CN105585570A - 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 - Google Patents

异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 Download PDF

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CN105585570A
CN105585570A CN201510929055.5A CN201510929055A CN105585570A CN 105585570 A CN105585570 A CN 105585570A CN 201510929055 A CN201510929055 A CN 201510929055A CN 105585570 A CN105585570 A CN 105585570A
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isoxazole
cdcl
pyrroles
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刘雄利
姚震
刘雄伟
张文会
陈智勇
周根
周英
俸婷婷
余章彪
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Guizhou University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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Abstract

本发明公开了一种异恶唑拼接吡咯螺环氧化吲哚化合物，本发明以各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸或肌氨酸，在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接吡咯螺环氧化吲哚化合物，该类骨架包含潜在的生物活性异恶唑基团，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。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。且该化合物对三种肿瘤细胞株如人***（PC-3）,人肺癌细胞（A549）以及人白血病细胞（K562）所进行的肿瘤生长抑制活性筛选。

Description

异恶唑拼接吡咯螺环氧化吲哚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领域，尤其是一种异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用。
背景技术
把具有生物活性基团拼接到具有活性分子骨架中在有机化学和医药化学中是极其重要的研究领域。（1）多官能团氧化吲哚广泛存在天然产物和合成药物分子中，其中，尤其3-吡咯螺环氧化吲哚因为具有广泛的生物活性，吸引了许多化学工作者及医药化学团队的广泛关注，例如，MI-219I是一种MDM2-p53抑制剂，可以抑制癌细胞生长和促进凋亡；SpirotryprostatinsB(II)是从烟曲霉的发酵液中分离得到，已被证明完全抑制tsFT210细胞，在阻断细胞***的G2/M期；并且，天然产物台钩藤碱III已被证明具有调节大脑皮层M受体亚型和5-羟色胺受体的功能；此外，alstonisineVI，天然生物碱，是首先从灯台muelleriana和几种alstonisine仿生类似物的分离出来。（2）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（CloxacillinV,muscimolVI,IsoxicamVII,leflunomideVIII,等）共享一个异恶唑分子单元，这些化合物在解除病痛、经济发展中起着重大作用。鉴于3-吡咯螺环氧化吲哚骨架化合物具有潜在的生物活性，异恶唑基团属于潜在的生物活性官能团。因此，把异恶唑基团拼接到3-吡咯螺环氧化吲哚骨架，合成一系列新的潜在多活性官能团的氧化吲哚衍生物，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(如附图8所示)。
发明内容
本发明的目的是：提供一种异恶唑拼接吡咯螺环氧化吲哚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：异恶唑拼接吡咯螺环氧化吲哚化合物，该化合物具有如下通式（Ⅰ）的结构：
式中，R1为烷基或芳基；R2为烷基或卤素；R3为烷基或卤素；R4为不同取代的芳基；R5为H或烷基；R6为H或芳基。
异恶唑拼接吡咯螺环氧化吲哚化合物的制备方法，由各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸、硫代脯氨酸或肌氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接吡咯螺环氧化吲哚化合物；
合成路线如下：
其中各种取代的靛红的结构式合成路线中的化合物1，其取代基满足R1为烷基或芳基；R2为烷基或卤素；R3为烷基或卤素。
所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、***、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸、硫代脯氨酸或肌氨酸，在有机溶剂中反应温度为50-100℃，反应时间为5-20小时。
异恶唑拼接吡咯螺环氧化吲哚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，以各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸或肌氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接吡咯螺环氧化吲哚化合物，该类骨架包含潜在的生物活性异恶唑基团，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。且该化合物对三种肿瘤细胞株如人***（PC-3），人肺癌细胞（A549）以及人白血病细胞（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1的化合物3aa谱图数据；
附图3及附图4为本发明的实施例2的化合物4aa谱图数据；
附图5及附图6为本发明的实施例3的化合物5aa谱图数据。
附图7为本发明的实施例2和实施例3的化合物4ah和5dc单晶图；
附图8为本发明的合成路线图。
具体实施方式
本发明的实施例1：在反应管中依次加入64.4mgN-甲基靛红1a(0.4mmol)，138.0mg(E)-硝基异恶唑烯烃化合物2a(0.6mmol)，92.0mg脯氨酸(0.8mmol)和15ml甲苯溶液，80oC反应24h，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）=4:1）纯化得159.8mg化合物3aa，黄色固体，熔点：237.1-237.6oC，dr：20:1；产率90.0%。核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.62-1.75(m,1H),1.80-1.83(m,1H),1.95-1.99(m,2H),2.21(s,3H),2.58-2.62(m,1H),2.98-3.04(m,1H),3.16(s,3H),3.87(t,J=10.0Hz,1H),4.41-4.46(m,1H),4.90(d,J=12Hz,1H),6.67-6.78(m,3H),7.13-7.28(m,2H),7.21-7.29(m,2H),7.49(d,J=8.0Hz,2H);13CNMR(CDCl3,100MHz)δ:11.3,25.3,26.5,27.9,49.2,52.9,56.7,71.3,73.9,108.6,121.7,124.7,125.7,127.5,128.3,129.0,130.0,138.5,144.7,155.8,172.7,178.5;HRMS(ESI-TOF)m/z:Calcd.forC25H25N4O4[M+H]+:445.1875;Found:445.1881.
化合物3ab-3gc的制备方法同化合物3aa，投料比与化合物3aa相同，可得到化合物化合物3ab-3gc，反应产率和反应时间见表1，但需强调的是本发明的化合物不限于表1所表示的内容。
本实施例制备化合物3ab：黄色固体;熔点：164.7-165.4oC;产率：86%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.74-1.77(m,1H),1.88-1.93(m,1H),2.00-2.10(m,2H),2.28(s,3H),2.52(s,3H),2.67-2.72(m,1H),3.09-3.15(m,1H),3.24(s,3H),4.37(t,J=10.0Hz,1H),4.47-4.52(m,1H),4.99(d,J=12.0Hz,1H),6.75-6.86(m,3H),7.10-7.13(m,2H),7.21-7.29(m,2H),7.89(d,J=8.0Hz,1H);13CNMR(CDCl3,100MHz)δ:11.3,20.0,25.3,26.5,27.8,47.0,49.1,57.3,72.6,74.0,108.6,121.7,124.7,125.6,126.9,127.1,127.6,130.0,130.5,136.7,137.0,144.0,155.9,173.0,178.5;HRMS(ESI-TOF)m/z:Calcd.forC26H26N4NaO4[M+Na]+:481.4988;Found:481.4990.
本实施例制备化合物3ac：黄色固体;熔点：177.2-178.1oC;产率：82%,20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.76-1.82(m,1H),1.88-1.96(m,1H),2.03-2.10(m,2H),2.31(s,3H),2.66-2.70(m,1H),3.03-3.10(m,1H),3.24(s,3H),3.94(t,J=10.0Hz,1H),4.47-4.52(m,1H),4.92(d,J=12.0Hz,1H),6.74-6.78(m,2H),6.81-6.85(m,1H),6.91-6.96(m,1H),7.22-7.36(m,4H);13CNMR(CDCl3,100MHz)δ:11.3,25.3,26.5,27.8,49.2,52.5,56.7,71.1,73.9,108.7,114.4(d,JCF=21.0Hz),115.1(d,JCF=21.6Hz),121.7,123.8(d,JCF=2.8Hz),125.6,130.1,130.5,141.2,141.3,144.7,155.9,163.1(d,JCF=245.5Hz),172.4,178.4;HRMS(ESI-TOF)m/z:Calcd.forC25H23FN4NaO4[M+Na]+:485.1601;Found:485.1602.
本实施例制备化合物3ad：黄色固体;熔点：161.7-162.8oC;产率：Yield64%,18:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.72-1.79(m,1H),1.92-1.95(m,1H),2.06-2.09(m,2H),2.32(s,3H),2.69-2.73(m,1H),3.06-3.12(m,1H),3.26(s,3H),4.07(t,J=10.0Hz,1H),4.53-4.57(m,1H),4.95(d,J=12.0Hz,1H),6.72(d,J=8.0Hz,1H),6.78-6.86(m,2H),7.24-7.28(m,1H),7.77(d,J=8.0Hz,2H),8.20(d,J=8.0Hz,2H);13CNMR(100MHz,CDCl3)δ:11.3,25.2,26.5,27.8,49.2,52.6,56.8,71.3,74.1,108.8,121.8,124.2,124.3,125.5,129.2,130.3,144.7,146.6,147.4,156.0,172.0,178.3;HRMS(ESI-TOF)m/z:Calcd.forC25H23N5NaO6[M+Na]+:512.1546;Found:512.1550.
本实施例制备化合物3bc：黄色固体;熔点：168.2-169.1oC;产率：Yield81%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.67-1.71(m,1H),1.85-1.88(m,1H),1.95-2.02(m,2H),2.22(s,3H),2.57-2.62(m,1H),2.92-2.98(m,1H),3.85-3.91(m,1H),4.38-4.41(m,1H),4.72-4.76(m,1H),4.95-5.02(m,2H),6.52-6.56(m,1H),6.72-6.77(m,2H),6.84-6.88(m,1H),7.00-7.04(m,1H),7.16-7.28(m,8H);13CNMR(CDCl3,100MHz)δ:11.4,25.7,28.1,44.3,48.6,52.9,56.5,71.1,73.7,109.7,114.5(d,JCF=20.8Hz),115.2(d,JCF=21.4Hz),121.8,123.7(d,JCF=2.7Hz),124.6,125.8,127.4,127.7,128.8,129.9,130.5,130.6,135.6,141.3,143.8,155.9,163.3(d,JCF=245.1Hz),172.1,178.3;HRMS(ESI-TOF)m/z:Calcd.forC31H27FN4NaO4[M+Na]+:561.1914;Found:561.1915.
本实施例制备化合物3bf：黄色固体;熔点：88.7-89.2oC;产率：Yield71%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.76-1.80(m,1H),1.93-1.98(m,1H),2.04-2.09(m,2H),2.31(s,3H),2.68-2.74(m,1H),3.01-3.07(m,1H),4.03(t,J=10.1Hz,1H),4.50-4.54(m,1H),4.83(d,J=16.0Hz,1H),5.05(d,J=16.2Hz,1H),5.10(d,J=8.1Hz,1H),6.64(d,J=8.2Hz,1H),6.82(d,J=4.3Hz,2H),7.10-7.14(m,1H),7.25-7.29(m,1H),7.30-7.35(m,4H),7.60(d,J=8.3Hz,2H),7.70(d,J=8.5Hz,2H);13CNMR(100MHz,CDCl3)δ:11.3,25.5,28.0,44.3,48.7,53.0,56.5,71.2,73.8,109.7,121.8,125.7,125.9,127.3,127.6,128.6,128.8,130.0,142.7,143.7,155.9,171.8,178.3;HRMS(ESI-TOF)m/z:Calcd.forC32H27F3N4NaO4[M+Na]+:611.1882;Found:611.1887.
本实施例制备化合物3cb：黄色固体;熔点：213.5-213.9oC;产率：Yield88%,>20:dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.65-1.70(m,1H),1.94-2.00(m,3H),2.26(s,3H),2.27(s,3H),2.62-2.67(m,1H),2.82-2.88(m,1H),3.79(t,J=12.0Hz,1H),4.26-4.31(m,1H),5.05(d,J=12.0Hz,1H),6.65-6.68(m,1H),6.70-6.73(m,1H),6.82-6.87(m,1H),6.99(d,J=8.0Hz,1H),7.12-7.22(m,4H),8.26(s,1H);13CNMR(100MHz,CDCl3)δ:11.4,21.5,26.4,28.9,48.3,53.1,56.2,71.5,74.3,111.1,114.0(d,JCF=35.8Hz),116.5(d,JCF=20.6Hz),125.1,126.6,128.5,128.7,128.9,137.7,138.7,155.7,158.2(d,JCF=236.1Hz),171.1,180.1;HRMS(ESI-TOF)m/z:Calcd.forC25H23FN4NaO4[M+Na]+:485.1601;Found:485.1601.
本实施例制备化合物3dc：黄色固体;熔点：214.7-215.4oC;产率：Yield88%,19:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.72-1.78(m,1H),1.90-1.98(m,3H),2.20(s,3H),2.33(s,3H),2.68-2.72(m,1H),2.97-3.03(m,1H),3.93(t,J=10.0Hz,1H),4.37-4.41(m,1H),5.01(d,J=12.0Hz,1H),6.60(s,1H),6.70(d,J=8.0Hz,1H),6.92-6.99(m,2H),7.23-7.31(m,4H),7.79(brs,1H);13CNMR(CDCl3,100MHz)δ:11.3,21.0,25.8,28.4,48.6,52.6,56.4,71.1,74.2,110.1,114.4(d,JCF=21.0Hz),115.1(d,JCF=22.3Hz),126.8,130.4,130.5,130.6,131.2,139.1,141.1,155.8,163.1(d,JCF=244.0Hz),171.9,179.8;HRMS(ESI-TOF)m/z:Calcd.forC25H23FN4NaO4[M+Na]+:485.1601;Found:485.1600.
本实施例制备化合物3ee：黄色固体;熔点：157.8-158.6oC;产率：Yield72%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.71-1.74(m,1H),1.97-2.08(m,3H),2.34(s,3H),2.59-2.64(m,1H),2.87-2.93(m,1H),3.83(s,3H),3.90(s,3H),4.36-4.41(m,1H),5.13(d,J=12.0Hz,1H),5.28-5.44(m,2H),6.79-6.89(m,3H),7.01-7.13(m,3H),7.24-7.29(m,5H);13CNMR(100MHz,CDCl3)δ:11.5,26.4,28.5,45.4,47.7,53.1,55.9,56.0,56.8,71.0,72.5,110.6,111.4,115.9,120.3,122.7,124.5,126.5,127.1,127.9,128.5,130.4,132.5,137.5,139.8,148.5,149.3,155.8,171.5,179.0;HRMS(ESI-TOF)m/z:Calcd.forC33H31ClN4NaO6[M+Na]+:637.1829;Found:637.1831.
本实施例制备化合物3fb：黄色固体;熔点：209.7-210.5oC;产率：Yield81%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.74-1.78(m,1H),1.86-1.91(m,1H),2.00-2.07(m,2H),2.29(s,3H),2.33(s,3H),2.34(s,3H),2.67-2.71(m,1H),2.97-3.02(m,1H),3.90(t,J=12.2Hz,1H),4.38-4.42(m,1H),5.09-5.12(m,1H),6.73-6.79(m,2H),6.99-7.06(m,2H),7.20-7.26(m,1H),7.29-7.33(m,2H),9.86(brs,1H);13CNMR(100MHz,CDCl3)δ:11.5,16.6,21.6,25.9,28.7,49.1,53.5,55.9,71.5,75.1,120.3,121.6,123.6,124.7,125.3,12.8.4,128.9,129.0,130.6,131.4,138.7,140.9,155.9,172.1,181.4;HRMS(ESI-TOF)m/z:Calcd.forC26H26N4NaO4[M+Na]+:481.1851;Found:481.1854.
本实施例制备化合物3gc：黄色固体;熔点：166.4-166.7oC;产率：Yield83%,19:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.77-1.81(m,1H),1.94-1.98(m,1H),2.07-2.11(m,2H),2.35(s,3H),2.75-2.80(m,1H),3.13-3.17(m,1H),3.99(t,J=8.5Hz,1H),4.52-4.55(m,1H),5.01(d,J=8.1Hz,1H),6.70(d,J=8.1Hz,1H),6.76(d,J=4.2Hz,1H),6.83-6.86(m,1H),6.91-6.95(m,1H),7.13-7.16(m,1H),7.26-7.31(m,2H),7.36-7.45(m,2H),7.50-7.57(m,4H);13CNMR(100MHz,CDCl3)δ:11.3,25.1,27.5,48.9,52.3,57.3,71.0,74.0,109.9,114.4(d,JCF=17.0Hz),115.2(d,JCF=17.2Hz),122.0,125.7,126.9,128.3,129.7,129.9,141.4(d,JCF=5.1Hz),144.9,156.0,163.1(d,JCF=196.7Hz),172.8,177.8;HRMS(ESI-TOF)m/z:Calcd.forC30H25FN4NaO4[M+Na]+:547.1757;Found:547.1759.
本发明的实施例2：在反应管中依次加入64.4mgN-甲基靛红1a(0.4mmol)，138.0mg(E)-硝基异恶唑烯烃化合物2a(0.6mmol)，106.4mg硫代脯氨酸(0.8mmol)和15ml甲苯溶液，80oC反应24h，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）=4:1）纯化得140.5mg化合物4aa，黄色固体;熔点：181.3-181.9oC;产率：Yield76%,17:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.23(s,3H),2.94-3.00(m,1H),3.02-3.06(m,1H),3.19(s,3H),3.61(d,J=8.2Hz,1H),3.84(d,J=8.1Hz,1H),4.00-4.03(m,1H),4.49-4.53(m,1H),5.05(d,J=12.3Hz,1H),6.73(d,J=8.4Hz,1H),6.93-6.95(m,1H),7.22-7.30(m,2H),7.31-7.37(m,3H),7.52(d,J=8.2Hz,2H);13CNMR(CDCl3,100MHz)δ:11.2,26.5,34.8,50.8,51.9,56.2,73.0,73.9,108.3,122.3,123.5,126.2,127.9,128.1,129.1,130.3,137.3,143.9,155.4,170.2,177.3;HRMS(ESI-TOF)m/z:Calcd.forC24H22N4NaO4S[M+Na]+:485.1259;Found:485.1261.
化合物4aa-4gk的制备方法同化合物4aa，投料比与化合物4aa相同，可得到化合物化合物4aa-4gk，反应产率和反应时间见表2，但需强调的是本发明的化合物不限于表2所表示的内容。
本实施例制备化合物4ag：黄色固体;熔点：202.5-203.7oC;产率：Yield82%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.26(s,3H),2.91-3.01(m,1H),3.02-3.06(m,1H),3.20(m,3H),3.60(d,J=8.1Hz,1H),3.82(d,J=8.3Hz,1H),3.95-4.00(m,1H),4.46-4.49(m,1H),4.98(d,J=12.4Hz,1H),6.73(d,J=8.2Hz,1H),6.91-6.95(m,1H),7.23-7.29(m,3H),7.42(d,J=8.1Hz,1H),7.49(d,J=8.4Hz,1H),7.65(s,1H);13CNMR(CDCl3,100MHz)δ:11.2,26.5,34.6,50.2,51.6,56.2,72.9,73.7,108.4,122.4,123.1,123.3,126.1,126.7,130.4,130.7,131.2,131.3,139.8,143.9,155.6,169.9,177.2;HRMS(ESI-TOF)m/z:Calcd.forC24H21BrN4NaO4S[M+Na]+:563.036;Found:563.038.
本实施例制备化合物4ah：黄色固体;熔点：217.2-218.1oC;产率：Yield83%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.27(s,3H),3.00-3.03(m,1H),3.04-3.06(m,1H),3.21(s,3H),3.59(d,J=7.2Hz,1H),3.79(d,J=7.3Hz,1H),4.40-4.43(m,1H),4.74-4.78(m,1H),5.04(m,1H),6.75(d,J=6.4Hz,1H),6.92-6.96(m,1H),7.23-7.31(m,3H),7.40(d,J=1.6Hz,1H),7.77(d,J=4.4Hz,1H);13CNMR(CDCl3,100MHz)δ:11.2,26.5,34.4,45.0,51.3,55.7,72.9,74.4,108.4,122.5,123.2,126.2,128.1,129.7,130.5,133.9,134.1,135.3,144.0,155.5,169.9,177.2;HRMS(ESI-TOF)m/z:Calcd.forC24H20Cl2N4NaO4S[M+Na]+:553.0480;Found:553.0480.
本实施例制备化合物4bi：黄色固体;熔点：108.1-108.7oC;产率：Yield81%,19:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.26(s,3H),2.92-2.95(m,1H),3.00-3.04(m,1H),3.58(d,J=8.4Hz,1H),3.84(d,J=8.4Hz,1H),3.99-4.03m,1H),4.48-4.51(m,1H),4.66(d,J=16.0Hz,1H),5.11(d,J=16.0Hz,2H),6.64(d,J=8.1Hz,1H),6.88-6.92(m,1H),7.11-7.33(m,1H),7.26-7.33(m,6H),7.43(d,J=8.8Hz,2H),7.48(d,J=8.4Hz,2H);13CNMR(CDCl3,100MHz)δ:11.3,34.4,44.3,50.5,51.3,56.0,72.6,73.6,109.4,122.4,126.4,127.3,127.7,128.8,129.8,130.4,132.3,135.4,136.3,143.1,155.6,169.8,177.2;HRMS(ESI-TOF)m/z:Calcd.forC30H25BrN4NaO4S[M+Na]+:639.0677;Found:639.0679.
本实施例制备化合物4da：黄色固体;熔点：131.5-131.9oC;产率：Yield67%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.23(s,3H),2.27(s,3H),2.97-3.06(m,2H),3.67(d,J=8.1Hz,1H),3.90-3.97(m,2H),4.42-4.47(m,1H),5.10(d,J=12.3Hz,1H),6.74(d,J=8.1Hz,1H),6.95-6.99(m,1H),7.24-7.28(m,1H),7.30-7.35(m,3H),7.48(d,J=8.3Hz,2H),8.97(brs,1H);13CNMR(CDCl3,100MHz)δ:11.5,21.2,35.4,51.6,53.6,55.0,55.1,74.5,110.4,123.6,127.9,128.1,128.2,129.2,130.8,131.8,137.1,138.9,155.5,169.7;HRMS(ESI-TOF)m/z:Calcd.forC24H22N4NaO4S[M+Na]+:485.1259;Found:485.1262.
本实施例制备化合物4dc：黄色固体;熔点：227.9-228.7oC;产率：Yield79%,19:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.27(s,3H),2.29(s,3H),2.98-3.01(m,1H),3.06-3.11(m,1H),3.70(d,J=8.0Hz,1H),3.93-4.03(m,2H),4.43-4.47(m,1H),5.10(d,J=12.0Hz,1H),6.80(d,J=8.0Hz,1H),6.95-7.00(m,2H),7.21-7.32(m,4H),9.2(s,1H);13CNMR(CDCl3,100MHz)δ:11.3,21.1,35.2,51.0,52.9,55.0,74.1,74.2,110.5,115.0(d,JCF=22.0Hz),123.5(d,JCF=21.7Hz),127.6,130.6,130.8,130.9,131.8,138.9,139.7(d,JCF=8.6Hz),155.5,163.1(d,JCF=246.2Hz),169.4,179.9;HRMS(ESI-TOF)m/z:Calcd.forC24H21FN4NaO4S[M+Na]+:503.1165;Found:503.1168.
本实施例制备化合物4dk：黄色固体;熔点：272.3-273.1oC;产率：Yield70%,19:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.24(s,3H),2.27(s,3H),2.53(s,3H),2.92-2.96(m,1H),3.00-3.02(m,1H),3.69(d,J=8.2Hz,1H),3.90-3.93(m,1H),4.37-4.42(m,2H),5.15(d,J=12.4Hz,1H),6.73-6.77(m,1H),6.96-6.99(m,1H),7.11-7.15(m,2H),7.22-7.28(m,2H),7.65(d,J=8.3Hz,1H),8.78(brs,1H);13CNMR(CDCl3,100MHz)δ:11.5,20.1,21.2,29.8,35.0,45.8,53.6,55.7,75.6,110.2,123.8,123.9,124.0,127.0,127.5,127.6,127.7,130.8,131.0,131.9,132.0,135.5,137.1,155.6,170.2;HRMS(ESI-TOF)m/z:Calcd.forC25H24N4NaO4S[M+Na]+:499.1416;Found:499.1419.
本实施例制备化合物4gb：黄色固体;熔点：213.1-213.5oC;产率：Yield65%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.27(s,3H),2.32(s,3H),2.90-2.95(m,1H),2.96-3.00(m,1H),3.68-3.71(m,1H),3.86-3.89(m,1H),4.00-4.06(m,1H),4.52-4.57(m,1H),5.11-5.16(m,1H),6.67-6.70(m,1H),6.90-6.95(m,1H),7.05-7.08(m,1H),7.11-7.16(m,1H),7.18-7.25(m,2H),7.33(s,2H),7.41-7.44(m,3H),7.51-7.56(m,2H);13CNMR(CDCl3,100MHz)δ:11.5,21.5,21.6,34.1,50.3,57.4,72.4,73.7,109.9,122.9,123.8,125.5,126.2,126.6,128.5,128.9,129.1,129.8,130.3,137.5,139.0,144.2,155.8,171.1,176.8;HRMS(ESI-TOF)m/z:Calcd.forC30H26N4NaO4S[M+Na]+:561.1572;Found:561.1572.
本实施例制备化合物4gj：黄色固体;熔点：193.1-193.6oC;产率：Yield65%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.28(s,9H),2.29(s,3H),2.92-3.03(m,2H),3.70(d,J=8.3Hz,1H),3.90(d,J=4.5Hz,1H),4.05(t,J=10.0Hz,1H),4.54-4.58(m,1H),5.15(d,J=12.3Hz,1H),6.69(d,J=8.3Hz,1H),6.93(t,J=8.0Hz,1H),7.15(t,J=6.8Hz,1H),7.23(d,J=4.4Hz,1H),7.33-7.56(m,9H);13CNMR(CDCl3,100MHz)δ:11.4,31.3,34.1,34.5,49.8,50.2,57.4,72.3,73.6,109.7,122.8,126.0,126.1,126.6,127.8,128.4,129.7,130.2,133.9,134.4,144.1,150.9,155.7,171.1,176.7;HRMS(ESI-TOF)m/z:Calcd.forC33H32N4NaO4S[M+Na]+:603.2042;Found:603.2048.
本实施例制备化合物4gk：黄色固体;熔点：236.3-236.8oC;产率：Yield71%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.28(s,3H),2.54(s,3H),2.91-2.94(m,1H),2.95-2.98(m,1H),3.71(d,J=7.8Hz,1H),3.86-3.88(m,1H),4.47-4.56(m,2H),5.20(d,J=9.2Hz,1H),6.68-6.71(m,1H),6.93-6.95(m,1H),7.12-7.15(m,4H),7.17-7.25(m,1H),7.42-7.45(m,3H),7.51-7.55(m,2H),7.78(d,J=8.1Hz,1H);13CNMR(CDCl3,100MHz)δ:11.5,20.1,33.8,44.8,49.9,57.9,72.3,74.9,109.9,123.0,126.7,127.1,127.5,127.6,128.5,129.8,130.8,136.0,144.2,155.9,171.4,176.9;HRMS(ESI-TOF)m/z:Calcd.forC30H26N4NaO4S[M+Na]+:561.1572;Found:561.1575.
本发明的实施例3：在反应管中依次加入64.4mgN-甲基靛红1a(0.4mmol)，138.0mg(E)-硝基异恶唑烯烃化合物2a(0.6mmol)，71.2mg肌氨酸(0.8mmol)和15ml甲苯溶液，80oC反应24h，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）=4:1）纯化得140.4mg化合物5aa，黄色固体;熔点：121.1-121.7oC;产率：Yield84%,12:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.19(s,3H),2.27(s,3H),3.23(s,3H),3.42-3.46(m,1H),3.79-3.84(m,1H),4.44-4.48(m,1H),4.68(d,J=10.2Hz,1H),6.70-6.76(m,2H),6.82-6.85(m,1H),7.18-7.25(m,2H),7.26-7.33(m,2H),7.55(d,J=7.8Hz,2H);13CNMR(CDCl3,100MHz)δ:11.4,26.2,34.8,45.5,55.0,60.4,74.6,108.2,122.7,124.5,126.2,127.6,128.4,128.9,129.0,129.9,139.4,144.6,155.9,172.8,177.9;HRMS(ESI-TOF)m/z:Calcd.forC23H22N4NaO4[M+Na]+:441.1538;Found:441.1541.
化合物5aa-5ih的制备方法同化合物5aa，投料比与化合物5aa相同，可得到化合物化合物5aa-5ih，反应产率和反应时间见表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。
本实施例制备化合物5ab：黄色固体;熔点：171.2-171.7oC;产率：Yield82%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.19(s,3H),2.27(s,3H),2.33(s,3H),3.23(s,3H),3.39-3.43(m,1H),3.78-3.83(m,1H),4.40-4.44(m,1H),4.68(d,J=10.1Hz,1H),6.70(d,J=8.1Hz,1H),6.75-6.77(m,1H),6.81-6.84(m,1H),7.04-7.06(m,1H),7.17-7.25(m,2H),7.36(d,J=8.1Hz,2H);13CNMR(CDCl3,100MHz)δ:11.4,21.5,26.2,34.8,45.5,54.9,60.4,74.5,108.2,122.7,124.5,125.5,126.3,128.4,128.9,129.0,129.9,138.6,139.3,144.6,155.8,172.9,177.9;HRMS(ESI-TOF)m/z:Calcd.forC24H24N4NaO4[M+Na]+:455.1695;Found:455.1698.
本实施例制备化合物5ag：黄色固体;熔点：187.9-188.3oC;产率：Yield81%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.17(s,3H),2.29(s,3H),3.23(s,3H),3.39-3.44(m,1H),3.75-3.81(m,1H),4.38-4.41(m,1H),4.61-4.64(m,1H),6.69-6.72(m,2H),6.81-6.85(m,1H),7.17-7.25(m,2H),7.35-7.37(m,1H),7.51-7.53(m,1H),7.64(s,1H);13CNMR(CDCl3,100MHz)δ:11.4,26.3,34.8,45.1,54.8,60.1,74.5,108.3,122.7,122.9,124.5,126.0,127.0,130.0,130.6,130.8,131.5,141.9,144.6,155.9,172.4,177.8;HRMS(ESI-TOF)m/z:Calcd.forC23H21BrN4NaO4[M+Na]+:519.0643;Found:519.0647.
本实施例制备化合物5ak：黄色固体;熔点：192.4-192.7oC;产率：Yield77%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.19(s,3H),2.26(s,3H),2.49(s,3H),3.24(s,3H),3.40-3.44(m,1H),3.68-3.73(m,1H),4.76-4.80(m,2H),6.71-6.77(m,2H),6.82-6.86(m,1H),7.10-7.12(m,2H),7.17-7.21(m,1H),7.24-7.27(m,1H),7.84(d,J=7.8Hz,1H);13CNMR(CDCl3,100MHz)δ:11.4,20.0,26.2,34.8,40.6,54.8,60.8,74.5,108.3,122.7,124.5,127.1,127.2,127.9,129.9,130.4,136.8,137.6,144.6,155.9,173.0,178.0;HRMS(ESI-TOF)m/z:Calcd.forC24H24N4NaO4[M+Na]+:455.1695;Found:455.1698.
本实施例制备化合物5ba：黄色固体;熔点：175.4-175.8oC;产率：Yield87%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.25(s,3H),2.29(s,3H),3.45-3.49(m,1H),3.83-3.88(m,1H),4.75-4.79(m,1H),4.58(d,J=15.8Hz,1H),4.76-4.79(m,1H),5.27-5.31(m,1H),6.58(d,J=8.1Hz,1H),6.77-6.80(m,2H),7.05-7.07(m,1H),7.24-7.26(m,2H),7.30-7.35(m,6H),7.56-7.58(m,2H);13CNMR(CDCl3,100MHz)δ:11.5,34.9,44.3,45.7,54.9,60.4,74.5,109.3,122.8,124.7,126.2,127.5,127.6,127.8,128.4,128.9,129.0,129.9,135.9,139.4,143.9,155.9,172.8,177.9;HRMS(ESI-TOF)m/z:Calcd.forC29H26N4NaO4[M+Na]+:517.1851;Found:517.1855.
本实施例制备化合物5bg：黄色固体;熔点：187.1-187.4oC;产率：Yield88%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.23(s,3H),2.31(s,3H),3.44-3.48(m,1H),3.79-3.83(m,1H),4.41-4.45(m,1H),4.58(d,J=16.1Hz,1H),4.72(d,J=11.5Hz,1H),5.28(d,J=15.8Hz,1H),6.59(d,J=7.8Hz,1H),6.72-6.74(m,1H),6.78-6.82(m,1H),7.05-7.09(m,1H),7.19-7.39(m,7H),7.55(d,J=8.1Hz,1H),7.66-7.67(m,1H);13CNMR(CDCl3,100MHz)δ:11.5,34.9,44.3,45.3,54.7,60.1,74.5,109.4,122.8,122.9,124.7,127.0,127.5,127.8,128.9,130.0,130.7,130.8,131.5,135.8,141.9,156.0,172.4,177.8;HRMS(ESI-TOF)m/z:Calcd.forC29H25BrN4NaO4[M+Na]+:595.0956;Found:595.0956.
本实施例制备化合物5dc：黄色固体;熔点：230.1-230.4oC;产率：Yield84%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.12(s,3H),2.27(s,3H),2.32(s,3H),3.43-3.47(m,1H),3.73-3.79(m,1H),4.42-4.50(m,1H),4.71-4.74(m,1H),6.50(s,1H),6.67(d,J=8.1Hz,1H),6.92-6.94(m,2H),7.24-7.30(m,3H),8.40(brs,1H);13CNMR(CDCl3,100MHz)δ:11.4,20.9,34.8,45.1,54.4,59.9,74.8,100.0,109.9,114.5(d,JCF=21.1Hz),115.3(d,JCF=21.5Hz),125.5,126.5,130.3,132.3,139.3,142.1(d,JCF=7.3Hz),155.9,163.1(d,JCF=245.2Hz),172.5,179.8;HRMS(ESI-TOF)m/z:Calcd.forC23H21FN4NaO4[M+Na]+:459.1444;Found:459.1448.
本实施例制备化合物5df：黄色固体;熔点：190.1-191.2oC;产率：Yield71%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.07(s,3H),2.22(s,3H),2.26(s,3H),3.42(t,J=8.2Hz,1H),3.75(t,J=10.1Hz,1H),4.44-4.51(m,1H),4.70(d,J=12.2Hz,1H),6.46(s,1H),6.62(d,J=8.3Hz,1H),6.88(d,J=4.3Hz,1H),7.50-7.63(m,4H),8.42(s,1H);13CNMR(CDCl3,100MHz)δ:11.2,20.8,34.8,45.2,54.4,59.9,74.8,109.8,125.5,125.8,125.9,126.4,128.7,129.6,130.0,130.3,132.3,139.3,143.6,155.9,172.3,179.8;HRMS(ESI-TOF)m/z:Calcd.forC24H21F3N4NaO4[M+Na]+:509.1412;Found:509.1415.
本实施例制备化合物5dg：黄色固体;熔点：168.7-169.3oC;产率：Yield85%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.15(s,3H),2.29(s,3H),2.34(s,3H),3.45-3.49(m,1H),3.79(t,J=10.2Hz,1H),4.42-4.48(m,1H),4.75(d,J=12.1Hz,1H),6.52(s,1H),6.72(d,J=8.3Hz,1H),6.95(d,J=8.2Hz,1H),7.21(t,J=8.1Hz,1H),7.39(d,J=8.3Hz,1H),7.53(d,J=8.3Hz,1H),7.70(s,1H),8.61(s,1H);13CNMR(CDCl3,100MHz)δ:11.3,20.8,34.8,45.0,54.3,60.0,74.9,109.9,122.8,125.5,126.4,126.9,130.2,130.5,130.7,131.4,132.2,139.3,141.9,155.8,172.4,179.8;HRMS(ESI-TOF)m/z:Calcd.forC23H21BrN4NaO4[M+Na]+:519.0643;Found:519.0642.
本实施例制备化合物5dk：黄色固体;熔点：221.7-222.1oC;产率：Yield77%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.14(s,3H),2.29(s,3H),2.51(s,3H),3.42-3.46(m,1H),3.66-3.71(m,1H),4.78-4.82(m,1H),4.89(d,J=6.4Hz,1H),6.56(s,1H),6.69(d,J=8.0Hz,1H),6.92-6.95(m,1H),7.11-7.13(m,2H),7.24-7.26(m,1H),7.84(d,J=7.8Hz,1H),8.44(brs,1H);13CNMR(CDCl3,100MHz)δ:11.4,20.0,20.9,34.9,40.7,54.3,60.7,74.8,109.8,125.6,126.8,127.0,127.2,127.7,130.2,130.5,132.3,136.9,137.6,139.4,155.9,173.1,180.0;HRMS(ESI-TOF)m/z:Calcd.forC24H24N4NaO4[M+Na]+:455.1695;Found:455.1691.
本实施例制备化合物5dl：黄色固体;熔点：191.7-192.5oC;产率：Yield85%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(DMSO-d6,400MHz)δ:2.07(s,3H),2.12(s,3H),2.26(s,3H),3.50-3.61(m,2H),4.56-4.61(m,1H),4.65(d,J=8.6Hz,1H),6.31(s,1H),6.65(d,J=7.2Hz,1H),6.96(d,J=8.4Hz,1H),7.65-7.69(m,1H),7.98(d,J=8.0Hz,1H),8.11-8.14(m,1H),8.40(s,1H),10.56(brs,1H);13CNMR(DMSO-d6,100MHz)δ:11.2,20.8,34.8,44.4,53.6,59.9,74.9,109.9,122.7,123.2,125.4,126.5,130.4,130.6,130.8,130.9,135.3,140.9,142.7,148.5,156.3,172.3,179.2;HRMS(ESI-TOF)m/z:Calcd.forC23H21N5NaO6[M+Na]+:486.1389;Found:486.1386.
本实施例制备化合物5gc：黄色固体;熔点：145.6-146.4oC;产率：Yield90%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.34(s,6H),3.47-3.51(m,1H),3.86(t,J=10.2Hz,1H),4.49-4.55(m,1H),4.78(d,J=12.3Hz,1H),6.67(d,J=8.2Hz,1H),6.78(d,J=8.1Hz,1H),6.86-6.95(m,2H),7.13(t,J=8.3Hz,1H),7.24-7.30(m,2H),7.34-7.36(m,1H),7.47-7.58(m,5H);13CNMR(CDCl3,100MHz)δ:11.4,34.6,45.0,54.9,60.0,74.6,109.5,114.5(d,JCF=21.3Hz),115.4(d,JCF=21.5Hz),123.1,124.8,126.8,128.4,129.8,129.9,142.0(d,JCF=8.2Hz),144.7,156.0,163.0(d,JCF=245.7Hz),172.5,177.2;HRMS(ESI-TOF)m/z:Calcd.forC28H23FN4NaO4[M+Na]+:521.1601;Found:521.1600.
本实施例制备化合物5gj：黄色固体;熔点：165.4-166.3oC;产率：Yield74%,>20:1;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:1.28(s,9H),2.33(m,6H),3.44-3.48(m,1H),3.87(t,J=10.0Hz,1H),4.48-4.55(m,1H),4.81(d,J=12.0Hz,1H),6.66(d,J=4.6Hz,1H),6.79-6.89(m,2H),7.11(t,J=8.3Hz,1H),7.33(d,J=8.2Hz,2H),7.41-7.57(m,7H);13CNMR(CDCl3,100MHz)δ:11.4,31.3,34.5,34.7,44.9,55.0,60.3,74.7,109.4,123.0,124.8,125.8,125.9,126.9,128.0,128.4,129.7,130.5,134.0,136.3,144.7,150.4,155.9,173.0,177.3;HRMS(ESI-TOF)m/z:Calcd.forC32H32N4NaO4[M+Na]+:559.2321;Found:559.2323.
本实施例制备化合物5gk：黄色固体;熔点：191.4-191.8oC;产率：Yield78%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.31(s,3H),2.33(s,3H),2.51(s,3H),3.44-3.48(m,1H),3.72-3.78(m,1H),4.81-4.91(m,2H),6.65-6.68(m,1H),6.78-6.80(m,1H),6.85-6.90(m,1H),7.11-7.12(m,3H),7.20-7.25(m,1H),7.42-7.57(m,5H),7.86(d,J=7.8Hz,1H);13CNMR(CDCl3,100MHz)δ:11.5,20.0,34.7,40.4,55.0,60.8,74.7,109.5,123.2,126.9,127.1,127.2,128.0,128.5,129.8,129.9,130.4,144.7,156.0,173.1,177.5;HRMS(ESI-TOF)m/z:Calcd.forC29H26N4NaO4[M+Na]+:517.1851;Found:517.1857.
本实施例制备化合物5ha：黄色固体;熔点：235.1-236.0oC;产率：Yield72%,17:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.29(s,3H),2.36(s,3H),3.43-3.49(m,1H),3.75-3.79(m,1H),4.45-4.49(m,1H),4.77(d,J=8.2Hz,1H),6.74-6.76(m,2H),7.12-7.15(m,1H),7.25-7.37(m,3H),7.53(d,J=8.2Hz,2H),8.43(s,1H);13CNMR(CDCl3,100MHz)δ:11.2,34.8,45.4,54.6,60.1,74.8,111.0,125.4,127.6,128.0,128.2,128.6,128.9,129.1,129.8,139.0,140.2,155.8,172.2,179.5;HRMS(ESI-TOF)m/z:Calcd.forC22H19ClN4NaO4[M+Na]+:461.0992;Found:461.0994.
本实施例制备化合物5hc：黄色固体;熔点：209.4-209.9oC;产率：Yield75%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.28(s,3H),2.35(s,3H),3.44-3.48(m,1H),3.74-3.79(m,1H),4.42-4.49(m,1H),4.75(d,J=9.8Hz,1H),6.67(d,J=3.8Hz,1H),6.81-6.83(m,1H),6.97-7.01(m,1H),7.14-7.17(m,1H),7.26-7.31(m,3H),8.54(brs,1H);13CNMR(CDCl3,100MHz)δ:11.3,34.7,45.2,54.4,59.7,75.4,114.5(d,JCF=20.0Hz),115.2(d,JCF=22.2Hz),123.3(d,JCF=26.0Hz),123.8,129.9,130.4,139.5,141.6(d,JCF=7.0Hz),155.9,163.0(d,JCF=245.0Hz),171.8,178.9;HRMS(ESI-TOF)m/z:Calcd.forC22H18ClFN4NaO4[M+Na]+:479.0898;Found:479.0896.
本实施例制备化合物5hh：黄色固体;熔点：146.2-146.9oC;产率：Yield88%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(DMSO-d6,400MHz)δ:2.10(s,3H),2.27(s,3H),3.32-3.44(m,1H),3.45-3.50(m,1H),4.65(d,J=4.6Hz,1H),4.81-4.85(m,1H),6.51(s,1H),6.77(d,J=8.2Hz,1H),7.20-7.23(m,1H),7.52-7.59(m,2H),7.83(d,J=8.1Hz,1H),10.85(brs,1H);13CNMR(DMSO-d6,100MHz)δ:10.8,34.3,40.1,52.5,59.0,74.2,111.3,124.4,125.7,127.8,128.3,128.8,129.8,130.2,130.4,132.6,134.2,136.1,141.8,155.8,171.2,178.4;HRMS(ESI-TOF)m/z:Calcd.forC22H17Cl3N4NaO4[M+Na]+:529.0213;Found:529.0215.
本实施例制备化合物5ib：黄色固体;熔点：198.4-198.9oC;产率：Yield73%,>20:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.27(s,3H),2.30(s,3H),2.34(s,3H),3.40-3.44(m,1H),3.74-3.77(m,1H),4.41-4.44(m,1H),4.77-4.81(m,1H),6.59(d,J=7.9Hz,1H),6.73-6.76(m,1H),6.95-6.97(m,1H),7.04-7.08(m,1H),7.19-7.25(m,1H),7.25-7.37(m,2H);13CNMR(CDCl3,100MHz)δ:11.5,16.3,21.6,34.9,45.6,54.5,60.3,75.2,122.3,122.6,125.4,126.4,126.5,128.3,128.8,129.0,130.4,131.2,138.6,139.5,155.9,172.8;HRMS(ESI-TOF)m/z:Calcd.forC24H24N4NaO4[M+Na]+:455.1695;Found:455.1698.
本实施例制备化合物5ih：黄色固体;熔点：207.4-208.6oC;产率：Yield86%,19:1dr;核磁共振和高分辨质谱测试等结果如下：1HNMR(CDCl3,400MHz)δ:2.26(s,3H),2.27(s,3H),2.34(s,3H),3.50-3.54(m,1H),3.63-3.67(m,1H),4.77(d,J=8.3Hz,1H),5.04-5.07(m,1H),6.58(d,J=4.3Hz,1H),6.75-6.79(m,1H),6.99(d,J=8.1Hz,1H),7.25-7.30(m,1H),7.36(s,1H),7.89(d,J=4.5Hz,1H),8.82(brs,1H);13CNMR(CDCl3,100MHz)δ:11.4,16.1,34.7,40.6,53.4,59.7,75.2,119.2,122.4,122.7,125.7,127.9,129.3,130.2,131.3,133.6,135.1,136.0,140.3,155.7,172.1,180.5;HRMS(ESI-TOF)m/z:Calcd.forC23H20Cl2N4NaO4[M+Na]+:509.0759;Found:509.0758.
本发明的式（1）化合物具有重要的生物活性，体外对人***（PC-3）,人肺癌细胞（A549）以及人白血病细胞（K562）共三株肿瘤细胞的细胞毒性试验表明：此类式（1）所示的结构的异恶唑拼接吡咯螺环氧化吲哚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***（PC-3）,人肺癌细胞（A549）以及人白血病细胞（K562）表示的细胞毒性。
药理实施例1：化合物3fb,4da,4dc,4dk,5dc,5df,5dg,5dk,5ha,5hh和5ib对PC-3细胞的细胞毒性
PC-3（人***癌）细胞用RPMI-1640培养基培养，培养基中含10%的胎牛血清，100U/mL青霉素及100U/mL的链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37oC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3fb,4da,4dc,4dk,5dc,5df,5dg,5dk,5ha,5hh和5ib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10μLMTT（5mg/mL)的磷酸盐缓冲液，再继续在37oC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3fb,4da,4dc,4dk,5dc,5df,5dg,5dk,5ha,5hh和5ib对PC-3细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3fb对PC-3肿瘤细胞的IC50为28.8μmol/L；化合物4da对PC-3肿瘤细胞的IC50为32.2μmol/L；化合物4dc对PC-3肿瘤细胞的IC50为26.4μmol/L；化合物4dk对PC-3肿瘤细胞的IC50为13.7μmol/L；化合物5dc对PC-3肿瘤细胞的IC50为25.8μmol/L；化合物5dg对PC-3肿瘤细胞的IC50为14.1μmol/L；化合物5dk对PC-3肿瘤细胞的IC50为18.7μmol/L；化合物5ha对PC-3肿瘤细胞的IC50为19.8μmol/L；化合物5hh对PC-3肿瘤细胞的IC50为13.1μmol/L；化合物5ib对PC-3肿瘤细胞的IC50为58.4μmol/L；而阳性对照顺铂对PC-3肿瘤细胞的IC50为27.9μmol/L。
实验结论：PC-3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）所示的异恶唑拼接吡咯螺环氧化吲哚化合物对PC-3细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级或活性比顺铂更好，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例2：化合物3fb,4da,4dc,4dk,5dc,5df,5dg,5dk,5ha,5hh和5ib对A549细胞的细胞毒性
A549（人非小细胞肺癌肺癌）用DMEM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4000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。具体方法如药理实施例1。化合物3fb对A549肿瘤细胞的IC50为65.9μmol/L；化合物4da对A549肿瘤细胞的IC50为68.7μmol/L；化合物4dc对A549肿瘤细胞的IC50为44.1μmol/L；化合物4dk对A549肿瘤细胞的IC50为54.4μmol/L；化合物5dc对A549肿瘤细胞的IC50为62.8μmol/L；化合物5df对A549肿瘤细胞的IC50为27.6μmol/L；化合物5dg对A549肿瘤细胞的IC50为22.7μmol/L；化合物5dk对A549肿瘤细胞的IC50为46.2μmol/L；化合物5ha对A549肿瘤细胞的IC50为26.9μmol/L；化合物5hh对A549肿瘤细胞的IC50为21.5μmol/L；化合物5ib对A549肿瘤细胞的IC50为37.1μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为25.2μmol/L。
实验结论：A549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）所示的异恶唑拼接吡咯螺环氧化吲哚化合物对PC-3细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级或活性比顺铂更好，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例3：化合物3aa,3ad,3bf,3cb,3dc,3ee,3fb,4aa,4ag,4ah,4bi,4da,4dc,4dk,4gb,4gk,5aa,5ab,5ag,5ak,5bg,5dc,5df,5dg,5dk,5gc,5ha,5hc,5hh,5ib,5ih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。具体方法如药理实施例1。化合物3aa对K562肿瘤细胞的IC50为74.7μmol/L；化合物3ad对K562肿瘤细胞的IC50为62.7μmol/L；化合物3bf对K562肿瘤细胞的IC50为65.3μmol/L；化合物3cb对K562肿瘤细胞的IC50为33.5μmol/L；化合物3dc对K562肿瘤细胞的IC50为30.4μmol/L；化合物3ee对K562肿瘤细胞的IC50为77.4μmol/L；化合物3fb对K562肿瘤细胞的IC50为13.2μmol/L；化合物4aa对K562肿瘤细胞的IC50为25.9μmol/L；化合物4ag对K562肿瘤细胞的IC50为43.0μmol/L；化合物4ah对K562肿瘤细胞的IC50为43.5μmol/L；化合物4bi对K562肿瘤细胞的IC50为40.1μmol/L；化合物4da对K562肿瘤细胞的IC50为16.1μmol/L；化合物4dc对K562肿瘤细胞的IC50为20.5μmol/L；化合物4dk对K562肿瘤细胞的IC50为11.8μmol/L；化合物4gb对K562肿瘤细胞的IC50为85.2μmol/L；化合物4gk对K562肿瘤细胞的IC50为88.7μmol/L；化合物5aa对K562肿瘤细胞的IC50为37.1μmol/L；化合物5ab对K562肿瘤细胞的IC50为34.2μmol/L；化合物5ag对K562肿瘤细胞的IC50为54.0μmol/L；化合物5ak对K562肿瘤细胞的IC50为54.1μmol/L；化合物5bg对K562肿瘤细胞的IC50为83.1μmol/L；化合物5dc对K562肿瘤细胞的IC50为12.5μmol/L；化合物5df对K562肿瘤细胞的IC50为19.2μmol/L；化合物5dg对K562肿瘤细胞的IC50为12.4μmol/L；化合物5dk对K562肿瘤细胞的IC50为14.5μmol/L；化合物5gc对K562肿瘤细胞的IC50为71.0μmol/L；化合物5ha对K562肿瘤细胞的IC50为14.2μmol/L；化合物5hc对K562肿瘤细胞的IC50为75.8μmol/L；化合物5hh对K562肿瘤细胞的IC50为10.4μmol/L；化合物5ib对K562肿瘤细胞的IC50为22.1μmol/L；化合物5ih对K562肿瘤细胞的IC50为43.1μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为23.2μmol/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）所示的异恶唑拼接吡咯螺环氧化吲哚化合物对K562细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级或活性比顺铂更好，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化合物对这三株肿瘤细胞都显示有一定的细胞毒性。可见这些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 (5)

1.一种异恶唑拼接吡咯螺环氧化吲哚化合物，其特征在于：该化合物具有如通式（Ⅰ）所示的结构：
式中，R1为烷基或芳基；R2为烷基或卤素；R3为烷基或卤素；R4为不同取代的芳基；R5为H或烷基；R6为H或芳基。
2.一种如权利要求1所述的异恶唑拼接吡咯螺环氧化吲哚化合物的制备方法，其特征在于：将各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸、硫代脯氨酸或肌氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接吡咯螺环氧化吲哚化合物，
合成路线如下：
。
3.根据权利要求2所述的异恶唑拼接吡咯螺环氧化吲哚化合物的制备方法，其特征在于：所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、***、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
4.根据权利要求2所述的异恶唑拼接吡咯螺环氧化吲哚化合物的制备方法，其特征在于：各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸或肌氨酸，在有机溶剂中的反应温度为50-100℃，反应时间为5-20小时。
5.一种如权利要求1所述的异恶唑拼接吡咯螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
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