CN114805367B - 一种三氮唑并嘧啶类衍生物及其制备方法和应用 - Google Patents

一种三氮唑并嘧啶类衍生物及其制备方法和应用 Download PDF

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CN114805367B
CN114805367B CN202210573652.9A CN202210573652A CN114805367B CN 114805367 B CN114805367 B CN 114805367B CN 202210573652 A CN202210573652 A CN 202210573652A CN 114805367 B CN114805367 B CN 114805367B
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刘宏民
孙凯
张怡秋
刘珍珍
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Abstract

本发明属于药物化学领域，具体涉及一种三氮唑并嘧啶类衍生物及其制备方法和应用。本发明的三氮唑并嘧啶类衍生物，为具有通式Ⅰ或通式Ⅱ或通式Ⅲ的化合物；通式Ⅰ、通式Ⅱ、通式Ⅲ如下所示：

Description

一种三氮唑并嘧啶类衍生物及其制备方法和应用
技术领域
本发明属于药物化学领域，具体涉及一种三氮唑并嘧啶类衍生物及其制备方法和应用。
背景技术
人类基因组编码近100多种去泛素化酶(DUBs)。去泛素化酶家族根据序列和结构域保守性分为六类：USPs(泛素特异性蛋白酶)、UCHs(泛素羧基末端水解酶)、OTUs(卵巢肿瘤样蛋白酶)、MJDs(Machado-Josephin结构域蛋白酶)、JAMMs(MPN(+)/JAMM蛋白酶)和MINDYs(MINDYs蛋白酶)。研究发现，蛋白质泛素化的失调会致使多种疾病的发生发展，例如肿瘤、神经退行性疾病以及炎症等。因此，靶向泛素化信号通路可以作为相关疾病的治疗手段。
2001年，研究人员首次从人类基因组的11号染色体上发现并鉴定出泛素特异性蛋白酶28(USP28)。USP28由一个UBA(Ub相关结构域)、两个UIMs(Ub相互作用基序)、一个USP(催化结构域)和C端一段非结构卷曲组成。其中，UBA与UIMs组成了UBR(N端泛素结合域)，主要功能是识别、招募泛素底物，并正向调控USP28。UBR包含了三螺旋束的泛素相关域和一个单螺旋的Ub相互作用基序。研究发现，USP28位于真核生物细胞核内，可调控细胞周期及凋亡、DNA损伤修复等多种生命活动。并且已有研究证实，USP28参与调节肿瘤中多种信号通路，参与肿瘤的发生和发展，因此敲除、敲低以及抑制USP28能减缓肿瘤的发展。
鉴于USP28与多种肿瘤的发生发展密切相关，USP28被认为是肿瘤治疗的潜在靶点。但有关USP28抑制剂的报道较少，且尚未有USP28抑制剂进入临床阶段研究。目前仅有2017年在ACS Chemical Biology报道的抑制剂AZ1以及2020年APSB报道的抑制剂化合物。因此，开发不同结构的USP28抑制化合物，对基于USP28靶点的抑制剂和抗肿瘤药物的研发以及相关疾病的研究治疗具有重要意义。
发明内容
为了解决上述问题，本发明的第一目的在于提供一种三氮唑并嘧啶类衍生物，该化合物结构新颖，对USP28蛋白具有较好的抑制活性。本发明的第二目的在于提供一种三氮唑并嘧啶类衍生物的制备方法，其工艺操作简单，且能够有效制备得到对USP28蛋白具有较好抑制活性的三氮唑并嘧啶类衍生物。本发明的第三目的在于提供一种三氮唑并嘧啶类衍生物的应用，具体是在制备基于USP28靶点的抑制剂或抗肿瘤药物中的应用。
为实现上述目的，本发明的三氮唑并嘧啶类衍生物，所采用的技术方案是：
一种三氮唑并嘧啶类衍生物，为具有通式Ⅰ或通式Ⅱ或通式Ⅲ的化合物，通式Ⅰ、通式Ⅱ、通式Ⅲ如下所示：
Figure BDA0003659842600000021
其中，通式Ⅰ中，R1为环丙基、环己基、4-甲基哌啶基、4-甲基哌嗪基、正丙基、2-羟基乙基、2-甲氧基乙基、2-氨基乙基、2-(乙酰基氨基)乙基、2-(苯基氨基)乙基、2-(苯甲酸酯基氨基)乙基、2-(叔丁氧羰基氨基)乙基、2-(二甲基氨基)乙基、2-(叔丁氧羰基甲基氨基)乙基、(2-(4-苯基哌嗪-1-基)乙基、苄基、4-吡啶基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-甲氧基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-三氟甲基苄基、3,5-二甲氧基苄基、4-甲氧基苯基、4-氯苯基、2,3-二氢-1H-茚-1-基、苯并[d][1,3]二氧戊环-4-基中的任意一种；通式Ⅱ中，R2为环丙基、环丁基、环戊基、环己基、4-苄基哌啶基、2-(乙酰基氨基)乙基、2-(苯基氨基)乙基、2-(苯甲酸酯基氨基)乙基、(2-(4-苯基哌嗪-1-基)乙基、(2-(4-苯甲酰基哌嗪-1-基)乙基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-吡啶基、3,5-二甲氧基苄基、3,4,5-二甲氧基苄基、4-甲氧基苯基、2,3-二氢-1H-茚-1-基、1,2,3,4-四氢萘-1-基中的任意一种；通式Ⅲ中，R3为环丙基、环丁基、环戊基、2-(4-苯基哌嗪-1-基)乙基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-甲氧基苄基、3-三氟甲基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-三氟甲基苄基、萘-1-基甲基、1,2,3,4-四氢萘-1-基、2,3-二氢-1H-茚-1-基中的任意一种。
本发明的三氮唑并嘧啶类衍生物，结构新颖。USP28抑制活性试验证实，本发明化合物对USP28具有较好的抑制能力，从而具有良好的潜在抗肿瘤药物应用价值，能够为开发基于USP28靶点的抑制剂或抗肿瘤药物提供全新的药物选择。
基于有效提高三氮唑并嘧啶类衍生物对USP28抑制活性的目的，优选地，所述三氮唑并嘧啶类衍生物为具有通式Ⅰ的化合物，R1选自环己基、2-氯苄基、4-氯苄基中的一种。或者，所述三氮唑并嘧啶类衍生物为具有通式Ⅱ的化合物，R2选自环丙基、2-(苯基氨基)乙基、(2-(4-苯甲酰基哌嗪-1-基)乙基、2,3-二氢-1H-茚-1-基、1,2,3,4-四氢萘-1-基中的一种。或者，所述三氮唑并嘧啶类衍生物为具有通式Ⅲ的化合物，R3选自2-(4-苯基哌嗪-1-基)乙基、2-溴苄基、2-甲基苄基、3-甲氧基苄基、3-三氟甲基苄基、4-溴苄基中的一种。
为了最大幅度提高三氮唑并嘧啶类衍生物对USP28抑制活性，更优选地，所述三氮唑并嘧啶类衍生物为具有通式Ⅰ的化合物，R1为4-氯苄基；或者，所述三氮唑并嘧啶类衍生物为具有通式Ⅱ的化合物，R2为2,3-二氢-1H-茚-1-基。
本发明的三氮唑并嘧啶类衍生物的制备方法，当所述三氮唑并嘧啶类衍生物具有通式Ⅰ时，其制备过程包括以下步骤：
1)化合物A、化合物B、碱性物质在溶剂A中，于64～130℃反应18～30h，得化合物C；
2)将化合物C与亚硝酸钠、溶剂B于-10～20℃反应0.5～2.0h，得化合物D；
3)将化合物D、胺类物质、碱性物质、溶剂C于室温反应2～12h，得到式Ⅰ所示的三氮唑并嘧啶类衍生物；
当所述三氮唑并嘧啶类衍生物具有通式Ⅱ时，其制备过程包括以下步骤：
A)化合物A、化合物B、碱性物质在溶剂A中，于64～130℃反应18～30h，得化合物C；
B)将化合物C与亚硝酸钠、溶剂B于-10～20℃反应0.5～2.0h，得化合物D；
C)将化合物D、胺类物质、碱性物质、溶剂C于室温反应2～12h，得化合物E；
D)惰性气氛下，于冰浴中将氨基磺酰氯的乙腈溶液滴加到化合物E的乙腈溶液中，在碱性物质作用下反应0.5～2.0h，反应结束后向反应体系中滴加醇类溶剂淬灭反应，然后直接向体系中滴加酸性物质，室温反应4～12h，得到式Ⅱ所示的三氮唑并嘧啶类衍生物；
当所述三氮唑并嘧啶类衍生物具有通式Ⅲ时，其制备过程包括以下步骤：
a)将化合物F、化合物B、碱性物质在溶剂A中，于64～130℃反应18～30h，得化合物G；
b)将化合物G与亚硝酸钠、溶剂B于-10～20℃反应0.5～2.0h，得化合物H；
c)将化合物H、胺类物质与碱性物质、溶剂C于室温反应2～12h，得化合物J；
d)惰性气氛下，于冰浴中将氨基磺酰氯的乙腈溶液滴加到化合物J的乙腈溶液中，在碱性物质作用下反应0.5～2.0h，反应结束后向反应体系中滴加醇类溶剂淬灭反应，然后向体系中滴加酸性物质，室温反应4～12h，得到式Ⅲ所示的三氮唑并嘧啶类衍生物；
其中，步骤3)中的胺类物质选自通式化合物NH2-R1中的一种；步骤C)中的胺类物质选自通式化合物NH2-R2中的一种；步骤c)中的胺类物质选自通式NH2-R3中的一种；所述化合物A、B、C、D、E、F、G、H、J的结构式如下所示：
Figure BDA0003659842600000041
本发明的三氮唑并嘧啶类衍生物制备方法，具有反应条件温和、操作简单的特点，并且制备所得三氮唑并嘧啶类衍生物，具有较好的USP28抑制活性。
为促进原料的转化，减少副反应的发生，所述碱性物质为三乙胺、吡啶、N,N-二异丙基乙胺中的一种。基于提高原料溶解性和反应选择性的目的，优选地，所述溶剂A为甲醇、乙醇、丙醇中的一种；所述溶剂B为醋酸；所述溶剂C为乙腈。
为了提高反应猝灭的效率，进一步地，步骤D)和步骤d)中，所述醇类溶剂为甲醇。进一步优选地，步骤D)和步骤d)中，所述惰性气氛为氮气或氩气
本发明的三氮唑并嘧啶类衍生物的应用，具体是三氮唑并嘧啶类衍生物在制备基于USP28靶点的抑制剂或抗肿瘤药物中的应用。
本发明提供的三氮唑并嘧啶类衍生物的应用，所涉及的化合物对USP28表现出了较好的抑制活性，显示出良好的药物开发潜力，为基于USP28靶点的药物研发提供了新方向。
具体实施方式
以下实施例中，化合物结构的确定是通过核磁共振(NMR)和高分辨率质谱(HRMS)确定的。核磁共振仪为瑞典Bruker DPX-400型超导核磁共振仪，四甲基硅烷(TMS)为内标；高分辨质谱为Q-Tof质谱仪(Waters-Micromass)。
实施例1
本实施例的三氮唑并嘧啶类衍生物，为具有通式Ⅰ的化合物，通式Ⅰ中，R1为环丙基。该三氮唑并嘧啶类衍生物记为化合物1。化合物1的制备方法具体如下：
1)化合物C的合成，将化合物A(50.0g，1.02eq.)和化合物B(75.6g，1.0eq.)置于5L的高压反应釜中，加入750mL乙醇，形成悬浊液。搅拌下，向悬浊液中加入三乙胺(62.50g，3.0eq.)，加热至125℃，保温搅拌反应30h。冷却至室温后，用TLC(PE:EA＝1:1)监测反应。减压蒸馏除去大部分溶剂，加入乙酸乙酯和水，并在搅拌下加入6M盐酸溶液调节水相pH＝5。静置分层后，有机相水洗三次，饱和食盐水洗一次。将有机相收集，经无水硫酸钠干燥后，过滤、减压浓缩。中间体粗产物化合物C不经分离直接进行下步反应。
2)化合物D的合成：将中间体化合物C(89.3g，1.0eq.)置于1L的三口圆底烧瓶中，加入200mL醋酸溶解。置于冰浴下，待内温为2℃，滴加7M亚硝酸钠水溶液(127.9g，10.0eq.)并保持内温在0-7℃之间，搅拌反应1h。经TLC(PE:EA＝2:1)监测反应完全后，加入乙酸乙酯和水。有机相水洗三次后，经饱和碳酸氢钠水溶液调节水相pH＝7，再使用饱和食盐水洗一次。有机相经无水硫酸钠干燥后，过滤、减压蒸馏浓缩，粗产物使用柱层析(PE:EA＝1.5:1)纯化，得到中间体化合物D。中间体化合物D为黄色油状液体，产率88％。
3)化合物1的合成：将中间体化合物D(200mg，1.0eq.)置于25mL的厚壁茄形瓶中，无水乙腈溶解后加入N,N-二异丙基乙胺(92mg，1.5eq.)。冰浴下，滴加胺类物质—环丙胺(40mg，1.5eq.)。室温下搅拌8h，反应经TLC(PE:EA＝2:1)监测后，减压蒸馏除去溶剂。使用乙酸乙酯萃取三次、水洗一次。有机相经无水硫酸钠干燥、减压浓缩，粗产物经柱层析(PE:EA＝4:1)分离得到化合物1。该三氮唑并嘧啶类衍生物为黄色油状液体，产率78％，全称为2-(((3S,4R,6S,6R)-6-(7-(环丙基氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。表征结果为：1H NMR(400MHz,Chloroform-d)δ6.19(d,J＝177.0Hz,1H),5.51(d,J＝6.2Hz,1H),5.30(s,2H),5.15(d,J＝6.4Hz,1H),4.87(d,J＝6.3Hz,1H),4.01(d,J＝5.1Hz,1H),3.67–3.53(m,3H),3.49(m,1H),3.16(s,2H),3.05(s,1H),2.64(m,2H),2.47(s,1H),1.54(s,3H),1.36(s,3H),1.06(t,J＝7.4Hz,3H),0.92(s,2H),0.69(d,J＝4.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ154.10,148.88,112.44,83.71,81.95,81.82,70.67,61.32,60.00,26.86,24.73,23.68,22.74,13.34,5.89.HR-MS(ESI):Calcd.C20H30N6O4S.[M+H]+m/z:451.2122,found:451.2130.
实施例2～38
实施例2～38的三氮唑并嘧啶类衍生物，均具有通式Ⅰ，R1依次选自环己基、4-甲基哌啶基、4-甲基哌嗪基、正丙基、2-羟基乙基、2-甲氧基乙基、2-氨基乙基、2-(乙酰基氨基)乙基、2-(苯基氨基)乙基、2-(苯甲酸酯基氨基)乙基、2-(叔丁氧羰基氨基)乙基、2-(二甲基氨基)乙基、2-(叔丁氧羰基甲基氨基)乙基、(2-(4-苯基哌嗪-1-基)乙基、苄基、4-吡啶基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-甲氧基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-三氟甲基苄基、3,5-二甲氧基苄基、4-甲氧基苯基、4-氯苯基、2,3-二氢-1H-茚-1-基、苯并[d][1,3]二氧戊环-4-基，所得三氮唑并嘧啶类衍生物依次记为化合物2～38。化合物2～38的制备方法与实施例1基本相同，区别仅在于步骤3)中，采用的胺类物质不同，化合物2～38制备时采用的胺类物质具有通式NH2-R1，R1的选择和上述实施例2～38化合物依次对应。表征结果如下：
化合物2：2-(((3S,4R,6S,6R)-6-(7-(环己氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率80％。1H NMR(400MHz,Chloroform-d)δ6.29–5.74(m,1H),5.49(m,1H),5.14(m,1H),4.87(d,J＝6.4Hz,1H),4.24–4.13(m,1H),4.05–3.99(m,1H),3.69–3.55(m,3H),3.56–3.47(m,1H),3.13(t,J＝7.3Hz,2H),2.72(s,1H),2.65(m,1H),2.45(m,1H),2.15–2.05(m,2H),1.81(m,5H),1.73–1.62(m,1H),1.53(s,3H),1.44(d,J＝12.3Hz,2H),1.35(s,3H),1.32–1.23(m,2H),1.06(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ152.70,112.04,83.99,83.59,82.89,70.24,62.32,61.66,49.64,36.01,33.43,32.82,26.71,25.51,24.84,24.41,23.16,13.66.HR-MS(ESI):Calcd.C23H36N6O4S.[M+H]+m/z:493.2592,found:493.2598.
化合物3：2-(((3S,4R,6S,6R)-2,2-二甲基-6-(7-((1-甲基哌啶-4-基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。无色油状液体，产率72％。1H NMR(400MHz,Chloroform-d)δ5.44(d,J＝6.1Hz,1H),5.13(d,J＝6.8Hz,1H),4.82(d,J＝6.3Hz,1H),4.40(s,1H),4.01(d,J＝5.4Hz,1H),3.75–3.43(m,5H),3.33(s,2H),3.09(t,J＝7.4Hz,2H),2.83–2.59(m,5H),2.52–2.42(m,1H),2.20(d,J＝52.2Hz,3H),1.76(q,J＝7.4Hz,2H),1.50(s,3H),1.46(d,J＝6.6Hz,2H),1.31(s,3H),1.23(s,3H),1.03(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ170.94,112.18,84.06,83.48,82.76,70.37,62.37,61.58,44.40,35.87,33.31,29.69,26.75,24.47,22.90,13.62.HR-MS(ESI):Calcd.C23H37N7O4S.[M+H]+m/z:508.2701,found:508.2705.
化合物4：2-(((3S,4R,6S,6R)-2,2-二甲基-6-(7-(4-甲基哌嗪-1-基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率74％。1H NMR(600MHz,Chloroform-d)δ5.46(m,1H),5.15(m,1H),4.85(d,J＝6.4Hz,1H),4.70(s,2H),4.02–4.00(m,1H),3.66–3.47(m,5H),3.11(t,J＝7.2Hz,2H),2.71–2.59(m,5H),2.44(d,J＝30.7Hz,4H),1.78(m,2H),1.53(s,3H),1.34(s,3H),1.04(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ170.06,152.44,150.97,112.03,84.07,83.65,82.87,70.29,62.27,61.70,45.69,35.74,33.28,26.73,24.43,22.91,13.58.HR-MS(ESI):Calcd.C23H37N7O4S.[M+H]+m/z:494.2544,found:494.2550.
化合物5：无色油状液体，产率81％。1H NMR(400MHz,Chloroform-d)δ6.05(d,J＝168.8Hz,1H),5.51(d,J＝6.2Hz,1H),5.14(d,J＝6.3Hz,1H),4.87(d,J＝6.3Hz,1H),4.02(d,J＝5.2Hz,1H),3.67–3.54(m,4H),3.51(d,J＝9.3Hz,1H),3.14(t,J＝7.4Hz,2H),2.64(m,2H),2.46(d,J＝14.7Hz,1H),1.80(q,J＝7.5Hz,2H),1.76–1.66(m,4H),1.54(s,3H),1.36(s,3H),1.04(m,6H).13C NMR(100MHz,Chloroform-d)δ171.07,153.59,123.48,112.08,84.01,83.55,82.79,70.28,62.31,61.65,42.47,35.95,33.36,26.71,24.41,22.99,22.61,13.58,11.41.HR-MS(ESI):Calcd.C20H32N6O4S.[M+H]+m/z:453.2279,found:453.2282.
化合物6：2-((3-((3R,4S,6R,6S)-6-(2-羟基乙氧基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙烷-1-醇。黄色油状液体，产率65％。1H NMR(400MHz,DMSO-d6)δ8.91–8.51(m,1H),5.19(m,1H),5.01(m,1H),4.67(m,1H),4.00(m,1H),3.58(m,4H),3.52–3.48(m,1H),3.43(m,4H),3.14–3.02(m,2H),2.67(m,1H),1.72(q,J＝7.1Hz,2H),1.49(s,3H),1.27(s,3H),1.00(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ153.80,149.48,123.45,111.98,84.06,83.69,82.79,70.26,62.60,61.62,43.55,35.67,33.32,26.68,24.38,22.85,13.58.HR-MS(ESI):Calcd.C19H30N6O5S.[M+H]+m/z:455.2071,found:455.2075.
化合物7：2-(((3S,4R,6S,6R)-6-(7-((2-甲氧基乙基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]-4H-环戊二烯[d][1,3]二氧戊环-4-基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙烷-1-醇。黄色油状液体，产率71％。1H NMR(400MHz,Chloroform-d)δ6.74–6.20(m,1H),5.50(d,J＝6.3Hz,1H),5.16(d,J＝6.3Hz,1H),4.87(d,J＝6.3Hz,1H),4.01(d,J＝5.2Hz,1H),3.84(q,J＝5.4Hz,2H),3.62(m,5H),3.55–3.47(m,1H),3.40(s,3H),3.13(t,J＝7.4Hz,2H),2.65(m,2H),2.48(m,1H),1.87(s,1H),1.79(m,2H),1.54(s,3H),1.36(s,3H),1.06(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ153.49,112.04,84.01,83.59,82.84,70.60,70.28,62.40,61.66,58.88,40.35,35.92,33.33,26.71,24.42,22.91,13.59.HR-MS(ESI):Calcd.C20H32N6O5S.[M+H]+m/z:469.2228,found:469.2234.
化合物8：2-(((3S,4R,6S,6R)-6-(7-((2-氨基乙基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-22-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率57％。1H NMR(400MHz,Chloroform-d)δ5.47(d,J＝6.1Hz,1H),5.11(t,J＝5.7Hz,1H),4.85(d,J＝6.2Hz,1H),4.00(t,J＝4.9Hz,1H),3.78(s,1H),3.57(m,3H),3.48(d,J＝7.3Hz,1H),3.12(m,4H),2.72(s,4H),2.66–2.58(m,1H),2.43(d,J＝14.6Hz,1H),1.79(q,J＝7.3Hz,2H),1.53(s,3H),1.36(s,3H),1.06(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.36,153.30,148.94,123.15,112.46,83.70,81.93,81.83,70.67,61.32,59.99,35.37,32.43,26.86,24.73,22.69,13.32.HR-MS(ESI):Calcd.C19H31N7O4S.[M+H]+m/z:454.2231,found:454.2236.
化合物9：N-(2-((3-((3R,4S,6R,6S)-6-(2-羟基乙氧基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基))-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙基)乙酰胺。黄色油状液体，67％。1H NMR(400MHz,Chloroform-d)δ7.49(t,J＝6.0Hz,1H),6.91(t,J＝5.3Hz,1H),5.52(m,1H),5.21–5.11(m,1H),4.87(d,J＝6.3Hz,1H),4.07–3.99(m,1H),3.82(q,J＝6.0Hz,1H),3.59(m,5H),3.49(m,1H),3.14(t,J＝7.2Hz,2H),2.74(s,1H),2.65(m,1H),2.51(m,1H),1.97(s,3H),1.80(q,J＝7.3Hz,2H),1.54(s,3H),1.37(s,3H),1.07(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.40,153.30,148.97,112.47,83.69,81.92,81.85,70.68,61.29,60.00,37.86,35.40,32.41,26.86,24.73,22.69,22.58,13.29.HR-MS(ESI):Calcd.C21H33N7O5S.[M+H]+m/z:496.2337,found:496.2343.
化合物10：黄色油状液体，产率72％。1H NMR(400MHz,Chloroform-d)δ7.18(t,J＝7.8Hz,2H),6.79(t,J＝5.9Hz,1H),6.71(t,J＝7.3Hz,1H),6.65(d,J＝7.9Hz,2H),5.52(m,1H),5.16(d,J＝6.7Hz,1H),4.87(d,J＝6.3Hz,1H),4.05–3.99(m,1H),3.91(q,J＝5.9Hz,2H),3.67–3.53(m,3H),3.53–3.43(m,3H),3.15(t,J＝7.3Hz,2H),2.65(m,1H),2.49(m,1H),1.80(q,J＝7.3Hz,2H),1.54(s,3H),1.36(s,3H),1.07(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ153.26,148.97,148.43,128.89,115.67,112.44,111.93,83.71,81.95,81.84,70.67,61.36,60.01,41.71,32.37,26.87,24.73,22.65,13.31.HR-MS(ESI):Calcd.C25H35N7O4S.[M+H]+m/z:530.2544,found:530.2550.
化合物11：苄基(2-((3-((3R,4S,6R,6S)-6-(2-羟基乙氧基)-2,2-二甲基四氢-4H-环戊[d][1,3]二氧戊环-4-基))-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙基)氨基甲酸酯。黄色油状液体，产率59％。1H NMR(400MHz,Chloroform-d)δ7.32(d,J＝4.4Hz,5H),7.21(s,1H),5.64(s,1H),5.56–5.48(m,1H),5.13(d,J＝6.6Hz,1H),5.08(s,2H),4.85(s,1H),4.02–3.94(m,1H),3.81(d,J＝6.2Hz,2H),3.64–3.49(m,5H),3.45(m,1H),3.13(t,J＝7.3Hz,2H),2.66–2.56(m,2H),2.48(d,J＝13.8Hz,1H),1.82(d,J＝5.2Hz,1H),1.80–1.72(m,2H),1.54(s,3H),1.36(s,3H),1.05(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.41,156.15,153.31,137.06,128.26,127.70,127.66,112.49,83.70,81.92,81.84,70.70,65.24,61.27,60.01,35.42,32.44,26.87,24.73,22.69,13.30.HR-MS(ESI):Calcd.C27H37N7O6S.[M+Na]+m/z:610.2418,found:610.2422.
化合物12：叔丁基(2-((3-((3R,4S,6R,6S)-6-(2-羟基乙氧基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙基)氨基甲酸酯。白色固体，产率78％，熔点：110.7-111.4℃。1H NMR(400MHz,DMSO-d6)δ9.05–8.41(m,1H),6.91(t,J＝5.8Hz,1H),5.23–5.16(m,1H),5.06–4.99(m,1H),4.67(m,1H),4.56(t,J＝5.3Hz,1H),4.01(m,1H),3.59–3.50(m,2H),3.45(m,3H),3.20(q,J＝6.1Hz,2H),3.10(m,2H),2.67(m,1H),2.59–2.53(m,1H),1.77–1.68(m,2H),1.49(s,3H),1.36(s,9H),1.27(s,3H),1.00(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.40,155.57,153.27,148.98,112.47,83.71,81.95,81.84,77.62,70.69,61.29,60.02,35.41,32.46,28.16,26.87,24.74,22.69,13.29.HR-MS(ESI):Calcd.C24H39N7O6S.[M+H]+m/z:554.2756,found:554.2762.
化合物13：黄色油状液体，产率55％。1H NMR(400MHz,DMSO-d6)δ8.67(m,1H),5.20(m,1H),5.01(m,1H),4.67(m,1H),4.56(s,1H),4.01(m,1H),3.60(q,J＝6.4Hz,2H),3.50(m,1H),3.43(m,3H),3.33(s,2H),3.09(m,2H),2.67(m,1H),2.20(s,6H),1.72(m,2H),1.49(s,3H),1.27(s,3H),1.00(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.37,153.07,112.43,83.69,81.95,81.83,70.67,61.29,60.00,57.47,45.10,32.42,26.86,24.72,22.73,13.33.HR-MS(ESI):Calcd.C21H35N7O4S.[M+H]+m/z:482.2544,found:482.2550.
化合物14：叔丁基(2-((3-((3R,4S,6R,6S)-6-(2-羟基乙氧基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙基)甲基)氨基甲酸酯。黄色油状液体，产率61％。1H NMR(400MHz,DMSO-d6)δ9.03(d,J＝55.9Hz,1H),5.18(m,1H),5.02(s,1H),4.67(m,1H),4.01(m,1H),3.60(s,2H),3.53–3.40(m,7H),3.09(m,2H),2.82(d,J＝7.9Hz,3H),2.66(m,1H),1.72(m,2H),1.49(s,3H),1.26(s,6H),1.07(s,6H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.43,154.72,112.50,83.70,81.90,81.80,78.03,70.69,61.30,60.00,35.43,32.39,27.60,26.87,24.73,22.70,13.30.HR-MS(ESI):Calcd.C25H41N7O6S.[M+H]+m/z:568.2462,found:568.2469.
化合物15：2-(((3S,4R,6S,6R)-2,2-二甲基-6-(7-((2-(4-苯基哌嗪-1-基)乙基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)四氢-4H-环戊二烯[d][1,3]二氧五环-4基)氧基)乙烷-1-醇。黄色固体，产率57％，132.4-133.1℃。1H NMR(400MHz,Chloroform-d)δ7.28(d,J＝8.4Hz,2H),6.94(d,J＝8.1Hz,2H),6.87(t,J＝7.3Hz,1H),6.71(s,1H),5.51(d,J＝6.4Hz,1H),5.16(s,1H),4.88(d,J＝6.3Hz,1H),4.02(s,1H),3.77(d,J＝5.9Hz,2H),3.67–3.48(m,4H),3.23(d,J＝5.0Hz,4H),3.15(t,J＝7.2Hz,2H),2.68(m,6H),2.47(d,J＝15.0Hz,2H),1.80(q,J＝7.3Hz,2H),1.54(s,3H),1.36(s,3H),1.07(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.39,150.97,128.84,118.70,115.26,112.45,83.69,81.94,81.84,70.67,61.30,60.00,56.37,52.67,48.13,35.38,32.44,26.86,24.73,22.75,13.35.HR-MS(ESI):Calcd.C29H42N8O4S.[M+H]+m/z:599.3123,found:599.3129.
化合物16：2-(((3S,4R,6S,6R)-6-(7-(苄基氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率73％。1H NMR(400MHz,Chloroform-d)δ7.41–7.26(m,5H),6.91(d,J＝9.6Hz,1H),5.48(d,J＝6.3Hz,1H),5.14(d,J＝6.9Hz,1H),4.85(d,J＝6.0Hz,2H),4.01(d,J＝5.4Hz,1H),3.66–3.52(m,3H),3.49(m,1H),3.12(t,J＝7.3Hz,2H),2.65(m,2H),2.49(m,1H),1.96–1.83(m,1H),1.77(m,2H),1.53(s,3H),1.35(s,3H),1.03(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ171.19,153.31,137.53,128.75,127.85,127.72,112.14,84.06,83.56,82.78,70.34,62.35,61.64,44.63,35.92,33.38,26.73,24.45,22.88,13.53.HR-MS(ESI):Calcd.C29H42N8O4S.[M+H]+m/z:501.2279,found:501.2282.
化合物17：黄色油状液体，产率68％。1H NMR(400MHz,Chloroform-d)δ8.59–8.54(m,2H),7.37(t,J＝6.4Hz,1H),7.29(d,J＝5.2Hz,2H),5.44(m,1H),5.14(m,1H),4.91(d,J＝6.1Hz,2H),4.83(d,J＝6.5Hz,1H),4.04–3.99(m,1H),3.62(m,3H),3.54–3.47(m,1H),3.06(t,J＝7.3Hz,2H),2.65(m,1H),2.45(m,1H),1.71(m,2H),1.54(s,3H),1.35(s,3H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ153.65,150.01,148.28,122.41,112.97,84.18,82.44,82.36,71.19,61.83,60.51,32.90,27.35,25.22,23.09,13.73.HR-MS(ESI):Calcd.C23H31N7O4S.[M+H]+m/z:502.2231,found:502.2238.
化合物18：黄色油状液体，产率70％。1H NMR(400MHz,DMSO-d6)δ9.59–9.06(m,1H),7.32(m,2H),7.22–7.11(m,2H),5.25–5.17(m,1H),5.02(m,1H),4.77(d,J＝5.8Hz,2H),4.67(m,1H),4.03–3.98(m,1H),3.53–3.47(m,1H),3.47–3.39(m,4H),3.00(m,2H),2.67(m,1H),1.60(q,J＝7.3Hz,2H),1.49(s,3H),1.26(d,J＝3.6Hz,4H),0.90(t,J＝7.3Hz,3H).13CNMR(100MHz,DMSO-d6)δ169.38,153.05,149.16,129.04,128.99,124.30,124.27,123.09,115.15,114.94,112.46,83.68,81.95,81.86,70.69,61.30,60.00,37.06,35.39,32.38,26.85,24.72,22.63,13.21.HR-MS(ESI):Calcd.C24H31FN6O4S.[M+H]+m/z:519.2185,found:519.2193.
化合物19：2-(((3S,4R,6S,6R)-6-(7-((2-氯苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率67％。1H NMR(400MHz,Chloroform-d)δ7.46–7.35(m,2H),7.23(m,1H),7.10–6.99(m,1H),5.51–5.38(m,1H),5.18–5.10(m,1H),4.96(d,J＝6.0Hz,2H),4.84(d,J＝6.4Hz,1H),4.00(d,J＝5.1Hz,1H),3.59(q,J＝9.6Hz,3H),3.50(m,1H),3.10(t,J＝7.3Hz,2H),2.73–2.59(m,2H),2.47(m,1H),1.89(d,J＝19.5Hz,1H),1.53(s,3H),1.35(s,3H),1.01(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ153.31,135.03,133.60,129.79,129.60,129.03,127.02,112.13,83.98,83.51,82.79,70.29,62.31,61.64,42.37,35.96,33.38,26.71,24.42,22.90,13.54.HR-MS(ESI):Calcd.C24H31ClN6O4S.[M+H]+m/z:566.1850,found:566.1854.
化合物20：黄色油状液体，产率74％。1H NMR(400MHz,Chloroform-d)δ7.47(d,J＝8.1Hz,2H),7.24(s,1H),6.78(t,J＝5.9Hz,1H),5.49(m,1H),5.15(m,1H),4.86(d,J＝6.4Hz,1H),4.81(d,J＝5.9Hz,2H),4.04–3.99(m,1H),3.67–3.53(m,3H),3.53–3.46(m,1H),3.11(t,J＝7.3Hz,2H),2.54(s,1H),2.48(t,J＝9.7Hz,1H),1.77(m,2H),1.54(s,3H),1.36(s,3H),1.03(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ136.52,131.88,129.52,112.02,83.94,83.56,82.82,62.48,61.66,43.93,33.35,26.67,24.36,22.85,13.57.HR-MS(ESI):Calcd.C24H31BrN6O4S.[M+H]+m/z:579.1384,found:579.1388.
化合物21：2-(((3S,4R,6S,6R)-2,2-二甲基-6-(7-((2-甲基苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率70％。1H NMR(400MHz,DMSO-d6)δ9.29(m,1H),7.26–7.09(m,4H),5.25–5.13(m,1H),5.03(m,1H),4.71–4.65(m,3H),4.01(m,1H),3.54–3.48(m,1H),3.47–3.40(m,3H),2.99(m,2H),2.67(m,1H),2.60–2.52(m,1H),2.36(s,3H),1.59(m,2H),1.48(d,J＝3.3Hz,3H),1.26(d,J＝5.5Hz,3H),0.89(t,J＝7.3Hz,3H).13CNMR(100MHz,DMSO-d6)δ169.40,153.06,136.35,135.32,129.86,126.92,126.74,125.69,112.44,83.72,81.98,81.87,70.69,61.33,60.03,41.14,35.38,32.41,24.74,22.60,18.73,13.23.HR-MS(ESI):Calcd.C25H34N6O4S.[M+H]+m/z:515.2435,found:515.2241.
化合物22：2-(((3S,4R,6S,6R)-6-(7-((2-甲氧基苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率75％。1H NMR(400MHz,Chloroform-d)δ7.35(m,1H),7.29(m,1H),6.95–6.86(m,2H),6.73–6.41(m,1H),5.53–5.46(m,1H),5.14(m,1H),4.85(m,2H),4.03–3.99(m,1H),3.89(s,3H),3.68–3.54(m,3H),3.52–3.47(m,1H),3.14(m,2H),2.62(m,2H),2.54–2.40(m,1H),1.86–1.75(m,2H),1.54(d,J＝5.6Hz,3H),1.35(d,J＝5.7Hz,3H),1.06(t,J＝7.5Hz,3H).13C NMR(100MHz,Chloroform-d)δ157.73,153.29,129.99,129.26,125.43,120.58,112.00,110.39,83.98,83.61,82.88,70.23,62.37,61.66,55.41,40.46,35.95,33.39,26.69,24.40,22.98,13.60.HR-MS(ESI):Calcd.C25H34N6O5S.[M+H]+m/z:531.2384,found:531.2387.
化合物23：2-(((3S,4R,6S,6R)-6-(7-((3-氟苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率71％。1H NMR(400MHz,DMSO-d6)δ9.36(m,1H),7.37(m,1H),7.24–7.13(m,2H),7.07(m,1H),5.20(m,1H),5.03(m,1H),4.74(d,J＝6.1Hz,2H),4.68(m,1H),4.61–4.54(m,1H),4.02(m,1H),3.53–3.48(m,1H),3.45(m,4H),3.02(m,2H),2.69(m,1H),1.63(m,2H),1.49(s,3H),1.27(s,3H),0.92(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.40,153.04,149.15,130.29,123.08,113.92,113.71,113.51,112.45,83.71,81.97,81.86,70.69,61.32,60.01,42.77,35.39,32.42,26.86,24.73,22.61,13.24.HR-MS(ESI):Calcd.C24H31FN6O4S.[M+H]+m/z:519.2185,found:519.2193.
化合物24：2-(((3S,4R,6S,6R)-6-(7-((3-氯苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率71％。1H NMR(400MHz,DMSO-d6)δ9.36(m,1H),7.46–7.40(m,1H),7.39–7.33(m,1H),7.34–7.27(m,2H),5.24–5.14(m,1H),5.02(m,1H),4.72(d,J＝6.1Hz,2H),4.67(m,1H),4.55(s,1H),4.01(m,1H),3.55–3.48(m,1H),3.47–3.40(m,3H),3.02(m,2H),2.67(m,1H),2.59–2.52(m,1H),1.63(m,2H),1.49(s,3H),1.26(s,3H),0.92(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.42,153.01,149.15,141.39,132.93,130.19,127.02,126.82,125.78,123.08,112.44,83.72,81.98,81.87,70.70,61.33,60.02,42.74,35.39,32.44,26.87,24.74,22.60,13.24.HR-MS(ESI):Calcd.C24H31ClN6O4S.[M+H]+m/z:566.1850,found:566.1855.
化合物25：黄色油状液体，79％。1H NMR(400MHz,DMSO-d6)δ9.36(m,1H),7.60–7.54(m,1H),7.45(m,1H),7.37–7.27(m,2H),5.20(m,1H),5.02(m,1H),4.75–4.63(m,3H),4.56(t,J＝5.2Hz,1H),4.01(m,1H),3.55–3.48(m,1H),3.43(m,4H),3.08–2.96(m,2H),2.67(m,1H),1.63(m,1H),1.49(s,3H),1.26(s,3H),0.92(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.40,149.15,130.51,129.94,129.73,126.18,121.55,112.46,83.70,81.96,81.86,70.69,61.31,60.01,42.68,35.39,32.43,26.87,24.74,22.61,13.26.HR-MS(ESI):Calcd.C24H31BrN6O4S.[M+H]+m/z:579.1384,found:579.1393.
化合物26：黄色油状液体，产率70％。1H NMR(400MHz,DMSO-d6)δ9.32(m,1H),7.22–7.11(m,3H),7.05(d,J＝7.5Hz,1H),5.23–5.12(m,1H),5.02(m,1H),4.67(t,J＝6.1Hz,3H),4.01(m,1H),3.55–3.48(m,1H),3.48–3.38(m,4H),3.10–2.99(m,2H),2.67(m,1H),2.27(s,3H),1.65(q,J＝7.3Hz,2H),1.49(s,3H),1.26(s,3H),0.93(t,J＝7.3Hz,3H).13CNMR(100MHz,DMSO-d6)δ169.41,153.01,138.71,137.30,128.18,127.77,127.48,124.24,112.45,83.72,81.97,81.86,70.69,61.30,60.02,43.14,35.40,32.43,26.88,24.75,22.65,20.98,13.26.HR-MS(ESI):Calcd.C25H34N6O4S.[M+H]+m/z:515.2435,found:515.2440.
化合物27：2-(((3S,4R,6S,6R)-6-(7-((3-甲氧基苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率69％。1H NMR(400MHz,Chloroform-d)δ7.08–6.90(m,3H),6.82(m,1H),5.54–5.43(m,1H),5.15(d,J＝5.9Hz,1H),4.88–4.77(m,3H),4.01(t,J＝5.0Hz,1H),3.78(d,J＝3.1Hz,3H),3.68–3.45(m,5H),3.12(q,J＝5.2Hz,2H),2.65(m,2H),2.49(t,J＝10.6Hz,1H),1.91(s,1H),1.77(q,J＝7.4Hz,2H),1.53(d,J＝3.0Hz,3H),1.34(d,J＝3.2Hz,3H),1.02(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ160.02,153.39,139.24,129.89,123.52,120.21,113.65,113.25,112.24,84.12,83.64,82.89,70.42,62.43,61.74,55.36,44.69,36.06,33.49,26.83,24.54,23.01,13.67.HR-MS(ESI):Calcd.C25H34N6O5S.[M+H]+m/z:531.2384,found:531.2388.
化合物28：2-(((3S,4R,6S,6R)-6-(7-((4-氟苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率70％。1H NMR(400MHz,Chloroform-d)δ7.35(m,2H),7.02(t,J＝8.8Hz,2H),6.84(s,1H),5.48(d,J＝6.3Hz,1H),5.15(d,J＝6.6Hz,1H),4.93–4.80(m,2H),4.01(d,J＝5.3Hz,1H),3.66–3.53(m,3H),3.49(m,1H),3.15–3.09(m,2H),2.66(m,1H),2.49(d,J＝12.1Hz,2H),1.77(d,J＝6.7Hz,2H),1.53(s,3H),1.35(s,3H),1.04(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ153.23,133.40,129.62,129.55,123.38,115.71,115.50,112.14,84.04,83.54,82.78,70.32,62.40,61.64,43.88,35.91,33.36,26.71,24.42,22.86,13.54.HR-MS(ESI):Calcd.C24H31FN6O4S.[M+H]+m/z:519.2185,found:519.2194.
化合物29：2-(((3S,4R,6S,6R)-6-(7-((4-氯苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率72％。1H NMR(400MHz,DMSO-d6)δ9.38(m,1H),7.41–7.33(m,4H),5.23–5.12(m,1H),5.02(m,1H),4.73–4.64(m,3H),4.59(s,1H),4.01(m,1H),3.50(m,1H),3.44(m,3H),3.01(m,2H),2.67(m,1H),1.62(m,2H),1.49(s,3H),1.27(s,3H),0.91(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ152.99,137.82,131.38,128.95,128.21,112.44,83.70,81.95,81.86,70.68,61.32,59.99,42.57,35.38,32.42,26.85,24.72,22.62,13.25.HR-MS(ESI):Calcd.C24H31ClN6O4S.[M+H]+m/z:535.1889,found:535.1896.
化合物30：黄色油状液体，产率75％。1H NMR(400MHz,DMSO-d6)δ9.62–9.06(m,1H),7.51(d,J＝8.0Hz,2H),7.31(m,2H),5.23–5.10(m,1H),5.01(d,J＝7.1Hz,1H),4.68(d,J＝5.7Hz,3H),4.54(d,J＝5.3Hz,1H),4.00(s,1H),3.49(d,J＝7.3Hz,1H),3.44(d,J＝6.9Hz,3H),3.00(s,2H),2.72–2.60(m,1H),1.62(q,J＝7.3Hz,2H),1.48(s,3H),1.26(s,3H),0.91(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.38,153.10,136.96,132.34,128.83,128.03,127.70,121.98,112.48,83.68,81.94,81.87,70.70,61.29,60.01,43.77,35.42,32.45,26.86,24.72,22.66,13.21.HR-MS(ESI):Calcd.C24H31BrN6O4S.[M+H]+m/z:579.1384,found:579.1390.
化合物31：2-(((3S,4R,6S,6R)-6-(7-((4-甲基苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率70％。1H NMR(400MHz,DMSO-d6)δ9.32(m,1H),7.22(d,J＝7.8Hz,2H),7.12(d,J＝7.8Hz,2H),5.20(m,1H),5.06–4.95(m,1H),4.66(d,J＝6.2Hz,3H),4.57(s,1H),4.00(m,1H),3.49(d,J＝6.8Hz,1H),3.44(d,J＝6.8Hz,4H),3.13–2.98(m,2H),2.66(m,1H),2.26(s,3H),1.67(m,2H),1.48(s,3H),1.26(s,3H),0.93(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.40,149.10,135.74,128.80,127.14,112.45,83.70,81.95,81.85,70.68,61.29,59.99,42.92,35.38,32.43,26.87,24.74,22.66,20.63,13.29.HR-MS(ESI):Calcd.C25H34N6O4S.[M+H]+m/z:515.2435,found:515.2439.
化合物32：2-(((3S,4R,6S,6R)-6-(7-((4-甲氧基苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率69％。1H NMR(400MHz,Chloroform-d)δ7.29(d,J＝8.3Hz,2H),6.87(d,J＝7.8Hz,2H),6.68(d,J＝6.5Hz,1H),5.53–5.44(m,1H),5.15(d,J＝6.7Hz,1H),4.85(d,J＝6.4Hz,1H),4.77(d,J＝5.5Hz,1H),4.01(d,J＝5.1Hz,1H),3.79(d,J＝2.9Hz,3H),3.61(m,3H),3.50(m,1H),3.14(t,J＝7.3Hz,2H),2.64(m,2H),2.56–2.42(m,1H),1.79(q,J＝7.6Hz,3H),1.53(s,3H),1.35(s,3H),1.05(t,J＝7.3Hz,3H).13CNMR(100MHz,Chloroform-d)δ171.16,159.25,153.17,129.32,114.17,112.08,84.00,83.55,82.80,70.28,62.36,61.64,55.31,44.16,35.94,33.38,26.71,24.42,22.91,13.58.HR-MS(ESI):Calcd.C25H34N6O5S.[M+H]+m/z:531.2384,found:531.2391.
化合物33：2-(((3S,4R,6S,6R)-6-(7-((4-三氟甲基苄基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率74％。1H NMR(400MHz,DMSO-d6)δ9.61–9.14(m,1H),7.43–7.30(m,4H),5.20(m,1H),5.07–4.98(m,1H),4.74–4.62(m,3H),4.59–4.55(m,1H),4.00(s,1H),3.49(d,J＝7.1Hz,1H),3.43(m,3H),3.01(m,2H),2.67(m,1H),1.73–1.57(m,2H),1.48(s,3H),1.26(s,3H),0.91(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ153.00,137.82,131.38,128.94,128.24,112.46,83.68,81.94,81.85,70.68,61.31,60.00,42.56,35.37,26.86,24.73,22.63,13.27.HR-MS(ESI):Calcd.C25H31F3N6O4S.[M+H]+m/z:569.2153,found:569.2157.
化合物34：黄色固体，产率68％，熔点：105.0-106.1℃。1H NMR(400MHz,Chloroform-d)δ6.62(t,J＝5.9Hz,1H),6.51–6.34(m,2H),5.55–5.46(m,1H),5.21–5.10(m,1H),4.86(d,J＝6.4Hz,1H),4.75(d,J＝5.8Hz,2H),4.04–3.98(m,1H),3.85(d,J＝6.2Hz,3H),3.79(d,J＝9.4Hz,3H),3.67–3.54(m,3H),3.53–3.47(m,1H),3.14(m,2H),2.63(q,J＝6.8Hz,2H),2.45(m,1H),1.80(m,3H),1.54(d,J＝6.4Hz,3H),1.36(d,J＝6.6Hz,3H),1.07(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ159.61,157.53,153.13,127.98,118.10,112.46,104.19,98.14,83.70,81.95,81.85,70.69,61.27,60.01,55.37,55.13,35.39,32.40,26.85,24.72,22.70,13.21.HR-MS(ESI):Calcd.C26H36N6O6S.[M+H]+m/z:561.2490,found:561.2496.
化合物35：2-(((3S,4R,6S,6R)-6-(7-((4-甲氧基苯基)氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色固体，产率55％，熔点：124.2-125.0℃。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.75(s,2H),7.00–6.92(m,2H),5.25(m,1H),5.06(m,1H),4.69(m,1H),4.56(t,J＝5.3Hz,1H),4.03(m,1H),3.77(s,3H),3.54–3.49(m,1H),3.48–3.39(m,3H),3.08(m,2H),2.70(m,1H),2.65–2.55(m,1H),1.70(m,2H),1.50(s,3H),1.28(s,3H),0.98(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ131.04,123.49,123.16,113.69,112.43,83.73,82.00,81.88,70.67,61.48,60.02,55.21,35.35,32.43,26.87,24.74,22.68,13.29.HR-MS(ESI):Calcd.C24H32N6O5S.[M+H]+m/z:517.2228,found:517.2234.
化合物36：黄色油状液体，产率60％。1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.92(d,J＝8.4Hz,2H),7.46(d,J＝8.4Hz,2H),5.26(t,J＝5.9Hz,1H),5.08(d,J＝6.8Hz,1H),4.75–4.66(m,1H),4.56(d,J＝5.0Hz,1H),4.03(s,1H),3.50(d,J＝7.1Hz,1H),3.48–3.40(m,3H),3.11(m,2H),2.70(m,1H),2.59(m,1H),1.72(q,J＝7.3Hz,2H),1.50(s,3H),1.28(s,3H),0.99(t,J＝7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.43,150.91,137.25,128.40,123.25,123.21,112.40,83.71,82.01,81.88,70.65,61.61,60.01,35.30,32.48,26.84,24.71,22.55,13.29.HR-MS(ESI):Calcd.C23H29ClN6O4S.[M+H]+m/z:521.1733,found:521.1737.
化合物37：黄色油状液体，产率67％。1H NMR(400MHz,Chloroform-d)δ7.34(s,1H),7.29(s,1H),7.21(s,1H),6.57–6.41(m,1H),5.92(q,J＝7.5Hz,1H),5.49(m,1H),5.21–5.13(m,1H),4.87(d,J＝6.4Hz,1H),4.03(m,1H),3.67–3.53(m,3H),3.53–3.46(m,1H),3.21–3.04(m,3H),2.96(q,J＝8.0Hz,1H),2.76–2.59(m,2H),2.47(m,1H),2.09–1.98(m,1H),1.87–1.73(m,3H),1.55(s,3H),1.37(s,3H),1.05(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ153.15,143.50,128.34,126.89,124.95,124.35,112.10,83.99,83.57,82.87,70.29,70.25,62.37,61.65,55.91,36.00,33.82,33.44,30.29,26.71,24.42,22.98,13.60.HR-MS(ESI):Calcd.C26H34N6O4S.[M+H]+m/z:527.2435,found:527.2437.
化合物38：2-(((3S,4R,6S,6R)-6-(7-(苯并[d][1,3]二氧戊环-4-基氨基)-5-(丙硫基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,2-二甲基四氢-4H-环戊二烯[d][1,3]二氧戊环-4-基)氧基)乙烷-1-醇。黄色油状液体，产率62％。1H NMR(400MHz,Chloroform-d)δ8.14(s,1H),7.52(s,1H),7.04(m,1H),6.81(d,J＝8.3Hz,1H),6.00(s,2H),5.52(m,1H),5.18(m,1H),4.89(d,J＝6.4Hz,1H),4.06–3.98(m,1H),3.63(m,3H),3.56–3.48(m,1H),3.14(t,J＝7.3Hz,2H),2.77(s,1H),2.67(m,1H),2.49(m,1H),1.84–1.78(m,2H),1.76(d,J＝3.1Hz,2H),1.54(s,3H),1.36(s,3H),1.06(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.36,146.90,132.30,123.16,112.42,107.82,101.15,83.70,81.99,81.87,70.66,61.49,60.01,35.33,32.43,26.84,24.71,22.70,13.27.HR-MS(ESI):Calcd.C24H30N6O6S.[M+H]+m/z:531.2021,found:531.2025.
实施例39
本实施例的三氮唑并嘧啶类衍生物，为具有通式Ⅱ的化合物，通式Ⅱ中，R2为环丙基。该三氮唑并嘧啶类衍生物记为化合物39。化合物39的制备方法具体如下：其中，步骤1)化合物C的合成，步骤2)化合物D的合成同实施例1。
3)化合物E的合成：将中间体化合物D(200mg，1.0eq.)置于25mL的厚壁茄形瓶中，无水乙腈溶解后加入N,N-二异丙基乙胺(92mg，1.5eq.)。冰浴下，滴加胺类物质—环丙胺(40mg，1.5eq.)。室温下搅拌8h，反应经TLC(PE:EA＝2:1)监测后，减压蒸馏除去溶剂。使用乙酸乙酯萃取三次、水洗一次。有机相经无水硫酸钠干燥、减压浓缩，粗产物经柱层析(PE:EA＝4:1)分离得到化合物E。
4)化合物39的合成：将化合物E(200mg，1.0eq.)置于50mL的两颈圆底烧瓶中，经超干乙腈溶解，随后加入三乙胺(158mg，4.0eq.)。氮气吹扫5min后，置于冰浴下，加入溶于氨基磺酰氯的乙腈溶液(135mg，3.0eq.)。搅拌45min，补加氨基磺酰氯(45mg，1.0eq)。继续搅拌15min，使用TLC(DCM:MeOH＝100:3)监测反应。随后，加入4mL甲醇淬灭反应。直接向体系加入6M盐酸水溶液(70.84mg，5eq.)进行水解。室温搅拌8h，经TLC(DCM:MeOH＝20:1)监测反应。减压蒸馏除去溶剂。加入饱和碳酸氢钠水溶液中和，加入乙酸乙酯萃取三次，水洗一次、饱和食盐水洗一次。有机相经无水硫酸钠干燥、浓缩得到粗产物，粗产物使用柱层析二氯甲烷甲醇体系梯度洗脱纯化，得到化合物39。所得化合物39为白色固体，产率66％，熔点：138.9-140.6℃。全称为2-(((1R,2R,3R,4S)-4-(7-(环丙基氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。表征结果为：1H NMR(400MHz,DMSO-d6)δ9.16–8.68(m,1H),7.50(s,1H),5.17(d,J＝6.2Hz,1H),5.09(d,J＝4.2Hz,1H),4.96(q,J＝9.2Hz,1H),4.63–4.50(m,1H),4.14(t,J＝4.6Hz,2H),3.97(s,1H),3.74(m,3H),3.12(m,2H),2.65(m,1H),2.13–2.00(m,1H),1.80–1.65(m,2H),0.99(t,J＝7.3Hz,3H),0.91–0.64(m,4H).13C NMR(100MHz,DMSO-d6)δ154.13,149.21,81.89,74.21,73.65,68.16,66.86,60.44,32.95,32.51,23.66,22.65,13.26,7.45,5.91.HR-MS(ESI):Calcd.C17H27N7O6S.[M+Na]+m/z:512.1356,found:512.1359.
实施例40～59
实施例40～59的三氮唑并嘧啶类衍生物，均具有通式Ⅱ，R2依次选自环丁基、环戊基、环己基、4-苄基哌啶基、2-(乙酰基氨基)乙基、2-(苯基氨基)乙基、2-(苯甲酸酯基氨基)乙基、(2-(4-苯基哌嗪-1-基)乙基、(2-(4-苯甲酰基哌嗪-1-基)乙基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-吡啶基、3,5-二甲氧基苄基、3,4,5-二甲氧基苄基、4-甲氧基苯基、2,3-二氢-1H-茚-1-基、1,2,3,4-四氢萘-1-基，所得三氮唑并嘧啶类衍生物依次记为化合物40～59。化合物40～59的制备方法与实施例39基本相同，区别仅在于步骤3)中，采用的胺类物质不同，化合物40～59制备时采用的胺类物质具有通式NH2-R2，R2的选择和上述实施例40～59化合物依次对应。表征结果如下：
化合物40：2-(((1R,2R,3R,4S)-4-(7-(环丁基氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率67％，熔点：109.3-109.6℃。1H NMR(400MHz,DMSO-d6)δ9.08(m,1H),7.50(s,2H),5.16(q,J＝8.0Hz,2H),4.96(q,J＝9.2Hz,1H),4.66(m,1H),4.55(m,1H),4.15(t,J＝4.6Hz,2H),3.97(m,1H),3.81(m,1H),3.73(m,2H),3.16–3.03(m,2H),2.65(m,1H),2.37(m,1H),2.27(m,2H),2.21–2.00(m,3H),1.70(m,4H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.04,152.00,149.44,122.85,81.88,74.21,73.63,68.16,66.86,60.41,45.27,32.43,32.06,30.31,29.72,22.64,14.82,13.24.HR-MS(ESI):Calcd.C18H29N7O7S.[M+Na]+m/z:526.1513,found:526.1516.
化合物41：2-(((1R,2R,3R,4S)-4-(7-(环戊基氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率62％，熔点：110.2-111.1℃。1H NMR(400MHz,DMSO-d6)δ8.82(m,1H),7.51(s,2H),5.14(d,J＝25.3Hz,2H),4.96(d,J＝8.9Hz,1H),4.51(m,2H),4.15(t,J＝4.6Hz,2H),3.99–3.95(m,1H),3.81(m,1H),3.73(m,2H),3.09(m,2H),2.71–2.60(m,1H),2.05(m,2H),1.79–1.52(m,8H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.00,152.67,123.08,81.92,74.22,73.68,68.17,66.87,60.38,51.86,38.84,31.78,23.54,22.76,13.25.HR-MS(ESI):Calcd.C19H31N7O6S2.[M+Na]+m/z:540.1669,found:540.1667.
化合物42：白色固体，产率68％，熔点：116.1-116.8℃。1H NMR(400MHz,DMSO-d6)δ8.70(m,1H),7.51(s,2H),5.21–5.03(m,2H),5.02–4.89(m,1H),4.65–4.45(m,1H),4.15(t,J＝4.6Hz,2H),3.96(d,J＝4.4Hz,1H),3.80(m,1H),3.73(m,2H),3.07(m,2H),2.65(m,1H),2.06(m,1H),1.94–1.84(m,2H),1.81–1.55(m,5H),1.46–1.22(m,4H),1.18(t,J＝7.1Hz,2H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ168.99,152.22,81.92,74.25,73.66,68.16,66.86,60.34,49.33,32.96,32.78,32.51,31.83,24.93,22.86,13.34.HR-MS(ESI):Calcd.C20H33N7O6S2.[M+H]+m/z:532.2007,found:532.2011.
化合物43：白色固体，产率：67％，熔点：117.2-117.8℃。1H NMR(400MHz,DMSO-d6)δ8.77(m,1H),7.50(s,2H),7.33(d,J＝6.7Hz,4H),7.27(d,J＝6.5Hz,1H),5.16(d,J＝6.3Hz,1H),5.09(t,J＝4.2Hz,1H),4.95(q,J＝9.4Hz,1H),4.66–4.48(m,1H),4.14(t,J＝4.6Hz,3H),3.96(q,J＝3.9,1H),3.83–3.67(m,3H),3.51(s,2H),3.07(m,2H),2.88(d,J＝11.0Hz,2H),2.64(m,1H),2.06(m,3H),1.92(d,J＝9.2Hz,1H),1.85(d,J＝10.8Hz,1H),1.70(m,4H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ150.13,149.59,148.73,135.50,135.47,133.53,133.34,133.26,117.70,117.49,113.91,101.83,59.45,50.32,42.50.HR-MS(ESI):Calcd.C26H38N8O6S2.[M+H]+m/z:623.2429,found:623.2436.
化合物44：2-(((1R,2R,3R,4S)-4-(7-((2-乙酰氨基乙基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率52％，熔点：105.8-106.7℃。1H NMR(400MHz,DMSO-d6)δ8.74(m,1H),8.00(t,J＝5.7Hz,1H),7.51(s,2H),5.19(d,J＝6.4Hz,1H),5.16–5.10(m,1H),4.97(q,J＝9.2Hz,1H),4.54(m,1H),4.15(t,J＝4.6Hz,2H),3.97(d,J＝5.7Hz,1H),3.84–3.79(m,1H),3.74(m,2H),3.56(q,J＝6.1Hz,2H),3.32–3.25(m,2H),3.10(m,2H),2.66(m,1H),2.05(m,1H),1.80(s,3H),1.75–1.65(m,2H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.40,169.10,153.30,149.28,123.15,81.89,74.23,73.65,68.16,66.87,60.45,37.91,32.40,22.59,13.21.HR-MS(ESI):Calcd.C18H30N8O7S2.[M-H]-m/z:533.1606,found:533.1608.
化合物45：：2-(((1R,2R,3R,4S)-4-(7-((2-苯基乙基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。无色油状液体，产率57％。1H NMR(400MHz,DMSO-d6)δ9.03–8.51(m,1H),7.51(s,2H),7.45–7.32(m,4H),7.32–7.24(m,1H),7.01(s,2H),5.14(d,J＝23.9Hz,2H),4.95(q,J＝8.9Hz,1H),4.53(m,1H),4.15(t,J＝4.6Hz,2H),3.96(m,1H),3.76(m,5H),3.57(q,J＝6.5Hz,2H),2.98(m,2H),2.65(m,1H),2.04(s,1H),1.64(m,2H),0.96(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ153.27,149.26,148.41,128.90,123.17,115.71,111.95,81.87,74.18,73.65,68.16,66.87,60.55,41.79,32.35,22.52,13.22.HR-MS(ESI):Calcd.C22H32N8O6S2.[M+H]+m/z:569.1959,found:569.1966.
化合物46：2-(((1R,2R,3R,4S)-4-(7-((2-(((苄氧基)羰基)氨基)乙基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率50％，熔点：126.4-127.2℃。1H NMR(400MHz,DMSO-d6)δ8.98–8.54(m,1H),7.51(s,2H),7.40(t,J＝5.9Hz,1H),7.37–7.26(m,5H),5.18(d,J＝6.3Hz,1H),5.11(d,J＝4.1Hz,1H),5.01(s,2H),4.99–4.91(m,1H),4.59–4.48(m,1H),4.14(t,J＝4.6Hz,2H),3.96(s,1H),3.80(t,J＝7.5Hz,1H),3.72(m,2H),3.58(q,J＝6.2Hz,2H),3.29(t,J＝6.0Hz,2H),3.10(m,2H),2.65(m,1H),2.04(m,1H),1.69(q,J＝7.2Hz,2H),0.98(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.12,153.30,149.30,137.06,128.28,127.67,81.89,74.23,73.65,68.17,66.86,65.25,60.42,32.98,32.43,22.59,13.22.HR-MS(ESI):Calcd.C24H34N8O8S2.[M+H]+m/z:627.2014,found:627.2018.
化合物47：2-(((1R,2R,3R,4S)-2,3-二羟基-4-(7-((2-(4-苯基哌嗪-1-基)乙基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)环戊基)氧基)氨基磺酸乙酯。白色固体，产率45％，熔点：107.2-107.9℃。1H NMR(400MHz,DMSO-d6)δ8.94–8.48(m,1H),7.50(s,2H),7.25–7.15(m,2H),6.92(d,J＝8.1Hz,2H),6.76(t,J＝7.3Hz,1H),5.17(m,1H),5.10(d,J＝4.1Hz,1H),4.96(q,J＝9.4Hz,1H),4.61–4.50(m,1H),4.15(t,J＝4.6Hz,2H),3.97(t,J＝3.8Hz,1H),3.85–3.63(m,5H),3.18–3.06(m,6H),2.71–2.58(m,6H),2.06(m,1H),1.71(m,2H),1.00(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ153.12,150.93,128.86,118.74,115.29,81.88,74.24,73.63,68.16,66.85,60.42,52.65,48.08,32.43,22.65,13.28.HR-MS(ESI):Calcd.C24H34N8O8S2.[M-H]-m/z:636.2392,found:636.2388.
化合物48：2-(((1R,2R,3R,4S)-4-(7-((2-(4-苯甲酰基哌嗪-1-基)乙基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率58％，熔点：92.2-92.9℃。1H NMR(400MHz,DMSO-d6)δ8.91–8.49(m,1H),7.51(s,2H),7.46–7.41(m,3H),7.37(m,2H),5.17(d,J＝6.3Hz,1H),5.11(d,J＝4.2Hz,1H),4.96(q,J＝9.1Hz,1H),4.62–4.45(m,1H),4.14(t,J＝4.7Hz,2H),4.04(d,J＝6.5Hz,1H),3.96(s,1H),3.86–3.47(m,7H),3.13–3.03(m,2H),2.78–2.53(m,4H),2.47(d,J＝21.0Hz,4H),2.11–1.99(m,1H),1.69(q,J＝7.2Hz,2H),0.98(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.08,168.83,135.90,129.41,128.36,126.81,123.09,81.86,74.26,73.62,68.15,66.85,60.43,56.21,37.26,32.97,32.39,22.60,13.26.HR-MS(ESI):Calcd.C27H39N9O7S2.[M+H]+m/z:666.2487,found:666.2488.
化合物49：白色固体，产率69％，熔点：153.6-154.8℃。1H NMR(400MHz,DMSO-d6)δ9.32(m,1H),7.50(s,2H),7.38(m,2H),7.15(m,2H),5.15(d,J＝11.3Hz,1H),5.10(s,1H),4.97(q,J＝8.9Hz,1H),4.70(d,J＝6.0Hz,2H),4.54(s,1H),4.15(t,J＝4.6Hz,2H),3.96(d,J＝4.5Hz,1H),3.81(m,1H),3.73(m,2H),3.03(m,2H),2.66(m,1H),2.06(m,1H),1.62(q,J＝7.3Hz,2H),0.92(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.13,152.96,149.44,129.13,123.06,115.12,114.91,81.87,74.28,73.63,68.16,66.85,60.45,42.49,32.97,32.40,22.54,13.20.HR-MS(ESI):Calcd.C21H28FN7O6S2.[M+H]+m/z:558.1600,found:558.1608.
化合物50：2-(((1R,2R,3R,4S)-4-(7-((4-氯苄基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率68％，熔点：157.0-157.8℃。1H NMR(400MHz,DMSO-d6)δ9.58–9.09(m,1H),7.51(s,2H),7.41–7.32(m,4H),5.18(d,J＝6.3Hz,1H),5.11(d,J＝4.2Hz,1H),4.96(q,J＝9.0Hz,1H),4.70(d,J＝6.1Hz,2H),4.58–4.45(m,1H),4.14(t,J＝4.6Hz,2H),3.96(s,1H),3.83–3.78(m,1H),3.78–3.67(m,2H),3.00(m,2H),2.65(m,1H),2.05(m,1H),1.60(q,J＝7.3Hz,2H),0.90(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ152.92,149.38,137.84,128.84,128.17,81.80,74.22,73.56,68.09,66.78,60.39,42.50,32.91,32.33,22.46,13.12.HR-MS(ESI):Calcd.C21H28ClN7O6S2.[M+H]+m/z:574.1304,found:574.1301.
化合物51：2-(((1R,2R,3R,4S)-4-(7-((4-溴苄基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率79％，熔点：163.2-163.9℃。1H NMR(400MHz,DMSO-d6)δ9.60–9.03(m,1H),7.64(m,1H),7.50(s,2H),7.36–7.30(m,1H),7.30–7.19(m,2H),5.18(d,J＝6.3Hz,1H),5.11(d,J＝4.3Hz,1H),4.98(q,J＝9.0Hz,1H),4.74(d,J＝5.7Hz,2H),4.54(m,1H),4.15(t,J＝4.6Hz,2H),3.96(d,J＝5.9Hz,1H),3.85–3.78(m,1H),3.75(m,2H),2.93(m,2H),2.67(m,1H),2.06(m,1H),1.50(m,2H),0.83(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.11,153.10,149.58,137.05,132.35,128.82,128.01,127.71,121.98,81.91,74.35,73.65,68.17,66.86,60.43,43.79,33.03,32.44,22.57,13.13.HR-MS(ESI):Calcd.C21H28BrN7O6S2.[M+H]+m/z:618.0799,found:618.0804.
化合物52：2-(((1R,2R,3R,4S)-4-(7-((4-甲基苄基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率71％，熔点：184.7-185.8℃。1H NMR(400MHz,DMSO-d6)δ9.28(m,1H),7.50(s,2H),7.28–7.20(m,2H),7.12(d,J＝7.8Hz,2H),5.22–5.04(m,2H),4.96(q,J＝9.0Hz,1H),4.67(d,J＝6.0Hz,2H),4.53(m,1H),4.14(q,J＝4.0Hz,2H),3.96(m,1H),3.85–3.79(m,1H),3.73(m,2H),3.03(m,2H),2.65(m,1H),2.26(s,3H),2.05(m,1H),1.63(m,2H),0.92(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.10,135.89,135.82,128.80,127.11,81.87,74.27,73.63,68.16,66.84,60.42,42.91,32.97,32.40,22.58,20.63,13.22.HR-MS(ESI):Calcd.C22H31N7O6S2.[M+H]+m/z:554.1850,found:554.1856.
化合物53：2-(((1R,2R,3R,4S)-4-(7-((4-甲氧基苄基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率73％，熔点：124.3-124.9℃。1H NMR(400MHz,DMSO-d6)δ9.27(m,1H),7.51(s,2H),7.30(m,2H),6.92–6.85(m,2H),5.27–5.06(m,2H),4.96(q,J＝8.9Hz,1H),4.64(d,J＝6.0Hz,2H),4.53(m,1H),4.15(t,J＝4.6Hz,2H),3.97(m,1H),3.84–3.78(m,1H),3.75(m,1H),3.71(s,4H),3.11–3.00(m,2H),2.72–2.59(m,1H),2.05(m,1H),1.66(m,2H),1.02–0.91(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ158.23,152.90,149.39,130.80,128.54,113.67,81.86,74.26,73.63,68.16,66.84,60.44,55.01,42.60,32.96,32.41,22.57,13.24.HR-MS(ESI):Calcd.C22H31N7O7S2.[M+H]+m/z:570.1799,found:570.1800.
化合物54：2-(((1R,2R,3R,4S)-2,3-二羟基-4-(5-丙硫基-7-((吡啶-4-基甲基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)环戊基)氧基)氨基磺酸乙酯。白色固体，产率42％，熔点：111.1-111.7℃。1H NMR(400MHz,DMSO-d6)δ9.60(t,J＝6.2Hz,1H),8.57–8.45(m,2H),7.51(s,2H),7.31(d,J＝5.1Hz,2H),5.19(d,J＝6.4Hz,1H),5.12(d,J＝4.4Hz,1H),4.97(q,J＝9.1Hz,1H),4.74(d,J＝6.0Hz,2H),4.54(m,1H),4.15(t,J＝4.7Hz,2H),3.96(d,J＝6.2Hz,1H),3.84–3.77(m,2H),3.73(m,2H),2.95(m,2H),2.67(m,1H),2.06(m,1H),1.54(m,2H),0.86(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.12,153.13,149.51,147.90,121.90,81.86,74.33,73.61,68.17,66.85,60.44,42.37,33.00,32.38,22.50,13.15.HR-MS(ESI):Calcd.C20H28N8O6S2.[M+H]+m/z:541.1646,found:541.1651.
化合物55：2-(((1R,2R,3R,4S)-4-(7-((3,5-二甲氧基苄基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率65％，熔点：130.2-131.1℃。1H NMR(400MHz,DMSO-d6)δ9.02(m,1H),7.50(s,2H),7.09(m,1H),6.57(d,J＝2.4Hz,1H),6.45(m,1H),5.18(d,J＝6.2Hz,1H),5.09(d,J＝4.1Hz,1H),4.96(q,J＝9.1Hz,1H),4.62(d,J＝5.8Hz,2H),4.54(m,1H),4.15(t,J＝4.6Hz,2H),3.97(d,J＝5.7Hz,1H),3.80(d,J＝10.0Hz,4H),3.73(s,5H),3.04–2.95(m,2H),2.66(m,1H),2.06(m,1H),1.60(m,2H),0.89(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.07,159.59,157.52,153.12,127.93,118.19,104.24,98.16,81.88,74.27,73.63,68.16,66.85,60.40,55.39,55.14,38.07,32.97,32.38,22.62,13.13.HR-MS(ESI):Calcd.C23H33N7O8S2.[M+H]+m/z:560.1905,found:560.1909.
化合物56：2-(((1R,2R,3R,4S)-4-(7-((3,4,5-二甲氧基苄基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率67％，熔点：118.4-119.4℃。1H NMR(400MHz,DMSO-d6)δ9.23(m,1H),7.50(s,2H),6.74(d,J＝7.9Hz,2H),5.16(d,J＝6.3Hz,1H),5.10(d,J＝4.2Hz,1H),4.97(q,J＝9.1Hz,1H),4.63(d,J＝6.0Hz,2H),4.54(m,1H),4.15(t,J＝4.6Hz,2H),3.97(d,J＝3.3Hz,1H),3.81(m,1H),3.74(d,J＝3.6Hz,9H),3.08(m,2H),2.71–2.62(m,1H),2.05(m,1H),1.67(q,J＝7.3Hz,2H),0.94(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ152.94,152.69,136.44,134.44,123.11,105.03,81.87,74.24,73.64,68.16,66.85,60.48,59.93,55.76,43.59,32.97,32.40,22.50,13.14.HR-MS(ESI):Calcd.C24H35N7O9S2.[M+H]+m/z:630.2011,found:630.2010.
化合物57：2-(((1R,2R,3R,4S)-2,3-二羟基-4-(7-((4-甲氧基苯基)氨基)-5-丙硫基-3H-[1,2,3]三唑[4,5-d]嘧啶-3-基)环戊基)氧基)氨基磺酸乙酯。白色固体，产率55％，熔点：134.8-135.6℃。1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),7.74(s,2H),7.51(s,2H),7.00–6.93(m,2H),5.18(s,2H),5.01(q,J＝9.0Hz,1H),4.57(m,1H),4.15(t,J＝4.6Hz,2H),3.98(m,1H),3.82(m,1H),3.80–3.70(m,5H),3.08(m,2H),2.69(m,1H),2.09(m,1H),1.69(m,2H),0.97(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ169.17,156.05,151.01,149.71,131.08,123.52,123.17,113.68,81.91,74.29,73.68,68.19,66.89,55.24,55.21,32.98,32.42,22.61,13.22.HR-MS(ESI):Calcd.C21H29N7O7S2.[M+H]+m/z:556.1643,found:556.1651.
化合物58：2-(((1R,2R,3R,4S)-4-(7-((2,3-二氢-1H-茚-1-基)氨基)-5-丙硫基-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率75％，熔点：114.1-114.7℃。1H NMR(400MHz,DMSO-d6)δ9.17(m,1H),7.52(s,2H),7.29(d,J＝7.8Hz,1H),7.25–7.20(m,2H),7.16(d,J＝6.2Hz,1H),5.91(q,J＝8.0Hz,1H),5.17(s,1H),5.01(m,1H),4.56(m,1H),4.16(t,J＝4.6Hz,2H),3.98(m,1H),3.78(m,4H),3.07(m,4H),2.88(m,1H),2.67(m,1H),2.48–2.43(m,1H),2.26–2.14(m,1H),2.08(m,2H),1.70(m,2H),0.94(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ153.00,149.12,137.82,131.38,128.93,128.24,112.46,83.68,81.94,81.85,70.68,61.31,60.00,42.56,35.37,32.42,26.86,24.73,22.63,13.27.HR-MS(ESI):Calcd.C23H31N7O6S2.[M+H]+m/z:566.1850,found:566.1854.
化合物59：白色固体，产率68％，熔点：104.1-104.7℃。1H NMR(400MHz,DMSO-d6)δ9.14(m,1H),7.51(s,2H),7.15(m,4H),5.62(s,1H),5.20(t,J＝5.8Hz,1H),5.11(q,J＝1.5Hz,1H),5.00(m,1H),4.58(m,1H),4.15(t,J＝4.6Hz,2H),3.97(d,J＝5.4Hz,1H),3.88–3.65(m,3H),3.13–3.01(m,2H),2.79(d,J＝5.9Hz,2H),2.67(m,1H),2.17–1.89(m,4H),1.78(t,J＝7.5Hz,1H),1.74–1.64(m,2H),0.94(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ152.83,149.57,137.20,136.91,128.78,127.50,126.75,125.77,122.89,81.90,74.27,73.63,68.17,66.86,60.42,48.06,32.48,29.15,28.76,22.66,22.47,20.50,13.24.HR-MS(ESI):Calcd.C24H33N7O6S2.[M+H]+m/z:580.2007,found:580.2013.
实施例60～83
实施例60～83的三氮唑并嘧啶类衍生物，均具有通式Ⅲ，R3依次选自环丙基、环丁基、环戊基、2-(4-苯基哌嗪-1-基)乙基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-甲氧基苄基、3-三氟甲基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-三氟甲基苄基、萘-1-基甲基、1,2,3,4-四氢萘-1-基、2,3-二氢-1H-茚-1-基，所得三氮唑并嘧啶类衍生物依次记为化合物60～83。化合物60～83的制备方法与实施例39基本相同，区别仅在于步骤1)中，将反应原料化合物A替换成化合物F，所得中间产物也依次变成化合物G、化合物H和化合物J；此外，步骤3)中采用的胺类物质不同，化合物60～83制备时采用的胺类物质具有通式NH2-R3，R3的选择和上述实施例60～83化合物依次对应。表征结果如下：
化合物60：2-(((1R,2R,3R,4S)-4-(7-(环丙基氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。无色油状液体，产率53％。1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝107.7Hz,1H),8.34(d,J＝60.6Hz,1H),7.52(s,2H),5.20(d,J＝6.3Hz,1H),5.13(d,J＝4.2Hz,1H),5.06(q,J＝9.1Hz,1H),4.55(s,1H),4.16(t,J＝4.6Hz,2H),3.98(s,1H),3.85–3.66(m,3H),3.10(s,1H),2.68(m,1H),2.13–2.03(m,1H),0.89(s,1H),0.78(d,J＝6.7Hz,1H),0.70(q,J＝3.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ156.43,153.18,148.70,124.31,81.91,74.45,73.61,68.19,66.85,60.49,23.75,7.50,5.98.HR-MS(ESI):Calcd.C14H21N7O6S.[M+H]+m/z:416.1347,found:416.1353.
化合物61：2-(((1R,2R,3R,4S)-4-(7-(环丁基氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。无色油状液体，产率54％。1H NMR(400MHz,DMSO-d6)δ9.07(m,1H),8.31(d,J＝33.3Hz,1H),7.51(s,2H),5.27–4.99(m,3H),4.75(m,1H),4.54(t,J＝6.3Hz,1H),4.16(t,J＝4.6Hz,2H),4.03–3.89(m,1H),3.85–3.66(m,3H),2.68(m,1H),2.31–2.06(m,4H),1.73(m,2H).13C NMR(100MHz,DMSO-d6)δ156.36,153.18,148.70,124.31,81.94,74.43,73.62,68.20,66.86,60.50,45.15,33.07,29.79,14.76.HR-MS(ESI):Calcd.C15H23N7O6S.[M+H]+m/z:430.1304,found:430.1312.
化合物62：2-(((1R,2R,3R,4S)-4-(7-(环戊基氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。无色油状液体，产率57％。1H NMR(400MHz,DMSO-d6)δ8.81(m,1H),8.31(d,J＝43.9Hz,1H),7.52(s,2H),5.15(s,1H),5.07(t,J＝8.9Hz,1H),4.67–4.47(m,2H),4.16(t,J＝4.6Hz,2H),3.98(m,1H),3.77(m,3H),2.68(m,1H),2.12–1.93(m,3H),1.80–1.54(m,7H).13C NMR(100MHz,DMSO-d6)δ156.36,153.84,148.58,124.53,81.92,74.43,73.61,68.20,66.86,60.46,51.69,33.07,31.77,23.50.HR-MS(ESI):Calcd.C16H25N7O6S.[M+H]+m/z:444.1660,found:444.1666.
化合物63：2-(((1R,2R,3R,4S)-2,3-二羟基-4-(7-((2-(4-苯基哌嗪-1-基)乙基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)环戊基)氧基)氨基磺酸乙酯。无色油状液体，产率39％。1H NMR(400MHz,DMSO-d6)δ8.90–8.47(m,1H),8.31(d,J＝44.9Hz,1H),7.52(s,2H),7.48–7.33(m,5H),5.11(m,3H),4.55(q,J＝7.4Hz,1H),4.16(t,J＝4.6Hz,2H),4.03(d,J＝41.1Hz,2H),3.89–3.39(m,9H),2.74–2.60(m,3H),2.08(m,1H).13C NMR(100MHz,DMSO-d6)δ168.84,156.40,154.28,148.56,135.92,129.40,128.36,126.82,124.58,81.93,74.46,73.61,68.20,66.86,60.53,56.21,33.09.HR-MS(ESI):Calcd.C23H33N9O6S.[M+H]+m/z:592.2297,found:592.2305.
化合物64：2-(((1R,2R,3R,4S)-4-(7-((2-氟苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率45％，熔点：147.8-148.9℃。1H NMR(400MHz,DMSO-d6)δ9.52–9.04(m,1H),8.38(s,1H),7.52(s,2H),7.42–7.27(m,2H),7.24–7.11(m,2H),5.29–5.03(m,3H),4.82(d,J＝5.9Hz,2H),4.56(m,1H),4.16(t,J＝4.6Hz,2H),3.99(m,1H),3.86–3.68(m,3H),2.69(m,1H),2.10(m,1H).13CNMR(100MHz,DMSO-d6)δ156.36,154.24,148.69,129.15,128.82,124.58,115.17,81.91,74.49,73.59,68.20,66.85,60.59,37.00,33.09.HR-MS(ESI):Calcd.C18H22FN7O6S.[M+H]+m/z:484.1409,found:484.1415.
化合物65：2-(((1R,2R,3R,4S)-4-(7-((2-氯苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率51％，熔点：168.1-169.0℃。1H NMR(400MHz,DMSO-d6)δ9.57–9.02(m,1H),8.36(s,1H),7.52(d,J＝5.6Hz,2H),7.50–7.44(m,1H),7.38–7.23(m,3H),5.32–4.99(m,3H),4.83(d,J＝5.9Hz,2H),4.57(m,1H),4.16(q,J＝4.1Hz,2H),3.99(m,1H),3.85–3.67(m,3H),2.70(m,1H),2.12(m,1H).13C NMR(100MHz,DMSO-d6)δ161.22,156.36,154.24,148.69,129.12,128.82,124.59,115.17,114.96,81.92,74.48,73.61,68.20,66.85,60.60,37.00,33.09.HR-MS(ESI):Calcd.C18H22ClN7O6S.[M+H]+m/z:500.1114,found:500.1120.
化合物66：2-(((1R,2R,3R,4S)-4-(7-((2-溴苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率56％，熔点：142.1-142.8℃。1H NMR(400MHz,DMSO-d6)δ9.54–9.04(m,1H),8.36(s,1H),7.64(d,J＝8.1Hz,1H),7.52(d,J＝5.9Hz,2H),7.36–7.27(m,2H),7.22(m,1H),5.30–5.02(m,3H),4.78(d,J＝5.8Hz,2H),4.57(m,1H),4.16(q,J＝4.4Hz,2H),4.01–3.94(m,1H),3.88–3.69(m,4H),2.70(m,1H),2.11(m,1H).13C NMR(100MHz,DMSO-d6)δ156.40,154.29,148.73,137.13,132.36,128.85,128.12,127.71,124.59,122.07,81.91,74.53,73.59,68.21,66.86,60.61,43.70,33.13.HR-MS(ESI):Calcd.C18H22BrN7O6S.[M+H]+m/z:544.0609,found:544.0616.
化合物67：2-(((1R,2R,3R,4S)-4-(7-((2-甲基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率56％，熔点：137.6-138.6℃。1H NMR(400MHz,DMSO-d6)δ9.47–9.02(m,1H),8.34(d,J＝14.5Hz,1H),7.52(d,J＝4.1Hz,2H),7.29–7.09(m,4H),5.41–4.97(m,3H),4.75(d,J＝5.9Hz,2H),4.57(m,1H),4.16(t,J＝4.7Hz,2H),3.99(m,1H),3.87–3.69(m,3H),2.69(m,1H),2.10(m,1H).13CNMR(100MHz,DMSO-d6)δ156.39,154.27,148.68,136.53,135.37,129.86,126.85,126.72,125.70,124.58,81.93,74.47,73.62,68.20,66.85,60.58,41.08,33.09,18.73.HR-MS(ESI):Calcd.C19H25N7O6S.[M+H]+m/z:480.1660,found:480.1667.
化合物68：2-(((1R,2R,3R,4S)-4-(7-((2-甲氧基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率53％，熔点：142.0-142.8℃。1H NMR(400MHz,DMSO-d6)δ9.38–8.87(m,1H),8.38(d,J＝9.9Hz,1H),7.55(s,2H),7.28(m,1H),7.20(m,1H),7.06(d,J＝8.0Hz,1H),6.98–6.86(m,1H),5.24(d,J＝6.3Hz,1H),5.17–5.06(m,2H),4.79(d,J＝6.0Hz,2H),4.62(m,1H),4.21(t,J＝4.6Hz,2H),4.03(d,J＝5.4Hz,1H),3.89(d,J＝5.6Hz,4H),3.79(m,2H),2.75(m,1H),2.16(m,1H).13CNMR(100MHz,DMSO-d6)δ156.56,156.41,154.47,127.90,126.84,126.15,120.06,110.41,81.95,74.47,73.63,68.20,66.86,60.59,55.32.HR-MS(ESI):Calcd.C19H25N7O7S.[M+H]+m/z:496.1609,found:496.1613.
化合物69：2-(((1R,2R,3R,4S)-4-(7-((3-氟苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率55％，熔点：138.0-138.6℃。1H NMR(400MHz,DMSO-d6)δ9.55–9.12(m,1H),8.35(d,J＝22.5Hz,1H),7.51(s,2H),7.36(m,1H),7.27–7.15(m,2H),7.07(m,1H),5.27–5.01(m,3H),4.79(d,J＝6.1Hz,2H),4.56(m,1H),4.16(t,J＝4.5Hz,2H),3.99(m,1H),3.84–3.66(m,3H),2.69(m,1H),2.10(m,1H).13C NMR(100MHz,DMSO-d6)δ160.93,156.37,154.20,148.70,142.05,130.29,130.20,124.56,123.20,123.17,113.99,113.77,113.50,81.93,74.48,73.63,68.20,66.85,42.64,33.08.HR-MS(ESI):Calcd.C18H22FN7O6S.[M-H]-m/z:482.1263,found:482.1258.
化合物70：2-(((1R,2R,3R,4S)-4-(7-((3-氯苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率55％，熔点：133.0-133.8℃。1H NMR(400MHz,DMSO-d6)δ9.33(m,1H),8.36(d,J＝23.2Hz,1H),7.52(s,2H),7.42(d,J＝2.1Hz,1H),7.39–7.28(m,3H),5.22–5.07(m,3H),4.78(d,J＝6.1Hz,2H),4.56(m,1H),4.16(t,J＝4.6Hz,2H),3.98(s,1H),3.86–3.67(m,3H),2.69(m,1H),2.10(m,1H).13C NMR(100MHz,DMSO-d6)δ156.37,154.16,148.70,141.61,132.91,130.20,127.03,126.81,125.91,124.56,81.93,74.48,73.63,68.20,66.85,60.63,42.59,33.09.HR-MS(ESI):Calcd.C18H22ClN7O6S.[M+H]+m/z:500.1114,found:500.1121.
化合物71：2-(((1R,2R,3R,4S)-4-(7-((3-溴苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率58％，熔点：134.7-135.1℃。1H NMR(400MHz,DMSO-d6)δ9.55–9.12(m,1H),8.36(d,J＝23.8Hz,1H),7.64–7.55(m,1H),7.51(s,2H),7.48–7.41(m,1H),7.37(d,J＝7.7Hz,1H),7.29(t,J＝7.7Hz,1H),5.20(d,J＝6.1Hz,1H),5.17–5.04(m,2H),4.77(d,J＝6.1Hz,2H),4.56(m,1H),4.16(t,J＝4.5Hz,2H),3.98(d,J＝5.5Hz,1H),3.77(m,3H),2.69(m,1H),2.10(m,1H).13CNMR(100MHz,DMSO-d6)δ156.37,154.15,148.70,141.87,130.52,129.93,129.72,126.31,121.55,81.93,74.48,73.62,68.19,66.85,60.63,42.53,33.08.HR-MS(ESI):Calcd.C18H22BrN7O6S.[M+H]+m/z:544.0609,found:544.0615.
化合物72：2-(((1R,2R,3R,4S)-4-(7-((3-甲基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率56％，熔点：144.8-145.4℃。1H NMR(400MHz,DMSO-d6)δ9.28(m,1H),8.34(d,J＝28.0Hz,1H),7.51(s,2H),7.24–7.10(m,3H),7.05(d,J＝7.3Hz,1H),5.25–5.01(m,3H),4.74(d,J＝6.1Hz,2H),4.56(m,1H),4.16(t,J＝4.6Hz,2H),3.98(m,1H),3.87–3.63(m,3H),2.69(m,1H),2.27(s,3H),2.08(m,1H).13C NMR(100MHz,DMSO-d6)δ156.39,154.18,148.65,135.94,135.85,128.79,127.22,124.55,81.94,74.46,73.63,68.20,66.85,60.58,42.81,33.07,20.63.HR-MS(ESI):Calcd.C19H25N7O6S.[M-H]-m/z:478.1514,found:478.1510.
化合物73：2-(((1R,2R,3R,4S)-4-(7-((3-甲氧基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率51％，熔点：132.0-132.9℃。1H NMR(400MHz,DMSO-d6)δ9.50–9.07(m,1H),8.34(d,J＝27.3Hz,1H),7.50(s,2H),7.23(t,J＝7.8Hz,1H),7.03–6.90(m,2H),6.81(m,1H),5.18(d,J＝6.3Hz,1H),5.13–5.00(m,2H),4.74(d,J＝6.2Hz,2H),4.56(m,1H),4.16(t,J＝4.6Hz,2H),3.98(d,J＝5.5Hz,1H),3.72(s,3H),2.77–2.64(m,1H),2.10(m,1H).13C NMR(100MHz,DMSO-d6)δ159.23,156.38,154.22,148.67,140.58,129.34,119.36,113.06,112.09,81.94,74.46,73.64,68.20,66.85,60.61,54.94,43.02,33.08.HR-MS(ESI):Calcd.C19H25N7O7S.[M+H]+m/z:496.1609,found:496.1616.
化合物74：2-(((1R,2R,3R,4S)-4-(7-((3-三氟甲基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率61％，熔点：157.2-157.7℃。1H NMR(400MHz,DMSO-d6)δ9.64–9.15(m,1H),8.39(s,1H),7.83–7.54(m,4H),7.52(s,2H),5.34–5.03(m,3H),4.87(d,J＝6.0Hz,2H),4.57(m,1H),4.16(t,J＝4.6Hz,2H),3.99(m,1H),3.87–3.68(m,3H),2.70(m,1H),2.10(m,1H).13C NMR(100MHz,DMSO-d6)δ156.36,154.18,148.70,140.48,131.41,129.40,124.55,123.87,123.65,81.92,74.49,73.61,68.20,66.85,62.75,60.63,42.72,33.09.HR-MS(ESI):Calcd.C19H22F3N7O6S.[M+H]+m/z:534.1377,found:534.1385.
化合物75：2-(((1R,2R,3R,4S)-4-(7-((4-氟苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率56％，熔点：121.0-121.8℃。1H NMR(400MHz,DMSO-d6)δ9.60–9.06(m,1H),8.34(d,J＝23.0Hz,1H),7.50(s,2H),7.38(s,4H),5.18(d,J＝6.2Hz,1H),5.13–5.01(m,2H),4.75(d,J＝6.2Hz,2H),4.56(m,1H),4.16(t,J＝4.5Hz,2H),3.98(q,J＝4.8Hz,1H),3.77(m,3H),2.68(m,1H),2.09(m,1H).13C NMR(100MHz,DMSO-d6)δ156.37,154.17,148.68,138.01,131.38,129.09,129.01,128.22,124.56,81.94,74.50,73.63,68.21,66.86,60.62,42.47,33.09.HR-MS(ESI):Calcd.C18H22FN7O6S.[M-H]-m/z:482.1263,found:482.1259.
化合物76：2-(((1R,2R,3R,4S)-4-(7-((4-氯苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率56％，熔点：142.0-142.4℃。1H NMR(400MHz,DMSO-d6)δ9.55–9.12(m,1H),8.34(d,J＝22.7Hz,1H),7.51(s,2H),7.38(s,4H),5.19(d,J＝6.4Hz,1H),5.15–4.99(m,2H),4.75(d,J＝6.1Hz,2H),4.56(m,1H),4.16(t,J＝4.5Hz,2H),3.98(s,1H),3.76(m,3H),2.74–2.65(m,1H),2.09(m,1H).13C NMR(100MHz,DMSO-d6)δ156.37,154.17,148.68,138.03,131.37,129.09,128.22,124.55,81.93,74.48,73.62,68.20,66.85,60.61,42.46,33.08.HR-MS(ESI):Calcd.C18H22ClN7O6S.[M+H]+m/z:500.1114,found:500.1121.
化合物77：2-(((1R,2R,3R,4S)-4-(7-((4-溴苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率61％，熔点：137.2-137.8℃。1H NMR(400MHz,DMSO-d6)δ9.31(m,1H),8.34(d,J＝22.1Hz,1H),7.51(d,J＝7.9Hz,4H),7.34(m,2H),5.17(t,J＝5.7Hz,1H),5.13–5.01(m,2H),4.73(d,J＝6.2Hz,2H),4.55(m,1H),4.16(t,J＝4.6Hz,2H),3.97(d,J＝5.6Hz,1H),3.86–3.67(m,3H),2.68(m,1H),2.09(m,1H).13C NMR(100MHz,DMSO-d6)δ156.36,154.17,138.45,131.27,131.13,129.45,124.55,119.84,81.93,74.49,73.63,68.20,66.86,60.61,42.53,33.09.HR-MS(ESI):Calcd.C18H22BrN7O6S.[M+H]+m/z:544.0609,found:544.0613.
化合物78：2-(((1R,2R,3R,4S)-4-(7-((4-甲基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率67％，熔点：135.1-136.2℃。1H NMR(400MHz,DMSO-d6)δ9.27(d,J＝154.0Hz,1H),8.33(d,J＝28.6Hz,1H),7.51(s,2H),7.27(m,2H),7.11(d,J＝7.6Hz,2H),5.29–5.02(m,3H),4.72(d,J＝6.1Hz,2H),4.56(m,1H),4.16(t,J＝4.6Hz,2H),3.98(m,1H),3.77(m,3H),2.68(m,1H),2.26(s,3H),2.09(m,1H).13C NMR(100MHz,DMSO-d6)δ156.40,154.17,148.64,135.93,135.85,128.80,127.21,81.91,74.47,73.60,68.20,66.85,60.56,42.80,33.08,20.63.HR-MS(ESI):Calcd.C19H25N7O6S.[M-H]-m/z:478.1514,found:478.1511.
化合物79：2-(((1R,2R,3R,4S)-4-(7-((4-甲氧基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率62％，熔点：130.0-130.5℃。1H NMR(400MHz,DMSO-d6)δ9.24(m,1H),8.33(d,J＝35.5Hz,1H),7.50(s,2H),7.36–7.26(m,2H),6.92–6.85(m,2H),5.17(d,J＝6.3Hz,1H),5.13–5.02(m,2H),4.69(d,J＝6.1Hz,2H),4.55(m,1H),4.15(t,J＝4.6Hz,2H),3.98(d,J＝5.3Hz,1H),3.87–3.71(m,3H),3.71(s,3H),2.68(m,1H),2.09(m,1H).13C NMR(100MHz,DMSO-d6)δ158.21,156.40,154.10,130.91,128.65,124.55,113.65,81.91,74.46,73.60,68.20,66.85,60.55,55.00,54.98,42.51,33.07.HR-MS(ESI):Calcd.C19H25N7O7S.[M+H]+m/z:496.1609,found:496.1614.
化合物80：2-(((1R,2R,3R,4S)-4-(7-((4-三氟甲基苄基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2,3-二羟基环戊基)氧基)氨基磺酸乙酯。白色固体，产率56％，熔点：108.8-109.5℃。1H NMR(400MHz,DMSO-d6)δ9.40(m,1H),8.37(s,1H),7.63(m,4H),7.52(s,2H),5.32–5.03(m,3H),4.86(d,J＝6.0Hz,2H),4.57(m,1H),4.16(t,J＝4.6Hz,2H),3.99(m,1H),3.86–3.68(m,3H),2.70(m,1H),2.10(m,1H).13C NMR(100MHz,DMSO-d6)δ156.37,154.22,148.70,143.88,127.81,125.20,125.17,124.56,81.92,74.49,73.60,68.20,66.86,60.62,42.78,33.09.HR-MS(ESI):Calcd.C19H22F3N7O6S.[M+H]+m/z:534.1377,found:534.1383.
化合物81：2-(((1R,2R,3R,4S)-2,3-二羟基-4-(7-((萘-1-基甲基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)环戊基)氧基)氨基磺酸乙酯。白色固体，产率56％，熔点：112.0-112.7℃。1H NMR(400MHz,DMSO-d6)δ9.60–9.14(m,1H),8.39(s,1H),8.22(m,1H),8.00–7.94(m,1H),7.85(d,J＝8.0Hz,1H),7.63–7.42(m,6H),5.25(d,J＝5.9Hz,2H),5.19(d,J＝6.3Hz,1H),5.13–5.03(m,2H),4.57(m,1H),4.16(t,J＝4.6Hz,2H),4.01–3.94(m,1H),3.86–3.69(m,3H),2.69(m,1H),2.10(m,1H).13C NMR(100MHz,DMSO-d6)δ156.42,154.30,133.86,133.25,128.51,127.41,126.22,125.76,125.39,124.93,124.63,123.34,81.94,74.49,73.63,68.20,66.86,60.61,33.11,14.06.HR-MS(ESI):Calcd.C22H25N7O6S.[M+H]+m/z:516.1660,found:516.1663.
化合物82：2-(((1R,2R,3R,4S)-2,3-二羟基-4-(7-((1,2,3,4-四氢萘-1-基)氨基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-3-基)环戊基)氧基)氨基磺酸乙酯。无色油状液体，产率59％。1H NMR(400MHz,DMSO-d6)δ9.12(m,1H),8.36(d,J＝44.7Hz,1H),7.52(s,2H),7.15(m,4H),5.27–4.98(m,3H),4.57(s,1H),4.16(t,J＝4.6Hz,2H),3.99(s,1H),3.87–3.67(m,3H),2.88–2.62(m,3H),2.23–1.88(m,4H),1.79(t,J＝8.2Hz,1H).13C NMR(100MHz,DMSO-d6)δ156.53,148.83,137.26,137.08,128.76,127.57,126.72,125.73,124.34,81.96,74.48,73.63,68.21,66.86,60.52,47.86,33.10,29.22,28.78,20.43.HR-MS(ESI):Calcd.C21H27N7O6S.[M+H]+m/z:506.1817,found:506.1823.
化合物83：无色油状液体，产率52％。1H NMR(400MHz,DMSO-d6)δ9.14(m,1H),8.37(d,J＝47.9Hz,1H),7.50(s,2H),7.35–7.10(m,4H),5.19(d,J＝6.2Hz,1H),5.18–5.02(m,2H),4.57(m,1H),4.16(t,J＝4.6Hz,2H),3.99(t,J＝5.3Hz,1H),3.88–3.68(m,3H),3.06(m,1H),2.89(m,1H),2.70(m,1H),2.26–2.05(m,2H).13C NMR(100MHz,DMSO-d6)δ156.46,154.18,148.81,143.63,143.08,127.48,126.27,124.55,124.41,123.91,81.97,74.54,74.46,73.67,68.23,66.88,60.54,54.76,33.12,31.92,29.82.HR-MS(ESI):Calcd.C20H25N7O6S.[M+H]+m/z:492.1660,found:492.1667.
试验例
USP28蛋白抑制活性测定：采用本领域的通用方法，使用万分之一天平分别称量本发明实施例1～83所制备得到的三氮唑并嘧啶类衍生化合物1～83，每个样品称取1～2mg置于1.5mL的EP管中，加入DMSO配置成浓度为10mM溶液作为储备液备用。实验时需要根据所测浓度用Tris溶液稀释，然后加入不同体积的Ub-AMC底物溶液。避光下，室温摇床孵育5min。通过酶标仪，在发射波长355nm处测定释放AMC(4-甲基香豆素)的荧光强度，利用GraphPadPrism 6.0软件计算化合物对USP28蛋白的抑制率和IC50。此外，以AZ1作为阳性对照化合物，以相同方法测定其在20μM下的抑制率。结果见表1～2所示。抑制率(％)＝(100％组荧光强度-化合物组荧光强度)/(100％组荧光强度-空白组荧光强度)*100％。
表1本发明三氮唑并嘧啶类衍生物的USP28蛋白抑制活性
Figure BDA0003659842600000291
Figure BDA0003659842600000301
注：AZ1为阳性对照；“--”为化合物不溶解或有荧光干扰。
表2本发明代表性化合物的USP28蛋白抑制活性
Figure BDA0003659842600000302
由表1可知，本发明提供的三氮唑并嘧啶类衍生物对USP28有不同程度的抑制活性，其中，化合物29和58对USP28抑制能力最优。对化合物29和58进一步进行了USP28蛋白的半数浓度抑制测试，两者IC50分别为1.15±0.21μM和1.20±0.53μM，其抑制能力优于测试所用的的阳性对照化合物AZ1近10倍(表2)。综上，本发明提供的化合物对USP28具有良好的抑制活性，显示出良好的开发潜力，为新型抗肿瘤药物以及新型USP28抑制剂药物的开发开辟了一条有效途径。

Claims (10)

1.一种三氮唑并嘧啶类衍生物，其特征在于，所述三氮唑并嘧啶类衍生物为具有通式Ⅰ或通式Ⅱ或通式Ⅲ的化合物，通式Ⅰ、通式Ⅱ、通式Ⅲ如下所示：
Figure FDA0004099939100000011
其中，通式Ⅰ中，R1为环丙基、环己基、4-甲基哌啶基、4-甲基哌嗪基、正丙基、2-羟基乙基、2-甲氧基乙基、2-氨基乙基、2-(乙酰基氨基)乙基、2-(苯基氨基)乙基、2-(苯甲酸酯基氨基)乙基、2-(叔丁氧羰基氨基)乙基、2-(二甲基氨基)乙基、2-(叔丁氧羰基甲基氨基)乙基、(2-(4-苯基哌嗪-1-基)乙基、苄基、4-吡啶基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-甲氧基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-三氟甲基苄基、3,5-二甲氧基苄基、4-甲氧基苯基、4-氯苯基、2,3-二氢-1H-茚-1-基、苯并[d][1,3]二氧戊环-4-基中的任意一种；
通式Ⅱ中，R2为环丙基、环丁基、环戊基、环己基、4-苄基哌啶基、2-(乙酰基氨基)乙基、2-(苯基氨基)乙基、2-(苯甲酸酯基氨基)乙基、(2-(4-苯基哌嗪-1-基)乙基、(2-(4-苯甲酰基哌嗪-1-基)乙基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-吡啶基、3,5-二甲氧基苄基、3,4,5-三甲氧基苄基、4-甲氧基苯基、2,3-二氢-1H-茚-1-基、1,2,3,4-四氢萘-1-基中的任意一种；
通式Ⅲ中，R3为环丙基、环丁基、环戊基、2-(4-苯基哌嗪-1-基)乙基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-甲氧基苄基、3-三氟甲基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-甲氧基苄基、4-三氟甲基苄基、萘-1-基甲基、1,2,3,4-四氢萘-1-基、2,3-二氢-1H-茚-1-基中的任意一种。
2.如权利要求1所述的三氮唑并嘧啶类衍生物，其特征在于，所述三氮唑并嘧啶类衍生物为具有通式Ⅰ的化合物，R1选自环己基、2-氯苄基、4-氯苄基中的一种。
3.如权利要求1所述的三氮唑并嘧啶类衍生物，其特征在于，所述三氮唑并嘧啶类衍生物为具有通式Ⅱ的化合物，R2选自环丙基、2-(苯基氨基)乙基、(2-(4-苯甲酰基哌嗪-1-基)乙基、2,3-二氢-1H-茚-1-基、1,2,3,4-四氢萘-1-基中的一种。
4.如权利要求1所述的三氮唑并嘧啶类衍生物，其特征在于，所述三氮唑并嘧啶类衍生物为具有通式Ⅲ的化合物，R3选自2-(4-苯基哌嗪-1-基)乙基、2-溴苄基、2-甲基苄基、3-甲氧基苄基、3-三氟甲基苄基、4-溴苄基中的一种。
5.一种权利要求1所述的三氮唑并嘧啶类衍生物的制备方法，其特征在于，当所述三氮唑并嘧啶类衍生物具有通式Ⅰ时，其制备过程包括以下步骤：
1)化合物A、化合物B、碱性物质在溶剂A中，于64～130℃反应18～30h，得化合物C；
2)将化合物C与亚硝酸钠、溶剂B于-10～20℃反应0.5～2.0h，得化合物D；
3)将化合物D、胺类物质、碱性物质、溶剂C于室温反应2～12h，得到式Ⅰ所示的三氮唑并嘧啶类衍生物；
当所述三氮唑并嘧啶类衍生物具有通式Ⅱ时，其制备过程包括以下步骤：
A)化合物A、化合物B、碱性物质在溶剂A中，于64～130℃反应18～30h，得化合物C；
B)将化合物C与亚硝酸钠、溶剂B于-10～20℃反应0.5～2.0h，得化合物D；
C)将化合物D、胺类物质、碱性物质、溶剂C于室温反应2～12h，得化合物E；
D)惰性气氛下，于冰浴中将氨基磺酰氯的乙腈溶液滴加到化合物E的乙腈溶液中，在碱性物质作用下反应0.5～2.0h，反应结束后向反应体系中滴加醇类溶剂淬灭反应，然后直接向体系中滴加酸性物质，室温反应4～12h，得到式Ⅱ所示的三氮唑并嘧啶类衍生物；
当所述三氮唑并嘧啶类衍生物具有通式Ⅲ时，其制备过程包括以下步骤：
a)将化合物F、化合物B、碱性物质在溶剂A中，于64～130℃反应18～30h，得化合物G；
b)将化合物G与亚硝酸钠、溶剂B于-10～20℃反应0.5～2.0h，得化合物H；
c)将化合物H、胺类物质与碱性物质、溶剂C于室温反应2～12h，得化合物J；
d)惰性气氛下，于冰浴中将氨基磺酰氯的乙腈溶液滴加到化合物J的乙腈溶液中，在碱性物质作用下反应0.5～2.0h，反应结束后向反应体系中滴加醇类溶剂淬灭反应，然后向体系中滴加酸性物质，室温反应4～12h，得到式Ⅲ所示的三氮唑并嘧啶类衍生物；
其中，步骤3)中的胺类物质选自通式化合物NH2-R1中的一种；步骤C)中的胺类物质选自通式化合物NH2-R2中的一种；步骤c)中的胺类物质选自通式NH2-R3中的一种；
所述化合物A、B、C、D、E、F、G、H、J的结构式如下所示：
Figure FDA0004099939100000031
6.如权利要求5所述的三氮唑并嘧啶类衍生物的制备方法，其特征在于，所述碱性物质为三乙胺、吡啶、N,N-二异丙基乙胺中的一种。
7.如权利要求5所述的三氮唑并嘧啶类衍生物的制备方法，其特征在于，所述溶剂A为甲醇、乙醇、丙醇中的一种；所述溶剂B为醋酸；所述溶剂C为乙腈。
8.如权利要求5所述的三氮唑并嘧啶类衍生物的制备方法，其特征在于，步骤D)和步骤d)中，所述醇类溶剂为甲醇。
9.如权利要求5所述的三氮唑并嘧啶类衍生物的制备方法，其特征在于，步骤D)和步骤d)中，所述惰性气氛为氮气或氩气。
10.如权利要求1～4任一项所述的三氮唑并嘧啶类衍生物的应用，其特征在于，所述三氮唑并嘧啶类衍生物在制备基于USP28靶点的抑制剂或抗肿瘤药物中的应用。
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