CN116265440B - 一种水杨酮拼接吡啶酮类化合物及其制备方法及应用 - Google Patents
一种水杨酮拼接吡啶酮类化合物及其制备方法及应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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Abstract
本发明公开了一种水杨酮拼接吡啶酮类化合物，本发明以各种取代的3‑烯烃色酮氧化吲哚/苯并呋喃酮1与各种胺源2，在溶剂中，在无催化剂和室温作用下，进行Michael加成引发的开环和重新关环反应，获得水杨酮拼接吡啶酮类化合物3，该类化合物包含潜在生物活性水杨酮骨架和吡啶酮，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。且该骨架化合物可以作为新型冠状病毒3CL水解酶潜在抑制剂。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。
Description
技术领域
本发明涉及化学技术和药学技术领域，尤其是一种水杨酮拼接吡啶酮类化合物及其制备方法及应用。
背景技术
根据药物设计的活性骨架拼接原理，把两个或多个具有生物活性骨架拼接成一个潜在生物活性的多骨架分子在有机化学和医药化学中是极其重要的研究领域。(1)水杨酮骨架广泛存在许多天然产物中，具有较强的生物活性，例如，Tenellone A、Oxybenzone、Dioxybenzone、Mexenone和Sulisobenzone。这些化合物在解除病痛、经济发展中起着重要作用。(2)吡啶酮骨架也广泛存在许多天然产物中，例如，Tenellin,Ilicicolin H,LeporinA,Leporin B和Sambutoxin，在生物碱中占有重要的地位。由于其明显的生物活性以及独特的结构，吸引了许多化学工作者及医药化学团队的广泛关注。鉴于水杨酮骨架和吡啶酮骨架具有潜在的生物活性。因此，把茶香酮骨架拼接到氧化吲哚骨架上，合成一系列新的潜在多活性官能团的水杨酮拼接吡啶酮类化合物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。
新型冠状病毒3CL水解酶(3CLpro)在病毒复制过程中能将病毒复制酶多聚蛋白切割成必须的功能蛋白。因此,以新型冠状病毒3CL水解酶为COVID-19的治疗靶点进行药物筛选具有重要意义。分子对接技术通过特定靶点与配体的化学结合作用，可以达到分析活性成分的潜在抑制作用。
发明内容
本发明的目的是：提供水杨酮拼接吡啶酮类化合物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。
本发明还发现该类化合物在作为新型冠状病毒3CL水解酶抑制剂的药物应用。
本发明是这样实现的：一种水杨酮拼接吡啶酮类化合物，该化合物具有如下通式(Ⅰ)的结构：
式中，R1为氟、氯、甲氧基、羟基或氢；R2为氟、氯、溴、异丙基、甲基、甲氧基或氢；R’为烷基或氢；X为NBoc或O。
具体为如下化合物之一：
水杨酮拼接吡啶酮类化合物的制备方法，将各种取代的3-烯烃色酮氧化吲哚/苯并呋喃酮1与各种胺源2，在溶剂中，在无催化剂和室温作用下，进行Michael加成引发的开环和重新关环反应，获得水杨酮拼接吡啶酮类化合物3。
合成路线举例如下：
式中，R1为氟、氯、甲氧基、羟基或氢；R2为氟、氯、溴、异丙基、甲基、甲氧基或氢；R’为烷基或氢；X为NBoc或O。
反应机理举例如下：
所述的各种胺源2为醋酸铵、碳酸氢铵、碳酸铵、氨水或烷基胺。
所述的有机溶剂为水、甲苯、乙醇、二氯甲烷、氯仿或乙腈。
将各种取代的3-烯烃色酮氧化吲哚/苯并呋喃酮1与各种胺源2，在溶剂中，在无催化剂和室温作用下，进行Michael加成引发的开环和重新关环反应，获得水杨酮拼接吡啶酮类化合物3,反应时间为2-6小时。
水杨酮拼接吡啶酮类化合物作为新型冠状病毒3CL水解酶潜在抑制剂的药物应用。
通过采用上述技术方案，以各种取代的3-烯烃色酮氧化吲哚/苯并呋喃酮1与各种胺源2，在溶剂中，在无催化剂和室温作用下，进行Michael加成引发的开环和重新关环反应，获得水杨酮拼接吡啶酮类化合物3，该类化合物包含潜在生物活性水杨酮骨架和吡啶酮，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。且该骨架化合物可以作为新型冠状病毒3CL水解酶潜在抑制剂。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。
附图说明
图1及图2为本发明的实施例的化合物3aa谱图数据；
图3及图4为本发明的实施例的化合物3ca谱图数据；
图5及图6为本发明的实施例的化合物3ka谱图数据；
图7为本发明的实施例的化合物3ab和3ga单晶图；
图8为本发明新型冠状病毒3CL水解酶蛋白信息图。
图9为本发明化合物3ab和3ga的分子对接模型示意图。
具体实施方式
本发明的实施例一：在反应管中依次加入116.7mg 3-烯烃色酮氧化吲哚酮1a(0.30mmol)和1.5mL氨水溶液，在室温中搅拌反应5h，TLC检测至基本反应完全，旋干溶剂后，经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯)＝7:1)纯化得106.0mg化合物3aa，淡黄色固体,熔点：189.8-190.5℃；产率87％。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.36(s,9H),6.81-6.85(m,1H),6.98(d,J＝8.4Hz,1H),7.03-7.07(m,1H),7.14(d,J＝7.6Hz,1H),7.26-7.30(m,1H),7.41-7.45(m,1H),7.50(d,J＝8.0Hz,1H),7.58(s,1H),7.65(br s,1H),7.84(s,1H),7.93(s,1H),11.35(br s,1H),13.14(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,79.4,117.6,117.7,118.2,118.3,123.1,123.6,127.4,128.5,130.0,130.8,135.5,135.8,138.3,141.4,152.8,161.5,162.7,194.0；HRMS(ESI-TOF)m/z:Calcd.for C23H22N2NaO5[M+Na]+:429.1421；Found:429.1425。
化合物3ab至3bg的制备方法同化合物3aa，投料比与化合物3aa相同，反应产率见表1和表2，但需强调的是本发明的化合物不限于表1和表2所表示的内容。
表1为一种水杨酮拼接吡啶酮类化合物的化学结构
表2为一种水杨酮拼接吡啶酮类化合物的化学结构
本实施例一制备化合物3ab:黄色固体,熔点：228.2-229.3℃；产率82％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.35(s,9H),6.92(d,J＝8.8Hz,1H),7.03-7.07(m,1H),7.13-7.15(m,1H),7.23-7.27(m,1H),7.34-7.37(m,1H),7.45(s,1H),7.48(s,1H),7.63(br s,1H),7.77(s,1H),7.89(s,1H),11.12(br s,1H),12.94(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,79.5,117.6,118.6,119.3,122.9,123.7,127.5,128.5,129.5,129.9,130.4,135.2,135.7,138.5,140.8,152.8,159.7,162.5,192.9；HRMS(ESI-TOF)m/z:Calcd.for C23H21ClN2NaO5[M+Na]+:463.1031；Found:463.1026。
本实施例一制备化合物3ac:黄色固体,熔点：200.1-201.3℃；产率73％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.36(s,9H),6.90(d,J＝9.2Hz,1H),7.06-7.09(m,1H),7.16-7.19(m,1H),7.26-7.31(m,1H),7.46(s,1H),7.49-7.52(m,1H),7.62(s,1H),7.66(br s,1H),7.82(s,1H),7.91(s,1H),11.16(br s,1H),12.92(br s,1H)；13C NMR(CDCl3,100MHz)δ:26.1,78.3,108.6,116.4,118.0,118.5,122.5,128.7,131.3,134.6,136.8,137.2,139.7,151.6,159.0,161.4,191.7；HRMS(ESI-TOF)m/z:Calcd.for C23H21BrN2NaO5[M+Na]+:507.0526；Found:507.0527。
本实施例一制备化合物3ad:黄色固体,熔点：192.9-193.5℃；产率73％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.36(s,9H),2.22(s,3H),6.90(d,J＝8.8Hz,1H),7.05-7.09(m,1H),7.15-7.18(m,1H),7.24-7.31(m,3H),7.55(s,1H),7.67(br s,1H),7.85(s,1H),7.94(s,1H),11.13(br s,1H),13.16(br s,1H)；13C NMR(CDCl3,100MHz)δ:20.7,28.3,80.4,118.5,118.6,119.5,124.6,128.5,129.5,131.0,131.2,131.4,136.9,137.7,139.1,142.5,153.8,160.5,163.8,195.0；HRMS(ESI-TOF)m/z:Calcd.for C24H24N2NaO5[M+Na]+:443.1577；Found:443.1581。
本实施例一制备化合物3ae:黄色固体,熔点：165.8-166.3℃；产率84％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.12(d,J＝7.2Hz,6H),1.35(s,9H),2.78-2.81(m,1H),6.92(d,J＝9.2Hz,1H),7.02-7.06(m,1H),7.14-7.17(m,1H),7.24-7.28(m,1H),7.31-7.34(m,2H),7.56(s,1H),7.64(br s,1H),7.82(d,J＝2.4Hz,1H),7.93(d,J＝2.4Hz,1H),11.11(br s,1H),13.06(br s,1H)；13C NMR(CDCl3,100MHz)δ:23.0,27.3,32.2,79.4,117.5,117.6,118.5,123.5,128.0,128.4,129.9,133.9,135.9,138.1,138.5,141.5,152.7,159.6,162.6,194.0；HRMS(ESI-TOF)m/z:Calcd.for C26H28N2NaO5[M+Na]+:471.1890；Found:471.1883。
本实施例一制备化合物3af:黄色固体,熔点：237.2-237.8℃；产率71％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.36(s,9H),2.32(s,3H),6.88(s,1H),7.05-7.08(m,1H),7.15-7.19(m,1H),7.26-7.30(m,1H),7.47(s,1H),7.51(s,1H),7.65(br s,1H),7.81(s,1H),7.91(s,1H),11.23(br s,1H),13.00(br s,1H)；13C NMR(CDCl3,100MHz)δ:19.8,27.3,79.4,116.6,117.9,119.8,123.5,123.6,128.5,129.9,130.0,130.4,135.8,138.0,141.0,144.9,152.7,159.9,162.6,192.7；HRMS(ESI-TOF)m/z:Calcd.for C24H23ClN2NaO5[M+Na]+:477.1188；Found:477.1193。
本实施例一制备化合物3ag:黄色固体,熔点：151.2-151.9℃；产率77％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.36(s,9H),6.84-6.88(m,1H),7.00(d,J＝8.0Hz,1H),7.14(d,J＝2.4Hz,1H),7.24-7.26(m,1H),7.43-7.51(m,3H),7.62(br s,1H),7.92-7.95(m,2H)；13C NMR(CDCl3,100MHz)δ:28.3,80.8,118.6,118.9,119.3,119.4,129.4,129.7,130.5,131.7,135.6,136.7,142.8,153.6,162.6,163.5,194.7；HRMS(ESI-TOF)m/z:Calcd.for C23H21ClN2NaO5[M+Na]+:463.1031；Found:463.1036。
本实施例一制备化合物3ah:黄色固体,熔点：208.2-209.7℃；产率72％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.34(s,9H),3.68(s,3H),6.69(d,J＝2.8Hz,1H),6.81-6.86(m,2H),6.98(d,J＝8.0Hz,1H),7.32(br s,1H),7.40-7.45(m,2H),7.49-7.52(m,1H),7.85(s,1H),7.93(d,J＝2.8Hz,1H),11.35(br s,1H),13.15(br s,1H)；13CNMR(CDCl3,100MHz)δ:28.4,55.6,80.2,114.7,116.0,118.7,119.1,119.3,129.7,130.8,131.8,136.5,139.5,142.2,156.8,162.5,163.5,195.0；HRMS(ESI-TOF)m/z:Calcd.for C24H24N2NaO6[M+Na]+:459.1527；Found:459.1531。
本实施例一制备化合物3ai:黄色固体,熔点：245.7-246.8℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.37(s,9H),6.97-7.01(m,1H),7.13-7.28(m,4H),7.50-7.53(m,1H),7.90(s,2H),8.41(br s,1H),10.14(br s,1H),12.63(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:28.4,79.4,115.5(d,JCF＝22.1Hz),115.9(d,JCF＝24.4Hz),117.5(d,JCF＝20.5Hz),117.6,118.3(d,JCF＝7.3Hz),119.4(d,JCF＝23.3Hz),126.4(d,JCF＝6.7Hz),128.5,133.3,139.7,142.8,151.9,153.7,156.8(d,JCF＝233.7Hz),158.9(d,JCF＝240.2Hz),161.9,190.3；HRMS(ESI-TOF)m/z:Calcd.for C23H20F2N2NaO5[M+Na]+:465.1232；Found:465.1230。
本实施例一制备化合物3aj:黄色固体,熔点：223.4-224.3℃；产率72％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.35(s,9H),6.89-7.02(m,3H),7.37-7.40(m,2H),7.47(s,1H),7.56(br s,1H),7.90-7.92(m,1H),11.10(br s,1H),12.99(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,79.7,115.2(d,JCF＝22.4Hz),116.2(d,JCF＝23.4Hz),117.5,118.5,119.4,123.0,129.4,131.8,135.2,138.7,141.0,158.6(d,JCF＝237.7Hz),162.3,192.7；HRMS(ESI-TOF)m/z:Calcd.for C23H20ClFN2NaO5[M+Na]+:481.0937；Found:481.0941。
本实施例一制备化合物3ak:黄色固体,熔点：240.5-241.4℃；产率76％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.13(d,J＝7.2Hz,6H),1.34(s,9H),2.78-2.82(m,1H),6.88-6.94(m,2H),6.96-7.01(m,1H),7.31-7.35(m,2H),7.44(s,1H),7.57(br s,1H),7.93-7.94(m,2H),11.06(br s,1H),13.07(br s,1H)；13C NMR(CDCl3,100MHz)δ:23.0,27.2,32.2,79.5,115.1(d,JCF＝22.3Hz),116.2(d,JCF＝23.3Hz),117.4,117.7,118.4,127.9,131.8,131.9,134.0,138.5,138.6,141.7,152.9,158.0(d,JCF＝240.1Hz),159.6,162.3,193.8；HRMS(ESI-TOF)m/z:Calcd.for C26H27FN2NaO5[M+Na]+:489.1796；Found:489.1791。
本实施例一制备化合物3al:黄色固体,熔点：161.4-161.9℃；产率70％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.33(s,9H),2.22(s,3H),6.88(d,J＝8.4Hz,2H),6.96-7.01(m,1H),7.24-7.27(m,1H),7.43(s,1H),7.57(br s,1H),7.91-7.93(m,2H),11.07(br s,1H),13.13(br s,1H)；13C NMR(CDCl3,100MHz)δ:19.6,27.2,79.6,115.1(d,JCF＝22.1Hz),116.2(d,JCF＝23.2Hz),117.4,117.6,118.4,127.5,130.2,131.8,136.7,138.4,141.6,152.9,158.7(d,JCF＝243.2Hz),159.6,162.4,193.7；HRMS(ESI-TOF)m/z:Calcd.for C24H22ClFN2NaO5[M+Na]+:495.1093；Found:495.1094。
本实施例一制备化合物3am:黄色固体,熔点：250.2-251.0℃；产率84％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.35(s,9H),6.94-6.97(m,1H),7.09-7.12(m,1H),7.19-7.24(m,1H),7.34(d,J＝2.4Hz,1H),7.37-7.40(m,1H),7.55(d,J＝8.8Hz,1H),7.84-7.87(m,2H),8.47(br s,1H),10.11(br s,1H),12.61(br s,1H)；13CNMR(DMSO-d6,100MHz)δ:28.4,79.7,115.9(d,JCF＝24.4Hz),117.5,118.3(d,JCF＝7.2Hz),119.5(d,JCF＝23.2Hz),126.1,126.3,126.4,128.4,128.6,130.7,132.1,136.1,139.8,142.9,152.0,153.4,155.7(d,JCF＝235.6Hz),161.9,190.3；HRMS(ESI-TOF)m/z:Calcd.forC23H20ClFN2NaO5[M+Na]+:481.0937；Found:481.0941。
本实施例一制备化合物3an:黄色固体,熔点：156.4-156.7℃；产率71％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.37(s,9H),6.98(d,J＝8.8Hz,1H),7.16(d,J＝2.4Hz,1H),7.26-7.29(m,1H),7.40-7.43(m,2H),7.49(d,J＝2.4Hz,1H),7.65(br s,1H),7.92-7.95(m,2H),11.13(br s,1H),12.85(br s,1H)；13C NMR(CDCl3,100MHz)δ:26.3,78.8,116.6,117.4,118.5,122.0,127.4,127.6,128.4,128.5,133.5,134.4,137.6,140.2,158.9,161.2,191.7；HRMS(ESI-TOF)m/z:Calcd.for C23H20Cl2N2NaO5[M+Na]+:497.0641；Found:497.0646。
本实施例一制备化合物3ao:黄色固体,熔点：165.4-166.4℃；产率73％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.36(s,9H),2.24(s,3H),6.91(d,J＝8.4Hz,1H),7.16(d,J＝2.4Hz,1H),7.25-7.29(m,3H),7.49(s,1H),7.65(br s,1H),7.94-7.96(m,2H),11.08(br s,1H),13.10(br s,1H)；13C NMR(CDCl3,100MHz)δ:19.6,27.3,79.7,117.3,117.7,118.5,127.5,128.4,129.6,130.2,134.6,136.8,138.3,141.8,152.5,159.5,162.3,193.7；HRMS(ESI-TOF)m/z:Calcd.for C24H23ClN2NaO5[M+Na]+:477.1188；Found:477.1191。
本实施例一制备化合物3ap:黄色固体,熔点：197.7-198.5℃；产率72％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.42(s,9H),6.98-7.01(m,1H),7.15-7.35(m,4H),7.72(s,1H),7.86-7.91(m,2H),8.62(br s,1H),10.15(br s,1H),12.67(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:28.4,80.0,115.9(d,JCF＝23.2Hz),117.6,118.3(d,JCF＝8.1Hz),119.4(d,JCF＝23.2Hz),123.2,124.2,126.4,126.5,128.5,128.7,132.9,133.2,138.6,139.9,142.8,151.9,153.3,155.6(d,JCF＝235.3Hz),162.0,190.3；HRMS(ESI-TOF)m/z:Calcd.for C23H20ClFN2NaO5[M+Na]+:481.0937；Found:481.0951。
本实施例一制备化合物3aq:黄色固体,熔点：200.2-200.5℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.40(s,9H),6.98(d,J＝8.8Hz,1H),7.20-7.23(m,1H),7.30-7.32(m,2H),7.40-7.43(m,1H),7.69(s,1H),7.83(d,J＝2.4Hz,1H),7.89(d,J＝2.4Hz,1H),8.60(br s,1H),10.41(br s,1H),12.64(br s,1H)；13CNMR(DMSO-d6,100MHz)δ:28.4,80.0,117.6,118.8,123.4,124.2,127.5,128.5,128.8,129.2,132.3,132.9,133.2,138.6,139.9,142.8,153.2,154.4,162.1,190.1；HRMS(ESI-TOF)m/z:Calcd.for C23H20Cl2N2NaO5[M+Na]+:497.0641；Found:497.0641。
本实施例一制备化合物3ar:黄色固体,熔点：181.4-182.3℃；产率75％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.44(s,9H),6.98(d,J＝8.8Hz,1H),7.25-7.28(m,1H),7.35(d,J＝8.4Hz,1H),7.46(d,J＝2.4Hz,1H),7.57-7.60(m,1H),7.73(d,J＝1..6Hz,1H),7.87(d,J＝2.4Hz,1H),7.92(d,J＝2.8Hz,1H),8.64(br s,1H),10.48(br s,1H),12.68(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:28.4,80.0,110.8,117.6,119.3,123.2,124.2,128.0,128.5,128.7,132.0,132.9,133.2,135.2,138.5,139.8,142.8,153.2,154.8,162.0,190.0；HRMS(ESI-TOF)m/z:Calcd.for C23H20BrClN2NaO5[M+Na]+:541.0136；Found:541.0142。
本实施例一制备化合物3as:黄色固体,熔点：214.5-215.5℃；产率72％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.34(s,9H),3.70(s,3H),6.70(d,J＝2.8Hz,1H),6.82-6.85(m,1H),6.94-6.98(m,1H),7.15-7.22(m,3H),7.47(br s,1H),7.88(s,1H),7.92(d,J＝2.4Hz,1H),10.99(br s,1H),13.04(br s,1H)；13C NMR(CDCl3,100MHz)δ:26.3,53.6,78.3,112.9,114.7(d,JCF＝23.4Hz),116.6(d,JCF＝22.4Hz),118.1,121.9,127.7,137.5,139.7,153.6(d,JCF＝239.9Hz),154.9,156.6,161.5,192.0；HRMS(ESI-TOF)m/z:Calcd.for C24H23FN2NaO6[M+Na]+:477.1432；Found:477.1435。
本实施例一制备化合物3at:黄色固体,熔点：183.2-184.4℃；产率84％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.36(s,9H),3.77(s,3H),6.87(d,J＝3.2Hz,1H),6.94-6.97(m,1H),7.00(d,J＝8.8Hz,1H),7.32(d,J＝2.4Hz,1H),7.37-7.44(m,2H),7.86-7.88(m,2H),8.15(br s,1H),10.42(br s,1H),12.58(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:28.5,55.8,79.1,114.4,116.0,117.5,118.8,123.4,127.5,129.2,129.7,129.9,132.3,139.5,142.6,153.9,154.4,156.5,162.0,190.1；HRMS(ESI-TOF)m/z:Calcd.for C24H23ClN2NaO6[M+Na]+:493.1137；Found:493.1138。
本实施例一制备化合物3au:黄色固体,熔点：158.5-158.7℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.27(s,9H),3.68(s,3H),6.78(d,J＝2.8Hz,1H),6.85-6.88(m,2H),7.28(d,J＝8.0Hz,1H),7.34(d,J＝2.4Hz,1H),7.44-7.47(m,2H),8.06(br s,1H),10.36(br s,1H),12.48(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:28.5,55.8,79.1,110.8,114.4,116.0,117.5,119.3,128.1,129.7,129.9,132.0,135.1,139.5,142.6,153.9,154.9,156.5,162.0,190.0；HRMS(ESI-TOF)m/z:Calcd.forC24H23BrN2NaO6[M+Na]+:537.0632；Found:537.0627。
本实施例一制备化合物3av:黄色固体,熔点：154.8-155.5℃；产率70％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.13(d,J＝7.2Hz,6H),1.33(s,9H),2.79-2.82(m,1H),3.70(s,3H),6.71(d,J＝2.8Hz,1H),6.81-6.84(m,1H),6.93(d,J＝7.2Hz,1H),7.27-7.35(m,3H),7.47(br s,1H),7.86(s,1H),7.94(d,J＝2.4Hz,1H),11.13(br s,1H),13.07(br s,1H)；13C NMR(CDCl3,100MHz)δ:22.3,26.6,31.4,53.8,78.3,113.0,114.3,116.7,116.9,117.6,127.3,128.0,129.2,133.1,137.4,137.8,140.5,152.5,155.0,158.9,161.7,193.3；HRMS(ESI-TOF)m/z:Calcd.for C27H30N2NaO6[M+Na]+:501.1996；Found:501.1992。
本实施例一制备化合物3aw:黄色固体,熔点：152.3-152.9℃；产率89％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.33(s,9H),2.30(s,3H),3.69(s,3H),6.69(d,J＝3.2Hz,1H),6.79-8.02(m,1H),6.87(s,1H),7.27(br s,1H),7.47-7.48(m,2H),7.83(d,J＝2.0Hz,1H),7.89(d,J＝2.4Hz,1H),11.22(br s,1H),13.02(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:19.8,27.3,54.5,79.2,113.9,114.7,116.7,117.6,119.7,123.5,128.7,130.0,130.1,138.3,140.8,144.8,155.8,159.8,162.4,192.6；HRMS(ESI-TOF)m/z:Calcd.for C25H25ClN2NaO6[M+Na]+:507.1293；Found:507.1297。
本实施例一制备化合物3ba:黄色固体,熔点：102.7-102.9℃；产率91％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:6.84-6.99(m,4H),7.18-7.22(m,1H),7.29-7.42(m,3H),7.75(s,1H),7.93-7.95(m,1H),9.54(br s,1H),10.23(br s,1H),12.43(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:117.0,117.7,119.5,119.7,123.8,125.6,129.0,129.7,130.2,131.2,133.0,139.1,141.6,155.6,155.9,162.3,192.1；HRMS(ESI-TOF)m/z:Calcd.for C18H13NNaO4[M+Na]+:330.0737；Found:330.0742。
本实施例一制备化合物3bb:黄色固体,熔点：100.8-101.2℃；产率89％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:6.87-7.02(m,3H),7.20-7.34(m,4H),7.81(d,J＝2.4Hz,1H),7.97(s,1H),9.56(br s,1H),10.15(br s,1H),12.47(brs,1H)；13CNMR(DMSO-d6,100MHz)δ:115.9(d,JCF＝24.3Hz),116.9,117.3,118.1(d,JCF＝7.3Hz),119.2(d,JCF＝23.1Hz),119.5,123.7,126.6,126.7,129.1,129.7,131.2,138.7,142.1,151.8,155.4(d,JCF＝235.5Hz),155.5,162.3,190.5；HRMS(ESI-TOF)m/z:Calcd.forC18H12FNNaO4[M+Na]+:348.0643；Found:348.0641。
本实施例一制备化合物3bc:黄色固体,熔点：103.2-104.4℃；产率92％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:6.89-6.96(m,2H),7.03(d,J＝8.8Hz,1H),7.23-7.27(m,1H),7.33-7.35(m,1H),7.40(d,J＝2.8Hz,1H),7.45-7.48(m,1H),7.81(d,J＝2.4Hz,1H),7.97(d,J＝2.4Hz,1H),9.55(br s,1H),10.43(br s,1H),12.46(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:116.9,117.2,118.7,119.4,123.3,123.7,127.7,129.1,129.2,129.7,131.2,132.1,138.6,142.1,154.3,155.5,162.3,190.2；HRMS(ESI-TOF)m/z:Calcd.for C18H12ClNNaO4[M+Na]+:364.0347；Found:364.0349。
本实施例一制备化合物3bd:黄色固体,熔点：82.5-83.4℃；产率91％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.71(s,3H),6.84-6.91(m,4H),6.98-7.01(m,1H),7.18-7.22(m,1H),7.28-7.30(m,1H),7.76(d,J＝2.4Hz,1H),7.94(d,J＝2.8Hz,1H),9.53(br s,1H),9.68(br s,1H),12.41(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:56.0,114.0,117.0,117.6,118.0,119.1,119.5,123.8,126.0,129.0,129.7,131.2,139.0,141.8,149.4,152.5,155.6,162.3,191.6；HRMS(ESI-TOF)m/z:Calcd.forC19H15NNaO5[M+Na]+:360.0842；Found:360.0841。
本实施例一制备化合物3be:黄色固体,熔点：123.2-124.3℃；产率88％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.17(d,J＝7.2Hz,6H),2.81-2.88(m,1H),6.84-6.93(m,3H),7.18-7.22(m,2H),7.26-7.31(m,2H),7.78(d,J＝2.4Hz,1H),7.97(d,J＝2.4Hz,1H),9.56(br s,1H),10.04(br s,1H),12.44(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:24.4,32.9,117.0,117.1,117.8,119.6,123.9,125.1,127.7,129.0,129.7,131.0,131.2,139.3,139.6,141.6,154.1,155.6,162.4,192.3；HRMS(ESI-TOF)m/z:Calcd.for C21H19NNaO4[M+Na]+:372.1206；Found:372.1211。
本实施例一制备化合物3bf:黄色固体,熔点：100.3-101.1℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:6.67-6.70(m,1H),6.75-6.80(m,2H),7.00-7.03(m,1H),7.21-7.31(m,2H),7.82(s,1H),7.98(s,1H),8.84(d,J＝7.6Hz,2H),10.14(br s,1H),12.52(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:115.9(d,JCF＝24.4Hz),116.5,117.2,117.4,117.9,118.2,119.2(d,JCF＝23.0Hz),124.0,126.6(d,JCF＝6.1Hz),129.0,138.9,141.9,148.0,150.3,151.8,155.6(d,JCF＝234.4Hz),162.4,190.5；HRMS(ESI-TOF)m/z:Calcd.for C18H12FNNaO5[M+Na]+:364.0592；Found:364.0592。
本实施例一制备化合物3bg:黄色固体,熔点：120.7-120.9℃；产率92％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:6.62-6.65(m,1H),6.72(d,J＝8.0Hz,2H),6.98(d,J＝8.8Hz,1H),7.36(d,J＝2.4Hz,1H),7.41(d,J＝8.8Hz,1H),7.77(s,1H),7.93(s,1H),8.79(d,J＝7.2Hz,2H),10.38(br s,1H),12.48(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:116.6,117.2,117.5,117.9,118.7,123.3,124.0,127.7,129.0,129.2,132.2,138.9,142.0,148.0,150.3,154.3,162.4,190.3；HRMS(ESI-TOF)m/z:Calcd.forC18H12ClNNaO5[M+Na]+:380.0296；Found:380.0291。
本发明的实施例二：在反应管中依次加入116.7mg 3-烯烃色酮氧化吲哚酮1a(0.30mmol),NH4OAc(0.60mmol)和1.5mL乙醇溶液，在室温中搅拌反应5h，TLC检测至基本反应完全，旋干溶剂后，经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯)＝7:1)纯化得103.5mg化合物3aa，产率85％。
表3化合物3的制备方法同化合物3aa，投料比与化合物3aa相同，反应产率见表3，但需强调的是本发明的化合物不限于表3所表示的内容。
表3为一种水杨酮拼接吡啶酮类化合物的化学结构
本发明的实施例三：在反应管中依次加入116.7mg 3-烯烃色酮氧化吲哚酮1a(0.30mmol),烷基胺(0.60mmol)和1.5mL乙醇溶液，在室温中搅拌反应5h，TLC检测至基本反应完全，旋干溶剂后，经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯)＝7:1)纯化得119.7mg化合物3ca，淡黄色固体,熔点：99.2-99.8℃；产率86％。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.40(s,9H),3.31(s,3H),3.66-3.68(m,1H),4.23-4.25(m,1H),6.85-6.89(m,1H),7.00(d,J＝8.4Hz,1H),7.04-7.08(m,1H),7.14-7.16(m,1H),7.29-7.33(m,1H),7.42-7.47(m,1H),7.59-7.62(m,2H),7.71-7.74(m,1H),7.86(d,J＝2.4Hz,1H),8.02(d,J＝2.8Hz,1H),11.45(br s,1H)；13C NMR(CDCl3,100MHz)δ:28.4,51.2,59.1,69.7,79.9,117.2,118.7,118.8,119.0,124.0,129.0,129.3,131.0,132.0,136.4,137.0,140.7,144.2,153.8,161.4,162.7,195.2；HRMS(ESI-TOF)m/z:Calcd.for C26H28N2NaO6[M+Na]+:487.1840；Found:487.1843。
化合物3cb至3lc的制备方法同化合物3ca，投料比与化合物3ca相同，反应产率见表4至表5，但需强调的是本发明的化合物不限于表4至表5所表示的内容。
表4为一种水杨酮拼接吡啶酮类化合物的化学结构
表5为一种水杨酮拼接吡啶酮类化合物的化学结构
本实施例三制备化合物3cb:黄色固体,熔点：99.0-99.8℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.41(s,9H),3.32(s,3H),3.66-3.68(m,1H),4.24-4.26(m,1H),6.85-6.89(m,1H),6.99-7.08(m,3H),7.43-7.47(m,1H),7.58-7.60(m,1H),7.66(s,1H),7.83(br s,1H),8.03(d,J＝2.4Hz,1H),11.41(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,50.2,58.1,68.6,79.4,116.2,117.7,117.8,118.0,122.3,123.1,125.9,128.9,130.9,134.1,135.5,137.2,139.8,143.4,152.3,160.2,161.6,194.0；HRMS(ESI-TOF)m/z:Calcd.for C26H27ClN2NaO6[M+Na]+:521.1450；Found:521.1456。
本实施例三制备化合物3cc:黄色固体,熔点：93.8-94.4℃；产率91％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.39(s,9H),3.35(s,3H),3.64-3.67(m,1H),4.22-4.25(m,1H),6.94-6.97(m,1H),7.05-7.08(m,1H),7.15-7.21(m,2H),7.29-7.35(m,2H),7.51(br s,1H),7.70-7.72(m,1H),7.86(d,J＝2.4Hz,1H),8.02(d,J＝2.4Hz,1H),11.13(br s,1H)；13C NMR(CDCl3,100MHz)δ:28.4,50.9,59.0,79.9,116.4,117.1(d,JCF＝24.4Hz),118.4,120.0,120.1,123.7(d,JCF＝23.3Hz),124.4,129.3,131.0,131.5,137.0,140.2,144.5,153.6,154.8(d,JCF＝238.8Hz),158.7,161.3,194.1；HRMS(ESI-TOF)m/z:Calcd.for C26H27FN2NaO6[M+Na]+:505.1745；Found:505.1748。
本实施例三制备化合物3cd:黄色固体,熔点：103.6-104.7℃；产率74％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.40(s,9H),3.37(s,3H),3.66-3.68(m,2H),4.26-4.28(m,2H),6.98-7.01(m,1H),7.17-7.24(m,2H),7.27-7.30(m,1H),7.32-7.35(m,1H),7.44(br s,1H),7.70(d,J＝7.6Hz,1H),7.88(d,J＝2.4Hz,1H),8.06(d,J＝2.8Hz,1H),11.13(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,49.9,58.1,68.7,79.3,115.3,115.9(d,JCF＝24.1Hz),117.3,119.1(d,JCF＝7.3Hz),122.9(d,JCF＝23.3Hz),124.1,128.2,129.3,129.6,134.7,139.5,143.8,152.5,153.9(d,JCF＝238.7Hz),157.8,160.0,192.9；HRMS(ESI-TOF)m/z:Calcd.for C26H26ClFN2NaO6[M+Na]+:539.1356；Found:539.1353。
本实施例三制备化合物3ce:黄色固体,熔点：135.7-136.6℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.41(s,9H),3.37(s,3H),3.66-3.68(m,2H),4.25-4.27(m,2H),6.96-7.00(m,1H),7.03-7.10(m,2H),7.18-7.23(m,1H),7.32-7.35(m,1H),7.58(br s,1H),7.85(d,J＝2.8Hz,1H),8.05(d,J＝2.8Hz,1H),11.12(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,49.9,58.0,68.7,79.4,115.4,115.9(d,JCF＝24.2Hz),117.3,119.1(d,JCF＝8.3Hz),122.4,122.8(d,JCF＝23.3Hz),123.2,125.8,129.5,130.9,134.3,137.1,139.4,143.7,152.2,153.8(d,JCF＝238.8Hz),157.8,160.2,193.0；HRMS(ESI-TOF)m/z:Calcd.for C26H26ClFN2NaO6[M+Na]+:539.1356；Found:539.1357。
本实施例三制备化合物3cf:黄色固体,熔点：103.5-104.4℃；产率77％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.40(s,9H),3.39(s,3H),3.68-3.70(m,1H),4.26-4.28(m,1H),6.98(d,J＝9.2Hz,1H),7.08-7.12(m,1H),7.18-7.20(m,1H),7.32-7.36(m,1H),7.40-7.43(m,1H),7.50(br s,1H),7.63(d,J＝2.4Hz,1H),7.73-7.74(m,1H),7.89(d,J＝2.4Hz,1H),8.01(d,J＝2.8Hz,1H),11.32(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.4,50.2,58.3,68.7,78.9,115.4,118.5,119.4,122.8,123.4,128.4,129.8,130.0,130.7,135.1,136.0,139.2,143.4,152.8,160.1,160.3,193.1；HRMS(ESI-TOF)m/z:Calcd.for C26H27ClN2NaO6[M+Na]+:521.1450；Found:521.1456。
本实施例三制备化合物3cg:黄色固体,熔点：154.5-155.3℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.38(s,9H),3.38(s,3H),3.66-3.68(m,2H),4.24-4.26(m,2H),6.89-6.93(m,1H),6.97(d,J＝9.2Hz,1H),7.00-7.05(m,1H),7.35(br s,1H),7.39-7.42(m,1H),7.60-7.64(m,2H),7.87(d,J＝2.8Hz,1H),8.10(d,J＝2.4Hz,1H),11.27(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,50.2,58.2,68.6,79.0,114.9(d,JCF＝21.5Hz),115.3,116.3(d,JCF＝23.4Hz),118.4,119.4,122.8,129.5,129.8,132.0,135.2,139.5,143.8,152.8,158.8(d,JCF＝243.4Hz),160.0,192.8；HRMS(ESI-TOF)m/z:Calcd.for C26H26ClFN2NaO6[M+Na]+:539.1356；Found:539.1352。
本实施例三制备化合物3ch:黄色固体,熔点：96.7-97.5℃；产率79％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.39(s,9H),3.38(s,3H),3.66-3.68(m,2H),4.24-4.26(m,2H),6.97(d,J＝8.8Hz,1H),7.17-7.19(m,1H),7.27-7.29(m,1H),7.39-7.42(m,1H),7.44(br s,1H),7.61(d,J＝2.4Hz,1H),7.69(d,J＝7.6Hz,1H),7.88(d,J＝2.4Hz,1H),8.02(d,J＝2.4Hz,1H),11.27(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.3,50.2,58.2,68.6,79.2,115.4,118.4,119.4,122.8,128.2,128.3,129.3,129.6,129.8,134.7,135.2,139.6,143.8,152.4,160.0,160.1,192.8；HRMS(ESI-TOF)m/z:Calcd.forC26H26Cl2N2NaO6[M+Na]+:555.1060；Found:555.1065。
本实施例三制备化合物3ci:黄色固体,熔点：107.1-108.1℃；产率76％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.37(s,9H),3.39(s,3H),3.67-3..69(m,2H),3.74(s,3H),4.25-4.27(m,2H),6.73(d,J＝2.8Hz,1H),6.87-6.90(m,1H),6.97(d,J＝8.8Hz,1H),7.19(s,1H),7.40-7.43(m,1H),7.54(br s,1H),7.62(d,J＝2.8Hz,1H),7.88(d,J＝2.8Hz,1H),8.00(d,J＝2.4Hz,1H),11.31(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.4,50.2,54.6,58.2,68.7,78.7,113.8,114.9,115.3,118.5,119.4,122.8,128.9,129.8,130.5,135.1,139.1,143.5,153.1,155.6,160.1,193.0；HRMS(ESI-TOF)m/z:Calcd.for C27H29ClN2NaO7[M+Na]+:551.1556；Found:551.1554。
本实施例三制备化合物3cj:黄色固体,熔点：114.9-115.5℃；产率78％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.40(s,9H),3.39(s,3H),3.67-3.69(m,1H),4.24-4.26(m,1H),6.91(d,J＝8.8Hz,1H),7.07-7.11(m,1H),7.17-7.20(m,1H),7.31-7.35(m,1H),7.50-7.55(m,2H),7.72-7.76(m,2H),7.88(d,J＝2.8Hz,1H),7.99(d,J＝2.8Hz,1H),11.31(br s,1H)；13C NMR(CDCl3,100MHz)δ:27.4,50.3,58.3,68.6,78.9,109.7,115.4,119.2,119.7,123.4,128.4,130.0,130.7,132.8,136.0,137.9,139.2,143.4,152.7,160.3,160.5,192.9；HRMS(ESI-TOF)m/z:Calcd.for C26H27BrN2NaO6[M+Na]+:565.0945；Found:565.0948。
本实施例三制备化合物3ck:黄色固体,熔点：149.3-150.2℃；产率73％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.39(s,9H),3.40(s,3H),3.67-3.69(m,1H),4.25-4.27(m,1H),6.91-6.94(m,2H),7.01-7.06(m,1H),7.35(br s,1H),7.53-7.56(m,1H),7.64(br s,1H),7.75(d,J＝2.4Hz,1H),7.88(d,J＝2.8Hz,1H),8.01(d,J＝2.4Hz,1H),11.29(br s,1H)；13C NMR(CDCl3,100MHz)δ:28.4,51.4,59.4,69.6,80.1,110.7,116.0(d,JCF＝21.4Hz),116.4,117.3(d,JCF＝23.5Hz),120.1,120.8,130.6,133.0,133.7,139.0,140.5,144.8,153.8,159.5(d,JCF＝230.4Hz),161.0,161.5,193.8；HRMS(ESI-TOF)m/z:Calcd.for C26H26BrFN2NaO6[M+Na]+:583.0850；Found:583.0854。
本实施例三制备化合物3cl:黄色固体,熔点：143.6-143.9℃；产率82％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.40(s,9H),2.25(s,3H),3.32(s,3H),3.67-3.69(m,1H),4.21-4.24(m,1H),6.90(d,J＝8.8Hz,1H),7.05-7.08(m,1H),7.15-7.18(m,1H),7.25-7.33(m,2H),7.40(s,1H),7.60(br s,1H),7.72-7.74(m,1H),7.87(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),11.23(br s,1H)；13C NMR(CDCl3,100MHz)δ:19.6,27.4,58.1,68.7,78.8,116.3,117.5,123.3,127.2,128.2,130.0,130.1,130.6,136.0,136.3,139.7,143.1,152.7,159.5,160.3,194.1；HRMS(ESI-TOF)m/z:Calcd.forC27H30N2NaO6[M+Na]+:501.1996；Found:501.1997。
本实施例三制备化合物3cm:黄色固体,熔点：95.4-95.7℃；产率76％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.40(s,9H),2.27(s,3H),3.33(s,3H),3.67-3.70(m,2H),4.24-4.26(m,2H),6.92(d,J＝8.4Hz,1H),7.17(d,J＝2.4Hz,1H),7.27-7.30(m,2H),7.39(s,1H),7.54(br s,1H),7.70(d,J＝6.8Hz,1H),7.88(d,J＝2.4Hz,1H),8.02(d,J＝2.4Hz,1H),11.21(br s,1H)；13C NMR(CDCl3,100MHz)δ:19.6,27.3,50.5,58.2,68.6,79.2,116.3,117.4,117.6,127.2,128.1,129.6,130.5,134.8,136.5,143.5,152.5,159.6,160.1,193.9；HRMS(ESI-TOF)m/z:Calcd.for C27H29ClN2NaO6[M+Na]+:535.1606；Found:535.1608。
本实施例三制备化合物3cn:黄色固体,熔点：92.8-93.4℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.18(d,J＝7.2Hz,6H),1.39(s,9H),2.79-2.86(m,1H),3.30(s,3H),3.67-3.70(m,1H),4.19-4.22(m,1H),6.92(d,J＝8.8Hz,1H),7.04-7.08(m,1H),7.17-7.19(m,1H),7.28-7.35(m,2H),7.44(d,J＝2.4Hz,1H),7.58(br s,1H),7.72(d,J＝7.2Hz,1H),7.89(d,J＝2.8Hz,1H),7.99(d,J＝7.2Hz,1H),11.20(br s,1H)；13CNMR(CDCl3,100MHz)δ:23.0,27.3,32.3,50.8,58.1,68.6,78.8,116.4,117.5,123.3,128.2,129.9,130.1,133.7,136.0,138.4,139.8,143.1,152.7,159.6,160.4,194.1；HRMS(ESI-TOF)m/z:Calcd.for C29H34N2NaO6[M+Na]+:529.2309；Found:529.2314。
本实施例三制备化合物3co:黄色固体,熔点：140.2-141.0℃；产率80％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.18(d,J＝7.2Hz,6H),1.37(s,9H),2.81-2.85(m,1H),3.31(s,3H),3.70-3.72(m,2H),3.73(s,3H),4.21-4.23(m,2H),6.74(d,J＝3.2Hz,1H),6.86-6.89(m,1H),6.95(d,J＝8.8Hz,1H),7.28-7.36(m,2H),7.44(d,J＝2.4Hz,1H),7.55(br s,1H),7.91(d,J＝2.4Hz,1H),7.98(d,J＝2.4Hz,1H),11.21(br s,1H)；13C NMR(CDCl3,100MHz)δ:24.1,28.4,33.4,51.9,55.6,59.1,69.6,79.6,114.6,116.0,117.3,118.5,118.6,129.2,130.0,131.1,134.7,139.4,140.6,144.2,154.2,156.6,160.7,161.2,195.1；HRMS(ESI-TOF)m/z:Calcd.for C30H36N2NaO7[M+Na]+:559.2415；Found:559.2412。
本实施例三制备化合物3cp:黄色固体,熔点：150.8-151.1℃；产率78％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.18(d,J＝6.8Hz,6H),1.38(s,9H),2.81-2.84(m,1H),3.30(s,3H),3.68-3.70(m,2H),4.21-4.23(m,2H),6.91-6.95(m,2H),6.98-7.03(m,1H),7.33-7.36(m,1H),7.41-7.43(m,2H),7.64(br s,1H),7.89(d,J＝2.4Hz,1H),8.01(d,J＝2.4Hz,1H),11.17(br s,1H)；13C NMR(CDCl3,100MHz)δ:24.0,28.4,33.4,51.9,59.1,69.5,80.0,115.8(d,JCF＝22.2Hz),117.3(d,JCF＝22.4Hz),118.4,118.6,129.1,133.1,134.8,139.5,141.1,144.5,153.8,159.5(d,JCF＝242.1Hz),160.7,161.1,194.9；HRMS(ESI-TOF)m/z:Calcd.for C29H33FN2NaO6[M+Na]+:547.2215；Found:547.2219。
本实施例三制备化合物3cq:黄色固体,熔点：96.9-97.9℃；产率80％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.40(s,9H),2.34(s,3H),3.39(s,3H),3.67-3.69(m,2H),4.24-4.26(m,2H),6.90(s,1H),7.066-7.10(m,1H),7.17-7.19(m,1H),7.30-7.35(m,1H),7.53(br s,1H),7.62(s,1H),7.72-7.74(m,1H),7.87(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),11.36(br s,1H)；13C NMR(CDCl3,100MHz)δ:19.8,27.4,50.2,58.2,68.7,78.9,115.6,116.7,119.8,123.4,128.3,130.0,130.3,130.6,136.0,139.3,143.1,144.6,152.7,160.1,160.3,192.8；HRMS(ESI-TOF)m/z:Calcd.for C27H29ClN2NaO6[M+Na]+:535.1606；Found:535.1605。
本实施例三制备化合物3cr:黄色固体,熔点：94.7-95.5℃；产率92％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.37(s,9H),2.34(s,3H),3.38(s,3H),3.66-3.69(m,2H),3.73(s,3H),4.23-4.25(m,2H),6.73(d,J＝2.8Hz,1H),6.86-6.90(m,2H),7.25(br s,1H),7.54(br s,1H),7.61(s,1H),7.88(d,J＝2.4Hz,1H),7.98(d,J＝2.4Hz,1H),11.35(br s,1H)；13C NMR(CDCl3,100MHz)δ:20.9,28.4,51.2,55.6,59.3,69.7,79.6,114.8,115.9,116.6,117.8,120.8,124.4,130.0,131.3,131.4,140.2,144.2,145.7,154.1,156.6,161.1,193.8；HRMS(ESI-TOF)m/z:Calcd.for C28H31ClN2NaO7[M+Na]+:565.1712；Found:565.1715。
本实施例三制备化合物3da:黄色固体,熔点：95.4-96.6℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.39(s,9H),2.87-2.90(m,2H),4.19-4.22(m,2H),6.86-6.90(m,1H),6.97(d,J＝7.6Hz,1H),7.06-7.09(m,1H),7.14-7.16(m,1H),7.30-7.36(m,2H),7.42-7.46(m,1H),7.63-7.69(m,2H),7.87(d,J＝2.4Hz,1H),8.01(d,J＝2.4Hz,1H),11.30(br s,1H)；13C NMR(CDCl3,100MHz)δ:17.3,28.4,47.9,80.3,117.0,118.5,118.6,118.7,119.4,124.7,129.6,131.0,131.4,132.2,136.7,136.8,141.2,142.4,153.7,161.1,162.5,194.8；HRMS(ESI-TOF)m/z:Calcd.for C26H25N3NaO5[M+Na]+:482.1686；Found:482.1689。
本实施例三制备化合物3db:黄色固体,熔点：86.6-87.7℃；产率81％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.39(s,9H),2.91-2.94(m,2H),4.25-4.28(m,2H),6.95-6.99(m,1H),7.08-7.12(m,1H),7.15-7.20(m,2H),7.29-7.36(m,3H),7.68(d,J＝7.6Hz,1H),7.88(d,J＝2.4Hz,1H),8.03(d,J＝2.8Hz,1H),10.98(br s,1H)；13CNMR(CDCl3,100MHz)δ:17.3,28.3,48.0,80.3,116.8(d,JCF＝28.4Hz),117.0,118.1,118.2,118.3,120.2(d,JCF＝7.4Hz),124.2(d,JCF＝23.3Hz),124.7,129.7,131.0,131.8,136.8,140.8,142.4,153.6,155.1(d,JCF＝246.4Hz),158.6,161.1,193.8；HRMS(ESI-TOF)m/z:Calcd.for C26H24FN3NaO5[M+Na]+:500.1592；Found:500.1592。
本实施例三制备化合物3de:黄色固体,熔点：82.9-82.9℃；产率92％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.37(s,9H),2.23(s,3H),2.92-2.95(m,2H),4.23-4.26(m,2H),6.88-6.92(m,2H),7.00-7.05(m,1H),7.21(s,1H),7.25-7.28(m,1H),7.43(s,1H),7.60(br s,1H),7.89(d,J＝2.4Hz,1H),8.01(d,J＝2.4Hz,1H),11.05(br s,1H)；13C NMR(CDCl3,100MHz)δ:17.3,20.3,28.3,48.1,80.4,116.2(d,JCF＝21.3Hz),116.9,117.4(d,JCF＝24.4Hz),118.3,118.6,129.1,130.4,131.4,137.9,141.5,142.7,153.8,159.4(d,JCF＝243.1Hz),160.4,160.8,194.6；HRMS(ESI-TOF)m/z:Calcd.forC27H26FN3NaO5[M+Na]+:514.1749；Found:514.1752。
本实施例三制备化合物3ea:黄色固体,熔点：88.7-89.9℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.83-0.87(m,3H),1.35(s,9H),1.73-1.81(m,2H),3.11(s,1H),3.76(d,J＝4.0Hz,2H),4.98(s,1H),6.81-6.84(m,1H),6.96(d,J＝8.0Hz,1H),7.02-7.06(m,1H),7.11-7.13(m,1H),7.25-7.29(m,1H),7.39-7.43(m,1H),7.46(br s,1H),7.52-7.55(m,1H),7.63(d,J＝6.4Hz,1H),7.79(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),11.40(br s,1H)；13C NMR(CDCl3,100MHz)δ:9.5,22.2,27.3,59.4,62.0,79.0,116.7,117.7,117.8,118.1,123.1,123.6,128.2,128.5,129.4,129.8,130.9,135.3,135.7,138.9,139.9,152.8,161.1,161.5,194.3；HRMS(ESI-TOF)m/z:Calcd.forC27H30N2NaO6[M+Na]+:501.1996；Found:501.1996。
本实施例三制备化合物3eb:黄色固体,熔点：94.9-95.3℃；产率78％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.86-0..90(m,3H),1.36(s,9H),1.81-1.86(m,2H),2.75(s,1H),3.84(s,2H),5.02(s,1H),6.94-6.98(m,1H),7.05-7.09(m,1H),7.15-7.20(m,2H),7.27-7.32(m,2H),7.38(s,1H),7.65(d,J＝6.0Hz,1H),7.81(d,J＝2.4Hz,1H),8.12(d,J＝2.0Hz,1H),11.11(br s,1H)；13C NMR(CDCl3,100MHz)δ:9.5,22.2,27.3,59.4,62.1,79.0,115.8(d,JCF＝24.3Hz),116.1,117.4,119.0(d,JCF＝8.2Hz),122.7(d,JCF＝24.5Hz),123.2,123.6,128.3,129.8,129.9,135.7,138.4,140.2,152.8,153.7(d,JCF＝238.8Hz),157.6,161.0,193.2；HRMS(ESI-TOF)m/z:Calcd.for C27H29FN2NaO6[M+Na]+:519.1902；Found:519.1908。
本实施例三制备化合物3ec:黄色固体,熔点：97.6-98.5℃；产率72％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.86-0.90(m,3H),1.33(s,9H),1.77-1.84(m,2H),2.20(s,3H),2.86(s,1H),3.82(d,J＝4.4Hz,2H),5.02(s,1H),6.86-6.89(m,2H),6.95-7.00(m,1H),7.23-7.34(m,3H),7.56(s,1H),7.82(d,J＝2.4Hz,1H),8.08(s,1H),11.17(br s,1H)；13C NMR(CDCl3,100MHz)δ:9.5,19.4,22.2,27.3,59.5,62.1,79.1,114.7(d,JCF＝22.4Hz),116.1(d,JCF＝23.1Hz),116.6,117.4(d,JCF＝8.3Hz),127.3,128.5,130.6,131.8,136.4,139.1,152.9,158.7(d,JCF＝242.1Hz),159.4,160.7,194.0；HRMS(ESI-TOF)m/z:Calcd.for C28H31FN2NaO6[M+Na]+:533.2058；Found:533.2056。
本实施例三制备化合物3fa:黄色固体,熔点：95.9-96.7℃；产率74％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.37(s,9H),1.41(d,J＝7.2Hz,3H),2.88(br s,1H),3.72-3.76(m,1H),3.80-3.84(m,1H),5.16-5.21(m,1H),6.83-6..87(m,1H),6.99(d,J＝8.0Hz,1H),7.03-7.07(m,1H),7.11-7.13(m,1H),7.27-7.31(m,1H),7.41-7.47(m,2H),7.55-7.57(m,1H),7.66(br s,1H),7.81(d,J＝2.4Hz,1H),8.11(d,J＝2.4Hz,1H),11.42(br s,1H)；13C NMR(CDCl3,100MHz)δ:15.9,28.3,55.1,64.3,80.2,117.8,118.7,119.2,124.5,129.3,130.5,130.9,131.9,136.4,136.8,140.0,140.5,153.9,161.8,162.6,195.4；HRMS(ESI-TOF)m/z:Calcd.for C26H28N2NaO6[M+Na]+:487.1840；Found:487.1841。
本实施例三制备化合物3fb:黄色固体,熔点：97.8-98.9℃；产率72％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.37(s,9H),1.44(d,J＝6.8Hz,3H),2.70(br s,1H),3.76-3.80(m,1H),3.84-3.87(m,1H),5.22(br s,1H),6.95-6.98(m,1H),7.06-7.09(m,1H),7.13-7.20(m,2H),7.27-7.33(m,2H),7.39(br s,1H),7.67(br s,1H),7.81(d,J＝2.0Hz,1H),8.14(d,J＝2.4Hz,1H),11.11(br s,1H)；13C NMR(CDCl3,100MHz)δ:15.8,28.3,54.8,64.3,80.2,116.8(d,JCF＝24.1Hz),117.1,118.4,118.5,120.1,123.8(d,JCF＝23.5Hz),124.6,129.3,130.9,136.8,139.5,140.8,153.8,154.7(d,JCF＝238.3Hz),158.6,161.7,194.3；HRMS(ESI-TOF)m/z:Calcd.for C26H27FN2NaO6[M+Na]+:505.1745；Found:505.1742。
本实施例三制备化合物3fc:黄色固体,熔点：89.7-90.5℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.35(s,9H),1.40(d,J＝7.2Hz,3H),2.21(s,3H),2.88(br s,1H),3.73-3.76(m,1H),3.81-3..85(m,1H),5.21(s,1H),6.84-6.90(m,2H),6.96-7.01(m,1H),7.24-7.31(m,1H),7.32(br s,1H),7.35(s,1H),7.57(brs,1H),7.81(d,J＝2.4Hz,1H),8.12(d,J＝2.0Hz,1H),11.17(br s,1H)；13C NMR(CDCl3,100MHz)δ:15.9,20.5,28.3,54.7,64.2,80.3,115.8(d,JCF＝22.4Hz),117.3(d,JCF＝23.3Hz),117.6,118.4(d,JCF＝9.1Hz),128.4,131.6,132.9,137.5,140.1,141.0,154.0,159.8(d,JCF＝243.2Hz),160.4,161.4,195.0；HRMS(ESI-TOF)m/z:Calcd.for C27H29FN2NaO6[M+Na]+:519.1902；Found:519.1906。
本实施例三制备化合物3ga:黄色固体,熔点：120.7-121.8℃；产率91％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.26(s,3H),3.61-3.64(m,2H),4.23-4.25(m,2H),6.83-6.87(m,1H),6.91-6.97(m,2H),7.00(d,J＝8.0Hz,1H),7.17-7.22(m,1H),7.27-7.30(m,1H),7.38-7.44(m,2H),7.87(d,J＝2.4Hz,1H),8.20(d,J＝2.4Hz,1H),9.43(br s,1H),10.30(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:49.7,58.5,69.7,116.7,116.8,117.1,119.4,119.6,124.0,125.1,128.0,129.6,130.4,131.4,133.2,138.7,145.7,155.4,156.6,161.3,192.5；HRMS(ESI-TOF)m/z:Calcd.for C21H19NNaO5[M+Na]+:388.1155；Found:388.1152。
本实施例三制备化合物3gb:黄色固体,熔点：100.6-101.2℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.26(s,3H),3.60-3.63(m,2H),4.22-4.25(m,2H),6.83-6.86(m,1H),6.90-6.92(m,1H),7.00(d,J＝8.8Hz,1H),7.17-7.21(m,1H),7.26-7.28(m,1H),7.34(d,J＝2.8Hz,1H),7.41-7.44(m,1H),7.85(d,J＝2.8Hz,1H),8.19(d,J＝2.8Hz,1H),9.41(br s,1H),10.39(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:49.6,58.5,69.6,116.4,116.6,118.8,119.3,123.2,123.9,127.4,128.1,129.2,129.6,131.4,132.2,138.2,146.2,154.8,155.4,161.2,190.5；HRMS(ESI-TOF)m/z:Calcd.forC21H18ClNNaO5[M+Na]+:422.0766；Found:422.0768。
本实施例三制备化合物3gc:黄色固体,熔点：134.8-135.4℃；产率89％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.27(s,3H),3.60-3.63(m,2H),4.22-4.24(m,2H),6.83-6.87(m,1H),6.90-6.92(m,1H),6.96(d,J＝8.8Hz,1H),7.17-7.21(m,1H),7.26-7.29(m,1H),7.46(d,J＝2.4Hz,1H),7.52-7.55(m,1H),7.85(d,J＝2.8Hz,1H),8.18(d,J＝2.4Hz,1H),9.41(br s,1H),10.42(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:49.6,58.5,69.6,110.6,116.5,116.7,119.3,123.9,128.0,128.1,129.6,131.4,132.0,135.1,138.2,146.2,155.2,155.4,161.3,190.4；HRMS(ESI-TOF)m/z:Calcd.forC21H18BrNNaO5[M+Na]+:466.0261；Found:466.0267。
本实施例三制备化合物3gd:黄色固体,熔点：105.7-106.4℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:2.31(s,3H),3.28(s,3H),3.62-3.64(m,2H),4.23-4.26(m,2H),6.77-6.92(m,4H),7.17-7.21(m,1H),7.27-7.29(m,1H),7.35(d,J＝7.6Hz,1H),7.85(d,J＝2.8Hz,1H),8.20(d,J＝2.4Hz,1H),9.41(br s,1H),10.47(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:21.7,49.7,58.6,70.0,116.7,116.8,117.6,119.3,120.6,121.6,124.0,127.9,129.6,131.0,131.4,139.0,144.4,145.4,155.4,157.7,161.2,192.7；HRMS(ESI-TOF)m/z:Calcd.for C22H21NNaO5[M+Na]+:402.1312；Found:402.1317。
本实施例三制备化合物3ge:黄色固体,熔点：100.8-101.3℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.25(s,3H),3.61-3.63(m,2H),3.73(s,3H),4.22-4.25(m,2H),6.83-6.86(m,1H),6.90-6.93(m,3H),7.00-7.03(m,1H),7.17-7.21(m,1H),7.26-7.28(m,1H),7.85(d,J＝2.4Hz,1H),8.21(d,J＝2.4Hz,1H),9.41(br s,1H),9.74(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:49.8,56.0,58.5,69.7,114.1,116.7,118.1,119.3,119.5,124.0,125.4,127.9,129.6,131.4,138.6,145.8,150.1,152.4,155.4,161.3,192.0；HRMS(ESI-TOF)m/z:Calcd.for C22H21NNaO6[M+Na]+:418.1261；Found:418.1265。
本实施例三制备化合物3gf:黄色固体,熔点：145.3-146.6℃；产率91％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:1.19(d,J＝6.8Hz,6H),2.83-2.90(m,1H),3.26(s,3H),3.62-3.64(m,2H),4.22-4.25(m,2H),6.83-6.87(m,1H),6.91-6.94(m,2H),7.17-7.31(m,4H),7.87(d,J＝2.4Hz,1H),8.19(d,J＝2.4Hz,1H),9.41(br s,1H),10.09(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:24.4,33.0,49.9,58.6,69.7,116.7,116.9,117.1,119.3,124.0,124.6,127.9,128.0,129.6,131.3,131.4,138.8,139.4,145.7,154.8,155.5,161.3,192.6；HRMS(ESI-TOF)m/z:Calcd.for C24H25NNaO5[M+Na]+:430.1625；Found:430.1627。
本实施例三制备化合物3gg:黄色固体,熔点：130.2-131.1℃；产率93％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.29(s,3H),3.34(s,3H),3.62-3.65(m,2H),4.20-4.22(m,2H),6.84(s,1H),6.87(d,J＝7.6Hz,1H),6.91(d,J＝8.0Hz,1H),7.17-7.22(m,2H),7.53(s,1H),7.93(d,J＝7.2Hz,1H),8.84(s,1H),11.32(s,1H)；13CNMR(CDCl3,100MHz)δ:20.9,51.4,59.2,69.6,117.7,117.8,119.7,120.8,121.0,124.2,124.5,130.6,130.8,131.3,131.4,140.3,143.1,145.8,156.0,161.1,162.6,193.8；HRMS(ESI-TOF)m/z:Calcd.for C22H20ClNNaO5[M+Na]+:436.0922；Found:436.0927。
本实施例三制备化合物3gh:黄色固体,熔点：120.3-121.3℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.28(s,3H),3.63-3.66(m,2H),4.26-4.28(m,2H),6.63-6.66(m,1H),6.72-6.74(m,2H),6.95-7.02(m,2H),7.39-7.46(m,2H),7.86(d,J＝2.4Hz,1H),8.21(d,J＝2.4Hz,1H),8.67(br s,1H),8.80(br s,1H),10.28(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:49.8,58.5,69.6,116.4,116.9,117.1,117.4,117.6,119.6,124.3,125.1,127.9,130.4,133.2,138.9,145.5,147.8,150.2,156.5,161.3,192.5；HRMS(ESI-TOF)m/z:Calcd.for C21H19NNaO6[M+Na]+:404.1105；Found:404.1109。
本实施例三制备化合物3ha:黄色固体,熔点：110.6-111.1℃；产率92％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.70(s,2H),4.12-4.14(m,2H),5.00(s,1H),6.84-7.02(m,4H),7.18-7.22(m,1H),7.27-7.30(m,1H),7.40-7.44(m,2H),7.88(s,1H),8.21(d,J＝2.4Hz,1H),9.42(br s,1H),10.30(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:53.2,589,116.6,116.8,117.2,119.4,119.6,124.1,125.2,127.9,129.6,130.4,131.4,133.2,138.9,145.9,155.5,156.5,161.4,192.5；HRMS(ESI-TOF)m/z:Calcd.for C20H17NNaO5[M+Na]+:374.0999；Found:374.0992。
本实施例三制备化合物3hb:黄色固体,熔点：98.7-99.9℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.68(s,2H),4.11-4.13(m,2H),4.97(s,1H),6.83-6.87(m,1H),6.91(d,J＝8.0Hz,1H),7.01(d,J＝8.8Hz,1H),7.17-7.21(m,1H),7.26-7.28(m,1H),7.36(d,J＝2.8Hz,1H),7.40-7.43(m,1H),7.85(d,J＝2.8Hz,1H),8.21(d,J＝2.4Hz,1H),9.40(br s,1H),10.40(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:53.1,58.9,116.3,116.7,118.8,119..4,123.3,124.0,127.5,128.0,129.2,129.6,131.4,132.2,138.4,146.4,154.7,155.4,161.4,190.6；HRMS(ESI-TOF)m/z:Calcd.forC20H16ClNNaO5[M+Na]+:408.0609；Found:408.0614。
本实施例三制备化合物3hc:黄色固体,熔点：100.7-101.2℃；产率92％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:2.32(s,3H),3.68(s,2H),4.11-4.13(m,2H),4.97(br s,1H),6.83-6.87(m,1H),6.90(d,J＝8.0Hz,1H),6.95(s,1H),7.17-7.21(m,1H),7.26-7.28(m,1H),7.38(s,1H),7.84(d,J＝2.8Hz,1H),8.22(d,J＝2.4Hz,1H),9.40(br s,1H),10.38(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:20.4,53.1,58.9,116.4,116.8,119.4,119.6,123.7,124.0,124.8,127.9,129.6,130.0,131.4,138.6,140.5,146.2,155.1,155.4,161.3,190.7；HRMS(ESI-TOF)m/z:Calcd.for C21H18ClNNaO5[M+Na]+:422.0766；Found:422.0761。
本实施例三制备化合物3hd:黄色固体,熔点：85.6-86.4℃；产率89％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:3.72(d,J＝4.0Hz,2H),4.15-4.18(m,2H),5.02(s,1H),6.65-6.68(m,1H),6.74-6.76(m,2H),6.97-7.04(m,2H),7.43-7.48(m,2H),7.89(d,J＝2.8Hz,1H),8.24(d,J＝2.4Hz,1H),8.68(br s,1H),8.83(br s,1H),10.31(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:53.3,58.9,116.4,116.8,117.2,117.4,117.7,119.6,124.4,125.1,127.8,130.4,133.2,139.0,145.7,147.9,150.2,156.5,161.4,192.5；HRMS(ESI-TOF)m/z:Calcd.for C20H17NNaO6[M+Na]+:390.0948；Found:390.0951。
本实施例三制备化合物3ia:黄色固体,熔点：97.2-97.6℃；产率92％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:4.70-4.76(m,2H),6.84-6.96(m,3H),7.00(d,J＝8.4Hz,1H),7.15-7.17(m,1H),7.23-7.27(m,1H),7.44-7.50(m,2H),7.87(s,1H),7.94(d,J＝2.4Hz,1H),8.22(br s,1H),11.28(br s,1H)；13C NMR(CDCl3,100MHz)δ:49.5(q,JC,F＝35.3Hz),118.5,119.0,119.4,119.8,120.0,121.3,121.7,123.7,124.4,124.6(q,JC,F＝270.4Hz),130.8,131.0,131.7,131.9,137.0,140.8,141.0,155.8,162.3,162.8,194.7；HRMS(ESI-TOF)m/z:Calcd.for C20H14F3NNaO4[M+Na]+:412.0767；Found:412.0762。
本实施例三制备化合物3ib:黄色固体,熔点：106.9-107.9℃；产率77％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:5.04-5.11(m,2H),6.61-6.64(m,1H),6.71-6.74(m,2H),6.93-7.00(m,2H),7.35-7.43(m,2H),7.87(d,J＝2.4Hz,1H),8.28(d,J＝2.4Hz,1H),8.73(br s,1H),8.80(br s,1H),10.23(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:48.0(q,JC,F＝35.5Hz),116.5,117.1,117.2,117.4,117.8,119.7,123.1,123.6,124.3(q,JC,F＝270.5Hz),125.2,125.8,128.3,130.3,133.3,139.0,145.1,147.7,150.0,156.3,160.8,192.1；HRMS(ESI-TOF)m/z:Calcd.for C20H14F3NNaO5[M+Na]+:428.0716；Found:428.0717。
本实施例三制备化合物3jc:黄色固体,熔点：109.7-110.5℃；产率83％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:2.25(s,3H),5.04-5.11(m,2H),6.62-6.65(m,1H),6.72-6.74(m,2H),6.89(d,J＝8.4Hz,1H),7.18(d,J＝2.0Hz,1H),7.21-7.24(m,1H),7.87(d,J＝2.8Hz,1H),8.29(d,J＝2.0Hz,1H),8.73(br s,1H),8.80(br s,1H),10.03(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:20.4,48.1(q,JC,F＝35.8Hz),116.5,117.0,117.2,117.4,117.8,123.1,123.6,124.3(q,JC,F＝270.6Hz),124.7,125.9,128.3,130.5,134.0,139.2,145.0,147.7,150.0,154.3,160.8,192.3；HRMS(ESI-TOF)m/z:Calcd.for C21H16F3NNaO5[M+Na]+:442.0873；Found:442.0876。
本实施例三制备化合物3ja:黄色固体,熔点：145.3-146.6℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:2.99-3.00(m,2H),4.29-4.32(m,2H),6.79-6.83(m,1H),6.87-6.92(m,2H),6.96(d,J＝8.0Hz,1H),7.13-7.17(m,1H),7.24-7.26(m,1H),7.36-7.40(m,2H),7.85(d,J＝2.4Hz,1H),8.35(d,J＝2.4Hz,1H),9.36(br s,1H),10.27(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:17.3,46.3,116.7,117.3,117.5,118.7,119.3,119.7,123.6,124.9,128.2,129.7,130.6,131.4,133.4,139.1,144.8,155.4,156.9,161.1,192.5；HRMS(ESI-TOF)m/z:Calcd.for C21H16N2NaO4[M+Na]+:383.1002；Found:383.1009。
本实施例三制备化合物3ka:黄色固体,熔点：155.2-156.1℃；产率91％；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.87-0.90(m,3H),1.74-1.93(m,2H),2.63(br s,1H),3.85(d,J＝4.0Hz,2H),5.03-5.09(m,1H),6.81-7.01(m,4H),7.15-7.18(m,1H),7.21-7.25(m,1H),7.42-7.46(m,1H),7.52-7.54(m,1H),7.31(d,J＝2.4Hz,1H),8.10(d,J＝2.4Hz,1H),8.88(br s,1H),11.42(br s,1H)；13C NMR(CDCl3,100MHz)δ:10.6,23.1,53.5,62.9,118.7,118.8,119.0,119.2,119.6,121.1,124.5,130.6,130.7,130.9,131.9,136.6,139.6,140.0,155.9,162.7,163.2,195.5；HRMS(ESI-TOF)m/z:Calcd.for C22H21NNaO5[M+Na]+:402.1312；Found:402.1317。
本实施例三制备化合物3kb:黄色固体,熔点：175.6-176.7℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:0.85-0.88(m,3H),1.17-1.20(m,6H),1.67-1.74(m,1H),1.81-1.88(m,1H),2.83-2.89(m,1H),3.62-3.65(m,1H),3.73-3.76(m,1H),4.91(br s,1H),5.09(br s,1H),6.84-6.88(m,1H),6.92-6.96(m,2H),7.18-7.22(m,1H),7.28-7.32(m,3H),7.88(d,J＝2.4Hz,1H),8.18(d,J＝2.4Hz,1H),9.41(br s,1H),10.20(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:10.8,23.3,24.3,24.4,33.0,61.8,116.8,116.9,117.2,119.4,124.3,124.4,128.0,129.6,131.4,131.6,138.0,139.4,155.0,155.5,161.7,192.7；HRMS(ESI-TOF)m/z:Calcd.for C25H27NNaO5[M+Na]+:444.1781；Found:444.1786。
本实施例三制备化合物3la:黄色固体,熔点：135.9-136.2℃；产率89％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:0.77(d,J＝7.2Hz,3H),1.04(d,J＝6.4Hz,3H),2.14(br s,1H),3.64(d,J＝10.4Hz,1H),3.87(d,J＝6.4Hz,1H),4.71(brs,1H),5.05(br s,1H),6.84-6.88(m,1H),6.90-6.97(m,2H),7.00(d,J＝8.0Hz,1H),7.17-7.22(m,1H),7.27-7.30(m,1H),7.38-7.43(m,2H),7.87(d,J＝2.8Hz,1H),8.24(d,J＝2.4Hz,1H),9.40(br s,1H),10.28(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:19.6,21.2,28.5,60.2,116.8,116.9,117.1,119.4,119.7,124.4,125.2,127.9,129.5,130.4,131.4,133.2,137.9,155.5,156.4,161.9,170.8,192.5；HRMS(ESI-TOF)m/z:Calcd.forC23H23NNaO5[M+Na]+:416.1468；Found:416.1472。
本实施例三制备化合物3lb:黄色固体,熔点：126.5-127.2℃；产率90％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:2.31(s,3H),3.28(s,3H),3.62-3.64(m,2H),4.23-4.26(m,2H),6.77-6.92(m,4H),7.17-7.21(m,1H),7.27-7.30(m,1H),7.35(d,J＝7.6Hz,1H),7.84(d,J＝2.8Hz,1H),8.20(d,J＝2.4Hz,1H),9.41(br s,1H),10.47(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:19.6,21.1,28.5,60.2,115.9(d,JCF＝24.4Hz),116.4,116.7,118.1(d,JCF＝7.3Hz),119.3,119.4(d,JCF＝23.3Hz),124.3,126.4,126.5,127.9,129.5,131.4,137.4,152.0,155.4,155.5(d,JCF＝234.5Hz),161.8,170.8,190.7；HRMS(ESI-TOF)m/z:Calcd.for C23H22FNNaO5[M+Na]+:434.1374；Found:434.1374。
本实施例三制备化合物3lc:黄色固体,熔点：176.5-177.1℃；产率87％；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:0.78(d,J＝6.8Hz,3H),1.05(d,J＝6.4Hz,3H),2.15(s,1H),2.25(s,3H),3.64(d,J＝12.0Hz,1H),3.87-3.89(m,1H),4.71(br s,1H),5.06(br s,1H),6.83-6.92(m,3H),7.17-7.24(m,3H),7.27-7.30(m,1H),7.86(d,J＝2.8Hz,1H),8.24(s,1H),9.40(br s,1H),10.11(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:19.7,20.4,21.2,28.5,60.2,116.8,116.9,117.0,119.4,124.4,124.6,127.8,128.3,129.5,130.7,131.4,134.0,137.9,154.5,155.4,161.8,192.6；HRMS(ESI-TOF)m/z:Calcd.for C24H25NNaO5[M+Na]+:430.1625；Found:430.1627。
本发明的式(1)化合物具有潜在的重要生物活性，成分靶点分子对接筛选活性成分试验表明：本发明的式(1)化合物具有潜在的重要生物活性，可以作为新型冠状病毒3CL水解酶潜在抑制剂。
药理实施例：成分靶点分子对接筛选活性成分
分子对接配体与受体的准备的具体方法是：本发明的式(1)化合物的mo12结构，通过Open Babel GUI选用MMFF94力场进行能量优化，并保存为mol2格式；通过AutoDockTools-1.5.6赋予配体原子类型、进行电荷计算，并定义所有柔性键可旋转，保存为pdbqt格式；从PDB数据库中下载SARS-CoV-23CL水解酶的PDB格式，导入PyMOL软件去水分子，分离蛋白；导入AutoDockTools-1.5.6中进行添加极性氢，计算Gasteiger电荷并分配电荷，保存为pdbqt文件。
成分靶点分子对接筛选活性成分的具体方法是：AutoDockTools软件分别设置受体的格点参数文本文件,energy_range＝3,num_modes＝10,exhaustiveness＝8；运用Autodock Vina软件在linux虚拟环境下进行对接，选取结合自由能小且构象较好的作为结果；选取结合能≤-5.0kJ/mol的化合物作为新型冠状病毒3CL水解酶潜在抑制剂的活性成分。
本专利以蛋白结构上的配体所在部位为活性位点中心，通过分子对接方法来计算小分子化合物与蛋白的结合能和潜在结合模式。活性位点主要有氨基酸Thr26、His41、Met49等组成，大部分为中性、亲水性氨基酸(图8)，故活性化合物与蛋白间的疏水作用力较弱。
活性位点氨基酸信，息、
对本发明的式(1)水杨酮拼接吡啶酮类化合物-3CL水解酶的分子对接模型分析结果，其中3ab和3ga结果最好，分别为3ab结合能为-7.8 kg/mol；3ga结合能为-8.6 kg/mol。分子对接模型图见图9，其中氢键在配体与受体结合中起关键作用。
(1)小分子3ab与蛋白6LU7分子对接结果；将蛋白结构6LU7与小分子3ab进行分子对接，其结合能为-7.8kg/mol，苯环上的羟基-OH与氨基酸Glu166、Phe140有氢键作用，键长分别为和吡啶环上的N原子与Ser144有氢键作用，键长为与苯环相连的是-N-原子与氨基酸Asn有氢键作用，键长为
(2)小分子3ga与蛋白6LU7分子对接结果；将蛋白结构6LU7与小分子3ga进行分子对接，其结合能为-8.6kg/mol，苯环上的羟基与氨基酸Gln189有氢键作用，键长为吡啶环上的＝O原子与Gly143有氢键作用，键长为小分子3ga呈三角形分布于活性位点中，苯环和其它基团受到的疏水作用力和范德华力较强。
实验结论：一般认为配体与受体结合的构象越稳定时，所需能量能量越低，其发生作用的可能性越大。配体与受体结合能≤-5.0kJ/mol，表明活性成分与新冠肺炎相关靶点有较好的结合活性。本发明使用分子对接技术，对本发明的式(1)化合物的活性成分进行分子对接筛选。筛选表明：以-5.0kcal/mol为筛选标准，3CL水解酶与式(1)化合物活性成分有较好的结合活性，表明此类式(1)所示的水杨酮拼接吡啶酮类化合物活性成分可能直接作用于新冠病毒3CL水解酶进行复制的过程，可以作为新型冠状病毒3CL水解酶潜在抑制剂，值得继续深入研究下去。
Claims (5)
1.一种水杨酮拼接吡啶酮类化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
具体为如下结构式之一:
2.一种如权利要求1所述的水杨酮拼接吡啶酮类化合物的制备方法，其特征在于：将各种取代的3-烯烃色酮氧化吲哚/苯并呋喃酮1与各种胺源2，在溶剂中，在无催化剂和室温作用下，进行Michael加成引发的开环和重新关环反应，获得水杨酮拼接吡啶酮类化合物；所述的各种胺源2为醋酸铵、碳酸氢铵、碳酸铵、氨水或烷基胺。
3.根据权利要求2所述的水杨酮拼接吡啶酮类化合物的制备方法，其特征在于：所述的溶剂为水、甲苯、乙醇、二氯甲烷、氯仿或乙腈。
4.根据权利要求2所述的水杨酮拼接吡啶酮类化合物的制备方法，其特征在于：反应时间为2-6小时。
5.一种如权利要求1所述的水杨酮拼接吡啶酮类化合物在制备新型冠状病毒3CL水解酶潜在抑制剂的药物中的应用。
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