CN107098887B - 嘧啶类化合物 - Google Patents
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
本发明属药物合成领域，涉及嘧啶类化合物，其制备方法和应用，含有它们作为活性成分的药物组合物，及其在制备抗肿瘤药物中的应用。本发明公开了一种具有式I所示结构的嘧啶类化合物，其中W为NH，R1为含氮五元杂环,R2为含氮碱性基团；本发明的嘧啶类化合物，可以抑制多种肿瘤细胞，尤其能够选择性作用于EGFRL858R/T790M肺癌细胞，对比野生型细胞，该类化合物的IC50高10‑100倍数量级差别，该类化合物能够克服现有EGFR抑制剂耐药。
Description
技术领域
本发明属药物合成领域，涉及嘧啶类化合物，尤其涉及一种含有假环的嘧啶类化合物，及其制备方法和应用。本发明的嘧啶类化合物，可以抑制多种肿瘤细胞，尤其能够选择性作用于EGFR L858R/T790M肺癌细胞，该类化合物能够克服现有EGFR抑制剂耐药。
背景技术
据统计显示，全球由癌症引起的死亡中，大约有三分之一死于肺癌，这其中80％属于非小细胞肺癌。外科治疗是目前肺癌首选和最主要的治疗方法，但是大约有70％的病人会出现继发性疾病以及转移。小分子酪氨酸激酶抑制剂(TKIs)的发展取得了显著进展，多种小分子药物上市。
EGFR是ErbB酪氨酸激酶受体家族成员之一，该信号通路对细胞的生长、增值和分化等生理过程有重要作用。研究表明，许多肿瘤中EGFR高度表达或异常表达。
EGFR广泛分布于哺乳动物的上皮细胞，由细胞为的配体结合区、疏水跨膜结构域和细胞内的激酶区三部分组成。酪氨酸蛋白激酶过度表达时，会阻碍细胞程序死亡，使细胞的生长调控失控，始终处于增生状态，发展成为恶性肿瘤。临床研究表明，许多类型的实质性肿瘤如神经胶质细胞瘤、乳腺癌、肺癌、卵巢癌、头颈部鳞癌、***、胃癌等有高水平表达。
现有技术公开了酪氨酸激酶抑制剂是研究最为广泛的小分子抑制剂之一，其通过竞争性结合胞外配体结合位点，阻断分子内酪氨酸的自身磷酸化，抑制酪氨酸激酶激活，从而阻断细胞周期，加速细胞凋亡。
EGFR T790M突变是EGFR抑制剂最为主要的耐药机制，目前的EGFR抑制剂仍不能完全解决药物耐药所导致的临床局限，而且现有的药物多以喹唑啉为基本母核的EGFR可逆或不可逆抑制剂，其对野生型EGFR(EGFR WT)选择性差所导致的毒副作用不可避免。因此迫切需要具有选择性的新颖骨架化合物来解决EGFR T790M导致的耐药性问题。
发明内容
本发明主要解决的技术问题是提供新的嘧啶类化合物，尤其涉及一种含有假环的嘧啶类化合物，及其制备方法和应用。该化合物能抑制肿瘤细胞生长。
为解决上述技术问题，本发明采用的一个技术方案是：提供一种含有假环的嘧啶类化合物，其特征在于，所述化合物具有的结构为式I：
其中W为NH，R1为含氮五元杂环,R2为含氮碱性基团。
在本发明一个较佳实施例中所述含氮五元杂环的结构为：
在本发明一个较佳实施例中，所述R2为：
在本发明一个较佳实施例中，所述嘧啶类化合物用于制备***的药物及其药物组合物中。
在本发明一个较佳实施例中，所述肿瘤为非小细胞肺癌、小细胞肺癌、胰腺癌、鼻咽癌中的任一种。
本发明的有益效果是：
本发明的含有假环的嘧啶类化合物，可以抑制多种肿瘤细胞，尤其能够选择性作用于EGFR L858R/T790M肺癌细胞，对比野生型细胞，该类化合物的IC50高10-100倍数量级差别，该类化合物是一类新的能够克服现有EGFR抑制剂耐药并具有选择性的络氨酸激酶抑制剂。
具体实施方式
下面将对本发明实施例中的技术方案进行描述，所描述实施例仅是本发明的一部分实施例，而不是全部实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
下列是本发明中使用的术语定义。除另外指出，本文提供的基团或术语的最初定义单独或作为其他基团的一部分应用于本说明书中。
“取代杂环”和“取代杂环的”是指杂环或杂环基团中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不局限于一个或多个以下取代基：如氢、卤素、氰基、硝基、三氟甲基、三氟甲氧基、环烷基。
本发明特别优选的通式(I)所示的化合物包括
在一个实施方案中，本发明提供了上述本发明化合物的制备方法。
本发明上述化合物可以采用下述流程中描述的方法和/或本领域普通技术人员已知的其它技术来合成，但不仅限于以下方法。
为方便起见，本发明使用众所周知的缩写代表多种化合物，包括但不限于DMF:N,N-二甲基甲酰胺；THF:四氢呋喃；DIPEA:N,N-二异丙基乙胺反应路线：
反应步骤：
实施例1
步骤1中间体2a的制备
将2-硝基苯乙酮(100mg,0.6mmol)溶于DMF-DMA，加热(100℃)搅拌反应过夜。冷却，蒸干溶剂，得到中间体1。不经纯化直接用于下步反应。220.9[M+H]+
步骤2中间体3a的制备
将中间体1(114mg,0.6mmol)与溶剂量乙醇混合，加入约两当量水合肼，搅拌反应数小时至中间体1消失。冷却，蒸干溶剂，得90mg中间体2，收率90％，190[M+H]+。
步骤3中间体4a的制备
将中间体2(90mg,0.5mmol)溶于THF，冰浴条件下加入NaH(40mg,1mmol)，搅拌一小时后加入碘甲烷(31Ul,0.5MMOL)。室温搅拌反应数小时至中间体2消失，浓缩反应体系，柱层析，得168mg中间体3，收率62％,204[M+H]+。
步骤4中间体5a的制备
将中间体4(168mg,0.8mmol)溶于甲醇，加入Pd/C，氢气加压，室温反应过夜。过滤，浓缩，得44mg中间体4，直接用于下步反应,173.9[M+H]+。
实施例2
中间体9a的制备
将中间体5a(60mg,0.3mmol)溶于2-丁醇，加入2,6-二氯嘧啶(44mg,0.3mmol)，DIPEA(110uL,0.6MMOL)，加热搅拌过夜，冷却，蒸干溶剂，经柱层析纯化(流动相90:10Hexane/EtOAc)得66mg中间体9a，收率73％,286[M+H]+。
实施例3
将中间体9a(57mg，0.2mmol)与中间体4-氟-2-甲氧基-5-硝基苯胺(50mg，0.2mmol)混合，加入2-戊醇，一次性加入对甲苯磺酸(19mg，0.07mmol)加热搅拌过夜，冷却，析出固体，过滤，得26mg中间体10a，不纯化直接用于下步反应,436[M+H]+。
实施例4 N2-(4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)-N4-(2-(1-甲基-1H-吡唑-3-yl)苯基)嘧啶-2,4-二胺(11a)
中间体10a(56mg，0.13mmol)溶于DMF，加入DIPEA(6uL,0.036mmol)，N,N,N-三甲基乙二胺(13mg，0.13mmol)，加热搅拌两小时，蒸干溶剂，经柱层析(流动相1:15甲醇/二氯甲烷)纯化得28mg中间体11a.
1H NMR(400MHz,Chloroform-d)δ10.56(s,1H),9.05(s,1H),8.26(d,J＝8.3Hz,1H),8.05(d,J＝5.8Hz,1H),7.63(dd,J＝7.8,1.5Hz,1H),7.40(d,J＝2.3Hz,1H),7.34(s,1H),7.33–7.28(m,1H),7.09(t,J＝7.6Hz,1H),6.65(s,1H),6.58(d,J＝2.3Hz,1H),6.31(d,J＝5.8Hz,1H),4.01(s,3H),3.95(s,3H),3.24(t,J＝7.2Hz,2H),2.86(s,3H),2.56(t,J＝7.2Hz,2H),2.27(s,6H).13C NMR(150MHz,CDCl3)δ161.8,160.7,159.4,156.9,152.0,143.5,142.2,137.9,136.6,129.8,128.6,124.8,122.5,120.6,118.6,116.3,102.1,56.2,55.9,55.3,55.2,52.7,52.3,52.2,46.1,36.5.HRMS(ESI)(m/z):[M+H]+calcd forC26H32N9O3518.2550；found 518.2548.Mp.110-112℃。
实施例5 N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基-N4-(4-((2-(1-甲基-1H-吡唑-3-yl)苯基)氨基)嘧啶-2-yl)苯基-1,2,4-***(12a)
中间体11a(28mg，0.05mmol)溶于甲醇，加入Pd/C，催化氢化得中间体12a。过滤，蒸干溶剂，不经纯化直接用于下步反应。
1H NMR(400MHz,Chloroform-d)δ10.50(s,1H),8.50(d,J＝8.3Hz,1H),8.03(d,J＝5.7Hz,1H),8.01(s,1H),7.64(dd,J＝7.7,1.4Hz,1H),7.44(s,1H),7.41(d,J＝2.4Hz,1H),7.37(t,J＝7.9Hz,1H),7.08(t,J＝7.5Hz,1H),6.68(s,1H),6.59(d,J＝2.3Hz,1H),6.19(d,J＝5.8Hz,1H),4.01(s,3H),3.82(s,3H),2.96(t,J＝6.9Hz,2H),2.66(s,3H),2.42(t,J＝6.9Hz,2H),2.27(s,6H).13C NMR(150MHz,CDCl3)δ160.4,159.7,157.2,141.1,135.2,135.0,135.0,132.4,131.3,129.8,128.2,126.5,124.0,123.4,123.2,107.1,104.1,98.8,62.8,56.9,51.2,41.0,28.6.HRMS(ESI)(m/z):[M+H]+calcd for C26H34N9O488.2886；found 488.2870.。
实施例6 N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-yl)苯基)氨基)嘧啶-2-yl)氨基)苯基)丙烯酰胺(13a)
中间体12a(17mg,0.035mmol)溶于二氯甲烷，冰浴，加入DIPEA(7L,0.038mmol)，丙烯酰氯(3L,0.035mmol)，反应半小时后蒸干溶剂，经柱层析(流动相1:15甲醇/二氯甲烷)纯化得目标产物17mg，收率53％。
1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),10.07(s,1H),9.49(s,1H),8.41(d,J＝8.3Hz,1H),8.11(d,J＝5.7Hz,1H),7.72–7.55(m,1H),7.39(s,0H),7.35(s,1H),7.02(t,J＝7.6Hz,1H),6.76(s,1H),6.57(d,J＝2.4Hz,1H),6.47–6.26(m,1H),6.22(d,J＝5.8Hz,1H),5.66(dd,J＝9.5,2.4Hz,1H),3.99(s,3H),3.85(s,3H),2.88(t,J＝5.6Hz,2H),2.69(s,3H),2.27(s,6H).13C NMR(150MHz,CDCl3)δ163.24,161.09,159.92,156.61,151.11,145.25,137.22,135.68,132.57,130.95,129.47,128.10,128.05,127.15,125.92,122.20,121.71,121.63,112.36,104.68,104.48,99.48,57.51,56.16,45.56,43.80,39.27,29.84.HRMS(ESI)(m/z):[M+H]+calcd for C29H36N9O2542.2992；found542.2990.。
实施例7 N2-(4-(2-(二甲氨基)乙氧基)-2-甲氧基-5-硝基苯基)-N4-(2-(1-甲基-1H-吡唑-3-yl)苯基)嘧啶-2,4-二胺(11b)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ10.53(s,1H),8.51(d,J＝8.3Hz,1H),8.02(d,J＝5.8Hz,1H),8.00(s,1H),7.64(dd,J＝7.8,1.6Hz,1H),7.41(d,J＝2.3Hz,1H),7.40–7.32(m,2H),7.08(d,J＝1.2Hz,0H),6.59(d,J＝2.3Hz,1H),6.54(s,1H),6.17(d,J＝5.7Hz,1H),4.09(s,1H),4.00(s,3H),3.81(s,3H),2.75(s,1H),2.38(s,6H).13C NMR(150MHz,CDCl3)δ160.8,159.8,156.4,151.2,141.2,140.6,137.2,131.0,130.7,128.1,127.9,124.4,122.2,121.9,121.4,108.3,104.4,100.3,99.1,68.0,58.6,57.0,45.8,39.3.HRMS(ESI)(m/z):[M+H]+calcd for C25H36N8O4505.2312；found 505.2315.。
实施例8 N2-(5-氨基-4-(2-(二甲氨基)乙氧基)-2-甲氧基苯基)-N4-(2-(1-甲基-1H-吡唑-3-苯基)嘧啶-2,4-二胺(12b)
步骤同实施例5
1H NMR(400MHz,Chloroform-d)δ10.57(s,1H),9.22(s,1H),8.24(d,J＝8.3Hz,1H),8.06(d,J＝5.8Hz,1H),7.64(dd,J＝7.8,1.5Hz,1H),7.41(d,J＝2.3Hz,1H),7.34(s,1H),7.30(td,J＝8.3,7.9,1.6Hz,1H),7.09(td,J＝7.6,1.2Hz,1H),6.61(s,1H),6.59(d,J＝2.3Hz,1H),6.33(d,J＝5.8Hz,1H),4.20(t,J＝5.8Hz,2H),4.01(s,3H),3.97(s,3H),2.82(t,J＝5.8Hz,2H),2.38(s,6H).13C NMR(150MHz,CDCl3)δ161.0,159.5,156.6,152.7,151.0,148.8,136.7,133.1,131.0,128.3,128.1,123.7,122.7,121.7,121.3,116.2,104.4,99.6,98.4,69.7,58.2,56.4,46.2,39.3.HRMS(ESI)(m/z):[M+H]+calcd forC25H31N8O2475.2570；found 475.2569.。
实施例9 N-(2-(2-(2-(二甲氨基)乙氧基)-4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-苯基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(13b)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ10.39(s,1H),9.78(s,1H),9.34(s,1H),8.41(d,J＝8.3Hz,1H),8.09(d,J＝5.8Hz,1H),7.61(dd,J＝7.8,1.6Hz,1H),7.40(d,J＝2.4Hz,1H),7.24(t,J＝4.0Hz,2H),7.02(t,J＝7.6Hz,1H),6.61(s,1H),6.57(d,J＝2.3Hz,1H),6.42(d,J＝1.8Hz,0H),6.38(d,J＝1.8Hz,1H),6.29(d,J＝10.1Hz,1H),6.24(d,J＝10.0Hz,0H),6.21(d,J＝5.8Hz,1H),5.68(dd,J＝10.0,1.8Hz,1H),4.11(t,J＝5.2Hz,2H),4.00(s,3H),3.85(s,3H),2.62–2.50(m,2H),2.36(s,6H).13C NMR(150MHz,CDCl3)δ163.3,161.1,160.0,156.6,151.1,145.7,142.8,137.2,132.1,130.9,128.1,128.0,126.3,125.0,124.40,122.1,121.3,113.9,104.4,101.8,99.4,70.3,58.1,56.2,45.3,39.2,29.8.HRMS(ESI)(m/z):[M+H]+calcd for C28H31N8O3529.2676；found 529.2680。
实施例10 N2-(4-(4-(二甲氨基)哌啶-1-基)-2-甲氧基-5-硝基苯基)-N4-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-2,4-二胺(11c)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ10.62(s,1H),9.15(s,1H),8.27(d,J＝8.2Hz,1H),8.04(d,J＝5.8Hz,1H),7.76(d,J＝8.1Hz,1H),7.62(dd,J＝7.8,1.6Hz,1H),7.40(d,J＝2.3Hz,1H),7.33–7.25(m,1H),7.17(d,J＝7.9Hz,1H),7.07(td,J＝7.5,1.2Hz,1H),6.57–6.56(m,2H),6.30(d,J＝5.8Hz,1H),3.98(s,3H),3.92(s,3H),3.31(d,J＝11.7Hz,2H),2.89–2.75(m,3H),2.00(d,J＝11.9Hz,2H),1.83-1.81(m,1H).13C NMR(150MHz,Chloroform-d)δ160.8,159.2,156.3,151.9,150.8,142.2,141.9,140.1,136.6,136.4,131.0,128.8,128.1,128.0,125.8,124.8,122.5,121.4,121.0,115.9,104.2,102.4,62.4,56.1,51.7,46.1,40.5,39.1,27.3,21.3.HRMS(ESI)(m/z):[M+H]+calcd forC28H34N9O3544.2779；found 544.2786。
实施例11 N2-(5-氨基-4-(4-(二甲氨基)哌啶-1-基)-2-甲氧基苯基)-N4-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-2,4-二胺(12c)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ10.53(s,1H),8.53(d,J＝8.3Hz,1H),8.05(t,J＝2.9Hz,2H),7.66(dd,J＝7.8,1.5Hz,1H),7.48–7.34(m,3H),7.28(d,J＝0.9Hz,1H),7.11(td,J＝7.6,1.2Hz,1H),6.67–6.59(m,2H),6.20(d,J＝5.7Hz,1H),4.03(s,3H),3.83(s,3H),3.22(d,J＝11.6Hz,2H),2.70–2.59(m,2H),2.46(s,6H),2.02(d,J＝12.4Hz,2H),1.73(dd,J＝11.8,3.7Hz,2H).13C NMR(150MHz,MeOD)δ163.0,151.3,143.5,141.7,133.0,129.8,129.5,129.1,126.9,125.9,125.2,105.9,105.7,100.2,65.0,57.1,51.2,40.5,39.1,28.3,21.3.HRMS(ESI)(m/z):[M+H]+calcd for C28H36N9O,514.3037；found514.3040。
实施例12 N-(2-(4-(二甲氨基)哌啶-1-基)-4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(13c)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),9.41(s,1H),8.51(s,1H),8.38(d,J＝8.3Hz,1H),8.10(d,J＝5.8Hz,1H),7.62(dd,J＝7.8,1.6Hz,1H),7.40(d,J＝2.3Hz,1H),7.32(s,1H),7.04(t,J＝7.6Hz,1H),6.72(s,1H),6.58(d,J＝2.3Hz,1H),6.41–6.25(m,2H),6.23(d,J＝6.0Hz,1H),5.72(d,J＝9.8Hz,1H),3.99(s,3H),3.86(s,3H),3.04(d,J＝11.6Hz,2H),2.71(t,J＝11.4Hz,2H),2.38(s,6H),2.30-2.28(m,2H),2.20-2.15(m,1H).13C NMR(150MHz,MeOD)δ162.8,161.1,159.8,156.5,151.0,145.2,137.1,135.9,132.3,130.9,128.1,128.0,126.7,126.6,126.4,122.3,121.7,112.1,104.4,103.2,99.5,62.1,56.1,52.4,42.0,39.2,30.0.HRMS(ESI)(m/z):[M+H]+calcd for C31H38N9O2,568.3134,found 568.3137.。
实施例13 N2-(2-甲氧基-4-(4-甲基哌啶-1-基)-5-5-硝基苯基)-N4-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-2,4-二胺(11d)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ10.59(s,1H),9.20(s,1H),8.25(d,J＝8.3Hz,1H),8.06(d,J＝5.8Hz,1H),7.64(dd,J＝7.8,1.5Hz,1H),7.47–7.38(m,2H),7.35–7.25(m,2H),7.09(td,J＝7.6,1.2Hz,1H),6.64(s,1H),6.59(d,J＝2.3Hz,1H),6.33(d,J＝5.8Hz,1H),3.99(s,3H),3.97(s,3H),3.25(t,J＝4.7Hz,4H),2.88(t,J＝4.6Hz,4H),2.54(s,3H).13C NMR(150MHz,CDCl3)δ161.8,160.7,159.4,156.9,152.0,143.5,142.2,137.9,136.6,129.8,128.6,124.8,122.5,120.6,118.6,116.3,102.1,56.2,55.9,55.3,55.2,52.7,52.3,52.2,46.1,36.5.Mp.110-113HRMS(ESI)(m/z):[M+H]+calcd for C26H30N9O3,516.2472,found 5516.2468.。
实施例14 N2-(5-氨基-2-甲氧基-4-(4-甲基哌啶-1-基)-5-5-硝基苯基)-N4-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-2,4-二胺(12d)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ10.55(s,1H),9.17(s,1H),8.24(d,J＝8.2Hz,1H),8.05(d,J＝5.8Hz,1H),7.63(dd,J＝7.8,1.5Hz,1H),7.40(d,J＝2.1Hz,2H),7.33–7.28(m,1H),7.13–7.06(m,1H),6.61(s,1H),6.58(d,J＝2.2Hz,1H),6.32(d,J＝5.8Hz,1H),4.00(s,3H),3.96(s,3H),3.09(t,J＝4.7Hz,4H),2.62(t,J＝4.7Hz,4H).13C NMR(150MHz,CDCl3)δ162.1,160.7,159.7,156.6,143.3,141.3,138.3,135.3,132.3,129.6,128.5,126.7,122.1,121.7,118.3,107.2,104.3,99.4,56.9,56.0,51.4,46.3,36.5,29.8；HRMS(ESI)(m/z):[M+Na]+calcd for C26H31N9ONa,508.2544,found 508.2541.。
实施例15 N-(4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)苯基)-2-(4-甲基哌啶-1-基)苯基)丙烯酰胺(13d)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ10.52(s,1H),9.42(s,1H),8.55(s,1H),8.42(d,J＝8.2Hz,1H),8.17(d,J＝5.8Hz,1H),7.76(d,J＝8.1Hz,1H),7.62(dd,J＝7.8,1.6Hz,1H),7.40(d,J＝2.3Hz,1H),7.33–7.25(m,1H),7.17(d,J＝7.9Hz,1H),7.07(td,J＝7.5,1.2Hz,1H),6.57–6.56(m,2H),6.30(d,J＝5.8Hz,1H),4.01(s,3H),3.85(s,3H),2.95-2.89(m,4H),2.60-2.58(m,4H),2.38(s,3H).13C NMR(150MHz,CDCl3)δ162.1,160.7,159.8,156.6,143.3,141.3,138.4,135.4,132.2,129.7,128.5,126.8,122.1,121.7,118.4,107.3,104.3,99.4,56.9,56.0,51.3,46.2,36.5.HRMS(ESI)(m/z):[M+H]+calcd forC29H34N9O2,540.2830；found540.2835.。
实施例16 N2-(2-甲氧基-4-吗啉-5-硝基苯基)-N4-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-2,4-二胺(11e)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ10.55(s,1H),9.18(s,1H),8.05(s,2H),7.63(dd,J＝7.8,1.6Hz,1H),7.43–7.39(m,2H),7.30(td,J＝8.3,7.8,1.6Hz,1H),7.09(td,J＝7.6,1.3Hz,1H),6.60(s,1H),6.58(d,J＝2.3Hz,1H),6.32(d,J＝5.8Hz,1H),4.00(s,3H),3.97(s,3H),3.89–3.84(m,4H),3.07–3.02(m,4H).13C NMR(151MHz,MeOD)δ161.0,159.4,156.5,151.9,151.0,141.7,137.2,136.7,131.0,128.3,128.1,125.3,122.7,121.7,121.3,116.1,104.4,102.1,99.7,67.3,67.2,66.5,56.2,52.9,45.4,40.6,39.0.HRMS(ESI)(m/z):[M+H]+calcd for C25H27N8O4,503.2150,found 503.2155.。
实施例17 N2-(5-氨基-2-甲氧基-4-吗啉苯基)-N4-(2-(1-甲基-1H-吡唑-3-基)苯基)嘧啶-2,4-二胺(12e)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ10.53(s,1H),8.52(d,J＝8.3Hz,1H),8.07(t,J＝4.2Hz,2H),8.04(s,0H),7.66(dd,J＝7.8,1.6Hz,1H),7.48(s,1H),7.44(d,J＝2.4Hz,1H),7.38(t,J＝8.1Hz,1H),7.11(t,J＝7.6Hz,1H),6.66(s,1H),6.62(d,J＝2.5Hz,1H),6.21(d,J＝5.7Hz,1H),4.03(s,3H),3.87(t,J＝4.5Hz,4H),3.85(s,3H),2.92(t,J＝4.6Hz,4H).13C NMR(151MHz,MeOD)δ161.0,160.8,159.7,156.4,151.2,141.3,137.2,135.3,132.0,131.0,128.1,127.8,127.0,122.2,122.0,121.5,107.3,104.5,104.2,99.3,67.9,67.3,66.6,56.9,52.0,45.9,40.7,39.3.HRMS(ESI)(m/z):[M+H]+calcd forC25H29N8O2,573.2408；found 473.2411.。
实施例18 N-(4-甲氧基-5-((4-((2-(1-甲基-1H-吡唑-3-基)苯基)氨基)嘧啶-2-基)氨基)-2-吗啉苯基)丙烯酰胺(13e)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ10.40(s,1H),9.46(s,1H),8.53(s,1H),8.39(d,J＝8.3Hz,1H),8.10(d,J＝5.7Hz,1H),8.06(s,1H),7.64–7.61(m,1H),7.40(d,J＝2.5Hz,2H),7.25(d,J＝7.4Hz,1H),7.04(t,J＝7.5Hz,1H),6.74(s,1H),6.58(d,J＝2.3Hz,1H),6.41–6.26(m,2H),6.23(d,J＝5.9Hz,1H),5.74(d,J＝9.9Hz,1H),4.00(s,3H),3.88-3.85(m,7H),2.88(t,J＝4.5Hz,4H).13C NMR(151MHz,MeOD)δ162.7,161.0,160.9,159.8,156.4,151.0,145.3,137.1,135.0,132.2,130.9,128.1,128.0,127.2,126.8,126.6,122.3,121.6,112.2,104.4,103.8,99.6,67.8,67.3,66.5,56.2,52.9,45.5,40.7,39.2.HRMS(ESI)(m/z):[M+H]+calcd for C28H31N8O3,527.2514,found 527.2516.。
实施例19 N2-(4-((2-(甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)-N4-(2-(1-甲基-1H-1,2,4-***-3-yl)苯基)嘧啶-2,4-二胺(11n)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ10.72(s,1H),9.12(s,1H),8.22(s,1H),8.20(s,2H),8.09(d,J＝5.8Hz,1H),7.41(t,J＝7.9Hz,1H),7.36(s,1H),7.12(t,J＝7.6Hz,1H),6.66(s,1H),6.42(d,J＝5.8Hz,1H),4.04(s,3H),3.96(s,3H),3.29–3.23(m,2H),2.87(s,3H),2.57(t,J＝7.2Hz,2H),2.28(s,6H).13C NMR(150MHz,CDCl3)δ162.0,160.8,159.6,157.0,152.2,143.5,142.4,138.0,135.1,129.9,128.7,123.4,122.5,120.6,118.7,116.5,102.2,99.0,57.1,56.2,54.2,45.9,41.5,36.5.HRMS(ESI)(m/z):[M+H]+calcd forC25H31N10O3519.2581；found 519.2584.。
实施例20 N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基-N4-(4-((2-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)嘧啶-2-基)氨基)苯基-1,2,4-三胺(12n)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ10.74(s,1H),8.46(d,J＝8.3Hz,1H),8.19(dd,J＝7.9,1.6Hz,1H),8.15(s,1H),7.99(d,J＝5.9Hz,1H),7.90(s,1H),7.48–7.39(m,1H),7.19–7.10(m,1H),6.62(s,1H),6.25(d,J＝5.9Hz,1H),4.01(s,3H),3.81(s,3H),3.47(s,2H),3.30(t,J＝6.0Hz,2H),3.06(t,J＝6.2Hz,2H),2.82(s,6H).13C NMR(150MHz,CDCl3)δ161.9,160.8,158.6,143.4,141.6,137.8,137.3,130.4,129.8,129.7,128.6,127.4,122.8,121.6,118.7,107.7,105.4,99.5,57.0,55.6,51.1,50.8,43.6,43.4,36.6.HRMS(ESI)(m/z):[M+H]+calcd for C25H33N10O 489.2839；found 489.2840.。
实施例21 N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)嘧啶-2-基)氨基)苯基)丙烯酰胺(13n)
步骤同实施例6。
1H NMR(600MHz,Chloroform-d)δ10.52(s,1H),10.03(s,1H),9.45(s,1H),8.44(d,J＝8.3Hz,1H),8.16(d,J＝7.8Hz,1H),8.13(s,1H),8.13(s,2H),7.54(d,J＝8.6Hz,1H),7.37(d,J＝12.3Hz,2H),7.33(t,J＝7.8Hz,1H),7.14–7.12(m,1H),7.05(t,J＝7.6Hz,1H),6.76(s,1H),4.00(s,3H),3.86(s,3H),2.89(t,J＝5.6Hz,2H),2.69(s,3H),2.32(t,J＝5.8Hz,2H),2.28(s,6H).13C NMR(15MHz,CDCl3)δ163.3,162.1,160.9,159.9,156.8,145.3,143.4,138.3,135.8,132.6,129.8,129.3,128.4,127.0,125.9,124.8,121.9,121.1,118.3,104.6,99.5,56.1,45.4,43.8,36.5.HRMS(ESI)(m/z):[M+H]+calcd forC28H35N10O2543.2944；found 543.2950.。
实施例22
邻硝基氯苯(3g,19mmol)溶于DMF，加入吡唑(1.5g,22.8mmol)，碳酸钾(3.1g,22.8mmol)，CuI(36mg,0.19mmol)，110℃反应过夜，过滤，浓缩，得1.9g黄色固体。
实施例23
操作同实施例2.。273[M+H]+。
实施例24
操作同实施例3。422[M+H]+。
实施例25 N4-(2-(1H-吡唑-1-基)苯基)-N2-(4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氨基-5-硝基苯基)嘧啶-2,4-二胺(11f)
操作同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.55(s,1H),8.93(s,1H),8.20(dd,J＝8.2,1.4Hz,1H),8.05(d,J＝5.8Hz,1H),7.86(d,J＝1.9Hz,1H),7.80(d,J＝2.4Hz,1H),7.40–7.32(m,4H),7.16(td,J＝7.7,1.4Hz,1H),6.64(s,1H),6.49(t,J＝2.2Hz,1H),6.18(d,J＝5.8Hz,1H),3.94(s,4H),3.26–3.22(m,2H),2.86(s,4H),2.55(dd,J＝8.0,6.4Hz,3H),2.27(s,6H).13C NMR(150MHz,MeOD)δ160.5,159.4,157.0,152.1,142.3,141.2,135.1,132.5,130.2,130.2,128.1,123.5,123.5,123.2,123.1,116.4,107.1,102.1,99.2,57.0,56.1,54.2,45.8,41.4.。
实施例26 N4-(4-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-2-基)-N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基苯基-1,2,4-***(12f)
同实施例5
1H NMR(400MHz,Chloroform-d)δ9.35(s,1H),8.36(dd,J＝8.3,1.3Hz,1H),8.02(d,J＝5.7Hz,1H),7.92(s,1H),7.81(dd,J＝9.8,2.2Hz,2H),7.49–7.39(m,2H),7.36(dd,J＝8.0,1.5Hz,1H),7.21–7.12(m,1H),6.67(s,1H),6.48(t,J＝2.2Hz,1H),6.09(d,J＝5.7Hz,1H),3.80(s,3H),2.96(dd,J＝7.6,6.1Hz,2H),2.65(s,3H),2.42(dd,J＝7.6,6.1Hz,2H),2,27(s,6H).13C NMR(150MHz,MeOD)δ155.7,155.0,152.3,136.5,136.4,131.8,128.3,127.7,125.7,125.6,123.0,122.0,119.5,118.9,118.5,102.4,102.2,100.4,94.1,53.1,52.2,50.1,41.2,38.1.。
实施例27 N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(13f)
操作同实施例6。
1H NMR(400MHz,Chloroform-d)δ10.07(s,1H),9.42(s,1H),9.20(s,1H),8.25(d,J＝8.1Hz,1H),8.09(d,J＝5.7Hz,1H),7.82(d,J＝1.9Hz,1H),7.78(d,J＝2.5Hz,1H),7.32(q,J＝3.5,3.0Hz,3H),7.13–7.06(m,1H),6.75(s,1H),6.50–6.42(m,1H),6.42–6.28(m,2H),6.11(d,J＝5.8Hz,1H),5.68(dd,J＝9.2,2.6Hz,1H),3.84(s,3H),2.88(t,J＝5.6Hz,2H),2.69(s,3H),2.29(s,9H).13C NMR(150MHz,CDCl3)δ163.2,160.6,159.8,157.2,145.2,141.2,135.8,132.9,132.5,130.6,130.3,129.3,127.9,126.8,126.0,123.8,123.7,123.2,112.3,107.1,104.6,98.6,57.4,56.4,56.1,45.5,43.7.HRMS(ESI)(m/z):[M+H]+calcd for C28H34N9O2,528.2830；found 528.2828.。
实施例28 N4-(2-(1H-吡唑-1-基)-N2-(4-(4-(二甲氨基)哌啶-1-基)-2-甲氧基-5-硝基苯基)嘧啶-2,4-二胺(11g)
操作同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.56(s,1H),9.03(s,1H),8.18(d,J＝8.1Hz,1H),8.04(d,J＝5.8Hz,1H),7.85(d,J＝1.9Hz,1H),7.79(d,J＝2.5Hz,1H),7.38–7.32(m,3H),7.18–7.12(m,1H),6.56(s,1H),6.47(t,J＝2.3Hz,1H),6.18(d,J＝5.8Hz,1H),3.93(s,3H),3.32(d,J＝11.7Hz,2H),2.79(td,J＝11.7,2.3Hz,2H),2.34(s,6H),1.91-1.89(m,2H),1.91-1.77(m,1H).13C NMR(150MHz,CDCl3)δ160.5,159.3,157.0,151.9,142.6,141.3,141.2,136.3,132.5,130.2,130.2,128.0,124.2,123.6,123.4,123.3,116.4,107.1,102.2,99.3,62.0,56.1,52.2,41.6,28.4.HRMS(ESI)(m/z):[M+H]+calcd for C27H32N9O3,530.2623；found 530.2628.。
实施例29 N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-2-基)氨基)-2-(4-(二甲氨基)哌啶-1-基)-4-甲氧基苯基)丙烯酰胺(12g)
操作同实施例5。
1H NMR(400MHz,Chloroform-d)δ9.36(s,1H),8.06–8.00(m,2H),7.94(s,1H),7.81(dd,J＝8.3,2.1Hz,2H),7.49–7.32(m,3H),7.21–7.12(m,1H),6.63(s,1H),6.49(t,J＝2.2Hz,1H),6.08(d,J＝5.7Hz,1H),4.40(ddd,J＝15.7,4.8,2.3Hz,2H),3.80(s,3H),3.69-3.63(m,2H),3.17(d,J＝11.5Hz,2H),3.07(td,J＝12.6,3.0Hz,2H),2.44-2.36(m,2H),2.37(s,3H),2.34-2.31(m,2H),2.29(s,6H),1.68-1.62(m,3H).13C NMR(150MHz,CDCl3)δ160.5,160.2,159.5,156.8,140.9,140.9,135.0,132.8,130.4,130.1,127.5,126.1,124.1,123.4,123.1,107.0,106.8,103.9,98.5,62.1,62.0,56.7,51.4,44.9,41.7,41.5,38.6,29.3,29.0,27.4.HRMS(ESI)(m/z):[M+H]+calcd for C27H34N9O,500.2881；found 500.2877.。
实施例30 N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-2-基)氨基)-2-(4-(二甲氨基)哌啶-1-基)-4-甲氧基苯基)丙烯酰胺(13g)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ9.36(s,1H),9.25(s,1H),8.44(s,1H),8.24(d,J＝8.2Hz,1H),8.08(d,J＝5.8Hz,1H),7.82(d,J＝1.8Hz,1H),7.78(d,J＝2.4Hz,1H),7.36–7.28(m,3H),7.10(t,J＝7.6Hz,1H),6.70(s,1H),6.47(t,J＝2.2Hz,1H),6.41–6.29(m,2H),6.13(d,J＝5.8Hz,1H),5.74(d,J＝9.8Hz,1H),5.30(s,1H),3.85(s,3H),3.05(d,J＝11.6Hz,2H),2.77–2.66(m,2H),2.46(s,6H),2.08(d,J＝12.4Hz,2H),1.78-1.74(m,1H).13CNMR(150MHz,CDCl3)δ160.6,159.8,157.2,141.2,132.9,132.3,130.5,130.3,127.9,126.6,126.5,123.6,123.3,112.2,107.1,103.25,98.7,62.3,56.1,52.3,41.8,29.8,29.6.HRMS(ESI)(m/z):[M+H]+calcd for C30H36N9O2,554.2986；found 554.2981。
实施例31 N4-(2-(1H-吡唑-1-基)苯基)-N2-(2-methoxy-4-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-2,4-二胺(11h)
同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.58(s,1H),9.07(s,1H),8.23–8.17(m,1H),8.07(d,J＝5.8Hz,1H),7.87(d,J＝1.9Hz,1H),7.82(d,J＝2.5Hz,1H),7.41–7.35(m,2H),7.18(td,J＝7.6,1.3Hz,1H),6.62(s,1H),6.50(t,J＝2.2Hz,1H),6.21(d,J＝5.8Hz,1H),3.97(s,3H),3.11(t,J＝4.8Hz,4H),2.66(t,J＝4.7Hz,4H),2.40(s,3H).13C NMR(150MHz,MeOD)δ160.5,159.3,157.0,151.89,141.9,141.2,136.9,132.5,130.2,130.2,128.0,124.7,123.6,123.5,123.3,116.2,107.1,102.2,99.4,56.2,55.2,52.3,46.1.HRMS(ESI)(m/z):[M+H]+calcd for C25H28N9O3,502.2310；
found 502.2306.。
实施例32 N4-(2-(1H-吡唑-1-基)苯基)-N2-(5-氨基-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)嘧啶-2,4-二胺(12h)
同实施例5。
1H NMR(400MHz,Chloroform-d)δ9.35(s,1H),8.37(dd,J＝8.3,1.4Hz,1H),8.03(t,J＝2.8Hz,2H),7.95(s,1H),7.82(d,J＝1.9Hz,1H),7.80(d,J＝2.5Hz,1H),7.47–7.40(m,2H),7.36(dd,J＝8.0,1.5Hz,1H),7.16(td,J＝7.7,1.4Hz,1H),6.66(s,1H),6.49(t,J＝2.2Hz,1H),6.09(d,J＝5.7Hz,1H),3.80(s,3H),3.43–3.36(m,4H),2.44–2.39(m,4H),2.32(s,6H).13C NMR(150MHz,MeOD)δ160.8,160.4,159.6,157.0,141.2,135.2,133.0,132.3,130.4,130.3,127.7,126.6,124.2,123.5,123.2,107.1,107.0,104.2,98.8,56.8,56.0,55.5,54.3,51.5,46.3,46.2,45.6,39.99.HRMS(ESI)(m/z):[M+H]+calcd forC25H30N9O,472.2568；found 472.2565.。
实施例33 N-(5-((4-((2-(1H-吡唑-1-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺(13h)
同实施例6。
1H NMR(400MHz,Chloroform-d)δ10.55(s,1H),9.45(s,1H),8.60–8.55(m,1H),8.45(d,J＝8.4Hz,1H),8.25–8.12(m,4H),8.04(s,0H),7.37(d,J＝8.0Hz,2H),7.08(t,J＝7.4Hz,1H),6.79(s,1H),6.39–6.29(m,2H),5.76(d,J＝9.7Hz,1H),4.03(s,3H),3.88(s,3H),2.99-2.94(m,4H),2.63-2.61(m,4H),2.41(s,3H).13C NMR(151MHz,CDCl3)δ162.7,160.6,159.8,157.2,145.1,141.2,135.3,132.9,132.3,130.5,130.2,127.9,126.8,126.7,126.4,123.6,123.3,111.9,107.1,107.1,103.5,98.7,56.1,56.1,52.5,46.2.HRMS(ESI)(m/z):[M+H]+calcd for C28H32N9O2,526.2673；found 526.2669.。
实施例34 N4-(2-(1H-吡唑-1-基)苯基)-N2-(2-甲氧基-4-吗啉-5-硝基苯基)嘧啶-2,4-二胺(11i)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.58(s,1H),9.07(s,1H),8.18(d,J＝8.2Hz,1H),8.06(d,J＝5.8Hz,1H),7.86(d,J＝1.9Hz,1H),7.80(d,J＝2.5Hz,1H),7.37(dd,J＝15.1,7.5Hz,3H),7.17(td,J＝7.6,1.4Hz,1H),6.59(s,1H),6.49(t,J＝2.2Hz,1H),6.21(d,J＝5.8Hz,1H),3.96(s,3H),3.91–3.83(m,4H),3.07–3.00(m,4H).13C NMR(151MHz,CDCl3)δ160.5,159.3,157.0,151.8,141.7,141.2,137.2,132.5,130.3,130.2,128.0,125.1,123.6,123.5,123.3,116.1,107.1,102.1,99.4,67.1,56.2,52.9.HRMS(ESI)(m/z):[M+H]+calcd for C24H25N8O4,489.1993；found489.1987.。
实施例35 N4-(2-(1H-吡唑-1-基)苯基)-N2-(5-氨基-2-甲氧基-4-吗啉苯基)嘧啶-2,4-二胺(12i)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ9.38(s,1H),8.38(d,J＝8.4Hz,1H),8.03(d,J＝5.7Hz,1H),7.97(s,1H),7.83(d,J＝1.9Hz,1H),7.80(d,J＝2.4Hz,1H),7.49(s,1H),7.46–7.40(m,1H),7.36(dd,J＝8.1,1.5Hz,1H),7.26(d,J＝0.9Hz,3H),7.17(t,J＝7.8Hz,1H),6.64(s,1H),6.50(t,J＝2.2Hz,1H),6.10(d,J＝5.7Hz,1H),3.85(t,J＝4.5Hz,4H),3.82(s,3H),2.90(t,J＝4.5Hz,4H).13C NMR(151MHz,CDCl3)δ160.4,159.6,156.9,141.3,141.2,135.3,133.1,132.1,130.5,130.3,127.7,126.8,124.2,123.5,123.2,107.2,107.1,104.2,98.9,67.9,56.9,52.0.。
实施例36 N-(5-((4-((吡唑-1-基)苯基)氨基)嘧啶-2基)氨基)-4-甲氧基-2-吗啉苯基)丙烯酰胺(13i)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ9.41(s,1H),9.27(s,1H),8.50(s,1H),8.23(d,J＝8.2Hz,1H),8.09(d,J＝5.8Hz,1H),7.82(d,J＝1.9Hz,1H),7.78(d,J＝2.4Hz,1H),7.38–7.27(m,3H),7.10(t,J＝7.6Hz,1H),6.72(s,1H),6.46(t,J＝2.2Hz,1H),6.42–6.24(m,2H),6.14(d,J＝5.8Hz,1H),5.80–5.71(m,1H),3.86-3.79(m,7H),2.86(t,J＝4.5Hz,4H).13C NMR(150MHz,CDCl3)δ162.7,160.6,159.7,157.1,145.1,141.2,135.0,132.8,132.2,130.5,130.2,127.8,126.9,126.7,126.5,123.6,123.3,112.1,107.1,103.4,98.8,67.8,56.1,52.9.。
实施例37
操作同实施例3。422.9[M+H]+。
实施例38 N4-(2-(2H-1,2,3-***-2-基)苯基)-N2-(4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)嘧啶-2,4-二胺(11j)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.82(s,1H),9.01(s,1H),8.16(d,J＝8.3Hz,1H),8.08(d,J＝5.8Hz,1H),7.99(dd,J＝8.4,1.7Hz,1H),7.93(s,2H),7.43–7.35(m,2H),7.23–7.17(m,1H),6.65(s,1H),6.31(d,J＝5.8Hz,1H),3.94(s,4H),3.26(t,J＝7.2Hz,2H),2.86(s,3H),2.58(t,J＝7.2Hz,2H).13C NMR(150MHz,CDCl3)δ160.5,159.4,157.3,152.2,142.5,135.1,135.0,135.0,131.0,129.7,128.5,123.5,123.4,123.1,122.8,116.5,102.1,98.7,57.0,56.1,54.0,45.8,41.4.HRMS(ESI)(m/z):[M+H]+calcd forC24H29N10O3,505.2419；found 505.2418.。
实施例39 N4-(4-((2-(2H-1,2,3-***-2-基)苯基)氨基)嘧啶-2-基)-N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲基苯基-1,2,4-三胺(12j)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ9.63(s,1H),8.40(d,J＝8.3Hz,1H),8.07(d,J＝5.7Hz,1H),8.01(s,1H),7.95–7.88(m,5H),7.52–7.43(m,2H),7.22(t,J＝7.7Hz,1H),6.67(s,1H),6.18(d,J＝5.7Hz,1H),3.81(s,3H),2.96(t,J＝6.6Hz,2H),2.66(s,3H),2.42(dd,J＝8.6,5.1Hz,2H),2.29(s,3H),2.28(s,3H).13C NMR(150MHz,MeOD)δ160.4,159.7,157.2,141.1,135.2,135.0,135.0,132.4,131.3,129.8,128.2,126.5,124.0,123.4,123.2,107.1,104.1,98.8,62.8,56.9,51.2,41.0,28.6.HRMS(ESI)(m/z):[M+H]+calcd forC24H31N10O,475.2677；found 475.2674.。
实施例40 N-(5-((4-((2-(2H-1,2,3-***-2-基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(13j)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ10.09(s,1H),9.67(s,1H),9.48(s,1H),8.24(d,J＝8.2Hz,1H),8.13(d,J＝5.6Hz,1H),7.95(dd,J＝8.2,1.6Hz,1H),7.91(s,2H),7.39–7.31(m,2H),7.17–7.11(m,1H),6.76(s,1H),6.26(d,J＝5.8Hz,1H),5.71–5.66(m,1H),3.85(s,3H),2.88(t,J＝5.6Hz,2H),2.69(s,3H),2.33–2.26(m,9H).13C NMR(150MHz,CDCl3)δ163.2,160.6,159.9,157.5,145.1,135.8,135.0,134.9,132.6,131.4,129.9,129.4,128.4,126.8,125.9,123.3,123.3,123.1,112.3,104.6,98.4,57.5,56.1,45.5,43.7.HRMS(ESI)(m/z):[M+H]+calcd for C27H33N10O2,529.2782；found 529.2780。
实施例41 N4-(2-(2H-1,2,3-***-2-基)苯基)-N2-(4-(4-(二甲氨基)哌啶-1-基)-2-甲氧基-5硝基苯基)嘧啶-2,4-二胺(11k)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.82(s,1H),9.11(s,1H),8.15(d,J＝8.1Hz,1H),8.08(d,J＝5.8Hz,1H),8.01–7.97(m,2H),7.93(s,2H),7.43–7.36(m,2H),7.21(ddd,J＝8.5,7.3,1.4Hz,1H),6.56(s,1H),6.31(d,J＝5.8Hz,1H),3.94(s,3H),3.34(d,J＝11.6Hz,2H),2.80(m,2H),2.40-2.36(m,2H),2.34(s,6H),1.90-1.88(m,2H),1.78(m,1H).13C NMR(150MHz,MeOD)δ160.5,159.3,157.3,152.1,142.9,135.9,135.2,135.1,135.0,130.9,129.7,128.5,124.0,123.6,123.4,122.8,116.5,102.0,98.7,61.9,56.2,56.1,52.2,41.6,41.5,41.4,28.3.HRMS(ESI)(m/z):[M+H]+calcd for C26H31N10O3,531.2575；found 531.2570.。
实施例42 N4-(2-(2H-1,2,3-***-2-基)苯基)-N2-(5-氨基-4-(4-(二甲氨基)哌啶-1-基)-2-甲氧基苯基)嘧啶-2,4-二胺(12k)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ9.62(s,1H),8.38(d,J＝8.0Hz,1H),8.05(d,J＝5.7Hz,1H),8.00(d,J＝7.1Hz,1H),7.92(s,1H),7.90(s,2H),7.49–7.43(m,3H),7.21(t,J＝7.7Hz,1H),6.60(s,1H),6.17(d,J＝5.7Hz,1H),3.80(s,3H),3.2-3.18(m,2H),2.65-2.59(m,2H),2.50(s,6H),2.07-2.04(m,2H),1.76(m,2H).13C NMR(150MHz,MeOD)δ160.4,159.7,157.2,141.1,135.2,135.0,135.0,132.4,131.3,129.8,128.2,126.5,124.0,123.4,123.2,107.1,104.1,98.8,62.8,56.9,51.2,41.0,28.6.HRMS(ESI)(m/z):[M+H]+calcd for C26H33N10O,501.2833；found501.2835.。
实施例43 N-(5-((4-((2-(2H-1,2,3-***-2-基)苯基)氨基)嘧啶-2-基)氨基)-2-(4-(二甲氨基)哌啶-1-基)-4-甲氧基苯基)丙烯酰胺(13k)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ9.67(s,1H),9.41(s,1H),8.49(s,1H),8.22(d,J＝8.2Hz,1H),8.12(d,J＝5.7Hz,1H),7.96(d,J＝9.3Hz,1H),7.91(s,2H),7.38–7.31(m,2H),7.16(t,J＝7.7Hz,1H),6.71(s,1H),6.39–6.29(m,1H),6.27(d,J＝5.7Hz,1H),5.77–5.72(m,1H),3.85(s,3H),3.05(d,J＝11.4Hz,2H),2.78–2.68(m,2H),2.43(s,6H),2.39-2.35(m,2H),2.09-2.01(m,2H),1.79–1.65(m,2H).13C NMR(150MHz,CDCl3)δ162.8,160.6,159.9,157.4,135.1,132.3,131.4,129.9,128.2,126.7,126.4,123.4,123.3,112.0,103.2,98.4,62.2,56.2,52.3,41.8,29.8.HRMS(ESI)(m/z):[M+H]+calcd for C29H35N10O2,555.2939；found 555.2928.。
实施例44 N4-(2-(2H-1,2,3-***-2-基)苯基)-N2-(2-甲氧基-4-(4-甲基哌啶-1-基)-5-硝基苯基)嘧啶-2,4-二胺(11l)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.82(s,1H),9.13(s,1H),8.15(d,J＝8.3Hz,1H),8.10(d,J＝6.2Hz,1H),8.02–7.98(m,1H),7.93(s,1H),7.43–7.36(m,2H),7.22(t,J＝7.8Hz,1H),6.60(s,1H),6.32(d,J＝5.8Hz,1H),3.96(s,3H),3.10(t,J＝4.7Hz,5H),2.63(t,J＝4.6Hz,5H),2.38(s,3H).13C NMR(150MHz,CDCl3)δ160.5,159.4,157.3,152.0,142.2,136.7,135.1,135.1,130.9,129.8,128.5,124.6,123.6,123.5,122.9,116.3,102.1,98.9,56.2,55.2,52.3,46.1.HRMS(ESI)(m/z):[M+H]+calcd for C24H27N10O3,503.2262；found 503.2263.。
实施例45 N4-(2-(2H-1,2,3-***-2-基)苯基)-N2-(5-氨基-2-甲氧基-4-(4-甲基哌啶-1-基)苯基)嘧啶-2,4-二胺(12l)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ9.63(s,1H),8.39(dd,J＝8.4,1.4Hz,1H),8.07(d,J＝5.7Hz,1H),8.01(dd,J＝8.1,1.6Hz,1H),7.95(s,1H),7.91(s,2H),7.50(s,1H),7.46(td,J＝8.4,7.8,1.6Hz,1H),7.22(ddd,J＝8.5,7.3,1.3Hz,1H),6.66(s,1H),6.19(d,J＝5.7Hz,1H),3.82(s,3H),3.07(t,J＝4.9Hz,4H),2.54(s,3H).13C NMR(151MHz,CDCl3)δ160.5,159.7,157.1,141.3,135.1,135.08,131.4,129.9,128.2,127.0,124.0,123.4,123.2,107.1,104.3,98.9,56.9,55.6,50.4,45.5.HRMS(ESI)(m/z):[M+H]+calcd forC24H29N10O,473.2520；found 573.2524.。
实施例46 N-(5-((4-((2-(2H-1,2,3-***-2-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-甲基哌啶-1-基)苯基)嘧啶-2,4-二胺(13l)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ9.69(s,1H),9.43(s,1H),8.50(s,1H),8.22(d,J＝8.3Hz,1H),8.12(d,J＝5.8Hz,1H),7.96(dd,J＝8.1,1.5Hz,1H),7.91(s,2H),7.45(s,1H),7.34(t,J＝7.8Hz,1H),7.16(t,J＝7.7Hz,1H),6.76(s,1H),6.37(d,J＝1.7Hz,1H),6.32(d,J＝9.9Hz,1H),6.27(d,J＝5.8Hz,1H),5.75(d,J＝10.0Hz,1H),3.85(s,3H),2.95-2.90(m,4H),2.74-2.63(m,4H)2.46(s,3H).13C NMR(151MHz,CDCl3)δ162.7,160.7,159.7,157.1,135.1,132.3,131.3,129.9,128.4,126.8,126.5,123.4,123.3,112.0,103.6,98.5,56.1,55.9,52.2,45.9.HRMS(ESI)(m/z):[M+H]+calcd for C27H31N10O2,527.2626；found527.2626.。
实施例47 N4-(2-(2H-1,2,3-***-2-基)苯基)-N2-(2-甲氧基-4-吗啉-5-硝基苯基)嘧啶-2,4-二胺(11m)
步骤同实施例4。
1H NMR(400MHz,Chloroform-d)δ9.82(s,1H),9.16(s,1H),8.15(d,J＝8.3Hz,1H),8.10(d,J＝5.8Hz,1H),8.00(dd,J＝8.2,1.5Hz,1H),7.94(s,2H),7.44–7.37(m,2H),7.22(ddd,J＝8.4,7.4,1.3Hz,1H),6.60(s,1H),6.34(d,J＝5.8Hz,1H),5.30(s,0H),3.98(s,3H),3.92–3.82(m,4H),3.13–3.01(m,4H).13C NMR(151MHz,CDCl3)δ160.6,159.4,157.4,151.9,141.9,137.0,135.1,130.9,129.9,128.5,125.0,123.7,123.5,122.9,116.3,102.1,99.0,67.2,56.2,52.9.HRMS(ESI)(m/z):[M+H]+calcd for C23H24N9O4,490.1946；found 490.1943。
实施例48 N4-(2-(2H-1,2,3-***-2-基)苯基)-N2-(5-氨基-2-甲氧基-4-(4-甲基哌啶-1-基)苯基)嘧啶-2,4-二胺(12m)
步骤同实施例5。
1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.41(d,J＝8.3Hz,1H),8.07(d,J＝5.7Hz,1H),8.01(dd,J＝8.2,1.4Hz,1H),7.96(s,1H),7.91(s,1H),7.52–7.42(m,2H),7.22(t,J＝8.0Hz,1H),6.64(s,1H),6.19(d,J＝5.7Hz,1H),3.86(t,J＝4.5Hz,4H),3.83(s,3H),2.94–2.87(m,4H).13C NMR(151MHz,CDCl3)δ160.5,159.7,157.2,141.3,135.4,135.0,132.2,131.4,129.9,128.2,126.7,124.0,123.4,123.2,107.1,104.2,98.9,67.9,56.9,52.0.HRMS(ESI)(m/z):[M+H]+calcd for C23H26N9O2,460.2204；found 460.2206.。
实施例49 N-(5-((4-((2-(2H-1,2,3-***-2-基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-吗啉苯基)丙烯酰胺(13m)
步骤同实施例6。
1H NMR(400MHz,Chloroform-d)δ9.69(s,1H),9.47(s,1H),8.53(s,1H),8.21(d,J＝8.4Hz,11H),8.13(d,J＝5.8Hz,11H),7.97(dd,J＝8.1,1.4Hz,10H),7.92(d,J＝0.9Hz,19H),7.34(t,J＝7.6Hz,9H),7.16(t,J＝7.7Hz,11H),6.74(s,11H),6.43–6.29(m,18H),6.28(d,J＝6.0Hz,14H),5.76(d,J＝10.0Hz,10H),5.30(s,10H),2.88(t,J＝4.5Hz,47H).13C NMR(151MHz,CDCl3)δ160.7,135.1,132.3,128.4,126.5,123.4,103.5,98.5,67.8,56.2,53.5,53.0,29.8,29.4.HRMS(ESI)(m/z):[M+H]+calcd for C26H28N9O3,514.2310；found 514.2314.。
实施例50药学实验
1)嘧啶衍生物的激酶抑制活性测试
检测本发明化合物对激酶的抑制活性，采用方法为酶联免疫吸附法(Enzyme-Linked ImmunosorbentAssay,ELISA)检测激酶磷酸化底物的能力，计算化合物对激酶活性的抑制作用。采用Bac-to-BacTM杆状病毒表达***(Invitrogen,Carlsbad,CA,USA)进行野生型EGFR和EGFRT790M/L858R突变的激酶区表达，经镍柱(QIAGEN Inc.,Valencia,CA,USA)纯化。
ELISA主要步骤如下：酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mMNaCl,pH 7.2-7.4)稀释成20μg/mL，于37℃反应12-16h包被酶标板，然后用含0.1％Tween-20的PBS(T-PBS)洗板，每孔加入用反应缓冲液(50mM HEPES pH 7.4,50mMMgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP(终浓度5μM)溶液，加入不同浓度的待测化合物或溶剂对照，然后分别加入相应激酶启动反应，37℃摇床反应1h。T-PBS洗板三次，加入抗体PY99100μL/孔(用含BSA的T-PBS稀释)于37℃摇床反应0.5h。T-PBS洗板后，加入辣根过氧化物酶标记的羊抗鼠的IgG 100μL/孔(用含BSA的T-PBS稀释)，37℃摇床反应0.5h，再次洗板后，加入2mg/mL的OPD显色液100μL/孔，25℃避光反应1-10min。加入2M H2SO4终止反应，用可调波长式微孔板酶标仪SPECTRAMAX 190读数，波长为492nm。IC50值由抑制曲线得到。
表1受试化合物对激酶的抑制活性(IC50,nM)
实验结果表明，受试化合物对EGFR T790M/L858R具有较强的抑制活性，对野生型EGFR抑制活性较弱，表现出较好的选择性，其中化合物13a，13f和13n对EGFR T790M/L858R的激酶抑制活性稍强于对照化合物AZD9291，且选择性优于AZD9291；
2)嘧啶衍生物的体外人肿瘤细胞增值抑制实验
检测本发明化合物对体外人肿瘤细胞增殖抑制活性，采用的方法为磺酰罗丹明B(sulforodamine B，SRB)法。
选用含野生型EGFR人表皮细胞癌A431细胞株和含EGFR T790M/L858R突变人非小细胞肺癌NCI-H1975细胞株(均购自ATCC)进行检测。细胞以一定密度接种于96孔板，贴壁过夜，加入不同浓度化合物作用72h，用预冷的10％三氯乙酸于4℃固定1h，蒸馏水洗去固定液后烘干，使用4mg/mL的SRB溶液(溶于1％醋酸)室温染色15分钟，洗去多余染色液，室温烘干，在使用酶标仪检测前加入10mmol/L Tris 100μL每孔，约15分钟后，SRB完全溶解，使用多功能酶标仪(VERSAmax,Molecular Devices)测定515nm的吸收波长，抑制率计算公为：[1–(A515treated/A515control)]×100％。
表2受试化合物对细胞的增值抑制活性(IC50,μM)
结果表明，受试化合物13a，13f和13n对含EGFR T790M/L858R突变的NCI-H1975细胞的体外生长具有很强的抑制活性，与对照化合物AZD9291活性相当，且化合物13a和13f对含野生型EGFR的A431细胞的增殖抑制活性弱，其选择性优于AZD9291；其他化合物对其也具有较强的抑制活性。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (9)
1.式I结构的嘧啶类化合物，
其中，W为NH，R1为含氮五元杂环,R2为含氮碱性基团。
2.根据权利要求1所述的嘧啶类化合物，其特征在于，所述含氮五元杂环为下述结构中的一种：
所述R2为下述结构中的一种：
3.根据权利要求2所述的嘧啶类化合物，其特征在于，所述R2为
4.根据权利要求1所述的嘧啶类化合物，所述化合物为下述化合物中的一种：
5.根据权利要求4所述的嘧啶类化合物，所述化合物为下述化合物中的一种：
6.根据权利要求4所述的嘧啶类化合物，所述化合物为下述化合物中的一种：
7.权利要求1所述的嘧啶类化合物在用于制备***的药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述肿瘤为非小细胞肺癌、小细胞肺癌、胰腺癌或鼻咽癌中的任一种。
9.一种药物组合物，所述组合物包含治疗有效量的权利要求1～6中任一项所述的嘧啶类化合物。
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| WO2008049123A2 (en) * | 2006-10-19 | 2008-04-24 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine derivatives as inhibitors of jak kinases for the treatment of autoimmune diseases |
| CN102083800A (zh) * | 2008-06-27 | 2011-06-01 | 阿维拉制药公司 | 杂芳基化合物和其用途 |
| CN102482277A (zh) * | 2009-05-05 | 2012-05-30 | 达纳-法伯癌症研究所有限公司 | 表皮生长因子受体抑制剂及治疗障碍的方法 |
| CN103153064A (zh) * | 2010-10-14 | 2013-06-12 | 阿里亚德医药股份有限公司 | 抑制egfr导致的癌症中细胞增殖的方法 |
| CN103702990A (zh) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症 |
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| CN102083800A (zh) * | 2008-06-27 | 2011-06-01 | 阿维拉制药公司 | 杂芳基化合物和其用途 |
| CN102482277A (zh) * | 2009-05-05 | 2012-05-30 | 达纳-法伯癌症研究所有限公司 | 表皮生长因子受体抑制剂及治疗障碍的方法 |
| CN103153064A (zh) * | 2010-10-14 | 2013-06-12 | 阿里亚德医药股份有限公司 | 抑制egfr导致的癌症中细胞增殖的方法 |
| CN103702990A (zh) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症 |
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