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CN118638077A - 酰胺/磺酰胺类cxcr4/hdac双重抑制剂及其制备方法和应用 - Google Patents

酰胺/磺酰胺类cxcr4/hdac双重抑制剂及其制备方法和应用 Download PDF

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CN118638077A
CN118638077A CN202410714281.0A CN202410714281A CN118638077A CN 118638077 A CN118638077 A CN 118638077A CN 202410714281 A CN202410714281 A CN 202410714281A CN 118638077 A CN118638077 A CN 118638077A
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hdac
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白仁仁
卢柳欣
葛嘉敏
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Hangzhou Normal University
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Abstract

本发明公开了一类酰胺/磺酰胺类CXCR4/HDAC双重抑制剂及其制备方法和应用。本发明基于合理药物设计原则，设计合成了具有CXCR4及HDAC抑制活性的多靶点、具有潜在抗肿瘤、抗炎和抗抑郁活性的新型小分子化合物。本发明化合物引入了可提高抗肿瘤、抗炎和抗抑郁活性的异羟肟酸结构，提高了抗肿瘤、抗炎和抗抑郁活性，并且对目前使用的抗肿瘤、抗炎和抗抑郁化合物的治疗时间长、副作用大等缺点具有良好的改善。本发明的CXCR4/HDAC双重抑制剂，其既具有CXCR4拮抗作用又具有HDAC抑制作用，是一类以苯甲酰胺/苯磺酰胺基团与异羟肟酸协同实现抗肿瘤、抗炎和抗抑郁的多靶点异羟肟酸类衍生物。

Description

酰胺/磺酰胺类CXCR4/HDAC双重抑制剂及其制备方法和应用
技术领域
本发明涉及药物化学领域，具体涉及一类酰胺/磺酰胺类CXCR4/HDAC双重抑制剂及其制备方法和应用。
背景技术
CXC趋化因子受体4(CXCR4)是一类七跨膜G蛋白偶联受体，它通过与CXC家族趋化因子配体12(CXCL12)结合，参与多种下游信号通路，在肿瘤侵袭转移、人类免疫缺陷病毒(HIV)感染和炎症反应过程中发挥着重要作用。研究表明，CXCR4拮抗剂能够阻断CXCR4/CXCL12信号通路从而发挥抑制肿瘤细胞侵袭和炎症细胞趋化的作用，目前已有多个CXCR4拮抗剂处于抗肿瘤和抗炎临床研究阶段。此外，还有研究显示，CXCR4能够通过调节神经元突触前膜上神经递质的释放，介导抑郁症的发生。因此，CXCR4是一个有潜力的抗肿瘤、抗炎和抗抑郁的有效靶点。
组蛋白去乙酰化酶(HDACs)是一类表观遗传酶，它与组蛋白乙酰化转移酶(HATs)共同调控组蛋白的乙酰化水平。在生物体内，乙酰化水平的失调会影响细胞的增殖与分化，还会影响免疫系统的正常功能，从而引发癌症和炎症等多种疾病。HDAC抑制剂在癌症治疗中备受关注，合理使用HDAC抑制剂可在正常细胞相对耐受的情况下干扰肿瘤细胞的细胞周期、分化和凋亡。目前已有五种HDAC抑制剂在临床上用于恶性肿瘤的治疗。此外，HDACs还参与多种炎症信号通路的调控，影响多种炎症因子的表达。除此之外，有实验表明HDAC可以改变中枢神经系统中的表观遗传并影响大脑活动。根据大量临床前数据及对动物抑郁症模型的研究发现，HDAC抑制剂能在抑郁症的病理生理过程中发挥重要作用。比如经典的HDAC抑制剂伏立诺他能有效减轻小鼠的抑郁样行为、抵消抑郁引起的炎症反应，并逆转海马中辅酶Q10的水平。因此，HDACs是一个有潜力的抗肿瘤、抗炎和抗抑郁靶点。申请人已在先研究开发了一些可作用于HDAC的多靶点抑制剂，具体可参见公开号为CN118084732A、CN117924217A、CN113956182A的专利说明书等。
如上文介绍，CXCR4和HDAC是两个前景较大的抗肿瘤、抗炎和抗抑郁靶点，因此，通过合理药物设计原则将CXCR4拮抗剂药效团和HDAC抑制剂药效团相融合，开发具有CXCR4/HDAC双重抑制效果的新型小分子抑制剂，有希望为抗肿瘤、抗炎和抗抑郁治疗开辟新的方向。目前相关研究较少，具有很好的研究意义和转化价值。
发明内容
针对上述技术问题以及本领域存在的不足之处，本发明提供了一类酰胺/磺酰胺类CXCR4/HDAC双重抑制剂，有望改善单靶点抗肿瘤、抗炎和抗抑郁药物的不足，同时提高其生物活性。
酰胺/磺酰胺类CXCR4/HDAC双重抑制剂为具有如式(I)或(II)所示结构的化合物和/或其可药用盐：
式(I)、(II)中：
R1选自以下结构：
R2选自H、C1～C4烷基；
R3选自以下结构：
R4选自以下结构：-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2-，其中n为1～4的整数，表示与R3连接的位点。
进一步的，所述酰胺/磺酰胺类CXCR4/HDAC双重抑制剂可为具有如下所示结构的化合物和/或其可药用盐：
本发明还提供了所述的酰胺/磺酰胺类CXCR4/HDAC双重抑制剂的制备方法，合成路线包括：
所述制备方法包括：
4-溴甲基苯磺酰氯或4-氯甲基苯酰氯与化合物11进行缩合反应得到中间体2或7；
中间体2或7与化合物12进行亲核取代反应得到中间体3或8；
中间体3或8脱去Boc(叔丁氧羰基)保护基生成中间体4或9；
中间体4或9与化合物13进行取代或缩合反应得到中间体5或10；
中间体5或10经过胺酯交换反应得到所述酰胺/磺酰胺类CXCR4/HDAC双重抑制剂。
本发明还提供了所述的酰胺/磺酰胺类CXCR4/HDAC双重抑制剂在制备通过拮抗CXCR4和/或抑制HDAC来防治相关疾病的药物中的应用。进一步的，所述疾病可包括癌症、炎症、抑郁症等。
作为一个总的发明构思，本发明还提供了一种药物组合物，含有安全有效量的所述的酰胺/磺酰胺类CXCR4/HDAC双重抑制剂。
所述药物组合物还可包括药理上可接受的赋形剂、载体、辅料中的至少一种。
所述药物组合物可通过拮抗CXCR4和/或抑制HDAC来防治相关疾病。进一步的，所述疾病可包括癌症、炎症、抑郁症等。
本发明与现有技术相比，有益效果有：
本发明基于合理药物设计原则，设计合成了具有CXCR4及HDAC抑制活性的多靶点、具有潜在抗肿瘤、抗炎和抗抑郁活性的新型小分子化合物。
本发明化合物在设计策略上优于以往的CXCR4化合物，引入了可提高抗肿瘤、抗炎和抗抑郁活性的异羟肟酸结构，提高了抗肿瘤、抗炎和抗抑郁活性，并且对目前使用的抗肿瘤、抗炎和抗抑郁化合物的治疗时间长、副作用大等缺点具有良好的改善。
本发明的CXCR4/HDAC双重抑制剂，其既具有CXCR4拮抗作用又具有HDAC抑制作用，是一类以苯甲酰胺/苯磺酰胺基团与异羟肟酸协同实现抗肿瘤、抗炎和抗抑郁的多靶点异羟肟酸类衍生物。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法，通常按照常规条件，或按照制造厂商所建议的条件。
中间体2的制备，反应式1：
反应试剂和条件：4-二甲氨基吡啶(DMAP)，二氯甲烷(DCM)，0℃-室温。
如反应式1所示，向装有磁力搅拌子的125mL圆底烧瓶中依次加入原料1(10mmol)、DMAP(2mmol)和DCM(40mL)，在0℃下搅拌5min，随后加入N-甲基苄胺(15mmol),继续在0℃下反应30min，随后移至室温下继续搅拌2-3h。TLC监测反应进程，展开剂为二氯甲烷：石油醚(体积比4：1)。反应完成后，向圆底烧瓶中加DCM(30mL)稀释，用10％的稀盐酸溶液洗涤(50mL×2)，随后用饱和食盐水洗涤(60mL×2)。合并有机液，无水硫酸钠干燥，减压蒸馏除去溶剂，硅胶柱层析纯化，洗脱剂为二氯甲烷：石油醚(体积比2：1)，最终获得白色固体，即中间体2a(85％)。
按照反应式1和上述相同的方法，更换反应物，制得中间体2b-2n。
中间体7的制备，反应式2：
反应试剂和条件：三乙胺(TEA)，DCM，0℃。
如反应式2所示，向装有磁力搅拌子的50mL圆底烧瓶中加入N-甲基苄胺(4mmol)、TEA(10mmol)和DCM(15mL)，于0℃下搅拌5min，随后用恒压滴液漏斗缓慢滴加4-氯甲基苯甲酰胺(5mmol)的DCM(15mL)溶液，继续在0℃下搅拌反应1-2h。TLC监测反应进程，展开剂为二氯甲烷。反应完成后，向反应液中加入水(30mL×2)洗涤，收集有机液，用饱和食盐水(20mL)洗涤，随后用无水硫酸钠干燥，减压蒸馏除去溶剂，硅胶柱层析纯化，洗脱剂为二氯甲烷，最终获得白色固体，即中间体7a(70-85％)。
按照反应式2和上述相同的方法，更换反应物，制得中间体7b-7o。
中间体3和8的制备，反应式3：
反应试剂和条件：N,N-二异丙基乙胺(DIPEA)，乙腈(MeCN)，50℃。
如反应式3所示，向装有磁力搅拌子的100mL圆底烧瓶中依次加入中间体2(6mmol)、1-叔丁氧羰基哌嗪(7.2mmol)、DIPEA(12mmol)和乙腈(30mL)，于50℃下搅拌反应。TLC监测反应进程，展开剂为正己烷：乙酸乙酯(体积比1：1)。反应完成后，冷却至室温，减压浓缩除去反应溶剂，加入水(30mL)，用DCM(30mL×2)进行萃取，合并有机液，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，硅胶柱层析纯化，洗脱剂为石油醚：乙酸乙酯(2：1)，最终获得白色固体，即中间体3a(90％)。
按照反应式3和上述相同的方法，更换反应物，制得中间体3b-3c、8a-8c。
中间体4和9的制备，反应式4：
反应试剂和条件：CF3COOH，DCM，0℃。
如反应式4所示，向装有磁力搅拌子的100mL圆底烧瓶中加入中间体3(3mmol)和DCM(9mL)，在0℃下搅拌10min，随后通过恒压滴液漏斗将三氟乙酸(9mL)的DCM(9mL)溶液缓慢滴加至反应瓶中，继续在0℃下搅拌反应0.5-1h。TLC监测反应进程，展开剂为二氯甲烷：甲醇(体积比9：1)。反应完成后，向反应液中加入饱和碳酸氢钠溶液，调节PH值7-8。随后加入水(10mL)，用DCM(30mL×5)萃取，合并有机液，无水硫酸钠干燥，减压蒸馏除去溶剂，随后用正己烷和DCM重结晶析出固体，过滤干燥，最终获得白色固体，即中间体4(80％)。
按照反应式4和上述相同的方法，更换反应物，制得中间体9。
中间体5和10的制备，反应式5：
反应试剂和条件：Cs2CO3，四丁基碘化铵(TBAI)，CH3CN，60℃，4-6h。
如反应式5所示，向装有磁力搅拌子的50mL圆底烧瓶中加入中间体4(0.3mmol)、碳酸铯(0.45mmol)、四丁基碘化铵(0.03mmol)、乙腈(9mL)和对应的对溴甲基苯酯(0.45mmol)，加热至60℃反应4-6h。TLC监测反应进程，展开剂为二氯甲烷：甲醇(体积比50：1)。反应完成后，冷却至室温，减压浓缩除去溶剂，随后向反应液中加入水(10mL)，用DCM(10mL×2)进行萃取，合并有机液，无水硫酸钠干燥，减压蒸馏除去溶剂，硅胶柱层析纯化，洗脱剂为二氯甲烷：甲醇(体积比100:1)，最终获得淡黄色液体，即中间体5a(45-72％)
按照反应式5和上述相同的方法，更换反应物，制得中间体5c、10a和10c。
向装有磁力搅拌子的50mL圆底烧瓶中加入中间体4(0.5mmol)和DCM(9mL)，于0℃下搅拌15min，随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(0.6mmol)和1-羟基苯并三唑(HOBT)(0.6mmol)，在0℃下搅拌15min，随后加入三乙胺(1.0mmol)，搅拌15min，最后加入丙二酸单甲酯，移至室温下继续反应6-8h。TLC监测反应进程，展开剂为二氯甲烷：甲醇(体积比20：1)。反应完成后，向反应液中加入DCM(15mL)稀释，用水(15mL×2)洗涤有机液，收集有机液，用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，硅胶柱层析纯化，洗脱剂为二氯甲烷：甲醇(体积比100：1)，最终获得淡黄色液体，即中间体5b(68-80％)。
按照反应式5和上述相同的方法，更换反应物，制得中间体10b。
CXCR4/HDAC双重抑制剂终产物(Ⅰ)和(Ⅱ)的制备，反应式6：
反应试剂和条件：NH2OH，NaOH，DCM，MeOH，0℃，0.5-1h。
如反应式6所示，向装有磁力搅拌子的50mL圆底烧瓶中加入中间体5或10(0.3mmol)、DCM(3mL)和甲醇(6mL)，于0℃下搅拌10min，随后依次加入氢氧化钠(3.0mmol)和羟胺水溶液(9.0mmol)，继续在0℃下搅拌反应0.5-1h。TLC监测反应进程，展开剂为二氯甲烷：甲醇(体积比9：1)。反应完成后，在0℃下向反应液中缓慢滴加10％盐酸溶液调节pH值至7-8。减压蒸馏除去有机溶剂，薄层层析纯化，最后用正己烷和DCM进行重结晶析出固体，过滤干燥，最终获得白色固体，即目标化合物(50-89％)。
所采用的各中间体、终产物均可按上述过程进行制备，在此不再赘述。
实施例1：2-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基乙酰胺(化合物A-1)的制备
将中间体5a(0.3mmol)、DCM(3mL)和甲醇(6mL)，于0℃下搅拌10min，随后依次加入氢氧化钠(3.0mmol)和羟胺水溶液(9.0mmol)，继续在0℃下搅拌反应0.5-1h。TLC监测反应进程，展开剂为二氯甲烷：甲醇(体积比9：1)。反应完成后，在0℃下向反应液中缓慢滴加10％盐酸溶液调节pH值至7-8。减压蒸馏除去有机溶剂，薄层层析纯化，最后用正己烷和DCM进行重结晶析出固体，过滤干燥，获得化合物A-1(62.5％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.38(s,1H),8.76(s,1H),7.80(d,J＝8.3Hz,2H),7.57(d,J＝8.2Hz,2H),7.38–7.33(m,2H),7.30(t,J＝6.7Hz,3H),4.13(s,2H),3.58(s,2H),2.87(s,2H),2.54(s,3H),2.44(d,J＝25.8Hz,8H).13CNMR(125MHz,DMSO-d6)δ166.14,144.44,136.50,136.00,129.93,129.00,128.62,128.14,127.66,61.71,59.51,53.74,53.21,52.94,34.92.HRMScalcd for C21H29N4O4S433.1904[M+H]+,found 433.1982.
实施例2：3-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基丙酰胺(化合物A-2)的制备
制备方法基本同实施例1，本实施例得到化合物A-2(60.6％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.36(s,1H),8.71(s,1H),7.79(d,J＝8.3Hz,2H),7.56(d,J＝8.2Hz,2H),7.38–7.27(m,5H),4.13(s,2H),3.57(s,2H),2.54(s,4H),2.39(s,8H),2.11(t,J＝7.2Hz,2H).13C NMR(125MHz,DMSO-d6)δ168.45,144.43,136.50,136.00,129.94,129.00,128.62,128.14,127.65,61.74,54.30,53.74,53.08,52.93,34.92,30.77.HRMS calcd forC22H31N4O4S 447.2061[M+H]+,found 447.2135.
实施例3：4-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基丁酰胺(化合物A-3)的制备
制备方法基本同实施例1，本实施例得到化合物A-3(88.9％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),8.65(s,1H),7.80(d,J＝8.3Hz,2H),7.57(d,J＝8.2Hz,2H),7.38–7.33(m,2H),7.30(t,J＝6.9Hz,3H),4.13(s,2H),3.57(s,2H),2.54(s,3H),2.34(d,J＝57.6Hz,8H),2.24(s,2H),1.96(t,J＝7.4Hz,2H),1.63(p,J＝7.3Hz,2H).13C NMR(125MHz,DMSO-d6)δ169.05,143.96,136.03,135.53,129.48,128.53,128.15,127.67,127.18,61.31,57.19,53.27,52.68,39.52,34.44,30.23,22.42.HRMS calcd forC23H33N4O4S 461.2217[M+H]+,found 461.2276.
实施例4：5-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基戊酰胺(化合物A-4)的制备
制备方法基本同实施例1，本实施例得到化合物A-4(50.2％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.65(s,1H),7.79(d,J＝8.2Hz,2H),7.57(d,J＝8.2Hz,2H),7.38–7.33(m,2H),7.30(t,J＝7.0Hz,3H),4.13(s,2H),3.57(s,2H),2.54(s,3H),2.40(s,8H),2.26(s,2H),1.95(t,J＝7.2Hz,2H),1.48(p,J＝7.2Hz,2H),1.38(p,J＝7.1,6.7Hz,2H).13C NMR(125MHz,DMSO-d6)δ169.03,143.99,136.03,135.53,129.46,128.53,128.15,127.67,127.19,61.30,57.41,53.27,52.72,52.68,39.52,34.45,32.10,25.77,23.05.HRMS calcd for C24H35N4O4S 475.2374[M+H]+,found 475.2436.
实施例5：6-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基己酰胺(化合物A-5)的制备
制备方法基本同实施例1，本实施例得到化合物A-5(66.8％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.65(s,1H),7.79(d,J＝8.3Hz,2H),7.56(d,J＝8.3Hz,2H),7.38–7.33(m,2H),7.30(t,J＝6.8Hz,3H),4.13(s,2H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.23(s,2H),1.93(t,J＝7.4Hz,2H),1.48(p,J＝7.4Hz,2H),1.39(p,J＝7.5Hz,2H),1.22(dt,J＝15.1,7.5Hz,2H).13C NMR(125MHz,DMSO-d6)δ169.06,144.00,136.03,135.53,129.47,128.53,128.15,127.67,127.18,61.32,57.79,53.28,52.78,52.70,39.52,34.45,32.25,26.54,26.02,25.08.HRMS calcd for C25H37N4O4S 489.2530[M+H]+,found 489.2584.
实施例6：4-((4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-6)的制备
制备方法基本同实施例1，本实施例得到化合物A-6(30.2％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),7.79(d,J＝8.2Hz,2H),7.70(d,J＝8.1Hz,2H),7.56(d,J＝8.2Hz,2H),7.35(t,J＝7.3Hz,4H),7.29(t,J＝7.1Hz,3H),4.13(s,2H),3.58(s,2H),3.51(s,2H),2.53(s,3H),2.41(s,8H).13C NMR(125MHz,DMSO-d6)δ164.12,143.95,141.54,136.02,135.53,131.48,129.46,128.66,128.53,128.14,127.66,127.19,126.79,61.54,61.23,53.26,52.57,39.52,34.44.HRMS calcd for C27H33N4O4S509.2217[M+H]+,found 509.2273.
实施例7：3-(4-(4-(N-苄基-N-甲基磺酰基)苄基)哌嗪-1-基)-N-羟基-3-氧代丙酰胺(化合物A-7)的制备
制备方法基本同实施例1，本实施例得到化合物A-7(％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.51(s,1H),8.89(s,1H),7.81(d,J＝8.3Hz,2H),7.60(d,J＝8.3Hz,2H),7.38–7.33(m,2H),7.30(t,J＝6.7Hz,3H),4.14(s,2H),3.61(s,2H),3.50(dd,J＝11.3,6.3Hz,4H),3.16(s,2H),2.55(s,3H),2.44–2.37(m,2H),2.37–2.30(m,2H).13CNMR(125MHz,DMSO-d6)δ165.98,164.24,143.78,136.37,136.10,130.31,129.10,128.62,128.27,127.66,61.45,53.80,53.07,52.58,46.18,41.75,39.52,34.96.LCMS(ESI)m/z:461.0[M+H]+.
实施例8：4-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基-4-氧代丁酰胺(化合物A-8)的制备
制备方法基本同实施例1，本实施例得到化合物A-8(66.8％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.35(s,1H),8.64(s,1H),7.81(d,J＝8.3Hz,2H),7.59(d,J＝8.2Hz,2H),7.40–7.33(m,2H),7.30(t,J＝6.7Hz,3H),4.14(s,2H),3.61(s,2H),3.46(s,4H),2.54(d,J＝7.8Hz,5H),2.40(s,2H),2.36–2.31(m,2H),2.19(t,J＝7.1Hz,2H).13C NMR(125MHz,DMSO-d6)δ170.02,169.00,144.09,136.50,136.13,130.02,129.01,128.62,128.15,127.71,61.55,53.75,53.27,52.83,45.15,41.57,40.49,40.41,40.32,40.24,40.15,40.08,39.99,39.91,39.82,39.65,39.49,34.93,28.09,27.96.HRMS calcd forC23H31N4O5S 475.2010[M+H]+,found 475.2057.
实施例9：5-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基-5-氧代戊酰胺(化合物A-9)的制备
制备方法基本同实施例1，本实施例得到化合物A-9(56.1％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),8.66(s,1H),7.81(d,J＝8.3Hz,2H),7.59(d,J＝8.3Hz,2H),7.36(td,J＝7.0,1.5Hz,2H),7.30(t,J＝6.7Hz,3H),4.14(s,2H),3.61(s,2H),3.49–3.42(m,4H),2.55(s,3H),2.41–2.37(m,2H),2.35–2.32(m,2H),2.28(t,J＝7.4Hz,2H),1.98(t,J＝7.3Hz,2H),1.70(p,J＝7.4Hz,2H).13C NMR(125MHz,DMSO-d6)δ170.11,168.89,143.61,136.04,135.68,129.57,128.56,128.17,127.70,127.25,61.09,53.30,52.92,52.40,44.85,40.98,39.52,34.48,31.60,20.91.HRMS calcd for C24H33N4O5S489.2166[M+H]+,found 489.2217.
实施例10：6-(4-(4-(N-苄基-N-甲基磺酰)苄基)哌嗪-1-基)-N-羟基-6-氧代己酰胺(化合物A-10)的制备
制备方法基本同实施例1，本实施例得到化合物A-10(80.2％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),8.66(s,1H),7.81(d,J＝8.3Hz,2H),7.59(d,J＝8.3Hz,2H),7.38–7.33(m,2H),7.30(t,J＝7.2Hz,3H),4.14(s,2H),3.61(s,2H),3.49–3.43(m,4H),2.55(s,3H),2.42–2.37(m,2H),2.35–2.31(m,2H),2.28(t,J＝7.1Hz,2H),1.95(t,J＝6.9Hz,2H),1.53–1.42(m,4H).13C NMR(125MHz,DMSO-d6)δ170.44,168.99,143.63,136.04,135.68,129.58,128.57,128.17,127.70,127.26,61.10,53.31,52.98,52.43,44.93,40.99,39.52,34.48,32.13,31.95,24.89,24.39.HRMS calcd for C25H35N4O5S503.2323[M+H]+,found 503.2371.
实施例11：3-((2-((4-(N-苄基-N-甲基磺酰)苄基)(甲基)氨基)乙基)(甲基)氨基)-N-羟基丙酰胺(化合物A-11)的制备
制备方法基本同实施例1，本实施例得到化合物A-11(63.0％)，黄色液体。1H NMR(500MHz,DMSO-d6)δ10.41(s,1H),8.70(s,1H),7.79(d,J＝8.3Hz,2H),7.58(d,J＝8.3Hz,2H),7.39–7.27(m,5H),4.12(s,2H),3.60(s,2H),2.56(t,J＝7.1Hz,2H),2.53(s,3H),2.47(s,4H),2.15(s,3H),2.13(s,3H),2.11(t,J＝7.1Hz,2H).13C NMR(125MHz,MeOD)δ171.49,145.39,137.51,137.32,131.20,129.67,129.44,128.92,128.62,62.85,55.62,55.52,55.13,54.15,49.00,42.75,42.15,34.84,31.44.HRMS calcd for C22H33N4O4S 449.2217[M+H]+,found 449.2284.
实施例12：5-((2-((4-(N-苄基-N-甲基磺酰)苄基)(甲基)氨基)乙基)(甲基)氨基)-N-羟基戊酰胺(化合物A-12)的制备
制备方法基本同实施例1，本实施例得到化合物A-12(56.1％)，黄色液体。1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),8.66(s,1H),7.79(d,J＝8.3Hz,2H),7.57(d,J＝8.3Hz,2H),7.39–7.27(m,5H),4.12(s,2H),3.60(s,2H),2.53(s,3H),2.45(s,4H),2.27(d,J＝14.2Hz,2H),2.15(s,3H),2.11(s,3H),1.94(t,J＝7.3Hz,2H),1.51–1.43(m,2H),1.35(dt,J＝12.3,6.2Hz,2H).13C NMR(125MHz,DMSO-d6)δ169.09,145.06,136.06,135.36,129.39,128.58,128.17,127.71,127.17,61.13,57.13,55.22,54.88,53.33,42.34,42.16,40.02,39.95,39.86,39.69,39.61,39.52,39.44,39.35,39.19,39.02,34.47,32.15,26.27,23.05.HRMS calcd for C24H37N4O4S 447.2530[M+H]+,found 447.2575.
实施例13：6-((2-((4-(N-苄基-N-甲基磺酰)苄基)(甲基)氨基)乙基)(甲基)氨基)-N-羟基己酰胺(化合物A-13)的制备
制备方法基本同实施例1，本实施例得到化合物A-13(89.3％)，黄色液体。1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),7.79(d,J＝8.3Hz,2H),7.57(d,J＝8.2Hz,2H),7.38–7.33(m,2H),7.32–7.27(m,3H),4.12(s,2H),3.60(s,2H),2.53(s,3H),2.46(s,4H),2.26(t,J＝7.2Hz,2H),2.16(s,3H),2.12(s,3H),1.92(t,J＝7.4Hz,2H),1.48(p,J＝7.4Hz,2H),1.37(p,J＝7.5Hz,2H),1.23–1.18(m,2H).13C NMR(125MHz,DMSO-d6)δ169.03,145.05,136.04,135.34,129.35,128.54,128.14,127.68,127.14,61.12,57.38,55.24,54.86,53.31,42.34,42.18,39.52,34.44,32.26,26.46,25.07.HRMS calcd forC25H39N4O4S 491.2687[M+H]+,found 491.2732.
实施例14：N-苄基-4-((4-(5-(羟胺基)-5-氧代戊基)哌嗪-1-基)甲基)-N-甲基苯甲酰胺(化合物A-14)的制备
制备方法基本同实施例1，本实施例得到化合物A-14(47.7％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.64(s,1H),7.33(d,J＝30.8Hz,8H),7.17(s,1H),4.57(d,J＝95.7Hz,2H),3.48(s,2H),2.85(d,J＝15.8Hz,3H),2.35(s,7H),2.24–2.18(m,2H),1.93(t,J＝7.2Hz,2H),1.46(q,J＝7.3Hz,2H),1.36(q,J＝7.1Hz,2H).13CNMR(125MHz,DMSO)δ169.51,140.32,135.31,129.10,128.06,127.64,127.33,127.24,127.22,127.03,127.01,62.15,57.92,53.24,53.17,32.58,26.29,23.53.HRMS calcd for C25H35N4O3439.2704[M+H]+,found 439.2733.
实施例15：N-苄基-4-((4-(2-(羟基氨基)-2-氧代乙基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-15)的制备
制备方法基本同实施例1，本实施例得到化合物A-15(45.2％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.37(s,1H),8.99(t,J＝6.0Hz,1H),8.74(s,1H),7.87–7.83(m,2H),7.38(d,J＝8.2Hz,2H),7.34–7.29(m,4H),7.23(tt,J＝5.6,2.7Hz,1H),4.47(d,J＝6.0Hz,2H),3.50(d,J＝4.7Hz,2H),2.85(s,2H),2.44(s,4H),2.38(s,4H).13C NMR(125MHz,DMSO)δ39.52,42.73,52.61,52.94,59.28,61.75,126.86,127.33,127.36,128.42,128.75,133.18,139.91,141.92,165.88,166.22.HRMS calcd for C21H27N4O3 383.2078[M+H]+,found 383.2090.
实施例16：N-苄基-4-((4-(5-(羟基氨基)-5-氧代戊基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-16)的制备
制备方法基本同实施例1，本实施例得到化合物A-16(59.3％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.99(t,J＝5.9Hz,1H),8.65(s,1H),7.84(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),7.34–7.29(m,4H),7.24(dt,J＝8.2,4.2Hz,1H),4.47(d,J＝6.0Hz,2H),3.49(s,2H),2.35(s,8H),2.22(t,J＝7.2Hz,2H),1.93(t,J＝7.2Hz,2H),1.47(p,J＝7.2Hz,2H),1.36(q,J＝7.5Hz,2H).13C NMR(125MHz,DMSO)δ23.53,26.30,32.58,43.02,53.18,53.22,57.92,62.12,127.15,127.63,127.64,128.71,129.05,133.47,140.21,142.26,166.52,169.50.HRMS calcd for C24H33N4O3 425.2547[M+H]+,found425.2567.
实施例17：N-苄基-4-((4-(2-(羟氨基)-2-氧代乙基)哌嗪-1-基)甲基)-N-甲基苯甲酰胺(化合物A-17)的制备
制备方法基本同实施例1，本实施例得到化合物A-17(47.8％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.35(s,1H),8.77(s,1H),7.33(d,J＝40.7Hz,8H),7.16(s,1H),4.57(d,J＝95.0Hz,2H),3.48(s,2H),2.84(s,5H),2.47(d,J＝34.1Hz,9H).13C NMR(125MHz,DMSO)δ166.11,140.27,135.32,129.08,128.05,127.67,127.30,62.06,59.56,53.25,52.90,39.74.HRMS calcd for C22H29N4O3 397.2234[M+H]+,found 397.2257.
实施例18：N-苄基-4-((4-(3-(羟基氨基)-3-氧代丙基)哌嗪-1-基)甲基)-N-甲基苯甲酰胺(化合物A-18)的制备
制备方法基本同实施例1，本实施例得到化合物A-18(21.3％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.36(s,1H),8.72(s,1H),7.46–7.24(m,8H),7.17(s,1H),4.67(s,1H),4.48(s,1H),3.49(s,2H),2.85(d,J＝19.1Hz,3H),2.56–2.51(m,1H),2.37(s,7H),2.10(t,J＝7.0Hz,2H).13C NMR(125MHz,DMSO)δ168.43,140.20,135.34,129.12,128.06,127.79,127.69,127.30,127.26,127.16,126.98,62.06,54.28,52.99,52.92,30.73.HRMScalcd for C23H31N4O3 411.2391[M+H]+,found 411.2410.
实施例19：N-苄基-4-((4-(4-(羟氨基)-4-氧代丁基)哌嗪-1-基)甲基)-N-甲基苯甲酰胺(化合物A-19)的制备
制备方法基本同实施例1，本实施例得到化合物A-19(62.1％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),7.33(d,J＝41.0Hz,8H),7.17(s,1H),4.57(d,J＝95.7Hz,2H),3.48(s,2H),2.85(d,J＝17.5Hz,3H),2.42(d,J＝69.8Hz,8H),2.21(s,2H),1.94(t,J＝7.4Hz,2H),1.61(p,J＝7.1Hz,2H).13C NMR(125MHz,DMSO)δ166.11,140.27,135.32,129.08,128.05,127.67,127.30,127.24,127.17,127.08,127.00,62.06,59.56,53.25,52.90,39.74.HRMS calcd for C24H33N4O3 425.2547[M+H]+,found425.2578.
实施例20：N-苄基-4-((4-(6-(羟胺基)-6-氧代己基)哌嗪-1-基)甲基)-N-甲基苯甲酰胺(化合物A-20)的制备
制备方法基本同实施例1，本实施例得到化合物A-20(38.0％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.64(s,1H),7.34(d,J＝32.9Hz,8H),7.16(s,1H),4.57(d,J＝95.9Hz,2H),3.48(s,2H),2.85(d,J＝17.5Hz,3H),2.35(s,7H),2.24–2.16(m,2H),1.92(t,J＝7.3Hz,2H),1.52–1.43(m,2H),1.37(d,J＝13.9Hz,2H),1.21(d,J＝14.7Hz,2H).13C NMR(125MHz,DMSO)δ169.50,140.31,135.32,129.09,128.07,127.67,127.31,62.14,58.28,53.28,53.15,50.30,32.71,27.00,26.51,25.55.HRMS calcd for C26H37N4O3453.2860[M+H]+,found 453.2896.
实施例21：N-苯甲基-4-((4-(4-(羟基甲酰胺)苯甲基)哌嗪-1-基)甲基)-N-甲基苯甲酰胺(化合物A-21)的制备
制备方法基本同实施例1，本实施例得到化合物A-21(26.2％)，黄色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.98(s,1H),7.70(s,2H),7.33(d,J＝27.1Hz,10H),7.17(s,1H),4.57(d,J＝97.6Hz,2H),3.49(s,5H),2.84(d,J＝16.2Hz,3H),2.38(s,8H).13C NMR(126MHz,DMSO)δ164.60,142.04,140.24,135.31,131.90,129.09,128.05,127.73,127.24,62.04,53.07.HRMS calcd for C28H33N4O3 473.2547[M+H]+,found473.2569.
实施例22：N-苯甲基-4-((4-(3-(羟基氨基)-3-氧代丙基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-22)的制备
制备方法基本同实施例1，本实施例得到化合物A-22(76.0％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.35(s,1H),8.99(t,J＝6.0Hz,1H),8.71(s,1H),7.85(d,J＝8.2Hz,2H),7.37(d,J＝8.2Hz,2H),7.32(d,J＝5.7Hz,4H),7.26–7.21(m,1H),4.47(d,J＝6.0Hz,2H),3.49(s,2H),2.48(s,2H),2.36(s,8H),2.10(t,J＝7.1Hz,2H).13C NMR(125MHz,DMSO)δ30.77,43.03,52.93,53.03,54.30,62.06,127.16,127.63,128.72,129.07,133.48,140.20,142.18,166.52,168.46.HRMS calcd for C22H29N4O3 397.2234[M+H]+,found397.2250.
实施例23：N-苯甲基-4-((4-(4-(羟基氨基)-4-氧代丁基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-23)的制备
制备方法基本同实施例1，本实施例得到化合物A-23(57.0％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),9.00(t,J＝6.0Hz,1H),8.65(s,1H),7.86(d,J＝8.1Hz,2H),7.39(d,J＝8.1Hz,2H),7.34(d,J＝6.3Hz,4H),7.27–7.22(m,1H),4.48(d,J＝6.0Hz,2H),3.51(d,J＝6.3Hz,2H),2.37(s,8H),2.23(t,J＝7.1Hz,2H),1.96(t,J＝7.4Hz,2H),1.62(p,J＝7.3Hz,2H).13C NMR(125MHz,DMSO)δ169.06,166.05,141.73,139.74,133.01,128.61,128.25,127.16,126.69,61.63,57.19,54.91,52.63,42.56,39.52,30.22,22.41.HRMS calcd for C23H31N4O3 411.2391[M+H]+,found 411.2402.
实施例24：N-苯甲基-4-((4-(6-(羟基氨基)-6-氧代己基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-24)的制备
制备方法基本同实施例1，本实施例得到化合物A-24(79.5％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.99(t,J＝6.0Hz,1H),8.64(s,1H),7.84(d,J＝8.1Hz,2H),7.37(d,J＝8.2Hz,2H),7.35–7.28(m,4H),7.23(tt,J＝5.6,2.7Hz,1H),4.47(d,J＝6.0Hz,2H),3.49(s,2H),2.35(s,7H),2.24–2.19(m,2H),1.92(t,J＝7.3Hz,2H),1.48(q,J＝7.4Hz,2H),1.38(p,J＝7.6Hz,2H),1.20(d,J＝7.8Hz,2H).13C NMR(125MHz,DMSO)δ169.51,166.52,142.26,140.20,133.46,129.05,128.72,127.64,127.63,127.16,62.12,58.28,53.27,53.17,43.02,32.71,27.00,26.52,25.55.HRMS calcd for C25H35N4O3439.2704[M+H]+,found 439.2729.
实施例25：N-苯甲基-4-((4-(4-羟基甲酰氨基)苄基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-25)的制备
制备方法基本同实施例1，本实施例得到化合物A-25(28.9％)，黄色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(t,J＝5.8Hz,2H),7.84(d,J＝8.1Hz,2H),7.69(d,J＝8.1Hz,2H),7.39–7.28(m,8H),7.23(tt,J＝6.3,2.8Hz,1H),4.47(d,J＝5.9Hz,2H),3.50(d,J＝7.6Hz,4H),2.38(s,8H).13C NMR(125MHz,DMSO)δ39.52,42.55,52.61,61.58,126.68,126.75,127.16,127.17,128.24,128.58,133.01,139.73,141.71,166.04.HRMScalcd for C27H31N4O3 459.2391[M+H]+,found 459.2426.
实施例26：2-(4-(4-(N-苯甲基磺酰氨基)苄基)哌嗪-1-基)-N-羟基乙酰胺(化合物A-26)的制备
制备方法基本同实施例1，本实施例得到化合物A-26(35.2％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.38(s,1H),8.75(s,1H),8.12(t,J＝6.0Hz,1H),7.72(d,J＝8.0Hz,2H),7.46(d,J＝7.9Hz,2H),7.28–7.16(m,5H),3.99(d,J＝6.0Hz,2H),3.52(s,2H),2.86(s,2H),2.42(d,J＝38.8Hz,8H).13C NMR(125MHz,DMSO-d6)δ165.74,143.12,139.37,137.64,129.21,128.17,127.56,127.06,126.45,61.32,59.09,52.75,52.44,46.13,39.52.HRMS calcd for C20H27N4O4S 419.1748[M+H]+,found 419.1779.
实施例27：3-(4-(4-(N-苯甲基磺酰氨基)苄基)哌嗪-1-基)-N-羟基丙酰胺(化合物A-27)的制备
制备方法基本同实施例1，本实施例得到化合物A-27(62.5％)，白色固体。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.73(s,1H),8.14(t,J＝6.4Hz,1H),7.72(d,J＝8.2Hz,2H),7.45(d,J＝8.2Hz,2H),7.28–7.15(m,5H),3.99(d,J＝6.3Hz,2H),3.51(s,2H),2.35(s,10H),2.10(t,J＝7.0Hz,2H).13C NMR(125MHz,DMSO-d6)δ168.44,143.55,139.82,138.09,129.68,128.62,128.01,127.52,126.89,61.78,54.30,53.02,52.92,46.57,30.77.HRMS calcd for C21H29N4O4S 433.1904[M+H]+,found 433.1951.
实施例28：4-(4-(4-(N-苯甲基磺酰氨基)苄基)哌嗪-1-基)-N-羟基丁酰胺(化合物A-28)的制备
制备方法基本同实施例1，本实施例得到化合物A-28(81.4％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),8.11(t,J＝6.3Hz,1H),7.72(d,J＝8.3Hz,2H),7.45(d,J＝8.3Hz,2H),7.27–7.22(m,2H),7.22–7.17(m,3H),3.99(d,J＝6.3Hz,2H),3.51(s,2H),2.49–2.19(m,10H),1.95(t,J＝7.4Hz,2H),1.62(p,J＝7.3Hz,2H).13C NMR(125MHz,DMSO-d6)δ169.53,143.56,139.82,138.09,129.69,128.62,128.01,127.52,126.89,61.83,57.68,53.16,53.09,46.58,40.49,40.41,40.32,40.25,40.15,40.07,39.99,39.90,39.82,39.65,39.49,30.71,22.91.HRMS calcd for C22H31N4O4S447.2061[M+H]+,found 447.2110.
实施例29：N-羟基-5-((4-(4-(N-苄基磺酰)苯甲基)哌嗪-1-基)-戊酰胺(化合物A-29)的制备
制备方法基本同实施例1，本实施例得到化合物A-29(48.3％)，淡黄色固体。1HNMR(400MHz,DMSO-d6)δ10.33(s,1H),8.66(s,1H),8.13(t,J＝6.2Hz,1H),7.72(d,J＝8.1Hz,2H),7.45(d,J＝8.1Hz,2H),7.23(d,J＝6.0Hz,2H),7.20(d,J＝6.3Hz,3H),3.99(d,J＝6.2Hz,2H),3.51(s,2H),2.35(s,8H),2.26–2.20(m,2H),1.94(t,J＝7.1Hz,2H),1.48(dt,J＝14.3,7.0Hz,2H),1.37(dt,J＝13.8,7.5Hz,2H).13C NMR(125MHz,DMSO-d6)δ169.01,143.14,139.34,137.62,129.20,128.15,127.54,127.54,127.05,126.43,126.43,61.38,57.47,52.75,52.75,46.11,39.85,39.52,32.11,25.84,23.08.HRMS calcd forC23H33N4O4S 461.2217[M+H]+,found 461.2262.
实施例30：6-(4-(4-(N-苄基磺酰氨基)苄基)哌嗪-1-基)-N-羟基己酰胺(化合物A-30)的制备
制备方法基本同实施例1，本实施例得到化合物A-30(60.8％)，淡黄色固体。1HNMR(500MHz,DMSO-d6)δ10.31(s,1H),8.65(s,1H),8.11(t,J＝6.3Hz,1H),7.72(d,J＝8.3Hz,2H),7.45(d,J＝8.3Hz,2H),7.27–7.22(m,2H),7.22–7.17(m,3H),3.99(d,J＝6.2Hz,2H),3.51(s,2H),2.36(s,8H),2.25–2.20(m,2H),1.93(t,J＝7.3Hz,2H),1.48(p,J＝7.4Hz,2H),1.39(p,J＝7.4Hz,2H),1.22(dt,J＝15.1,7.4Hz,2H).13C NMR(125MHz,DMSO-d6)δ169.04,143.13,139.34,137.62,129.19,128.15,127.54,127.04,126.42,61.37,57.81,52.79,52.66,46.10,39.52,32.24,26.54,26.04,25.08.HRMS calcd for C24H35N4O4S475.2374[M+H]+,found 475.2423.
实施例31：4-((4-(4-(N-苄基磺酰氨基)苄基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-31)的制备
制备方法基本同实施例1，本实施例得到化合物A-31(35.3％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),8.11(s,1H),7.71(dd,J＝10.6,8.3Hz,4H),7.45(d,J＝8.3Hz,2H),7.36(d,J＝8.2Hz,2H),7.26–7.22(m,2H),7.19(d,J＝7.1Hz,3H),3.98(s,2H),3.52(d,J＝8.5Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO-d6)δ164.14,143.06,141.57,139.35,137.62,131.46,129.19,128.63,128.14,127.54,127.03,126.79,126.43,61.57,61.29,52.58,46.10,39.52.HRMS calcd for C26H31N4O4S 495.2061[M+H]+,found 495.2108.
实施例32：4-((4-(4-(N-(2-氟苄基)磺酰氨基)苄基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-32)的制备
制备方法基本同实施例1，本实施例得到化合物A-32(66.7％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(s,1H),8.15(t,J＝6.2Hz,1H),7.70(dd,J＝8.2,2.6Hz,4H),7.44(d,J＝8.3Hz,2H),7.36(d,J＝8.2Hz,2H),7.29(td,J＝7.9,1.6Hz,1H),7.24(qd,J＝7.4,6.5,2.2Hz,1H),7.10–7.03(m,2H),4.03(s,2H),3.51(d,J＝4.6Hz,4H),2.38(s,8H).13C NMR(125MHz,DMSO-d6)δ161.27,159.32,143.60,142.04,139.58,131.93,130.67,130.64,129.79,129.73,129.63,129.10,127.26,126.87,124.90,124.78,124.66,124.63,115.36,62.04,61.75,53.05.HRMS calcd for C26H30FN4O4S513.1966[M+H]+,found 513.1983.
实施例33：4-((4-(4-(N-(3-氟苄基)磺酰氨基)苄基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-33)的制备
制备方法基本同实施例1，本实施例得到化合物A-33(63.5％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(s,1H),8.20(t,J＝6.4Hz,1H),7.74–7.67(m,4H),7.44(d,J＝8.3Hz,2H),7.36(d,J＝8.2Hz,2H),7.30–7.24(m,1H),7.04(d,J＝7.7Hz,1H),7.02–6.96(m,2H),4.03(d,J＝6.2Hz,2H),3.51(d,J＝3.0Hz,4H),2.38(s,8H).13C NMR(125MHz,DMSO-d6)δ163.40,161.47,143.65,142.04,141.20,141.14,139.79,131.92,130.58,130.52,129.64,129.10,127.26,126.88,123.95,123.93,114.66,114.49,114.29,114.12,62.04,61.76,53.05,45.93.HRMS calcd for C26H30FN4O4S 513.1966[M+H]+,found 513.1985.
实施例34：4-((4-(4-(N-(4-氟苄基)磺酰氨基)苄基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-34)的制备
制备方法基本同实施例1，本实施例得到化合物A-34(32.6％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(s,1H),8.14(t,J＝6.3Hz,1H),7.69(dd,J＝8.3,2.6Hz,4H),7.44(d,J＝8.3Hz,2H),7.36(d,J＝8.1Hz,2H),7.22(dd,J＝8.6,5.6Hz,2H),7.04(t,J＝8.9Hz,2H),3.98(d,J＝6.1Hz,2H),3.51(d,J＝5.0Hz,4H),2.38(s,8H).13CNMR(125MHz,DMSO-d6)δ164.60,162.67,160.74,143.56,142.04,134.30,134.28,131.91,130.05,129.98,129.62,129.10,127.26,126.88,115.40,115.23,62.05,61.77,53.06,45.81.HRMS calcd for C26H30FN4O4S 513.1966[M+H]+,found 513.1987.
实施例35：4-((4-(4-(N-(3-氯苄基)磺酰)苯基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-35)的制备
制备方法基本同实施例1，本实施例得到化合物A-35(58.1％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),8.20(t,J＝6.4Hz,1H),7.70(d,J＝8.0Hz,4H),7.44(d,J＝8.3Hz,2H),7.36(d,J＝8.2Hz,2H),7.28–7.21(m,3H),7.16(d,J＝7.4Hz,1H),4.03(d,J＝6.3Hz,2H),3.51(d,J＝4.3Hz,4H),2.38(s,8H).13C NMR(125MHz,DMSO-d6)δ164.60,143.67,142.04,140.75,139.78,133.28,131.92,130.46,129.61,129.10,127.76,127.38,127.26,126.87,126.62,62.04,61.76,53.06,45.85.HRMS calcd forC26H30ClN4O4S 529.1671[M+H]+,found 529.1688.
实施例36：4-((4-(4-(N-(4-氯苄基)磺酰氨基)苄基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-36)的制备
制备方法基本同实施例1，本实施例得到化合物A-36(35.4％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.02(s,1H),8.18(t,J＝6.3Hz,1H),7.69(d,J＝8.3Hz,4H),7.44(d,J＝8.2Hz,2H),7.36(d,J＝8.2Hz,2H),7.28(d,J＝8.5Hz,2H),7.21(d,J＝8.5Hz,2H),3.99(d,J＝6.2Hz,2H),3.51(d,J＝7.0Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO-d6)δ164.09,143.16,141.54,139.32,136.74,131.62,131.45,129.36,129.15,128.64,128.05,126.78,126.42,61.58,61.29,52.60,45.33,39.52.HRMS calcd forC26H30ClN4O4S 529.1671[M+H]+,found 529.1687.
实施例37：N-羟基-4-((4-(4-(N-(3-甲基苯甲基磺酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-37)的制备
制备方法基本同实施例1，本实施例得到化合物A-37(41.7％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),8.07(t,J＝6.3Hz,1H),7.71(t,J＝7.7Hz,4H),7.45(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.14–7.09(m,1H),7.03–6.96(m,3H),3.94(d,J＝6.3Hz,2H),3.52(d,J＝7.9Hz,4H),2.39(s,8H),2.21(s,3H).13CNMR(125MHz,DMSO-d6)δ164.63,143.51,142.02,139.86,137.90,137.66,131.93,129.60,129.11,128.66,128.53,128.11,127.27,126.91,125.13,62.04,61.78,53.05,46.58,21.38.HRMScalcd for C27H33N4O4S 509.2217[M+H]+,found 509.2237.
实施例38：N-羟基-4-((4-(4-(N-(4-甲基苄基)磺酰)苯基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-38)的制备
制备方法基本同实施例1，本实施例得到化合物A-38(53.6％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),9.02(s,1H),8.05(t,J＝6.3Hz,1H),7.71(t,J＝8.0Hz,4H),7.45(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.05(q,J＝8.2Hz,4H),3.92(s,2H),3.52(d,J＝10.5Hz,4H),2.39(s,8H),2.22(s,3H).13C NMR(125MHz,DMSO-d6)δ164.58,143.51,142.01,139.85,136.62,135.02,131.93,129.64,129.15,129.11,127.99,127.26,126.91,62.05,61.78,53.06,46.37,21.11.HRMS calcd for C27H33N4O4S509.2217[M+H]+,found 509.2238.
实施例39：N-(2-氟苄基)-4-((4-(4-(羟基甲酰氨基)苄基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-39)的制备
制备方法基本同实施例1，本实施例得到化合物A-39(54.8％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,2H),7.85(d,J＝8.0Hz,2H),7.70(d,J＝7.9Hz,2H),7.42–7.27(m,6H),7.17(q,J＝8.5,6.9Hz,2H),4.51(d,J＝5.5Hz,2H),3.52(s,4H),2.40(s,8H).13C NMR(125MHz,DMSO)δ166.64,161.43,159.49,133.30,131.95,129.85,129.81,129.25,129.19,129.10,127.71,127.28,126.74,126.62,124.76,124.74,115.58,115.41,61.98,53.01,39.72,36.85,36.81.HRMS calcd for C27H30FN4O3477.2296[M+H]+,found 477.2320.
实施例40：N-(2-氯苄基)-4-((4-(4-(羟基甲酰氨基)苄基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-40)的制备
制备方法基本同实施例1，本实施例得到化合物A-40(63.9％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.00(t,J＝5.9Hz,2H),7.87(d,J＝8.3Hz,2H),7.69(d,J＝8.2Hz,2H),7.45(dd,J＝7.5,1.6Hz,1H),7.39(d,J＝8.2Hz,2H),7.37–7.32(m,3H),7.32–7.26(m,2H),4.53(d,J＝5.8Hz,2H),3.51(d,J＝10.6Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO)δ166.12,163.94,141.73,141.44,136.25,132.58,131.73,131.29,128.92,128.45,128.43,128.34,128.33,127.09,126.97,126.62,61.41,52.45,40.35,39.52.HRMScalcd for C27H30ClN4O3 493.2001[M+H]+,found 493.2013.
实施例41：N-(3-氯苄基)-4-((4-(4-(羟基甲酰氨基)苄基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-41)的制备
制备方法基本同实施例1，本实施例得到化合物A-41(69.7％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.03(t,J＝6.0Hz,1H),8.98(s,1H),7.84(d,J＝8.2Hz,2H),7.69(d,J＝8.2Hz,2H),7.37(dd,J＝17.7,7.9Hz,6H),7.32–7.25(m,2H),4.46(d,J＝5.9Hz,2H),3.50(d,J＝8.0Hz,4H),2.38(s,8H).13C NMR(125MHz,DMSO)δ166.58,164.57,142.85,133.38,133.28,131.95,130.63,129.12,127.69,127.48,127.28,127.13,126.37,61.96,52.99,42.57,39.74.HRMS calcd for C27H30ClN4O3 493.2001[M+H]+,found493.2015.
实施例42：N-羟基-4-[(4-(4-[(吡啶-2-基甲基)氨甲酰]苄基)哌嗪-1-基)甲基]苯甲酰胺(化合物A-42)的制备
制备方法基本同实施例1，本实施例得到化合物A-42(55.6％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.06(t,J＝6.0Hz,1H),8.99(s,1H),8.50(d,J＝5.5Hz,1H),7.87(d,J＝8.2Hz,2H),7.74(td,J＝7.7,1.8Hz,1H),7.69(d,J＝8.2Hz,2H),7.39(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H),7.31(d,J＝7.9Hz,1H),7.25(dd,J＝6.8,5.1Hz,1H),4.56(d,J＝5.9Hz,2H),3.51(d,J＝10.0Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO)δ166.69,159.31,149.27,142.30,142.08,137.15,133.34,131.92,129.08,127.69,127.26,122.51,121.33,62.05,53.09,45.13.HRMS calcd for C26H30N5O3 460.2343[M+H]+,found460.2361.
实施例43：4-((5-(4-(N-苄基-N-甲基磺酰)苯基)六氢噻吩[3,4-c]吡咯-2(1H)-基)甲基)N-羟基苯甲酰胺(化合物A-43)的制备
制备方法基本同实施例1，本实施例得到化合物A-43(68.4％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),7.79(d,J＝8.2Hz,2H),7.70(d,J＝8.1Hz,2H),7.58(d,J＝8.2Hz,2H),7.36(dd,J＝14.1,7.6Hz,4H),7.30(t,J＝5.5Hz,3H),4.13(s,2H),3.66(s,2H),3.58(s,2H),2.59(dd,J＝15.8,7.4Hz,6H),2.54(s,3H),2.33–2.25(m,4H).13C NMR(125MHz,DMSO)δ34.44,39.52,41.45,53.29,58.17,58.45,59.20,59.28,126.78,127.18,127.66,128.14,128.17,128.52,129.06,131.29,135.36,136.04,142.59,144.90,164.10.HRMS calcd for C29H35N4O4S 535.2374[M+H]+,found535.2396.
实施例44：4-((4-(4-(N-(2-氯苯甲基)磺酰)苯甲基)哌嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物A-44)的制备
制备方法基本同实施例1，本实施例得到化合物A-44(44.2％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.00(s,1H),8.19(t,J＝6.0Hz,1H),7.71(dd,J＝14.8,8.2Hz,4H),7.46(d,J＝8.2Hz,2H),7.40–7.32(m,4H),7.24(qd,J＝7.5,3.6Hz,2H),4.07(d,J＝5.9Hz,2H),3.52(d,J＝9.1Hz,4H),2.44(d,J＝52.5Hz,8H).13C NMR(125MHz,DMSO-d6)δ164.11,143.20,141.55,139.05,134.79,132.08,131.46,129.76,129.22,129.02,128.95,128.63,127.04,126.79,126.43,64.91,61.56,61.27,52.57,43.55,39.52.HRMScalcd for C26H30ClN4O4S 529.1671[M+H]+,found 529.1705.
实施例45：N-羟基-4-((4-(4-(N-(2-甲苯甲基)磺酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-45)的制备
制备方法基本同实施例1，本实施例得到化合物A-45(35.4％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(s,1H),7.93(t,J＝6.0Hz,1H),7.74(d,J＝8.2Hz,2H),7.70(d,J＝8.1Hz,2H),7.47(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.15(d,J＝7.4Hz,1H),7.13–7.04(m,3H),3.94(d,J＝6.0Hz,2H),3.52(d,J＝14.2Hz,4H),2.40(s,8H),2.17(s,3H).13C NMR(125MHz,DMSO-d6)δ164.14,143.07,141.57,139.12,135.98,135.15,131.46,129.91,129.20,128.63,127.32,126.79,126.45,125.62,61.56,61.29,52.58,44.24,40.02,39.85,39.52,18.45.HRMS calcd for C27H33N4O4S509.2217[M+H]+,found 509.2257.
实施例46：N-羟基-4-((4-(4-(N-(2-甲氧基苯甲基)磺酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-46)的制备
制备方法基本同实施例1，本实施例得到化合物A-46(30.1％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.00(s,1H),7.91(t,J＝6.2Hz,1H),7.70(d,J＝8.0Hz,4H),7.44(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.22–7.13(m,2H),6.88–6.79(m,2H),3.94(d,J＝6.2Hz,2H),3.68(s,3H),3.51(d,J＝6.0Hz,4H),2.39(s,8H).13CNMR(125MHz,DMSO-d6)δ164.14,156.40,142.96,141.57,139.31,131.46,129.09,128.63,128.49,128.43,126.79,126.40,125.04,119.93,110.32,64.91,61.56,61.30,55.14,52.58,40.98,39.52.HRMS calcd for C27H33N4O5S 525.2166[M+H]+,found 525.2176.
实施例47：N-羟基-4-((4-(4-(N-(3-甲氧基苯甲基)磺酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-47)的制备
制备方法基本同实施例1，本实施例得到化合物A-47(32.0％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),7.71(dd,J＝8.1,5.3Hz,4H),7.45(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.14(t,J＝7.7Hz,1H),6.79–6.71(m,3H),3.97(d,J＝6.3Hz,2H),3.66(s,3H),3.51(d,J＝4.1Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO-d6)δ164.61,159.58,143.55,142.03,139.87,139.62,131.94,129.67,129.61,129.12,127.27,126.91,120.12,113.34,113.15,62.04,61.77,55.38,53.06,46.52.HRMS calcd forC27H33N4O5S 525.2166[M+H]+,found 525.2195.
实施例48：N-羟基-4-((4-(4-(N-(4-甲氧基苯甲基)磺酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-48)的制备
制备方法基本同实施例1，本实施例得到化合物A-48(30.1％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.98(s,1H),8.02(t,J＝6.3Hz,1H),7.70(dd,J＝8.2,3.3Hz,4H),7.45(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.09(d,J＝8.7Hz,2H),6.78(d,J＝8.7Hz,2H),3.91(d,J＝6.2Hz,2H),3.67(s,3H),3.51(d,J＝8.4Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO-d6)δ165.90,158.14,141.61,141.59,133.10,131.69,128.60,128.55,128.53,127.15,126.78,113.64,61.56,55.04,52.60,42.00,39.85,39.52.HRMScalcd for C27H33N4O5S 525.2166[M+H]+,found 525.2185.
实施例49：N-(4-氯苯甲基)-4-((4-(4-(羟基甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-49)的制备
制备方法基本同实施例1，本实施例得到化合物A-49(65.9％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.02(t,J＝5.8Hz,1H),8.98(s,1H),7.83(d,J＝8.0Hz,2H),7.69(d,J＝8.0Hz,2H),7.37(t,J＝6.8Hz,5H),7.35–7.28(m,3H),4.45(d,J＝5.8Hz,2H),3.51(d,J＝6.6Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO)δ166.09,164.16,141.74,141.55,138.79,132.87,131.46,131.24,129.06,128.62,128.20,127.19,126.79,61.54,61.54,52.57,52.57,41.96,41.96,39.52.HRMS calcd for C27H30ClN4O3493.2001[M+H]+,found 493.2032.
实施例50：N-(3-氟苯甲基)-4-((4-(4-(羟基甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-50)的制备
制备方法基本同实施例1，本实施例得到化合物A-50(46.8％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.03(t,J＝6.0Hz,1H),8.98(s,1H),7.84(d,J＝8.1Hz,2H),7.69(d,J＝8.1Hz,2H),7.37(dd,J＝16.3,8.1Hz,5H),7.18–7.03(m,3H),4.48(d,J＝5.9Hz,2H),3.50(d,J＝8.0Hz,4H),2.38(s,8H).13C NMR(125MHz,DMSO)δ166.15,163.17,161.23,142.81,142.75,141.82,141.59,132.83,131.45,130.23,130.16,128.61,127.20,126.79,123.13,113.89,113.72,113.54,113.37,61.56,52.60,42.14,39.52.HRMS calcdfor C27H30FN4O3 477.2296[M+H]+,found 477.2348.
实施例51：N-(4-氟苯甲基)-4-((4-(4-(羟基甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-51)的制备
制备方法基本同实施例1，本实施例得到化合物A-51(44.3％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.00(t,J＝5.9Hz,2H),7.84(d,J＝8.2Hz,2H),7.69(d,J＝8.2Hz,2H),7.37(d,J＝8.3Hz,2H),7.36(s,2H),7.34(d,J＝6.0Hz,2H),7.17–7.11(m,2H),4.44(d,J＝5.9Hz,2H),3.51(d,J＝5.3Hz,4H),2.39(s,8H).13CNMR(125MHz,DMSO)δ166.04,164.16,162.08,160.16,141.69,141.55,135.93,135.91,132.95,131.47,129.20,129.13,128.62,128.61,127.19,126.80,115.04,114.87,61.54,52.57,41.90,39.69,39.52.HRMS calcd for C27H30FN4O3 477.2296[M+H]+,found477.2339.
实施例52：N-羟基-4-((4-(4-((2-甲基苯甲基)氨甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-52)的制备
制备方法基本同实施例1，本实施例得到化合物A-52(51.5％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(s,1H),8.85(t,J＝5.8Hz,1H),7.85(d,J＝8.2Hz,2H),7.69(d,J＝8.2Hz,2H),7.36(dd,J＝12.1,8.2Hz,4H),7.22(q,J＝4.0,3.4Hz,1H),7.15(dh,J＝7.0,4.0,3.4Hz,3H),4.44(d,J＝5.7Hz,2H),3.50(d,J＝7.1Hz,4H),2.38(s,8H),2.32(s,3H).13C NMR(125MHz,DMSO)δ166.03,164.15,141.66,141.60,137.19,135.42,133.04,131.45,129.84,128.60,128.56,127.22,126.79,126.69,125.68,61.57,52.61,40.62,39.52,18.72.HRMS calcd for C28H33N4O3 473.2547[M+H]+,found473.2586.
实施例53：N-羟基-4-((4-(4-((3-甲基苯甲基)氨甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-53)的制备
制备方法基本同实施例1，本实施例得到化合物A-53(38.9％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.04–8.90(m,2H),7.84(d,J＝7.8Hz,2H),7.69(d,J＝7.8Hz,2H),7.44–7.30(m,4H),7.20(t,J＝7.4Hz,1H),7.14–7.07(m,2H),7.04(d,J＝7.2Hz,1H),4.43(d,J＝5.6Hz,2H),3.50(d,J＝6.0Hz,4H),2.38(s,8H),2.28(s,3H).13CNMR(125MHz,DMSO)δ165.98,164.12,141.68,141.60,139.65,137.28,133.03,131.45,128.59,128.17,127.80,127.32,127.19,126.79,124.30,61.58,52.61,42.53,39.52,21.04.HRMS calcd for C28H33N4O3 473.2547[M+H]+,found 473.2582.
实施例54：N-羟基-4-((4-(4-((4-甲基苯甲基)氨甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-54)的制备
制备方法基本同实施例1，本实施例得到化合物A-54(52.3％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.00(s,1H),8.94(t,J＝6.0Hz,1H),7.83(d,J＝8.2Hz,2H),7.69(d,J＝8.2Hz,2H),7.36(t,J＝8.5Hz,4H),7.19(d,J＝7.9Hz,2H),7.12(d,J＝7.9Hz,2H),4.42(d,J＝5.9Hz,2H),3.50(d,J＝5.3Hz,4H),2.38(s,8H),2.26(s,3H).13CNMR(125MHz,DMSO)δ165.97,164.13,141.64,136.70,135.69,133.08,131.45,128.78,128.60,128.56,127.17,126.79,61.57,52.60,42.31,39.52,20.67.HRMS calcd forC28H33N4O3 473.2547[M+H]+,found 473.2581.
实施例55：N-羟基-4-((4-(4-((2-甲氧基苯甲基)氨甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-55)的制备
制备方法基本同实施例1，本实施例得到化合物A-55(56.4％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.98(s,1H),8.80(t,J＝5.9Hz,1H),7.86(d,J＝8.2Hz,2H),7.69(d,J＝8.2Hz,2H),7.37(dd,J＝13.0,8.2Hz,4H),7.23(t,J＝8.5Hz,1H),7.16(d,J＝7.4Hz,1H),6.99(d,J＝8.1Hz,1H),6.89(t,J＝7.4Hz,1H),4.44(d,J＝5.8Hz,2H),3.82(s,3H),3.51(d,J＝8.1Hz,4H),2.39(s,8H).13C NMR(125MHz,DMSO)δ166.65,164.61,156.98,142.00,133.57,131.94,129.09,129.06,128.30,127.68,127.62,127.40,127.27,120.55,110.86,62.02,55.79,53.05,38.02.HRMS calcd for C28H33N4O4489.2496[M+H]+,found 489.2524.
实施例56：N-羟基-4-((4-(4-((3-甲氧基苯甲基)氨甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-56)的制备
制备方法基本同实施例1，本实施例得到化合物A-56(63.7％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.99(s,1H),8.97(d,J＝5.8Hz,1H),7.84(d,J＝7.9Hz,2H),7.69(d,J＝7.8Hz,2H),7.36(d,J＝20.4Hz,4H),7.23(t,J＝7.9Hz,1H),6.88(d,J＝6.4Hz,2H),6.80(d,J＝8.4Hz,1H),4.44(d,J＝5.5Hz,2H),3.72(s,3H),3.50(d,J＝6.8Hz,4H),2.38(s,8H).13C NMR(125MHz,DMSO)δ166.06,164.13,159.27,141.72,141.61,141.35,133.02,131.45,129.32,128.59,127.18,126.79,119.33,112.92,111.99,61.58,54.95,52.61,42.51,39.85,39.69,39.52.HRMS calcd for C28H33N4O4 489.2496[M+H]+,found489.2512.
实施例57：N-羟基-4-((4-(4-((4-甲氧基苯甲基)氨甲酰)苯甲基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-57)的制备
制备方法基本同实施例1，本实施例得到化合物A-57(58.1％)，白色固体。1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),8.92(t,J＝5.4Hz,1H),7.83(d,J＝7.9Hz,2H),7.70(d,J＝7.9Hz,2H),7.36(t,J＝7.4Hz,4H),7.23(d,J＝8.4Hz,2H),6.88(d,J＝8.5Hz,2H),4.39(d,J＝5.7Hz,2H),3.72(s,3H),3.51(s,4H),2.39(s,8H).13C NMR(125MHz,DMSO)δ166.38,164.63,158.62,142.07,133.58,132.17,131.92,129.08,129.03,129.01,127.63,127.26,114.12,62.02,55.51,53.06,42.49.HRMS calcd for C28H33N4O4 489.2496[M+H]+,found 489.2503.
实施例58：N-苄基-4-((4-(7-(羟胺基)-7-氧代庚基)哌嗪-1-基)甲基)苯甲酰胺(化合物A-58)的制备
制备方法基本同实施例1，本实施例得到化合物A-58(43.2％)，白色固体。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.99(t,J＝6.0Hz,1H),8.64(s,1H),7.85(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),7.35–7.28(m,4H),7.23(ddd,J＝8.6,6.4,2.7Hz,1H),4.47(d,J＝6.0Hz,2H),4.09(d,J＝5.1Hz,2H),3.51(s,2H),3.17(d,J＝4.5Hz,6H),2.38(s,8H),1.92(t,J＝7.3Hz,2H),1.47(d,J＝7.1Hz,2H),1.40(s,2H),1.23(s,4H).13CNMR(125MHz,DMSO)δ25.52,27.02,28.92,32.68,40.49,43.02,49.07,52.63,53.01,58.04,61.93,127.16,127.63,127.66,128.72,129.09,133.52,140.20,142.04,166.50,169.54.HRMScalcd for C26H37N4O3 453.2860[M+H]+,found 453.2901.
药效学实验
1.化合物对HDAC1/HDAC6抑制活性的测定
1.1实验方法
HDAC1/HDAC6抑制活性测试采用荧光检测法，底物Ac-Lys-Tyr-Lys(Ac)-AMC经HDAC1/HDAC6去乙酰化后，利用胰酶水解得到的产物AMC在荧光检测仪的发射光下可被检测到荧光信号。通过测定空白组、对照组和实验组随时间荧光信号的变化，计算得到测试化合物抑制率。选取抑制率大于50％的化合物，将其配制成不同浓度的样品溶液并测试其抑制率，使用GraphPad Prism软件计算出相应的IC50值。
1.2实验结果
表1展示了实施例A-1至A-58化合物对HDAC1/HDAC6的抑制率和IC50值。
表1
由表1可知，在所有化合物中，化合物A-30(IC50＝0.07μM)和A-31(IC50＝0.08μM)对HDAC6的抑制活性最强，接近阳性对照药伏立诺他(IC50＝0.07μM)。其中，共有53个化合物对HDAC6具有一定的选择性。有研究证明，HDAC6深度参与炎症、肿瘤以及抑郁症的发生和发展过程。同时，在所有化合物中，共有38个化合物对HDAC1和HDAC6的抑制率都超过了50％。
2.化合物对CXCR4竞争性亲和力的测定。
2.1实验方法
由于CXCR4的天然配体CXCL12分子较大，不易于合成和标记，我们选择了TN14003(一种有效的CXCR4肽拮抗剂)来模拟CXCL12，并以生物素对其进行标记。生物素标记后的TN14003可与MDA-MB-231细胞膜表面的CXCR4强效结合，在共聚焦显微镜下细胞周围显示出强烈的红色荧光信号。将待测化合物先与细胞孵化一段时间后，再加入生物素标后的TN14003进行孵育，则细胞膜上的荧光信号显著减弱。因此，通过对荧光信号进行定量，根据荧光信号的减弱程度，计算出受试化合物对CXCR4的亲和力。
2.2实验结果
基于表1中各化合物对HDAC1/HDAC6的抑制率和IC50值的测定结果，我们选择了对HDAC1/HDAC6的抑制率(20μM)都大于80％的化合物进行CXCR4的结合亲和力测定。表2展示了优选实施例化合物与CXCR4的结合亲和力。
表2
由表2可知，在上述优选化合物中，共有12个化合物对CXCR4的结合亲和力超过了50％，优于阳性对照药普乐沙福。其中，化合物A-36对CXCR4的结合亲和力最强，达到了86.90％，这表明化合物A-36可能在体内起到良好的CXCR4拮抗作用。
综上所述，化合物A-36对HDAC6的抑制活性接近于阳性对照药伏立诺他，更重要的是，化合物A-36对CXCR4的结合亲和力达到了86.90％，远高于阳性对照药普乐沙福(45.32％)。基于以上活性数据，我们有理由推测化合物A-36可能在体内发挥比伏立诺他和普乐沙福更强的抗肿瘤、抗炎和抗抑郁效果，具有良好的开发潜力。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (9)

1.酰胺/磺酰胺类CXCR4/HDAC双重抑制剂，其特征在于，为具有如式(I)或(II)所示结构的化合物和/或其可药用盐：
式(I)、(II)中：
R1选自以下结构：
R2选自H、C1～C4烷基；
R3选自以下结构：
R4选自以下结构：-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2-，其中n为1～4的整数，表示与R3连接的位点。
2.根据权利要求1所述的酰胺/磺酰胺类CXCR4/HDAC双重抑制剂，其特征在于，所述酰胺/磺酰胺类CXCR4/HDAC双重抑制剂为具有如下所示结构的化合物和/或其可药用盐：
3.根据权利要求1或2所述的酰胺/磺酰胺类CXCR4/HDAC双重抑制剂的制备方法，其特征在于，合成路线包括：
所述制备方法包括：
4-溴甲基苯磺酰氯或4-氯甲基苯酰氯与化合物11进行缩合反应得到中间体2或7；
中间体2或7与化合物12进行亲核取代反应得到中间体3或8；
中间体3或8脱去Boc保护基生成中间体4或9；
中间体4或9与化合物13进行取代或缩合反应得到中间体5或10；
中间体5或10经过胺酯交换反应得到所述酰胺/磺酰胺类CXCR4/HDAC双重抑制剂。
4.根据权利要求1或2所述的酰胺/磺酰胺类CXCR4/HDAC双重抑制剂在制备通过拮抗CXCR4和/或抑制HDAC来防治相关疾病的药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述疾病包括癌症、炎症、抑郁症。
6.一种药物组合物，其特征在于，含有安全有效量的权利要求1或2所述的酰胺/磺酰胺类CXCR4/HDAC双重抑制剂。
7.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物还包括药理上可接受的赋形剂、载体、辅料中的至少一种。
8.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物通过拮抗CXCR4和/或抑制HDAC来防治相关疾病。
9.根据权利要求8所述的药物组合物，其特征在于，所述疾病包括癌症、炎症、抑郁症。
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