CN109912571B - 具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成方法和应用 - Google Patents

具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成方法和应用 Download PDF

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CN109912571B
CN109912571B CN201910373042.2A CN201910373042A CN109912571B CN 109912571 B CN109912571 B CN 109912571B CN 201910373042 A CN201910373042 A CN 201910373042A CN 109912571 B CN109912571 B CN 109912571B
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benzoquinoline
triazole compound
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CN109912571A (zh
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时蕾
杨晓岚
冯婷婷
张贵生
刘统信
刘青锋
张志国
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Henan Normal University
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Abstract

本发明公开了一种具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成方法和应用，属于具有生物活性的苯并喹啉及三氮唑衍生物技术领域。本发明的技术方案要点为：具有生物活性的新型苯并喹啉取代三氮唑类化合物，其结构式为：

Description

具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成 方法和应用
技术领域
本发明属于具有生物活性的苯并喹啉及三氮唑衍生物技术领域，具体涉及一种具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成方法和应用。
背景技术
目前，非传染性疾病已经成为全球人群的主要死因，癌症也将预计成为21世纪全球范围内致死率第一的疾病。而且在经济发展水平较高的国家中，脑卒和冠心病的死亡率相对下降，导致癌症将会是阻碍寿命增长的主要和唯一的的疾病[1]。因此，加紧展开预防和治疗癌症的各种工作，如何有效治疗癌症已成为当前的热点研究领域。
含氮杂环化合物因为具有在自然界中广泛存在、是药物的重要组成结构等特点而备受关注[2]。其中，喹啉及其衍生物是一类具有生物活性的含氮杂环化合物，该类化合物会表现出抗菌[3]、抗结核[4]等活性。另外，由于喹啉及其衍生物的低毒、高效、对环境友好、结构变化多样等特点，还被广泛的应用于农药研究[5]。
1,2,3-三氮唑类化合物具有抗真菌、抗肿瘤和抗炎等多种生物活性[6]，并且1,2,3-三氮唑类化合物还拥有稳定性良好、易于制备、可形成多种非共价键作用等特点，在药物化学领域备受关注。
参考文献：
[1]王宁，刘硕，杨雷.等2018全球癌症统计报告解读[J].肿瘤综合治疗电子杂志,2019,5(1):87-97.
[2]BrichacekM,Villalobos M,Plichta A,et al.Stereospecificringexpansion of chiral vinyl aziridines[J].Organic Letters,2011,13:1110-1113.
[3]Dolan N，Gavind P，Eshwika A，et al.Synthesis，antibacterial and anti-MRSA activity，in vivo toxicity and a structure-activity relationship study ofa quinolinethiourea[J].Bioorganic &Medicinal ChemistryLetters，2016，26(2):630-635.
[4]Jain P P，Degani M S，Raju A，et al.Identification of a novel classof quinoline-oxadiazole hybrids as anti-tuber-culosis agents[J].Bioorganic&Medicinal ChemistryLetters，2016，26(2):645-649.
[5]Jun-fengTian,Jun Liu,Xu-feng Sun,et al.Recent Advance on QuinolineDerivatives with Biological Activities[J].Agrochemicals,2011,50(8):553.
[6]Zheng Zhang,Jianfeng Zhang,XiaoqiangXie,Et al.Synthesis andBiological Activity Detection of Three Azole Antifungals[J].Science andTechnology&Innovation,2015,22:98.
发明内容
本发明解决的技术问题是提供了一种具有生物活性的新型苯并喹啉取代三氮唑类化合物及其合成方法，该新型苯并喹啉取代三氮唑类化合物对SHP1(含有SH2结构域的蛋白酪氨酸磷酸酶1)和SHP2(含有SH2结构域的蛋白酪氨酸磷酸酶2)均具有较好的抑制作用，能够作为SHP1靶点的酶活抑制剂和SHP1靶点的酶活抑制剂进一步用于制备抗癌类药物。
本发明为解决上述技术问题采用如下技术方案，具有生物活性的新型苯并喹啉取代三氮唑类化合物，其特征在于该新型苯并喹啉取代三氮唑类化合物的结构式为：
Figure BDA0002050662290000021
其中R1为氢、氟、氯、溴、甲基、三氟甲基、甲氧基或二甲基氨基；
Figure BDA0002050662290000022
其中R1为氢、氟、氯、溴、甲基、甲氧基、三氟甲基或二甲基氨基，R2为氯或甲氧基；
Figure BDA0002050662290000023
其中R1为氢、氟、氯、溴、甲基、三氟甲基、甲氧基或二甲基氨基；
该新型苯并喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂通过直接去磷酸化调节细胞内信号蛋白分子的酪氨酸磷酰化水平抑制细胞的有丝分裂增殖、分化和生物活性，在造血系统中抑制白细胞生长，在乳腺癌、卵巢癌或前列腺癌细胞中，抑制SHP1表达量下调，进而抑制对应癌症的发生；该新型苯并喹啉取代三氮唑类化合物作为SHP2靶点的酶活抑制剂通过参与多个信号传导通路介导细胞的生长、分化、迁移、粘附和调亡，在肺癌、胃癌、宫颈癌、甲状腺癌和乳腺癌细胞中，抑制SHP2表达量下调，进而抑制对应癌症的发生。
本发明所述的具有生物活性的新型苯并喹啉取代三氮唑类化合物合成方法，其特征在于具体合成路线为：
Figure BDA0002050662290000031
本发明所述的具有生物活性的新型苯并喹啉取代三氮唑类化合物在制备抗癌药物中的应用。
本发明所述的具有生物活性的新型苯并喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂和SHP1靶点的酶活抑制剂用于制备抗癌药物。
本发明鉴于喹啉基团和三氮唑类化合物的良好活性，根据活性拼接原理，将喹啉基团引入到三氮唑中获得具有生物活性的新型苯并喹啉取代三氮唑类化合物，该新型苯并喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂，通过直接去磷酸化调节细胞内信号蛋白分子的酪氨酸磷酰化水平抑制细胞的有丝分裂增殖、分化和生物活性，在造血系统中抑制白细胞生长，在乳腺癌、卵巢癌或前列腺癌细胞中，抑制SHP1表达量下调，进而抑制对应癌症的发生；该新型苯并喹啉取代三氮唑类化合物作为SHP2靶点的酶活抑制剂通过参与多个信号传导通路介导细胞的生长、分化、迁移、粘附和调亡，在肺癌、胃癌、宫颈癌、甲状腺癌和乳腺癌细胞中，抑制SHP2表达量下调，进而抑制对应癌症的发生，在抗癌药物制备领域具有较好的应用前景。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
1、化合物的合成
4-(2-芳基)苯并[h]喹啉甲酸甲酯1的合成
合成路线：
Figure BDA0002050662290000041
反应步骤：
向100mL圆底烧瓶中加入30mmol1-萘胺和等当量的取代苯甲醛，用40mL乙醇将其溶解，再加入丙酮酸甲酯，于85℃回流反应，每小时采用薄层色谱监测法监测一次，反应约4h，反应结束后加水淬灭反应，然后用(4×30mL)乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，有机相减压蒸馏后采用柱色谱分离(石油醚、乙酸乙酯的体积比为100:1)得到化合物1。
4-(2-芳基)苯并[h]喹啉甲醇2的合成
合成路线：
Figure BDA0002050662290000042
反应步骤：
在250mL圆底烧瓶中加入10mmol化合物1和1.16g硼氢化钠，再加入25mL无水乙醇将两者溶解，于85℃回流反应，每小时采用薄层色谱监测法监测一次至反应结束。将反应体系冷却至室温，然后加入约100mL水淬灭反应，有白色固体析出，抽滤并真空干燥得化合物2。
2-(R苯基)-4-((丙-2-炔-1-基氧基)甲基)苯并[h]喹啉3的合成
合成路线：
Figure BDA0002050662290000051
反应步骤：
在氮气保护下将20mmol化合物2和1.2倍当量的氢化钠溶解在25mL干燥四氢呋喃中，放入25℃油浴锅中搅拌1小时后，滴加等当量比的溴丙炔，每8小时采用薄层色谱监测法监测一次直至反应结束。向反应体系中加饱和氯化铵淬灭反应，然后用乙酸乙酯(3×40mL)萃取水相，合并有机相并用无水硫酸钠干燥除水，有机相减压蒸馏得到粗产物，然后采用柱色谱分离(石油醚与乙酸乙酯的体积比为40:1)粗产物得到产物3。
4-(((1-R1基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(R苯基)苯并[h]喹啉4的合成
合成路线：
Figure BDA0002050662290000052
反应步骤：
将0.55mmol化合物3溶于6mL的THF溶液中，再加入0.66mmol的抗坏血酸钠，将0.33mmol无水硫酸铜用0.5mL水溶解后加入到上述混合溶液中，在N2氛围下反应，每20min采用薄层色谱监测法监测一次至反应结束。加入饱和氯化铵溶液淬灭反应，然后用(3×10mL)二氯甲烷萃取，合并有机相并用无水硫酸钠干燥，有机相减压蒸馏，后采用柱色谱分离(石油醚与乙酸乙酯体积比为2:1)得到化合物4。
化合物的数据表征：
Figure BDA0002050662290000061
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-氟苯基)苯并[h]喹啉(IV-4a):米白色固体,收率:82％,m.p.133-134℃；1H NMR(400MHz,CDCl3)δ9.52(d,J＝8.4Hz,1H),8.39(dd,J＝8.8,5.6Hz,2H),8.08(s,1H),7.95(d,J＝7.6Hz,1H),7.89–7.82(m,2H),7.81–7.71(m,2H),7.53(s,1H),7.41(d,J＝6.4Hz,3H),7.31(t,J＝4.2Hz,3H),7.28(s,1H),5.57(s,2H),5.18(s,2H),4.90(s,2H).13C NMR(101MHz,CDCl3)δ165,2,162.7,154.3,146.3,143.8,136.0,136.0,134.5,133.7,132.1,129.5,129.4,129.3,129.0,128.3(d,J＝3.1Hz),127.8,127.7,127.1,125.1,123.0,122.8,120.7,117.4,115.9,115.7,69.6,64.4,54.4.HRMS(ESI),m/z calcd.forC30H24FN4O([M+H]+)475.1929,found:475.1929。
Figure BDA0002050662290000062
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-氯苯基)苯并[h]喹啉(IV-4b):米白色固体,收率:84％,m.p.137-139℃；1H NMR(400MHz,CDCl3)δ9.45(d,J＝8.4Hz,1H),8.27(d,J＝8.4Hz,2H),8.02(s,1H),7.88(d,J＝8.4Hz,1H),7.77(d,J＝4.4Hz,2H),7.75–7.66(m,2H),7.50(d,J＝8.8Hz,2H),7.46(s,1H),7.35(s,1H),7.34(d,J＝2.4Hz,2H),7.24(d,J＝6.0Hz,2H),5.50(s,2H),5.11(s,2H),4.83(s,2H).13C NMR(101MHz,CDCl3)δ154.0,146.3,145.2,143.8,138.2,135.5,134.5,133.6,132.1,129.3,129.1,128.0,128.8,128.4,128.3,127.9,127.8,127.2,125.1,123.2,122.8,120.6,117.3,69.5,64.4,54.4.HRMS(ESI),m/z calcd.forC30H24ClN4O([M+H]+)491.1633,found:491.1641。
Figure BDA0002050662290000071
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-溴苯基)苯并[h]喹啉(IV-4c):米白色固体,收率:92％,m.p.121-123℃；1H NMR(400MHz,CDCl3)δ9.45(d,J＝7.6Hz,1H),8.21(d,J＝8.8Hz,2H),8.02(s,1H),7.89(d,J＝8.8Hz,1H),7.78(d,J＝3.6Hz,2H),7.76–7.68(m,2H),7.66(d,J＝8.8Hz,2H),7.47(s,1H),7.35(d,J＝4.4Hz,2H),7.34(s,1H),7.24(d,J＝5.2Hz,2H),5.51(s,2H),5.12(s,2H),4.83(s,2H).13C NMR(101MHz,CDCl3)δ154.1,146.3,145.2,143.8,138.7,134.5,133.6,132.1,132.0,129.3,129.1,129.0,128.4,128.3,128.0,127.9,127.2,125.1,123.9,123.2,122.8,120.6,117.3,77.5,64.4,54.4.HRMS(ESI),m/z calcd.forC30H24BrN4O([M+H]+)535.1128,found:535.1131。
Figure BDA0002050662290000072
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(对甲苯基)苯并[h]喹啉(IV-4d):米白色固体,收率:85％,m.p.137-139℃；1H NMR(400MHz,CDCl3)δ9.51(d,J＝7.6Hz,1H),8.25(d,J＝8.0Hz,2H),8.04(s,1H),7.89(d,J＝8.0Hz,1H),7.82(d,J＝9.2Hz,1H),7.75(d,J＝9.1Hz,1H),7.72–7.66(m,2H),7.46(s,1H),7.37-7.34(m,5H),7.26–7.23(m,2H),5.50(s,2H),5.12(s,2H),4.83(s,2H),2.46(s,2H).13C NMR(101MHz,CDCl3)δ155.4,146.3,143.4,139.4,137.0,134.5,133.6,132.2,129.6,129.3,128.9,128.3,128.2,127.8,127.5,127.4,127.0,125.2,123.0,120.8,117.7,69.8,64.4,54.4,21.5.HRMS(ESI),m/z calcd.forC31H27N4O([M+H]+)471.2179,found:471.2180。
Figure BDA0002050662290000081
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-(三氟甲基)苯基)苯并[h]喹啉(IV-4e):米白色固体,收率:80％,m.p.147-149℃；1H NMR(400MHz,CDCl3)δ9.46(d,J＝8.8Hz,1H),8.43(d,J＝8.0Hz,2H),8.08(s,1H),7.89(d,J＝8.8Hz,1H),7.78(d,J＝9.2Hz,4H),7.76–7.66(m,2H),7.47(s,1H),7.34(d,J＝6.0Hz,3H),7.24(t,J＝2.8Hz,2H),5.51(s,2H),5.13(s,2H),4.84(s,2H).13C NMR(101MHz,CDCl3)δ153.7,146.4,145.2,144.1,143.2,134.5,133.7,132.1,129.3,129.0,128.5,128.3,127.9,127.8,127.3,125.82(d,J＝3.8Hz),125.1,123.5,122.8,120.5,117.7,69.4,64.4,54.3.HRMS(ESI),m/zcalcd.for C30H24FN4O([M+H]+)525.1897,found:525.1899。
Figure BDA0002050662290000082
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-甲氧苯基)苯并[h]喹啉(VI-5f):米白色固体,收率:94％,m.p.140-142℃；1H NMR(600MHz,CDCl3)δ9.49(d,J＝8.4Hz,1H),8.31(d,J＝7.8Hz,2H),8.01(s,1H),7.89(d,J＝7.8Hz,1H),7.82(d,J＝9.0Hz,1H),7.73(t,J＝9.0Hz,2H),7.68(t,J＝7.2Hz,1H),7.46(s,1H),7.34(s,3H),7.07(d,J＝7.8Hz,2H),5.51(s,2H),5.12(s,2H),4.84(s,2H),3.91(s,3H).13C NMR(151MHz,CDCl3)δ160.9,155.0,146.3,145.3,143.4,134.4,133.6,132.5,132.1,129.3,128.9,128.9,128.9,127.8,127.2,126.9,125.2,122.8,122.7,120.8,117.3,114.3,69.7,64.4,55.5,54.3.HRMS(ESI),m/z calcd.forC31H27N4O2([M+H]+)487.2129,found:487.2138。
Figure BDA0002050662290000091
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-苯基苯并[h]喹啉(IV-4g):米白色固体,收率:82％,m.p.131-133℃；1H NMR(400MHz,CDCl3)δ9.51(d,J＝8.0Hz,1H),8.34(d,J＝7.2Hz,2H),8.06(s,1H),7.89(d,J＝7.6Hz,1H),7.82(d,J＝9.2Hz,1H),7.77(s,1H),7.76–7.73(m,1H),7.72-7.67(m,1H),7.55(t,J＝8.0Hz,2H),7.48(d,J＝7.2Hz,1H),7.46(s,1H),7.34(d,J＝6.8Hz,3H),7.24(d,J＝6.4Hz,2H),5.50(s,2H),5.13(s,2H),4.83(s,2H).13C NMR(101MHz,CDCl3)δ155.35(s),146.4,145.3,143.6,139.8,134.6,133.6,132.2,129.4,129.3,129.0,128.9,128.3,128.2,128.7,127.7,127.6,127.1,125.2,123.2,122.8,120.8,117.8,69.7,64.4,54.4。
Figure BDA0002050662290000092
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(2-氯苯基)苯并[h]喹啉(IV-4h):淡绿色固体,收率:81％,m.p.120-121℃；1H NMR(400MHz,CDCl3)δ9.39(d,J＝6.9Hz,1H),7.98(s,1H),7.92–7.87(m,1H),7.86(t,J＝3.8Hz,2H),7.82(d,J＝9.2Hz,1H),7.72–7.67(m,2H),7.53(d,J＝8.0Hz,1H),7.47(s,1H),7.45–7.36(m,2H),7.34(d,J＝5.2Hz,3H),7.24(d,J＝6.8Hz,2H),5.50(s,2H),5.14(s,2H),4.83(s,2H).13C NMR(101MHz,CDCl3)δ155.4,146.4,145.3,142.6,139.8,134.6,133.5,132.6,132.5,132.0,130.4,129.8,129.3,128.9,128.3,128.3,128.2,127.8,127.2,125.2,123.2,122.7,122.0,120.7,69.6,64.4,54.4.HRMS(ESI),m/z calcd.forC30H24ClN4O([M+H]+)491.1633,found:491.1625。
Figure BDA0002050662290000101
4-(4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉-2-基)-N，N-二甲基苯胺(IV-4i):橙色固体,收率:89％,m.p.161-163℃；1H NMR(400MHz,CDCl3)δ9.51(d,J＝8.0Hz,1H),8.28(d,J＝8.8Hz,2H),7.98(s,1H),7.87(d,J＝7.6Hz,1H),7.80(d,J＝9.2Hz,1H),7.74–7.63(m,3H),7.44(s,1H),7.34(d,J＝4.8Hz,3H),7.25(d,J＝4.0Hz,2H),6.87(d,J＝8.8Hz,2H),5.49(s,2H),5.10(s,2H),4.82(s,2H),3.07(s,6H).13C NMR(101MHz,CDCl3)δ155.6,151.5,146.4,145.4,142.9,134.6,133.7,132.2,129.3,128.9,128.5,128.3,128.0,127.7,126.8,126.6,125.2,122.8,122.4,121.0,117.1,112.4,70.0,64.3,54.3,40.6.HRMS(ESI),m/z calcd.forC32H30FN5O([M+H]+)500.2445,found:500.2446。
Figure BDA0002050662290000102
4-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(3-氟苯基)苯并[h]喹啉(IV-4j):米白色固体,收率:80％,m.p.124-125℃；1H NMR(400MHz,CDCl3)δ9.46(d,J＝8.0Hz,1H),8.13–8.04(m,2H),8.03(s,1H),7.88(d,J＝7.6Hz,1H),7.78(t,J＝4.2Hz,2H),7.75–7.66(m,2H),7.49(dd,J＝14.8,7.2Hz,2H),7.34(d,J＝5.2Hz,3H),7.24(d,J＝2.4Hz,2H),7.15(t,J＝7.2Hz,1H),5.50(s,2H),5.12(s,2H),4.84(s,2H).13C NMR(101MHz,CDCl3)δ164.8,162.3,153.8,146.3,143.7,142.2,142.1,134.5,133.6,132.1,130.4,130.3,129.3,129.0,128.4,128.3,128.0,127.8,127.2,125.2,123.4,123.07(d,J＝2.8Hz),120.6,117.6,116.3,116.1,114.6,114.3,69.5,64.4,54.4.HRMS(ESI),m/zcalcd.forC30H24FN4O([M+H]+)475.1929,found:475.1930。
Figure BDA0002050662290000111
2-(4-氟苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉(IV-5a):米白色固体,收率:80％,m.p.124-126℃；1H NMR(400MHz,CDCl3)δ9.46(d,J＝8.0Hz,1H),8.30(d,J＝8.4Hz,2H),8.09(s,1H),7.92–7.84(m,2H),7.81(d,J＝9.2Hz,1H),7.75(t,J＝7.6Hz,1H),7.70(t,J＝7.2Hz,1H),7.59(d,J＝8.8Hz,2H),7.51(d,J＝8.4Hz,2H),6.99(d,J＝8.8Hz,2H),5.22(s,2H),4.93(s,2H),3.85(s,3H).13C NMR(151MHz,CDCl3)δ156.0,148.2,144.2,138.4,132.0,130.3,129.9,129.3,126.8,125.3,124.1,123.2 117.1,69.3,64.5,58.6,47.6,32.5.HRMS(ESI),m/z calcd.forC30H24FN4O2([M+H]+)491.1878,found:491.1874。
Figure BDA0002050662290000112
2-(4-氯苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉(IV-5b):黄棕色固体,收率:84％,m.p.133-135℃；1H NMR(400MHz,CDCl3)δ9.40(d,J＝9.6Hz,1H),8.04(s,1H),7.97–7.89(m,3H),7.87(d,J＝9.2Hz,2H),7.74–7.68(m,2H),7.59(d,J＝8.8Hz,2H),7.54(d,J＝8.0Hz,1H),7.45(t,J＝7.6Hz,1H),7.40(t,J＝7.6Hz,1H),7.00(d,J＝9.2Hz,2H),5.23(s,2H),4.94(s,2H),3.86(s,3H).13C NMR(151MHz,CDCl3)δ160.0,155.5,146.4,145.5,142.6,139.8,133.5,132.8,132.5,132.1,130.6,130.4,129.9,128.4,128.3,127.8,127.2,125.3,123.2,122.4,122.0,121.2,120.8,114.9,69.8,64.5,55.8.HRMS(ESI),m/z calcd.forC30H24ClN4O2([M+H]+)507.1582,found:507.1582。
Figure BDA0002050662290000113
2-(4-溴苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉(IV-6c):米白色固体,收率:82％,m.p.135-137℃；1H NMR(400MHz,CDCl3)δ9.46(d,J＝9.4Hz,1H),8.23(d,J＝6.8Hz,2H),8.08(s,1H),7.90(d,J＝8.8Hz,2H),7.84(q,J＝9.2Hz,2H),7.78–7.69(m,2H),7.67(d,J＝8.8Hz,2H),7.59(d,J＝9.2Hz,2H),6.99(d,J＝9.2Hz,2H),5.19(s,2H),4.94(s,2H),3.85(s,3H).13C NMR(151MHz,CDCl3)δ160.0,154.1,146.3,143.8,138.7,133.6,132.1,132.0,129.1,128.4,128.0,127.9,127.2,125.1,123.9,123.2,122.3,120.6,117.3,114.9,69.6,64.4,55.7.HRMS(ESI),m/zcalcd.forC30H24FBrN4O2([M+H]+)551.1077,found:551.1064。
Figure BDA0002050662290000121
4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(对甲苯基)苯并[h]喹啉(IV-5d):米白色固体,收率:81％,m.p.134-136℃；1H NMR(600MHz,CDCl3)δ9.51(d,J＝7.8Hz,1H),8.27(d,J＝7.8Hz,2H),8.10(s,1H),7.88(t,J＝7.8Hz,2H),7.79(d,J＝9.0Hz,1H),7.74(t,J＝7.2Hz,1H),7.69(t,J＝7.2Hz,1H),7.58(d,J＝9.0Hz,2H),7.36(d,J＝7.6Hz,2H),6.97(d,J＝8.6Hz,2H),5.20(s,2H),4.92(s,2H),3.83(s,3H),2.45(s,3H).13C NMR(151MHz,CDCl3)δ156.0,155.4,146.3,143.4,139.4,137.0,133.6,132.2,129.6,128.2,127.8,127.5,127.0,125.2,123.0,122.4,120.8,117.7,114.9,69.9,64.4,55.7,21.5.HRMS(ESI),m/z calcd.forC31H27N4O2([M+H]+)487.2129,found:487.2132。
Figure BDA0002050662290000122
4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-(三氟甲基)苯基)苯并[h]喹啉(IV-5e):米白色固体,收率:81％,m.p.62-64℃；1H NMR(600MHz,CDCl3)δ9.48(d,J＝7.8Hz,1H),8.46(d,J＝10.8Hz,2H),8.14(s,1H),7.91(d,J＝10.8Hz,2H),7.86(dd,J＝11.4,9.0Hz,2H),7.80(d,J＝7.6Hz,2H),7.76(t,J＝7.6Hz,1H),7.71(t,J＝7.2Hz,1H),7.60(d,J＝9.0Hz,2H),7.00(d,J＝9.0Hz,2H),5.22(s,2H),4.95(s,2H),3.85(s,3H).13C NMR(151MHz,CDCl3)δ160.1,153.7,146.4,145.2,144.0,143.1,133.7,132.1,130.9,130.5,128.5,128.4,127.9,127.9,127.3,125.83(d,J＝3.8Hz),125.1,123.5,122.4,121.3,120.6,117.7,114.9,69.6,64.4,55.8.HRMS(ESI),m/zcalcd.forC31H24F3N4O2([M+H]+)541.1740,found:541.1846。
Figure BDA0002050662290000131
2-(4-甲氧基苯基)-4-(((1-(4-甲氧苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉(IV-5f):棕色固体,收率:89％,m.p.170-172℃；1H NMR(400MHz,CDCl3)δ9.50(d,J＝7.9Hz,1H),8.33(d,J＝8.8Hz,2H),8.06(s,1H),7.90-7.87(m,3H),7.79(d,J＝9.2Hz,1H),7.71(dt,J＝20.8,7.2Hz,3H),7.59(d,J＝9.2Hz,2H),7.08(d,J＝8.8Hz,2H),6.99(d,J＝9.2Hz,2H),5.19(s,2H),4.93(s,2H),3.90(s,2H),3.85(s,3H).13C NMR(151MHz,CDCl3)δ160.9,160.0,155.1,146.4,143.4,133.7,132.5,132.2,129.0,128.2,127.8,127.3,127.0,125.2,122.8,122.4,121.3,120.8,117.4,114.9,114.3,69.9,64.4,55.8,55.6.HRMS(ESI),m/z calcd.forC31H27N4O3([M+H]+)503.2078,found:503.2074。
Figure BDA0002050662290000132
4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-苯基苯并[h]喹啉(IV-5g):米白色固体,收率:78％,m.p.102-104℃；1H NMR(400MHz,CDCl3)δ9.47(d,J＝8.7Hz,1H),8.35(dd,J＝8.8,5.2Hz,2H),8.07(s,1H),7.96–7.85(m,2H),7.81(d,J＝8.8Hz,1H),7.74(t,J＝7.6Hz,1H),7.70(t,J＝8.2Hz,1H),7.59(d,J＝9.2Hz,2H),7.23(t,J＝8.8Hz,3H),6.99(d,J＝9.2Hz,2H),5.20(s,2H),4.94(s,2H),3.85(s,3H).13C NMR(151MHz,CDCl3)δ164.5,162.9,159.9,154.2,146.1,143.6,135.8,133.5,131.9,129.3,129.2,128.2,127.7,127.6,127.0,125.0,122.9,122.2,120.5,117.2,115.7,115.6,114.8,69.5,64.3,55.6。
Figure BDA0002050662290000133
2-(2-氯苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉(IV-5h):米白色固体,收率:87％,m.p.142-144℃；1H NMR(600MHz,CDCl3)δ9.40(d,J＝7.6Hz,1H),8.04(s,1H),7.92(dd,J＝10.2,8.6Hz,3H),7.89–7.84(m,2H),7.70(p,J＝6.6Hz,2H),7.59(s,1H)7.58(s,1H),7.54(d,J＝7.8Hz,1H),7.45(t,J＝7.2Hz,1H),7.39(t,J＝7.6Hz,1H),6.99(d,J＝8.6Hz,2H),5.22(s,2H),4.93(s,2H),3.85(s,3H).13C NMR(151MHz,CDCl3)δ160.0,155.5,146.4,142.6,139.8,133.5,132.6,132.5,132.0,130.6,130.4,129.9,128.4,128.3,127.8,127.2,125.2,123.2,122.4,122.0,121.3,120.7,114.9,69.8,64.4,55.8.HRMS(ESI),m/z calcd.forC30H24ClN4O2([M+H]+)507.1582,found:507.1575。
Figure BDA0002050662290000141
4-(4-(((1-(4-甲氧苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉-2-基)-N，N-二甲基苯胺(IV-5i):红棕色固体,收率:86％,m.p.75-77℃；1H NMR(600MHz,CDCl3)δ9.51(d,J＝7.8Hz,1H),8.30(d,J＝8.6Hz,1H),8.03(s,1H),7.89–7.83(m,3H),7.74(d,J＝9.0Hz,1H),7.74(d,J＝7.8Hz,1H),7.66(t,J＝7.8Hz,1H),7.58(d,J＝9.0Hz,2H),6.98(d,J＝9.0Hz,2H),6.87(d,J＝8.6Hz,2H),5.16(s,2H),4.91(s,2H),3.84(s,4H),3.06(s,6H).13C NMR(151MHz,CDCl3)δ160.0,155.6,146.4,145.5,142.9,133.7,132.2,130.6,128.5,128.0,127.7,126.8,126.6,125.2,122.4,122.3,121.3,123.0,117.1,114.9,112.4,70.1,64.3,55.7,40.6.HRMS(ESI),m/z calcd.forC32H30N5O2([M+H]+)516.2394,found:516.2395。
Figure BDA0002050662290000142
2-(3-氟苯基)-4-(((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)苯并[h]喹啉(IV-5j):米白色固体,收率:90％,m.p.113-115℃；1H NMR(400MHz,CDCl3)δ9.48(d,J＝8.0Hz,1H),8.14-8.09(m,3H),7.90(d,J＝8.8Hz,2H),7.83(q,J＝9.2Hz,2H),7.90(t,J＝7.6Hz,1H),7.90(t,J＝7.6Hz,1H),7.59(d,J＝8.8Hz,2H),7.50(dd,J＝13.6,8.0Hz,1H),7.16(t,J＝8.0Hz,1H),6.99(d,J＝9.2Hz,2H),5.19(s,2H),4.94(s,2H),3.84(s,3H).13C NMR(151MHz,CDCl3)δ164.4,162.7,160.0,153.8,146.3,145.3,143.8,142.2,142.1,133.6,132.1,130.5,130.4,130.3,128.4,128.1,127.8,127.2,125.2,123.4,123.05(d,J＝2.6Hz),122.3,121.3,120.6,117.5,116.2,116.1,114.9,114.5,114.3,69.6,64.4,55.7.HRMS(ESI),m/z calcd.forC30H24FN4O2([M+H]+)491.1878,found:491.1871。
Figure BDA0002050662290000151
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-氟苯基)苯并[h]喹啉酮(IV-6a):米黄色固体,收率:88％,m.p.140-142℃；1H NMR(600MHz,CDCl3)δ9.47(d,J＝7.8Hz,1H),8.37–8.31(m,2H),8.05(s,1H),7.94(s,1H),7.90(d,J＝7.8Hz,1H),7.86(d,J＝9.0Hz,1H),7.80(d,J＝9.0Hz,1H),7.75(t,J＝7.6Hz,1H),7.70(t,J＝7.6Hz,1H),7.63(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,1H),7.23(t,J＝8.8Hz,2H),5.19(s,2H),4.93(s,2H).13C NMR(151MHz,CDCl3)δ164.8,163.1,154.3,146.4,145.8,143.6,135.9,135.5,134.8,133.7,132.1,130.1,129.5,129.4,128.4,127.9,127.8,127.2,125.1,123.0,121.8,121.0,120.6,117.4,115.9,115.8,69.9,64.32.HRMS(ESI),m/zcalcd.forC29H21ClFN4O([M+H]+)495.1382,found:495.1370。
Figure BDA0002050662290000152
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(对甲苯基)苯并[h]喹啉(IV-6d):米黄色固体,收率:81％,m.p.131-133℃；1H NMR(400MHz,CDCl3)δ9.50(d,J＝9.6Hz,1H),8.25(d,J＝8.4Hz,2H),8.06(s,1H),7.90(d,J＝4.8Hz,1H),7.87(d,J＝9.2Hz,2H),7.78(d,J＝8.8Hz,1H),7.76–7.66(m,1H),7.61(d,J＝8.8Hz,2H),7.45(d,J＝8.8Hz,2H),7.35(d,J＝8.0Hz,2H),5.18(s,2H),4.91(s,2H).13C NMR(151MHz,CDCl3)δ155.4,146.4,143.3,139.5,137.0,135.5,134.7,133.6,132.2,130.0,129.7,128.2,127.8,127.5,127.5,127.1,125.2,123.0,121.8,120.8,117.7,70.0,64.3,21.5。
Figure BDA0002050662290000161
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-(三氟甲基)苯基)苯并[h]喹啉(IV-6e):米黄色固体,收率:90％,m.p.126-127℃；1H NMR(400MHz,CDCl3)δ9.47(d,J＝8.4Hz,1H),8.46(d,J＝8.0Hz,2H),8.13(s,1H),7.96(s,1H),7.94–7.88(d,J＝7.6Hz,1H),7.86(q,J＝9.0Hz,1H),7.80(d,J＝8.0Hz,2H),7.78–7.69(m,2H),7.64(d,J＝8.8Hz,2H),7.47(d,J＝8.8Hz,2H),5.19(s,2H),4.95(s,2H).13C NMR(151MHz,CDCl3)δ153.6,146.4,145.7,143.9,143.0,135.5,134.8,133.6,132.0,131.1,130.9,130.1,128.5,128.4,127.9,127.8,127.3,125.80(d,J＝3.7Hz),125.3,125.0,123.5,121.8,121.0,120.5,117.6,69.7,64.3.HRMS(ESI),m/z calcd.forC30H21ClF3N4O([M+H]+)545.1351,found:545.1354。
Figure BDA0002050662290000162
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-(4-甲氧苯基)苯并[h]喹啉(IV-6f):米黄色固体,收率:84％,m.p.163-165℃；1H NMR(400MHz,CDCl3)δ9.49(d,J＝9.6Hz,1H),8.32(d,J＝9.2Hz,2H),8.04(s,1H),7.92(s,1H),7.91–7.84(m,2H),7.78(d,J＝9.2Hz,1H),7.74(t,J＝7.6Hz,2H),7.69(t,J＝7.6Hz,2H),7.62(d,J＝9.2Hz,2H),7.46(d,J＝8.8Hz,2H),7.07(d,J＝9.2Hz,2H),5.18(s,2H),4.92(s,2H),3.90(s,3H).13CNMR(151MHz,CDCl3)δ161.0,155.0,146.3,145.9,143.2,135.5,134.7,133.6,132.4,132.1,130.0,128.9,128.2,127.8,127.3,127.0,125.2,122.7,121.8,121.0,120.8,117.4,114.3,70.0,64.3,55.5.HRMS(ESI),m/z calcd.forC30H24ClN4O2([M+H]+)507.1582,found:507.1577。
Figure BDA0002050662290000163
4-(((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲氧基)甲基)-2-苯基苯并[h]喹啉(IV-6g):米黄色固体,收率:87％,m.p.163-165℃；1H NMR(400MHz,CDCl3)δ9.51(d,J＝8.8Hz,1H),8.36(d,J＝8.4Hz,2H),8.11(s,1H),7.98(s,1H),7.92–7.86(m,2H),7.81(d,J＝9.2Hz,1H),7.75(t,J＝7.8Hz,1H),7.70(t,J＝8.0Hz,1H),7.62(d,J＝8.8Hz,2H),7.56(t,J＝7.8Hz,2H),7.47(dd,J＝13.6,8.8Hz,2H),5.21(s,2H),4.93(s,2H).13C NMR(151MHz,CDCl3)δ155.4,146.4,143.4,139.8,134.7,133.6,132.2,130.1,129.4,128.9,128.3,127.8,127.7,127.6,127.1,125.2,123.2,121.9,120.7,117.9,70.0,64.4.HRMS(ESI),m/z calcd.forC29H22ClN4O([M+H]+)477.1477,found:477.1476。
Figure BDA0002050662290000171
3-(4-(((2-(4-氟苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7a):黄棕色固体,收率:85％,m.p.101-103℃；1H NMR(600MHz,CDCl3)δ9.44(d,J＝8.1Hz,1H),8.35–8.30(m,2H),8.01(s,1H),7.88(d,J＝7.8Hz,1H),7.79(dd,J＝22.2,9.0Hz,2H),7.73(t,J＝7.5Hz,1H),7.68(t,J＝7.2Hz,1H),7.6(s,H),7.22(t,J＝7.2Hz,2H),5.11(s,2H),4.83(s,2H),4.47(t,J＝6.6Hz,2H),3.58(t,J＝6.0Hz,2H),2.15(s,1H),2.09–1.84(m,2H).13C NMR(151MHz,CDCl3)δ164.7,163.1,154.3,146.2,144.7,143.8,135.9,133.6,132.0,129.4,129.4,128.3,127.8,127.7,127.1,125.1,123.4,123.0,120.6,117.4,115.9,115.7,69.6,64.4,58.8,47.1,32.6.HRMS(ESI),m/zcalcd.forC26H24FN4O2([M+H]+)443.1878,found:443.1875。
Figure BDA0002050662290000172
3-(4-(((2-(4-氯苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(VI-7b):棕色油状物,收率:91％,；1H NMR(600MHz,CDCl3)δ9.44(d,J＝8.0Hz,1H),8.29(d,J＝7.8Hz,2H),8.06(s,1H),7.88(d,J＝7.2Hz,1H),7.81(dd,J＝24.0,8.4Hz,2H),7.74(t,J＝7.3Hz,1H),7.69(t,J＝7.1Hz,1H),7.50(d,J＝7.7Hz,2H),5.17(s,2H),4.83(s,2H),4.51(s,2H),3.59(s,2H),2.2(s,1H),2.1(s,3H).13C NMR(151MHz,CDCl3)δ154.0,146.3,143.9,138.2,135.5,133.6,132.0,129.1,128.9,128.4,127.9,127.8,127.2,125.1,123.2,120.6,117.4,69.6,64.5,58.9,47.7,32.5.HRMS(ESI),m/zcalcd.forC26H24ClN4O2([M+H]+)459.1582,found:495.1581。
Figure BDA0002050662290000181
3-(4-(((2-(4-溴苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7c):黄绿色油状物,收率:96％；1H NMR(600MHz,CDCl3)δ9.44(d,J＝7.8Hz,1H),8.22(d,J＝8.4Hz,2H),8.03(s,1H),7.89(d,J＝7.8Hz,1H),7.80(q,J＝9.0Hz,2H),7.74(t,J＝7.2Hz,1H),7.70(d,J＝7.8Hz,1H),7.66(d,J＝7.8Hz,2H),7.57(s,1H),5.12(s,2H),4.85(s,2H),4.48(t,J＝6.6Hz,2H),3.60(t,J＝6.0Hz,2H),2.16–2.04(m,2H),1.96(s,2H).13C NMR(151MHz,CDCl3)δ154.1,146.3,144.8,143.9,138.6,133.6,132.0,129.1,128.4,128.0,127.9,127.2,125.1,123.9,123.3,123.2,120.6,117.3,69.6,64.4,58.9,47.1,32.6。
Figure BDA0002050662290000182
3-(4-(((2-(对甲苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7d):黄棕色固体,收率:90％,m.p.111-113℃；1H NMR(600MHz,CDCl3)δ9.50(d,J＝7.8Hz,1H),8.25(d,J＝8.4Hz,2H),8.04(s,1H),7.88(d,J＝7.8Hz,1H),7.84(d,J＝9.0Hz,1H),7.78(d,J＝9.0Hz,1H),7.73(t,J＝7.2Hz,1H),7.68(t,J＝7.2Hz,1H),7.53(s,1H),7.36(d,J＝7.8Hz,2H),5.12(s,2H),4.84(s,2H),4.45(t,J＝6.8Hz,2H),3.56(t,J＝5.8Hz,2H),2.45(s,2H),2.14(s,1H),2.08–1.96(m,2H).13C NMR(151MHz,CDCl3)δ155.4,146.3,144.8,143.5,139.5,137.0,133.6,132.1,129.7,128.2,127.8,127.5,127.0,125.2,123.3,123.0,120.8,117.7,69.8,64.4,58.8,47.0,32.6,21.5.HRMS(ESI),m/zcalcd.forC27H27N4O2([M+H]+)439.2129,found:439.2131。
Figure BDA0002050662290000191
3-(4-(((2-(4-(三氟甲基)苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7e):红棕色油状物,收率:81％,；1H NMR(600MHz,CDCl3)δ9.43(d,J＝7.8Hz,1H),8.09(d,J＝10.2Hz,1H),8.06(d,J＝7.8Hz,1H),8.00(s,1H),7.85(d,J＝7.8Hz,1H),7.75(s,2H),7.73(t,J＝7.8Hz,1H),7.67(t,J＝7.8Hz,1H),7.56(s,1H),7.47(dd,J＝13.8,7.8Hz,1H),7.14(t,J＝7.8Hz,1H),5.07(s,2H),4.81(s,2H),4.45(t,J＝6.6Hz,2H),3.57(t,J＝6.0Hz,2H),2.39(s,1H),2.16–1.94(m,2H).13C NMR(151MHz,CDCl3)δ164.3,162.7,153.7,153.7,146.2,144.6,143.8,142.1,142.0,133.6,132.0,130.3,130.3,128.4,128.0,127.8,127.2,125.1,123.4,123.3,123.01(d,J＝2.7Hz),120.5,117.4,116.2,116.1,114.4,114.3,69.5,64.3,58.7,47.1,32.6.HRMS(ESI),m/zcalcd.forC27H24F3N4O2([M+H]+)493.1846,found:493.1847。
Figure BDA0002050662290000192
3-(4-(((2-(4-甲氧苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7f):红棕色油状物,收率:94％；1H NMR(600MHz,CDCl3)δ9.47(d,J＝8.4Hz,1H),8.31(d,J＝7.8Hz,2H),8.03(s,1H),7.87(d,J＝7.8Hz,1H),7.83(d,J＝8.4Hz,1H),7.76(d,J＝8.4Hz,1H),7.72(t,J＝7.2Hz,1H),7.67(t,J＝7.2Hz,1H),7.06(d,J＝8.4Hz,2H),5.14(s,2H),4.81(s,2H),4.47(s,2H),3.89(s,3H),3.55(s,2H),2.05(s,2H),1.92(s,1H).13C NMR(151MHz,CDCl3)δ160.9,155.0,146.3,143.5,133.6,132.4,132.1,128.9,128.2,127.8,127.3,127.0,125.1,122.8,120.8,117.3,114.3,69.8,64.4,58.8,55.5,47.4,32.5。
Figure BDA0002050662290000201
3-(4-(((2-苯基苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7g):绿色固体,收率:83％m.p.79-81℃；1H NMR(600MHz,CDCl3)δ9.50(d,J＝8.4Hz,1H),8.35(s,2H),8.13(s,1H),7.89(d,J＝7.8Hz,2H),7.80(s,1H),7.74(t,J＝7.2Hz,1H),7.69(t,J＝7.2Hz,1H),7.55(s,2H),7.47(t,J＝6.6Hz,1H),5.24(s,2H),4.79(s,2H),4.53(s,2H),3.56(s,2H),2.09(s,3H),1.75(s,1H).13C NMR(151MHz,CDCl3)δ155.3,146.3,143.7,139.8,133.6,132.1,129.4,128.9,128.3,127.9,127.8,127.6,127.1,125.2,123.2,120.8,117.9,69.8,64.8,58.9,32.3。
Figure BDA0002050662290000202
3-(4-(((2-(4-(二甲基氨基)苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7i):血红色固体,收率:87％,m.p.65-67℃；1H NMR(600MHz,CDCl3)δ9.41(d,J＝8.1Hz,1H),8.20(d,J＝8.4Hz,2H),7.91(s,1H),7.79(d,J＝7.8Hz,1H),7.75(d,J＝8.4Hz,1H),7.64(t,J＝9.0Hz,2H),7.58(t,J＝7.2Hz,1H),6.78(d,J＝8.4Hz,2H),5.04(s,2H),4.74(s,2H),4.36(t,J＝5.4Hz,2H),3.45(s,2H),2.97(s,6H),2.10(s,1H),1.95(s,2H).13C NMR(151MHz,CDCl3)δ155.5,151.4,146.2,143.0,133.6,132.0,128.4,127.9,127.6,127.5,126.7,126.5,125.1,122.3,120.9,117.0,112.3,100.0,70.0,64.3,58.7,47.1,40.4,32.4。
Figure BDA0002050662290000203
3-(4-(((2-(3-氟苯基)苯并[h]喹啉-4-基)甲氧基)甲基)-1H-1,2,3-三唑-1-基)丙-1-醇(IV-7j):绿色固体,收率:90％,m.p.107-109℃；1H NMR(600MHz,CDCl3)δ9.46(d,J＝8.4Hz,1H),8.46(s,2H),8.19(s,1H),7.90(d,J＝7.8Hz,1H),7.86(s,1H),7.83(d,J＝6.6Hz,1H),7.79(d,J＝5.9Hz,2H),7.76(t,J＝7.2Hz,1H),7.71(t,J＝7.2Hz,1H),5.26(s,2H),4.83(s,2H),4.57(s,2H),3.60(s,2H),2.13(s,2H),2.04(s,1H).13C NMR(151MHz,CDCl3)δ164.7,163.1,154.3,146.2,144.7,143.8,135.9,133.6,132.0,129.40(d,J＝8.3Hz),128.3,127.8,127.7,127.1,125.1,123.4,123.0,120.6,117.4,115.9,115.7,69.6,64.4,58.8,47.1,32.6。
2、活性研究
SHP-1作为筛选模型
SHP1是含有SH2结构域的蛋白酪氨酸磷酸酶1，其通过直接去磷酸化调节细胞内信号蛋白分子的酪氨酸磷酸化水平抑制细胞的有丝分裂增殖，分化和生物活性。SHP1是近年来发现的重要抑癌基因之一，它在造血系统中抑制白血病细胞生长已经得到证实。而且在乳腺癌、卵巢癌、前列腺癌细胞中，SHP1的的表达量均发生了下调，说明了SHP1在癌症发生中的重要性，所以关于SHP1靶点的激活剂对这些癌症病人有很高的临床应用价值。
测试过程：采用荧光底物D iFM U P，观察不同化合物对重组酶活性的抑制。D iFMU P水解后得到的产物D iFM U在被358nM激发光激发后可发射出波长为455nM的可检测的荧光信号，通过检测荧光信号的变化，反应酶的活性，从而观察酶的活性变化以及化合物对其的抑制情况。
表1部分化合物4a-7j对SHP1靶点的酶活抑制率如下：
Figure BDA0002050662290000211
SHP-2作为筛选模型
SHP2是含有SH2结构域的蛋白酪氨酸磷酸酶2，其在各种细胞和组织中均有广泛的表达，参与多个信号传导通路，介导细胞的生长、分化、迁移、粘附及凋亡，目前SHP2在血液肿瘤细胞中的作用相对而言已比较清楚，近来又发现SHP2在肺癌、胃癌、宫颈癌、甲状腺癌和乳腺癌等多种实体肿瘤组织中呈现高表达，并且这种高表达与肿瘤的发生、发展和预后有关，所以SHP2很可能是个很有潜力的靶分子。
采用荧光底物D iFM U P，观察不同化合物对重组酶活性的抑制。D iFM U P水解后得到的产物D iFM U在被358nM激发光激发后可发射出波长为455nM的可检测的荧光信号，通过检测荧光信号的变化，反应酶的活性，从而观察酶的活性变化以及化合物对其的抑制情况。
表2部分化合物4a-7j对SHP2靶点的酶活抑制率如下：
Figure BDA0002050662290000221
以上实施例描述了本发明的基本原理、主要特征，本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (3)

1.具有生物活性的苯并喹啉取代三氮唑类化合物，其特征在于该苯并喹啉取代三氮唑类化合物的结构式为：
Figure FDA0003132226520000011
Figure FDA0003132226520000021
该苯并喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂通过直接去磷酸化调节细胞内信号蛋白分子的酪氨酸磷酰化水平抑制细胞的有丝分裂增殖、分化和生物活性，在造血系统中抑制白细胞生长，在乳腺癌、卵巢癌或前列腺癌细胞中，抑制SHP1表达量下调，进而抑制对应癌症的发生；该苯并喹啉取代三氮唑类化合物作为SHP2靶点的酶活抑制剂通过参与多个信号传导通路介导细胞的生长、分化、迁移、粘附和调亡，在肺癌、胃癌、宫颈癌、甲状腺癌和乳腺癌细胞中，抑制SHP2表达量下调，进而抑制对应癌症的发生。
2.权利要求1所述的具有生物活性的苯并喹啉取代三氮唑类化合物在制备抗癌药物中的应用。
3.权利要求1所述的具有生物活性的苯并喹啉取代三氮唑类化合物作为SHP1靶点的酶活抑制剂和SHP2靶点的酶活抑制剂用于制备抗癌药物。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000623A2 (en) * 2000-06-26 2002-01-03 Neurogen Corporation Aryl fused substituted 4-oxy-pyridines
WO2016153948A1 (en) * 2015-03-20 2016-09-29 Deuterx, Llc Combination therapy using enantiopure, oxy-substituted, deuterium-enriched 5-(benzyl)-5-deutero-thiazolidine-2, 4-diones for treatment of medical disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000623A2 (en) * 2000-06-26 2002-01-03 Neurogen Corporation Aryl fused substituted 4-oxy-pyridines
WO2016153948A1 (en) * 2015-03-20 2016-09-29 Deuterx, Llc Combination therapy using enantiopure, oxy-substituted, deuterium-enriched 5-(benzyl)-5-deutero-thiazolidine-2, 4-diones for treatment of medical disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates;Hassan M. Faidallah等;《Bioorganic & Medicinal Chemistry》;20160530;第24卷(第16期);3527-3539 *

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