CN114920695A - 一种喹唑啉衍生物及其制备方法、药物组合物和应用 - Google Patents

一种喹唑啉衍生物及其制备方法、药物组合物和应用 Download PDF

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CN114920695A
CN114920695A CN202210745831.6A CN202210745831A CN114920695A CN 114920695 A CN114920695 A CN 114920695A CN 202210745831 A CN202210745831 A CN 202210745831A CN 114920695 A CN114920695 A CN 114920695A
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CN114920695B (zh
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于力
张立
杨光
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Shenzhen University
Shenzhen University General Hospital
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    • C—CHEMISTRY; METALLURGY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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Abstract

本发明公开了一种喹唑啉衍生物及其制备方法、药物组合物和应用。该喹唑啉衍生物的结构如式(I)所示，其中，R1为酰基或磺酰基。本发明发现的一类新型喹唑啉衍生物，其对于AE+AML白血病细胞的增殖具有明显的抑制效果，并且对AML细胞具有明显的分化作用，有望开发成为新一代治疗AE阳性AML的药物。

Description

一种喹唑啉衍生物及其制备方法、药物组合物和应用
技术领域
本发明属于化药领域，具体涉及一种喹唑啉衍生物及其制备方法、药物组合物和应用。
背景技术
急性髓系白血病(AML)是一种具有高度异质性的恶性血液肿瘤，以骨髓中原始/幼稚髓系细胞增殖、分化及细胞周期调控异常为主要特征。在正常髓系细胞分化发育的不同阶段中，造血祖细胞发生恶性转化，这一过程常常伴随染色体易位和某些特定基因的突变，这些遗传学异常会扰乱正常造血细胞的增殖、分化和成熟，最终导致白血病的发生。
急性髓系白血病(AML)常伴有遗传学异常，最常见的是t(8；21)异位，其发生率为10％-15％，在M2亚型中达40％-50％，在2016年WHO分型标准中已将AML伴t(8；21)(q22；q22)作为一种独立亚型(M2亚型)。t(8；21)染色体异位形成AML1-ETO(又称RUNX1-RUNX1T1)融合基因，其编码形成的AML1-ETO(AE)融合蛋白是这一类型白血病特征性标志，同时亦是导致本病发生的始动因素。近年来有多篇文献对AML1-ETO融合蛋白对下游基因的调控机制进行了深入研究，发现AML1-ETO融合蛋白通过ETO募集DNA甲基转移酶(DNMTs)和组蛋白去乙酰化酶(HDACs)等结合在下游基因启动子区的AML1结合位点，靶向调控具有抑癌功能的基因，使其发生DNA甲基化或组蛋白去乙酰化等表观遗传学改变、表达沉默，参与了t(8；21)AML的发生发展。尽管如此，t(8；21)AML细胞中AML1-ETO基因是如何被调控的，如何通过抑制AE融合蛋白的表达从根本上达到治疗此类疾病，目前研究报道的甚少。
AML是一组高度异质性疾病，年轻患者治疗后完全缓解率约80％，复发率大于40％，总生存40％-45％，根据细胞遗传学、分子生物学可分为低危、中危、高危三个亚组。AML伴t(8；21)为预后良好组，但该组患者经常规和化疗后，仍有47％-56％的患者出现复发/耐药，复发后预后极差，生存率通常低于15％。目前国际上没有专门针对t(8；21)AML的诱导化疗方案，多采取常规AML的化疗“3+7柔红霉素和阿糖胞苷方案，”复发后无非常有效的治疗手段。对于难治/复发的AML1-ETO阳性AML患者，国内目前采用去甲基化药物(地西他滨、阿扎胞苷)、组蛋白去乙酰化酶抑制剂+常规化疗联合治疗。国际上新药研究更多聚焦于靶向治疗，包括抗CD33、CD123、CD47单抗和IDH1/2、BCL2、FLT3抑制剂等。临床上依然亟待开发新的治疗药物。
发明内容
本发明发现一类化合物具有明显的抑制AE+AML白血病细胞的增殖，并且对AML细胞具有明显的分化作用，有望开发成为新一代治疗AE阳性AML的药物。具体如下：
一种如式(I)所示的化合物或其药学上可接受的盐：
Figure BDA0003719312790000021
其中，R1为酰基或磺酰基。
优选的，R1的结构为1-22中的任一结构；
Figure BDA0003719312790000022
本发明还提供了上述化合物或其药学上可接受的盐的制备方法，其制备路线为：
Figure BDA0003719312790000031
上述化合物或其药学上可接受的盐可用于制备治疗急性髓性白血病药物。具体为含有t(8；21)融合基因的急性髓性白血病。
本发明还提供了一种包括上述化合物或其药学上可接受的盐的药物组合物；该药物组合物还可以包括一种或多种药学上可接受的赋形剂。该药物组合物的剂型为药学上可接受的任一剂型。
本发明的有益效果为：本发明发现了一类新型喹唑啉衍生物，其对于AE+AML白血病细胞的增殖具有明显的抑制效果，并且对AML细胞具有明显的分化作用，有望开发成为新一代治疗AE阳性AML的药物。
具体实施方式
以下将结合实施例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的制备，化合物1的结构如下所示：
Figure BDA0003719312790000032
具体制备方法包括以下步骤：
(1)化合物(1-1)的制备，化合物(1-1)的结构如下所示：
Figure BDA0003719312790000041
具体制备过程为：
氩气保护下，将2-氟-4-硝基苯胺(2.00g，12.8mmol)溶解在四氢呋喃(60mL)中，加入BOC酸酐(6.00mL，26.9mmol)，然后再加入DMAP(39.1mg，0.32mmol)，室温反应，3小时后TLC监测反应完全，反应液减压浓缩，饱和食盐水(100mL×3)洗反应液，乙酸乙酯萃取(100mL×2)，再用饱和碳酸氢钠(150mL)洗有机相，有机相干燥浓缩，柱层析纯化(石油醚：乙酸乙酯＝25：1至20：1)得化合物1-1(白色固体，3.90g，产率：95％)。
核磁测试结果为：
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),8.02(s,1H),7.91(s,1H),8.88(s,1H),1.40(s,9H).13C NMR(100MHz,DMSO-d6)δ163.0,158.9,125.7,124.9,116.9,110.8,150.4,89.5,29.6,29.5,29.1.HRMS(ESI):m/z calculated for C11H13FN2NaO4 +:279.0752,found279.0757.
(2)化合物(1-2)的制备，化合物(1-2)的结构如下所示：
Figure BDA0003719312790000042
具体制备过程为：
氩气保护下，将化合物1-1(7.23g，20.3mmol)溶解于乙醇/水(乙醇：水＝100mL：40mL)中，然后加入铁粉(4.50g，81.2mmol)，加入冰醋酸(10mL)，油浴下升温至95℃，3小时后TLC监测反应完全，反应液用硅藻土抽滤，旋去乙醇，饱和碳酸钠(100mL×3)洗反应液，乙酸乙酯萃取(150mL×2)，有机相干燥浓缩，柱层析纯化(石油醚：乙酸乙酯＝7：1至3：1)得化合物1-2(棕色油状液体，24.2g，产率：94％)。
核磁测试结果为：
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),8.02(s,1H),7.91(s,1H),8.88(s,1H),4.33(q,J＝7.0Hz,2H),1.40(s,9H).13C NMR(100MHz,DMSO-d6)δ163.8,153.6,146.0,124.3,112.4,109.3,105.7,89.5,28.7,28.6,28.6.HRMS(ESI):m/z calculated forC11H15FN2NaO2 +:249.1015,found 249.1016.
(3)化合物(1-3)的制备，化合物(1-3)的结构如下所示：
Figure BDA0003719312790000043
具体制备过程为：
0℃，氩气保护下，将N-(4-氯-3-氰基-7-乙氧基喹啉-6-基)乙酰胺(2.00g，6.92mmol)溶解于浓盐酸(70mL)中，10分钟后，室温过夜，次日TLC监测反应完全，饱和碳酸钠(100mL×3)洗反应液，乙酸乙酯萃取(100mL×2)，有机相干燥浓缩，柱层析纯化(二氯甲烷：无水甲醇＝150：1至120：1)得化合物1-3(黄色固体，1.40g，产率：81％)。
核磁测试结果为：
1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.29(s,1H),7.16(s,1H),4.21(s,2H),3.99(q,J＝7.0Hz,2H),1.34(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ162.3,145.6,141.5,140.8,138.2,120.4,119.4,117.9,106.5,101.6,64.7,15.8.HRMS(ESI):m/zcalculated forC12H10ClN2NaO+:270.0405,found 270.0410.
(4)化合物(1-4)的制备，化合物(1-4)的结构如下所示：
Figure BDA0003719312790000051
具体制备过程为：
0℃，氩气保护下，将化合物1-3(1.40g，5.60mmol)溶解于N-甲基吡咯烷酮(40mL)中，然后再加入丙烯酰氯(916μL，11.2mmol)，室温反应，3小时后TLC监测反应完全，饱和碳酸氢钠(100mL×3)洗反应液，乙酸乙酯萃取(100mL×2)，再用饱和氯化钠(150mL)洗有机相，有机相干燥浓缩，柱层析纯化(二氯甲烷：无水甲醇＝200：1至190：1)得化合物1-4(淡黄色固体，1.43g，产率：85％)。
核磁测试结果为：
1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),7.29(s,1H),7.26(s,1H),6.49-6.43(m,1H),6.15-6.09(m,1H),5.75-5.68(m,1H),4.21(s,2H),3.97(q,J＝7.0Hz,2H),1.36(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.3,157.6,146.2,143.5,141.1,138.3,130.7,129.6,121.9,120.4,119.4,109.5,101.7,64.8,14.8.HRMS(ESI):m/z calculat ed forC15H12ClN3NaO2 +:324.0510,found 324.0515.
(5)化合物(1-5)的制备，化合物(1-5)的结构如下所示：
Figure BDA0003719312790000061
具体制备过程为：
氩气保护下，将化合物1-4(1.00g，3.32mmol)溶解于异丙醇(25mL)中，然后加入吡啶盐酸盐(384mg，3.32mmol)，再加入化合物1-2(1.13g，4.98mmol)，油浴下升温至85℃，3小时后TLC监测反应完全，旋去异丙醇，饱和碳酸氢钠(100mL×3)洗反应液，乙酸乙酯萃取(100mL×2)，有机相干燥浓缩，柱层析纯化(二氯甲烷：无水甲醇＝150：1至100：1)得化合物1-5(黄色固体，1.42g，产率：87％)。
核磁测试结果为：
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),9.78(s,1H),9.63(s,1H),9.01(s,1H),7.96(t,J＝8.7Hz,1H),7.45(s,1H),7.13(dd,J＝12.0,2.2Hz,1H),7.08(dd,J＝8.7,1.8Hz,1H),6.76(dd,J＝16.9,10.2Hz,1H),6.32(dd,J＝17.0,1.8Hz,1H),5.83(dd,J＝10.2,1.8Hz,1H),4.26(s,1H),3.98(q,J＝7.0Hz,2H),1.41(s,9H),1.33(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.4,163.5,155.6,154.3,153.6,147.1,145.8,141.2,137.2,131.8,129.3,124.6,118.9,118.0,117.5,112.7,110.92,108.7,107.5,89.5,81.4,65.1,29.9,29.3,28.7,15.1.HRMS(ESI):m/z calculated for C26H26FN5NaO4 +:514.1861,found 514.1866.
(6)化合物(1-6)的制备，化合物(1-6)的结构如下所示：
Figure BDA0003719312790000062
具体制备过程为：
0℃下，将化合物7(1.00g，2.04mmol)溶解于二氯甲烷中(15mL)，然后缓慢滴加三氟乙酸(20mL)，半小时后TLC监测反应完全，旋去三氟乙酸，饱和碳酸氢钠(100mL×3)洗反应液，乙酸乙酯萃取(100mL×2)，有机相干燥浓缩，柱层析纯化(二氯甲烷：无水甲醇＝100：1至80：1)得化合物8(白色固体，900mg，产率：91％)。
核磁测试结果为：
1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.04(s,1H),7.92(s,1H),7.73(s,1H),7.97(t,J＝8.7Hz,1H),7.23(dd,J＝12.0,2.2Hz,1H),7.08(dd,J＝8.7,1.8Hz,1H),6.77(dd,J＝16.9,10.2Hz,1H),6.38(dd,J＝17.0,1.8Hz,1H),5.81(dd,J＝10.2,1.8Hz,1H),4.26(s,3H),3.99(q,J＝7.0Hz,2H),1.38(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.4,165.6,158.5,156.4,153.8,148.5,145.5,137.2,136.4,130.8,129.5,127.5,118.9,117.5,115.5,114.6,107.5,106.7,89.5,64.1,14.09.HRMS(ESI):m/z calculatedfor C21H18FN5NaO2 +:414.1337,found 414.1342.
(7)化合物1的制备：0℃，氩气保护下，将化合物1-6(100mg，0.256mmol)溶解于四氢呋喃溶液(3.0mL)中，然后加入3-溴丙酰氯(78μL，0.766mmol)，油浴下升温至70℃，3h后TLC监测反应完全，旋去四氢呋喃，饱和食盐水洗反应液，乙酸乙酯萃取，再用饱和碳酸氢钠洗有机相，有机相干燥浓缩，柱层析纯化(二氯甲烷：甲醇＝30：1至20：1)得化合物1(白色固体，92mg，产率：68％)。
数据表征如下：
M.p.190.7-192.9℃；IR(KBr):3363,3256,2997,2974,1916,1785,1648,1624,1539,1473cm-1.1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),9.78(s,1H),9.63(s,1H),9.00(s,1H),8.57(s,1H),7.92(t,J＝8.8Hz,1H),7.42(s,1H),7.16(dd,J＝12.0,2.2Hz,1H),7.04(dd,J＝8.7,1.8Hz,1H),6.77(dd,J＝16.9,10.2Hz,1H),6.30(dd,J＝17.0,1.8Hz,1H),5.81(dd,J＝10.2,1.8Hz,1H),4.33(q,J＝7.0Hz,2H),3.73(t,J＝6.4Hz,2H),3.05(t,J＝6.4Hz,2H),1.47(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.0,164.1,154.6,154.0,153.0,152.5,150.5,148.1,132.2,128.3,127.9,124.6,122.7,118.9,117.5,115.7,114.4,110.4,108.9,89.5,65.1,39.3,29.6,14.7.HRMS(ESI):m/z calculated forC24H21BrFN5NaO3 +:548.0704,found 548.0710.
实施例2：
化合物2-22的制备，按照与化合物1相类似的制备方法替换原料后得到，具体结构如下：
Figure BDA0003719312790000071
Figure BDA0003719312790000081
Figure BDA0003719312790000091
(1)化合物2的数据表征如下：
M.P.199.2-202.1℃；IR(KBr):3182,3096,2994,2875,1869,1735,1628,1549,1445,1386cm-1.1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.69(s,1H),9.62(s,1H),8.99(d,J＝7.3Hz,1H),8.55(s,1H),7.86(q,J＝8.9Hz,1H),7.43(s,1H),7.13(d,J＝11.7Hz,1H),7.02(d,J＝8.4Hz,1H),6.81–6.69(m,1H),6.29(dd,J＝17.0,1.7Hz,1H),5.86–5.73(m,1H),4.33(q,J＝6.9Hz,2H),3.57(t,J＝6.6Hz,2H),2.42(t,J＝7.2Hz,2H),1.92–1.81(m,2H),1.75–1.67(m,2H),1.47(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ174.6,171.8,164.1,155.1,154.9,152.5,152.4,150.42,132.0,128.8,128.1,124.5,124.5,120.9,116.7,115.8,113.5,112.5,112.2,88.2,65.63,45.6,35.3,32.0,22.9,14.7.HRMS(ES I):m/z calculated for C26H25BrFN5NaO3 +:576.1017,found 576.1023.
(2)化合物3的数据表征如下：
M.P.196.6-198.5℃；IR(KBr):3283,3197,3072,2962,2838,1927,1826,1682,1526,1472,1416cm-1.1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.65(s,1H),9.61(s,1H),8.98(s,1H),8.55(s,1H),7.85(t,J＝8.6Hz,1H),7.42(s,1H),7.12(d,J＝11.9Hz,1H),7.01(d,J＝8.5Hz,1H),6.76(dd,J＝16.8,10.3Hz,1H),6.29(d,J＝16.9Hz,1H),5.80(d,J＝10.2Hz,1H),4.33(dd,J＝13.5,6.7Hz,2H),3.53(t,J＝6.6Hz,2H),2.38(t,J＝7.0Hz,2H),1.88–1.75(m,2H),1.64–1.55(m,2H),1.47(t,J＝6.8Hz,3H),1.42–1.39(m,J＝7.1Hz,2H),1.35–1.30(m,J＝6.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ171.5,163.6,153.6,152.2,151.9,151.8,150.2,146.,131.69,127.9,127.5,124.3,123.0,118.7,116.8,115.3,113.7,110.9,107.9,88.8,64.7,35.6,35.1,32.1,27.7,27.3,24.9,14.7.HRMS(ES I):m/zcalculated for C28H29BrFN5NaO3 +:604.1336,found 604.1337.
(3)化合物4的数据表征如下：
M.P.192.9-194.7℃；IR(KBr):3158,3106,3021,2862,2817,1872,1761,1625,1581,1504,1432cm-1.1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),10.02(s,1H),9.82(s,1H),9.14(s,1H),8.91(s,1H),8.05(t,J＝8.6Hz,1H),7.60(s,1H),7.38(dd,J＝11.7,1.9Hz,1H),7.20(d,J＝8.6Hz,1H),6.79(dd,J＝17.0,10.2Hz,1H),6.40–6.26(m,1H),5.84(d,J＝11.7Hz,1H),4.34(q,J＝6.9Hz,2H),3.89(t,J＝6.1Hz,2H),2.95(t,J＝6.1Hz,2H),1.49(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.6,163.7,154.9,154.1,152.6,151.7,149.4,135.0,131.8,128.7,127.8,124.7,123.7,121.2,116.1,114.9,112.7,112.5,103.4,87.3,65.2,40.6,38.7,14.0.HRMS(ESI):m/z calculated for C24H21ClFN5NaO3 +:504.1209,found 504.1215.
(4)化合物5的数据表征如下：
M.P.195.3-197.9℃；IR(KBr):3303,3274,3176,2969,2812,1830,1745,1622,1573,1512,1469cm-1.1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.68(s,1H),9.58(s,1H),8.98(s,1H),8.55(s,1H),7.84(t,J＝8.7Hz,1H),7.43(s,1H),7.12(d,J＝10.7Hz,1H),7.01(d,J＝8.4Hz,1H),6.76(dd,J＝17.0,10.2Hz,1H),6.30(dd,J＝17.0,1.8Hz,1H),5.80(dd,J＝10.2,1.8Hz,1H),4.33(q,J＝7.0Hz,2H),3.70(t,J＝6.5Hz,2H),2.55(t,J＝7.2Hz,2H),2.08–1.99(m,2H),1.47(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.5,163.5,154.3,153.5,152.7,151.9,151.9,150.1,131.7,127.8,127.4,124.3,122.62,118.5,116.9,115.2,113.8,110.1,108.2,89.0,64.6,44.9,32.8,28.0,14.2.HRMS(ES I):m/z calculated for C25H23ClFN5NaO3 +:518.1366,found 518.1371.
(5)化合物6的数据表征如下：
M.P.210.9-213.1℃；IR(KBr):3325,3291,3196,3029,2934,1896,1679,1618,1535,1476,1413cm-1.1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.72(s,1H),9.59(s,1H),8.98(s,1H),8.57(s,1H),7.81(t,J＝8.5Hz,1H),7.43(s,1H),7.14(d,J＝11.8Hz,1H),7.03(d,J＝8.7Hz,1H),6.76(dd,J＝17.0,10.2Hz,1H),6.29(dd,J＝17.0,1.8Hz,1H),5.80(dd,J＝10.2,1.7Hz,1H),4.71(s,2H),4.33(q,J＝7.0Hz,2H),2.12(s,3H),1.47(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.9,169.9,165.8,163.5,153.4,152.0,149.8,131.7,129.5,128.5,127.8,127.3,124.3,121.5,118.22,117.0,115.1,114.0,109.8,108.6,89.4,64.6,62.3,20.4,14.1.HRMS(ESI):m/z calculated for C25H22FN5NaO5 +:514.1497,found 514.1503.
(6)化合物7的数据表征如下：
M.P.197.1-199.3℃；IR(KBr):3287,3244,3136,3094,2963,1916,1785,1638,1595,1528,1422cm-1.1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.74(s,1H),9.62(s,1H),8.99(s,1H),8.56(s,1H),7.94(t,J＝8.8Hz,1H),7.43(s,1H),7.16(d,J＝10.5Hz,1H),7.04(d,J＝8.4Hz,1H),6.76(dd,J＝16.9,10.2Hz,1H),6.30(dd,J＝17.0,1.8Hz,1H),5.81(dd,J＝10.2,1.8Hz,1H),4.33(q,J＝7.0Hz,2H),3.67(s,3H),3.58(s,2H),1.47(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.3,164.4,163.6,154.0,153.4,152.3,152.2,149.9,147.9,131.7,127.8,127.4,123.6,122.2,118.47,117.1,115.2,113.9,109.9,108.6,89.1,64.6,52.0,42.9,14.2.HRMS(ESI):m/z calculated for C25H22FN5NaO5 +:514.1497,found 514.1503.
(7)化合物8的数据表征如下：
M.P.200.6-204.5℃；IR(KBr):3238,3206,3064,2983,2894,1916,1875,1639,1524,1508,1417cm-1.1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.73(s,1H),9.62(s,1H),8.98(s,1H),8.55(s,1H),7.92(t,J＝8.8Hz,1H),7.43(s,1H),7.15(d,J＝11.1Hz,1H),7.04(d,J＝8.0Hz,1H),6.76(dd,J＝16.9,10.2Hz,1H),6.29(d,J＝17.0Hz,1H),5.80(d,J＝10.4Hz,1H),4.33(dd,J＝13.6,6.7Hz,2H),4.13(q,J＝7.1Hz,2H),3.56(s,2H),1.47(t,J＝3.2Hz,3H),1.22(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.7,164.4,163.6,154.4,153.4,152.1,152.0,149.8,147.9,131.7,127.8,127.4,123.7,122.0,118.3,117.1,115.2,113.9,109.9,108.7,89.2,64.6,60.6,43.0,28.0,14.2,14.0.HRMS(ES I)calculated for C26H24FN5NaO5 +:528.1654,found 528.1659.
(8)化合物9的数据表征如下：
M.P.191.5-194.4℃；IR(KBr):3289,3203,3097,2938,2816,1929,1794,1671,1533,1421,1392cm-1.1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.67(s,1H),9.65(s,1H),8.98(s,1H),8.55(s,1H),7.87(t,J＝8.7Hz,1H),7.42(s,1H),7.13(dd,J＝12.0,2.1Hz,1H),7.02(dd,J＝8.6,1.6Hz,1H),6.77(dd,J＝16.9,10.2Hz,1H),6.29(dd,J＝17.0,1.7Hz,1H),5.80(dd,J＝10.3,1.7Hz,1H),4.32(q,J＝6.9Hz,2H),2.39(q,J＝7.5Hz,2H),1.46(t,J＝6.9Hz,3H),1.08(t,J＝7.5Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.3,163.6,162.4,154.3,153.5,152.6,152.1,150.0,131.7,127.8,127.4,124.2,122.7,118.5,117.1,115.,113.9,110.1,108.5,88.9,64.6,29.0,14.2,9.7.HRMS(ESI):m/z calculatedfor C24H22FN5NaO3 +:470.1599,found 470.1604.
(9)化合物10的数据表征如下：
M.P.206.3-208.1℃；IR(KBr):3319,3283,3129,2930,2829,1926,1795,1646,1542,1492,1421cm-1.1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.61(s,1H),9.59(s,1H),8.98(s,1H),8.55(s,1H),7.82(t,J＝8.7Hz,1H),7.43(s,1H),7.12(dd,J＝12.1,2.2Hz,1H),7.01(dd,J＝8.6,1.9Hz,1H),6.76(dd,J＝17.0,10.2Hz,1H),6.29(dd,J＝17.0,1.7Hz,1H),5.80(dd,J＝10.3,1.7Hz,1H),4.33(q,J＝7.0Hz,2H),2.74(dt,J＝13.6,6.9Hz,1H),1.47(t,J＝6.9Hz,3H),1.11(s,3H),1.10(s,3H).13C NMR(100MHz,DMSO-d6)δ175.5,163.6,153.4,152.6,152.2,149.9,147.9,137.4,131.7,127.7,127.4,124.6,122.6,118.3,117.1,115.2,113.9,109.8,108.7,89.1,64.6,34.2,19.5,19.5,14.2.HRMS(ES I):m/z calculated for C25H24FN5NaO3 +:484.1755,found 484.1761.
(10)化合物11的数据表征如下：
M.P.209.3-212.6℃；IR(KBr):3265,3201,3026,2891,2828,1852,1771,1612,1535,1481,1427cm-1.1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),9.64(s,1H),9.08(s,1H),9.01(s,1H),8.61(s,1H),7.48–7.41(m,2H),7.12(dd,J＝11.7,2.2Hz,1H),7.03(dd,J＝8.5,2.0Hz,1H),6.77(dd,J＝17.0,10.2Hz,1H),6.30(dd,J＝17.0,1.7Hz,1H),5.81(dd,J＝10.2,1.7Hz,1H),4.33(q,J＝6.8Hz,2H),1.47(t,J＝6.9Hz,3H),1.23(s,9H).13C NMR(100MHz,DMSO-d6)δ176.5,163.6,156.8,154.3,153.6,151.8,150.0,147.1,131.7,127.9,127.4,127.2,122.2,117.9,116.8,115.2,114.04,109.8,108.0,89.4,64.7,40.1,27.2,27.2,27.2,14.2.HRMS(ESI):m/z calculated for C26H26FN5NaO3 +:498.1912,found498.1917.
(11)化合物12的数据表征如下：
M.P.190.8-193.8℃；IR(KBr):3314,3264,3178,3084,2994,1749,1643,1598,1545,1479,1419cm-1.1H NMR(400MHz,DMSO-d6)δ9.70(s,2H),9.59(s,1H),8.98(s,1H),8.55(s,1H),7.95(t,J＝8.6Hz,1H),7.43(s,1H),7.13(dd,J＝12.2,2.2Hz,1H),7.02(d,J＝8.7Hz,1H),6.79(ddd,J＝19.1,16.1,8.6Hz,2H),6.41–6.20(m,2H),5.80(dd,J＝10.2,1.8Hz,1H),4.33(q,J＝6.9Hz,2H),1.94–1.81(m,3H),1.47(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ164.1,164.0,164.0,154.0,152.5,150.5,140.7,140.7,132.2,128.3,128.3,127.8,126.0,124.6,124.6,118.9,117.5,115.7,114.4,110.5,108.9,89.6,65.1,18.0,14.6.HRMS(ESI):m/z calculated for C25H22FN5NaO3 +:482.1599,found 482.1604.
(12)化合物13的数据表征如下：
M.P.194.5-196.1℃；IR(KBr):3258,3206,3172,3099,2841,1946,1795,1682,1562,1508,1438cm-1.1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.62(s,1H),9.61(s,1H),8.98(s,1H),8.55(s,1H),7.81(t,J＝8.7Hz,1H),7.42(s,1H),7.12(dd,J＝12.0,2.1Hz,1H),7.01(d,J＝8.5Hz,1H),6.76(dd,J＝17.0,10.2Hz,1H),6.29(dd,J＝17.0,1.6Hz,1H),5.80(dd,J＝10.3,1.5Hz,1H),4.32(q,J＝6.9Hz,2H),2.25(d,J＝7.1Hz,2H),2.10–2.04(m,1H),1.47(t,J＝6.9Hz,3H),0.95(s,3H),0.94(s,3H).13C NMR(100MHz,DMSO-d6)δ170.9,163.6,153.4,152.6,152.3,149.9,147.9,137.6,131.7,127.8,127.4,124.7,122.5,118.3,117.1,115.2,113.9,109.9,108.7,89.2,64.6,44.9,25.7,22.3,22.3,14.2.HRMS(ESI):m/z calculated for C26H26FN5NaO3+:498.1912,found 498.1917.
(13)化合物14的数据表征如下：
M.p.199.4-201.7℃；IR(KBr):3172,3084,3021,2973,2831,1866,1739,1626,1583,1501,1428cm-1.1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.66(s,1H),9.63(s,1H),8.98(s,1H),8.54(s,1H),7.85(s,1H),7.43(s,1H),7.20–7.08(m,1H),7.02(d,J＝8.4Hz,1H),6.76(dd,J＝16.9,10.2Hz,1H),6.30(dd,J＝17.0,1.7Hz,1H),5.80(dd,J＝10.3,1.6Hz,1H),4.32(q,J＝6.9Hz,2H),2.37(t,J＝7.4Hz,2H),1.61–1.52(m,2H),1.47(t,J＝6.9Hz,3H),1.33(dd,J＝14.7,7.3Hz,2H),0.90(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.6,163.6,153.6,152.7,152.2,152.2,150.0,147.8,131.7,127.8,127.4,124.4,122.7,118.5,117.1,115.3,113.9,110.1,108.63,89.0,64.7,35.5,27.3,21.8,14.2,13.8.HRMS(ESI):m/z calculated for C26H26FN5NaO3 +:498.1912,found 498.1917.
(14)化合物15的数据表征如下：
M.P.194.6-196.5℃；IR(KBr):3372,3287,3129,2903,2862,1872,1762,1622,1576,1519,1421cm-1.1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.64(s,1H),9.61(s,1H),8.98(s,1H),8.54(s,1H),7.85(t,J＝8.6Hz,1H),7.42(s,1H),7.12(dd,J＝12.0,2.1Hz,1H),7.01(d,J＝8.4Hz,1H),6.76(dd,J＝17.0,10.2Hz,1H),6.29(dd,J＝17.0,1.5Hz,1H),5.87–5.74(m,1H),4.33(dd,J＝13.8,6.8Hz,2H),2.36(t,J＝7.3Hz,2H),1.63–1.55(m,2H),1.47(t,J＝6.9Hz,3H),1.35–1.30(m,2H),1.26–1.21(m,2H),0.88(t,J＝6.7Hz,3H).13C NMR(100MHz,DMSO-d6)δ171.5,163.6,154.8,153.4,152.3,152.2,149.9,147.9,131.7,127.8,127.3,124.3,122.7,118.3,117.1,115.2,113.9,110.0,108.7,89.0,64.6,35.7,30.8,24.8,21.9,14.2,13.8.HRMS(ESI):m/z calculated for C27H28FN5NaO3 +:512.2068,found 512.2074.
(15)化合物16的数据表征如下：
M.P.182.4-184.9℃；IR(KBr):3292,3149,3106,3024,2874,1916,1792,1638,1593,1490,1436cm-1.1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.63(s,1H),9.61(s,1H),8.98(s,1H),8.55(s,1H),7.85(t,J＝8.7Hz,1H),7.42(s,1H),7.15–7.09(m,1H),7.01(d,J＝8.3Hz,1H),6.76(dd,J＝16.9,10.2Hz,1H),6.29(dd,J＝17.0,1.8Hz,1H),5.80(dd,J＝10.2,1.8Hz,1H),4.33(q,J＝7.0Hz,2H),2.36(t,J＝7.4Hz,2H),2.18(t,J＝7.4Hz,2H),1.61–1.56(m,2H),1.51–1.48(m,2H),1.47–1.44(m,2H),1.30(t,J＝7.0Hz,3H),1.29–1.25(m,2H),0.86(t,J＝7.7Hz,3H).13C NMR(100MHz,DMSO-d6)δ174.9,172.0,164.0,154.8,153.9,153.2,152.7,150.4,132.2,128.2,127.7,124.8,123.1,118.8,117.6,115.7,114.3,110.3,109.1,89.5,65.11,34.13,31.6,29.0,25.6,24.9,22.5,14.7,14.4.HRMS(ESI):m/z calculated for C29H32FN5NaO3 +:540.2381,found 540.2387.
(16)化合物17的数据表征如下：
M.P.201.3-204.5℃；IR(KBr):3096,3006,2979,2874,2801,1956,1739,1651,1555,1508,1401cm-1.1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.73(s,1H),9.60(s,1H),8.98(s,1H),8.59(s,1H),7.74–7.69(m,2H),7.44(s,1H),7.36(t,J＝8.8Hz,2H),7.16(t,J＝8.8Hz,1H),7.00–6.95(m,2H),6.77(dd,J＝17.0,10.2Hz,1H),6.29(dd,J＝17.0,1.8Hz,1H),5.81(dd,J＝10.2,1.8Hz,1H),4.33(q,J＝6.9Hz,2H),1.47(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.1,163.6,163.4,157.4,155.8,153.3,151.9,149.5,148.0,140.8,136.0,131.7,129.8,128.7,128.0,127.4,117.6,117.0,116.3,116.1,114.7,114.4,109.1,108.6,90.5,64.7,14.1.HRMS(ESI):m/z calculated for C27H21F2N5NaO4S+:572.1175,found 572.1180.
(17)化合物18的数据表征如下：
M.P.197.7-200.5℃；IR(KBr):3261,3206,3082,2952,2882,1945,1791,1652,1603,1584,1521cm-1.1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.72(s,1H),9.60(s,1H),8.97(s,1H),8.58(s,1H),7.55(dd,J＝11.1,6.7Hz,2H),7.44–7.39(m,2H),7.19(t,J＝8.7Hz,1H),6.98(dd,J＝15.9,5.1Hz,2H),6.76(dd,J＝16.9,10.2Hz,1H),6.29(dd,J＝17.0,1.8Hz,1H),5.80(dd,J＝10.2,1.8Hz,1H),4.33(q,J＝6.9Hz,2H),1.47(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.6,157.8,156.2,155.4,153.7,153.4,151.9,149.4,148.0,131.7,129.6,129.1,128.1,127.4,119.2,119.0,117.5,116.9,116.6,116.4,114.7,114.5,108.7,108.6,90.8,64.7,14.2.HRMS(ESI):m/z calculated forC27H20F3N5Na O4S+:590.1080,found 590.1086.
(18)化合物19的数据表征如下：
M.P.199.9-203.4℃；IR(KBr):3372,3316,3169,3088,2926,1886,1815,1634,1562,1500,1427cm-1.1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.71(s,1H),9.60(s,1H),8.98(s,1H),8.55(s,1H),8.41(s,1H),8.30(s,1H),8.07(t,J＝8.8Hz,1H),7.43(s,1H),7.34(s,1H),7.32(s,1H),7.16(dd,J＝12.3,2.1Hz,1H),7.04(d,J＝8.8Hz,1H),6.85(d,J＝9.0Hz,1H),6.76(dd,J＝16.9,10.2Hz,1H),6.29(dd,J＝17.0,1.6Hz,1H),5.80(dd,J＝10.3,1.8Hz,1H),4.33(q,J＝6.9Hz,2H),3.71(s,3H),1.47(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.6,159.8,154.3,153.4,152.9,152.2,151.3,149.9,147.9,137.2,132.9,131.7,127.8,127.4,122.7,121.9,119.8,119.8,118.6,117.1,115.2,113.9,113.9,110.0,108.7,89.1,64.6,55.1,14.2.HRMS(ESI):m/z calculated forC29H25FN6NaO4 +:563.1814,found 563.1819.
(19)化合物20的数据表征如下：
M.P.196.3-199.1℃；IR(KBr):3271,3206,3169,2902,2865,1949,1835,1628,1599,1503,1444cm-1.1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),9.71(s,1H),9.59(s,1H),8.98(s,1H),8.60(s,1H),8.55(s,1H),8.30(s,1H),8.07(t,J＝8.8Hz,1H),7.43(s,1H),7.33(s,1H),7.31(s,1H),7.16(d,J＝12.5Hz,1H),7.08(s,1H),7.06(s,1H),6.76(dd,J＝16.9,10.3Hz,1H),6.29(d,J＝17.1Hz,1H),5.80(d,J＝11.4Hz,1H),4.33(q,J＝6.8Hz,2H),2.23(s,3H),1.47(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ164.0,160.3,154.2,153.9,153.1,152.6,150.4,148.3,137.7,132.2,130.9,129.60,129.6,128.3,127.8,123.2,122.3,119.0,118.6,118.6,117.5,115.6,114.4,110.4,109.1,89.6,65.1,20.7,14.6.HRMS(ESI):m/z calculated for C29H25FN6NaO3 +:547.1864,found 547.1870.
(20)化合物21的数据表征如下：
M.p.245-247℃.1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),9.77(s,1H),9.62(s,1H),9.01(s,1H),8.60(s,1H),7.56(d,J＝7.5Hz,2H),7.46(d,J＝7.7Hz,2H),7.16(d,J＝11.9Hz,1H),7.09(d,J＝8.8Hz,1H),6.85–6.68(m,1H),6.30(d,J＝17.1Hz,2H),5.81(d,J＝11.2Hz,1H),4.35(s,2H),1.48(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ164.1,162.9,156.1,153.9,152.5,150.2,148.5,139.4,136.7 132.2,131.7,128.6,128.4,127.8,125.6,118.2,117.6,115.6,114.8,109.9,109.2,90.5,65.2,14.7.HRMS(ESI):m/zcalculated for C28H20F3N5NaO3 +:554.1410,found 554.1412.
(21)化合物22的数据表征如下：
M.p.262-264℃.1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),9.76(s,1H),9.61(s,1H),9.01(s,1H),8.60(s,1H),7.86(t,J＝8.6Hz,1H),7.57(s,1H),7.55(s,1H),7.50(d,J＝6.9Hz,1H),7.15(d,J＝11.9Hz,1H),7.08(d,J＝8.5Hz,1H),6.77(dd,J＝16.9,10.2Hz,1H),6.30(d,J＝17.1Hz,1H),5.81(d,J＝11.3Hz,1H),4.34(q,J＝6.8Hz,2H),1.48(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ164.1,162.9,155.6,153.9,152.5,150.1,148.5,139.5,136.7,132.2,131.7,131.7,128.6,128.4,127.8,125.6,121.4,121.3,118.1,117.6,115.60,114.8,109.8,109.7,109.2,90.5,65.2,14.7.HRMS(ESI):m/z calculate dfor C28H20Cl2FN5NaO3 +:586.0819,found 586.0821.
实施例3：
抗细胞增殖试验：
采用CCK-8法评价不同细胞株的药物敏感性。将细胞以8.0-10.0×103细胞/孔的方式接种于96孔板，最终体积为90μL，然后加入10μL不同浓度的化合物。置于37℃，5％CO2培养箱孵育72h后，每孔加入10μL CCK-8(Vazyme,A311-01)溶液，继续孵育3-4h。用THERMOFISHER Multiskan FC在450nm处读取OD值。用GraphPad Prizm7计算抑制50％生长所需的浓度(IC50)。实验结果如表1所示。
通过合成得到的22个化合物均具有显著的抑制AE阳性急性髓性白血病细胞的增殖的活性。尤其是化合物2，5，7，8，17等化合物，显示出来极强的杀灭急性髓性白血病细胞的活性。IC50值均在nM级别的。
表1
Figure BDA0003719312790000161
+代表IC50在1-2uM；++代表IC50在0.2-1uM；+++代表IC50在0.2-0.02uM；++++代表IC50<0.02uM。
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 (8)

1.一种如式(I)所示的化合物或其药学上可接受的盐：
Figure FDA0003719312780000011
其中，R1为酰基或磺酰基。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R1的结构为1-22中的任一结构；
Figure FDA0003719312780000012
3.一种权利要求1或2所述的化合物或其药学上可接受的盐的制备方法，其特征在于，其制备路线为：
Figure FDA0003719312780000021
4.权利要求1或2所述的化合物或其药学上可接受的盐在制备治疗急性髓性白血病药物中的应用。
5.根据权利要求4所述的应用，其特征在于，具体为含有t(8；21)融合基因的急性髓性白血病。
6.一种药物组合物，其特征在于，包括权利要求1或2所述的化合物或其药学上可接受的盐。
7.根据权利要求6所述的药物组合物，其特征在于，还包括一种或多种药学上可接受的赋形剂。
8.根据权利要求6所述的药物组合物，其特征在于，其剂型为药学上可接受的任一剂型。
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