CN111138449A - 双靶向erk1和erk5抑制剂的制备及其抗肿瘤应用 - Google Patents
双靶向erk1和erk5抑制剂的制备及其抗肿瘤应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一种双靶向ERK1和ERK5抑制剂的制备及其应用,属于抗肿瘤药学技术领域。
背景技术
肿瘤是影响健康的主要慢性疾病之一,严重地影响着人类的健康生活,给社会和家庭带来了沉重的负担。手术切除结合放化疗法对患者的身心都会带来极大伤害,靶向治疗是一种新型的治疗手段,具有靶点明确、副作用少、可直接作用于病变组织等优点,已成为肿瘤治疗的重要研究方向。目前,肿瘤靶向治疗面临的最重要问题是可供选择的药物靶标缺乏及相应靶向小分子研究较少,因此通过发现新的治疗靶标和设计靶向药物是***的重要途径。
丝裂原激活蛋白激酶(Mitogen-activated protein kinase,MAPK)级联是一个高度保守的模块,参与细胞存活、增殖和分化等过程。MAPK家族由ERK1/5(extracellularsignal- regulated kinase 1/5)和JNK(c-Jun-N-terminal kinases)等成员组成。目前,越来越多的临床证据表明,在许多类型的癌症中,ERK1或ERK5信号参与肿瘤的发生和进展。因此,一系列选择性ERK1抑制剂或ERK5抑制剂已被作为候选抗肿瘤小分子药物进行研究,但迄今为止还没有报道ERK1和ERK5的任何双靶抑制剂或其联合治疗策略。
重要的是,研究表明ERK5会在ERK1信号传导被抑制后发挥代偿作用,挽救肿瘤细胞的增殖,因此ERK5为ERK1提供了一种代偿途径。基于此,我们提出了同时靶向 ERK1和ERK5的科学观点,这样不仅可以根据它们的共同基序提高其抗增殖作用,而且提供了一个完整的和克服代偿机制的治疗策略。同样,迄今为止还没有用于***的双靶向 ERK1和ERK5抑制剂的相关开发工作。因此,针对于具有ERK1或ERK5的新型双靶向 ERK1和ERK5小分子抑制剂的开发,具有很广阔的研究前景。
发明内容
本发明解决的技术问题是提供一种作为双靶向ERK1和ERK5新型抑制剂的化合物。
本发明提供如下所示的化合物或其药学上可接受的盐:
R3为硫原子(S)或氧原子(O)。
本发明还提供上述化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
进一步的,所述抗肿瘤药物优选为新型双靶向ERK1和ERK5抑制剂类药物。
所述抗肿瘤药物优选为抗肿瘤的药物,所对应的肿瘤具有ERK1和/或ERK5高表达特点的肿瘤。
本发明制备的化合物或其药学上可接受的盐,可以作为双靶向ERK1和ERK5抑制剂,具有一定的抗肿瘤活性,能有效的抑制癌细胞的生长。本发明化合物对多种肿瘤细胞,特别是乳腺癌细胞具有明显的抑制作用。
表1和表2为上述化合物的ERK1、ERK5酶活性检测及其对HL-60、MKN-74的抗增殖活性测试结果。
表1.关于式I相关化合物的体外酶活性检测和抗增殖活性结果
表2.关于式II相关化合物的体外酶活性检测和抗增殖活性结果
附图说明
图1A为进行化合物25不同剂量给药后,HL-60细胞异种移植鼠模型的相对体积变化图,数据为肿瘤体积均值±SEM(n=8)。
图1B为进行化合物25不同剂量给药后,MKN-74细胞异种移植鼠模型的相对体积变化图,数据为肿瘤体积均值±SEM(n=8)。
图1C为进行化合物25不同剂量给药后,HL-60、MKN-74细胞异种移植鼠模型的相对肿瘤重量图,***,p<0.001,与对照组相比。
图1D为化合物25治疗后,Ki-67、p-ERK1/2、p-ERK5的免疫组化分析结果图 (Scalebar=200μm)。
图1E为化合物25治疗后,Ki-67、p-ERK1/2、p-ERK5的免疫组化分析结果的统计柱状图。
图1F为检测动物肿瘤组织中ERK1/2、p-ERK1/2(T202,Y204)、ERK5、p-ERK5 (T218,T220)蛋白的表达水平。
具体实施方式
本发明提供如下所示的化合物或其药学上可接受的盐:
R3为硫原子(S)或氧原子(O)。
下面是本发明的化合物的一些优选结构。
本发明还提供上述化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
进一步的,所述抗肿瘤药物优选为双靶向ERK1/2和ERK5抑制剂类药物。
所述抗肿瘤药物优选为治疗乳腺癌的药物。
本发明还提供一种药物组合物,它是包含有效剂量的上述化合物或其药学上可接受的盐的制剂。
可以通过本领域已知的方法可将本发明化合物制成以下形式:片剂、胶囊剂、水性或油性溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、凝胶剂、喷鼻剂、栓剂、用于吸入的细小分散的粉剂或气雾剂或喷雾剂、用于胃肠道外(包括静脉内、肌内或输注)的无菌水性或油性溶液或混悬剂或无菌乳剂。可采用无菌水或水-丙二醇溶液作为溶剂来制备液体制剂,还可将活性组分配制在聚乙二醇水溶液中。用于口服给予的水性溶液可通过将活性组分溶解在水中并按需要加入合适的着色剂、矫味剂、稳定剂和增稠剂来制备。口服使用的水性混悬剂可通过将细小分散的活性组分与粘性物质一道分散在水中,所述粘性物质如为天然合成胶、树脂、甲基纤维素、羧甲基纤维素和其他药剂领域已知的悬浮剂。
药物组合物可为单位剂量形式。在这些形式中,将所述组合物分成含适量活性组分的单位剂量。该单位剂量形式可为包装制剂,包装中包括分隔量的制剂,例如盒装片剂、胶囊剂和在管形瓶或安瓿中的粉剂。单位剂量形式还可为胶囊剂、扁囊剂或片剂或其可为适当数量的任何这些包装形式。
本发明的药物组合物,其活性成分可仅为本发明的化合物,也可与其它抗肿瘤化合物组合作为活性成分。
在***的过程中,可采用本发明的药物组合物与其他抗肿瘤药进行联合治疗。例如,与用于医学肿瘤学的抗增殖/抗肿瘤药、细胞生长抑制剂、抗入侵药物、生长因子功能抑制剂、抗血管生成剂、血管损伤剂等联用。
在***时,可通过同时、序贯或单独给予各种治疗成分可实现这种联合治疗。此类组合产品应用有效剂量范围内的本发明化合物和准许剂量范围内的其他药学活性剂。
下面结合实施例对本发明的具体实施方式做进一步的描述,并不因此将本发明限制在所述的实施例范围之中。
实施例1优选化合物的合成。
优选化合物采用如下反应式合成:
i乙醇,加热回流;ii DIEA,酰氯,室温;iii甲醇饱和盐酸溶液,0℃;iv苄基氯,K2CO3,DMF,80℃;v异硫氰酸酯,DIEA,二氯甲烷,室温。
1.中间体1-3的合成通法
在无水乙醇(200mL)溶液中加入叔丁基4-奥泊哌啶-1-羧酸酯(30.0mmol)、2-氰乙酰胺(30.0 mmol)和硫(30.0mmol),吗啉(30.0mmol)。搅拌回流8小时,混合液冷却至常温,过滤,用30ml的乙醇洗涤三次,滤液悬干浓缩至干燥。粗品经95%乙醇(30mL)稀释,过滤后为白色固体,得到中间体1。
在二氯甲烷(60ml)溶液中加入中间体1(10mmol)和DIEA(20mmol),在室温下逐滴滴加酰氯。混合物搅拌8小时后,用水,饱和碳酸氢钠和盐水萃取,然后用无水硫酸钠干燥。将溶剂除去后,用硅胶柱层析法纯化粗品,用二氯甲烷/甲醇(5-10%)洗脱,得到中间体 2。
在0℃下100毫升甲醇饱和盐酸溶液加入250毫升圆底烧瓶中,加入中间体2(15mmol) 快速搅拌6小时。完成后,将混合物浓缩,加入50mL水,用氢氧化钠(1mol/L)碱化至pH =10,用乙酸乙酯萃取。用饱和碳酸氢钠和盐水洗涤有机层,然后用无水硫酸钠干燥。在减压除去溶剂后,产生粗产物。粗产物经硅胶柱层析(二氯甲烷/甲醇10∶1)纯化,为白色固体,得到中间体3。
2.化合物1-80合成通法
中间体3(10mmol)和K2CO3加入到DMF(60mL)中,氯化苄(15mmol)在0℃下逐滴添加。混合物加热至80℃搅拌回流8h。反应完毕后,反应液用50mL水稀释,用乙酸乙酯萃取三次。有机层用水、饱和碳酸氢钠和盐水洗涤,然后用无水硫酸钠干燥。在减压条件下除去溶剂后,出现产物粗品。采用硅胶柱层析法纯化,洗脱***为二氯甲烷/甲醇,纯化得到的化合物1-22。
在二氯甲烷(70mL)中加入中间体3(10mmol)、DIEA(10mmol)、异硫氰酸酯(11mmol)分别在0℃下逐滴加入,移至室温反应8h。混合物分别用水、饱和碳酸氢钠溶液和盐水洗涤,然后用无水硫酸钠干燥。减压除去溶剂后,用硅胶柱层析法纯化,洗脱***为二氯甲烷/ 甲醇,纯化得到化合物23-80。
化合物1,白色固体,收率73.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm):7.66(1H, dd,J=6.8,2.4Hz),7.48(1H,dd,J=7.3,1.8Hz),7.41(1H,m),7.38(1H,m),3.97(2H,s),3.11(2H,t,J=5.6Hz),2.92(2H,t,J=5.6Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.3,167.3,130.5,130.3,130.3,130.0,130.0,129.9,129.9,129.9,128.7,127.1,42.8,42.0,25.0;HR- ESI-MS[M+H]+:m/z 336.0599。
化合物2,白色固体,收率70.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.38 (1H,brs),7.73(1H,dd,J=7.5,1.4Hz),7.62(1H,dd,J=8.0,1.3Hz),7.58(1H,td,J=8.0,1.3Hz),7.50(1H,td,J=7.5,1.4Hz),7.37(2H,m),7.35(2H,m),7.28(1H,m),3.69(2H,s),3.57(2H, s),2.83(2H,t,J=5.1Hz),2.71(2H,t,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm): 167.6,162.7,142.8,138.7,134.2,133.0,130.9,130.6,130.3,129.3,129.3,128.7,128.7,128.5, 128.2,127.6,125.2,117.0,61.2,51.4,49.7,25.9;HR-ESI-MS[M+H]+:m/z 426.1043。
化合物3,白色固体,收率65.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.39 (1H,brs),7.73(1H,d,J=7.5,1.3Hz),7.62(1H,td,J=7.9,1.4Hz),7.60(1H,td,J=8.0,1.6Hz), 7.57(1H,td,J=7.5,1.7Hz),7.29(1H,d,J=7.6Hz),7.17(1H,m),7.16(1H,m),7.15(1H,m), 3.64(2H,s),3.58(2H,s),2.82(2H,brt,J=4.8Hz),2.72(2H,brt,J=4.8Hz),2.34(3H,s);13C- NMR(100MHz,DMSO-d6),δ(ppm):167.1,167.1,162.2,142.2,137.1,136.3,133.7,132.5, 130.4,130.1,129.8,129.5,128.0,127.7,127.1,125.5,124.8,116.6,58.8,51.1,49.3,25.4,18.8; HR-ESI-MS[M+H]+:m/z 440.1183。
化合物4,白色固体,收率69.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.40 (1H,brs),7.85(1H,m),7.73(2H,m),7.62(2H,m),7.60(1H,m),7.52(2H,m),3.86(2H,s),3.65(2H,s),2.85(2H,m),2.78(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.5,162.7,142.8,142.6,134.2,133.6,133.5,133.0,130.9,130.6,130.3,129.7,128.6,128.4,128.2,124.9,118.1,117.1,112.6,59.0,51.4,49.8,25.8;HR-ESI-MS[M+H]+:m/z 451.1041。
化合物5,白色固体,收率66.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.38 (1H,brs),7.73(1H,d,J=7.5,1.5Hz),7.62(1H,td,J=8.0,1.5Hz),7.60(1H,dd,J=7.0,1.7Hz), 7.56(1H,m),7.51(1H,td,J=7.6,1.7Hz),7.47(1H,dd,J=7.5,1.4Hz),7.36(1H,td,J=7.4,1.4 Hz),7.31(1H,td,J=7.5,1.6Hz),3.79(2H,s),3.66(2H,s),2.86(2H,m),2.77(2H,m);13C-NMR (100MHz,DMSO-d6),δ(ppm):167.1,162.2,142.3,133.7,133.4,132.5,130.8,130.4,130.4, 130.1,129.8,129.8,129.3,128.8,128.0,127.7,127.1,116.6,57.4,50.9,49.4,25.4;HR-ESI-MS [M+H]+:m/z 460.0683。
化合物6,白色固体,收率69.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.37 (1H,brs),7.72(1H,d,J=6.6Hz),7.61(1H,m),7.59(1H,m),7.51(1H,d,J=7.9Hz),7.59(1H,dd,J=8.6,7.9Hz),7.35(1H,dd,J=13.4,6.1Hz),7.23(1H,d,J=7.0,2.4Hz),7.20(1H,d,J= 13.4,6.8Hz),3.75(2H,s),3.60(2H,s),2.84(2H,brt,J=5.1Hz),2.74(2H,brt,J=5.1Hz);13C- NMR(100MHz,DMSO-d6),δ(ppm):167.5,165.7,162.8,161.5(244.0Hz),142.8,134.2,133.0, 130.9,130.8(3.0Hz),130.6,130.5(26.5Hz),130.3,128.4,128.2,128.2,124.8(3.4Hz),117.1, 115.7(21.1Hz),53.8,51.0,49.7,25.7;HR-ESI-MS[M+H]+:m/z444.0926。
化合物7,白色固体,收率64.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.40 (1H,brs),7.72(1H,d,J=7.0Hz),7.62(1H,m),7.60(2H,m),7.51(1H,dd,J=7.0,6.8Hz),7.40(2H,m),7.39(1H,m),3.68(2H,s),3.57(2H,s),2.84(2H,m),2.71(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.6,162.7,142.8,134.2,133.0,132.1,131.1,131.1,130.9,130.8,130.6, 130.3,129.4,128.7,128.7,128.4,128.2,117.0,60.2,51.2,49.7,25.8;HR-ESI-MS[M+H]+:m/z 460.0662。
化合物8,白色固体,收率64.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.08 (1H,brs),8.22(2H,d,J=8.6Hz),7.88(1H,m),7.83(1H,d,J=7.7Hz),7.74(1H,d,J=7.5Hz),7.67(2H,d,J=8.6Hz),7.64(1H,dd,J=7.9,7.7Hz),3.84(2H,s),3.61(2H,s),2.88(2H,brt,J= 5.4Hz),2.75(2H,brt,J=5.4Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):168.1,161.7, 147.3,147.2,137.1,134.3,132.8,132.6,131.6,130.2,130.2,128.4,127.4,126.1,123.9,123.9, 116.4,109.4,60.2,51.4,49.9,25.9;HR-ESI-MS[M+H]+:m/z471.0918。
化合物9,类白色固体,收率66.1%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.37 (1H,brs),9.39(1H,brs),7.74(1H,dd,J=7.4,1.4Hz),7.62(1H,m),7.59(1H,dd,J=7.0,1.4Hz), 7.52(3H,m),7.38(1H,m),3.91(2H,s),3.69(2H,s),2.83(2H,m),2.83(2H,m);13C-NMR(100 MHz,DMSO-d6),δ(ppm):166.8,163.3,143.6,134.2,134.0133.0,132.9,130.9,130.7,130.6,130.3,129.2,128.2,128.1,127.8,119.5,117.5,117.1,60.0,50.0,41.3,22.6;HR-ESI-MS[M+H]+: m/z 494.0288。
化合物10,类白色固体,收率62.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 13.09(1H,brs),7.88(1H,m),7.84(1H,d,J=7.8Hz),7.73(1H,d,J=8.0Hz),7.65(1H,t,J=7.8Hz),7.60(1H,d,J=2.1Hz),7.57(1H,d,J=8.4Hz),7.43(1H,dd,J=8.4,2.1Hz),3.76(2H,s), 3.70(2H,s),3.44(2H,m),2.76(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm):168.1,168.1, 161.5,144.0,135.5,134.9,134.7,134.3,132.8,132.5,131.6,129.2,128.4,127.7,127.4,126.1, 124.9,116.3,57.4,51.4,49.9,25.9;HR-ESI-MS[M+H]+:m/z494.0285。
化合物11,白色固体,收率67.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.37 (1H,brs),7.73(1H,dd,J=7.5,1.5Hz),7.62(1H,dd,J=8.1,1.3Hz),7.58(1H,td,J=8.1,1.5Hz),7.52(1H,d,J=1.8Hz),7.51(1H,m),7.43(2H,d,J=1.8Hz),3.71(2H,s),3.61(2H,s),2.84 (2H,t,J=5.1Hz),2.71(2H,t,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.6,162.7,143.6,142.8,134.4,134.4,134.2,133.0,130.9,130.9,130.6,130.3,128.4,128.2,127.7, 127.2,124.9,117.1,59.6,51.3,49.6,25.8;HR-ESI-MS[M+H]+:m/z495.8214。
化合物12,类白色固体,收率69.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 13.17(1H,brs),8.09(2H,d,J=8.1Hz),8.00(2H,brd,J=8.1Hz),7.49(1H,ddd,J=7.6,7.3,1.8Hz),7.36(1H,ddm,J=13.4,6.0Hz),7.21(1H,d,J=7.3Hz),7.19(1H,m),3.74(2H,s),3.60(2H, s),2.88(2H,brt,J=5.1Hz),2.74(2H,brt,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):172.1,168.1,161.2(245.2Hz),131.9(3.4Hz),129.7(5.7Hz),128.6,128.5,128.5,128.5, 127.8,126.6(3.3Hz),126.6(3.3Hz),125.5(30.5Hz),125.4,125.2,125.2,124.4(272.5Hz),116.7, 115.8(21.4Hz),54.0,51.4,49.7,25.8;HR-ESI-MS[M+H]+:m/z478.1233。
化合物13,类白色固体,收率69.1%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 13.18(1H,brs),8.08(2H,d,J=8.3Hz),7.99(2H,d,J=8.3Hz),7.41(2H,m),7.39(2H,m),3.68(2H,s),3.58(2H,s),2.87(2H,m),2.72(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm): 181.4,167.8,161.9,144.1,142.9,142.9,136.4,132.6,130.0,129.4,128.6,128.6,126.7(3.0Hz),126.7(3.0Hz),125.4,125.4,124.4(276.0Hz),124.2,124.1(33.9Hz),54.2,47.7,46.0,25.8; HR-ESI-MS[M+H]+:m/z 494.0954。
化合物14,类白色固体,收率62.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 13.16(1H,brs),8.08(2H,d,J=8.1Hz),7.98(2H,d,J=8.1Hz),7.49(2H,d,J=7.8Hz),7.37(1H,t,J=7.8Hz),3.90(2H,s),3.69(2H,s),2.84(2H,m),2.84(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.6,167.6,161.1,136.1,136.1,133.8,132.0(24.6Hz),130.0,128.7, 128.7,128.0,128.0,127.9(4.8Hz),127.9(4.8Hz),126.2,126.2,124.6,121.3(230.0Hz),116.0,54.6,50.6,49.4,25.3;HR-ESI-MS[M+H]+:m/z 528.0551。
化合物15,白色固体,收率67.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.19 (1H,brs),8.09(2H,d,J=8.2Hz),7.98(2H,d,J=8.2Hz),7.60(1H,brs),7.57(1H,d,J=8.2Hz), 7.43(1H,dd,J=8.2,1.5Hz),3.75(2H,s),3.65(2H,s),2.89(2H,m),2.77(2H,m);13C-NMR (100MHz,DMSO-d6),δ(ppm):168.0,168.0,161.7,143.9,136.5,135.5,134.7,132.6(32.1Hz), 129.2,128.5,128.5,127.7,126.6(4.2Hz),126.6(4.2Hz),126.6,125.1,121.6(272.1Hz),116.5, 115.5,57.3,51.3,49.8,25.9;HR-ESI-MS[M+H]+:m/z 528.0546。
化合物16,白色固体,收率62.9%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.02 (1H,brs),7.79(2H,d,J=7.7Hz),7.49(2H,d,J=8.0Hz),7.41(2H,d,J=7.7Hz),7.36(1H,t,J=8.0Hz),3.88(2H,s),3.67(2H,s),2.83(2H,m),2.83(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm):168.2,167.7,144.7,143.5,143.4,134.7,132.8,132.5,130.2,130.2,130.2,130.2,129.2, 127.8,127.6,127.6,127.5,127.5,115.6,57.3,51.4,49.9,21.6;HR-ESI-MS[M+H]+:m/z 474.0848。
化合物17,类白色固体,收率64.1%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 13.03(1H,brs),9.48(1H,brs),7.79(2H,d,J=7.7Hz),7.61(1H,brs),7.57(1H,brd,J=8.4Hz),7.44(1H,m),7.42(2H,d,J=7.7Hz),3.76(2H,s),3.63(2H,s),2.88(2H,brt,J=4.3Hz),2.77 (2H,brt,J=4.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):168.2,167.7,163.2,162.8,144.7,143.5,143.4,135.5,134.7,132.8,132.5,130.1,130.1,129.2,127.6,127.6,127.5,124.5, 115.6,57.4,51.4,49.9,21.6;HR-ESI-MS[M+H]+:m/z 474.0851。
化合物18,类白色固体,收率64.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 12.73(1H,brs),9.46(1H,brs),8.03(1H,ddd,J=7.7,7.5,1.9Hz),7.71(1H,m),7.50(1H,d,J=7.6Hz),7.46(1H,m),7.42(1H,m),7.34(1H,m),7.33(1H,m),7.29(1H,m),5.14(2H,s),4.27(2H,s),4.21(2H,brt,J=5.1Hz),3.02(2H,brt,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.0,167.4,160.3(248.9Hz),159.6(2.8Hz),143.5,138.6,135.4(9.3Hz),132.5,131.9, 131.8,129.8,129.3,128.4,127.7,125.8(3.9Hz),124.0,117.2(23.2Hz),116.5,47.5,45.7,41.5, 25.9;HR-ESI-MS[M+H]+:m/z 444.0964。
化合物19,白色固体,收率61.0%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.85 (1H,brs),12.83(1H,brs),8.02(1H,td,J=7.8,1.6Hz),7.70(1H,m),7.44(1H,m),7.41(1H,m),7.37(1H,dd,J=8.5,7.6Hz),3.89(2H,s),3.68(2H,s),3.33(2H,m),2.83(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.6,160.4(250.2Hz),159.5(2.8Hz),143.3,136.6,136.6,135.2(9.1Hz),134.3,131.9,130.5,129.1,129.1,128.3,125.8(3.2Hz),125.1,120.2,117.2(23.1 Hz),116.7,55.2,51.1,50.0,25.8;HR-ESI-MS[M+H]+:m/z 478.0551。
化合物20,白色固体,收率68.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.16 (1H,brs),8.79(1H,brs),8.48(1H,dd,J=8.2,1.3Hz),8.39(1H,d,J=7.9Hz),7.87(1H,dd,J=8.2,7.9Hz),7.51(1H,brs),7.49(1H,brs),7.37(1H,dd,J=8.2,7.9Hz),3.91(2H,s),3.67(2H,s), 2.93(2H,brt,J=5.3Hz),2.63(2H,brt,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm): 182.0,167.3,163.9,151.4,148.1,148.1,142.3,136.6,135.3,134.3,130.7,130.6,129.2,129.2, 127.3,127.2,123.6,122.7,114.5,54.6,49.4,23.7;HR-ESI-MS[M+H]+:m/z 478.0587。
化合物21,类白色固体,收率66.9%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 12.16(1H,brs),8.79(1H,brs),8.48(1H,dd,J=8.2,1.3Hz),8.39(1H,d,J=7.9Hz),7.87(1H,dd, J=8.2,7.9Hz),7.51(1H,brs),7.49(1H,brs),7.37(1H,dd,J=8.2,7.9Hz),3.91(2H,s),3.67(2H, s),2.93(2H,brt,J=5.3Hz),2.63(2H,brt,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ (ppm):182.0,167.3,163.9,151.4,148.1,148.1,142.3,136.6,135.3,134.3,130.7,130.6,129.2, 129.2,127.3,127.2,123.6,122.7,114.5,54.6,49.4,23.7;HR-ESI-MS[M+H]+:m/z 505.0518。
化合物22,白色固体,收率62.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.16 (1H,brs),8.79(1H,t,J=1.8Hz),8.47(1H,d,J=8.2Hz),8.40(1H,d,J=8.0Hz),7.86(1H,dd,J=8.2,8.0Hz),7.61(1H,brs),7.58(1H,d,J=8.2Hz),7.44(1H,d,J=8.2Hz),3.79(2H,s),3.65 (2H,s),2.85(2H,m),2.67(2H,m);13C-NMR(100MHz,DMSO-d6),δ(ppm):168.0,163.9,059.5,148.1,135.3,134.7,133.0,132.8,132.6,130.7,129.2,127.8,127.3,127.0,126.9,125.6, 123.6,120.9,114.5,50.7,49.3,24.1;HR-ESI-MS[M+H]+:m/z 505.0517。
化合物23,白色固体,收率68.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.94 (1H,brs),9.50(1H,brs),7.89(1H,m),7.84(1H,d,J=7.8Hz),7.74(1H,d,J=8.0Hz),7.64(1H,dd,J=8.0,7.8Hz),7.32(3H,m),7.13(1H,m),5.09(2H,s),4.21(2H,brt,J=5.1Hz),3.01(2H, brt,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.7,167.8,161.7,144.1,141.3, 134.7,134.3,132.9,131.6,129.4,128.5,128.5,127.5,126.2,126.1,126.1,125.1,123.9,116.8, 47.6,45.8,25.8;HR-ESI-MS[M+H]+:m/z 471.0722。
化合物24,白色固体,收率64.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.91 (1H,brs),9.71(1H,brs),7.95(1H,m)7.91(1H,m),7.87(1H,m),7.86(2H,dd,J=7.6,6.4Hz),7.75(1H,d,J=8.0Hz),7.66(1H,dd,J=8.0,7.6Hz),7.54(1H,d,J=8.0Hz),7.51(1H,m),7.50 (1H,dd,J=6.8,3.0Hz),7.36(1H,d,J=7.2Hz),5.22(2H,s),4.30(2H,brt,J=5.4Hz),3.09(2H, brt,J=5.4Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.7,167.9,161.8,144.1,137.6, 134.8,134.4,134.3,132.9,131.6,131.2,129.5,128.4,127.5,127.5,127.1,126.7,126.4,126.4, 126.2,126.0,124.2,117.0,55.4,47.7,45.7;HR-ESI-MS[M+H]+:m/z 521.0885,found 521.0873。
化合物25,白色固体,收率62.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.26 (1H,brs),9.41(1H,brs),7.75(1H,dd,J=7.5,1.5Hz),7.63(1H,dd,J=8.0,1.4Hz),7.59(1H,td, J=8.0,1.5Hz),7.52(1H,td,J=7.5,1.4Hz),7.50(1H,m),7.35(1H,m),7.33(1H,m),7.29(1H, m),5.13(2H,s),4.20(2H,brt,J=5.4Hz),2.98(2H,brt,J=5.4Hz);13C-NMR(100MHz, DMSO-d6),δ(ppm):182.0,167.3,162.9,142.7,138.6,134.1,133.0,132.5,131.8,130.9,130.6, 130.4,129.8,129.4,128.4,128.2,127.7,124.0,117.7,47.6,45.7,25.8;HR-ESI-MS[M+H]+:m/z 505.0332。
化合物26,白色固体,收率66.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.28 (1H,brs),8.38(1H,brs),7.74(1H,dd,J=7.4,1.4Hz),7.62(1H,dd,J=8.0,1.5Hz),7.59(1H,td, J=8.0,1.6Hz),7.52(2H,m),7.47(1H,dd,J=8.0,1.4Hz),7.45(1H,td,J=7.6,1.5Hz),.7.16 (1H,t,J=7.9,1.7Hz),4.67(2H,s),3.75(2H,t,J=5.6Hz),2.90(2H,t,J=5.6Hz);13C-NMR (100MHz,DMSO-d6),δ(ppm):168.8,162.4,154.8,142.2,136.4,133.7,132.5,130.4,130.1, 129.9,129.2,128.7,128.5,127.7,127.4,127.2,125.8,124.0,117.2,42.7,41.3,25.4;HR-ESI-MS [M+H]+:m/z 489.0587。
化合物27,白色固体,收率78.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.26 (1H,brs),9.32(1H,brs),7.75(1H,dd,J=7.4,1.1Hz),7.61(1H,m),7.60(1H,m),7.52(1H,td,J=7.5,1.5Hz),7.28(1H,m),7.27(1H,m),7.19(1H,m),7.18(1H,m),5.11(2H,s),,4.20(2H,t,J =5.2Hz),2.98(2H,t,J=5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.3,167.3,162.9,157.9(245.0Hz),142.8,134.1,133.0,130.9,130.8,130.6,130.4,129.4,129.1(12.1Hz), 128.3(7.8Hz),128.2,124.5(3.1Hz),123.9,117.6,116.2(20.1Hz),47.6,45.9,25.8;HR-ESI-MS [M+H]+:m/z 489.0622。
化合物28,白色固体,收率77.0%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.26 (1H,brs),9.43(1H,brs),7.75(1H,dd,J=7.6,1.5Hz),7.66(1H,dd,J=8.0,1.2Hz),7.63(1H,dd, J=8.0,1.2Hz),7.59(1H,td,J=8.0,1.2Hz),7.52(1H,td,J=7.6,1.5Hz),7.39(1H,td,J=8.0, 1.2Hz),7.33(1H,dd,J=7.9,1.7Hz),7.21(1H,td,J=7.9,1.7Hz),5.13(2H,s),4.20(2H,t,J= 5.3Hz),2.98(2H,t,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.9,167.2,162.9, 142.7,140.0,134.1,133.0,132.9,132.0,130.9,130.6,130.4,129.4,128.7,128.3,128.2,124.0, 123.7,117.7,47.6,45.7,25.9;HR-ESI-MS[M+H]+:m/z548.9821。
化合物29,白色固体,收率75.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.27 (1H,brs),9.47(1H,brs),7.87(1H,dd,J=7.9,1.2Hz),7.75(1H,dd,J=7.4,1.5Hz),7.63(1H,dd, J=8.0,1.4Hz),7.59(1H,td,J=8.0,1.4Hz),7.52(1H,td,J=7.4,1.5Hz),7.40(1H,td,J=7.9, 1.2Hz),7.28(1H,dd,J=8.0,1.4Hz),7.03(1H,td,J=7.8,1.5Hz),5.14(2H,s),4.21(2H,t,J=5.4Hz),2.99(2H,t,J=5.4Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.7,167.2,162.9, 143.2,142.8,139.0,134.1,133.0,131.2,130.9,130.9,130.6,130.4,129.4,129.0,128.8,128.2, 117.7,102.1,47.6,45.7,26.0;HR-ESI-MS[M+H]+:m/z596.9683。
化合物30,白色固体,收率74.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.27 (1H,brs),9.40(1H,brs),7.75(1H,dd,J=7.9,1.2Hz),7.73(1H,d,J=8.0Hz),7.68(1H,t,J=7.7 Hz),7.63(1H,d,J=7.9Hz),7.59(1H,t,J=8.0Hz),7.53(1H,dd,J=7.9,1.2Hz),7.50(1H,t,J =7.7Hz),7.40(1H,d,J=7.9Hz),5.10(2H,s),4.19(2H,t,J=5.3Hz),2.97(2H,t,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.6,167.2,163.0,142.7,139.3(2.1Hz),134.1, 133.8,133.0,130.9,130.6,130.4,129.4,128.2,128.0(31.2Hz),127.9,127.4(28.3Hz),126.6(4.7 Hz),124.1(274.7Hz),123.9,117.7,47.5,45.7,25.8;HR-ESI-MS[M+H]+:m/z 539.0590。
化合物31,白色固体,收率72.9%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.26 (1H,brs),9.26(1H,brs),7.75(1H,dd,J=7.4,1.5Hz),7.62(1H,dd,J=8.0,1.3Hz),7.59(1H,td, J=8.0,1.3Hz),7.52(1H,td,J=7.4,1.5),7.23(1H,dd,J=6.4,2.4Hz),7.18(1H,m),7.17(1H, m),7.09(1H,dd,J=6.4,2.4Hz),5.11(2H,s),4.18(2H,t,J=5.4Hz),2.97(2H,t,J=5.4Hz), 2.18(3H,s);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.8,167.3,162.9,142.7,139.9,136.1, 134.1,133.0,130.9,130.6,130.6,130.4,129.4,129.3,128.2,126.9,126.5,124.2,117.7,47.5,45.6, 25.8,18.3;HR-ESI-MS[M+H]+:m/z 485.0873。
化合物32,白色固体,收率78.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.27 (1H,brs),8.99(1H,brs),7.75(1H,dd,J=7.6,1.4Hz),7.63(1H,dd,J=8.0,1.5Hz),7.59(1H,td, J=8.0,1.5Hz),7.52(1H,td,J=7.3,1.5Hz),7.23(1H,d,J=7.3Hz),7.20(1H,dd,J=7.4,1.6 Hz),7.04(1H,d,J=7.4Hz),6.92(1H,td,J=7.6,1.4Hz),5.09(2H,s),4.18(2H,t,J=5.5Hz), 3.77(3H,s),2.96(2H,t,J=5.5Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.3,167.3, 162.9,154.8,142.8,134.1,133.0,130.9,130.6,130.4,130.1,129.8,129.4,128.2,127.6,124.1, 120.3,117.6,112.2,56.0,47.4,45.7,25.8;HR-ESI-MS[M+H]+:m/z 501.0822。
化合物33,白色固体,收率74.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.27 (1H,brs),9.26(1H,brs),7.75(1H,d,J=7.2Hz),7.61(1H,m),7.60(1H,m),7.51(1H,t,J=7.2Hz),7.29(1H,m),7.28(1H,m),7.16(1H,m),7.15(1H,m),5.10(2H,s),4.18(2H,t,J=5.0Hz), 2.97(2H,t,J=5.0Hz),2.38(3H,s);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.0,167.3, 163.0,142.7,138.3,138.2,134.1,133.0,130.9,130.6,130.4,130.3,129.4,128.2,127.7,125.9, 125.0,124.1,117.7,47.5,45.6,25.9,15.0;HR-ESI-MS[M+H]+:m/z517.0593。
化合物34,白色固体,收率75.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.31 (1H,brs),9.24(1H,brs),7.75(1H,dd,J=7.4,1.3Hz),7.63(1H,dd,J=8.0,1.3Hz),7.59(1H,td,J=8.0,1.5Hz),7.52(1H,td,J=7.4,1.3Hz),7.44(1H,m),7.37(1H,m),7.36(1H,m),7.35(1H, m),7.30(1H,m),7.29(1H,m),7.28(1H,m),7.26(1H,m),7.25(1H,m),4.94(2H,s),4.04(2H,t, J=5.3Hz),2.81(2H,t,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.6,167.3, 162.9,142.8,139.6,139.6,138.4,134.2,133.0,131.5,130.9,130.9,130.6,130.4,130.3,129.3, 129.1,129.1,128.4,128.4,128.2,127.9,127.4,124.1,117.5,47.4,45.7,25.7;HR-ESI-MS [M+H]+:m/z 547.1025。
化合物35,白色固体,收率61.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.94 (1H,brs),9.77(1H,brs),7.89(1H,m),7.85(1H,brd,J=7.8Hz),7.73(1H,d,J=8.1Hz),7.67(2H, d,J=8.6Hz),7.65(1H,dd,J=8.1,7.8Hz),7.59(2H,d,J=8.1Hz),5.10(2H,s),4.22(2H,brt,J =5.1Hz),3.04(2H,brt,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.5,167.8, 161.8,145.2,144.2,134.7,134.3,132.9,131.6,129.4,127.5,126.2,125.6(3.9Hz),125.6(3.9Hz), 125.1,125.1,124.9(271.6Hz),124.5(32.4Hz),123.7,116.8,47.8,46.2,25.8;HR-ESI-MS [M+H]+:m/z 539.0618。
化合物36,白色固体,收率61.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.94 (1H,brs),9.37(1H,brs),7.89(1H,dd,J=2.1,1.6Hz),7.84(1H,brd,J=7.8Hz),7.73(1H,d,J= 8.1Hz),7.65(1H,dd,J=8.1,7.8Hz),7.20(2H,d,J=8.9Hz),6.89(2H,d,J=8.9Hz),5.09(2H, s),4.20(2H,brt,J=5.4Hz),3.75(3H,s),3.00(2H,brt,J=5.4Hz);13C-NMR(100MHz, DMSO-d6),δ(ppm):181.8,167.8,161.7,157.1,144.0,134.7,134.4,134.1,132.8,131.6,129.4, 128.1,128.1,127.5,126.2,124.1,116.8,113.7,113.7,55.7,47.5,45.5,25.8;HR-ESI-MS[M+H]+: m/z 501.0845。
化合物37,类白色固体,收率65.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.26(1H,brs),9.49(1H,brs),7.75(1H,dd,J=7.4,1.3Hz),7.63(1H,dd,J=8.1,1.4Hz),7.60 (1H,td,J=8.1,1.4Hz),7.53(1H,m),7.52(2H,d,J=8.1Hz),7.33(1H,t,J=7.9Hz),5.14(2H,s), 4.19(2H,t,J=5.2Hz),2.98(2H,t,J=5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.0,166.7,162.5,142.2,135.9,135.0,135.0,133.6,132.5,130.3,130.1,129.9,128.9,128.8, 128.3,128.3,127.7,123.4,117.3,47.2,45.2,25.4;HR-ESI-MS[M+H]+:m/z538.9962。
化合物38,白色固体,收率66.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.29 (1H,brs),8.61(1H,brs),7.74(1H,dd,J=7.6,1.5Hz),7.62(1H,d,J=8.0,1.5Hz),7.59(1H,td,J =7.0,1.7Hz),7.52(1H,m),7.51(2H,d,J=8.0Hz),7.30(1H,t,J=8.0Hz),4.67(2H,s),3.76 (2H,t,J=5.2Hz),2.90(2H,t,J=5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):166.8, 162.4,154.7,142.2,134.5,134.5,133.7,132.5,130.4,130.1,129.9,129.2,128.7,128.4,128.3, 128.3,127.7,124.0,117.2,42.7,41.3,25.5;HR-ESI-MS[M+H]+:m/z523.0194。
化合物39,类白色固体,收率69.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 12.93(1H,brs),10.12(1H,brs),8.17(2H,brs),7.90(1H,m),7.84(1H,d,J=7.7Hz),7.78(1H,brs),7.49(1H,brs),7.31(1H,d,J=7.6Hz),7.65(1H,dd,J=7.7,7.6Hz),5.16(2H,s),4.26(2H, brt,J=5.4Hz),3.07(2H,brt,J=5.4Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.0, 167.8,161.8,144.2,143.5,143.5,134.7,134.3,132.9,131.6,130.2(33.4Hz),130.2(33.4Hz), 129.4,129.2(284.1Hz),129.2(284.1Hz),127.5,126.2,125.1(3.2Hz),125.1(3.2Hz),122.4, 117.3(3.4,3.2Hz),47.9,46.3,25.8;HR-ESI-MS[M+H]+:m/z607.0492。
化合物40,类白色固体,收率69.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 12.26(1H,brs),9.37(1H,brs),8.26(2H,brs),7.74(1H,d,J=7.5,1.3Hz),7.62(1H,m),7.61(1H, m),7.59(1H,td,J=8.0,1.6Hz),.7.52(1H,td,J=7.3,1.5Hz),4.71(2H,s),3.79(2H,t,J=5.4 Hz),2.93(2H,t,J=5.4Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):166.8,162.4,154.3, 142.4(32.4Hz),142.4(32.4Hz),133.6,132.5,130.5,130.4,130.2,130.1,129.9,128.7,127.7, 123.7,123.3(273.2Hz),123.3(273.2Hz),118.8(3.4Hz),118.8(3.4Hz),117.2,114.3(3.2Hz), 42.8,41.3,25.3;HR-ESI-MS[M+H]+:m/z 591.0714。
化合物41,白色固体,收率78.9%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.26 (1H,brs),9.61(1H,brs),8.51(1H,d,J=1.7Hz),8.33(1H,d,J=4.0Hz),7.76(1H,m),7.74(1H,m),7.63(1H,dd,J=8.1,1.4Hz),7.59(1H,td,J=8.1,1.7Hz),7.52(1H,td,J=7.1,1.4Hz),7.36 (1H,dd,J=8.1,4.7Hz),5.13(2H,s),4.22(2H,t,J=5.4Hz),3.00(2H,t,J=5.4Hz);13C-NMR (100MHz,DMSO-d6),δ(ppm):181.9,167.3,162.9,147.3,145.8,142.9,138.1,134.1,133.7, 133.0,130.9,130.6,130.4,129.4,128.2,123.8,123.4,117.6,47.6,46.0,25.8;HR-ESI-MS [M+H]+:m/z 472.0669。
化合物42,白色固体,收率75.9%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.95 (1H,brs),9.41(1H,brs),7.92(2H,d,J=7.1Hz),7.68(1H,t,J=7.4Hz),7.62(2H,t,J=7.1Hz),7.50(1H,d,J=7.1Hz),7.34(1H,m),7.33(1H,m),7.29(1H,m),5.12(2H,s),4.21(2H,t,J=5.3 Hz),3.02(2H,t,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.1,168.0,163.0, 144.7,138.6,133.2,132.5,132.4,131.8,129.8,129.7,129.7,129.2,128.4,127.7,127.5,127.5, 123.6,116.2,47.5,45.7,26.0;HR-ESI-MS[M+H]+:m/z471.0716。
化合物43,白色固体,收率69.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.73 (1H,brs),9.41(1H,brs),8.04(1H,td,J=7.7,1.6Hz),7.71(1H,m),7.49(1H,d,J=7.5Hz),7.44 (2H,m),7.34(1H,m),7.33(1H,m),7.29(1H,m),5.13(2H,brs),4.20(2H,t,J=5.3Hz),3.01(2H, t,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.5,166.9,159.8(248.5Hz),159.1, 143.0,138.1,134.9(8.4Hz),131.9,131.4,131.3,129.3,128.8,127.9,127.2,125.3(3.2Hz),123.5,119.5(11.6Hz),116.8,116.6(3.2Hz),47.0,45.2,25.4;HR-ESI-MS[M+H]+:m/z 489.0657。
化合物44,白色固体,收率73.1%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.74 (1H,brs),8.37(1H,brs),8.03(1H,td,J=7.7,1.6Hz),7.70(1H,m),7.51(1H,dd,J=8.0,1.4Hz), 7.47(1H,m),7.43(1H,d,J=7.2Hz),7.41(1H,m),7.30(1H,td,J=7.7,1.3Hz),7.15(1H,td,J= 7.7,1.5Hz),4.67(2H,brs),3.75(2H,t,J=5.4Hz),2.93(2H,t,J=5.4Hz);13C-NMR(100MHz, DMSO-d6),δ(ppm):167.0,167.0,159.7(250.0Hz),159.3,154.8,136.4,134.8(8.5Hz),131.4, 129.2,128.6,128.4,127.4,127.2,125.8,125.3(3.4Hz),123.8(17.8Hz),116.8,116.6(3.4Hz), 116.6,42.7,41.2,25.5;HR-ESI-MS[M+H]+:m/z473.0861。
化合物45,白色固体,收率77.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.13 (1H,brs),9.43(1H,brs),7.78(1H,dd,J=7.9,0.8Hz),7.67(1H,dd,J=7.5,1.7Hz),7.55(1H,td, J=7.5,0.9Hz),7.50(1H,m),7.49(1H,m),7.35(1H,m),7.33(1H,m),7.29(1H,m),5.13(2H,s), 4.19(2H,t,J=5.2Hz),2.97(2H,t,J=5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm): 182.1,167.2,164.0,142.8,138.6,136.7,133.9,132.9,132.4,131.8,129.9,129.8,129.4,128.6, 128.4,127.7,124.0,119.5,117.7,47.6,45.8,25.9;HR-ESI-MS[M+H]+:m/z 548.9821。
化合物46,白色固体,收率76.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.06 (1H,brs),9.42(1H,brs),8.00(1H,d,J=7.9Hz),7.59(1H,dd,J=7.6,1.9Hz),7.55(1H,t,J=7.5 Hz),7.50(1H,d,J=7.5Hz),7.34(1H,m),7.33(1H,m),7.29(1H,m),7.28(1H,m),5.13(2H,s), 4.20(2H,t,J=5.4Hz),2.97(2H,t,J=5.4Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm): 182.1,167.3,165.7,143.0,140.7,140.3,138.6,132.6,132.5,131.8,129.8,129.4,129.0,128.9, 128.4,127.7,124.0,117.5,93.9,47.6,45.7,25.9;HR-ESI-MS[M+H]+:m/z 596.9683。
化合物47,白色固体,收率71.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.12 (1H,brs),9.43(1H,brs),7.90(1H,d,J=7.8Hz),7.83(1H,m),7.82(1H,m),7.81(1H,m),7.50(1H,d,J=7.4Hz),7.35(1H,m),7.33(1H,m),7.28(1H,m),5.13(2H,s),4.20(2H,t,J=5.1Hz), 2.97(2H,t,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.4,166.6,163.4,141.8, 138.0,133.8(2.1Hz),132.9,131.9,131.2,131.1(13.3Hz),129.2,128.9,128.5,127.8,127.1, 126.7(4.7Hz),126.1(31.4Hz),123.5,123.4(273.2Hz),117.5,47.0,45.1,25.2;HR-ESI-MS [M+H]+:m/z 538.0590。
化合物48,白色固体,收率75.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.24 (1H,brs),9.41(1H,brs),7.59(1H,dd,J=8.4,1.4Hz),7.50(1H,dd,J=8.4,1.0Hz),7.47(1H,m), 7.38(1H,m),7.37(1H,m),7.34(1H,m),7.33(1H,m),7.29(1H,m),5.12(2H,s),4.20(2H,t,J= 5.3Hz),2.99(2H,t,J=5.3Hz),2.47(3H,s);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.0, 167.6,165.6,144.0,138.6,137.2,134.2,132.5,132.0,131.8,131.6,129.8,129.2,128.4,127.7,127.7,126.8,123.4,116.6,47.6,45.8,25.9,20.3;HR-ESI-MS[M+H]+:m/z 485.0873。
化合物49,白色固体,收率72.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.06 (1H,brs),9.39(1H,brs),8.10(1H,dd,J=7.8,1.7Hz),7.63(1H,td,J=7.6,1.7Hz),7.50(1H,brd, J=7.6Hz),7.34(1H,m),7.33(1H,m),7.29(1H,m),7.26(1H,d,J=7.8Hz),7.15(1H,t,J=7.2 Hz),5.11(2H,s),4.20(2H,t,J=5.3Hz),4.09(3H,s),2.99(2H,t,J=5.3Hz);13C-NMR(100 MHz,DMSO-d6),δ(ppm):181.9,167.2,161.6,158.1,143.3,138.6,134.9,132.5,132.1,131.8,129.8,129.2,128.4,127.7,123.6,121.5,119.3,117.2,112.9,56.4,47.5,45.8,26.0;HR-ESI-MS [M+H]+:m/z 501.0822。
化合物50,白色固体,收率76.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.27 (1H,brs),9.25(1H,brs),7.75(1H,dd,J=7.4,1.2Hz),7.62(1H,dd,J=8.0,1.2Hz),7.59(1H,td, J=8.0,1.2Hz),7.52(1H,td,J=7.4,1.2Hz),7.29(1H,m),7.28(1H,m),7.16(1H,m),7.15(1H, m),5.10(2H,s),4.19(2H,t,J=5.3Hz),2.97(2H,t,J=5.3Hz),2.38(3H,s);13C-NMR(100 MHz,DMSO-d6),δ(ppm):182.1,167.3,162.9,142.8,138.4,138.2,134.1,133.0,130.9,130.6, 130.4,130.3,129.4,128.2,127.7,126.0,125.1,124.1,117.7,47.5,45.7,25.9,15.0;HR-ESI-MS [M+Na]+:m/z 539.0413。
化合物51,白色固体,收率67.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.02 (1H,brs),9.42(1H,brs),8.10(2H,d,J=8.3Hz),8.00(2H,d,J=8.3Hz),7.49(1H,d,J=7.6Hz), 7.34(1H,m),7.33(1H,m),7.29(1H,m),5.13(2H,s),4.21(2H,t,J=5.6Hz),3.02(2H,t,J=5.6 Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.5,167.3,167.3,161.5,143.5,138.1,135.9, 131.9,131.3,129.3,129.1(38.4Hz),128.1,128.1,127.9,127.2,126.2(3.5Hz),126.2(3.5Hz), 123.8(271.6Hz),123.6,116.6,47.1,45.2,25.4;HR-ESI-MS[M+H]+:m/z 539.0571。
化合物52,白色固体,收率69.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.05 (1H,brs),8.38(1H,brs),8.10(2H,d,J=8.2Hz),7.99(2H,d,J=8.2Hz),7.50(1H,dd,J=8.0,1.4Hz),7.46(1H,dd,J=8.0,1.3Hz),7.29(1H,td,J=8.0,1.4Hz),7.15(1H,td,J=8.0,1.5Hz), 4.68(2H,t,J=5.6Hz),3.76(2H,t,J=5.6Hz),2.94(2H,brs);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.4,167.4,161.4,154.8,136.4,132.3,131.1,129.2,128.6(32.1Hz),128.4,128.0, 128.0,127.4,127.2,126.1(3.3Hz),126.1(3.3Hz),125.8,124.1,123.8(271.5Hz),116.6,42.8, 41.2,25.4;HR-ESI-MS[M+H]+:m/z 523.0846。
化合物53,类白色固体,收率67.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 12.91(1H,brs),9.41(1H,brs),7.81(2H,d,J=8.0Hz),7.50(1H,d,J=7.4Hz),7.43(2H,d,J=8.0Hz),7.35(1H,m),7.33(1H,s),7.29(1H,m),5.12(2H,brs),4.21(2H,m)3.02(2H,m),2.41 (3H,s);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.0,168.0,162.9,144.9,143.5,138.6,138.6,132.4,131.8,130.2,130.2,129.8,1229.8,128.4,127.7,127.5,127.5,123.4,116.0,47.5, 45.7,26.0,21.6;HR-ESI-MS[M+H]+:m/z 485.0896。
化合物54,白色固体,收率66.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.93 (1H,brs),8.37(1H,brs),7.80(2H,d,J=8.2Hz),7.51(1H,dd,J=8.1,1.6Hz),7.45(1H,dd,J=8.1,1.5Hz),7.41(2H,d,J=8.2Hz),7.29(1H,td,J=8.1,1.5Hz),7.15(1H,td,J=8.1,1.6Hz), 4.67(2H,s),3.75(2H,t,J=5.6Hz),2.94(2H,t,J=5.6Hz),2.40(3H,s);13C-NMR(100MHz, DMSO-d6),δ(ppm):167.6,167.6,162.4,154.8,142.9,136.4,129.7,129.7,129.5,129.2,128.5, 128.4,127.3,127.2,127.0,127.0,125.8,123.3,115.5,42.8,41.2,25.5,21.1;HR-ESI-MS[M+H]+: m/z 469.1123。
化合物55,类白色固体,收率68.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 13.08(1H,brs),9.42(1H,brs),8.67(1H,s),8.49(1H,d,J=7.8Hz),8.32(1H,d,J=7.6Hz),7.91(1H,t,J=7.8Hz),7.50(1H,d,J=7.6Hz),7.34(1H,m),7.33(1H,m),7.29(1H,m),5.14(2H,s), 4.22(2H,t,J=5.1Hz),3.02(2H,t,J=5.1Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.5,167.2,160.7,148.0,143.2,138.1,133.7,133.3,131.9,131.3,130.9,129.3,129.0,127.9, 127.2,126.9,123.7,121.9,116.9,47.1,45.2,25.4;HR-ESI-MS[M+H]+:m/z516.0592。
化合物56,类白色固体,收率70.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm): 13.03(1H,brs),8.66(1H,brs),8.48(1H,dd,J=8.0,1.2Hz),8.37(1H,brs),8.31(1H,d,J=8.0Hz),7.90(1H,t,J=8.0Hz),7.51(1H,dd,J=8.1,1.2Hz),7.47(1H,dd,J=7.9,1.1Hz),7.30(1H, td,J=8.1,1.1Hz),7.16(1H,td,J=7.9,1.2Hz),4.68(2H,s),3.77(2H,t,J=5.5Hz),2.94(2H,t, J=5.5Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):167.3,167.3,160.7,154.8,148.0,146.4, 136.4,133.3,130.8,129.2,128.9,128.4,127.3,127.2,126.8,125.8,124.0,121.9,116.8,42.8,41.3, 25.5;HR-ESI-MS[M+H]+:m/z 500.0813。
化合物57,白色固体,收率74.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.24 (1H,brs),9.44(1H,brs),9.42(1H,brs),9.17(1H,d,J=5.1Hz),8.16(1H,dd,J=5.1,1.2Hz),7.50(1H,d,J=7.5Hz),7.33(1H,m),7.32(1H,m),7.29(1H,m),5.15(2H,s),4.21(2H,t,J=5.3 Hz),3.03(2H,t,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.0,167.1,160.7,160.1,158.7,154.9,142.5,138.6,132.4,131.8,129.8,129.6,128.4,127.7,124.5,119.4,118.3, 47.6,45.7,25,9;HR-ESI-MS[M+H]+:m/z 473.0621。
化合物58,白色固体,收率76.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):11.46 (1H,brs),7.76(1H,t,J=5.2Hz),4.88(2H,s),4.03(2H,t,J=5.4Hz),3.50(2H,dd,J=12.5,7.0 Hz),2.82(2H,t,J=5.4Hz),2.42(2H,t,J=7.4Hz),1.59(2H,m),1.52(2H,m),1.30(2H,m),1.29 (2H,m),1.26(2H,m),0.89(3H,t,J=7.3Hz),0.87(3H,t,J=8.7Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.4,170.2,167.3,143.2,128.9,123.1,116.2,46.6,45.6,45.1,36.0,31.3, 31.1,25.7,24.9,22.3,20.1,14.3,14.3;HR-ESI-MS[M+H]+:m/z411.1888。
化合物59,白色固体,收率74.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.97 (1H,brs),9.48(1H,brs),7.92(2H,d,J=7.1Hz),7.68(1H,t,J=7.1Hz),7.62(2H,t,J=7.6Hz), 7.33(2H,m),7.32(2H,m),7.14(1H,m),5.09(2H,s),4.21(2H,t,J=5.4Hz),3.02(2H,t,J=5.4 Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.7,168.0,163.0,144.8,141.3,133.2,132.6, 129.7,129.7,129.3,128.5,128.5,127.5,127.5,126.1,126.1,125.1,123.6,116.1,47.6,45.9, 25.9;HR-ESI-MS[M+H]+:m/z 437.1106。
化合物60,白色固体,收率61.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.77 (1H,brs),12.74(1H,brs),9.96(1H,brs),8.14(2H,brs),8.04(1H,td,J=7.8,1.8Hz),7.80(1H, brs),7.71(1H,m),7.45(1H,td,J=8.7,1.3Hz),7.42(1H,m),5.16(2H,s),4.25(2H,m),3.06(2H, m);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.0,167.4,160.4(251.2Hz),159.7,143.5 (25.3Hz),135.4(9.1Hz),131.9,130.1(32.0Hz),130.1(32.0Hz),129.3,125.8(3.0Hz),125.2, 123.8(272.1Hz),123.8(272.1Hz),123.7,122.4,120.0(11.2Hz),117.3(3.4,3.0Hz),117.3,117.0, 116.9,47.8,46.3,25.8;HR-ESI-MS[M+H]+:m/z591.0779。
化合物61,白色固体,收率78.0%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.13 (1H,brs),9.33(1H,brs),7.78(1H,dd,J=7.8,1.0Hz),7.68(1H,dd,J=7.5,1.8Hz),7.55(1H,td, J=7.4,1.0Hz),7.50(1H,td,J=7.8,1.8Hz),7.27(1H,m),7.26(1H,m),7.19(1H,m),7.18(1H, m),5.11(2H,s),4.19(2H,t,J=5.2Hz),2.97(2H,t,J=5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.3,167.3,164.0,157.9(246.1Hz),142.8,136.7,133.9,132.9,130.7,129.9,129.4, 129.1(12.8Hz),128.6,128.3(8.2Hz),124.5(3.1Hz),123.9,119.5,117.7,116.2(20.6Hz),47.6, 45.9,25.8;HR-ESI-MS[M+H]+:m/z 533.0117。
化合物62,白色固体,收率75.0%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.13 (1H,brs),9.45(1H,brs),7.78(1H,d,J=7.9Hz),7.67(1H,td,J=7.4,1.7Hz),7.66(1H,td,J=7.4,1.7Hz),7.55(1H,td,J=6.6,1.7Hz),7.52(1H,td,J=7.4,1.7Hz),7.39(1H,td,J=7.9,1.0 Hz),7.32(1H,dd,J=6.6,1.7Hz),7.21(1H,td,J=7.9,1.7Hz),5.13(2H,s),4.19(2H,t,J=5.2 Hz),2.98(2H,t,J=5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.9,167.2,164.0,142.7,140.0,136.7,133.9,132.9,132.9,132.0,129.9,129.4,128.7,128.6,128.3,124.0,123.7, 119.5,117.7,47.6,45.7,25.9;HR-ESI-MS[M+H]+:m/z592.9316。
化合物63,白色固体,收率70.2%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.14 (1H,brs),9.41(1H,brs),7.78(1H,brd,J=7.9Hz),7.73(1H,brd,J=7.9Hz),7.69(1H,m),7.68(1H,m),7.55(1H,m),7.54(1H,m),7.50(1H,m),7.49(1H,m),7.40(1H,brd,J=7.9Hz),5.10(2H,s),4.18(2H,t,J=5.2Hz),2.96(2H,t,J=5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.6,167.2,164.1,142.8,139.3(2.0Hz),136.7,133.9,133.8,133.0(12.3Hz),129.9, 129.4,128.6,127.9,127.4(29.2Hz),126.8(15.7Hz),126.7(5.9Hz),124.1(274.4Hz),123.9, 119.5,117.7,47.5,45.7,25.8;HR-ESI-MS[M+H]+:m/z 583.0085。
化合物64,白色固体,收率73.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.13 (1H,brs),9.26(1H,brs),7.78(1H,dd,J=7.9,0.8Hz),7.67(1H,dd,J=7.5,1.7Hz),7.55(1H,td, J=7.4,1.1Hz),7.49(1H,td,J=7.5,1.7Hz),7.23(1H,dd,J=6.3,2.7Hz),7.17(1H,m),7.16 (1H,m),7.08(1H,dd,J=6.6,2.4Hz),5.11(2H,s),4.18(2H,t,J=5.4Hz),2.96(2H,t,J=5.4 Hz),2.18(3H,s);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.9,167.3,164.0,142.8,139.9, 136.7,136.1,133.9,132.9,130.6,129.9,129.4,129.3,128.6,126.9,126.5,124.2,119.5,117.7, 47.5,45.6,25.8,18.3;HR-ESI-MS[M+H]+:m/z 529.0368。
化合物65,白色固体,收率77.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.13 (1H,brs),9.43(1H,brs),7.77(1H,d,J=7.9Hz),7.67(1H,m),7.66(1H,td,J=7.3,1.7Hz),7.55 (1H,td,J=7.5,0.9Hz),7.49(1H,td,J=7.5,1.6Hz),7.39(1H,td,J=7.3,1.2Hz),7.32(1H,dd,J =7.9,1.6Hz),7.21(1H,td,J=7.3,1.7Hz),5.13(2H,s),4.20(2H,t,J=5.3Hz),2.98(2H,t,J= 5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.9,167.2,164.0,142.8,140.0, 136.7,133.9,132.9,132.9,132.0,129.9,129.4,128.7,128.6,128.3,124.9,123.7,119.5,117.7, 47.6,45.7,25.9;HR-ESI-MS[M+H]+:m/z 640.9177。
化合物66,白色固体,收率74.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.07 (1H,brs),9.40(1H,brs),7.99(1H,d,J=7.9Hz),7.72(1H,d,J=7.9Hz),7.68(1H,t,J=7.7Hz), 7.59(1H,dd,J=7.7,1.8Hz),7.55(1H,t,J=7.7Hz),7.50(1H,t,J=7.7Hz),7.40(1H,d,J=7.9 Hz),7.30(1H,t,J=6.8Hz),5.11(2H,s),4.19(2H,t,J=5.0Hz),2.97(1H,t,J=5.0Hz);13C- NMR(100MHz,DMSO-d6),δ(ppm):182.6,167.3,165.7,143.0,140.7,140.3,139.3(1.7Hz), 133.7,133.0,132.6,129.4,129.0(9.1Hz),127.9,127.4(29.1Hz),126.7(5.2Hz),126.6,124.1 (274.0Hz),123.9,117.5,93.9,47.5,45.7,25.8;HR-ESI-MS[M+H]+:m/z 630.9946。
化合物67,白色固体,收率79.1%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.14 (1H,brs),8.97(1H,brs),7.78(1H,brt,J=7.8Hz),7.67(1H,dd,J=7.5,1.7Hz),7.55(1H,td,J= 7.4,1.1Hz),7.49(1H,td,J=7.5,1.1),7.22(1H,m),7.21(1H,m),7.04(1H,dd,J=8.2,0.8Hz), 6.92(1H,td,J=7.5,1.1Hz),5.09(2H,s),4.18(2H,brt,J=5.3Hz),3.77(3H,s),2.95(2H,t,J= 5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.3,167.3,164.0,154.8,142.7,136.7, 133.9,132.9,130.1,129.9,129.8,129.4,128.6,127.7,124.1,120.3,119.5,117.6,112.2,56.0,47.4, 45.7,25.8;HR-ESI-MS[M+H]+:m/z 593.0178。
化合物68,白色固体,收率73.8%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.11 (1H,brs),9.32(1H,brs),7.91(1H,d,J=7.7Hz),7.82(1H,m),7.81(1H,m),7.80(1H,m),7.28(1H,m),7.27(1H,m),7.19(1H,m),7.18(1H,m),5.11(2H,s),4.19(2H,d,J=5.3Hz),2.97(2H, d,J=5.3Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.3,167.2,164.0,157.9(246.7Hz), 142.5,134.3,133.5,131.7,130.8,129.4,129.1(12.1Hz),129.1,128.3(7.8Hz),127.2(4.9Hz), 126.7(31.6Hz),124.5(3.5Hz),124.3(55.0Hz),124.0(274.1Hz),118.0,116.2(20.1Hz),47.6, 45.9,25.8;HR-ESI-MS[M+H]+:m/z 523.0886。
化合物69,白色固体,收率74.0%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.11 (1H,brs),9.45(1H,brs),7.91(1H,d,J=7.7Hz),7.82(1H,m),7.81(1H,m),7.80(1H,m),7.66(1H,dd,J=8.0,1.2Hz),7.39(1H,td,J=7.9,1.3Hz),7.32(1H,dd,J=7.9,1.3Hz),7.21(1H,td, J=7.9,1.8Hz),5.13(2H,s),4.19(2H,d,J=5.3Hz),2.97(2H,d,J=5.3Hz);13C-NMR(100 MHz,DMSO-d6),δ(ppm):181.9,167.1,164.0,142.4,140.0,134.3(2.2Hz),133.5,132.9,132.0, 131.7,129.4,129.1,128.7,128.3,127.2(4.9Hz),126.7(31.7Hz),124.1,123.9(274.4Hz),123.7, 118.1,47.6,45.7,25.8;HR-ESI-MS[M+H]+:m/z 583.0085。
化合物70,白色固体,收率72.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.12 (1H,brs),9.28(1H,brs),7.91(1H,d,J=7.7Hz),7.82(1H,m),7.81(1H,m),7.80(1H,m),7.23(1H,dd,J=6.4,2.2Hz),7.18(1H,m),7.17(1H,m),7.08(1H,dd,J=7.5,2.2Hz),5.12(2H,s), 4.18(2H,t,J=5.2Hz),2.95(2H,t,J=5.2Hz),2.18(3H,s);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.8,167.2,167.2,164.0,142.4,139.9,136.1,134.4(2.1Hz),133.5,131.7,130.6,129.5, 129.4(13.1Hz),129.1,127.2(5.0Hz),126.9,126.7(31.6Hz),124.3,123.9(274.0Hz),118.0,47.5, 45.6,25.8,18.3;HR-ESI-MS[M+H]+:m/z 519.1136。
化合物71,白色固体,收率73.5%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.12 (1H,brs),8.97(1H,brs),7.90(1H,d,J=7.7Hz),7.84(1H,m),7.81(1H,m),7.78(1H,m),7.23(1H,m),7.21(1H,m),7.04(1H,dd,J=8.2,0.8Hz),6.92(1H,td,J=7.6,1.1Hz),5.09(2H,s), 4.18(2H,brt,J=5.4Hz),3.31(3H,s),2.94(2H,brt,J=5.4Hz);13C-NMR(100MHz,DMSO- d6),δ(ppm):182.3,167.2,164.0,154.8,142.4,134.4,133.5,131.7,130.1,129.8,129.5,129.1, 127.6,127.2(4.8Hz),126.7(31.5Hz),124.2,123.9(274.1Hz),120.3,118.0,112.2,56.0,47.4, 45.7,25.8;HR-ESI-MS[M+H]+:m/z 535.1085。
化合物72,白色固体,收率79.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.25 (1H,brs),9.45(1H,brs),7.66(1H,dd,J=8.0,1.2Hz),7.59(1H,dd,J=7.2,1.4Hz),7.48(1H,t,J =7.9Hz),7.40(1H,m),7.38(1H,m),7.37(1H,m),7.32(1H,dd,J=8.0,1.7Hz),7.21(1H,td,J= 7.9,1.7Hz),5.12(2H,s),4.20(2H,t,J=5.4Hz),3.00(2H,t,J=5.4Hz),2.47(3H,s);13C-NMR (100MHz,DMSO-d6),δ(ppm):181.8,167.6,167.6,165.5,143.9,140.0,137.2,134.2,132.9, 132.0,132.0,131.6,129.2,128.7,128.3,127.7,126.8,123.7,116.6,47.6,45.7,26.0,20.4;HR- ESI-MS[M+H]+:m/z 529.0368。
化合物73,白色固体,收率74.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.25 (1H,brs),9.40(1H,brs),7.72(1H,d,J=7.9Hz),7.68(1H,t,J=7.9Hz),7.59(1H,dd,J=7.1,1.4 Hz),7.50(1H,t,J=7.9Hz),7.47(1H,d,J=8.0Hz),7.40(1H,d,J=8.0Hz),7.37(1H,m),7.36 (1H,m),5.09(2H,s),4.19(2H,t,J=5.0Hz),2.98(2H,t,J=5.0Hz),2.47(3H,s);13C-NMR (100MHz,DMSO-d6),δ(ppm):182.6,167.6,165.6,144.0,139.3(2.1Hz),137.2,134.2,133.8, 133.0,131.9,131.6,129.2,127.8(13.7Hz),127.4(29.2Hz),126.7,126.7(15.6Hz),126.6(5.4Hz), 124.1(273.9Hz),123.4,116.6,47.5,45.7,25.9,20.3;HR-ESI-MS[M+H]+:m/z 519.1136。
化合物74,白色固体,收率73.7%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.26 (1H,brs),9.28(1H,brs),7.59(1H,dd,J=7.2,1.4Hz),7.48(1H,td,J=7.2,1.4Hz),7.37(1H,m), 7.36(1H,m),7.23(1H,dd,J=6.4,2.6Hz),7.18(1H,m),7.17(1H,m),7.08(1H,dd,J=6.7,2.3 Hz),5.11(2H,s),4.19(2H,t,J=5.4Hz),2.98(2H,t,J=5.4Hz),2.47(3H,s),2.18(3H,s);13C- NMR(100MHz,DMSO-d6),δ(ppm):181.8,167.6,167.6,165.5,143.9,140.0,137.2,136.1, 134.2,132.0,131.6,130.6,129.3,129.2,127.7,126.9,126.8,126.5,116.6,47.4,45.6,25.9,20.4, 18.3;HR-ESI-MS[M+H]+:m/z 465.1419。
化合物75,白色固体,收率77.3%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.06 (1H,brs),8.95(1H,brs),8.09(1H,dd,J=7.8,1.6Hz),7.63(1H,td,J=7.8,1.6Hz),7.27(1H,d, J=8.4Hz),7.22(1H,m),7.21(1H,m),7.15(1H,t,J=7.6Hz),7.04(1H,d,J=7.6Hz),6.91(1H, td,J=7.6,1.1Hz),5.07(2H,s),4.18(2H,t,J=5.2Hz),4.09(3H,s),3.77(3H,s),2.97(2H,t,J= 5.2Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):182.1,167.2,161.5,158.1,154.8,143.2, 134.9,132.1,130.1,129.8,129.2,127.6,123.8,121.5,120.3,119.3,117.2,112.9,112.2,56.4,55.9, 47.3,45.8,26.0;HR-ESI-MS[M+H]+:m/z497.1329。
化合物76,白色固体,收率66.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.03 (1H,brs),9.75(1H,brs),8.11(2H,d,J=8.2Hz),8.00(2H,d,J=8.2Hz),7.67(2H,d,J=8.6Hz), 7.59(2H,d,J=8.6Hz),5.12(2H,s),4.24(2H,brt,J=5.0Hz),3.05(2H,brt,J=5.0Hz);13C- NMR(100MHz,DMSO-d6),δ(ppm):181.5,167.8,161.9,145.2,144.1,136.4,129.4,128.6, 128.6,126.7(4.0Hz),126.7(4.0Hz),125.6(3.6Hz),125.6(3.6Hz),125.1,125.1,124.9(272.2 Hz),124.5(32.7Hz),124.5(32.7Hz),124.3(272.2Hz),123.8,116.9,47.8,46.2,25.8;HR-ESI- MS[M+H]+:m/z 573.0883。
化合物77,类白色固体,收率63.9%;1H-NMR(400MHz,DMSO-d6),δ(ppm):13.19(1H,brs),9.97(1H,brs),8.14(2H,s),8.11(2H,d,J=8.0Hz),8.00(2H,d,J=8.0Hz),7.80(1H,brs),5.15(2H,s),4.25(2H,brt,J=5.2Hz),3.07(2H,brt,J=5.2Hz);13C-NMR(100MHz, DMSO-d6),δ(ppm):181.0,167.7,162.0,144.2,143.4,136.4,132.7(31.7Hz),130.2(33.0Hz), 130.2(33.0Hz),128.6,128.6,127.9(275.9Hz),127.9(275.9Hz),126.6(3.7Hz),126.6(3.7Hz), 125.2(4.3Hz),125.2(4.3Hz),124.3(272.8Hz),123.7,122.4,117.4(3.4,3.2Hz),116.9,47.8, 46.2,25.8;HR-ESI-MS[M+H]+:m/z 641.0754。
化合物78,白色固体,收率63.6%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.92 (1H,brs),9.95(1H,brs),8.14(2H,s),7.81(2H,d,J=7.8Hz),7.80(1H,m),7.43(2H,d,J=7.8Hz),5.14(2H,brs),4.25(2H,m),3.07(2H,m),2.41(3H,s);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.0,168.0,162.9,145.1,143.5,143.4,130.3(32.4Hz),130.3(32.4Hz),129.7,129.3 (287.2Hz),129.3(287.2Hz),129.2,127.5,127.5,125.3,125.2(5.3Hz),125.2(5.3Hz),123.0, 122.4,117.4(3.4,3.2Hz),115.8,47.8,46.2,25.8,21.5;HR-ESI-MS[M+H]+:m/z 587.1046。
化合物79,白色固体,收率65.4%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.28 (1H,brs),9.96(1H,s),8.81(1H,t,J=1.8Hz),8.50(1H,ddd,J=8.3,2.2,1.0Hz),8.40(1H,dt,J =8.2,1.4Hz),8.14(2H,brs),7.88(1H,dd,J=8.3,8.2Hz),7.80(1H,brs),5.16(2H,s),4.26(2H, brt,J=5.7Hz),2.88(2H,brt,J=5.7Hz);13C-NMR(100MHz,DMSO-d6),δ(ppm):181.6, 170.7,164.0,148.1,143.4,135.4,134.1(3.4Hz),134.1(3.4Hz),130.8,130.2(32.9Hz),130.2 (32.9Hz),127.5,125.7,125.3,125.1,123.7(273.1Hz),123.7(273.1Hz),123.7,117.4(3.4,3.2 Hz),114.2,95.8,47.8,45.9,24.4;HR-ESI-MS[M+H]+:m/z 618.0739。
化合物80,白色固体,收率77.0%;1H-NMR(400MHz,DMSO-d6),δ(ppm):12.43 (1H,brs),12.00(1H,brs),9.58(1H,brs),8.50(1H,d,J=2.3Hz),8.32(1H,dd,J=4.7,1.3Hz),7.75(1H,ddd,J=8.2,2.3,1.5Hz),7.36(1H,dd,J=8.1,4.7Hz),7.08(1H,brs),6.72(1H,brs), 6.25(1H,m),5.09(2H,s),4.22(2H,t,J=5.4Hz),3.01(2H,t,J=5.4Hz);13C-NMR(100MHz, DMSO-d6),δ(ppm):181.8,168.0,157.1,147.4,145.9,145.2,138.0,133.6,129.0,124.8,124.8, 123.4,122.6,114.9,111.5,110.3,47.6,46.0,25.9;HR-ESI-MS[M+H]+:m/z 427.1011。
试验例1化合物1~80对多种肿瘤细胞的抗增值试验。
采用多种肿瘤细胞(包括MDA-MB-231,MDA-MB-436,MCF-7细胞系)的抗增值活性试验,其结果见表1和表2。用优选化合物处理MDA-MB-231,MDA-MB-436,MCF-7 细胞,测定了对不同肿瘤细胞的半数抑制浓度。
从表1和表2中可以明显看出,该系列化合物对多种肿瘤细胞具有显著的较强的抗增殖活性。
试验例2化合物1~80的激酶抑制活性。
本实验的目的是检测本发明的化合物对体外ERK1和ERK5酶抑制活性,结果见表1和表2。
实验结果表明,优选化合物对ERK1和ERK5具有较强的抑制活性,各个化合物的抑制活性都较好,其中最优化合物25的抑制作用最强。
试验例3化合物25的体内抗肿瘤实验。
本实验的目的是检测发明化合物的体内抗肿瘤效果。本实验采用裸鼠异种植瘤模型,测试发明化合物25的体内抗肿瘤活性。所用细胞株为HL-60、MKN-74。
我们采用HL-60异种植瘤裸鼠模型评价化合物25在动物体内是否能够起到很好的抗肿瘤作用,结果表明化合物25能够很好的抑制动物体内肿瘤的生长(图1A)。采用MKN- 74异种植瘤裸鼠模型评价化合物25在动物体内是否能够起到很好的抗肿瘤作用,结果表明化合物25能够很好的抑制动物体内肿瘤的生长(图1B)。给予化合物25后,HL-60和 MKN-74异种植瘤裸鼠模型的肿瘤重量也明显变小,表现出很好的抗肿瘤活性(图1C)。取动物组织做免疫组化分析,发现肿瘤增殖标记物ki-67明显变少,表明肿瘤水平降低,同时p-ERK1/2、p-ERK5的免疫组化表明化合物25抗肿瘤是通过靶向ERK1/2和ERK5发挥作用的(图1D,1E)。用免疫印迹法Western blot检测ERK1/2、p-ERK1/2、ERK5、p- ERK5的表达水平,以GAPDH作为内参,结果表明化合物25能够在动物肿瘤组织中抑制 ERK1和ERK5的磷酸化,与免疫组化分析及体外实验结果一致(图1F)。
综合以上实验表明,化合物25能够通过双靶向抑制ERK1和ERK5在体外和体内发挥很好的抗肿瘤效果,为肿瘤的靶向治疗提供了一个好的方法。
Claims (7)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:结构式如式I或式II所示。
4.权利要求1~3任一项所述的化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
5.根据权利要求4所述的用途,其特征在于:所述抗肿瘤药物为双靶向ERK1和ERK5的抑制剂类药物。
6.根据权利要求4所述的用途,其特征在于:所述抗肿瘤药物为治疗具有ERK1或ERK5过表达特点的肿瘤类型的药物。
7.一种药物组合物,其特征在于:它是包含有效剂量的权利要求1~3任一项所述的化合物或其药学上可接受的盐的制剂。
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