CN116925078A - 靶向atad2抑制剂及其在制备抗肿瘤药物中的应用 - Google Patents
靶向atad2抑制剂及其在制备抗肿瘤药物中的应用 Download PDFInfo
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- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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Abstract
本发明涉及靶向ATAD2抑制剂及其在制备抗肿瘤药物中的应用,属于抗肿瘤药学技术领域。本发明提供了如下结构的ATAD2抑制剂的化合物或其药学上可接受的盐、异构体。其中,R1、R2如权利要求和说明书所述。本发明的化合物或其药学上可接受的盐、异构体或其药物组合物具有抗肿瘤活性,可以作为HDAC抑制剂,用于制备抗肿瘤药物。
Description
技术领域
本发明涉及靶向ATAD2抑制剂及其在制备抗肿瘤药物中的应用,属于肿瘤治疗药物发现技术领域。
背景技术
ATP酶家族AAA结构域蛋白2(ATAD2)包含一个溴结构域和一个atp酶结构域,是组蛋白修饰中重要的表观遗传调节因子,是致癌转录因子的辅激活因子,包括c-Myc和E2F转录因子2(E2F2)等。ATAD2在肿瘤染色质重塑、DAN复制、DNA损伤和DNA修复中发挥重要作用,并与肿瘤细胞增殖、迁移、自噬和细胞周期相关。ATAD2被募集到BRCA1的启动子,增强了DNA损伤性化疗药物和辐射的疗效。ATAD2可与染色质组蛋白乙酰化位点直接结合,提高染色质可及性和组蛋白动力学,有利于致癌基因的表达。ATAD2与SOX10形成复合体,通过染色质重塑促进黑色素瘤表型。此外,ATAD2被证明是卵巢癌细胞增殖的标志物和驱动因子。由于其关键而广泛的调控作用,ATAD2已成为肿瘤治疗的一个有前景的药物靶点。在过去的几年中,一些用于癌症治疗的ATAD2抑制剂被报道,如AM879,GSK232,GSK8814,AZ4347等,这些抑制剂表现出强效的ATAD2抑制活性,但大多数缺乏明显的细胞活性,尤其是在抑制肿瘤生长方面,这限制了ATAD2抑制剂的临床应用。有针对性的设计出新型靶向治疗小分子药物,并深入探讨其作用机制是解决临床问题的关键,具有重要的研究意义和价值。
发明内容
本发明解决的技术问题是提供一种作为ATAD2抑制剂的化合物。
本发明提供结构式如式Ⅰ所示的化合物或其药学上可接受的盐、异构体:
其中,R1为氢、C1-C6烷基、C1-C6烷氧基、卤素、卤代C1-C6烷基;
R2为C2-C10脂肪胺、X为CH2,O,S,CF2,NH,NCH3,/>n=0-5。
本发明优选如下结构的化合物或其药学上可接受的盐、异构体:
其中,R1为氢、C1-C4烷基、C1-C4烷氧基、卤素、卤代C1-C4烷基;R2为X为CH2,O,S,CF2,NH,NCH3,/>n=0-3。
本发明优选如下结构的化合物或其药学上可接受的盐、异构体:
其中,R1为氢、C1-C4烷基、C1-C4烷氧基、卤素、卤代C1-C4烷基时;R2为X为O;
或R1为C1-C4烷基、C1-C4烷氧基、卤素、卤代C1-C4烷基时;
R2为X为S;
且R1均为4位取代。
本发明优选如下结构的化合物或其药学上可接受的盐、异构体:
R1为氢、C1-C4烷基、C1-C4烷氧基、卤素、卤代C1-C4烷基;
R2为
n=0-3;
R1为4-位取代。
本发明优选如下结构的化合物或其药学上可接受的盐、异构体:
本发明所述的化合物的药学上可接受的盐可以为所述化合物的硝酸盐、盐酸盐、硫酸盐、磷酸盐或柠檬酸盐等。
本发明还提供一种药物组合物,包含有效剂量的上述化合物或其药学上可接受的盐、异构体。该药物组合物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,也可与其他抗肿瘤化合物组合作为活性成分。
本发明还提供了上述化合物或其药学上可接受的盐、异构体或它们的药物组合物在制备ATAD2抑制剂中的应用。
本发明还提供了上述化合物或其药学上可接受的盐、异构体或它们的药物组合物在制备治疗与ATAD2相关的疾病的药物中的应用。
本发明还提供了上述化合物或其药学上可接受的盐、异构体或它们的药物组合物在制备抗肿瘤药物中的用途。
在治疗肿瘤过程中,可以单独使用本发明的化合物或其药学上可接受的盐,也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。
在治疗肿瘤时,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。
附图说明
图1为化合物17抑制BT-549细胞中ATAD2-Myc的激活。
A:免疫荧光法检测p-c-Myc Ser62的表达;B:p-c-Myc Ser62的相对强度;C:p-c-Myc Ser62的表达水平;D:相对p-c-Myc Ser62强度;E:ATAD2、c-Myc和p-c-Myc Ser62的表达水平;F:ATAD2、c-Myc和p-c-Myc Ser62的表达量统计图。
图2为化合物17的抑制BT-549细胞增殖。
A:新合成的DNA量;B:EdU-488相对表达量;C:细胞增殖能力检测;D:克隆形成能力检测。
图3为化合物17与AM879抗增殖能力比较。
A:新合成的DNA量;B:克隆形成能力检测。
图4为化合物17诱导BT-549细胞发生凋亡
A:凋亡率流式分析;B:凋亡率统计;C:凋亡标志物Bax,Bcl-2,Caspase-3,Caspase-8,Caspase-9和PARP表达量;D:凋亡标志物Bax,Bcl-2,Caspase-3,Caspase-8,Caspase-9和PARP相对表达量分析统计分析。
图5为化合物17抑制BT-549细胞转移
A:细胞划痕实验;B:划痕实验定量分析;C:划痕实验定量分析;D:细胞迁移实验统计;E:迁移标志物mmp2和E-cadherin的表达水平;F:mmp2和E-cadherin的相对表达水平统计。
具体实施方式
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化合物1~11的合成
化合物1~11采用如下反应式合成:
合成路线和条件(i)K2CO3,DMF,60℃,6h;(ii)methanol,LiOH,r.t.,8h;(iii)HATU,DIEA,r.t.,24h;(iv)Fe,NH4Cl,refluxed;(v)HATU,DIEA,r.t.,24h。
其中,R1和X如前所述。
中间体3制备
将茶碱1(10mmol)溶于DMF(15ml)的溶液中,加入K2CO3(30mmol),并将所得混合物加热至60℃保温30min后加入溴乙酸乙酯2(12mmol)。反应完全后,向反应物中加50ml蒸馏水,并用乙酸乙酯(3×50ml)萃取。用饱和碳酸氢钠水溶液和盐水洗涤有机层,然后经无水硫酸钠干燥。去除溶剂后得到无色油状物。粗品经快速色谱(二氯甲烷/甲醇50:1)纯化为无色油状物,产率为89%。1H-NMR(600MHz,DMSO-d6),δ(ppm):8.06(1H,s),5.17(2H,s),4.17(2H,q,J=7.1Hz),3.44(3H,s),3.20(3H,s),1.22(3H,t,J=7.1Hz);13C-NMR(150MHz,DMSO-d6),δ(ppm):168.1,154.8,151.4,148.4,143.6,106.7,61.8,47.6,29.9,27.9,14.4.
中间体4合成
将中间体3(10mmol)溶于75% MeOH(15ml)-LiOH(30mmol)的溶液中,室温搅拌8小时。完成后,将残余物蒸发以去除多余的MeOH,并用1M HCl酸化至pH=3。所得沉淀通过过滤收集,得到白色固体中间体4,并直接用于下一次反应,无需纯化,产率为88%。
中间体7的合成
将原料5(5mmol)、仲胺衍生物6(15mmol)和DIEA(10mmol)溶于DMF(10ml)的溶液中,在室温下加入HATU并搅拌24小时。向反应物中加水(50ml),用乙酸乙酯(30ml)萃取3次。然后用水、饱和碳酸氢钠水溶液和盐水洗涤有机层,无水硫酸钠干燥。去除溶剂后,硅胶快速层析纯化,用二氯甲烷/甲醇(1-2%)洗脱,产率为83-95%。
中间体7a浅黄色固体,收率83%。1H-NMR(600MHz,CDCl3),δ(ppm):8.30(1H,d,J=8.1Hz),8.25(1H,m),7.73(1H,dd,J=7.6,1.3Hz),7.64(1H,t,J=7.6Hz),4.05(2H,br.s),3.68(2H,br.s),2.76(2H,br.s),2.61(2H,br.s);13C-NMR(100MHz,CDCl3),δ(ppm):168.0,148.1,137.3,132.8,129.9,124.5,122.0,50.1,44.8,27.8.
中间体7b浅黄色固体,收率89%。1H-NMR(600MHz,CDCl3),δ(ppm):8.01(1H,d,J=1.5Hz),7.54(1H,dd,J=7.8,1.5Hz),7.42(1H,d,J=7.8Hz),4.02(2H,br.s),3.71(2H,br.s),2.69(4H,br.s),2.64(3H,s);13C-NMR(150MHz,CDCl3),δ(ppm):168.1,149.0,135.3,134.7,133.3,131.2,123.3,50.2,44.7,27.7,20.3.
中间体7c浅黄色固体,收率92%。1H-NMR(600MHz,CDCl3),δ(ppm):7.93(1H,d,J=2.1Hz),7.65(1H,dd,J=8.6,2.1Hz),7.16(1H,d,J=8.6Hz),4.01(3H,s),3.91(4H,br.s),2.68(4H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):168.1,154.0,139.1,133.2,127.6,124.9,113.7,56.8,50.3,45.1,27.6.
中间体7d浅黄色固体,收率87%。1H-NMR(600MHz,CDCl3),δ(ppm):8.41(1H,br.s),8.32(1H,dd,J=8.2,1.4Hz),7.93(1H,d,J=7.7Hz),7.77(1H,d,J=8.0Hz),4.03(4H,br.s),3.67(4H,br.s),3.26(4H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):167.7,148.2,137.2,133.6,130.7,124.9,122.4,51.0,46.0.
中间体7e浅黄色固体,收率94%。1H-NMR(600MHz,CDCl3),δ(ppm):8.01(1H,d,J=1.5Hz),7.54(1H,dd,J=7.8,1.5Hz),7.42(1H,d,J=7.8Hz),3.86(4H,br.s),3.26(4H,br.s),2.30(3H,s);13C-NMR(150MHz,CDCl3),δ(ppm):167.8,153.3,139.2,133.6,127.5,124.6,114.9,57.4,51.1,20.3.
中间体7f浅黄色固体,收率86%。1H-NMR(600MHz,CDCl3),δ(ppm):8.07(1H,d,J=2.1Hz),7.79(1H,dd,J=8.6,2.1Hz),7.45(1H,d,J=8.6Hz),3.97(3H,s),3.86(4H,br.s),3.26(4H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):167.8,153.3,139.2,133.6,127.5,124.6,114.9,57.4,51.1.
中间体7g浅黄色固体,收率89%。1H-NMR(600MHz,CDCl3),δ(ppm):7.90(1H,d,J=1.9Hz),7.82(1H,d,J=8.2Hz),7.49(1H,dd,J=8.2,1.9Hz),3.74(6H,br.s),3.48(2H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):166.7,149.7,135.7,135.5,131.6,124.5,116.2,66.6,48.2,42.7.中间体7h浅黄色固体,收率86%。1H-NMR(600MHz,CDCl3),δ(ppm):8.04(1H,d,J=1.5Hz),7.58(1H,dd,J=7.8,1.5Hz),7.43(1H,d,J=7.8Hz),3.74(6H,br.s),3.50(2H,br.s),2.65(3H,s);13C-NMR(150MHz,CDCl3),δ(ppm):167.8,149.0,135.4,134.3,133.2,131.5,123.6,66.7,48.2,42.7,20.3.
中间体7i浅黄色固体,收率86%。1H-NMR(600MHz,CDCl3),δ(ppm):7.96(1H,d,J=1.9Hz),7.68(1H,dd,J=8.6,1.9Hz),7.16(1H,d,J=8.6Hz),4.02(3H,s),3.73(6H,br.s),3.66(2H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):167.7,154.0,139.1,133.5,127.2,125.1,113.6,66.7,56.8,48.2,42.7.
中间体7j浅黄色固体,收率78%。1H-NMR(600MHz,CDCl3),δ(ppm):7.95(1H,s),7.64(1H,d,J=8.3Hz),7.58(1H,d,J=8.3Hz),3.77(2H,br.s),3.69(2H,br.s),3.46(2H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):166.7,147.8,135.0,132.3,131.8,128.7,124.6,66.7,48.2,42.7.中间体7k浅黄色固体,收率90%。1H-NMR(600MHz,CDCl3),δ(ppm):8.12(1H,t,J=7.6Hz),7.70(1H,t,J=6.7Hz),7.40(1H,t,J=7.9Hz),3.83(2H,br.s),3.80(2H,br.s),3.68(2H,br.s),3.35(2H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):162.7,137.5,134.6,134.6,127.2,127.2,126.9,126.7,125.2,125.1,66.6,47.4,42.6.
中间体8的合成
将中间体7(3mmol)、铁粉(12mmol)和氯化铵(NH4Cl,15mmol)溶于95%乙醇(20ml)中,在剧烈搅拌下加入催化量的冰醋酸,加热回流4h。过滤去除额外的铁粉,滤液浓缩干燥得到粗产物,不纯化直接用于下一次反应,产率87-97%。
中间体8a浅棕色固体,收率88%。1H-NMR(600MHz,CDCl3),δ(ppm):7.17(1H,t,J=7.7Hz),6.71(1H,t,J=7.2Hz),6.67(2H,s),3.99(2H,brs),3.84(2H,brs),3.67(2H,brs),2.72(2H,brs),2.55(2H,brs);13C-NMR(150MHz,CDCl3),δ(ppm):170.9,146.7,136.9,129.5,116.4,116.2,113.1,50.0,44.4,28.1,27.4.
中间体8b浅棕色固体,收率84%。1H-NMR(600MHz,CDCl3),δ(ppm):7.05(1H,d,J=7.5Hz),6.68(1H,brs Hz),6.65(1H,d,J=7.5Hz),3.96(2H,brs),3.84(2H,brs),3.70(2H,brs),2.66(4H,brs);13C-NMR(150MHz,CDCl3),δ(ppm):171.0,144.8,134.5,130.4,123.9,116.6,113.1,50.1,44.5,29.6,27.7,17.2.
中间体8c浅棕色固体,收率91%。1H-NMR(600MHz,CDCl3),δ(ppm):6.77-6.73(3H,m),3.89(2H,br.s),3.88(4H,br.s),3.87(3H,s),2.64(4H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):171.1,148.3,136.3,128.3,117.3,113.5,109.8,55.5,49.8,44.9,27.8,27.8.
中间体8d浅棕色固体,收率96%。1H-NMR(600MHz,CDCl3),δ(ppm):7.22(1H,t,J=7.8Hz),6.73(1H,s),6.78(1H,d,J=7.8Hz),6.75(1H,d,J=7.5Hz),6.72(1H,br.s),4.10(4H,br.s),3.06(4H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):171.2,147.0,135.0,129.8,117.0,116.3,113.0,52.1,45.8,29.7.
中间体8e浅棕色固体,收率85%。1H-NMR(600MHz,CDCl3),δ(ppm):7.10(1H,d,J=7.6Hz),6.73(1H,s),6.71(1H,d,J=7.6Hz),4.9(4H,br.s),3.06(4H,br.s),2.19(3H,s);13C-NMR(150MHz,CDCl3),δ(ppm):171.4,145.2,132.6,130.7,124.9,116.5,113.0,52.0,45.9,41.1,17.3.中间体8f浅棕色固体,收率81%。1H-NMR(600MHz,CDCl3),δ(ppm):6.80(3H,s),4.10(4H,br.s),3.90(3H,s),3.06(4H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):171.5,149.0,136.6,126.3,117.5,113.4,109.8,55.6,52.0.
中间体8g浅棕色固体,收率80%。1H-NMR(400MHz,CDCl3),δ(ppm):7.15(1H,t,J=7.7Hz),6.72-6.70(3H,m),3.75(4H,br.s),3.60(2H,br.s),3.47(4H,m);13C-NMR(100MHz,CDCl3),δ(ppm):170.6,146.6,136.3,129.4,116.7,116.4,113.5,66.9,48.1,42.4.
中间体8h浅棕色固体,收率96%。1H-NMR(600MHz,CDCl3),δ(ppm):7.05(1H,d,J=7.5Hz),6.71(1H,d,J=1.4Hz),6.68(1H,dd,J=7.5,1.4Hz),3.71-3.50(10H,m),2.17(3H,s);13C-NMR(150MHz,CDCl3),δ(ppm):1170.7,144.8,134.1,130.4,124.1,116.9,113.4,66.9,48.2,42.5,17.2.
中间体8i浅棕色固体,收率94%。1H-NMR(600MHz,CDCl3),δ(ppm):6.78(1H,d,J=8.1Hz),6.77(2H,br.s),3.89(2H,br.s),3.87(3H,s),3.67(8H,m);13C-NMR(150MHz,CDCl3),δ(ppm):170.7,148.4,136.3,127.9,117.6,113.8,109.7,66.9,55.5.
中间体8j浅棕色固体,收率92%。1H-NMR(600MHz,CDCl3),δ(ppm):7.26(1H,d,J=8.0Hz),6.80(1H,d,J=1.8Hz),6.67(1H,dd,J=8.0,1.8Hz),4.23(2H,br.s),3.72-3.45(8H,m);13C-NMR(150MHz,CDCl3),δ(ppm):169.7,143.3,134.8,129.4,120.5,117.0,114.3,66.8,48.1,42.5.
中间体8k浅棕色固体,收率97%。1H-NMR(600MHz,CDCl3),δ(ppm):6.97(1H,t,J=7.8Hz),6.81(1H,t,J=8.3Hz),6.68(1H,t,J=6.9Hz),3.83(2H,br.s),3.81(2H,br.s),3.77(2H,d,J=4.2Hz),3.64(2H,br.s),3.36(2H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):165.5,147.7,146.1,134.8,134.8,125.0,125.0,123.7,123.6,117.8,117.8,117.3,66.9,66.8,47.4,42.3.
化合物1~11的合成
取中间体4(1mmol)、中间体8(1mmol)和DIEA(2mmol)溶于DMF(10ml),加入HATU(1mmol),室温搅拌24小时。反应完全后,向混合物中加入蒸馏水(50ml),并用乙酸乙酯(30ml)萃取3次。再用水、饱和碳酸氢钠水溶液和盐水洗涤有机层,无水硫酸钠干燥。减压去除溶剂后,硅胶快速色谱纯化,用二氯甲烷/甲醇(2-4%)洗脱,产率为78-93%。
化合物1:白色固体,收率79%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.58(1H,s),8.07(1H,s),7.67(1H,s),7.58(1H,d,J=8.1Hz),7.40(1H,t,J=7.8Hz),7.09(1H,d,J=7.8Hz),5.22(2H,s),3.85(2H,br.s),3.54(2H,br.s),3.46(3H,s),3.19(3H,s),2.66(2H,br.s),2.58(2H,br.s);13C-NMR(150MHz,DMSO-d6),δ(ppm):169.4,165.6,154.9,151.4,148.4,144.2,139.1,137.1,129.7,122.1,120.3,117.6,106.9,50.0,49.2,44.3,29.9,27.9,27.4,27.0;HRMS(ESI)+calculated for C20H22N6O4S,[M+H]+:m/z 443.5015,found443.5.
化合物2:白色固体,收率86%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.82(1H,s),8.09(1H,s),8.08(1H,s),7.48(1H,s),7.30(1H,d,J=7.8Hz),7.12(1H,d,J=6.9Hz),5.25(2H,s),3.82(2H,br.s),3.56(2H,br.s),3.46(3H,s),3.22(3H,s),2.63(2H,br.s),2.56(2H,br.s),2.29(3H,s);13C-NMR(150MHz,DMSO-d6),δ(ppm):169.4,165.9,154.9,151.5,148.4,144.1,136.0,134.1,133.2,131.0,124.0,123.3,107.0,49.1,29.9,27.9,27.0,18.1;HRMS(ESI)+calculated for C21H24N6O4S,[M+H]+:m/z 457.1653,found 457.1.
化合物3:白色固体,收率90%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.88(1H,s),8.07(1H,s),8.08(1H,s),7.17-7.12(2H,m),5.29(2H,s),3.92(3H,s),3.69(4H,br.s),3.46(3H,s),3.20(3H,s),2.59(4H,br.s);13C-NMR(150MHz,DMSO-d6),δ(ppm):169.6,166.0,162.7,154.9,151.4,150.5,148.4,144.2,128.1,127.0,123.9,120.5,111.5,106.9,56.4,55.3,49.4,29.9,27.9;HRMS(ESI)+calculated for C21H24N6O5S,[M+H]+:m/z473.1602,found 473.0.
化合物4:白色固体,收率95%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.59(1H,s),8.07(1H,s),7.75(1H,s),7.60(1H,d,J=7.6Hz),7.42(1H,t,J=7.9Hz),7.21(1H,d,J=7.5Hz),5.75(1H,s),5.22(2H,s),4.00(2H,br.s),3.70(2H,br.s),3.45(3H,s),3.25(4H,br.s),3.22(4H,br.s),3.20(3H,s);13C-NMR(150MHz,DMSO-d6),δ(ppm):169.4,165.6,154.9,151.4,148.4,144.2,139.1,136.1,129.6,122.3,120.7,118.0,106.9,55.3,51.2,49.2,29.9,27.9;HRMS(ESI)+calculated for C20H22N6O6S,[M+H]+:m/z 475.1394,found475.1.
化合物5:白色固体,收率92%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.93(1H,s),8.09(1H,s),7.58(1H,s),7.32(1H,d,J=7.6Hz),7.22(1H,d,J=7.6Hz),5.26(2H,s),3.96(2H,s),3.70(2H,br.s),3.45(3H,s),3.22(4H,br.s),3.21(3H,s),2.30(3H,s);13C-NMR(150MHz,DMSO-d6),δ(ppm):169.5,165.8,154.9,151.5,148.4,144.1,136.1,133.7,133.1,131.0,124.2,123.6,107.0,51.2,49.0,29.9,27.9,18.2;HRMS(ESI)+calculatedfor C21H24N6O6S,[M+H]+:m/z489.1551,found 489.0.
化合物6:白色固体,收率96%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.89(1H,s),8.12(1H,s),8.07(1H,s),7.26(1H,dd,J=8.3,1.5Hz),7.15(1H,d,J=8.3Hz),5.29(2H,s),3.94(3H,s),3.85(4H,br.s),3.46(3H,s),3.22(4H,br.s),3.20(3H,s);13C-NMR(150MHz,DMSO-d6),δ(ppm):169.6,166.0,154.9,151.4,150.8,148.4,144.2,127.0,124.2,120.9,111.4,106.9,56.4,51.2,49.4,40.4,29.9,27.9;HRMS(ESI)+calculatedfor C21H24N6O7S,[M+H]+:m/z 505.1500,found505.1.
化合物7:白色固体,收率96%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.58(1H,s),8.08(1H,s),7.67(1H,s),7.59(1H,d,J=8.2Hz),7.40(1H,t,J=7.8Hz),7.11(1H,d,J=7.6Hz),5.22(2H,s),3.61(6H,br.s),3.54(2H,s),3.45(3H,s),3.19(3H,s);13C-NMR(150MHz,DMSO-d6),δ(ppm):169.1,165.6,154.9,151.4,148.4,144.2,139.1,136.6,129.6,122.4,120.4,118.0,106.9,66.5,55.3,49.2,48.1,42.5,29.9,27.9;HRMS(ESI)+calculated for C20H22N6O5,[M+H]+:m/z427.1724,found 427.2.
化合物8:白色固体,收率88%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.83(1H,s),8.09(1H,s),8.08(1H,s),7.49(1H,s),7.30(1H,d,J=7.8Hz),7.14(1H,d,J=7.6Hz),5.25(2H,s),3.57(8H,br.s),3.45(3H,s),3.22(3H,s),2.29(3H,s);13C-NMR(100MHz,CDCl3),δ(ppm):169.0,165.8,154.9,151.5,148.4,144.1,136.0,133.6,133.4,130.9,124.4,123.8,107.0,66.5,49.0,29.9,27.9,18.1;HRMS(ESI)+calculated for C21H24N6O5,[M+H]+:m/z 441.1881,found 441.0.
化合物9:白色固体,收率94%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.87(1H,s),8.07(1H,d,J=8.8Hz),7.19(1H,d,J=8.7Hz),7.13(1H,d,J=8.7Hz),5.29(2H,s),3.93(3H,s),3.55(4H,br.s),3.46(4H,br.s),3.45(3H,s),3.21(3H,s);13C-NMR(100MHz,CDCl3),δ(ppm):169.2,166.0,154.9,151.5,150.6,148.4,144.2,127.6,127.0,124.3,120.9,111.4,106.9,66.5,56.4,49.4,29.9,27.9;HRMS(ESI)+calculated for C21H24N6O6,[M+H]+:m/z 457.1830,found 457.1.
化合物10:白色固体,收率91%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.16(1H,s),8.09(1H,s),7.81(1H,d,J=1.3Hz),7.60(1H,d,J=8.2Hz),7.24(1H,dd,J=8.2,1.3Hz),5.31(2H,s),3.59(6H,br.s),3.52(2H,s),3.45(3H,s),3.21(3H,s);13C-NMR(100MHz,CDCl3),δ(ppm):169.8,166.3,154.9,151.4,148.3,144.2,138.8,138.6,131.1,131.0,128.7,128.5,128.0,127.5,106.9,57.0,48.5,40.4,34.3,29.9,27.9;HRMS(ESI)+calculated for C20H21ClN6O5,[M+H]+:m/z461.1335,found 461.0.
化合物11:白色固体,收率91%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.39(1H,s),8.08(1H,s),7.98(1H,t,J=7.8Hz),7.28(1H,d,J=6.5Hz),7.24(1H,t,J=7.9Hz),7.15(1H,t,J=6.2Hz),5.29(2H,s),3.66(6H,br.s),3.53(2H,s),3.46(3H,s),3.20(3H,s);13C-NMR(100MHz,CDCl3),δ(ppm):169.0,166.3,154.8,151.4,148.3,144.1,136.9,129.2,128.7,128.4,106.8,53.8,51.5,48.3,44.0,41.2,29.9,27.9;HRMS(ESI)+calculated forC20H21FN6O5,[M+H]+:m/z 445.1630,found 445.2.
实施例2化合物12~23的合成
化合物12~23采用如下反应式合成:
R1和n如前所述。
合成路线和条件(i)HATU,DIEA,r.t.,24h;(ii)Fe,NH4Cl,refluxed;(iii)HATU,DIEA,r.t.,
24h。
中间体10的合成
将中间体5(5mmol)、仲胺衍生物9(15mmol)和DIEA(10mmol)溶于DMF(10ml)的溶液中,在室温下加入HATU并搅拌24小时。向反应物中加水(50ml),用乙酸乙酯(30ml)萃取3次。然后用水、饱和碳酸氢钠水溶液和盐水洗涤有机层,无水硫酸钠干燥。去除溶剂后,硅胶快速层析纯化,用二氯甲烷/甲醇(1-2%)洗脱,产率为79-96%。
中间体10a白色固体,收率79%。1H-NMR(600MHz,CDCl3),δ(ppm):8.56(1H,s),8.33(1H,d,J=8.1Hz),8.16(1H,d,J=7.7Hz),7.63(1H,d,J=7.7Hz),6.72(1H,br.s),2.94(1H,m),0.92-0.88(2H,m),0.70-0.68(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.5,148.1,136.0,133.3,129.8,126.0,121.6,23.4,6.7.
中间体10b白色固体,收率90%。1H-NMR(600MHz,CDCl3),δ(ppm):8.32(1H,s),7.96(1H,dd,J=8.0,1.5Hz),7.43(1H,d,J=8.0Hz),6.56(1H,br.s),2.94(1H,m),2.65(3H,s),0.93-0.88(2H,m),0.71-0.66(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.5,148.9,137.0,133.4,133.2,131.4,122.8,23.3,20.4,6.7.
中间体10c白色固体,收率76%。1H-NMR(600MHz,CDCl3),δ(ppm):8.22(1H,d,J=2.1Hz),8.05(1H,dd,J=8.7,2.1Hz),7.14(1H,d,J=8.7Hz),6.57(1H,br.s),4.02(3H,s),2.91(1H,m),2.65(3H,s),0.91-0.85(2H,m),0.69-0.66(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.3,155.1,138.8,133.4,126.5,124.2,113.4,56.8,23.3,23.1,6.6.
中间体10d白色固体,收率89%。1H-NMR(600MHz,CDCl3),δ(ppm):8.56(1H,br.s),8.34(1H,ddd,J=8.1,2.1,0.9Hz),8.17(1H,d,J=8.1Hz),7.65(1H,t,J=8.0Hz),6.36(1H,d,J=5.3Hz),4.44(1H,m),2.18-2.10(2H,m),1.80-1.74(2H,m),1.71-1.66(2H,m),1.60-1.52(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):164.8,148.1,136.4,133.3,129.8,125.8,121.6,52.1,52.0,33.1,33.1,23.8.
中间体10e白色固体,收率84%。1H-NMR(600MHz,CDCl3),δ(ppm):8.30(1H,d,J=1.5Hz),7.94(1H,dd,J=8.0,1.5Hz),7.41(1H,d,J=8.0Hz),6.27(1H,d,J=4.6Hz),4.40(1H,m),2.64(3H,s),2.13-2.07(2H,m),1.77-1.70(2H,m),1.70-1.64(2H,m),1.56-1.49(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):164.7,148.9,136.7,134.0,133.1,131.4,122.8,52.0,33.1,23.8,20.4.
中间体10f白色固体,收率76%。1H-NMR(600MHz,CDCl3),δ(ppm):8.13(1H,d,J=2.1Hz),7.96(1H,dd,J=8.8,2.1Hz),7.05(1H,d,J=8.8Hz),6.17(1H,d,J=6.4Hz),4.31(1H,m),3.93(3H,s),2.04–1.98(2H,m),1.70-1.63(2H,m),1.62-1.55(2H,m),1.48-1.42(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):164.4,154.9,138.9,133.4,127.0,124.1,113.4,56.8,51.8,33.1,33.1,29.6,23.8.
中间体10g白色固体,收率88%。1H-NMR(600MHz,CDCl3),δ(ppm):8.19(1H,s),7.84(1H,d,J=8.5Hz),7.81(1H,d,J=8.5Hz),6.12(1H,d,J=6.6Hz),3.96(1H,m),2.04-2.02(2H,br.s),1.79-1.77(2H,br.s),1.68-1.66(1H,m),1.45-1.38(2H,m),1.29-1.22(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):163.3,149.6,135.5,135.4,131.4,123.9,117.5,49.4,33.1,25.4,24.9.中间体10h白色固体,收率86%。1H-NMR(400MHz,CDCl3),δ(ppm):8.30(1H,s),7.94(1H,d,J=7.9Hz),7.42(1H,d,J=7.9Hz),6.12(1H,d,J=6.7Hz),3.97(1H,m),2.04-2.02(2H,br.s),1.81-1.76(2H,br.s),1.69-1.66(1H,m),1.45-1.38(2H,m),1.29-1.22(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):164.1,148.9,136.7,134.1,133.2,131.5,122.8,49.1,33.1,25.5,24.9,20.5.
中间体10i白色固体,收率92%。1H-NMR(600MHz,CDCl3),δ(ppm):8.22(1H,d,J=2.1Hz),8.05(1H,dd,J=8.7,2.1Hz),7.14(1H,d,J=8.7Hz),6.08(1H,d,J=7.3Hz),4.02(3H,s),3.96(1H,m),2.04-2.02(2H,br.s),1.81-1.76(2H,br.s),1.69-1.66(1H,m),1.45-1.38(2H,m),1.29-1.22(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):163.8,163.8,155.0,138.9,133.3,127.2,124.0,113.4,56.8,49.1,49.0,33.1,25.4,24.9.
中间体10j白色固体,收率92%。1H-NMR(600MHz,CDCl3),δ(ppm):8.56(1H,t,J=2.1Hz),8.35(1H,ddd,J=8.2,2.1,0.9Hz),8.16(1H,d,J=8.2Hz),7.65(1H,t,J=8.2Hz),6.28(1H,d,J=6.7Hz),4.18(1H,m),2.10-2.04(2H,m),1.70-1.68(4H,m),1.57-1.56(6H,m);13C-NMR(150MHz,CDCl3),δ(ppm):163.9,148.1,136.7,133.2,129.7,125.8,121.5,51.5,35.1,27.9,24.1.中间体10k白色固体,收率82%。1H-NMR(600MHz,CDCl3),δ(ppm):8.30(1H,s),7.93(1H,d,J=7.9Hz),7.41(1H,d,J=7.9Hz),6.23(1H,d,J=6.7Hz),4.15(1H,m),2.64(3H,s),2.06-2.02(2H,m),1.70-1.67(4H,m),1.57-1.55(6H,m);13C-NMR(150MHz,CDCl3),δ(ppm):163.8,148.9,136.7,134.2,133.2,131.4,122.8,51.3,35.1,28.0,24.1,20.5.
中间体10l白色固体,收率89%。1H-NMR(600MHz,CDCl3),δ(ppm):8.21(1H,d,J=2.2Hz),8.05(1H,dd,J=8.7,2.2Hz),7.14(1H,d,J=8.7Hz),6.17(1H,d,J=7.40Hz),4.14(1H,m),4.02(3H,s),2.06-2.02(2H,m),1.70-1.67(4H,m),1.57-1.55(6H,m);13C-NMR(150MHz,CDCl3),δ(ppm):163.5,154.9,138.9,133.3,127.2,124.0,113.4,56.8,51.3,51.2,35.1,35.1,28.0,24.1.
中间体11的合成
取中间产物10(3mmol)、铁粉(12mmol)和氯化铵(NH4Cl,15mmol)溶于95%乙醇(20ml)中,在剧烈搅拌下加入催化量的冰醋酸,加热回流4h。过滤去除额外的铁粉,滤液浓缩干燥得到粗产物,不纯化直接用于下一次反应,收率80-96%。
中间体11a棕色固体,收率86%。1H-NMR(600MHz,CDCl3),δ(ppm):7.16(1H,t,J=7.8Hz),7.11(1H,s),7.00(1H,d,J=7.8Hz),6.77(1H,dd,J=7.8,1.5Hz),6.31(1H,s),3.80(2H,br.s),2.87(1H,m),0.84(2H,m),0.59(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):169.1,146.8,135.6,129.3,117.8,116.2,113.7,23.1,6.7.
中间体11b棕色固体,收率89%。1H-NMR(600MHz,CDCl3),δ(ppm):7.12(1H,d,J=1.5Hz),7.04(1H,d,J=7.7Hz),6.95(1H,dd,J=7.7,1.5Hz),6.27(1H,br.s),3.72(2H,br.s),2.87(1H,m),2.17(3H,s),0.84(2H,m),0.59(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):169.0,144.8,133.3,130.3,125.8,116.2,113.6,23.0,17.3,6.7.
中间体11c棕色固体,收率81%。1H-NMR(600MHz,CDCl3),δ(ppm):7.16(1H,d,J=2.1Hz),7.07(1H,dd,J=8.3,2.1Hz),6.74(1H,d,J=8.3Hz),6.23(1H,br.s),3.87(5H,br.s),2.86(1H,m),0.84(2H,m),0.59(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):168.8,149.7,136.2,127.2,117.1,113.5,109.4,55.5,23.0,6.7.
中间体11d棕色固体,收率81%。1H-NMR(600MHz,CDCl3),δ(ppm):7.18(1H,t,J=7.8Hz),7.12(1H,s),7.04(1H,d,J=7.6Hz),6.78(1H,dd,J=7.6,1.5Hz),6.07(1H,s),4.38(1H,m),2.11-2.05(2H,m),1.74-1.71(2H,m),1.68-1.62(2H,m),1.51-1.45(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):167.4,146.7,136.1,129.3,117.7,116.2,113.7,51.6,33.2,23.8.
中间体11e棕色固体,收率83%。1H-NMR(600MHz,CDCl3),δ(ppm):7.14(1H,s),7.07(1H,d,J=7.7Hz),6.99(1H,d,J=7.7Hz),6.05(1H,br.s),4.38(1H,m),2.19(3H,s),2.11-2.05(2H,m),1.74-1.71(2H,m),1.68-1.62(2H,m),1.51-1.45(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):167.3,144.8,133.8,130.3,125.6,116.2,113.6,51.5,33.2,23.8,17.3.
中间体11f棕色固体,收率79%。1H-NMR(600MHz,CDCl3),δ(ppm):7.15(1H,d,J=1.2Hz),7.09(1H,dd,J=8.2,1.2Hz),6.75(1H,d,J=8.2Hz),5.98(1H,d,J=5.4Hz),4.39-4.34(1H,m),3.88(2H,s),3.87(3H,s),2.09-2.04(2H,m),1.74-1.68(2H,m),1.67-1.62(2H,m),1.49-1.43(2H,m);13C-NMR(150MHz,CDCl3),δ(ppm):167.1,149.5,136.1,127.8,117.1,113.5,109.5,55.6,51.5,33.2,33.2,23.8,23.8.
中间体11g棕色固体,收率86%。1H-NMR(600MHz,CDCl3),δ(ppm):7.18(1H,t,J=7.7Hz),7.12(1H,s),7.04(1H,d,J=7.5Hz),6.78(1H,d,J=7.1Hz),5.99(1H,br.s),3.96(1H,m),2.02(2H,m),1.75(2H,m),1.65(1H,m),1.43(2H,m),1.22(3H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.9,146.7,136.3,129.3,117.6,116.2,113.7,48.5,33.2,25.5,24.9.
中间体11h棕色固体,收率80%。1H-NMR(600MHz,CDCl3),δ(ppm):7.14(1H,s),7.07(1H,d,J=7.7Hz),7.00(1H,dd,J=7.7,1.5Hz),5.97(1H,br.s),3.96(1H,m),2.19(3H,s),2.02(2H,m),1.75(2H,m),1.65(1H,m),1.43(2H,m),1.22(3H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.8,144.8,133.9,130.3,125.6,116.2,113.6,48.4,33.2,25.6,24.9,17.3.
中间体11i棕色固体,收率82%。1H-NMR(600MHz,CDCl3),δ(ppm):7.17(1H,d,J=1.9Hz),7.11(1H,dd,J=8.3,1.9Hz),6.77(1H,d,J=8.3Hz),5.92(1H,br.s),3.95(1H,m),3.89(3H,s),2.02(2H,m),1.75(2H,m),1.65(1H,m),1.43(2H,m),1.22(3H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.6,149.5,136.1,127.9,117.1,113.5,109.4,55.5,48.4,33.3,25.6,24.9.
中间体11j棕色固体,收率87%。1H-NMR(600MHz,CDCl3),δ(ppm):7.19(1H,t,J=7.8Hz),7.12(2H,s),7.04(1H,d,J=7.5Hz),6.79(1H,d,J=7.3Hz),6.05(1H,d,J=5.3Hz),4.15(1H,m),2.02(2H,m),1.66(4H,m),1.55(6H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.6,146.7,136.3,129.3,117.6,116.2,113.7,50.7,35.1,28.0,24.1.
中间体11k棕色固体,收率88%。1H-NMR(600MHz,CDCl3),δ(ppm):7.11(1H,d,J=1.0Hz),7.05(1H,d,J=7.7Hz),6.97(1H,dd,J=7.7,1.0Hz),6.02(1H,d,J=6.6Hz),4.13(1H,m),3.72(2H,br.s),2.17(3H,s),2.01-1.97(2H,m),1.64-1.49(10H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.5,144.8,134.1,130.3,125.5,116.2,113.6,50.7,35.2,28.1,24.1,17.3.
中间体11l棕色固体,收率91%。1H-NMR(600MHz,CDCl3),δ(ppm):7.15(1H,d,J=1.0Hz),7.08(1H,d,J=8.0Hz),6.75(1H,dd,J=8.0,1.0Hz),5.96(2H,d,J=5.7Hz),4.12(1H,s),3.88(5H,br.s),2.01-2.00(2H,m),1.64(4H,br.s),1.53(6H,m);13C-NMR(150MHz,CDCl3),δ(ppm):166.3,149.5,136.1,128.0,117.0,113.5,109.5,55.5,50.6,35.2,28.1,24.1.
化合物12~23的合成
取中间体4(1mmol)、中间体11(1mmol)和DIEA(2mmol)溶于DMF(10ml),再加入HATU(1mmol),室温反应24小时。完全反应后,加水(50ml),用乙酸乙酯(30ml)萃取3次。用水、饱和碳酸氢钠水溶液和盐水洗涤有机层,无水硫酸钠干燥。在减压去除溶剂后,经快速色谱柱纯化,二氯甲烷/甲醇(2-4%)洗脱,产率为75-90%。
化合物12:白色固体,收率76%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.56(1H,s),8.44(1H,d,J=4.1Hz),8.08(1H,s),7.98(1H,s),7.73(1H,d,J=8.0Hz),7.49(1H,d,J=7.7Hz),7.38(1H,t,J=7.9Hz),5.21(2H,s),3.46(3H,s),3.19(3H,s),2.83(1H,m),0.68(2H,br.s),0.56(2H,br.s);13C-NMR(150MHz,CDCl3),δ(ppm):167.8,165.5,154.9,151.4,148.4,144.2,139.0,135.7,129.2,122.4,122.0,118.7,106.9,49.1,29.9,27.9,23.5,6.1;HRMS(ESI)+calculated for C19H20N6O4,[M+H]+:m/z 397.1619,found 397.0.
化合物13:白色固体,收率80%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.85(1H,s),8.39(1H,d,J=4.0Hz),8.09(1H,s),7.84(1H,s),7.56(1H,d,J=8.0Hz),7.29(1H,d,J=8..0Hz),5.25(2H,s),3.45(3H,s),3.22(3H,s),2.82(1H,m),2.27(3H,s),0.67(2H,br.s),0.54(2H,br.s);13C-NMR(150MHz,DMSO-d6),δ(ppm):167.4,165.7,154.9,151.5,148.4,144.1,136.0,135.8,132.9,130.6,124.7,124.5,106.9,48.9,29.9,27.9,23.4,18.2,6.1;HRMS(ESI)+calculated for C20H22N6O4,[M+H]+:m/z 411.1775,found 411.1.
化合物14:白色固体,收率86%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.81(1H,s),8.39(1H,s),8.28(1H,d,J=3.8Hz),8.08(1H,s),7.58(1H,dd,J=8.5,1.7Hz),7.10(1H,d,J=8.6Hz),5.29(2H,s),3.92(3H,s),3.45(3H,s),3.21(3H,s),2.79(1H,m),0.65(2H,br.s),0.53(2H,br.s);13C-NMR(150MHz,DMSO-d6),δ(ppm):167.5,165.7,154.9,152.1,151.5,148.3,144.2,127.0,126.8,124.3,121.7,110.8,106.9,56.4,49.3,29.9,27.9,23.4,6.1;HRMS(ESI)+calculated for C20H22N6O5,[M+H]+:m/z 427.1724,found 427.2.
化合物15:白色固体,收率87%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.06(1H,s),8.40(1H,d,J=7.2Hz),8.11(1H,s),8.03(1H,d,J=1.7Hz),7.77(1H,d,J=8.3Hz),7.61(1H,d,J=7.2Hz),5.30(2H,s),4.19(1H,m),3.45(3H,s),3.22(3H,s),1.86(2H,br.s),1.67(2H,br.s),1.51(4H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):166.2,165.5,162.7,154.9,151.4,148.9,148.4,144.2,138.9,136.2,129.1,128.9,122.6,121.8,118.8,116.5,114.9,113.3,106.9,51.3,51.2,49.1,36.2,32.5,31.2,29.9,27.9,24.0;HRMS(ESI)+calculated for C21H24N6O4,[M+H]+:m/z 425.1932,found 425.1.
化合物16:白色固体,收率89%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.84(1H,s),8.23(1H,d,J=7.3Hz),8.09(1H,s),7.84(1H,d,J=1.5Hz),7.60(1H,dd,J=7.9,1.5Hz),7.29(1H,d,J=7.9Hz),5.26(2H,s),4.19(1H,m),3.45(3H,s),3.22(3H,s),2.27(3H,s),1.86(2H,br.s),1.67(2H,br.s),1.50(2H,br.s);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.8,165.7,154.9,151.5,148.4,144.1,135.9,135.6,133.3,130.5,124.8,124.7,106.9,51.3,48.9,32.5,29.9,27.9,24.0,18.2;HRMS(ESI)+calculated for C22H26N6O4,[M+H]+:m/z 439.2088,found 439.2.
化合物17:白色固体,收率81%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.80(1H,s),8.38(1H,s),8.12(1H,d,J=7.3Hz),8.08(1H,s),7.62(1H,dd,J=8.0,2.0Hz),7.11(1H,d,J=8.6Hz),5.29(2H,s),4.17(1H,m),3.93(3H,s),3.46(3H,s),3.21(3H,s),1.84(2H,br.s),1.66(2H,br.s),1.49(4H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.9,165.7,154.9,152.0,151.5,148.4,144.2,127.5,126.7,124.4,121.9,110.7,106.9,56.4,51.3,49.3,32.5,29.9,27.9,24.0;HRMS(ESI)+calculated for C22H26N6O5,[M+H]+:m/z455.2037,found 455.2.
化合物18:白色固体,收率88%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.56(1H,s),8.26(1H,d,J=7.9Hz),8.08(1H,s),7.95(1H,s),7.74(1H,d,J=8.0Hz),7.52(1H,d,J=7.7Hz),7.38(1H,t,J=7.9Hz),5.21(2H,s),3.93(1H,m),3.46(3H,s),3.20(3H,s),1.82(2H,br.s),1.64(2H,br.s),1.57(4H,m),1.42(2H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.5,165.4,154.9,151.5,148.4,144.2,138.9,136.4,129.1,122.6,121.8,118.8,106.9,50.9,49.1,40.4,34.7,29.9,28.2,27.9,24.3;HRMS(ESI)+calculated forC22H26N6O4,[M+H]+:m/z 439.2088,found439.1.
化合物19:白色固体,收率85%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.84(1H,s),8.15(1H,d,J=8.0Hz),8.09(1H,s),7.85(1H,s),7.60(1H,d,J=8.0Hz),7.29(1H,d,J=7.9Hz),5.26(2H,s),3.73(1H,m),3.45(3H,s),3.20(3H,s),2.28(3H,s),1.78(2H,br.s),1.72(2H,br.s),1.59(1H,d,J=12.4Hz),1.29(4H,m),1.10(1H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.7,165.2,154.9,151.5,148.4,144.1,135.9,135.6,133.4,130.5,124.9,124.7,106.9,48.9,48.7,32.8,29.9,27.9,25.7,25.4,18.2;HRMS(ESI)+calculated forC23H28N6O4,[M+H]+:m/z 453.2245,found 453.2.
化合物20:白色固体,收率86%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.80(1H,s),8.39(1H,s),8.08(1H,s),8.02(1H,d,J=7.9Hz),7.62(1H,dd,J=8.6,1.7Hz),7.11(1H,d,J=8.6Hz),5.29(2H,s),3.92(3H,s),3.71(1H,m),3.45(3H,s),3.21(3H,s),1.77(2H,br.s),1.71(2H,br.s),1.59(1H,d,J=12.4Hz),1.31-1.23(4H,m),1.10-1.08(1H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.7,165.3,154.9,152.0,151.5,148.4,144.2,127.5,126.7,124.4,121.9,110.7,106.9,56.4,49.3,48.7,32.9,29.9,27.9,25.7,25.4;HRMS(ESI)+calculated for C23H28N6O5,[M+H]+:m/z 469.2194,found 469.2.
化合物21:白色固体,收率85%。1H-NMR(600MHz,DMSO-d6),δ(ppm):10.55(1H,s),8.25(1H,d,J=7.9Hz),8.08(1H,s),7.95(1H,s),7.74(1H,d,J=8.1Hz),7.52(1H,d,J=7.7Hz),7.38(1H,t,J=7.9Hz),5.21(2H,s),3.94(1H,m),3.46(3H,s),3.22(3H,s),1.82(2H,br.s),1.64(2H,br.s),1.56(4H,m),1.49(2H,m),1.40(2H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.5,165.4,154.9,151.4,148.4,144.2,138.9,136.4,129.1,122.6,121.8,118.8,106.9,50.9,49.1,34.7,29.9,28.2,27.9,24.3;HRMS(ESI)+calculated forC23H28N6O4,[M+H]+:m/z 453.2245,found 453.2.
化合物22:白色固体,收率87%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.84(1H,s),8.19(1H,d,J=7.9Hz),8.09(1H,s),7.83(1H,s),7.59(1H,dd,J=7.9,1.3Hz),7.29(1H,d,J=7.9Hz),5.26(2H,s),3.93(1H,m),3.45(3H,s),3.22(3H,s),2.27(3H,s),1.82(2H,br.s),1.64(2H,br.s),1.56(4H,m),1.49(2H,m),1.40(2H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.7,165.1,154.9,151.5,148.4,144.1,135.9,135.7,133.4,130.5,124.8,124.7,106.9,50.8,48.9,40.4,34.7,29.9,28.2,27.9,24.3,18.2;HRMS(ESI)+calculatedfor C24H30N6O4,[M+H]+:m/z 467.2401,found 467.2.
化合物23:白色固体,收率94%。1H-NMR(600MHz,DMSO-d6),δ(ppm):9.79(1H,s),8.38(1H,d,J=1.5Hz),8.08(1H,s),8.07(1H,d,J=8.0Hz),7.62(1H,dd,J=8.0,1.8Hz),7.10(1H,d,J=8.6Hz),5.29(2H,s),3.92(3H,s),3.91(1H,m),3.45(3H,s),3.21(3H,s),1.79(2H,br.s),1.63(2H,br.s),1.54(4H,m),1.48(2H,m),1.39(2H,m);13C-NMR(150MHz,DMSO-d6),δ(ppm):165.7,165.1,154.9,152.0,151.5,148.3,144.2,127.6,126.7,124.4,121.8,110.7,106.9,56.4,50.8,49.3,34.8,29.9,28.2,27.9,24.4;HRMS(ESI)+calculated for C24H30N6O4,[M+H]+:m/z 483.2350,found 483.2.
试验例1化合物1~23的ATAD2抑制活性及抗增殖活性
本实验的目的是检测本发明的化合物对体外ATAD2抑制活性和体外对MDA-MB-231肿瘤细胞的抗增值活性(表1)。
所有的酶促反应在37℃反应30分钟。50ul反应混合物包含25mM Tris,pH 8.0,1mMMgCl2,0.1mg/ml BSA,1 37mM NaCl,2.7mM KCl,HDACs和酶底物。将化合物用10%的DMSO稀释,在50ul的反应中加入5ul稀释剂,使DMSO在所有反应中的最终浓度为1%。该分析是通过定量荧光产物的数量在溶液中酶反应。然后在350-360nm的激发和450-460nm的发射波长下,用SpectraMax M5微量滴定板阅读器进行荧光分析。IC50值的计算采用非线性回归和归一化剂量-响应拟合Prism GraphPad软件。
细胞以5x104个细胞/ml的密度分布在96孔板中。细胞被不同浓度的化合物处理24小时。MTT法测定细胞存活率。
表1化合物1~11的ATAD2抑制活性及抗肿瘤抑制活性
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表2化合物12~23的ATAD2抑制活性及抗肿瘤抑制活性
实验结果表明,本发明的化合物大多对ATAD2展现出较好的抑制活性及抗肿瘤增值活性,化合物17是最优选化合物。
试验例1化合物17抑制BT-549细胞中ATAD2-Myc的激活
由于ATAD2主要通过激活c-Myc发挥促肿瘤作用,我们首先检测了BT-549细胞经化合物17处理后c-Myc在Ser62位点的磷酸化水平。免疫荧光结果显示化合物17可以以剂量依赖性的方式降低p-c-Myc Ser62的荧光强度(图1)。与ATAD2抑制剂AM879相比,化合物17对p-c-Myc Ser62水平的影响更显著。随后,采用免疫印迹法分别检测AM879和化合物17处理BT-549细胞后ATAD2、c-Myc和p-c-Myc的表达水平。结果表明,AM879和化合物17对ATAD2的表达均无显著影响,但以剂量依赖的方式抑制了c-Myc和p-c-Myc Ser62的表达水平,其中化合物17的作用更为显著。综上所述,化合物17抑制了三阴性乳腺癌细胞中ATAD2活性和c-Myc活化。
试验例2化合物17的抑制BT-549细胞增殖
接下来,我们继续检测化合物17对BT-549细胞增殖能力的影响。如图2所示,化合物17可以以剂量依赖的方式降低EdU-488的荧光强度,说明化合物17可以以剂量依赖的方式抑制BT-549细胞中新DNA的合成,证明化合物17可以抑制TNBC细胞的增殖。与对照组相比,化合物17可以浓度依赖性地抑制BT-549细胞的集落形成能力,说明化合物17也可以抑制BT-549细胞的长期增殖。比较AM879和化合物17对BT-549细胞增殖能力的影响,结果表明,化合物17在处理48h后表现出更好的抗增殖活性,而长期的抗增殖活性无差异(图3)。综上,化合物17在BT-549细胞中表现出良好的抗增殖活性。
试验例3化合物17诱导BT-549细胞发生凋亡
由于ATAD2与细胞凋亡密切相关,抑制ATAD2可诱导细胞凋亡。因此,接下来我们检测化合物17是否能诱导BT-549细胞凋亡。有趣的是,化合物17可以以剂量依赖的方式诱导明显的凋亡,早期凋亡和晚期凋亡比例增加(图4)。然后,我们研究了经典的凋亡标志蛋白的表达。结果表明,化合物17促进Bax的表达,促进caspase-3、caspase-8、caspase-9和PARP的裂解。同时,化合物17处理后Bcl-2的表达显著降低。因此,化合物17抑制ATAD2可诱导BT-549细胞凋亡。
试验例4化合物17抑制BT-549细胞转移
为了进一步评估化合物17在TNBC中的潜在应用,我们随后检测了其对TNBC细胞迁移的影响。化合物17处理后,BT-549细胞的迁移能力明显下降。划痕愈合分析显示化合物17以剂量依赖性方式增加相对伤口面积(图5)。同时,化合物17也以剂量依赖性的方式减少了迁移细胞的数量。接下来,我们检查了两个关键迁移标志物MMP-2和E-cadherin的表达,发现化合物17上调了E-cadherin的表达,下调了MMP-2的表达。综上所述,化合物17在体外表现出良好的抗迁移活性。
Claims (10)
1.式Ⅰ所示的化合物或其药学上可接受的盐、异构体:
其中,R1为氢、C1-C6烷基、C1-C6烷氧基、卤素、卤代C1-C6烷基;
R2为C2-C10脂肪胺、
X为CH2,O,S,CF2,NH,NCH3,
n=0-5。
2.根据权利要求1所述的化合物或其药学上可接受的盐、异构体,其特征在于:
R1为氢、C1-C4烷基、C1-C4烷氧基、卤素、卤代C1-C4烷基。
3.权利要求1或2所述的化合物或其药学上可接受的盐、异构体,其特征在于:
R2为
X为CH2,O,S;
n=0-5,优选为0-3。
4.权利要求1-3任何一项所述的化合物或其药学上可接受的盐、异构体,其特征在于:
R1为氢、C1-C4烷基、C1-C4烷氧基、卤素、卤代C1-C4烷基时;
R2为
X为O;
R1为4-位取代;
或R1为C1-C4烷基、C1-C4烷氧基、卤素、卤代C1-C4烷基时;
R2为
X为S;
R1为4-位取代。
5.如下的化合物或其药学上可接受的盐、异构体:
6.权利要求1-5任一项所述的化合物或其药学上可接受的盐、异构体,其特征在于,所述的药学上可接受的盐为所述化合物的硝酸盐、盐酸盐、硫酸盐、磷酸盐或柠檬酸盐。
7.药物组合物,包含权利要求1-6任何一项所述的化合物或其药学上可接受的盐、异构体。
8.权利要求1所述的化合物或其药学上可接受的盐的制备方法,其特征在于:
R1、n如权利要求1所述。
9.权利要求1-6任一项所述的化合物或其药学上可接受的盐、异构体或权利要求7所述的药物组合物在制备ATAD2抑制剂中的应用。
10.权利要求1-6任一项所述的化合物或其药学上可接受的盐、异构体或权利要求7所述的药物组合物在制备抗肿瘤药物中的应用。
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