CN110981819A - 一种喹喔啉类信号通路抑制剂及其制备方法和应用 - Google Patents
一种喹喔啉类信号通路抑制剂及其制备方法和应用 Download PDFInfo
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- CN110981819A CN110981819A CN201911346689.2A CN201911346689A CN110981819A CN 110981819 A CN110981819 A CN 110981819A CN 201911346689 A CN201911346689 A CN 201911346689A CN 110981819 A CN110981819 A CN 110981819A
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- quinoxaline
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- compound
- carboxamide
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Abstract
本发明属于药物化学领域，具体提供了一种喹喔啉类信号通路抑制剂及其制备方法和应用，喹喔啉类信号通路抑制剂的通式为
Description
技术领域
本发明属于药物化学领域，具体涉及一种喹喔啉类信号通路抑制剂及其制备方法和应用。
背景技术
癌症是威胁人们健康的主要疾病，死亡率很高，特别是在发展中国家。2015年，我国新诊断的癌症就有约430万例,，仅在这一年就导致280多万人死亡，高毒性、低疗效是抗肿瘤药物的共同缺点，因此，研发更多更有效的抗肿瘤药物显得尤为迫切。
目前认为有三条主要的信号通路对肿瘤细胞发挥着重要的作用，分别是MAPk/Ras、PKC和PI3K/Akt信号通路，其中PI3K/Akt/mTOR信号通路对哺乳动物细胞的生长和增殖起到最关键的作用。
磷脂酰肌醇3激酶(phosphatidylinositol-3kinase:PI3K)信号通路是极为关键的抗肿瘤通路，在促进细胞增殖、抑制细胞凋亡、促进肿瘤血管生成和肿瘤细胞迁移和侵袭等方面都发挥着重要作用，而且PI3K通常以异常活化的形式存在于人类许多肿瘤细胞中，PI3K是细胞信号通路中一个重要且庞大的激酶家族，是PI3K/Akt/mTOR信号通路上的关键位点。大量研究结果表明，人体内肿瘤的发生发展和PI3K/Akt/mTOR信号通路的调节和异常活化密切相关，PI3k/Akt/mTOR信号通路抑制剂可以抑制肿瘤细胞的增殖、分化、转移,从而促进肿瘤细胞的凋亡。所以，基于该信号通路的药物研发是当前抗肿瘤药物新药研究的重要领域.。
发明内容
本发明提供了一种喹喔啉类信号通路抑制剂及其制备方法和应用，该类制备方法可制备更多的喹喔啉类类化合物，其在体外及体内均显示良好的抗癌效果，在抗癌新药研发等方面具有良好应用前景。
为实现上述目的，本发明的技术方案为：
具有通式(I)的喹喔啉类信号通路抑制剂：
其中，X为NH或S，R1为H、卤素、烷基、烷氧基或卤烷基，R2为氨基或烷氨基，n为2或3。
进一步的，R1为4-OCH3、4-Cl、4-CH3、2-OCH3、3-CH3、2-F、2-Cl、2-Br、3-Cl、3-Br、4-F、4-Br或2,4-Cl，R2为N(CH3)2、NH2、N(C2H5)2或N(CH(CH3)2)2。
更进一步的，当X为NH时，R1为4-OCH3、4-Cl、4-CH3、2-OCH3、3-CH3、2-F、2-Cl、2-Br、3-Cl、3-Br或4-F；
当X为S时，R1为4-F、4-Cl、4-Br、2,4-Cl、2-Cl、2-Br、3-Cl或3-Br。
更进一步的，当n＝2时，R2为N(CH3)2、NH2或N(C2H5)2；当n＝3时，R2为N(CH3)2、NH2、N(C2H5)2或N(CH(CH3)2)2。
本发明还提供了一种具有通式(I)的喹喔啉类信号通路抑制剂的制备方法，包括以下步骤：
S1.
与
在有溶剂的条件下反应得
S2.
与
在有溶剂的条件下反应得到目标化合物喹喔啉类信号通路抑制剂
进一步的，所述步骤S1的反应是在氮气或惰性气体保护、搅拌条件下进行，溶剂为无水乙醇，反应温度为75～80℃；
所述步骤S2的反应是在氮气或惰性气体保护、搅拌条件下进行，溶剂为无水乙醇，反应温度为75～80℃。
进一步的，所述步骤S1中，反应完成后，还包括提纯步骤：冷却、抽滤、无水乙醇洗涤、干燥；
所述步骤S2中，反应完成后，还包括提纯步骤：冷却、除去溶剂、硅胶柱层析提纯。
本发明还提供了一种以上所述的信号通路抑制剂或以上制备方法制备得到的目标化合物在制备信号通路抑制剂中的应用，所述信号通路为PI3K/Akt/mTOR信号通路。
本发明进一步提供了以上制备方法制备得到的目标化合物在制备抗肿瘤药物中的应用。
更进一步的，所述肿瘤为人胃癌肿瘤、人肺癌肿瘤、人宫颈癌细胞、人肝癌肿瘤或人膀胱癌肿瘤。
本发明发展了一条合成喹喔啉-2-甲酰胺衍生物的路线，使得制备获得的喹喔啉各多样化，为制备抗肿瘤药物提供了更多选择。
经试验证明，本发明制备方法制得的化合物对MGC-803、A549、Hela、HepG-2、T24和WI38均具有很好的抑制活性，为制备治疗人胃癌肿瘤、人肺癌肿瘤、人宫颈癌细胞、人肝癌肿瘤或人膀胱癌肿瘤的药物提供了新的方向。
本发明制备获得的代表化合物对PI3K/Akt/mTOR信号通路有较为显著的抑制作用，且可促进胃癌细胞MGC-803基于线粒体途径的细胞凋亡，为抗肿瘤药物的开发提供了更广阔的思路。
附图说明
图1a是化合物6bc诱导MGC-803细胞发生凋亡的示意图。
图1b是化合物6bc诱导MGC-803细胞发生凋亡的western blot测定结果图。
图1c是化合物6bc处理MGC-803细胞后用Hoechst 33258染色的实验结果图。
图1d是化合物6bc诱导MGC-803细胞线粒体膜电位变化的示意图。
图1e是化合物6bc诱导MGC-803细胞内ROS变化的示意图。
图1f是化合物6bc诱导MGC-803细胞内Ca2+浓度变化的示意图。
图2a、2b为化合物6bc对PI3K/Akt/m-TOR信号通路影响的示意图：(2a)用6bc和LY294002(0.1、0.25和0.5μM)处理MGC-803细胞24h后的western blot测定图，(2b)直方图表示三个不同浓度实验的平均值±SD。
图2c、2d为化合物6bc对Akt/m-TOR信号通路影响的示意图：(2c)用6bc(0.5和1.0μM)和LY294002(2.5和5μM)处理MGC-803细胞24h后的western blot测定图，(2d)直方图表示三个不同浓度实验的平均值±SD。
图2e、2f为化合物6bc对Akt/m-TOR信号通路影响的示意图：(2e)用6bc(0.5和1.0μM)和LY294002(2.5和5μM)处理SMMC-7721细胞24h后的western blot测定图，(2f)直方图表示三个不同浓度实验的平均值±SD。
图2g、2h为化合物6bc对Akt/m-TOR信号通路影响的示意图.(2g)用6bc(1.0,2.5和5.0μM)处理MGC-803细胞24h后的western blot测定图,(2h)直方图表示三个不同浓度实验的平均值±SD。
具体实施方式
以下将结合具体实施例对本发明作进一步说明，但本发明的保护范围不限于以下实施例。
以下实施例的合成路线为：
本实施例涉及的具体目标化合物结构式包括：
实施例1：化合物2的合成
在电磁搅拌下，依次向100mL的圆底烧瓶中加入化合物1和POCl3，在氮气保护下,加热至90℃，搅拌反应1h，冷却至室温，减压除去溶剂，向烧瓶中加入冰水，用二氯甲烷萃取，合并有机相，依次用饱和碳酸氢钠、饱和氯化钠溶液洗涤，无水硫酸钠干燥，经硅胶柱层析提纯，得到化合物2。
实施例2:2-乙氧羰基-3-(4-甲氧基苯胺基)喹喔啉(4a)的合成
在电磁搅拌下，依次向50mL的圆底烧瓶中加入化合物2(1.5g,6.36mmol)、对甲氧基苯胺(1.56g,12.7mmol)和乙醇(15mL)，在氮气保护下，加热至80℃，搅拌反应22h(TLC监测反应进程,展开剂:V乙酸乙酯:V石油醚＝1:4)，反应结束后，冷却至室温，抽滤，用无水乙醇洗涤(2×10mL)，烘干，得到1.29g化合物4a的砖红色固体。
4a:brick red solid,产率63％.m.p.129～130°C；1H NMR(400MHz,CDCl3)δ:10.14(s,1H),8.03–7.99(m,1H),7.82–7.77(m,2H),7.76–7.72(m,1H),7.70–7.64(m,1H),7.47–7.41(m,1H),6.98–6.92(m,2H),4.59(q,J＝7.1Hz,2H),3.84(s,4H),1.53(t,J＝7.1Hz,4H).13C NMR(100MHz,CDCl3)δ:166.5,155.8,149.6,143.4,136.3,132.9,132.3,130.5,130.2,126.6,125.6,122.2,114.1,63.0,55.6,14.3.1。
实施例3:2-乙氧羰基-3-(4-氯苯胺基)喹喔啉(4b)
用对氯苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4b:brownish yellow solid,产率82％,m.p.156～158℃；1H NMR(400MHz,CDCl3)δ:10.37(s,1H),8.07–(m,1H),7.91–7.86(m,2H),7.82–7.77(m,1H),7.74–7.69(m,1H),7.53–7.48(m,1H),7.37–7.33(m,2H),4.60(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13CNMR(100MHz,CDCl3)δ:166.5,149.1,143.0,137.9,136.5,133.1,130.5,130.3,128.9,127.9,126.7,126.3,121.4,63.1,14.3。
实施例4:2-乙氧羰基-3-(4-甲基苯胺基)喹喔啉(4c)
用对甲基苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4c:yellow solid,产率49％,m.p.124～126℃；1H NMR(400MHz,CDCl3)δ:10.22(s,1H),8.04–8.00(m,1H),7.81–7.75(m,3H),7.71–7.65(m,1H),7.48–7.42(m,1H),7.22–7.2.(m\,2H),4.60(q,J＝7.1Hz,2H),2.36(s,3H),1.53(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.5,149.5,143.4,136.6,136.3,132.9,132.9,130.6,130.2,129.4,126.7,125.8,120.5,63.0,20.9,14.3。
实施例5:2-乙氧羰基-3-(2-甲氧基苯胺基)喹喔啉(4d)
用邻氟苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4d产率:82％.brownish yellow solid,产率29％,m.p.146～148℃；1H NMR(400MHz,CDCl3)δ:10.74(s,1H),9.04–8.97(m,1H),8.04(dd,J＝8.4,0.9Hz,1H),7.83(dd,J＝8.4,0.8Hz,1H),7.73–7.67(m,1H),7.50–7.44(m,1H),7.09–7.03(m,2H),7.00–6.94(m,1H),4.62(q,J＝7.1Hz,2H),4.01(s,3H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.0,149.1,149.0,143.2,136.2,132.8,131.5,130.2,129.3,126.7,125.8,122.6,120.8,119.6,110.1,62.9,56.1,14.3。
实施例6:2-乙氧羰基-3-(3-甲基苯胺基)喹喔啉(4e)
用间甲基苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4e:brownish yellow solid,产率40％,m.p.114～116℃；1H NMR(400MHz,CDCl3)δ:10.28(s,1H),8.03(d,J＝8.3Hz,1H),7.84–7.78(m,2H),7.73–7.67(m,1H),7.66(s,1H),7.52–7.44(m,1H),7.29(t,J＝7.8Hz,1H),6.94(d,J＝7.5Hz,1H),4.60(q,J＝7.1Hz,2H),2.41(s,3H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.5,149.4,143.3,139.1,138.7,136.4,132.9,130.6,130.2,128.8,126.7,125.9,124.2,121.0,117.5,63.0,21.7,14.3。
实施例7:2-乙氧羰基-3-(2-氟苯胺基)喹喔啉(4f)
用邻氟苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
合成方法同实施例1.4f:yellow solid,产率82％,m.p.75～77℃；1H NMR(400MHz,CDCl3)δ:10.60(s,1H),8.93(td,J＝8.2,1.5Hz,1H),8.23–8.15(m,1H),8.12–8.03(m,2H),7.85–7.83(m,1H),7.76–7.71(m,1H),7.52(ddd,J＝8.3,6.9,1.3Hz,1H),7.08–7.01(m,1H),4.63(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.4,164.3,152.2,149.2,144.2,143.1,142.5,139.8,136.7,133.1(d,J＝18.4Hz),131.3,130.42,129.8,128.5,126.9,126.5,123.11(d,J＝7.6Hz),121.4,114.9(d,J＝19.4Hz),63.3,14.4。
实施例8:2-乙氧羰基-3-(2-氯苯胺基)喹喔啉(4g)
用邻氯苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4g:yellow solid,产率52％,m.p.109～111℃；1H NMR(400MHz,CDCl3)δ:10.77(s,1H),8.99(dd,J＝8.3,1.4Hz,1H),8.09–8.06(m,1H),7.85–7.82(m,1H),7.78–7.71(m,1H),7.57–7.50(m,1H),7.46(dd,J＝8.0,1.4Hz,1H),7.39–7.32(m,1H),7.04(td,J＝7.8,1.5Hz,1H),4.64(q,J＝7.1Hz,1H),1.56–1.52(d,J＝7.1Hz,1H).13C NMR(100MHz,CDCl3)δ:166.3,149.0,142.9,136.8,136.5,133.2,130.4,129.5,128.5,127.4,126.9,126.6,123.0,123.5,121.4,63.3,14.3。
实施例9:2-乙氧羰基-3-(2-溴苯胺基)喹喔啉(4h)
用邻溴苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4h:yellow solid,产率76％,m.p.157～159℃；1H NMR(400MHz,CDCl3)δ:10.62(s,1H),8.89(dd,J＝8.3,1.5Hz,1H),8.07(dd,J＝8.4,0.9Hz,1H),7.81(dd,J＝8.4,0.9Hz,1H),7.75–7.70(m,1H),7.63(dd,J＝8.0,1.5Hz,1H),7.55–7.50(m,1H),7.42–7.36(m,1H),7.00–6.95(m,1H),4.64(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.0,148.9,142.7,137.5,136.7,133.0,132.7,131.3,130.2,127.8,126.8,126.5,124.1,121.8,114.5,63.1,14.4。
实施例10:2-乙氧羰基-3-(3-氯苯胺基)喹喔啉(4i)
用间氯苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
合成方法同实施例1.4i:yellow solid,产率57％,m.p.117～119℃；1H NMR(400MHz,CDCl3)δ:10.42(s,1H),8.17(t,J＝2.0Hz,1H),8.07–8.02(m,1H),7.86–7.81(m,1H),7.76–7.71(m,1H),7.71–7.67(m,1H),7.54–7.48(m,1H),7.30(t,J＝8.1Hz,1H),7.09–7.05(m,1H),4.60(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.5,149.0,142.9,140.5,136.6,134.5,133.1,130.5,130.2,129.8,126.8,126.4,123.1,120.1,118.2,63.2,14.3。
实施例11:2-乙氧羰基-3-(3-溴苯胺基)喹喔啉(4j)
用间溴苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4j:yellow solid,产率98％,m.p.126～128℃；1H NMR(400MHz,CDCl3)δ:10.41(s,1H),8.30–8.27(m,1H),8.06–8.03(m,1H),7.85–7.79(m,1H),7.79–7.70(m,2H),7.54–7.48(m,1H),7.25–7.20(m,2H),4.60(q,J＝7.1Hz,2H),1.53(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.4,149.0,142.9,140.6,136.6,133.1,130.5,130.2,130.1,126.8,126.4,126.0,122.9,122.6,118.6,63.2,14.3。
实施例12:2-乙氧羰基-3-(4-氟苯氨基)-喹喔啉(4k)
用对氟苯胺代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
4k:yellow solid,产率36％,m.p.154～156℃；1H NMR(400MHz,CDCl3)δ:10.27(s,1H),8.06–8.01(m,1H),7.89–7.83(m,2H),7.79–7.74(m,1H),7.73–7.66(m,1H),7.51–7.44(m,1H),7.13–7.04(m,2H),4.60(q,J＝7.1Hz,2H),1.53(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:166.5,160.0,157.6,149.3,143.1,136.5,135.22(d,J＝3.0Hz),133.0,130.5,130.2,126.6,126.0,122.0(d,J＝7.0Hz),115.5(d,J＝23.0Hz),63.1,14.3。
实施例13:2-乙氧羰基-3-(4-氟苯硫基)-喹喔啉(5a)
用对氟苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5a:light yellow solid,产率78％,m.p.114～116℃；1H NMR(400MHz,CDCl3)δ:8.13(d,J＝7.8Hz,1H),7.69(ddd,J＝17.0,10.8,6.6Hz,3H),7.58(dd,J＝8.0,5.6Hz,2H),7.16(t,J＝8.5Hz,2H),4.62(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ:164.55(d,J＝6.3Hz),162.6,156.2,142.7,140.5,138.6,138.0(d,J＝8.8Hz),132.3,129.9,129.3,128.1,124.8(d,J＝3.9Hz),116.4,116.2,62.9,14.3。
实施例14:2-乙氧羰基-3-(4-氯苯硫基)-喹喔啉(5b)
用对氯苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5b:light yellow solid,产率88％,m.p.108～110℃；1H NMR(400MHz,CDCl3)δ:8.14(dd,J＝8.8,1.4Hz,1H),7.74–7.65(m,3H),7.57–7.51(m,2H),7.46–7.39(m,2H),4.62(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ:164.6,155.8,142.7,140.5,138.6,137.1,135.6,132.4,129.9,129.4,129.3,128.1,63.0,14.3。
实施例15:2-乙氧羰基-3-(4-溴苯硫基)-喹喔啉(5c)
用对溴苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5c:light yellow solid,产率86％,m.p.130～132℃；1H NMR(400MHz,CDCl3)δ:8.19–8.09(m,1H),7.74–7.65(m,3H),7.62–7.55(m,2H),7.50–7.44(m,2H),4.61(q,J＝7.1Hz,2H),1.53(t,J＝7.1Hz,3H).13C NMR(125MHz,CDCl3)δ:164.5,155.6,142.7,140.5,140.5,138.6,137.3,132.4,132.4,132.2,129.9,129.4,128.7,128.1,123.8,63.0,14.3。
实施例16:2-乙氧羰基-3-(2,4-二氯苯硫基)-喹喔啉(5d)
用2,4-二氯苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5d:light yellow solid,产率76％,m.p.132～134℃；1H NMR(400MHz,CDCl3)δ:8.15(d,J＝8.0Hz,1H),7.71–7.65(m,3H),7.63(d,J＝8.3Hz,1H),7.58(d,J＝2.1Hz,1H),7.33(dd,J＝8.2,2.1Hz,1H),4.63(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:164.5,154.7,142.7,141.2,140.1,138.6,136.4,132.5,130.0,129.5,128.12,128.1,127.7,63.0,14.3。
实施例17:2-乙氧羰基-3-(2-氯苯硫基)-喹喔啉(5e)
用邻氯苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5e:light yellow solid,产率62％,m.p.132～134℃；1H NMR(400MHz,CDCl3)δ:8.16–8.14(m,1H),7.72–7.65(m,3H),7.64–7.62(m,1H),7.56(dd,J＝8.0,1.4Hz,1H),7.43(td,J＝7.6,1.7Hz,1H),7.35(td,J＝7.6,1.4Hz,1H),4.62(t,J＝7.2Hz,2H),1.55(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:164.6,155.1,142.8,140.3,140.2,138.6,137.9,132.3,130.9,130.1,129.9,129.3,129.3,128.2,127.3,63.0,14.3。
实施例18:2-乙氧羰基-3-(2-溴苯硫基)-喹喔啉(5f)
用邻溴苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5f:light yellow solid,产率93％,m.p.138～140℃；1H NMR(400MHz,CDCl3)δ:8.16–8.13(m,1H),7.76–7.73(m,2H),7.70–7.65(m,2H),7.64–7.62(m,1H),7.39(td,J＝7.4,1.4Hz,1H),7.33(td,J＝7.7,1.8Hz,1H),4.63(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:164.6,155.2,142.8,140.4,138.6,137.9,133.5,132.3,131.6,131.3,130.9,129.9,129.3,128.2,128.0,63.0,14.3。
实施例19:2-乙氧羰基-3-(3-氯苯硫基)-喹喔啉(5g)
用间氯苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5g:light yellow solid,产率88％,m.p.131～133℃；1H NMR(400MHz,CDCl3)δ:8.31–8.27(m,2H),8.18–8.15(m,1H),7.80–7.77(m,2H),7.73(m,2H),7.69–7.38(m,1H),4.66–4.63(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:164.4,154.4,148.1,142.5,140.4,138.8,135.9,135.4,133.8,132.8,132.4,130.0,129.9,128.0,123.8,63.1,14.3.
实施例20:2-乙氧羰基-3-(3-溴苯硫基)-喹喔啉(5h)
用间溴苯硫酚代替实施例2中的对甲氧基苯胺，其它实验操作方法同实施例2。
5h:light yellow solid,产率76％,m.p.130～132℃；1H NMR(400MHz,CDCl3)δ:8.15–
8.13(m,1H),7.78(t,J＝1.8Hz,1H),7.72–7.65(m,3H),7.60–7.57(m,1H),7.55–7.52(m,1H),7.34–7.32(m,1H),4.61(q,J＝7.1Hz,2H),1.53(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ:164.5,155.5,142.7,140.5,138.7,138.2,134.3,132.4,132.3,131.8,130.3,129.9,129.5,128.2,122.5,63.0,14.3。
实施例21:N-(3-(二甲氨基)丙基)-3-((4-甲氧基苯基)氨基)喹喔啉-2-甲酰胺(6aa)的合成
在电磁搅拌下，依次向25mL的圆底烧瓶中加入化合物4a(0.15g,0.49mmol)、N,N-二甲基-1,3-丙二胺(0.3mL,2.45mmol)和乙醇(3mL)，在氮气保护下，加热至80℃，搅拌反应3h(TLC监测反应进程,展开剂:V甲醇:V二氯甲烷＝1:15)，反应结束后，冷却至室温，减压除去溶剂，用硅胶柱层析提纯(洗脱剂:V甲醇:V二氯甲烷＝1:30)得到0.14g化合物6a的红色固体，产率93％。
N-(3-(dimethylamino)propyl)-3-((4-methoxyphenyl)amino)quinoxaline-2-carboxamide(6aa):red solid,产率93.3％,m.p.67～68℃；1H NMR(400MHz,CDCl3)δ:11.29(s,1H),9.42(s,1H),7.86(d,J＝8.6Hz,2H),7.80(d,J＝8.1Hz,1H),7.75(d,J＝8.1Hz,1H),7.63(t,J＝7.3Hz,1H),7.40(t,J＝7.3Hz,1H),6.94(d,J＝8.6Hz,2H),3.83(s,3H),3.62–3.54(m,2H),2.50(t,J＝6.2Hz,2H),2.34(s,6H),1.92–1.78(m,2H).13C NMR(100MHz,CDCl3)δ:165.7,155.4,149.5,143.6,135.3,132.9,132.1,131.8,129.1,126.5,125.1,121.6,114.1,58.2,55.6,45.5,39.1,26.4.HRMS(ESI)m/z calcd for C21H26N5O2[M+H]+380.2081,found 380.2077.
实施例22:N-(3-(二乙氨基)丙基)-3-((4-甲氧基苯基)氨基)喹喔啉-2-甲酰胺(6ab)的合成
用N,N-二乙基-1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-(diethylamino)propyl)-3-((4-methoxyphenyl)amino)quinoxaline-2-carboxamide(6ab):red solid,产率95.4％,m.p.59～60℃；1H NMR(400MHz,CDCl3)δ:11.34(s,1H),9.67(s,1H),7.90–7.84(m,2H),7.81(dd,J＝8.3,1.1Hz,1H),7.75(dd,J＝8.4,1.1Hz,1H),7.66–7.60(m,1H),7.43–7.37(m,1H),6.97–6.91(m,2H),3.83(s,3H),3.60(q,J＝6.4Hz,2H),2.70–2.56(m,6H),1.84(t,J＝6.2Hz,2H),1.12(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ:165.8,155.4,149.5,143.5,135.3,133.0,132.3,131.7,129.0,126.5,125.1,121.6,114.1,55.6,52.1,47.1,39.8,25.7,11.7.HRMS(ESI)m/z calcd forC23H30N5O2[M+H]+408.2394,found 408.2390.
实施例23:N-(3-氨基丙基)-3-((4-甲氧基苯基)氨基)喹喔啉-2-甲酰胺(6ac)的合成.
用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((4-methoxyphenyl)amino)quinoxaline-2-carboxamide(6ac):yellow solid,产率96.0％,m.p.115～116℃；1H NMR(400MHz,CDCl3)δ:11.21(s,1H),8.74(s,1H),7.88–7.83(m,2H),7.83–7.79(m,1H),7.77–7.70(m,1H),7.66–7.60(m,1H),7.44–7.36(m,1H),6.98–6.89(m,2H),3.83(s,3H),3.66–3.54(m,2H),2.95–2.83(m,2H),1.90–1.76(m,2H),1.43(s,2H).13C NMR(100MHz,CDCl3)δ:165.8,155.5,149.5,143.7,135.1,132.8,131.9,131.7,129.1,126.5,125.2,121.7,114.1,55.6,39.9,37.5,32.7.HRMS(ESI)m/z calcd for C19H22N5O2[M+H]+352.1768,found 352.1773.
实施例24:N-(2-(二甲胺基)乙基)-3-((4-甲氧基苯基)氨基)喹喔啉-2-甲酰胺(6ad)的合成
用N,N-二甲基乙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(2-(dimethylamino)ethyl)-3-((4-methoxyphenyl)amino)quinoxaline-2-carboxamide(6ad):red solid,产率95.5％,m.p.128～129℃；1H NMR(400MHz,CDCl3)δ:11.20(s,1H),8.65(s,1H),7.89–7.83(m,3H),7.74(d,J＝7.9Hz,1H),7.66–7.60(m,1H),7.43–7.37(m,1H),6.97–6.90(m,2H),3.83(s,3H),3.59(q,J＝6.0Hz,2H),2.60(t,J＝6.2Hz,2H),2.34(s,6H).13C NMR(100MHz,CDCl3)δ:165.8,155.5,149.5,143.6,135.2,132.9,131.9,131.8,129.2,126.5,125.2,121.7,114.1,58.0,55.6,45.5,37.3.HRMS(ESI)m/z calcd for C20H24N5O2[M+H]+366.1925,found 366.1924。
实施例25:N-(3-(二甲基氨基)丙基)-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6ba)的合成
用化合物代4b替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((4-Chlorophenyl)amino)quinoxaline-2-carboxamide(6ba):yellow solid,产率96.8％,m.p.111～112℃；1H NMR(400MHz,CDCl3)δ:11.52(s,1H),9.46(s,1H),7.88(d,J＝8.9Hz,2H),7.75(d,J＝8.3Hz,1H),7.71(d,J＝8.4Hz,1H)7.63–7.58(m,1H),7.43–7.35(m,1H),7.27(d,J＝8.8Hz,2H),3.55(q,J＝6.2Hz,2H),2.47(t,J＝6.4Hz,2H),2.31(s,6H),1.86–1.76(m,2H).13C NMR(100MHz,CDCl3)δ:165.5,149.0,143.0,138.4,135.3,132.0,131.9,129.1,128.7,127.1,126.6,125.7,120.9,58.3,45.5,39.2,26.2.HRMS(ESI)m/z calcd for C20H23ClN5O[M+H]+384.1586,found 384.1584.
实施例26:N-(3-(二乙基氨基)丙基)-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6bb)的合成
用化合物代4b替化合物4a，用N,N-二乙基-1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-(diethylamino)propyl)-3-((4-Chlorophenyl)amino)quinoxaline-2-carboxamide(6bb):yellow oil,产率96.6％；1H NMR(400MHz,CDCl3)δ:11.60(s,1H),9.75(s,1H),7.91(d,J＝8.8Hz,2H),7.80(d,J＝8.2Hz,1H),7.74(d,J＝8.3Hz,1H),7.62(t,J＝7.1Hz,1H),7.41(t,J＝7.1Hz,1H),7.29(d,J＝8.8Hz,2H),3.57(q,J＝5.7Hz,2H),2.64–2.56(m,6H),1.85–1.76(m,2H),1.11(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ:165.5,149.1,143.0,138.4,135.4,132.2,131.9,129.0,128.7,127.1,126.6,125.7,121.0,52.3,47.0,39.9,25.6,11.8.HRMS(ESI)m/z calcd for C22H27ClN5O[M+H]+412.1899,found412.1896。
实施例27:N-(3-氨基丙基)-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6bc)的合成
用化合物代4b替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((4-chlorophenyl)amino)quinoxaline-2-carboxamide(6bc):yellow solid,产率92.0％,m.p.143～144℃；1H NMR(400MHz,CDCl3)δ:11.47(s,1H),8.78(s,1H),7.94–7.89(m,2H),7.86–7.81(m,1H),7.80–7.75(m,1H),7.69–7.63(m,1H),7.48–7.42(m,1H),7.34–7.28(m,2H),3.61(q,J＝6.5Hz,2H),2.89(t,J＝6.6Hz,2H),1.88–1.77(m,2H).13C NMR(100MHz,CDCl3)δ:165.7,149.1,143.2,138.3,135.3,132.1,131.6,129.1,128.8,127.4,126.7,125.9,121.1,39.9,37.7,32.7.HRMS(ESI)m/z calcdfor C18H19ClN5O[M+H]+356.1273,found 356.1271。
实施例28:N-(2-二甲胺基)丙基-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6bd)的合成
用化合物代4b替化合物4a，用N,N-二甲基乙二胺替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(2-(dimethylamino)ethyl)-3-((4-Chlorophenyl)amino)quinoxaline-2-carboxamide(6bd):yellow solid,产率96.2％,m.p.140～141℃；1H NMR(400MHz,CDCl3)δ:11.46(s,1H),8.66(s,1H),7.96–7.86(m,3H),7.82–7.75(m,1H),7.71–7.63(m,1H),7.50–7.42(m,1H),7.36–7.28(m,2H),3.63–3.55(m,2H),2.64–2.56(m,2H),2.34(s,6H).13C NMR(100MHz,CDCl3)δ:165.7,149.1,143.2,138.3,135.4,132.1,131.7,129.3,128.8,127.4,126.6,125.8,121.1,58.0,45.5,37.3.HRMS(ESI)m/z calcd for C19H21ClN5O[M+H]+370.1429,found 370.1428。
实施例29:N-(3-二甲胺基)丙基-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6ca)的合成
用化合物代4c替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-(p-tolylamino)quinoxaline-2-carboxamide(6ca):yellow solid,产率99.0％,m.p.85～88℃；1H NMR(400MHz,CDCl3)δ:11.37(s,1H),9.45(s,1H),7.85(d,J＝8.4Hz,2H),7.82–7.76(m,2H),7.68–7.62(m,1H),7.45–7.40(m,1H),7.19(d,J＝8.3Hz,2H),3.60(q,J＝6.1Hz,2H),2.52(t,J＝6.3Hz,2H),2.35(s,9H),1.90–1.81(m,2H).13C NMR(100MHz,CDCl3)δ:165.7,149.5,143.5,137.1,135.3,132.3,131.8,129.4,129.1,126.6,125.3,120.1,58.2,45.5,39.1,26.3,20.9.HRMS(ESI)m/zcalcd for C21H26N5O[M+H]+364.2132,found364.2129。
实施例30:N-(3-二乙胺基)丙基-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6cb)的合成
用化合物代4c替化合物4a，用N,N-二乙基-1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-(diethylamino)propyl)-3-(p-tolylamino)quinoxaline-2-carboxamide(6cb):yellow solid,产率95.4％,m.p.73～74℃；1H NMR(400MHz,CDCl3)δ:11.41(s,1H),9.66(s,1H),7.84(d,J＝8.5Hz,2H),7.83–7.73(m,2H),7.67–7.62(m,1H),7.44–7.39(m,1H),7.19(d,J＝8.3Hz,2H),3.63–3.58(m,2H),2.71–2.59(m,6H),2.35(s,3H),1.91–1.81(m,2H),1.14(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ:165.8,149.5,143.4,137.1,135.3,132.3,1318,129.4,129.0,126.6,125.3,120.1,52.0,47.0,39.6,29.7,25.6,20.9,11.6.HRMS(ESI)m/z calcd for C23H30N5O[M+H]+392.2445,found 392.2442.
实施例31:N-(3-氨基丙基)-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6cc)的合成
用化合物代4c替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-(p-tolylamino)quinoxaline-2-carboxamide(6cc):yellow solid,产率81.0％,m.p.114～115℃；1H NMR(400MHz,CDCl3)δ:11.29(s,1H),8.75(s,1H),7.86–7.80(m,3H),7.80–7.75(m,1H),7.67–7.62(m,1H),7.45–7.39(m,1H),7.18(d,J＝8.3Hz,2H),3.62(q,J＝6.5Hz,2H),2.90(t,J＝6.6Hz,2H),2.35(s,3H),1.90–1.80(m,2H).13C NMR(100MHz,CDCl3)δ:165.8,149.5,143.6,137.0,135.1,132.4,132.0,131.7,129.4,129.1,126.7,125.4,120.1,39.8,37.5,32.6,20.9.HRMS(ESI)m/z calcd forC19H22N5O[M+H]+336.1819,found 336.1822
实施例32:N-(3-二甲胺基)乙基-3-((4-氯苯基)氨基)喹喔啉-2-甲酰胺(6cd)的合成
用化合物代4c替化合物4a，用N,N-二甲基乙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(2-(dimethylamino)ethyl)-3-(p-tolylamino)quinoxaline-2-carboxamide(6cd):yellow solid,产率97.0％,m.p.110～113℃；1H NMR(400MHz,CDCl3)δ:11.29(s,1H),8.66(s,1H),7.87(d,J＝8.7Hz,1H),7.84(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,1H),7.68–7.62(m,1H),7.45–7.39(m,1H),7.19(d,J＝8.3Hz,2H),3.63–3.56(m,2H),2.61(t,J＝6.2Hz,2H),2.35(s,3H),2.34(s,6H).13C NMR(100MHz,CDCl3)δ:165.8,149.5,143.6,137.0,135.2,132.3,131.9,131.8,129.4,129.2,126.6,125.3,120.1,58.0,45.5,37.3,20.9.HRMS(ESI)m/z calcd for C20H24N5O[M+H]+350.1975,found 350.1975。
实施例33:N-(3-氨基丙基)-3-((2-甲氧基苯基)氨基)喹喔啉-2-甲酰胺(6dc)的合成.
用化合物代4d替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((2-methoxyphenyl)amino)quinoxaline-2-carboxamide(6dc):yellow solid,产率85.5％,m.p.165～166℃；1H NMR(400MHz,CDCl3)δ:11.70(s,1H),9.06–9.02(m,1H),8.72(s,1H),7.78–7.80(m,2H),7.68–7.63(m,1H),7.46–7.40(m,1H),7.09–6.99(m,2H),6.97–6.93(m,1H),4.02(s,3H),3.64(q,J＝6.6Hz,2H),2.89(t,J＝6.6Hz,2H),1.87–1.80(m,2H),1.34(s,2H).13C NMR(100MHz,CDCl3)δ:165.6,149.3,149.2,143.5,135.1,132.5,131.9,129.6,129.1,126.7,125.5,122.3,120.7,119.5,110.1,56.2,40.0,37.6,32.8.HRMS(ESI)m/z calcd for C19H22N5O2[M+H]+352.1769,found 352.1767。
实施例34:N-(3-氨基丙基)-3-((3-甲苯基)氨基)喹喔啉-2-甲酰胺(6ec)的合成
用化合物代4e替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-(m-tolylamino)quinoxaline-2-carboxamide(6ec):yellow solid,产率34.5％,m.p.81～83℃；1H NMR(400MHz,CDCl3)δ:11.32(s,1H),8.74(s,1H),7.86(d,J＝7.9Hz,1H),7.82(d,J＝8.2Hz,1H),7.78(d,J＝8.4Hz,1H),7.69–7.61(m,2H),7.42(t,J＝7.5Hz,1H),7.30–7.22(m,1H),6.89(d,J＝7.4Hz,1H),3.66–3.56(m,2H),2.91(t,J＝6.6Hz,2H),2.39(s,3H),1.92–1.81(m,2H).13C NMR(100MHz,CDCl3)δ:165.9,149.4,143.5,139.5,138.6,135.2,132.0,131.7,129.1,128.7,126.7,125.5,123.7,120.7,117.1,39.6,37.4,32.3,21.7.HRMS(ESI)m/z calcd for C19H22N5O[M+H]+336.1819,found 336.1819.
实施例35:N-(3-氨基丙基)-3-((2-氟苯基)氨基)喹喔啉-2-甲酰胺(6fc)的合成
用化合物代4f替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((2-fluorophenyl)amino)quinoxaline-2-carboxamide(6fc):yellow solid,产率62.3％,m.p.122～124℃；1H NMR(400MHz,CDCl3)δ:11.69(s,1H),9.04–8.90(m,1H),8.75(s,1H),7.91–7.78(m,2H),7.72–7.63(m,1H),7.52–7.40(m,1H),7.23–7.11(m,2H),7.06–6.96(m,1H),3.69–3.58(m,2H),2.93–2.86(m,2H),1.90–1.78(m,2H),1.34(s,2H).13C NMR(100MHz,CDCl3)δ:165.5,154.5,152.1,149.1,143.2,135.4,132.1,129.2,128.4(d,J＝9.8Hz),126.7,126.0,124.1(d,J＝3.7Hz),122.5(d,J＝5.4Hz),121.0,114.7(d,J＝19.15Hz),40.0,37.7,32.7.HRMS(ESI)m/z calcd forC18H19FN5O[M+H]+340.1568,found 340.1569。
实施例36:N-(3-氨基丙基)-3-((2-氯苯基)氨基)喹喔啉-2-甲酰胺(6gc)的合成
用化合物代4g替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((2-chlorophenyl)amino)quinoxaline-2-carboxamide(6gc):yellow solid,产率43.6％,m.p.120～123℃；1H NMR(400MHz,CDCl3)δ:11.80(s,1H),9.04(dd,J＝8.3,1.2Hz,1H),8.77(s,1H),7.87(d,J＝8.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.71–7.65(m,1H),7.51–7.41(m,2H),7.36–7.30(m,1H),7.04–7.97(m,1H),3.65(q,J＝6.5Hz,2H),2.90(t,J＝6.6Hz,2H),1.90–1.79(m,2H),1.47(s,2H).13C NMR(100MHz,CDCl3)δ:165.4,149.0,143.0,136.8,135.5,132.2,132.1,129.4,129.1,127.1,126.8,126.1,123.8,123.0,121.0,40.0,37.7,32.7.HRMS(ESI)m/z calcd for C18H19ClN5O[M+H]+356.1273,found 356.1272。
实施例37:N-(3-氨基丙基)-3-((2-溴苯基)氨基)喹喔啉-2-甲酰胺(6hc)的合成
用化合物代4h替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((2-bromophenyl)amino)quinoxaline-2-carboxamide(6hc):yellow solid,产率63.3％,m.p.71～73℃；1H NMR(400MHz,CDCl3)δ:11.60(s,1H),8.92(dd,J＝8.3,1.3Hz,1H),8.74(s,1H),7.89–7.83(m,1H),7.80–7.73(m,1H),7.69–7.63(m,1H),7.61(dd,J＝8.0,1.4Hz,1H),7.49–7.43(m,1H),7.38–7.32(m,1H),6.96–6.88(m,1H),3.65(q,J＝6.4Hz,2H),2.93(t,J＝6.6Hz,2H),2.17(s,3H),1.93–1.82(m,2H).13C NMR(100MHz,CDCl3)δ:165.4,149.0,142.9,137.9,135.5,132.7,132.1,132.0,129.1,127.6,126.7,126.1,123.7,121.6,114.4,39.7,37.6,32.3.HRMS(ESI)m/z calcd for C18H19BrN5O[M+H]+400.0767,found400.0770。
实施例38:N-(3-氨基丙基)-3-((3-氯苯基)氨基)喹喔啉-2-甲酰胺(6ic)的合成
用化合物代4i替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((3-chlorophenyl)amino)quinoxaline-2-carboxamide(6ic):yellow solid,产率58.5％,m.p.91～93℃；1H NMR(400MHz,CDCl3)δ:11.54(s,1H),8.79(s,1H),8.23(t,J＝2.0Hz,1H),7.88–7.79(m,2H),7.73–7.64(m,2H),7.50–7.43(m,1H),7.27(t,J＝8.0Hz,1H),7.08–6.98(m,1H),3.62(q,J＝6.5Hz,2H),2.90(t,J＝6.6Hz,2H),1.89–1.78(m,2H),1.37(s,2H).13C NMR(100MHz,CDCl3)δ:165.7,149.1,143.1,140.9,135.4,134.4,132.2,131.6,129.8,129.1,126.8,126.0,122.6,119.7,117.9,39.9,37.7,32.7.HRMS(ESI)m/z calcd for C18H19ClN5O[M+H]+356.1273,found 356.1273。
实施例39:N-(3-氨基丙基)-3-((3-溴苯基)氨基)喹喔啉-2-甲酰胺(6jc)的合成
用化合物代4j替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((3-bromophenyl)amino)quinoxaline-2-carboxamide(6jc):yellow solid,产率15.7％,m.p.89～90℃；1H NMR(400MHz,CDCl3)δ:11.53(s,1H),8.79(s,1H),8.36(d,J＝1.4Hz,1H),7.84(t,J＝8.5Hz,2H),7.78(d,J＝7.6Hz,1H),7.72–7.66(m,1H),7.50–7.44(m,1H),7.24–7.16(m,2H),3.62(q,J＝6.4Hz,2H),2.90(t,J＝6.5Hz,2H),1.88–1.80(m,2H),1.36(s,2H).13C NMR(100MHz,CDCl3)δ:165.7,149.1,143.1,141.0,135.4,132.2,131.6,130.1,129.1,126.8,126.1,125.5,122.6,122.5,118.4,39.9,37.7,32.7.HRMS(ESI)m/z calcd for C18H19BrN5O[M+H]+400.0767,found 400.0769。
实施例40:N-(3-氨基丙基)-3-((4-氟苯基)氨基)喹喔啉-2-甲酰胺(6kc)的合成
用化合物代4k替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((4-fluorophenyl)amino)quinoxaline-2-carboxamide(6kc):yellow solid,产率94.6％,m.p.113～115℃；1H NMR(400MHz,CDCl3)δ:11.38(s,1H),8.77(s,1H),7.94–7.88(m,2H),7.87–7.82(m,1H),7.79–7.75(m,1H),7.69–7.63(m,1H),7.47–7.41(m,1H),7.10–7.04(m,2H),3.66–3.58(m,2H),2.93–2.86(m,4H),1.88–1.79(m,2H),1.35(s,2H).13C NMR(100MHz,CDCl3)δ:165.7,159.8,157.4,149.3,143.4,135.7(d,J＝40Hz),132.1,131.7,129.1,126.6,125.6,121.5(d,J＝7Hz),115.4(d,J＝22Hz),39.9,37.6,32.7.HRMS(ESI)m/z calcd for C18H19FN5O[M+H]+340.1568,found 340.1569。
实施例41:N-(3-(二甲氨基)丙基)-3-((4-氟苯硫基)氨基)喹喔啉-2-甲酰胺(7aa)的合成
用化合物代5a替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((4-fluorophenyl)thio)quinoxaline-2-carboxamide(7aa):lightyellow solid,产率67％,m.p.114～116℃；1H NMR(400MHz,CDCl3)δ:9.07(s,1H),7.96–7.93(m,1H),7.65–7.63(m,3H),7.59–7.56(m,2H),7.14(t,J＝9.5Hz,2H),3.64(q,J＝6.1Hz,2H),2.52(t,J＝6.6Hz,2H),2.34(s,6H),1.87(dd,J＝13.0,6.5Hz,2H).13C NMR(100MHz,CDCl3)δ:164.6,163.9,162.2,156.5,142.9,140.5,138.0,137.9,137.6,131.6,129.0,129.0,128.2,125.9,125.8,116.2,115.9,58.2,45.5,39.0,26.5.HRMS(ESI)m/z calcd for C20H22FN4OS[M+H]+385.1493,found 385.1491。
实施例42:N-(3-(二甲氨基)丙基)-3-((4-氯苯硫基)氨基)喹喔啉-2-甲酰胺(7ba)的合成
用化合物代5b替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((4-chlorophenyl)thio)quinoxaline-2-carboxamide(7ba):light yellow solid,产率68％,m.p.136～138℃；1H NMR(400MHz,CDCl3)δ:9.10(s,1H),7.94(d,J＝7.6Hz,1H),7.66–7.63(m,3H),7.53(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),3.63(q,J＝6.2Hz,2H),2.49(t,J＝6.5Hz,2H),2.32(s,6H),1.88–1.82(m,2H).13C NMR(100MHz,CDCl3)δ:163.8,156.0,142.8,140.5,137.7,137.2,135.2,131.7,129.2,129.1,129.0,129.0,128.2,58.3,45.6,39.1,26.5.HRMS(ESI)m/z calcdfor C20H22ClN4OS[M+H]+401.1197,found401.1196。
实施例43:N-(3-(二甲氨基)丙基)-3-((4-溴苯硫基)氨基)喹喔啉-2-甲酰胺(7ca)的合成
用化合物代5c替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((4-bromophenyl)thio)quinoxaline-2-carboxamide(7ca):light yellow solid,产率68％,m.p.143～145℃；1H NMR(400MHz,CDCl3)δ:9.08(s,1H),7.96–7.94(m,1H),7.68–7.64(m,3H),7.58–7.55(m,2H),7.49–7.45(m,2H),3.63(q,J＝6.1Hz,2H),2.52(t,J＝6.6Hz,2H),2.33(s,6H),1.90–1.83(m,2H).13CNMR(100MHz,CDCl3)δ:163.9,155.9,142.9,140.5,137.7,137.4,132.0,131.7,129.8,129.1,129.0,128.2,123.5,58.2,45.5,39.0,26.5.HRMS(ESI)m/z calcd for C20H22BrN4OS[M+H]+445.0692,found 445.0694。
实施例44:N-(3-(二甲氨基)丙基)-3-((2,4-氯苯硫基)氨基)喹喔啉-2-甲酰胺(7da)的合成
用化合物代5d替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((2,4-dichlorophenyl)thio)quinoxaline-2-carboxamide(7da):light yellow solid,产率87％,m.p.141～143℃；1H NMR(500MHz,CDCl3)δ:9.14(s,1H),7.97–7.95(m,1H),7.67–7.62(m,4H),7.57(d,J＝2.2Hz,1H),7.31(m,1H),3.64(q,6.1Hz,2H),2.52(t,J＝6.6Hz,2H),2.34(s,6H),1.87(m,2H).13C NMR(125MHz,CDCl3)δ:163.8,154.5,142.9,141.4,140.3,138.5,137.7,136.0,131.7,129.8,129.1,129.1,129.0,128.2,127.5,58.3,45.5,39.1,26.5.HRMS(ESI)m/z calcd forC20H22FN4OS[M+H]+385.1493,found 385.1491。
实施例45:N-(3-(二甲氨基)丙基)-3-((2-氯苯硫基)氨基)喹喔啉-2-甲酰胺(7ea)的合成
用化合物代5e替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((2-chlorophenyl)thio)quinoxaline-2-carboxamide(7ea):light yellow solid,产率75％,m.p.127～129℃；1H NMR(400MHz,CDCl3)δ:9.07(s,1H),8.96–7.93(m,1H),7.72(dd,J＝7.6,1.7Hz,1H),7.63–7.61(m,3H),7.54(dd,J＝7.8,1.2Hz,1H),7.40(td,J＝7.5,1.7Hz,1H),7.32(td,J＝7.5,1.4Hz,1H),3.64(dd,J＝12.6,6.1Hz,2H),2.54(t,J＝6.6Hz,2H),2.35(s,6H),1.92–1.85(m,2H).13CNMR(100MHz,CDCl3)δ:163.9,155.0,143.0,140.5,140.4,137.9,137.6,131.6,130.7,130.3,129.9,129.1,129.0,128.3,127.2,58.1,45.4,38.9,26.5.HRMS(ESI)m/z calcdfor C20H22FN4OS[M+H]+385.1493,found 385.1491。
实施例46:N-(3-(二甲氨基)丙基)-3-((2-溴苯硫基)氨基)喹喔啉-2-甲酰胺(7fa)的合成
用化合物代5f替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((2-bromophenyl)thio)quinoxaline-2-carboxamide(7fa):light yellow solid,产率41％,m.p.109～111℃；1H NMR(400MHz,CDCl3)δ:9.02(s,1H),7.97–7.95(m,1H),7.75–7.71(m,2H),7.65–7.59(m,3H),7.37(td,J＝7.4,1.2Hz,1H),7.31(td,J＝7.6,1.6Hz,1H),3.65(q,J＝6.2Hz,2H),2.60(t,J＝6.7Hz,2H),2.40(s,6H),1.96–1.90(m,2H).13C NMR(100MHz,CDCl3)δ:164.0,155.1,143.0,140.3,137.9,137.6,133.3,132.4,131.7,131.6,130.7,129.1,129.0,128.3,127.9,57.99,45.2,38.7,26.3.HRMS(ESI)m/z calcd for C20H22FN4OS[M+H]+385.1493,found 385.1491。
实施例47:N-(3-(二甲氨基)丙基)-3-((3-氯苯硫基)氨基)喹喔啉-2-甲酰胺(7ga)的合成
用化合物代5g替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((3-chlorophenyl)thio)quinoxaline-2-carboxamide(7ga):light yellow solid,产率72％,m.p.84～86℃；1H NMR(500MHz,CDCl3)δ:9.10(s,1H),7.96–7.94(m,1H),7.69–7.63(m,3H),7.62(t,J＝2.0Hz,1H),7.50–7.48(m,1H),7.43–7.40(m,1H),7.38–7.35(m,1H),3.63(q,6.1Hz,2H),2.53(t,J＝6.6Hz,2H),2.34(s,6H),1.90–1.85(m,2H).13C NMR(125MHz,CDCl3)δ:163.9,155.8,142.8,140.4,137.7,135.6,134.3,133.9,132.5,131.7,129.4(s),129.1,128.2,58.2,45.4,39.0,26.4.HRMS(ESI)m/z calcd for C20H22FN4OS[M+H]+385.1493,found 385.1491。
实施例48:N-(3-(二甲氨基)丙基)-3-((3-溴苯硫基)氨基)喹喔啉-2-甲酰胺(7ha)的合成
用化合物代5h替化合物4a，其它实验操作与实施例21相同。
N-(3-(dimethylamino)propyl)-3-((3-bromophenyl)thio)quinoxaline-2-carboxamide(7ha):light yellow solid,产率73％,m.p.82～84℃；1H NMR(500MHz,CDCl3)δ:9.11(s,1H),7.95(d,J＝8Hz 1H),7.78(t,J＝1.7Hz,1H),7.68–7.62(m,3H),7.58–7.56(m,2H),7.55–7.53(m,1H),7.31(t,J＝7.9Hz,1H),3.63(m,6.1Hz,2H),2.52(t,J＝6.6Hz,2H),2.34(s,6H),1.89–1.84(m,2H).13C NMR(125MHz,CDCl3)δ:163.8,155.7,142.8,140.4,138.3,137.7,134.4,132.8,132.0,131.7,130.1,129.1,129.0,128.2,122.3,58.2,45.5,39.0,26.5.HRMS(ESI)m/z calcd for C20H22FN4OS[M+H]+385.1493,found 385.1491。
实施例49:N-(3-(二甲氨基)丙基)-3-((4-氯氟苯硫基)氨基)喹喔啉-2-甲酰胺(7bb)的合成
用化合物代5b替化合物4a，用N,N-二乙基-1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同.
N-(3-(diethylamino)propyl)-3-((4-bromophenyl)thio)-quinoxaline-2-carboxamide(7bb):light yellow solid,产率67％,m.p.91～93℃；1H NMR(400MHz,CDCl3)δ:9.41(s,1H),7.96–7.93(m,1H),7.67–7.60(m,3H),7.55–7.52(m,2H),7.42–7.39(m,2H),3.64(q,J＝5.7Hz,2H),2.66–2.63(m,2H),2.63–2.58(m,4H),1.86–1.80(m,2H),1.10(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ:163.9,156.1,142.8,140.71,137.7,137.2,135.1,131.6,129.3,129.3,129.1,129.0,128.9,128.2,52.3,47.0,39.9,25.8,11.8.HRMS(ESI)m/z calcd for C22H26ClN4OS[M+H]+429.1510,found 429.1518。
实施例50:N-(3-氨基丙基)-3-((4-氯苯硫基)氨基)喹喔啉-2-甲酰胺(7bc)的合成.
用化合物代5b替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((4-chlorophenyl)thio)quinoxaline-2-carboxamide(7bc):light yellow solid,产率67％,m.p.147～149℃；1H NMR(400MHz,CDCl3)δ:7.98–7.91(m,1H),7.69–7.58(m,3H),7.52–7.45(m,2H),7.41–7.34(m,2H),3.58(t,J＝6.7Hz,2H),2.80(t,J＝6.8Hz,2H),1.86–1.77(m,2H).13C NMR(100MHz,CDCl3)δ:164.2,155.9,142.9,140.0,137.5,137.1,135.3,131.9,129.2,129.1,129.0,128.8,128.1,39.0,37.0,32.5.HRMS(ESI)m/z calcd for C18H18ClN4OS[M+H]+373.0884,found 373.0893。
实施例51:N-(3-(二乙氨基)丙基)-3-((4-溴氟苯硫基)氨基)喹喔啉-2-甲酰胺(7cb)的合成
用化合物代5c替化合物4a，用N,N-二乙基-1,3-丙二胺代替N,N-二甲基-1,3-丙二胺,其它实验操作与实施例21相同.
N-(3-(diethylamino)propyl)-3-((4-bromophenyl)thio)quinoxaline-2-carboxamide(7cb):light yellow solid,产率83％,m.p.91～92℃；1H NMR(400MHz,CDCl3)δ:9.39(s,1H),7.95(d,J＝7.8Hz,1H),7.67–7.61(m,3H),7.57–7.55(m,2H),7.48–7.46(m,2H),3.64(q,J＝5.7Hz,2H),2.67–2.60(m,6H),1.88–1.82(m,2H),1.11(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ:163.9,155.9,142.8,140.7,137.7,137.4,132.0,131.6,129.9,129.0,128.9,128.2,123.4,52.2,48.0,39.8,25.7,11.7.HRMS(ESI)m/z calcd forC22H26BrN4OS[M+H]+473.1005,found 473.1016。
实施例52:N-(3-氨基丙基)-3-((4-溴氟苯硫基)氨基)喹喔啉-2-甲酰胺(7cc)的合成.
用化合物代5c替化合物4a，用1,3-丙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(3-aminopropyl)-3-((4-bromophenyl)thio)quinoxaline-2-carboxamide(7cc):light yellow solid,产率90％,m.p.191～193℃；1H NMR(400MHz,MeOD)δ:8.05–7.99(m,1H),7.74–7.65(m,1H),7.62–7.55(m,2H),7.48–7.42(m,1H),3.55(t,J＝6.8Hz,1H),2.78(t,J＝6.9Hz,1H),1.90–1.78(m,1H).13C NMR(100MHz,MeOD)δ:164.9,155.1,142.5,141.5,137.7,137.3,131.9,131.8,129.6,129.1,128.9,127.5,123.2,38.4,36.6,32.1.HRMS(ESI)m/z calcd for C18H18BrN4OS[M+H]+417.0379,found 417.0387。
实施例53:N-(2-(二甲氨基)乙基)-3-((4-溴氟苯硫基)氨基)喹喔啉-2-甲酰胺(7cd)的合成
用化合物代5c替化合物4a，用N,N-二甲基乙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(2-(dimethylamino)ethyl)-3-((4-bromophenyl)thio)quinoxaline-2-carboxamide(7cd):light yellow solid,产率88％,m.p.134～136℃；1H NMR(400MHz,CDCl3)δ:8.37(s,1H),8.02(d,J＝7.7Hz,1H),7.68–7.62(m,3H),7.58–7.56(m,2H),7.49–7.46(m,2H),3.65(q,J＝6.0Hz,2H),2.63(t,J＝6.2Hz,2H),2.35(s,6H).13C NMR(100MHz,CDCl3)δ:164.0,155.8,142.9,140.2,137.6,137.4,132.1,131.8,129.7,129.2,129.1,128.1,123.5,58.1,45.4,37.2.HRMS(ESI)m/z calcd for C19H20BrN4OS[M+H]+431.0536,found 431.0548。
实施例54:N-(2-氨乙基)-3-((4-溴氟苯硫基)氨基)喹喔啉-2-甲酰胺(7ce)的合成
用化合物代5c替化合物4a，用乙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(2-aminoethyl)-3-((4-bromophenyl)thio)quinoxaline-2-carboxamide(7ce):light yellow solid,产率75％,m.p.176～178℃；1H NMR(400MHz,DMSO)δ:9.16(s,1H),8.11–8.06(m,1H),7.83–7.78(m,2H),7.71–7.67(m,2H),7.66–7.62(m,1H),7.55–7.51(m,2H),3.50–3.41(m,2H),2.87(t,J＝6.3Hz,2H),1.84(s,3H).13C NMR(100MHz,DMSO)δ:173.3,164.4,155.0,142.7,142.2,137.9,137.7,132.7,132.6,130.2,130.2,129.4,128.1,123.3,41.2,22.4.HRMS(ESI)m/z calcd for C17H16BrN4OS[M+H]+403.0223,found403.0230.
实施例55:N-(2-(二乙氨基)乙基)-3-((4-溴氟苯硫基)氨基)喹喔啉-2-甲酰胺(7cf)的合成
用化合物代5c替化合物4a，用N,N-二乙基乙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(2-(diethylamino)ethyl)-3-((4-bromophenyyl)thio)quinoxaline-2-carboxamide(7cf):light yellow solid,产率88％,m.p.126～128℃；1H NMR(400MHz,CDCl3)δ:8.54(s,1H),8.00–7.98(M,1H),7.69–7.61(m,3H),7.58–7.55(m,2H),7.49–7.45(m,2H),3.62(q,J＝6.0Hz,2H),2.77(t,J＝6.2Hz,2H),2.66(q,J＝7.1Hz,4H),1.12(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ:163.9,155.8,142.9,140.3,137.7,137.4,132.1,131.8,129.7,129.2,129.1,128.1,123.5,51.7,47.3,37.4,12.0.HRMS(ESI)m/z calcdfor C21H24BrN4OS[M+H]+459.0849,found459.0858。
实施例56:N-(2-(二异丙基氨基)乙基)-3-((4-溴氟苯硫基)氨基)喹喔啉-2-甲酰胺(7cg)的合成
用化合物代5c替化合物4a，用N,N-二异丙基乙二胺代替N,N-二甲基-1,3-丙二胺，其它实验操作与实施例21相同。
N-(2-(diisopropylamino)ethyl)-3-((4-bromophenyl)thio)quinoxaline-2-carboxamide(7cg):light yellow solid,产率78％,m.p.143～145℃；1H NMR(400MHz,CDCl3)δ:8.62(s,1H),7.95(d,J＝7.8Hz,1H),7.66–7.61(m,3H),7.57(d,J＝8.4Hz,2H),7.48(d,J＝8.4Hz,2H),3.51(q,J＝5.8Hz,2H),3.11(dt,J＝13.1,6.6Hz,2H),2.76(t,J＝6.1Hz,2H),1.09(d,J＝6.6Hz,12H).13CNMR(100MHz,CDCl3)δ:163.6,155.9,142.9,140.5,137.7,137.4,132.0,131.7,129.8,129.1,129.0,128.1,123.5,47.8,43.1,38.5,21.0.HRMS(ESI)m/z calcd for C23H28BrN4OS[M+H]+487.1162,found 487.1169。
实施例57:
采用MTT(3-[4,5-二甲基-2-噻唑基]-2,5-二苯基-2H-四唑溴化物)法测定体外抗增殖试验。所有细胞系均在含有10％FBS的DMEM培养基，37℃，5％CO2的培养箱中培养。将细胞在给药前一天接种到96孔板中，使其生长至贴壁，然后用不同浓度的化合物处理48h。向每个孔中加入10μL 0.5％MTT溶液，培养4～6h后，加入100μL DMSO震荡10min，溶解生成的甲臜结晶物。使用多功能酶标仪(Tecan,M1000)，在570nm和630nm处测定光密度值(OD值)，通过SPSS软件计算每种化合物对不同细胞系的IC50值。所有实验均重复三次后取平均值，并算出相对误差。
本实施例涉及的化合物结构及其对不同癌细胞株的体外抗增殖活性及IC50值测定结果见表1:
表1.化合物结构及其对不同癌细胞的IC50(μM)
LY294002b：PI3K抑制剂；HCPTc：羟基喜树碱，阳性对照。
实施例58：代表化合物6bc诱导MGC-803细胞凋亡
将MGC-803细胞接种到6孔板中，并在37℃,5％CO2培养箱中培养，细胞贴壁后，加入不同浓度的化合物6bc作用24h，收集细胞并离心，弃去上清液，加Binding Buffer悬浮细胞，用FITC标记的Annexin V溶液和PI避光孵育30min，再加入1×Binding Buffer悬浮细胞，使用FACS Aria II流式细胞仪进行细胞凋亡分析。
化合物6bc诱导MGC-803细胞发生凋亡，结合图1a所示，6bc在MGC-803细胞中以剂量依赖性方式诱导细胞发生凋亡，随着6bc浓度的增加，细胞凋亡水平明显增加。
图1b是化合物6bc诱导MGC-803细胞发生凋亡的western blot测定结果，6bc以浓度依赖性方式上调促凋亡蛋白Bax、Bak和Bim的表达水平，并下调抑凋亡蛋白Bcl-2和Bcl-xl的表达。
图1c是化合物6bc处理MGC-803细胞后用Hoechst 33258染色的实验结果，结果显示，随着6bc浓度的增加细胞核皱缩和破裂的程度越加明显，细胞发生凋亡水平程度越大。
图1d是化合物6bc诱导MGC-803细胞线粒体膜电位变化的实验结果，结果显示，P1代表具有高线粒体膜电位的区域，P2代表具有低线粒体膜电位的区域。当化合物与MGC-803细胞作用24h后，越来越多的细胞失去了它们的MMP。P1区的比例由空白对照组的95.0％下降到1.0μM(92.6％)、2.5μM(44.1％)、5.0μM(12.7％)，说明6bc可以靶向作用于线粒体并诱导细胞发生凋亡。
图1e是化合物6bc诱导MGC-803细胞内ROS的变化的实验结果，用1、2.5、5μM的6bc处理MGC-803细胞24h，与空白对照组相比，随着化合物浓度的增加,MGC-803细胞的DCF荧光强度曲线逐渐往右偏移，并且随着浓度的增大往右偏移越明显，说明细胞内的活性氧水平呈剂量性方式增加。
图1f是化合物6bc诱导MGC-803细胞内Ca2+浓度变化的实验结果，用1、2.5、5μM的6bc处理MGC-803细胞24h，与空白对照组相比，随着化合物浓度的增加，样品组Fluo-3的荧光强度均发生偏移，荧光强度曲线随着浓度的增大逐渐往右偏移。表明6bc能够诱导MGC-803细胞中Ca2+浓度升高，并以剂量依赖的方式诱导细胞发生凋亡。
实施例59：代表化合物6bc对PI3K/Akt/mTOR信号通路的抑制作用实验
将MGC-803细胞在蛋白质裂解液中裂解，将总蛋白质在4℃、12,000rpm离心10min，通过BCA蛋白质测定试剂盒测定蛋白质浓度，并通过SDS-PAGE凝胶电泳分离蛋白质样品，将凝胶中的蛋白质转移到PVDF膜上，封闭，在一抗中孵育过夜，转移至二抗中温育1-2h，然后对其显影成像。
图2a、2b为6bc对PI3K/Akt/m-TOR信号通路的影响示意图，其中：图2a为用6bc和LY294002(0.1、0.25和0.5μM)处理MGC-803细胞24h，通过western blot测定显示的图片，6bc和LY294002均能抑制PI3K、Akt、p-Akt(S473)的表达，β-actin用作上样控制。图2b为用直方图表示三个不同实验的平均值±SD。
图2c、2d为6bc对Akt/m-TOR信号的影响示意图，其中：图2c为用6bc(0.5和1.0μM)和LY294002(2.5和5μM)处理MGC-803细胞24h，通过western blot测定显示的图片，6bc和LY294002均能抑制p-Akt(T308)、p-mTOR的表达，β-actin用作上样控制。图2d为用直方图表示三个不同实验的平均值±SD。
图2e、2f为6bc对Akt/m-TOR信号的影响示意图，其中：图2e为用6bc(0.5和1.0μM)和LY294002(2.5和5μM)处理SMMC-7721细胞24h，通过western blot测定显示的图片，6bc和LY294002均能抑制p-Akt(T308)、p-mTOR的表达，β-actin用作上样控制。图2f为用直方图表示三个不同实验的平均值±SD。
图2g和2h为6bc对PI3K/Akt/m-TOR信号通路及与相关蛋白的影响示意图，其中：图2g为用6bc(0、1、2.5和5μM)处理MGC-803细胞24h，通过western blot测定显示的图片，6bc能够下调Bcl-2、Bcl-xl并且上调p-p53、p27的表达，β-actin用作上样控制。图2h为用直方图表示三个不同实验的平均值±SD。
Claims (10)
1.具有通式（I）的喹喔啉类信号通路抑制剂：
其中，X为NH或S，R1为H、卤素、烷基、烷氧基或卤烷基，R2为氨基或烷氨基，n为2或3。
2.根据权利要求1所述的喹喔啉类信号通路抑制剂，其特征在于：
R1为4-OCH3、4-Cl、4-CH3、2-OCH3、3-CH3、2-F、2-Cl、2-Br、3-Cl、3-Br、4-F、4-Br、或2,4-Cl，R2为N(CH3)2、NH2、N(C2H5)2或N(CH(CH3)2)2。
3.根据权利要求1所述的喹喔啉类信号通路抑制剂，其特征在于：
当X为NH时，R1为4-OCH3、4-Cl、4-CH3、2-OCH3、3-CH3、2-F、2-Cl、2-Br、3-Cl、3-Br或4-F；
当X为S时，R1为4-F、4-Cl、4-Br、2,4-Cl、2-Cl、2-Br、3-Cl或3-Br。
4.根据权利要求1所述的喹喔啉类信号通路抑制剂，其特征在于：
当n=2时，R2为N(CH3)2、NH2或N(C2H5)2；当n=3时，R2为N(CH3)2、NH2、N(C2H5)2或N(CH(CH3)2)2。
5.具有通式（I）的喹喔啉类信号通路抑制剂的制备方法，其特征在于包括以下步骤：
S1. 
与
在有溶剂的条件下反应得
；
S2. 
与
在有溶剂的条件下反应得到目标化合物喹喔啉类信号通路抑制剂
。
6.根据权利要求4所述的制备方法，其特征在于：
所述步骤S1的反应是在氮气或惰性气体保护、搅拌条件下进行，溶剂为无水乙醇，反应温度为75~80°C；
所述步骤S2的反应是在氮气或惰性气体保护、搅拌条件下进行，溶剂为无水乙醇，反应温度为75~80°C。
7.根据权利要求4所述的制备方法，其特征在于：
所述步骤S1中，反应完成后，还包括提纯步骤：冷却、抽滤、无水乙醇洗涤、干燥；
所述步骤S2中，反应完成后，还包括提纯步骤：冷却、除去溶剂、硅胶柱层析提纯。
8.权利要求1~4任一项所述的信号通路抑制剂或权利要求5~7任一项制备得到的目标化合物在制备信号通路抑制剂中的应用，其特征在于：所述信号通路为PI3K/Akt/mTOR信号通路。
9.权利要求1~6任一项制备得到的目标化合物在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的应用，其特征在于：所述肿瘤为人胃癌肿瘤、人肺癌肿瘤、人宫颈癌细胞、人肝癌肿瘤或人膀胱癌肿瘤。
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