δ-61.52.HRMS(ESI)m/z calculated for C
30H
22Cl
2F
3N
4O
4
+[M+H]
+:629.0965,found:629.0966；
化合物7n：1-(4-氯-3-(三氟甲基)苯基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，60％)；
对化合物7n进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.81(s,1H),9.86(d,J＝6.1Hz,1H),8.50(d,J＝4.6Hz,2H),8.25-7.97(m,2H),7.75-7.48(m,4H),7.48-7.15(m,2H),3.99(d,J＝6.2Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ165.1,155.1,152.7,152.5,150.4,149.4,148.1,139.6,133.5,132.7,123.7,123.4,123.2,122.1,117.3,117.2,110.1,109.4,101.6,56.5.
19F NMR(376MHz,DMSO-d
6)δ-61.51.HRMS(ESI)m/z calculated for C
23H
16Cl
2F
3N
4O
4
+[M+H]
+:539.0496,found:539.0496；
化合物9n：1-(4-氯-3-(三氟甲基)苯基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧)苯基)脲(白色固体，75％)；
对化合物9n进行检测，其检测结果如下：M.p.197.3-198.4℃；IR(KBr):3312,3087,2968,2758,1670,1417,1269,1248,1014,967,792cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.71(s,1H),8.81(d,J＝7.0Hz,1H),8.58(s,1H),8.21-8.11(m,2H),7.70(dd,J＝8.8,2.5Hz,1H),7.65(s,1H),7.57(d,J＝2.4Hz,2H),7.40(d,J＝2.3Hz,1H),7.32(dd,J＝9.0,2.7Hz,1H),4.31(d,J＝5.8Hz,2H),4.00(s,3H),3.26(s,6H),2.28(t,J＝7.5Hz,2H),1.96(d,J＝6.2Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.15,155.17,152.88,152.66,150.52,149.25,147.92,143.15,139.80,133.72,132.58,124.63,123.82,123.60,123.29,123.08,121.95,115.82,110.18,107.98,101.30,66.80,56.58,56.52,53.46,51.73,25.63,23.21.
19F NMR(376MHz,DMSO-d
6)δ-61.49.HRMS(ESI)m/z calculated for C
30H
29Cl
2F
3N
5O
4
+[M+H]
+:650.1544,found:650.1545；
化合物4o：1-(2-氯-4-羟基苯基)-3-(2,4-二甲氧基苯基)脲(白色固体，80％)；
对化合物4o进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.59(s,1H),8.47(d,J＝10.3Hz,2H),7.88(d,J＝8.8Hz,1H),7.67(d,J＝8.9Hz,1H),6.83(d,J＝2.6Hz,1H),6.70(dd,J＝8.9,2.8Hz,1H),6.61(d,J＝2.6Hz,1H),6.46(dd,J＝8.9,2.7Hz,1H),3.85(s,3H),3.73(s,3H).
13C NMR(100MHz,DMSO-d
6)δ155.4,154.1,153.4,149.9,128.1,125.5,125.1,122.4,120.6,115.8,114.9,104.5,99.2,56.2,55.7.HRMS(ESI)m/z calculated for C
15H
16ClN
2O
4
+[M+H]
+:323.0799,found:323.0799；
化合物6o：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(2,4-二甲氧基苯基)脲(粉白色固体，82％)；
对化合物6o进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ8.83(d,J＝24.5Hz,2H),8.57(s,1H),8.17(d,J＝9.1Hz,1H),7.90(d,J＝8.8Hz,1H),7.64-7.49(m,5H),7.48-7.37(m,3H),7.28(dd,J＝9.0,2.7Hz,1H),6.64(d,J＝2.7Hz,1H),6.50(dd,J＝8.9,2.7Hz,1H),5.35(s,2H),3.98(s,3H),3.88(s,3H),3.75(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.3,155.8,155.1,153.1,152.7,150.7,149.2,147.3,136.5,134.5,129.1,128.7,128.6,123.5,123.1,121.9,121.1,110.2,108.5,104.6,101.3,99.3,70.7,56.6,56.3,55.7.HRMS(ESI)m/z m/z calculated for C
31H
28ClN
4O
6
+[M+H]
+:587.1692,found:587.1693；
化合物7o：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2,4-二甲氧基苯基)脲(白色固体，57％)；
对化合物7o进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.80(s,1H),8.81(d,J＝24.7Hz,2H),8.50(d,J＝1.0Hz,1H),8.26-8.09(m,1H),8.00-7.79(m,1H),7.68-7.45(m,2H),7.34-7.11(m,2H),6.73-6.42(m,2H),3.98(s,3H),3.88(s,3H),3.75(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.8,155.0,153.1,152.5,150.3,150.3,149.4,147.4,134.4,123.5,123.1,123.0,121.9,121.9,121.1,110.1,109.4,104.6,101.6,99.3,56.5,56.3,55.8.HRMS(ESI)m/z m/z calculated for C
24H
22ClN
4O
6
+[M+H]
+:497.1223,found:497.1224；
化合物9o：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2,4-二甲氧基苯基)脲(白色固体，64％)；
对化合物9o进行检测，其检测结果如下：M.p.215.2-216.3℃；IR(KBr):3333,3076,2964,2701,1652,1417,1283,1238,1004,984,787cm
-1.
1H NMR(400MHz,DMSO-d
6)δ8.85(d,J＝29.6Hz,2H),8.58(d,J＝1.5Hz,1H),8.32-8.10(m,1H),7.89(dd,J＝8.8,1.5Hz,1H),7.63-7.50(m,2H),7.42(s,1H),7.38-7.21(m,1H),6.63(t,J＝2.0Hz,1H),6.49(dd,J＝9.0,2.4Hz,1H),4.32(t,J＝6.3Hz,2H),3.99(s,3H),3.88(s,3H),3.75(s,3H),3.17(dd,J＝5.2,1.5Hz,6H),2.32-2.21(m,2H),1.94(s,4H).
13C NMR(100MHz,DMSO-d
6)δ165.3,155.2,153.1,152.7,150.6,150.3,149.3,147.3,134.5,123.5,123.1,123.1,121.9,121.9,121.2,110.2,108.0,104.6,101.3,99.3,66.8,56.6,56.3,55.8,55.4,53.4,51.7,23.2.HRMS(ESI)m/z calculated for C
31H
35ClN
5O
6
+[M+H]
+:608.2271,found:608.2272；
化合物4p：1-(2-氯-4-羟基苯基)-3-(2-苯氧基苯基)脲(白色固体，81％)；
对化合物4p进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.67(s,1H),8.89(s,1H),8.67(s,1H),8.25(dd,J＝8.2,2.1Hz,1H),7.67(dd,J＝9.0,2.0Hz,1H),7.48-7.37(m,2H),7.16(t,J＝7.3Hz,1H),7.07(dd,J＝11.3,8.0Hz,3H),6.94(t,J＝7.7Hz,1H),6.87-6.79(m,2H),6.73(dd,J＝9.0,2.5Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ157.3,154.4,153.3,145.7,131.9,130.5,127.6,125.9,125.5,124.3,124.0,122.7,120.5,119.0,118.8,115.9,114.9.HRMS(ESI)m/z calculated for C
19H
16ClN
2O
3
+[M+H]
+:355.0850,found:355.0851；
化合物6p：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(2-苯氧基苯基)脲(粉白色固体，77％)；
对化合物6p进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.20(s,1H),9.00(s,1H),8.57(s,1H),8.38-8.09(m,2H),7.62-7.49(m,5H),7.49-7.34(m,5H),7.30(dd,J＝9.0,2.7Hz,1H),7.25-7.07(m,4H),6.98(td,J＝7.7,1.6Hz,1H),6.84(dd,J＝8.1,1.5Hz,1H),5.35(s,2H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,157.2,155.2,153.0,152.7,150.8,149.2,147.7,146.2,136.6,134.1,131.5,130.6,129.0,128.7,128.5,124.3,124.1,123.6,123.5,123.2,121.9,121.0,119.2,118.7,110.2,108.5,101.4,70.8,56.6.HRMS(ESI)m/z calculated for C
35H
27ClN
4O
5
+[M+H]
+:618.1665,found:618.1666；
化合物7p：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2-苯氧基苯基)脲(白色固体，62％)；
对化合物7p进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.19(s,1H),8.99(s,1H),8.49(s,1H),8.25(dd,J＝8.2,1.6Hz,1H),8.14(d,J＝9.0Hz,1H),7.54(s,1H),7.53-7.50(m,1H),7.48-7.41(m,2H),7.28(dd,J＝9.0,2.7Hz,1H),7.23(s,1H),7.21-7.15(m,2H),7.14-7.05(m,3H),6.99(ddd,J＝8.8,3.7,2.2Hz,1H),6.84(dd,J＝8.1,1.3Hz,1H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,157.2,155.1,153.0,152.6,152.5,150.4,149.4,147.8,143.1,134.0,130.6,124.3,124.1,123.6,123.5,123.1,122.2,121.9,121.0,119.2,118.8,115.8,110.1,109.4,101.6,56.5.HRMS(ESI)m/z calculated for C
28H
22ClN
4O
5
+[M+H]
+:529.1274,found:529.1275；
化合物9p：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2-苯氧基苯基)脲(白色固体，69％)；
对化合物9p进行检测，其检测结果如下：M.p.221.1-222.3℃；IR(KBr):3267,2959,2809,1715,1588,1270,1208,1166,740,667cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.19(s,1H),9.00(s,1H),8.56(s,1H),8.25(dd,J＝8.2,1.6Hz,1H),8.15(d,J＝9.0Hz,1H),7.61-7.51(m,2H),7.49-7.41(m,2H),7.38(s,1H),7.30(dd,J＝9.0,2.7Hz,1H),7.21-7.15(m,1H),7.14-7.06(m,3H),6.98(td,J＝7.7,1.6Hz,1H),6.84(dd,J＝8.1,1.5Hz,1H),4.25(t,J＝6.4Hz,2H),3.98(s,3H),2.63(t,J＝7.2Hz,2H),2.52(s,4H),2.03-1.98(m,2H),1.72(p,J＝3.1Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ 165.2,157.2,155.6,153.0,152.7,150.7,149.4,147.8,146.2,134.1,131.4,130.6,124.3,124.1,123.6,123.5,123.2,121.9,121.0,119.2,118.7,110.0,107.8,101.3,67.6,56.6,54.1,52.6,23.6.HRMS(ESI)m/z calculated for C
35H
35ClN
5O
5
+[M+H]
+:640.2322,found:640.2323；
化合物4q：1-(2-氯-4-羟基苯基)-3-(3-(三氟甲氧基)苯基)脲(白色固体，77％)；
对化合物4q进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.72(s,1H),9.52-9.45(m,1H),8.14(s,1H),7.76(dp,J＝4.5,2.4Hz,2H),7.45(td,J＝8.2,2.2Hz,1H),7.32(d,J＝8.2Hz,1H),6.99(d,J＝8.2Hz,1H),6.91(t,J＝2.4Hz,1H),6.79(dt,J＝8.9,2.5Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ153.0,149.2,142.0,131.0,127.4,125.5,125.3,117.1,117.0,115.9,115.0,114.1,110.4,110.3.
19F NMR(376MHz,DMSO-d
6)δ-56.60.HRMS(ESI)m/z calculated for C
14H
11ClF
3N
2O
3
+[M+H]
+:347.0404,found:347.0406；
化合物6q：1-([1,1'-联苯]-4-基)-3-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)脲(粉白色固体，69％)；
对化合物6q进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.62(s,1H),8.57(s,1H),8.43(s,1H),8.21(d,J＝9.0Hz,1H),7.60(d,J＝2.2Hz,1H),7.60-7.55(m,3H),7.55-7.49(m,3H),7.47-7.41(m,2H),7.41-7.23(m,4H),5.35(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.7,152.6,150.7,149.3,147.7,143.3,139.2,136.5,133.9,129.0,128.6,128.5,123.6,123.1,122.7,122.3,122.0,119.8,110.2,108.5,101.3,70.7,56.5.
19F NMR(376MHz,DMSO-d
6)δ-56.59.HRMS(ESI)m/z calculated for C
30H
23ClF
3N
4O
5
+[M+H]
+:611.1303,found:611.1305；
化合物7q：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(2-氟苯基)脲(白色固体，59％)；
对化合物7q进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.77(s,1H),9.70(s,1H),8.47(d,J＝21.7Hz,2H),8.19(d,J＝9.0Hz,1H),7.74(s,1H),7.65-7.51(m,2H),7.44(t,J＝8.2Hz,1H),7.30(dd,J＝8.8,2.4Hz,2H),7.24(s,1H),7.05-6.93(m,1H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.7,152.5,150.4,149.4,149.3,147.9,141.7,133.7,131.0,123.7,123.3,122.9,122.1,117.3,114.5,110.6,110.1,109.4,101.6,56.5.
19F NMR(376MHz,DMSO-d
6)δ-56.59.HRMS(ESI)m/z calculated for C
23H
17ClF
3N
4O
5
+[M+H]
+:521.0834,found:521.0835；
化合物9q：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲氧基)苯基)脲(白色固体，74％)；
对化合物9q进行检测，其检测结果如下：M.p.239.5-241.5℃；IR(KBr):3291,2957,2854,1722,1537,1257,1207,1186,846,683cm
-1.
1H NMR(400MHz,DMSO-d
6)δ10.21(s,1H),8.67(s,1H),8.58(s,1H),8.18(d,J＝9.0Hz,1H),7.74(s,1H),7.61-7.53(m,2H),7.47-7.40(m,2H),7.33(ddd,J＝14.7,8.6,2.4Hz,2H),7.04-6.89(m,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.20(q,J＝7.6Hz,6H),2.24(t,J＝7.3Hz,2H),2.01-1.90(m,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.3,152.8,152.7,150.6,149.3,149.2,147.8,141.9,133.9,131.0,123.6,123.5,123.1,122.0,117.2,114.3,110.5,110.2,108.0,101.4,66.9,56.6,53.6,51.9,25.9,23.2.
19F NMR(376MHz,DMSO-d
6)δ-56.59.HRMS(ESI)m/z calculated for C
30H
30ClF
3N
5O
5
+[M+H]
+:632.1882,found:632.1884；
化合物4r：1-(2-氯-4-羟基苯基)-3-(2-氟苯基)脲(白色固体，83％)；
对化合物4r进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.63(s,1H),9.03(d,J＝2.5Hz,1H),8.49(s,1H),8.15(td,J＝8.3,1.7Hz,1H),7.72(d,J＝8.9Hz,1H),7.23(ddd,J＝11.7,8.2,1.5Hz,1H),7.12(td,J＝7.8,1.5Hz,1H),6.99(tdd,J＝7.5,5.0,1.7Hz,1H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝8.9,2.8Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.3,153.6,152.9,151.2,128.1,127.6,125.3,125.1,124.9,122.8,121.0,115.9,115.4,114.9.
19F NMR(376MHz,DMSO-d
6)δ-129.69.HRMS(ESI)m/z calculated for C
13H
10ClFN
2NaO
2
+[M+Na]
+:303.0307,found:303.0309；
化合物6r：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(3-(三氟甲氧基)苯基)脲(粉白色固体，80％)；
对化合物6r进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.35(d,J＝2.4Hz,1H),8.87(s,1H),8.57(s,1H),8.19(td,J＝8.6,6.1Hz,2H),7.59-7.56(m,2H),7.53(dd,J＝10.3,3.2Hz,3H),7.47-7.42(m,2H),7.41-7.36(m,1H),7.33-7.23(m,2H),7.19-7.13(m,1H),7.04(tdd,J＝7.6,5.1,1.7Hz,1H),5.36(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,153.8,152.6,150.7,149.2,147.7,136.5,133.9,129.0,128.6,128.5,127.7,125.0,123.6,123.3,123.2,122.9,122.0,121.3,115.7,115.5,110.2,108.5,101.4,70.8,56.6.
19F NMR(376MHz,DMSO-d
6)δ-129.19.HRMS(ESI)m/z calculated for C
29H
23ClFN
4O
4
+[M+H]
+:545.1386,found:545.1388；
化合物7r：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-(三氟甲氧基)苯基)脲(白色固体，55％)；
对化合物7r进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.78(s,1H),9.34(d,J＝2.4Hz,1H),8.87(s,1H),8.50(s,1H),8.18(td,J＝8.8,2.7Hz,2H),7.55(d,J＝2.4Hz,2H),7.32-7.26(m,2H),7.24(d,J＝2.7Hz,1H),7.16(td,J＝7.8,1.5Hz,1H),7.07-7.01(m,1H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.7,152.5,149.4,147.8,133.9,127.7,125.1,123.7,123.3,123.2,122.9,122.0,121.3,115.6,115.5,110.1,109.4,101.6,56.5,29.5.
19F NMR(376MHz,DMSO-d
6)δ-129.20.HRMS(ESI)m/z calculated for C
22H
17ClFN
4O
4
+[M+H]
+:455.0917,found:455.0917；
化合物9r：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(2-氟苯基)脲(白色固体，68％)；
对化合物9r进行检测，其检测结果如下：1H NMR(400MHz,DMSO-d
6)δ9.41(d,J＝2.4Hz,1H),8.94(s,1H),8.58(s,1H),8.23-8.13(m,2H),7.61-7.52(m,2H),7.42(s,1H),7.33-7.20(m,2H),7.16(td,J＝7.8,1.5Hz,1H),7.10-6.97(m,1H),4.32(t,J＝6.2Hz,2H),3.99(s,3H),3.27-2.91(m,6H),2.23(t,J＝7.4Hz,2H),1.91(s,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.3,153.9,152.7,150.6,149.3,147.7,134.0,125.0,123.6,123.3,123.1,121.9,121.4,115.5,110.2,108.0,101.3,66.9,56.6,53.6,51.9,23.3.
19F NMR(376MHz,DMSO-d
6)δ-128.94.HRMS(ESI)m/z calculated for C
29H
30ClFN
5O
4
+[M+H]
+:566.1965,found:566.1969；
化合物4s：1-(2-氯-4-羟基苯基)-3-(3-氟苯基)脲(白色固体，82％)；
对化合物4s进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.66(d,J＝1.9Hz,1H),9.34(s,1H),8.07(s,1H),7.70(dd,J＝8.9,1.9Hz,1H),7.49(dq,J＝12.0,2.1Hz,1H),7.34-7.26(m,1H),7.08(d,J＝8.2Hz,1H),6.85(t,J＝2.2Hz,1H),6.81-6.70(m,2H).
13C NMR(100MHz,DMSO-d
6)δ154.4,153.0,142.2,130.8,127.5,125.3,115.9,115.0,114.2,105.3.
19F NMR(376MHz,DMSO-d
6)δ-112.12.HRMS(ESI)m/z calculated for C
13H
11ClFN
2O
2
+[M+H]
+:281.0488,found:281.0489；
化合物6s：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(二苯并[b,d]呋喃-4-基)脲(粉白色固体，80％)；
对化合物6s进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.62(s,1H),8.57(d,J＝1.4Hz,1H),8.45(s,1H),8.20(dd,J＝9.0,1.4Hz,1H),7.61-7.29(m,11H),7.13(d,J＝8.1Hz,1H),6.83(ddd,J＝11.1,5.7,2.1Hz,1H),5.36(s,2H),3.98(d,J＝1.4Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,164.1,161.7,155.1,152.6,150.7,149.1,147.7,136.4,133.8,130.9,129.0,128.7,128.5,123.6,123.3,122.9,122.0,114.4,110.2,108.4,105.5,105.2,101.3,70.7,56.5,55.3.
19F NMR(376MHz,DMSO-d
6)δ-111.96.HRMS(ESI)m/z calculated for C
29H
23ClFN
4O
4
+[M+H]
+:545.1386,found:545.1388；
化合物7s：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-氟苯基)脲(白色固体，55％)；
对化合物7s进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.77(s,1H),9.63(s,1H),8.58-8.33(m,2H),8.33-8.09(m,1H),7.54(d,J＝9.7Hz,3H),7.41-7.04(m,4H),6.83(t,J＝8.9Hz,1H),3.98(d,J＝5.8Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.6,150.3,149.4,147.8,133.8,131.0,130.9,123.6,123.2,122.8,122.0,114.4,110.1,109.4,109.0,108.8,105.5,105.2,101.5,56.4.
19F NMR(376MHz,DMSO-d
6)δ-111.98.HRMS(ESI)m/z calculated for C
22H
17ClFN
4O
4
+[M+H]
+:455.0917,found:455.0915；
化合物9s：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-氟苯基)脲(白色固体，64％)；
对化合物9s进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.22(d,J＝3.4Hz,1H),8.70(s,1H),8.58(s,1H),8.17(d,J＝9.0Hz,1H),7.60-7.48(m,3H),7.41(s,1H),7.41-7.27(m,2H),7.17(dd,J＝8.0,2.0Hz,1H),6.81(td,J＝8.5,2.6Hz,1H),4.31(t,J＝6.3Hz,2H),3.99(s,3H),3.17(d,J＝4.5Hz,6H),2.22(d,J＝9.0Hz,2H),1.99-1.81(m,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.8,152.7,150.5,149.3,147.7,133.9,130.9,123.5,123.4,123.0,121.9,114.3,110.1,108.8,108.0,105.3,105.1,101.3,66.5,56.6,55.4,53.5,51.8,23.2.
19F NMR(376MHz,DMSO-d
6)δ-112.00.HRMS(ESI)m/z calculated for C
29H
30ClFN
5O
4
+[M+H]
+:566.1965,found:66.1966；
化合物4t：1-([1,1'-联苯]-4-基)-3-(2-氯-4-羟基苯基)脲(白色固体，83％)；
对化合物4t进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.63(s,1H),9.23(s,1H),8.05(s,1H),7.77(d,J＝8.8Hz,1H),7.69-7.51(m,6H),7.44(t,J＝7.7Hz,2H),7.35-7.28(m,1H),6.86(d,J＝2.7Hz,1H),6.75(dd,J＝8.9,2.8Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ154.2,153.0,140.3,139.8,133.9,129.3,127.8,127.5,127.2,126.5,124.9,124.9,118.8,115.9,115.0,21.6.HRMS(ESI)m/z calculated for C
19H
16ClN
2O
2
+[M+H]
+:399.0895,found:399.0898；
化合物6t(粉白色固体，72％)。
对化合物6t进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.53(s,1H),8.58(s,1H),8.43(s,1H),8.27(s,1H),7.80-7.27(m,21H),5.36(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.6,149.2,147.5,140.2,139.4,136.5,134.3,134.1,129.3,129.0,128.6,128.5,127.6,127.3,126.6,123.5,122.5,122.0,119.0,110.2,108.4,101.3,70.7,56.5.HRMS(ESI)m/z calculated for C
35H
28ClN
4O
4
+[M+H]
+:603.1794,found:603.1794；
化合物7t：1-([1,1'-联苯]-4-基)-3-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)脲(白色固体，55％)；
对化合物7t进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.78(s,1H),9.53(s,1H),8.50(s,1H),8.42(s,1H),8.24(d,J＝9.0Hz,1H),7.73-7.39(m,10H),7.37-7.19(m,3H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.6,152.4,150.3,147.6,140.3,139.4,134.3,134.0,129.3,127.6,127.3,126.6,123.6,122.9,122.5,122.0,119.0,110.1,109.4,101.6,56.4,29.8.HRMS(ESI)m/z calculated for C
28H
22ClN
4O
4
+[M+H]
+:513.1324,found:513.1322；
化合物9t：1-([1,1'-联苯]-4-基)-3-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)脲(粉白色固体，64％)；
对化合物9t进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.11(d,J＝4.4Hz,1H),8.71(d,J＝4.4Hz,1H),8.67-8.51(m,1H),8.33-8.13(m,1H),7.77-7.12(m,13H),4.30(q,J＝5.8Hz,2H),4.03-3.90(m,3H),3.02(d,J＝18.2Hz,6H),2.19(q,J＝6.8Hz,2H),1.87(d,J＝6.2Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.3,152.8,152.6,150.5,149.3,147.5,134.2,134.1,129.3,127.5,127.3,126.6,123.5,123.2,122.8,121.9,118.9,110.1,107.9,101.3,67.1,56.5,53.6,52.0,26.5,23.4.HRMS(ESI)m/z calculated for C
35H
35ClN
5O
4
+[M+H]
+:625.1455,found:625.1453；
化合物4u：1-(2-氯-4-羟基苯基)-3-(3-氟-4-甲基苯基)脲(白色固体，74％)；
对化合物4u进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.62(s,1H),9.20(s,1H),8.01(s,1H),7.71(d,J＝8.9Hz,1H),7.43(d,J＝12.4Hz,1H),7.16(d,J＝8.5Hz,1H),7.00(s,1H),6.85(d,J＝2.7Hz,1H),6.73(dd,J＝9.0,2.6Hz,1H),2.16(s,3H).
13C NMR(100MHz,DMSO-d
6)δ154.3,153.0,139.7,139.6,131.9,131.8,127.6,125.2,125.1,117.2,117.1,115.8,115.0,114.0,105.3,105.0,14.0.
19F NMR(376MHz,DMSO-d
6)δ-116.30.HRMS(ESI)m/z calculated for C
14H
13ClFN
2O
2
+[M+H]
+:295.0644,found:295.0645；
化合物6u:1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(3-氟-4-甲基苯基)脲(粉白色固体，83％)；
对化合物6u进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.53(s,1H),8.57(s,1H),8.41(s,1H), 8.21(d,J＝9.0Hz,1H),7.60-7.29(m,10H),7.19(t,J＝8.6Hz,1H),7.04(dd,J＝8.2,2.1Hz,1H),5.35(s,2H),3.98(s,3H),2.18(d,J＝1.7Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,159.8,155.1,152.65,150.7,149.2,147.6,136.5,134.0,132.0,129.0,128.6,128.5,123.5,123.0,122.6,122.0,117.7,117.5,114.2,110.2,108.4,105.5,105.2,101.3,70.7,56.5,29.5,14.0.
19F NMR(376MHz,DMSO-d
6)δ-116.12.HRMS(ESI)m/z calculated for C
30H
25ClFN
4O
4
+[M+H]
+:559.1543,found:559.1544；
化合物7u:1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(3-氟-4-甲基苯基)脲(白色固体，45％)；
对化合物7u进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.74(s,1H),9.50(s,1H),8.44(d,J＝40.3Hz,2H),8.20(d,J＝9.1Hz,1H),7.57-7.42(m,3H),7.36-7.18(m,3H),7.04(dd,J＝8.2,2.1Hz,1H),3.98(s,3H),2.18(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.1,155.2,152.6,152.4,150.4,149.4,147.7,139.3,133.9,132.0,131.9,123.6,123.0,122.6,122.0,117.7,114.2,110.1,109.3,105.5,105.2,101.5,56.4,29.5,14.0.
19F NMR(376MHz,DMSO-d
6)δ-116.13.HRMS(ESI)m/z calculated for C
23H
19ClFN
4O
4
+[M+H]
+:469.1073,found:469.1075；
化合物9u:1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(3-氟-4-甲基苯基))脲(白色固体，65％)；
对化合物9g进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.03(s,1H),8.71-8.50(m,2H),8.18(d,J＝9.0Hz,1H),7.66-7.38(m,4H),7.37-7.02(m,3H),4.31(t,J＝6.2Hz,2H),3.99(s,3H),3.03(d,J＝108.6Hz,6H),2.20(d,J＝19.2Hz,5H),1.90(s,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.8,152.7,150.5,147.6,134.0,131.9,123.5,123.3,122.8,121.9,117.5,114.2,110.2,108.0,105.4,105.1,101.3,66.9,56.6,53.5,51.8,23.3,14.04.
19F NMR(376MHz,DMSO-d
6)δ-116.13.HRMS(ESI)m/z calculated for C
30H
31ClFN
5NaO
4
+[M+Na]
+:602.1941,found:602.1943；
化合物4v：1-(2-氯-4-羟基苯基)-3-(二苯并[b,d]呋喃-4-基)脲(白色固体，77％)；
对化合物4v进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.66(s,1H),9.54(s,1H),8.64(s,1H),8.18(ddd,J＝18.4,8.0,1.2Hz,2H),7.86-7.72(m,3H),7.62-7.54(m,1H),7.44(t,J＝7.5Hz,1H),7.33(t,J＝7.9Hz,1H),6.88(d,J＝2.7Hz,1H),6.76(dd,J＝8.9,2.8Hz,1H).
13C NMR(100MHz,DMSO-d
6)δ155.5,154.3,153.1,145.5,128.0,127.7,125.6,125.1,124.9,124.5,124.2,124.0,123.8,121.8,117.3,115.9,115.0,114.5,112.1,55.4,29.5.HRMS(ESI)m/z calculated for C
19H
14ClN
2O
3
+[M+H]
+:353.0687,found:353.0688；
化合物6v:1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(二苯并[b,d]呋喃-4-基)脲(粉白色固体，82％)；
对化合物6v进行检测，其检测结果如下：
1HNMR(400MHz,DMSO-d
6)δ9.85(s,1H),9.02(s,1H),8.57(d,J＝5.8Hz,1H),8.33-8.13(m,2H),7.78(t,J＝8.0Hz,2H),7.67-7.27(m,12H),5.36(d,J＝2.3Hz,2H),3.99(d,J＝3.3Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ156.5,152.9,152.0,145.0,134.0,131.9,124.5,124.3,123.7,123.5,117.5,116.9,116.5,114.2,111.5,106.4HRMS(ESI)m/z calculated for C
35H
26ClN
4O
5
+[M+H]
+:617.1586,found:617.1586；
化合物7v：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(二苯并[b,d]呋喃-4-基)脲(白色固体，46％)；
对化合物7v进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.85(s,1H),9.01(s,1H),8.53-8.42(m,1H),8.31-8.10(m,3H),7.77(q,J＝9.3,8.5Hz,2H),7.67-7.14(m,8H),3.98(d,J＝5.3Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.0,152.8,152.4,150.3,149.4,147.7,145.7,134.0,128.2,125.3,124.5,124.0,123.7,123.1,122.9,122.0,121.9,117.6,114.9,112.1,110.1,109.4,101.5,56.5.HRMS(ESI)m/z calculated for C
28H
20ClN
4O
5
+[M+H]
+:527.1117,found:527.1118；
化合物9v：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(二苯并[b,d]呋喃-4-基)脲(白色固体，68％)；
对化合物9v进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.90(s,1H),9.07(s,1H),8.59(s,1H),8.36-8.10(m,3H),7.78(t,J＝8.6Hz,2H),7.59(d,J＝4.1Hz,3H),7.53-7.28(m,4H),4.31(t,J＝6.4Hz,2H),4.00(s,3H),3.08(s,6H),2.30-2.13(m,2H),1.89(s,4H).
13C NMR(100MHz,DMSO-d
6)δ166.2,156.6,156.3,153.9,153.7,151.6,150.3,148.7,146.8,135.1,129.1,126.3,125.5,125.4,125.0,124.9,124.7,124.2,123.9,123.0,122.9,118.8,116.0,113.1,111.2,109.0,68.0,57.6,54.6,52.9,24.4.HRMS(ESI)m/z calculated for C
35H
33ClN
5O
5
+[M+H]
+:638.2165,found:638.2166；
化合物4w：1-(2-氯-4-羟基苯基)-3-(1-甲基-1H-吡唑-5-基)脲(白色固体，80％)；
对化合物4w进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.66(s,1H),9.01(s,1H),8.25(s,1H),7.71(d,J＝8.9Hz,1H),7.29(dd,J＝9.4,1.9Hz,1H),6.86(d,J＝2.7Hz,1H),6.79-6.68(m,1H),6.17(d,J＝2.0Hz,1H),3.68(s,3H).
13C NMR(100MHz,DMSO-d
6)δ154.4,152.4,137.8,137.8,137.4,127.6,125.2,121.6,116.2,115.9,115.0,97.2,35.8,35.8.HRMS(ESI)m/z calculated for C
11H
12ClN
4O
2
+[M+H]
+:267.0643,found:267.0644；
化合物6w：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-甲基-1H-吡唑-5-基)脲(粉白色固体，81％)；
对化合物6w进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.37(s,1H),8.67(s,1H),8.57(s,1H),8.19(d,J＝9.0Hz,1H),7.62-7.49(m,5H),7.49-7.28(m,5H),6.23(d,J＝1.9Hz,1H),5.36(s,2H),3.98(s,3H),3.72(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.6,152.0,150.7,149.2,147.7,137.9,136.5,133.9,129.0,128.6,128.5,123.6,123.1,122.7,122.1,110.2,108.5,101.3,97.2,70.7,56.5,35.8.HRMS(ESI)m/z calculated for C
27H
24ClN
6O
4
+[M+H]
+:531.1542,found:531.1545；
化合物7w：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-5-基)脲(白色固体，44％)；
对化合物7w进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.40(s,1H),8.90(s,1H),8.55-8.47(m,2H),7.58(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.30(s,3H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ163.2,153.1,152.6,152.5,149.4,148.3,147,1,137.8,137.7,132.8,128.37,123.5,122.5,122.0,121.9,110.9,110.3,106.4,101.2,56.4,38.0.HRMS(ESI)m/z calculated for C
20H
18ClN
6O
4
+[M+H]
+:441.8440,found:441.8445；
化合物9w：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-5-基)脲(白色固体，65％)；
对化合物9w进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.94(s,1H),8.98(s,1H),8.57(s,1H),8.16(d,J＝9.0Hz,1H),7.55(d,J＝3.1Hz,2H),7.44-7.22(m,3H),6.22(d,J＝2.0Hz,1H),4.27(t,J＝6.4Hz,2H),3.98(s,3H),3.76(s,3H),2.80(d,J＝26.7Hz,6H),2.10(p,J＝7.0Hz,2H),1.78(d,J＝5.6Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.1,155.4,152.6,152.1,150.6,149.3,147.7,137.9,137.7,134.0,123.6,123.0,121.9,110.0,107.8,101.2,96.8,67.3,56.5,53.8,52.2,36.0,27.3,23.5.HRMS(ESI)m/z calculated for C
27H
31ClN
7O
4
+[M+H]
+:553.0395,found:553.0397；
化合物4x：1-(2-氯-4-羟基苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(白色固体，78％)；
对化合物4x进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.54(dd,J＝51.6,2.9Hz,2H),7.92(d,J＝9.0Hz,1H),7.60(d,J＝3.1Hz,1H),7.03-6.64(m,2H),6.03(s,1H),5.76(d,J＝2.8Hz,1H),4.57(pd,J＝7.2,2.7Hz,1H),2.20-1.52(m,8H).
13C NMR(100MHz,DMSO-d
6)δ153.8,152.5,148.2,129.9,128.1,124.1,123.8,115.8,114.9,94.2,62.3,55.3,32.6,24.2.HRMS(ESI)m/z calculated for C
15H
18ClN
4O
2
+[M+H]
+:321.7845,found:321.7844；
化合物6x：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(粉白色固体，76％)；
对化合物6x进行检测，其检测结果如下：
1HNMR(400MHz,DMSO-d
6)δ9.73(s,1H),8.56(s,1H),8.33(d,J＝9.1Hz,1H),7.78-7.18(m,10H),5.35(s,2H),4.60(p,J＝7.2Hz,1H),3.98(s,3H),2.17-1.54(m,8H).
13C NMR(100MHz,DMSO-d
6)δ165.2,152.7,152.2,150.7,149.2,147.4,136.5,134.3,129.1,128.7,128.5,123.5,122.3,122.2,122.0,110.2,108.5,101.4,70.7,62.3,56.5,32.7,24.2.HRMS(ESI)m/z calculated for C
31H
30ClN
6O
4
+[M+H]
+:585.2017,found:585.2018；
化合物7x：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(白色固体，48％)；
对化合物7x进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.65(s,1H),8.60(s,1H),8.55-8.47(m,2H),7.61(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.60(s,1H),2.40-1.62(m,8H).
13C NMR(100MHz,DMSO-d
6)δ165.2,153.1,152.6,152.5,151.4,149.4,146.6,138.4,136.7,123.5,122.5,122.0,121.9,121.7,112.0,109.1,106.4,101.6,98.8,61.2,56.4,32.1,24.0.HRMS(ESI)m/z calculated for C
24H
24ClN
6O
4
+[M+H]
+:495.1542,found:495.1544；
化合物9x：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-5-基)脲(白色固体，65％)；
对化合物9x进行检测，其检测结果如下：
1HNMR(400MHz,DMSO-d
6)δ9.83(s,1H),8.62(s,1H),8.36(d,J＝9.1Hz,1H),7.77-7.67(m,1H),7.60(s,2H),7.44(s,1H),7.35(dd,J＝9.0,2.8Hz,1H),6.12(s,1H),4.65(p,J＝7.2Hz,1H),4.34(t,J＝6.3Hz,2H),4.04(s,3H),3.00(dd,J＝27.8,15.4Hz,6H),2.26-1.77(m,12H),1.68(td,J＝7.3,3.7Hz,2H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.3,152.7,152.3,150.5,149.3,134.3,123.5,122.4,122.3,122.0,110.1,107.9,101.2,67.1,62.3,56.5,53.6,52.0,32.6,24.2,23.3.HRMS(ESI)m/z calculated for C
31H
36ClN
7NaO
4
+[M+Na]
+:628.2517,found:628.2519；
化合物4y：1-(2-氯-4-羟基苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(白色固体，82％)。
对化合物4y进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.70-9.48(m,1H),8.76(d,J＝2.6Hz,1H),7.98-7.70(m,3H),7.36(d,J＝2.5Hz,1H),6.83(d,J＝2.9Hz,1H),6.70(dt,J＝9.0,2.9Hz,1H),5.84-5.65(m,1H),4.60(pd,J＝7.2,2.3Hz,1H),2.12-1.50(m,8H).
13C NMR(100MHz,DMSO-d
6)δ153.9,153.0,129.8,128.1,124.7,122.2,118.8,115.8,114.9,62.5,55.3,32.9,24.2.HRMS(ESI)m/z calculated for C
15H
18ClN
4O
2
+[M+H]
+:321.1118,found:321.1119；
化合物6y：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(粉白色固体，80％)；
对化合物6y进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ8.56(s,1H),8.22(d,J＝9.0Hz,1H),7.80(s,1H),7.65-7.24(m,10H),5.35(s,2H),4.64(p,J＝7.0Hz,1H),3.98(s,3H),2.89(s,1H),2.73(s,1H),2.13-1.54(m,8H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.6,150.7,149.2,147.1,134.5,129.8,129.0,128.6,128.5,123.4,122.6,122.1,121.9,118.9,108.4,101.3,70.7,62.5,56.5,32.9,24.2.HRMS(ESI)m/z calculated for C
31H
30ClN
6O
4
+[M+H]
+:585.2017,found:585.2015；
化合物7y：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(白色固体，48％)；
对化合物7y进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.65(s,1H),8.60(s,1H),8.55-8.47(m,2H),7.61(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.60(s,1H),2.40-1.62(m,8H).
13C NMR(100MHz,DMSO-d
6)δ165.2,153.1,152.6,152.5,151.4,149.4,146.6,138.4,136.7,130,89,124.2,123.5,122.5,122.0,121.9,121.7,112.0,109.1,106.4,67.0,56.5,31.7,24.0.HRMS(ESI)m/z calculated for C
24H
24ClN
6O
4
+[M+H]
+:495.1542,found:495.1544；
化合物9y：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-环戊基-1H-吡唑-4-基)脲(白色固体，66％)；
对化合物9y进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.33(s,1H),8.57(s,1H),8.39(s,1H), 8.23(d,J＝9.0Hz,1H),7.80(s,1H),7.73-7.38(m,4H),7.27(dd,J＝9.1,2.8Hz,1H),4.65(q,J＝7.0Hz,1H),4.30(t,J＝6.2Hz,2H),3.99(d,J＝4.9Hz,3H),3.14(d,J＝28.9Hz,6H),2.37-1.59(m,14H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.3,152.7,152.6,150.5,149.2,147.1,134.5,129.8,123.4,122.5,122.1,121.9,121.8,118.9,110.1,107.9,101.3,67.0,62.5,56.6,53.6,52.0,32.9,24.2,23.3.HRMS(ESI)m/z calculated for C
31H
37ClN
7O
4
+[M+H]
+:607.2596,found:607.2599；
化合物4z：1-(2-氯-4-羟基苯基)-3-(1-甲基-1H-吡唑-4-基)脲(白色固体，82％)；
对化合物4z进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.56(s,1H),8.78(s,1H),7.87(s,1H),7.79-7.69(m,2H),7.34(s,1H),6.82(d,J＝2.7Hz,1H),6.70(dd,J＝8.9,2.7Hz,1H),3.77(s,3H).
13C NMR(100MHz,DMSO-d
6)δ153.9,152.9,129.9,128.1,124.6,122.4,120.9,115.8,114.9,39.1.HRMS(ESI)m/z calculated for C
11H
12ClN
4O
2
+[M+H]
+:267.0649,found:267.0650；
化合物6z：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氯苯基)-3-(1-甲基-1H-吡唑-4-基)脲(粉白色固体，83％)；
对化合物6z进行检测，其检测结果如下：
1HNMR(400MHz,DMSO-d
6)δ9.15(s,1H),8.56(s,1H),8.31(d,J＝9.8Hz,1H),8.23(d,J＝9.0Hz,1H),7.77(s,1H),7.65-7.35(m,9H),7.28(dd,J＝9.1,2.7Hz,1H),5.35(s,2H),3.98(s,3H),3.79(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.7,152.5,150.7,149.2,136.5,129.9,129.0,128.6,128.7,123.5,122.2,121.9,110.2,108.49,101.38,70.7,56.5,39.1.HRMS(ESI)m/z calculated for C
27H
24ClN
6O
4
+[M+H]
+:531.1548,found:531.1549；
化合物7z：1-(2-氯-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-4-基)脲(白色固体，47％)；
对化合物7z进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.40(s,1H),8.90(s,1H),8.55-8.47(m,2H),7.61(d,J＝0.8Hz,1H),7.54-7.40(m,2H),7.40(d,J＝0.8Hz,1H),7.35-7.18(m,2H),4.30(s,3H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,153.1,152.6,152.5,151.4,149.4,148.3,137.4,136.7,131.1,127.72,123.5,122.5,122.0,121.9,121.7,118.0,109.1,106.7,56,5,39.0.HRMS(ESI)m/z calculated for C
20H
18ClN
6O
4
+[M+H]
+:441.8440,found:441.8441；
化合物9z：1-(2-氯-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-甲基-1H-吡唑-4-基)脲(白色固体，68％)；
对化合物9z进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.16(s,1H),8.56(s,1H),8.31(d,J＝11.2Hz,1H),8.23(d,J＝9.0Hz,1H),7.78(s,1H),7.54(q,J＝2.8Hz,2H),7.39(d,J＝15.3Hz,2H),7.28(dd,J＝9.0,2.7Hz,1H),4.24(t,J＝6.4Hz,2H),3.98(s,3H),2.56(t,J＝7.1Hz,2H),2.46(d,J＝5.6Hz,4H),2.03-1.95(m,2H),1.73-1.63(m,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.6,152.6,152.5,150.6,149.3,147.2,134.4,130.0,123.2,122.4,122.1,122.0,121.1,109.9,107.7,101.2,67.6,56.5,54.1,52.6,39.1,28.4,23.6.HRMS(ESI)m/z calculated for C
27H
31ClN
7O
4
+[M+H]
+:552.2126,found:552.2127；
化合物11：(2-氟-4-羟基苯基)氨基甲酸苯酯(淡黄固体，88％)；
对化合物11进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.84(s,1H),9.53(s,1H),7.40(t,J＝7.9Hz,2H),7.35-7.27(m,1H),7.27-7.11(m,3H),6.71-6.57(m,2H).
13C NMR(100MHz,DMSO-d
6)δ153.3,151.3,129.8,125.7,122.3,116.8,116.7,111.6,111.6,103.5,103.3.
19F NMR(376MHz,DMSO-d
6)δ-121.42.HRMS(ESI)m/z calculated for C
13H
12FNO
3
+[M+H]
+:249.0801,found:249.0808；
化合物15a：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，75％)；
对化合物12a进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.56(s,1H),8.90(s,1H),8.10(d,J＝1.7Hz,1H),7.67(t,J＝9.2Hz,1H),7.59-7.29(m,2H),7.29-7.03(m,2H),6.81-6.46(m,2H).
13C NMR(100MHz,DMSO-d
6)δ158.9,156.5,155.5,154.3,153.2,136.6,124.2,120.1,118.8,115.8,111.4,103.2.
19F NMR(376MHz,DMSO-d
6)δ-121.66,-126.10.HRMS(ESI)m/z calculated for C
13H
11F
2N
2O
2
+[M+H]
+:265.0783,found:265.0784；
化合物13a：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-3-(4-氟苯基)脲(粉白色固体，74％)；
对化合物13a进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.11(s,1H),8.57(d,J＝3.9Hz,2H),8.17(t,J＝9.1Hz,1H),7.57(s,1H),7.54-7.41(m,7H),7.41-7.33(m,2H),7.27-7.06(m,3H),5.35(s,2H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.8,152.6,151.3,150.7,149.2,136.5,136.2,129.0,128.7,128.5,121.6,120.4,120.3,118.6,115.9,115.7,110.7,110.5,110.2,108.5,101.3,70.7,56.5.
19F NMR(376MHz,DMSO-d
6)δ-121.15,-126.84.HRMS(ESI)m/z calculated for C
29H
23F
2N
4O
4
+[M+H]
+:529.1681,found:529.1683；
化合物14a：1-(2-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，62％)；
对化合物14a进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ10.77(s,1H),9.10(s,1H),8.57(d,J＝2.4Hz,1H),8.49(s,1H),8.16(t,J＝9.1Hz,1H),7.54(s,1H),7.52-7.45(m,2H),7.37(dd,J＝11.8,2.7Hz,1H),7.23(s,1H),7.18-7.10(m,3H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.1,155.0,152.8,152.4,151.3,150.3,149.4,136.2,121.6,120.3,120.3,118.6,115.9,115.7,110.5,110.1,109.4,101.6,56.4,55.3.
19F NMR(376MHz,DMSO-d
6)δ-121.15,-126.86.HRMS(ESI)m/z calculated for C
22H
17F
2N
4O
4
+[M+H]
+:439.1212,found:439.1214；
化合物15a：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(4-氟苯基)脲(白色固体，73％)；
对化合物15a进行检测，其检测结果如下：M.p.200.2-201.7℃；IR(KBr):3302,3075,2997,2830,1751,1374,1272,1029,867,766cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.54(s,1H),8.84-8.74(m,1H),8.58(s,1H),8.17(t,J＝9.1Hz,1H),7.57(s,1H),7.54-7.48(m,2H),7.41(s,1H),7.38(dd,J＝9.7,2.0Hz,1H),7.20-7.11(m,3H),4.31(d,J＝5.9Hz, 2H),3.99(s,3H),3.26-3.14(m,6H),2.25(d,J＝7.5Hz,2H),1.93(d,J＝6.6Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.9,152.7,150.5,149.2,147.2,136.4,125.7,121.8,120.2,120.1,118.5,115.9,115.7,110.7,110.5,110.2,108.0,101.3,66.7,56.6,53.5,51.7,25.5,23.1.
19F NMR(376MHz,DMSO-d
6)δ-121.15,-126.86.HRMS(ESI)m/z calculated for C
29H
30F
2N
5O
4
+[M+H]
+:550.2260,found:550.2262；
化合物12b：1-(2-氟-4-羟基苯基)-3-苯基脲(白色固体，75％)；
对化合物12b进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.56(s,1H),8.86(s,1H),8.12(d,J＝1.8Hz,1H),7.71(t,J＝9.2Hz,1H),7.55-7.41(m,2H),7.41-7.20(m,2H),7.14-6.79(m,1H),6.75-6.52(m,2H).
13C NMR(100MHz,DMSO-d
6)δ155.5,154.3,153.2,140.2,129.2,124.1,124.0,122.1,118.4,111.4,103.1.
19F NMR(376MHz,DMSO-d
6)δ-126.30.HRMS(ESI)m/z calculated for C
13H
12FN
2O
2
+[M+H]
+:247.0877,found:247.0879；
化合物13b：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-3-苯基脲(粉白色固体，74％)；
对化合物13b进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.06(s,1H),8.57(d,J＝8.1Hz,2H),8.20(t,J＝9.1Hz,1H),7.57(s,1H),7.55-7.41(m,7H),7.41-7.35(m,2H),7.31(t,J＝7.9Hz,2H),7.19-7.09(m,1H),7.00(t,J＝7.3Hz,1H),5.35(s,2H),3.98(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.24,155.2,152.7,152.7,150.8,149.2,147.2,147.1,139.9,136.6,129.4,129.0,128.6,128.5,125.7,125.6,122.6,121.6,118.6,110.7,110.5,110.3,108.5,101.3,70.7,56.7.
19F NMR(376MHz,DMSO-d
6)δ-126.95.HRMS(ESI)m/z calculated for C
29H
24FN
4O
4
+[M+H]
+:511.1776,found:511.1778；
化合物14b：1-(2-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-苯基脲(白色固体，62％)；
对化合物14b进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.09(s,1H),8.60(d,J＝2.4Hz,1H),8.49(s,1H),8.20(t,J＝9.1Hz,1H),7.54(s,1H),7.48(d,J＝7.8Hz,2H),7.37(dd,J＝11.8,2.6Hz,1H),7.31(t,J＝7.8Hz,2H),7.24(s,1H),7.13(dt,J＝8.9,1.8Hz,1H),7.02-6.97(m,1H),3.99(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.8,152.6,152.5,150.4,149.5,139.9,129.5,129.4,122.6,121.6,118.7,118.6,110.8,110.6,110.2,109.4,109.3,101.6,101.5,56.4,55.4.
19F NMR(376MHz,DMSO-d
6)δ-122.27.HRMS(ESI)m/z calculated for C
22H
18FN
4O
4
+[M+H]
+:421.1306,found:421.1308；
化合物15b：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-苯基脲(白色固体，73％)；
对化合物15b进行检测，其检测结果如下：M.p.190.4-191.9℃；IR(KBr):3306,3062,2954,2853,1649,1501,1233,1069,845,785cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.71(s,1H),8.93(t,J＝2.8Hz,1H),8.58(s,1H),8.17(t,J＝9.1Hz,1H),7.57(s,1H),7.53-7.47(m,2H),7.41(s,1H),7.36(dd,J＝11.7,2.7Hz,1H),7.33-7.26(m,2H),7.13(dt,J＝9.1,1.9Hz,1H),6.98(td,J＝7.3,1.3Hz,1H),4.33(t,J＝6.2Hz,2H),3.99(s,3H),3.30-2.94(m,6H),2.29(dq,J＝12.7,6.5Hz,2H),1.94(d,J＝14.8Hz,4H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.1,152.9,152.7,150.6,149.2,140.1,129.3,125.7,125.6,122.4,118.5,118.4,110.7,110.5,110.2,108.0,101.3,66.7,56.6,53.4,51.6,25.5,23.2.
19F NMR(376MHz,DMSO-d
6)δ-125.98.HRMS(ESI)m/z calculated for C
29H
31FN
5O
4
+[M+H]
+:532.2354,found:532.2356；
化合物12c：1-(2-氟-4-羟基苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，68％)；
对化合物12c进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ9.60(s,1H),8.54(s,1H),8.07(d,J＝1.6Hz,1H),7.75(s,1H),7.67(t,J＝9.2Hz,1H),7.37(s,1H),6.70–6.49(m,2H),4.48–4.35(m,1H),1.38(dd,J＝6.9,2.0Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ155.44,154.16,154.05,153.18,153.04,129.58,124.09,124.05,122.15,119.19,119.07,117.73,111.33,111.30,103.13,102.91,53.36,23.09.
19F NMR(376MHz,DMSO-d
6)δ-126.30(t,J＝11.1Hz).HRMS(ESI)m/z calculated for C
13H
16FN
4O
2
+[M+H]
+:278.2874,found:278.2876；
化合物13c：1-(4-((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，62％)；
对化合物13c进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ8.75(s,1H),8.55(d,J＝11.2Hz,2H),8.18(t,J＝9.1Hz,1H),7.80(d,J＝0.8Hz,1H),7.63–7.31(m,9H),7.11(ddd,J＝8.9,2.7,1.3Hz,1H),5.35(s,2H),4.44(hept,J＝6.7Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).
13C NMR(101MHz,DMSO-d
6)δ165.26,155.15,152.71,152.65,150.75,149.21,136.55,129.70,129.05,128.68,128.56,121.73,121.28,118.56,117.97,110.67,110.44,110.23,108.48,101.33,70.75,56.55,53.42,23.12.
19F NMR(376MHz,DMSO-d
6)δ-127.17(t,J＝10.3Hz).HRMS(ESI)m/z calculated for C
29H
28FN
6O
4
+[M+H]
+:542.5714,found:542.5715.
化合物14c:1-(2-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，58％)；
对化合物14c进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ8.75(s,1H),8.55(d,J＝11.2Hz,2H),8.18(t,J＝9.1Hz,1H),7.80(d,J＝0.8Hz,1H),7.82-7.42(m,9H),7.33(ddd,J＝8.9,2.7,1.3Hz,1H),5.45(s,2H),4.44(hept,J＝6.7Hz,1H),3.98(s,3H),1.40(d,J＝6.7Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.2,152.7,152.6,150.7,149.2,136.5,129.7,129.0,128.6,128.5,121.7,121.2,118.5,117.9,110.6,110.4,110.2,108.4,101.3,70.7,56.5,53.4,23.1.
19F NMR(376MHz,DMSO-d
6)δ-127.17.HRMS(ESI)m/z calculated for C
22H
22FN
6O
4
+[M+H]
+:453.1687,found:453.1688；
化合物15c：1-(2-氟-4-((6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，62％)；
对化合物15c进行检测，其检测结果如下：
1H NMR(400MHz,DMSO-d
6)δ8.94(s,1H),8.63(d,J＝2.4Hz,1H),8.56(s,1H),8.18(t,J＝9.1Hz,1H),7.80(s,1H),7.54(s,1H),7.37(dd,J＝15.7,9.7Hz,3H),7.11(ddd,J＝8.9,2.7,1.3Hz,1H),4.44(hept,J＝6.7Hz,1H),4.27(t,J＝6.4Hz,2H),3.98(s,3H),2.80(d,J＝28.0Hz,6H),2.09(p,J＝6.5Hz,2H),1.86-1.71(m,4H),1.40(d,J＝6.7Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ165.2,155.4,152.7,152.6,150.6,149.3,129.6,121.7,121.3,118.5,117.9,110.6,110.4,110.0,107.8,101.2,67.3,56.5,53.8,53.4,52.3,23.4,23.1.
19F NMR(376MHz,DMSO-d
6)δ-126.93.HRMS(ESI)m/z calculated for C
29H
35FN
7O
4
+[M+H]
+:564.2735,found:564.2738；
化合物17：1-(2-氯-4-((6-甲氧基-7-(2-(吡咯烷-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-3-(1-异丙基-1H-吡唑-4-基)脲(白色固体，60％)；
对化合物17进行检测，其检测结果如下：M.p.247.2-248.7℃；IR(KBr):3300,3070,2998,2832,1752,1381,1282,1039,877,765cm
-1.
1H NMR(400MHz,DMSO-d
6)δ9.20(s,1H),8.57(s,1H),8.32(s,1H),8.23(d,J＝9.1Hz,1H),7.81(s,1H),7.61-7.51(m,2H),7.42(d,J＝4.0Hz,2H),7.27(dd,J＝9.0,2.7Hz,1H),4.45(h,J＝6.7Hz,1H),4.34(t,J＝5.7Hz,2H),3.98(s,3H),2.97(d,J＝22.9Hz,2H),2.68(s,4H),1.77-1.70(m,4H),1.40(d,J＝6.6Hz,6H).
13C NMR(100MHz,DMSO-d
6)δ155.3,152.6,150.6,149.3,147.1,134.5,123.5,122.4,122.0,121.9,121.7,117.9,110.1,107.9,101.3,56.5,54.5,54.2,53.4,23.5,23.1.HRMS(ESI)m/z calculated for C
28H
33ClN
7O
4
+[M+H]
+:566.2283,found:566.2284。
测试例
酶学测试实验步骤：
采用了HTRF KinEASE-TKkit方法进行VEGFR激酶活性测定：(1)制备1X激酶反应缓冲液:1倍体积的5X激酶反应缓冲液和4倍体积的水；5mM MgCl
2；1mM DTT；(2)1mM MnCl
2在稀释板中用DMSO对化合物进行3倍梯度稀释，化合物最终起始浓度为1μM；(3)将步骤(2)中的化合物40倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟；(4)用1X的酶反应缓冲液配制准备2X激酶，向反应板中每孔加入2μL激酶；(5)向每孔加入1μl在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，室温放置10分钟；(6)用1X的酶反应缓冲液配制2.5xTK-substrate-biotin和ATP混合液，向反应板中加入2μl TK-substrate-biotin/ATP混合液；(7)用封板膜封住板子1000g离心30秒，室温反应50分钟；(8)用HTRF检测缓冲液配制4X Sa-XL 665；(9)每孔加入5μl Sa-XL 665和5μLTK-antibody-Cryptate，1000g离心30秒，室温反应1小时。(10)用BMG酶标仪读615nm(Cryptate)和665nm(XL665)的荧光信号。计算IC50并绘制化合物的抑制曲线：利用非线性拟合公式来得到化合物的IC50(半数抑制浓度)：用Graphpad7.0软件进行数据分析，测试结果如表2所示：
表2激酶活性测试结果(对VEGFR蛋白的IC
50值)
| 化合物 | VEGFR1 | VEGFR2 | VEGFR3 |
| 9a | 1.41 | 0.21 | 4.18 |
| 9b | 1.51 | 0.56 | 7.88 |
| 9c | 22.44 | 6.22 | 11.59 |
| 9d | 2.18 | 0.26 | 0.39 |
| 9e | 0.73 | 0.51 | 0.35 |
| 9f | 1.36 | 1.36 | 1.43 |
| 9g | 1.03 | 0.66 | 0.58 |
| 9h | 0.86 | 0.76 | 0.38 |
| 9i | 1.07 | 0.51 | 4.93 |
| 9j | 0.76 | 0.67 | 0.58 |
| 9k | 0.98 | 0.71 | 0.42 |
| 9l | 2.89 | 0.34 | 0.80 |
| 9m | 7.45 | 0.74 | 3.56 |
| 9n | 69.89 | 4.74 | 8.97 |
| 9o | 3.16 | 0.59 | 0.87 |
| 9p | 10.22 | 6.43 | 7.10 |
| 9q | 13.66 | 1.85 | 3.32 |
| 9r | 8.87 | 0.70 | 3.41 |
| 9s | 3.43 | 0.55 | 2.04 |
| 9t | 3.12 | 0.36 | 1.23 |
| 9u | 0.88 | 0.19 | 0.18 |
| 9v | 8.39 | 1.13 | 2.46 |
| 9w | 535.90 | 28.25 | 500.80 |
| 9x | 3.52 | 0.32 | 5.10 |
| 9y | 0.99 | 0.26 | 0.18 |
| 9z | 36.96 | 2.96 | 16.55 |
| 15a | 9.29 | 3.88 | 48.52 |
| 15b | 12.04 | 1.95 | 54.55 |
| 15c | 2.11 | 0.51 | 0.43 |
| 17 | 5.31 | 0.93 | 1.21 |
| 瑞格菲尼 | 15 | 5.2 | 51 |
由表2可知，合成的化合物在VEGFR1、VEGFR2和VEGFR3上都显示出来强效的抑制效果；大多数化合物对于VEGFR1、VEGFR2和VEGFR3的抑制活性均超过了阳性药物瑞格菲尼。
测试例2
动物实验：
实验过程为：收集生长状态良好的肿瘤细胞，用1×PBS洗涤2次，细胞计数仪计算细胞总数，用1XPBS将细胞液稀释成1×10
7个/mL。每只小鼠接种细胞量为1×10
6个，取100μL细胞悬浮液接种至小鼠前肢腋窝处。待肿瘤平均体积超过100cm
3时(个体间肿瘤体积差异不超过10％)，将小鼠随机分组，每组8只。药物每两天口服灌胃给药，100mg/kg。给药结束后，用安乐死的方法处死小鼠，测量肿瘤重量与体积，并计算肿瘤抑制率；测试结果如表3所示：
表3不同物质对不同肿瘤细胞的抑制率(％)
由表3可知，相对于阳性对照药物瑞格菲尼来说，化合物9a，9h，9u和9y都表现出来强效的抑制多种肿瘤细胞增殖的活性。大多数化合物抑制肿瘤增殖的效果都强于或不弱于阳性对照药物瑞格菲尼。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (17)
- 一种喹唑啉衍生物，其特征在于，具有式Ⅰ所示结构：
其中，n为1～10的正整数；R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基；X为卤素。 - 如权利要求1所述的喹唑啉衍生物，其特征在于，所述取代的苯基中的取代基团为卤素、取代或未取代的烷基、取代或未取代的烷氧基、或芳香基；所述取代的苯基中的取代基团的个数为1或2；所述取代的杂环基或未取代的杂环基中杂环基中的杂原子为N、O和S中的一种或几种；所述取代的杂环基中的取代基团为烷基；X为F或Cl。
- 如权利要求1或2所述的喹唑啉衍生物，其特征在于，所述喹唑啉衍生物为：
- 权利要求1～3任一项所述喹唑啉衍生物的制备方法，其特征在于，包括以下步骤：将具有式Ⅷ所示结构的化合物、碳酸钾、具有式Ⅸ所示结构的化合物和第五有机溶剂混合，进行第一缩合反应，得到所述喹唑啉衍生物；
式Ⅷ～式Ⅸ中，X为卤素；n为1～10的正整数；R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。 - 如权利要求4所述的制备方法，其特征在于，所述具有式Ⅷ所示结构的化合物的制备方法，包括以下步骤：将具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物、吡啶和第一有机溶剂混合，进行酰胺化反应，所述具有式Ⅳ所示结构的化合物；将具有式Ⅳ所示结构的化合物、R-NH 2、N,N-二异丙基乙胺和第二有机溶剂混合，进行回流反应，得到具有式Ⅴ所示结构的化合物；将所述具有式Ⅴ所示结构的化合物、具有式Ⅵ所示结构的化合物和第三有机溶剂混合，在碱性条件下进行第二缩合反应，得到具有式Ⅶ所示结构的化合物；将所述具有式Ⅶ所示结构的化合物、钯碳催化剂和第四有机溶剂混合后，通入氢气，进行脱保护反应，得到具有式Ⅷ所示结构的化合物；
式Ⅱ～式Ⅶ中，X为卤素；n为1～10的正整数；式Ⅱ～式Ⅶ和R-NH 2中，R为烷基、取代的苯基、未取代的苯基、取代的杂环基或未取代的杂环基。 - 如权利要求4所述的制备方法，其特征在于，所述具有式Ⅷ所示结构的化合物、碳酸钾和具有式Ⅸ所示结构的化合物的摩尔比为(0.72～0.75):1.45:(0.798～0.89)。
- 如权利要求4所述的制备方法，其特征在于，所述第一缩合反应的温度为60～80℃，时间为6～8h。
- 如权利要求5所述的制备方法，其特征在于，所述第二缩合反应的温度为60～80℃，时间为4～6h。
- 如权利要求5所述的制备方法，其特征在于，所述具有式Ⅱ所示结构的化合物、具有式Ⅲ所示结构的化合物和吡啶的摩尔比为1：(1.1～1.2)：3。
- 如权利要求5所述的制备方法，其特征在于，所述具有式Ⅳ所示结构的化合物、R-NH 2和N,N-二异丙基乙胺的摩尔比为1：(2～2.5)：(3～4)。
- 如权利要求5所述的制备方法，其特征在于，所述具有式Ⅴ所示结构的化合物和具有式Ⅵ所示结构的化合物的摩尔比为(1.2～1.5)：1。
- 权利要求1～3任一项所述喹唑啉衍生物或权利要求4～11任一项所述的制备方法制备得到的喹唑啉衍生物的溶剂合物及其可溶性盐。
- 权利要求1～3任一项所述喹唑啉衍生物或权利要求12所述的喹唑啉衍生物的溶剂合物及其可溶性盐在制备治疗和/或预防癌症的药物中的应用。
- 如权利要求13所述的应用，其特征在于，所述癌症为VEGFR高表达的恶性肿瘤。
- 如权利要求13或14所述的应用，其特征在于，所述癌症为结直肠癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、肾癌或神经母细胞癌。
- 一种治疗和/或预防癌症的方法，其特征在于，采用权利要求1～3任一项所述喹唑啉衍生物或权利要求12所述的喹唑啉衍生物的溶剂合物进行治疗和/或预防。
- 根据权利要求16所述的方法，其特征在于，所述喹唑啉衍生物的给药量为100mg/kg，每两天口服灌胃给药。
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| CN114920703A (zh) * | 2022-05-26 | 2022-08-19 | 天津济坤医药科技有限公司 | 一种喹唑啉衍生物及其制备方法和应用 |
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| CN104292170B (zh) * | 2014-09-22 | 2016-06-29 | 广西师范大学 | 具有抗肿瘤作用的喹唑啉-芳基脲衍生物及其应用 |
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