CN113527263B - 一种蛋白水解靶向嵌合体及其药物组合物和应用 - Google Patents

一种蛋白水解靶向嵌合体及其药物组合物和应用 Download PDF

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CN113527263B
CN113527263B CN202110816479.6A CN202110816479A CN113527263B CN 113527263 B CN113527263 B CN 113527263B CN 202110816479 A CN202110816479 A CN 202110816479A CN 113527263 B CN113527263 B CN 113527263B
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杨光
李辰
黄袆磊
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Abstract

本发明公开了一种蛋白水解靶向嵌合体，其可以以剂量依赖性和时间依赖性的方式有效诱导FLT3‑ITD阳性细胞MOM‑13和MV‑4‑11中的FLT3‑ITD降解。体内研究表明其可以显著降低急性髓系白血病小鼠体内CD45+阳性细胞水平，显示出对急性髓系白血病较好的治疗效果。

Description

一种蛋白水解靶向嵌合体及其药物组合物和应用
技术领域
本发明属于化学药物领域，具体涉及一种蛋白水解靶向嵌合体及其药物组合物和应用。
背景技术
FLT3突变是AML患者中最常见的基因突变，这种突变会引起FLT3发生无需配体参与的自磷酸化和二聚化，系统性的激活FLT3信号通路，促进细胞的增殖分化，导致AML的发生与发展。FLT3-内部串联重复(ITD)是FLT3突变的主要类型，发病率约占所有AML的25％，而活化环中的点突变(FLT3-TKD)发病率较低，只有7-10％。与没有FLT3-ITD突变的患者相比，FLT3-ITD突变的患者预后往往不良，复发风险增加，总生存期(OS)更短，因此FLT3-ITD成为治疗AML的一个重要靶点。
目前已有多款治疗FLT3-ITD突变AML有效的抑制剂被批准上市或用于临床研究。基于抑制剂的选择性，被分为一代FLT3-ITD抑制剂和二代FLT3-ITD抑制剂。第一代FLT3-ITD抑制剂如多韦替尼(Dovitinib)已被用于多项临床研究，然而临床研究评估发现Dovitinib在治疗中存在用药剂量大，治疗效率低的缺陷。第二代FLT3-ITD抑制剂如奎扎替尼(Quizartinib)治疗效率虽然明显提升，但却出现了耐药性问题。
Craig.Crews最早提出了PROTAC(蛋白水解靶向嵌合体)概念。PROTAC是通过适当的Linker缀合的异双功能小分子。它们可以将靶蛋白拖至接近E3连接酶的位置，从而导致蛋白酶体降解靶蛋白。到目前为止，PROTAC技术已成为化学降解特定蛋白质以治疗肿瘤的重要工具。例如AR，MDM2，CDK6，CDK9，BRD，BET，ALK，PARP-1等，已经开发成为PROTAC分子。但是，关于GPCR降解的报道非常有限(例如，FLT3)。
发明内容
本发明旨在针对FLT3-ITD突变患者治疗中的问题，开发一种增强对急性髓系白血病具有显著疗效的新型PROTAC分子。为实现以上技术目的，本发明采用以下技术方案：
一种蛋白水解靶向嵌合体，所述蛋白质水解靶向嵌合体或其药学上可接受的盐具有如式(I)所示的通式：
Figure BDA0003170291790000021
其中，X为CH2或C＝O，Linker为饱和脂肪链、不饱和脂肪链或脂肪酸链。
作为优选，所述蛋白质水解靶向嵌合体或其药学上可接受的盐具有如式(Ia)所示的结构：
Figure BDA0003170291790000022
其中，n为4、5或6。
作为优选，所述蛋白质水解靶向嵌合体或其药学上可接受的盐具有如式(Ib)所示的结构：
Figure BDA0003170291790000023
其中，n为2、3、4、5、6或7。
作为优选，所述蛋白质水解靶向嵌合体或其药学上可接受的盐具有如式(Ic)所示的结构
Figure BDA0003170291790000024
其中，n为2、3或4。
在上述技术方案的基础上，发明人发现上述的蛋白水解靶向嵌合体或其药学上可接受的盐能够应用于制备用于降低荷瘤动物骨髓中CD45+急性髓性白血病细胞的药物，进一步能够用于制备癌症治疗药物，特别针对于急性髓系白血病。
本发明还提供了一种药物组合物，包括上述的蛋白水解靶向嵌合体或其药学上可接受的盐。作为优选还包括药学上可接受的赋形剂或载体。
本发明的有益效果为：本发明合成了一种新的化合物作为PROTAC降解剂化合物，其可以以剂量依赖性和时间依赖性的方式有效诱导FLT3-ITD阳性细胞MOM-13和MV-4-11中的FLT3-ITD降解。体内研究表明其可以显著降低急性髓系白血病小鼠体内CD45+阳性细胞水平，显示出对急性髓系白血病较好的治疗效果。
附图说明
图1所示为合成的PROTAC分子1和2降解FLT3-ITD蛋白的结果图；
图2所示为本发明化合物1的1H NMR及13C NMR光谱图；
图3所示为本发明化合物2的1H NMR及13C NMR光谱图；
图4所示为本发明化合物1和2抑制FLT3下游信号通路结果图；
图5所示为本发明化合物1和2依赖于细胞内泛素-蛋白酶体途径降解FLT3-ITD试验结果图；
图6所示为本发明化合物1和2降低FLT3-ITD阳性细胞MOM-13和MV-4-11中ROS水平的结果图；
图7所示为本发明化合物1和2对急性髓系白血病小鼠CD45+细胞影响试验结果图。
具体实施方式
以下将结合实施例和附图对本发明的构思及产生的技术效果进行清楚、完整的描述，以充分地理解本发明的目的、方案和效果。
实施例1：化合物1和2的合成
化合物1(n＝4)、2(n＝5)和14(n＝6)的合成路线如下：
Figure BDA0003170291790000031
技术路线中的中间体4的具体制备步骤为：将5-氟-2-硝基苯胺(4.68g，30.0mmol)溶解于干燥的1-甲基-2-吡咯烷酮(NMP，150mL)中，然后加入三乙胺(10.4mL，75.0mm ol)和1-叔丁氧羰基哌嗪(6.15g，33.0mmol)，将混合物加热至110℃，反应15h。将反应液冷却至室温，倒入150mL水，出现黄色沉淀物。通过玻璃漏斗减压过滤、滤饼用乙醚洗涤2次。收集滤饼，并在真空下干燥，得到黄色固体化合物4(7.93g，82％)。
对中间体4进行检测，其检测数据为：M.p.244.2-245.1℃；IR(KBr):3468,3335,2974,1676,1656,1618,1566,1474,1424,1370,1246,1222,1170,1120,1038cm-1.1H NMR(400MHz,C DCl3)δ8.02(d,J＝9.7Hz,1H),6.36–6.21(m,1H),6.19(s,2H),5.95(d,J＝2.3Hz,1H),3.68–3.47(m,4H),3.36(d,J＝5.3Hz,4H),1.49(s,9H).13C NMR(100MHz,CDCl3)δ155.3,154.8,147.3,128.6,125.2,105.6,98.6,80.6,46.9,42.9,28.6.HRMS(ESI)calculated for C15H23N4O4 +[M+H]+:323.1714,found 323.1713。
技术路线中的中间体6的具体制备步骤为：将化合物4(3.22g 10.0mmol)溶于乙醇(300mL)中，再向混合溶液中添加Pd/C(10％w/w，322mg)，在真空下排空瓶内空气，然后通入H2。将反应液在室温下反应过夜，用氩气置换烧瓶内氢气，随后迅速加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(3.91g，20.0mmol)，再置换氩气。将反应物加热至50℃反应5h，将反应液冷却至室温，硅藻土过滤，收集滤液减压浓缩。所得残余物用用饱和NaHCO3(150mL)洗涤，乙酸乙酯(200mL)萃取，收集有机相，用Na2SO4干燥，过滤并减压浓缩得到粗品。粗品经硅胶柱层析(CH2Cl2:CH3OH＝50:1)，得到浅黄色固体化合物6(3.30g，收率85％)。
对中间体6进行检测，其检测数据为：M.p.177.7-178.5℃；IR(KBr):3501,3322,2935,1720,1658,1542,1455,1403,1277,1246,1235,1170,852,771cm-1.1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.8Hz,1H),7.05(s,1H),6.97(dd,J＝8.8,2.3Hz,1H),4.22(q,J＝7.1Hz,2H),4.03(s,2H),3.61(t,J＝5.1Hz,4H),3.09(t,J＝5.1Hz,4H),1.49(s,9H),1.28(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ169.7,154.8,148.3,146.7,115.5,80.0,61.7,51.2,43.7,34.7,28.4,14.1.HRMS(ESI)calculated for C20H29N4O4 +[M+H]+:389.2183,found 389.2185。
技术路线中的中间体8的具体制备步骤为：将LiHMDS(22.5mL，1M in THF，22.5mmol)逐滴添加到化合物6(2.50g，6.44mmol)、2-氨基-6-氟苯甲腈(0.88g，6.44mmol)和无水THF(22.5mL)的混合溶液中。反应混合液在室温下反应8h，然后将反应液用H2O(50mL)淬灭，再用乙酸乙酯(150mL)萃取，收集有机相，并用无水Na2SO4干燥，过滤，减压浓缩得到粗品。向粗品中添加EtOH(30mL)，并在50℃下搅拌1h。随后将混合液冷却至室温后，有黄色沉淀析出，过滤并收集滤饼，干燥后得到黄色固体8(1.73g，56％)。
对中间体8进行检测，其检测数据为：M.p.>280℃；IR(KBr):3515,3430,3307,2974,2858,2819,1734,1700,1618,1593,1412,1365,1208,819cm-1.1H NMR(400MHz,DMSO-d6)δ12.78(d,J＝3.1Hz,1H),11.62(s,1H),11.38(dt,J＝35.8,3.6Hz,1H),7.74(dd,J＝15.3,11.3Hz,1H),7.61–7.42(m,2H),7.28–7.10(m,2H),7.01(dd,J＝14.0,8.1Hz,1H),6.93(ddd,J＝14.4,8.8,2.2Hz,1H),3.64–3.41(m,4H),3.20–2.90(m,4H),1.41(s,9H).13CN MR(100MHz,DMSO-d6)δ162.0,161.5,159.0,153.9,151.9,151.7,151.6,150.9,147.4,147.4,141.9,139.7,135.8,132.7,132.3,126.7,117.4,114.9,113.8,112.4,112.0,108.2,107.9,104.5,102.8,102.7,99.0,91.0,79.0,50.8,50.4,43.8，28.2.19F NMR(376MHz,DMSO-d6)δ-111.54–-118.49(m).HRMS(ESI)calculated for C25H28FN6O3 +[M+H]+:479.2201,found 479.2202。
技术路线中的中间体10a的具体制备步骤为：将化合物8(574mg,1.20mmol)加入到C H2Cl2(6mL)溶液中加入TFA(4mL)中，室温反应2h，减压浓缩，得到粗产品。向上述粗中间体化合物加入到DMF(12mL)中，然后依次加入EDCI(345mg，1.80mmol)，HOBt(195mg，1.44mmol)，DIPEA(775mg，6.00mmol)和5-((叔丁氧基羰基)氨基)戊酸(261mg，1.20mmol)。将混合物在室温搅拌反应8h。然后将混合物用乙酸乙酯(80mL)萃取，饱和NaCl(50mL)溶液洗涤，用Na2SO4干燥，过滤并在减压下浓缩。将残余物通过硅胶上的柱色谱法纯化(二氯甲烷：甲醇＝60:1)，得到黄色固体化合物10a(534mg，77％)。
对中间体10a进行检测，其检测数据为：M.p.195.6-196.5℃；IR(KBr):3515,3410,2924,1650,1591,1525,1411,1363,1236,1202,820,797,671cm-1.1H NMR(400MHz,DMSO-d6)δ12.76(d,J＝5.5Hz,1H),11.61(s,1H),11.33(s,1H),7.74(dd,J＝15.9,10.1Hz,1H),7.60–7.53(m,1H),7.48(d,J＝8.8Hz,1H),7.27–7.11(m,2H),7.02(dd,J＝14.0,8.0Hz,1H),6.95(ddd,J＝13.1,8.8,2.2Hz,1H),6.80(t,J＝5.7Hz,1H),3.61(dt,J＝10.0,4.7Hz,4H),3.07(dt,J＝19.5,4.9Hz,4H),2.92(q,J＝6.5Hz,2H),2.33(t,J＝7.3Hz,2H),1.49(q,J＝7.6,7.0Hz,2H),1.44–1.38(m,6H),1.36(s,9H).13C NMR(100MHz,DMSO-d6)δ170.5,162.0,161.4,155.5,151.7,151.5,151.4,150.7,147.3,147.1,141.8,139.7,139.5,135.6,132.6,132.1,132.0,126.6,117.2,114.6,113.5,112.1,112.0,108.1,108.0,104.2,102.6,102.5,98.8,91.0,79.1,77.3,51.1,50.6,50.1,45.0,41.0,32.0,29.1,28.2,22.1.19F NMR(376MHz,DMSO-d6)δ-114.00–-114.18(m).HRMS(ESI)calculated forC30H37FN7O4+[M+H]+:578.2886,found 578.2889。
技术路线中的中间体10b的制备方法同10a，制得的中间体10b为黄色固体，收率为82％。对其进行检测，其检测数据为：M.p.197.8-198.6℃；IR(KBr):3514,3412,2927,1647,1587,1530,1477,1415,1358,1241,1200,823,801,673cm-1.1H NMR(400MHz,DMSO-d6)δ12.78(d,J＝3.7Hz,1H),11.61(d,J＝4.8Hz,1H),11.38(d,J＝35.3Hz,1H),7.81–7.69(m,1H),7.56(t,J＝8.7Hz,1H),7.51–7.44(m,1H),7.26–7.10(m,2H),7.05–6.99(m,1H),6.99–6.87(m,1H),6.76(t,J＝5.7Hz,1H),3.62–3.54(m,4H),3.05(dq,J＝10.5,4.8Hz,4H),2.89(q,J＝6.6Hz,2H),2.30(td,J＝7.5,2.4Hz,2H),1.49(q,J＝7.3Hz,2H),1.35(s,11H),1.28–1.20(m,3H).13C NMR(100MHz,DMSO-d6)δ170.5,161.8,161.7,161.3,158.8,155.5,151.7,151.4,151.3,150.6,147.3,147.0,141.8,139.7,139.5,135.6,132.5,132.1,132.0,126.5,117.2,114.5,113.5,112.2,111.8,108.0,107.7,104.2,102.7,102.5,98.8,90.8,90.7,77.2,51.3,50.7,49.8,45.0,41.0,32.1,29.3,28.2,26.0,24.5.19F NMR(376MHz,DMSO-d6)δ-114.02–-114.17(m).HRMS(ESI)calc ulated for C31H39FN7O4 +[M+H]+:592.3042,found 592.3040。
技术路线中的中间体10c的制备方法同10a，制得的中间体10c为黄色固体，收率为81％。对其进行检测，其检测数据为：M.p.201.3-202.1℃；IR(KBr):3515,3414,2930,1642,1583,1537,1470,1411,1359,1245,1202,827,803,679cm-1.1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),11.57(s,1H),11.30(s,1H),7.70(s,1H),7.55–7.48(m,1H),7.46–7.38(m,1H),7.21–7.07(m,2H),7.01–6.94(m,1H),6.88(d,J＝9.4Hz,1H),6.70(t,J＝5.7Hz,1H),3.54(dt,J＝19.3,4.8Hz,4H),3.00(dt,J＝10.5,4.9Hz,4H),2.84(q,J＝6.6Hz,2H),2.25(t,J＝7.4Hz,2H),1.43(p,J＝7.9,7.3Hz,2H),1.31(s,9H),1.23–1.16(m,5H).13C NMR(100MHz,DMSO-d6)δ170.7,161.9,161.5,158.9,155.7,151.7,151.6,150.8,147.3,147.2,141.9,139.8,135.8,132.7,132.3,126.7,117.4,114.7,113.7,112.7,111.4,111.1,107.8,107.7,104.2,102.6,102.5,98.8,90.8,77.2,54.8,50.7,50.6,50.5,45.0,41.0,32.1,29.3,28.4,28.2,26.11,24.7.19F NMR(376MHz,DM SO-d6)δ-114.02–-114.18(m).HRMS(ESI)calculated for C32H41FN7O4 +[M+H]+:606.3199,fo und 606.3198。
技术路线中的中间体11的具体制备步骤为：向9-氟邻苯二甲酸酐6(3.30g，20.0mmol)的CH3COOH(100mL)溶液中加入3-氨基哌啶-2,6-二酮7(3.30g，20.0mmol)。将混合物回流12小时。然后将混合物用EtOAc(200mL)稀释，并用饱和HCl溶液(1N，50mL)洗涤，经Na2SO4干燥，在减压下浓缩。将残余物通过硅胶上的柱色谱法纯化(二氯甲烷:甲醇＝50:1)，得到化合物8(4.78g，80％)，为白色固体。
对中间体11进行检测，其检测数据为：Mp:289℃；IR(KBr):3180,1725,1706,739.6c m-1.1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),7.95(ddd,J＝8.3,7.3,4.5Hz,1H),7.89–7.65(m,2H),5.17(dd,J＝12.9,5.4Hz,1H),2.97–2.76(m,1H),2.63–2.49(m,2H),2.18–1.95(m,1H).13C NMR(100MHz,DMSO-d6)δ172.8,169.7,166.2,164.0,158.1,155.5,138.1,133.5,123.0,120.1,49.1,30.9,21.9.HRMS(ESI)calculated for C13H9FN2NaO4+[M+Na]+:299.0438,found.299.0436。
化合物1的具体制备步骤为：向化合物10a(130mg，0.225mmol)中加入的CH2Cl2(1.5mL)，TFA(1mL)，室温下搅拌反应2h。减压浓缩混合物，得到粗的中间体化合物，为黄绿色固体。接着将上述所得中间体溶于NMP(2.3mL)中，用DIPEA将混合液调酸碱性直到pH＝7。最后在所得溶液依次添加DIPEA(87.0mg，0.630mmol)和中间体11(69mg，0.250mmol)。混合物加热至110℃搅拌过夜，用TLC检测原料，原料消失后停止反应。向反应液中加入饱和NaCl溶液(30mL)、用EtOAc(50mL)萃取，收集有机相，并用无水Na2SO4干燥，过滤、将有机相减压浓缩得粗品。通过硅胶柱层析(CH2Cl2:CH3OH＝40:1)纯化粗品，得到黄色固体形式的化合物1(139mg，38％)。
对化合物1进行检测，其检测数据为：M.p.177.4-178.4.1℃；IR(KBr):3306,2926,1699,1637,1617,1559,1457,1436,1257,1200,797,748cm-1.1H NMR(400MHz,DMSO-d6)δ12.76(d,J＝8.7Hz,1H),11.60(s,1H),11.36(d,J＝33.8Hz,1H),11.09(s,1H),7.83–7.67(m,1H),7.61–7.40(m,3H),7.31–7.05(m,3H),7.05–6.84(m,3H),6.57(d,J＝5.7Hz,1H),5.04(dd,J＝12.3,5.1Hz,1H),3.71–3.54(m,4H),3.31(d,J＝10.6Hz,2H),3.06(d,J＝19.6Hz,4H),2.85(d,J＝13.3Hz,1H),2.61–2.51(m,2H),2.41(d,J＝6.6Hz,2H),2.01(t,J＝10.1Hz,1H),1.60(s,4H).13C NMR(100MHz,DMSO-d6)δ172.7,170.4,170.3,170.0,168.8,167.2,161.8,161.3,151.7,151.4,151.3,150.6,147.1,147.0,146.3,141.7,139.5,139.4,136.1,135.5,132.5,132.0,132.0,126.5,117.1,114.5,113.4,112.0,110.3,109.0,107.8,107.7,104.2,102.5,102.6,98.8,90.8,90.7,51.0,50.5,50.1,48.4,44.8,41.5,41.0,31.8,31.0,28.2,22.0.19F NMR(376MHz,DMSO-d6)δ-114.07–-114.14(d).HRMS(ESI)calculated for C38H37FN9O6 +[M+H]+:734.2845,found 734.2846。
技术路线中的化合物2的制备方法同化合物1，制得的化合物2为黄色固体，收率为42％。对其进行检测，其检测数据为：M.p.178.0-178.5℃；IR(KBr):3305,2928,1705,1635,1619,1556,1459,1439,1259,1201,799,746cm-1.1H NMR(400MHz,DMSO-d6)δ12.77(d,J＝7.3H z,1H),11.60(s,1H),11.37(d,J＝34.1Hz,1H),11.10(s,1H),7.73(dd,J＝14.3,8.8Hz,1H),7.63–7.39(m,3H),7.39–7.10(m,2H),7.08–6.87(m,4H),6.51(t,J＝6.0Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),3.60(dt,J＝10.8,4.8Hz,4H),3.31–3.15(m,2H),3.06(dd,J＝16.4,4.9Hz,4H),2.87(ddd,J＝18.7,13.9,5.5Hz,1H),2.70–2.48(m,2H),2.34(t,J＝7.4Hz,2H),2.17–1.92(m,1H),1.56(dt,J＝13.9,7.0Hz,4H),1.38–1.28(m,2H).13C NMR(100MHz,DMSO-d6)δ172.9,170.6,170.5,170.2,168.9,167.4,161.9,161.9,161.5,158.9,151.9,151.6,151.5,150.8,147.5,147.2,146.5,141.9,140.1,139.8,139.5,136.4,135.8,126.7,117.3,117.2,114.7,113.7,112.4,111.9,110.5,109.1,107.9,107.8,104.4,102.8,102.7,98.9,90.9,90.8,51.2,50.9,50.5,49.9,48.6,45.1,41.9,41.2,32.3,31.0,28.6,26.2,24.7,22.3.19F NMR(376MHz,DMSO-d6)δ-114.00–-114.18(m).HRMS(ESI)calculated for C39H39FN9O6 +[M+H]+:748.3002,found 748.3004。
其中，化合物1和化合物2的1H NMR光谱和13C NMR光谱分别如图2(上面的图为1HNMR光谱谱图，下面的图为13C NMR光谱谱图)、图3(上面的图为1H NMR光谱谱图，下面的图为13C NMR光谱谱图)所示。
技术路线中的化合物14的制备方法同化合物1，制得的化合物14为黄色固体，收率为26％。对其进行检测，其检测数据为：M.p.179.2.0-179.9℃；IR(KBr):3303,2927,1706,1633,1617,1559,1463,1438,1252,1200,702,750cm-1.1H NMR(400MHz,DMSO-d6)δ12.77(t,J＝3.7Hz,1H),11.60(s,1H),11.38(d,J＝34.2Hz,1H),11.10(s,1H),7.72(d,J＝12.8Hz,2H),7.63–7.35(m,4H),7.31–7.11(m,3H),7.11–6.82(m,5H),6.51(d,J＝5.8Hz,1H),5.05(ddd,J＝13.0,5.5,2.7Hz,1H),3.82–3.46(m,6H),3.27(d,J＝6.7Hz,3H),3.07(d,J＝16.4Hz,6H),2.88(tq,J＝12.4,4.7,3.9Hz,1H),2.64–2.53(m,3H),2.37–2.23(m,3H),2.03(dt,J＝11.1,3.3Hz,1H),1.65–1.47(m,6H),1.40–1.25(m,6H).13C NMR(100MHz,DMSO-d6)δ172.7,170.7,170.6,170.2,169.1,167.4,161.9,161.8,161.5,158.9,151.9,151.7,151.5,150.8,147.5,147.2,146.5,141.9,140.1,139.7,139.3,136.1,135.8,132.7,132.3,126.7,117.3,117.2,114.7,113.7,112.4,112.1,110.5,109.1,108.2,107.9,102.8,102.7,98.9,90.9,90,51.2,50.7,50.5,50.3,48.6,45.1,41.9,41.2,32.3,31.1,28.7,26.3,24.9,22.3.19F NMR(376MHz,DMSO-d6)δ-114.00–-114.18(m).H RMS(ESI)calculated for C40H41FN9O6 +[M+H]+:762.3158,found 762.3159。
实施例2：化合物19a-i的合成
化合物19a-i的合成路线如下：
Figure BDA0003170291790000081
技术路线中的中间体18a的具体制备步骤为：将中间体15(273mg，1.00mmol)加到干燥的四氢呋喃(5mL)中，随后将3-溴丙酰氯A2a(514mg，3.00mmol)加入上述混合液中。将混合物加热回流6h。冷至室温，减压浓缩反应液。随后加入饱和NaHCO3(50mL)洗涤，并用二氯甲烷(50mL)萃取。收集有机相，经Na2SO4干燥。过滤，减压浓缩得到粗品，粗品经硅胶色谱柱纯化(CH2Cl2:CH3OH＝60:1)，最终得到白色固体化合物18a(290mg，71％)。
对中间体15进行检测，其检测数据为：M.p.180.6-181.7℃；IR(KBr):3354,3208,3100,1767,1697,1617,1521,1476,1398,1352,1330,1205,1144,1059,1021,745,686cm- 1.1H NMR(400MHz,CDCl3)δ9.48(s,1H),8.84(d,J＝8.5Hz,1H),8.28(s,1H),7.75(t,J＝7.9Hz,1H),7.59(d,J＝7.3Hz,1H),4.97(dd,J＝12.1,5.3Hz,1H),3.70(t,J＝6.5Hz,2H),3.07(t,J＝6.5Hz,2H),2.97–2.88(m,1H),2.86–2.75(m,2H),2.18(dt,J＝8.4,5.2Hz,1H).13C N MR(100MHz,CDCl3)δ170.9,169.3,169.1,167.9,166.8,137.5,136.8,131.3,125.6,119.2,115.8,49.6,40.9,31.6,26.2,22.9.HRMS(ESI)calculated for C16H15BrN3O5 +[M+H]+:408.0190,found408.0191。
技术路线中的中间体18b的制备方法同18a，制得的中间体18b为白色固体，收率为62％。对其进行检测，其检测数据为：M.p.182.8-183.7℃；IR(KBr):3349,3209,3099,1760,1685,1632,1483,1410,1325,1310,1222,1103,1060,741,695cm-1.1H NMR(400MHz,CDCl3)δ9.45(s,1H),8.81(d,J＝8.5Hz,1H),8.32(s,1H),7.73(t,J＝7.9Hz,1H),7.57(d,J＝7.3Hz,1H),4.97(dd,J＝12.2,5.4Hz,1H),3.54(t,J＝6.3Hz,2H),2.98–2.86(m,1H),2.85–2.75(m,2H),2.69(t,J＝7.1Hz,2H),2.29(p,J＝6.7Hz,2H),2.23–2.16(m,1H).13C NMR(100MHz,CDCl3)δ171.1,170.9,169.3,168.1,166.9,137.8,136.7,131.3,125.5,118.9,115.6,49.5,35.9,32.9,31.6,27.8,22.9.HRMS(ESI)calculated for C17H17BrN3O5 +[M+H]+:422.0346,found 422.0344。
技术路线中的中间体18c的制备方法同18a，制得的中间体18c为白色固体，收率为57％。对其进行检测，其检测数据为：M.p.183.3-184.1℃；IR(KBr):3352,3215,3103,1765,1681,1652,1454,1428,1310,1303,1211,1115,1051,737,683cm-1.1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.33(d,J＝8.3Hz,1H),7.70(dd,J＝8.4,7.3Hz,1H),7.50(d,J＝7.2Hz,1H),5.03(dd,J＝12.7,5.4Hz,1H),3.45(t,J＝6.6Hz,2H),2.79(ddd,J＝16.7,13.7,5.3Hz,1H),2.55–2.45(m,1H),2.44–2.38(m,3H),1.98–1.93(m,1H),1.77–1.72(m,1H),1.67–1.58(m,2H).13C NMR(100MHz,CDCl3)δ171.6,170.8,169.2,168.0,166.7,137.7,136.6,131.1,125.3,118.6,115.3,49.3,36.8,33.0,32.0,31.4,23.7,22.7.HRMS(ESI)calculated for C18H19BrN3O5 +[M+H]+:436.0503,found 436.0504。
技术路线中的中间体18d的制备方法同18a，制得的中间体18d为白色固体，收率为66％。对其进行检测，其检测数据为：M.p.183.7-184.6℃；IR(KBr):3355,3210,3101,1758,1677,1659,1457,1438,1321,1313,1205,1109,1047,750,682cm-1.1H NMR(400MHz,CDCl3)δ9.40(s,1H),8.80(d,J＝8.6Hz,1H),8.57(s,1H),7.70(t,J＝7.8Hz,1H),7.53(d,J＝7.4Hz,1H),5.06–4.87(m,1H),3.40(t,J＝6.5Hz,2H),2.95–2.87(m,1H),2.83–2.73(m,2H),2.47(t,J＝7.4Hz,2H),2.23–2.10(m,1H),1.90(p,J＝7.2Hz,2H),1.76(t,J＝7.7Hz,2H),1.53(q,J＝7.9Hz,2H).13C NMR(100MHz,CDCl3)δ172.0,171.2,169.3,168.1,166.7,137.8,136.5,131.1,125.3,118.6,115.3,49.3,37.6,33.5,32.4,31.4,27.6,24.3,22.7.HRMS(ESI)calculated for C19H21BrN3O5 +[M+H]+:450.0659,found 450.0660。
技术路线中的中间体18e的制备方法同18a，制得的中间体18e为白色固体，收率为77％。对其进行检测，其检测数据为：M.p.184.2-185.0℃；IR(KBr):3344,3223,3113,1769,1666,1643,1471,1429,1320,1301,1217,1141,1025,747,696cm-1.1H NMR(400MHz,CDCl3)δ9.41(s,1H),8.82(d,J＝8.5Hz,1H),8.48(s,1H),7.72(dd,J＝8.5,7.3Hz,1H),7.55(d,J＝7.3Hz,1H),5.10–4.89(m,1H),3.41(t,J＝6.8Hz,2H),2.97–2.86(m,1H),2.85–2.74(m,2H),2.47(t,J＝7.5Hz,2H),2.17(ddd,J＝8.3,6.3,4.1Hz,1H),1.89(q,J＝7.1Hz,2H),1.82–1.72(m,2H),1.55–1.39(m,4H).13C NMR(100MHz,CDCl3)δ172.2,171.0,169.2,168.0,166.7,137.8,136.5,131.1,125.3,118.5,115.3,49.3,37.8,33.8,32.5,31.4,28.2,27.8,25.1,22.7.HRMS(ESI)calculated for C20H23BrN3O5 +[M+H]+:464.0816,found 464.0815。
技术路线中的中间体18f的制备方法同18a，制得的中间体18f为白色固体，收率为71％。对其进行检测，其检测数据为：M.p.185.2-186.1℃；IR(KBr):3347,3231,3124,1729,1673,1652,1491,1447,1336,1314,1240,1127,1052,729,683cm-1.1H NMR(400MHz,CDCl3)δ9.41(s,1H),8.84(dd,J＝8.5,0.8Hz,1H),8.09(s,1H),7.72(dd,J＝8.5,7.3Hz,1H),7.55(d d,J＝7.3,0.8Hz,1H),5.12–4.79(m,1H),3.41(t,J＝6.8Hz,2H),2.98–2.89(m,1H),2.86–2.71(m,2H),2.46(t,J＝7.5Hz,2H),2.23–2.14(m,1H),1.86(p,J＝6.8Hz,2H),1.76(p,J＝7.4Hz,2H),1.51–1.36(m,6H).13C NMR(100MHz,CDCl3)δ172.2,170.8,169.2,168.0,166.7,137.8,136.5,131.1,125.3,118.5,115.3,49.3,37.8,33.8,32.5,31.4,28.2,27.8,25.0,22.7.HRMS(ESI)calculated for C21H25BrN3O5 +[M+H]+:478.0972,found 478.0973。
技术路线中的中间体18g的具体制备步骤为：将中间体16(259mg，1.00mmol)加到干燥的四氢呋喃(5mL)中，随后将4-溴丁酰氯(598mg，3.00mmol)加入上述混合液中。将混合物加热回流过夜。用TLC检测原料，原料消失后停止反应，减压浓缩反应混合液。随后加入饱和NaHCO3，并用二氯甲烷萃取。收集有机相，经Na2SO4干燥。过滤，减压浓缩得到粗品，粗品经硅胶色谱柱纯化(CH2Cl2:CH3OH＝70:1)，最终得到白色固体化合物18g(278mg，63％)。
对中间体18g进行检测，其检测数据为：M.p.265.6-266.4℃；IR(KBr):3330,3095,2937,1734,1685,1653,1606,1537,1463,1435,1355,1237,1209,1195,1153,844,751cm- 1.1H NMR(400
MHz,DMSO-d6)δ11.03(s,1H),9.83(s,1H),7.83(dd,J＝7.0,1.9Hz,1H),7.58–7.41
(m,2H),5.16(dd,J＝13.3,5.1Hz,1H),4.66–4.26(m,2H),3.64(dt,J＝41.8,6.3Hz,2H),2.93(ddd,J＝17.3,13.6,5.4Hz,1H),2.62(dt,J＝17.0,3.4Hz,1H),2.44–2.29(m,3H),2.04(ddd,J＝9.8,5.2,2.6Hz,1H),1.82(ddt,J＝48.1,14.9,7.0Hz,4H).13C NMR(100M Hz,DMSO-d6)δ173.4,171.6,171.5,168.4,134.3,133.3,129.2,125.8,119.4,52.0,46.8,45.5,35.1,32.1,32.0,31.6,24.0,23.0,22.8.HRMS(ESI)calculated forC18H21BrN3O4 +[M+H]+:422.0710,fou nd 422.0711。
技术路线中的中间体18h的制备方法同18g，制得的中间体18h为白色固体，收率为63％。对其进行检测，其检测数据为：M.p.279.8-280.5℃；IR(KBr):3332,3094,2939,1736,1688,1651,1601,1535,1465,1435,1353,1236,1208,1194,1156,847,748cm-1.1H NMR(400MHz,DMS O-d6)δ11.03(s,1H),9.80(s,1H),7.81(dd,J＝7.0,1.9Hz,1H),7.65–7.41(m,2H),5.16(dd,J＝13.3,5.1Hz,1H),4.53–4.25(m,2H),3.56(t,J＝6.6Hz,2H),2.93(ddd,J＝17.2,13.6,5.4Hz,1H),2.62(dt,J＝15.4,2.8Hz,1H),2.36(dt,J＝12.5,5.9Hz,3H),2.04(dtd,J＝10.4,5.2,2.6Hz,1H),1.91–1.80(m,2H),1.65(p,J＝7.4Hz,2H),1.45(tt,J＝9.5,6.1Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.7,171.1,171.0,167.7,133.6,132.6,128.5,125.2,119.0,51.4,46.4,35.5,35.0,32.0,31.1,27.1,24.1,22.5.HRMS(ESI)calculated for C19H23BrN3O4 +[M+H]+:436.0866,found 436.0867。
技术路线中的中间体18i的制备方法同18g，制得的中间体18i为白色固体，收率为65％。对其进行检测，其检测数据为：M.p.275.2-275.9℃；IR(KBr):3330,3095,2937,1737,1689,1653,1600,1535,1464,1433,1353,1239,1207,1195,1157,849,747cm-1.1H NMR(400MHz,DMS O-d6)δ11.03(s,1H),9.81(s,1H),7.82(dd,J＝7.0,2.0Hz,1H),7.71–7.38(m,2H),5.16(dd,J＝13.3,5.1Hz,1H),4.56–4.18(m,2H),3.55(t,J＝6.7Hz,2H),3.03–2.83(m,1H),2.62(ddd,J＝17.3,4.5,2.3Hz,1H),2.37(q,J＝6.9,6.3Hz,3H),2.04(ddq,J＝10.6,5.5,3.3,2.8Hz,1H),1.82(p,J＝6.8Hz,2H),1.63(p,J＝7.4Hz,2H),1.50–1.26(m,4H).13C NMR(100MHz,DMSO-d6)δ173.4,171.9,171.6,168.2,134.1,133.2,129.2,125.9,119.6,52.1,47.1,36.2,35.7,32.7,31.8,28.3,27.8,25.5,23.2.HRMS(ESI)calculatedfor C20H25BrN3O4 +[M+H]+:450.1023,found 450.1025。
化合物19a的的制备过程如下：向中间体8(215mg，0.45mmol)中加入CH2Cl2(2mL)溶液中加入TFA(0.67mL)，室温下反应2h。减压浓缩，得到粗中间体化合物，为黄绿色固体。将粗的中间体化合物加入到DMF(4.5mL)中，然后加入DIPEA(291mg，2.25mmol)和化合物18a183mg，0.450mmol)。将混合物加热至80℃搅拌过夜。用TLC检测原料，原料消失后停止反应。然后反应混合液中加入饱和NaCl溶液(40mL)，用EtOAc(50mL)萃取，收集有机相，经Na2SO4干燥，过滤，滤液减压浓缩得粗品。通过硅胶柱层析(CH2Cl2:CH3OH＝20:1)纯化粗品，得到黄色固体化合物19a(121mg，38％)。
对化合物19a进行检测，其检测数据为：M.p.200.6-201.5℃；IR(KBr):3510,3317,2822,1707,1640,1615,1524,1480,1457,1398,1261,1198,1134,799,747cm-1.1H NMR(400MHz,D MSO-d6)δ12.75(d,J＝13.1Hz,1H),11.61(s,1H),11.41(d,J＝35.7Hz,1H),11.14(s,1H),10.42(d,J＝6.3Hz,1H),8.58(dd,J＝8.4,2.9Hz,1H),7.85(dd,J＝8.5,7.3Hz,1H),7.74(d,J＝14.2Hz,1H),7.65–7.45(m,3H),7.31–7.00(m,3H),6.96(ddd,J＝11.4,8.8,2.3Hz,1H),5.14(dd,J＝12.7,5.4Hz,1H),3.19(q,J＝4.7Hz,4H),2.97–2.81(m,1H),2.81–2.65(m,8H),2.60–2.54(m,1H),2.06(dd,J＝10.1,4.9Hz,1H).13C NMR(100MHz,DMSO-d6)δ173.3,171.9,170.2,167.8,167.1,162.5,162.4,161.8,159.4,152.2,151.8,148.2,1478,142.4,140.1,141.0,137.0,136.4,135.8,133.1,132.5,132.4,132.0,126.8,126.7,118.7,117.6,117.3,114.6,113.5,112.7,112.3,108.5,108.3,104.2,103.2,103.1,98.8,91.5,91.4,79.8,79.4,79.1,53.8,53.2,53.1,50.7,50.0,49.4,34.5,30.4,31.4,22.5.19F NMR(376MHz,DMSO-d6)δ-112.91–-114.14(m).HRMS(ESI)calculated forC36H33FN9O6 +[M+H]+:706.2532,found 706.2533。
技术路线中的化合物19b的制备方法同19a，制得的化合物19b为黄色固体，收率为31％。对其进行检测，其检测数据为：M.p.203.7-201.4℃；IR(KBr):3509,3319,2821,1703,1641,1617,1527,1484,1450,1400,1257,1200,1133,797,749cm-1.1H NMR(400MHz,DMSO-d6)δ12.75(d,J＝8.9Hz,1H),11.61(d,J＝4.5Hz,1H),11.40(d,J＝39.0Hz,1H),11.17(s,1H),9.69(d,J＝1.9Hz,1H),8.51(d,J＝8.4Hz,1H),7.81(t,J＝7.9Hz,1H),7.78–7.68(m,1H),7.65–7.52(m,3H),7.47(dd,J＝17.6,8.8Hz,1H),7.29–7.12(m,3H),7.09–6.85(m,3H),5.16(dd,J＝12.9,5.4Hz,1H),3.65(d,J＝8.4Hz,1H),3.52–3.39(m,4H),3.15–3.04(m,4H),2.91(ddd,J＝17.5,14.1,5.5Hz,1H),2.68–2.55(m,2H),2.41(q,J＝7.5,6.7Hz,3H),2.15–2.01(m,1H),1.84(td,J＝6.9,2.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.1,171.0,170.2,168.2,167.0,162.3,162.2,161.8,159.5,152.9,151.5,148.4,147.7,146.9,142.5,140.2,137.3,136.6,135.9,135.8,133.2,132.7,131.9,126.7,125.6,118.7,117.7,117.2,114.6,113.5,112.8,112.3,108.5,108.4,104.1,103.3,103.2,99.5,98.7,91.5,60.8,57.4,53.4,51.2,50.9,50.8,50.2,49.5,35.2,31.5,29.5,28.8,22.6.19FNMR(376MHz,DMSO-d6)δ-114.03–-114.23(m).HRMS(ESI)calculated f or C37H35FN9O6 +[M+H]+:720.2689,found 720.2688。
技术路线中的化合物19c的制备方法同19a，制得的化合物19c为黄色固体，收率为31％。对其进行检测，其检测数据为：M.p.207.9-208.6℃；IR(KBr):3507,3320,2823,1706,1644,1615,1526,1483,1455,1401,1253,1201,1129,798,752cm-1.1H NMR(400MHz,DMSO-d6)δ12.74(d,J＝11.2Hz,1H),11.59(d,J＝1.6Hz,1H),11.38(d,J＝36.8Hz,1H),11.15(s,1H),9.71(s,1H),8.50(d,J＝8.4Hz,1H),7.84(t,J＝7.9Hz,1H),7.72(dd,J＝15.5,9.5Hz,1H),7.62(d,J＝7.3Hz,1H),7.60–7.52(m,1H),7.47(d,J＝8.8Hz,2H),7.27–6.87(m,4H),5.15(dd,J＝12.8,5.4Hz,1H),3.52(s,1H),3.32(s,4H),3.12(s,4H),2.90(ddd,J＝18.0,13.9,5.3Hz,1H),2.71–2.56(m,3H),2.38(s,2H),2.12–2.02(m,1H),1.69(t,J＝7.5Hz,2H),1.58(s,2H).13C NMR(100MHz,DMSO-d6)δ172.9,172.1,169.9,167.8,166.8,161.9,161.5,158.9,151.8,151.5,150.6,141.9,139.7,136.7,136.2,135.4,132.8,132.3,131.6,126.4,118.4,117.3,117.1,114.2,113.1,111.9,108.2,107.9,103.6,102.8,102.7,98.4,91.1,69.9,57.4,52.9,50.2,50.1,49.9,48.9,36.4,30.9,22.8,22.1.19F NMR(376MHz,DMSO-d6)δ-114.02–-114.15(d).HRMS(ESI)calculated for C38H37FN9O6 +[M+H]+:734.2845,found 734.2847。
技术路线中的化合物19d的制备方法同19a，制得的化合物19d为白色固体，收率为44％。对其进行检测，其检测数据为：M.p.211.3-212.3℃；IR(KBr):3505,3317,2825,1709,1645,1617,1528,1479,1450,1404,1255,1200,1127,799,751cm-1.1H NMR(400MHz,DMSO-d6)δ12.75(d,J＝10.6Hz,1H),11.70–11.57(m,1H),11.38(d,J＝37.1Hz,1H),11.16(s,1H),9.72(s,1H),8.50(d,J＝8.4Hz,1H),7.84(t,J＝7.9Hz,1H),7.74(t,J＝12.9Hz,1H),7.62(d,J＝7.2Hz,1H),7.60–7.43(m,2H),7.27–7.01(m,3H),6.95(ddd,J＝11.1,8.8,2.2Hz,1H),5.16(dd,J＝12.7,5.4Hz,1H),3.52(s,1H),3.12(s,4H),2.90(s,1H),2.71–2.52(m,7H),2.36(d,J＝15.0Hz,2H),2.09(dd,J＝9.0,3.7Hz,1H),1.69(t,J＝7.5Hz,2H),1.55(s,2H),1.45–1.33(m,2H).13C NMR(100MHz,DMSO-d6)δ173.3,172.6,170.3,168.3,167.2,162.5,161.9,159.5,151.9,151.1,148.1,147.8,142.4,140.2,137.1,136.7,135.9,133.2,132.7,131.9,126.8,118.9,117.7,117.5,114.7,113.6,112.8,112.4,108.6,108.4,104.1,103.1,103.0,98.6,91.3,58.0,55.3,53.2,50.4,50.1,49.3,36.8,31.3,29.4,26.7,26.1,25.1,22.4.19F NMR(376MHz,DMSO-d6)δ-114.06–-114.20(d).HRMS(ESI)calculated for C39H39FN9O6 +[M+H]+:748.3002,found 748.3004。
技术路线中的化合物19e的制备方法同19a，制得的化合物19e为白色固体，收率为33％。对其进行检测，其检测数据为：M.p.214.6-215.4℃；IR(KBr):3503,3314,2820,1706,1644,1617,1522,1481,1450,1402,1259,1201,1129,795,752cm-1.1H NMR(400MHz,DMSO-d6)δ12.76(d,J＝8.0Hz,1H),11.61(s,1H),11.35(d,J＝33.9Hz,1H),11.16(s,1H),9.70(s,1H),8.46(dd,J＝8.5,5.8Hz,1H),7.85(t,J＝7.9Hz,1H),7.74(s,1H),7.61(d,J＝7.4Hz,1H),7.51(dd,J＝19.7,8.1Hz,2H),7.35–7.00(m,4H),6.95(t,J＝10.2Hz,1H),5.16(d d,J＝12.7,5.4Hz,1H),3.28–3.26(m,4H),2.96–2.87(m,4H),2.69–2.57(m,3H),2.47(d,J＝7.4Hz,2H),2.11–2.07(m,2H),1.64(d,J＝7.3Hz,5H),1.35(s,5H).13C NMR(100MHz,DMSO-d6)δ173.1,172.1,170.2,168.2,167.0,162.3,161.8,159.3,152.8,152.7,151.6,151.1,142.2,140.0,137.0,136.4,136.0,133.0,132.6,131.8,126.6,118.7,117.7,117.4,114.4,113.6,112.6,112.3,108.4,108.2,104.3,103.0,99.0,91.3,91.2,57.0,52.3,52.2,52.0,49.3,36.8,31.3,28.6,26.7,25.0,22.4.19F NM R(376MHz,DMSO-d6)δ-114.07–-114.21(d).HRMS(ESI)calculated for C40H41FN9O6 +[M+H]+:762.3158,found762.3159。
技术路线中的化合物19f的制备方法同19a，制得的化合物19f为白色固体，收率为39％。对其进行检测，其检测数据为：M.p.217.4-218.4℃；IR(KBr):3500,3313,2821,1703,1644,1618,1523,1481,1450,1401,1262,1200,1120,797,757cm-1.1H NMR(400MHz,DMSO-d6)δ12.75(d,J＝11.0Hz,1H),11.76–11.56(m,1H),11.39(d,J＝37.0Hz,1H),11.17(s,1H),9.70(s,1H),8.49(d,J＝8.3Hz,1H),7.89–7.80(m,1H),7.74(s,1H),7.62(d,J＝7.3Hz,1H),7.60–7.41(m,2H),7.27–7.01(m,3H),6.94(ddd,J＝11.4,8.8,2.3Hz,1H),5.16(dd,J＝12.7,5.4Hz,1H),3.12(s,4H),2.91(ddd,J＝16.6,13.5,5.3Hz,1H),2.61(m,6H),2.47(d,J＝7.4Hz,2H),2.35(s,2H),2.15–2.04(m,1H),1.65(t,J＝7.2Hz,2H),1.49(s,2H),1.35(d,J＝4.9Hz,6H).13C NMR(100MHz,DMSO-d6)δ173.3,172.4,170.2,168.1,167.0,162.3,161.8,159.3,152.1,151.8,151.7,151.0,148.0,147.7,142.2,140.0,137.0,136.5,135.7,133.1,132.5,131.8,126.6,118.7,117.5,117.3,114.65,113.4,112.6,112.4,108.6,108.4,104.1,103.1,103.0,98.6,91.3,91.2,58.1,53.2,50.5,50.1,49.2,49.0,37.0,31.5,29.0,28.8,27.1,26.4,25.1,22.4.19F NMR(376MHz,DMSO-d6)δ-114.07–-114.21(d).HRMS(ESI)calculated for C41H43FN9O6 +[M+H]+:776.3315,found 776.3317。
技术路线中的化合物19g的制备方法同19a，制得的化合物19g为白色固体，收率为33％。对其进行检测，其检测数据为：M.p.251.9-252.8℃；IR(KBr):3477,3415,2932,1697,1640,1617,1524,1489,1457,1432,1408,1357,1280,1235,1204,1141,798,752cm-1.1H NMR(400MHz,DMSO-d6)δ12.79(d,J＝8.2Hz,1H),11.63(s,1H),11.38(d,J＝33.4Hz,1H),11.04(s,1H),9.99(s,1H),7.85(dd,J＝6.9,2.1Hz,1H),7.76(t,J＝13.0Hz,1H),7.67–7.47(m,4H),7.35–7.15(m,2H),7.01(ddd,J＝29.0,12.1,5.1Hz,2H),5.17(dd,J＝13.2,5.1Hz,1H),4.42(q,J＝17.6Hz,2H),3.25–3.06(m,4H),3.04–2.88(m,3H),2.80–2.56(m,4H),2.52–2.42(m,4H),2.37(dt,J＝13.0,6.5Hz,1H),2.14–2.00(m,1H),1.69(s,4H).13C NMR(100MHz,DMSO-d6)δ173.5,171.7,171.6,168.4,162.5,159.5,152.4,152.2,151.9,151.2,147.2,142.2,136.0,134.2,133.0,132.6,129.0,127.0,125.7,119.4,117.7,114.4,113.7,112.7,112.4,108.4,108.2,104.4,103.1,103.0,99.1,91.3,91.2,55.3,52.0,48.8,47.1,35.7,34.4,31.6,23.0.19F NMR(376MHz,DM SO-d6)δ-113.94–-114.14(m).HRMS(ESI)calculated for C38H39FN9O5 +[M+H]+:720.3053,found 720.3055。
技术路线中的化合物19h的制备方法同19a，制得的化合物19h为白色固体，收率为36％。对其进行检测，其检测数据为：M.p.253.9-254.2℃；IR(KBr):3475,3415,2933,1699,1639,1617,1525,1486,1457,1432,1405,1363,1279,1234,1200,1142,797,751cm-1.1H NMR(400MHz,DMSO-d6)δ12.74(d,J＝9.4Hz,1H),11.62(s,1H),11.38(d,J＝38.4Hz,1H),11.06(s,1H),9.81(s,1H),7.83(dd,J＝6.8,2.1Hz,1H),7.81–7.69(m,1H),7.61–7.43(m,4H),7.26–7.00(m,3H),6.93(ddd,J＝11.4,8.8,2.2Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.52–4.27(m,2H),3.10(s,3H),3.04–2.84(m,1H),2.67–2.52(m,4H),2.50–2.22(m,6H),2.03(ddq,J＝10.6,5.5,2.8Hz,1H),1.64(p,J＝7.6Hz,2H),1.51(d,J＝8.0Hz,2H),1.36(q,J＝7.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.5,171.9,171.7,168.4,162.5,162.0,159.5,152.3,151.9,151.1,148.2,142.4,140.2,134.4,134.2,132.8,129.2,125.8,119.6,117.7,114.7,113.6,112.8,112.4,108.6,108.4,104.1,103.2,103.1,98.6,91.3,58.1,53.3,52.0,50.2,46.8,36.1,31.6,27.0,25.4,23.0.19F NMR(376MHz,DMSO-d6)δ-114.01–-114.19(m).HRMS(ESI)calculated for C39H41FN9O5 +[M+H]+:734.3209,found734.3208。
技术路线中的化合物19i的制备方法同19a，制得的化合物19i为白色固体，收率为35％。对其进行检测，其检测数据为：M.p.256.5-257.3℃；IR(KBr):3471,3409,2939,1702,1635,1613,1528,1487,1455,1435,1407,1363,1277,1234,1201,1144,799,751cm-1.1H NMR(400MHz,DMSO-d6)δ12.74(d,J＝9.5Hz,1H),11.62(s,1H),11.38(d,J＝37.7Hz,1H),11.06(s,1H),9.81(s,1H),7.82(dd,J＝7.0,2.0Hz,1H),7.76(dd,J＝15.3,11.1Hz,2H),7.60–7.40(m,4H),7.27–7.00(m,3H),6.95(ddd,J＝11.5,8.9,2.2Hz,1H),5.18(dd,J＝13.3,5.1H z,1H),4.47–4.28(m,2H),3.10(s,4H),2.92(ddd,J＝17.2,13.6,5.4Hz,1H),2.68–2.52(m,4H),2.51–2.18(m,6H),2.03(ddd,J＝12.7,6.2,2.2Hz,1H),1.62(t,J＝7.2Hz,2H),1.47(d,J＝8.0Hz,2H),1.33(dt,J＝10.9,5.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ172.8,171.3,171.1,167.8,161.8,161.3,159.0,151.3,151.2,150.4,147.6,141.8,139.5,135.2,133.7,133.6,132.6,132.1,128.6,126.1,125.2,119.0,117.1,114.1,113.0,112.2,111.8,108.0,107.8,103.4,102.6,102.5,98.1,91.0,90.8,57.8,55.0,51.4,50.1,49.8,46.4,35.7,31.1,28.6,26.7,25.0,22.6.19F NMR(376MHz,D MSO-d6)δ-113.97–-114.19(m).HRMS(ESI)calculated for C40H43FN9O5 +[M+H]+:748.3366,found748.3367。
实施例3：化合物24a-c的合成
化合物24a-c的合成路线如下：
Figure BDA0003170291790000151
技术路线中的中间体21的制备方法同11，制得的中间体21为紫灰色固体，收率为79％。对其进行检测，其检测数据为：M.p.>300℃；IR(KBr):3177,1725,1702,740cm-1.1HNMR(400MHz,CDCl3)δ11.13(s,1H),8.27(d,J＝7.9Hz,1H),7.92(d,J＝7.3Hz,1H),7.58(t,J＝7.6Hz,1H),5.16(dd,J＝12.7,5.4Hz,1H),2.89(ddd,J＝18.1,13.9,5.4Hz,1H),2.69–2.52(m,2H),2.18–1.90(m,1H).13C NMR(100MHz,CDCl3)δ172.7,169.7,166.0,165.3,145.4,135.6,133.2,131.8,123.2,90.3,49.1,30.9,21.8.HRMS(ESI)calculated forC13H10IN2O4 +[M+H]+:384.9680,found 384.9682。
技术路线中的中间体23a的具体制备步骤为：向中间体8(574mg，1.20mmol)中加入C H2Cl2(6mL)，TFA(4mL)，室温搅拌反应2h。减压浓缩混合物，得到粗中间体化合物，为黄绿色固体。将上述粗制中间体化合物溶解于DMF(12mL)中。向所得溶液中加入EDCI(345mg，1.80mmol)，HOBt(195mg，1.44mmol)，DIPEA(775mg，6.00mmol)和五-4-壬酸(118mg，1.20mmol)。将混合物在室温搅拌8h，加入乙酸乙酯(80mL)萃取，并用饱和NaCl溶液(50mL)洗涤，收集有机相，用Na2SO4干燥，过滤并在减压下浓缩。硅胶柱层析(二氯甲烷：甲醇＝60:1)，得到化合物23a(352mg，64％)，为黄色固体。
对中间体23a进行检测，其检测数据为：M.p.202.3-203.3℃；IR(KBr):3301,1636,1617,1359,1285,1235,799cm-1.1H NMR(400MHz,DMSO-d6)δ12.76(d,J＝8.2Hz,1H),11.58(s,1H),11.36(d,J＝33.7Hz,1H),7.73(t,J＝12.6Hz,1H),7.65–7.40(m,2H),7.28–7.11(m,2H),7.08–6.83(m,2H),3.63(d,J＝5.3Hz,4H),3.09(d,J＝22.5Hz,4H),2.76(d,J＝0.9Hz,1H),2.60(td,J＝7.9,7.4,2.0Hz,2H),2.40(td,J＝7.4,2.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ168.8,161.8,161.7,161.3,159.0,151.7,151.4,151.3,150.6,147.3,147.1,141.8,139.5,139.4,135.6,132.6,132.3,126.7,117.2,114.6,113.6,112.2,112.0,108.0,104.2,102.6,102.5,99.0,90.8,84.1,71.2,51.0,50.5,50.1,44.7,41.2,31.2,29.0,14.0.19F NMR(376MHz,DMSO-d6)δ-114.02–-114.19(m).HRMS(ESI)calculatedfor C25H24FN6O2 +[M+H]+:459.1939,found 459.1938。
技术路线中的中间体23b的制备方法同23a，制得的中间体23b为黄色固体，收率为71％。对其进行检测，其检测数据为：M.p.204.6-205.4℃；IR(KBr):3303,1635,1617,1356,1287,1236,798cm-1.1H NMR(400MHz,DMSO-d6)δ12.77(d,J＝6.0Hz,1H),11.59(t,J＝1.9Hz,1H),11.37(dd,J＝34.3,4.7Hz,1H),7.72(dd,J＝15.1,10.6Hz,1H),7.63–7.38(m,2H),7.34–7.08(m,2H),7.09–6.85(m,2H),3.61(dt,J＝10.5,4.8Hz,4H),3.08(dt,J＝19.8,4.9Hz,4H),2.78(t,J＝2.6Hz,1H),2.44(t,J＝7.3Hz,2H),2.21(td,J＝7.1,2.6Hz,2H),1.85–1.52(m,2H).13C NMR(100MHz,DMSO-d6)δ170.4,162.3,162.2,161.8,159.3,152.2,152.0,151.9,147.7,147.5,142.2,140.1,140.0,136.0,133.0,132.5,132.4,127.0,115.0,114.0,112.6,112.3,108.3,108.2,104.7,103.0,99.3,91.3,84.5,72.0,51.4,51.0,50.5,45.2,41.4,31.4,24.3,17.7.19F NMR(376MHz,DMSO-d6)δ-114.01–-114.17(m).HRMS(ESI)calculated for C26H26FN6O2 +[M+H]+:473.2096,found 473.2097。
技术路线中的中间体23c的制备方法同23a，制得的中间体23c为黄色固体，收率为73％。对其进行检测，其检测数据为：M.p.201.1-201.9℃；IR(KBr):3300,1633,1617,1355,1285,1235,799cm-1.1H NMR(400MHz,DMSO-d6)δ12.81(d,J＝5.5Hz,1H),11.76–11.56(m,1H),11.51–11.26(m,1H),7.88–7.67(m,1H),7.66–7.41(m,2H),7.33–7.13(m,2H),7.11–6.88(m,2H),3.64(dd,J＝8.5,4.5Hz,4H),3.11(dd,J＝17.0,5.0Hz,4H),2.77(t,J＝2.7Hz,1H),2.38(t,J＝7.4Hz,2H),2.21(td,J＝7.0,2.7Hz,2H),1.63(p,J＝7.3Hz,2H),1.51(q,J＝7.1Hz,2H).13C NMR(100MHz,DMSO-d6)δ170.5,161.9,161.6,159.1,151.7,150.9,147.5,142.0,139.8,135.8,132.6,132.5,126.8,117.4,114.8,113.8,112.3,112.2,107.9,104.4,102.8,102.7,99.1,90.9,84.4,71.2,51.1,50.1,50.2,45.0,41.0,31.6,27.5,24.0,17.5.19F NMR(376MHz,DMSO-d6)δ-114.04–-114.17(m).HRMS(ESI)calculated for C27H28FN6O2 +[M+H]+:487.2252,foun d 487.2254。
技术路线中的化合物24a的具体制备步骤为：将中间体23a(170mg,0.37mmol)溶解于DMF(2mL)中，随后依次加入中间体21(142mg,0.37mmol)，Pd(PPh3)2Cl2(18mg,0.04mmol)，CuI(7.1mg,0.04mmol)，DIPEA(1mL,3.7mmol),混合物在80℃下反应12h。用TLC检测原料，原料消失后停止反应，冷却至室温，用乙酸乙酯(50mL)萃取，饱和食盐水(30mL)洗，收集有机相，经Na2SO4干燥，过滤，浓缩得到粗品。粗品经硅胶色谱柱纯化(CH2Cl2:CH3OH＝30:1)，得到黄色固体化合物24a(172mg,65％)。
对化合物24a进行检测，其检测数据为：M.p.207.0-207.7℃；IR(KBr):3423,1771,1716,1637,1615,1389,1234,1198,1118,799,744cm-1.1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),11.60(s,1H),11.44–11.21(m,1H),11.14(s,1H),8.21–7.70(m,4H),7.64–7.30(m,4H),7.17(d,J＝8.4Hz,1H),7.11–6.84(m,2H),5.13(dd,J＝12.9,5.4Hz,1H),3.82–3.57(m,4H),3.09(dt,J＝21.3,5.0Hz,4H),2.86(td,J＝17.8,16.2,5.5Hz,1H),2.75(s,4H),2.64–2.51(m,2H),2.11–1.95(m,1H).13C NMR(100MHz,DMSO-d6)δ170.5,170.4,161.8,161.7,161.3,158.8,151.7,151.6,151.4,150.6,147.3,147.1,141.7,140.3,140.0,139.0,135.6,132.5,132.0,126.5,117.2,114.5,113.5,112.2,112.1,112.0,108.1,108.0,104.3,102.7,102.6,98.7,90.8,77.2,54.8,51.0,50.5,50.4,50.1,45.0,41.0,31.8,29.1,28.2,22.1.19F NMR(376MHz,DMSO-d6)δ-114.06–-114.12(d).HRMS(ESI)calculated for C38H32FN8O6 +[M+H]+:715.2423,found 715.2425。
技术路线中的化合物24b的制备方法同24a，制得的化合物24b为黄色固体，收率为54％。对其进行检测，其检测数据为：M.p.209.8-210.6℃；IR(KBr):3425,1770,1716,1636,1613,1389,1235,1200,1117,799,745cm-1.1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),11.60(s,1H),11.37(d,J＝31.5Hz,1H),11.16(s,1H),7.91–7.67(m,4H),7.52(dd,J＝8.4,5.9Hz,3H),7.17(d,J＝8.3Hz,2H),7.05–6.83(m,2H),5.15(dd,J＝12.6,5.4Hz,1H),3.65(d,J＝6.0Hz,4H),3.23–2.96(m,4H),2.87(ddd,J＝18.2,13.8,5.4Hz,1H),δ2.74–2.51(m,6H),2.24–2.00(m,1H),1.93–1.75(m,2H).13C NMR(100MHz,DMSO-d6)δ172.7,170.1,170.0,166.3,165.8,161.8,161.3,159.0,151.1,151.0,147.2,139.6,139.5,138.1,134.5,132.1,132.0,130.1,122.6,120.0,112.2,108.1,108.0,102.6,102.5,98.3,90.8,76.5,50.6,50.3,50.2,49.0,44.8,41.1,30.8,23.5,22.0,18.5.19F NMR(376MHz,DMSO-d6)δ-112.32–-115.93(m).HRMS(ESI)calculated for C39H34FN8O6 +[M+H]+:729.2580,found729.2580。
技术路线中的化合物24c的制备方法同24a，制得的化合物24c为黄色固体，收率为54％。对其进行检测，其检测数据为：M.p.213.4-214.3℃；IR(KBr):3423,1767,1715,1636,1611,1379,1231,1201,1118,799,745cm-1.1H NMR(400MHz,DMSO-d6)δ12.78(d,J＝10.5Hz,1H),11.62(s,1H),11.39(d,J＝34.6Hz,1H),11.16(s,1H),8.13–7.63(m,4H),7.63–7.42(m,3H),7.28–7.08(m,2H),7.08–6.89(m,2H),5.15(dd,J＝12.9,5.4Hz,1H),3.63(d,J＝5.2Hz,4H),3.07(dt,J＝15.6,4.8Hz,4H),2.85(d,J＝5.6Hz,1H),2.58(td,J＝11.6,4.2Hz,4H),2.43(d,J＝7.4Hz,2H),2.16–2.02(m,1H),1.69(dq,J＝28.1,7.4Hz,4H).13C NMR(100MHz,DMSO-d6)δ172.9,170.6,169.9,166.4,165.8,161.9,161.8,161.5,158.9,151.8,151.6,151.5,150.8,147.5,147.2,140.2,139.8,139.3,138.4,135.8,134.7,132.7,132.1,130.2,126.7,122.6,120.1,117.2,114.5,113.4,112.4,111.9,108.1,107.9,104.3,102.8,102.7,98.9,98.8,90.9,90.8,76.3,54.9,51.2,50.7,50.6,50.3,49.1,45.1,41.2,31.9,30.9,27.6,24.2,22.1,18.9.19F NMR(376MHz,DMSO-d6)δ-113.9–-114.3(m).HRMS(ESI)calculated for C40H36FN8O6 +[M+H]+:743.2736,found 743.2737。
效果试验例：
对于所有的PROTACs，用标准CCK-8法检测在MOM-13和MV-4-11的抗增殖能力(如表1所示)。通过分析结果，化合物1和2表现出强的抗肿瘤细胞增殖活性，IC50为低纳摩尔水平，比阳性药Dovitinib高出几十倍。
表1.15种PROTACs化合物对MOM-13和MV-4-11细胞增殖的影响
Figure BDA0003170291790000181
Figure BDA0003170291790000191
随后，应用蛋白质免疫印迹法对PROTAC分子降解FLT3-ITD的能力进行了评估，发明人在MOM-13和MV-4-11细胞中进行了蛋白质免疫印迹分析。结果显示化合物1和2这两种化合物以浓度伊利方式显著降解细胞中的FLT3-ITD(如图1所示)，DC50表现出低纳摩尔水平。
此外，化合物1和2可有效抑制FLT3-ITD阳性细胞下游FLT3信号通路的激活。发明人将不同浓度的化合物1、2分别作用于MOM-13和MV-4-11细胞，分析FLT3下游效应蛋白STAT5、AKT、ERK磷酸化水平的变化。结果显示，在MOLM-13和MV-4-11细胞系中，15nm的浓度下化合物1和2在均能显著抑制STAT5、AKT和ERK的磷酸化，且具有时间依赖性(如图4所示)。表明化合物1和2可显著下调细胞中FLT3-ITD水平，抑制FLT3下游信号通路的激活。
为了验证化合物1和2处理后的FLT3-ITD蛋白的降解作用为PROTAC所介导，发明人首先分别用MG132、Pomalidomide(POM)和Dovitinib(DOV)对MV-4-11细胞进行预处理。发现用MG132预处理后FLT3-ITD蛋白降解明显受阻(图5A-B)。结果表明化合物1和2依赖于细胞内蛋白酶体降解FLT3-ITD蛋白。为进一步证明FLT3-ITD是通过泛素-蛋白酶体系统(ubitin-protease system,UPS)降解的，发明人通过蛋白质免疫印迹法检测环己酰亚胺(Cycloheximide,CHX)处理的AML细胞FLT3-ITD。与CHX处理组相比，化合物1和2促进了FLT3-ITD的更快的降解，说明FLT3-ITD水平的下降不是由于核糖体功能障碍所致(图5C-D)。随后，发明人在AML细胞与化合物1和2孵育前，通过免疫沉淀从裂解液中收集FLT3-ITD蛋白，通过免疫印迹检测泛素化FLT3-ITD水平。与对照组相比，化合物1和2给药组均观察到泛素化FLT3-ITD的显著积累(图5E)。结果表明化合物1和2均以泛素-蛋白酶体依赖的方式降解FLT3-ITD蛋白。
之后发明人评估了化合物1和2对MOLM-13和MV-4-11细胞ROS含量水平的影响。ROS水平升高是FLT3-ITD阳性AML细胞的一个重要标志，ROS升高会导致DNA损伤、DNA双链断裂(DSBs)和修复错误的增加，这也FLT3-ITD阳性AML患者预后不良的重要原因。发明人将化合物1和2对MOLM-13和MV-4-11细胞内ROS水平的影响进行了检测，两种化合物都以浓度依赖方式降低FLT3-ITD阳性AML细胞中ROS水平，且对MV-4-11细胞更为敏感(图6)。结果表明化合物1和2均可显著降低AML细胞中ROS水平，可能对急性髓系白血病患者预后具有改善作用。
之后发明人评估了化合物1和2的体内活性。以150mg/Kg的剂量腹腔注射环磷酰胺，连续注射2d后，静息1d。通过尾静脉将MV-4-11细胞注射到NOD/SCID小鼠中，注射8d后，将化合物1和2以3mg/Kg的剂量尾静脉注射，每2d给药一次，连续注射12d。每天记录小鼠的体重，第12d处死小鼠，通过流式细胞仪检测对照组和给药组小鼠骨髓中CD45+细胞的百分比。Control中CD45+细胞数量与空白组相比显著提高，表明造模成功。给药化合物1和2后，CD45+细胞显著下降，且体重没有显著变化(图7)，表明化合物1和2具有显著的抗白血病效果。
综上所述，对Dovitinib进行PROTAC结构改造与优化，筛选得到了可以在低纳摩尔浓度有效降解FLT3-ITD蛋白并杀伤AML细胞的先导化合物，相对Dovitinib增效几十倍。体内异种移植瘤模型实验结果表明，先导化合物可安全、有效杀伤AML小鼠模型中CD45+细胞，表现出良好的开发与应用前景。
以上所述，只是本发明的较佳实施例而已，本发明并不局限于上述实施方式，只要其以相同的手段达到本发明的技术效果，都应属于本发明的保护范围。在本发明的保护范围内其技术方案和/或实施方式可以有各种不同的修改和变化。

Claims (4)

1.一种蛋白水解靶向嵌合体，其特征在于，所述蛋白质水解靶向嵌合体或其药学上可接受的盐具有如式(Ia)所示的结构：
Figure FDA0003802006990000011
其中，n为4或5。
2.权利要求1所述的蛋白水解靶向嵌合体或其药学上可接受的盐在制备用于降低荷瘤动物骨髓中CD45+急性髓性白血病细胞的药物中的应用。
3.一种药物组合物，其特征在于，包括权利要求1所述的蛋白水解靶向嵌合体或其药学上可接受的盐。
4.根据权利要求3所述的药物组合物，其特征在于，还包括药学上可接受的赋形剂或载体。
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