CN114736156A - 一种白叶藤碱简化衍生物的制备方法及用途 - Google Patents

一种白叶藤碱简化衍生物的制备方法及用途 Download PDF

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CN114736156A
CN114736156A CN202210563116.0A CN202210563116A CN114736156A CN 114736156 A CN114736156 A CN 114736156A CN 202210563116 A CN202210563116 A CN 202210563116A CN 114736156 A CN114736156 A CN 114736156A
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刘映前
李海昕
崔艮中
吕卫鹏
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Abstract

本发明公开了一种白叶藤碱简化衍生物的制备方法及用途，属于药物化学领域。本发明公开了白叶藤碱简化衍生物A‑01～A‑32、H‑01～H‑06、N‑01～N‑05、M‑01～M‑08以及L‑01～L‑15的新用途，具体涉及白叶藤碱简化衍生物A‑01～A‑32、H‑01～H‑06、N‑01～N‑05、M‑01～M‑08以及L‑01～L‑15在防治立枯丝核菌(Rhizoctonia solani)，核盘菌(Sclerotinia sclerotiorum)，禾谷镰孢菌(Gibberella zeae)，灰葡萄孢菌(Botrytis cinerea)，辣椒疫霉(Phytophthora capsici)，稻瘟病菌(Magnaporthe oryzae)、稻黄单胞菌(Xanthomonas oryzae ACCC 11602)、柑桔黄单胞菌(Xanthomonas citri)、马铃薯黑胫病菌(Pectobacterium atroseptica ACCC 19901)中的应用。

Description

一种白叶藤碱简化衍生物的制备方法及用途
技术领域
本发明涉及药物化学领域，更具体的说是涉及一种白叶藤碱简化衍生物的制备方法及用途。
背景技术
植物病原菌是危害最大的植物病原微生物之一，可造成严重的植物疾病以及农作物的减产。目前人们主要通过化学农药来控制植物病原菌感染，但随着化学农药的使用，其耐药性，环境污染以及残留物毒性等问题不断出现，对植物真菌及细菌病害的防控提出了新的挑战。因此，寻找新型抗植物病原菌药物成为现阶段急需解决的问题。
白叶藤碱是从西非传统药用植物血红白叶藤(Cryptolepis sanguinolenta)中分离得到的一种吲哚喹啉类天然生物碱，其具有很长药用历史。通过研究发现，白叶藤碱及其类似物有着广泛的生物活性，在抗疟疾、抗肿瘤、抗菌、降血糖以及抗炎领域都有广泛应用。
现有技术已经报道了白叶藤碱在农业病原真菌防治中的应用(专利号：CN112106779A)。在专利CN112106779A中，发明人主要通过Takumi Abe等人报道的方法进行白叶藤碱的合成。合成路线由5步反应组成，以吲哚为起始合成原料，与对甲基苯磺酸进行偶联得到N-对甲基苯磺酸吲哚，然后在碱性条件下与NBS反应得N-对甲基苯磺酸-2-羟基吲哚-3-三乙基铵溴化物(HITAB),再与N-甲基苯胺反应脱水，并通过Vilsmeier-Haack反应在吲哚2-位引入醛基，最后在高温下环合生成紫色的白叶藤碱。然而，该方法在合成白叶藤碱时对实验操作具有较高的要求，且反应后处理及纯化较为困难。该方法较低的原子利用率以及较长的合成周期使得白叶藤碱的成本效益较低，限制了白叶藤碱在抗菌领域的应用。
因此，提供一种结构简单，合成难度更低，产率更高，活性更优的白叶藤碱简化衍生物在农业植物病害防治中的用途是本领域技术人员亟需解决的问题。
发明内容
有鉴于此，本发明提供了一种白叶藤碱简化衍生物的制备方法及用途；
为了实现上述目的，本发明采用如下技术方案：
一种白叶藤碱简化衍生物，包括白叶藤碱简化衍生物A-01～A-32、H-01～H-06、N-01～N-05、M-01～M-08、L-01～L-15中的至少一种；
所述白叶藤碱简化衍生物的结构式为：
Figure BDA0003650581180000021
R1为6-甲基取代、6-甲氧基取代、6-氟取代、6-硝基取代、8-甲基取代、8-氟取代、8-硝基取代、8-氯取代、7,8-氟取代、6,8-氟取代；R2与R3为2‘-氟取代、3‘-氟取代、2’,4’-氟取代、3’-三氟甲氧基取代、4’-三氟甲氧基取代、2‘-三氟甲基取代、3‘-三氟甲基取代、4‘-三氟甲基取代、2‘-氯取代、3‘-氯取代、2’,4’-氯取代、2’-甲氧基取代、3’-甲氧基取代、4‘-甲氧基取代、3’-二氟甲氧基取代、4’-二氟甲氧基取代、2‘-甲基取代；X1为NH、O、S、N-甲基、N-乙基、N-丙基、N-环丙基甲基、N-烯丙基；X2、X3、X4、Y1、Y2为C，N。
一种白叶藤碱简化衍生物的制备方法，如下所示：
Figure BDA0003650581180000022
Figure BDA0003650581180000031
本发明与白叶藤碱的合成路线相比(化学式7)，本发明所涉及的白叶藤碱简化衍生物具有更加简单的合成路线，合成步骤均少于白叶藤碱且具有更高的产率，显著缩短了合成周期，提高了原子利用率。除此之外，相比于白叶藤碱，简化衍生物的合成原料更为简单易得，具有更高的成本效益。
Figure BDA0003650581180000032
一种白叶藤碱简化衍生物在防治农业植物病害中的用途。
进一步的，所述农业植物病害包括由立枯丝核菌、核盘菌、禾谷镰孢菌、灰葡萄孢菌、辣椒疫霉、稻瘟病菌、稻黄单胞菌、柑桔黄单胞菌、马铃薯黑胫病菌引发的病害。
经由上述的技术方案可知，与现有技术相比，本发明的有益效果在于：
本发明对防治立枯丝核菌(Rhizoctonia solani)，核盘菌(Sclerotiniasclerotiorum)，禾谷镰孢菌(Gibberella zeae)，灰葡萄孢菌(Botrytis cinerea)，辣椒疫霉(Phytophthora capsici)，稻瘟病菌(Magnaporthe oryzae)、稻黄单胞菌(Xanthomonasoryzae ACCC 11602)、柑桔黄单胞菌(Xanthomonas citri)、马铃薯黑胫病菌(Pectobacterium atroseptica ACCC 19901)均表现出一定程度的抑制作用，其中灰葡萄孢菌(Botrytis cinerea)的抑制作用最强。本发明通过打开白叶藤碱的骈环结构对其进行了简化，合成了一系列简化衍生物。本发明所涉及的简化衍生物其合成难度明显低于白叶藤碱，显著缩短了合成周期，提高了原子利用率。除此之外，相比于白叶藤碱，简化衍生物的合成原料更为简单易得，具有更高的成本效益。在植物病原菌的体外活性测试中，简化衍生物表现出了不错的抗菌活性，并且高活性化合物A18具有比白叶藤碱更广的抗菌谱。因此，本发明成功简化了白叶藤碱结构，获得了合成成本更低，合成周期更短，成本效益更高，抗菌谱更广的简化衍生物。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
菌种来源：
实施例1：化合物A-01的合成
Figure BDA0003650581180000051
本发明所述化合物A-01的合成方法按如下反应式进行：
Figure BDA0003650581180000052
将喹啉(1mmol)置于含有搅拌子的100mL圆底烧瓶中，加入适量乙腈(10mL)搅拌溶解，随后加入过量叔丁基过氧化氢(8～16mmol)，80℃加热回流反应24～48h。反应完全后，通过减压蒸馏除去溶剂，用饱和Na2S2O3溶液与二氯甲烷进行萃取(×3)，收集有机相，并进行柱层析纯化，得到中间体Ⅰ。将中间体Ⅰ(1mmol)、3-氟苯胺(1.5mmol)、醋酸钯(0.05mmol)、Xantphos(0.05mmol)、碳酸铯(2mmol)依次加入含有搅拌子的100mL封管中，将封管中的空气置换为氩气后，加入二氧六环(10mL),100℃反应12h。反应结束后，用硅藻土进行抽滤，收集滤液，减压蒸馏除去溶剂，用饱和NaCl溶液与二氯甲烷进行萃取(×3)，收集有机相，并进行柱层析纯化，最终得到化合物A-01。
产率：77％；淡黄色固体；1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),7.95(d,J＝8.3Hz,1H),7.71(s,1H),7.59(d,J＝9.2Hz,1H),7.53–7.38(m,2H),7.23–7.14(m,1H),6.86–6.76(m,2H),6.61(t,J＝8.4,7.9Hz,1H),6.20(s,1H).13C NMR(101MHz,Chloroform-d)δ163.91(d,J＝245.2Hz),145.47,144.24,144.13(d,J＝2.9Hz),136.12,130.96(d,J＝9.8Hz),129.14,128.78,127.44,127.24,126.77,119.02,113.40,108.61(d,J＝21.4Hz),104.67(d,J＝24.9Hz).MS-ESI m/z:calcd for C15H11FN2:239.2654[M+H]+；found:239.1008.
实施例2：化合物A-02的合成
Figure BDA0003650581180000053
实验步骤与实施例1相同，仅以4-三氟甲氧基苯胺代替3-氟苯胺。产率：85％；淡黄色固体；1H NMR(400MHz,Chloroform-d)δ8.70(s,1H),8.02(d,J＝8.2Hz,1H),7.73–7.70(m,2H),7.65(dd,J＝8.1,1.6Hz,1H),7.58–7.39(m,4H),7.08–7.03(m,2H),6.08(s,1H).13CNMR(101MHz,Chloroform-d)δ145.08,143.86,141.26,136.60,132.69,129.10,128.97,128.85,127.48,127.10,126.65,120.03,118.08,114.39.MS-ESI m/z:calcdforC16H11F3N2:289.2732[M+H]+；found:289.0981.
实施例3：化合物A-03的合成
Figure BDA0003650581180000061
实验步骤与实施例1相同，仅以3-三氟甲基苯胺代替3-氟苯胺。产率：75％；淡黄色固体；1H NMR(400MHz,Chloroform-d)δ8.70(s,1H),8.02(d,J＝8.3Hz,1H),7.72(s,1H),7.66(d,J＝7.9Hz,1H),7.59–7.45(m,2H),7.22–7.12(m,4H),6.14(s,1H).13C NMR(101MHz,Chloroform-d)δ145.17,144.04,143.91,141.01,136.69,129.21,128.84,128.66,127.46,127.09,126.66,122.74,122.01,119.45,119.28,118.03.MS-ESI m/z:calcd forC16H11F3N2O:305.2722[M+H]+；found:305.0930.
实施例4：化合物A-04的合成
Figure BDA0003650581180000062
实验步骤与实施例1相同，仅以3-氯苯胺代替3-氟苯胺。产率：68％；淡黄色固体；1H NMR(400MHz,Chloroform-d)δ8.70(d,J＝2.8Hz,1H),8.03(d,J＝8.3Hz,1H),7.76(d,J＝2.7Hz,1H),7.68(dd,J＝8.1,1.6Hz,1H),7.59–7.45(m,2H),7.23(t,J＝8.1Hz,1H),7.14(s,1H),7.04–6.95(m,2H),6.19(s,1H).13C NMR(101MHz,Chloroform-d)δ145.46,144.19,143.72,136.08,135.42,130.76,129.19,128.77,127.43,127.25,126.77,121.99,119.05,117.71,115.97.MS-ESI m/z:calcd for C15H11ClN2:255.7170[M+H]+；found:255.0714.
实施例5：化合物A-05的合成
Figure BDA0003650581180000071
实验步骤与实施例1相同，仅以3-甲氧基苯胺代替3-氟苯胺。产率：81％；淡黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.62(d,J＝2.8Hz,1H),7.93(d,J＝8.2Hz,1H),7.67(d,J＝2.7Hz,1H),7.56(dd,J＝7.9,1.6Hz,1H),7.48–7.36(m,2H),7.16(t,J＝8.1Hz,1H),6.69(dd,J＝7.9,2.1Hz,1H),6.65(t,J＝2.3Hz,1H),6.51(dd,J＝8.2,2.4Hz,1H),6.05(s,1H),3.72(s,3H).13C NMR(101MHz,Chloroform-d)δ160.97,145.36,143.83,143.43,136.89,130.54,129.15,128.93,127.26,126.76,126.64,117.84,110.93,107.51,104.37,55.42.MS-ESI m/z:calcd for C16H14N2O:251.3010[M+H]+；found:251.1211.
实施例6：化合物A-06的合成
Figure BDA0003650581180000072
实验步骤与实施例1相同，仅以4-三氟甲基苯胺代替3-氟苯胺。产率：80％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.75(d,J＝2.8Hz,1H),8.05(d,J＝8.3Hz,1H),7.86(d,J＝2.7Hz,1H),7.70(dd,J＝8.0,1.5Hz,1H),7.63–7.48(m,4H),7.17(d,J＝8.3Hz,2H),6.35(s,1H).13C NMR(101MHz,Chloroform-d)δ145.97,145.86,144.67,135.26,129.31,128.67,127.74,127.57,127.12(q,J＝3.7Hz),126.89,125.88,123.23(q,J＝32.9Hz),120.88,116.29.MS-ESI m/z:calcd for C16H11F3N2:289.2732[M+H]+；found:289.0983.
实施例7：化合物A-07的合成
Figure BDA0003650581180000081
实验步骤与实施例1相同，仅以2-三氟甲基苯胺代替3-氟苯胺。产率：73％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.76(d,J＝2.7Hz,1H),8.05(d,J＝8.4Hz,1H),7.75(d,J＝2.7Hz,1H),7.70–7.62(m,2H),7.59(t,J＝7.5Hz,1H),7.53–7.42(m,2H),7.39(d,J＝8.2Hz,1H),7.07(t,J＝7.6Hz,1H),6.23(s,1H).13C NMR(101MHz,Chloroform-d)δ146.12,144.65,141.12,135.79,133.13,129.33,128.72,127.62,127.44,127.35(q,J＝5.5Hz),126.80,126.02,123.31,121.52,121.32,118.78.MS-ESI m/z:calcd forC16H11F3N2:289.2732[M+H]+；found:289.0984.
实施例8：化合物A-08的合成
Figure BDA0003650581180000082
实验步骤与实施例1相同，仅以2,4-二氯苯胺代替3-氟苯胺。产率：88％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.69(d,J＝2.7Hz,1H),7.98(d,J＝8.3Hz,1H),7.71(d,J＝2.7Hz,1H),7.62(dd,J＝8.1,1.5Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(t,J＝7.9Hz,1H),7.35(d,J＝2.4Hz,1H),7.20–7.14(m,1H),7.09(dd,J＝8.7,2.4Hz,1H),6.17(s,1H).13C NMR(101MHz,Chloroform-d)δ146.24,144.83,138.38,135.09,129.84,129.39,128.61,127.97,127.82,127.53,126.88,125.96,123.09,121.55,116.90.MS-ESI m/z:calcd for C15H10Cl2N2:290.1590[M+H]+；found:289.0331.
实施例9：化合物A-09的合成
Figure BDA0003650581180000083
实验步骤与实施例1相同，仅以2,4-二氟苯胺代替3-氟苯胺。产率：89％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.69(d,J＝2.8Hz,1H),8.02(d,J＝8.2Hz,1H),7.63(dd,J＝8.0,1.7Hz,1H),7.57–7.45(m,3H),7.37–7.30(m,1H),6.95(t,J＝9.5Hz,1H),6.88(t,J＝8.8,8.2Hz,1H),5.92(s,1H).13C NMR(101MHz,Chloroform-d)δ158.02(dd,J＝244.6,11.1Hz),154.35(dd,J＝246.4,11.9Hz),144.71,144.01,136.90,129.27,128.81,127.40,126.93,126.59,126.45(dd,J＝11.8,3.6Hz),120.87(dd,J＝9.2,2.9Hz),117.11,111.48(dd,J＝22.2,3.8Hz),104.89(dd,J＝26.4,23.5Hz).MS-ESI m/z:calcd forC15H10F2N2:257.2558[M+H]+；found:257.0921.
实施例10：化合物A-10的合成
Figure BDA0003650581180000091
实验步骤与实施例1相同，仅以2-氟苯胺代替3-氟苯胺。产率：80％；白色固体；1HNMR(400MHz,Chloroform-d)δ8.75(d,J＝2.8Hz,1H),8.03(d,J＝8.3Hz,1H),7.73(d,J＝2.7Hz,1H),7.66(d,J＝8.0Hz,1H),7.58–7.45(m,2H),7.39(t,J＝8.7,7.5Hz,1H),7.20–7.06(m,2H),7.01–6.93(m,1H),6.10(s,1H).13C NMR(101MHz,Chloroform-d)δ153.70(d,J＝242.4Hz),145.40,144.19,136.12,130.59(d,J＝11.3Hz),129.28,128.79,127.34,127.07,126.70,124.66,122.28(d,J＝7.3Hz),118.52,118.22,116.05(d,J＝19.1Hz).MS-ESI m/z:calcd for C15H11FN2:239.2654[M+H]+；found:239.1013.
实施例11：化合物A-11的合成
Figure BDA0003650581180000092
实验步骤与实施例1相同，仅以2-氯苯胺代替3-氟苯胺。产率：88％；白色固体；1HNMR(400MHz,Chloroform-d)δ8.79(d,J＝2.8Hz,1H),8.05(d,J＝8.4Hz,1H),7.80(d,J＝2.7Hz,1H),7.68(dd,J＝8.1,1.6Hz,1H),7.58(t,J＝7.5Hz,1H),7.50(t,J＝7.2Hz,1H),7.42(dd,J＝8.0,1.5Hz,1H),7.34(dd,J＝8.2,1.5Hz,1H),7.20(t,J＝8.4,7.9Hz,1H),6.92(t,J＝8.0Hz,1H),6.31(s,1H).13C NMR(101MHz,Chloroform-d)δ146.26,144.61,139.39,135.54,130.22,129.34,128.72,127.81,127.49,127.38,126.82,122.75,121.97,120.83,116.42.MS-ESI m/z:calcd for C15H11ClN2:255.7170[M+H]+；found:255.0720.
实施例12：化合物A-12的合成
Figure BDA0003650581180000101
实验步骤与实施例1相同，仅以4-甲氧基苯胺代替3-氟苯胺。产率：87％；黄色固体；1H NMR(400MHz,Chloroform-d)δ8.63(d,J＝2.8Hz,1H),7.98(d,J＝8.0Hz,1H),7.57(d,J＝8.1Hz,1H),7.50–7.39(m,3H),7.17(d,J＝8.9Hz,2H),6.93(d,J＝8.7Hz,2H),5.90(s,1H),3.83(s,3H).13C NMR(101MHz,Chloroform-d)δ156.27,144.10,143.07,139.20,134.40,129.23,129.03,127.21,126.34,126.02,123.01,115.11,114.36,55.73.MS-ESIm/z:calcd for C16H14N2O:251.3010[M+H]+；found:251.1215.
实施例13：化合物A-13的合成
Figure BDA0003650581180000102
实验步骤与实施例1相同，仅以6-甲氧基喹啉替代喹啉，以3-三氟甲基苯胺代替3-氟苯胺。产率：92％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.49(s,1H),7.84(d,J＝9.1Hz,1H),7.60(s,1H),7.34(t,J＝7.9Hz,1H),7.29(s,1H),7.23(d,J＝8.1,2.2Hz,1H),7.20–7.10(m,2H),6.86(s,1H),6.15(s,1H),3.84(s,3H).13C NMR(101MHz,Chloroform-d)δ158.71,143.10,142.62,140.36,136.35,132.41,132.09,130.59,130.29,130.00,125.45,122.74,120.77,120.05,118.43,114.41(q,J＝3.9Hz),55.67.MS-ESI m/z:calcd forC17H13F3N2O:319.2992[M+H]+；found:319.1098.
实施例14：化合物A-14的合成
Figure BDA0003650581180000111
实验步骤与实施例1相同，仅以6-氟喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：91％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.67(d,J＝2.7Hz,1H),8.01(dd,J＝9.2,5.4Hz,1H),7.65(d,J＝7.9Hz,1H),7.61(d,J＝2.7Hz,1H),7.51–7.40(m,2H),7.33–7.27(m,1H),7.27–7.21(m,1H),7.11(t,J＝7.5Hz,1H),6.22(s,1H).13C NMR(101MHz,Chloroform-d)δ161.33(d,J＝248.1Hz),144.75,141.35,140.48–140.21(m),136.91,133.38–133.06(m),131.71(d,J＝9.7Hz),129.70(d,J＝10.5Hz),127.44(q,J＝5.3Hz),125.89,123.18,122.33,119.88,118.97(d,J＝5.3Hz),117.42(d,J＝25.8Hz),109.76(d,J＝22.3Hz).MS-ESI m/z:calcd for C16H10F4N2:307.2636[M+H]+；found:307.0895.
实施例15：化合物A-15的合成
Figure BDA0003650581180000112
实验步骤与实施例1相同，仅以8-甲基喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：77％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.79(d,J＝2.7Hz,1H),7.73(d,J＝2.8Hz,1H),7.64(d,J＝8.0Hz,1H),7.53(d,J＝7.9Hz,1H),7.47–7.35(m,4H),7.06(t,J＝7.5Hz,1H),6.22(s,1H),2.81(s,3H).13C NMR(101MHz,Chloroform-d)δ144.86,143.75,141.33,137.14,135.53,133.11,128.76,128.05,127.32,126.07,124.97,123.37,122.13,121.32,119.05,118.62,18.22.MS-ESI m/z:calcd for C17H13F3N2:303.3002[M+H]+；found:303.1144.
实施例16：化合物A-16的合成
Figure BDA0003650581180000121
实验步骤与实施例1相同，仅以6-甲基喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：82％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.68(d,J＝2.7Hz,1H),7.94(d,J＝8.4Hz,1H),7.67(d,J＝2.6Hz,1H),7.63(d,J＝7.9Hz,1H),7.47–7.40(m,3H),7.36(d,J＝8.2Hz,1H),7.05(t,J＝7.6Hz,1H),6.21(s,1H),2.51(s,3H).13C NMR(101MHz,Chloroform-d)δ145.26,143.29,141.33,137.41,135.72,133.10,130.02,128.95,128.77,127.31(q,J＝5.3Hz),126.06,125.72,123.35,121.28(d,J＝3.3Hz),118.88(d,J＝29.4Hz),118.56,21.79.MS-ESI m/z:calcd for C17H13F3N2:303.3002[M+H]+；found:303.1144.
实施例17：化合物A-17的合成
Figure BDA0003650581180000122
实验步骤与实施例1相同，仅以6-甲氧基喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：84％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.59(d,J＝2.7Hz,1H),7.93(d,J＝9.2Hz,1H),7.67–7.61(m,2H),7.47–7.37(m,2H),7.23(dd,J＝9.2,2.8Hz,1H),7.07(t,J＝7.5Hz,1H),6.93(d,J＝2.8Hz,1H),6.20(s,1H),3.90(s,3H).13C NMR(101MHz,Chloroform-d)δ158.61,143.24,141.13,140.63,136.25,133.09,130.66,129.94,127.32(q,J＝5.3Hz),126.02,123.31,121.49,120.29(d,J＝7.8Hz),119.20(d,J＝29.5Hz),119.02,104.46,55.64.MS-ESI m/z:calcd for C17H13F3N2O:319.2992[M+H]+；found:319.1093.
实施例18：化合物A-18的合成
Figure BDA0003650581180000131
实验步骤与实施例1相同，仅以8-氟喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：85％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.77(d,J＝2.7Hz,1H),7.72–7.64(m,2H),7.52–7.39(m,4H),7.23(d,J＝8.3Hz,1H),7.13(t,J＝7.5Hz,1H),6.26(s,1H).13C NMR(101MHz,Chloroform-d)δ158.35(d,J＝256.5Hz),145.57,140.29(d,J＝2.1Hz),137.19,134.33(d,J＝12.2Hz),133.19,130.63(d,J＝2.1Hz),127.46(d,J＝8.1Hz),125.87,123.16,122.41,122.28,120.18(d,J＝29.6Hz),119.86,119.29(d,J＝2.8Hz),111.49(d,J＝18.9Hz).MS-ESI m/z:calcd for C16H10F4N2:307.2636[M+H]+；found:307.0892.
实施例19：化合物A-19的合成
Figure BDA0003650581180000132
实验步骤与实施例1相同，仅以6-硝基喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：88％；棕色固体；1H NMR(400MHz,Chloroform-d)δ8.86(d,J＝2.8Hz,1H),8.58(d,J＝2.5Hz,1H),8.27(dd,J＝9.2,2.5Hz,1H),8.13(d,J＝9.2Hz,1H),7.75(d,J＝2.8Hz,1H),7.72(d,J＝7.5Hz,1H),7.59–7.48(m,2H),7.23(t,J＝7.9Hz,1H),6.31(s,1H).13C NMR(101MHz,Chloroform-d)δ148.26,146.42,145.74,139.21,138.39,133.35,131.01,128.00,127.64(q,J＝5.2Hz),125.69,123.66,123.18,121.70,121.35,120.34,118.45.MS-ESI m/z:calcd for C16H10F3N3O2:334.2702[M+H]+；found:334.0839.
实施例20：化合物A-20的合成
Figure BDA0003650581180000141
实验步骤与实施例1相同，仅以8-硝基喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：83％；棕色固体；1H NMR(400MHz,Chloroform-d)δ8.84(d,J＝2.7Hz,1H),7.83(t,J＝8.6Hz,2H),7.70(d,J＝8.0Hz,1H),7.66(d,J＝2.7Hz,1H),7.58–7.46(m,3H),7.21(t,J＝7.6Hz,1H),6.29(s,1H).13C NMR(101MHz,Chloroform-d)δ148.37,146.89,139.29,138.32,134.92,133.30,130.74,130.02,127.57(q,J＝5.2Hz),126.16,125.68,123.54,122.97,121.37,121.26,117.48.MS-ESI m/z:calcd for C16H10F3N3O2:334.2702[M+H]+；found:334.0836.
实施例21：化合物A-21的合成
Figure BDA0003650581180000142
实验步骤与实施例1相同，仅以4二氟甲基苯胺代替3-氟苯胺。产率：77％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.68(d,J＝2.8Hz,1H),8.01(d,J＝8.1Hz,1H),7.66(d,J＝2.7Hz,1H),7.63(dd,J＝8.0,1.7Hz,1H),7.56–7.44(m,2H),7.19–7.10(m,4H),6.49(t,J＝74.1Hz,1H),6.12(s,1H).13C NMR(101MHz,Chloroform-d)δ146.02,144.86,143.72,139.60,137.24,129.10,128.92,127.42,126.84,126.58,121.60,120.17,117.02,116.19(t,J＝260.2Hz).MS-ESI m/z:calcd for C16H12F2N2O:287.2818[M+H]+；found:287.1025.
实施例22：化合物A-22的合成
Figure BDA0003650581180000143
实验步骤与实施例1相同，仅以3-二氟甲基苯胺代替3-氟苯胺。产率：74％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝2.8Hz,1H),8.03(d,J＝8.2Hz,1H),7.79(d,J＝2.7Hz,1H),7.67(dd,J＝8.1,1.6Hz,1H),7.59–7.46(m,2H),7.29(t,J＝8.2Hz,1H),6.98(dd,J＝8.1,2.2Hz,1H),6.94–6.90(m,1H),6.74(dd,J＝8.1,2.2Hz,1H),6.52(t,J＝73.9Hz,1H),6.24(s,1H).13C NMR(101MHz,Chloroform-d)δ152.52(t,J＝2.8Hz),145.45,144.14,144.04,136.07,130.90,129.15,128.78,127.46,127.29,126.79,119.12,115.98(t,J＝259.8Hz),114.59,112.31,108.90.MS-ESI m/z:calcd for C16H12F2N2O:287.2818[M+H]+；found:287.1026.
实施例23：化合物A-23的合成
Figure BDA0003650581180000151
实验步骤与实施例1相同，仅以3-三氟甲氧基苯胺代替3-氟苯胺。产率：79％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.73(d,J＝2.7Hz,1H),8.04(d,J＝8.3Hz,1H),7.80(d,J＝2.6Hz,1H),7.68(dd,J＝8.1,1.6Hz,1H),7.60–7.48(m,2H),7.32(t,J＝8.2Hz,1H),7.06(dd,J＝8.1,2.2Hz,1H),7.00(d,J＝2.8Hz,1H),6.87–6.81(m,1H),6.28(s,1H).13CNMR(101MHz,Chloroform-d)δ150.50,145.39,144.16,144.02,135.93,130.86,129.12,128.76,127.53,127.43,126.81,121.87,119.35,115.81,113.88,110.13.MS-ESI m/z:calcd for C16H11F3N2O:305.2722[M+H]+；found:305.0931.
实施例24：化合物A-24的合成
Figure BDA0003650581180000152
实验步骤与实施例1相同，仅以8-氟喹啉替代喹啉，以3-三氟甲氧基苯胺代替3-氟苯胺。产率：74％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.76(s,1H),7.78(s,1H),7.43(qd,J＝8.1,3.0Hz,2H),7.34(t,J＝8.0Hz,1H),7.25–7.20(m,1H),7.10(d,J＝8.1Hz,1H),7.04(s,1H),6.89(d,J＝8.1Hz,1H),6.38(s,1H).13C NMR(126MHz,Chloroform-d)δ158.26(d,J＝256.4Hz),150.46,145.14,143.26,137.19,133.85(d,J＝12.1Hz),130.95,130.68,127.53(d,J＝8.2Hz),122.33(d,J＝3.5Hz),121.60,117.52(d,J＝2.3Hz),116.57,114.55,111.30(d,J＝19.0Hz),110.90.MS-ESI m/z:calcd for C16H10F4N2:323.2626[M+H]+；found:323.0796.
实施例25：化合物A-25的合成
Figure BDA0003650581180000161
实验步骤与实施例1相同，仅以8-氟喹啉替代喹啉，以4-三氟甲基苯胺代替3-氟苯胺。产率：51％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.79(s,1H),7.86(s,1H),7.57(d,J＝7.8Hz,2H),7.49–7.42(m,2H),7.27–7.25(m,1H),7.23(d,J＝9.0Hz,2H),6.51(s,1H).13C NMR(126MHz,Chloroform-d)δ158.24(d,J＝256.6Hz),145.59,145.06,136.58,134.13(d,J＝12.2Hz),130.58,127.63(d,J＝8.3Hz),127.16(q,J＝3.6Hz),125.50,122.41(d,J＝4.4Hz),118.94(d,J＝2.4Hz),117.07,111.63(d,J＝18.9Hz).MS-ESI m/z:calcd for C16H10F4N2:307.2636[M+H]+；found:307.0891.
实施例26：化合物A-26的合成
Figure BDA0003650581180000162
实验步骤与实施例1相同，仅以8-氟喹啉替代喹啉，以2-甲基苯胺代替3-氟苯胺。产率：76％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.72(d,J＝2.7Hz,1H),7.36–7.33(m,3H),7.30(t,J＝8.6Hz,2H),7.23(t,J＝7.2Hz,1H),7.17–7.12(m,1H),7.10(t,J＝8.1,7.7Hz,1H),5.82(s,1H),2.30(s,3H).13C NMR(126MHz,Chloroform-d)δ158.36(d,J＝255.8Hz),144.41,139.44,139.15,133.08(d,J＝12.1Hz),131.56,131.08(d,J＝2.0Hz),130.95,127.26,127.15(d,J＝8.4Hz),124.53,121.99,121.53,114.75(d,J＝2.7Hz),110.27(d,J＝18.7Hz),18.07.MS-ESI m/z:calcd for C16H13FN2:253.2924[M+H]+；found:253.1163.
实施例27：化合物A-27的合成
Figure BDA0003650581180000171
实验步骤与实施例1相同，仅以8-氟喹啉替代喹啉，以2-甲氧基苯胺代替3-氟苯胺。产率：74％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.77(d,J＝2.6Hz,1H),7.78(dd,J＝2.7,1.6Hz,1H),7.44–7.40(m,2H),7.40–7.36(m,1H),7.20–7.15(m,1H),7.04–6.95(m,3H),6.48(s,1H),3.92(s,3H).13C NMR(126MHz,Chloroform-d)δ158.19(d,J＝256.0Hz),149.27,145.32,137.79,133.21(d,J＝12.0Hz),130.83(d,J＝2.3Hz),130.77,127.07(d,J＝8.4Hz),122.19,122.04(d,J＝4.5Hz),120.89,116.38,115.77(d,J＝2.6Hz),110.98,110.49(d,J＝19.0Hz),55.69.MS-ESI m/z:calcd forC16H13FN2O:269.2914[M+H]+；found:269.1118.
实施例28：化合物A-28的合成
Figure BDA0003650581180000172
实验步骤与实施例1相同，仅以8-氟喹啉替代喹啉，以2-氟基苯胺代替3-氟苯胺。产率：82％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.78(d,J＝2.7Hz,1H),7.70(s,1H),7.46–7.38(m,3H),7.24–7.11(m,3H),7.05–6.98(m,1H),6.17(s,1H).13C NMR(126MHz,Chloroform-d)δ158.20(d,J＝256.1Hz),153.96(d,J＝243.1Hz),144.84,137.28,133.68,130.62(d,J＝1.8Hz),129.60(d,J＝11.2Hz),127.26(d,J＝8.4Hz),124.64(d,J＝3.7Hz),123.05(d,J＝7.3Hz),122.12(d,J＝4.4Hz),119.11,116.70(d,J＝2.6Hz),116.14(d,J＝19.3Hz),110.92(d,J＝19.0Hz).MS-ESI m/z:calcd for C15H10F2N2:257.2558[M+H]+；found:257.0917.
实施例29：化合物A-29的合成
Figure BDA0003650581180000181
实验步骤与实施例1相同，仅以8-氟喹啉替代喹啉，以2-氯苯胺代替3-氟苯胺。产率：78％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.75(d,J＝2.7Hz,1H),7.72–7.68(m,1H),7.39–7.34(m,3H),7.32(dd,J＝8.2,1.5Hz,1H),7.20–7.14(m,2H),6.90(t,J＝7.7Hz,1H),6.31(s,1H).13C NMR(126MHz,Chloroform-d)δ157.15(d,J＝256.5Hz),144.57,137.44,135.68,132.99(d,J＝12.0Hz),129.49,129.21,126.70,126.28(d,J＝8.3Hz),122.39,121.62,121.18(d,J＝4.5Hz),117.78(d,J＝2.8Hz),116.20,110.27(d,J＝18.8Hz).MS-ESI m/z:calcd for C15H10ClFN2:273.7074[M+H]+；found:273.0622.
实施例30：化合物A-30的合成
Figure BDA0003650581180000182
实验步骤与实施例1相同，仅以7,8-二氟喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：80％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.74(d,J＝2.6Hz,1H),7.62(s,1H),7.60(d,J＝8.1Hz,1H),7.42(t,J＝7.8Hz,1H),7.36–7.28(m,3H),7.07(t,J＝7.6Hz,1H),6.17(s,1H).13C NMR(126MHz,Chloroform-d)δ147.03(dd,J＝248.2,10.9Hz),145.44,143.92(dd,J＝256.9,12.3Hz),139.11,135.55,133.96(d,J＝8.7Hz),132.08,126.34(q,J＝5.2Hz),125.46,124.42,122.26,121.33,120.83(dd,J＝7.9,5.7Hz),119.05(d,J＝29.5Hz),118.61(d,J＝4.7Hz),117.31(d,J＝21.0Hz).MS-ESI m/z:calcd forC16H9F5N2:325.2540[M+H]+；found:325.0802.
实施例31：化合物A-31的合成
Figure BDA0003650581180000191
实验步骤与实施例1相同，仅以6,8-二氟喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：83％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.70(d,J＝2.6Hz,1H),7.69(dd,J＝8.0,1.4Hz,1H),7.58(dd,J＝2.6,1.4Hz,1H),7.55–7.50(m,1H),7.48(d,J＝8.1Hz,1H),7.19(t,J＝7.5Hz,1H),7.09–7.02(m,2H),6.28(s,1H).13C NMR(126MHz,Chloroform-d)δ160.56(dd,J＝212.7,12.9Hz),159.53–157.53(m),144.13,139.40,138.31,133.12,131.09(d,J＝11.6Hz),130.48(dd,J＝11.9,3.3Hz),127.41(q,J＝5.2Hz),125.33,123.09,120.87,117.11(dd,J＝5.4,3.3Hz),105.46(dd,J＝22.1,4.7Hz),102.84(d,J＝22.8Hz),102.60(d,J＝22.6Hz).MS-ESI m/z:calcd for C16H9F5N2:325.2540[M+H]+；found:325.0801.
实施例32：化合物A-32的合成
Figure BDA0003650581180000192
实验步骤与实施例1相同，仅以8-氯喹啉替代喹啉，以2-三氟甲基苯胺代替3-氟苯胺。产率：77％；白色固体；1H NMR(500MHz,Chloroform-d)δ8.86(d,J＝2.6Hz,1H),7.69(d,J＝2.5Hz,1H),7.67(d,J＝7.4Hz,2H),7.57(d,J＝8.0Hz,1H),7.48(t,J＝7.8Hz,1H),7.45–7.38(m,2H),7.13(t,J＝7.5Hz,1H),6.27(s,1H).13C NMR(126MHz,Chloroform-d)δ144.69,139.19,139.08,135.98,132.31,132.04,129.14,126.35,126.32,126.27,124.70,124.43,122.26,121.34,119.22,118.82.MS-ESI m/z:calcd for C16H10ClF3N2:323.7152[M+H]+；found:323.0549.
实施例33：化合物H-01的合成
Figure BDA0003650581180000201
实验步骤与实施例1相同，仅以3-氨基吡啶代替3-氟苯胺。产率：73％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝2.8Hz,1H),8.52(d,J＝2.8Hz,1H),8.26(d,J＝4.7Hz,1H),8.01(d,J＝8.3Hz,1H),7.74(d,J＝2.7Hz,1H),7.63(d,J＝7.9Hz,1H),7.57–7.44(m,3H),7.26–7.22(m,1H),6.80(s,1H).13C NMR(101MHz,Chloroform-d)δ145.13,144.12,143.08,140.81,139.08,136.25,129.17,128.74,127.48,127.19,126.69,124.43,124.12,118.05.MS-ESI m/z:calcd for C14H11N3:222.2630[M+H]+；found:222.1049.
实施例34：化合物H-02的合成
Figure BDA0003650581180000202
本发明所述化合物H-02的合成方法按如下反应式进行：
Figure BDA0003650581180000203
将5-溴-1-甲基-1H-吡咯[2,3-b]吡啶(1mmol)、3-三氟甲基苯胺(1.5mmol)、醋酸钯(0.05mmol)、Xantphos(0.05mmol)、碳酸铯(2mmol)依次加入100mL封管中，将封管中的空气置换为氩气后，加入二氧六环(10mL),100℃反应12h。反应结束后，用硅藻土进行抽滤，收集滤液，减压蒸馏除去溶剂，用饱和NaCl溶液与二氯甲烷进行萃取(×3)，收集有机相，并进行柱层析纯化，最终得到化合物H-02。
产率：65％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.19(s,1H),7.73(s,1H),7.25–7.12(m,2H),7.01–6.91(m,3H),6.36(dd,J＝3.4,1.5Hz,1H),5.93(s,1H),3.86(s,3H).13C NMR(101MHz,Chloroform-d)δ146.77,144.83,139.02,130.98,130.71,129.97,125.64,124.33,122.93,121.48,117.73,115.89(q,J＝3.5Hz),111.10,99.56,31.92.MS-ESI m/z:calcd for C15H12F3N3:292.2772[M+H]+；found:292.1088.
实施例35：化合物H-03的合成
Figure BDA0003650581180000211
实验步骤与实施例34相同，仅以5-溴-1-甲基-1H-吡唑并[3,4-b]吡啶代替5-溴-1-甲基-1H-吡咯[2,3-b]吡啶。产率：72％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.44(d,J＝2.4Hz,1H),7.95(s,1H),7.85(d,J＝2.4Hz,1H),7.32(t,J＝7.9Hz,1H),7.13–7.08(m,2H),7.03(d,J＝8.5Hz,1H),4.17(s,3H).13C NMR(101MHz,Chloroform-d)δ148.10,146.15,145.80,131.98,131.34,130.17,125.51,122.80,122.23,118.18,116.73(q,J＝3.8Hz),115.81,111.71(q,J＝3.8Hz),34.30.MS-ESI m/z:calcd for C14H11F3N4:293.2652[M+H]+；found:293.1040.
实施例36：化合物H-04的合成
Figure BDA0003650581180000212
实验步骤与实施例34相同，仅以2-溴喹喔啉代替5-溴-1-甲基-1H-吡咯[2,3-b]吡啶。产率：40％；黄色固体；1H NMR(400MHz,Chloroform-d)δ8.43(s,1H),8.21(s,1H),7.95(d,J＝8.2Hz,2H),7.85(d,J＝8.4Hz,1H),7.67(t,J＝8.4Hz,1H),7.50(q,J＝8.4,7.8Hz,2H),7.35(d,J＝7.8Hz,1H),7.09(s,1H).13C NMR(101MHz,Chloroform-d)δ148.78,140.89,140.06,138.56,138.16,130.69,129.78,128.98,127.34,126.32,122.27,119.73(q,J＝3.8Hz),116.06(q,J＝3.9Hz).MS-ESI m/z:calcd forC15H10F3N3:290.2612[M+H]+；found:290.0933.
实施例37：化合物H-05的合成
Figure BDA0003650581180000221
实验步骤与实施例34相同，仅以6-溴-3-甲基-3H-咪唑并[4,5-b]吡啶代替5-溴-1-甲基-1H-吡咯[2,3-b]吡啶。产率：52％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.32(s,1H),8.10(s,1H),7.90(s,1H),7.31(t,J＝7.9Hz,1H),7.15–7.04(m,3H),6.09(s,1H),3.93(s,3H).13C NMR(101MHz,Chloroform-d)δ145.58,145.31,140.58,135.35,134.14,130.09,120.73,118.29,116.69(q,J＝3.7Hz),111.83(q,J＝4.0,3.5Hz),30.11.MS-ESIm/z:calcd for C14H11F3N4:293.2652[M+H]+；found:293.1041.
实施例38：化合物H-06的合成
Figure BDA0003650581180000222
实验步骤与实施例1相同，仅以2-氨基嘧啶代替3-氟苯胺。产率：78％；白色固体；1H NMR(400MHz,Chloroform-d)δ8.88(d,J＝2.7Hz,1H),8.84(d,J＝2.6Hz,1H),8.52(d,J＝4.8Hz,2H),8.23(s,1H),8.04(d,J＝8.3Hz,1H),7.81(d,J＝7.5Hz,1H),7.58(t,J＝7.3Hz,1H),7.51(t,J＝7.8,7.0Hz,1H),6.82(t,J＝4.8Hz,1H).13C NMR(101MHz,Chloroform-d)δ160.20,158.22,144.93,144.47,133.33,129.14,128.67,127.56,127.49,127.15,121.88,113.49.MS-ESI m/z:calcd for C13H10N4:223.2510[M+H]+；found:223.1006.
实施例39：化合物N-01的合成
Figure BDA0003650581180000223
本发明所述化合物N-01的合成方法按如下反应式进行：
Figure BDA0003650581180000224
将N-(3-(三氟甲基)苯基)喹啉-3-胺(1mmol)置于含有搅拌子的100mL圆底烧瓶中，加入N,N-二甲基甲酰胺(DMF)(10mL)搅拌溶解，在冰浴条件下，将NaH(3mmol)分批加入圆底烧瓶，反应30min，随后缓慢滴加碘甲烷(3mmol)，常温反应4h。反应结束后，通过减压蒸馏除去DMF，用饱和NaCl溶液与二氯甲烷进行萃取(×3)，收集有机相，并进行柱层析纯化，最终得到化合物N-01。
产率：83％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.74(d,J＝2.7Hz,1H),8.05(d,J＝8.4Hz,1H),7.74–7.69(m,2H),7.61(t,J＝7.2Hz,1H),7.52(t,J＝7.5Hz,1H),7.38(t,J＝8.0Hz,1H),7.28(t,J＝1.8Hz,1H),7.24(d,J＝7.8Hz,1H),7.19(d,J＝8.7Hz,1H),3.48(s,3H).13C NMR(101MHz,Chloroform-d)δ148.75,147.65,144.50,141.69,131.99,130.08,129.31,128.90,127.88,127.35,127.00,125.48,124.18,122.68,118.31(q,J＝3.8Hz),115.91(q,J＝3.8Hz),40.67.MS-ESI m/z:calcd for C17H13F3N2:303.3002[M+H]+；found:303.1136.
实施例40：化合物N-02的合成
Figure BDA0003650581180000231
实验步骤与实施例39相同，仅以1-溴乙烷代替碘甲烷。产率：75％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.70(d,J＝2.7Hz,1H),8.05(d,J＝8.4Hz,1H),7.74–7.68(m,2H),7.61(t,J＝7.4Hz,1H),7.52(t,J＝7.4Hz,1H),7.37(t,J＝7.9Hz,1H),7.25–7.18(m,2H),7.14(dd,J＝8.3,2.4Hz,1H),3.94(q,J＝7.1Hz,2H),1.32(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ148.23,147.64,144.56,140.41,132.35,132.04,130.14,129.30,128.97,127.86,127.30,126.99,124.91,122.87,118.01(q,J＝3.8Hz),116.00(q,J＝3.8Hz),47.11,12.72.MS-ESI m/z:calcd for C18H15F3N2:317.3272[M+H]+；found:317.1295.
实施例41：化合物N-03的合成
Figure BDA0003650581180000241
实验步骤与实施例39相同，仅以1-溴丙烷代替碘甲烷。产率：77％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.70(d,J＝2.7Hz,1H),8.04(d,J＝8.3Hz,1H),7.73–7.67(m,2H),7.60(t,J＝7.4Hz,1H),7.52(t,J＝7.6Hz,1H),7.36(t,J＝7.9Hz,1H),7.24–7.18(m,2H),7.14(dd,J＝8.3,2.3Hz,1H),3.81(t,J＝7.6Hz,2H),1.76(h,J＝7.4Hz,3H),1.00(t,J＝7.4Hz,3H).13C NMR(101MHz,Chloroform-d)δ148.24,148.06,144.52,140.77,132.32,132.01,130.12,129.30,128.95,127.85,127.30,126.98,124.92,122.91,118.01(q,J＝3.8Hz),116.10(q,J＝3.7Hz),54.48,20.69,11.52.MS-ESI m/z:calcd forC19H17F3N2:331.3542[M+H]+；found:331.1452.
实施例42：化合物N-04的合成
Figure BDA0003650581180000242
实验步骤与实施例39相同，仅以溴甲基环丙烷代替碘甲烷。产率：90％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝2.7Hz,1H),8.06(d,J＝8.4Hz,1H),7.77(d,J＝2.6Hz,1H),7.72(d,J＝8.1Hz,1H),7.62(t,J＝8.5,7.4Hz,1H),7.52(t,J＝8.5Hz,1H),7.36(t,J＝7.9Hz,1H),7.21(d,J＝7.8Hz,1H),7.14(dd,J＝8.2,2.3Hz,1H),3.71(d,J＝6.5Hz,2H),1.24–1.15(m,1H),0.58–0.49(m,2H),0.17–0.12(m,2H).13C NMR(101MHz,Chloroform-d)δ148.65,148.32,144.66,141.00,132.29,131.97,130.08,129.29,128.96,128.01,127.29,127.08,125.94,123.00,117.99(q,J＝3.7Hz),116.15(q,J＝3.5Hz),57.18,9.65,4.35.MS-ESI m/z:calcd for C20H17F3N2:343.3652[M+H]+；found:343.1453.
实施例43：化合物N-05的合成
Figure BDA0003650581180000251
实验步骤与实施例39相同，仅以3-溴丙烯代替碘甲烷。产率：88％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.75(s,1H),8.05(d,J＝8.4Hz,1H),7.76–7.68(m,2H),7.61(t,J＝7.0Hz,1H),7.51(t,J＝7.8,7.0Hz,1H),7.37(t,J＝7.9Hz,1H),7.27(s,1H),7.24–7.16(m,2H),6.03–5.92(m,1H),5.33(d,J＝17.8Hz,1H),5.26(d,J＝11.6Hz,1H),4.51(d,J＝5.2Hz,2H).13C NMR(101MHz,Chloroform-d)δ147.75,144.55,140.57,132.93,132.32,132.00,130.10,129.27,128.89,127.96,127.34,127.04,125.47,124.92,122.72,118.25(q,J＝3.7Hz),117.82,116.02(q,J＝3.8Hz),55.16.MS-ESI m/z:calcd forC19H15F3N2:329.3382[M+H]+；found:329.1294.
实施例44：化合物M-01的合成
Figure BDA0003650581180000252
本发明所述化合物M-01的合成方法按如下反应式进行：
Figure BDA0003650581180000253
将3-碘喹啉(1mmol)、磷酸钾(2mmol)、2-吡啶甲酸(0.2mmol)、3-F苯酚(1.2mmol)、碘化亚铜(0.1mmol)依次加入含有搅拌子的100mL封管中，将封管中的空气置换为氩气后，加入二甲基亚砜(10mL),80℃反应24h。反应结束后，加入大量饱和NaCl溶液稀释反应液，用乙酸乙酯萃取(×3)，收集有机相，并进行柱层析纯化，最终得到化合物M-01。
实施例45：化合物M-02的合成
Figure BDA0003650581180000261
实验步骤与实施例44相同，仅以3,4-二氟苯胺代替3-氟苯胺。产率：53％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.78(d,J＝2.8Hz,1H),8.11(d,J＝8.4Hz,1H),7.74–7.63(m,2H),7.58–7.51(m,2H),7.23–7.15(m,1H),6.99–6.90(m,1H),6.86–6.78(m,1H).13C NMR(101MHz,Chloroform-d)δ152.43(dd,J＝8.1,2.9Hz),150.86(dd,J＝250.8,14.1Hz),150.67,147.38(dd,J＝245.1,12.6Hz),145.11,144.91,129.42,128.56,128.48,127.68,127.25,120.79,118.13(dd,J＝18.8,1.3Hz),114.92(dd,J＝6.0,3.7Hz),109.12(d,J＝19.9Hz).MS-ESI m/z:calcd for C15H9F2NO:258.2398[M+H]+；found:258.0757.
实施例46：化合物M-03的合成
Figure BDA0003650581180000262
实验步骤与实施例44相同，仅以4-叔丁基苯胺代替3-氟苯胺。产率：49％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.82(d,J＝2.8Hz,1H),8.10(d,J＝8.4Hz,1H),7.69–7.58(m,2H),7.54–7.47(m,2H),7.42(d,J＝9.6Hz,2H),7.03(d,J＝8.2Hz,2H),1.36(s,9H).13C NMR(101MHz,Chloroform-d)δ153.86,151.58,147.46,145.37,144.74,129.40,128.77,127.82,127.30,127.14,127.08,119.78,118.96,34.59,31.63.MS-ESI m/z:calcdfor C19H19NO:278.3670[M+H]+；found:278.1575.
实施例47：化合物M-04的合成
Figure BDA0003650581180000263
实验步骤与实施例44相同，仅以4-甲基苯胺代替3-氟苯胺。产率：54％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.82(d,J＝2.8Hz,1H),8.11(d,J＝8.4Hz,1H),7.68–7.58(m,2H),7.54–7.47(m,2H),7.22(d,J＝8.1Hz,2H),7.03–6.99(m,2H),2.39(s,3H).13C NMR(101MHz,Chloroform-d)δ153.79,151.86,145.02,134.31,130.77,130.14,129.15,128.79,127.91,127.41,127.12,119.59,115.41,20.93.MS-ESI m/z:calcd forC16H13NO:236.2860[M+H]+；found:236.1103.
实施例48：化合物M-05的合成
Figure BDA0003650581180000271
实验步骤与实施例44相同，仅以3,4-二甲氧基苯胺代替3-氟苯胺。产率：66％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.81(d,J＝2.8Hz,1H),8.08(d,J＝8.4Hz,1H),7.68–7.58(m,2H),7.54–7.46(m,1H),7.42(d,J＝2.8Hz,1H),6.88(d,J＝8.7Hz,1H),6.71(d,J＝2.7Hz,1H),6.65(dd,J＝8.6,2.7Hz,1H),3.91(s,3H),3.85(s,3H).13C NMR(101MHz,Chloroform-d)δ152.26,150.32,149.56,146.31,144.84,144.58,129.37,128.73,127.71,127.34,127.08,118.71,111.98,111.24,104.64,56.43,56.17.MS-ESI m/z:calcd for C17H15NO3:282.3110[M+H]+；found:282.1164.
实施例49：化合物M-06的合成
Figure BDA0003650581180000272
实验步骤与实施例44相同，仅以3-碘-6-甲氧基喹啉代替3-碘喹啉。产率：53％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.62(d,J＝2.7Hz,1H),7.99(d,J＝9.1Hz,1H),7.51(d,J＝2.7Hz,1H),7.39–7.28(m,2H),6.97(s,1H),6.92–6.84(m,2H),6.81(dd,J＝10.0,2.5Hz,1H),3.90(s,3H).13C NMR(101MHz,Chloroform-d)δ163.72(d,J＝247.7Hz),158.65,158.05(d,J＝10.6Hz),150.79,142.48,141.35,131.00(d,J＝9.6Hz),130.86,129.96,121.18,120.64,114.51(d,J＝3.2Hz),111.08(d,J＝21.2Hz),106.80(d,J＝24.5Hz),104.81,55.69.MS-ESI m/z:calcd for C16H12FNO2:270.2754[M+H]+；found:270.0959.
实施例50：化合物M-07的合成
Figure BDA0003650581180000281
实验步骤与实施例44相同，仅以3-碘-6-甲基喹啉代替3-碘喹啉。产率：48％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝2.7Hz,1H),8.01(d,J＝9.0Hz,1H),7.56(d,J＝2.7Hz,1H),7.50(dd,J＝6.6,2.2Hz,2H),7.37–7.29(m,1H),6.92–6.84(m,2H),6.80(d,J＝8.9Hz,1H),2.53(s,3H).13C NMR(101MHz,Chloroform-d)δ163.72(d,J＝247.8Hz),158.07(d,J＝10.5Hz),150.34,144.19,143.67,137.72,131.02(d,J＝9.7Hz),130.91,128.87,128.76,126.19,121.38,114.37(d,J＝3.2Hz),111.08(d,J＝21.2Hz),106.69(d,J＝24.6Hz),21.76.MS-ESI m/z:calcd for C16H12FNO:254.2764[M+H]+；found:254.1005.
实施例51：化合物M-08的合成
Figure BDA0003650581180000282
实验步骤与实施例44相同，仅以3-碘-8-氟喹啉代替3-碘喹啉。产率：44％；黄色油状液体；1H NMR(500MHz,Chloroform-d)δ8.85(d,J＝2.7Hz,1H),7.61(dd,J＝2.7,1.5Hz,1H),7.52–7.47(m,2H),7.41–7.32(m,2H),6.93(t,J＝8.2Hz,1H),6.89(dd,J＝8.2,2.3Hz,1H),6.84(d,J＝9.7Hz,1H).13C NMR(126MHz,Chloroform-d)δ163.64(d,J＝248.7Hz),158.16(d,J＝243.4Hz),151.35,145.11,131.11(d,J＝9.8Hz),130.43(d,J＝1.5Hz),127.70(d,J＝8.2Hz),122.75(d,J＝4.6Hz),120.60(d,J＝2.2Hz),114.73(d,J＝3.0Hz),112.50(d,J＝19.1Hz),111.61(d,J＝21.1Hz),111.23(d,J＝2.8Hz),107.12(d,J＝24.7Hz),103.26(d,J＝24.5Hz).MS-ESI m/z:calcd for C15H9F2NO:258.2398[M+H]+；found:258.0756.
实施例52：化合物L-01的合成
Figure BDA0003650581180000291
本发明所述化合物L-01的合成方法按如下反应式进行：
Figure BDA0003650581180000292
将3-碘-8-氟喹啉(1mmol)、碳酸钾(2mmol)、乙二醇(2mmol)、碘化亚铜(0.05mmol)、4-氟硫酚(1.5mmol)依次加入含有搅拌子的100mL圆底烧瓶中，加入异丙醇(10mL)溶解，在氩气保护下，80℃回流反应24h。反应结束后，减压蒸馏除去溶剂，用饱和NaCl溶液与二氯甲烷萃取(×3)，收集有机相，经柱层析纯化，最终得到产物L-01。
产率：72％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.78(d,J＝2.3Hz,1H),7.89(s,1H),7.50–7.47(m,2H),7.47–7.45(m,2H),7.38–7.32(m,1H),7.10(t,J＝8.6Hz,2H).13C NMR(101MHz,Chloroform-d)δ163.16(d,J＝249.8Hz),158.19(d,J＝257.4Hz),151.00,136.60(d,J＝12.1Hz),135.31(d,J＝8.4Hz),134.52(d,J＝2.8Hz),133.10,129.93(d,J＝2.0Hz),127.80(d,J＝3.4Hz),127.50(d,J＝8.1Hz),122.83(d,J＝4.7Hz),117.16(d,J＝22.1Hz),113.63(d,J＝18.9Hz).MS-ESI m/z:calcd forC15H9F2NS:274.3008[M+H]+；found:274.0601.
实施例53：化合物L-02的合成
Figure BDA0003650581180000293
实验步骤与实施例52相同，仅以3-碘-6-氟喹啉代替3-碘-8-氟喹啉。产率：88％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.69(d,J＝2.3Hz,1H),8.05(dd,J＝9.2,5.3Hz,1H),7.82(d,J＝2.4Hz,1H),7.51–7.39(m,3H),7.31–7.25(m,1H),7.10(t,J＝8.5Hz,2H).13C NMR(101MHz,Chloroform-d)δ163.35(d,J＝209.5Hz),160.86(d,J＝209.2Hz),150.14,143.56,135.29(d,J＝8.4Hz),134.18(d,J＝5.4Hz),132.77,131.93(d,J＝9.4Hz),129.07(d,J＝10.2Hz),127.91(d,J＝3.5Hz),119.66(d,J＝25.8Hz),117.15(d,J＝22.1Hz),110.28(d,J＝22.1Hz).MS-ESI m/z:calcd for C15H9F2NS:274.3008[M+H]+；found:274.0536.
实施例54：化合物L-03的合成
Figure BDA0003650581180000301
实验步骤与实施例52相同，仅以3-碘-8-硝基喹啉代替3-碘-8-氟喹啉。产率：78％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.82(d,J＝2.3Hz,1H),7.97(d,J＝7.5Hz,1H),7.91–7.84(m,2H),7.62–7.50(m,3H),7.14(t,J＝8.5Hz,2H).13C NMR(101MHz,Chloroform-d)δ163.52(d,J＝250.7Hz),152.40,148.35,137.47,136.27(d,J＝8.5Hz),135.02,133.30,131.26,129.10,126.48(d,J＝3.5Hz),126.31,123.45,117.44(d,J＝22.2Hz).MS-ESI m/z:calcd for C15H9FN2O2S:301.3074[M+H]+；found:301.0475.
实施例55：化合物L-04的合成
Figure BDA0003650581180000302
实验步骤与实施例52相同，仅以3-碘-6-甲基喹啉代替3-碘-8-氟喹啉。产率：63％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.70(d,J＝2.2Hz,1H),7.96(d,J＝8.6Hz,1H),7.90(d,J＝2.3Hz,1H),7.51(dd,J＝8.5,2.0Hz,1H),7.47–7.38(m,3H),7.05(dd,J＝9.6,7.6Hz,2H),2.51(s,3H).13C NMR(101MHz,Chloroform-d)δ162.80(d,J＝248.8Hz),150.64,145.23,137.58,135.82,134.34(d,J＝8.3Hz),132.06,130.66,129.19(d,J＝3.3Hz),129.01,128.38,126.17,116.90(d,J＝22.1Hz),21.73.MS-ESI m/z:calcdfor C16H12FNS:270.3374[M+H]+；found:270.0779.
实施例56：化合物L-05的合成
Figure BDA0003650581180000311
实验步骤与实施例52相同，仅以3-碘-6-甲氧基喹啉代替3-碘-8-氟喹啉。产率：61％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.61(d,J＝2.2Hz,1H),7.95(d,J＝9.2Hz,1H),7.85(d,J＝2.3Hz,1H),7.47–7.41(m,2H),7.32(dd,J＝9.2,2.8Hz,1H),7.07(t,J＝8.6Hz,2H),6.93(d,J＝2.8Hz,1H),3.90(s,3H).13C NMR(101MHz,Chloroform-d)δ162.86(d,J＝248.9Hz),158.54,148.78,142.74,134.85,134.58(d,J＝8.3Hz),131.33,130.76,129.50,128.98(d,J＝3.3Hz),122.49,116.93(d,J＝22.1Hz),104.70,55.71.MS-ESI m/z:calcd for C16H12FNOS:286.3364[M+H]+；found:286.0731.
实施例57：化合物L-06的合成
Figure BDA0003650581180000312
实验步骤与实施例52相同，仅以3-碘-6-硝基喹啉代替3-碘-8-氟喹啉。产率：62％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.86(d,J＝2.4Hz,1H),8.59(d,J＝2.5Hz,1H),8.39(dd,J＝9.2,2.6Hz,1H),8.18(d,J＝9.2Hz,1H),7.90(d,J＝2.3Hz,1H),7.60–7.51(m,2H),7.16(t,J＝8.6Hz,2H).13C NMR(101MHz,Chloroform-d)δ163.61(d,J＝251.0Hz),153.37,148.04,146.24,136.33(d,J＝8.6Hz),135.37,134.54,131.25,127.32,126.27(d,J＝3.5Hz),123.69,122.57,117.56(d,J＝22.2Hz).MS-ESI m/z:calcd forC15H9FN2O2S:301.3074[M+H]+；found:301.0475.
实施例58：化合物L-07的合成
Figure BDA0003650581180000313
实验步骤与实施例52相同，仅以3-碘喹啉代替3-碘-8-氟喹啉，以4-甲氧基硫酚代替4-氟硫酚。产率：82％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.73(d,J＝2.3Hz,1H),8.04(d,J＝8.6Hz,1H),7.82(d,J＝2.3Hz,1H),7.67–7.60(m,2H),7.53–7.44(m,3H),6.96–6.89(m,2H),3.83(s,3H).13C NMR(101MHz,Chloroform-d)δ160.37,150.62,146.29,135.55,134.03,132.86,129.36,129.14,128.39,127.30,127.14,123.03,115.48,55.56.MS-ESI m/z:calcd for C16H13NOS:268.3460[M+H]+；found:268.0823.
实施例59：化合物L-08的合成
Figure BDA0003650581180000321
实验步骤与实施例52相同，仅以3-碘喹啉代替3-碘-8-氟喹啉，以3-氟硫酚代替4-氟硫酚。产率：61％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.84(d,J＝2.3Hz,1H),8.19(d,J＝2.3Hz,1H),8.11(d,J＝8.4Hz,1H),7.78–7.70(m,2H),7.60–7.53(m,1H),7.30–7.23(m,1H),7.09(d,J＝7.9Hz,1H),7.00(d,J＝9.8Hz,1H),6.94(t,J＝8.8,8.4Hz,1H).13C NMR(101MHz,Chloroform-d)δ163.16(d,J＝249.5Hz),152.95,147.12,139.10,137.67(d,J＝7.8Hz),130.82(d,J＝8.5Hz),130.27,129.51,128.28,127.60(d,J＝5.1Hz),125.83(d,J＝3.0Hz),117.25,117.02,114.58,114.37.MS-ESI m/z:calcd forC15H10FNS:256.3104[M+H]+；found:256.0622.
实施例60：化合物L-09的合成
Figure BDA0003650581180000322
实验步骤与实施例52相同，仅以3-碘喹啉代替3-碘-8-氟喹啉，以2-氟硫酚代替4-氟硫酚。产率：81％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.82(d,J＝2.3Hz,1H),8.12–8.06(m,2H),7.74–7.66(m,2H),7.55(t,J＝8.4,7.4Hz,1H),7.38–7.29(m,2H),7.17–7.07(m,2H).13C NMR(101MHz,Chloroform-d)δ161.57(d,J＝247.9Hz),152.00,146.86,137.45,133.99,130.37(d,J＝7.9Hz),129.91,129.45,128.63,128.31,127.47(d,J＝7.1Hz),125.14(d,J＝3.8Hz),121.40(d,J＝17.6Hz),116.55,116.33.MS-ESI m/z:calcd for C15H10FNS:256.3104[M+H]+；found:256.0619.
实施例61：化合物L-10的合成
Figure BDA0003650581180000331
实验步骤与实施例52相同，仅以3-碘喹啉代替3-碘-8-氟喹啉，以4-甲基硫酚代替4-氟硫酚。产率：70％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.78(d,J＝2.3Hz,1H),8.06(d,J＝8.5Hz,1H),7.96(d,J＝2.3Hz,1H),7.67(t,J＝7.6Hz,2H),7.52(td,J＝7.4,7.0,1.2Hz,1H),7.35(d,J＝7.9Hz,2H),7.17(d,J＝7.8Hz,2H),2.36(s,3H).13C NMR(101MHz,Chloroform-d)δ151.58,146.50,138.48,135.80,132.54,131.43,130.53,130.00,129.43,129.37,128.37,127.34,127.26,21.30.MS-ESI m/z:calcd for C16H13NS:252.3470[M+H]+；found:252.0871.
实施例62：化合物L-11的合成
Figure BDA0003650581180000332
实验步骤与实施例52相同，仅以3-碘喹啉代替3-碘-8-氟喹啉，以4-氯硫酚代替4-氟硫酚。产率：72％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.81(d,J＝2.2Hz,1H),8.12–8.07(m,2H),7.72(t,J＝7.8Hz,2H),7.59–7.54(m,1H),7.31(s,4H).13C NMR(101MHz,Chloroform-d)δ152.23,146.87,137.74,134.00,133.23,132.53,130.04,129.83,129.50,129.46,128.32,127.61,127.44.MS-ESI m/z:calcd for C15H10ClNS:272.7620[M+H]+；found:272.0324.
实施例63：化合物L-12的合成
Figure BDA0003650581180000333
实验步骤与实施例52相同，仅以3-碘喹啉代替3-碘-8-氟喹啉。产率：63％；黄色油状液体；1H NMR(400MHz,Chloroform-d)δ8.77(d,J＝2.3Hz,1H),8.07(d,J＝8.6Hz,1H),7.98(d,J＝2.3Hz,1H),7.68(dd,J＝8.2,6.4Hz,2H),7.57–7.51(m,1H),7.48–7.40(m,2H),7.07(t,J＝8.6Hz,2H).13C NMR(101MHz,Chloroform-d)δ162.87(d,J＝248.9Hz),151.51,146.64,136.17,134.51(d,J＝8.3Hz),130.88,129.71,129.43,128.96(d,J＝3.4Hz),128.31,127.41(d,J＝20.8Hz),117.07,116.85.MS-ESI m/z:calcd for C15H10FNS:256.0518[M+H]+；found:256.0618.
实施例64：化合物L-13的合成
Figure BDA0003650581180000341
实验步骤与实施例52相同，仅以3-碘-8-氯喹啉代替3-碘-8-氟喹啉。产率：67％；白色粉末状固体；1H NMR(500MHz,Chloroform-d)δ8.83(d,J＝2.3Hz,1H),7.91(d,J＝2.3Hz,1H),7.78(dd,J＝7.5,1.2Hz,1H),7.60(dd,J＝8.2,1.2Hz,1H),7.49(d,J＝5.2Hz,1H),7.48(d,J＝5.2Hz,1H),7.44(t,J＝7.8Hz,1H),7.12–7.07(m,2H).13C NMR(126MHz,Chloroform-d)δ162.05(d,J＝250.0Hz),150.20,141.53,134.28(d,J＝8.3Hz),133.99,132.52,131.86,128.48,128.46,126.56(d,J＝3.0Hz),126.39,125.19,116.02(d,J＝22.1Hz).MS-ESI m/z:calcd for C15H9ClFNS:290.7524[M+H]+；found:290.0193.
实施例65：化合物L-14的合成
Figure BDA0003650581180000342
实验步骤与实施例52相同，仅以3-碘-7,8-二氟喹啉代替3-碘-8-氟喹啉。产率：72％；白色粉末状固体；1H NMR(600MHz,Chloroform-d)δ8.78(s,1H),7.86(s,1H),7.46(dd,J＝8.3,5.3Hz,2H),7.45–7.29(m,2H),7.12–7.05(m,2H).13C NMR(151MHz,Chloroform-d)δ163.14(d,J＝250.0Hz),151.94,149.34(dd,J＝250.7,10.6Hz),144.95(dd,J＝258.2,11.7Hz),137.58(d,J＝7.8Hz),135.26(d,J＝8.2Hz),134.63,132.28,127.70,125.97,122.71,118.43(d,J＝20.8Hz),117.16(d,J＝22.1Hz).MS-ESI m/z:calcdfor C15H8F3NS:292.2912[M+H]+；found:292.0391.
实施例66：化合物L-15的合成
Figure BDA0003650581180000351
实验步骤与实施例52相同，仅以3-碘-6,8-二氟喹啉代替3-碘-8-氟喹啉。产率：59％；白色粉末状固体；1H NMR(600MHz,Chloroform-d)δ8.68(d,J＝2.1Hz,1H),7.72(t,J＝1.7Hz,1H),7.53–7.48(m,2H),7.17–7.14(m,1H),7.14–7.10(m,2H),7.08(d,J＝8.5Hz,1H).13C NMR(151MHz,Chloroform-d)δ163.40(d,J＝250.5Hz),160.36(dd,J＝217.9,12.7Hz),158.66(dd,J＝228.5,12.4Hz),149.66,135.95(d,J＝8.3Hz),135.05,133.84(d,J＝11.4Hz),132.71,129.72(d,J＝13.7Hz),126.81,117.32(d,J＝22.1Hz),106.13(dd,J＝21.9,4.7Hz),105.01(dd,J＝29.4,22.6Hz).MS-ESI m/z:calcd for C15H8F3NS:292.2912[M+H]+；found:292.0387.
白叶藤碱简化衍生物抗植物病原真菌活性
1)供试药剂：实施例1-66制备的白叶藤碱简化衍生物A-01～A-32、H-01～H-06、N-01～N-05、L-01～L-15以及M-01～M-08；
2)供试菌种：立枯丝核菌(Rhizoctonia solani)，核盘菌(Sclerotiniasclerotiorum)，禾谷镰孢菌(Gibberella zeae)，灰葡萄孢菌(Botrytis cinerea)，辣椒疫霉(Phytophthora capsici)，稻瘟病菌(Magnaporthe oryzae)；
3)抗植物真菌病原活性测试：
测试方法：抗菌活性测定采用马铃薯葡萄糖琼脂培养基(PDA培养基)进行。其制备方法如下：先将马铃薯洗净去皮，称取200g切成小块，加水煮烂(煮沸20-30分钟，马铃薯块能被玻璃棒戳破即可)，用八层纱布过滤，加热，再加15g琼脂，继续加热搅拌混匀，待琼脂溶解完后，加入葡萄糖，搅拌均匀，稍冷却后再补足水分至1000毫升，分装锥形瓶，加塞、包扎，115℃灭菌2h，备用。将白叶藤碱简化衍生物A-01～A-32、H-01～H-06、N-01～N-05、L-01～L-15以及M-01～M-08分别用DMSO溶解，加入培养基中，混合均匀，使培养基中的化合物浓度分别为50μg/mL，25μg/mL，以等浓度的DMSO作为空白对照，以上市药物嘧霉胺为阳性对照。倒平板，冷却后分别接菌，置于23℃培养箱中培养，以空白对照菌丝长满培养皿为限，测定各化合物的抑菌率。
所有试验设三个平行组或重复三次。
抑菌率的计算按下述计算公式进行：
抑菌率＝(空白对照菌丝生长直径-菌丝生长直径)/(空白对照菌丝生长直径-菌饼直径)×100％
白叶藤碱简化衍生物对6种植物病原真菌的体外活性测试结果见表1。
表1白叶藤碱简化衍生物在50、25ppm下对植物病原真菌的抑制率
Figure BDA0003650581180000361
Figure BDA0003650581180000371
Figure BDA0003650581180000381
注：“-”表示该浓度下抑制率未进行测试。
由表1可知，白叶藤碱衍生物对6种植物真菌具有不错的体外抑制活性，其中对灰葡萄孢菌的抑制作用最强，大部分化合物在10ppm浓度下抑制率仍在50％以上；而对核盘菌、禾谷镰孢菌、稻瘟病菌、辣椒疫霉的抑制活性则相对较差。
测试白叶藤碱衍生物对灰葡萄孢菌的体外活性，并计算高活性化合物的半数有效浓度(EC50)及毒力方程，详细数据见表2。
表2灰葡萄孢菌高活性化合物的毒力方程及EC50
Figure BDA0003650581180000391
注：毒力方程中y＝log(p/(1-p)),x＝c；其中p为抑制率，c为浓度。
由表2可知，大部分高活性化合物对灰葡萄孢菌的EC50均低于10ppm，且基本都优于阳性对照药嘧霉胺。其中L-01具有最优的抗灰葡萄孢菌活性，EC50值为0.156ppm，其对其他植物病原真菌的抑制活性较弱，对灰葡萄孢菌具有选择性；A-18对灰葡萄孢菌的抑制活性稍弱于L-01，EC50值为0.249ppm，但其具有较广的杀菌谱，对其他植物病原真菌同样具有较高的抑制活性，在5ppm时抑制率均高于50％。
白叶藤碱简化衍生物抗植物病原细菌活性
1)供试药剂：实施例1-66制备的白叶藤碱简化衍生物A-01～A-32、H-01～H-06、N-01～N-05、L-01～L-15、M-01～M-08；
2)供试菌种：稻黄单胞菌(Xanthomonas oryzae ACCC 11602)、柑桔黄单胞菌(Xanthomonas citri)、马铃薯黑胫病菌(Pectobacterium atroseptica ACCC 19901)
3)抗抗植物病原细菌活性测试：
测试方法：挑取稻黄单胞菌、柑桔黄单胞菌和马铃薯黑胫病病原菌单菌落至NB液体培养基中，在25℃、180rpm的恒温摇床振荡培养到对数生长期。将处于对数生长期的细菌用NB液体培养基稀释至约1×106CFU/mL备用。将化合物和商品对照药剂分别用DMSO溶解，加入NB液体培养基中，混合均匀，配制成浓度为200μg/mL的含药NB液体培养基。取50μL含药培养基和相同体积的含约1×106CFU/mL细菌培养物加入到96孔板的孔中，最终给药浓度为100μg/mL。含等量DMSO的相同浓度100μL菌液做对照。将96孔板在25℃恒温培养箱中培养24h，在酶标仪上测定孔中菌液的OD值(OD600)。并且另外测定100μLNB液体培养基和浓度为100μg/mL药剂的OD值，对培养基和药剂本身造成的OD值进行矫正。校正OD值和抑制率的计算公式如下：
校正OD值＝含菌培养基OD值-无菌培养物OD值；
抑制率＝(校正后对照培养基菌液OD值-校正后含药培养基OD值)/校正后对照培养基菌液OD值×100％
白叶藤碱简化衍生物对3种植物病原细菌的体外活性测试结果见表3。
表3白叶藤碱简化衍生物在100ppm下对植物病原细菌的抑制率
Figure BDA0003650581180000401
Figure BDA0003650581180000411
Figure BDA0003650581180000421
由表3可知，白叶藤碱简化衍生物对植物病原细菌表现出一定的抑制活性，但总体活性不理想，化合物的体外活性均低于阳性对照药噻菌铜。
综上所述，白叶藤碱衍生物对植物病原菌具有一定的体外抑制活性，其中对植物病原真菌的体外抑制活性较强，对植物病原细菌的体外抑制活性较弱。在植物病原真菌中，对灰葡萄孢菌的体外抑制活性最强。在此基础上我们发现了两个先导化合物，分别为A-18与L-01，其中A-18具有广谱性，而L-01对灰葡萄孢菌具有较好的选择性，两者对灰葡萄孢菌的抑制活性均优于阳性对照药嘧霉胺，A-18具有比白叶藤碱更广的杀菌谱。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (4)

1.一种白叶藤碱简化衍生物，其特征在于，包括白叶藤碱简化衍生物A-01～A-32、H-01～H-06、N-01～N-05、M-01～M-08、L-01～L-15中的至少一种；
所述白叶藤碱简化衍生物的结构式为：
Figure FDA0003650581170000011
R1为6-甲基取代、6-甲氧基取代、6-氟取代、6-硝基取代、8-甲基取代、8-氟取代、8-硝基取代、8-氯取代、7,8-氟取代、6,8-氟取代；R2与R3为2‘-氟取代、3‘-氟取代、2’,4’-氟取代、3’-三氟甲氧基取代、4’-三氟甲氧基取代、2‘-三氟甲基取代、3‘-三氟甲基取代、4‘-三氟甲基取代、2‘-氯取代、3‘-氯取代、2’,4’-氯取代、2’-甲氧基取代、3’-甲氧基取代、4‘-甲氧基取代、3’-二氟甲氧基取代、4’-二氟甲氧基取代、2‘-甲基取代；X1为NH、O、S、N-甲基、N-乙基、N-丙基、N-环丙基甲基、N-烯丙基；X2、X3、X4、Y1、Y2为C，N。
2.权利要求1所述一种白叶藤碱简化衍生物的制备方法，其特征在于，如下所示：
Figure FDA0003650581170000012
Figure FDA0003650581170000021
3.权利要求1所述的一种白叶藤碱简化衍生物在防治农业植物病害中的用途。
4.根据权利要求3所述的一种白叶藤碱简化衍生物在防治农业植物病害中的用途，所述农业植物病害包括由立枯丝核菌、核盘菌、禾谷镰孢菌、灰葡萄孢菌、辣椒疫霉、稻瘟病菌、稻黄单胞菌、柑桔黄单胞菌、马铃薯黑胫病菌引发的病害。
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