CN117777160A - 具有环状n,o-半缩醛胺的双四氢异喹啉衍生物的制备及用途 - Google Patents
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Abstract
本发明属于药物化学领域，具体涉及一种具有环状N,O‑半缩醛胺的双四氢异喹啉衍生物的制备及用途，该类具有环状N,O‑半缩醛胺的双四氢异喹啉衍生物制备方法简单，结构新颖，对多种人源癌细胞表现出了良好的体外抗增殖活性，为潜在的DNA烷基化试剂提供了新的结构设计思路，为双四氢异喹啉类抗癌药物的研究与发展提供了新的方案。
Description
技术领域
本发明属于药物化学领域，特别涉及一种具有环状N,O-半缩醛胺的双四氢异喹啉衍生物的制备及其在制备抗肿瘤药物中的应用。
背景技术
以ET-743为代表的双四氢异喹啉生物碱是一类具有优秀生物活性的天然产物，也是一类优秀的DNA烷基化试剂，主要是利用C21位的半缩醛胺形成的亚胺阳离子，与DNA上的鸟嘌呤发生烷基化作用，生成ET-743-DNA共价复合物，从而抑制肿瘤细胞增殖。但是，半缩醛胺结构片段在大部分的双四氢异喹啉生物碱中是难以稳定存在的，目前普遍采用的解决方案是在C21引入胺基氰片段来替代半缩醛胺片段，但是这无疑会给复杂的生产工艺提出危险品控制要求，以及增强代谢物的潜在毒性。因此，亟待开发一种化学性质可以稳定存在的、不需要使用氰化物和氰基的、天然半缩醛胺的等价官能团来承担相应的功能，最终发展出一类具有新颖结构的抗肿瘤DNA烷基化试剂。
发明内容
本发明解决现有技术中存在的上述技术问题，提供一类新型的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物，并提供了该类化合物的制备方法及其在制备抗肿瘤药物中的应用。
本发明的技术方案如下：
一种新型的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物，包括通式(Ⅰ)的化合物：
其中环A为芳环、取代芳环、杂芳环、取代杂芳环、稠环或取代稠环等；环B为芳环、取代芳环、杂芳环、取代杂芳环、稠环或取代稠环等；
R1为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R2为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R3为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R4为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R5为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R6为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R7为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R8为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基等；
R1和R2、R2和R3、R3和R4、R5和R6、R6和R7、R7和R8可以形成1,3-二氧戊环；
R9为H、烷基、取代烷基、环烷基、取代环烷基、芳基、取代芳基、杂芳基、取代杂芳基、炔基、取代炔基、烯基、取代烯基或烷氧基等。
优选地，R1为H、OH或OMe；R2为H、OH或OMe；R3为H、OH或OMe；R4为H、OH或OMe；R5为H、OH或OMe；R6为H、OH或OMe；R7为H、OH或OMe；R8为H、OH或OMe。
优选地，R9选自
中任意一种。
本发明所述的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物的第一种制备方法，合成路线如下：
所述制备方法包括以下步骤：
步骤1，以化合物Ⅱ为初始原料，经过酸脱除苄基保护基得到化合物Ⅲ；
步骤2，再经过酰胺还原并环化得到化合物Ⅳ。
优选地，所述步骤1的具体方法为：氮气保护下，化合物II溶于有机溶剂中，于-78℃向其中加入三氯化硼，缓慢升至0℃，反应过夜；加入饱和碳酸氢钠水溶液淬灭，萃取，旋干，将剩余物用硅胶柱层析纯化得到式III。更优选地，所述有机溶剂为二氯甲烷(DCM)。
优选地，所述步骤2的具体方法为：氮气保护下，于0℃向氢化铝锂的四氢呋喃(THF)悬浊液中滴加化合物III的THF溶液，反应1h；加入水淬灭，干燥，旋干，将剩余物用硅胶柱层析纯化得到化合物IV。
本发明所述的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物的第二种制备方法，合成路线如下：
所述制备方法包括以下步骤：
步骤A，以化合物Ⅱ为初始原料，经过酸脱除苄基保护基得到化合物Ⅲ；
步骤B，氧化伯醇得到化合物V；
步骤C，与不同亲核试剂作用，引入取代基R9，得到化合物VI；
步骤D，经过酰胺还原并环化得到化合物VII。
优选地，所述步骤A的具体方法为：氮气保护下，化合物II溶于有机溶剂中，于-78℃向其中加入三氯化硼，缓慢升至0℃，反应过夜；加入饱和碳酸氢钠水溶液淬灭，萃取，旋干，将剩余物用硅胶柱层析纯化得到化合物III。更优选地，所述有机溶剂为DCM。
优选地，所述步骤B的具体方法为：化合物III的DCM溶液于0℃下加入戴斯-马丁氧化剂(DMP)，反应3h；硅藻土抽滤，旋干，将剩余物用硅胶柱层析纯化得到化合物V。
优选地，所述步骤C的具体方法为：氮气保护下，化合物V溶于THF中，于0℃向其中加入亲核试剂，反应过夜；加入饱和氯化铵水溶液淬灭，萃取，旋干，将剩余物用硅胶柱层析纯化得到化合物VI。更优选地，所述亲核试剂为烷基溴化镁、芳基溴化镁、芳基氯化镁、杂芳基溴化镁或杂芳基氯化镁。
优选地，所述步骤D的具体方法为：氮气保护下，于0℃向氢化铝锂的THF悬浊液中滴加化合物VI的THF溶液，反应1h。加入水淬灭，干燥，旋干，将剩余物用硅胶柱层析纯化得到化合物VII。
本发明还提供了具有环状N,O-半缩醛胺的双四氢异喹啉衍生物在抗癌药物方面的应用，对多种人源肿瘤细胞进行了体外毒活性测试。
相对于现有技术，本发明的优点如下：
该类具有环状N,O-半缩醛胺的双四氢异喹啉衍生物制备方法简单，结构新颖，对多种人源癌细胞表现出了良好的体外抗增殖活性，为潜在的DNA烷基化试剂提供了新的结构设计思路，为双四氢异喹啉类抗癌药物的研究与发展提供了新的方案。
具体实施方式
化合物1通过文献(Org.Biomol.Chem.,2022,20,8438-8442.)报道的方法合成。
实施例1中的原料2a通过以下方法合成:
合成路线：
具体合成方法为：
将化合物1(1.34g,2.47mmol,1.0eq.)称入反应瓶中，抽换N2，加入溶剂无水DCM(40mL)，于-78℃向体系中滴加三氯化硼(7.41mL,7.41mmol,3.0eq.)，缓慢升至0℃，TLC监测。反应结束后，加饱和碳酸氢钠水溶液淬灭，DCM萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩。柱层析(DCM/MeOH＝80/1)得到白色固体2a(1.06g,产率95％)。
实施例2中原料3通过以下方法合成:
合成路线：
具体合成方法为：
将化合物2a(1.36g,3.0mmol,1.0eq.)称入反应瓶中，加入溶剂DCM(50mL)。于0℃向其中加DMP(1.9g,4.5mmol,1.5eq.)，TLC监测，反应结束后，经硅藻土抽滤，浓缩。柱层析(DCM/acetone＝5/1)，得到白色固体3(1.4g，产率98％)。
实施例1：
4a的合成，R1，R4，R5，R8为氢，R2，R3，R6，R7为甲氧基,R9为氢。
将氢化铝锂(7.6mg,0.2mmol,2.0eq.)称入反应瓶中，抽换N2，加入重蒸过的溶剂THF(2mL)。于0℃向其中滴加溶于THF的化合物2a(45.4mg,0.1mmol,1.0eq.)，反应1h。向其中加入水(76μL)淬灭，无水硫酸钠干燥，抽滤，浓缩。柱层析(Et2O/acetone＝1/1)，得到白色固体4a(28.5mg，产率65％)。
4a核磁及质谱表征：1H NMR(400MHz,CDCl3)δ6.59(s,1H),6.54(s,1H),6.50(s,1H),6.32(s,1H),4.40(t,J＝4.1Hz,1H),4.18(d,J＝3.2Hz,1H),3.89(s,3H),3.82(s,3H),3.80(s,3H),3.78(s,3H),3.60-3.57(m,2H),3.55(d,J＝3.7Hz,1H),3.33(dd,J＝7.8,3.2Hz,1H),3.27(ddd,J＝9.7,6.0,3.5Hz,1H),2.83(d,J＝17.7Hz,1H),2.77-2.64(m,3H),2.40(s,3H).13C NMR(101MHz,CDCl3)δ148.4,148.1,147.3,146.2,128.2,126.5,125.5,123.6,113.8,112.1,111.6,107.8,92.4,70.4,61.9,59.5,56.5,56.4,56.2,56.1,55.9,55.4,42.8,30.2,20.7.HRMS(ESI,m/z):[M+H]+calcd for C25H31N2O5 +439.2227,found439.2224.
实施例2：
4b的合成，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为
将化合物3(22.6mg,0.05mmol,1.0eq.)称入反应管中，抽换氮气，加入重蒸的THF(1mL)。于0℃向体系中滴加环丙基溴化镁(0.1mL,1.0M in THF,0.1mmol,2.0equiv.)，TLC监测。反应结束后，向体系中加入饱和氯化铵水溶液淬灭反应，DCM萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析(PE/acetone＝1/1)，得到化合物2b(10.2mg,39％)。
将氢化铝锂(2.5mg,0.066mmol,2.0equiv.)称入反应瓶中，抽换N2，加入重蒸过的溶剂THF(1mL)。于0℃向其中滴加溶于THF的化合物2b(17.2mg,0.033mmol,1.0eq.)，TLC监测。反应结束后向其中加入水(25μL)淬灭，无水硫酸钠干燥，抽滤，浓缩，柱层析(DCM/acetone＝2/1)，得到产物4b(13.0mg,78％)。
4b核磁及质谱表征：1H NMR(400MHz,CDCl3)δ6.58(s,1H),6.57(s,1H),6.53(s,1H),6.49(s,1H),4.18(d,J＝3.1Hz,1H),3.99(dd,J＝8.5,2.6Hz,1H),3.89(s,3H),3.81(s,3H),3.80(s,3H),3.79(s,3H),3.53(d,J＝3.5Hz,1H),3.36(d,J＝8.5Hz,1H),3.33(dd,J＝8.0,3.3Hz,1H),3.24(ddd,J＝9.9,6.8,3.5Hz,1H),2.86(d,J＝17.7Hz,1H),2.74-2.65(m,3H),2.38(s,3H),2.38-2.31(m,1H),1.92-1.48(m,8H).13C NMR(101MHz,CDCl3)δ148.3,148.0,146.9,146.1,128.4,127.2,126.4,123.7,113.8,112.3,111.6,107.8,92.1,83.7,62.8,62.1,56.7,56.5,56.4,56.1,55.9,55.4,44.6,42.8,30.6,30.3,26.7,25.7,25.5,20.8.HRMS(ESI,m/z):[M+H]+calcd for C30H39N2O5 +507.2853,found 507.2848.
实施例3：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4c。
4c核磁及质谱表征：1H NMR(400MHz,CDCl3)δ6.58(s,1H),6.52(s,2H),6.48(s,1H),4.14(d,J＝3.1Hz,1H),3.89(s,3H),3.81(s,3H),3.79(s,3H),3.79(s,3H),3.75(dd,J＝8.6,2.3Hz,1H),3.54(d,J＝3.5Hz,1H),3.47(d,J＝8.5Hz,1H),3.33(dd,J＝8.0,3.1Hz,1H),3.26(ddd,J＝9.6,6.3,3.5Hz,1H),2.86(d,J＝17.7Hz,1H),2.76-2.62(m,3H),2.39(s,3H),1.95(d,J＝12.8Hz,1H),1.88-1.69(m,5H),1.58-1.48(m,1H),1.44-1.35(m,1H),1.35-1.19(m,3H).13C NMR(101MHz,CDCl3)δ148.3,148.0,146.9,146.2,128.3,127.3,126.6,123.5,113.7,112.3,111.6,108.0,91.6,86.1,62.1,60.3,56.7,56.5,56.4,56.0,55.8,55.3,42.8,42.6,31.9,30.2,27.1,26.5,20.7.HRMS(ESI,m/z):[M+H]+calcd forC31H41N2O5 +521.3010,found 521.3015.
实施例4：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4d。
4d核磁及质谱表征：1H NMR(400MHz,CDCl3)δ6.93(s,1H),6.58(s,1H),6.54(s,1H),6.49(s,1H),4.32(d,J＝3.2Hz,1H),3.89(s,3H),3.81(s,3H),3.81(s,6H),3.55(d,J＝3.6Hz,1H),3.48(d,J＝8.4Hz,1H),3.34(dd,J＝7.8,3.2Hz,1H),3.26(ddd,J＝9.7,6.3,3.7Hz,1H),3.11(t,J＝8.7Hz,1H),2.83(d,J＝17.7Hz,1H),2.73-2.64(m,3H),2.40(s,3H),1.32-1.22(m,1H),0.83(dd,J＝3.0,1.5Hz,1H),0.81(dd,J＝2.9,1.4Hz,1H),0.67-0.60(m,1H),0.57-0.52(m,1H).13C NMR(101MHz,CDCl3)δ148.3,147.9,147.0,146.2,128.2,126.7,124.9,123.6,113.8,112.0,111.6,108.3,91.3,87.4,65.4,62.0,56.5,56.2,56.1,56.0,55.9,55.4,42.9,30.4,20.8,14.4,4.4,3.7.HRMS(ESI,m/z):[M+H]+calcd for C28H35N2O5 +479.2540,found 479.2546.
实施例5：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4e。
4e核磁及质谱表征：1H NMR(400MHz,CDCl3)δ6.59(s,1H),6.53(s,1H),6.52(s,1H),6.49(s,1H),4.19(d,J＝3.2Hz,1H),3.89(s,3H),3.87(dd,J＝8.0,3.6Hz,1H),3.82(s,3H),3.80(s,3H),3.79(s,3H),3.53(d,J＝3.5Hz,1H),3.32(dd,J＝8.0,3.2Hz,1H),3.27-3.19(m,2H),2.86(d,J＝17.7Hz,1H),2.74-2.65(m,3H),2.39(s,3H),1.92-1.83(m,2H),1.78-1.67(m,1H),1.64-1.53(m,1H),1.04(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ148.3,148.1,147.0,146.2,128.3,127.1,125.9,123.7,113.8,112.3,111.7,107.5,91.1,81.8,64.1,62.0,56.6,56.5,56.3,56.1,55.9,55.3,42.8,37.8,30.3,20.8,19.7,14.5.HRMS(ESI,m/z):[M+H]+calcd for C28H37N2O5 +481.2697,found 481.2700.
实施例6：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4f。
4f核磁及质谱表征：1H NMR(400MHz,CDCl3)δ6.58(s,1H),6.53(s,1H),6.51(s,1H),6.49(s,1H),4.15(d,J＝3.2Hz,1H),3.89(s,3H),3.82(s,3H),3.81-3.79(m,1H),3.80(s,3H),3.78(s,3H),3.53(d,J＝3.6Hz,1H),3.42(d,J＝8.5Hz,1H),3.33(dd,J＝8.0,3.2Hz,1H),3.24(ddd,J＝10.0,6.6,3.6Hz,1H),2.86(d,J＝17.6Hz,1H),2.76-2.65(m,3H),2.38(s,3H),2.13(dtd,J＝13.7,6.9,2.2Hz,1H),1.20(d,J＝7.0Hz,3H),1.12(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ148.3,147.9,146.9,146.1,128.4,127.2,126.5,123.7,113.8,112.3,111.6,107.6,91.9,86.3,62.1,61.1,56.8,56.5,56.3,56.1,55.8,55.3,42.8,32.2,30.3,21.7,20.8,16.5.HRMS(ESI,m/z):[M+H]+calcd for C28H37N2O5 +481.2697,found 481.2704.
实施例7：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4g。
4g核磁及质谱表征：1H NMR(400MHz,CDCl3)δ6.67(s,1H),6.60(s,1H),6.53(s,1H),6.50(s,1H),5.25-5.22(m,1H),5.17-5.14(m,1H),4.33(d,J＝3.3Hz,1H),4.22(d,J＝8.7Hz,1H),3.90(s,3H),3.83(s,3H),3.80(s,3H),3.70(s,3H),3.57-3.53(m,2H),3.34(dd,J＝8.0,3.2Hz,1H),3.28(ddd,J＝10.0,6.7,3.5Hz,1H),2.88(d,J＝17.7Hz,1H),2.75-2.67(m,3H),2.40(s,3H),1.97(s,3H).13C NMR(101MHz,CDCl3)δ148.4,147.9,147.1,146.2,145.0,128.3,126.6,125.4,123.6,116.6,113.8,111.9,111.6,107.5,92.3,86.6,62.0,60.3,56.5,56.4,56.1,56.0,55.9,55.4,42.9,30.2,20.7,17.8.HRMS(ESI,m/z):[M+H]+calcd for C28H35N2O5 +479.2540,found 479.2545.
实施例8:
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4h。
4h核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.58-7.54(m,2H),7.46-7.40(m,2H),7.39-7.34(m,1H),6.64(s,1H),6.52(s,2H),6.17(s,1H),4.69-4.64(m,2H),3.91(s,3H),3.85(s,3H),3.78(s,3H),3.71(d,J＝8.6Hz,1H),3.60(d,J＝3.5Hz,1H),3.49(s,3H),3.41(dd,J＝8.1,3.5Hz,1H),3.38-3.32(m,1H),2.95(d,J＝17.8Hz,1H),2.75(dd,J＝18.0,8.0Hz,1H),2.71(d,J＝7.5Hz,2H),2.44(s,3H).13C NMR(101MHz,CDCl3)δ148.4,147.9,146.9,146.2,140.7,128.8,128.5,128.3,126.5,124.6,123.6,113.9,111.9,111.6,107.5,92.8,84.9,66.4,62.0,56.5,56.1,56.0,55.9,55.7,55.5,42.9,30.4,20.7.HRMS(ESI,m/z):[M+H]+calcd for C31H35N2O5 +515.2540,found 515.2544.
实施例9：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4i。
4i核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.45-7.41(m,2H),7.24-7.20(m,2H),6.63(s,1H),6.52(s,2H),6.21(s,1H),4.66-4.61(m,2H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.68(d,J＝8.6Hz,1H),3.60(d,J＝3.5Hz,1H),3.51(s,3H),3.40(dd,J＝7.9,3.2Hz,1H),3.38-3.32(m,1H),2.95(d,J＝17.7Hz,1H),2.74(dd,J＝17.6,8.0Hz,1H),2.71(d,J＝7.6Hz,2H),2.43(s,3H),2.38(s,3H).13C NMR(101MHz,CDCl3)δ148.4,147.9,146.9,146.2,138.5,137.6,129.5,128.3,126.5,124.8,123.6,113.9,111.9,111.6,107.6,92.7,84.8,66.3,62.0,56.6,56.1,56.0,55.9,55.8,55.5,42.9,30.4,21.4,20.7.HRMS(ESI,m/z):[M+H]+calcd for C32H37N2O5 +529.2697,found 529.2702.
实施例10：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4j。
4j核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.55(dd,J＝7.6,1.7Hz,1H),7.33(ddd,J＝8.7,7.5,1.7Hz,1H),7.04(td,J＝7.5,1.0Hz,1H),6.95(dd,J＝8.3,1.0Hz,1H),6.63(s,1H),6.52(s,1H),6.51(s,1H),6.22(s,1H),5.11(d,J＝8.7Hz,1H),4.70(d,J＝3.2Hz,1H),3.94-3.90(m,1H),3.91(s,3H),3.84(s,3H),3.84(s,3H),3.77(s,3H),3.62(d,J＝3.5Hz,1H),3.51(s,3H),3.45-3.38(m,2H),2.99(d,J＝17.8Hz,1H),2.74(dd,J＝16.3,8.0Hz,1H),3.72(d,J＝7.8Hz,2H),2.45(s,3H).13C NMR(101MHz,CDCl3)δ157.6,148.4,147.8,146.8,146.2,130.3,129.9,128.3,126.3,125.1,123.4,121.1,113.9,111.8,111.7,111.2,107.8,92.2,79.5,64.8,62.1,56.6,56.2,56.0,55.9,55.6,42.9,30.2,20.8.HRMS(ESI,m/z):[M+H]+calcd for C32H37N2O6 +545.2646,found 545.2648.
实施例11：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4k。
4k核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.35-7.30(m,1H),7.15-7.11(m,2H),6.93-6.88(m,1H),6.63(s,1H),6.52(s,2H),6.24(s,1H),4.66-4.62(m,2H),3.91(s,3H),3.84(s,3H),3.83(s,3H),3.78(s,3H),3.70(d,J＝8.6Hz,1H),3.59(d,J＝3.6Hz,1H),3.52(s,3H),3.40(dd,J＝7.9,3.2Hz,1H),3.35(td,J＝7.8,3.5Hz,1H),2.94(d,J＝17.8Hz,1H),2.75(dd,J＝17.8,8.1Hz,1H),2.70(d,J＝7.8Hz,2H),2.43(s,3H).13C NMR(101MHz,CDCl3)δ160.1,148.4,147.9,146.9,146.2,142.3,129.7,128.3,126.5,124.5,123.6,120.8,114.4,113.8,113.6,111.9,111.6,107.6,92.8,84.8,66.4,61.9,56.5,56.1,56.0,55.9,55.7,55.5,55.4,42.9,30.4,20.7.HRMS(ESI,m/z):[M+H]+calcd for C32H37N2O6 +545.2646,found 545.2649.
实施例12：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4l。
4l核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.50-7.45(m,2H),6.98-6.93(m,2H),6.63(s,1H),6.52(s,1H),6.51(s,1H),6.18(s,1H),4.70(d,J＝3.2Hz,1H),4.64(d,J＝8.6Hz,1H),3.91(s,3H),3.84(s,3H),3.83(s,3H),3.77(s,3H),3.70(d,J＝8.8Hz,1H),3.67(d,J＝3.5Hz,1H),3.50(s,3H),3.48-3.42(m,2H),3.00(d,J＝17.8Hz,1H),2.76(dd,J＝18.0,8.1Hz,1H),2.74-2.68(m,2H),2.47(s,3H).13C NMR(101MHz,CDCl3)δ160.1,148.6,148.0,146.9,146.4,132.4,129.7,127.9,126.3,124.6,122.9,114.3,113.8,111.9,111.6,107.5,92.1,84.6,65.9,62.1,56.5,56.0,55.9,55.8,55.7,55.5,42.7,30.2,20.8.HRMS(ESI,m/z):[M+H]+calcd for C32H37N2O6 +545.2646,found 545.2649.
实施例13：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4m。
4m核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.62-7.57(m,2H),7.32-7.27(m,2H),6.64(s,1H),6.53(s,1H),6.52(s,1H),6.06(s,1H),4.73(s,1H),4.67(d,J＝8.6Hz,1H),3.91(s,3H),3.85(s,3H),3.78(s,3H),3.71(d,J＝8.8Hz,1H),3.68-3.66(m,1H),3.49(s,3H),3.48-3.42(m,2H),2.98(d,J＝17.8Hz,1H),2.78(dd,J＝18.0,8.1Hz,1H),2.73-2.68(m,2H),2.48(s,3H).13C NMR(101MHz,CDCl3)δ149.6,148.7,148.1,147.0,146.4,139.3,130.0,127.8,126.4,123.9,122.8,121.4,120.6(q,JC-F＝257.5Hz),113.8,112.0,111.6,107.3,92.3,84.1,66.4,62.0,56.5,56.0,55.9,55.6,42.7,30.2,20.7.19F NMR(376MHz,CDCl3)δ-58.0(s).HRMS(ESI,m/z):[M+H]+calcd for C32H34F3N2O6 +599.2363,found599.2368.
实施例14：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4n。
4n核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.50-7.46(m,2H),7.46-7.42(m,2H),6.63(s,1H),6.52(s,1H),6.52(s,1H),6.18(s,1H),4.65(d,J＝6.0Hz,1H),4.64(s,1H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.70(d,J＝8.6Hz,1H),3.60(d,J＝3.5Hz,1H),3.49(s,3H),3.39(dd,J＝8.1,3.2Hz,1H),3.37-3.32(m,1H),2.95(d,J＝17.8Hz,1H),2.74(dd,J＝17.7,8.0Hz,1H),2.71(d,J＝7.6Hz,2H),2.44(s,3H),1.32(s,9H).13C NMR(101MHz,CDCl3)δ151.9,148.4,147.9,146.8,146.2,137.4,128.3,128.1,126.5,125.7,124.7,123.6,113.9,111.9,111.6,107.7,92.7,84.7,66.2,62.0,56.5,56.1,56.0,55.9,55.7,55.5,42.9,34.8,31.4,30.4,20.7.HRMS(ESI,m/z):[M+H]+calcd for C35H43N2O5 +571.3166,found 571.3168.
实施例15：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4o。
4o核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.42-7.37(m,2H),6.79-6.74(m,2H),6.63(s,1H),6.52(s,1H),6.51(s,1H),6.27(s,1H),4.62(s,1H),4.60(d,J＝4.7Hz,1H),3.91(s,3H),3.84(s,3H),3.77(s,3H),3.68(d,J＝8.7Hz,1H),3.59(d,J＝3.5Hz,1H),3.53(s,3H),3.39(dd,J＝7.8,3.2Hz,1H),3.37-3.32(m,1H),2.99-2.93(m,1H),2.96(s,6H),2.77-2.69(m,3H),2.43(s,3H).13C NMR(101MHz,CDCl3)δ151.0,148.4,147.8,146.8,146.2,129.2,128.4,127.8,126.4,125.1,123.6,113.9,112.7,111.8,111.6,107.7,92.4,84.9,65.7,62.1,56.5,56.1,56.0,55.9,55.9,55.6,42.9,40.7,30.3,20.8.HRMS(ESI,m/z):[M+H]+calcd for C33H40N3O5 +558.2962,found 558.2964.
实施例16：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4p。
4p核磁及质谱表征：1H NMR(500MHz,CDCl3)δ7.56-7.51(m,2H),7.16-7.10(m,2H),6.63(s,1H),6.52(s,1H),6.52(s,1H),6.11(s,1H),4.66-4.63(m,2H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.68(d,J＝8.6Hz,1H),3.60(d,J＝3.6Hz,1H),3.50(s,3H),3.40(dd,J＝7.9,3.2Hz,1H),3.39-3.34(m,1H),2.93(d,J＝17.8Hz,1H),2.75(dd,J＝17.8,8.1Hz,1H),2.71(d,J＝7.8Hz,2H),2.44(s,3H).13C NMR(126MHz,CDCl3)δ163.0(d,JC-F＝247.4Hz),148.4,148.0,146.9,146.3,136.5(d,JC-F＝3.1Hz),130.2(d,JC-F＝8.1Hz),128.1,126.5,124.3,123.5,115.8(d,JC-F＝21.7Hz),113.8,112.0,111.6,107.3,92.6,84.2,66.4,61.9,56.5,56.0,56.0,55.9,55.7,55.5,42.9,30.3,20.7.19F NMR(471MHz,CDCl3)δ-113.1(s).HRMS(ESI,m/z):[M+H]+calcd for C31H34FN2O5 +533.2446,found533.2450.
实施例17：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4q。
4q核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.52-7.47(m,2H),7.43-7.39(m,2H),6.63(s,1H),6.52(s,1H),6.52(s,1H),6.13(s,1H),4.66-4.62(m,2H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.66(d,J＝8.5Hz,1H),3.61(d,J＝3.7Hz,1H),3.52(s,3H),3.40(dd,J＝8.0,3.3Hz,1H),3.39-3.32(m,1H),2.93(d,J＝17.7Hz,1H),2.76(dd,J＝17.8,8.0Hz,1H),2.71(d,J＝8.0Hz,2H),2.44(s,3H).13C NMR(101MHz,CDCl3)δ148.5,148.1,146.9,146.3,139.3,134.6,129.8,129.0,128.1,126.5,124.2,123.4,113.8,112.0,111.6,107.4,92.6,84.1,66.5,61.9,56.5,56.0,56.0,55.9,55.8,55.5,42.9,30.3,20.7.HRMS(ESI,m/z):[M+H]+calcd for C31H34ClN2O5 +549.2151,found 549.2153.
实施例18：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4r。
4r核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.58-7.54(m,2H),7.46-7.41(m,2H),6.62(s,1H),6.52(s,1H),6.52(s,1H),6.13(s,1H),4.64-4.60(m,2H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.65(d,J＝8.6Hz,1H),3.59(d,J＝3.6Hz,1H),3.52(s,3H),3.39(dd,J＝8.1,3.4Hz,1H),3.37-3.31(m,1H),2.91(d,J＝17.7Hz,1H),2.75(dd,J＝17.8,8.0Hz,1H),2.70(d,J＝7.9Hz,2H),2.43(s,3H).13C NMR(101MHz,CDCl3)δ148.4,148.1,146.9,146.3,139.9,132.0,130.1,128.1,126.6,124.2,123.5,122.7,113.8,112.0,111.6,107.4,92.8,84.1,66.5,61.9,56.5,56.1,56.0,55.9,55.9,55.4,42.9,30.4,20.7.HRMS(ESI,m/z):[M+H]+calcd for C31H34BrN2O5 +593.1646,found 593.1646.
实施例19：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4s。
4s核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.72-7.67(m,4H),6.63(s,1H),6.53(s,1H),6.52(s,1H),6.09(s,1H),4.72(d,J＝8.5Hz,1H),4.67(d,J＝3.3Hz,1H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.70(d,J＝8.5Hz,1H),3.61(d,J＝3.6Hz,1H),3.51(s,3H),3.42(dd,J＝7.8,3.2Hz,1H),3.40-3.35(m,1H),2.93(d,J＝17.8Hz,1H),2.76(dd,J＝17.8,8.0Hz,1H),2.71(d,J＝7.7Hz,2H),2.44(s,3H).13C NMR(126MHz,CDCl3)δ148.5,148.1,146.9,146.3,145.0,131.0(q,JC-F＝32.5Hz),128.8,128.0,126.6,125.7(q,JC-F＝3.9Hz),124.1(q,JC-F＝272.1Hz),124.0,123.4,113.8,112.0,111.6,107.4,92.8,84.1,66.7,61.9,56.5,56.0,56.0,55.9,55.8,55.4,42.9,30.4,20.7.19F NMR(471MHz,CDCl3)δ-62.6(s).HRMS(ESI,m/z):[M+H]+calcd for C32H34F3N2O5 +583.2414,found 583.2418.
实施例20：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4t。
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4t核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.70-7.66(m,2H),7.65-7.60(m,4H),7.48-7.43(m,2H),7.39-7.34(m,1H),6.65(s,1H),6.54(s,2H),6.25(s,1H),4.72(d,J＝8.5Hz,1H),4.68(d,J＝3.3Hz,1H),3.92(s,3H),3.85(s,3H),3.79(s,3H),3.76(d,J＝8.6Hz,1H),3.61(d,J＝3.5Hz,1H),3.52(s,3H),3.42(dd,J＝7.8,3.2Hz,1H),3.40-3.35(m,1H),2.97(d,J＝17.7Hz,1H),2.77(dd,J＝17.9,8.0Hz,1H),2.73(d,J＝7.5Hz,2H),2.45(s,3H).13C NMR(101MHz,CDCl3)δ148.4,148.0,146.9,146.2,141.6,140.7,139.7,129.0,128.9,128.3,127.6,127.5,127.2,126.5,124.6,123.6,113.9,111.9,111.6,107.6,92.8,84.6,66.4,62.0,56.5,56.2,56.0,55.9,55.8,55.5,42.9,30.4,20.7.HRMS(ESI,m/z):[M+H]+calcd for C37H39N2O5 +591.2853,found 591.2859.
实施例21：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4u。
4u核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.75-7.69(m,6H),7.67-7.63(m,4H),7.50-7.44(m,2H),7.40-7.34(m,1H),6.66(s,1H),6.54(s,2H),6.27(s,1H),4.74(d,J＝8.6Hz,1H),4.72(d,J＝3.6Hz,1H),3.93(s,3H),3.86(s,3H),3.79(s,3H),3.79-3.76(m,1H),3.64(d,J＝3.6Hz,1H),3.53(s,3H),3.45(dd,J＝7.8,3.2Hz,1H),3.44-3.39(m,1H),2.99(d,J＝17.8Hz,1H),2.78(dd,J＝17.9,8.1Hz,1H),2.74(d,J＝7.8Hz,2H),2.47(s,3H).13C NMR(101MHz,CDCl3)δ148.5,148.0,146.9,146.3,141.1,140.7,140.6,139.8,139.6,129.0,128.9,128.2,127.7,127.6,127.4,127.2,126.5,124.5,123.4,113.9,111.9,111.6,107.6,92.7,84.6,66.4,62.0,56.6,56.0,55.9,55.8,55.6,42.9,30.3,20.7.HRMS(ESI,m/z):[M+H]+calcd for C43H43N2O5 +667.3166,found 667.3170.
实施例22：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4v。
4v核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.61-7.50(m,6H),7.39-7.34(m,2H),7.29-7.24(m,1H),7.19-7.09(m,2H),6.64(s,1H),6.53(s,1H),6.53(s,1H),6.22(s,1H),4.71(d,J＝3.2Hz,1H),4.68(d,J＝8.5Hz,1H),3.92(s,3H),3.85(s,3H),3.78(s,3H),3.74(d,J＝8.6Hz,1H),3.66(d,J＝3.5Hz,1H),3.52(s,3H),3.45(dd,J＝7.9,3.4Hz,1H),3.45-3.40(m,1H),2.99(d,J＝17.8Hz,1H),2.77(dd,J＝17.9,8.1Hz,1H),2.72(d,J＝7.9Hz,2H),2.47(s,3H).13C NMR(101MHz,CDCl3)δ148.5,148.0,146.9,146.3,139.9,137.9,137.2,129.3,128.8,128.8,128.2,128.1,127.9,126.9,126.7,126.4,124.5,123.2,113.8,111.9,111.6,107.6,92.5,84.7,66.3,62.1,56.6,56.0,55.9,55.8,55.6,42.8,30.3,20.8.HRMS(ESI,m/z):[M+H]+calcd for C39H41N2O5 +617.3010,found 617.3016.
实施例23：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4w。
4w核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.62-7.58(m,2H),7.58-7.52(m,4H),7.39-7.31(m,3H),6.64(s,1H),6.53(s,2H),6.18(s,1H),4.69-4.65(m,2H),3.91(s,3H),3.85(s,3H),3.78(s,3H),3.71(d,J＝8.6Hz,1H),3.62(d,J＝3.5Hz,1H),3.53(s,3H),3.43(dd,J＝8.0,3.2Hz,1H),3.41-3.34(m,1H),2.96(d,J＝17.8Hz,1H),2.76(dd,J＝17.9,8.1Hz,1H),2.71(d,J＝7.9Hz,2H),2.45(s,3H).13C NMR(101MHz,CDCl3)δ148.5,148.0,147.0,146.3,140.9,132.0,131.8,128.5,128.5,128.5,128.1,126.5,124.3,123.8,123.4,123.2,113.9,112.0,111.6,107.4,92.7,90.2,89.2,84.6,66.5,62.0,56.5,56.0,56.0,55.9,55.8,55.5,42.9,30.3,20.7.HRMS(ESI,m/z):[M+H]+calcd for C39H39N2O5 +615.2853,found 615.2861.
实施例24：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4x。
4x核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.07(d,J＝1.6Hz,1H),6.99(dd,J＝8.0,1.7Hz,1H),6.83(d,J＝7.9Hz,1H),6.62(s,1H),6.52(s,1H),6.52(s,1H),6.24(s,1H),6.00(d,J＝1.5Hz,1H),5.99(d,J＝1.5Hz,1H),4.61(d,J＝3.3Hz,1H),4.59(d,J＝8.6Hz,1H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.64(d,J＝8.5Hz,1H),3.60(d,J＝3.5Hz,1H),3.54(s,3H),3.39(dd,J＝8.0,3.3Hz,1H),3.37-3.33(m,1H),2.93(d,J＝17.7Hz,1H),2.74(dd,J＝17.9,8.0Hz,1H),2.70(d,J＝7.5Hz,2H),2.44(s,3H).13C NMR(101MHz,CDCl3)δ148.4,148.3,148.1,148.0,146.9,146.3,134.5,128.2,126.5,124.5,123.5,122.1,113.9,111.9,111.6,108.4,108.2,107.6,101.4,92.5,84.8,66.0,62.0,56.5,56.0,56.0,55.9,55.8,55.5,42.9,30.3,20.7.HRMS(ESI,m/z):[M+H]+calcd forC32H35N2O7 +559.2439,found 559.2438.
实施例25：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4y。/>
4y核磁及质谱表征：1H NMR(400MHz,CDCl3)δ8.00-7.99(m,1H),7.93(d,J＝8.5Hz,1H),7.90-7.82(m,2H),7.71(dd,J＝8.4,1.7Hz,1H),7.53-7.48(m,2H),6.66(s,1H),6.54(s,1H),6.52(s,1H),6.24(s,1H),4.86(d,J＝8.5Hz,1H),4.79(d,J＝3.2Hz,1H),3.92(s,3H),3.86(s,3H),3.82(d,J＝8.6Hz,1H),3.77(s,3H),3.68-3.63(m,1H),3.51-3.43(m,2H),3.39(s,3H),3.02(d,J＝17.8Hz,1H),2.79(dd,J＝18.0,8.3Hz,1H),2.74(d,J＝7.8Hz,2H),2.49(s,3H).13C NMR(101MHz,CDCl3)δ148.5,147.9,146.9,146.3,138.2,133.7,133.4,128.9,128.2,128.0,127.9,127.7,126.6,126.5,125.7,124.6,123.3,113.9,111.9,111.6,107.5,92.7,85.1,66.2,62.1,56.6,56.0,55.9,55.7,55.6,42.9,30.3,20.8.HRMS(ESI,m/z):[M+H]+calcd for C35H37N2O5 +565.2697,found 565.2701.
实施例26：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4z。
4z核磁及质谱表征：1H NMR(400MHz,CDCl3)δ8.91(dd,J＝4.1,1.8Hz,1H),8.20(dd,J＝8.3,1.8Hz,1H),8.12(dd,J＝7.2,1.4Hz,1H),7.85(dd,J＝8.2,1.4Hz,1H),7.68(dd,J＝8.1,7.2Hz,1H),7.41(dd,J＝8.3,4.1Hz,1H),6.65(s,1H),6.54(s,1H),6.48(s,1H),6.21(d,J＝8.6Hz,1H),5.81(s,1H),4.92(d,J＝3.1Hz,1H),4.04(d,J＝8.6Hz,1H),3.92(s,3H),3.87(s,3H),3.74(s,3H),3.69-3.63(m,1H),3.52-3.44(m,2H),3.10(d,J＝17.8Hz,1H),2.96(s,3H),2.77(dd,J＝17.9,8.0Hz,1H),2.73(d,J＝7.0Hz,2H),2.50(s,3H).13C NMR(101MHz,CDCl3)δ150.0,148.5,147.7,146.5,146.5,146.2,139.1,136.6,130.0,128.5,128.4,128.3,126.8,126.3,124.6,121.2,113.8,111.7,108.1,92.6,78.7,67.6,62.2,56.6,56.3,56.0,56.0,55.9,55.0,42.9,30.3,20.8.HRMS(ESI,m/z):[M+H]+calcd for C34H36N3O5 +566.2649,found 566.2653.
实施例27：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4aa。
4aa核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.63(dd,J＝7.9,1.1Hz,1H),7.53(dd,J＝7.5,1.1Hz,1H),7.16(t,J＝7.6Hz,1H),6.97(d,J＝3.1Hz,1H),6.68(s,1H),6.55(s,1H),6.55(s,1H),6.50(d,J＝3.1Hz,1H),6.17(s,1H),5.49(d,J＝8.7Hz,1H),4.62(d,J＝3.2Hz,1H),4.06(d,J＝8.7Hz,1H),3.98(s,3H),3.92(s,3H),3.87(s,3H),3.78(s,3H),3.62(d,J＝3.5Hz,1H),3.43-3.36(m,2H),3.22(s,3H),2.97(d,J＝17.6Hz,1H),2.80(dd,J＝17.8,8.1Hz,1H),2.76(d,J＝7.6Hz,2H),2.43(s,3H).13C NMR(101MHz,CDCl3)δ148.4,148.0,146.9,146.3,135.1,131.5,130.9,128.2,126.7,124.5,123.8,123.0,121.7,121.6,119.6,113.9,112.0,111.7,107.8,101.5,92.5,78.9,65.2,62.0,56.5,56.4,56.0,55.9,55.5,55.4,42.9,37.6,30.5,21.0.HRMS(ESI,m/z):[M+H]+calcd for C34H38N3O5 +568.2806,found 568.2811.
实施例28：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4bb。
4bb核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.45-7.41(m,2H),7.30(dd,J＝4.9,1.5Hz,1H),6.63(s,1H),6.53(s,1H),6.52(s,1H),6.21(s,1H),4.78(d,J＝8.7Hz,1H),4.57(d,J＝3.3Hz,1H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.72(d,J＝8.7Hz,1H),3.59(d,J＝3.6Hz,1H),3.54(s,3H),3.37(dd,J＝8.1,3.7Hz,1H),3.35-3.31(m,1H),2.93(d,J＝17.7Hz,1H),2.74(dd,J＝18.3,8.0Hz,1H),2.71(d,J＝7.7Hz,2H),2.43(s,3H).13C NMR(126MHz,CDCl3)δ148.4,148.0,147.0,146.2,141.9,128.3,127.2,126.9,126.5,124.6,124.0,123.6,113.8,111.9,111.6,107.3,92.1,79.9,65.4,62.0,56.5,56.1,56.0,55.9,55.7,55.4,42.9,30.3,20.7.HRMS(ESI,m/z):[M+H]+calcd for C29H33N2O5S+521.2105,found 521.2110.
实施例29：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4cc。
4cc核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.41(dt,J＝5.1,0.9Hz,1H),7.24(dd,J＝3.5,1.2Hz,1H),7.05(dd,J＝5.1,3.5Hz,1H),6.62(s,1H),6.53(s,1H),6.51(s,1H),6.26(s,1H),4.96(d,J＝8.6Hz,1H),4.55(d,J＝3.3Hz,1H),3.91(s,3H),3.84(s,3H),3.78(s,3H),3.75(d,J＝8.6Hz,1H),3.58(d,J＝3.6Hz,1H),3.53(s,3H),3.39-3.32(m,2H),2.93(d,J＝17.8Hz,1H),2.78-2.69(m,3H),2.42(s,3H).13C NMR(101MHz,CDCl3)δ148.4,148.1,147.0,146.2,143.9,128.2,127.1,127.0,126.5,124.3,123.6,113.8,111.9,111.6,107.4,91.8,79.5,66.8,61.9,56.5,56.1,56.0,55.9,55.8,55.3,42.9,30.3,20.7.HRMS(ESI,m/z):[M+H]+calcd for C29H33N2O5S+521.2105,found 521.2100.
实施例30：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4dd。
4dd核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.53(dd,J＝1.9,0.8Hz,1H),6.62(s,1H),6.54-6.52(m,2H),6.51(s,1H),6.44(dd,J＝3.2,1.9Hz,1H),6.23(s,1H),4.72(d,J＝8.8Hz,1H),4.52(d,J＝3.3Hz,1H),3.92-3.88(m,1H),3.90(s,3H),3.84(s,3H),3.79(s,3H),3.61(d,J＝3.6Hz,1H),3.58(s,3H),3.42-3.35(m,2H),2.94(d,J＝17.8Hz,1H),2.78-2.69(m,3H),2.43(s,3H).13C NMR(101MHz,CDCl3)δ152.8,148.5,148.1,147.1,146.3,143.7,128.1,126.5,124.5,123.3,113.8,111.9,111.6,110.7,109.6,107.4,91.7,76.6,62.7,61.9,56.5,56.1,56.0,55.9,55.8,55.3,42.8,30.1,20.7.HRMS(ESI,m/z):[M+H]+calcd for C29H33N2O6 +505.2333,found 505.2339.
实施例31：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4ee。
4ee核磁及质谱表征：1H NMR(400MHz,CDCl3)δ8.79(d,J＝2.2Hz,1H),8.65(dd,J＝4.9,1.6Hz,1H),7.93(dt,J＝7.9,2.0Hz,1H),7.41(dd,J＝7.9,4.8Hz,1H),6.64(s,1H),6.53(s,2H),6.07(s,1H),4.74-4.69(m,2H),3.91(s,3H),3.85(s,3H),3.78(s,3H),3.74(d,J＝8.6Hz,1H),3.70-3.64(m,1H),3.51(s,3H),3.49-3.44(m,2H),2.97(d,J＝17.8Hz,1H),2.78(dd,J＝17.8,8.0Hz,1H),2.72(d,J＝7.6Hz,2H),2.48(s,3H).13C NMR(101MHz,CDCl3)δ150.3,149.9,148.7,148.2,147.1,146.5,136.3,136.1,127.8,126.4,123.9,123.8,113.8,112.1,111.6,107.1,92.4,82.5,66.4,62.0,56.6,56.0,55.9,55.8,55.8,55.6,42.8,30.2,20.7.HRMS(ESI,m/z):[M+H]+calcd for C30H34N3O5 +516.2493,found516.2495.
实施例32：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4ff。
4ff核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.62-7.58(m,1H),7.53-7.49(m,1H),7.34-7.29(m,1H),7.25(td,J＝7.5,1.1Hz,1H),6.91(s,1H),6.64(s,1H),6.54(s,2H),6.48(s,1H),4.87(d,J＝8.6Hz,1H),4.65(d,J＝3.2Hz,1H),3.99(d,J＝8.7Hz,1H),3.92(s,3H),3.85(s,3H),3.79(s,3H),3.69(d,J＝3.5Hz,1H),3.58(s,3H),3.52-3.44(m,2H),3.01(d,J＝17.8Hz,1H),2.82-2.70(m,3H),2.48(s,3H).13C NMR(101MHz,CDCl3)δ155.7,155.5,148.6,148.2,147.1,146.4,128.0,127.8,126.4,124.9,124.4,123.1,121.4,113.8,112.0,111.6,107.7,105.9,91.6,63.3,62.0,56.5,56.0,55.9,55.9,55.4,42.7,30.0,20.7.HRMS(ESI,m/z):[M+H]+calcd for C33H35N2O6 +555.2490,found 555.2495.
实施例33：
同实施例2的方法，R1，R4，R5，R8为H，R2，R3，R6，R7为甲氧基,R9为制得化合物4gg。
4gg核磁及质谱表征：1H NMR(400MHz,CDCl3)δ7.98-7.96(m,1H),7.96-7.93(m,1H),7.62(s,1H),7.49(ddd,J＝8.2,7.2,1.3Hz,1H),7.41(ddd,J＝8.3,7.2,1.2Hz,1H),6.64(s,1H),6.52(s,2H),5.22(d,J＝8.3Hz,1H),4.60(d,J＝3.2Hz,1H),3.92(s,3H),3.88(s,3H),3.85(s,3H),3.81(s,3H),3.72(d,J＝8.3Hz,1H),3.61(d,J＝3.6Hz,1H),3.51(dd,J＝8.0,3.2Hz,1H),3.37(td,J＝8.0,3.6Hz,1H),2.97(d,J＝17.8Hz,1H),2.80(dd,J＝17.9,8.1Hz,1H),2.73(d,J＝7.9Hz,2H),2.46(s,3H).13C NMR(101MHz,CDCl3)δ173.8,153.7,148.5,148.0,147.2,146.4,135.1,127.9,126.3,126.1,125.3,124.3,123.1,122.1,113.8,111.7,111.6,109.1,92.5,81.4,66.1,61.8,56.7,56.5,56.0,56.0,55.9,55.2,42.8,30.0,20.7.HRMS(ESI,m/z):[M+H]+calcd for C32H34N3O5S+572.2214,found572.2218.
实施例34：
部分目标化合物4a-4gg对肿瘤细胞的抗增殖活性考察：
本研究采用细胞系包括：人源肺癌细胞株A549、人源肝癌细胞株HepG2、人源乳腺癌细胞株MDA-MB-231。细胞接种于含10％胎牛血清、100μg/mL青霉素，100μg/mL链霉素和2mmol/mL谷氨酰胺的RPMI-1640或DMEM高糖培养液中常规培养(37℃，5％ CO2)。
利用MTT法检测具有环状N,O-半缩醛胺的双四氢异喹啉衍生物的细胞毒活性。消化处于对数生长期的细胞，调整细胞悬液浓度A549为0.18×105cells/mL，HepG2为0.12×104cells/mL以及MDA-MB-231为0.28×105cells/mL，向96孔板中每孔加入100μL细胞悬液，边缘孔用150μL无菌PBS填充。过夜培养使之贴壁后，向每孔加入100μL含双四氢异喹啉衍生物的新鲜培养液(2倍目标浓度)，同时设置消除溶媒影响的含有DMSO培养液的对照组，每个浓度设置3个复孔。于培养箱孵育72h后，每孔加入40μL的MTT(2.5mg/mL in PBS)，于培养箱孵育3-4h。取出待测96孔板，吸出培养液，每孔加入100μL的DMSO，振荡混匀20min后，用酶标仪读取在490nm的吸光度。实验重复三次，按下式计算细胞活力：细胞活力(％)＝A实验/A对照×100％，用GraphPad Prism 8软件通过非线性回归分析计算IC50。
实验结果如表1所示，所有具有环状N,O-半缩醛胺的双四氢异喹啉衍生物对以上三种癌细胞均呈现较强烈的细胞毒性。除了化合物4f，4j，4aa，其他化合物针对乳腺癌细胞MDA-MB-231的毒性均高于阳性对照(顺铂)。
表1
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需要说明的是上述实施例仅仅是本发明的较佳实施例，并没有用来限定本发明的保护范围，在上述基础上做出的等同替换或者替代均属于本发明的保护范围。
Claims (10)
1.一种具有环状N,O-半缩醛胺的双四氢异喹啉衍生物，其特征在于，包括通式(Ⅰ)的化合物：
其中，
环A为芳环、取代芳环、杂芳环、取代杂芳环、稠环或取代稠环；
环B为芳环、取代芳环、杂芳环、取代杂芳环、稠环或取代稠环；
R1为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R2为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R3为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R4为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R5为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R6为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R7为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R8为H、酚羟基、烷氧基、烷基、卤素、氰基、硝基、酰氧基、酯基或卤代烷基；
R1和R2、R2和R3、R3和R4、R5和R6、R6和R7、R7和R8可以形成1,3-二氧戊环；
R9为H、烷基、取代烷基、环烷基、取代环烷基、芳基、取代芳基、杂芳基、取代杂芳基、炔基、取代炔基、烯基、取代烯基或烷氧基。
2.如权利要求1所述的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物，其特征在于，R1为H、OH或OMe；R2为H、OH或OMe；R3为H、OH或OMe；R4为H、OH或OMe；
R5为H、OH或OMe；R6为H、OH或OMe；R7为H、OH或OMe；R8为H、OH或OMe。
3.如权利要求1所述的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物，其特征在于，R9选自
中任意一种。
4.如权利要求1所述的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物的制备方法，其特征在于，合成路线如下：
5.如权利要求4所述的制备方法，其特征在于，所述制备方法包括以下步骤：
步骤1，以化合物Ⅱ为初始原料，经过酸脱除苄基保护基得到化合物Ⅲ；
步骤2，再经过酰胺还原并环化得到化合物Ⅳ。
6.如权利要求4所述的制备方法，其特征在于，
所述步骤1的具体方法为：氮气保护下，化合物II溶于有机溶剂中，向其中加入三氯化硼，反应过夜；将反应淬灭，萃取，旋干，将剩余物用硅胶柱层析纯化得到式III；
所述步骤2的具体方法为：氮气保护下，向氢化铝锂的THF悬浊液中滴加化合物III的THF溶液，反应一段时间；将反应淬灭，干燥，旋干，将剩余物用硅胶柱层析纯化得到化合物IV。
7.如权利要求1所述的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物的制备方法，其特征在于，合成路线如下：
8.如权利要求7所述的制备方法，其特征在于，所述制备方法包括以下步骤：
步骤A，以化合物Ⅱ为初始原料，经过酸脱除苄基保护基得到化合物Ⅲ；
步骤B，氧化伯醇得到化合物V；
步骤C，与不同亲核试剂作用，引入取代基R9，得到化合物VI；
步骤D，经过酰胺还原并环化得到化合物VII。
9.如权利要求4所述的制备方法，其特征在于，
所述步骤A的具体方法为：氮气保护下，化合物II溶于有机溶剂中，向其中加入三氯化硼，反应过夜；将反应淬灭，萃取，旋干，将剩余物用硅胶柱层析纯化得到化合物III；
所述步骤B的具体方法为：化合物III的DCM溶液加入DMP，反应一段时间；抽滤，旋干，将剩余物用硅胶柱层析纯化得到化合物V；
所述步骤C的具体方法为：氮气保护下，化合物V溶于THF中，向其中加入亲核试剂，反应过夜；将反应淬灭，萃取，旋干，将剩余物用硅胶柱层析纯化得到化合物VI；
所述步骤D的具体方法为：氮气保护下，向氢化铝锂的THF悬浊液中滴加化合物VI的THF溶液，反应1h。加入水淬灭，干燥，旋干，将剩余物用硅胶柱层析纯化得到化合物VII。
10.如权利要求1-3任意一项所述的具有环状N,O-半缩醛胺的双四氢异喹啉衍生物在制备抗癌药物中的应用。
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