CN112250638B - 一种1,3-二芳基-1,2,4-三氮唑类化合物及其制备方法和应用 - Google Patents

一种1,3-二芳基-1,2,4-三氮唑类化合物及其制备方法和应用 Download PDF

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CN112250638B
CN112250638B CN202011270341.2A CN202011270341A CN112250638B CN 112250638 B CN112250638 B CN 112250638B CN 202011270341 A CN202011270341 A CN 202011270341A CN 112250638 B CN112250638 B CN 112250638B
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刘宏民
张鑫荟
高雅
马立英
陶源源
康慧琴
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Abstract

本发明公开了一种1,3‑二芳基‑1,2,4‑三氮唑类化合物，具有结构通式I
Figure DDA0002777472930000011
结构新颖，对HDAC6有较好的选择抑制活性。本发明还公开了上述化合物的制备方法，在1,2,4‑三氮唑基体上引入芳基基团、4‑氨基‑N‑羟基‑苯甲酰胺基团修饰，合成了一系列结构新颖的化合物，具有反应条件温和、操作简单、收率高等优点。本发明还公开了上述化合物在制备选择性抑制HDAC6药物中的应用。本发明提供的化合物能够显著地抑制HDAC6，其IC50值在纳摩尔水平，有利于患者减少用药量，降低药物对人体的毒副作用。本发明提供的化合物对亚型HDAC1有高选择性，可有效避免药物对人体正常组织的毒副作用，显示出良好的开发潜力。

Description

一种1,3-二芳基-1,2,4-三氮唑类化合物及其制备方法和 应用
技术领域
本发明属于医药化学领域，涉及一种1,3-二芳基-1,2,4-三氮唑类化合物及其制备方法和的应用。
背景技术
表观遗传调控主要与DNA甲基化、组蛋白修饰、染色质结构重塑和非编码RNA调控有关，在人体细胞和分子调控过程中发挥着重要作用。其中，组蛋白乙酰化和去乙酰化是广泛存在的翻译后修饰过程。组蛋白乙酰化是在组蛋白乙酰转移酶(HATs)催化下将乙酰基团转移到第五蛋白质赖氨酸残基上的过程，其逆反应由组蛋白去乙酰化酶(HDACs)催化，称为蛋白质的脱乙酰化。赖氨酸乙酰化的这一可逆过程维持着核蛋白和细胞质蛋白乙酰化水平之间的平衡，这对于维持机体内的稳态是至关重要的。值得注意的是，HDACs的异常表达往往会破坏这种平衡，从而导致各种疾病的发生。
迄今为止，研究人员已在哺乳动物中鉴定出18种HDAC亚型。根据与酵母蛋白同源性将其分为几个主族，其中I类(HDAC1,2,3,8)与酵母RPD3具有同源性，IIa类(HDAC4,5,7,9)酵母HDAC1具有同源性，另外还有IIb类(HDAC 6,10)和IV类(HDAC11)，这些亚型都是Zn2+-依赖性酶；而III类(sirtuins 1-7)则是NAD+-依赖性酶。据报道HDAC抑制剂可以通过改变各种细胞蛋白的乙酰化状态，提高p21和其他基因的表达水平，通过诱导细胞分化或凋亡抑制肿瘤细胞的增殖，已成为治疗人类各种疾病的有效化疗药物。然而，目前被批准用于临床的HDAC抑制剂，如伏立诺他(SAHA)、罗米地辛(romidepsin)、贝立司他(belinostat)和帕比司他(panobinstat)，都因缺乏对HDAC亚型选择性而可能导致较多的副作用，如疲劳、心脏毒性、血小板降低症和肠粘膜出血。因此，开发具有HDAC亚型选择性的小分子抑制剂具有重要的临床意义。
HDAC6是HDAC家族中最大的成员。HDAC6含有1215个氨基酸残基，两个独立的催化结构域(CD1和CD2，分别位于链的N端和中心区域)和一个锌指泛素结合结构域(ZnF-UBP)，该结构域介导HDAC6参与泛素蛋白酶体以及溶酶体途径清除体内错误折叠蛋白。此外，核输出信号(NES)使HDAC6能够转运到细胞质中，并作用于细胞质中的α-微管蛋白、皮动蛋白(cortactin)、热休克蛋白(HSP90)等非组蛋白底物。由于其独特的结构和底物多样性，HDAC6在细胞运动、内吞、细胞自噬、细胞凋亡、蛋白质转运和降解等多种细胞通路中发挥着特异性的生理作用，以至于HDAC6的异常表达与多种人类疾病密切相关，如癌症、神经退行性疾病(帕金森病、亨廷顿病和阿尔茨海默病)和自身免疫性疾病。
在过去的几十年里，无论是单独使用还是与其他上市药物联合使用，HDAC6选择性抑制剂均表现出了独特的疾病治疗功效。而最新的研究表明HDAC6抑制剂不仅能够介导炎性体的激活，还能提高肿瘤细胞免疫源性，增强肿瘤免疫治疗效果。2019年，基石药业开发的HDAC6抑制剂CS3003被中国国家药品监督管理局(NMPA)批准在中国开展首个人体I期临床试验，用于治疗晚期实体瘤和复发或难治性多发性骨髓瘤。由此可见，开发新型选择性的HDAC6抑制剂具有重要的临床意义以及开阔的市场前景。
发明内容
为了克服现有技术的不足，本发明的目的之一在于提供一种1,3-二芳基-1,2,4-三氮唑类化合物，该化合物对HDAC6具有较强的选择抑制活性。
本发明的目的之二在于提供1,3-二芳基-1,2,4-三氮唑类化合物的制备方法。
本发明的目的之三在于提供1,3-二芳基-1,2,4-三氮唑类化合物在制备选择性抑制HDAC6的药物中的应用。
本发明的目的之一采用如下技术方案实现：
一种1,3-二芳基-1,2,4-三氮唑类化合物，具有以下结构通式I：
Figure BDA0002777472910000021
其中R1为H，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，甲氧基，羟基，氟，氯，溴，硝基，三氟甲基；R2为苯基，取代苯基，杂芳基。
优选地，所述取代苯基上的取代基为甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，甲氧基，羟基，氟，氯，溴，硝基，三氟甲基中的一种；所述杂芳基为噻吩，呋喃，吡唑，吡咯，咪唑，吡啶，喹啉，苯并噻吩，苯并呋喃，吲哚，吲唑，苯并咪唑中的一种。
优选地，R1与R2选自下列基团的一种或多种：
Figure BDA0002777472910000022
Figure BDA0002777472910000031
Figure BDA0002777472910000041
本发明的目的之二采用如下技术方案实现：
1,3-二芳基-1,2,4-三氮唑类化合物的制备方法，包括以下步骤：
Figure BDA0002777472910000042
1)取代苯肼a与取代芳香醛b在醇水溶液中发生缩合反应，反应完成后冷却至室温，抽滤干燥得到化合物c；
2)将步骤1)得到的化合物c溶于有机溶剂中，经单质碘、叔丁基过氧化氢催化，与氨基乙醇发生反应得到化合物d；
3)将步骤2)得到的化合物d溶于有机溶剂中，经戴斯马丁氧化剂氧化，得到化合物e；
4)将步骤3)得到的化合物e溶于醇溶剂中，在酸催化以及氰基硼氢化钠作用下，与氨基苯甲酸甲酯发生反应，得到化合物f；
5)将步骤4)得到的化合物f溶于有机溶剂中，加入羟胺水溶液和碱，反应完成后用酸调节pH，抽滤干燥得到化合物g。
优选地，步骤1)中使用的醇选自甲醇、乙醇中一种，步骤4)中使用的醇选自甲醇、乙醇、正丁醇、异丁醇中的一种。
优选地，步骤2)中有机溶剂选自四氢呋喃、乙腈、乙酸乙酯、二氧六环中的一种，步骤3)中有机溶剂选自四氢呋喃、乙腈、二氯甲烷、乙酸乙酯、二氧六环中的一种。
优选地，步骤4)或步骤5)中使用的酸选自甲酸、乙酸、三氟乙酸、稀盐酸中的一种。
优选地，步骤5)中使用的有机溶剂选自二氯甲烷、甲醇、乙醇、乙酸乙酯、四氢呋喃、乙腈中的一种或两种。
优选地，步骤5)中使用的碱选自碳酸钾、碳酸钠、氢氧化钠、氢氧化钾中的一种。
本发明的目的之三是提供1,3-二芳基-1,2,4-三氮唑类化合物在制备选择性抑制HDAC6的药物中的应用。
相比现有技术，本发明的有益效果在于：
本发明提供了一种1,3-二芳基-1,2,4-三氮唑类化合物，结构新颖，对HDAC6有较好的选择抑制活性。本发明还提供了上述化合物的制备方法，在1,2,4-三氮唑基体上引入芳基基团、4-氨基-N-羟基-苯甲酰胺基团修饰，合成了一系列结构新颖的1,3-二芳基-1,2,4-三氮唑类化合物，具有反应条件温和、操作简单、收率高等优点。本发明还提供了上述化合物在制备选择性抑制HDAC6的药物中的应用。本发明提供的化合物能够显著地抑制HDAC6，且其IC50值在纳摩尔水平，表明用药后存活的细胞数量减少一半时所需药物浓度较低，有利于患者减少药物用量，降低化合物对人体的毒副作用。本发明提供的化合物对亚型HDAC1有高选择性，可有效避免药物对人体正常组织发挥药效从而产生副作用，显示出良好的开发潜力。
附图说明
图1：本发明HDAC6荧光分析法原理图。
具体实施方式
下面，结合具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
实施例1
Figure BDA0002777472910000051
(1)称取10mmol苯肼于100mL圆底烧瓶中，加入30mL 20％乙醇水溶液，超声溶解，室温搅拌状态下滴加苯甲醛11mmol，转至80℃加热回流6-8小时，TLC监测待反应完全，冷至室温、抽滤，固体用20％乙醇水溶液淋洗，干燥得灰白色固体化合物c，产率85％；
(2)称取2.5mmol步骤1)得到的化合物c于50mL圆底烧瓶中，加入15mL乙腈，超声溶解，室温状态下，依次加入氨基乙醇7.5mmol、叔丁基过氧化氢7.5mmol、单质碘0.5mmol，转至90℃加热回流4-5小时，TLC监测待反应完全，冷至室温，加入10mL水淬灭，用乙酸乙酯(3*15mL)萃取三次，合并有机相，饱和食盐水洗涤，减压蒸馏除掉有机相，柱层析(石油醚：乙酸乙酯＝2:1)，得白色固体d，产率70％；
(3)称取1mmol步骤2)得到的化合物d于25mL圆底烧瓶中，加入二氯甲烷8mL，超声溶解、冰浴，缓慢加入戴斯马丁氧化剂1.5mmol，恢复至室温搅拌过夜，加饱和硫代硫酸钠和碳酸氢钠混合溶液10mL淬灭反应，乙酸乙酯(3*15mL)萃取三次，合并有机相，用饱和食盐水洗涤，减压蒸馏除掉有机相，得灰白色固体e，无需纯化，直接用于下一步反应；
(4)称取0.5mmol步骤3)得到的化合物e于25mL圆底烧瓶中，加入甲醇5mL，超声溶解，加入4-氨基苯甲酸甲酯0.45mmol，随后滴加一滴甲酸，室温搅拌0.5小时后，加入氰基硼氢化钠0.55mmol，室温搅拌过夜，TLC监测待反应完全，加入乙酸乙酯(3*15mL)萃取三次，合并有机相，饱和食盐水洗涤，减压蒸馏除掉有机相，柱层析(石油醚：乙酸乙酯＝5:1)，得到白色固体f，产率65％；
(5)称取0.25mmol步骤4)得到的化合物f于25mL圆底烧瓶中，加入体积比CH2Cl2：MeOH＝1:2的混合溶剂5mL，超声促进溶解，之后加入羟胺水溶液5mmol，室温搅拌0.5h，将反应体系置于冰浴中，缓慢加入氢氧化钠1.25mmol，继续搅拌0.5～1h。利用TLC监测反应完全，减压蒸馏除掉有机溶剂，加水溶解残渣，重新将制备得到的物质置入冰浴中，加稀盐酸调节pH至5～6，静置析晶、抽滤，将所得的固体水洗、石油醚：乙酸乙酯＝5:1混合溶剂分别洗两遍，最终干燥得到白色固体g-1，收率85％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.84(s,1H),8.78(s,1H),8.05(d,J＝7.5Hz,2H),7.69(d,J＝7.8Hz,2H),7.61(td,J＝14.5,13.6,6.3Hz,4H),7.50(h,J＝7.7,6.9Hz,4H),6.76(t,J＝5.7Hz,1H),6.59(t,J＝7.9Hz,2H),4.55(dd,J＝9.5,5.5Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ160.33,154.30,154.15,150.28,136.82,130.95,130.32,129.54,129.47,129.09,128.82,128.15,125.85,124.67,124.61,120.15,111.26.LC-MS(ESI；C18column；column size2.1mm×50mm；mobile phase 10％-95％；acetonitrile-water-0.1％Formic acid):t＝4.193min,calcd.C22H19N5O2,[M+H]+m/z:386.16,found:386.16.
实施例2
Figure BDA0002777472910000061
将实施例1步骤1)中的苯甲醛换作对甲基苯甲醛，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.85(s,1H),8.80(s,1H),7.95(d,J＝7.9Hz,2H),7.68(d,J＝7.6Hz,2H),7.64–7.48(m,5H),7.30(d,J＝8.0Hz,2H),6.75(t,J＝5.6Hz,1H),6.58(d,J＝8.6Hz,2H),4.53(d,J＝5.8Hz,2H),2.36(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.79,160.42,154.12,150.28,138.99,136.85,129.52,129.37,129.02,128.15,127.61,125.82,124.58,120.14,111.26,20.91.LC-MS(ESI；C18 column；column size2.1mm×50mm；mobile phase 10％-95％；acetonitrile-water-0.1％Formic acid),t＝4.442min,calcd.C23H21N5O2,[M+H]+m/z:400.18,found:400.21.
实施例3
Figure BDA0002777472910000071
将实施例1步骤1)中的苯甲醛换作邻甲基苯甲醛，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(s,1H),7.97(d,J＝7.0Hz,1H),7.71(d,J＝7.6Hz,2H),7.61(t,J＝7.5Hz,2H),7.54(dd,J＝12.0,8.0Hz,2H),7.37–7.26(m,1H),6.74(t,J＝5.5Hz,3H),6.62(d,J＝8.7Hz,1H),4.56(d,J＝5.5Hz,2H),2.61(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ161.12,153.29,150.40,136.99,136.39,131.23,129.55,128.94,128.13,125.84,124.41,120.27,111.36,21.66.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％；acetonitrile-water-0.1％Formiccacid):t＝4.436min,calcd.C23H21N5O2,[M+H]+m/z:400.18,found:400.20.
实施例4
Figure BDA0002777472910000072
将实施例1步骤1)中的苯甲醛换作间甲基苯甲醛，其余与实施例1相同。收率82％。
1H NMR(400MHz,DMSO-d6,ppm-d6)δ7.92–7.81(m,2H),7.68(d,J＝7.9Hz,2H),7.65–7.48(m,5H),7.38(t,J＝7.6Hz,1H),7.27(d,J＝7.7Hz,1H),6.75(t,J＝5.7Hz,1H),6.55(dd,J＝11.3,8.4Hz,2H),4.53(d,J＝5.5Hz,2H),2.38(s,3H).13CNMR(101MHz,DMSO-d6,ppm)δ160.41,154.20,150.25,137.99,136.83,130.76,130.26,130.11,129.53,129.06,128.73,128.13,126.33,124.58,123.05,120.16,111.25,20.96.LC-MS(ESI；C18column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.469min,calcd.C23H21N5O2,[M+H]+m/z:400.18,found:400.19.
实施例5
Figure BDA0002777472910000081
将实施例1步骤1)中的苯甲醛换作对乙基苯甲醛，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm-d6)δ10.84(s,1H),8.78(s,1H),7.97(d,J＝8.0Hz,2H),7.68(d,J＝7.8Hz,2H),7.66–7.48(m,5H),7.33(d,J＝8.0Hz,2H),6.75(t,J＝5.6Hz,1H),6.58(t,J＝7.3Hz,2H),4.54(dd,J＝9.0,5.4Hz,2H),2.66(q,J＝7.6Hz,2H),1.21(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6,ppm)δ160.42,154.12,150.28,145.21,136.85,130.93,129.52,129.01,128.17,127.86,125.91,124.62,124.57,120.14,111.26,27.97,15.30.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.748min,calcd.C24H23N5O2,[M+H]+m/z:414.20,found:414.23.
实施例6
Figure BDA0002777472910000082
将实施例1步骤1)中的苯甲醛换作对异丙基苯甲醛，其余与实施例1相同。收率86％。
1H NMR(400MHz,DMSO-d6,ppm-d6)δ7.97(d,J＝8.0Hz,2H),7.68(d,J＝7.3Hz,3H),7.65–7.47(m,4H),7.36(d,J＝7.9Hz,2H),6.74(t,J＝5.6Hz,1H),6.55(dd,J＝15.3,8.3Hz,2H),4.52(t,J＝4.6Hz,2H),2.94(h,J＝7.0Hz,1H),1.23(d,J＝6.8Hz,6H).13C NMR(101MHz,DMSO-d6,ppm)δ160.41,154.20,154.13,150.26,149.80,136.87,129.52,129.01,128.10,128.01,126.71,125.94,124.56,111.27,33.25,23.67.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formicacid):t＝5.000min,calcd.C25H25N5O2,[M+H]+m/z:428.21,found:428.23.
实施例7
Figure BDA0002777472910000091
将实施例1步骤1)中的苯甲醛换作对甲氧基苯甲醛，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(s,1H),7.98(d,J＝8.4Hz,2H),7.68(d,J＝7.4Hz,2H),7.59(t,J＝7.2Hz,2H),7.52(d,J＝8.5Hz,3H),7.04(d,J＝8.4Hz,2H),6.75(s,1H),6.58(d,J＝8.4Hz,2H),4.51(d,J＝4.5Hz,2H),3.80(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.77,160.30,160.20,154.03,150.33,136.97,129.51,128.92,128.17,127.38,124.56,123.00,120.26,114.18,111.28,55.18.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formicacid):t＝4.165min,calcd.C23H21N5O3,[M+H]+m/z:416.18,found:416.20.
实施例8
Figure BDA0002777472910000092
将实施例1步骤1)中的苯甲醛换作4-氟苯甲醛，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm-d6)δ8.09(dd,J＝8.6,5.6Hz,2H),7.69(d,J＝7.6Hz,2H),7.65–7.48(m,5H),7.33(t,J＝8.7Hz,2H),6.75(t,J＝5.6Hz,1H),6.56(dd,J＝13.2,8.5Hz,2H),4.53(d,J＝5.5Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.02,161.57,159.56,154.43,150.24,136.75,130.76,129.54,129.13,128.13,128.05,126.91,124.62,120.17,115.93,115.71,111.27,110.97.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.322min,calcd.C22H18FN5O2,[M+H]+m/z:404.15,found:404.15.
实施例9
Figure BDA0002777472910000101
将实施例1步骤1)中的苯甲醛换作2-氯苯甲醛，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.70(s,1H),8.00–7.83(m,1H),7.71(d,J＝7.7Hz,2H),7.66–7.54(m,4H),7.53–7.44(m,4H),6.74(s,1H),6.60(d,J＝8.4Hz,2H),4.57(s,2H).13C NMR(101MHz,DMSO-d6,ppm-d6,ppm)δ164.74,158.90,153.70,150.34,136.82,131.56,131.27,130.71,130.65,129.56,129.37,129.07,128.13,127.25,124.53,120.30,111.35.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.265min,calcd.C22H18ClN5O2,[M+H]+m/z:420.12,found:420.14.
实施例10
Figure BDA0002777472910000102
将实施例1步骤1)中的苯甲醛换作3-氯苯甲醛，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(s,1H),8.21–7.94(m,1H),7.71(d,J＝7.2Hz,1H),7.61(t,J＝7.3Hz,1H),7.57(d,J＝7.0Hz,1H),7.56–7.52(m,1H),7.51(s,1H),6.75(t,J＝5.4Hz,1H),6.58(d,J＝8.7Hz,1H),4.54(d,J＝5.5Hz,1H).13C NMR(101MHz,DMSO-d6,ppm)δ164.72,159.07,154.70,150.26,136.75,133.60,132.44,130.95,129.56,129.30,129.22,128.17,125.36,124.67,124.42,120.33,111.28.LC-MS(ESI；C18column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.688min,calcd.C22H18ClN5O2,[M+H]+m/z:420.12,found:420.15.
实施例11
Figure BDA0002777472910000103
将实施例1步骤1)中的苯甲醛换作4-氯苯甲醛，其余与实施例1相同。收率82％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(s,1H),8.05(d,J＝8.2Hz,2H),7.69(d,J＝7.7Hz,2H),7.61(t,J＝7.3Hz,2H),7.58–7.54(m,3H),7.51(d,J＝8.3Hz,2H),6.74(d,J＝5.9Hz,1H),6.57(d,J＝8.4Hz,2H),4.53(d,J＝5.4Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.75,159.44,154.59,150.29,136.80,134.05,129.55,129.29,129.15,128.96,128.17,127.60,124.65,120.30,111.28.LC-MS(ESI；C18 column；column size2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.673min,calcd.C22H18ClN5O2,[M+H]+m/z:420.12,found:420.14.
实施例12
Figure BDA0002777472910000111
将实施例1步骤1)中的苯甲醛换作3,4-二氯苯甲醛，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(s,1H),8.18(s,1H),8.00(d,J＝8.4Hz,1H),7.77(d,J＝8.4Hz,1H),7.71(d,J＝7.8Hz,2H),7.66–7.56(m,3H),7.52(d,J＝8.4Hz,2H),6.75(t,J＝5.2Hz,1H),6.58(d,J＝8.5Hz,2H),4.54(d,J＝5.3Hz,2H).13CNMR(101MHz,DMSO-d6,ppm)δ164.72,158.33,154.91,150.24,136.67,132.01,131.73,131.36,130.96,129.57,125.90,124.68,120.34,111.28.LC-MS(ESI；C18 column；columnsize 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝5.077min,calcd.C22H17Cl2N5O2,[M+H]+m/z:454.08,found:454.07.
实施例13
Figure BDA0002777472910000112
将实施例1步骤1)中的苯甲醛换作4-溴苯甲醛，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.70(s,1H),7.98(d,J＝8.2Hz,2H),7.69(d,J＝8.3Hz,4H),7.60(t,J＝7.5Hz,2H),7.56(d,J＝7.0Hz,1H),7.51(d,J＝8.4Hz,2H),6.75(s,1H),6.57(d,J＝8.4Hz,2H),4.52(d,J＝4.1Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.75,159.50,154.61,150.29,136.80,131.88,129.63,129.55,129.16,128.17,127.86,124.65,122.77,120.29,111.27.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.762min,calcd.C22H18BrN5O2,[M+H]+m/z:464.07,found:464.05.
实施例14
Figure BDA0002777472910000121
将实施例1步骤1)中的苯甲醛换作4-三氟甲基苯甲醛，其余与实施例1相同。收率85％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(s,1H),8.18(d,J＝2.1Hz,1H),8.00(dd,J＝8.5,2.1Hz,1H),7.77(d,J＝8.4Hz,1H),7.70(d,J＝7.6Hz,2H),7.62(d,J＝7.5Hz,2H),7.60–7.54(m,2H),7.51(d,J＝8.4Hz,2H),6.74(d,J＝5.7Hz,1H),6.56(d,J＝8.3Hz,2H),4.53(d,J＝5.5Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.73,158.33,154.91,150.24,136.67,132.01,131.72,131.35,130.97,129.57,129.29,128.18,127.33,125.90,124.68,120.35,111.29,38.87.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝5.083min,calcd.C23H18F3N5O2,[M+H]+m/z:454.15,found:454.07.
实施例15
Figure BDA0002777472910000122
将实施例1步骤1)中的苯甲醛换作苯并(b)噻吩-2-甲醛，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(s,1H),8.01(d,J＝6.5Hz,2H),7.93(s,1H),7.71(d,J＝7.6Hz,2H),7.66–7.55(m,3H),7.52(d,J＝8.3Hz,2H),7.45–7.38(m,2H),6.79(s,1H),6.57(d,J＝8.5Hz,2H),4.54(d,J＝5.5Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ162.28,156.74,154.81,150.25,139.56,139.17,136.61,133.06,129.59,129.31,128.20,125.40,124.84,124.80,124.37,122.88,122.61,120.33,111.26,38.78.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.730min,calcd.C24H19N5O2S,[M+H]+m/z:442.13,found:442.11.
实施例16
Figure BDA0002777472910000131
将实施例1步骤1)中的苯甲醛换作3-甲基噻吩-2-甲醛，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(s,1H),7.68(d,J＝7.7Hz,2H),7.60(t,J＝7.3Hz,2H),7.55(d,J＝7.0Hz,1H),7.53–7.46(m,3H),7.01(d,J＝4.8Hz,1H),6.76(s,1H),6.56(d,J＝8.3Hz,2H),4.51(s,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.73,157.38,153.59,150.28,137.06,136.79,131.60,129.55,129.04,128.14,126.73,125.91,124.59,120.28,111.28,38.70,15.46.LC-MS(ESI；C18 column；columnsize 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.398min,calcd.C21H19N5O2S,[M+H]+m/z:406.13,found:406.12.
实施例17
Figure BDA0002777472910000132
将实施例1步骤1)中的苯甲醛换作3-溴噻吩-2-甲醛，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),7.78(d,J＝1.6Hz,1H),7.69–7.64(m,2H),7.60(d,J＝2.0Hz,2H),7.58(t,J＝3.0Hz,2H),7.51(s,1H),7.49(s,1H),6.74(s,1H),6.53(d,J＝8.5Hz,2H),4.50(s,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.73,155.60,154.71,150.17,136.51,134.71,129.57,129.33,128.18,127.89,125.09,124.77,120.34,111.23,109.54,38.72.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.569min,calcd.C20H16BrN5O2S,[M+H]+m/z:470.03,found:469.98.
实施例18
Figure BDA0002777472910000141
将实施例1步骤1)中的苯甲醛换作5-甲基噻吩-2-甲醛，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(s,1H),7.65(d,J＝7.3Hz,2H),7.58(dd,J＝14.5,6.7Hz,3H),7.50(d,J＝8.3Hz,2H),7.43(d,J＝3.2Hz,1H),6.85(d,J＝3.4Hz,1H),6.75(t,J＝5.5Hz,1H),6.53(d,J＝8.2Hz,2H),4.48(d,J＝5.2Hz,2H),2.48(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.74,156.83,154.15,150.23,140.98,136.68,130.65,129.53,129.08,128.16,126.41,126.29,124.67,120.27,111.22,15.00.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.270min,calcd.C21H19N5O2S,[M+H]+m/z:406.13,found:406.12.
实施例19
Figure BDA0002777472910000142
将实施例1步骤1)中的苯肼换作4-羟基苯肼，苯甲醛换作噻吩-2-甲醛，其余与实施例1相同。收率82％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),10.03(s,1H),8.71(s,1H),7.62(d,J＝4.3Hz,2H),7.51(d,J＝8.4Hz,2H),7.44(d,J＝8.5Hz,2H),7.15(t,J＝4.3Hz,1H),6.97–6.89(m,2H),6.74(t,J＝5.7Hz,1H),6.54(d,J＝8.4Hz,2H),4.42(d,J＝5.6Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.77,158.09,156.45,154.17,150.26,133.36,128.17,128.06,128.00,127.23,126.50,125.99,120.21,115.78,111.20,38.47.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formicacid):t＝3.530min,calcd.C20H17N5O3S,[M+H]+m/z:408.11,found:408.11.
实施例20
Figure BDA0002777472910000151
将实施例1步骤1)中的苯甲醛换作5-氯噻吩-2-甲醛，其余与实施例1相同。收率84％。
H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(s,1H),7.66(d,J＝6.9Hz,2H),7.59(dd,J＝16.2,8.2Hz,3H),7.50(d,J＝7.6Hz,3H),7.20(d,J＝3.5Hz,1H),6.75(s,1H),6.53(d,J＝8.3Hz,2H),4.50(d,J＝4.8Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ165.24,156.29,155.15,150.68,137.02,132.53,130.07,129.79,128.67,128.55,126.41,125.28,120.86,111.74,100.00,39.20.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.599min,calcd.C20H16ClN5O2S,[M+H]+m/z:426.08,found:426.11.
实施例21
Figure BDA0002777472910000152
将实施例1步骤1)中的苯甲醛换作噻吩-3甲醛，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(s,1H),8.03(t,J＝18.9Hz,1H),7.67(d,J＝6.5Hz,3H),7.60(t,J＝6.8Hz,3H),7.55(d,J＝7.1Hz,1H),7.51(d,J＝8.6Hz,2H),6.75(s,1H),6.56(t,J＝8.9Hz,2H),4.51(s,2H).13C NMR(101MHz,DMSO-d6,ppm)δ165.27,158.16,154.50,150.78,137.35,130.02,129.52,128.67,127.91,126.36,125.17,124.83,120.79,111.75,39.31.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝3.962min,calcd.C20H17N5O2S,[M+H]+m/z:392.12,found:392.10.
实施例22
Figure BDA0002777472910000153
将实施例1步骤1)中的苯甲醛换作呋喃甲醛，其余与实施例1相同。收率82％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.72(s,1H),7.83(s,1H),7.68(d,J＝7.7Hz,2H),7.60(t,J＝7.4Hz,2H),7.56(d,J＝7.1Hz,1H),7.51(d,J＝8.6Hz,2H),7.00(d,J＝3.3Hz,1H),6.76(t,J＝5.5Hz,1H),6.65(dd,J＝3.2,1.7Hz,1H),6.55(d,J＝8.6Hz,2H),4.56(t,J＝20.4Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ154.57,154.52,153.48,150.75,144.66,137.23,130.03,129.55,128.66,125.07,120.80,111.75,111.14,108.39,39.27,13.83.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝3.606min,calcd.C20H17N5O3,[M+H]+m/z:376.14,found:376.14.
实施例23
Figure BDA0002777472910000161
将实施例1步骤1)中的苯甲醛换作5-甲基-2呋喃甲醛，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.72(s,1H),7.66(d,J＝7.4Hz,2H),7.60(t,J＝7.4Hz,2H),7.55(d,J＝7.0Hz,1H),7.50(d,J＝8.5Hz,2H),6.87(d,J＝3.1Hz,1H),6.75(t,J＝5.3Hz,1H),6.54(d,J＝8.6Hz,2H),6.25(d,J＝2.4Hz,1H),4.51(d,J＝5.5Hz,2H),2.35(s,4H).13C NMR(101MHz,DMSO-d6,ppm)δ165.26,154.76,154.42,150.75,146.22,144.54,137.19,130.05,129.64,128.67,125.13,120.83,112.25,111.76,110.17,39.27.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝3.894min,calcd.C21H19N5O3,[M+H]+m/z:390.16,found:390.15.
实施例24
Figure BDA0002777472910000162
将实施例1步骤1)中的苯甲醛换作5-溴-2呋喃甲醛，其余与实施例1相同。收率82％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(s,1H),7.67(d,J＝7.3Hz,2H),7.63–7.55(m,3H),7.50(d,J＝8.6Hz,2H),7.04(d,J＝3.5Hz,1H),6.77(d,J＝3.5Hz,1H),6.75(s,1H),6.53(d,J＝8.7Hz,2H),4.52(d,J＝3.7Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ165.22,155.03,153.48,150.70,148.20,137.06,130.07,129.77,128.68,125.19,123.35,120.87,114.34,112.68,111.75,39.26.LC-MS(ESI；C18 column；column size2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.196min,calcd.C20H16BrN5O3,[M+H]+m/z:454.05,found:454.03.
实施例25
Figure BDA0002777472910000171
将实施例1步骤1)中的苯甲醛换作2-吡啶甲醛，其余与实施例1相同。收率85％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(s,1H),8.68(d,J＝4.4Hz,1H),8.10(d,J＝7.9Hz,1H),7.98–7.90(m,1H),7.71(d,J＝7.4Hz,2H),7.62(t,J＝7.4Hz,2H),7.57(d,J＝7.1Hz,1H),7.53(t,J＝7.4Hz,2H),7.46(dd,J＝6.9,5.2Hz,1H),6.77(t,J＝5.4Hz,1H),6.59(d,J＝8.6Hz,2H),4.57(d,J＝5.5Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ165.27,160.93,155.01,150.82,150.18,149.67,137.59,137.38,130.06,129.67,128.67,125.15,124.73,122.21,120.80,111.80,39.38.LC-MS(ESI；C18 column；column size2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝3.241min,calcd.C21H18N6O2,[M+H]+m/z:387.16,found:387.14.
实施例26
Figure BDA0002777472910000172
将实施例1步骤1)中的苯甲醛换作3-吡啶甲醛，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),9.22(s,1H),8.71(s,2H),8.37(d,J＝7.9Hz,1H),7.71(d,J＝7.3Hz,2H),7.62(t,J＝7.3Hz,2H),7.58(d,J＝7.0Hz,1H),7.53(dd,J＝11.0,7.0Hz,3H),6.76(s,1H),6.58(d,J＝8.6Hz,2H),4.55(d,J＝3.8Hz,2H).13CNMR(101MHz,DMSO-d6,ppm)δ165.27,158.76,155.30,150.86,150.77,147.39,137.24,133.78,130.08,129.77,128.68,126.80,125.24,124.53,120.84,111.80.LC-MS(ESI；C18column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝3.027min,calcd.C21H18N6O2,[M+H]+m/z:387.16,found:387.14.
实施例27
Figure BDA0002777472910000181
将实施例1步骤1)中的苯甲醛换作4-吡啶甲醛，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.71(d,J＝4.2Hz,3H),7.96(d,J＝5.4Hz,2H),7.71(d,J＝7.3Hz,2H),7.65–7.56(m,3H),7.52(d,J＝8.4Hz,2H),6.76(t,J＝5.1Hz,1H),6.57(d,J＝8.5Hz,2H),4.56(d,J＝5.3Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ165.25,158.96,155.64,150.98,150.74,137.97,137.17,130.10,129.91,128.68,125.30,120.87,120.52,111.78,29.49.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝2.738min,calcd.C21H18N6O2,[M+H]+m/z:387.16,found:387.15.
实施例28
Figure BDA0002777472910000182
将实施例1步骤1)中的苯甲醛换作喹啉6-甲醛，其余与实施例1相同。收率85％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.94(d,J＝2.7Hz,1H),8.70(s,1H),8.55(d,J＝8.5Hz,1H),8.42(dd,J＝8.8,1.7Hz,1H),8.13(d,J＝8.8Hz,1H),7.74(d,J＝7.5Hz,1H),7.63(t,J＝7.5Hz,1H),7.59(dd,J＝7.5,3.1Hz,1H),7.52(d,J＝8.6Hz,1H),6.79(s,1H),6.60(d,J＝8.7Hz,1H),4.58(d,J＝5.2Hz,1H).LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formicacid):t＝3.357min,calcd.C25H20N6O2,[M+H]+m/z:437.17,found:437.17.
实施例29
Figure BDA0002777472910000183
将实施例1步骤1)中的苯肼换作4-氟苯肼，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.78(s,1H),8.69(s,1H),8.05(d,J＝7.2Hz,2H),7.74(dd,J＝8.8,4.7Hz,2H),7.53(s,1H),7.50(d,J＝5.8Hz,2H),7.48–7.45(m,2H),7.43(d,J＝8.4Hz,1H),6.70(t,J＝5.7Hz,1H),6.57(d,J＝8.3Hz,2H),4.53(d,J＝5.3Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.76,163.09,160.65,160.33,154.54,150.26,133.37,133.34,130.38,129.45,128.80,128.16,127.19,127.10,125.88,120.32,116.50,116.27,111.28,38.83.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.269min,calcd.C22H18FN5O2,[M+H]+m/z:404.15,found:404.18.
实施例30
Figure BDA0002777472910000191
将实施例1步骤1)中的苯肼换作2-氯苯肼，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.76(s,1H),8.67(s,1H),8.16–7.97(m,2H),7.75(d,J＝8.1Hz,1H),7.68(d,J＝7.7Hz,1H),7.62(d,J＝7.8Hz,1H),7.56(d,J＝7.6Hz,1H),7.49(d,J＝1.9Hz,2H),7.47(s,3H),6.63(s,1H),6.49(d,J＝8.4Hz,2H),4.39(s,2H).13CNMR(101MHz,DMSO-d6,ppm)δ164.76,160.74,155.84,150.15,134.28,131.91,130.66,130.35,130.30,129.52,129.49,128.82,128.36,128.10,125.88,120.25,111.15,38.59.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.266min,calcd.C22H18ClN5O2,[M+H]+m/z:420.12,found:420.13.
实施例31
Figure BDA0002777472910000192
将实施例1步骤1)中的苯肼换作4-溴苯肼，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.78(s,1H),8.05(d,J＝7.2Hz,2H),7.79(d,J＝8.2Hz,2H),7.65(d,J＝8.2Hz,2H),7.53(s,1H),7.50(d,J＝5.9Hz,2H),7.47(d,J＝3.0Hz,2H),6.59(d,J＝8.3Hz,2H),4.56(s,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.75,160.49,154.57,150.26,136.20,132.45,130.27,129.52,128.82,128.16,126.60,125.92,121.94,120.37,111.33,38.97.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.663min,calcd.C22H18BrN5O2,[M+H]+m/z:464.07,found:464.05.
实施例32
Figure BDA0002777472910000201
将实施例1步骤1)中的苯肼换作4-氯苯肼，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(s,1H),8.09–7.98(m,2H),7.72(d,J＝8.2Hz,2H),7.66(d,J＝8.3Hz,2H),7.53(s,1H),7.52–7.48(m,2H),7.47(d,J＝3.2Hz,2H),6.72(s,1H),6.60–6.47(m,2H),4.56(d,J＝5.4Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.74,160.46,154.59,150.25,135.78,133.46,130.27,129.52,128.83,128.16,126.37,125.91,120.34,111.30,38.94.LC-MS(ESI；C18 column；column size2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.577min,calcd.C22H18ClN5O2,[M+H]+m/z:420.12,found:420.15.
实施例33
Figure BDA0002777472910000202
将实施例1步骤1)中的苯肼换作3-氯苯肼，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.81(s,1H),8.70(s,1H),8.15–7.95(m,2H),7.82(s,1H),7.70(s,1H),7.63(d,J＝4.5Hz,2H),7.55(s,1H),7.52(d,J＝6.7Hz,2H),7.49(d,J＝2.8Hz,2H),6.73(t,J＝5.7Hz,1H),6.61(d,J＝8.3Hz,2H),4.60(d,J＝5.4Hz,2H).13CNMR(101MHz,DMSO-d6,ppm)δ164.76,160.51,154.70,150.26,138.12,133.71,131.13,130.23,129.56,128.98,128.82,128.17,125.95,124.55,123.30,120.37,111.33,38.99.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.595min,calcd.C22H18ClN5O2,[M+H]+m/z:420.12,found:420.15.
实施例34
Figure BDA0002777472910000211
将实施例1步骤1)中的苯肼换作4-甲基苯肼，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.78(s,1H),8.69(s,1H),8.05(d,J＝7.3Hz,2H),7.59–7.55(m,2H),7.53(d,J＝2.0Hz,1H),7.52–7.49(m,2H),7.48–7.44(m,2H),7.40(d,J＝8.0Hz,2H),6.74(d,J＝6.7Hz,1H),6.68–6.46(m,2H),4.50(d,J＝4.2Hz,2H),2.41(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.79,160.26,154.22,150.34,138.75,134.49,130.52,129.92,129.36,128.78,128.17,125.85,124.52,120.29,111.29,38.81,20.68.LC-MS(ESI；C18column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.457min,calcd.C23H21N5O2,[M+H]+m/z:400.18,found:400.19.
实施例35
Figure BDA0002777472910000212
将实施例1步骤1)中的苯肼换作对三氟甲基苯肼，其余与实施例1相同。收率82％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.69(s,1H),8.12–8.01(m,2H),7.95(d,J＝2.6Hz,4H),7.53(d,J＝2.4Hz,1H),7.51(s,2H),7.48(d,J＝2.7Hz,2H),6.73(t,J＝5.7Hz,1H),6.60(d,J＝8.3Hz,2H),4.64(d,J＝5.4Hz,2H).13C NMR(101MHz,DMSO-d6,ppm)δ164.74,160.70,154.89,150.24,140.14,130.12,129.65,128.85,128.15,126.74,126.70,125.98,125.05,122.47,120.43,111.37,39.19.LC-MS(ESI；C18 column；column size2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.820min,calcd.C23H18F3N5O2,[M+H]+m/z:454.15,found:454.13.
实施例36
Figure BDA0002777472910000221
将实施例1步骤1)中的苯肼换作2-甲基苯肼，其余与实施例1相同。收率85％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.85(s,1H),8.79(s,1H),8.03(dd,J＝8.1,1.6Hz,2H),7.51(s,2H),7.49(d,J＝3.4Hz,2H),7.47(d,J＝7.3Hz,3H),7.45–7.43(m,1H),7.40(dd,J＝7.4,1.8Hz,1H),6.68(t,J＝5.8Hz,1H),6.57–6.39(m,2H),4.35(d,J＝5.7Hz,2H),2.03(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.74,160.38,155.20,150.26,135.81,135.13,131.19,130.58,130.07,129.35,128.80,128.13,127.18,126.89,125.80,120.05,111.07,38.30,16.95.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.261min,calcd.C23H21N5O2,[M+H]+m/z:400.18,found:400.21.
实施例37
Figure BDA0002777472910000222
将实施例1步骤1)中的苯肼换作3-甲基苯肼，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ8.05(dd,J＝8.2,1.7Hz,2H),7.53(s,1H),7.51(s,2H),7.48(d,J＝2.4Hz,3H),7.47(d,J＝1.7Hz,2H),7.35(s,1H),6.76(t,J＝5.6Hz,1H),6.61–6.55(m,2H),4.53(d,J＝5.6Hz,2H),2.38(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.62,160.27,154.30,150.27,139.29,136.83,130.45,129.64,129.40,129.27,128.80,128.13,125.85,125.10,121.62,120.31,111.27,38.84,20.80.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formicacid):t＝4.459min,calcd.C23H21N5O2,[M+H]+m/z:400.18,found:400.18.
实施例38
Figure BDA0002777472910000231
将实施例1步骤1)中的苯肼换作4-甲氧基苯肼，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.81(s,1H),8.72(s,1H),8.11–7.94(m,2H),7.62–7.58(m,2H),7.53(s,1H),7.51(s,1H),7.48(d,J＝2.0Hz,1H),7.47–7.40(m,2H),7.18–7.05(m,2H),6.75(t,J＝5.6Hz,1H),6.57(d,J＝8.5Hz,2H),4.47(d,J＝5.5Hz,2H),3.84(s,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.77,160.11,159.51,154.25,150.33,130.55,129.78,129.33,128.78,128.17,126.33,125.81,120.20,114.56,111.25,55.53,38.67.LC-MS(ESI；C18column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.229min,calcd.C23H21N5O3,[M+H]+m/z:416.18,found:416.21.
实施例39
Figure BDA0002777472910000232
将实施例1步骤1)中的苯肼换作4-甲氧基苯肼，苯甲醛换作对羟基苯甲醛，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),10.01(s,1H),8.70(s,1H),8.01–7.84(m,2H),7.53–7.49(m,2H),7.46–7.42(m,2H),7.28(d,J＝7.8Hz,2H),6.96–6.84(m,2H),6.71(s,1H),6.57(d,J＝8.3Hz,2H),4.48(dd,J＝48.9,5.5Hz,2H),2.34(s,3H).13CNMR(101MHz,DMSO-d6,ppm)δ164.78,160.05,157.97,153.98,150.35,138.71,129.32,128.37,128.16,127.93,126.39,125.74,120.16,115.75,111.23,38.60,20.92.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝3.981min,calcd.C23H21N5O4,[M+H]+m/z:432.17,found:432.17.
实施例40
Figure BDA0002777472910000241
将实施例1步骤1)中的苯肼换作3,5-二甲基苯肼，其余与实施例1相同。收率82％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.82(s,1H),8.74(s,2H),8.03(dd,J＝8.2,1.5Hz,1H),7.52(s,3H),7.51–7.46(m,1H),7.44(d,J＝6.8Hz,2H),7.26(s,1H),7.16(s,1H),6.74(t,J＝5.5Hz,1H),6.57(d,J＝8.4Hz,2H),4.52(d,J＝5.6Hz,2H),2.46(d,J＝29.6Hz,6H).1H NMR(400MHz,DMSO-d6,ppm)δ10.82,8.74,8.05,8.04,8.02,8.02,7.52,7.50,7.50,7.48,7.48,7.46,7.45,7.43,7.26,7.16,6.75,6.74,6.73,6.58,6.56,4.53,4.51,2.33.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.725min,calcd.C24H23N5O2,[M+H]+m/z:414.20,found:414.22.
实施例41
Figure BDA0002777472910000242
将实施例1步骤1)中的苯肼换作3,4-二甲基苯肼，其余与实施例1相同。收率83％。
1H NMR(400MHz,DMSO-d6,ppm)δ8.13–7.98(m,2H),7.53(s,1H),7.50(dd,J＝8.6,2.2Hz,3H),7.46(d,J＝5.0Hz,2H),7.44(d,J＝2.4Hz,1H),7.35(d,J＝3.7Hz,1H),6.76(t,J＝5.6Hz,1H),6.58(d,J＝8.5Hz,2H),4.50(d,J＝5.6Hz,2H),2.30(d,J＝7.1Hz,6H).13CNMR(101MHz,DMSO-d6,ppm)δ164.68,160.16,154.18,150.30,137.82,137.52,134.60,130.49,130.21,129.36,128.79,128.13,125.82,125.49,121.85,120.22,111.28,38.78,19.29,19.04.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.670min,calcd.C24H23N5O2,[M+H]+m/z:414.20,found:414.21.
实施例42
Figure BDA0002777472910000251
将实施例1步骤1)中的苯肼换作4-异丙基苯肼，其余与实施例1相同。收率81％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.80(s,1H),8.70(s,1H),8.04(d,J＝7.0Hz,2H),7.60(d,J＝8.2Hz,2H),7.52(d,J＝8.6Hz,2H),7.47(t,J＝7.2Hz,4H),6.76(s,1H),6.56(t,J＝17.9Hz,2H),4.50(d,J＝5.0Hz,2H),1.26(d,J＝6.9Hz,6H).13C NMR(101MHz,DMSO-d6,ppm)δ164.76,160.24,154.17,150.34,149.43,134.72,130.50,129.38,128.80,128.16,127.34,125.83,124.59,120.25,111.30,33.12,23.71.LC-MS(ESI；C18 column；column size 2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formicacid):t＝4.976min,calcd.C25H25N5O2,[M+H]+m/z:428.21,found:428.24.
实施例43
Figure BDA0002777472910000252
将实施例1步骤1)中的苯肼换作4-乙基苯肼，其余与实施例1相同。收率84％。
1H NMR(400MHz,DMSO-d6,ppm)δ10.79(s,1H),8.70(d,J＝3.9Hz,1H),8.13–7.86(m,2H),7.59(d,J＝7.8Hz,2H),7.51(dd,J＝5.3,3.3Hz,2H),7.50–7.45(m,2H),7.43(d,J＝8.0Hz,3H),6.75(dd,J＝7.6,4.8Hz,1H),6.59(dd,J＝8.8,2.8Hz,2H),4.50(d,J＝5.4Hz,2H),2.71(q,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO-d6,ppm)δ164.76,160.25,154.20,150.34,144.89,134.66,130.50,129.37,128.79,128.77,128.16,125.84,124.59,120.26,111.29,27.75,15.38.LC-MS(ESI；C18 column；column size2.1mm×50mm；mobile phase 10％-95％,acetonitrile-water-0.1％Formic acid):t＝4.741min,calcd.C24H23N5O2,[M+H]+m/z:414.20,found:414.20.
试验例
HDAC1/6体外酶活性实验：
采用HDAC6荧光分析法对上述g-1～g-43化合物进行初步的体外酶活性测试，荧光分析法原理图如图1所示。该方法分为两步进行：(1)将具有荧光基团的HDAC6底物Ac-Gly-Ala-Lys-AMC、人重组蛋白HDAC6、待测化合物于37℃下孵育，释放出能够被Trypsin(胰酶)水解的活性底物Gly-Ala-Lys-AMC；(2)用Trypsin水解Ac-Gly-Ala-Lys-AMC，释放AMC荧光片段，在激发波长355nm/发射波长460nm下检测荧光强度，根据不同浓度待测化合物作用下测得的荧光强度计算抑制率(抑制率＝(最大反应信号-样品孔反应信号)/(最大反应信号-空白反应信号)％)。HDAC1与HDAC6的检测原理相同，以相同的方法测试HDAC1的体外酶活性测试。
HDAC1/6选择性实验：
选定各个化合物浓度为100μM时对HDAC6酶的抑制活性，对抑制率大于60％的化合物进一步进行HDAC6半数抑制浓度IC50筛选，HDAC1与HDAC6的检测原理相同，以相同方法测试待测化合物对HDAC1半数抑制浓度IC50。该方法同HDAC1/6体外酶活性实验。以被批准临床使用的伏立诺他(SAHA)作对照，实验结果采用GraphPad Prism软件进行计算、拟合，得到所测化合物对HDAC6(HDAC1)的IC50值，结果如表1所示。HDAC1/6选择性＝(HDAC1IC50/HDAC6IC50)。
表1
Figure BDA0002777472910000261
Figure BDA0002777472910000271
由表1可知，本发明提供的一种1,3-二芳基-1,2,4-三氮唑类化合物对HDAC6和HDAC1均有一定的抑制活性，但对HDAC6的抑制率明显高于HDAC1。如g-1、g-2、g-4、g-7、g-8、g-9、g-10、g-11、g-15、g-16、g-17、g-18、g-19、g-29、g-30、g-31、g-33、g-34、g-37、g-38、g-39等抑制活性较好，对HDAC6抑制率较高达60％以上。本发明提供的化合物对HDAC1的抑制率均偏低，抑制活性与HDAC6相比差别较大。
选择性实验结果显示相比于HDAC1，本发明提供的化合物能够高效且选择性地抑制HDAC6。其IC50值均在纳摩尔水平，表明用药后存活的细胞数量减少一半时所需药物浓度较低，有利于患者减少药物用量，降低化合物对人体的毒副作用。对HDAC亚型HDAC1的高选择性也有利于避免药物对人体正常组织发挥药效从而产生副作用。其中化合物g-1、g-2、g-4、g-7、g-8、g-9、g-10、g-11、g-15、g-16、g-17、g-18、g-19、g-29、g-30、g-33、g-34、g-37、g-38、g-39的选择性均优于临床药物SAHA。g-16、g-17、g-18、g-19等化合物对HDAC6的抑制活性优于临床药物SAHA。
本发明提供的1,3-二芳基-1,2,4-三氮唑类化合物能够显著地抑制HDAC6，且其IC50值较低，对其亚型HDAC1有高选择性，显示出良好的开发潜力，可作为潜在的抗癌药物进一步开发。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。

Claims (8)

1.一种1,3-二芳基-1,2,4-三氮唑类化合物，其特征在于，具有以下结构通式I：
Figure FDA0003538911770000011
R1与R2选自下列基团的一种或多种：
Figure FDA0003538911770000012
Figure FDA0003538911770000021
2.如权利要求1所述的1,3-二芳基-1,2,4-三氮唑类化合物的制备方法，其特征在于，包括以下步骤：
Figure FDA0003538911770000022
1)取代苯肼a与取代芳香醛b在醇水溶液中发生缩合反应，反应完成后冷却至室温，抽滤干燥得到化合物c；
2)将步骤1)得到的化合物c溶于有机溶剂中，经单质碘、叔丁基过氧化氢催化，与氨基乙醇发生反应得到化合物d；
3)将步骤2)得到的化合物d溶于有机溶剂中，经戴斯马丁氧化剂氧化，得到化合物e；
4)将步骤3)得到的化合物e溶于醇溶剂中，在酸催化以及氰基硼氢化钠作用下，与氨基苯甲酸甲酯发生反应，得到化合物f；
5)将步骤4)得到的化合物f溶于有机溶剂中，加入羟胺水溶液和碱，反应完成后用酸调节pH，抽滤干燥得到化合物g。
3.如权利要求2所述的1,3-二芳基-1,2,4-三氮唑类化合物的制备方法，其特征在于，步骤1)中使用的醇选自甲醇、乙醇中一种，步骤4)中使用的醇选自甲醇、乙醇、正丁醇、异丁醇中的一种。
4.如权利要求2所述的1,3-二芳基-1,2,4-三氮唑类化合物的制备方法，其特征在于，步骤2)中有机溶剂选自四氢呋喃、乙腈、乙酸乙酯、二氧六环中的一种，步骤3)中有机溶剂选自四氢呋喃、乙腈、二氯甲烷、乙酸乙酯、二氧六环中的一种。
5.如权利要求2所述的含1,3-二芳基-1,2,4-三氮唑类化合物的制备方法，其特征在于，步骤4)或步骤5)中使用的酸选自甲酸、乙酸、三氟乙酸、稀盐酸中的一种。
6.如权利要求2所述的1,3-二芳基-1,2,4-三氮唑类化合物的制备方法，其特征在于，步骤5)中使用的有机溶剂选自二氯甲烷、甲醇、乙醇、乙酸乙酯、四氢呋喃、乙腈中的一种或两种。
7.如权利要求2所述的含1,3-二芳基-1,2,4-三氮唑类化合物的制备方法，其特征在于，步骤5)中使用的碱选自碳酸钾、碳酸钠、氢氧化钠、氢氧化钾中的一种。
8.如权利要求1所述的1,3-二芳基-1,2,4-三氮唑类化合物在制备选择性抑制HDAC6的药物中的应用。
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