CN114853672A - 作为CDKs抑制剂的他克林衍生物及其应用 - Google Patents

作为CDKs抑制剂的他克林衍生物及其应用 Download PDF

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CN114853672A
CN114853672A CN202210516927.5A CN202210516927A CN114853672A CN 114853672 A CN114853672 A CN 114853672A CN 202210516927 A CN202210516927 A CN 202210516927A CN 114853672 A CN114853672 A CN 114853672A
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赵庆春
刘文武
陆鸿远
许子华
吴丽萌
黄耀广
刘文杰
李德平
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Abstract

本发明涉及作为CDKs抑制剂的他克林衍生物及其应用，衍生物结构通式如式I所示，本发明的他克林衍生物具有结构新颖，高的抗增殖活性和CDK2和CDK9抑制活性。因此，该类化合物在制备预防或治疗肿瘤中具有重要作用；
Figure DDA0003640034410000011

Description

作为CDKs抑制剂的他克林衍生物及其应用
技术领域
本发明属于有机化合物合成与医药应用技术领域，具体涉及作为CDKs抑制剂的他克林衍生物及其应用。
背景技术
细胞周期是生命中的一个基本过程，细胞中发生着一系列事件，导致形成两个相同的子细胞。细胞周期控制从静止或胞质分裂到细胞增殖的过渡，并通过其检查点确保基因组稳定性。激酶是人类基因组中磷酸转移酶的主要组成部分，它催化ATP的γ-磷酸基团可逆地转移到目标底物上，介导信号转导，并调节细胞生命的大部分方面。目前，大约鉴定出了518种人类蛋白激酶和20种脂质激酶。蛋白激酶是几乎在细胞生物学的每个方面都发挥关键调节作用的酶，根据其底物中靶氨基酸的性质，它们分为酪氨酸激酶、丝氨酸/苏氨酸激酶、双特异性激酶(酪氨酸和丝氨酸/苏氨酸激酶都作用)和组氨酸激酶。激酶对蛋白质的Ser、Thr或Tyr残基进行磷酸化会导致构象变化，从而改变蛋白质底物的活性。细胞周期蛋白依赖性激酶(CDK)属于丝氨酸/苏氨酸蛋白激酶家族，参与细胞周期调节和转录调节。
CDK2在细胞周期调节中起着关键作用，并参与一系列生物过程。CDK2/Cyclin E复合物对正常的细胞周期进程和脱氧核糖核酸复制至关重要。对肿瘤来说，CDK2/Cyclin E复合物已被证明通过几种不同的机制干扰脱氧核糖核酸复制从而干扰癌症的发生和发展。CDK2/Cyclin E的过度激活会造成人类癌症的基因组不稳定，表现为染色体增加或丢失和重排的几率增加。另外，高水平的CDK2和Cyclin E活性的增加与癌症患者的不良预后和生存率降低密切相关。
CDK9是正性转录延长因子P-TEFb中的催化亚甲基，当负性转录延长因子(NELF、N-TEFs)参与细胞转录的负性调节，正性P-TEFb被招募至NELF和N-TEFs抑制转录延长的体系中，使负性转录延长因子脱离，从而使转录得以继续。故通过抑制CDK9，继而阻断P-TEFb对RNAPoly-IIC末端区域的磷酸化，使得转录被抑制，从而可以导致肿瘤细胞凋亡。因此，设计合成CDK2/9激酶抑制剂将有利于癌症的治疗。
他克林(1,2,3,4-四氢吖啶-9-胺)是FDA批准的第一个用于治疗阿尔茨海默病(AD)的药物，但由于其剂量依赖性的肝毒性而退出市场。由于其低分子量和优异的胆碱酯酶(包括AChE和BChE)抑制效果，他克林仍然是开发用于治疗AD的胆碱酯酶抑制剂或多靶点抑制剂的多功能骨架。然而，他克林的抗癌活性都被研究人员大大地忽视了。
但目前研究出的他克林及其衍生物对肿瘤细胞的抗增殖活性均不高，且未见他克林及其衍生物作为CDK2和CDK9抑制剂的报道，因此，他克林衍生物在制备预防或治疗肿瘤中仍需进一步研究。
发明内容
发明目的：本发明的目的在于提供一种具有抑制CDK2/9的他克林衍生物或其药学上可接受的盐。本发明的另一个目的是提供所述他克林衍生物的制备方法，同时还指出他克林衍生物在制备治疗癌症药物中的应用。
技术方案：
一种他克林衍生物或其药学上可接受的盐，所述的衍生物结构通式如式I所示：
Figure BDA0003640034390000021
其中：A环是4-12个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基，所述杂环芳基的芳杂环包括1-3个N、O、或S的杂原子；R1为酰胺上的取代基，选自CH3、环丙基、环丁基、环戊基、环己基或者苯基，所述苯基为取代或者未取代的苯基；R2选自NH2或者0-4个杂原子的3-12元环；n各自独立地为0、1。
他克林衍生物或其药学上可接受的盐，A环为
Figure BDA0003640034390000022
R2为
Figure BDA0003640034390000023
Figure BDA0003640034390000024
NH2或
Figure BDA0003640034390000025
n各自独立地为0、1或2。
下列化合物或其在药学上可接受的盐，选自：
Figure BDA0003640034390000026
Figure BDA0003640034390000031
Figure BDA0003640034390000041
一种药物组合物，含有所述的式I或其药学上可接受的盐以及药学上可接受的辅料。
所述式I添加一种或多种药学上可接受的辅料制成制剂，所述制剂的剂型为胶囊剂、丸剂、片剂、颗粒剂或注射剂。
所述化合物或其药学上可用的盐在制备治疗肿瘤中的应用。
所述化合物或其药学上可用的盐在制备CDK2抑制剂或者CDK9抑制剂中的应用。
与现有的技术相比，本发明具有如下显著的特点：所涉及的他克林衍生物具有结构新颖，高的抗增殖活性和CDK2和CDK9抑制活性。因此，该类化合物在制备预防或治疗肿瘤中具有重要作用。
附图说明
图1为化合物ZLWT-3到ZLWT-6制备方法示意图；
图2为化合物ZLWT-7到ZLWT-13制备方法示意图；
图3为化合物ZLWT-14-16、ZLWT-18-23、ZLWT-25-28、ZLWT-38和ZLWT-39制备方法示意图；
图4为化合物ZLWT-17制备方法示意图；
图5为化合物ZLWT-24制备方法示意图；
图6为化合物ZLWT-29制备方法示意图；
图7为化合物ZLWT-30到ZLWT-537制备方法示意图；
图8为化合物ZLWT-40到ZLWT-58制备方法示意图；
图9为ZLWT-37对CDK9的抑制活性。
具体实施方式
下面通过具体实施例对本发明进行说明，但本发明并不局限于这些实施例。通过核磁共振(NMR)和高分辨质谱(HR-MS)确定化合物的结构。NMR的测定是使用BrukerAVANCE-300/600核磁共振仪，测定的溶剂是DMSO-d6，内标为TMS。柱层析采用200-300目硅胶(青岛海洋化工厂生产)。
实施例1 7-溴-1,2,3,4-四氢吖啶-9-胺(ZLWT-2)
如图1所示，向2-氨基-5-溴苯甲腈(化合物1)(1当量)的环己酮(50mL)溶液中加入无水ZnCl2(3当量)。将混合物在140℃搅拌3小时。冷却后，过滤后，滤液经浓缩后通过硅胶色谱柱纯化得到目标化合物ZLWT-2。产率76％，灰白色固体。1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝1.9Hz,1H),7.66–7.55(m,2H),6.71(s,2H),2.82(t,J＝5.8Hz,2H),2.57–2.48(m,2H),1.81(dd,J＝7.6,4.4Hz,4H).ESI-MS m/z 277.2[M+H]+.
实施例2 6-溴-1,2,3,4-四氢吖啶-9-胺(化合物11)
如图4所示，2-氨基-4-溴苯甲腈(化合物10)为原料，合成方法如实施例1，得到化合物11。产率66％，灰白色固体化合物11。1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝2.1Hz,1H),7.53–7.26(m,2H),6.58(s,2H),2.76(m,2H),2.64–2.52(m,2H),1.78(m,4H).ESI-MS m/z277.1[M+H]+.
实施例3N-(4-溴吡啶-2-基)乙酰胺(化合物3a)
Figure BDA0003640034390000051
如图2所示，向4-溴-2-氨基吡啶(化合物2)(5g，28.90mmol)的乙酸酐(50mL)溶液中加入DMAP(0.035g，0.3mmol)。将混合物在140℃搅拌6小时后，倒入冰水中，用2M NaOH中和，过滤，得到化合物3a，为白色固体，收率78％。ESI-MS m/z 214.8[M+H]+。
实施例4N-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)吡啶-2-基)乙酰胺(化合物4a)
Figure BDA0003640034390000052
如图2所示，将化合物3a(1当量)和4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)(1.2当量)溶解在无水二氧六环中，加入KOAc(3当量)和Pd(dppf)Cl2(0.05％mol)。N2保护下90℃反应12h后，浓缩溶剂，向反应瓶中加入水，过滤收集滤饼，得到中间体化合物4a，该中间体无需进一步纯化，直接使用。
实施例5 N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)环丙烷甲酰胺(化合物4b)
Figure BDA0003640034390000053
如图2所示，向4-溴-2-氨基吡啶(化合物2)(1当量)和吡啶(1.5当量)在THF(50mL)中的溶液中，在冰浴下缓慢滴加环丙基甲酰氯(1.2当量)，反应4h之后，减压浓缩溶剂并加入冰水，然后过滤以获得中间体化合物3b。向化合物3b(1当量)和4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)(1.2当量)在无水二氧六环中的溶液中添加KOAc(3当量)和Pd(dppf)Cl2(0.05％mol)。在氮气保护下，在90℃下反应12h后，浓缩溶剂并向反应瓶中加水，然后收集滤饼以获得中间体化合物4b，该中间体直接使用，无需进一步纯化，产率90％，灰白色固体。
实施例6 N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)环丁烷甲酰胺(化合物4c)
Figure BDA0003640034390000061
如图2所示，环丁基甲酰氯替换环丙基甲酰氯，其他条件不变，合成方法如实施例5，得到化合物4c。产率76％，棕褐色固体。
实施例7 N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)环戊烷甲酰胺(化合物4d)
Figure BDA0003640034390000062
如图2所示，环戊基甲酰氯替换环丙基甲酰氯，其他条件不变，合成方法如实施例5，得到化合物4d。产率78％，棕褐色固体。
实施例8 N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)环己烷甲酰胺(化合物4e)
Figure BDA0003640034390000063
如图2所示，环己基甲酰氯替换环丙基甲酰氯，其他条件不变，合成方法如实施例5，得到化合物4e。产率43％，棕褐色固体。
实施例9 N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)苯甲酰胺(化合物4f)
Figure BDA0003640034390000064
如图2所示，苯甲酰氯替换环丙基甲酰氯，其他条件不变，合成方法如实施例5，得到化合物4f。产率65％，棕褐色固体。
实施例10 2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(化合物6)
Figure BDA0003640034390000071
如图2所示，向4-溴-2-甲基吡啶(化合物5)(1当量)和4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)(1.2当量)在无水二氧六环中的溶液中添加KOAc(3当量)和Pd(dppf)Cl2(0.05％mol)。在氮气保护下，在90℃下反应12h后，浓缩溶剂并向反应瓶中加水，然后收集滤饼以获得中间体化合物6，该中间体直接使用，无需进一步纯化。产率78％，灰褐色固体。
实施例11 6-溴-9-氯-1,2,3,4-四氢吖啶(化合物8a)
如图3所示，将环己酮(1.2当量)加入到含有2-氨基-4-溴苯甲酸(化合物7a)(1当量)的POCl3(30mL)溶液中，在回流下反应3h，然后冷却至室温，减压回收POCl3。残渣用乙酸乙酯稀释，用K2CO3水溶液调节Ph至9-10，并用盐水洗涤。粗产物通过快速色谱纯化，得到所需中间体化合物8a。产率87％，淡黄色固体。1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.97(d,J＝8.9Hz,1H),7.76–7.69(m,1H),2.94(m,4H),1.89–1.84(m,4H).ESI-MS m/z 295.9[M+H]+.
实施例12 7-溴-9-氯-1,2,3,4-四氢吖啶(化合物8b)
如图3所示，2-氨基-5-溴苯甲酸(化合物7b)替换化合物7a，合成方法如实施例11，得到化合物8b。产率87％，淡黄色固体。1H NMR(400MHz,DMSO-d6)δ8.22–8.14(m,1H),7.85(dd,J＝8.9,1.4Hz,2H),3.11–2.75(m,4H),1.87(m,4H).ESI-MS m/z 296.1[M+H]+.
实施例13 7-溴-9-氯-2,3-二氢-1H-环戊烷[b]喹啉(化合物8c)
如图8所示，2-氨基-5-溴苯甲酸(化合物7b)替换化合物7a，环戊酮替换环己酮，合成方法如实施例11，得到化合物8c。产率92％，淡黄色固体。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.1Hz,1H),7.94–7.83(m,2H),3.12(q,J＝7.3Hz,4H),2.18(m,2H).ESI-MS m/z291.0[M+H]+.
实施例14 7-(4-甲氧基苯基)-1,2,3,4-四氢吖啶-9-胺(ZLWT-3)
如图1所示，将化合物ZLWT-2(1当量)和4-甲氧基苯硼酸(1.2当量)溶解在二氧六环/水中(4:1)中，添加Cs2CO3(3当量)和Pd(dppf)Cl2(0.05％mol)。将反应混合物在95℃下搅拌12h，然后用水(100mL)稀释反应混合物并用乙酸乙酯(3×50mL)萃取。用盐水(200mL)清洗合并的有机层，然后用无水Na2SO4干燥，过滤，并减压浓缩。反应粗产物经快速柱层析纯化，得到目标化合物ZLWT-3。白色固体，产率45％。白色固体。1H NMR(600MHz,DMSO-d6)δ8.41(d,J＝1.8Hz,1H,H-7),7.80(d,J＝8.8Hz,3H,H-9,10,20),7.67(d,J＝8.7Hz,1H,H-16),7.12–6.98(m,2H,H-17,19),6.45(s,2H,H-21),3.82(s,3H,H-23),2.84(t,J＝6.0Hz,2H,H-11),2.58(t,J＝6.2Hz,2H,H-14),1.95–1.60(m,4H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ159.1(C-18),157.6(C-5),148.7(C-1),145.9(C-3),134.3(C-8),132.9(C-15),128.9(C-9),128.3(2C,C-16,20),126.9(C-10),119.0(C-7),117.7(C-6),114.7(2C,C-17,19),109.6(C-2),55.6(C-23),34.0(C-11),24.1(C-14),23.1(C-13),23.0(C-12).HR-ESI-MS:305.1640[M+H]+,(calcd for C20H20N2O,305.1648).
实施例15 7-(2H-1,3-苯并二氧醇-5-基)-1,2,3,4-四氢吖啶-9-胺(ZLWT-4)
如图1所示，苯并[d][1，3]二氧杂环戊烯-5-硼酸替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-4。产率32％，白色固体。1H NMR(600MHz,DMSO-d6)δ8.40(d,J＝1.9Hz,1H,H-7),7.79(dd,J＝8.8,1.9Hz,1H,H-9),7.66(d,J＝8.8Hz,1H,H-10),7.49(d,J＝1.8Hz,1H,H-20),7.33(dd,J＝8.1,1.9Hz,H-16),7.02(d,J＝8.1Hz,1H,H-17),6.46(s,2H,H-21),6.08(s,2H,H-23),2.84(t,J＝6.1Hz,2H,H-11),2.58(t,J＝6.2Hz,2H,H-14),1.96–1.66(m,4H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ157.8(C-5),148.7(C-18),148.4(C-19),147.0(C-1),146.1(C-3),134.8(C-8),134.2(C-15),128.9(C-9),127.0(C-10),120.7(C-16),119.3(C-7),117.6(C-6),109.6(C-2),109.0(C-17),107.6(C-20),101.5(C-23),34.0(C-11),24.1(C-14),23.1(C-13),23.0(C-12).HR-ESI-MS:319.1438[M+H]+,(calcd for C20H18N2O2,319.1441).
实施例16 7-(吡啶-3-基)-1,2,3,4-四氢吖啶-9-胺(ZLWT-5)
如图1所示，3-吡啶苯硼酸替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-5。产率43％，白色固体。1H NMR(600MHz,DMSO-d6)δ9.10(d,J＝1.9Hz,1H,H-7),8.57(dd,J＝4.5,1.3Hz,2H,H-16,18),8.24(ddd,J＝8.0,2.2,1.7Hz,1H,H-20),7.90(dd,J＝8.7,1.9Hz,1H,H-9),7.73(d,J＝8.7Hz,1H,H-10),7.52(ddd,J＝7.9,4.8,0.5Hz,1H,H-19),6.55(s,2H,H-21),2.85(t,J＝6.0Hz,2H,H-11),2.58(t,J＝6.2Hz,2H,H-14),2.00–1.67(m,4H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ158.4(C-5),149.0(C-18),148.5(C-16),148.3(C-1),146.4(C-3),135.8(C-15),134.4(C-8),131.4(C-20),129.2(C-9),126.9(C-10),124.2(C-19),120.5(C-7),117.6(C-6),109.8(C-2),34.0(C-11),24.1(C-14),23.0(C-13),22.9(C-12).HR-ESI-MS:276.1499[M+H]+,(calcd for C18H17N3,276.1495).
实施例17 7-(吡啶-4-基)-1,2,3,4-四氢吖啶-9-胺(ZLWT-6)
如图1所示，4-吡啶苯硼酸替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-6。产率50％，白色固体。1H NMR(600MHz,DMSO-d6)δ8.68(d,J＝1.5Hz,1H,H-7),8.66(d,J＝6.0Hz,2H,H-17,19),7.96(dd,J＝8.9,2.0Hz,1H,H-9),7.90(dd,J＝4.7,1.3Hz,2H,H-16,20),7.74(d,J＝8.8Hz,1H,H-10),6.61(s,2H,H-21),2.85(t,J＝5.9Hz,2H,H-11),2.58(t,J＝6.1Hz,2H,H-14),1.91–1.71(m,4H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ158.9(C-5),150.6(2C,C-17,19),149.2(C-1),147.2(C-3),147.2(C-15),131.2(C-8),129.3(C-9),126.4(C-10),121.5(C-7),121.0(2C,C-16,20),117.5(C-6),109.9(C-2),34.1(C-11),24.1(C-14),23.0(C-13),22.9(C-12).HR-ESI-MS:276.1494[M+H]+,(calcd for C18H17N3,276.1495).
实施例18 7-(2-甲基吡啶-4-基)-1,2,3,4-四氢吖啶-9-胺(ZLWT-7)
如图2所示，2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(化合物6)替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-7。产率61％，白色固体。1H NMR(600MHz,DMSO-d6)δ8.65(d,J＝1.5Hz,1H,H-7),8.51(d,J＝5.2Hz,1H,H-17),7.93(dd,J＝8.8,1.8Hz,1H,H-9),7.78(s,1H,H-20),7.73(d,J＝8.8Hz,1H,H-10),7.70–7.65(m,1H,H-16),6.61(s,2H,H-21),2.85(t,J＝5.9Hz,2H,H-11),2.58(t,J＝6.1Hz,2H,H-14),2.56(s,3H,H-22),1.93–1.60(m,4H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ158.8(C-19),158.8(C-5),149.9(C-17),149.2(C-1),147.5(C-3),147.1(C-15),131.5(C-8),129.2(C-9),126.5(C-10),120.9(C-7),120.7(C-20),118.7(C-16),117.5(C-6),109.9(C-2),34.0(C-11),24.7(C-22),24.1(C-14),23.0(C-13),22.9(C-12).HR-ESI-MS:290.1641[M+H]+,(calcd for C19H19N3,290.1652).
实施例19 N-[4-(9-氨基-5,6,7,8-四氢吖啶-2-基)吡啶-2-基]乙酰胺(ZLWT-8)
如图2所示，N-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)吡啶-2-基)乙酰胺(化合物4a)替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-8。产率70％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.56(s,1H,H-22),8.59(s,1H,H-7),8.48(s,1H,H-20),8.38(d,J＝5.0Hz,1H,H-17),7.90–7.66(m,2H,H-9,10),7.59(d,J＝4.7Hz,1H,H-16),6.61(s,2H,H-21),2.85(t,J＝6.0Hz,2H,H-11),2.58(t,J＝6.2Hz,2H,H-14),2.14(s,3H,H-25),1.83(d,J＝4.3Hz,4H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ169.9(C-23),158.8(C-5),153.3(C-19),149.7(C-17),149.2(C-1),148.7(C-3),147.0(C-15),132.0(C-8),129.3(C-9),126.6(C-10),121.2(C-7),117.7(C-16),117.5(C-6),111.3(C-2),110.0(C-20),34.0(C-11),24.4(C-25),24.1(C-14),23.0(C-13),22.9(C-12).HR-ESI-MS:333.1706[M+H]+,(calcd for C20H20N4O,333.1710).
实施例20 N-[4-(9-氨基-5,6,7,8-四氢吖啶-2-基)吡啶-2-基]环丙烷甲酰胺(ZLWT-9)
如图2所示，N-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)吡啶-2-基)环丙烷甲酰胺(化合物4b)替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-9。产率38％，白色固体。1H NMR(600MHz,DMSO-d6)δ11.02(s,1H,H-22),9.01(s,1H,H-7),8.64(d,J＝8.8Hz,1H,H-17),8.47(d,J＝5.1Hz,1H,H-20),8.17(s,2H,H-10,H-21),7.93(dd,J＝8.8,1.8Hz,1H,H-9),7.52(dd,J＝5.2,1.7Hz,1H,H-16),2.99(t,J＝6.0Hz,2H,H-11),2.5(t,J＝5.5Hz,2H,H-14),2.17–1.99(m,1H,H-25),1.86(d,J＝4.0Hz,4H,H-12,13),0.85(t,J＝10.9Hz,4H,H-25,26)；13C NMR(151MHz,DMSO-d6)δ173.5(C-23),155.6(C-5),153.5(C-19),152.3(C-17),149.5(C-1),147.3(C-3),141.7(C-15),137.8(C-8),125.1(C-9),124.2(C-10),117.5(C-7),117.0(C-16),115.3(C-6),111.2(C-2),110.1(C-20),28.2(C-11),23.0(C-14),21.4(C-13),20.9(C-12),14.7(C-25),8.3(2C,C-26,27).HR-ESI-MS:359.1864[M+H]+,(calcd for C22H22N4O,359.1866).
实施例21 N-[4-(9-氨基-5,6,7,8-四氢吖啶-2-基)吡啶-2-基]环丁烷甲酰胺(ZLWT-10)
如图2所示，N-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)吡啶-2-基)环丁烷甲酰胺(化合物4c)替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-10。产率54％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.37(s,1H,H-22),8.60(d,J＝1.9Hz,1H,H-7),8.55(brs,1H,H-17),8.38(dd,J＝5.2,0.5Hz,1H,H-9),7.82(d,J＝2.0Hz,1H,H-20),7.76(d,J＝8.8Hz,1H,H-10),7.59(dd,J＝5.3,1.7Hz,1H,H-16),6.61(s,2H,H-21),3.43(dd,J＝16.9,8.5Hz,1H,H-25),2.86(t,J＝6.1Hz,2H,H-11),2.59(t,J＝6.2Hz,2H,H-14),2.26(dq,J＝11.5,9.2Hz,2H,H-26,28),2.19–2.07(m,2H,H-26,28),2.00–1.90(m,1H,H-27),1.90–1.76(m,5H,H-12,13,27)；13C NMR(151MHz,DMSO-d6)δ174.3(C-23),158.8(C-5),153.4(C-19),149.7(C-17),149.2(C-1),148.7(C-3),147.1(C-15),132.0(C-8),129.4(C-9),126.6(C-10),121.2(C-7),117.6(C-16),117.5(C-6),111.4(C-2),110.0(C-20),34.1(C-11),24.9(3C,C-25,26,28),24.1(C-14),23.0(C-13),22.9(C-12),18.1(C-27).HR-ESI-MS:373.2010[M+H]+,(calcd for C23H24N4O,373.2023).
实施例22 N-[4-(9-氨基-5,6,7,8-四氢吖啶-2-基)吡啶-2-基]环戊烷甲酰胺(ZLWT-11)
如图2所示，N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)环戊烷甲酰胺(化合物4d)替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-11。产率38％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.60(s,1H,H-22),8.92(d,J＝1.6Hz,1H,H-7),8.55(d,J＝0.8Hz,1H,H-17),8.50–8.35(m,1H,H-20),8.19(dd,J＝8.8,1.8Hz,1H,H-9),8.03(d,J＝8.8Hz,1H,H-10),7.62(dd,J＝5.2,1.7Hz,1H,H-16),3.07–2.92(m,3H,H-11,25),2.57(t,J＝5.7Hz,2H,H-14),1.95–1.80(m,6H,H-12,13,26,29),1.82–1.60(m,4H,H-27,28),1.62–1.48(m,2H,H-26,29)；13C NMR(151MHz,DMSO-d6)δ176.1(C-23),156.1(C-5),153.5(C-19),152.1(C-17),149.0(C-1),148.1(C-3),137.7(C-15),135.2(C-8),131.7(C-9),122.2(C-10),120.5(C-7),117.8(C-16),115.4(C-6),111.5(C-2),110.1(C-20),45.2(C-25),30.5(2C,C-26,29),28.2(C-11),26.2(2C,C-26,29),23.0(C-14),21.4(C-13),20.9(C-12).HR-ESI-MS:387.2164[M+H]+,(calcd for C24H26N4O,387.2179).
实施例23 N-[4-(9-氨基-5,6,7,8-四氢吖啶-2-基)吡啶-2-基]环己烷甲酰胺(ZLWT-12)
如图2所示，N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)环己烷甲酰胺(化合物4e)替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-12。产率43％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.42(s,1H,H-22),8.59(d,J＝1.7Hz,1H,H-7),8.51(d,J＝1.6Hz,1H,H-17),8.41–8.32(m,1H,H-20),7.81(dd,J＝8.7,2.0Hz,1H,H-9),7.74(d,J＝8.8Hz,1H,H-10),7.58(dd,J＝5.3,1.7Hz,1H,H-16),6.66(s,2H,H-21),2.85(t,J＝6.0Hz,2H,H-11),2.58(t,J＝6.2Hz,2H,H-14),2.55–2.53(m,1H,H-25),1.91–1.79(m,6H,H-12,13,26,30),1.76(dd,J＝9.7,3.2Hz,2H,H-26,30),1.66(d,J＝12.4Hz,1H,H-28),1.43(qd,J＝12.5,3.1Hz,2H,H-27,29),1.32–1.23(m,2H,H-27,29),1.22–1.16(m,1H,H-28)；13C NMR(151MHz,DMSO-d6)δ175.8(C-23),158.6(C-5),153.5(C-19),149.6(2C,C-1,17),148.7(2C,C-13,15),132.2(C-8),129.0(C-9),126.8(C-10),121.2(C-7),117.6(C-16),117.4(C-6),111.4(C-2),109.9(C-20),44.7(C-25),33.8(C-11),29.5(2C,C-23,30),25.8(C-28),25.6(2C,C-27,29),24.1(C-14),22.9(C-13),22.8(C-12).HR-ESI-MS:401.2325[M+H]+,(calcd for C25H28N4O,401.2336).
实施例24N-[4-(9-氨基-5,6,7,8-四氢吖啶-2-基)吡啶-2-基]苯甲酰胺(ZLWT-13)
如图2所示，N-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)苯甲酰胺(化合物4f)替换4-甲氧基苯硼酸，合成方法如实施例14，得到化合物ZLWT-13。产率36％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.86(s,1H,H-22),8.64(d,J＝1.8Hz,1H,H-7),8.61(d,J＝1.0Hz,1H,H-17),8.52–8.45(m,1H,H-20),8.08(dd,J＝8.3,1.2Hz,2H,H-26,30),7.89(dd,J＝8.8,2.0Hz,1H,H-9),7.77(d,J＝8.8Hz,1H,H-10),7.69(dd,J＝5.3,1.7Hz,1H,H-16),7.62(s,1H,H-28),7.55(d,J＝7.9Hz,2H,H-27,29),6.63(s,2H,H-21),2.86(t,J＝6.0Hz,2H,H-11),2.59(t,J＝6.0Hz,2H,H-14),1.95–1.68(m,4H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ166.5(C-23),158.8(C-5),153.4(C-19),149.7(C-17),149.3(C-1),148.8(C-3),147.1(C-15),134.5(C-8),132.4(C-25),131.9(C-28),129.4(C-9),128.9(2C,C-27,29),128.4(2C,C-26,30),126.7(C-10),121.3(C-7),118.3(C-16),117.5(C-6),112.8(C-2),110.0(C-20),34.0(C-11),24.1(C-14),23.0(C-13),22.9(C-12).HR-ESI-MS:395.1862[M+H]+,(calcd for C25H22N4O,395.1866).
实施例25 N-[4-(9-氨基-5,6,7,8-四氢吖啶-3-基)吡啶-2-基]环丙烷甲酰胺(ZLWT-17)
如图4所示，N-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)吡啶-2-基)环丙烷甲酰胺(化合物4b)替换4-甲氧基苯硼酸，11替换ZLWT-2，合成方法如实施例14，得到化合物ZLWT-17。产率44％，白色固体。1H NMR(600MHz,DMSO-d6)δ11.01(s,1H,H-22),8.60(d,J＝8.8Hz,1H,H-7),8.47(d,J＝5.2Hz,1H,H-18),8.16(d,J＝1.9Hz,1H,H-21),7.90(dd,J＝8.7,1.9Hz,1H,H-8),7.54(dd,J＝5.2,1.8Hz,1H,H-17),2.97(t,J＝5.9Hz,2H,H-11),2.57(t,J＝6.0Hz,2H,H-14),2.08(ddd,J＝12.3,7.0,5.4Hz,1H,H-25),1.86(td,J＝7.9,4.1Hz,4H,H-12,13),0.88–0.83(m,4H,H-26,27)；13C NMR(101MHz,DMSO-d6)δ173.5(C-4),155.6(C-19),153.5(C-7),152.3(C-11),149.4(C-25),147.4(C-17),141.8(C-9),137.8(C-15),125.2(C-14),124.2(C-13),117.5(C-16),117.0(C-10),115.4(C-26),111.2(C-24),110.1(C-8),28.2(C-20),23.0(C-23),21.4(C-22),20.9(C-21),14.7(C-1),8.8(2C,C-2,3).HR-ESI-MS:359.1863[M+H]+,(calcd for C22H22N4O,359.1866).
实施例26 N-(4-{9-[(2-羟乙基)氨基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-14)
如图3所示，在装有磁力搅拌器的圆底烧瓶(100mL)中，将中间体化合物8b(1当量)、碘化钠(0.2当量)和苯酚(2当量)在90℃下搅拌0.5h，然后加入乙醇胺(5当量)。将反应温度升至170℃并保持0.5h。将混合物冷却至室温，用乙酸乙酯稀释并用2M NaOH溶液碱化。有机层用水和盐水洗涤并用无水Na2SO4干燥。蒸发滤液，得到粗中间体化合物9a，其无需进一步纯化即可使用。向相应的中间体化合物9a和化合物4b(1.2equiv)在二氧六环/水(4:1)中的溶液中加入Cs2CO3(3当量)和Pd(dppf)Cl2(0.05％mol)。将反应混合物在95℃搅拌12小时，然后将反应混合物用水(100mL)稀释并用乙酸乙酯(3×50mL)萃取。合并的有机层用盐水(200mL)洗涤，经无水Na2SO4干燥，过滤并减压浓缩。反应粗产物经快速柱层析纯化，得到化合物ZLWT-14。产率64％，淡黄色固体。1H NMR(600MHz,DMSO-d6)δ10.96(s,1H,H-24),8.78(d,J＝1.9Hz,1H,H-28),8.50(d,J＝1.7Hz,1H,H-7),8.46(d,J＝5.3Hz,1H,H-25),8.17(dd,J＝8.7,1.8Hz,1H,H-9),7.93(d,J＝8.8Hz,1H,H-10),7.56(dd,J＝5.2,1.8Hz,1H,H-29),5.08(t,J＝5.3Hz,1H,H-18),3.99(q,J＝5.7Hz,2H,H-17),3.76(q,J＝5.4Hz,2H,H-16),3.01(d,J＝5.5Hz,2H,H-11),2.74(d,J＝5.3Hz,2H,H-14),2.15–2.00(m,1H,H-21),1.85(p,J＝3.7Hz,4H,H-12,13),0.85(d,J＝6.2Hz,4H,H-19,20)；13C NMR(151MHz,DMSO-d6)δ173.4(C-23),156.9(C-5),153.4(C-26),149.2(C-1),148.3(C-28),138.6(C-30),134.6(C-3),131.5(C-8),130.1(C-9),123.7(C-10),120.9(C-1),117.7(C-2),116.6(C-29),112.3(C-6),111.5(C-25),60.6(C-11),50.1(C-16),28.7(C-11),24.7(C-14),21.9(C-13),20.8(C-12),14.7(C-21),8.2(2C,C-19,20).HR-ESI-MS:403.2126[M+H]+,(calcdfor C24H26N4O2,403.2129).
实施例27 N-(4-{9-[(3-羟丙基)氨基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-15)
如图3所示，3-氨基-1-丙醇替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-15。产率73％，淡黄色固体。1H NMR(600MHz,DMSO-d6)δ10.89(s,1H,H-17),8.50(dd,J＝8.6,1.8Hz,2H,H-7,16),8.41(d,J＝5.2Hz,1H,H-13),7.85(dd,J＝8.8,1.8Hz,1H,H-9),7.82(d,J＝8.6Hz,1H,H-10),7.56(dd,J＝5.2,1.7Hz,1H,H-12),5.84(s,1H,H-23),4.57(t,J＝5.0Hz,1H,H-31),3.58(q,J＝6.7Hz,2H,H-30),3.50(q,J＝5.7Hz,2H,H-24),2.93(t,J＝6.3Hz,2H,H-26),2.74(t,J＝6.2Hz,2H,H-29),2.06(ddd,J＝7.8,5.2,3.0Hz,1H,H-20),1.83(ddtd,J＝20.0,8.4,6.2,2.4Hz,4H,H-27,28),1.76(p,J＝6.5Hz,2H,H-25),0.91–0.77(m,4H,H-21,22)；13C NMR(151MHz,DMSO-d6)δ173.3(C-18),159.2(C-5),153.3(C-15),15.5(C-1),149.6(C-13),148.9(2C,C-3,11),132.6(C-8),129.6(C-9),126.8(C-10),122.1(C-7),120.4(C-2),117.5(C-12),116.5(C-6),111.3(C-16),59.2(C-30),46.1(C-24),34.0(C-26),25.6(C-25),23.1(C-29),22.8(C-28),21.2(C-27),14.7(C-20),8.1(2C,C-21,22).HR-ESI-MS:417.2269[M+H]+,(calcd for C25H28N4O2,417.2285).
实施例28 N-(4-{9-[(4-羟基丁基)氨基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-16)
如图3所示，4-氨基-1-丁醇替换乙醇胺，合成方法如实施例26，得到ZLWT-16。产率72％，淡黄色固体。1H NMR(600MHz,DMSO-d6)δ10.94(s,1H,H-17),8.58(brs,1H,H-7),8.51(d,J＝1.7Hz,1H,H-16),8.44(d,J＝5.2Hz,1H,H-13),8.05(brs,1H,H-9),7.89(d,J＝8.8Hz,1H,H-10),7.55(dd,J＝5.2,1.7Hz,1H,H-12),4.46(t,J＝4.9Hz,1H,H-32),3.75(brs,2H,H-31),3.41(dd,J＝11.4,6.2Hz,2H,H-28),2.97(t,J＝5.8Hz,2H,H-24),2.72(t,J＝5.1Hz,2H,H-27),2.06(dq,J＝7.4,5.1Hz,1H,H-20),1.84(dd,J＝13.1,7.8Hz,4H,H-25,26),1.79–1.68(m,2H,H-29),1.57–1.37(m,2H,H-30),0.95–0.72(m,4H,H-22,23)；13CNMR(151MHz,DMSO-d6)δ173.4(C-18),153.4(3C,C-1,5,15),149.1(3C,C-3,11,13),117.6(3C,C-8,9,10),111.4(3C,C-2,7,12),60.8(C-31),48.0(C-28),30.1(2C,C-24,30),27.6(2C,C-27,29),25.0(C-26),22.4(C-25),14.7(C-20),8.2(2C,C-22,23).HR-ESI-MS:431.2430[M+H]+,(calcd for C26H30N4O2,431.2442).
实施例29 N-(4-{9-[(2-羟乙基)氨基]-5，6，7，8-四氢吖啶-3-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-18)
如图3所示，6-溴-9-氯-1,2,3,4-四氢吖啶(化合物8a)替换化合物8b，合成方法如实施例26，得到化合物ZLWT-18。产率43％，淡黄色固体。1H NMR(600MHz,DMSO-d6)δ10.91(s,1H,H-22),8.55(d,J＝1.7Hz,1H,H-18),8.41(d,J＝5.2Hz,1H,H-21),8.25(d,J＝8.7Hz,1H,H-7),8.05(d,J＝2.0Hz,1H,H-10),7.67(dd,J＝8.8,2.0Hz,1H,H-8),7.55(dd,J＝5.3,1.7Hz,1H,H-17),5.36(t,J＝5.8Hz,1H,H-15),4.85(t,J＝5.1Hz,1H,H-30),3.55(dt,J＝20.7,5.6Hz,4H,H-28,29),3.17(d,J＝5.1Hz,1H),2.93(t,J＝6.0Hz,2H,H-11),2.75(t,J＝6.1Hz,2H,H-14),2.10–1.95(m,1H,H-25),1.83(dd,J＝7.6,4.6Hz,4H,H-12,13),0.90–0.81(m,4H,H-26,27)；13C NMR(151MHz,DMSO-d6)δ173.3(C-23),159.3(C-5),153.4(C-20),150.8(C-1),149.1(C-18),149.0(C-3),147.6(C-16),137.2(C-9),126.7(C-8),125.0(C-7),121.8(C-10),120.7(C-2),117.4(C-17),117.0(C-6),111.2(C-21),61.1(C-29),51.0(C-28),34.0(C-11),25.1(C-14),23.0(C-13),22.8(C-12),14.7(C-25),8.2(2C,C-26,27).HR-ESI-MS:403.2116[M+H]+,(calcd for C24H26N4O2,403.2129).
实施例30 N-(4-{9-[(3-羟丙基)氨基]-5，6，7，8-四氢吖啶-3-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-19)
如图3所示，6-溴-9-氯-1,2,3,4-四氢吖啶(化合物8a)替换化合物8b，3-氨基-1-丙醇替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-19。产率52％，淡黄色固体。1HNMR(600MHz,DMSO-d6)δ11.01(s,1H,H-22),8.57–8.52(m,2H,H-18,H-7),8.47(d,J＝5.2Hz,1H,H-21),8.20(d,J＝2.1Hz,1H,H-10),7.83(dd,J＝9.1,1.9Hz,1H,H-8),7.49(dd,J＝5.3,1.8Hz,1H,H-17),4.99(brs,1H,H-31),3.98(q,J＝6.5Hz,2H,H-30),3.58(t,J＝5.7Hz,2H,H-28),2.99(d,J＝6.1Hz,2H,H-11),2.62(brs,2H,H-14),2.13–2.01(m,1H,H-25),1.92–1.86(m,2H,H-29),1.83(p,J＝3.1Hz,4H,H-12,13),0.88–0.84(m,4H,H-26,27)；13C NMR(101MHz,DMSO-d6)δ173.5(C-4),155.6(C-19),153.6(C-7),151.4(C-25),149.5(C-11),147.2(C-17),141.1(C-9),139.2(C-15),127.1(C-14),123.4(C-13),117.3(2C,C-16,26),116.0(C-10),112.0(C-24),111.1(C-8),59.0(C-30),46.0(C-28),32.8(C-20),28.5(C-29),24.1(C-23),21.8(C-22),20.8(C-21),14.7(C-1),8.3(2C,C-2,3).HR-ESI-MS:417.2279[M+H]+,(calcd for C25H28N4O2,417.2285).
实施例31 N-(4-{9-[(4-羟基丁基)氨基]-5，6，7，8-四氢吖啶-3-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-20)
如图3所示，6-溴-9-氯-1,2,3,4-四氢吖啶(化合物8a)替换化合物8b，4-氨基-1-丁醇替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-20。产率60％，淡黄色固体。1HNMR(600MHz,DMSO-d6)δ10.70(s,1H,H-24),8.34(brs,1H,H-29),8.19(d,J＝5.2Hz,1H,H-26),8.04(d,J＝8.8Hz,1H,H-6),7.83(d,J＝2.0Hz,1H,H-9),7.45(dd,J＝8.7,2.0Hz,1H,H-7),7.33(d,J＝5.2Hz,1H,H-28),5.35(t,J＝6.3Hz,1H,H-13),4.21(brs,1H,H-20),3.25(q,J＝6.9Hz,2H,H-19),3.17(t,J＝6.5Hz,1H,H-16),2.71(t,J＝6.3Hz,2H,H-12),2.51(t,J＝6.2Hz,2H,H-11),1.85(tt,J＝8.0,4.6Hz,1H,H-21),1.61(dq,J＝13.4,7.3,5.7Hz,4H,H-31,32),1.39(p,J＝7.3Hz,2H,H-17),1.23(p,J＝6.7Hz,2H,H-18),0.69–0.55(m,4H,H-31,32)；13C NMR(151MHz,DMSO-d6)δ173.3(C-22),159.3(C-2),153.4(C-25),150.7(C-4),149.1(C-29),149.0(C-10),147.5(C-27),137.1(C-8),126.7(C-7),124.9(C-6),121.7(C-9),120.7(C-5),117.4(C-28),116.6(C-3),111.2(C-26),60.9(C-19),48.3(C-16),34.0(C-12),30.3(C-18),27.8(C-17),25.5(C-11),23.1(C-14),22.8(C-15),14.7(C-21),8.2(2C,C-31,32).HR-ESI-MS:431.2430[M+H]+,(calcd for C26H30N4O2,431.2442).
实施例32 N-{4-[9-(环丙基氨基)-5,6,7,8-四氢吖啶-2-基]吡啶-2-基}环丙烷甲酰胺(ZLWT-21)
如图3所示，环丙胺替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-21。产率60％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.86(s,1H,H-17),8.58(d,J＝2.0Hz,1H,H-7),8.50(d,J＝1.5Hz,1H,H-16),8.40(d,J＝5.2Hz,1H,H-13),7.80(dd,J＝8.7,2.0Hz,1H,H-9),7.73(d,J＝8.8Hz,1H,H-10),7.59(dd,J＝5.2,1.7Hz,1H,H-12),6.61(s,2H,H-23),2.85(t,J＝6.0Hz,2H,H-27),2.58(t,J＝6.2Hz,2H,H-30),2.06(tt,J＝7.8,4.7Hz,1H,H-20),1.84(tdd,J＝13.3,6.4,2.7Hz,4H,H-28,29),0.84(dtd,J＝15.8,7.7,6.3,4.0Hz,4H,H-21,22)；13C NMR(151MHz,DMSO-d6)δ173.2,159.5,153.4,151.0,149.6,149.0,147.6,132.7,129.7,126.7,122.2,121.2,117.9,117.4,111.3,60.2,34.1,34.0,25.5,23.7,23.1,22.8,14.7,8.1(2C).HR-ESI-MS:399.2170[M+H]+,(calcd for C25H26N4O,399.2179).
实施例33 N-{4-[9-(环戊基氨基)-5，6，7，8-四氢吖啶-2-基]吡啶-2-基}环丙烷甲酰胺(ZLWT-22)
如图3所示，环戊胺替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-22。产率63％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.88(s,1H,H-22),8.54(s,1H,H-7),8.45(s,1H,H-20),8.40(d,J＝5.1Hz,1H,H-17),7.94–7.74(m,2H,H-9,10),7.52(d,J＝5.1Hz,1H,H-16),5.30(d,J＝9.1Hz,1H,H-21),4.09(dd,J＝15.3,6.8Hz,1H,H-28),2.93(t,J＝6.0Hz,2H,H-11),2.74(t,J＝5.6Hz,2H,H-14),2.12–2.01(m,1H,H-25),1.96–1.87(m,2H,H-29,32),1.87–1.76(m,4H,H-12,13),1.72(brs,2H,H-30,31),1.64(dd,J＝11.8,6.1Hz,2H,H-30,31),1.52(d,J＝4.2Hz,2H,H-29,32),0.92–0.73(m,4H,H-26,27)；13C NMR(151MHz,DMSO-d6)δ173.2(C-23),159.5(C-5),153.4(C-19),151.0(C-1),149.6(C-17),149.0(C-15),147.6(C-3),132.7(C-8),129.7(C-9),126.7(C-10),122.2(C-7),121.2(C-2),117.9(C-16),117.4(C-6),111.3(C-20),60.2(C-28),34.1(2C,29,32),34.0(C-11),25.5(C-14),23.7(2C,C-30,31),23.1(C-13),22.8(C-12),14.7(C-25),8.1(2C,C-26,27).HR-ESI-MS:427.2479[M+H]+,(calcd for C27H30N4O,427.2492).
实施例34 4-[7-(2-环丙酰胺基吡啶-4-基)-1，2，3，4-四氢吖啶-9-基]哌嗪-1-羧酸叔丁酯(ZLWT-23)
如图3所示，哌嗪-1-甲酸叔丁酯替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-23。产率62％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.90(s,1H,H-22),8.60(s,1H,H-7),8.46(s,1H,H-20),8.42(d,J＝5.2Hz,1H,H-17),7.96(d,J＝1.1Hz,2H,H-9,10),7.55(dd,J＝5.2,1.7Hz,1H,H-16),3.76(brs,2H,H-29,31),3.34–3.32(brs,2H,H-29,31),3.27(d,J＝2.9Hz,4H,H-28,32),3.02(t,J＝6.6Hz,2H,H-11),2.91(t,J＝6.3Hz,2H,H-14),2.05(ddd,J＝12.6,7.8,4.7Hz,1H,H-25),1.93–1.73(m,4H,H-12,13),1.46(s,9H,H-37,38,39),0.97–0.74(m,4H,H-26,27)；13C NMR(151MHz,DMSO-d6)δ173.3(C-23),161.5(C-33),154.5(C-5),153.4(C-19),153.0(C-1),149.2(2C,C-3,17),147.9(C-15),134.3(C-8),130.0(C-9),128.0(C-10),127.1(C-7),125.5(C-2),122.6(C-16),117.3(C-6),111.3(C-20),79.4(C-36),50.6(4C,C-28,29,31,32),34.1(C-11),28.5(3C,C-14,37,38,39),22.9(C-13),22.6(C-12),14.7(C-25),8.2(2C,C-26,27).HR-ESI-MS:528.2960[M+H]+,(calcd for C31H37N5O3,528.2969).
实施例35 N-{4-{9-[(2-氨基环己基)氨基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基}环丙烷甲酰胺(ZLWT-25)
如图3所示，环己烷-1，2-二胺替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-25。产率55％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.89(s,1H,H-22),8.56(d,J＝0.9Hz,1H,H-7),8.45(d,J＝1.7Hz,1H,H-20),8.40(dd,J＝5.2,0.4Hz,1H,H-17),7.89(dd,J＝8.8,2.0Hz,1H,H-9),7.84(d,J＝8.7Hz,1H,H-10),7.51(dd,J＝5.3,1.7Hz,1H,H-16),3.64(dd,J＝7.0,3.7Hz,1H,H-21),3.05(d,J＝1.9Hz,1H,H-28),2.94(s,2H,H-11),2.86–2.67(m,2H,H-14),2.06(dq,J＝7.5,5.0Hz,1H,H-25),1.84(t,J＝10.0Hz,4H,H-12,13),1.77–1.60(m,2H,H-31,34),1.56(dd,J＝12.3,5.6Hz,2H,H-32,33),1.53–1.45(m,1H,H-29),1.38–1.28(m,1H,H-30),1.28–1.19(m,1H,H-30),0.91–0.75(m,4H,H-26,27).13C NMR(151MHz,DMSO-d6)δ173.3(C-23),159.4(C-5),153.4(C-19),150.7(C-1),149.5(C-17),149.1(C-15),147.6(C-3),132.7(C-8),129.8(C-9),126.7(C-10),122.0(C-7),121.2(C-2),117.9(C-16),117.2(C-6),111.2(C-20),58.7(C-28),50.5(C-29),34.1(C-11),33.0(C-34),28.3(C-31),25.4(C-14),25.1(C-32),24.3(C-33),23.1(C-13),22.8(C-12),14.7(C-25),8.2(2C,C-26,27).HR-ESI-MS:456.2752[M+H]+,(calcd for C28H33N5O,456.2758).
实施例36 N-{4-[9-(吡咯烷-1-基)-5，6，7，8-四氢吖啶-2-基]吡啶-2-基}环丙烷甲酰胺(ZLWT-26)
如图3所示，四氢吡咯替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-26。产率66％，淡黄色固体。1H NMR(600MHz,DMSO-d6)δ10.90(s,1H,H-17),8.55(s,1H,H-7),8.41(d,J＝5.2Hz,1H,H-13),8.20(d,J＝1.9Hz,1H,H-16),7.96(d,J＝8.7Hz,1H,H-10),7.91(dd,J＝8.7,2.0Hz,1H,H-9),7.49(dd,J＝5.2,1.7Hz,1H,H-12),3.41(s,4H,H-22,23),3.01(t,J＝6.6Hz,2H,H-29),2.81(t,J＝6.3Hz,2H,H-26),2.12–2.08(m,4H,H-30,31),2.07–2.03(m,1H,H-20),1.87(dd,J＝7.5,4.2Hz,2H,H-27),1.79(dd,J＝7.5,4.1Hz,2H,H-28),0.94–0.76(m,4H,H-24,25)；13C NMR(151MHz,DMSO-d6)δ173.3(C-18),161.2(C-5),153.4(C-15),151.2(C-1),149.4(C-13),149.1(C-3),147.9(C-11),134.0(C-8),130.2(C-9),129.3(C-10),126.9(C-7),125.8(C-2),122.4(C-6),117.3(C-12),111.2(C-16),51.6(2C,C-22,23),33.9(C-26),26.4(2C,C-30,31),26.2(C-29),22.8(C-28),22.7(C-27),14.7(C-20),8.2(2C,C-24,25).HR-ESI-MS:413.2324[M+H]+,(calcd for C26H28N4O,413.2336).
实施例37 N-{4-[9-(吗啉-4-基)-5，6，7，8-四氢吖啶-2-基]吡啶-2-基}环丙烷甲酰胺(ZLWT-27)
如图3所示，吗啉替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-27。产率70％，淡黄色固体。1H NMR(600MHz,DMSO-d6)δ10.91(s,1H,H-17),8.58(s,1H,H-7),8.47(d,J＝1.1Hz,1H,H-16),8.42(d,J＝5.2Hz,1H,H-13),8.00–7.89(m,2H,H-9,10),7.51(dd,J＝5.2,1.6Hz,1H,H-12),3.83(t,J＝4.1Hz,4H,H-30,32),3.35(s,2H,H-22,23),3.28(s,2H,H-22,23),3.00(t,J＝6.5Hz,2H,H-29),2.91(t,J＝6.2Hz,2H,H-26),2.12–2.02(s,1H,H-20),1.85(dd,J＝7.6,3.7Hz,2H,H-27,28),1.81–1.73(m,2H,H-27,28),0.97–0.69(m,4H,H-24,25)；13C NMR(151MHz,DMSO-d6)δ173.3(C-18),161.5(C-5),153.5(C-15),152.6(C-1),149.3(C-13),149.2(C-3),147.9(C-11),134.3(C-8),130.0(C-9),128.0(C-10),127.0(C-2),125.6(C-7),122.5(C-6),117.3(C-12),111.2(C-16),67.6(2C,C-30,32),51.0(2C,C-22,23),34.1(C-26),26.6(C-29),22.9(C-28),22.6(C-27),14.7(C-20),8.2(2C,C-24,25).HR-ESI-MS:429.2277[M+H]+,(calcd for C26H28N4O2,429.2285).
实施例38 1-[7-(2-环丙酰胺基吡啶-4-基)-1，2，3，4-四氢吖啶-9-基]哌啶-4-羧酸甲酯(ZLWT-28)
如图3所示，哌啶-4-甲酸甲酯替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-28。产率72％，淡黄色固体。1H NMR(600MHz,DMSO-d6)δ10.90(s,1H,H-21),8.60(s,1H,H-7),8.42(d,J＝5.2Hz,2H,H-17,20),7.94(s,2H,H-9,10),7.50(d,J＝3.8Hz,1H,H-16),3.68(s,3H,H-36),3.33(s,2H,H-28,30),3.25(d,J＝10.5Hz,2H,H-28,30),3.01(t,J＝6.6Hz,2H,H-11),2.89(t,J＝6.2Hz,2H,H-14),2.70–2.55(m,1H,H-31),2.06(m,1H,H-24),2.00(dd,J＝8.9,3.8Hz,2H,H-29,32),1.93–1.82(m,4H,H-12,13),1.80(d,J＝5.6Hz,2H,H-29,32),0.94–0.72(m,4H,H-25,26)；13C NMR(151MHz,DMSO-d6)δ175.1(C-33),173.3(C-22),153.5(C-5),149.3(2C,C-1,19),149.2(2C,C-3,17),132.0(C-15),131.9(C-8),129.8(C-9),129.2(C-10),129.2(C-2),127.0(C-7),117.2(C-6),115.6(C-16),111.2(C-20),51.9(C-36),50.4(2C,C-28,30),40.5(C-31),34.0(C-11),29.4(3C,C-14,29,32),22.9(2C,C-12,13),14.7(C-24),8.1(2C,C-25,26).HR-ESI-MS:485.2528[M+H]+,(calcd forC29H32N4O3,485.2547).
实施例39叔丁基N-{1-[7-(2-环丙酰胺基吡啶-4-基)-1，2，3，4-四氢吖啶-9-基]哌啶-3-基}氨基甲酸酯(ZLWT-30)
如图7所示，哌啶-3-氨基甲酸叔丁酯替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-30。产率67％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.89(s,1H,H-21),8.59(s,1H,Ar-H),8.68–8.51(m,2H,Ar-H),7.98(t,J＝6.9Hz,2H,Ar-H),7.74–7.42(m,2H,Ar-H),3.63(m,1H,-CH),3.15(brs,1H,-CH),3.01(t,J＝6.5Hz,2H,H-11),2.87(brs,2H,H-14),2.07(dq,J＝8.6,4.3,3.5Hz,1H,H-24),1.91–1.82(m,2H,-CH2),1.79(brs,2H,-CH2),1.35–1.17(m,9H,3×CH3),0.98–0.77(m,4H,H-25,26)；13C NMR(151MHz,DMSO-d6)δ173.3(C-22),161.5(C-5),155.4(C-34),153.4(C-19),149.1(C-1),132.5(C-17),131.9(C-3),131.8(C-15),129.8(C-8),129.2(C-9),129.1(C-10),127.0(C-7),122.4(C-2),117.5(C-6),117.3(C-16),111.5(C-20),78.1(C-37),56.7(C-28),50.9(C-30),48.6(C-32),34.1(C-11),30.5(C-31),28.6(3C,C-38,39,40),25.7(C-14),22.9(2C,C-12,13),22.5(C-29),14.7(C-24),8.2(2C,C-25,26).HR-ESI-MS:542.3111[M+H]+,(calcd for C32H39N5O3,542.3126).
实施例40叔丁基N-{1-[7-(2-环丙酰胺基吡啶-4-基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-基}氨基甲酸酯(ZLWT-34)
如图7所示，吡咯烷-3-基氨基甲酸叔丁酯替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-34。产率61％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.92(s,1H,H-21),8.56(s,1H,H-17),8.41(d,J＝5.2Hz,1H,H-17),8.29(s,1H,H-7),7.97(d,J＝8.7Hz,1H,H-10),7.92(dd,J＝8.7,2.0Hz,1H,H-9),7.55(d,J＝4.4Hz,1H,H-16),7.18(d,J＝6.0Hz,1H,H-32),4.28(d,J＝6.1Hz,1H,H-28),3.69–3.52(m,2H,H-28,31),3.47–3.38(m,1H,H-31),3.25(dd,J＝8.9,5.6Hz,1H,H-29),3.02(t,J＝6.6Hz,2H,H-11),2.93–2.78(m,2H,H-14),2.33(dd,J＝12.5,5.5Hz,1H,H-30),2.12–1.99(m,2H,H-24,30),1.93–1.73(m,4H,H-12,13),1.37(s,9H,H-37,38,39),0.95–0.73(m,4H,H-25,26)；13C NMR(151MHz,DMSO-d6)δ173.5(C-22),161.2(C-5),155.8(C-33),153.4(2C,C-1,19),149.3(C-17),149.1(2C,C-3,15),134.1(2C,C-9,10),130.1(C-8),127.0(C-7),122.5(C-16),117.5(2C,C-2,6),111.4(C-20),78.2(C-36),57.1(C-28),51.4(C-31),50.2(C-29),33.9(C-11),32.2(C-30),28.6(3C,C-37,38,39),26.1(C-14),22.8(C-13),22.7(C-12),14.7(C-24),8.2(2C,C-25,26).HR-ESI-MS:528.2948[M+H]+,(calcd for C31H37N5O3,528.2969).
实施例41 N-(4-{9-[(3R)-3-羟基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-38)
如图3所示，(R)-吡咯烷-3-醇替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-38。产率61％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.89(s,1H,H-17),8.53(s,1H,H-16),8.50(d,J＝2.0Hz,1H,H-7),8.39(dd,J＝5.2,0.4Hz,1H,H-13),7.97(d,J＝8.7Hz,1H,H-10),7.90(dd,J＝8.7,2.0Hz,1H,H-9),7.53(dd,J＝5.2,1.7Hz,1H,H-12),5.11(d,J＝3.2Hz,1H,H-26),4.54(d,J＝2.2Hz,1H,H-23),3.62(dt,J＝9.5,6.5Hz,2H,H-22,25),3.41–3.36(m,1H,H-22),3.31–3.28(m,1H,H-25),3.02(t,J＝6.6Hz,2H,H-29),2.86(td,J＝6.2,2.6Hz,2H,H-32),2.32–2.17(m,1H,H-24),2.06(ddd,J＝12.6,7.7,4.7Hz,1H,H-20),2.03–1.97(m,1H,H-24),1.95–1.84(m,2H,H-30,31),1.84–1.75(m,2H,H-30,31),0.91–0.78(m,4H,H-27,28)；13C NMR(151MHz,DMSO-d6)δ173.3(C-18),161.0(C-5),153.4(C-15),151.0(C-1),149.4(C-13),149.0(2C,C-3,11),147.8(C-8),134.0(C-9),130.0(C-10),126.9(C-7),125.6(C-2),122.9(C-6),117.5(C-12),111.4(C-16),71.0(C-23),60.3(C-22),49.9(C-25),35.6(C-24),33.8(C-29),26.1(C-32),22.8(C-31),22.8(C-30),14.7(C-20),8.2(2C,C-27,28).HR-ESI-MS:429.2279[M+H]+,(calcd for C26H28N4O2,429.2285).
实施例42 N-(4-{9-[(3S)-3-羟基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺(ZLWT-39)
如图3所示，(S)-吡咯烷-3-醇替换乙醇胺，合成方法如实施例26，得到化合物ZLWT-39。产率67％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.90(s,1H,H-17),8.53(s,1H,H-16),8.50(d,J＝2.0Hz,1H,H-7),8.40(dd,J＝5.2,0.4Hz,1H,H-13),7.97(d,J＝8.7Hz,1H,H-10),7.90(dd,J＝8.7,2.1Hz,1H,H-9),7.53(dd,J＝5.2,1.7Hz,1H,H-12),5.12(d,J＝3.0Hz,1H,H-26),4.54(d,J＝2.1Hz,1H,H-23),3.62(dt,J＝9.5,6.5Hz,2H,H-22,25),3.38(dd,J＝8.3,3.3Hz,1H,H-22),3.30(dd,J＝9.6,1.3Hz,1H,H-25),3.02(t,J＝6.6Hz,2H,H-29),2.86(td,J＝6.1,2.4Hz,2H,H-32),2.29–2.14(m,1H,H-24),2.07(ddd,J＝12.6,7.8,4.7Hz,1H,H-20),2.04–1.98(m,1H,H-24),1.94–1.84(m,2H,H-30,31),1.85–1.74(m,2H,H-30,31),0.91–0.79(m,4H,H-27,28)；13C NMR(151MHz,DMSO-d6)δ173.3(C-18),161.1(C-5),153.4(C-15),150.9(C-1),149.4(C-13),149.0(2C,C-3,11),147.9(C-8),134.0(C-9),130.1(C-10),126.9(C-7),125.7(C-2),122.8(C-6),117.5(C-12),111.4(C-16),71.0(C-23),60.3(C-22),49.9(C-25),35.6(C-24),33.92(C-29),26.0(C-32),22.8(C-31),22.8(C-30),14.7(C-20),8.2(2C,C-27,28).HR-ESI-MS:429.2271[M+H]+,(calcd forC26H28N4O2,429.2285).
实施例43 N-{4-[9-(哌嗪-1-基)-5，6，7，8-四氢吖啶-2-基]吡啶-2-基}环丙烷甲酰胺(ZLWT-24)
如图5所示，在装有磁力搅拌器的圆底烧瓶(100mL)中，加入化合物ZLWT-23，用4MHCl-EtOAc在25℃脱保护1h，得到化合物ZLWT-24。产率48％，白色固体。1H NMR(600MHz,DMSO-d6)δ10.95(s,1H,H-22),8.55(d,J＝0.8Hz,1H,H-7),8.45(d,J＝5.1Hz,1H,H-17),8.37(d,J＝1.1Hz,1H,H-20),8.07(s,2H,H-9,10),7.59(dd,J＝5.2,1.7Hz,1H,H-16),3.64(s,4H,H-28,32),3.54–3.43(m,4H,H-29,31),3.11(t,J＝6.1Hz,2H,H-11),2.93(t,J＝6.2Hz,2H,H-14),2.15–1.97(m,1H,H-25),1.97–1.77(m,4H,H-12,13),0.98–0.77(m,4H,H-26,27)；13C NMR(151MHz,DMSO-d6)δ173.4(C-23),158.6(C-5),158.4(C-19),158.2(C-1),153.4(C-15),149.1(C-3),149.0(C-15),135.5(C-8),128.1(C-9),124.8(C-10),122.4(C-7),119.2(C-2),117.7(C-6),116.7(C-16),111.7(C-20),47.8(2C,C-28,32),44.1(2C,C-29,31),26.4(2C,C-11,14),22.6(2C,C-12,13),14.7(C-25),8.2(2C,C-26,27).HR-ESI-MS:428.2450[M+H]+,(calcd for C26H29N5O,428.2445).
实施例44 N-{4-[9-(3-氨基哌啶-1-基)-5，6，7，8-四氢吖啶-2-基]吡啶-2-基}环丙烷甲酰胺盐酸盐(ZLWT-31)
如图7所示，化合物ZLWT-30为原料，合成方法如实施例43，得到化合物ZLWT-31。产率85％，黄色固体。1H NMR(600MHz,DMSO-d6)δ11.47(s,1H,H-21),8.51(d,J＝1.7Hz,1H,H-7),8.49(d,J＝5.4Hz,1H,H-17),8.48–8.44(m,1H,H-10),8.32(dd,J＝5.1,3.0Hz,3H,H-33),8.31(d,J＝1.8Hz,1H,H-20),8.28(d,J＝8.8Hz,1H,H-9),7.73(dd,J＝5.6,1.8Hz,1H,H-16),4.01–3.96(m,1H,H-28),3.73–3.68(m,1H,H-30),3.62(ddd,J＝20.0,12.7,10.1Hz,2H,H-28,30),3.51(dt,J＝16.0,6.9Hz,1H,H-32),3.27(t,J＝6.5Hz,2H,H-11),2.89(ddt,J＝48.1,16.3,6.1Hz,2H,H-14),2.33–2.16(m,1H,H-29),2.10(p,J＝6.1Hz,1H,H-24),1.94(dtd,J＝25.2,14.5,12.4,7.7Hz,3H,H-12,13,29,31),1.83(p,J＝5.9Hz,2H,H-12,13),1.71(qd,J＝11.6,4.6Hz,1H,H-31),0.95–0.64(m,4H,H-25,26)；13C NMR(151MHz,DMSO-d6)δ174.0(C-22),161.5(C-5),156.9(C-19),152.4(C-1),149.4(C-17),147.4(C-3),138.6(C-15),135.8(C-8),131.9(C-9),125.5(C-10),124.9(C-7),123.3(C-2),121.6(C-6),118.0(C-16),112.2(C-20),54.9(C-28),52.4(C-30),47.5(C-32),29.2(C-31),28.4(C-11),26.4(C-14),24.3(C-13),22.1(C-29),20.6(C-12),14.9(C-24),9.6(2C,C-25,26).HR-ESI-MS:442.2586[M+H]+,(calcd for C27H31N5O,442.2601).
实施例45 N-{4-[9-(3-氨基吡咯烷-1-基)-5，6，7，8-四氢吖啶-2-基]吡啶-2-基}环丙烷甲酰胺盐酸盐(ZLWT-35)
如图7所示，化合物ZLWT-34替换化合物ZLWT-30，合成方法如实施例43，得到化合物ZLWT-35。产率90％，黄色固体。1H NMR(600MHz,DMSO-d6)δ12.94(s,1H,H-17),8.79(d,J＝5.4Hz,2H,H-32),8.63(d,J＝1.8Hz,1H,H-7),8.45(d,J＝1.9Hz,1H,H-16),8.43(d,J＝6.2Hz,1H,H-13),8.20(d,J＝1.8Hz,1H,H-9),8.18(d,J＝8.8Hz,1H,H-10),7.98(dd,J＝6.2,1.9Hz,1H,H-12),4.52(dd,J＝12.2,6.3Hz,1H,H-23),4.41(dt,J＝11.4,7.5Hz,1H,H-22),4.23(ddd,J＝15.9,11.9,5.5Hz,2H,H-22,23),4.08–3.94(m,1H,H-31),3.09(t,J＝6.8Hz,2H,H-26),2.93(tq,J＝15.9,9.7,7.8Hz,2H,H-29),2.38(dq,J＝14.2,7.5Hz,1H,H-30),2.28(ddd,J＝12.8,7.5,3.9Hz,1H,H-30),2.18(tt,J＝7.8,4.5Hz,1H,H-20),1.85(h,J＝6.1Hz,2H,H-27,28),1.67(dddd,J＝18.7,12.2,7.1,3.8Hz,2H,H-27,28),1.04–0.94(m,4H,H-24,25)；13C NMR(151MHz,DMSO-d6)δ175.6(C-18),172.4(C-5),159.4(C-15),153.5(C-1),152.4(C-13),149.1(C-3),141.0(C-11),139.5(C-8),130.5(C-9),126.7(C-10),119.9(C-7),117.9(C-2),117.9(C-6),114.2(C-12),112.6(C-16),58.7(C-22),53.9(C-31),49.4(C-23),29.5(C-30),28.2(C-26),28.1(C-29),22.6(C-28),20.7(C-27),15.2(C-20),9.8(2C,C-24,25).HR-ESI-MS:428.2430[M+H]+,(calcd for C26H29N5O,428.2445).
实施例46 N-(4-{9-[(3R)-3-氨基哌啶-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺盐酸盐(ZLWT-32)
如图7所示，在装有磁力搅拌器的圆底烧瓶(100mL)中，将中间体化合物8b(1当量)、碘化钠(0.2当量)和苯酚(2当量)在90℃下搅拌0.5h，然后加入叔丁基(R)-哌啶-3-基氨基甲酸酯(5当量)。将反应温度升至170℃并保持0.5h。将混合物冷却至室温，用乙酸乙酯稀释并用2M NaOH溶液碱化。有机层用水和盐水洗涤并用无水Na2SO4干燥。蒸发滤液，得到粗中间体化合物9q，其无需进一步纯化即可使用。向中间体化合物9q(1当量)和化合物4b(1.2equiv)在二氧六环/水(4:1)中的溶液中加入Cs2CO3(3当量)和Pd(dppf)Cl2(0.05％mol)。将反应混合物在95℃搅拌12小时，然后将反应混合物用水(100mL)稀释并用乙酸乙酯(3×50mL)萃取。合并的有机层用盐水(200mL)洗涤，经无水Na2SO4干燥，过滤并减压浓缩。反应粗产物经快速柱层析纯化，得到化合物12a。化合物12a的Boc基团用4M HCl-EtOAc在25℃下脱保护1h得到化合物ZLWT-32。产率33％，黄色固体。1H NMR(600MHz,DMSO-d6)δ12.21(s,1H,H-21),8.55(d,J＝4.2Hz,3H,H-33),8.49(dd,J＝8.3,4.9Hz,3H,H-7,17,20),8.39(d,J＝8.8Hz,1H,H-10),8.32(dd,J＝8.9,1.7Hz,1H,H-9),7.87(dd,J＝6.0,1.5Hz,1H,H-16),4.05–4.01(m,1H,H-30),3.79–3.65(m,2H,H-28,30),3.62(t,J＝10.9Hz,1H,H-28),3.52(d,J＝4.5Hz,1H,H-32),3.28(t,J＝6.5Hz,2H,H-11),3.00–2.89(m,1H,H-14),2.84(dt,J＝16.1,5.9Hz,1H,H-14),2.30–2.20(m,1H,H-29),2.16(dq,J＝7.3,5.2Hz,1H,H-24),1.96(s,1H,H-29),1.93–1.87(m,3H,H-12,13,31),1.83(dd,J＝11.7,5.8Hz,2H,H-12,13),1.74(dt,J＝11.4,7.6Hz,1H,H-31),0.97(dd,J＝10.8,3.3Hz,4H,H-25,26)；13C NMR(151MHz,DMSO-d6)δ174.8(C-22),161.5(C-5),157.1(C-19),151.2(C-1),150.5(C-17),144.5(C-3),138.8(C-15),134.7(C-8),131.6(C-9),125.6(C-10),125.4(C-7),123.2(C-2),121.6(C-6),118.2(C-16),112.7(C-20),54.9(C-28),52.5(C-30),47.5(C-32),29.2(C-31),28.4(C-11),26.44(C-14),24.3(C-13),22.1(C-29),20.6(C-12),15.0(C-24),9.2(2C,C-25,26).HR-ESI-MS:442.2598[M+H]+,(calcd for C27H31N5O,442.2601).
实施例47 N-(4-{9-[(3S)-3-氨基哌啶-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺盐酸盐(ZLWT-33)
如图7所示，叔丁基(S)-哌啶-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，合成方法如实施例46，得到化合物ZLWT-33。产率31％，黄色固体。1H NMR(600MHz,DMSO-d6)δ11.97(s,1H,H-21),8.56(d,J＝4.2Hz,3H,H-33),8.50(d,J＝1.3Hz,1H,H-7),8.49(brs,1H,H-17),8.48(brs,1H,H-20),8.40(d,J＝8.8Hz,1H,H-10),8.32(dd,J＝8.9,1.7Hz,1H,H-9),7.82(dd,J＝5.7,1.6Hz,1H,H-16),4.03(dt,J＝10.4,4.4Hz,1H,H-28),3.73–3.66(m,2H,H-28,30),3.61(t,J＝10.8Hz,1H,H-30),3.52(dd,J＝9.0,4.5Hz,1H,H-32),3.28(t,J＝6.4Hz,2H,H-11),3.03–2.77(m,2H,H-14),2.32–2.20(m,1H,H-29),2.19–2.10(m,1H,H-24),1.94–1.86(m,4H,H-12,13,29,31),1.83(dd,J＝11.5,5.7Hz,2H,H-12,13),1.74(qd,J＝12.0,4.5Hz,1H,H-31),0.99–0.89(m,4H,H-25,26)；13C NMR(151MHz,DMSO-d6)δ174.5(C-22),161.4(C-5),157.0(C-19),151.5(C-1),150.5(C-17),145.7(C-3),138.7(C-15),135.1(C-8),131.7(C-9),125.6(C-10),125.2(C-7),123.2(C-2),121.6(C-6),118.1(C-16),112.5(C-20),54.9(C-28),52.5(C-30),47.5(C-32),29.2(C-31),28.4(C-11),26.4(C-14),24.3(C-13),22.1(C-29),20.6(C-12),15.0(C-24),9.0(2C,C-25,26).HR-ESI-MS:442.2584[M+H]+,(calcd for C27H31N5O,442.2601).
实施例48 N-(4-{9-[(3R)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺盐酸盐(ZLWT-36)
如图7所示，叔丁基(R)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，合成方法如实施例46，得到化合物ZLWT-36。产率31％，黄色固体。1H NMR(600MHz,DMSO-d6)δ12.11(s,1H,H-27),8.66(d,J＝5.5Hz,2H,H-21),8.57(d,J＝1.9Hz,1H,H-7),8.46(d,J＝1.8Hz,H-26),8.44(d,J＝5.8Hz,H-23),8.19(dd,J＝8.8,1.8Hz,1H,H-9),8.14(d,J＝8.8Hz,1H,H-10),7.80(dd,J＝5.8,1.8Hz,1H,H-22),4.47(dd,J＝12.2,6.3Hz,1H,H-14),4.38(dt,J＝11.5,7.6Hz,1H,H-13),4.22(ddd,J＝11.7,8.1,4.9Hz,2H,H-13,14),4.17(dd,J＝12.3,3.7Hz,1H,H-20),3.10(t,J＝6.8Hz,2H,H-15),2.92(q,J＝6.2Hz,2H,H-16),2.37(dq,J＝14.4,7.8Hz,1H,H-19),2.24(ddt,J＝12.6,8.1,4.7Hz,1H,H-19),2.14(tt,J＝7.4,4.8Hz,1H,H-30),1.87(dtd,J＝11.5,6.7,4.9Hz,2H,H-16,17),1.75–1.62(m,2H,H-16,17),1.00–0.89(m,4H,H-31,32)；13C NMR(151MHz,DMSO-d6)δ174.6(C-28),172.4(C-5),170.8(C-1),159.4(C-25),152.3(C-23),151.1(C-3),139.1(C-11),131.9(C-8),130.7(C-9),126.0(C-10),119.8(C-7),118.0(C-2),117.8(C-6),114.1(C-22),112.1(C-26),58.5(C-13),53.7(C-20),49.4(C-14),29.5(C-19),28.2(C-15),28.1(C-18),22.6(C-17),20.7(C-16),14.5(C-30),9.0(2C,C-31,32).HR-ESI-MS:428.2428[M+H]+,(calcd forC26H29N5O,428.2445).
实施例49 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丙烷甲酰胺盐酸盐(ZLWT-37)
如图7所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，合成方法如实施例46，得到化合物ZLWT-37。产率38％，黄色固体。1H NMR(600MHz,DMSO-d6)δ12.60(s,1H,H-17),8.74(d,J＝4.5Hz,2H,H-32),8.61(d,J＝1.4Hz,1H,H-7),8.46(d,J＝1.5Hz,1H,H-16),8.44(d,J＝6.1Hz,H-13),8.21(dd,J＝8.9,1.7Hz,1H,H-9),8.17(d,J＝8.8Hz,1H,H-10),7.90(dd,J＝6.1,1.7Hz,1H,H-12),4.53–4.46(m,1H,H-23),4.39(dt,J＝11.4,7.6Hz,1H,H-22),4.27–4.15(m,2H,H-22,23),4.01–3.96(m,1H,H-31),3.10(t,J＝6.8Hz,2H,H-26),3.00–2.83(m,2H,H-29),2.46–2.32(m,1H,H-30),2.26(tt,J＝12.5,4.7Hz,1H,H-30),2.17(tt,J＝7.7,4.7Hz,1H,H-20),1.86(dtt,J＝9.0,6.9,3.5Hz,2H,H-27,28),1.76–1.61(m,2H,H-27,28),1.03–0.93(m,4H,H-24,25)；13C NMR(151MHz,DMSO-d6)δ175.1(C-21),172.4(C-13),159.3(C-15),152.3(C-28),150.1(C-30),143.0(C-8),139.3(C-32),131.2(C-5),130.5(C-6),126.4(C-7),119.9(C-10),117.9(C-9),117.9(C-14),114.2(C-31),112.3(C-27),58.6(C-25),53.8(C-24),49.4(C-22),29.5(C-23),28.2(C-1),28.1(C-4),22.6(C-3),20.7(C-2),15.1(C-19),9.4(2C,C-17,18).HR-ESI-MS:428.2431[M+H]+,(calcd for C26H29N5O,428.2445).
实施例50(3S)-1-(7-苯基-1，2，3，4-四氢吖啶-9-基)吡咯烷-3-胺盐酸盐(ZLWT-40)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，苯硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-40。产率35％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.39(d,J＝1.7Hz,1H,H-7),8.29(brs,3H,H-26),8.18(dd,J＝8.8,1.8Hz,1H,H-9),7.92(d,J＝8.8Hz,1H,H-10),7.80(dd,J＝8.2,1.1Hz,2H,H-12,16),7.55(t,J＝7.7Hz,2H,H-13,15),7.49–7.40(m,1H,H-14),4.43(dd,J＝11.9,6.2Hz,1H,H-19),4.27(dt,J＝11.1,7.6Hz,1H,H-18),4.19(ddd,J＝23.8,14.2,10.1Hz,1H,H-19),4.03–3.97(m,2H,H-18,25),3.14–2.99(m,2H,H-20),2.89(t,J＝5.9Hz,2H,H-23),2.43–2.30(m,1H,H-24),2.15(dq,J＝7.7,4.5Hz,1H,H-24),1.95–1.78(m,2H,H-21,22),1.70(dd,J＝11.6,5.8Hz,2H,H-21,22)；13C NMR(151MHz,DMSO-d6)δ159.4(C-5),158.9(C-1),158.7(C-3),151.8(C-11),139.2(C-8),137.7(C-9),136.4(C-10),131.6(C-14),129.6(C-13),128.5(C-15),127.5(C-12),124.2(C-16),119.5(C-7),118.5(C-2),114.4(C-6),58.4(C-18),53.2(C-25),49.5(C-19),29.6(C-24),28.2(C-20),28.1(C-23),22.6(C-22),20.8(C-21).HR-ESI-MS:344.2113[M+H]+,(calcd for C23H25N3,344.2121).
实施例51 2-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}苯甲醛盐酸盐(ZLWT-41)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，(2-甲酰基苯基)硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-41。产率31％，黄色固体。1H NMR(600MHz,DMSO-d6)δ9.94(s,1H),8.72(d,J＝5.5Hz,3H),8.22(d,J＝1.8Hz,1H),8.15(d,J＝8.6Hz,1H),7.98(ddd,J＝9.1,6.8,1.7Hz,2H),7.92(dd,J＝8.6,1.7Hz,1H),7.81(td,J＝7.5,1.4Hz,1H),7.71–7.60(m,2H),4.29(ddd,J＝27.2,13.3,6.5Hz,2H),4.12(ddd,J＝11.9,7.5,4.4Hz,2H),3.97–3.85(m,2H),3.11(dt,J＝24.7,6.8Hz,3H),2.90(dq,J＝23.5,5.9Hz,3H),2.29(pt,J＝13.6,6.5Hz,2H),2.20(ddt,J＝12.3,7.9,4.9Hz,1H),1.89–1.82(m,3H),1.68(dq,J＝12.2,6.0Hz,3H).HR-ESI-MS:372.2074[M+H]+,(calcd for C24H25N3O,372.2070).
实施例52(3S)-1-[7-(4-甲氧基苯基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-胺盐酸盐(ZLWT-42)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，4-甲氧基苯硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-42。产率36％，黄色固体。1H NMR(400MHz,DMSO-d6)δ8.91–8.72(m,3H,H-26),8.34(s,1H,H-7),8.17–8.06(m,2H,H-9,10),7.83–7.69(m,2H,H-16,20),7.16–6.92(m,2H,H-17,19),4.37(ddd,J＝15.1,11.5,7.0Hz,2H,H-22,25),4.12(ddd,J＝17.2,11.7,5.8Hz,2H,H-22,25),3.99(d,J＝7.6Hz,1H,H-23),3.82(s,3H,H-28),3.10(q,J＝5.5,4.5Hz,2H,H-11),2.94–2.81(m,2H,H-14),2.35(dq,J＝14.4,7.6Hz,1H,H-24),2.29–2.18(m,1H,H-24),1.85(t,J＝6.3Hz,2H,H-12,13),1.69(q,J＝6.0Hz,2H,H-12,13)；13C NMR(101MHz,DMSO-d6)δ159.8(C-24),158.9(C-11),151.9(C-19),137.3(C-13),136.2(C-16),131.5(C-21),131.1(C-15),128.8(2C,C-22,26),123.1(C-14),119.5(C-17),119.2(C-18),115.4(C-20),115.0(2C,C-23,25),57.9(C-2),55.7(C-28),53.4(C-3),49.5(C-5),29.7(C-4),28.2(C-10),28.0(C-7),22.6(C-8),20.7(C-9).HR-ESI-MS:374.2212[M+H]+,(calcd for C24H27N3O,374.2227).
实施例53(3S)-1-[7-(2H-1，3-苯并二氧杂环戊二醇-5-基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-胺盐酸盐(ZLWT-43)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，(2,3-二氢苯并[b][1,4]二恶英-6-基)硼酸替换化合物4b，合成方法如实施例46，化合物ZLWT-43。产率20％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.97(d,J＝5.8Hz,2H,Ar-H),8.82(s,1H,Ar-H),8.77(brs,3H,H-29),8.50(d,J＝5.7Hz,2H,Ar-H),8.41(d,J＝8.8Hz,1H,Ar-H),8.19(d,J＝8.8Hz,1H,Ar-H),4.49(ddd,J＝25.9,13.8,7.2Hz,2H,H-25,28),4.22(td,J＝12.1,4.2Hz,2H,H-25,28),3.97(brs,1H,26),3.10(t,J＝6.8Hz,2H,H-11),3.05(dt,J＝12.1,6.0Hz,1H,H-26),2.94(q,J＝6.0Hz,2H,H-14),2.33(dq,J＝14.4,7.5Hz,1H,H-27),2.25(d,J＝5.5Hz,1H,H-27),1.88(q,J＝14.3,11.2Hz,2H,H-12,13),1.68(d,J＝19.5Hz,2H,H-12,13)；13C NMR(151MHz,DMSO-d6)δ159.6(C-5),153.2(C-1),152.2(C-18),143.8(2C,C-3,19),139.7(2C,C-8,15),131.0(C9),130.1(C-10),127.4(C-7),124.2(2C,C-2,6),123.5(C-16),119.8(C-17),117.9(C-20),113.8(C-22),58.4(C-25),53.9(C-26),49.4(C-28),45.7(C-27),29.4(C-11),28.3(C-14),22.6(C-13),20.7(C-12).HR-ESI-MS:388.2005[M+H]+,(calcd for C24H25N3O2,388.2020).
实施例54(3S)-1-[7-(2，3-二氢-1，4-苯并二恶英-6-基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-胺盐酸盐(ZLWT-44)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，苯并[d][1,3]二恶英-5-基硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-44。产率34％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.69(d,J＝5.2Hz,3H,H-22),8.31(d,J＝1.9Hz,1H,H-7),8.10(dd,J＝8.8,1.8Hz,1H,H-9),8.07(d,J＝8.8Hz,1H,H-10),7.35–7.21(m,2H,H-12,16),6.99(d,J＝8.2Hz,1H,H-13),4.39(dd,J＝12.0,6.4Hz,1H,H-21),4.36–4.24(m,5H,H-18,28,29),4.11(ddd,J＝18.9,9.8,4.1Hz,2H,H-18,21),3.97(h,J＝5.0Hz,1H,H-19),3.10(t,J＝6.7Hz,2H,H-23),2.90(q,J＝5.8Hz,2H,H-26),2.39–2.05(m,2H,H-20),1.90–1.80(m,2H,H-24,25),1.69(p,J＝6.5Hz,2H,H-24,25)；13C NMR(151MHz,DMSO-d6)δ157.9(C-5),150.7(C-1),143.2(C-3),143.0(C-14),136.3(C-15),134.8(C-8),131.4(C-11),130.2(C-9),122.3(C-10),119.4(C-7),118.4(C-12),117.8(C-2),117.1(C-6),114.9(C-13),113.8(C-16),63.6(C-28),63.5(C-29),57.0(C-18),52.3(C-19),48.4(C-21),28.5(C-20),27.0(2C,C-23,26),21.6(C-25),19.7(C-24).HR-ESI-MS:402.2165[M+H]+,(calcd for C25H27N3O2,402.2176).
实施例55(4-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}苯基)甲醇盐酸盐(ZLWT-45)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，(4-(羟甲基)苯基)硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-45。产率37％，黄色固体。1H NMR(400MHz,DMSO-d6)δ8.72(s,3H,H-28),8.40(d,J＝1.8Hz,1H,H-7),8.19–8.03(m,2H,H-9,10),7.81–7.77(m,2H,H-16,20),7.47(d,J＝8.0Hz,2H,H-17,19),4.57(s,2H,H-22),4.49–4.28(m,2H,H-24,27),4.14(dd,J＝11.4,4.4Hz,2H,H-24,27),4.03–3.92(m,1H,H-25),3.11(t,J＝6.7Hz,2H,H-11),2.90(q,J＝5.3Hz,2H,H-14),2.41–2.28(m,1H,H-26),2.23(dq,J＝12.7,6.0Hz,1H,H-26),1.87(h,J＝6.8,6.3Hz,2H,H-12,13),1.69(q,J＝6.0Hz,2H,H-12,13)；13C NMR(101MHz,DMSO-d6)δ159.1(C-15),151.9(C-21),143.0(C-13),137.6(C-3),137.5(C-6),136.3(C-10),131.3(C-11),129.3(C-12),127.6(2C,C-4,8),127.3(2C,C-5,7),123.9(C-9),119.5(C-22),118.9(C-20),62.9(C-1),58.1(C-24),53.4(C-25),49.5(C-27),29.6(C-26),28.1(2C,C-16,19),22.7(C-18),20.7(C-17).HR-ESI-MS:374.2213[M+H]+,(calcd for C24H27N3O,374.2227).
实施例56(3S)-1-[7-(吡啶-3-基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-胺盐酸盐(ZLWT-46)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，3-吡啶硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-46。产率36％，黄色固体。1H NMR(400MHz,DMSO-d6)δ9.44(d,J＝2.2Hz,1H,H-16),9.04(dt,J＝8.3,1.7Hz,1H,H-18),8.94(d,J＝5.4Hz,3H,H-26),8.89(dd,J＝5.6,1.3Hz,1H,H-20),8.69(d,J＝1.9Hz,1H,H-7),8.29(dd,J＝8.9,1.7Hz,1H,H-9),8.20(d,J＝8.8Hz,1H,H-10),8.10(dd,J＝8.2,5.5Hz,1H,H-19),4.64–4.37(m,2H,H-22,25),4.20(ddt,J＝19.1,7.8,4.2Hz,2H,H-22,25),4.03–3.87(m,1H,H-23),3.10(t,J＝6.7Hz,2H,H-11),2.92(q,J＝6.0Hz,2H,H-14),2.41–2.21(m,2H,H-24),1.83(tq,J＝13.4,8.6,7.3Hz,2H,H-12,13),1.66(qd,J＝7.4,6.9,3.5Hz,2H,H-12,13)；13C NMR(101MHz,DMSO-d6)δ159.3(C-11),152.4(C-19),143.5(C-25),141.6(C-21),141.2(C-13),138.7(C-22),137.7(C-16),131.1(C-23),129.9(C-14),127.5(C-15),126.1(C-24),119.8(C-17),118.5(C-18),114.9(C-20),58.2(C-2),53.8(C-3),49.5(C-5),29.6(C-4),28.2(C-10),28.1(C-7),22.6(C-8),20.6(C-9).HR-ESI-MS:345.2076[M+H]+,(calcd for C22H24N4,345.2074).
实施例57(3R)-1-[7-(吡啶-4-基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-胺盐酸盐(ZLWT-47)
如图8所示，叔丁基(R)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，4-吡啶硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-47。产率21％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.99(d,J＝6.5Hz,2H,H-23,25),8.85(d,J＝1.4Hz,3H,H-7,21),8.58(d,J＝6.6Hz,2H,H-22,26),8.42(dd,J＝8.9,1.5Hz,1H,H-9),8.21(d,J＝8.9Hz,1H,H-10),4.51(ddd,J＝19.1,14.1,7.0Hz,2H,H-13,14),4.37–4.17(m,2H,H-13,14),3.99(s,1H,H-20),3.16–3.07(m,2H,H-15),2.95(dd,J＝12.3,6.6Hz,2H,H-18),2.34(dt,J＝14.1,6.9Hz,1H,H-19),2.32–2.22(m,1H,H-19),1.98–1.77(m,2H,H-16,17),1.77–1.59(m,2H,H-16,17)；13C NMR(151MHz,DMSO-d6)δ159.6(C-5),154.0(C-1),152.2(C-3),142.9(2C,C-23,25),139.8(C-11),131.0(C-8),129.8(C-9),127.6(C-10),124.5(2C,C-22,26),119.8(C-7),117.8(C-2),113.9(C-6),58.4(C-13),54.0(C-20),49.5(C-14),29.4(C-19),28.3(C-15),28.1(C-18),22.6(C-17),20.7(C-16).HR-ESI-MS:345.2071[M+H]+,(calcd for C22H24N4,345.2074).
实施例58(3S)-1-[7-(吡啶-4-基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-胺盐酸盐(ZLWT-48)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，4-吡啶硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-48。产率28％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.98(d,J＝6.0Hz,2H,H-23,25),8.90(d,J＝5.4Hz,3H,H-21),8.85(d,J＝2.0Hz,1H,H-7),8.58(d,J＝6.1Hz,2H,H-22,26),8.40(dd,J＝8.9,1.8Hz,1H,H-9),8.21(d,J＝8.8Hz,1H,H-10),4.56–4.47(m,2H,H-13,14),4.28–4.18(m,2H,H-13,14),3.99–3.96(m,1H,H-20),3.09(t,J＝6.8Hz,2H,H-15),3.02–2.77(m,2H,H-18),2.39–2.19(m,2H,H-19),1.89–1.80(m,2H,H-16,17),1.73–1.53(m,2H,H-16,17)；13CNMR(151MHz,DMSO-d6)δ157.8(C-5),152.4(C-1),150.6(C-3),141.1(2C,C-23,25),138.1(C-11),129.3(C-8),128.1(C-9),125.9(C-10),122.8(2C,C-22,26),118.1(C-7),116.2(C-2),112.3(C-6),56.7(C-13),52.3(C-20),47.8(C-14),27.7(C-19),26.6(C-15),26.4(C-18),20.9(C-17),18.9(C-16).HR-ESI-MS:345.2063[M+H]+,(calcd for C22H24N4,345.2074).
实施例59(3R)-1-[7-(吡啶-4-基)-1H，2H，3H-环戊烷-9-基]吡咯烷-3-胺盐酸盐(ZLWT-49)
如图8所示，7-溴-9-氯-2,3-二氢-1H-环戊烷[b]喹啉(化合物8c)替换化合物8b、叔丁基(R)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，4-吡啶硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-49。产率33％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.98–8.96(m,2H,H-22,24),8.95(d,J＝1.9Hz,1H,H-7),8.79(d,J＝5.5Hz,3H,H-20),8.54–8.50(m,2H,H-21,25),8.43(dd,J＝8.9,1.9Hz,1H,H-9),8.13(d,J＝8.8Hz,1H,H-10),4.76(dt,J＝11.1,7.8Hz,1H,H-14),4.64(dd,J＝12.0,5.8Hz,1H,H-13),4.32(dd,J＝12.0,2.8Hz,1H,H-14),4.20(ddd,J＝11.5,7.9,4.2Hz,1H,H-13),3.98(td,J＝6.0,3.0Hz,1H,H-19),3.58–3.44(m,2H,H-15),3.24–3.12(m,2H,H-17),2.33–2.20(m,2H,H-18),2.15(qt,J＝8.3,4.2Hz,1H,H-16),2.06(dp,J＝12.4,8.4Hz,1H,H-16)；13CNMR(151MHz,DMSO-d6)δ160.1(C-5),156.7(C-1),144.0(2C,C-22,24),140.7(2C,C-3,11),131.3(C-8),130.8(C-9),128.1(C-10),124.2(2C,C-21,25),120.6(C-7),118.8(C-6),117.7(C-2),57.3(C-13),53.2(C-19),49.8(C-14),33.6(C-15),31.8(C-18),29.6(C-17),23.0(C-16).HR-ESI-MS:331.1918[M+H]+,(calcd for C21H22N4,331.1917).
实施例60(3S)-1-[7-(吡啶-4-基)-1H，2H，3H-环戊烷[b]喹啉-9-基]吡咯烷-3-胺盐酸盐(ZLWT-50)
如图8所示，7-溴-9-氯-2,3-二氢-1H-环戊烷[b]喹啉(化合物8c)替换化合物8b、叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，4-吡啶硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-50。产率48％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.98(brs,3H,H-7,22,24),8.89(s,3H,H-20),8.57(d,J＝5.9Hz,2H,H-21,25),8.43(d,J＝8.7Hz,1H,H-9),8.16(d,J＝8.9Hz,1H,H-10),4.79(brs,1H,H-14),4.66(brs,1H,H-13),4.34(d,J＝12.0Hz,1H,H-14),4.18(brs,1H,H-13),3.98(s,1H,H-19),3.54–3.42(m,2H,H-15),3.17(tt,J＝18.3,9.9Hz,2H,H-17),2.27(s,2H,H-18),2.18–2.07(m,1H,H-16),2.05(q,J＝9.9Hz,1H,H-16)；13C NMR(151MHz,DMSO-d6)δ160.1(C-5),156.6(C-1),143.5(2C,C-22,24),140.8(2C,C-3,11),131.3(C-8),130.6(C-9),128.2(C-10),124.3(2C,C-21,25),120.6(C-7),118.8(C-6),117.7(C-2),57.3(C-13),53.3(C-19),49.8(C-14),33.6(C-15),31.8(C-18),29.6(C-17),22.9(C-16).HR-ESI-MS:331.1903[M+H]+,(calcd for C21H22N4,331.1917).
实施例61(3S)-1-[7-(1-甲基-1H-吡唑-4-基)-1，2，3，4-四氢吖啶-9-基]吡咯烷-3-胺盐酸盐(ZLWT-51)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，(1-甲基-1H-吡唑-4-基)硼酸替换化合物4b，合成方法如实施例46，得到化合物ZLWT-51。产率42％，黄色固体。1H NMR(600MHz,DMSO-d6)δ8.32(s,1H,H-25),8.27(s,2H,H-21),8.25(d,J＝1.2Hz,1H,H-7),8.06(dd,J＝10.3,1.1Hz,2H,H-9,22),7.84(d,J＝8.7Hz,1H,H-10),4.33(dd,J＝10.2,5.9Hz,1H,H-14),4.13(dd,J＝14.4,6.4Hz,2H,H-13,14),4.02(s,1H,H-13),3.93(s,1H,H-20),3.91(s,3H,H-26),3.06(td,J＝6.6,2.2Hz,2H,H-15),2.86(t,J＝6.0Hz,2H,H-18),2.46–2.34(m,1H,H-19),2.21–2.08(m,1H,H-19),1.95–1.78(m,2H,H-16,17),1.70(dt,J＝11.6,5.9Hz,2H,H-16,17)；13C NMR(151MHz,DMSO-d6)δ158.7(C-5),158.5(C-1),158.3(C-3),137.0(C-25),130.3(C-10),129.5(C-9),129.0(2C,C-8,22),121.3(C-11),120.8(C-6),118.6(C-2),116.6(C-7),57.9(C-13),52.6(C-20),49.6(C-14),29.9(2C,C-15,19),27.8(C-26),22.6(2C,C-16,17),20.9(C-18).HR-ESI-MS:348.2180[M+H]+,(calcd for C21H25N5,348.2183).
实施例62 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-1H，2H，3H-环戊烷[b]喹啉-7-基}吡啶-2-基)乙酰胺盐酸盐(ZLWT-52)
如图8所示，7-溴-9-氯-2,3-二氢-1H-环戊烷[b]喹啉(化合物8c)替换化合物8b、叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，化合物4a替换化合物4b，合成方法如实施例46，得到化合物ZLWT-52。产率51％，黄色固体。1H NMR(400MHz,DMSO-d6)δ11.75(s,1H,H-17),8.80(d,J＝5.1Hz,3H,H-26),8.66(d,J＝1.8Hz,1H,H-16),8.44(d,J＝5.6Hz,2H,H-7,13),8.19(dd,J＝8.8,1.6Hz,1H,H-9),8.12(d,J＝8.8Hz,1H,H-10),7.81(dd,J＝5.7,1.7Hz,1H,H-12),4.63(td,J＝11.9,10.8,4.5Hz,2H,H-22,25),4.29(ddd,J＝30.4,12.9,5.3Hz,2H,H-22,25),3.99(dd,J＝13.9,7.2Hz,1H,H-23),3.64–3.38(m,2H,H-27),3.26–3.00(m,2H,H-29),2.23(s,5H,H-20,28),2.18–1.88(m,2H,H-24)；13C NMR(101MHz,DMSO-d6)δ170.9(C-1),159.9(C-12),156.4(C-14),151.8(C-5),150.3(C-9),146.1(C-20),140.0(C-7),132.8(C-17),130.9(C-18),126.6(C-19),120.6(C-16),118.8(C-13),117.9(C-15),117.5(C-8),111.9(C-6),57.5(C-25),52.9(C-26),49.7(C-28),33.7(C-23),31.8(C-27),29.6(C-21),24.4(C-2),23.0(C-22).HR-ESI-MS:388.2118[M+H]+,(calcd for C23H25N5O,388.2132).
实施例63 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-1H，2H，3H-环戊烷[b]喹啉-7-基}吡啶-2-基)环己烷甲酰胺盐酸盐(ZLWT-53)
如图8所示，7-溴-9-氯-2,3-二氢-1H-环戊烷[b]喹啉(化合物8c)替换化合物8b、叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，化合物4e替换化合物4b，合成方法如实施例46，得到化合物ZLWT-53。产率38％，黄色固体。1H NMR(600MHz,DMSO-d6)12.18(s,1H,H-17),8.84(d,J＝4.3Hz,2H,H-26),8.70(s,1H,H-16),8.51(d,J＝1.4Hz,1H,H-7),8.44(d,J＝6.1Hz,1H,H-13),8.22(dd,J＝8.8,1.4Hz,1H,H-9),8.13(d,J＝8.8Hz,1H,H-10),7.98–7.89(m,1H,H-12),4.77–4.60(m,2H,H-22,25),4.36–4.31(m,1H,H-25),4.29–4.23(m,1H,H-22),3.98(d,J＝3.9Hz,1H,H-23),3.62–3.36(m,2H,H-27),3.24–3.04(m,2H,H-29),2.64(tt,J＝11.4,3.4Hz,1H,H-20),2.40–2.20(m,2H,H-28),2.19–2.00(m,2H,H-30,34),1.93(s,2H,H-24),1.77(dd,J＝9.8,3.1Hz,2H,H-30,34),1.66(d,J＝12.3Hz,1H,H-32),1.44(tt,J＝12.5,6.3Hz,2H,H-31,33),1.37–1.13(m,3H,H-31,32,33)；13C NMR(101MHz,DMSO-d6)δ176.6(C-7),159.9(C-17),156.5(C-19),152.5(C-10),149.7(C-14),146.5(C-25),139.9(C-12),133.3(C-22),131.1(C-23),126.4(C-24),120.5(C-18),118.7(C-21),117.8(C-20),117.5(C-13),111.9(C-11),57.5(C-30),52.8(C-31),49.7(C-33),44.8(C-1),33.7(C-28),31.8(C-32),29.6(C-26),29.3(2C,C-2,6),25.8(C-4),25.5(2C,C-3,5),23.0(C-27).HR-ESI-MS:456.2741[M+H]+,(calcdfor C28H33N5O,456.2758).
实施例64 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)乙酰胺盐酸盐(ZLWT-54)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，化合物4a替换化合物4b，合成方法如实施例46，得到化合物ZLWT-54。产率32％，黄色固体。1H NMR(600MHz,DMSO-d6)δ11.95(s,1H,H-23),8.83(d,J＝5.3Hz,1H,H-19),8.76(d,J＝5.3Hz,2H,H-17),8.57(s,1H,H-19),8.43(brs,2H,H-7,22),8.17(d,J＝5.0Hz,2H,H-9,10),7.84(d,J＝5.8Hz,1H,H-18),4.49(td,J＝12.9,12.2,6.1Hz,1H,H-14),4.39(dq,J＝17.3,8.2Hz,1H,H-13),4.21(ddd,J＝15.4,11.8,7.4Hz,2H,H-13,14),3.99(brs,1H,H-16),3.10(t,J＝6.7Hz,2H,H-27),2.92(m,2H,H-30),2.37(dq,J＝14.5,7.7Hz,1H,H-15),2.24(s,3H,H-26),1.85(brs,2H,H-28,29),1.67(brs,2H,H-28,29)；13C NMR(151MHz,DMSO-d6)δ172.4(C-24),171.4(C-5),159.3(C-1),154.9(C-21),152.3(C-19),139.1(C-3),130.6(C-11),126.1(C-8),119.9(C-9),118.0(C-10),117.9(C-7),114.3(C-2),112.0(C-6),110.9(C-18),110.4(C-22),58.5(C-13),53.8(C-16),49.4(C-14),29.5(C-15),28.1(C-27),24.4(C-30),22.6(C-26),21.5(C-29),20.7(C-28).HR-ESI-MS:402.2279[M+H]+,(calcd for C24H27N5O,402.2288).
实施例65 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环丁烷甲酰胺盐酸盐(ZLWT-55)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，化合物4c替换化合物4b，合成方法如实施例46，得到化合物ZLWT-55。产率41％，黄色固体。1H NMR(400MHz,DMSO-d6)δ12.06(s,1H,H-27),8.81(d,J＝5.4Hz,3H,H-21),8.60(d,J＝1.5Hz,1H,H-26),8.51(d,J＝1.8Hz,1H,H-7),8.45(d,J＝6.0Hz,1H,H-23),8.20(d,J＝2.3Hz,2H,H-9,10),7.91(dd,J＝6.1,1.9Hz,1H,H-22),4.59–4.34(m,2H,H-13,14),4.23(td,J＝12.1,4.4Hz,2H,H-13,14),3.99(dt,J＝10.2,4.3Hz,1H,H-20),3.64–3.37(m,1H,H-30),3.10(t,J＝6.7Hz,2H,H-15),2.92(q,J＝6.0Hz,2H,H-18),2.42–2.33(m,1H,H-19),2.29(ddd,J＝10.3,6.0,2.4Hz,3H,H-19,31,33),2.24–2.13(m,2H,H-31,33),1.99(dq,J＝10.9,8.6Hz,1H,H-32),1.91–1.76(m,3H,H-16,17,32),1.67(h,J＝6.5Hz,2H,H-16,17)；13C NMR(101MHz,DMSO-d6)δ175.9(C-5),159.3(C-20),152.4(C-26),152.0(C-8),150.5(C-12),143.3(C-18),139.3(C-10),131.3(C-15),130.5(C-16),126.3(C-17),119.9(C-14),118.1(C-27),117.9(C-25),114.4(C-11),112.4(C-9),58.5(C-29),55.4(C-30),53.8(C-32),49.4(C-1),29.5(C-31),28.2(C-21),28.1(C-24),24.9(2C,C-2,4),22.6(C-23),20.7(C-22),18.1(C-3).HR-ESI-MS:442.2592[M+H]+,(calcd for C27H31N5O,442.2601).
实施例66 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环戊烷甲酰胺盐酸盐(ZLWT-56)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，化合物4d替换化合物4b，合成方法如实施例46，得到化合物ZLWT-56。产率40％，黄色固体。1H NMR(400MHz,DMSO-d6)δ12.57(d,J＝23.2Hz,1H,H-27),8.87(d,J＝6.9Hz,3H,H-21),8.62(s,1H,H-26),8.53(d,J＝2.2Hz,1H,H-7),8.44(d,J＝6.3Hz,1H,H-23),8.26–8.10(m,2H,H-9,10),8.05–7.89(m,1H,H-22),4.53(dd,J＝12.4,6.3Hz,1H,H-14),4.42(dt,J＝11.4,7.5Hz,1H,H-13),4.23(dd,J＝11.8,4.5Hz,2H,H-13,14),4.03–3.98(m,1H,H-20),3.17–3.07(m,3H,H-15,30),3.01–2.84(m,2H,H-18),2.34(dh,J＝32.8,6.9,6.5Hz,2H,H-19),2.06–1.35(m,12H,H-16,17,31,32,33,34)；13C NMR(101MHz,DMSO-d6)δ177.9(C-6),159.2(C-21),152.8(C-27),152.4(C-9),149.8(C-13),141.9(C-19),139.4(C-11),130.7(C-16),130.4(C-17),126.5(C-18),119.9(C-15),118.0(C-28),117.9(C-26),114.4(C-12),112.6(C-10),58.6(C-30),53.9(C-31),49.4(C-33),45.6(C-1),30.2(2C,C-2,5),29.5(C-33),28.2(C-32),28.1(C-25),26.1(2C,C-3,4),22.6(C-24),20.7(C-23).HR-ESI-MS:456.2747[M+H]+,(calcd for C28H33N5O,456.2758).
实施例67 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)环己烷甲酰胺盐酸盐(ZLWT-57)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，化合物4e替换化合物4b，合成方法如实施例46，得到化合物ZLWT-57。产率42％，黄色固体。1H NMR(600MHz,DMSO-d6)12.39(s,1H,H-27),8.78(d,J＝4.2Hz,3H,H-21),8.64(s,1H,H-7),8.56(d,J＝1.0Hz,1H,H-26),8.45(d,J＝6.1Hz,1H,H-23),8.24(dd,J＝8.9,1.4Hz,1H,H-9),8.19(d,J＝8.8Hz,1H,H-10),7.96(dd,J＝6.0,1.1Hz,1H,H-22),4.52(dd,J＝12.1,6.3Hz,1H,H-14),4.41(dt,J＝10.9,7.6Hz,1H,H-13),4.27–4.19(m,2H,H-13,20),4.04–3.96(m,1H,H-14),3.11(t,J＝6.6Hz,2H,H-15),3.01–2.81(m,2H,H-18),2.66(tt,J＝11.5,3.4Hz,1H,H-30),2.45–2.31(m,1H,H-19),2.28(dt,J＝15.0,4.9Hz,1H,H-19),1.97–1.90(m,2H,H-16,17),1.87(td,J＝12.0,6.6Hz,2H,H-16,17),1.77(dd,J＝9.8,3.2Hz,2H,H-31,35),1.74–1.61(m,3H,H-31,33,35),1.46(qd,J＝12.5,3.1Hz,2H,H-32,34),1.35–1.15(m,3H,H-32,33,34)；13C NMR(151MHz,DMSO-d6)δ177.7(C-28),172.4(C-5),159.3(C-1),152.7(C-25),152.4(C-23),150.1(C-3),142.3(C-11),139.4(C-8),130.9(C-9),130.5(C-10),126.5(C-7),119.9(C-2),117.9(C-6),114.2(C-22),112.6(C-26),58.6(C-13),53.9(C-20),49.4(C-14),44.9(C-30),29.5(C-19),29.0(2C,C-31,35),28.2(C-15),28.1(C-18),25.6(C-33),25.4(2C,C-32,34),22.6(C-17),20.7(C-16).HR-ESI-MS:470.2909[M+H]+,(calcd for C29H35N5O,470.2914).
实施例68 N-(4-{9-[(3S)-3-氨基吡咯烷-1-基]-5，6，7，8-四氢吖啶-2-基}吡啶-2-基)苯甲酰胺盐酸盐(ZLWT-58)
如图8所示，叔丁基(S)-吡咯烷-3-基氨基甲酸酯替换叔丁基(R)-哌啶-3-基氨基甲酸酯，化合物4f替换化合物4b，合成方法如实施例46，得到化合物ZLWT-58。产率45％，黄色固体。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H,H-27),8.93(d,J＝1.8Hz,1H,H-26),8.83(d,J＝5.4Hz,3H,H-21),8.66(d,J＝1.8Hz,1H,H-7),8.59–8.52(m,1H,H-9),8.28(dt,J＝7.0,1.3Hz,2H,H-31,35),8.20(d,J＝8.9Hz,1H,H-10),8.00(dd,J＝6.0,1.8Hz,1H,H-22),7.72–7.64(m,1H,H-33),7.58(dd,J＝8.3,7.0Hz,2H,H-32,34),4.64–4.34(m,2H,H-13,14),4.25(td,J＝12.5,4.5Hz,2H,H-13,14),4.08–3.96(m,1H,H-20),3.09(q,J＝7.8,7.2Hz,2H,H-18),2.92(q,J＝6.0Hz,2H,H-18),2.45–2.19(m,2H,H-19),1.85(q,J＝6.9Hz,2H,H-16,17),1.75–1.58(m,2H,H-16,17)；13C NMR(101MHz,DMSO-d6)δ167.4(C-1),159.3(C-22),152.4(C-10),151.9(C-28),150.7(C-14),143.5(C-20),139.3(C-12),133.5(C-17),132.7(C-5),131.3(C-2),130.6(C-18),129.1(2C,C-4,6),129.0(2C,C-3,7),126.3(C-19),120.0(C-16),118.5(C-29),118.1(C-27),114.5(C-13),113.6(C-11),58.6(C-31),55.4(C-32),53.9(C-34),49.4(C-33),29.5(C-23),28.2(C-26),22.6(C-25),20.7(C-24).HR-ESI-MS:464.2437[M+H]+,(calcd for C29H29N5O,464.2445).
实施例69 1-[7-(2-氨基吡啶-4-基)-1，2，3，4-四氢吖啶-9-基]哌啶-4-羧酸(ZLWT-29)
如图6所示，将化合物ZLWT-28(50mg，0.1mmol)加入到2M NaOH/EtOH(1：1，10mL)中，溶液在90℃下搅拌1h。减压除去溶剂，加水(10mL)后，用2M HCl调节pH值至6-7，抽滤得到目标化合物ZLWT-29。收率78％，黄色固体。1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝2.0Hz,1H,H-7),8.08(d,J＝2.8Hz,1H,H-20),8.06(d,J＝5.6Hz,1H,H-17),7.99(dd,J＝8.7,1.9Hz,1H,H-9),7.22–7.12(m,2H,H-21),7.09(d,J＝6.1Hz,2H,H-10,16),3.61–3.34(m,4H,H-23,25),3.09(t,J＝6.5Hz,2H,H-11),2.88(t,J＝6.2Hz,2H,H-14),2.68–2.56(m,1H,H-26),2.02(dd,J＝13.3,3.6Hz,2H,H-24,27),1.94–1.68(m,6H,H-12,13,24,27).HR-ESI-MS:402.2054[M+H]+,(calcd for C24H26N4O2,402.2056).
实施例76：胆碱酯酶抑制活性的评价
采用改进的Ellman方法测试化合物抗AChE活性。在96孔板中，各孔加入140μL PBS缓冲液(0.1M,pH＝8.0)，样品孔中加入20μL待测样品溶液和15μL酶溶液；样品本底对照孔用15μL PBS缓冲液代替15μL酶溶液，其他条件不变；空白对照孔用20μL PBS缓冲液代替20μL待测样品溶液，其他条件不变。完全抑制对照孔用20μL PBS缓冲液配的阳性药代替20μL待测样品溶液，其他条件不变。各孔混合均匀后在4℃保存20min。取出加入10μL DTNB(2mM)和10μL ATChI(15mM)，在37℃反应20min后即可在405nm读取吸光度值。按如下公式计算出待测样品的抑制率，使用GraphPad prism 8.0确定线性回归参数并计算IC50。BChE酶活力测定与AChE类似。结论：实验结果如表1-5所示，本发明所制备的大部分化合物对AChE和BChE的活性都在微摩尔级别，与他克林相比，活性明显降低，可能避免化合物的神经毒副作用。
实施例77：抗增殖活性的评价
通过MTT测定法评估化合物的抗增殖活性。将细胞接种在96孔板中并使其粘附过夜。然后将细胞暴露于不同浓度的化合物72h后。将MTT溶液(20μL，0.5mg/mL)添加到每个孔中，将细胞与MTT在37℃下孵育4h。吸去上清液后，加入DMSO(150μL)，在490nm处读取吸光度。所有测定平行重复上次。使用GraphPad prism 8.0软件用于确定线性回归参数并计算IC50值。结论：实验结果如表1-5所示，本发明所制备的大部分化合物的抗增殖活性较强，部分化合物达到纳摩尔水平，相比他克林具有显著提升。
表1化合物ZLWT-1-13的抗增殖活性和ChE抑制活性
Figure BDA0003640034390000301
aIC50values are average±SD of at least three independent experimentsin triplicate.bGI50 values are average±SD of at least three independentexperiments in triplicate.ceeAChE:AChE from electric eel.deqBChE:BChE fromequine serum.
表2化合物ZLWT-14-29的抗增殖活性和ChE抑制活性
Figure BDA0003640034390000311
aIC50values are average±SD of at least three independent experimentsin triplicate.bGI50 values are average±SD of at least three independentexperiments in triplicate.ceeAChE:AChE from electric eel.deqBChE:BChE fromequine serum.eND:not determined.
表3化合物ZLWT-30-39的抗增殖活性和ChE抑制活性
Figure BDA0003640034390000321
aIC50values are average±SD of at least three independent experimentsin triplicate.bGI50 values are average±SD of at least three independentexperiments in triplicate.ceeAChE:AChE from electric eel.deqBChE:BChE fromequine serum.eND:not determined.
表4化合物ZLWT-40-51的抗增殖活性和ChE抑制活性
Figure BDA0003640034390000331
aIC50values are average±SD of at least three independent experimentsin triplicate.bGI50values are average±SD of at least three independentexperiments in triplicate.ceeAChE:AChE from electric eel.deqBChE:BChE fromequine serum.eND:not determined.
表5化合物ZLWT-52-58的抗增殖活性和ChE抑制活性
Figure BDA0003640034390000341
aIC50values are average±SD of at least three independent experimentsin triplicate.bGI50values are average±SD of at least three independentexperiments in triplicate.ceeAChE:AChE from electric eel.deqBChE:BChE fromequine serum.eND:not determined.
实施例78：抗增殖活性的评价
CDK2和CDK9抑制活性通过Mobility shift assay测得。Dinaciclib用作阳性对照化合物。将测试化合物在384孔板中与重组CDK2/CycA2(Carna)或CDK4/CycT1(Carna)在室温下孵育10min，然后加入激酶底物和ATP的混合物以启动1x激酶缓冲液中的激酶反应。30min后加入30μL终止缓冲液终止反应。转化率在室温下在Caliper(Caliper EZ ReaderII,PE)中测量。目标化合物的IC50值通过GraphPad Prism 8.0软件计算。结果如表6显示，所选择的化合物对CDK2具有中等至强效的抑制活性。抗增殖活性最好的化合物ZLWT-37展示了最好的CDK2抑制活性，IC50为0.026μM。测定了化合物ZLWT-37的CDK9抑制活性，结果如图9显示，ZLWT-37展示了2.32nM的抑制活性。综合表明ZLWT-37是一种强的CDK2/9抑制剂。
表6部分化合物对CDK2的抑制活性
Figure BDA0003640034390000342
Figure BDA0003640034390000351
aAll values are average±SD of at least three independentexperiments.bInhibition％at 10μM.cInhibition％at 500nM.dInhibition％at 500μM.eND＝Not Determined.fSelectivity Index(SI)＝IC50(CDK4)/IC50(CDK2).
通过酶活力测试和细胞毒性实验结果，该类他克林衍生物可为发现新的肿瘤治疗药物提供理论依据。

Claims (7)

1.一种他克林衍生物或其药学上可接受的盐，其特征在于，所述的衍生物结构通式如式I所示：
Figure FDA0003640034380000011
其中：
A环是4-12个碳原子的芳基或取代芳基、杂环芳基或取代杂环芳基，所述杂环芳基的芳杂环包括1-3个N、O、或S的杂原子；
R1为酰胺上的取代基，选自CH3、环丙基、环丁基、环戊基、环己基或者苯基，所述苯基为取代或者未取代的苯基；
R2选自NH2或者0-4个杂原子的3-12元环；
n各自独立地为0、1。
2.根据权利要求1所述的他克林衍生物或其药学上可接受的盐，其特征在于，A环为
Figure FDA0003640034380000012
R2为
Figure FDA0003640034380000013
Figure FDA0003640034380000014
Figure FDA0003640034380000015
NH2或
Figure FDA0003640034380000016
n各自独立地为0、1或2。
3.下列化合物或其在药学上可接受的盐，选自：
Figure FDA0003640034380000017
Figure FDA0003640034380000021
Figure FDA0003640034380000031
Figure FDA0003640034380000041
Figure FDA0003640034380000051
4.一种药物组合物，其特征在于，含有权利要求1-3任意一项所述的式I或其药学上可接受的盐以及药学上可接受的辅料。
5.根据权利要求4所述的药物组合物，其特征在于，由如权利要求1-3任意一项所述式I添加一种或多种药学上可接受的辅料制成制剂，所述制剂的剂型为胶囊剂、丸剂、片剂、颗粒剂或注射剂。
6.如权利要求1-3任意一项所述化合物或其药学上可用的盐在制备治疗肿瘤中的应用。
7.如权利要求1-3任意一项所述化合物或其药学上可用的盐在制备CDK2抑制剂或者CDK9抑制剂中的应用。
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