CN111393363B - 4-苯氧基喹啉并n-磺酰脒类化合物及其制备方法和用途 - Google Patents

4-苯氧基喹啉并n-磺酰脒类化合物及其制备方法和用途 Download PDF

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CN111393363B
CN111393363B CN202010346927.6A CN202010346927A CN111393363B CN 111393363 B CN111393363 B CN 111393363B CN 202010346927 A CN202010346927 A CN 202010346927A CN 111393363 B CN111393363 B CN 111393363B
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吴彦超
南祥
李惠静
李芹英
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Abstract

本发明涉及一种4‑苯氧基喹啉并N‑磺酰脒类化合物I，该4‑苯氧基喹啉并N‑磺酰脒类化合物I作为酪氨酸激酶抑制剂，特别是c‑Met抑制剂。本发明还涉及该类化合物的制备方法；本发明更涉及含有4‑苯氧基喹啉并N‑磺酰脒类化合物I作为药物用以治疗与酪氨酸激酶c‑Met相关的疾病，特别是c‑Met相关的癌症的用途。

Description

4-苯氧基喹啉并N-磺酰脒类化合物及其制备方法和用途
技术领域
本发明涉及一种4-苯氧基喹啉并N-磺酰脒类化合物，其制备方法及其作为药物用以治疗与酪氨酸激酶c-Met相关的疾病，特别是c-Met相关的癌症的用途。
发明背景
信号转导作为细胞的一种基础调节机制将胞外的各种信号传递到细胞内部，使细胞做出诸如增殖、分化、凋亡等各种生理过程的应答。蛋白激酶(PKs)在这一过程起着重要作用，主要通过催化蛋白质的酪氨酸、丝氨酸和苏氨酸残基上的羟基磷酸化，介导多种生物学过程包括细胞生长、分化和增殖，器官的形成，新血管的生成，组织的修复与再生。除在正常组织/器官发挥重要功能外，许多异常蛋白激酶也在包括恶性肿瘤在内的许多疾病发挥着更特殊的作用。蛋白激酶的亚群(致癌蛋白激酶)在失调时可导致肿瘤的形成和生长，且进一步引起肿瘤的进展。到目前，致癌蛋白激酶已是用于癌症干预及药物研发最具吸引力的靶标之一。
受体酪氨酸激酶c-Met，为MET原癌基因编码的一类多效性的细胞活素，在正常细胞与肿瘤细胞中均有表达。成熟的Met由一条胞外高度糖基化的α链(50KDa)和跨膜的β链(145KDa)通过二硫键连接而成的异二聚跨膜受体。其内源性配体为肝细胞生长因子(HGF)，配体结合并诱导c-Met二聚化，生成自磷酸化的活化前体，促进下游的信号传导进而导致多种生理过程。正常生理条件下的HGF/c-Met信号转导在胚胎发育、组织损伤修复中起重要作用。但异常的HGF/c-Met信号转导则与肿瘤增殖、侵袭、迁移，抑制细胞凋亡、促进血管生成，尤其与穿入性生长和肿瘤新陈代谢密切相关。c-Met在绝大部分的实体瘤及部分肉瘤中均有高表达且和预后不良密切相关，如肺癌、乳腺癌、结肠癌、前列腺癌、肝癌、胃癌及神经胶质瘤等。此外，具有高表达HGF/c-Met水平的患者对化疗和放疗有更强的抵抗力。除HGF/c-Met的异常表达外，c-Met在癌症患者中也可以通过基因突变和基因扩增得到激活。尽管基因扩增和基因突变是已在患者中报告的最常见的遗传改变，但也可以通过缺失、截短、基因重排及异常受体加工和有缺陷的负调控机制得到激活。
不同于其它激酶，c-Met与细胞表面其他肿瘤因子也存在交联作用，例如整合素家族、其它受体酪氨酸激酶等，进而激活并放大肿瘤相关效应，极大的促进了肿瘤的形成及发展，其中c-Met起到了枢纽作用，抑制c-Met即可抑制多个肿瘤通路。c-Met激酶结构域的激活位点突变还与遗传性和偶发性乳状肾癌相关。此外，研究表明临床应用的EGFR受体酪氨酸激酶抑制剂获得性耐药正是由于MET基因扩增激活ERBB3信号传导通路而引起的。体外试验得出，阻断c-Met信号后，易瑞沙可以恢复疗效。因此，c-Met抑制剂与EGFR抑制剂的联合用药能够减缓EGFR-TKIs获得性耐药的产生，延长其临床周期，具有重要的临床意义。
综上，抑制c-Met信号通路已成为肿瘤治疗的重要策略，尤其是针对c-Met催化区域的小分子抑制剂目前已成为研究热点。目前已有基于c-Met为靶点的小分子药物上市，如：cabozantinib、crizotinib。此外，还有许多能够有效阻断c-Met信号传导途径的化合物正在进行相关的临床前或临床研究，如Exelixis公司的XL-184、XL-180，Pfizer公司的PF-4217903，MethylGene公司的MGCD-265，Johnson&Johnson的JNJ-38877605等。故在c-Met受体活化起到关键作用的原发型或继发型肿瘤中，靶向HGF/c-Met的物质尤其是c-Met靶向的小分子抑制剂被寄予了厚望。
本发明涉及作为酪氨酸激酶抑制剂的4-苯氧基喹啉并N-磺酰脒类化合物，尤其是c-Met抑制剂，未见诸报道。
发明内容
本发明所要解决的技术问题之一是提供一种4-苯氧基喹啉并N-磺酰脒类化合物。
本发明所要解决的技术问题之二是提供一种4-苯氧基喹啉并N-磺酰脒类化合物的制备方法。
本发明所要解决的技术问题之三是提供上述4-苯氧基喹啉并N-磺酰脒类化合物的应用。
作为本发明第一方面的4-苯氧基喹啉并α-酰氧基酰胺类化合物，为具有如式I所示的化合物：
Figure BDA0002469322020000021
其中，R1选自苯基、4-甲基苯基、3-甲基苯基、2-甲基苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-氯苯基、4-溴苯基、3,4-二氯苯基、4-三氟甲基苯基；R2选自正丁基、苯基、甲氧基甲基、氢、1-环己烯基、3-吡啶基、3-噻吩基；R3选自甲基、正丁基、3-(吗啉基)丙基、3-(哌啶-1-基)丙基、3-(4-甲基哌嗪-1-基)丙基、3-(4-甲基哌啶-1-基)丙基。
所述式I的4-苯氧基喹啉并N-磺酰脒类化合物为药学上可接受的衍生物。
本发明所述式I的化合物可以以药学上可接受的盐的形式存在。
本发明所述药学上可接受的盐为式I化合物的盐酸盐、硫酸盐、磷酸盐、三氟乙酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、琥珀酸盐。
作为本发明第二方面的4-苯氧基喹啉并N-磺酰脒类化合物I的制备方法，通过中间体II与末端炔、磺酰基叠氮进行三组分反应获得，具体反应式如下：
Figure BDA0002469322020000031
式中R1、R2、R3的定义同权利要求1。
其中胺、炔、磺酰基叠氮进行偶联时所用铜试剂为碘化亚铜、溴化亚铜、氯化亚铜、氰基亚铜、氧化亚铜，优选碘化亚铜。
其中偶联反应所用的碱为三乙胺、二乙胺、N,N-二异丙基乙胺、4-二甲胺基吡啶、三乙烯二胺、1,8-二氮杂二环十一碳-7-烯、1,5-二氮杂双环[4.3.0]壬-5-烯、吗啉、吡啶、哌啶、4-甲基哌嗪、四氢吡咯、N-甲基吗啉、四甲基乙二胺，优选吡啶。
作为本发明第三方面的应用，其中是4-苯氧基喹啉并N-磺酰脒类化合物I在制备调节蛋白激酶催化活性制品中的应用。
作为本发明第三方面的应用，其中是4-苯氧基喹啉并N-磺酰脒类化合物I的药学可接受的衍生物在制备调节蛋白激酶催化活性制品中的应用。
作为本发明第三方面的应用，其中是4-苯氧基喹啉并N-磺酰脒类化合物I的可药用盐在制备调节蛋白激酶催化活性制品中的应用。
作为本发明第三方面的应用，其中是药物组合物在制备治疗与蛋白质激酶有关的疾病的药物中的应用。
所述蛋白激酶为c-Met受体酪氨酸激酶。
所述癌症选自肺癌、结肠癌、胃癌、乳腺癌。
本发明所涉及的4-苯氧基喹啉并N-磺酰脒类化合物I还可用于生物学或药理学现象、酪氨酸激酶参与的信号传导通路的研究，以及对于新型酪氨酸激酶抑制剂的评价。
本发明所涉及的4-苯氧基喹啉并N-磺酰脒类化合物经体外抗肿瘤活性筛选结果表明，本发明所涉及的式I类化合物对人肺癌细胞、人结肠癌细胞、人胃癌细胞和人乳腺癌细胞均表现出较强的抑制活性。本发明所述的4-苯氧基喹啉并N-磺酰脒类化合物I结构新颖、合成工艺简单、产品纯度高，对肿瘤细胞表现出较强的抑制活性，具有优良的应用前景。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
“药学上可接受的酸加成盐”指这样的盐，他们保留了游离碱的生物学效应和性质，不会在生物学或其他方面产生不良后果，可以为盐酸、硫酸、磷酸、三氟乙酸、甲磺酸、对甲苯磺酸、酒石酸、马来酸、琥珀酸，但不限于上述酸。
同时，尽管本发明的化合物的受保护的衍生物本身可能不具有药理学活性，但它们可以被给药至哺乳动物，然后在体内代谢而形成具有药理活性的化合物。此种衍生物被描述为“前药”。因此，本发明化合物的所有前药亦保括在本发明的范围内。
一、化合物的制备
实施例1：目标化合物Ia的合成
Figure BDA0002469322020000041
将0.2mmol 3-氟-4-[(6,7-二甲氧基喹啉)-4-氧基]苯胺溶于10mL氯仿，加入0.24mmol苄磺酰基叠氮和0.26mmol己炔。之后在氮气保护下，加入0.02mmol碘化亚铜和0.25mmol吡啶，在室温下搅拌4h。反应结束后，用氯仿稀释，加入饱和的氯化铵溶液继续在室温下搅拌30min，混合液用氯仿反复萃取，合并有机层，无水硫酸镁干燥，过滤，加压蒸除溶剂后，粗产物经硅胶柱层析纯化，得目标产物Ia。白色固体,收率:76％,熔点:141–143℃。1HNMR(400MHz,CDCl3)δ8.46(d,J＝5.2Hz,1H),7.65(d,J＝11.6Hz,1H),7.56(s,1H),7.50–7.41(m,3H),7.37(s,1H),7.30–7.29(m,2H),7.22–7.20(m,1H),7.12(t,J＝8.4Hz,1H),6.36(d,J＝4.4Hz,1H),4.33(s,2H),4.02(s,3H),3.98(s,3H),2.78(m,2H),1.72(m,2H),1.22–1.20(m,4H),0.80(t,J＝6.0Hz,3H).13C NMR(100MHz,CDCl3)δ167.9,160.1,154.0(d,J＝246.5Hz),153.1,149.8,148.5,146.7,137.8(d,J＝12.7Hz),136.3(d,J＝9.5Hz),130.8,129.8,128.6,128.4,123.4,118.2,115.6,111.7(d,J＝23.3Hz),107.4,102.2,99.5,61.1,56.2,56.1,35.6,31.6,27.9,22.2,13.8.Anal.Calcd.For C30H32FN3O5S:C,63.70；H,5.70；N,7.43.Found:C,63.71；H,5.72；N,7.46.ESI-MS:m/z 566.2[M+H]+.
实施例2：目标化合物Ib的合成
Figure BDA0002469322020000042
实验步骤与实施例Ia相同，仅以对氟苄磺酰基叠氮代替苄磺酰基叠氮。白色固体，收率：68％,熔点:152–154℃。1H NMR(400MHz,CDCl3)δ8.47(d,J＝4.4Hz,1H),7.65(d,J＝11.6Hz,1H),7.57(s,1H),7.51–7.38(m,3H),7.16(s,1H),7.01(t,J＝8.0Hz,2H),6.83-6.76(m,1H),6.37(d,J＝5.2Hz,1H),4.31(s,2H),4.04(s,3H),4.01(s,3H),2.26–2.17(m,2H),1.74–1.54(m,2H),1.25(m,4H),0.82(t,J＝5.6Hz,3H).13C NMR(100MHz,CDCl3)δ168.0,162.9(d,J＝245.2Hz),160.1,154.0(d,J＝249.3Hz),153.2,149.8,148.4,146.7,137.9(d,J＝13.9Hz),136.3(d,J＝10.0Hz),132.5(d,J＝7.6Hz),125.7,123.4,118.2,115.6,115.5(d,J＝21.5Hz),111.9(d,J＝23.2Hz),107.4,102.2,99.5,60.2,56.2,56.1,35.7,31.6,27.9,22.2,13.8.Anal.Calcd.For C30H31F2N3O5S:C,61.74；H,5.35；N,7.20.Found:C,61.76；H,5.35；N,7.21.ESI-MS:m/z 606.2[M+Na]+.
实施例3：目标化合物Ic的合成
Figure BDA0002469322020000051
实验步骤与实施例Ia相同，仅以苯乙炔代替己炔。浅黄色固体，收率:54％，熔点:104–106℃。1H NMR(400MHz,CDCl3)δ8.47(d,J＝4.8Hz,1H),7.55(s,1H),7.48–7.47(m,3H),7.41(s,2H),7.40–7.27(m,6H),7.12(t,J＝8.4Hz,1H),6.86–6.82(m,2H),6.33(d,J＝5.2Hz,1H),4.40(s,2H),4.36(s,2H),4.05(s,3H),4.03(s,3H).13C NMR(100MHz,CDCl3)δ164.8,159.9,154.0(d,J＝249.3Hz),153.1,149.8,148.5,146.8,138.4(d,J＝13.4Hz),135.3(d,J＝8.6Hz),132.8,130.9,130.0,129.8,129.6,128.6,128.5,128.4,123.5,118.3,115.5,111.9(d,J＝22.7Hz),107.7,102.2,99.3,61.1,56.2,56.1,40.6.Anal.Calcd.For C32H28FN3O5S:C,65.63；H,4.82；N,7.18.Found:C,65.64；H,4.81；N,7.20.ESI-MS:m/z 586.2[M+H]+.
实施例4：目标化合物Id的合成
Figure BDA0002469322020000052
实验步骤与实施例Ia相同，仅以苯乙炔代替己炔、对氟苄磺酰基叠氮代替苄磺酰基叠氮。淡黄色固体，收率:62％，熔点:93–95℃。1H NMR(400MHz,CDCl3)δ8.47(d,J＝5.2Hz,1H),7.55(s,1H),7.51(d,J＝11.6Hz,1H),7.45–7.42(m,5H),7.28(d,J＝6.4Hz,2H),7.14(t,J＝8.4Hz,1H),7.05(t,J＝8.4Hz,2H),6.93–6.80(m,2H),6.33(d,J＝4.8Hz,1H),4.39(s,2H),4.36(s,2H),4.05(s,3H),4.04(s,3H).13C NMR(100MHz,CDCl3)δ164.8,164.1,161.7,161.1(d,J＝247.0Hz),154.0(d,J＝248.7Hz),153.1,149.8,148.5,146.9,138.5(d,J＝12.8Hz),135.2(d,J＝9.6Hz),132.8,132.6(d,J＝8.2Hz),129.9,129.6,128.4,125.7,123.5,118.3,115.6(d,J＝21.5Hz),112.0(d,J＝22.4Hz),107.6,102.2,99.4,60.1,56.2,56.1,40.6.Anal.Calcd.For C32H27F2N3O5S:C,63.67；H,4.51；N,6.96.Found:C,63.69；H,4.52；N,6.97.ESI-MS:m/z 603.2[M]+.
实施例5：目标化合物Ie的合成
Figure BDA0002469322020000061
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔。黄色固体,收率：73％，熔点：148–150℃。1H NMR(400MHz,CDCl3)δ8.85(br s,1H),8.51(d,J＝5.2Hz,1H),7.61(dd,J＝2.4,12.0Hz,1H),7.58(s,1H),7.46–7.44(m,3H),7.37-7.32(m,3H),7.19(t,J＝8.4Hz,1H),7.05-7.03(m,1H),6.38(d,J＝5.2Hz,1H),4.35(s,2H),4.07(s,3H),4.05(s,3H),3.70(t,J＝5.2Hz,2H),3.44(s,3H),3.21(t,J＝5.2Hz,2H).13C NMR(100MHz,CDCl3)δ165.4,160.0,154.1(d,J＝248.8Hz),153.0,149.7,148.6,146.8,138.0(d,J＝12.3Hz),135.8(d,J＝9.3Hz),130.8,129.8,128.6,128.4,123.5,118.1(d,J＝3.2Hz),115.5,111.7(d,J＝22.6Hz),107.7,102.2,99.4,68.8,60.9,58.9,56.2,56.1,33.9.Anal.Calcd.ForC28H28FN3O6S:C,60.75；H,5.10；N,7.59.Found:C,60.73；H,5.12；N,7.60.ESI-MS:m/z554.2[M+H]+.
实施例6：目标化合物If的合成
Figure BDA0002469322020000062
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、对氟苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：76％，熔点：145–147℃。1H NMR(400MHz,CDCl3)δ8.89(br s,1H),8.51(d,J＝5.2Hz,1H),7.63(dd,J＝1.6,12.0Hz,1H),7.58(s,1H),7.44(s,2H),7.42–7.40(m,1H),7.20(t,J＝8.4Hz,1H),7.06–7.02(m,3H),6.38(d,J＝5.2Hz,1H),4.32(s,2H),4.07(s,3H),4.05(s,3H),3.73(t,J＝5.2Hz,2H),3.45(s,3H),3.24(t,J＝4.8Hz,2H).13C NMR(100MHz,CDCl3)δ165.4,162.9(d,J＝246.2Hz),159.9,154.1(d,J＝248.4Hz),153.0,149.7,148.6,146.9,138.1(d,J＝12.4Hz),135.7(d,J＝9.3Hz),132.5(d,J＝8.2Hz),125.7(d,J＝3.0Hz),123.5,118.1(d,J＝2.9Hz),115.6(d,J＝21.5Hz),111.8(d,J＝22.8Hz),107.7,102.2,99.3,68.8,60.0,58.9,56.2,56.1,34.0.Anal.Calcd.ForC28H27F2N3O6S:C,58.84；H,4.76；N,7.35.Found:C,58.87；H,4.75；N,7.37.ESI-MS:m/z572.3[M+H]+.
实施例7：目标化合物Ig的合成
Figure BDA0002469322020000071
实验步骤与实施例Ia相同，仅以乙炔代替己炔。淡黄色固体，收率：46％，熔点：126–128℃。1H NMR(400MHz,CDCl3)δ8.75(br s,1H),8.46(d,J＝5.2Hz,1H),7.64(d,J＝11.6Hz,1H),7.57(s,1H),7.50–7.43(m,3H),7.38(s,1H),7.35–7.32(m,2H),7.20–7.11(m,2H),6.38(d,J＝4.8Hz,1H),4.35(s,2H),4.04(s,3H),4.01(s,3H),2.46(s,3H).13C NMR(100MHz,CDCl3)δ164.3,160.2,154.0(d,J＝248.4Hz),153.2,149.8,148.4,146.6,138.0(d,J＝12.3Hz),136.1(d,J＝9.2Hz),130.9,129.6,128.7,128.6,123.5,118.2(d,J＝3.1Hz),115.6,111.7(d,J＝22.6Hz),107.3,102.3,99.5,61.0,56.2,21.9.Anal.Calcd.For C26H24FN3O5S:C,61.29；H,4.75；N,8.25.Found:C,61.30；H,4.77；N,8.24.ESI-MS:m/z 532.2[M+Na]+.
实施例8：目标化合物Ih的合成
Figure BDA0002469322020000072
实验步骤与实施例Ia相同，仅以乙炔代替己炔、对氟苄磺酰基叠氮代替苄磺酰基叠氮。淡黄色固体，收率：49％，熔点：119–121℃。1H NMR(400MHz,CDCl3)δ8.68(br s,1H),8.48(d,J＝5.2Hz,1H),7.65(d,J＝12.0Hz,1H),7.57(s,1H),7.43–7.40(m,2H),7.38(s,1H),7.18–7.11(m,2H),7.03(t,J＝8.4Hz,2H),6.38(d,J＝4.8Hz,1H),4.32(s,2H),4.05(s,3H),4.02(s,3H),2.53(s,3H).13C NMR(100MHz,CDCl3)δ164.3,163.0(d,J＝247.1Hz),160.1,154.0(d,J＝248.0Hz),153.3,149.9,148.5,146.7,138.2(d,J＝12.7Hz),136.0(d,J＝9.5Hz),132.6(d,J＝8.0Hz),125.6(d,J＝3.3Hz),123.5,118.2,115.7(d,J＝21.5Hz),115.6,111.8(d,J＝22.7Hz),107.4,102.3,99.5,60.1,56.2,22.0.Anal.Calcd.ForC26H23F2N3O5S:C,59.20；H,4.39；N,7.97.Found:C,59.21；H,4.37；N,7.94.ESI-MS:m/z528.1[M+H]+.
实施例9：目标化合物Ii的合成
Figure BDA0002469322020000081
实验步骤与实施例Ia相同，仅以1-乙炔基环己烯代替己炔。白色固体，收率：68％，熔点：141–143℃。1H NMR(400MHz,CDCl3)δ8.50(d,J＝4.4Hz,1H),7.60–7.58(m,2H),7.47(d,J＝11.6Hz,2H),7.44–7.43(m,2H),7.37–7.33(m,3H),7.19(t,J＝8.4Hz,1H),7.02–7.00(m,1H),6.38(d,J＝4.8Hz,1H),4.36(s,2H),4.06(s,3H),4.04(s,3H),3.63(s,2H),2.11(m,2H),1.95(m,2H),1.65–1.60(m,4H).13C NMR(100MHz,CDCl3)δ164.6,159.9,154.2(d,J＝249.0Hz),153.1,149.8,148.7,147.0,138.4(d,J＝12.5Hz),135.4(d,J＝9.2Hz),132.1,130.9,130.7,129.9,128.6,128.5,123.6,117.9(d,J＝2.8Hz),115.6,111.7(d,J＝22.6Hz),107.8,102.3,99.4,61.0,56.2,43.0,28.5,25.5,22.7,21.8.Anal.Calcd.ForC32H32FN3O5S:C,65.18；H,5.47；N,7.13.Found:C,65.17；H,5.49；N,7.13.ESI-MS:m/z 590.2[M+H]+.
实施例10：目标化合物Ij的合成
Figure BDA0002469322020000082
实验步骤与实施例Ia相同，仅以1-乙炔基环己烯代替己炔、对氟苄磺酰基叠氮代替苄磺酰基叠氮。白色固体，收率：71％，熔点：132–134℃。1H NMR(400MHz,CDCl3)δ8.50(d,J＝4.8Hz,1H),7.61(dd,J＝1.6,12.0Hz,1H),7.57(s,1H),7.51(s,1H),7.43–7.40(m,3H),7.21(t,J＝8.4Hz,1H),7.06–6.98(m,3H),6.37(d,J＝4.8Hz,1H),4.32(s,2H),4.07(s,3H),4.04(s,3H),3.66(s,2H),2.12(m,2H),1.97(m,2H),1.66–1.60(m,4H).13C NMR(100MHz,CDCl3)δ164.7,163.0(d,J＝246.4Hz),159.9,154.2(d,J＝249.4Hz),153.1,149.8,148.7,147.0,138.5(d,J＝12.2Hz),135.3(d,J＝8.6Hz),132.6(d,J＝8.2Hz),132.0,130.8,125.8(d,J＝2.5Hz),123.7,118.0,115.6(d,J＝21.4Hz),111.8(d,J＝23.0Hz),107.9,102.2,99.4,60.2,56.2,43.1,28.5,25.5,22.7,21.8.Anal.Calcd.ForC32H31F2N3O5S:C,63.25；H,5.14；N,6.91.Found:C,63.26；H,5.12；N,6.92.ESI-MS:m/z630.2[M+Na]+.
实施例11：目标化合物Ik的合成
Figure BDA0002469322020000091
实验步骤与实施例Ia相同，仅以3-乙炔基吡啶代替己炔。黄色固体,收率：42％，熔点：121–123℃。1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.46(d,J＝4.8Hz,1H),8.17(s,1H),7.70(d,J＝7.2Hz,1H),7.58(d,J＝12.0Hz,1H),7.55(s,1H),7.46–7.45(m,2H),7.39(s,1H),7.36–7.29(m,4H),7.14(t,J＝8.4Hz,1H),7.06–7.04(m,1H),6.66-6.62(m,1H),6.36(d,J＝4.8Hz,1H),4.40(s,2H),4.24(s,2H),4.04(s,3H),4.02(s,3H).13C NMR(100MHz,CDCl3)δ163.5,159.9,154.1(d,J＝248.1Hz),153.1,150.1,149.8,148.6,148.5,146.9,138.4(d,J＝11.9Hz),137.5,135.8(d,J＝7.6Hz),131.0,130.6,129.6,128.7,124.4,124.1,123.6,118.5,115.6,112.0(d,J＝22.9Hz),107.7,102.3,99.4,61.1,56.2,37.8.Anal.Calcd.For C31H27FN4O5S:C,63.47；H,4.64；N,9.55.Found:C,63.44；H,4.66；N,9.56.ESI-MS:m/z 587.2[M+H]+.
实施例12：目标化合物Il的合成
Figure BDA0002469322020000092
实验步骤与实施例Ia相同，仅以3-乙炔基吡啶代替己炔、对氟苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：44％，熔点：112–114℃。1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.46(d,J＝4.8Hz,1H),8.15(s,1H),7.74(d,J＝7.2Hz,1H),7.61(d,J＝12.0Hz,1H),7.55(s,1H),7.44–7.41(m,2H),7.38(s,1H),7.33(m,1H),7.24(m,1H),7.15(t,J＝8.4Hz,1H),7.06–7.03(t,J＝8.0Hz,3H),6.35(d,J＝4.8Hz,1H),4.37(s,2H),4.27(s,2H),4.04(s,3H),4.02(s,3H).13C NMR(100MHz,CDCl3)δ164.2,163.6,161.8,159.9,154.0(d,J＝248.9Hz),153.1,151.2(d,J＝245.9Hz),149.8,148.6,146.9,138.5(d,J＝11.8Hz),137.4,135.8(d,J＝8.5Hz),132.7(d,J＝8.1Hz),130.6,125.5,124.5,123.6,118.4,115.7(d,J＝21.5Hz),115.6,112.1(d,J＝21.8Hz),107.6,102.3,99.4,60.2,56.2,37.9.Anal.Calcd.For C31H26F2N4O5S:C,61.58；H,4.33；N,9.27.Found:C,61.60；H,4.31；N,9.30.ESI-MS:m/z 605.2[M+H]+.
实施例13：目标化合物Im的合成
Figure BDA0002469322020000101
实验步骤与实施例Ia相同，仅以3-乙炔基噻吩代替己炔。淡黄色固体，收率：62％，熔点:116–118℃。1H NMR(400MHz,CDCl3)δ8.48(d,J＝5.2Hz,1H),7.55(s,1H),7.51(d,J＝12.0Hz,1H),7.47–7.35(m,7H),7.16–7.12(m,2H),7.00(d,J＝4.4Hz,1H),6.89–6.87(m,1H),6.34(d,J＝5.2Hz,1H),4.39(s,2H),4.37(s,2H),4.05(s,3H),4.03(s,3H).13C NMR(100MHz,DMSO-d6)δ163.7,159.1,153.1(d,J＝245.1Hz),152.6,149.5,148.8,146.4,136.9(d,J＝12.1Hz),136.6(d,J＝9.7Hz),134.7,130.9,130.5,128.5,128.1,127.9,126.1,123.8,123.3,118.5(d,J＝2.4Hz),114.5,110.7(d,J＝22.6Hz),107.8,102.2,98.9,59.9,55.7,34.4.Anal.Calcd.For C30H26FN3O5S2:C,60.90；H,4.43；N,7.10.Found:C,60.91；H,4.45；N,7.08.ESI-MS:m/z 614.2[M+Na]+.
实施例14：目标化合物In的合成
Figure BDA0002469322020000102
实验步骤与实施例Ia相同，仅以3-乙炔基噻吩代替己炔、对氟苄磺酰基叠氮代替苄磺酰基叠氮。淡黄色固体，收率：56％，熔点：107–109℃。1H NMR(400MHz,CDCl3)δ8.47(d,J＝4.0Hz,1H),7.55(s,1H),7.42–7.42(m,3H),7.40(s,1H),7.29–7.26(m,2H),7.15(t,J＝8.4Hz,1H),7.04(t,J＝8.4Hz,3H),6.88–6.86(m,1H),6.33(d,J＝5.2Hz,1H),4.40(s,2H),4.34(s,2H),4.05(s,3H),4.02(s,3H).13C NMR(100MHz,CDCl3)δ164.4,164.2,161.7,158.7(d,J＝246.4Hz),154.0(d,J＝248.7Hz),153.1,149.8,148.6,146.8,138.5(d,J＝11.9Hz),135.2(d,J＝8.8Hz),132.6(d,J＝8.4Hz),132.5,128.5,127.9,125.6(d,J＝2.3Hz),125.5,123.5,118.3,115.6(d,J＝21.5Hz),111.9(d,J＝22.5Hz),107.6,102.2,99.4,60.1,56.2,35.2.Anal.Calcd.For C30H25F2N3O5S2:C,59.10；H,4.13；N,6.89.Found:C,59.09；H,4.15；N,6.90.ESI-MS:m/z 610.2[M+H]+.
实施例15：目标化合物Io的合成
Figure BDA0002469322020000103
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、2-甲基苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体,收率：78％，熔点：115–117℃。1H NMR(400MHz,CDCl3)δ8.84(brs,1H),8.51(d,J＝5.2Hz,1H),7.58(s,1H),7.56(dd,J＝2.0,12.0Hz,1H),7.43(s,1H),7.41(d,J＝7.2Hz,1H),7.22–7.16(m,4H),7.10–7.08(m,1H),6.39(d,J＝5.2Hz,1H),4.42(s,2H),4.07(s,3H),4.05(s,3H),3.66(t,J＝5.2Hz,2H),3.43(s,3H),3.17(t,J＝5.2Hz,2H),2.41(s,3H).13C NMR(100MHz,CDCl3)δ165.7,160.0,154.1(d,J＝249.0Hz),153.0,149.7,148.7,147.0,138.3(d,J＝12.1Hz),138.2,135.7(d,J＝9.5Hz),131.8,130.8,128.7,128.1,126.1,123.6,118.4(d,J＝3.1Hz),115.5,111.8(d,J＝22.5Hz),107.8,102.2,99.4,68.8,58.9,58.0,56.2,33.5,20.0.Anal.Calcd.ForC29H30FN3O6S:C,61.36；H,5.33；N,7.40.Found:C,61.37；H,5.33；N,7.42.ESI-MS:m/z 568.2[M+H]+.
实施例16：目标化合物Ip的合成
Figure BDA0002469322020000111
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、3-甲基苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：72％，熔点：124–126℃。1H NMR(400MHz,CDCl3)δ8.87(brs,1H),8.50(d,J＝5.2Hz,1H),7.65(dd,J＝2.0,11.6Hz,1H),7.58(s,1H),7.43(s,1H),7.27(s,1H),7.24–7.23(m,2H),7.18(t,J＝8.8Hz,1H),7.13(t,J＝3.6Hz,1H),7.08–7.06(m,1H),6.38(d,J＝5.2Hz,1H),4.32(s,2H),4.06(s,3H),4.05(s,3H),3.69(t,J＝5.2Hz,2H),3.44(s,3H),3.22(t,J＝5.2Hz,2H),2.31(s,3H).13C NMR(100MHz,CDCl3)δ165.4,159.9,154.1(d,J＝248.9Hz),153.0,149.7,148.7,146.9,138.3,138.0(d,J＝12.2Hz),135.8(d,J＝9.4Hz),131.5,129.6,129.3,128.5,128.0,123.5,118.0(d,J＝3.0Hz),115.5,111.6(d,J＝22.9Hz),107.8,102.3,99.4,68.8,60.9,58.9,56.2,33.8,21.3.Anal.Calcd.For C29H30FN3O6S:C,61.36；H,5.33；N,7.40.Found:C,61.35；H,5.31；N,7.43.ESI-MS:m/z 568.2[M+H]+.
实施例17：目标化合物Iq的合成
Figure BDA0002469322020000112
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、4-甲基苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：82％，熔点：129–131℃。1H NMR(400MHz,CDCl3)δ8.85(brs,1H),8.51(d,J＝5.2Hz,1H),7.64(dd,J＝2.4,12.0Hz,1H),7.59(s,1H),7.44(s,1H),7.33(d,J＝7.6Hz,2H),7.21–7.15(m,3H),7.06-7.04(m,1H),6.39(d,J＝5.2Hz,1H),4.31(s,2H),4.07(s,3H),4.05(s,3H),3.69(t,J＝5.2Hz,2H),3.44(s,3H),3.22(t,J＝5.2Hz,2H),2.31(s,3H).13C NMR(100MHz,CDCl3)δ165.4,160.0,154.1(d,J＝248.5Hz),153.0,149.7,148.7,146.9,138.4,138.1(d,J＝12.5Hz),135.8(d,J＝9.3Hz),130.7,129.3,126.7,123.5,118.1(d,J＝3.2Hz),115.5,111.7(d,J＝22.7Hz),107.8,102.2,99.4,68.8,60.7,58.9,56.2,33.8,21.2.Anal.Calcd.For C29H30FN3O6S:C,61.36；H,5.33；N,7.40.Found:C,61.38；H,5.34；N,7.43.ESI-MS:m/z 590.2[M+Na]+.
实施例18：目标化合物Ir的合成
Figure BDA0002469322020000121
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、2-氟苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：71％，熔点：137–139℃。1H NMR(400MHz,CDCl3)δ8.89(br s,1H),8.51(d,J＝5.2Hz,1H),7.58(s,1H),7.57(m,1H),7.55(dd,J＝1.6,7.2Hz,1H),7.44(s,1H),7.32–7.28(m,1H),7.21-7.13(m,2H),7.08–7.06(m,2H),6.39(d,J＝5.2Hz,1H),4.44(s,2H),4.07(s,3H),4.04(s,3H),3.73(t,J＝5.2Hz,2H),3.45(s,3H),3.25(t,J＝5.2Hz,2H).13C NMR(100MHz,CDCl3)δ165.5,161.2(d,J＝247.4Hz),160.0,154.1(d,J＝248.7Hz),153.0,149.7,148.7,146.9,138.2(d,J＝12.5Hz),135.7(d,J＝9.4Hz),132.6(d,J＝2.3Hz),130.4(d,J＝8.3Hz),124.3(d,J＝3.6Hz),123.5,118.2(d,J＝3.0Hz),117.4(d,J＝14.4Hz),115.7(d,J＝21.7Hz),115.5,111.7(d,J＝22.7Hz),107.8,102.3,99.4,68.6,59.0,56.2,53.5,33.9.Anal.Calcd.For C28H27F2N3O6S:C,58.84；H,4.76；N,7.35.Found:C,58.85；H,4.78；N,7.35.ESI-MS:m/z 572.2[M+H]+.
实施例19：目标化合物Is的合成
Figure BDA0002469322020000122
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、3-氟苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：68％，熔点：134–136℃。1H NMR(400MHz,CDCl3)δ8.90(br s,1H),8.51(d,J＝5.2Hz,1H),7.58(s,1H),7.53(dd,J＝2.4,12.0Hz,1H),7.43(s,1H),7.34–7.29(m,1H),7.22-7.15(m,3H),7.07–7.01(m,2H),6.39(d,J＝5.2Hz,1H),4.33(s,2H),4.06(s,3H),4.04(s,3H),3.73(t,J＝5.2Hz,2H),3.45(s,3H),3.25(t,J＝5.2Hz,2H).13CNMR(100MHz,CDCl3)δ165.5,162.6(d,J＝245.1Hz),159.9,154.1(d,J＝248.8Hz),153.0,149.7,148.7,146.9,138.3(d,J＝12.3Hz),135.6(d,J＝9.3Hz),132.1(d,J＝8.0Hz),130.1(d,J＝8.1Hz),126.6(d,J＝2.6Hz),123.6,118.4(d,J＝3.3Hz),117.8(d,J＝22.0Hz),115.6(d,J＝7.1Hz),115.4,111.7(d,J＝22.6Hz),107.8,102.3,99.4,68.8,60.4,59.0,56.2,33.9.Anal.Calcd.For C28H27F2N3O6S:C,58.84；H,4.76；N,7.35.Found:C,58.83；H,4.78；N,7.36.ESI-MS:m/z 572.2[M+H]+.
实施例20：目标化合物It的合成
Figure BDA0002469322020000131
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、4-氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：76％，熔点：146–148℃。1H NMR(400MHz,CDCl3)δ8.90(br s,1H),8.52(d,J＝5.2Hz,1H),7.62(dd,J＝2.4,12.0Hz,1H),7.58(s,1H),7.43(s,1H),7.38(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,2H),7.20(t,J＝8.4Hz,1H),7.03-7.01(m,1H),6.39(d,J＝5.2Hz,1H),4.31(s,2H),4.07(s,3H),4.05(s,3H),3.72(t,J＝5.2Hz,2H),3.45(s,3H),3.24(t,J＝5.2Hz,2H).13C NMR(100MHz,CDCl3)δ165.5,159.9,154.1(d,J＝248.2Hz),153.0,149.8,148.8,146.9,138.3(d,J＝12.3Hz),135.6(d,J＝10.0Hz),134.7,132.2,128.8,128.4,123.6,118.2,115.5,111.9(d,J＝22.6Hz),107.9(d,J＝3.4Hz),102.3,99.4,68.8,60.2,59.0,56.2,34.0.Anal.Calcd.For C28H27ClFN3O6S:C,57.19；H,4.63；N,7.15.Found:C,57.22；H,4.62；Cl,6.03；N,7.18.ESI-MS:m/z 588.2[M+H]+.
实施例21：目标化合物Iu的合成
Figure BDA0002469322020000132
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、4-溴苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：82％，熔点：151–153℃。1H NMR(400MHz,CDCl3)δ8.90(br s,1H),8.53(d,J＝4.8Hz,1H),7.62(dd,J＝2.0,11.6Hz,1H),7.59(s,1H),7.49(s,1H),7.45(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),7.20(t,J＝8.4Hz,1H),7.03–7.00(m,1H),6.39(d,J＝5.2Hz,1H),4.29(s,2H),4.07(s,3H),4.05(s,3H),3.72(t,J＝5.2Hz,2H),3.45(s,3H),3.24(t,J＝5.2Hz,2H).13C NMR(100MHz,CDCl3)δ165.5,159.9,154.1(d,J＝248.4Hz),153.1,149.8,148.8,146.9,138.3(d,J＝12.3Hz),135.6(d,J＝9.3Hz),132.5,131.8,128.9,123.6,122.9,118.2(d,J＝3.2Hz),115.6,111.9(d,J＝22.8Hz),107.9,102.3,99.4,68.8,60.3,59.0,56.2,33.9.Anal.Calcd.For C28H27BrFN3O6S:C,53.17；H,4.30；N,6.64.Found:C,53.20；H,4.31；N,6.65.ESI-MS:m/z 654.1[M+Na]+.
实施例22：目标化合物Iv的合成
Figure BDA0002469322020000141
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、3,4-二氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：71％，熔点：135–137℃。1H NMR(400MHz,CDCl3)δ8.93(br s,1H),8.51(d,J＝5.2Hz,1H),7.58(s,1H),7.55(dd,J＝2.4,12.0Hz,1H),7.52(d,J＝2.0Hz,1H),7.43(s,1H),7.41(d,J＝8.4Hz,1H),7.27(dd,J＝2.0,8.0Hz,1H),7.22(d,J＝8.8Hz,1H),7.09–7.07(m,1H),6.41(d,J＝5.2Hz,1H),4.27(s,2H),4.07(s,3H),4.05(s,3H),3.74(t,J＝5.6Hz,2H),3.46(s,3H),3.25(t,J＝5.6Hz,2H).13C NMR(100MHz,CDCl3)δ165.7,159.9,154.1(d,J＝249.0Hz),153.1,149.8,148.7,147.0,138.5(d,J＝12.5Hz),135.4(d,J＝9.3Hz),132.9,132.7,132.6,130.5,130.2,130.1,123.6,118.5(d,J＝3.1Hz),115.6,111.8(d,J＝22.6Hz),107.8,102.4,99.4,68.7,59.7,59.0,56.2,34.0.Anal.Calcd.For C28H26Cl2FN3O6S:C,54.02；H,4.21；N,6.75.Found:C,54.04；H,4.20；N,6.77.ESI-MS:m/z 622.1[M+H]+.
实施例23：目标化合物Iw的合成
Figure BDA0002469322020000142
实验步骤与实施例Ia相同，仅以甲基丙炔基醚代替己炔、4-三氟甲基苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：54％，熔点：154–156℃。1H NMR(400MHz,CDCl3)δ8.92(br s,1H),8.51(d,J＝5.2Hz,1H),7.62–7.56(m,6H),7.44(s,1H),7.20(t,J＝8.4Hz,1H),7.01–6.99(m,1H),6.38(d,J＝5.2Hz,1H),4.39(s,2H),4.07(s,3H),4.05(s,3H),3.73(t,J＝5.2Hz,2H),3.45(s,3H),3.25(t,J＝5.2Hz,2H).13C NMR(100MHz,CDCl3)δ165.6,159.9,154.1(d,J＝248.4Hz),153.1,149.8,148.7,147.0,138.4(d,J＝12.4Hz),135.5(d,J＝9.2Hz),133.9,131.2,130.7(q,J＝32.4Hz),125.6(q,J＝3.7Hz),124.0(q,J＝270.6Hz),123.6,118.3(d,J＝3.3Hz),115.6,112.0(d,J＝22.7Hz),107.9,102.2,99.4,68.7,60.5,59.0,56.2,34.0.Anal.Calcd.For C29H27F4N3O6S:C,56.03；H,4.38；N,6.76.Found:C,56.04；H,4.37；N,6.78.ESI-MS:m/z 644.2[M+Na]+.
实施例24：目标化合物Ix的合成
Figure BDA0002469322020000151
实验步骤与实施例Ia相同，仅以3-氟-4-[(6-甲氧基-7-丁氧基喹啉)-4-氧基]苯胺代替3-氟-4-[(6,7-二甲氧基喹啉)-4-氧基]苯胺、甲基丙炔基醚代替己炔、4-氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：68％，熔点：115–117℃。1H NMR(400MHz,CDCl3)δ8.91(br s,1H),8.50(d,J＝5.2Hz,1H),7.62(dd,J＝2.4,12.0Hz,1H),7.57(s,1H),7.43(s,1H),7.38(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),7.19(t,J＝8.4Hz,1H),7.02–7.00(m,1H),6.37(d,J＝5.2Hz,1H),4.30(s,2H),4.20(t,J＝6.4Hz,2H),4.05(s,3H),3.72(t,J＝5.2Hz,2H),3.45(s,3H),3.24(t,J＝5.2Hz,2H),1.97-1.89(m,2H),1.59–1.50(m,2H),1.00(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ165.5,159.9,154.1(d,J＝248.6Hz),152.6,150.1,148.6,146.9,138.3(d,J＝12.3Hz),135.6(d,J＝9.4Hz),134.7,132.2,128.8,128.4,123.6,118.2(d,J＝2.9Hz),115.4,111.9(d,J＝22.8Hz),108.5,102.1,99.4,68.8,60.2,59.0,56.2,34.0,30.8,19.3,13.9.Anal.Calcd.For C31H33ClFN3O6S:C,59.09；H,5.28；N,6.67.Found:C,59.10；H,5.30；N,6.65.ESI-MS:m/z 630.2[M+H]+.
实施例25：目标化合物Iy的合成
Figure BDA0002469322020000152
实验步骤与实施例Ia相同，仅以3-氟-4-[(6-甲氧基-7-丁氧基喹啉)-4-氧基]苯胺代替3-氟-4-[(6,7-二甲氧基喹啉)-4-氧基]苯胺、甲基丙炔基醚代替己炔、3,4-二氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：61％，熔点：107–109℃。1H NMR(400MHz,CDCl3)δ8.94(br s,1H),8.50(d,J＝5.2Hz,1H),7.56(s,1H),7.55–7.51(m,2H),7.42-7.40(m,2H),7.28–7.26(m,1H),7.23(t,J＝8.4Hz,1H),7.08–7.06(m,1H),6.39(d,J＝5.2Hz,1H),4.27(s,2H),4.20(t,J＝6.8Hz,2H),4.05(s,3H),3.74(t,J＝5.2Hz,2H),3.46(s,3H),3.25(t,J＝5.2Hz,2H),1.96–1.89(m,2H),1.59-1.50(m,2H),1.00(t,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)δ165.6,159.9,154.1(d,J＝248.9Hz),152.6,150.1,148.6,146.9,138.5(d,J＝12.2Hz),135.4(d,J＝9.1Hz),132.9,132.7,132.6,130.5,130.2,130.1,123.6,118.5(d,J＝3.2Hz),115.4,111.8(d,J＝22.6Hz),108.5,102.3,99.4,68.8,68.7,59.7,59.0,56.2,34.0,30.8,19.3,13.9.Anal.Calcd.For C31H32Cl2FN3O6S:C,56.03；H,4.85；N,6.32.Found:C,56.04；H,4.85；N,6.35.ESI-MS:m/z 663.1[M]+.
实施例26：目标化合物Iz的合成
Figure BDA0002469322020000161
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(3-吗啉基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、4-氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：74％，熔点：122–124℃。1H NMR(400MHz,CDCl3)δ8.88(br s,1H),8.50(d,J＝5.2Hz,1H),7.62(dd,J＝2.4,12.0Hz,1H),7.57(s,1H),7.45(s,1H),7.38(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,2H),7.20(t,J＝8.4Hz,1H),7.02–7.01(m,1H),6.38(d,J＝5.2Hz,1H),4.30(s,2H),4.27(t,J＝6.4Hz,2H),4.05(s,3H),3.73–3.71(m,6H),3.45(s,3H),3.24(t,J＝4.8Hz,2H),2.58(t,J＝7.2Hz,2H),2.49(m,4H),2.17–2.10(m,2H).13C NMR(100MHz,CDCl3)δ165.5,159.9,154.1(d,J＝248.5Hz),152.5,150.0,148.7,146.9,138.3(d,J＝12.5Hz),135.6(d,J＝9.3Hz),134.7,132.2,128.8,128.4,123.6,118.2(d,J＝3.2Hz),115.5,111.9(d,J＝22.6Hz),108.7,102.2,99.5,68.8,67.3,67.0,60.2,59.0,56.2,55.4,53.7,33.9,26.0.Anal.Calcd.ForC34H38ClFN4O7S:C,58.24；H,5.46；N,7.99.Found:C,58.23；H,5.47；N,8.02.ESI-MS:m/z723.2[M+Na]+.
实施例27：目标化合物Iaa的合成
Figure BDA0002469322020000162
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(3-吗啉基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、3,4-二氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：72％，熔点：110–112℃。1H NMR(400MHz,CDCl3)δ8.92(br s,1H),8.49(d,J＝5.2Hz,1H),7.56(s,1H),7.55–7.51(m,2H),7.44(s,1H),7.41(d,J＝8.0Hz,1H),7.28–7.26(m,1H),7.23(t,J＝8.4Hz,1H),7.08–7.06(m,1H),6.39(d,J＝5.2Hz,1H),4.28–4.25(m,4H),4.04(s,3H),3.75–3.71(m,6H),3.46(s,3H),3.25(t,J＝5.2Hz,2H),2.58(t,J＝7.2Hz,2H),2.49(m,4H),2.16–2.09(m,2H).13C NMR(100MHz,CDCl3)δ165.7,159.8,154.1(d,J＝249.1Hz),152.5,150.0,148.6,146.9,138.5(d,J＝12.2Hz),135.4(d,J＝9.3Hz),132.9,132.7,132.6,130.5,130.2,130.1,123.6,118.5(d,J＝3.2Hz),115.5,111.8(d,J＝22.6Hz),108.7,102.3,99.5,68.7,67.3,67.0,59.7,59.0,56.2,55.4,53.7,34.0,26.0.Anal.Calcd.For C34H37Cl2FN4O7S:C,55.51；H,5.07；N,7.62.Found:C,55.50；H,5.09；N,7.60.ESI-MS:m/z 757.2[M+Na]+.
实施例28：目标化合物Iab的合成
Figure BDA0002469322020000171
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(3-哌啶基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、4-氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：64％，熔点：127–129℃。1H NMR(400MHz,CDCl3)δ9.26(s,1H),8.49(d,J＝6.4Hz,1H),7.67(dd,J＝2.0,12.0Hz,1H),7.56(s,1H),7.39(s,1H),7.36(d,J＝8.4Hz,2H),7.29(d,J＝8.8Hz,2H),7.19-7.12(m,2H),6.37(d,J＝4.8Hz,1H),4.30(s,2H),4.23(t,J＝5.6Hz,2H),4.01(s,3H),3.74(t,J＝5.2Hz,2H),3.41(s,3H),3.30–3.28(m,2H),3.23(t,J＝5.6Hz,2H),2.99-2.95(m,2H),2.48-2.33(m,4H),1.76-1.73(m,2H),1.64-1.56(m,4H).13C NMR(100MHz,CDCl3)δ165.5,160.1,154.0(d,J＝247.9Hz),151.8,149.8,148.9,146.5,138.0(d,J＝12.4Hz),135.9(d,J＝9.1Hz),134.6,132.2,128.8,128.5,123.5,118.3(d,J＝2.8Hz),115.8,111.8(d,J＝22.7Hz),109.7,102.4,99.7,68.9,66.3,60.2,59.0,56.1,55.3,53.7,34.1,24.0,23.2,22.4.Anal.Calcd.For C35H40ClFN4O6S:C,60.12；H,5.77；N,8.01.Found:C,60.10；H,5.78；N,8.03.ESI-MS:m/z 699.3[M+H]+.
实施例29：目标化合物Iac的合成
Figure BDA0002469322020000172
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(3-哌啶基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、3,4-二氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：67％，熔点：113–115℃。1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.50(d,J＝4.8Hz,1H),7.56(dd,J＝2.0,8.8Hz,1H),7.54(s,1H),7.51(d,J＝1.6Hz,1H),7.41(s,1H),7.35–7.33(m,1H),7.28(m,1H),7.21(t,J＝8.4Hz,1H),7.13–7.11(m,1H),6.39(d,J＝4.8Hz,1H),4.26(s,2H),4.19(t,J＝5.2Hz,2H),4.00(s,3H),3.74(t,J＝5.2Hz,2H),3.43(s,3H),3.25(t,J＝5.2Hz,2H),3.07-3.03(m,2H),2.94(m,4H),2.29–2.23(m,2H),1.81–1.75(m,2H),1.53(m,4H).13C NMR(100MHz,CDCl3)δ165.6,159.9,154.1(d,J＝248.7Hz),151.8,149.8,148.9,146.7,138.4(d,J＝12.1Hz),135.6(d,J＝9.4Hz),132.9,132.7,132.6,130.5,130.3,130.1,123.6,118.5,115.9,111.8(d,J＝22.5Hz),109.1,102.5,99.7,68.9,66.3,59.8,59.0,56.1,55.3,53.8,34.1,24.2,23.3,22.5.Anal.Calcd.For C35H39Cl2FN4O6S:C,57.30；H,5.36；N,7.64.Found:C,57.31；H,5.36；N,7.66.ESI-MS:m/z 733.2[M+H]+.
实施例30：目标化合物Iad的合成
Figure BDA0002469322020000181
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(4-甲基哌嗪-1-基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、4-氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：56％，熔点：132–134℃。1HNMR(400MHz,CDCl3)δ8.90(br s,1H),8.50(d,J＝5.2Hz,1H),7.62(dd,J＝2.0,12.0Hz,1H),.7.56(s,1H),7.43(s,1H),7.37(d,J＝8.4Hz,2H),7.31(d,J＝8.0Hz,2H),7.19(t,J＝8.4Hz,1H),7.02–7.00(m,1H),6.37(d,J＝5.2Hz,1H),4.30(s,2H),4.25(t,J＝6.8Hz,2H),4.04(s,3H),3.72(t,J＝5.2Hz,2H),3.45(s,3H),3.24(t,J＝5.2Hz,2H),2.59(t,J＝7.2Hz,4H),2.53(m,6H),2.31(s,3H),2.16-2.09(m,2H).13C NMR(100MHz,CDCl3)δ165.5,159.9,154.2(d,J＝248.3Hz),152.5,150.1,148.8,147.1,138.4(d,J＝12.2Hz),135.6(d,J＝9.4Hz),134.7,132.2,128.9,128.4,123.6,118.2(d,J＝3.2Hz),115.5,111.9(d,J＝22.8Hz),108.9,102.2,99.5,68.8,67.4,60.3,59.0,56.3,55.1,54.9,53.0,45.9,33.9,26.4.Anal.Calcd.For C35H41ClFN5O6S:C,58.86；H,5.79；N,9.81.Found:C,58.88；H,5.77；N,9.84.ESI-MS:m/z 714.3[M+H]+.
实施例31：目标化合物Iae的合成
Figure BDA0002469322020000182
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(4-甲基哌嗪-1-基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、3,4-二氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：53％，熔点：118–120℃。1H NMR(400MHz,CDCl3)δ9.02(br s,1H),8.48(d,J＝4.0Hz,1H),7.55(s,1H),7.51(dd,J＝2.0,11.6Hz,2H),7.42(s,1H),7.39(d,J＝8.0Hz,1H),7.26(dd,J＝1.6,8.4Hz,1H),7.21(t,J＝8.4Hz,1H),7.10–7.08(m,1H),6.38(d,J＝4.8Hz,1H),4.26(s,2H),4.23–4.22(m,2H),4.02(s,3H),3.73(t,J＝5.2Hz,2H),3.43(s,3H),3.23(t,J＝5.2Hz,2H),2.62-2.58(m,10H),2.36(s,3H),2.14-2.08(m,2H).13C NMR(100MHz,CDCl3)δ165.6,159.8,154.1(d,J＝249.1Hz),152.4,150.0,148.7,146.9,138.5(d,J＝12.4Hz),135.4(d,J＝9.0Hz),132.9,132.7,132.6,130.5,130.2,130.1,123.6,118.5(d,J＝3.0Hz),115.5,111.8(d,J＝22.6Hz),108.7,102.3,99.5,68.8,67.2,59.7,59.0,56.2,54.8,54.7,52.4,45.4,34.0,26.2.Anal.Calcd.For C35H40Cl2FN5O6S:C,56.15；H,5.39；N,9.35.Found:C,56.14；H,5.41；N,9.36.ESI-MS:m/z 748.2[M+H]+.
实施例32：目标化合物Iaf的合成
Figure BDA0002469322020000191
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(4-甲基哌啶-1-基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、4-氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：59％，熔点：110–113℃。1HNMR(400MHz,CDCl3)δ9.24(br s,1H),8.47(d,J＝5.2Hz,1H),7.64(dd,J＝2.0,12.0Hz,1H),7.53(s,1H),7.37(s,1H),7.34(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.17–7.09(m,2H),6.35(d,J＝4.8Hz,1H),4.27(s,2H),4.21(t,J＝5.6Hz,2H),3.98(s,3H),3.71(t,J＝5.2Hz,2H),3.38(s,3H),3.28–3.25(m,2H),3.21(t,J＝5.6Hz,2H),2.95(t,J＝7.2Hz,2H),2.46–2.40(m,2H),2.34–2.30(m,2H),1.73–1.70(m,2H),1.62–1.53(m,3H),0.94(d,J＝6.0Hz,3H).13C NMR(100MHz,CDCl3)δ165.4,159.9,154.0(d,J＝248.1Hz),151.9,149.7,148.7,146.7,138.0(d,J＝12.6Hz),135.8(d,J＝9.4Hz),134.5,132.1,128.7,128.4,123.4,118.3,115.6,111.7(d,J＝22.7Hz),108.9,102.3,99.6,69.0,66.6,60.2,58.9,56.1,55.0,53.3,34.2,31.9,29.6,24.8,21.1.Anal.Calcd.For C36H42ClFN4O6S:C,60.62；H,5.94；N,7.86.Found:C,60.65；H,5.95；N,7.88.ESI-MS:m/z 713.3[M+H]+.
实施例33：目标化合物Iag的合成
Figure BDA0002469322020000192
实验步骤与实施例Ia相同，仅以3-氟-4-((6-甲氧基-7-(4-甲基哌啶-1-基)丙氧基喹啉)-4-氧基)苯胺代替3-氟-4-((6,7-二甲氧基喹啉)-4-氧基)苯胺、甲基丙炔基醚代替己炔、3,4-二氯苄磺酰基叠氮代替苄磺酰基叠氮。黄色固体，收率：56％，熔点：107–109℃。1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.48(d,J＝4.8Hz,1H),7.58(d,J＝12.4Hz,1H),7.54(s,1H),7.49(s,1H),7.37(d,J＝8.0Hz,2H),7.24-7.14(m,3H),6.38(d,J＝4.8Hz,1H),4.25(s,2H),4.22(m,2H),3.99(s,3H),3.73(t,J＝5.2Hz,2H),3.40(s,3H),3.33–3.30(m,2H),3.23(t,J＝5.2Hz,2H),3.00(t,J＝7.6Hz,2H),2.49(t,J＝9.2Hz,2H),2.36(m,2H),1.76–1.73(m,2H),1.67-1.53(m,3H),0.96(d,J＝6.0Hz,3H).13C NMR(100MHz,CDCl3)δ165.6,159.8,154.0(d,J＝248.6Hz),151.9,149.8,148.8,146.7,138.3(d,J＝12.2Hz),135.7(d,J＝9.1Hz),132.8,132.6,130.5,130.3,130.2,123.5,118.5(d,J＝3.1Hz),115.8,111.8(d,J＝22.7Hz),109.0,102.6,99.7,68.9,66.5,59.7,59.0,56.1,55.0,53.3,34.2,31.7,29.6,24.6,21.1.Anal.Calcd.For C36H41Cl2FN4O6S:C,57.83；H,5.53；N,7.49.Found:C,57.82；H,5.56；N,7.51.ESI-MS:m/z769.2[M+Na]+.
二、化合物抗肿瘤活性的实验方法及结果
本发明的药理实验采用MTT染色法。肿瘤细胞培养选用含有10％胎牛血清(FBS)的RPMI-1640培养基，将肿瘤细胞接种于96孔板，接种量为3-5×103个/孔，培养12h待细胞贴壁后加入不同浓度的待测化合物溶液。培养72h后，每孔加入MTT溶液使终浓度为5μg/mL，培养4h后，倒掉上清液，PBS缓冲液洗涤三次，每孔加入DMSO 200μL，振摇溶解，测定492nm处光吸收值。所有试验均设3个平行组或重复3次。
化合物Ia-Iag的细胞毒活性测试结果见表1
表1 化合物Ia-Iag的细胞毒活性试验结果
Figure BDA0002469322020000201
Figure BDA0002469322020000211
体外实验表明，本发明所述的化合物Ia-Iag对人肺癌细胞、人结肠癌细胞、人胃癌细胞、人乳腺癌细胞表现出较好的抑制活性，大部分化合物均表现出了中等到优异的抗增殖活性。尤其Iz对于A549，HT-29及MDA-MB-231三种肿瘤细胞的抗增殖活性均优于阳性对照Foretinib，其IC50值在0.28～0.72μM之间。此外，本类化合物相较于人胃癌细胞、人乳腺癌细胞、人结肠癌细胞，对于人肺癌细胞表现出更高的选择性，因此本发明所制得的化合物可用于制备抗肿瘤药物。另外，由实施例可知，该类化合物合成方法简单、原料廉价易得，终产物易处理，产品纯度高等优点。
以上所述仅为本申请的优选实施例，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (7)

1.一种4-苯氧基喹啉并N-磺酰脒类化合物及其药学上可接受的盐，所述化合物具有如通式I的结构：
Figure DEST_PATH_IMAGE001
其中，R1选自苯基、4-甲基苯基、3-甲基苯基、2-甲基苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-氯苯基、4-溴苯基、3 ,4-二氯苯基、4-三氟甲基苯基；R2选自正丁基、苯基、甲氧基甲基、氢、1-环己烯基、3-吡啶基、3-噻吩基；R3选自甲基、正丁基、3-(吗啉基)丙基、3-(哌啶-1-基)丙基、3-(4-甲基哌嗪-1-基)丙基、3-(4-甲基哌啶-1-基)丙基。
2.根据权利要求1所述的4-苯氧基喹啉并N-磺酰脒类化合物及其药学上可接受的盐，其中所述药学上可接受的盐为式I化合物的盐酸盐、硫酸盐、磷酸盐、三氟乙酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、琥珀酸盐。
3.一种根据权利要求1所述的4-苯氧基喹啉并N-磺酰脒类化合物的制备方法，由芳胺类化合物II，炔和磺酰基叠氮类化合物的三组分反应获得，反应式如下：
Figure 103466DEST_PATH_IMAGE002
。
4.一种根据权利要求1所述的4-苯氧基喹啉并N-磺酰脒类化合物及其药学上可接受的盐在制备治疗与蛋白激酶有关的疾病中的药物的应用，所述的蛋白激酶为酪氨酸激酶。
5.根据权利要求4所述中的应用，所述的酪氨酸激酶为c-Met受体酪氨酸激酶。
6.根据权利要求4所述中的应用，所述的与酪氨酸激酶有关的疾病为癌症。
7.根据权利要求6所述中的应用，其特征在于，其中所述癌症包括肺癌、结肠癌、胃癌、乳腺癌。
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