CN110684032B - 山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物及其制备方法及应用 - Google Patents

山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物及其制备方法及应用 Download PDF

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CN110684032B
CN110684032B CN201910744693.8A CN201910744693A CN110684032B CN 110684032 B CN110684032 B CN 110684032B CN 201910744693 A CN201910744693 A CN 201910744693A CN 110684032 B CN110684032 B CN 110684032B
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刘雄利
姚一鸣
常顺琴
左雄
周英
韦启迪
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Guizhou University
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Abstract

本发明公开了一种山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物，该类化合物包含潜在的生物活性山酮素异恶唑骨架和螺环吡唑啉酮或螺环苯并呋喃酮骨架，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。且该新型骨架化合物对人白血病细胞(K562)具有抑制活性的作用。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。且该类骨架化合物对人白血病细胞(K562)具有肿瘤生长抑制活性作用。

Description

山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物及其 制备方法及应用
技术领域
本发明涉及化学技术和药学技术领域，尤其是一种山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃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和迁越原理，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)山酮素骨架也普遍存在天然产物和药物分子中。例如:天然产物分子Ergochrome DD，Diversonol，Desoxydiversonol，Applanatin B和Isocochlioquinone A共享一个山酮素分子单元，这些化合物在解除病痛、经济发展中起着重大作用。(2)螺环吡唑啉酮广泛存在天然产物和合成药物分子中，吸引了许多化学工作者及医药化学团队的广泛关注，例如，天然产物或活性小分子螺环吡唑啉酮phosphodiesterase inhibitor和anti-inflammatoryagent表现明显的生物活性。(3)螺六元碳环苯并呋喃酮化合物也广泛存在天然产物和合成药物分子中，例如附图5中，天然产物或活性小分子螺六元碳环苯并呋喃酮rosmadial和ferrubietolide表现明显的生物活性。(4)异恶唑基团也普遍存在天然产物和药物分子中。例如:异噁唑基团也普遍存在天然产物和药物分子中。如:许多天然产物和药物(Cloxacillin V,muscimol VI,Isoxicam VII,leflunomide VIII,等)。
鉴于山酮素骨架、螺环吡唑啉酮骨架、螺六元碳环苯并呋喃酮骨架和异恶唑基团具有潜在的生物活性。因此，把螺环吡唑啉酮、螺六元碳环苯并呋喃酮拼接到山酮素异恶唑骨架上，合成一系列新的潜在多活性官能团的山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物，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。
发明内容
本发明的目的是：提供一种山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃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制备防治肿瘤疾病药物中的应用。
本发明是这样实现的：一种山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物，该化合物具有如下通式(Ⅰ)的结构：
Figure GDA0002287383380000021
式中，R1为甲基或氟或氢；Ar为氟、氯、溴、硝基、甲基取代的苯环或噻吩环。
山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物的制备方法，将各种取代的双功能吡唑啉酮/苯并呋喃酮-色酮合成子、各种取代的硝基异恶唑烯烃在有机溶剂中，在有机小分子催化剂作用下，进行Michael/Michael环加成反应，获得山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物3或5。
合成路线举例如下：
Figure GDA0002287383380000022
其中合成路线中的化合物，其取代基满足R1为甲基或氟或氢；Ar为氟、氯、溴、硝基、甲基取代的苯环或噻吩环。
反应机理举例如下：
Figure GDA0002287383380000031
所述的有机溶剂为乙腈、甲苯、二氯甲烷、或氯仿。
所述的有机小分子碱性催化剂为DBU、DABCO、Et3N、DMAP、手性双功能金鸡纳碱衍生的硫脲或芳酰胺、环己基二胺衍生的硫脲或芳酰胺、1,2-二苯基二胺衍生的的硫脲或芳酰胺。
所述的有机小分子碱性催化剂部分举例如下：
Figure GDA0002287383380000032
各种取代的双功能吡唑啉酮/苯并呋喃酮-色酮合成子、各种取代的硝基异恶唑烯烃在有机溶剂中的反应温度为-10℃至40℃，反应时间为1至5天。
山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物在制备防治肿瘤疾病药物中的应用。
通过采用上述技术方案，以各种取代的双功能吡唑啉酮/苯并呋喃酮-色酮合成子、各种取代的硝基异恶唑烯烃在有机溶剂中，在有机小分子催化剂作用下，进行Michael/Michael环加成反应，获得山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物3或5，该类化合物包含潜在的生物活性山酮素异恶唑骨架和螺环吡唑啉酮或螺环苯并呋喃酮骨架，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。且该新型骨架化合物对人白血病细胞(K562)具有抑制活性的作用。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
附图1及附图2为本发明的实施例的化合物3a谱图数据；
附图3及附图4为本发明的实施例的化合物5a谱图数据；
附图5为本发明的实施例的化合物3r和5q单晶图。
附图6为本发明的化合物创造性设计图。
具体实施方式
本发明的实施例：在反应管中依次加入双功能吡唑啉酮-色酮合成子1a(0.10mmol)，硝基异恶唑烯烃2a(0.12mmol)，催化剂DBU(10mol％，0.01mmol)和2.0mL二氯甲烷，室温中搅拌反应3天，TLC检测基本反应完全，直接上样经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯)＝6:1)纯化得化合物3a，白色固体,熔点：197.3-198.1℃；产率82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.04-2.09(m,1H),2.18(s,3H),2.47(s,3H),2.63-2.66(m,1H),3.59-3.61(m,1H),4.19-4.24(m,1H),4.73-4.77(m,1H),5.93-5.95(m,1H),6.85(d,J＝7.0Hz,1H),7.07-7.16(m,5H),7.21-7.24(m,1H),7.38-7.41(m,2H),7.48-7.51(m,1H),7.69(d,J＝6.5Hz,2H),7.89-7.91(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,28.1,40.2,41.6,47.9,56.0,80.0,118.0,119.4,120.5,122.2,125.8,127.1,128.9,129.3,132.8,134.8,136.3,137.1,155.7,160.2,170.9,173.2,191.9；HRMS(ESI-TOF)m/z:Calcd.for C32H25ClN4NaO6[M+Na]+:619.1355；Found:619.1358.
化合物3b至3v和化合物5a至5r的制备方法同化合物3a，投料比与化合物3a相同，可得到化合物3b至3v和化合物5a至5r，反应产率和dr值见表1-4，但需强调的是本发明的化合物不限于表1-4所表示的内容。
表1为一种山酮素异恶唑骨架拼接吡唑啉酮类化合物的化学结构
Figure GDA0002287383380000051
表2为一种山酮素异恶唑骨架拼接吡唑啉酮类化合物的化学结构
Figure GDA0002287383380000061
表3为一种山酮素异恶唑骨架拼接苯并呋喃酮类化合物的制备方法的化学结构
Figure GDA0002287383380000062
表4为一种山酮素异恶唑骨架拼接苯并呋喃酮类化合物的制备方法的化学结构
Figure GDA0002287383380000071
本实施例制备化合物3b:白色固体,熔点：215.1-216.3℃；产率85％；>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.04-2.09(m,1H),2.19(s,3H),2.47(s,3H),2.64-2.67(m,1H),3.55-3.58(m,1H),4.20-4.25(m,1H),4.74-4.77(m,1H),5.92-5.93(m,1H),6.85(d,J＝7.0Hz,1H),6.99-7.02(m,1H),7.07-7.10(m,1H),7.16-7.24(m,2H),7.29-7.31(m,2H),7.38-7.41(m,2H),7.48-7.51(m,1H),7.68(d,J＝6.0Hz,2H),7.89-7.91(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,28.0,40.2,41.6,47.9,55.9,80.0,118.0,119.7,120.5,122.2,123.4,124.4,125.9,127.1,128.9,130.6,132.1,136.3,136.4,137.0,155.7,160.1,160.2,170.8,173.2,191.9；HRMS(ESI-TOF)m/z:Calcd.forC32H25BrN4NaO6[M+Na]+:663.0850；Found:663.0851.
本实施例制备化合物3c:白色固体,熔点：203.3-204.2℃；产率82％,9:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.05-2.10(m,1H),2.19(s,3H),2.35(s,3H),2.54-2.57(m,1H),4.17-4.22(m,1H),4.21-4.27(m,1H),4.88(d,J＝10.0Hz,1H),5.83-5.85(m,1H),6.76(d,J＝7.0Hz,1H),6.89-6.91(m,1H),6.95-7.00(m,2H),7.12-7.15(m,1H),7.30-7.33(m,3H),7.38-7.41(m,1H),7.44-7.46(m,1H),7.66-7.67(m,2H),7.81-7.83(m,1H)；13C NMR(CDCl3,125MHz)δ:10.6,13.3,27.6,39.6,40.5,45.3,54.9,78.4,116.9,118.4,118.5,119.6,121.1,123.2,124.7,126.0,127.2,127.7,127.8,127.9,129.2,132.5,132.8,135.2,136.2,154.6,159.3,160.0,169.7,172.6,191.0；HRMS(ESI-TOF)m/z:Calcd.for C32H25BrN4NaO6[M+Na]+:663.0850；Found:663.0846.
本实施例制备化合物3d:白色固体,熔点：198.6-199.2℃；产率84％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.94-1.97(m,1H),2.01(s,3H),2.07(s,3H),2.33(s,3H),2.53-2.56(m,1H),3.43-3.47(m,1H),4.13-4.18(m,1H),4.69-4.71(m,1H),5.83-5.85(m,1H),6.76(d,J＝6.5Hz,1H),6.83(d,J＝6.0Hz,2H),6.88-6.90(m,2H),6.97-7.00(m,1H),7.10-7.12(m,1H),7.27-7.30(m,2H),7.38-7.41(m,1H),7.58-7.59(m,2H),7.81-7.82(m,1H)；13C NMR(CDCl3,125MHz)δ:10.5,12.5,20.2,27.0,39.2,40.7,47.7,55.0,79.1,116.9,118.5,119.5,121.1,124.6,126.0,127.7,127.8,128.5,132.9,135.2,136.2,154.5,159.2,159.4,170.3,172.5,191.1；HRMS(ESI-TOF)m/z:Calcd.for C33H28N4NaO6[M+Na]+:599.1901；Found:599.1907.
本实施例制备化合物3e:白色固体,熔点：173.2-174.1℃；产率84％,18:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.17(s,3H),2.33(s,3H),2.46(s,3H),2.62-2.65(m,1H),3.58-3.61(m,1H),4.14-4.19(m,1H),4.68-4.72(m,1H),5.91-5.93(m,1H),6.75(d,J＝7.0Hz,1H),7.09-7.14(m,4H),7.21-7.23(m,1H),7.28-7.30(m,1H),7.38-7.41(m,2H),7.68-7.70(m,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,20.4,28.1,40.4,41.6,47.7,56.1,80.0,117.7,119.4,120.1,125.8,126.6,128.9,129.2,131.7,132.8,134.8,137.1,137.4,155.7,158.3,160.2,171.0,173.3,192.1；HRMS(ESI-TOF)m/z:Calcd.for C33H27ClN4NaO6[M+Na]+:633.1511；Found:633.1517.
本实施例制备化合物3f:白色固体,熔点：148.6-150.1℃；产率83％,19:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.17(s,3H),2.33(s,3H),2.44(s,3H),2.62-2.66(m,1H),3.58-3.61(m,1H),4.15-4.20(m,1H),4.70-4.74(m,1H),5.91-5.92(m,1H),6.74(d,J＝7.0Hz,1H),6.80-6.83(m,2H),7.16-7.22(m,3H),7.28-7.30(m,1H),7.37-7.40(m,2H),7.68(d,J＝6.5Hz,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,20.4,28.1,40.6,41.7,51.0,56.2,79.8,116.0(d,JCF＝17.5Hz),117.7,119.4,120.1,125.8,126.6,128.9,130.1,131.7,137.4,155.7,158.3,160.3,162.5(d,JCF＝206.3Hz),171.2,173.3,192.2；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1812.
本实施例制备化合物3g:白色固体,熔点：201.6-202.3℃；产率80％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.08(m,1H),2.18(s,3H),2.33(s,3H),2.45(s,3H),2.63-2.66(m,1H),3.60-3.62(m,1H),4.16-4.21(m,1H),4.69-4.73(m,1H),5.91-5.93(m,1H),6.74(d,J＝7.0Hz,1H),6.84-6.86(m,1H),6.90-6.92(m,1H),7.00-7.02(m,1H),7.09-7.12(m,1H),7.20-7.22(m,1H),7.28-7.30(m,1H),7.37-7.40(m,2H),7.69(d,J＝6.5Hz,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,20.4,28.1,40.4,41.6,48.1,56.0,80.0,115.9(d,JCF＝17.5Hz),117.7,119.5,120.1,125.8,126.6,128.9,130.7,131.7,136.7(d,JCF＝6.3Hz),137.1,137.4,155.7,158.3,160.2,162.5(d,JCF′＝206.3Hz),170.9,173.2,192.1；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1814.
本实施例制备化合物3h:白色固体,熔点：138.8-139.5℃；产率89％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.02-2.05(m,1H),2.18(s,3H),2.33(s,3H),2.46(s,3H),2.63-2.66(m,1H),3.55-3.58(m,1H),4.16-4.20(m,1H),4.69-4.73(m,1H),5.90-5.92(m,1H),6.74(d,J＝7.5Hz,1H),6.98-7.01(m,1H),7.16-7.23(m,2H),7.27-7.30(m,3H),7.38-7.41(m,2H),7.67(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,20.4,28.0,40.2,41.6,48.1,56.0,79.8,117.7,119.7,120.1,125.9,126.6,128.9,130.6,131.8,132.1,136.5,137.0,137.4,155.7,158.3,160.2,170.9,173.2,192.1；HRMS(ESI-TOF)m/z:Calcd.for C33H27BrN4NaO6[M+Na]+:677.1006；Found:677.1012.
本实施例制备化合物3i:白色固体,熔点：181.6-183.1℃；产率87％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.11-2.15(m,1H),2.24(s,3H),2.33(s,3H),2.48(s,3H),2.63-2.66(m,1H),4.19-4.24(m,1H),4.36(d,J＝10.0Hz,1H),4.84-4.87(m,1H),5.87-5.89(m,1H),6.74(d,J＝7.0Hz,1H),6.99-7.01(m,1H),7.23-7.25(m,2H),7.28-7.30(m,1H),7.40-7.43(m,2H),7.51(d,J＝7.5Hz,1H),7.68-7.69(m,1H),7.75(d,J＝7.0Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.7,13.8,20.4,28.6,40.2,41.5,50.9,55.9,79.6,117.7,119.3,120.1,125.9,126.6,127.9,129.0,129.6,129.9,130.9,131.8,134.2,135.2,137.1,137.4,155.7,158.3,160.8,170.6,173.4,192.0；HRMS(ESI-TOF)m/z:Calcd.for C33H26Cl2N4NaO6[M+Na]+:667.1122；Found:667.1125.
本实施例制备化合物3j:白色固体,熔点：175.6-176.2℃；产率83％,13:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.16(s,3H),2.17(s,3H),2.32(s,3H),2.43(s,3H),2.61-2.64(m,1H),3.55-3.57(m,1H),4.17-4.22(m,1H),4.72-4.73(m,1H),5.92-5.94(m,1H),6.74(d,J＝7.0Hz,1H),6.89(d,J＝7.0Hz,2H),7.03-7.05(m,2H),7.19-7.21(m,1H),7.27-7.29(m,1H),7.37-7.39(m,2H),7.68-7.71(m,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,20.4,21.0,28.2,40.6,41.7,56.2,80.0,117.7,119.5,120.1,125.6,126.6,128.8,129.6,131.1,131.6,137.3,138.5,155.6,158.4,160.6,171.6,173.6,192.4；HRMS(ESI-TOF)m/z:Calcd.for C34H30N4NaO6[M+Na]+:613.2058；Found:613.2058.
本实施例制备化合物3k:白色固体,熔点：230.6-231.5℃；产率81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.10(s,3H),2.16(s,3H),2.33(s,3H),2.42(s,3H),2.62-2.65(m,1H),3.50-3.52(m,1H),4.19-4.24(m,1H),4.72-4.74(m,1H),5.91-5.93(m,1H),6.75(d,J＝7.0Hz,1H),6.92(d,J＝6.5Hz,2H),6.97-6.99(m,2H),7.19-7.21(m,1H),7.28-7.30(m,1H),7.36-7.39(m,2H),7.68(d,J＝6.5Hz,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,20.4,21.2,28.1,40.5,41.7,50.9,56.0,80.1,117.7,119.5,120.1,125.6,126.7,128.7,128.8,129.5,131.6,134.0,137.2,137.3,138.7,155.5,158.4,160.5,171.5,173.6,192.4；HRMS(ESI-TOF)m/z:Calcd.for C34H30N4NaO6[M+Na]+:613.2058；Found:613.2054.
本实施例制备化合物3l:白色固体,熔点：153.3-155.1℃；产率85％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.05-2.09(m,1H),2.17(s,3H),2.41(s,3H),2.63-2.66(m,1H),3.57-3.59(m,1H),4.22-4.27(m,1H),4.76-4.80(m,1H),5.96-5.97(m,1H),6.83-6.86(m,1H),7.10-7.17(m,5H),7.19-7.23(m,2H),7.37-7.39(m,2H),7.54-7.56(m,1H),7.68(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,28.0,40.4,41.6,48.8,56.0,80.5,112.1(d,JCF＝20.5Hz),119.5,119.7(d,JCF′＝6.3Hz),123.8(d,JCF′＝20.1Hz),125.7,128.9,129.0,134.0,137.2,155.6,156.5,157.6(d,JCF′＝201.3Hz),160.3,171.1,173.4,191.3；HRMS(ESI-TOF)m/z:Calcd.for C32H25FN4NaO6[M+Na]+:603.1650；Found:603.1653.
本实施例制备化合物3m:白色固体,熔点：186.3-187.1℃；产率90％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.93-1.98(m,1H),2.07(s,3H),2.36(s,3H),2.53-2.56(m,1H),3.48-3.51(m,1H),4.07-4.13(m,1H),4.61-4.65(m,1H),5.82-5.84(m,1H),6.73-6.75(m,1H),6.99-7.03(m,4H),7.09-7.13(m,2H),7.28-7.31(m,2H),7.43-7.45(m,1H),7.59(d,J＝7.0Hz,2H)；13C NMR(CDCl3,125MHz)δ:10.6,12.5,26.9,39.2,40.5,46.8,54.9,79.2,111.0(d,JCF′＝20.3Hz),118.4,118.7,119.9,122.8(d,JCF′＝20.0Hz),124.8,127.9,128.3,131.6,133.8,136.0,154.7,155.3,156.6(d,JCF′＝201.3Hz),159.1,169.7,172.2,190.1；HRMS(ESI-TOF)m/z:Calcd.for C32H24ClFN4NaO6[M+Na]+:637.1261；Found:637.1265.
本实施例制备化合物3n:白色固体,熔点：167.1-168.3℃；产率85％,15:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.08(m,1H),2.17(s,3H),2.45(s,3H),2.63-2.66(m,1H),3.58-3.62(m,1H),4.19-4.24(m,1H),4.73-4.77(m,1H),5.91-5.93(m,1H),6.81-6.85(m,3H),7.16-7.23(m,4H),7.37-7.40(m,2H),7.54-7.56(m,1H),7.68(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,27.9,40.2,41.6,47.5,56.0,80.2,112.1(d,JCF′＝20.0Hz),116.1(d,JCF′＝17.5Hz),119.4,119.7,119.8,120.9,121.0,123.8(d,JCF＝20.0Hz),125.9,128.9,129.9,137.1,155.7,157.6(d,JCF＝201.3Hz),158.4,160.2,162.6(d,JCF＝206.3Hz),170.9,173.3,191.2；HRMS(ESI-TOF)m/z:Calcd.for C32H24F2N4NaO6[M+Na]+:621.1556；Found:621.1557.
本实施例制备化合物3o:白色固体,熔点：195.6-196.8℃；产率91％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.04-2.08(m,1H),2.18(s,3H),2.45(s,3H),2.63-2.67(m,1H),3.59-3.62(m,1H),4.19-4.24(m,1H),4.72-4.76(m,1H),5.92-5.94(m,1H),6.83-6.87(m,2H),6.89-6.90(m,1H),7.00-7.02(m,1H),7.09-7.13(m,1H),7.19-7.23(m,2H),7.38-7.40(m,2H),7.54-7.56(m,1H),7.68(d,J＝6.5Hz,2H)；13CNMR(CDCl3,125MHz)δ:11.6,13.5,28.0,40.3,41.5,48.1,55.9,80.0,112.1(d,JCF＝18.8Hz),116.1(d,JCF＝16.3Hz),119.5,119.7(d,JCF＝6.3Hz),120.9,121.0,123.9(d,JCF＝21.3Hz),125.9,128.9,130.8,136.5,136.6,137.0,155.7,156.4,157.6(d,JCF＝201.3Hz),160.1,170.7,173.2,191.1；HRMS(ESI-TOF)m/z:Calcd.for C32H24F2N4NaO6[M+Na]+:621.1556；Found:621.1558.
本实施例制备化合物3p:白色固体,熔点：182.4-183.5℃；产率82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.08(m,1H),2.18(s,3H),2.46(s,3H),2.63-2.67(m,1H),3.54-3.58(m,1H),4.19-4.23(m,1H),4.72-4.76(m,1H),5.91-5.93(m,1H),6.83-6.85(m,1H),6.98-7.01(m,1H),7.16-7.23(m,3H),7.27-7.33(m,1H),7.32-7.34(m,1H),7.37-7.40(m,2H),7.53-7.55(m,1H),7.67(d,J＝6.5Hz,2H)；13CNMR(CDCl3,125MHz)δ:11.6,13.6,27.9,40.2,41.5,48.1,55.8,80.1,112.0(d,JCF＝20.1Hz),119.7,119.8,123.9,125.9,128.9(d,JCF＝20.0Hz),132.2,136.3,137.0,155.7,156.4,157.6(d,JCF＝201.3Hz),160.0,170.6,173.1,191.1；HRMS(ESI-TOF)m/z:Calcd.forC32H24BrFN4NaO6[M+Na]+:681.0755；Found:681.0755.
本实施例制备化合物3q:白色固体,熔点：181.6-182.5℃；产率89％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.16(s,3H),2.17(s,3H),2.43(s,3H),2.61-2.64(m,1H),3.55-3.56(m,1H),4.20-4.25(m,1H),4.75-4.78(m,1H),5.93-5.95(m,1H),6.83-6.85(m,1H),6.90(d,J＝7.0Hz,2H),7.03-7.05(m,2H),7.19-7.22(m,2H),7.37-7.40(m,2H),7.54-7.56(m,1H),7.70(d,J＝6.5Hz,2H)；13CNMR(CDCl3,125MHz)δ:11.6,13.5,21.0,28.1,40.3,41.6,56.0,60.3,80.4,112.0(d,JCF＝18.8Hz),119.5,119.7(d,JCF＝6.3Hz),123.7(d,JCF＝20.3Hz),125.7,128.8,129.7,130.9,137.3,138.6,155.6,156.5,157.5(d,JCF＝201.3Hz),160.5,171.3,173.5,191.4；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1809.
本实施例制备化合物3r:白色固体,熔点：187.6-188.3℃；产率85％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.93-1.98(m,1H),2.00(s,3H),2.06(s,3H),2.32(s,3H),2.53-2.56(m,1H),3.42-3.44(m,1H),4.12-4.17(m,1H),4.65-4.69(m,1H),5.82-5.84(m,1H),6.73-6.76(m,1H),6.81-6.85(m,2H),6.87-6.90(m,2H),7.09-7.13(m,2H),7.27-7.30(m,2H),7.44-7.46(m,1H),7.58(d,J＝6.5Hz,2H)；13CNMR(CDCl3,125MHz)δ:10.5,12.5,20.1,26.9,39.3,40.6,47.8,54.9,79.3,111.0(d,JCF＝18.8Hz),118.5,118.7(d,JCF＝6.3Hz),119.9(d,JCF＝5.0Hz),122.6(d,JCF＝21.3Hz),124.7,127.8,128.6,132.8,136.1,154.5,155.5,156.7(d,JCF＝201.3Hz),159.4,170.1,172.5,190.4；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1813.
本实施例制备化合物3s:白色固体,熔点：140.1-141.3℃；产率86％,8:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.04-2.09(m,1H),2.19(s,3H),2.34(s,3H),2.54-2.57(m,1H),4.17-4.21(m,1H),4.25(d,J＝10.0Hz,1H),4.85-4.87(m,1H),5.82-5.84(m,1H),6.74-6.77(m,1H),6.89-6.92(m,1H),6.95-6.98(m,1H),7.10-7.15(m,2H),7.30-7.33(m,3H),7.43-7.47(m,2H),7.66(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:10.6,13.2,27.5,39.5,40.4,45.4,52.4,54.8,78.8,111.1(d,JCF＝20.1Hz),118.4,120.0,122.7(d,JCF＝21.3Hz),123.2,124.8,127.2,127.7,127.9,129.2,132.5,132.7,154.6,156.5(d,JCF＝202.5Hz),157.4,159.9,169.5,172.5,190.3；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1811.
本实施例制备化合物3t:白色固体,熔点：180.5-181.7℃；产率85％,7:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.12-2.16(m,1H),2.24(s,3H),2.28(s,3H),2.63-2.66(m,1H),4.22-4.27(m,1H),4.36(d,J＝10.0Hz,1H),4.87-4.94(m,1H),5.87-5.89(m,1H),6.83-6.85(m,1H),7.00-7.02(m,1H),7.20-7.26(m,3H),7.41-7.43(m,2H),7.49(d,J＝7.0Hz,1H),7.54-7.56(m,1H),7.75(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.7,13.8,28.4,41.4,42.6,55.8,60.5,79.9,112.1(d,JCF＝20.5Hz),119.3,119.7,123.8(d,JCF＝20.7Hz),126.0,128.0,129.0,129.5,129.9,130.7,134.2,135.3,155.8,156.4,157.6(d,JCF′＝202.6Hz),160.7,170.3,173.4,191.1；HRMS(ESI-TOF)m/z:Calcd.for C32H23Cl2FN4NaO6[M+Na]+:671.0871；Found:671.0877.
本实施例制备化合物3u:白色固体,熔点：153.3-155.1℃；产率90％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.11(s,3H),2.13(s,3H),2.23(s,3H),2.43(s,3H),2.60-2.63(m,1H),3.84(d,J＝9.5Hz,1H),4.28-4.34(m,1H),4.83-4.86(m,1H),5.99-6.02(m,1H),6.71(d,J＝6.5Hz,1H),6.77(s,1H),6.83-6.86(m,1H),7.19-7.25(m,2H),7.28-7.29(m,2H),7.40-7.43(m,2H),7.55-7.57(m,1H),7.77(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,19.2,20.8,28.8,40.8,41.6,56.0,80.5,112.0(d,JCF＝20.0Hz),119.5,119.7,123.8(d,JCF＝22.3Hz),125.7,126.6,127.6,128.9,129.4,131.8,137.4,138.0,155.7,157.2(d,JCF＝201.3Hz),160.4,171.3,174.0,191.6；HRMS(ESI-TOF)m/z:Calcd.for C34H29FN4NaO6[M+Na]+:631.1963；Found:631.1965.
本实施例制备化合物3v:白色固体,熔点：131.0-132.3℃；产率90％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.01-2.06(m,1H),2.20(s,3H),2.48(s,3H),2.64-2.67(m,1H),3.91-3.93(m,1H),4.15-4.20(m,1H),4.72-4.74(m,1H),5.91-5.93(m,1H),6.74-6.75(m,1H),6.83-6.86(m,1H),6.89(d,J＝2.5Hz,1H),7.02(d,J＝4.0Hz,1H),7.19-7.24(m,2H),7.38-7.41(m,2H),7.53-7.55(m,1H),7.76(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.4,27.9,39.6,41.4,50.9,56.3,79.8,112.1(d,JCF＝20.1Hz),119.4,119.7,123.9(d,JCF＝20.0Hz),125.6,125.7,126.3,127.4,128.9,135.7,155.7,156.4,157.6(d,JCF＝201.3Hz),160.2,170.8,173.2,191.1；HRMS(ESI-TOF)m/z:Calcd.for C30H23FN4NaO6S[M+Na]+:609.1215；Found:609.1211.
本实施例制备化合物5a:白色固体,熔点：270.0-273.5℃；产率75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.21-2.25(m,1H),2.43(s,3H),2.80-2.84(m,1H),3.74-3.76(m,1H),4.00-4.05(m,1H),4.84-4.86(m,1H),5.80-5.82(m,1H),6.83-6.87(m,2H),7.00-7.10(m,5H),7.20-7.21(m,2H),7.29(s,1H),7.36-7.38(m,1H),7.48-7.51(m,1H),7.91(d,J＝6.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,32.0,41.2,43.3,51.1,80.2,110.8,118.0,120.5,122.2,122.8,124.5,127.1,128.3,129.1,129.5,134.0,136.3,152.3,155.6,160.2,171.2,177.0,191.7；HRMS(ESI-TOF)m/z:Calcd.for C30H22N2NaO7[M+Na]+:545.1319；Found:545.1323.
本实施例制备化合物5b:白色固体,熔点：>300.0℃；产率61％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.12(s,3H),2.19-2.23(m,1H),2.44(s,3H),2.79-2.82(m,1H),3.72-3.74(m,1H),3.98-4.02(m,1H),4.82-4.84(m,1H),5.77-5.79(m,1H),6.78(s,3H),6.78-6.86(m,3H),7.06-7.09(m,1H),7.19-7.22(m,2H),7.36-7.37(m,1H),7.47-7.50(m,1H),7.89-7.91(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.9,32.0,41.4,43.3,51.2,80.3,110.8,118.0,120.5,122.2,122.8,124.4,127.1,129.3,129.4,130.9,136.2,138.0,152.3,155.6,160.2,171.4,177.0,191.7；HRMS(ESI-TOF)m/z:Calcd.for C31H24N2NaO7[M+Na]+:559.1476；Found:559.1477.
本实施例制备化合物5c:白色固体,熔点：>300.0℃；产率70％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.39-2.44(m,1H),2.47(s,3H),2.69-2.72(m,1H),3.48-3.53(m,1H),3.94(d,J＝11.0Hz,1H),4.86-4.90(m,1H),5.36-5.40(m,1H),6.74(s,2H),6.87(d,J＝7.0Hz,1H),6.95(s,2H),7.01(d,J＝6.5Hz,1H),7.11-7.13(m,1H),7.33-7.36(m,1H),7.39-7.42(m,1H),7.51-7.53(m,1H),7.88(d,J＝6.0Hz,1H),7.93(d,J＝5.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.9,42.2,44.5,50.2,52.8,80.3,111.9,117.9,120.6,122.6,124.7,125.0,127.0,127.4,128.7,130.3,132.2,134.5,136.5,152.8,155.5,160.0,170.5,176.6,190.3；HRMS(ESI-TOF)m/z:Calcd.forC30H21ClN2NaO7[M+Na]+:579.0929；Found:579.0934.
本实施例制备化合物5d:白色固体,熔点：196.1-200.8℃；产率69％,10:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.27-2.32(m,1H),2.48(s,3H),2.77-2.80(m,1H),3.98-7.03(m,1H),4.59(d,J＝10.0Hz,1H),4.91-4.95(m,1H),5.71-5.72(m,1H),6.85(d,J＝7.0Hz,1H),6.90(d,J＝7.0Hz,1H),7.01(s,1H),7.07-7.13(m,2H),7.15-7.18(m,1H),7.23-7.26(m,1H),7.47-7.50(m,3H),7.89(d,J＝6.5Hz,1H)；13CNMR(CDCl3,125MHz)δ:11.7,32.4,41.6,43.2,44.8,51.1,79.9,110.6,117.9,122.3,124.0,124.3,127.1,128.0,128.5,129.7,129.9,134.8,136.3,151.9,155.7,160.1,170.5,177.2,191.5；HRMS(ESI-TOF)m/z:Calcd.for C30H20Cl2N2NaO7[M+Na]+:613.0540；Found:613.0546.
本实施例制备化合物5e:白色固体,熔点：>300.0℃；产率75％,7:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.25-2.30(m,1H),2.46(s,3H),2.77-2.80(m,1H),4.00-4.05(m,1H),5.02-5.06(m,1H),5.14(d,J＝10.0Hz,1H),5.84-5.88(m,1H),6.83(d,J＝6.5Hz,1H),6.87(d,J＝7.0Hz,1H),7.09-7.11(m,1H),7.16-7.18(m,1H),7.23-7.29(m,3H),7.47-7.52(m,3H),7.77(d,J＝6.5Hz,1H),7.91-7.92(m,1H)；13CNMR(CDCl3,125MHz)δ:11.6,32.2,41.0,43.2,51.5,79.8,110.6,117.9,122.3,123.1,125.3,125.5,127.2,129.4,130.0,133.5,136.3,149.7,151.9,155.7,160.1,170.3,177.0,191.3；HRMS(ESI-TOF)m/z:Calcd.for C30H21N3NaO9[M+Na]+:590.1170；Found:590.1174.
本实施例制备化合物5f:白色固体,熔点：177.5-180.1℃；产率68％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.17-2.21(m,1H),2.49(s,3H),2.81-2.84(m,1H),3.95-3.99(m,1H),4.05-4.06(m,1H),4.80-4.81(m,1H),5.74-5.76(m,1H),6.68-6.70(m,1H),6.83-6.86(m,2H),6.89-6.90(m,1H),6.93-6.94(m,1H),7.07-7.09(m,1H),7.23-7.29(m,2H),7.37(d,J＝6.0Hz,1H),7.48-7.51(m,1H),7.89-7.90(m,1H)；13C NMR(CDCl3,125MHz)δ:11.7,31.7,43.1,51.6,79.8,110.9,118.0,120.5,122.2,122.7,124.8,125.4,126.1,127.1,129.8,136.3,152.6,155.7,160.1,171.0,176.8,191.5；HRMS(ESI-TOF)m/z:Calcd.for C28H20N2NaO7S[M+Na]+:551.0883；Found:551.0889.
本实施例制备化合物5g:白色固体,熔点：>300.0℃；产率69％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.20-2.25(m,1H),2.42(s,3H),2.80-2.83(m,1H),3.75(d,J＝9.5Hz,1H),3.99-4.03(m,1H),4.82-4.86(m,1H),5.79-5.81(m,1H),6.82-6.86(m,2H),6.98-7.03(m,5H),7.19-7.23(m,3H),7.36-7.37(m,1H),7.53-7.55(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.9,41.4,43.3,51.1,80.5,110.8,112.1(d,JCF＝18.8Hz),119.7,119.8,122.8,123.8(d,JCF＝21.3Hz),124.5,128.4,129.0,129.5,133.9,152.3,155.6,156.4,157.6(d,JCF＝18.8Hz),171.1,177.0,191.0；HRMS(ESI-TOF)m/z:Calcd.for C30H21FN2NaO7[M+Na]+:563.1225；Found:563.1229.
本实施例制备化合物5h:白色固体,熔点：261.8-265.0℃；产率80％,10:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.28-2.33(m,1H),2.44(s,3H),2.78-2.81(m,1H),4.01-4.06(m,1H),4.63(d,J＝10.5Hz,1H),4.95-4.99(m,1H),5.73-5.75(m,1H),6.84-6.86(m,2H),6.98(d,J＝3.0Hz,2H),7.11-7.14(m,1H),7.15(d,J＝6.5Hz,1H),7.19-7.23(m,2H),7.50-7.52(m,2H),7.54-7.56(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,32.3,41.6,43.1,45.3,51.0,80.1,110.4,112.1(d,JCF＝20.3Hz),123.7(d,JCF＝20.1Hz),124.0,124.2,127.4,127.6,127.7,129.5,129.7,134.0,151.9,155.6,156.4,157.6(d,JCF＝21.3Hz),170.6,177.3,190.9；HRMS(ESI-TOF)m/z:Calcd.forC30H20ClFN2NaO7[M+Na]+:597.0835；Found:597.0841.
本实施例制备化合物5i:白色固体,熔点：>300.0℃；产率73％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.28-2.33(s,1H),2.43(s,3H),2.77-2.80(m,1H),4.01-4.06(m,1H),4.63(d,J＝10.0Hz,1H),4.96-4.98(m,1H),5.73-5.75(m,1H),6.85-6.86(m,2H),6.98(s,2H),7.10-7.16(m,2H),7.19-7.23(m,2H),7.51-7.56(m,3H)；13C NMR(CDCl3,125MHz)δ:11.6,32.4,41.7,43.2,45.4,51.1,80.1,110.4,112.1(d,JCF＝18.8Hz),123.8(d,JCF＝21.3Hz),124.0,124.2,127.5,127.7,129.6,129.8,132.5,152.0,155.6,157.6(d,JCF＝201.3Hz),158.4,170.6,177.4,190.9；HRMS(ESI-TOF)m/z:Calcd.for C30H20ClFN2NaO7[M+Na]+:597.0835；Found:597.0831.
本实施例制备化合物5j:白色固体,熔点：>300.0℃；产率69％,15:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.24-2.29(m,1H),2.46(s,3H),2.85-2.88(m,1H),3.92(d,J＝10.5Hz,1H),3.97-4.02(m,1H),4.81-4.85(m,1H),5.82-5.85(m,1H),6.84-6.87(m,2H),7.22-7.32(m,5H),7.46(d,J＝6.0Hz,1H),7.54-7.56(m,1H),7.61-7.70(m,1H),7.93(d,J＝7.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.6,40.9,43.1,51.1,80.2,111.1,112.2(d,JCF＝20.1Hz),119.7,119.8,122.7,123.5,123.9(d,JCF＝20.5Hz),125.1,128.0,130.2,136.1,152.1,155.8,156.2,157.4(d,JCF＝201.3Hz),170.0,176.4,190.5；HRMS(ESI-TOF)m/z:Calcd.for C30H20FN3NaO9[M+Na]+:608.1076；Found:608.1079.
本实施例制备化合物5k:白色固体,熔点：201.2-205.3℃；产率65％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.26-2.31(m,1H),2.48(s,3H),2.77-2.80(m,1H),3.98-4.03(m,1H),4.58(d,J＝10.5Hz,1H),4.91-4.95(m,1H),5.70-5.72(m,1H),6.84-6.86(m,1H),6.90(d,J＝7.0Hz,1H),7.01(s,1H),7.11-7.13(m,1H),7.15-7.18(m,1H),7.20-7.26(m,2H),7.46-7.49(m,2H),7.53-7.55(m,1H)；13C NMR(CDCl3,125MHz)δ:11.7,32.3,41.5,43.1,44.8,51.0,80.1,110.7,112.2(d,JCF＝17.5Hz),123.9(d,JCF＝20.7Hz),124.4,127.4,128.0,128.4,129.7,130.0,134.9(d,JCF＝8.8Hz),151.9,155.8,156.3,157.6(d,JCF＝201.3Hz),170.3,177.2,190.7；HRMS(ESI-TOF)m/z:Calcd.for C30H19Cl2FN2NaO7[M+Na]+:631.0446；Found:631.0446.
本实施例制备化合物5l:白色固体,熔点：160.2-165.8℃；产率76％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.11(s,3H),2.18-2.22(m,1H),2.43(s,3H),2.78-2.81(m,1H),3.71-3.73(m,1H),3.96-4.01(m,1H),4.81-4.83(m,1H),5.76-5.78(m,1H),6.78(s,3H),6.83-6.85(m,2H),7.18-7.22(m,3H),7.35-7.36(m,1H),7.53-7.54(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.9,31.9,41.4,43.3,51.1,80.5,110.8,112.1(d,JCF＝20.1Hz),122.8,123.7(d,JCF＝20.1Hz),124.5,129.1,129.5,130.8,138.0,152.3,155.6,157.6(d,JCF＝202.5Hz),158.4,171.2,177.0,191.0；HRMS(ESI-TOF)m/z:Calcd.for C31H23FN2NaO7[M+Na]+:577.1382；Found:577.1387.
本实施例制备化合物5m:白色固体,熔点：263.2-265.1℃；产率67％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.34-2.39(m,1H),2.47(s,3H),2.70-2.73(m,1H),3.45-3.50(m,1H),4.28(d,J＝10.5Hz,1H),4.85-4.89(m,1H),5.30-5.31(m,1H),6.52(d,J＝2.5Hz,1H),6.62-6.64(m,1H),6.87-6.89(m,1H),6.93(d,J＝5.0Hz,1H),7.08(d,J＝7.0Hz,1H),7.22-7.26(m,1H),7.35-7.38(m,1H),7.44-7.47(m,1H),7.56-7.58(m,1H),7.86(d,J＝6.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.7,44.3,46.6,50.9,52.8,80.2,111.9,112.4(d,JCF＝18.8Hz),119.7,119.8,124.0(d,JCF＝21.3Hz),124.8,125.2,126.4,127.8,130.5,135.5,153.3,155.5,156.3,157.6(d,JCF＝202.5Hz),170.2,176.6,189.7；HRMS(ESI-TOF)m/z:Calcd.for C28H19FN2NaO7S[M+Na]+:569.0789；Found:569.0786.
本实施例制备化合物5n:白色固体,熔点：258.8-261.1℃；产率74％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.34(s,3H),2.37-2.42(m,1H),2.47(s,3H),2.68-2.71(m,1H),3.44-3.51(m,1H),3.93(d,J＝10.5Hz,1H),4.81-4.85(m,1H),5.32-5.38(m,1H),6.73(s,2H),6.76(d,J＝7.0Hz,1H),6.93-6.95(m,2H),7.00(d,J＝6.5Hz,1H),7.31-7.35(m,2H),7.39-7.42(m,1H),7.70(s,1H),7.88(d,J＝6.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.5,31.9,42.2,44.5,50.2,52.8,80.3,111.9,117.7,120.2,124.7,125.0,126.9,127.1,128.7,130.2,132.2,134.5,137.5,152.8,155.5,158.1,170.6,176.6,190.6；HRMS(ESI-TOF)m/z:Calcd.for C31H23ClN2NaO7[M+Na]+:593.1086；Found:593.1087.
本实施例制备化合物5o:白色固体,熔点：>300.0℃；产率67％,9:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.27-2.31(m,1H),2.33(s,3H),2.44(s,3H),2.77-2.80(m,1H),3.99-4.04(m,1H),4.62(d,J＝10.0Hz,1H),4.92-4.95(m,1H),5.68-5.74(m,1H),6.76(d,J＝7.0Hz,1H),6.86(d,J＝6.5Hz,1H),6.98(d,J＝3.5Hz,2H),7.10-7.13(m,1H),7.15(d,J＝6.5Hz,1H),7.19-7.22(m,1H),7.29-7.31(m,1H),7.51-7.53(m,2H),7.69(s,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.4,32.6,42.1,43.3,45.4,51.2,79.9,110.4,117.7,124.0,124.2,126.7,127.5,127.6,127.9,129.5,129.7,129.8,137.3,152.0,155.6,158.3,170.9,177.4,191.9；HRMS(ESI-TOF)m/z:Calcd.for C31H23ClN2NaO7[M+Na]+:593.1086；Found:593.1091.
本实施例制备化合物5p:白色固体,熔点：>300.0℃；产率65％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.33(s,3H),2.36-2.41(m,1H),2.45(s,3H),2.68-2.71(m,1H),3.45-3.50(m,1H),3.89(d,J＝11.0Hz,1H),4.82-4.86(m,1H),5.33-5.37(m,1H),6.73(s,1H),6.76(d,J＝7.0Hz,1H),6.84(s,1H),6.92(s,1H),7.00(d,J＝6.5Hz,1H),7.19(d,J＝6.5Hz,1H),7.30-7.32(m,1H),7.35-7.37(m,1H),7.40-7.42(m,1H),7.70(s,1H),7.90(d,J＝6.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.5,31.9,42.1,44.5,50.5,52.7,80.2,111.8,117.7,120.2,122.4,124.7,125.1,126.9,127.0,129.8,130.3,131.7,132.2,132.5,135.9,137.5,152.8,155.5,158.1,170.4,176.5,190.6；HRMS(ESI-TOF)m/z:Calcd.for C31H23BrN2NaO7[M+Na]+:637.0581；Found:637.0578.
本实施例制备化合物5q:白色固体,熔点：193.5-200.4℃；产率76％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.26-2.30(m,1H),2.32(s,3H),2.48(s,3H),2.76-2.79(m,1H),3.95-4.00(m,1H),4.58(d,J＝10.5Hz,1H),4.87-4.91(m,1H),5.69-5.71(m,1H),6.74(d,J＝7.0Hz,1H),6.89(d,J＝6.5Hz,1H),7.00(s,1H),7.10-7.12(m,1H),7.15-7.17(m,1H),7.23-7.25(m,1H),7.29-7.30(m,1H),7.47-7.50(m,2H),7.68(s,1H)；13C NMR(CDCl3,125MHz)δ:11.7,20.4,32.5,41.7,43.2,44.8,51.1,79.9,110.6,117.7,124.0,124.3,126.7,128.0,128.5,129.6,129.9,131.4,131.8,137.4,151.9,155.7,158.2,170.6,177.2,191.7；HRMS(ESI-TOF)m/z:Calcd.for C31H22Cl2N2NaO7[M+Na]+:627.0696；Found:627.0697.
本实施例制备化合物5r:白色固体,熔点：>300.0℃；产率80％,18:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.13(s,3H),2.34(s,3H),2.37-2.42(m,1H),2.43(s,3H),2.66-2.69(m,1H),3.45-3.50(m,1H),3.90(d,J＝6.0Hz,1H),4.83-4.86(m,1H),5.36-5.40(m,1H),6.65(s,2H),6.73-6.75(m,2H),6.77(d,J＝7.0Hz,1H),6.96(d,J＝6.5Hz,1H),7.31-7.34(m,2H),7.36-7.39(m,1H),7.71(s,1H),7.89(d,J＝6.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.5,21.0,32.0,42.4,44.6,50.6,52.9,80.4,111.6,117.7,120.2,124.5,125.1,126.9,127.6,129.1,129.9,130.5,132.0,137.4,138.1,152.9,155.4,158.2,171.1,176.9,190.8；HRMS(ESI-TOF)m/z:Calcd.forC32H26N2NaO7[M+Na]+:573.1632；Found:573.1637.
本发明的式(1)化合物具有重要的生物活性，体外对人白血病细胞(K562)的细胞毒性试验表明：此类式(1)所示结构的山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人白血病细胞(K562)表示的细胞毒性。
药理实施例：化合物3i,3m和5m对K562细胞的细胞毒性
K562(人慢性髓系白血病细胞)用RPMI-1640培养基培养，培养基中含10％的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后，分别将新配的化合物3i,3m和5m的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度分别为5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/L。48小时后，每孔加入10μL MTT(5mg/mL)的磷酸盐缓冲液，再继续在37℃培养4小时后，离心5分钟除去未转化的MTT，每孔中加入150μL二甲基亚砜。以溶解还原的MTT晶体甲臜(formazan)，用酶标仪在490nm波长测定OD值。其中化合物化合物3i,3m和5m对K562细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3i对K562肿瘤细胞的IC50为42.31μmol/L；化合物3m对K562肿瘤细胞的IC50为36.27μmol/L；化合物5m对K562肿瘤细胞的IC50为39.40μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为23.01μmol/L。
实验结论：K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物对K562细胞具有较强的细胞毒性，有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物具有开发成为抗肿瘤药物的潜力，值得继续深入研究下去。

Claims (3)

1.一种山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
Figure FDA0003480768820000011
式中，R1为甲基、氟或氢；Ar为氟、氯、溴、硝基或甲基取代的苯环或噻吩环。
2.一种如权利要求1所述的山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物的制备方法，其特征在于，其合成路线如下：
Figure FDA0003480768820000012
3.一种如权利要求1所述的山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物在制备防治白血病药物中的应用。
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