CN115819425A - 一种三唑并六元氮杂环-2-胺类化合物及其制备方法和应用 - Google Patents
一种三唑并六元氮杂环-2-胺类化合物及其制备方法和应用 Download PDFInfo
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Images
Abstract
本发明公开了一种三唑并六元氮杂环‑2‑胺类化合物及其制备方法和应用。包括式A所示结构的化合物及其药学上可接受的盐，所述式A为：
其中，R选自如式B或式C所示的取代基；所述式B为：
所述式C为：
n为1～5的整数，R1选自氢、羟基、氰基、硝基、氨基、苄氧基、C1～20的烷基、C1～20的烷氧基、卤素、卤素取代的C1～20的烷氧基或卤素取代的C1～20的烷基中的至少一种；R2选自氢或C1～10的烷基；X、Y、Z、W选自碳原子或氮原子；本发明提出一种三唑并六元氮杂环‑2‑胺类化合物，该类化合物对肿瘤细胞具有较好的抗增殖活性。能有效抑制人非小细胞肺癌肿瘤的生成，并能同时靶向微管蛋白和JAK2。
Description
技术领域
本发明涉及药物化学技术领域，尤其是涉及一种三唑并六元氮杂环-2-胺类化合物及其制备方法和应用。
背景技术
肿瘤因其高发病率和高死亡率，严重威胁着当今人类的生命健康。肿瘤治疗仍是人类面临的巨大挑战之一。癌症是复杂性疾病，其发生及发展受多种复杂的信号网络调控和影响。目前，由于肿瘤的异质性和耐药性的问题，单独使用一种药物往往难以取得较好的治疗效果。传统的化疗联合用药在临床上取得一定的成效，但联合用药所引起的药物相互作用常引发不良反应，甚至出现毒性反应。相比联合用药，多靶点药物能够作用于肿瘤的具有内在联系的多个靶点，阻断多条肿瘤增殖信号通路，能够协同提高治疗效果以及克服肿瘤耐药，同时产生更小的不良反应。
靶向微管蛋白的小分子化合物在肿瘤化疗方面显示出了显著的临床疗效，但现有的靶向微管蛋白药物存在耐药性出现、毒副作用大以及结构复杂合成难度大等问题。因此，迫切需要寻找新的微管蛋白抑制剂来克服多药耐药并减轻不良反应，以期获得理想的治疗效果。Janus激酶2(JAK2)是一种非受体酪氨酸激酶，介导JAK2/STAT等多种信号通路传导，参与细胞的增殖、分化以及免疫调节等许多重要的生物学过程。研究表明，微管蛋白作为JAK2激酶的底物，参与JAK2/STAT1依赖的信号转导。微管蛋白和JAK2在肿瘤细胞增殖中起着十分重要的作用，是极具潜力的抗肿瘤药物靶点。
因此，基于多靶点药物的优势，有必要提供一种新的化合物能同时靶向微管蛋白和JAK2，为肿瘤治疗提供更多的选择。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明第一方面提出一种三唑并六元氮杂环-2-胺类化合物，能同时靶向微管蛋白和JAK2。
本发明第二方面还提供一种三唑并六元氮杂环-2-胺类化合物的制备方法。
本发明第三方面还提供三唑并六元氮杂环-2-胺类化合物的应用。
本发明第四方面还提供一种药物组合物。
本发明第五方面还提供一种抗肿瘤药物。
根据本发明的第一方面实施例提供一种三唑并六元氮杂环-2-胺类化合物，包括式A所示结构的化合物及其药学上可接受的盐，所述式A为：
其中，R选自如式B或式C所示的取代基；
所述式B为：
所述式C为：
其中：
n为1～5的整数，R1选自氢、羟基、氰基、硝基、氨基、苄氧基、C1～20的烷基、C1～20的烷氧基、卤素、卤素取代的C1～20的烷氧基或卤素取代的C1～20的烷基中的至少一种；
R2选自氢或C1～10的烷基；
X、Y、Z、W选自碳原子或氮原子；
D环表示存在或不存在，若D环存在时，则D环表示取代或未取代的苯基。
根据本发明实施例的三唑并六元氮杂环-2-胺类化合物，至少具有如下有益效果：
本发明提出一种三唑并六元氮杂环-2-胺类化合物，该类化合物对肿瘤细胞具有较好的抗增殖活性。经进一步证实，其能有效抑制人非小细胞肺癌肿瘤的生成，能同时靶向微管蛋白和JAK2。本发明对增强药物的特异性、有效性以及克服耐药具有重要意义。
根据本发明的一些实施例，R1选自C1～10的烷基、C1～10的烷氧基、卤素取代的C1～10的烷氧基或卤素取代的C1～10的烷基中的至少一种。
根据本发明的一些实施例，R1选自C1～5的烷氧基。
根据本发明的一些实施例，所述三唑并六元氮杂环-2-胺类化合物选自如下结构式中的至少一种：
根据本发明的第二方面实施例提供一种三唑并六元氮杂环-2-胺类化合物的制备方法，包括以下步骤：
将式I化合物与式II化合物或式III化合物在催化剂、配体和溶剂存在下进行反应，其中式I化合物与式II化合物和式III化合物的结构式如下：
本发明的三唑并六元氮杂环-2-胺类化合物的制备方法，至少具有以下有益效果：
本发明的三唑并六元氮杂环-2-胺类化合物的制备方法简单，反应条件温和、无需添加额外的氧化还原剂，且绿色环保，价格低廉，方法简单、收率高，适用工业化生产。
根据本发明的一些实施例，所述溶剂包括1,4-二氧六环和甲苯中的至少一种。
根据本发明的一些实施例，所述催化剂包括钯盐。
根据本发明的一些实施例，所述钯盐包括醋酸钯、三(二亚苄基丙酮)二钯中的至少一种。
根据本发明的一些实施例，所述反应中还加入了碱。
根据本发明的一些实施例，所述碱包括叔丁醇钠、叔丁醇钾、碳酸铯中的至少一种。
根据本发明的一些实施例，所述配体包括联芳基膦类配体。
根据本发明的一些实施例，所述联芳基膦类配体包括BrettPhos(2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯，CAS号：1070663-78-3)、X-Phos(2-二环己基磷-2,4,6-三异丙基联苯，CAS号：564483-18-7)中的至少一种。
根据本发明的一些实施例，所述式I化合物、式II化合物或式III化合物、催化剂、配体的摩尔比为1：1～3：0.01～0.3：0.03～0.9。
根据本发明的一些实施例，所述反应的温度为100℃～115℃。
根据本发明的一些实施例，所述反应的时间为10h～72h。
本发明第三方面还提供一种上述所述的三唑并六元氮杂环-2-胺类化合物在制备治疗和/或预防肿瘤疾病药物中的应用。
根据本发明的一些实施例，所述三唑并六元氮杂环-2-胺类化合物同时靶向微管蛋白和JAK2。
本发明第四方面还提供一种药物组合物，包括如上述所述的三唑并六元氮杂环-2-胺类化合物或其药学上可接受的盐，和药学上可接受的辅料。
本发明第五方面还提供一种抗肿瘤药物，所述抗肿瘤药物包括如上述所述的三唑并六元氮杂环-2-胺类化合物或如上述所述的药物组合物。
定义和一般术语
“C1～20的烷基”表示碳原子总数为1～20的烷基，包括C1～20的直链烷基、C1～20的支链烷基和C3-20的环烷基，例如可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、甲基环丙基、乙基环丙基、环戊基、甲基环戊基、环己基等。针对“C1～10的烷基”具有与此相似的解释，所不同的是，碳原子数不同。
“卤素取代的C1～20的烷基”与“C1-20的烷基”的定义相似，所不同的是，“卤素取代的C1～20的烷基”中的任意一个或多个H原子由任意的卤素取代。
“C1～20的烷氧基”表示碳原子总数为1-20的烷氧基，包括C1-20的直链烷氧基、C1-20的支链烷氧基和C2-20的环烷氧基，例如可以为甲氧基、乙氧基、正丙氧基、异丙氧基等。针对“C1-10的烷氧基”、“C1-5的烷氧基”具有与此相似的解释，所不同的是，碳原子数不同。
“卤素取代的C1～20的烷氧基”与“C1-20的烷氧基”的定义相似，所不同的是，“卤素取代的C1～20的烷氧基”中的任意一个或多个H原子由任意的卤素取代。
“卤素”包括氟、氯、溴、碘中的任意一个或两个以上。
“取代或未取代的苯基”表示苯基中有至少一个H被本文定义的相应基团所取代。可以任选地被烷基、烷氧基、、羟基、氰基、硝基、氨基、苄氧基取代。
“药学上可接受的辅料”包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂、固体粘合剂、助流剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：InRemington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of PharmaceuticalTechnology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。
“药学上可接受的盐”包括其药学上可接受的盐、酯、水合物、溶剂化物、结晶形式、对映异构体、立体异构体、醚、代谢物和前药。
药学上可接受的盐，包括但不仅限于无机酸盐和有机酸盐中的至少一种。
具体地，其包括盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、碳酸盐、碳酸氢盐、亚硫酸盐、亚硫酸氢盐、焦硫酸盐、磷酸一氢盐、磷酸二氢盐、高氯酸盐、过硫酸盐、半硫酸盐、重硫酸盐、硫氰酸盐、磷酸盐、焦磷酸盐、偏磷酸盐；适宜的有机酸盐包括，但不限于：甲酸盐、乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、丙酮酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、柠檬酸盐、4-硝基苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、丙炔酸盐、2-丁炔酸盐、2-羟基-乙烷磺酸盐、乙烯基乙酸盐、酒石酸盐、L-酒石酸盐、富马酸盐、羟乙基磺酸盐、马来酸盐、乳酸盐、乳糖酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚糖酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、草酸盐、三氟乙酸盐、三氟甲磺酸盐、己二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、羟基乙酸盐、藻酸盐、抗坏血酸盐、异抗坏血酸盐、天冬氨酸盐、L-天冬氨酸盐、谷氨酸盐、L-谷氨酸盐、2-苯氧基苯甲酸盐、2-(4-羟基苯甲酰)苯甲酸盐、乙酰乙酸盐、2-羟基乙磺酸盐、苯磺酸盐、硼酸盐、氯代苯甲酸盐、樟脑酸盐、衣康酸盐、樟脑磺酸盐、左旋樟脑磺酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、氨基磺酸盐、乳糖醛酸盐、半乳糖醛酸盐、环戊基丙酸盐、十二烷基硫酸盐、丙烯酸盐、环戊烷丙酸盐、甘油磷酸盐、甲氧基苯甲酸盐、二葡萄糖酸盐、葡萄糖酸盐、庚酸盐、己酸盐、2-羟基-乙磺酸盐、三甲基乙酸盐、葡糖醛酸盐、月桂酸盐、邻苯二甲酸盐、苯乙酸盐、月桂基硫酸盐。
本发明化合物或其药学上可接受的盐或药物组合物可以是以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明的其它特征和优点将在随后的说明书中阐述，并且，部分地从说明书中变得显而易见，或者通过实施本发明而了解。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1是化合物的微管蛋白聚集抑制活性图。
具体实施方式
以下是本发明的具体实施例，并结合实施例对本发明的技术方案作进一步的描述，但本发明并不限于这些实施例。
本发明所采用的试剂、方法和设备，如无特殊说明，均为本技术领域常规试剂、方法和设备。
在本发明的实施方式中5-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺的CAS号为1010120-55-4；3,4,5-三甲氧基苯硼酸的CAS号为182163-96-8；四三苯基膦钯的CAS号为14221-01-3；碳酸钾的CAS号为584-08-7；N，N-二甲基甲酰胺的CAS号为2914-27-4；2-氯-4-甲氧基嘧啶的CAS号为22536-63-6；盐酸的CAS号为7647-01-0；三氯氧磷的CAS号为10025-87-3；甲苯的CAS号为108-88-3；水合肼的CAS号为7803-57-8；甲醇的CAS号为67-56-1；溴化氰的CAS号为506-68-3；6-氯吡嗪-2-胺的CAS号为33332-28-4；乙氧羰基异硫氰酸酯的CAS号为16182-04-0；1,4-二氧六环的CAS号为123-91-1；盐酸羟胺的CAS号为5470-11-1；DIPEA(N,N-二异丙基乙胺)的CAS号为7087-68-5；乙醇的CAS号为64-17-5；1-(3,4,5-三甲氧基苯基)乙-1-酮的CAS号为1136-86-3；1,1-二甲氧基-N,N-二甲基甲胺的CAS号为4637-24-5；1H-[1,2,4]三唑-3,5-二胺的CAS号为1455-77-2；醋酸的CAS号为64-19-7；醋酸钯的CAS号为3375-31-3；BrettPhos(2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)的CAS号为1070663-78-3；叔丁醇钠的CAS号为865-48-5。
其余所用试剂或仪器未标明生产厂商的，均为可通过正规渠道商购获得的常规产品。
在本发明的实施方式中未注明具体技术或条件的，按照本领域内的文献所描述的技术和条件，或者按照产品说明书进行。
下面实施例1至42中使用的三唑并六元氮杂环-2-胺原料，结构式包括：
5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-1)可通过如下方法制备得到：
步骤S1-1：5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-1)的制备：
取50mL反应管，分别加入5-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺(1.0mmol)，3,4,5-三甲氧基苯硼酸(1.1mmol)，四三苯基膦钯(0.1mmol)，碳酸钾(3.0mmol)以及N,N-二甲基甲酰胺(4mL)和水(1mL)，氮气保护下120℃反应12h。反应结束后加入二氯甲烷20mL淬灭反应，加入10mL饱和食盐水洗涤，分出有机相，水相再用二氯甲烷萃取3次，每次二氯甲烷用量为10mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(石油醚:乙酸乙酯＝3:1)，得到产物I-1，产率88％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,Chloroform-d)δ7.49–7.46(m,1H),7.42(dd,J＝8.7,1.4Hz,1H),7.13(s,2H),6.92(dd,J＝7.2,1.4Hz,1H),4.55(s,2H),3.94(m,9H).
5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺(I-2)可通过如下方法制备得到：
步骤S2-1：4-甲氧基-2-(3,4,5-三甲氧基苯基)嘧啶的制备：
取100mL反应瓶，分别加入2-氯-4-甲氧基嘧啶(10.0mmol)，3,4,5-三甲氧基苯硼酸(11.0mmol)，四三苯基膦钯(1.0mmol)，碳酸钾(30.0mmol)以及N,N-二甲基甲酰胺(30mL)和水(7.5mL)，氮气保护下120℃反应12h。反应结束后加入二氯甲烷50mL淬灭反应，加入50mL饱和食盐水洗涤，分出有机相，水相再用二氯甲烷萃取3次，每次二氯甲烷用量为100mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(石油醚:乙酸乙酯＝6:1)，得到产物2-1，产率86％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,Chloroform-d)δ8.44(d,J＝5.7Hz,1H),7.72(s,2H),6.56(d,J＝5.7Hz,1H),4.04(s,3H),3.94(s,6H),3.89(s,3H)；
步骤S2-2：4-氯-2-(3,4,5-三甲氧基苯基)嘧啶的制备：
取100mL反应瓶，加入4-甲氧基-2-(3,4,5-三甲氧基苯基)嘧啶(8.0mmol)和水(24mL)，搅拌下缓慢滴加37％盐酸(8mL),100℃反应6h。反应结束后过滤反应物，所得滤饼干燥后置于100mL反应瓶中，加入24mL甲苯，并在搅拌下缓慢滴加三氯氧磷(8mL)，110℃反应6h。反应结束后加入饱和碳酸氢钠调节pH至中性，加入二氯甲烷萃取3次，每次二氯甲烷用量为100mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(石油醚:乙酸乙酯＝6:1)，得到产物2-2，产率81％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,Chloroform-d)δ8.57(d,J＝5.2Hz,1H),7.69(s,2H),7.15(d,J＝5.3Hz,1H),3.94(s,6H),3.90(s,3H)；
步骤S2-3：4-肼基-2-(3，4，5-三甲氧基苯基)嘧啶的制备：
取100mL反应瓶，加入4-氯-2-(3,4,5-三甲氧基苯基)嘧啶(6.0mmol)和甲醇(20mL)，搅拌下缓慢滴加50％水合肼(6mL),70℃反应10h。反应结束后经减压蒸馏除去溶剂，加入40mL饱和食盐水洗涤，加入二氯甲烷萃取3次，每次二氯甲烷用量为80mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(二氯甲烷:甲醇＝50:1)，得到产物2-3，产率90％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.21(s,1H),7.68(s,2H),6.63(s,1H),4.46(s,2H),3.85(s,6H),3.72(s,3H)；
步骤S2-4：5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺(I-2)的制备：
取100mL反应瓶，加入4-肼基-2-(3，4，5-三甲氧基苯基)嘧啶(5.0mmol)、溴化氰(8.5mmol)和甲醇(30mL)，70℃反应4h。反应结束后加入饱和碳酸氢钠调节pH至碱性，减压蒸馏除去甲醇，加入二氯甲烷萃取3次，每次二氯甲烷用量为60mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(二氯甲烷:甲醇＝50:1)，得到产物I-2，产率63％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,Chloroform-d)δ8.22(d,J＝5.9Hz,1H),7.89(s,2H),7.28(d,J＝6.0Hz,1H),4.77(s,2H),3.97(s,6H),3.94(s,3H).
5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]吡嗪-2-胺(I-3)可通过如下方法制备得到：
步骤S3-1：5-氯-[1,2,4]三唑并[1,5-a]吡嗪-2-胺的制备：
取100mL反应瓶，加入6-氯吡嗪-2-胺(5.0mmol)和1,4-二氧六环(20mL)，搅拌下缓慢滴加乙氧羰基异硫氰酸酯(5.0mmol),氮气保护下室温反应18h。反应结束后经减压蒸馏除去溶剂，过滤反应物，所得滤饼干燥后置于100mL反应瓶中，加入盐酸羟胺(25mmol)、二异丙基乙胺(15mmol)、甲醇和乙醇各10mL，氮气保护下60℃反应18h。反应结束后将反应物冷却至室温，过滤反应物，滤饼用甲醇和水洗涤得到产物3-1，产率53％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,Chloroform-d)δ8.84(s,1H),8.11(s,1H),4.91(s,2H).
步骤S3-2：5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]吡嗪-2-胺(I-3)的制备：
取50mL反应管，分别加入5-氯-[1,2,4]三唑并[1,5-a]吡嗪-2-胺(2.0mmol)，3,4,5-三甲氧基苯硼酸(2.2mmol)，四三苯基膦钯(0.2mmol)，碳酸钾(6.0mmol)以及N,N-二甲基甲酰胺(8mL)和水(2mL)，氮气保护下120℃反应12h。反应结束后加入二氯甲烷20mL淬灭反应，加入20mL饱和食盐水洗涤，分出有机相，水相再用二氯甲烷萃取3次，每次二氯甲烷用量为20mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(二氯甲烷:甲醇＝50:1)，得到产物I-3，产率70％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.27(s,1H),7.40(s,2H),6.52(s,2H),3.86(s,6H),3.76(s,3H).
7-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]嘧啶-2-胺(I-4)可通过如下方法制备得到：
步骤S4-1：(E)-3-(二甲氨基)-1-(3，4，5-三甲氧基苯基)丙-2-烯-1-酮的制备：
取50mL反应瓶，分别加入1-(3,4,5-三甲氧基苯基)乙-1-酮(4mmol)，1,1-二甲氧基-N,N-二甲基甲胺(8mL)，100℃反应10h。反应结束后加入水10mL淬灭反应，加入20mL乙酸乙酯，分出有机相，水相再用乙酸乙酯萃取3次，每次乙酸乙酯用量为20mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(石油醚:乙酸乙酯＝2:1)，得到产物4-1，产率56％。
步骤S4-2：7-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]嘧啶-2-胺(I-4)的制备：
取50mL反应瓶，加入(E)-3-(二甲氨基)-1-(3，4，5-三甲氧基苯基)丙-2-烯-1-酮(2.0mmol)、1H-[1,2,4]三唑-3,5-二胺(4.0mmol)和醋酸(5mL)，120℃反应10h。反应结束后过滤反应物，所得滤饼用乙醇和水洗涤得到产物I-4，产率80％。
取上述中间体进行NMR表征，表征数据如下：
1H NMR(500MHz,DMSO-d6)δ8.52(d,J＝4.9Hz,1H),7.56(s,2H),7.35(d,J＝4.9Hz,1H),6.45(s,2H),3.88(s,6H),3.77(s,3H).
实施例制备通法
若无特殊说明，以下所有实施例均由如下方法制备得到：
具体制备过程：
取50mL反应管，分别加入三唑并六元氮杂环-2-胺(0.20mmol)、溴芳基化合物(0.22mmol)、醋酸钯(0.03mmol)、2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(0.09mmol)、叔丁醇钠(0.4mmol)以及1,4-二氧六环(3mL)，氮气保护下105℃反应24h。反应结束后加入二氯甲烷10mL淬灭反应，加入10mL饱和食盐水洗涤，分出有机相，水相再用二氯甲烷萃取3次，每次二氯甲烷用量为10mL，合并有机相，加入无水硫酸钠干燥，经减压蒸馏除去溶剂得到粗产物。粗产物经硅胶柱层析法纯化(二氯甲烷:甲醇＝50:1)，得到产物，产率32％-85％。
实施例1
本实施例制备了如下式所示的N-(邻甲苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ8.91(s,1H),8.28(d,J＝6.0Hz,1H),8.09(s,2H),7.89(d,J＝7.9Hz,1H),7.49(d,J＝6.0Hz,1H),7.20(d,J＝7.4Hz,1H),7.17–7.12(m,1H),7.02–6.97(m,1H),3.82(s,6H),3.76(s,3H),2.32(s,3H)；13C NMR(125MHz,DMSO-d6)δ163.8,153.3,152.3,146.3,144.4,140.3,138.5,130.5,129.6,126.3,126.1,123.3,121.5,107.5,106.8,60.2,55.9,18.1；HR-ESI-MS for C21H21N5O3([M+H]+)Calcd:392.1717；Found:392.1723.
实施例2
本实施例制备了如下式所示的N-(4-(叔丁基)苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.85(s,1H),8.31(d,J＝6.1Hz,1H),8.14(s,2H),7.67–7.63(m,2H),7.53(d,J＝6.0Hz,1H),7.32–7.28(m,2H),3.93(s,6H),3.80(s,3H),1.27(s,9H)；13C NMR(125MHz,DMSO-d6)δ162.7,152.9,152.4,146.5,144.6,143.4,140.4,138.1,126.5,125.3,117.1,107.6,106.9,60.3,55.9,33.9,31.3；HR-ESI-MS for C24H27N5O3([M+H]+)Calcd:434.2187；Found:434.2181.
实施例3
本实施例制备了如下式所示的N-(4-氟苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.01(s,1H),8.34(d,J＝6.1Hz,1H),8.10(s,2H),7.77–7.72(m,2H),7.56(d,J＝6.1Hz,1H),7.19–7.13(m,2H),3.92(s,6H),3.80(s,3H)；13CNMR(125MHz,DMSO-d6)δ162.5,156.9(C-F,1JC-F＝237.2Hz),153.0,152.5,146.7,144.7,140.4,137.1,126.5,118.5(C-F,3JC-F＝7.8Hz),115.4(C-F,2JC-F＝22.1Hz),107.6,107.1,60.3,56.0；HR-ESI-MS for C20H18FN5O3([M+H]+)Calcd:396.1466；Found:396.1463.
实施例4
本实施例制备了如下式所示的N-(4-溴苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.15(s,1H),8.34(d,J＝6.0Hz,1H),8.07(s,2H),7.72–7.68(m,2H),7.57(d,J＝6.0Hz,1H),7.48–7.44(m,2H),3.92(s,6H),3.81(s,3H)；13CNMR(125MHz,DMSO-d6)δ162.2,152.9,152.5,146.7,144.8,140.5,140.0,131.5,126.4,118.9,112.3,107.6,107.2,60.3,56.0；HR-ESI-MS for C20H18BrN5O3([M+H]+)Calcd:456.0666；Found:456.0658.
实施例5
本实施例制备了如下式所示的N-(4-氯苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.15(s,1H),8.35(d,J＝6.0Hz,1H),8.07(s,2H),7.77–7.74(m,2H),7.58(d,J＝6.1Hz,1H),7.36–7.33(m,2H),3.92(s,6H),3.81(s,3H)；13CNMR(125MHz,DMSO-d6)δ162.2,152.9,152.5,146.7,144.8,140.5,139.6,128.6,126.4,124.4,118.5,107.6,107.2,60.3,56.0；HR-ESI-MS for C20H18ClN5O3([M+H]+)Calcd:412.1171；Found:412.1162.
实施例6
本实施例制备了如下式所示的N-(4-(三氟甲氧基)苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.20(s,1H),8.34(d,J＝6.0Hz,1H),8.07(s,2H),7.83–7.79(m,2H),7.58(d,J＝6.0Hz,1H),7.31(d,J＝8.6Hz,2H),3.91(s,6H),3.80(s,3H)；13CNMR(125MHz,DMSO-d6)δ162.3,153.0,152.5,146.8,144.8,142.0,140.5,140.0,126.4,121.9,120.3(C-F,1JC-F＝255.4Hz),118.2,107.6,107.2,60.3,56.0；HR-ESI-MSfor C21H18F3N5O4([M+H]+)Calcd:462.1384；Found:462.1384.
实施例7
本实施例制备了如下式所示的N-(4-(三氟甲基)苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.46(s,1H),8.37(d,J＝6.0Hz,1H),8.06(s,2H),7.91(d,J＝8.5Hz,2H),7.65(d,J＝8.5Hz,2H),7.62(d,J＝6.0Hz,1H),3.92(s,6H),3.81(s,3H)；13CNMR(125MHz,DMSO-d6)δ162.0,152.9,152.5,146.9,144.8,144.2,140.5,126.4,126.1(C-F,3JC-F＝4.0Hz),124.7(C-F,1JC-F＝271.1Hz),120.8(C-F,2JC-F＝32.0Hz),116.7,107.6,107.4,60.3,56.0；HR-ESI-MS for C21H18F3N5O3([M+H]+)Calcd:446.1435；Found:446.1432.
实施例8
本实施例制备了如下式所示的N-(4-甲氧基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.75(s,1H),8.30(d,J＝6.0Hz,1H),8.13(s,2H),7.65(d,J＝9.0Hz,2H),7.51(d,J＝6.0Hz,1H),6.88(d,J＝9.0Hz,2H),3.92(s,6H),3.80(s,3H),3.73(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.8,153.9,153.0,152.4,146.4,144.6,140.4,134.0,126.5,118.6,114.0,107.5,106.8,60.3,56.0,55.3；HR-ESI-MS forC21H21N5O4([M+H]+)Calcd:408.1666；Found:408.1666.
实施例9
本实施例制备了如下式所示的N-(4-氰基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.61(s,1H),8.38(d,J＝6.0Hz,1H),8.04(s,2H),7.87(d,J＝8.7Hz,2H),7.75(d,J＝8.7Hz,2H),7.63(d,J＝6.0Hz,1H),3.92(s,6H),3.81(s,3H)；13CNMR(125MHz,DMSO-d6)δ161.6,152.9,152.5,147.0,144.9,144.8,140.5,133.4,126.3,119.6,116.9,107.6,102.2,60.3,56.1；HR-ESI-MS for C21H18N6O3([M+H]+)Calcd:403.1513；Found:403.1511.
实施例10
本实施例制备了如下式所示的N-(2-溴苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ8.91(s,1H),8.34(d,J＝6.1Hz,1H),8.06(s,2H),8.02(dd,J＝8.1,1.6Hz,1H),7.68(dd,J＝8.1,1.5Hz,1H),7.57(d,J＝6.0Hz,1H),7.38(td,J＝7.7,1.5Hz,1H),7.07(td,J＝7.6,1.6Hz,1H),3.83(s,6H),3.77(s,3H)；13C NMR(125MHz,DMSO-d6)δ163.1,153.4,152.4,146.5,144.6,140.4,138.1,132.9,128.2,126.2,125.1,123.4,116.0,107.6,107.2,60.2,55.9；HR-ESI-MS for C20H18BrN5O3([M+H]+)Calcd:456.0666；Found:456.0666.
实施例11
本实施例制备了如下式所示的N-(3-溴苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.20(s,1H),8.35(d,J＝6.1Hz,1H),7.98(s,2H),7.96(t,J＝2.0Hz,1H),7.73(dd,J＝8.3,2.1Hz,1H),7.60(d,J＝6.1Hz,1H),7.25(t,J＝8.1Hz,1H),7.11(dd,J＝7.9,1.9Hz,1H),3.91(s,6H),3.80(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.0,152.8,152.5,147.1,144.8,142.3,140.4,130.7,126.5,123.4,122.0,119.1,115.8,107.5,107.3,60.3,56.1；HR-ESI-MS for C20H18BrN5O3([M+H]+)Calcd:456.0666；Found:456.0658.
实施例12
本实施例制备了如下式所示的N-(2-氟苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.60(s,1H),8.35(d,J＝6.0Hz,1H),8.16(td,J＝8.3,1.7Hz,1H),8.10(s,2H),7.59(d,J＝6.1Hz,1H),7.29–7.24(m,1H),7.17(td,J＝7.7,1.5Hz,1H),7.09–7.04(m,1H),3.88(s,6H),3.78(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.9,153.2,153.1(C-F,1JC-F＝244.6Hz),152.4,146.6,144.6,140.4,128.3(C-F,2JC-F＝11.8Hz),126.4,124.3(C-F,3JC-F＝3.6Hz),123.2(C-F,3JC-F＝7.1Hz),121.5,115.6(C-F,2JC-F＝19.2Hz),107.6,107.2,60.3,56.0；HR-ESI-MS for C20H18FN5O3([M+H]+)Calcd:396.1466；Found:396.1464.
实施例13
本实施例制备了如下式所示的N-(2,4-二氟苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.55(s,1H),8.33(d,J＝6.1Hz,1H),8.08–8.02(m,3H),7.56(d,J＝6.1Hz,1H),7.37–7.30(m,1H),7.10–7.04(m,1H),3.86(s,6H),3.78(s,3H)；13CNMR(125MHz,DMSO-d6)δ163.2,157.4(dd,1JC-F＝241.8,3JC-F＝11.1Hz),153.5(dd,1JC-F＝248.2,3JC-F＝12.3Hz),153.4,152.4,146.5,144.6,140.4,126.3,124.9(dd,2JC-F＝11.7,4JC-F＝3.6Hz),123.2(dd,3JC-F＝9.1,3JC-F＝2.4Hz),110.9(dd,2JC-F＝22.1,4JC-F＝4.0Hz),107.6,107.2,104.3(dd,2JC-F＝26.8,2JC-F＝23.7Hz),60.2,55.9；HR-ESI-MS forC20H17F2N5O3([M+H]+)Calcd:414.1372；Found:414.1370.
实施例14
本实施例制备了如下式所示的N-(3-(苄氧基)苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.00(s,1H),8.32(d,J＝6.1Hz,1H),8.03(s,2H),7.55(d,J＝6.0Hz,1H),7.49(t,J＝2.3Hz,1H),7.44(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.34(d,J＝7.2Hz,1H),7.29(dd,J＝8.1,2.0Hz,1H),7.20(t,J＝8.1Hz,1H),6.62(dd,J＝8.1,2.5Hz,1H),5.05(s,2H),3.87(s,6H),3.74(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.4,159.1,152.7,152.4,146.9,144.7,141.8,140.4,137.1,129.6,128.4,127.9,126.5,110.0,107.5,107.1,106.3,104.3,69.2,60.2,56.0；HR-ESI-MS for C27H25N5O4([M+H]+)Calcd:484.1979；Found:484.1976.
实施例15
本实施例制备了如下式所示的N-(吡啶-3-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.19(s,1H),9.01(d,J＝2.7Hz,1H),8.32(d,J＝6.1Hz,1H),8.17(dd,J＝4.6,1.4Hz,1H),8.11–8.06(m,3H),7.56(d,J＝6.0Hz,1H),7.32(dd,J＝8.4,4.6Hz,1H),3.92(s,6H),3.79(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.1,153.0,152.4,146.7,144.8,142.0,140.4,139.1,137.3,126.3,123.5,123.5,107.5,107.2,60.2,56.0；HR-ESI-MS for C19H18N6O3([M+H]+)Calcd:379.1513；Found:379.1510.
实施例16
本实施例制备了如下式所示的N-(3,5-双(三氟甲基)苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ9.42(s,1H),8.38(d,J＝5.7Hz,1H),8.15(s,2H),7.84(s,2H),7.50(s,1H),7.43(d,J＝5.9Hz,1H),3.97(s,3H),3.93(s,6H)；13C NMR(125MHz,Chloroform-d)δ161.9,153.1,149.2,145.8,141.7,141.5,132.7(C-F,2JC-F＝33.3Hz),126.3,123.4(C-F,1JC-F＝272.9Hz),116.9(C-F,3JC-F＝4.2Hz),115.1(C-F,3JC-F＝8.1Hz),115.1,107.8,107.0,61.2,56.4；HR-ESI-MS for C22H17F6N5O3([M+H]+)Calcd:514.1308；Found:514.1306.
实施例17
本实施例制备了如下式所示的N-(3-硝基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.52(s,1H),8.62(t,J＝2.3Hz,1H),8.37(d,J＝6.1Hz,1H),8.12(dd,J＝8.2,2.3Hz,1H),7.95(s,2H),7.77(dd,J＝8.0,2.3Hz,1H),7.63(d,J＝6.1Hz,1H),7.58(t,J＝8.2Hz,1H),3.88(s,6H),3.81(s,3H)；13C NMR(125MHz,DMSO-d6)δ161.9,152.9,152.5,148.4,147.2,145.0,141.9,140.4,130.2,126.4,122.9,115.3,111.0,107.5,107.5,60.3,56.0；HR-ESI-MS for C20H18N6O5([M+H]+)Calcd:423.1411；Found:423.1411.
实施例18
本实施例制备了如下式所示的N-(3,4-二甲氧基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.32(d,J＝6.1Hz,1H),8.05(s,2H),7.54(d,J＝6.0Hz,1H),7.39(dd,J＝8.7,2.5Hz,1H),7.26(d,J＝2.5Hz,1H),6.88(d,J＝8.8Hz,1H),3.90(s,6H),3.80(s,3H),3.72(s,3H),3.71(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.8,152.9,152.4,149.1,146.7,144.6,143.6,140.4,134.5,126.6,112.5,108.9,107.7,106.9,103.3,60.3,56.1,56.0,55.5；HR-ESI-MS for C22H23N5O5([M+H]+)Calcd:438.1772；Found:438.1767.
实施例19
本实施例制备了如下式所示的N-(6-甲基吡啶-3-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.84(d,J＝2.8Hz,1H),8.34(d,J＝6.1Hz,1H),8.08(s,2H),8.02(dd,J＝8.4,2.7Hz,1H),7.57(d,J＝6.0Hz,1H),7.18(d,J＝8.4Hz,1H),3.92(s,6H),3.80(s,3H),2.41(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.4,153.0,152.5,150.0,146.7,144.8,140.4,138.5,134.9,126.4,124.3,122.7,107.5,107.1,60.3,56.0,23.3；HR-ESI-MS for C20H20N6O3([M+H]+)Calcd:393.1670；Found:393.1668.
实施例20
本实施例制备了如下式所示的N-(对甲苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.86(s,1H),8.32(d,J＝6.0Hz,1H),8.13(s,2H),7.66–7.62(m,2H),7.54(d,J＝6.0Hz,1H),7.10(d,J＝8.2Hz,2H),3.94(s,6H),3.81(s,3H),2.26(s,3H).13C NMR(125MHz,DMSO-d6)δ162.6,152.9,152.4,146.5,144.6,140.4,138.1,129.7,129.2,126.5,117.1,107.6,106.9,60.3,56.0,20.4.HR-ESI-MS for C21H21N5O3([M+H]+)Calcd:392.1717；Found:392.1712.
实施例21
本实施例制备了如下式所示的N-(4-甲氧基-3-硝基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.17(s,1H),8.35(d,J＝6.1Hz,1H),8.27(d,J＝2.8Hz,1H),7.96–7.93(m,3H),7.60(d,J＝6.0Hz,1H),7.36(d,J＝9.3Hz,1H),3.90(s,3H),3.87(s,6H),3.80(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.2,152.9,152.5,147.1,146.5,144.8,140.4,138.9,134.0,126.5,123.2,115.3,112.9,107.5,107.2,60.3,56.9,56.0；HR-ESI-MS for C21H20N6O6([M+H]+)Calcd:453.1517；Found:453.1509.
实施例22
本实施例制备了如下式所示的N-(4-甲氧基-3-氨基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.49(s,1H),8.30(d,J＝6.0Hz,1H),8.15(s,2H),7.50(d,J＝6.1Hz,1H),7.10(dd,J＝8.6,2.6Hz,1H),6.85(d,J＝2.6Hz,1H),6.71(d,J＝8.7Hz,1H),4.93(s,2H),3.92(s,6H),3.80(s,3H),3.73(s,3H)；13C NMR(125MHz,DMSO-d6)δ163.1,153.0,152.5,146.4,144.5,142.1,140.4,136.9,134.3,126.5,110.9,107.6,106.7,106.2,105.0,60.3,56.1,55.8；HR-ESI-MS for C21H22N6O4([M+H]+)Calcd:423.1775；Found:423.1768.
实施例23
本实施例制备了如下式所示的N-(4-甲氧基-3-羟基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.30(d,J＝6.0Hz,1H),8.14(s,2H),7.50(s,1H),7.43(d,J＝2.6Hz,1H),7.35(d,J＝6.0Hz,1H),6.96(dd,J＝8.6,2.7Hz,1H),6.81(d,J＝8.7Hz,1H),4.02(s,6H),3.98(s,3H),3.88(s,3H)；13C NMR(125MHz,Chloroform-d)δ161.5,153.0,152.5,148.1,146.3,145.4,142.5,141.5,133.5,126.1,111.4,109.6,108.0,106.2,105.6,61.2,56.6,56.5；HR-ESI-MS for C21H21N5O5([M+H]+)Calcd:424.1615；Found:424.1611.
实施例24
本实施例制备了如下式所示的N-(4-甲基-3-羟基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),9.22(s,1H),8.32(d,J＝6.0Hz,1H),8.13(s,2H),7.53(d,J＝6.1Hz,1H),7.27(dd,J＝8.1,2.2Hz,1H),7.06(d,J＝2.2Hz,1H),6.94(d,J＝8.1Hz,1H),3.92(s,6H),3.80(s,3H),2.07(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.8,155.6,152.9,152.5,146.5,144.5,140.4,139.3,130.3,126.5,116.8,108.0,107.6,106.8,104.4,60.3,56.0,15.5；HR-ESI-MS for C21H21N5O4([M+H]+)Calcd:408.1666；Found:408.1661.
实施例25
本实施例制备了如下式所示的N-(1H-吲哚-5-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),9.66(s,1H),8.31(d,J＝6.0Hz,1H),8.16(s,2H),8.01(d,J＝2.1Hz,1H),7.51(d,J＝6.0Hz,1H),7.39(dd,J＝8.6,2.1Hz,1H),7.35–7.30(m,2H),6.32(t,J＝2.5Hz,1H),3.92(s,6H),3.81(s,3H)；13C NMR(125MHz,DMSO-d6)δ163.3,152.9,152.5,146.5,144.5,140.4,132.9,131.8,127.8,126.7,125.9,113.8,111.4,107.9,107.7,106.6,100.6,60.3,56.1；HR-ESI-MS for C22H20N6O3([M+H]+)Calcd:417.1670；Found:417.1667.
实施例26
本实施例制备了如下式所示的N-(1H-吲哚-4-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),9.71(s,1H),8.34(d,J＝6.0Hz,1H),8.19(s,2H),7.89(d,J＝7.5Hz,1H),7.57(d,J＝6.0Hz,1H),7.27(t,J＝2.7Hz,1H),7.08(d,J＝8.0Hz,1H),7.04–6.99(m,2H),3.93(s,6H),3.80(s,3H)；13C NMR(125MHz,DMSO-d6)δ163.2,152.9,152.5,146.5,144.6,140.4,136.8,132.5,126.5,123.7,121.2,119.1,107.6,106.9,106.5,105.7,99.6,60.3,56.0；HR-ESI-MS for C22H20N6O3([M+H]+)Calcd:417.1670；Found:417.1668.
实施例27
本实施例制备了如下式所示的N-(1H-吲哚-6-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.94(s,1H),9.79(s,1H),8.33(d,J＝5.9Hz,1H),8.17(s,2H),7.82(s,1H),7.54(d,J＝6.0Hz,1H),7.46–7.40(m,2H),7.22(t,J＝2.7Hz,1H),6.35(t,J＝2.6Hz,1H),3.90(s,6H),3.82(s,3H)；13C NMR(125MHz,DMSO-d6)δ163.1,153.0,152.5,146.5,144.5,140.4,136.4,135.1,126.6,124.4,122.8,119.9,111.3,107.5,106.7,101.0,99.7,60.3,56.0；HR-ESI-MS for C22H20N6O3([M+H]+)Calcd:417.1670；Found:417.1664.
实施例28
本实施例制备了如下式所示的N-(1H-吲哚-7-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),9.65(s,1H),8.35(d,J＝6.0Hz,1H),8.15(s,2H),7.88(d,J＝7.6Hz,1H),7.58(d,J＝6.1Hz,1H),7.38(t,J＝2.7Hz,1H),7.26(d,J＝7.8Hz,1H),6.96(t,J＝7.7Hz,1H),6.47(t,J＝2.5Hz,1H),3.87(s,6H),3.79(s,3H)；13CNMR(125MHz,DMSO-d6)δ163.0,153.1,152.4,146.6,144.7,140.4,128.9,126.8,126.5,125.5,124.9,119.1,114.4,109.7,107.6,107.0,101.8,60.3,55.9；HR-ESI-MS forC22H20N6O3([M+H]+)Calcd:417.1670；Found:417.1663.
实施例29
本实施例制备了如下式所示的N-(1-甲基-1H-吲哚-7-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.24(d,J＝6.1Hz,1H),8.07(s,2H),7.53(dd,J＝8.0,1.0Hz,1H),7.32–7.28(m,2H),7.05(t,J＝7.7Hz,1H),6.95(d,J＝3.1Hz,1H),6.81(s,1H),6.49(d,J＝3.1Hz,1H),3.97(s,3H),3.88(s,3H),3.64(s,6H).13C NMR(125MHz,Chloroform-d)δ166.2,154.6,152.7,147.5,144.7,141.0,132.1,131.6,130.9,126.3,124.1,120.1,119.8,119.8,107.8,106.7,101.5,61.0,56.1,35.8.HR-ESI-MS forC23H22N6O3([M+H]+)Calcd:431.1826；Found:431.1817.
实施例30
本实施例制备了如下式所示的N-(1-甲基-1H-吲哚-4-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.27(d,J＝6.0Hz,1H),8.21(s,2H),8.04(d,J＝7.7Hz,1H),7.42(s,1H),7.34(d,J＝6.0Hz,1H),7.20(t,J＝8.0Hz,1H),7.08–7.06(m,2H),6.56(dd,J＝3.2,0.9Hz,1H),4.02(s,6H),3.99(s,3H),3.82(s,3H).13C NMR(125MHz,Chloroform-d)δ162.9,153.4,153.0,148.0,144.8,141.2,137.6,132.2,128.2,126.8,122.3,119.1,108.0,107.0,104.1,96.9,61.2,56.4,33.3.HR-ESI-MS for C23H22N6O3([M+H]+)Calcd:431.1826；Found:431.1819.
实施例31
本实施例制备了如下式所示的N-(1-甲基-1H-吲哚-6-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.27(d,J＝6.0Hz,1H),8.07(s,2H),7.76(d,J＝2.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.35(d,J＝6.1Hz,1H),7.31–7.26(m,2H),7.01(d,J＝3.1Hz,1H),6.46(dd,J＝3.1,0.9Hz,1H),3.97(s,3H),3.94(s,6H),3.74(s,3H).13C NMR(125MHz,DMSO-d6)δ163.0,152.8,152.4,146.9,144.6,140.4,136.9,135.4,128.7,126.7,122.9,120.3,111.3,107.9,106.9,100.3,97.8,60.3,56.2,32.2.HR-ESI-MS forC23H22N6O3([M+H]+)Calcd:431.1826；Found:431.1818.
实施例32
本实施例制备了如下式所示的N-(1-甲基-1H-吲哚-5-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.25(d,J＝6.0Hz,1H),8.18(s,2H),8.03(d,J＝2.1Hz,1H),7.49(s,1H),7.35(dd,J＝8.7,2.2Hz,1H),7.32(d,J＝6.0Hz,1H),7.27(d,J＝8.5Hz,1H),7.07(d,J＝3.1Hz,1H),6.41(d,J＝3.0Hz,1H),3.99–3.97(m,9H),3.80(s,3H).13C NMR(125MHz,Chloroform-d)δ163.6,153.6,152.9,147.9,144.7,141.1,133.4,132.5,129.9,128.9,126.9,114.6,110.1,109.6,107.9,106.7,100.7,61.1,56.5,33.1.HR-ESI-MS for C23H22N6O3([M+H]+)Calcd:431.1826；Found:431.1817.
实施例33
本实施例制备了如下式所示的N-(1H-吲哚-4-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ11.02(s,1H),9.30(s,1H),7.89(dd,J＝6.9,1.6Hz,1H),7.65(dd,J＝8.7,7.3Hz,1H),7.56(dd,J＝8.7,1.3Hz,1H),7.49(s,2H),7.29(dd,J＝7.3,1.3Hz,1H),7.22(t,J＝2.8Hz,1H),7.03–6.94(m,3H),3.90(s,6H),3.77(s,3H).13CNMR(125MHz,DMSO-d6)δ162.3,152.7,150.5,138.9,138.8,136.7,133.4,129.9,127.7,123.2,121.4,118.5,112.2,111.8,106.8,105.4,104.7,99.5,60.2,56.1.HR-ESI-MS forC23H21N5O3([M+H]+)Calcd:416.1717；Found:416.1709.
实施例34
本实施例制备了如下式所示的N-(1H-吲哚-4-基)-7-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.64(d,J＝4.9Hz,1H),8.42(s,1H),8.03(dd,J＝7.5,1.0Hz,1H),7.59(s,2H),7.40(s,1H),7.22(dd,J＝3.3,2.4Hz,1H),7.16(t,J＝7.8Hz,1H),7.14–7.09(m,2H),6.66–6.61(m,1H),4.02–3.96(m,9H).13C NMR(125MHz,Chloroform-d)δ163.7,155.9,153.4,152.9,146.4,141.2,136.6,132.2,125.2,123.6,122.8,118.6,107.3,107.2,107.1,105.7,98.6,61.2,56.5.HR-ESI-MS for C22H20N6O3([M+H]+)Calcd:417.1670；Found:417.1668.
实施例35
本实施例制备了如下式所示的N-(1H-吲哚-4-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]吡嗪-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),9.68(s,1H),9.05(s,1H),8.47(s,1H),7.88(dd,J＝7.5,1.1Hz,1H),7.58(s,2H),7.25(t,J＝2.8Hz,1H),7.06(d,J＝8.0Hz,1H),7.02(d,J＝7.6Hz,1H),7.00(t,J＝2.8Hz,1H),3.91(s,6H),3.78(s,3H).13C NMR(125MHz,DMSO-d6)δ163.1,152.9,146.0,139.2,136.7,136.6,132.7,132.5,129.8,124.6,123.5,121.3,119.0,106.8,106.2,105.5,99.5,60.2,56.1.HR-ESI-MS for C22H20N6O3([M+H]+)Calcd:417.1670；Found:417.1662.
实施例36
本实施例制备了如下式所示的N-(3-氟-4-甲氧基苯基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.28(d,J＝6.0Hz,1H),8.11(s,2H),7.74(dd,J＝13.0,2.7Hz,1H),7.33(d,J＝6.0Hz,1H),7.30(s,1H),7.12–7.07(m,1H),6.94(t,J＝9.0Hz,1H),4.02(s,6H),3.98(s,3H),3.89(s,3H).13C NMR(125MHz,Chloroform-d)δ162.6,153.6,153.1,152.7(C-F,1JC-F＝244.5Hz),148.1,145.0,142.9(C-F,2JC-F＝11.6Hz),141.4,133.7(C-F,2JC-F＝9.9Hz),126.6,114.6(C-F,3JC-F＝3.4Hz),113.3(C-F,3JC-F＝3.7Hz),107.9,107.0,106.8,61.2,57.0,56.5.HR-ESI-MS for C21H20FN5O4([M+H]+)Calcd:426.1572；Found:426.1566.
实施例37
本实施例制备了如下式所示的N-(5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-基)-9H-咔唑-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ11.26(s,1H),10.11(s,1H),8.35(d,J＝6.0Hz,1H),8.16(s,2H),7.99(t,J＝7.5Hz,2H),7.87(d,J＝2.1Hz,1H),7.62(dd,J＝8.5,1.9Hz,1H),7.58(d,J＝6.0Hz,1H),7.42(d,J＝8.0Hz,1H),7.30–7.26(m,1H),7.12–7.08(m,1H),3.93(s,6H),3.82(s,3H).13C NMR(125MHz,DMSO-d6)δ162.8,153.1,152.6,146.7,144.7,140.8,140.5,140.0,139.0,126.6,124.4,122.8,120.4,119.4,118.5,116.9,110.7,109.9,107.6,107.0,98.9,60.4,56.1.HR-ESI-MS for C26H22N6O3([M+H]+)Calcd:467.1826；Found:467.1821.
实施例38
本实施例制备了如下式所示的N-(5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-基)-9H-咔唑-4-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ11.39(s,1H),9.62(s,1H),8.32(d,J＝6.0Hz,1H),7.92(s,2H),7.87(d,J＝7.9Hz,1H),7.56(d,J＝6.0Hz,1H),7.47(dt,J＝8.1,0.9Hz,1H),7.43(dd,J＝7.4,1.2Hz,1H),7.36(t,J＝7.7Hz,1H),7.34–7.31(m,2H),7.06–7.02(m,1H),3.70(s,3H),3.56(s,6H).13C NMR(125MHz,DMSO-d6)δ164.5,153.8,152.2,146.2,144.4,141.0,140.2,139.6,134.7,126.3,125.6,125.1,122.5,121.4,118.4,116.6,113.6,110.6,107.4,107.3,106.9,60.2,55.6.HR-ESI-MS for C26H22N6O3([M+H]+)Calcd:467.1826；Found:467.1833.
实施例39
本实施例制备了如下式所示的N-(1-甲基-1H-吲哚-4-基)-7-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]嘧啶-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.61(d,J＝4.9Hz,1H),8.03(d,J＝7.7Hz,1H),7.58(s,2H),7.45(s,1H),7.18(t,J＝8.0Hz,1H),7.09(d,J＝4.8Hz,1H),7.06–7.00(m,2H),6.55(d,J＝3.2Hz,1H),4.00–3.95(m,9H),3.78(s,3H).13C NMR(125MHz,Chloroform-d)δ163.6,155.9,153.3,152.8,146.2,141.1,137.4,132.2,128.0,125.1,122.3,118.9,107.2,107.0,106.7,103.8,96.8,61.1,56.5,33.2.HR-ESI-MS for C23H22N6O3([M+H]+)Calcd:431.1826；Found:431.1819.
实施例40
本实施例制备了如下式所示的9-甲基-N-(5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-基)-9H-咔唑-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,DMSO-d6)δ10.18(s,1H),8.34(d,J＝6.0Hz,1H),8.06–8.01(m,4H),7.98(d,J＝2.0Hz,1H),7.62–7.56(m,2H),7.53(d,J＝8.1Hz,1H),7.39–7.34(m,1H),7.18–7.13(m,1H),3.90(s,6H),3.83(s,3H),3.77(s,3H).13C NMR(125MHz,DMSO-d6)δ162.7,152.7,152.5,147.1,144.7,141.6,140.8,140.5,139.4,126.7,124.5,122.4,120.5,119.3,118.8,116.2,109.9,108.9,107.9,107.1,96.8,60.3,56.2,28.8.HR-ESI-MSfor C27H24N6O3([M+H]+)Calcd:481.1983；Found:481.1974.
实施例41
本实施例制备了如下式所示的9-甲基-N-(5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-c]嘧啶-2-基)-9H-咔唑-3-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.44(d,J＝2.2Hz,1H),8.27(d,J＝6.0Hz,1H),8.12(s,2H),8.03(dt,J＝7.7,1.0Hz,1H),7.68(dd,J＝8.7,2.2Hz,1H),7.51–7.47(m,1H),7.40(d,J＝8.2Hz,1H),7.38–7.34(m,2H),7.26(s,1H),7.23–7.20(m,1H),4.00(s,3H),3.90(s,6H),3.87(s,3H).13C NMR(125MHz,Chloroform-d)δ163.7,153.6,153.0,148.1,144.8,141.7,141.2,137.5,132.1,126.9,126.1,123.3,122.6,120.6,118.9,118.2,110.5,108.7,108.7,108.0,106.8,61.1,56.5,29.3.HR-ESI-MS for C27H24N6O3([M+H]+)Calcd:481.1983；Found:481.1974.
实施例42
本实施例制备了如下式所示的N-(1-甲基-1H-吲哚-4-基)-5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[1,5-a]吡嗪-2-胺化合物，结构如下所示：
具体制备过程同实施例制备通法；所得产品的表征数据为：
1H NMR(500MHz,Chloroform-d)δ8.96(s,1H),8.24(s,1H),8.00(d,J＝7.7Hz,1H),7.42(s,2H),7.29(s,1H),7.23(t,J＝8.0Hz,1H),7.08–7.04(m,2H),6.54(d,J＝3.2Hz,1H),4.01–3.96(m,9H),3.82(s,3H).13C NMR(125MHz,Chloroform-d)δ163.0,153.5,146.5,140.2,137.6,137.1,133.7,132.2,129.9,128.2,124.7,122.5,119.0,106.7,106.6,104.0,96.8,61.2,56.5,33.3.HR-ESI-MS for C23H22N6O3([M+H]+)Calcd:431.1826；Found:431.1819.
性能检测
一、本发明提供化合物的抗肿瘤细胞增殖活性研究
采用MTT法测试上述实施例1-42的化合物的抗肿瘤细胞增殖活性。
所用试剂二甲基亚砜(碧云天)、四甲基偶氮唑蓝(碧云天)、RPMI-1640培养基(Gibco)、DMEM培养基(Gibco)以及胎牛血清(Gibco)。
操作步骤：(1)取对数生长期的肺癌细胞(A549)，消化，调整细胞数浓度为5×104/mL，按100μL/孔接种到96孔板中。在37℃，5％CO2细胞培养箱中培养过夜，待细胞贴壁。(2)吸出原有培养基，每组加入不同浓度的本发明提供化合物，化合物浓度分别为0.001,0.01,0.05,0.1,1,10μM。以0.1％的DMSO设为对照组，在细胞培养箱中继续培养72h。(3)每孔加入10μL MTT液，在培养箱中孵育4h。(4)弃去培养基，每孔加入100μL DMSO，振荡15min充分溶解甲瓒结晶。(5)用酶联免疫检测仪测定570nm下的吸光度值。(6)按以下公式计算细胞生长抑制率：抑制率＝[(As-Ab)/(Ac-Ab)]×100％；As：实验孔的吸光度(含细胞、MTT、化合物)；Ac：对照孔的吸光度(含细胞、MTT，无化合物)；Ab：空白孔的吸光度(不含细胞和化合物，含MTT)。
表1.化合物对肿瘤细胞生长的半数抑制浓度
二、本发明提供化合物的JAK2抑制活性研究
采用ADP-Glo方法检测提供化合物的JAK2抑制活性研究。
所用试剂：JAK2,Active(Signal Chem)；Poly(4:1Glu,Tyr)Peptide(SignalChem)；Kinase Assay Buffer)；DTT；ADP-GloTMKinase Assay(Promega)；DMSO(国药)；384well small volume white plate(Greiner).
根据检测要求，将待测化合物用100％ DMSO稀释至所需浓度，然后用1X缓冲液进行20倍稀释，配制成5X的化合物工作液，具体实验步骤如下。
(1)将1μL/孔5X待测化合物加入到白色微孔板中，微孔板在离心机上1000转离心1min；阳性对照孔(Pos.Ctrl):1μL/孔化合物稀释溶剂；空白对照孔(Blank):1μL/孔化合物稀释溶剂；
(2)JAK2酶完全解冻后，使用1X的缓冲液将JAK2酶稀释到0.5ng/μL，取2μL/孔加入到白色微孔板中，此时每孔中JAK2的酶量为1ng；空白对照孔加入2μL/孔1X缓冲液；此步骤请在冰上进行，加完后，微孔板在离心机上1000转离心1min；
(3)取2μL/孔Poly(4:1Glu,Tyr)Peptide/ATP的混合溶液到白色微孔板中，此时Poly(4:1Glu，
Tyr)Peptide浓度为0.2μg/μL，ATP浓度为5μM，加完后微孔板1000转离心1min；
(4)将Promega的试剂盒中需要用的ADP-GloTM reagent和Kinase Detection相关试剂平衡到室温，并按照说明书将Kinase Detection buffer和Kinase DetectionSubstrate混合备用；
(5)结束孵育后，取5μL/孔ADP-GloTM reagent加入到白色微孔板中，微孔板1000转离心1min，25℃中孵育40min；
(6)结束孵育后，取Kinase Detection混合液10μL/孔加入到微孔板中，微孔板1000转离心1
min，25℃中孵育30min；
(7)结束孵育后在读板器上进行化学发光(Luminescence)检测，读取发光值(RLU)。
化合物对JAK2抑制活性见表2。
表2.JAK2激酶抑制活性
三、本发明提供化合物的微管蛋白聚集抑制活性研究
使用基于比浊法的微管蛋白聚合测定试剂盒(Cytoskeleton,Inc.)，根据制造商的方案对需要测定化合物测试了对微管蛋白聚合的影响。将微管蛋白悬浮于冰冷的G-PEM缓冲液中(80mM PIPES,2mM MgCl2,0.5mM EGTA,1mM GTP,20％(v/v)甘油)，并加入到含有梯度浓度的化合物A26(10,1,0.5,0.1,0.05,0.01μM)或空白的96孔板。用酶标仪在37℃以1min为间隔监测(340nm)30min的微管蛋白的聚合情况，将吸光度值转化为对微管聚合的抑制率，结果见图1。研究结果表明，化合物A26可有效地抑制微管蛋白聚集，其IC50值为1.3μM，优于阳性对照秋水仙碱。
上面结合本发明实施例作了详细说明，但本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。
Claims (10)
1.一种三唑并六元氮杂环-2-胺类化合物，其特征在于，包括式A所示结构的化合物及其药学上可接受的盐，所述式A为：
其中，R选自如式B或式C所示的取代基；
所述式B为：
所述式C为：
其中：
n为1～5的整数，R1选自氢、羟基、氰基、硝基、氨基、苄氧基、C1～20的烷基、C1～20的烷氧基、卤素、卤素取代的C1～20的烷氧基或卤素取代的C1～20的烷基中的至少一种；
R2选自氢或C1～10的烷基；
X、Y、Z、W选自碳原子或氮原子；
D环表示存在或不存在，若D环存在时，则D环表示取代或未取代的苯基。
2.根据权利要求1所述的三唑并六元氮杂环-2-胺类化合物，其特征在于，R1选自C1～10的烷基、C1～10的烷氧基、卤素取代的C1～10的烷氧基或卤素取代的C1～10的烷基中的至少一种。
3.根据权利要求1所述的三唑并六元氮杂环-2-胺类化合物，其特征在于，所述三唑并六元氮杂环-2-胺类化合物选自如下结构式中的至少一种：
4.根据权利要求1～3任一项所述的三唑并六元氮杂环-2-胺类化合物的制备方法，其特征在于，包括以下步骤：
将式I化合物与式II化合物或式III化合物在催化剂、配体和溶剂存在下进行反应，其中式I化合物与式II化合物或式III化合物的结构式如下：
5.根据权利要求4所述的制备方法，其特征在于，所述溶剂包括1,4-二氧六环和甲苯中的至少一种。
6.根据权利要求4所述的制备方法，其特征在于，所述催化剂包括钯盐。
7.根据权利要求4所述的制备方法，其特征在于，所述配体包括联芳基膦类配体。
8.根据权利要求1～3任一项所述的三唑并六元氮杂环-2-胺类化合物在制备治疗和/或预防肿瘤疾病药物中的应用。
9.一种药物组合物，其特征在于，包括如权利要求1～3任一项所述的三唑并六元氮杂环-2-胺类化合物或其药学上可接受的盐，和药学上可接受的辅料。
10.一种抗肿瘤药物，其特征在于，所述抗肿瘤药物包括如权利要求1～3任一项所述的三唑并六元氮杂环-2-胺类化合物或如权利要求9所述的药物组合物。
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