[0001] 本发明涉及有机合成领域，具体而言，涉及一种4,6‑二芳基‑2‑取代嘧啶胍类化合物及其制备方法和应用。

[0002] 在转录前的组蛋白修饰中,赖氨酸甲基化被研究的最为广泛。组蛋白赖氨酸甲基化修饰是造成表观遗传变化的原因之一。调节赖氨酸甲基化的酶主要分为两类:组蛋白赖氨酸甲基转移酶(histone lysine methyltransferases,HKMTs)和组蛋白赖氨酸去甲基化酶(histone lysine demethylases,HKDMs)。HKMTs负责将甲基从甲基供体转移到组蛋白赖氨酸上,完成甲基化修饰。而HKDMs的功能主要是将甲基从组蛋白赖氨酸上移除,完成脱甲基过程。二者生物学功能相反,共同调节着组蛋白赖氨酸的甲基化状态。组蛋白赖氨酸去甲基化酶(HKDMs)的错误调控和诸多疾病的发生发展密切相关,如老年性疾病、肿瘤等，HKDMs还与肿瘤药物的耐药有关。因此,HKDMs已成为抗肿瘤新药开发的重要靶标,越来越受到人们的关注。

[0003] 至今已发现的组蛋白赖氨酸去甲基化酶(HKDMs)有两类:一类为赖氨酸特异性去甲基化酶(lysine specific demethylases,LSDs),也称FAD(flavin adenine dinucleotide)依赖性胺氧化酶 ,包括LSDl和LSD2。另一类为JmjC
(Jumonjidomaincontaining protein)组蛋白去甲基化酶,是一类分子中含有Jumonji结构域的蛋白家族,不同于LSD1，它可催化三甲基化赖氨酸去甲基化，其家族成员的N端和C端都包含一个Jumonji小的特征结构域，分别称为JmjN和JmjC，其中，JmjN结构域与转录调节相关，而JmjC是JmjC家族酶活性中心的组成部分，目前已发现的一些含有JmjC结构域的JmjC显示出不同的底物特异性，其去甲基催化过程依赖于Fe(II)和α‑酮戊二酸(2‑OG)的参与。

[0004] 组蛋白去甲基化酶是一个新兴的药物靶点，从第一类组蛋白去甲基化酶LSD家族被发现至今只有不到20年，第二类JmjC家族发现的时间更晚，目前对于JmjC家族的研究还处于发展阶段，虽然近年来陆续发现了各种类型的JmjC抑制剂，但是大多数是由其他靶点衍生而来，不可避免的存在选择性问题和临床疗效问题，JmjC组蛋白去甲基化酶已经逐渐成为研究表观遗传的重要靶点，受到越来越多的关注，开发出新型的JmjC抑制剂有望为抗肿瘤质量提供新的思路。

[0019] 为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。

[0020] 下面对本发明实施例的一种4,6‑二芳基‑2‑取代嘧啶胍类化合物及其制备方法和应用进行具体说明。

[0021] 一种4,6‑二芳基‑2‑取代嘧啶胍类化合物，其结构式为

[0022]

[0023] 其中，R1选自氢、C1～C9烷基、C1～C9取代烷基、C2～C9烯基、C2～C9取代烯基、C2～C9炔基、C2～C9取代炔基、C1～C9烷氧基、C1～C9取代烷氧基、C5～C10环烷基、C5～C10杂环烷基、C6～C10芳基、或C6～C10取代芳基；

[0024] R2和R3可以相同也可以不同，分别独立地选自C6～C10芳基，或C6～C10取代芳基。

[0025] 优选地，R1选自氢、C1～C6烷基、C1～C6取代烷基、C2～C6烯基、C2～C6取代烯基、C2～C6炔基、C2～C6取代炔基、C1～C6烷氧基、C1～C6取代烷氧基、C5～C8环烷基、C5～C8杂环烷基、C6～C8芳基、或C6～C8取代芳基；

[0026] R2和R3可以相同也可以不同，分别独立地选自C6～C8芳基，或C6～C8取代芳基。

[0027] 其中，烷基可以是直链烷基也可以是支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、叔丁基等。取代烷基是指烷基中的至少一个氢原子被卤素、羟基、烷氧基或芳基取代后的基团。烯基可以是直链烯基也可以是支链烯基，包括但不限于乙烯基、丙烯基、烯丙基、丁烯基等，双键的数量可以为单个也可以为多个。取代烯基是指烯基中的至少一个氢原子被卤素、羟基、烷氧基或芳基取代后的基团。炔基可以是直链炔基也可以是支链炔基，包括但不限于乙炔基、丙炔基、炔丙基、丁炔基等。取代炔基是指炔基中的至少一个氢原子被卤素、羟基、烷氧基或芳基取代后的基团。烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。取代烷氧基是指烷基中的至少一个氢原子被卤素、羟基、烷氧基或芳基取代后的基团，包括但不限于2‑甲氧基乙氧基、3‑甲氧基丙氧基等。环烷基包括但不限于环丙级、环丁基、环己基、甲基环己基等。杂环烷基是指环烷基中的至少一个碳原子被氧、氮、硫等取代后的基团。芳基包括但不限于苯基、吡啶基、萘基等。取代芳基是指芳基中的至少一个氢原子被卤素、羟基、烷氧基或芳基取代后的基团。

[0028] 本发明实施例还提供了一种上述4,6‑二芳基‑2‑取代嘧啶胍类化合物的制备方法，其包括：

[0029] 将化合物I与取代胺发生取代反应，得到化合物II；

[0030] 化合物II在碱试剂的作用下水解，得到4,6‑二芳基‑2‑取代嘧啶胍类化合物；

[0031] 其中，化合物I的结构式为 取代胺的结构式为R4NH2，化合物II的结构式为

[0032] 当R1为氢时，取代胺为对硝基苄胺，在对化合物II进行水解时，R4被水解为氢；当R1不为氢时，R4和R1为相同的基团。

[0033] 进一步地，化合物I和取代胺的摩尔比为1：2～2.5。由于取代胺的原料更加容易得到，因此将取代胺的用量过量，从而确保化合物I能够充分反应，提高产品收率。

[0034] 可选地，化合物I和取代胺的反应，是在EDCI和DIPEA的催化下进行的，化合物I、所EDCI和DIPEA的摩尔比为1：1.8～2.2：1.8～2.2。EDCI可以C＝S键进行活化，从而让取代胺能够更好地进行亲核反应，进攻C＝S键的碳原子，得到胍结构。

[0035] 进一步地，化合物I是由化合物III与苯甲酰异硫氰酸酯反应得到的，化合物III的结构式为

[0036]

[0037] 化合物III的氨基进攻异硫氰酸酯的碳原子，从而得到化合物I。其中，化合物III和苯甲酰异硫氰酸酯的摩尔比为1：3～5，反应温度为70～80℃，反应时间5～8h。在上述反应条件下，可以使得化合物III充分反应，提高产品收率。

[0038] 进一步地，化合物III是由化合物IV与盐酸胍在碱催化下缩合反应得到的，化合物IV的结构式为

[0039]

[0040] 化合物IV和胍在碱催化下发生1,4加成缩合反应，从而得到化合物III。化合物IV和盐酸胍的用量为1：2.5～3；反应温度为70～80℃，反应时间7～10h。在上述反应条件下，化合物IV可以充分转化为化合物III。

[0041] 此外，化合物IV的结构比较常见，可以直接通过商业渠道购买得到，也可以，以芳基甲醛和芳基乙酮作为原料，通过羟醛缩合反应合成得到。

[0042] 本发明实施例还提供了一种上述4,6‑二芳基‑2‑取代嘧啶胍类化合物在制备组蛋白去甲基化酶抑制剂中的应用。

[0043] 进一步地，该组蛋白去甲基化酶抑制剂包括4,6‑二芳基‑2‑取代嘧啶胍类化合物、其盐或其衍生物。

[0044] 在制备4,6‑二芳基‑2‑取代嘧啶胍类化合物的盐时只需将4,6‑二芳基‑2‑取代嘧啶胍类化合物与对应的酸反应即可，例如制备其盐酸盐时，只需要将4,6‑二芳基‑2‑取代嘧啶胍类化合物和浓盐酸进行反应即可。

[0045] 在制备4,6‑二芳基‑2‑取代嘧啶胍类化合物的衍生物时，通过常规的反应类型，进行取代、氧化还原、加成反应等。例如，将4,6‑二芳基‑2‑取代嘧啶胍类化合物与羧酸反应，制备得到酰胺化合物。

[0046] 以下结合实施例对本发明的特征和性能作进一步的详细描述。

[0047] 实施例1

[0048] 本实施例提供了一种2‑(4‑(4‑甲氧基苯基))‑6‑苯基嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)胍及其盐酸盐(记作A01)，其制备方法如下：

[0049] S1.制备化合物IV

[0050] 将苯甲醛(2.12g,20mmol)置于500mL圆底烧瓶中，用100mL甲醇溶解。冰浴下加入氢氧化钾水溶液(150mmol,6.0g氢氧化钾溶于54mL水中)和4‑甲氧基苯乙酮(3.00g,20mmol)，搅拌0.5h后撤去冰浴，室温搅拌10h后停止反应。反应完成后会析出大量沉淀，过滤并用200mL混合溶剂(甲醇：水＝1:1)洗涤，滤渣干燥后得到中间体1，可不需进一步纯化直接用于下一步，产率：82％。

[0051] S2.制备化合物III

[0052] 取250mL圆底烧瓶，将盐酸胍(3.58g,37.5mmol)用100mL乙醇溶解后，加入氢氧化钠(1.5g,37.5mmol)，搅拌0.5h使胍游离出来。再将(E)‑1‑(4‑甲氧基苯基)‑3‑苯基丙‑2‑烯‑1‑酮(化合物IV,3.57g,15mmol)置入另一个500mL圆底烧瓶中并用100mL乙醇溶解。将游离胍的乙醇溶液倒入中间体1的乙醇溶液中，75℃下回流8h。反应完毕后，减压蒸除溶剂，通过柱层析纯化(二氯甲烷：乙酸乙酯＝40:1)得到化合物III，产率：24％。

[0053] S3.制备化合物I

[0054] 将4‑(4‑甲氧基苯基)‑6‑苯基嘧啶‑2‑胺(化合物III,0.83g,3mmol)置于100mL圆底烧瓶中并用40mL乙腈溶解，加入苯甲酰基异硫氰酸酯(1.96g,12mmol)。75℃下回流5h，反应完毕后会有大量沉淀析出。过滤并用100mL乙醇洗涤。滤渣干燥后得到化合物I，可不需继续纯化直接用于下一步反应，产率：77％。

[0055] S4.制备化合物II

[0056] 将4‑氨基四氢吡喃(0.10g,1mmol)置于25mL圆底烧瓶中并用15mL二氯甲烷溶解后，加入DIPEA(0.13g,1mmol)，室温下搅拌0.5h。随后在反应液中加入N‑((4‑(4‑甲氧基苯基)‑6‑苯基嘧啶‑2‑基)氨基甲硫基)苯甲酰胺(化合物I,0.22g,0.5mmol)和EDCI(0.19g,1mmol)。室温搅拌10h后停止反应，在反应液中加入75mL的二氯甲烷稀释，用水洗涤三次(3×30mL)，饱和食盐水洗涤三次(3×30mL)。有机相用无水硫酸钠干燥，减压旋干后通过柱层析纯化得到化合物II，产率：87％。

[0057] S5.制备2‑(4‑(4‑甲氧基苯基))‑6‑苯基嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)胍[0058] 将(E)‑N‑(N‑(4‑(4‑甲氧基苯基))‑6‑苯基嘧啶‑2‑基)‑N'‑(四氢‑2H‑吡喃‑4‑基)氨甲酰基)苯甲酰胺(化合物II,0.22g,0.44mmol)置于50mL圆底烧瓶中，用10mL混合溶剂(四氢呋喃：甲醇＝1:1)溶解。向反应液中加入氢氧化钠水溶液(40mmol,1.5g氢氧化钠溶于3.5mL水中)，70℃下回流3h。反应完毕后，将反应液倒入100mL水中，有沉淀析出，过滤得到沉淀并用大量水洗涤，甲醇重结晶得到中间体5。产率：83％。

[0059] S6.制备2‑(4‑(4‑甲氧基苯基))‑6‑苯基嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍

[0060] 取25mL圆底烧瓶，加入全部的2‑(4‑(4‑甲氧基苯基))‑6‑苯基嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)胍(中间体5)和10mL甲醇。向溶液中加入5‑10滴浓盐酸，室温搅拌48h。有大量沉淀析出，过滤并用50mL甲醇洗涤，收集滤渣即得产物A01。产率：93％；白色固体。

[0061] 化合物A01的表征如下：

[0062] M.p.:186‑187℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.20(s,1H),9.87(d,J＝7.9Hz,1H),

[0063] 9.05(s,2H),8.32‑8.07(m,5H,aromatic),7.75‑7.38(m,3H,aromatic),7.12(d,J＝8.7Hz,2H,aromatic),4.02‑3.88(overlap,3H,tetrahydropyranyl),3.86(s,3H,OCH3),3.49‑3.40(overlap,2H,tetrahydropyranyl),2.06‑1.94(m,2H,tetrahydropyranyl),
13
1.64‑1.47(m,2H,tetrahydropyranyl)；CNMR(100MHz,DMSO‑d6,ppm)δ:165.3,165.2,
162.8,157.9,153.6,136.0,132.2,129.7,129.5,128.0,127.9,114.9,107.9,65.8,56.0,+
47.8,32.4.HRMS‑ESI:m/z calced for C23H26N5O2[M+H]404.2081,found 404.2075.[0064] 实施例2～68

[0065] 实施例2～68提供了一系列4,6‑二芳基‑2‑取代嘧啶胍类化合物，及其盐(分别记作A02～A68)，其制备方法参考实施例1，化合物A02～A68的结构式如表1所示，

[0066] 表1.4,6‑二芳基‑2‑取代嘧啶胍类化合物盐酸盐结构式

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] 化合物A02：2‑(4‑(2‑羟基苯基))‑6‑苯基嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0075] 白色固体；总产率14％；M.p.:173‑174℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.42(s,2H),9.73(s,1H),8.94(s,2H),8.32(s,1H,aromatic),8.20‑8.12(m,2H,aromatic),8.09(dd,J＝7.9,1.1Hz,1H,aromatic),7.68‑7.54(m,3H,aromatic),7.47‑7.39(m,1H,aromatic),7.08(d,J＝8.2Hz,1H,aromatic),7.05‑6.94(m,1H,aromatic),4.02‑3.81(m,
3H,tetrahydropyranyl),3.45(overlap,2H,tetrahydropyranyl),2.05‑1.89(m,2H,
13
tetrahydropyranyl),1.63‑1.46(m,2H,tetrahydropyranyl)；CNMR(100MHz,DMSO‑d6,ppm)δ:165.7,165.0,158.5,156.9,153.4,136.1,133.7,132.2,130.1,129.6,127.8,+
120.5,120.0,118.2,110.2,65.8,47.9,32.4.HRMS‑ESI:m/z calced for C22H24N5O2[M+H]
390.1925,found 390.1929.

[0076] 化合物A03：2‑(4‑(3‑硝基苯基))‑6‑苯基嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0077] 白色固体；总产率17％；M.p.:213‑215℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.30(s,1H),9.68(d,J＝7.9Hz,1H),9.02(s,2H),8.70(d,J＝7.8Hz,1H,aromatic),8.45(s,1H,aromatic),8.40(dd,J＝8.2,2.5Hz,1H,aromatic),8.23(d,J＝7.5Hz,2H,aromatic),7.86(t,J＝8.0Hz,1H,aromatic),7.67‑7.53(m,3H,aromatic),4.01‑3.94(m,1H,tetrahydropyranyl),3.93‑3.85(m,2H,tetrahydropyranyl),3.49‑3.41(m,2H,
tetrahydropyranyl),2.05‑1.94(m,2H,tetrahydropyranyl),1.66‑1.48(m,2H,
13
tetrahydropyranyl)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.7,162.9,157.5,152.9,148.4,
137.0,135.1,133.9,132.1,130.7,129.1,127.6,126.1,121.8,108.9,65.4,47.5,
+
32.0.HRMS‑ESI:m/z calced for C22H23N6O3[M+H]419.1826,found 419.1820.

[0078] 化合物A04：2‑(4‑(4‑溴苯)‑6‑(4‑甲氧基苯基)嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0079] 白色固体；总产率12％；M.p.:275‑276℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.26(s,1H),9.79(s,1H),9.04(s,2H),8.25‑8.09(m,5H,aromatic),7.77(d,J＝8.4Hz,2H,aromatic),7.10(d,J＝8.8Hz,2H,aromatic),4.00‑3.87(m,3H,tetrahydropyranyl),3.86(s,3H,OCH3),3.50‑3.40(overlap,2H,tetrahydropyranyl),2.05‑1.93(m,2H,13
tetrahydropyranyl),1.63‑1.46(m,2H,tetrahydropyranyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.9,163.5,162.4,157.5,153.1,134.7,132.0,129.3,129.3,127.4,125.5,+
114.4,107.3,65.4,55.6,47.4,32.0.HRMS‑ESI:m/z calced for C22H25BrN5O2[M+H]
482.1186,found 482.1185.

[0080] 化合物A05：2‑(4,6‑二(4‑甲氧基苯基))嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0081] 白色固体；总产率18％；M.p.:280‑282℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.12(s,1H),9.89(s,1H),9.05(s,2H),8.34‑8.01(overlap,5H,aromatic),7.11(d,J＝7.8Hz,4H,aromatic),4.03‑3.88(overlap,3H,tetrahydropyranyl),3.86(s,6H,2OCH3),3.50‑
3.41(overlap,2H,tetrahydropyranyl),2.10‑1.89(m,2H,tetrahydropyranyl),1.66‑
13
1.48(m,2H,tetrahydropyranyl). CNMR(100MHz,DMSO‑d6,ppm)δ:164.3,162.2,157.3,
153.2,129.1,127.7,114.4,106.5,65.4,55.5,47.4,40.1,39.9,39.7,39.5,39.3,39.1,+
38.9,32.0.HRMS‑ESI:m/z calced for C24H28N5O3[M+H]434.2187,found 434.2182.[0082] 化合物A06：2‑(4,6‑二(4‑溴苯基))嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0083] 白色固体；总产率16％；M.p.:285℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.29(s,1H),9.69(d,J＝7.6Hz,1H),9.01(s,2H),8.31(s,1H,aromatic),8.14(d,J＝8.5Hz,4H,aromatic),7.77(d,J＝8.6Hz,4H,aromatic),4.02‑3.79(overlap,3H,
tetrahydropyranyl),3.49‑3.41(overlap,2H,tetrahydropyranyl),2.05‑1.91(m,2H,
13
tetrahydropyranyl),1.64‑1.44(m,2H,tetrahydropyranyl). CNMR(100MHz,DMSO‑d6,ppm)δ:164.6,157.9,153.4,134.8,132.5,129.8,126.3,108.6,65.9,47.9,32.4.HRMS‑
81 +
ESI:m/z calced for C22H22N5OBr Br[M+H]532.0165,found 532.0158.

[0084] 化合物A07：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0085] 淡黄色固体；总产率21％；M.p.:207‑208℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.24(s,1H),9.73(d,J＝7.3Hz,1H),9.04(s,2H),8.92(s,1H,aromatic),8.73(d,J＝7.8Hz,1H,aromatic),8.45(d,J＝8.1Hz,1H,aromatic),8.39(s,1H,aromatic),8.24(d,J＝8.7Hz,2H,aromatic),7.90(t,J＝8.0Hz,1H,aromatic),7.14(d,J＝8.8Hz,2H,aromatic),4.06‑
3.94(m,3H,tetrahydropyranyl),3.92(s,3H,OCH3),3.55‑3.47(m,2H,
tetrahydropyranyl),2.15‑1.93(m,2H,tetrahydropyranyl),1.71‑1.57(m,2H,
13
tetrahydropyranyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.2,162.5,162.3,157.3,152.9,
148.3,137.0,133.8,130.6,129.4,127.2,126.0,121.6,114.4,107.9,65.5,55.6,48.6,+
47.5,32.0.HRMS‑ESI:m/z calced for C23H25N6O4[M+H]449.1932,found 449.1924.[0086] 化合物A08：1‑(2‑氯苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)盐酸胍的表征如下：

[0087] 白色固体；总产率19％；M.p.:247‑248℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.47(s,1H),9.96(s,1H),9.10(s,2H),8.91(s,1H,aromatic),8.58(d,J＝7.6Hz,1H,aromatic),8.42‑8.27(m,2H,aromatic),8.02(d,J＝8.1Hz,2H,aromatic),7.78(t,J＝
8.0Hz,1H,aromatic),7.70(d,J＝6.8Hz,1H,aromatic),7.57(d,J＝7.5Hz,1H,aromatic),
7.51‑7.38(m,2H,aromatic),6.94(d,J＝8.4Hz,2H,aromatic),4.79(d,J＝5.3Hz,2H,N‑
13
CH2),3.83(s,3H,OCH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.0,162.6,162.4,157.3,
154.1,148.3,137.0,133.6,133.2,133.0,130.5,130.3,129.8,129.3,127.8,127.0,+
125.9,121.9,114.3,108.0,55.5,43.3.HRMS‑ESI:m/z calced for C25H22N6O3Cl[M+H]
489.1436,found 489.1426.

[0088] 化合物A09：1‑(烯丙氧基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)盐酸胍的表征如下：

[0089] 白色固体；总产率22％；M.p.:179℃；1H NMR(600MHz,MeOD‑d1,ppm)δ:8.83(s,1H,aromatic),8.51(s,1H,aromatic),8.35(d,J＝6.3Hz,1H,aromatic),8.13‑7.97(m,3H,aromatic),7.76(s,1H,aromatic),7.02(d,J＝5.2Hz,2H,aromatic),6.18(m,1H,C‑CH＝C),5.56(d,J＝17.1Hz,1H,C＝CHA),5.48(d,J＝10.1Hz,1H,C＝CHB),4.60(d,J＝5.9Hz,2H,13
O‑CH2‑C),3.88(s,3H,OCH3)；C NMR(150MHz,MeOD‑d1,ppm)δ:166.1,163.2,163.0,157.3,
155.6,148.7,137.2,133.1,131.2,130.2,129.1,127.1,125.5,121.6,121.6,114.2,+
107.8,78.1,54.8.HRMS‑ESI:m/z calced for C21H21N6O4[M+H] 421.1619,found 
421.1619.

[0090] 化合物A10：1‑(4‑羟苯基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)盐酸胍的表征如下：

[0091] 白色固体；总产率24％；M.p.:190℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.32(s,1H),9.97‑9.67(overlap,2H),8.96‑8.70(overlap,3H),8.50(d,J＝7.8Hz,1H,aromatic),
8.34(dd,J＝8.1,1.6Hz,1H,aromatic),8.25(s,1H,aromatic),7.84‑7.69(m,3H,
aromatic),7.36(d,J＝8.4Hz,2H,aromatic),6.93‑6.74(m,4H,aromatic),4.49(d,J＝
13
4.2Hz,2H,N‑CH2‑),3.82(s,3H,OCH3)；CNMR(100MHz,DMSO‑d6,ppm)δ:164.5,162.5,162.2,
157.7,157.3,153.4,148.3,136.9,133.5,130.4,130.2,129.1,126.7,125.9,125.3,+
121.8,115.8,114.2,107.6,55.4,45.3.HRMS‑ESI:m/z calced for C25H23N6O4[M+H]
471.1775,found 471.1767.

[0092] 化合物A11：1‑(4‑氟苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)盐酸胍的表征如下：

[0093] 白色固体；总产率20％；M.p.:172‑173℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.40(s,1H),9.92(s,1H),9.05(s,2H),8.86(s,1H,aromatic),8.54(d,J＝7.8Hz,1H,aromatic),8.35(dd,J＝8.2,2.2Hz,1H,aromatic),8.27(s,1H,aromatic),7.91(d,J＝
8.5Hz,2H,aromatic),7.75(t,J＝8.0Hz,1H,aromatic),7.61(dd,J＝8.3,5.5Hz,2H,aromatic),7.29(t,J＝8.6Hz,2H,aromatic),6.87(d,J＝8.4Hz,2H,aromatic),4.67(d,J
13
＝5.2Hz,2H,N‑CH2),3.81(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.8,163.2(d,
1 4
JCF＝244.2Hz),162.4,162.3,157.3,153.8,148.3,136.9,133.5,132.0(d,JCF＝3.2Hz),
3 2
130.6,(d,JCF＝8.5Hz),130.4,129.1,126.9,125.9,121.8,115.8(d,JCF＝21.7Hz),+
114.1,107.8,55.4,44.4.HRMS‑ESI:m/z calced for C25H22N6O3F[M+H] 473.1732,found473.1722.

[0094] 化合物A12：4‑(2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍基)哌啶‑1‑羧酸乙酯盐酸盐的表征如下：

[0095] 白色固体；总产率15％；M.p.:186‑188℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.16(s,1H),9.62(d,J＝7.6Hz,1H),8.98(s,2H),8.89(s,1H,aromatic),8.69(d,J＝7.8Hz,1H,aromatic),8.41(dd,J＝8.2,2.3Hz,1H,aromatic),8.37(s,1H,aromatic),8.22(d,J＝8.6Hz,2H,aromatic),7.86(t,J＝8.0Hz,1H,aromatic),7.10(d,J＝8.4Hz,2H,aromatic),
4.05(q,J＝7.1Hz,2H,O‑CH2‑),3.96(overlap,3H,piperidinyl),3.86(s,3H,OCH3),3.12‑
2.89(m,2H,piperidinyl),2.09‑1.95(m,2H,piperidinyl),1.58‑1.42(m,2H,
13
piperidinyl),1.19(t,J＝7.1Hz,3H,CH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.4,162.5,
157.4,154.6,153.0,148.4,137.1,133.8,130.7,129.4,127.3,126.0,121.7,114.4,+
108.0,60.8,55.6,48.3,41.8,30.8,14.6.HRMS‑ESI:m/z calced for C26H30N7O5[M+H]
520.2303,found 520.2313.

[0096] 化合物A13：4‑((2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍基)甲基)苯甲酸盐酸盐的表征如下：

[0097] 白色固体；总产率17％；M.p.:232‑233℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.47(s,1H),9.99(s,1H),9.11(s,2H),8.88(s,1H,aromatic),8.58(d,J＝7.9Hz,1H,aromatic),8.34(dd,J＝8.2,1.5Hz,1H,aromatic),8.29(s,1H,aromatic),8.00(d,J＝
8.3Hz,2H,aromatic),7.92(d,J＝8.6Hz,2H,aromatic),7.76(t,J＝8.0Hz,1H,aromatic),
7.65(d,J＝8.3Hz,2H,aromatic),6.84(d,J＝8.8Hz,2H,aromatic),4.79(d,J＝5.2Hz,2H,
13
N‑CH2),3.79(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:167.1,164.8,162.5,162.3,
157.3,154.1,148.3,140.7,136.9,133.6,130.6,130.5,129.9,129.2,128.4,126.9,+
125.9,121.8,114.2,107.8,55.4,44.9.HRMS‑ESI:m/z calced for C26H23N6O5[M+H]
499.1724,found 499.1716.

[0098] 化合物A14：1‑(4‑甲氧苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)盐酸胍的表征如下：

[0099] 白色固体；总产率23％；M.p.:250℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.41(s,br,1H),9.89(s,1H),9.09‑8.75(overlap,3H),8.50(d,J＝7.3Hz,1H,aromatic),8.34(d,J＝
8.1Hz,1H,aromatic),8.23(s,1H,aromatic),7.89‑7.76(m,2H,aromatic),7.72(t,J＝
7.8Hz,1H,aromatic),7.48(d,J＝8.2Hz,2H,aromatic),7.00(d,J＝8.3Hz,2H,aromatic),
13
6.81(d,J＝6.4Hz,2H,aromatic),4.57(s,2H,N‑CH2),3.79(overlap,6H)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.50,162.37,162.18,159.27,157.31,153.52,148.22,136.82,133.50,
130.39,130.21,129.07,127.34,126.74,125.90,121.74,114.38,114.10,107.47,55.37,+
55.24,45.02.HRMS‑ESI:m/z calced for C26H25N6O4[M+H]485.1932,found 485.1922.[0100] 化合物A15：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(4‑(三氟甲氧基)苄基)胍盐酸盐的表征如下：

[0101] 白色固体；总产率14％；M.p.:170℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.41(s,br,1H),9.94(s,1H),9.08(s,2H),8.91(s,1H,aromatic),8.60(d,J＝7.6Hz,1H,aromatic),
8.41‑8.27(overlap,2H,aromatic),8.02(d,J＝7.6Hz,2H,aromatic),7.78(t,J＝7.8Hz,
1H,aromatic),7.67(d,J＝7.9Hz,2H,aromatic),7.45(d,J＝7.9Hz,2H,aromatic),6.94
13
(d,J＝8.0Hz,2H,aromatic),4.75(s,2H,N‑CH2),3.82(s,3H,OCH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.0,162.5,162.4,157.4,154.0,148.3,148.0,137.0,135.5,133.7,130.5,α
130.1,129.3,127.0,125.9,121.9,121.4,120.9(q,JCF＝259.4Hz),119.2,114.3,107.9,+
55.5,45.3.HRMS‑ESI:m/z calced for C26H22N6O4F3[M+H]539.1649,found 539.1641.[0102] 化合物A16：(1r,4r)‑4‑(2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基嘧啶‑2‑基)胍基)环己烷‑1‑羧酸盐酸盐的表征如下：

[0103] 白色固体；总产率18％；M.p.:311‑313℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:12.28(s,br,1H),11.10(s,1H),9.60(s,1H),8.80(overlap,3H),8.66(d,J＝7.8Hz,1H,aromatic),8.37(d,J＝8.1Hz,1H,aromatic),8.30(s,1H,aromatic),8.15(d,J＝8.3Hz,
2H,aromatic),7.83(t,J＝7.9Hz,1H,aromatic),7.06(d,J＝8.4Hz,2H,aromatic),3.85(s,3H,OCH3),3.62(overlap,1H,substituted cyclohexyl),2.33‑2.20(m,1H,
substituted cyclohexyl),2.10‑2.01(m,2H,substituted cyclohexyl),2.02‑1.88(m,
13
2H,substituted cyclohexyl),1.56‑1.27(m,4H,substituted cyclohexyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:176.4,165.3,162.6,162.2,157.4,152.9,148.4,137.0,133.8,
130.7,129.4,127.2,126.1,121.5,114.4,107.8,55.6,49.8,41.1,31.0,27.2.HRMS‑ESI:
+
m/z calced for C25H27N6O5[M+H]491.2037,found 491.2027.

[0104] 化合物A17：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(4‑(三氟甲基)苄基)胍盐酸盐的表征如下：

[0105] 白色固体；总产率16％；M.p.:157‑159℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.46(s,1H),9.98(s,1H),9.11(s,2H),8.92(s,1H,aromatic),8.62(d,J＝7.8Hz,1H,aromatic),8.41‑8.29(m,2H,aromatic),8.04(d,J＝8.5Hz,2H,aromatic),7.86‑7.65(m,
5H,aromatic),6.93(d,J＝8.4Hz,2H,aromatic),4.83(d,J＝5.6Hz,2H,N‑CH2),3.82(s,
13
3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.0,162.6,162.4,157.4,154.1,148.3,β
140.8,137.0,133.7,130.5,129.3,128.8,128.7(q,JCF＝32.7Hz),127.0,125.9,125.7(qγ α
, JCF＝3.8Hz),125.6(q,JCF＝271.9Hz),121.9,114.2,108.0,55.4,44.5.HRMS‑ESI:m/z +
calced for C26H22N6O3F3[M+H]523.1700,found 523.1695.

[0106] 化合物A18：1‑(3,4‑二甲氧基苄)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)‑嘧啶‑2‑基)胍盐酸盐的表征如下：

[0107] 白色固体；总产率23％；M.p.:158‑160℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.36(s,1H),9.97(s,1H),9.04‑8.66(overlap,3H),8.52(d,J＝7.5Hz,1H,aromatic),8.36(d,J＝8.1Hz,1H,aromatic),8.29(s,1H,aromatic),7.85(d,J＝7.7Hz,2H,aromatic),7.74(t,J＝7.9Hz,1H,aromatic),7.21(s,1H,aromatic),7.08(d,J＝8.1Hz,1H,aromatic),7.01(d,J＝8.1Hz,1H,aromatic),6.83(d,J＝8.1Hz,2H,aromatic),4.55(s,2H,N‑CH2),3.8113
(s,3H,OCH),3.78(s,3H,OCH),3.70(s,3H,OCH)；C NMR(150MHz,DMSO‑d6,ppm)δ:164.7,
162.6,162.3,157.4,153.5,149.0,148.8,148.3,137.0,133.6,130.5,129.2,127.7,
126.9,126.0,121.9,121.1,114.2,112.4,111.9,107.7,55.6,55.6,55.4,45.5.HRMS‑ESI:
+
m/z calced for C27H27N6O5[M+H]515.2037,found 515.2029.

[0108] 化合物A19：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑甲基胍盐酸盐的表征如下：

[0109] 白色固体；总产率23％；M.p.:110℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.23(s,br,1H),9.29(s,1H),9.02‑8.76(overlap,3H),8.63(d,J＝7.6Hz,1H,aromatic),8.35(d,J＝
8.0Hz,1H,aromatic),8.26(s,1H,aromatic),8.14(d,J＝8.3Hz,2H,aromatic),7.79(t,J＝7.9Hz,1H,aromatic),7.03(d,J＝8.5Hz,2H,aromatic),3.84(s,3H,OCH3),3.00(s,3H,
13
CH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.0,162.4,162.2,157.3,154.7,148.3,136.9,
133.7,130.5,129.4,127.1,125.9,121.7,114.3,107.6,55.5,28.4.HRMS‑ESI:m/z calced +
for C19H19N6O3[M+H]379.1513,found379.1510.

[0110] 化合物A20：1‑(2‑(6‑甲氧基‑1H‑吲哚‑3‑基))乙基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0111] 白色固体；总产率15％；M.p.:187‑188℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.30(br,1H),10.76(s,1H),9.70(s,1H),9.01‑8.60(overlap,3H),8.54(d,J＝7.7Hz,1H,aromatic),8.35(dd,J＝8.2,2.3Hz,1H,aromatic),8.27(s,1H,aromatic),7.99(d,J＝8.3Hz,2H,aromatic),7.74(t,J＝8.0Hz,1H,aromatic),7.28‑7.12(m,2H,aromatic),7.06(d,J＝2.4Hz,1H,aromatic),6.89(d,J＝8.3Hz,2H,aromatic),6.68(dd,J＝8.7,2.4Hz,
1H,aromatic),3.80(s,3H,OCH3),3.74(s,3H,OCH3),3.37(overlap,2H,CH2),3.07(t,J＝
13
6.9Hz,2H,CH2)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.0,162.3,162.3,157.5,154.0,
153.1,148.3,137.0,133.6,131.4,130.5,129.3,129.2,127.3,127.1,125.8,123.9,
121.7,114.3,112.2,111.3,110.1,107.6,100.0,55.5,55.3,42.1,24.1.HRMS‑ESI:m/z +
calced for C29H28N7O4[M+H]538.2197,found 538.2194.

[0112] 化合物A21：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(3,4,5‑三甲氧基苄)盐酸胍的表征如下：

[0113] 白色固体；总产率19％；M.p.:251‑252℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.40(s,1H),10.02(s,1H),8.99(s,2H),8.89(s,1H,aromatic),8.54(d,J＝7.5Hz,1H,aromatic),8.35(d,J＝8.0Hz,1H,aromatic),8.30(s,1H,aromatic),7.93(d,J＝8.0Hz,
2H,aromatic),7.74(t,J＝7.9Hz,1H,aromatic),6.93(s,2H,aromatic),6.88(d,J＝
8.3Hz,2H,aromatic),4.60(d,J＝4.4Hz,2H,N‑CH2),3.81(s,3H,OCH3),3.74(s,6H,2OCH3),
13
3.68(s,3H,OCH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:164.8,162.6,162.4,157.4,153.7,
153.2,148.3,137.3,137.0,133.5,131.1,130.4,129.2,126.9,125.9,121.8,114.2,+
107.8,106.0,60.0,56.0,55.4,45.7.HRMS‑ESI:m/z calced for C28H29N6O6[M+H]
545.2143,found 545.2133.

[0114] 化合物A22：1‑(4‑溴苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0115] 白色固体；总产率15％；M.p.:177℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.40(s,1H),9.93(s,1H),9.00(s,2H),8.90(s,1H,aromatic),8.58(d,J＝7.7Hz,1H,aromatic),
8.37(d,J＝8.1Hz,1H,aromatic),8.31(s,1H,aromatic),7.93(d,J＝8.0Hz,2H,
aromatic),7.78(t,J＝8.0Hz,1H,aromatic),7.65(d,J＝8.2Hz,2H,aromatic),7.52(d,J＝8.2Hz,2H,aromatic),6.90(d,J＝8.5Hz,2H,aromatic),4.67(d,J＝5.1Hz,2H,N‑CH2),
13
3.84(s,3H,OCH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.3,163.0,162.8,157.8,154.3,
148.8,137.4,135.6,134.0,132.3,131.1,130.9,129.6,127.3,126.4,122.3,121.9,+
114.7,108.3,56.0,45.0.HRMS‑ESI:m/z calced for C25H22N6O3Br[M+H] 533.0931,found533.0922.

[0116] 化合物A23：1‑(4‑氯苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0117] 白色固体；总产率19％；M.p.:147℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.40(s,1H),9.92(s,1H),9.02(s,2H),8.87(s,1H,aromatic),8.56(d,J＝7.7Hz,1H,aromatic),
8.36(dd,J＝8.1,1.4Hz,1H,aromatic),8.28(s,1H,aromatic),7.89(d,J＝8.2Hz,2H,aromatic),7.77(t,J＝8.0Hz,1H,aromatic),7.62‑7.48(overlap,4H),6.86(d,J＝8.5Hz,
13
2H,aromatic),4.68(d,J＝5.0Hz,2H,N‑CH2),3.82(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.8,162.5,162.3,157.3,153.8,148.3,136.9,134.8,133.6,132.9,130.4,
130.3,129.2,128.9,126.9,125.9,121.8,114.2,107.8,55.5,44.5.HRMS‑ESI:m/z calced +
for C25H22N6O3Cl[M+H]489.1436,found 489.1429.

[0118] 化合物A24：1‑(4‑羟基‑3‑甲氧苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0119] 白色固体；总产率21％；M.p.:198‑199℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.33(s,1H),9.95(s,1H),9.33(s,1H),8.93‑8.70(overlap,3H),8.52(d,J＝7.6Hz,1H,aromatic),8.35(d,J＝8.2Hz,1H,aromatic),8.28(s,1H,aromatic),7.82(d,J＝8.1Hz,2H,aromatic),7.74(t,J＝7.9Hz,1H,aromatic),7.18(s,1H,aromatic),6.96(d,J＝
7.9Hz,1H,aromatic),6.90‑6.73(m,3H),4.51(d,J＝4.1Hz,2H,N‑CH2),3.82(s,3H,OCH3),
13
3.73(s,3H,OCH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:164.6,162.6,162.3,157.3,153.4,
148.3,147.9,146.9,136.9,133.5,130.4,129.1,126.8,125.9,121.8,121.5,115.7,+
114.2,113.0,107.6,55.7,55.5,45.7.HRMS‑ESI:m/z calced for C26H25N6O5[M+H]
501.1881,found 501.1873.

[0120] 化合物A25：1‑(呋喃‑2‑基甲基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0121] 白色固体；总产率17％；M.p.:186℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.35(s,1H),9.96(s,1H),9.08(s,2H),8.87(s,1H,aromatic),8.56(d,J＝7.8Hz,1H,aromatic),
8.35(dd,J＝8.2,1.5Hz,1H,aromatic),8.28(s,1H,aromatic),8.02(d,J＝8.6Hz,2H,aromatic),7.83‑7.71(overlap,2H),6.97(d,J＝8.8Hz,2H,aromatic),6.65(d,J＝3.0Hz,
1H,aromatic),6.59‑6.48(m,1H,aromatic),4.74(d,J＝5.2Hz,2H,N‑CH2),3.84(s,3H,
13
OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.8,162.4,157.2,153.9,148.7,148.3,143.8,
136.9,133.5,130.5,129.2,126.9,125.9,121.8,114.3,110.8,109.4,107.8,55.5,+
38.4.HRMS‑ESI:m/z calced for C23H21N6O4[M+H]445.1619,found 445.1614.

[0122] 化合物A26：2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(4‑甲基‑苄基)胍盐酸盐的表征如下：

[0123] 淡黄色固体；总产率19％；M.p.:190‑191℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.37(s,1H),9.91(s,1H),8.95(s,2H),8.88(s,1H,aromatic),8.52(d,J＝7.6Hz,1H,aromatic),8.36(d,J＝8.1Hz,1H,aromatic),8.29(s,1H,aromatic),7.92(d,J＝8.4Hz,
2H,aromatic),7.74(t,J＝8.0Hz,1H,aromatic),7.41(d,J＝7.8Hz,2H,aromatic),7.25(d,J＝7.8Hz,2H,aromatic),6.86(d,J＝8.5Hz,2H,aromatic),4.61(s,2H,N‑CH2),3.82
13
(s,3H,OCH3),2.34(s,3H,CH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:164.8,162.5,162.3,
157.3,153.7,148.3,137.5,136.9,133.5,132.5,130.4,129.5,129.2,128.4,126.9,+
125.9,121.8,114.2,107.7,55.5,45.1,20.8.HRMS‑ESI:m/z calced for C26H25N6O3[M+H]
469.1983,found 469.1985.

[0124] 化合物A27：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(4‑苯氧基苄基)胍盐酸盐的表征如下：

[0125] 白色固体；总产率22％；M.p.:158‑160℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.37(s,1H),9.92(s,1H),9.05‑8.78(overlap,3H),8.66‑8.48(m,1H,aromatic),8.44‑8.28(m,2H,aromatic),8.05‑7.87(m,2H,aromatic),7.80‑7.66(m,1H,aromatic),7.59‑7.48(m,
2H,aromatic),7.45 ‑7.32(m,2H,aromatic),7.23‑7.10(m,1H,aromatic),7.08‑6.90(m,
13
6H,aromatic),4.63(d,J＝4.9Hz,2H,N‑CH2),3.83(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.9,162.6,162.4,157.3,156.7,156.3,153.7,151.0,148.3,137.0,133.6,
130.5,130.2,130.1,129.2,127.0,125.9,123.8,121.9,118.8,118.8,114.3,107.9,55.5,+
44.6.HRMS‑ESI:m/z calced for C31H27N6O4[M+H]547.2088,found547.2080.

[0126] 化合物A28：1‑(2‑氟苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0127] 白色固体；总产率20％；M.p.:144‑146℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.41(s,1H),9.94(s,1H),9.20‑8.89(overlap,3H),8.63(d,J＝7.8Hz,1H,aromatic),8.47‑8.35(m,2H,aromatic),8.10(d,J＝8.5Hz,2H,aromatic),7.82(t,J＝8.0Hz,1H,
aromatic),7.65(t,J＝7.4Hz,1H,aromatic),7.53‑7.40(m,1H,aromatic),7.39‑7.21(m,
2H,aromatic),7.00(d,J＝8.7Hz,2H,aromatic),4.77(d,J＝5.4Hz,2H,N‑CH2),3.85(s,
13 1
3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.1,162.7,162.4,161.6(d,JCF＝241.0Hz),
3 3
157.4,154.0,148.4,137.1,133.7,130.6(d,JCF＝7.7Hz),130.6,130.2(d,JCF＝4.4Hz),
4 2
129.3,127.1,126.0,124.9(d,JCF＝3.7Hz),122.9(C,d,JCF＝14.9Hz),121.9,115.8(CH,
2 3
d,JCF＝20.8Hz),114.4,108.1,55.5,39.9(CH2,d,JCF＝3.9Hz).HRMS‑ESI:m/zcalced for +
C25H22FN6O3[M+H]473.1732,found 473.1731.

[0128] 化合物A29：4‑(2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍基)丁酸盐酸盐的表征如下：

[0129] 白色固体；总产率20％；M.p.:77℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.24(s,1H),9.58(s,1H),9.02‑8.80(overlap,3H),8.63(d,J＝7.8Hz,1H,aromatic),8.35(dd,J＝8.2,
2.3Hz,1H,aromatic),8.27(s,1H,aromatic),8.14(d,J＝8.6Hz,2H,aromatic),7.80(t,J＝8.0Hz,1H,aromatic),7.03(d,J＝8.7Hz,2H,aromatic),3.84(s,3H,OCH3),3.40
(overlap,2H,carboxypropyl,CH2),2.40(t,J＝7.3Hz,2H,carboxypropyl,CH2),1.89(p,J
13
＝7.2Hz,2H,carboxypropyl,CH2)；C NMR(100MHz,DMSO‑d6,ppm)δ:174.0,165.1,162.5,
162.3,157.3,154.0,148.3,137.0,133.7,130.5,129.3,127.1,125.9,121.7,114.3,+
107.7,55.5,40.8,30.9,23.7.HRMS‑ESI:m/z calced for C22H23N6O5[M+H]451.1724,found 451.1717.

[0130] 化合物A30：N‑(2‑(2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基嘧啶‑2‑基)胍基)乙基)乙酰胺盐酸盐的表征如下：

[0131] 白色固体；总产率15％；M.p.:207‑208℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.23(s,1H),9.55(d,J＝7.0Hz,1H),9.02‑8.85(overlap,3H),8.67(d,J＝7.9Hz,1H,aromatic),8.42‑8.28(m,3H,aromatic),8.18(d,J＝8.6Hz,2H,aromatic),7.83(t,J＝
8.0Hz,1H,aromatic),7.10‑6.99(m,2H,aromatic),3.85(s,3H,OCH3),3.58‑3.46(m,2H,
13
CH2),3.38‑3.30(m,2H,CH2),1.76(s,3H,CO‑CH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:170.2,
165.1,162.5,162.4,157.3,154.3,148.3,137.0,133.7,130.6,129.4,127.1,125.9,+
121.8,114.4,107.8,55.5,41.2,37.5,22.5.HRMS‑ESI:m/zcalced for C22H24N7O4[M+H]
450.1884,found 450.1876.

[0132] 化合物A31：1‑(3‑羟丙基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0133] 白色固体；总产率18％；M.p.:129‑130℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.15(s,1H),9.47(s,1H),8.92‑8.68(overlap,3H),8.58(d,J＝7.9Hz,1H,aromatic),8.31(dd,J＝8.1,2.2Hz,1H,aromatic),8.18(s,1H,aromatic),8.08(d,J＝8.4Hz,2H,aromatic),7.76(t,J＝8.0Hz,1H,aromatic),6.98(d,J＝8.5Hz,2H,aromatic),4.84(s,1H,OH),3.82(s,3H,OCH3),3.56(t,J＝6.0Hz,2H,hydroxypropyl,CH2),3.45‑3.38(overlap,2H,
13
hydroxypropyl,CH2),1.81(p,J＝6.4Hz,2H,hydroxypropyl,CH2)；C NMR(100MHz,DMSO‑d6,ppm)δ:13C NMR(101MHz,DMSO)δ164.9,162.4,162.1,157.2,153.9,148.2,136.8,
133.6,130.4,129.3,127.0,125.8,121.6,114.2,107.5,57.9,55.5,39.3,31.0.HRMS‑ESI:
+
m/z calced for C21H23N6O4[M+H]423.1775,found 423.1771.

[0134] 化合物A32：1‑(2‑羟乙基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0135] 白色固体；总产率17％；M.p.:136‑138℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.15(br,1H),9.78(s,1H),8.87(s,1H,aromatic),8.79‑8.53(overlap,3H),8.34(dd,J＝8.2,2.4Hz,1H,aromatic),8.26(s,1H,aromatic),8.24‑8.17(m,2H,aromatic),7.78(t,J＝
8.0Hz,1H,aromatic),7.02(d,J＝8.9Hz,2H,aromatic),5.39(br,1H,OH),3.83(s,3H,
13
OCH3),3.70(t,J＝5.2Hz,2H,hydroxyethyl),3.50(t,J＝5.2Hz,2H,hydroxyethyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.0,162.4,162.3,157.3,154.1,148.3,136.9,133.7,
130.5,129.5,126.9,125.9,121.8,114.3,107.5,58.6,55.5,44.2.HRMS‑ESI:m/z calced +
for C20H21N6O4[M+H]409.1619,found 409.1616.

[0136] 化合物A33：1‑苄基‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0137] 白色固体；总产率16％；M.p.:175℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.44(s,1H),9.98(s,1H),9.09(s,2H),8.87(t,J＝2.0Hz,1H,aromatic),8.53(d,J＝7.8Hz,1H,aromatic),8.34(dd,J＝8.2,2.3Hz,1H,aromatic),8.29(s,1H,aromatic),7.95(d,J＝
8.6Hz,2H,aromatic),7.74(t,J＝8.0Hz,1H,aromatic),7.53(dt,J＝5.9,1.6Hz,2H,aromatic),7.49‑7.37(m,3H,aromatic),6.88(d,J＝8.7Hz,2H,aromatic),4.69(d,J＝
13
4.2Hz,2H,N‑CH2),3.81(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.8,162.4,162.3,
157.3,153.9,148.3,136.9,135.7,133.5,130.5,129.2,129.0,128.3,128.2,126.9,+
125.9,121.8,114.2,107.7,55.5,45.2.HRMS‑ESI:m/z calced for C25H23N6O3[M+H]
455.1826,found 455.1818.

[0138] 化合物A34：1‑乙基‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0139] 白色固体；总产率24％；M.p.:239‑241℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.18(s,1H),9.50(t,J＝5.3Hz,1H),8.92‑8.73(overlap,3H),8.63(d,J＝7.9Hz,1H,aromatic),8.35(d,J＝8.2Hz,1H,aromatic),8.25(s,1H,aromatic),8.12(d,J＝8.4Hz,
2H,aromatic),7.79(t,J＝8.0Hz,1H,aromatic),7.02(d,J＝8.4Hz,2H,aromatic),3.84
13
(s,3H,OCH3),3.43‑3.33(overlap,2H),1.28(t,J＝7.1Hz,3H,C‑CH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.0,162.4,162.1,157.3,153.7,148.2,136.9,133.7,130.5,129.3,
127.0,125.9,121.6,114.3,107.6,55.5,36.5,13.7.HRMS‑ESI:m/z calced for C20H21N6O3+
[M+H]393.1670,found 393.1667.

[0140] 化合物A35：1‑甲氧基‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0141] 白色固体；总产率20％；M.p.:236‑238℃；1H NMR(400MHz,Methanol‑d4,ppm)δ:8.78(t,J＝1.8Hz,1H,aromatic),8.47(d,J＝7.6Hz,1H,aromatic),8.31(dd,J＝8.1,
2.2Hz,1H,aromatic),8.08‑7.90(m,3H,aromatic),7.72(t,J＝7.9Hz,1H,aromatic),6.97
13
(d,J＝8.4Hz,2H,aromatic),3.94(s,3H,OCH3),3.85(s,3H,OCH3)；C NMR(100MHz,Methanol‑d4,ppm)δ:167.4,164.5,164.3,158.6,156.8,150.0,138.5,134.3,131.6,
130.4,128.4,126.9,122.9,115.5,109.0,65.7,56.1.HRMS‑ESI:m/zcalced for C19H19N6O4+
[M+H]395.1462,found 395.1457.

[0142] 化合物A36：1‑(4‑溴苯基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0143] 白色固体；总产率19％；M.p.:266‑268℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.60(s,1H),11.44(s,1H),9.46(s,1H),9.12‑8.82(overlap,2H),8.71(d,J＝7.8Hz,1H,aromatic),8.47‑8.32(overlap,2H,aromatic),8.23(d,J＝8.5Hz,2H,aromatic),7.85(t,J＝8.0Hz,1H,aromatic),7.73(d,J＝8.4Hz,2H,aromatic),7.42(d,J＝8.4Hz,2H,13
aromatic),7.08(d,J＝8.5Hz,2H,aromatic),3.85(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.3,162.6,162.4,157.2,153.5,148.4,137.0,133.8,133.4,132.9,130.6,
129.4,127.3,127.1,126.0,121.8,120.3,114.4,108.3,55.6.HRMS‑ESI:m/z calced for +
C24H20N6O3Br[M+H]519.0775,found 519.0767.

[0144] 化合物A37：1‑(2‑氰乙基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0145] 白色固体；总产率14％；M.p.:115‑118℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.43(br,1H),9.81(s,1H),9.03‑8.72(overlap,3H),8.62(d,J＝7.7Hz,1H,aromatic),8.36(d,J＝7.8Hz,1H,aromatic),8.27(s,1H,aromatic),8.18(d,J＝8.6Hz,2H,aromatic),7.79(t,J＝7.9Hz,1H,aromatic),7.04(s,2H,aromatic),3.85(s,3H,OCH3),3.60(t,J＝7.1Hz,13
2H,CH2),2.69(t,J＝5.7Hz,2H,CH2)；C NMR(150MHz,DMSO‑d6,ppm)δ:13C NMR 173.0,
165.1,162.4,162.2,157.3,153.9,148.3,136.9,133.6,130.5,129.4,127.1,125.8,+
121.8,114.3,107.6,55.5,37.6,33.2.HRMS‑ESI:m/z calced for C21H20N7O3[M+H]
418.1622,found 418.1614.

[0146] 化合物A38：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑丙基胍盐酸盐的表征如下：

[0147] 白色固体；总产率25％；M.p.:115‑118℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.08(s,1H),9.43(s,1H),8.84‑8.69(overlap,3H),8.61(d,J＝7.9Hz,1H,aromatic),8.34(dd,J＝8.1,1.6Hz,1H,aromatic),8.23(s,1H,aromatic),8.11(d,J＝8.8Hz,2H,aromatic),7.79(t,J＝8.0Hz,1H,aromatic),7.02(d,J＝8.9Hz,2H,aromatic),3.83(s,3H,OCH3),
13
3.30(q,J＝6.7Hz,2H,CH2),1.65(h,J＝7.3Hz,2H,CH2),0.96(t,J＝7.4Hz,3H,CH3)；C NMR(100MHz,DMSO‑d6,ppm)165.2,162.6,162.3,157.4,153.9,148.3,137.0,133.8,130.7,
129.4,127.1,126.0,121.6,114.4,107.7,55.6,43.2,21.6,11.3.HRMS‑ESI:m/z calced +
for C21H23N6O3[M+H]407.1826,found 407.1823.

[0148] 化合物A39：1‑环己基‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0149] 白色固体；总产率21％；M.p.:229‑230℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.21(s,1H),9.65(d,J＝7.1Hz,1H),8.93‑8.82(overlap,3H),8.69(d,J＝7.7Hz,1H,aromatic),8.40(d,J＝8.2Hz,1H,aromatic),8.35(s,1H,aromatic),8.20(d,J＝8.3Hz,
2H,aromatic),7.85(t,J＝7.9Hz,1H,aromatic),7.09(d,J＝8.3Hz,2H,aromatic),3.86(s,3H,OCH3),3.76‑3.62(m,1H,cyclohexyl),2.07‑1.91(m,2H,cyclohexyl),1.82‑1.69(m,2H,cyclohexyl),1.64‑1.52(m,1H,cyclohexyl),1.43‑1.32(m,4H,cyclohexyl),1.28‑
13
1.20(m,1H,cyclohexyl)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.7,163.0,162.7,157.9,
153.3,148.8,137.6,134.3,131.1,129.8,127.7,126.4,122.0,114.8,108.3,56.0,50.4,+
32.4,25.1,24.4.HRMS‑ESI:m/z calced for C24H27N6O3[M+H]447.2139,found 447.2132.[0150] 化合物A40：1‑(3‑溴丙基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0151] 白色固体；总产率18％；M.p.:279‑280℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:9.37(s,1H),9.09(s,1H),8.98(s,1H),8.72(d,J＝7.9Hz,1H,aromatic),8.49(s,1H,aromatic),
8.44‑8.35(m,1H,aromatic),8.29(d,J＝8.8Hz,2H,aromatic),7.85(t,J＝8.0Hz,1H,aromatic),7.11(d,J＝8.8Hz,2H,aromatic),4.27‑4.15(m,2H,CH2),3.86(s,3H,OCH3),
13
3.41(t,J＝5.7Hz,2H,CH2),2.20‑2.04(m,2H,CH2)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.2,
162.5,162.4,158.7,154.2,148.4,137.2,133.9,130.6,129.6,127.3,126.0,122.0,+
114.4,108.4,55.6,44.6,38.4,20.5.HRMS‑ESI:m/z calced for C21H22BrN6O3[M+H]
485.0931,found 485.0928.

[0152] 化合物A41：1‑(3‑氯丙基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0153] 白色固体；总产率17％；M.p.:262‑263℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:9.27(s,1H),9.17‑8.80(overlap,3H),8.74(d,J＝7.8Hz,1H,aromatic),8.53(s,1H,aromatic),
8.45‑8.39(m,1H,aromatic),8.32(d,J＝8.8Hz,2H,aromatic),7.88(t,J＝8.0Hz,1H,aromatic),7.13(d,J＝8.8Hz,2H,aromatic),4.24(t,J＝5.8Hz,2H,CH2),3.87(s,3H,
13
OCH3),3.42(td,J＝6.0,2.6Hz,2H,CH2),2.13(p,J＝5.8Hz,2H,CH2)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.3,162.6,162.5,158.8,154.2,148.5,137.3,133.9,130.7,129.7,127.4,
126.0,122.1,114.5,108.5,55.6,44.6,38.4,20.5.HRMS‑ESI:m/z calced for 
+
C21H22ClN6O3[M+H]441.1436,found 441.1430.

[0154] 化合物A42：1‑(4‑羟丁基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0155] 白色固体；总产率19％；M.p.:146‑147℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.16(s,1H),9.49(d,J＝5.6Hz,1H),8.95 ‑8.72(overlap,3H),8.61(d,J＝7.8Hz,1H,aromatic),8.34(dd,J＝8.2,2.3Hz,1H,aromatic),8.24(s,1H,aromatic),8.11(d,J＝
8.5Hz,2H,aromatic),7.79(t,J＝8.0Hz,1H,aromatic),7.01(d,J＝8.7Hz,2H,aromatic),
3.83(s,3H,OCH3),3.49‑3.33(overlap,4H,hydroxybutyl),1.68(p,J＝7.1Hz,2H,
13
hydroxybutyl),1.62‑1.46(m,2H,hydroxybutyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.0,
162.4,162.2,157.3,153.8,148.2,136.9,133.7,130.5,129.3,127.0,125.9,121.6,+
114.3,107.6,60.1,55.5,41.4,29.5,24.9.HRMS‑ESI:m/z calced for C21H25N6O4[M+H]
437.1932,found 437.1928.

[0156] 化合物A43：1‑环戊基‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0157] 白色固体；总产率23％；M.p.:234℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.17(s,1H),9.73(d,J＝7.4Hz,1H),8.91(s,2H),8.83(s,1H,aromatic),8.64(d,J＝7.8Hz,1H,aromatic),8.36(dd,J＝8.1,2.3Hz,1H,aromatic),8.29(s,1H,aromatic),8.15(d,J＝
8.4Hz,2H,aromatic),7.82(t,J＝8.0Hz,1H,aromatic),7.05(d,J＝8.5Hz,2H,aromatic),
4.11(q,J＝6.3Hz,1H,cyclopentyl),3.85(s,3H,OCH3),2.06(dt,J＝12.0,6.3Hz,2H,
13
cyclopentyl),1.80‑1.66(m,2H,cyclopentyl),1.64‑1.50(m,4H,cyclopentyl)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.1,162.4,162.2,157.3,153.3,148.2,137.0,133.7,130.5,
129.3,127.1,125.9,121.5,114.3,107.8,55.5,52.8,32.3,23.2.HRMS‑ESI:m/zcalced +
for C23H25N6O3[M+H]433.1983,found 433.1976.

[0158] 化合物A44：(S)‑2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(四氢呋喃‑3‑基)胍盐酸盐的表征如下：

[0159] 白色固体；总产率16％；M.p.:188℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.20(s,1H),9.99(s,1H),9.15‑8.76(overlap,3H),8.62(d,J＝7.9Hz,1H,aromatic),8.36(dd,J＝
8.1,2.3Hz,1H,aromatic),8.28(s,1H,aromatic),8.15(d,J＝8.5Hz,2H,aromatic),7.80(t,J＝8.0Hz,1H,aromatic),7.03(d,J＝8.7Hz,2H,aromatic),4.46(s,1H,
tetrahydrofuranyl),3.97‑3.67(overlap,7H),2.42‑2.26(m,1H,tetrahydrofuranyl),
13
1.96(dt,J＝12.8,6.5Hz,1H,tetrahydrofuranyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:
165.0,162.5,162.3,157.3,153.5,148.3,137.0,133.7,130.5,129.3,127.0,126.0,
121.7,114.3,107.7,72.3,66.2,55.6,52.3,32.5.HRMS‑ESI:m/z calced for C22H23N6O4[M+
+H]435.1775,found 435.1769.

[0160] 化合物A45：1‑(4‑氯苯基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0161] 白色固体；产率22％；M.p.:219‑221℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.60(s,1H),11.46(s,1H),9.47(s,1H),9.04‑8.85(overlap,2H),8.70(d,J＝7.9Hz,1H,
aromatic),8.41(s,1H,aromatic),8.38(dd,J＝8.1,2.3Hz,1H,aromatic),8.21(d,J＝
8.6Hz,2H,aromatic),7.83(t,J＝8.0Hz,1H,aromatic),7.66‑7.57(m,2H,aromatic),
13
7.52‑7.43(m,2H,aromatic),7.06(d,J＝8.7Hz,2H,aromatic),3.84(s,3H,OCH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:165.3,162.6,162.4,157.2,153.6,148.3,137.0,133.8,133.0,
131.9,130.6,130.0,129.5,127.1,127.1,126.0,121.8,114.4,108.2,55.6.HRMS‑ESI:m/z +
calced for C24H20N6O3Cl[M+H]475.1280,found 475.1274.

[0162] 化合物A46：1‑(4‑羟苯基)‑2‑(4‑(3‑硝基苯基)‑6‑苯基嘧啶‑2‑基)胍盐酸盐的表征如下：

[0163] 白色固体；总产率25％；M.p.:341‑342℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.53(s,1H),9.99‑9.76(overlap,2H),9.06(s,2H),8.94(s,1H,aromatic),8.54(d,J＝7.8Hz,1H,aromatic),8.46‑8.28(overlap,2H,aromatic),7.97(d,J＝7.7Hz,2H,aromatic),
7.83‑7.68(m,1H,aromatic),7.61‑7.50(m,1H,aromatic),7.48‑7.36(m,2H,aromatic),
7.37‑7.27(m,2H,aromatic),6.94‑6.81(m,2H,aromatic),4.54(d,J＝4.6Hz,2H,N‑CH2)；
13
C NMR(100MHz,DMSO‑d6,ppm)δ:165.2,163.1,157.7,157.5,153.5,148.4,136.9,134.7,
133.6,132.0,130.6,129.9,129.0,127.4,126.1,125.5,122.0,115.8,108.7,45.2.HRMS‑+
ESI:m/z calced for C24H21N6O3[M+H]441.1670,found 441.1673.

[0164] 化合物A47：1‑(2‑氯苄基)‑2‑(4‑(3‑硝基苯基)‑6‑苯基嘧啶‑2‑基)胍盐酸盐的表征如下：

[0165] 白色固体；总产率21％；M.p.:254‑256℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.59(s,1H),9.96(s,1H),9.15(s,2H),8.97(s,1H,aromatic),8.63(d,J＝7.9Hz,1H,aromatic),8.47(s,1H,aromatic),8.38(dd,J＝8.2,2.3Hz,1H,aromatic),8.08(d,J＝
7.7Hz,2H,aromatic),7.80(t,J＝8.0Hz,1H,aromatic),7.70(dd,J＝6.7,2.6Hz,1H,aromatic),7.65‑7.52(m,2H,aromatic),7.50‑7.38(m,4H,aromatic),4.79(s,2H,N‑CH2)
13
；C NMR(100MHz,DMSO‑d6,ppm)δ:165.4,163.1,157.5,154.1,148.4,136.9,134.9,133.7,
133.2,132.9,132.0,130.6,130.2,130.2,129.8,129.0,127.8,127.5,126.1,122.0,+
109.0,43.3.HRMS‑ESI:m/z calced for C24H20N6O2Cl[M+H]459.1331,found459.1323.[0166] 化合物A48：1‑(4‑溴苄基)‑2‑(4‑(4‑溴苯基)‑6‑(4‑甲氧基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0167] 白色固体；产率17％；M.p.:184‑186℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.37(br,1H),10.02(s,1H),8.93(s,2H),8.22(s,1H,aromatic),8.02(dd,J＝8.7,2.8Hz,4H,aromatic),7.68(d,J＝8.2Hz,4H,aromatic),7.51(d,J＝8.0Hz,2H,aromatic),6.98(d,J
13
＝8.4Hz,2H,aromatic),4.64(s,2H,CH2),3.86(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.2,164.0,162.8,157.9,154.4,135.6,135.0,132.4,131.2,129.7,129.6,127.7,
81 +
125.9,122.0,114.8,107.8,56.0,45.0.HRMS‑ESI:m/z calced for C25H22N5OBr Br[M+H]
568.0165,found 568.0156.

[0168] 化合物A49：2‑(4‑(4‑溴苯)‑6‑(4‑甲氧基苯基)嘧啶‑2‑基)‑1‑(4‑羟基‑苄基)胍盐酸盐的表征如下：

[0169] 白色固体；总产率17％；M.p.:192‑194℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.31(s,1H),9.97(s,1H),9.81(s,1H),8.81(s,2H),8.16(s,1H,aromatic),7.97(d,J＝8.2Hz,2H,aromatic),7.90(d,J＝8.5Hz,2H,aromatic),7.64(d,J＝8.2Hz,2H,aromatic),7.36(d,J＝8.0Hz,2H,aromatic),6.98‑6.81(m,4H,aromatic),4.48(d,J＝4.6Hz,2H,CH2),
13
3.83(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.5,163.5,162.2,157.7,157.3,
153.4,134.3,131.8,130.3,129.2,129.0,127.0,125.5,125.3,115.8,114.3,107.0,55.5,+
45.3.HRMS‑ESI:m/z calced for C25H23N5O2Br[M+H]504.1030,found 504.1025.[0170] 化合物A50：2‑(4,6‑二(4‑甲氧基苯基))嘧啶‑2‑基)‑1‑(4‑溴苄基)胍盐酸盐的表征如下：

[0171] 白色固体；总产率18％；M.p.:251‑253℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.33(s,1H),10.16(s,1H),9.01(s,2H),8.14‑7.85(overlap,5H,aromatic),7.67(d,J＝7.6Hz,2H,aromatic),7.52(d,J＝7.9Hz,2H,aromatic),7.09‑6.76(overlap,aromatic),4.65(s,
13
2H,CH2),3.83,3.84(s,6H,2OCH3)；C NMR(150MHz,DMSO‑d6,ppm)δ:164.1,162.1,157.2,
154.0,135.1,131.9,130.9,129.0,129.0,127.4,121.6,114.2,106.3,55.5,44.7.HRMS‑+
ESI:m/z calced for C26H25N5O2Br[M+H]518.1186,found 518.1176.

[0172] 化合物A51：2‑(4,6‑二(4‑溴苯基))嘧啶‑2‑基)‑1‑(4‑羟基苄基)胍盐酸盐的表征如下：

[0173] 白色固体；总产率14％；M.p.:268‑270℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.43(s,1H),9.84(s,1H),9.77(s,1H),8.87(s,2H),8.27(s,1H,aromatic),7.95(d,J＝8.2Hz,4H,aromatic),7.63(d,J＝8.1Hz,4H,aromatic),7.35(d,J＝8.0Hz,2H,aromatic),6.87
13
(d,J＝8.0Hz,2H,aromatic),4.50(d,J＝4.9Hz,2H,CH2)；C NMR(150MHz,DMSO‑d6,ppm)δ:
164.0,157.7,157.4,153.4,134.1,131.9,130.1,129.2,125.8,125.4,115.7,108.0,+
45.2.HRMS‑ESI:m/z calced for C24H20N5OBr2[M+H]552.0029,found 552.0020.[0174] 化合物A52：2‑(4,6‑二(4‑溴苯基))嘧啶‑2‑基)‑1‑(4‑溴苄基)胍盐酸盐的表征如下：

[0175] 白色固体；总产率17％；M.p.:317‑319℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.53(s,1H),9.93(s,1H),9.03(s,2H),8.23(s,1H,aromatic),7.93(d,J＝8.2Hz,4H,aromatic),7.70‑7.56(overlap,6H,aromatic),7.53(d,J＝8.0Hz,2H,aromatic),4.66(d,
13
J＝5.2Hz,2H,CH2)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.0,157.4,153.8,135.1,134.0,
131.9,130.8,129.2,125.8,121.6,108.1,44.6.HRMS‑ESI:m/z calced for 
81 +
C24H19N5OBr2 Br[M+H]615.9165,found 615.9162.

[0176] 化合物A53：2‑(4,6‑二苯基嘧啶‑2‑基)‑1‑(4‑羟基苄基)胍盐酸盐的表征如下：

[0177] 白色固体；总产率20％；M.p.:277‑280℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.37(s,1H),10.00(s,1H),9.80(s,1H,OH),8.85(s,2H),8.29(s,1H,aromatic),8.06(d,J＝7.6Hz,4H,aromatic),7.57(t,J＝7.3Hz,2H,aromatic),7.47(t,J＝7.6Hz,4H,aromatic),
7.34(d,J＝8.4Hz,2H,aromatic),6.86(d,J＝8.4Hz,2H,aromatic),4.50(d,J＝4.2Hz,2H,
13
N‑CH2)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.1,157.7,157.6,153.5,135.1,131.9,130.1,+
129.1,127.4,125.5,115.8,108.3,45.3.HRMS‑ESI:m/z calced for C24H22N5O[M+H]
396.1819,found 396.1813.

[0178] 化合物A54：1‑(4‑羟苯基)‑2‑(4‑(3‑硝基苯基)‑6‑(3,4,5‑三甲氧基苯基)‑嘧啶‑2‑基)胍盐酸盐的表征如下：

[0179] 白色固体；总产率23％；M.p.:226‑228℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.37(s,br,1H),9.69‑9.53(overlap,2H),9.21‑8.82(overlap,3H),8.57(d,J＝7.5Hz,1H,aromatic),8.43‑8.34(m,2H,aromatic),7.80(t,J＝8.0Hz,1H),7.46(s,2H,aromatic),7.26(d,J＝8.5Hz,2H,aromatic),6.79(d,J＝8.5Hz,2H,aromatic),4.56(s,2H,N‑CH2),
13
3.84(s,6H,2OCH3),3.75(s,3H,OCH3)；CNMR(150MHz,DMSO‑d6,ppm)δ:165.3,162.8,157.4,
157.3,153.8,153.2,148.3,140.9,137.1,133.8,130.5,130.3,129.0,125.9,122.0,+
115.5,108.8,105.2,60.2,56.2,44.5.HRMS‑ESI:m/z calced for C27H27N6O6[M+H]
531.1987,found 531.1984.

[0180] 化合物A55：1‑(2‑氯苄基)‑2‑(4‑(3‑硝基苯基)‑6‑(3,4,5‑三甲氧基苯基)‑嘧啶‑2‑基)胍盐酸盐的表征如下：

[0181] 白色固体；总产率21％；M.p.:213‑215℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.54(s,1H),9.81(s,1H),9.23(s,2H),8.94(s,1H,aromatic),8.68(d,J＝7.7Hz,1H,aromatic),8.54‑8.32(m,2H,aromatic),7.84(t,J＝8.0Hz,1H,aromatic),7.67‑7.57(m,
1H,aromatic),7.56‑7.45(m,3H,aromatic),7.43‑7.31(m,2H,aromatic),4.81(d,J＝
13
5.6Hz,2H,N‑CH2),3.84(s,6H,2OCH3),3.75(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:
165.3,163.0,157.3,154.3,153.2,148.3,140.1,137.1,133.9,133.5,132.4,130.6,
130.3,129.7,129.6,128.8,127.6,126.0,122.0,109.0,105.3,60.2,56.2,42.9.HRMS‑+
ESI:m/z calced for C27H26N6O5Cl[M+H]549.1648,found 549.1639.

[0182] 化合物A56：2‑(4‑(3‑硝基苯基))‑6‑(3,4,5‑三甲氧基苯基)嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)胍盐酸盐的表征如下：

[0183] 白色固体；总产率19％；M.p.:178℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.23(s,1H),9.50(d,J＝8.0Hz,1H),9.09(s,2H),8.88(t,J＝2.0Hz,1H,aromatic),8.74(d,J＝
7.9Hz,1H,aromatic),8.48‑8.35(overlap,2H,aromatic),7.88(t,J＝8.0Hz,1H,
aromatic),7.49(s,2H,aromatic),3.91(overlap,9H),3.77(s,3H,OCH3),3.44(td,J＝
11.5,2.1Hz,2H,tetrahydropyranyl),2.08‑1.94(m,2H,tetrahydropyranyl),1.60‑1.50
13
(m,2H,tetrahydropyranyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.4,162.8,157.3,153.3,
152.8,148.3,141.0,137.1,134.0,130.6,130.4,126.0,121.7,108.9,105.3,65.4,60.2,+
56.3,47.5,32.0.HRMS‑ESI:m/z calced for C25H29N6O6[M+H]509.2143,found509.2134.[0184] 化合物A57：2‑(4‑(4‑甲氧基苯基))‑6‑(4‑硝基苯基)嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0185] 淡黄色固体；总产率15％；M.p.:259℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.25(s,1H),9.70(s,1H),9.02(s,2H),8.46‑8.25(m,5H,aromatic),8.20‑8.15(m,2H,aromatic),
7.12‑7.04(m,2H,aromatic),3.98‑3.88(overlap,3H,tetrahydropyranyl),3.86(s,3H,OCH3),3.49‑3.38(m,2H,tetrahydropyranyl),2.07‑1.93(m,2H,tetrahydropyranyl),
13
1.63‑1.50(m,2H,tetrahydropyranyl)；CNMR(100MHz,DMSO‑d6,ppm)δ:165.2,162.5,
162.3,157.4,152.9,149.0,141.3,129.3,128.6,127.1,123.9,114.4,108.4,65.4,55.6,+
47.5,31.9.HRMS‑ESI:m/z calced for C23H25N6O4[M+H]449.1932,found 449.1925.[0186] 化合物A58：1‑(4‑羟苯基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(4‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0187] 白色固体；总产率16％；M.p.:238‑240℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.36(s,1H),9.95‑9.74(overlap,2H),8.77(s,2H),8.38‑8.21(m,4H,aromatic),8.05‑7.83(m,3H,aromatic),7.36(d,J＝8.3Hz,2H,aromatic),6.99‑6.82(m,4H,aromatic),4.49(d,J＝
13
4.8Hz,2H,CH2),3.84(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.9,162.5,162.4,
157.7,157.4,153.4,149.0,141.1,130.2,129.2,128.6,126.9,125.3,123.8,115.7,+
114.3,108.3,55.5,45.2.HRMS‑ESI:m/z calced for C25H23N6O4[M+H] 471.1775,found 
471.1770.

[0188] 化合物A59：1‑(2‑羟乙基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(4‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0189] 白色固体；总产率18％；M.p.:203‑204℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.21(s,1H),9.88(s,1H),8.61(s,2H),8.50(d,J＝8.5Hz,2H,aromatic),8.38‑8.29(m,3H,aromatic),8.27(d,J＝8.4Hz,2H,aromatic),7.08(d,J＝8.5Hz,2H,aromatic),5.46(s,1H,OH),3.86(s,3H,OCH3),3.76‑3.67(m,2H,hydroxyethyl,CH2),3.55‑3.45(m,2H,
13
hydroxyethyl,CH2)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.4,162.6,162.2,157.5,154.1,
149.0,141.1,129.5,128.8,127.0,123.9,114.4,108.3,58.6,55.5,44.2.HRMS‑ESI:m/z +
calced for C20H21N6O4[M+H]409.1619,found 409.1615.

[0190] 化合物A60：2‑(4‑(2,3‑二氢苯并[b][1,4]二恶英‑6‑基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(4‑羟基苄基)胍盐酸盐的表征如下：

[0191] 白色固体；总产率23％；M.p.:259‑260℃；1H NMR(600MHz,DMSO‑d6,ppm)δ:11.27(s,1H),9.80‑9.64(overlap,2H),8.98‑8.75(overlap,3H),8.49(d,J＝7.6Hz,1H,aromatic),8.35(d,J＝9.7Hz,1H,aromatic),8.28(s,1H,aromatic),7.78‑7.68(m,2H,aromatic),7.36‑7.27(m,3H,aromatic),6.88‑6.75(m,3H,aromatic),4.51(d,J＝4.8Hz,13
2H,N‑CH2),4.37‑4.19(overlap,4H,O‑CH2‑CH2‑O)；C NMR(150MHz,DMSO‑d6,ppm)δ:164.7,
162.5,157.6,157.3,153.4,148.3,146.9,143.7,136.9,133.5,130.4,129.8,127.7,
125.9,125.5,121.9,120.6,117.4,116.6,115.7,107.9,64.5,64.0,45.0.HRMS‑ESI:m/z +
calced for C26H23N6O5[M+H]499.1724,found 499.1717.

[0192] 化合物A61：2‑(4‑(2,3‑二氢苯并[b][1,4]二恶英‑6‑基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0193] 白色固体；总产率18％；M.p.:254‑255℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.17(s,1H),9.64(d,J＝7.7Hz,1H),9.01(s,2H),8.83(s,1H,aromatic),8.64(d,J＝7.8Hz,1H,aromatic),8.36(d,J＝7.8Hz,1H,aromatic),8.26(s,1H,aromatic),7.81(td,J＝8.1,2.9Hz,1H,aromatic),7.70(d,J＝2.3Hz,2H,aromatic),7.02–6.88(m,1H,aromatic),
4.38‑4.25(overlap,4H,O‑CH2‑CH2‑O),4.02‑3.80(overlap,3H,tetrahydropyranyl),
3.52‑3.39(overlap,2H,tetrahydropyranyl),2.09‑1.92(m,2H,tetrahydropyranyl),
13
1.67‑1.48(m,2H,tetrahydropyranyl)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.9,162.3,
157.2,152.9,148.3,147.0,143.7,136.9,133.8,130.5,127.9,125.9,121.6,121.0,
117.5,116.3,107.9,65.4,64.5,64.0,47.5,32.0.HRMS‑ESI:m/z calced for C24H25N6O5[M+
+H]477.1881,found 477.1873.

[0194] 化合物A62：2‑(4‑(4‑甲氧基苯基))‑6‑(2‑硝基苯基)嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0195] 白色固体；总产率23％；M.p.:262‑264℃；1H NMR(400MHz,Methanol‑d4,ppm)δ:8.09(d,J＝8.9Hz,2H,aromatic),7.98‑7.94(m,1H,aromatic),7.85(s,1H,aromatic),
7.82‑7.75(m,2H,aromatic),7.73‑7.67(m,1H,aromatic),7.01(d,J＝8.9Hz,2H,aromatic),3.89(dt,J＝11.8,3.6Hz,2H,tetrahydropyranyl),3.84‑3.73(overlap,4H),
3.47(td,J＝11.5,2.2Hz,2H,tetrahydropyranyl),2.00‑1.88(m,2H,
13
tetrahydropyranyl),1.60(dtd,J＝12.9,10.8,4.3Hz,2H,tetrahydropyranyl)；CNMR(100MHz,Methanol‑d4,ppm)δ:167.8,165.7,164.7,158.3,154.5,150.4,134.3,133.2,
132.5,132.5,130.5,129.4,125.8,115.6,111.6,67.1,56.1,49.5,33.2.HRMS‑ESI:m/z +
calced for C23H25N6O4[M+H]449.1932,found 449.1923.

[0196] 化合物A63：1‑(4‑羟苯基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(2‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0197] 白色固体；总产率20％；M.p.:167‑169℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.21(s,1H),9.78(overlap,2H),8.82(s,2H),8.15‑8.02(m,2H,aromatic),7.96‑7.84(m,4H,aromatic),7.81(t,J＝7.4Hz,1H,aromatic),7.29(d,J＝8.1Hz,2H,aromatic),6.97(d,J＝8.6Hz,2H,aromatic),6.84(d,J＝8.1Hz,2H,aromatic),4.48(d,J＝4.8Hz,2H,CH2),13
3.85(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.8,164.6,162.5,157.6,156.8,
153.4,148.3,133.5,131.6,131.6,131.5,129.8,129.2,126.8,125.5,124.7,115.7,+
114.5,110.4,55.6,45.1.HRMS‑ESI:m/z calced for C25H23N6O4[M+H] 471.1775,found 
471.1770.

[0198] 化合物A64：1‑(4‑溴苄基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(2‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0199] 白色固体；总产率21％；M.p.:238‑239℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.34(s,1H),9.82(s,1H),8.97(s,2H),8.19‑7.97(m,4H,aromatic),7.97‑7.77(m,3H,aromatic),7.62(d,J＝8.4Hz,2H,aromatic),7.43(d,J＝8.3Hz,2H,aromatic),7.04(d,J13
＝8.9Hz,2H,aromatic),4.64(d,J＝4.9Hz,2H,CH2),3.87(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.9,164.4,162.6,156.8,153.9,148.3,135.3,133.4,131.7,131.6,
131.5,131.5,130.1,129.3,126.9,124.7,121.2,114.5,110.5,55.6,44.3.HRMS‑ESI:m/z +
calced for C25H22N6O3Br[M+H]533.0931,found 533.0927.

[0200] 化合物A65：2‑(4,6‑二苯基嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0201] 白色固体；总产率20％；M.p.:167‑169℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.33(s,1H),9.89(d,J＝7.7Hz,1H),9.13(s,2H),8.33(s,1H,aromatic),8.24(d,J＝7.1Hz,4H,aromatic),7.70‑7.48(m,6H,aromatic),4.06‑3.84(overlap,3H,tetrahydropyranyl),3.49‑3.44(overlap,2H,tetrahydropyranyl),2.07‑1.92(m,2H,tetrahydropyranyl),
13
1.65‑1.42(m,2H,tetrahydropyranyl)；CNMR(100MHz,DMSO‑d6,ppm)δ:165.2,157.5,
153.2,135.4,131.9,129.1,127.5,108.4,65.4,47.4,32.0.HRMS‑ESI:m/z calced for +
C22H24N5O[M+H]374.1975,found 374.1971.

[0202] 化合物A66：1‑(4‑羟苯基)‑2‑(4‑(4‑甲氧基苯基)‑6‑(吡啶‑2‑基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0203] 白色固体；总产率22％；M.p.:188‑189℃；1H NMR(400MHz,DMSO‑d6,ppm)δ:11.43(s,1H),9.98(s,1H),8.89(s,2H),8.74(dt,J＝4.8,1.3Hz,1H,aromatic),8.35(s,1H,aromatic),8.00‑7.88(m,2H,aromatic),7.80(d,J＝8.4Hz,2H,aromatic),7.62(td,J＝4.9,3.3Hz,1H,aromatic),7.41‑7.31(m,2H,aromatic),6.98‑6.83(m,4H,aromatic),4.50
13
(d,J＝4.5Hz,2H,CH2),3.83(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:164.7,163.0,
162.3,157.7,157.4,153.4,151.5,149.3,138.3,130.3,128.9,126.9,126.5,125.4,+
121.7,115.8,114.5,107.0,55.5,45.3.HRMS‑ESI:m/z calced for C24H23N6O2[M+H]
427.1877,found 427.1881.

[0204] 化合物A67：2‑(4‑(4‑甲氧基苯基))‑6‑(吡啶‑2‑基)嘧啶‑2‑基)‑1‑(四氢‑2H‑吡喃‑4‑基)盐酸胍的表征如下：

[0205] 白色固体；总产率20％；M.p.:198‑200℃；1H NMR(400MHz,Methanol‑d4,ppm)δ:8.84‑8.80(m,2H,aromatic),8.64(t,J＝7.6Hz,1H,aromatic),8.44(s,1H,aromatic),
8.14‑7.99(m,3H,aromatic),7.00(d,J＝8.3Hz,2H,aromatic),3.96(dt,J＝12.0,3.4Hz,
2H,tetrahydropyranyl),3.90‑3.78(overlap,4H),3.53(td,J＝11.5,1.9Hz,2H,
tetrahydropyranyl),2.04(d,J＝12.6Hz,2H,tetrahydropyranyl),1.66(qd,J＝11.1,
13
4.1Hz,2H,tetrahydropyranyl)；C NMR(100MHz,Methanol‑d4,ppm)δ:168.3,165.1,
158.8,158.7,154.4,148.4,147.3,145.5,130.8,130.7,130.0,129.4,128.0,126.9,+
115.9,110.5,67.1,56.3,49.6,33.4.HRMS‑ESI:m/z calced for C22H25N6O2[M+H]
405.2034,found 405.2039.

[0206] 化合物A68：2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍盐酸盐的表征如下：

[0207] 化合物A68的制备方法同化合物A07，所不同的是使用4‑硝基苄胺代替4‑氨基四氢吡喃。在将中间体6的苯甲酰基水解脱除的时候，胍上的苄基也一起脱除掉，得到2‑(4‑(4‑甲氧基苯基))‑6‑(3‑硝基苯基)嘧啶‑2‑基)胍。随后用相同的方法制备成盐酸盐，得到化合1
物A68。黄色固体；总产率13％；M.p.:126‑127℃；H NMR(400MHz,DMSO‑d6,ppm)δ:11.32(s,
1H),8.96(s,1H),8.70(d,J＝7.8Hz,1H,aromatic),8.66‑8.45(overlap,4H),8.41‑8.33(overlap,2H,aromatic),8.25(d,J＝8.6Hz,2H,aromatic),7.84(t,J＝8.0Hz,1H,
13
aromatic),7.08(d,J＝8.7Hz,2H,aromatic),3.85(s,3H,OCH3)；C NMR(100MHz,DMSO‑d6,ppm)δ:165.3,162.6,162.5,157.4,155.5,148.4,137.1,133.8,130.6,129.5,127.2,+
125.9,121.9,114.4,108.0,55.6.HRMS‑ESI:m/z calced for C18H17N6O3[M+H]365.1357,found 365.1349.

[0208] 试验例

[0209] 采用实施例1～68所提供的化合物A01～A68，测试其对于组蛋白去甲基化酶的抑制户型，测试方法如下：

[0210] KDM6B酶抑制活性测试中，GSK‑J1作为参照化合物；其它KDM亚家族酶抑制活性测试中，吡啶‑2,4‑二羧酸(2,4‑PDCA)作为参照化合物。初步筛选是在单一化合物浓度(50μM)下测试了重复的抑制率。对于IC50的计算，每个化合物测试了5个浓度，起始浓度为50μM，梯度为5倍稀释。在1x实验缓冲液中加入肽、抗坏血酸、2‑OG和Fe(II)制备底物溶液。将5μL酶溶液转移到复配液的测定板上，室温孵育15分钟。每孔加入5μL底物溶液，室温孵育60分钟。在1xAlphalisa缓冲液中加入15μL受体溶液和供体溶液，在室温、弱光下孵育60分钟，使用Alpha模式的EnSpire读取端点。曲线拟合计算，通过公式(1)：Inh％＝(Max‑Signal)/(Max‑∧
Min)*100计算抑制率。通过公式(2)：Y＝Bottom+(Top‑Bottom)/(1+10 ((LogIC50‑X)*Hill Slope))在GraphPad拟合数据得到IC50值。(其中Y为抑制率％，X为复合浓度)，测试结果如表
2所示。

[0211] 表2.部分化合物对KDM6B酶抑制活性

[0212]

[0213]

[0214] 挑选了其中50个化合物进行了KDM6B酶抑制活性测试。表1结果显示30个化合物对KDM6B酶具有一定程度的抑制活性(IC50<20μM)，其中A10、A24、A57‑A61、A68这8个化合物具有显著的抑制活性(IC50值处于1.22‑2.90μM范围)。

[0215] 表3.部分化合物对KDM其他亚家族抑制活性

[0216]

[0217] [a]ND,no data available.

[0218] 挑选了部分活性较好的化合物测试了对JMJD KDM酶其他亚型的抑制活性，结果如表2所示。部分化合物对KDM其他亚家族也有一定程度的抑制效果。其中化合物A07,A10,A11,A22,A57在KDM6亚家族中对KDM6B酶选择性抑制，表现出优于GSK‑J1的选择性。该类化合物展现出良好的开发前景。

[0219] 综上所述，本发明实施例提供了一种4,6‑二芳基‑2‑取代嘧啶胍类化合物及其制备方法和应用，该化合物结构新颖，对于组蛋白去甲基化酶具有一定的抑制作用，属于一种新型的抑制剂结构类型。此外该化合物的制备方法简单，易于操作，对于设备要求不高，适合后期进行大规模的工业化生产使用。该化合物进行结构修饰及深入的药理学研究，在制备组蛋白去甲基化酶抑制剂中有着较好的应用前景。

[0220] 以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。