阅读说明：本技术 靶向hdac抑制剂及其在抗肿瘤治疗药物中的应用 (Targeted HDAC inhibitor and application thereof in antitumor therapeutic drugs ) 是由 姚大红 贺震旦 宋勋 于 2020-07-09 设计创作，主要内容包括：本发明涉及靶向HDAC抑制剂及其在抗肿瘤治疗药物中的应用,属于抗肿瘤药学技术领域。本发明提供了如下结构的HDAC抑制剂的化合物或其药学上可接受的盐、异构体。其中,R<Sub>1</Sub>、n如权利要求和说明书所述。本发明的化合物或其药学上可接受的盐、异构体或其药物组合物具有抗肿瘤活性,可以作为HDAC抑制剂,用于制备抗肿瘤药物。<Image he="397" wi="700" file="DDA0002577017940000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a targeting HDAC inhibitor and application thereof in antitumor therapeutic drugs, belonging to the technical field of antitumor medicine. The present invention provides a compound of an HDAC inhibitor having the structure below or a pharmaceutically acceptable salt, isomer thereof. Wherein R is 1 N are as described in the claims and specification. The compound or the pharmaceutically acceptable salt, the isomer or the pharmaceutical composition thereof has antitumor activity, and can be used as an HDAC inhibitor for preparing antitumor drugs.)

靶向HDAC抑制剂及其在抗肿瘤治疗药物中的应用

技术领域

本发明涉及靶向HDAC抑制剂及其在抗肿瘤治疗药物中的应用，属于肿瘤治疗药物发现技术领域。

背景技术

恶性肿瘤严重威胁人类的生命健康，每年全世界约有700万人死于癌症，约占总死亡人数的四分之一。目前我国现有癌症患者死亡率逾30％，已成为我国居民死亡的第二大因素。药物治疗已成为对恶性肿瘤有效而又普遍使用的一种治疗方法。尽管自1942年耶鲁大学的Gilman等首次证明盐酸氮芥对小鼠Gardner淋巴瘤有治疗作用以来，肿瘤的药物治疗取得了长足的进展，并成为当前临床治疗不可或缺的主要措施。但高毒副作用、耐药等问题仍然是临床肿瘤药物治疗遇到的主要障碍。临床上应用的抗肿瘤药物种类繁多，其中化疗药物主要有烷化剂钼络合物抗肿瘤药物、蒽环类抗肿瘤药物、破坏DNA的抗生素等。此外，天然抗肿瘤药物的研究也占有相当大的比例，如目前临床上常用一些药物有喜树碱、长春新碱、紫杉醇等。

在恶性肿瘤药物治疗领域，如何发现新的治疗靶标，有针对性的设计出新型靶向治疗小分子药物，并深入探讨其作用机制是解决临床问题的关键，具有重要的研究意义和价值。HDAC作为一个重要的癌基因，在恶性肿瘤中异常高表达，针对其设计靶向性的小分子抑制剂，是治疗乳腺癌，也别是三阴性乳腺癌重要的策略。

发明内容

本发明解决的技术问题是提供一种作为HDAC抑制剂的化合物。

本发明提供结构式如式Ⅰ所示的化合物或其药学上可接受的盐、异构体：

其中，R₁为氢、C1-C6烷基、6-10元芳基氨基、C1-C6烷基氨基，或其中n’＝0-3；R’为氢、C1-C6烷基、卤素、硝基、羟基、氨基；X为CH₂，O，CF₂，NH，NCH₃，S或砜；

n＝0-5。

本发明优选如下结构的化合物或其药学上可接受的盐、异构体

其中，R₁为其中n’＝0-3；R’为氢，C1-C4烷基；X为CH₂，O，CF₂，NH，NCH₃，S或砜；n＝1-5。

本发明优选如下结构的化合物或其药学上可接受的盐、异构体：

其中，R₁为其中n’＝0-1；R’为氢、C1-C4烷基；X为CH₂，CF₂，O，NH，NCH₃，S或砜；n＝1-5；

本发明优选如下结构的化合物或其药学上可接受的盐、异构体：

其中，R₁为

其中n’＝0；R’为氢、C1-C4烷基；X为CH₂；n＝1-5；

本发明优选如下结构的化合物或其药学上可接受的盐、异构体：

其中，R₁为其中n’＝1；R’为氢、C1-C4烷基；X为CH₂，CF₂，O，NH，NCH₃，S或砜；n＝1-5；

本发明优选如下结构的化合物或其药学上可接受的盐、异构体：

本发明所述的化合物的药学上可接受的盐可以为所述化合物的硝酸盐、盐酸盐、硫酸盐、磷酸盐或柠檬酸盐等。

本发明还提供上述化合物或其药学上可接受的盐、异构体在制备抗肿瘤药物中的用途

进一步的，所述抗肿瘤药物优选为HDAC抑制剂类药物，其用途为用于肿瘤相关治疗。

本发明还提供一种药物组合物，它是包含有效剂量的上述化合物或其药学上可接受的盐、异构体的制剂。可以通过本领域已知的方法可将本发明化合物制成以下形式：片剂、胶囊剂、水性或油性溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、凝胶剂、喷鼻剂、栓剂、用于吸入的细小分散的粉剂或气雾剂或喷雾剂、用于胃肠道外(包括静脉内、肌内或输注)的无菌水性或油性溶液或混悬剂或无菌乳剂。可采用无菌水或水-丙二醇溶液作为溶剂来制备液体制剂，还可将活性组分配制在聚乙二醇水溶液中。用于口服给予的水性溶液可通过将活性组分溶解在水中并按需要加入合适的着色剂、矫味剂、稳定剂和增稠剂来制备。口服使用的水性混悬剂可通过将细小分散的活性组分与粘性物质一道分散在水中，所述粘性物质如为天然合成胶、树脂、甲基纤维素、羧甲基纤维素和其他药剂领域已知的悬浮剂。

药物组合物可为单位剂量形式。在这些形式中，将所述组合物分成含适量活性组分的单位剂量。该单位剂量形式可为包装制剂，包装中包括分隔量的制剂，例如盒装片剂、胶囊剂和在管形瓶或安瓿中的粉剂。单位剂量形式还可为胶囊剂、扁囊剂或片剂或其可为适当数量的任何这些包装形式。

本发明的药物组合物，其活性成分可仅为本发明的化合物，也可与其他抗肿瘤化合物组合作为活性成分。

在***过程中，可采用本发明的药物组合物与其他抗肿瘤药进行联合治疗。

在***时，可通过同时、序贯或单独给予各种治疗成分可实现这种联合治疗。此类组合产品应用有效剂量范围内的本发明化合物和准许剂量范围内的其他药学活性剂。

附图说明

图1为MDA-MB-231细胞化合物34处理24小时，Hoechst33258荧光染色图。

图2为MDA-MB-231细胞化合物34处理24小时，Annexin V-PI流式检测细胞凋亡率。

图3为MDA-MB-231细胞用化合物34处理24小时，划痕检测细胞的迁移。

图4为化合物34在MDA-MB-231细胞的斑马鱼移植瘤模型中的抗肿瘤活性评价。

具体实施方式

下面结合实施例对本发明的具体实施方式做进一步的描述，并不因此将本发明限制在所述的实施例范围之中。

实施例1化合物1～36的合成

化合物1～36采用如下反应式合成：

合成路线和条件：(i)K₂CO₃,DMF,80℃,8h；(ii)HCl(g),Et₂O；(iii)Oxalylchloride,170℃,40min；(iv)33％NaOH/30％H₂O₂,then NH3(g),HOBt,EDC,NMM,THF；(v)3,NaHSO₃,PTSA,DMAc；(vi)thionyl chloride,60℃；(vii)DIEA,R1(R₂)NH,isopropanol,reflux；(viii)NH₂OH.HCl,NaOH,CH₃OH；

其中，R₁和n如权利要求书所述。

中间体3a-d制备

取4-羟基-3,5-二甲基苯甲醛(1)(25mmol)溶于DMF(60ml)溶液，加入K2CO3(50mmol)和催化量的碘化钾，80℃加热4小时。待原料消耗完全后，将热反应悬浊液倒入50ml水中，用3×50ml二氯甲烷萃取。有机层用饱和的碳酸氢钠和盐水清洗，然后在无水硫酸钠上干燥。在减压下除去溶剂后给油。采用硅胶sel闪光色谱(二氯甲烷/甲醇50:1)对原油进行纯化，得到无色油，收率82-93％。

中间体3a ¹H-NMR(400MHz,CDCl₃),δ(ppm):9.89(1H,s),7.56(2H,s),4.46(2H,s),4.31(2H,q,J＝7.1Hz),2.37(6H,s),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):177.1,168.5,160.5,132.7,131.8,131.8,130.8,130.8,69.0,61.4,16.4,16.4,14.2；

中间体3b ¹H-NMR(400MHz,CDCl₃),δ(ppm):9.87(1H,s),7.55(2H,s),4.17(2H,q,J＝7.1Hz),3.86(2H,t,J＝6.5Hz),2.60(2H,t,J＝7.4Hz),2.32(6H,s),2.16(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):191.6,173.1,161.2,132.3,131.9,131.1,130.7,130.7,70.9,60.5,30.7,25.6,16.3,16.3,14.2；

中间体3c ¹H-NMR(400MHz,CDCl₃),δ(ppm):9.87(1H,s),7.55(2H,s),4.46(2H,s),4.16(2H,q,J＝7.1Hz),3.84(2H,t,J＝5.9Hz),2.33(6H,s),1.87(4H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):191.6,173.4,161.5,132.2,131.9,131.1,130.7,130.7,71.8,60.4,34.0,29.8,21.6,16.1,16.4,14.2；

中间体3d ¹H-NMR(400MHz,CDCl₃),δ(ppm):9.87(1H,s),7.55(2H,s),4.14(2H,q,J＝7.1Hz),3.82(2H,t,J＝6.5Hz),2.33(2H,m),2.32(6H,s),1.85(2H,m),1.73(2H,m),1.57(2H,m),1.26(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):191.6,173.6,161.6,132.1,131.9,131.1,130.7,130.7,72.2,60.3,34.2,30.1,25.6,24.8,16.4,16.4,14.2；

中间体7合成

将3,5-二甲氧基苯胺1(20mmol)溶于***(120ml)中，将HCl(气)鼓入反应残留物中，0℃搅拌2h,10℃加热45min后过滤；滤饼用冷却的乙酸乙酯洗涤，在真空中干燥得到白色盐酸盐。盐酸盐溶解于草酰氯(6ml)，加热到170℃反应40分钟。减压蒸除溶剂，0℃用甲醇稀释(15ml),然后加热回流1h。反应混合物热过滤，沉淀用甲醇洗净得4,6-dimethoxyindoline-2,3-dione红色粉末,使用前未经纯化。

将4,6-二甲氧基吲哚-2,3-二酮在NaOH中的溶液(33％的水，20mL)加热至70℃。将H2O2(30％水，5ml)滴加到溶液中。将混合物在70℃保持40min，在10℃将饱和Na2S2O3溶液(18mL)加入上述混合物中。用HCl调整反应混合物至pH＝8，然后用AcOH调整反应混合物至pH＝5。收集沉淀干燥得到2-氨基-4,6-二甲氧基苯甲酸，然后将EDC(1.5eq)、HOBt(1.5eq)和NMM(1.8eq)分别加入2-氨基-4,6-二甲氧基苯甲酸(15mmol)THF(30mL)溶液中。搅拌4h后，NH3(g)在室温下鼓出1h。加水，用DCM(3×20mL)提取水层。将有机层合并，用饱和的碳酸氢钠和盐水清洗，然后用无水硫酸钠烘干。减压去除溶剂后，利用闪光柱层析(DCM/MeOH＝80:1)得到2-氨基-4,6-二甲氧基苯甲酰胺(7)。¹H-NMR(400MHz,DMSO-d⁶),δ(ppm):7.46(1H,s),7.03(1H,s),6.91(2H,s),5.88(1H,d,J＝2.3Hz),5.76(1H,d,J＝2.3Hz),3.76(3H,s),3.68(3H,s)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.9,162.3,160.9,154.3,97.7,93.0,87.5,56.1,55.3；

中间体8a-d合成

将2-氨基-4,6-二甲氧基苯甲酰胺(7)(5mmol)溶于DMAc(8mL)，中间3a(5.5mmol)溶液中，加入亚硫酸钠(6mmol)和PTSA(0.2mmol)。反应混合物在120C加热，搅拌16h，将热反应混合物倒入冰中，用乙酸乙酯(3x30 mL)萃取。有机层用饱和的碳酸氢钠和盐水清洗，然后在无水硫酸钠上干燥。减压去除溶剂，硅胶柱色谱纯化(二氯甲烷/甲醇5-15％)为浅黄色固体，收率84％。

中间体8a ¹H-NMR(400MHz,CDCl₃),δ(ppm):10.89(1H,s),7.84(2H,s),6.83(2H,d,J＝2.3Hz),6.45(2H,d,J＝2.3Hz),4.45(2H,s),4.32(2H,q,J＝7.1Hz),3.95(3H,s),3.93(3H,s),2.41(6H,s),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):168.7,165.1,161.5,161.4,158.3,154.0,152.4,131.6,131.6,128.2,128.2,127.5,105.0,101.3,98.2,69.1,61.4,56.3,55.7,16.4,16.4,14.2；

中间体8b ¹H-NMR(400MHz,CDCl₃),δ(ppm):10.37(1H,s),7.77(2H,s),6.83(2H,d,J＝2.3Hz),6.45(2H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.96(3H,s),3.93(3H,s),3.85(2H,t,J＝6.2Hz),2.61(2H,t,J＝6.2Hz),2.35(6H,s),2.15(2H,m),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.2,165.1,161.5,161.4,161.1,158.9,154.0,152.5,131.8,127.8,127.8,127.7,105.0,101.2,98.1,70.9,60.5,56.3,55.7,30.8,25.7,16.4,16.4,14.2；

中间体8c ¹H-NMR(400MHz,CDCl₃),δ(ppm):10.35(1H,s),7.77(2H,s),6.83(2H,d,J＝2.3Hz),6.45(2H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.96(3H,s),3.93(3H,s),3.82(2H,t,J＝6.2Hz),2.42(2H,t,J＝6.2Hz),2.36(6H,s),1.87(4H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.4,165.1,161.4,161.2,159.2,154.0,152.5,131.8,127.8,127.8,127.6,105.0,101.3,98.1,71.9,60.3,56.3,55.7,34.1,29.8,21.7,16.4,16.4,14.2；

中间体8d ¹H-NMR(400MHz,CDCl₃),δ(ppm):10.41(1H,s),7.78(2H,s),6.83(1H,d,J＝2.3Hz),6.45(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.96(3H,s),3.93(3H,s),3.80(2H,t,J＝6.5Hz),2.36(6H,s),2.36(2H,t,J＝6.5Hz),1.84(2H,m),1.74(2H,m),1.57(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.6,165.1,161.4,161.2,159.2,154.0,152.5,131.8,131.8,127.8,127.8,127.5,105.0,101.3,98.1,72.2,60.2,56.3,55.7,34.2,30.1,25.7,24.8,16.4,16.4,14.2；

中间体9a-d合成

取中间8(3mmol)溶于二氯亚砜10ml中，反应混合物加热60度，反应8h。冷却到室温后，减压蒸除溶剂,硅胶柱层析纯化(二氯甲烷/甲醇3-10％)得白色固体。

中间体9a ¹H-NMR(400MHz,CDCl₃),δ(ppm):818(2H,s),6.98(1H,d,J＝2.3Hz),6.53(1H,d,J＝2.3Hz),4.46(2H,s),4.32(2H,q,J＝7.1Hz),3.96(6H,s),2.40(6H,s),1.35(2H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):168.9,164.9,160.1,158.8,157.9,157.3,156.3,132.6,130.9,130.9,129.5,129.5,110.2,100.2,99.7,69.1,61.3,56.0,55.9,16.5,16.5,14.2；

中间体9b ¹H-NMR(400MHz,CDCl₃),δ(ppm):8.18(2H,s),6.98(1H,d,J＝2.3Hz),6.52(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.97(3H,s),3.96(3H,s),3.85(2H,t,J＝6.5Hz),2.62(2H,t,J＝6.5Hz),2.36(6H,s),2.16(2H,m),1.28(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,164.9,160.3,158.7,158.5,157.3,156.3,131.9,131.1,131.1,129.3,129.3,110.1,100.1,99.7,70.8,60.4,56.0,55.9,30.1,25.7,16.4,16.4,14.2；

中间体9c ¹H-NMR(400MHz,CDCl₃),δ(ppm):8.18(2H,s),6.98(1H,d,J＝2.3Hz),6.52(1H,d,J＝2.3Hz),4.16(2H,q,J＝7.1Hz),3.97(3H,s),3.96(3H,s),3.83(2H,t,J＝6.5Hz),2.42(2H,t,J＝6.5Hz),2.37(6H,s),1.88(4H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.4,164.8,160.3,158.8,158.7,157.3,156.3,131.8,131.1,131.1,129.3,129.3,110.1,100.1,99.7,71.7,60.3,56.0,55.9,34.1,29.8,21.7,16.4,16.4,14.2；

中间体9d ¹H-NMR(400MHz,CDCl₃),δ(ppm):8.18(2H,s),6.98(1H,d,J＝2.3Hz),6.52(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),3.97(3H,s),3.96(3H,s),3.81(2H,t,J＝6.5Hz),2.37(6H,s),2.36(2H,t,J＝6.5Hz),1.85(2H,m),1.74(2H,m),1.57(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.6,165.1,161.4,161.2,159.2,154.0,152.5,131.8,131.8,127.8,127.8,127.5,105.0,101.3,98.1,72.2,60.2,56.3,55.7,34.2,30.1,25.7,24.8,16.4,16.4,14.2；

中间体10a-aj合成

将中间9(3mmol)溶于异丙醇(15mL)溶液，随后加入胺衍生物(3.6mmol)和DIEA(3.6mmol)。反应液加热回流搅拌8h，将反应液倒入水中，用乙酸乙酯(3x30 mL)提取。有机层用饱和的碳酸氢钠和盐水洗，然后在无水硫酸钠上干燥。减压去除溶剂，硅胶柱色谱纯化(二氯甲烷/甲醇5-10％)为白色固体。

中间体10a,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.87(1H,br.s),6.36(1H,d,J＝2.3Hz),4.44(2H,s),4.32(2H,q,J＝7.1Hz),3.93(3H,s),3.91(3H,s),3.75(4H,t,J＝6.1Hz),2.38(6H,s),1.91(4H,t,J＝6.1Hz),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.1,163.2,163.1,159.2,157.1,156.9,156.8,134.8,130.4,130.4,129.1,129.1,102.1,99.7,97.6,69.2,61.2,55.7,55.6,51.1,26.1,24.8,16.5,16.5,14.2；

中间体10b,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.14(2H,s),6.89(1H,d,J＝2.3Hz),6.39(1H,d,J＝2.3Hz),4.44(2H,s),4.32(2H,q,J＝7.1Hz),3.93(3H,s),3.92(3H,s),3.57(4H,t,J＝4.5Hz),2.39(6H,s),1.75(4H,m),1.70(2H,m),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.1,163.2,163.1,159.2,157.1,156.9,156.8,134.8,130.4,130.4,129.1,129.1,102.1,99.7,97.6,69.2,61.2,55.7,55.6,51.1,26.1,24.8,16.5,16.5,14.2；

中间体10c,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.14(2H,s),6.89(1H,d,J＝2.3Hz),6.39(1H,d,J＝2.3Hz),4.44(2H,s),4.32(2H,q,J＝7.1Hz),3.93(3H,s),3.92(3H,s),3.57(4H,t,J＝4.5Hz),2.39(6H,s),1.75(4H,m),1.70(2H,m),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.1,163.2,163.1,159.2,157.1,156.9,156.8,134.8,130.4,130.4,129.1,129.1,102.1,99.7,97.6,69.2,61.2,55.7,55.6,51.1,26.1,24.8,16.5,16.5,14.2；

中间体10d,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.95(1H,d,J＝2.3Hz),6.42(1H,d,J＝2.3Hz),4.44(2H,s),4.32(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.89(4H,t,J＝4.5Hz),3.64(4H,t,J＝4.5Hz),2.39(6H,s),1.35(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.1,163.5,163.0,159.2,157.4,156.7,156.6,134.3,130.5,130.5,129.1,129.1,102.1,99.8,98.1,69.1,67.0,61.2,55.8,55.7,50.6,16.5,16.5,14.2；

中间体10e,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.44(2H,s),4.36(1H,m),4.32(2H,q,J＝7.1Hz),3.95(1H,t,J＝11.2Hz),3.94(3H,s),3.92(3H,s),3.85(1H,dd,J＝11.2,2.3Hz),3.80-3.59(4H,m),2.39(6H,s),2.17(4H,m),1.36(3H,d,J＝6.7Hz),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.1,163.2,162.6,159.1,157.3,156.9,156.6,134.5,130.4,130.4,129.1,129.1,102.1,99.9,97.9,71.2,69.2,67.2,61.2,55.7,55.6,52.7,44.6,16.5,16.5,14.4,14.2；

中间体10f,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.44(2H,s),4.36(1H,m),4.32(2H,q,J＝7.1Hz),3.95(1H,t,J＝11.2Hz),3.94(3H,s),3.92(3H,s),3.85(1H,dd,J＝11.2,2.3Hz),3.80-3.59(4H,m),2.39(6H,s),2.17(4H,m),1.36(3H,d,J＝6.7Hz),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.1,163.2,162.6,159.1,157.3,156.9,156.6,134.5,130.4,130.4,129.1,129.1,102.1,99.9,97.9,71.2,69.2,67.2,61.2,55.7,55.6,52.7,44.6,16.5,16.5,14.4,14.2；

中间体10g,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.91(1H,d,J＝2.3Hz),6.41(1H,d,J＝2.3Hz),4.44(2H,s),4.32(2H,q,J＝7.1Hz),3.93(3H,s),3.92(3H,s),3.68(4H,br.s),2.59(4H,t,J＝4.1Hz),2.39(6H,s),2.36(3H,s),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.1,163.2,162.8,159.2,157.2,156.8,156.7,134.6,130.4,130.4,129.2,129.2,102.1,99.8,97.8,69.2,61.2,55.7,55.6,55.2,49.7,46.2,16.5,16.5,14.2；

中间体10h,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.10(2H,s),6.97(1H,d,J＝2.3Hz),6.47(1H,d,J＝2.3Hz),4.45(2H,s),4.32(2H,q,J＝7.1Hz),4.13(4H,br.s),3.96(3H,s),3.95(3H,s),3.24(4H,t,J＝4.6Hz),2.40(6H,s),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):168.9,163.8,162.4,159.1,157.6,157.1,156.4,133.8,130.7,130.7,129.1,129.1,102.2,100.4,98.9,69.2,61.3,56.2,55.8,51.7,48.4,16.5,16.5,14.2；

中间体10i,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.16(2H,s),7.10(1H,br.s),6.45(1H,d,J＝2.3Hz),4.45(2H,s),4.32(2H,q,J＝7.1Hz),3.96(3H,s),3.95(3H,s),3.76(4H,br.s),2.40(6H,s),2.17(4H,m),1.34(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.0,163.8,162.6,159.0,157.7,156.7,156.2,133.8,130.7,130.7,129.3,129.3,99.5,99.4,98.4,69.2,61.3,56.0,55.8,46.8,34.4,34.2,34.0,16.5,16.5,14.2；

中间体10j,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.86(1H,d,J＝2.3Hz),6.35(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.92(3H,s),3.91(3H,s),3.83(2H,t,J＝6.2Hz),3.74(4H,br.s),2.61(2H,t,J＝7.4Hz),2.35(6H,s),2.14(2H,m),1.90(4H,br.s),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.1,160.4,159.4,157.5,157.2,156.2,134.3,130.4,130.4,129.0,129.0,101.3,98.9,96.3,70.7,60.4,55.6,55.3,53.4,50.5,30.9,26.8,29.7,25.7,25.5,16.5,16.5,14.2；

中间体10k,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.90(1H,d,J＝2.3Hz),6.38(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.93(3H,s),3.92(3H,s),3.83(2H,t,J＝6.2Hz),3.57(4H,br.s),2.62(2H,t,J＝6.2Hz),2.35(6H,s),2.15(2H,m),1.74(4H,m),1.70(2H,m),1.35(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.2,163.0,159.4,157.6,156.9,156.8,134.1,130.5,130.5,129.0,129.0,102.1,99.8,97.5,70.7,67.0,60.4,55.8,55.6,51.1,30.9,26.1,25.7,24.8,16.5,16.5,14.2；

中间体10l,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.41(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.89(4H,br.s),3.84(2H,t,J＝6.1Hz),2.84(4H,t,J＝4.6Hz),2.62(2H,t,J＝7.1Hz),2.35(6H,s),2.15(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.4,163.3,159.3,157.8,156.9,156.6,137.4,130.6,130.6,129.0,129.0,102.2,99.9,98.0,70.7,60.4,55.8,55.6,52.6,30.9,27.6,25.7,16.5,16.5,14.2；

中间体10m,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.93(1H,d,J＝2.3Hz),6.42(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.89(4H,t,J＝4.5Hz),3.84(2H,t,J＝6.1Hz),3.63(4H,t,J＝4.5Hz),2.62(2H,t,J＝6.1Hz),2.35(6H,s),2.15(2H,m),1.35(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.3,163.1,159.5,157.8,156.9,156.6,133.8,130.6,130.6,129.0,129.0,102.1,99.8,98.1,70.7,67.0,60.4,55.8,55.7,50.6,30.9,25.7,16.5,16.5,14.2；

中间体10n,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.35(1H,m),4.17(2H,q,J＝7.1Hz),3.95(1H,t,J＝11.2Hz),3.93(3H,s),3.92(3H,s),3.87-3.70(6H,m),3.62(1H,m),2.62(2H,t,J＝7.1Hz),2.35(6H,s),2.15(2H,m),1.36(3H,d,J＝6.7Hz),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.2,162.5,159.3,157.7,157.0,156.6,133.8,130.6,130.6,129.0,129.0,102.0,99.8,97.9,71.2,70.7,67.2,60.4,55.7,55.6,52.7,44.6,30.9,25.7,16.5,16.5,14.4,14.2；

中间体10o,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.35(1H,m),4.17(2H,q,J＝7.1Hz),3.95(1H,t,J＝11.2Hz),3.93(3H,s),3.92(3H,s),3.87-3.70(6H,m),3.62(1H,m),2.62(2H,t,J＝7.1Hz),2.35(6H,s),2.15(2H,m),1.36(3H,d,J＝6.7Hz),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.2,162.5,159.3,157.7,157.0,156.6,133.8,130.6,130.6,129.0,129.0,102.0,99.8,97.9,71.2,70.7,67.2,60.4,55.7,55.6,52.7,44.6,30.9,25.7,16.5,16.5,14.4,14.2；

中间体10p,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.86(1H,d,J＝2.3Hz),6.35(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.92(3H,s),3.91(3H,s),3.83(2H,t,J＝6.2Hz),3.74(4H,br.s),2.61(2H,t,J＝7.4Hz),2.35(6H,s),2.14(2H,m),1.90(4H,br.s),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.1,160.4,159.4,157.5,157.2,156.2,134.3,130.4,130.4,129.0,129.0,101.3,98.9,96.3,70.7,60.4,55.6,55.3,53.4,50.5,30.9,26.8,29.7,25.7,25.5,16.5,16.5,14.2；

中间体10q,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.09(2H,s),6.97(1H,d,J＝2.3Hz),6.47(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),4.13(4H,br.s),3.94(3H,s),3.93(3H,s),3.85(2H,t,J＝6.1Hz),3.24(4H,br.s),2.62(2H,t,J＝7.1Hz),2.35(6H,s),2.15(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):168.9,163.8,162.4,159.1,157.6,157.1,156.4,133.8,130.7,130.7,129.1,129.1,102.2,99.9,98.0,70.7,60.4,55.8,55.6,52.6,30.9,27.6,25.7,16.5,16.5,14.2；

中间体10r,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.94(1H,d,J＝2.3Hz),6.43(1H,d,J＝2.3Hz),4.17(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.84(2H,t,J＝6.1Hz),3.73(4H,t,J＝4.5Hz),2.62(2H,t,J＝7.1Hz),2.35(6H,s),2.22-2.11(6H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.4,162.7,159.4,157.8,156.9,156.7,133.6,130.7,130.7,129.0,129.0,102.2,100.0,98.2,70.7,60.4,55.9,55.6,46.7,34.4,34.2,33.9,30.9,27.6,25.7,16.5,16.5,14.2；

中间体10s,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.86(1H,d,J＝2.3Hz),6.35(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.92(3H,s),3.91(3H,s),3.81(2H,t,J＝6.2Hz),3.74(4H,br.s),2.41(2H,t,J＝7.4Hz),2.35(6H,s),1.88(8H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.1,160.4,159.4,157.7,157.3,156.3,134.2,130.4,130.4,129.0,129.0,101.3,98.9,96.3,71.6,60.3,55.6,55.3,50.6,34.2,29.9,25.6,21.8,16.5,16.5,14.2；

中间体10t,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.90(1H,d,J＝2.3Hz),6.39(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.93(3H,s),3.92(3H,s),3.81(2H,t,J＝6.2Hz),3.57(4H,br.s),2.42(2H,t,J＝6.2Hz),2.36(6H,s),1.88(4H,m),1.74(4H,m),1.70(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.2,163.0,159.4,157.8,156.9,156.8,134.0,130.5,130.5,129.0,129.0,102.1,99.7,97.5,71.6,60.3,55.7,55.6,51.1,34.2,29.8,26.1,24.9,21.8,16.5,16.5,14.2；

中间体10u,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.41(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.88(4H,br.s),3.82(2H,t,J＝6.1Hz),2.84(4H,t,J＝4.6Hz),2.42(2H,t,J＝7.1Hz),2.36(6H,s),1.88(4H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.4,163.3,159.3,158.0,156.9,156.6,133.6,130.7,130.7,129.0,129.0,102.2,99.9,98.0,71.7,60.3,55.8,55.6,52.6,34.2,29.9,27.6,21.8,16.5,16.5,14.2；

中间体10v,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.93(1H,d,J＝2.3Hz),6.42(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.89(4H,t,J＝4.5Hz),3.82(2H,t,J＝6.1Hz),3.64(4H,t,J＝4.5Hz),2.42(2H,t,J＝6.1Hz),2.36(6H,s),1.88(4H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.3,163.1,159.5,158.0,156.9,156.6,133.6,130.7,130.7,129.0,129.0,102.1,99.9,98.1,71.7,67.0,60.3,55.8,55.7,50.6,34.2,29.8,21.8,16.5,16.5,14.2；

中间体10w,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.39(1H,d,J＝2.3Hz),4.35(1H,m),4.15(2H,q,J＝7.1Hz),3.95(1H,t,J＝11.2Hz),3.93(3H,s),3.92(3H,s),3.87-3.70(6H,m),3.63(1H,m),2.42(2H,t,J＝7.1Hz),2.36(6H,s),1.88(4H,m),1.36(3H,d,J＝6.7Hz),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.2,162.5,159.3,157.9,157.0,156.6,133.8,130.6,130.6,129.0,129.0,102.1,99.8,97.9,71.7,71.2,67.2,60.3,55.7,55.6,52.7,44.6,34.2,29.8,21.8,16.5,16.5,14.4,14.2；

中间体10x,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.39(1H,d,J＝2.3Hz),4.35(1H,m),4.15(2H,q,J＝7.1Hz),3.95(1H,t,J＝11.2Hz),3.93(3H,s),3.92(3H,s),3.87-3.70(6H,m),3.63(1H,m),2.42(2H,t,J＝7.1Hz),2.36(6H,s),1.88(4H,m),1.36(3H,d,J＝6.7Hz),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.2,162.5,159.3,157.9,157.0,156.6,133.7,130.6,130.6,129.0,129.0,102.1,99.8,97.8,71.7,71.2,67.2,60.3,55.7,55.6,52.7,44.6,34.2,29.8,21.8,16.5,16.5,14.4,14.2；

中间体10y,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.92(3H,s),3.91(3H,s),3.82(2H,t,J＝6.2Hz),3.68(4H,2H,t,J＝5.0Hz),2.59(4H,t,J＝5.0Hz),2.42(2H,t,J＝6.2Hz),2.37(6H,s),2.36(3H,s),1.88(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.2,162.8,159.4,159.4,157.9,156.9,156.7,133.8,130.6,130.6,129.0,129.0,102.0,99.8,97.8,71.7,60.3,55.7,55.6,55.2,49.8,46.2,34.2,29.8,21.8,16.5,16.5,14.2；

中间体10z,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.09(2H,s),6.97(1H,d,J＝2.3Hz),6.47(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),4.13(4H,br.s),3.94(3H,s),3.93(3H,s),3.83(2H,t,J＝6.1Hz),3.24(4H,br.s),2.42(2H,t,J＝7.1Hz),2.36(6H,s),1.88(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.9,163.8,162.4,159.3,158.4,157.1,156.4,132.9,130.9,130.9,129.0,129.0,102.2,100.4,98.8,71.7,60.3,56.2,55.8,51.7,48.4,34.1,29.9,21.8,16.5,16.5,14.2；

中间体10aa,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.94(1H,d,J＝2.3Hz),6.43(1H,d,J＝2.3Hz),4.15(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.82(2H,t,J＝6.1Hz),3.73(4H,t,J＝4.5Hz),2.42(2H,t,J＝7.1Hz),2.36(6H,s),2.17(4H,m),1.88(4H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.4,162.7,159.4,158.1,156.9,156.7,133.5,130.7,130.7,129.0,129.0,102.2,100.0,98.2,71.7,60.3,55.9,55.6,46.8,34.4,34.2,33.9,29.8,21.8,16.5,16.5,14.2；

中间体10ab,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.11(2H,s),6.85(1H,d,J＝2.3Hz),6.35(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),3.93(3H,s),3.91(3H,s),3.79(2H,t,J＝6.4Hz),3.75(4H,t,J＝6.5Hz),2.36(2H,t,J＝6.5Hz),2.35(6H,s),1.90(2H,t,J＝6.5Hz),1.84(2H,m),1.73(2H,t,J＝6.5Hz),1.57(2H,m),1.26(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.0,160.4,159.4,157.7,157.2,156.3,134.1,130.4,130.4,129.0,129.0,101.3,98.9,96.3,71.9,60.2,55.6,55.3,50.6,34.3,30.1,25.8,25.6,24.9,16.5,16.5；

中间体10ac,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.89(1H,d,J＝2.3Hz),6.39(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),3.93(3H,s),3.92(3H,s),3.79(2H,t,J＝6.5Hz),3.57(4H,t,J＝4.8Hz),2.36(2H,t,J＝6.5Hz),2.35(6H,s),1.84(2H,m),1.74(8H,m),1.59(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.2,163.0,159.4,157.9,156.9,156.8,133.9,130.5,130.5,129.0,129.0,102.1,99.7,97.5,71.9,60.2,55.7,55.6,51.1,34.3,30.1,26.1,25.8,24.9,24.8,16.5,16.5,14.3；

中间体10ad,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.92(1H,d,J＝2.3Hz),6.41(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),3.94(3H,s),3.93(3H,s),3.88(4H,br.s),3.80(4H,t,J＝6.5Hz),2.84(4H,t,J＝4.8Hz),2.36(2H,t,J＝6.5Hz),2.35(6H,s),1.85(2H,m),1.74(2H,m),1.59(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.4,163.3,159.3,158.1,157.0,156.6,133.6,130.7,130.7,129.0,129.0,102.2,99.9,98.0,71.9,60.3,55.8,55.6,52.6,50.6,34.3,30.1,27.6,25.7,24.9,16.5,16.5,14.2；

中间体10ae,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.12(2H,s),6.93(1H,d,J＝2.3Hz),6.42(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),3.94(3H,s),3.92(3H,s),3.88(4H,t,J＝3.8Hz),3.80(2H,t,J＝5.7Hz),3.64(4H,t,J＝3.8Hz),2.35(6H,s),2.32(2H,t,J＝6.5Hz),1.84(2H,m),1.74(2H,t,J＝6.5Hz),1.57(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.3,163.1,159.5,158.1,156.8,156.6,133.6,130.7,130.7,129.0,129.0,102.1,99.9,98.1,71.9,67.0,60.2,55.8,55.6,50.6,50.6,34.3,30.1,25.7,24.9,25.2,16.5,16.5,14.2；

中间体10af,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.11(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.35(1H,m),4.14(2H,q,J＝7.1Hz),3.94(1H,m),3.94(3H,s),3.92(3H,s),3.87-3.70(6H,m),3.63(1H,td,J＝13.0,2.9Hz),2.36(2H,t,J＝6.5Hz),2.35(6H,s),1.84(2H,m),1.74(2H,m),1.59(2H,m),1.36(3H,d,J＝6.7Hz),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.2,162.5,159.3,158.0,157.0,156.6,133.7,130.7,130.7,129.0,129.0,102.0,99.8,97.8,71.9,71.2,67.2,60.2,55.7,55.6,52.7,44.6,34.3,30.1,25.7,24.9,16.5,16.5,14.4,14.2；

中间体10ag,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.11(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.35(1H,m),4.14(2H,q,J＝7.1Hz),3.94(1H,m),3.94(3H,s),3.92(3H,s),3.87-3.70(6H,m),3.63(1H,td,J＝13.0,2.9Hz),2.36(2H,t,J＝6.5Hz),2.35(6H,s),1.84(2H,m),1.74(2H,m),1.59(2H,m),1.36(3H,d,J＝6.7Hz),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.2,162.5,159.3,158.0,157.0,156.6,133.7,130.7,130.7,129.0,129.0,102.0,99.8,97.8,71.9,71.2,67.2,60.2,55.7,55.6,52.7,44.6,34.3,30.1,25.7,24.9,16.5,16.5,14.4,14.2；

中间体10ah,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.92(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),3.93(6H,s),3.80(2H,t,J＝6.5Hz),3.68(4H,t,J＝4.8Hz),2.59(4H,t,J＝4.8Hz),2.37(2H,t,J＝6.5Hz),2.35(9H,s),1.84(2H,m),1.74(2H,m),1.59(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.2,162.7,159.4,158.0,156.8,156.7,133.7,130.6,130.6,129.0,129.0,102.0,99.8,97.7,71.9,60.2,55.7,55.6,55.2,49.7,46.2,34.3,30.1,25.7,24.9,16.5,16.5,14.2；

中间体10ai,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.09(2H,s),6.97(1H,d,J＝2.3Hz),6.47(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),4.13(4H,t,J＝4.8Hz),3.96(3H,s),3.95(3H,s),3.82(2H,t,J＝6.5Hz),3.25(4H,t,J＝4.8Hz),2.36(2H,t,J＝6.5Hz),2.35(6H,s),1.85(2H,m),1.74(2H,m),1.59(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.7,163.7,162.4,159.3,158.4,157.1,156.4,132.9,130.9,130.9,129.0,129.0,102.2,100.3,98.8,72.0,60.2,56.2,55.8,51.7,48.4,34.3,30.1,25.7,24.9,16.6,16.6,14.2；

中间体10aj,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.08(2H,s),6.94(1H,d,J＝2.3Hz),6.44(1H,d,J＝2.3Hz),4.14(2H,q,J＝7.1Hz),3.95(3H,s),3.94(3H,s),3.80(2H,t,J＝6.4Hz),3.73(4H,t,J＝6.5Hz),2.36(2H,t,J＝6.5Hz),2.35(6H,s),2.17(2H,m),1.85(2H,m),1.84(2H,m),1.74(2H,m),1.58(2H,m),1.27(3H,t,J＝7.1Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.6,163.4,162.7,159.4,158.2,156.9,156.7,133.5,130.7,130.7,129.0,129.0,102.2,100.0,98.1,71.9,60.2,55.9,55.7,46.8,34.4,34.3,34.2,33.9,30.1,25.7,24.9,16.5,16.5,14.2；

化合物1-36合成通法

取盐酸羟胺(40.0mmol)和NaOH(80mmol)溶于15ml甲醇中，0℃反应15分钟，收集滤液，待用。另取中间体22(1.0mmol)溶于1ml二氯甲烷中，将上述制备的滤液缓慢加入，室温反应10分钟，减压出去大部分甲醇，加入15ml水，调节pH＝8,乙酸乙酯萃取，有机层依次用蒸馏水，饱和食盐水洗涤，无水硫酸钠干燥。滤液加压出去溶剂后，硅胶柱层析纯化得产品，收率72-85％

以下为化合物1-36的核磁检测结果。

化合物1,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.02(2H,s),6.80(1H,br.s),6.30(1H,br.s),4.33(2H,s),3.87(6H,s),3.67(4H,br.s),2.26(6H,s),1.83(4H,br.s)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):164.9,162.8,160.3,159.1,157.1,156.3,156.2,134.9,130.2,130.2,129.2,129.2,101.3,99.0,96.2,69.9,55.5,55.2,50.6,50.6,25.5,25.5,16.4,16.4；HRMS(ESI)+calculated for C₂₄H₂₈N₄O₅,[M+H]⁺:m/z 453.2132,found 453.2127；HPLC(t_R＝2.191min,98.0％).

化合物2,¹H-NMR(400MHz,CDCl₃),δ(ppm):9.10(1H,s),8.09(2H,s),6.92(1H,s),6.41(1H,s),4.39(2H,s),3.94(3H,s),3.93(3H,s),3.59(4H,br.s),2.30(6H,br.s),1.75(6H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):165.6,163.3,163.1,158.9,156.9,156.9,155.8,135.2,130.2,130.2,129.4,129.4,101.7,99.3,97.7,69.6,55.8,55.7,51.0,51.0,26.1,26.1,24.8,16.4,16.4；HRMS(ESI)+calculated for C₂₅H₃₀N₄O₅,[M+H]⁺:m/z 467.2289,found 467.2289；HPLC(t_R＝2.481min,98.5％).

化合物3,¹H-NMR(400MHz,CDCl₃),δ(ppm):9.26(2H,s),8.11(2H,s),6.94(1H,s),6.43(1H,d,J＝1.7Hz),4.43(2H,s),3.94(6H,s),3.89(4H,br.s),2.84(4H,t,J＝4.1Hz),2.33(6H,s)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):165.8,163.5,163.4,158.9,156.7,156.6,155.9,134.9,130.3,130.3,129.4,129.4,102.1,99.7,98.2,69.6,55.8,55.7,52.5,52.5,27.6,27.6,16.5,16.5；HRMS(ESI)+calculated for C₂₄H₂₈N₄O₅S,[M+H]⁺:m/z 485.1853,found 485.1854；HPLC(t_R＝2.189min,97.4％).

化合物4,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.13(2H,s),6.94(1H,d,J＝1.9Hz),6.44(1H,d,J＝1.9Hz),4.46(2H,s),3.94(3H,s),3.93(3H,s),3.88(4H,br.s),3.64(4H,br.s),2.34(6H,s)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):165.6,163.5,163.0,159.0,156.7,156.6,155.9,135.1,130.2,130.2,129.4,129.4,102.1,99.8,98.3,69.6,67.0,55.8,55.7,50.6,16.5,16.5；HRMS(ESI)+calculated for C₂₄H₂₈N₄O₆,[M+H]⁺:m/z 469.2082,found 469.2078；HPLC(t_R＝2.783min,97.3％).

化合物5,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.08(2H,s),6.90(1H,d,J＝1.7Hz),6.39(1H,d,J＝1.7Hz),4.41(2H,s),4.38(1H,m),3.94(1H,t,J＝11.2Hz),3.94(3H,s),3.92(3H,s),3.85(1H,dd,J＝11.2,2.3Hz),3.80-3.57(4H,m),2.31(6H,s),1.36(3H,d,J＝6.7Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):165.7,163.3,162.5,158.9,156.8,156.6,156.0,134.9,130.2,129.3,129.3,101.9,99.7,97.9,71.2,69.7,67.2,55.7,55.6,52.6,44.6,16.4,16.4,14.4；HRMS(ESI)+calculatedfor C₂₅H₃₀N₄O₆,[M+H]⁺:m/z 483.2238,found483.2236；HPLC(t_R＝1.765min,96.1％).

化合物6,¹H-NMR(400MHz,CDCl₃),δ(ppm):9.31(1H,br.s),8.08(2H,s),6.90(1H,d,J＝1.7Hz),6.39(1H,d,J＝1.7Hz),4.41(2H,s),4.38(1H,m),3.94(1H,t,J＝11.2Hz),3.94(3H,s),3.92(3H,s),3.85(1H,dd,J＝11.2,2.3Hz),3.80-3.57(4H,m),2.31(6H,s),1.36(3H,d,J＝6.7Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):165.7,163.5,162.5,161.2,158.8,156.6,155.9,134.9,130.3,130.3,129.4,129.4,101.8,99.6,98.1,71.2,69.6,67.2,55.8,55.7,52.6,44.7,16.5,16.5,14.5；HRMS(ESI)+calculated for C₂₅H₃₀N₄O₆,[M+H]⁺:m/z 483.2238,found 483.2235；HPLC(t_R＝1.763min,95.6％).

化合物7,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.10(2H,s),6.92(1H,s),6.43(1H,s),4.40(2H,s),3.94(6H,s),3.68(4H,br.s),2.67(4H,br.s),2.43(3H,s),2.32(3H,s)；¹³C-NMR(100MHz,DMSO-d⁶),δ(ppm):164.6,163.6,162.7,158.1,157.3,157.1,156.4,134.2,130.7,130.7,129.0,129.0,101.5,99.9,98.3,70.3,56.3,56.1,55.1,55.1,49.7,46.2,16.7,16.7；HRMS(ESI)+calculated for C₂₅H₃₁N₅O₅,[M+H]⁺:m/z 482.2398,found482.2400；HPLC(t_R＝1.472min,97.1％).

化合物8,¹H-NMR(400MHz,CDCl₃),δ(ppm):7.94(2H,s),6.86(1H,s),6.39(1H,s),4.33(2H,s),4.00(4H,br.s),3.89(6H,s),3.17(4H,br.s),2.25(6H,s)；¹³C-NMR(100MHz,DMSO-d⁶),δ(ppm):164.5,163.9,162.6,158.1,157.7,156.9,156.6,133.7,130.9,130.9,129.0,129.0,101.8,100.3,99.0,70.7,56.7,56.2,55.8,51.4,51.4,48.6,16.5,16.5；HRMS(ESI)+calculated for C₂₄H₂₈N₄O₇S,[M+H]⁺:m/z 517.1751,found 517.1750；HPLC(t_R＝1.701min,97.0％).

化合物9,¹H-NMR(400MHz,CDCl₃),δ(ppm):9.34(1H,s),8.11(2H,s),7.01(1H,s),6.45(1H,s),4.43(2H,s),3.96(3H,s),3.95(3H,s),3.76(4H,br.s),2.33(6H,s),2.17(4H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):165.7,163.8,158.7,156.7,156.7,156.2,130.4,129.5,129.5,122.1,101.8,99.5,98.5,98.5,69.5,61.3,56.0,55.8,34.4,34.2,33.9,29.7,16.4,16.4；HRMS(ESI)+calculated for C₂₅H₂₈F₂N₄O₅,[M+H]⁺:m/z 503.2101,found503.2101；HPLC(t_R＝2.194min,97.5％).

化合物10,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.03(2H,s),6.83(1H,d,J＝2.0Hz),6.29(1H,d,J＝2.0Hz),3.87(3H,s),3.85(3H,s),3.73-3.68(6H,m),2.29(2H,m),2.25(6H,s),2.05(2H,m),1.83(4H,br.s)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):169.8,162.9,160.3,159.4,157.5,157.2,156.2,134.0,130.4,130.4,129.0,129.0,101.2,98.8,96.2,71.2,55.6,55.2,50.5,29.9,26.4,25.5,16.5,16.5；HRMS(ESI)+calculated for C₂₆H₃₂N₄O₅,[M+H]⁺:m/z 481.2445,found 481.2447；HPLC(t_R＝2.018min,96.8％).

化合物11,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.06(2H,s),6.87(1H,d,J＝1.7Hz),6.34(1H,d,J＝1.7Hz),3.89(6H,s),3.74(2H,t,J＝6.2Hz),3.52(4H,br.s),2.34(2H,t,J＝6.2Hz),2.27(6H,s),2.08(2H,m),1.71(4H,m),1.65(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.2,163.1,163.0,159.4,157.5,156.9,156.7,134.0,130.5,130.5,129.0,129.0,102.0,99.6,97.4,71.1,55.7,55.6,51.1,51.1,29.9,26.3,26.1,26.1,24.8,16.5,16.5；HRMS(ESI)+calculated for C₂₇H₃₄N₄O₅,[M+H]⁺:m/z 495.2602,found 495.2600；HPLC(t_R＝3.281min,95.4％).

化合物12,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.00(2H,s),6.88(1H,d,J＝1.7Hz),6.34(1H,d,J＝2.3Hz),3.86(6H,s),3.81(4H,br.s),3.71(2H,t,J＝6.1Hz),2.76(4H,t,J＝4.6Hz),2.33(2H,t,J＝7.1Hz),2.24(6H,s),2.04(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.7,163.4,163.3,159.2,157.6,156.7,156.6,133.7,130.6,130.6,129.1,129.1,102.0,99.7,98.1,70.8,55.8,55.7,52.6,52.6,29.7,27.6,27.6,25.9,16.5,16.5；HRMS(ESI)+calculated for C₂₆H₃₂N₄O₅S,[M+H]⁺:m/z 513.2166,found 513.2163；HPLC(t_R＝2.566min,96.7％).

化合物13,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.07(2H,s),6.96(1H,d,J＝1.7Hz),6.41(1H,d,J＝1.7Hz),3.93(3H,s),3.92(3H,s),3.88(4H,t,J＝4.5Hz),3.78(2H,t,J＝6.1Hz),3.63(4H,t,J＝4.5Hz),2.40(2H,t,J＝6.1Hz),2.30(6H,s),2.10(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.6,163.5,162.9,159.3,157.6,156.6,156.5,133.7,130.6,130.6,129.1,129.1,101.9,99.6,98.2,70.9,67.0,55.8,55.7,50.6,50.6,29.7,26.0,16.5,16.5；HRMS(ESI)+calculated for C₂₆H₃₂N₄O₆,[M+H]⁺:m/z 497.2395,found497.2396；HPLC(t_R＝2.178min,97.7％).

化合物14,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.06(2H,s),6.94(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.37(1H,m),3.97(1H,t,J＝11.2Hz),3.93(3H,s),3.91(3H,s),3.86-3.70(6H,m),3.62(1H,m),2.40(2H,t,J＝7.1Hz),2.31(6H,s),2.11(2H,m),1.37(3H,d,J＝6.7Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.7,163.4,162.5,159.2,157.5,156.8,156.6,133.9,130.5,130.5,129.1,129.1,101.9,99.6,97.9,71.2,70.8,67.2,55.7,55.6,52.7,44.6,30.9,25.7,16.5,16.5,14.4,14.2；HRMS(ESI)+calculated for C₂₇H₃₄N₄O₆,[M+H]⁺:m/z 511.2551,found 511.2553；HPLC(t_R＝2.280min,95.6％).

化合物15,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.06(2H,s),6.94(1H,d,J＝2.3Hz),6.40(1H,d,J＝2.3Hz),4.37(1H,m),3.97(1H,t,J＝11.2Hz),3.93(3H,s),3.91(3H,s),3.86-3.70(6H,m),3.62(1H,m),2.40(2H,t,J＝7.1Hz),2.31(6H,s),2.11(2H,m),1.37(3H,d,J＝6.7Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.7,163.4,162.5,159.3,157.5,156.8,156.6,133.9,130.5,130.5,129.1,129.1,101.8,99.6,97.9,71.2,70.8,55.8,55.7,52.6,44.6,29.7,26.0,16.5,16.5,14.4；HRMS(ESI)+calculated for C₂₇H₃₄N₄O₆,[M+H]⁺:m/z511.2551,found 511.2552；HPLC(t_R＝2.285min,95.1％).

化合物16,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.11(2H,s),6.93(1H,d,J＝2.2Hz),6.41(1H,d,J＝2.2Hz),3.94(3H,s),3.93(3H,s),3.83(2H,t,J＝5.8Hz),3.69(4H,br.s),2.62(4H,t,J＝br.s),2.49(2H,t,J＝7.0Hz),2.39(3H,s),2.33(6H,s),2.16(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.3,163.2,162.5,159.3,157.7,157.0,156.6,133.8,130.6,130.6,129.0,129.0,102.0,99.8,97.9,70.9,55.7,55.6,55.1,49.6,46.1,25.8,16.5,16.5；HRMS(ESI)+calculated for C₂₇H₃₅N₅O₅,[M+H]⁺:m/z 510.2711,found510.2712；HPLC(t_R＝1.456min,96.1％).

化合物17,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.09(2H,s),6.95(1H,d,J＝1.7Hz),6.44(1H,d,J＝1.7Hz),3.94(6H,s),3.82(2H,t,J＝6.1Hz),3.73(4H,br.s),2.45(2H,t,J＝7.1Hz),2.34(6H,s),2.15(6H,m)；¹³C-NMR(100MHz,DMSO-d⁶),δ(ppm):169.1,164.4,162.4,158.6,157.3,157.1,156.2,133.8,130.9,130.9,129.3,129.3,101.1,99.9,98.7,71.6,56.7,56.3,46.7,34.2,34.1,33.8,29.3,26.5,16.7,16.7；HRMS(ESI)+calculatedfor C₂₆H₃₂N₄O₇S,[M+H]⁺:m/z 545.2064,found545.2069；HPLC(t_R＝2.580min,95.3％).

化合物18,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.78(1H,br.s),8.06(2H,s),6.98(1H,d,J＝1.7Hz),6.47(1H,d,J＝1.7Hz),4.11(2H,J＝7.1Hz),3.95(6H,s),3.82(2H,t,J＝6.1Hz),2.45(2H,t,J＝7.1Hz),2.32(6H,s),2.14(2H,m)；¹³C-NMR(100MHz,DMSO-d⁶),δ(ppm):169.2,164.1,162.6,158.2,158.1,157.0,156.5,133.0,130.8,130.8,129.1,129.1,101.7,100.1,98.9,71.6,56.7,56.2,51.4,51.4,48.6,29.3,26.5,16.7,16.7；HRMS(ESI)+calculated for C₂₇H₃₂F₂N₄O₅,[M+H]⁺:m/z 531.2414,found 531.2414；HPLC(t_R＝1.728min,95.4％).

化合物19,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.06(2H,s),6.85(1H,d,J＝1.7Hz),6.32(1H,d,J＝1.7Hz),3.89(3H,s),3.87(3H,s),3.71(6H,br.s),2.28(6H,s),2.11(2H,t,J＝7.1Hz),1.85(4H,t,J＝7.1Hz),1.76(4H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.2,163.0,160.3,159.4,157.6,157.2,156.2,134.1,130.4,130.4,129.1,129.1,101.2,98.9,96.2,71.8,55.6,55.2,50.5,50.5,32.9,29.7,25.5,22.4,16.5,16.5；HRMS(ESI)+calculated for C₂₇H₃₄N₄O₅,[M+H]⁺:m/z 495.2602,found 495.2601；HPLC(t_R＝2.905min,95.7％).

化合物20,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.08(2H,s),6.94(1H,d,J＝1.7Hz),6.38(1H,d,J＝1.7Hz),3.93(3H,s),3.92(3H,s),3.75(2H,t,J＝6.2Hz),3.57(4H,br.s),2.32(6H,s),2.16(2H,t,J＝6.2Hz),1.82(2H,m),1.74(4H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.8,163.2,163.1,159.4,157.7,156.9,156.5,133.9,130.6,130.6,129.1,129.1,101.8,99.3,97.5,71.7,55.7,55.6,51.1,51.1,32.7,29.6,26.1,26.1,24.8,22.4,16.5,16.5；HRMS(ESI)+calculated for C₂₈H₃₆N₄O₅,[M+H]⁺:m/z 509.2758,found509.2757；HPLC(t_R＝3.524min,97.1％).

化合物21,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.08(2H,s),6.95(1H,d,J＝1.7Hz),6.41(1H,d,J＝1.7Hz),3.93(6H,s),3.88(4H,br.s),3.77(2H,t,J＝6.1Hz),2.84(4H,t,J＝4.6Hz),2.33(6H,s),2.20(2H,t,J＝6.1Hz),1.86(2H,m),1.78(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.9,163.4,163.3,159.4,157.8,156.8,156.6,133.6,130.7,130.7,129.1,129.1,102.0,99.7,98.1,71.7,55.8,55.7,52.5,52.5,32.7,29.6,27.6,27.6,22.4,16.5,16.5；HRMS(ESI)+calculated for C₂₇H₃₄N₄O₅S,[M+H]⁺:m/z 527.2323,found527.2321；HPLC(t_R＝2.884min,96.8％).

化合物22,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.06(2H,s),6.90(1H,d,J＝2.0Hz),6.37(1H,d,J＝2.0Hz),3.89(3H,s),3.88(3H,s),3.85(4H,t,J＝4.0Hz),3.73(2H,t,J＝6.1Hz),3.59(4H,t,J＝4.0Hz),2.29(6H,s),2.17(2H,m),1.82(2H,m),1.77(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.3,163.3,162.9,159.4,157.8,156.8,156.6,133.6,130.6,130.6,129.0,129.0,102.1,99.8,98.0,71.8,67.0,55.7,55.6,50.6,32.9,29.8,29.7,22.5,16.5,16.5；HRMS(ESI)+calculatedfor C₂₇H₃₄N₄O₆,[M+H]⁺:m/z 511.2551,found511.2552；HPLC(t_R＝2.249min,95.3％).

化合物23,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.07(2H,s),6.94(1H,d,J＝1.7Hz),6.39(1H,d,J＝1.7Hz),4.37(1H,m),3.95(1H,t,J＝11.2Hz),3.93(3H,s),3.91(3H,s),3.87-3.70(6H,m),3.62(1H,m),2.33(6H,s),2.20(2H,t,J＝7.1Hz),1.86(2H,m),1.78(2H,m),1.36(3H,t,J＝6.6Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.8,163.3,162.5,159.3,157.7,156.8,156.6,133.8,130.6,130.6,129.1,129.1,101.9,99.6,97.9,71.8,71.2,67.2,55.7,55.6,52.6,52.6,44.6,32.7,29.6,22.4,16.5,16.5,14.4；HRMS(ESI)+calculated for C₂₈H₃₆N₄O₆,[M+H]⁺:m/z 525.2708,found 525.2710；HPLC(t_R＝2.488min,95.9％).

化合物24,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.07(2H,s),6.94(1H,d,J＝1.7Hz),6.39(1H,d,J＝1.7Hz),4.37(1H,m),3.95(1H,t,J＝11.2Hz),3.93(3H,s),3.91(3H,s),3.87-3.70(6H,m),3.62(1H,m),2.33(6H,s),2.20(2H,t,J＝7.1Hz),1.86(2H,m),1.78(2H,m),1.36(3H,t,J＝6.6Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.9,163.3,162.5,159.3,157.8,156.8,156.6,133.8,130.6,130.6,129.1,129.1,101.9,99.6,97.9,71.8,71.2,67.2,55.7,55.6,52.6,44.6,32.7,29.6,22.4,16.5,16.5,14.4；HRMS(ESI)+calculatedfor C₂₈H₃₆N₄O₆,[M+H]⁺:m/z 525.2708,found525.2707；HPLC(t_R＝2.458min,95.6％).

化合物25,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.08(2H,s),6.93(1H,d,J＝1.7Hz),6.40(1H,d,J＝1.7Hz),3.93(3H,s),3.92(3H,s),3.75(2H,t,J＝6.2Hz),3.68(4H,t,J＝5.0Hz),2.62(4H,t,J＝5.0Hz),2.37(3H,s),2.31(6H,s),2.18(2H,t,J＝6.2Hz),1.85(2H,m),1.77(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.7,163.4,162.7,159.4,157.8,156.6,156.6,133.7,130.6,130.6,129.1,129.1,101.9,99.6,97.9,71.7,60.4,55.7,55.6,55.0,55.0,49.5,46.0,32.7,29.6,22.5,21.0,16.5,16.5,14.2；HRMS(ESI)+calculated for C₂₈H₃₇N₅O₅,[M+H]⁺:m/z 524.2867,found524.2870；HPLC(t_R＝1.454min,99.2％).

化合物26,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.05(2H,s),6.96(1H,d,J＝1.7Hz),6.45(1H,d,J＝1.7Hz),4.10(4H,br.s),3.94(6H,s),3.78(2H,t,J＝6.1Hz),3.23(4H,br.s),2.32(6H,s),2.24(2H,t,J＝6.1Hz),1.87(2H,m),1.81(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):173.5,163.8,162.4,159.3,158.4,157.1,156.4,133.1,130.8,130.8,129.0,129.0,102.2,100.3,98.8,71.8,56.1,55.8,51.7,51.7,48.4,29.7,24.5,16.6,16.6；HRMS(ESI)+calculated for C₂₇H₃₄N₄O₇S,[M+H]⁺:m/z 559.2221,found 559.2221；HPLC(t_R＝1.745min,95.3％).

化合物27,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.08(2H,s),6.94(1H,d,J＝1.7Hz),6.42(1H,d,J＝1.7Hz),3.93(6H,s),3.77(2H,t,J＝6.1Hz),3.72(4H,t,J＝4.5Hz),2.32(6H,s),2.17(4H,m),1.85(2H,m),1.78(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.9,163.4,162.7,159.4,157.9,156.8,156.7,133.6,130.7,130.7,129.1,129.1,124.6,122.2,119.9,102.1,99.9,98.2,71.8,55.9,55.7,46.8,34.4,34.2,33.9,29.6,22.4,16.5,16.5；HRMS(ESI)+calculated for C₂₈H₃₄F₂N₄O₅,[M+H]⁺:m/z 545.2570,found545.2568；HPLC(t_R＝2.881min,96.3％).

化合物28,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.06(2H,s),6.89(1H,d,J＝2.0Hz),6.35(1H,d,J＝2.0Hz),3.92(3H,s),3.90(3H,s),3.75(6H,m),2.32(6H,s),2.05(2H,t,J＝6.5Hz),1.90(4H,br.s),1.75(2H,m),1.65(2H,m),1.45(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.8,163.2,160.3,159.5,157.8,157.2,155.9,133.9,130.4,130.4,129.1,129.1,101.1,98.6,96.4,71.8,55.6,55.3,50.6,32.7,30.0,25.7,25.5,25.2,16.5,16.5；HRMS(ESI)+calculated for C₂₈H₃₆N₄O₅,[M+H]⁺:m/z 509.2758,found 509.2761；HPLC(t_R＝1.749min,96.3％).

化合物29,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.09(2H,s),6.94(1H,d,J＝2.3Hz),6.38(1H,d,J＝2.3Hz),3.93(3H,s),3.92(3H,s),3.77(2H,t,J＝6.5Hz),3.58(4H,t,J＝4.8Hz),2.33(6H,s),2.11(2H,m),1.79-1.68(10H,m),1.48(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.9,163.3,163.1,159.3,157.9,156.9,156.3,133.6,130.6,130.6,129.1,129.1,101.7,99.2,97.5,71.8,55.7,55.6,51.1,32.7,30.0,26.1,25.7,25.2,24.8,16.5,16.5；HRMS(ESI)+calculated for C₂₉H₃₈N₄O₅,[M+H]⁺:m/z 523.2915,found523.2918；HPLC(t_R＝2.278min,98.0％).

化合物30,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.09(2H,s),6.95(1H,d,J＝2.3Hz),6.43(1H,d,J＝2.3Hz),3.95(3H,s),3.94(3H,s),3.88(4H,br.s),3.77(2H,t,J＝6.5Hz),3.01(2H,m),2.83(2H,t,J＝4.8Hz),2.35(6H,s),2.14(2H,m),1.78(2H,m),1.69(2H,m),1.51(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):171.0,163.4,162.7,159.4,158.1,156.8,156.7,133.3,130.8,130.8,129.0,129.0,102.1,100.0,98.4,71.9,55.8,55.7,52.6,46.1,41.5,32.8,30.0,27.6,25.7,25.2,16.6,16.6；HRMS(ESI)+calculated forC₂₈H₃₆N₄O₅S,[M+H]⁺:m/z 541.2479,found 541.2477；HPLC(t_R＝1.741min,96.7％).

化合物31,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.67(1H,br.s),8.08(2H,s),6.95(1H,d,J＝1.7Hz),6.41(1H,d,J＝1.7Hz),3.94(3H,s),3.92(3H,s),3.88(4H,t,J＝3.8Hz),3.77(2H,t,J＝5.7Hz),3.64(4H,t,J＝3.8Hz),2.33(6H,s),2.12(2H,t,J＝6.5Hz),1.78(2H,m),1.69(2H,t,J＝6.5Hz),1.51(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):171.1,163.4,162.9,159.5,158.0,156.7,156.6,133.5,130.7,129.1,129.1,101.9,99.7,98.1,71.8,67.0,55.8,55.7,50.5,50.5,32.7,30.0,25.7,25.7,25.2,16.5,16.5；HRMS(ESI)+calculated for C₂₈H₃₆N₄O₆,[M+H]⁺:m/z 525.2708,found 525.2708；HPLC(t_R＝2.528min,98.5％).

化合物32,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.07(2H,s),6.89(1H,d,J＝2.3Hz),6.35(1H,d,J＝2.3Hz),4.32(1H,m),3.92(2H,m),3.94(1H,m),3.89(3H,s),3.87(3H,s),3.77-3.66(5H,m),3.58(1H,td,J＝13.0,2.9Hz),2.30(6H,s),2.09(2H,m),1.76(2H,m),1.67(2H,m),1.49(2H,m),1.33(3H,d,J＝6.7Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.2,163.2,162.4,159.3,157.9,156.9,156.6,133.6,130.6,130.6,129.0,129.0,101.9,99.7,97.8,72.0,71.2,67.2,55.7,55.6,52.6,44.6,33.2,30.2,25.9,25.6,16.5,16.5,14.4；HRMS(ESI)+calculated for C₂₉H₃₈N₄O₆,[M+H]⁺:m/z 539.2864,found 539.2867；HPLC(t_R＝1.750min,98.9％).

化合物33,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.07(2H,s),6.89(1H,d,J＝2.3Hz),6.35(1H,d,J＝2.3Hz),4.32(1H,m),3.92(2H,m),3.94(1H,m),3.89(3H,s),3.87(3H,s),3.77-3.66(5H,m),3.58(1H,td,J＝13.0,2.9Hz),2.30(6H,s),2.09(2H,m),1.76(2H,m),1.67(2H,m),1.49(2H,m),1.33(3H,d,J＝6.7Hz)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.2,163.2,162.4,159.3,157.9,156.9,156.6,133.6,130.6,130.6,129.0,129.0,101.9,99.7,97.8,72.0,71.2,67.2,55.7,55.6,52.6,44.6,33.2,30.2,25.9,25.6,16.5,16.5,14.4；HRMS(ESI)+calculated for C₂₉H₃₈N₄O₆,[M+H]⁺:m/z 539.2864,found 539.2860；HPLC(t_R＝1.742min,98.1％).

化合物34,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.08(2H,s),6.89(1H,d,J＝2.3Hz),6.36(1H,d,J＝2.3Hz),3.90(3H,s),3.89(3H,s),3.73(2H,t,J＝6.5Hz),3.65(4H,t,J＝4.8Hz),2.56(4H,t,J＝4.8Hz),2.33(3H,s),2.35(6H,s),2.09(2H,m),1.76(2H,m),1.67(2H,m),1.49(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.3,163.2,162.7,159.4,157.9,156.8,156.7,133.7,130.6,130.6,129.0,129.0,101.9,99.7,97.7,71.9,55.7,55.6,55.2,49.7,46.2,33.1,30.1,25.9,25.5,16.5,16.5；HRMS(ESI)+calculated forC₂₉H₃₉N₅O₅,[M+H]⁺:m/z 538.3024,found 538.3026；HPLC(t_R＝1.404min,97.7％).

化合物35,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.06(2H,s),6.96(1H,d,J＝2.3Hz),6.45(1H,d,J＝2.3Hz),4.10(4H,t,J＝4.8Hz),3.94(3H,s),3.93(3H,s),3.77(2H,t,J＝6.5Hz),3.23(4H,t,J＝4.8Hz),2.33(6H,s),2.16(2H,m),1.79(2H,m),1.72(2H,m),1.53(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.9,163.8,162.4,159.3,158.3,157.0,156.3,132.7,130.8,130.8,129.0,129.0,102.1,100.3,98.8,71.9,56.1,55.8,51.6,48.4,32.8,30.1,25.8,25.2,16.5,16.5；HRMS(ESI)+calculated for C₂₈H₃₆N₄O₇S,[M+H]⁺:m/z573.2377,found 573.2375；HPLC(t_R＝1.624min,96.6％).

化合物36,¹H-NMR(400MHz,CDCl₃),δ(ppm):8.09(2H,s),6.95(1H,d,J＝2.3Hz),6.43(1H,d,J＝2.3Hz),3.95(3H,s),3.94(6H,s),3.78(2H,t,J＝6.4Hz),3.73(4H,t,J＝6.5Hz),2.34(6H,s),2.16(6H,m),1.80(2H,m),1.72(2H,m),1.53(2H,m)；¹³C-NMR(100MHz,CDCl₃),δ(ppm):170.9,163.4,162.7,159.4,158.1,156.8,156.7,133.4,130.7,130.7,129.0,129.0,102.1,99.8,98.2,71.9,55.9,55.7,46.7,34.4,34.2,33.9,32.7,30.0,25.7,25.2,16.5,16.5；HRMS(ESI)+calculatedfor C₂₉H₃₆F₂N₄O₅,[M+H]⁺:m/z 559.2727,found 559.2731；HPLC(t_R＝1.737min,96.0％).

试验例1化合物1～36的HDAC酶抑制活性及抗增殖活性

本实验的目的是检测本发明的化合物对体外HDAC6抑制活性和体外对MDA-MB-231肿瘤细胞的抗增值活性(表1)。

所有的酶促反应在37℃反应30分钟。50ul反应混合物包含25mM Tris,pH 8.0,1mMMgCl2,0.1mg/ml BSA,1 37mM NaCl,2.7mM KCl,HDACs和酶底物。将化合物用10％的DMSO稀释，在50ul的反应中加入5ul稀释剂，使DMSO在所有反应中的最终浓度为1％。该分析是通过定量荧光产物的数量在溶液中酶反应。然后在350-360nm的激发和450-460nm的发射波长下，用SpectraMax M5微量滴定板阅读器进行荧光分析。IC50值的计算采用非线性回归和归一化剂量-响应拟合Prism GraphPad软件。

细胞以5x10⁴个细胞/ml的密度分布在96孔板中。细胞被不同浓度的化合物处理24小时。MTT法测定细胞存活率。

表1化合物1～36酶抑制活性及抗肿瘤抑制活性

实验结果表明，本发明的化合物大多对HDAC6展现出纳摩尔水平的强抑制活性，化合物34显示出11.68nM的抑制活性。

试验例2化合物34,35对HDACs的选择性实验

为了进一步研究化合物34,35对HDACs家族选择性，我们进行了酶活选择性测试，结果如表2所示。

表2化合物34,35对HDACs的选择性.

结果显示化合物34，35对HDAC class I和class IIb强效的抑制活性。

试验例3化合物34的诱导肿瘤细胞凋亡

为了检测化合物34是否能够诱导肿瘤细胞凋亡，我们使用Hoechst 33258对不同浓度的化合物34处理后的MDA-MB-231细胞进行荧光染色，结果显示随着化合物34浓度的增加，荧光染色亮度增强，证明化合物34诱导了MDA-MB-231细胞DNA片段化，即凋亡的发生(见图1)。随后，应用Annexin V-PI双染的流式细胞术检测了不同浓度化合物34处理后MDA-MB-231细胞的凋亡率，结果表明随着化合物34浓度升高，凋亡率增加(见图2)。

试验例4化合物34的抑制肿瘤细胞转移

为了检测化合物34是否能够抑制肿瘤细胞迁移，我们使用划痕实验对不同浓度的化合物34处理后的MDA-MB-231细胞进行检测，结果显示化合物34可以剂量依赖的抑制MDA-MB-231细胞转移，结果见图3。

试验例5化合物34的在斑马鱼肿瘤移植瘤模型中抗肿瘤活性评价

为了检测化合物34是否能够在体内抑制肿瘤生长，我们使用MDA-MB-231细胞斑马鱼移植瘤模型，不同浓度的化合物34处理后检测肿瘤大小，结果显示化合物34可以剂量依赖的抑制MDA-MB-231细胞体内生长和转移，结果见图4。