WO2020172932A1 - 苯胺类wdr5蛋白-蛋白相互作用抑制剂及其制法和用途 - Google Patents

苯胺类wdr5蛋白-蛋白相互作用抑制剂及其制法和用途 Download PDF

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WO2020172932A1
WO2020172932A1 PCT/CN2019/079160 CN2019079160W WO2020172932A1 WO 2020172932 A1 WO2020172932 A1 WO 2020172932A1 CN 2019079160 W CN2019079160 W CN 2019079160W WO 2020172932 A1 WO2020172932 A1 WO 2020172932A1
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amino
methylpiperazin
preparation
substituted
phenyl
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PCT/CN2019/079160
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French (fr)
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尤启冬
郭小可
陈维琳
李冬冬
顾婧
徐俊
陈鑫
姜正羽
徐晓莉
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中国药科大学
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Priority to AU2019431157A priority Critical patent/AU2019431157A1/en
Priority to US17/434,353 priority patent/US20220152027A1/en
Priority to SG11202109305XA priority patent/SG11202109305XA/en
Priority to MX2021010218A priority patent/MX2021010218A/es
Priority to CA3131285A priority patent/CA3131285A1/en
Priority to BR112021016861A priority patent/BR112021016861A2/pt
Application filed by 中国药科大学 filed Critical 中国药科大学
Priority to JP2021549174A priority patent/JP2022526219A/ja
Priority to EP19917469.9A priority patent/EP3932910A4/en
Priority to KR1020217030807A priority patent/KR20210137064A/ko
Publication of WO2020172932A1 publication Critical patent/WO2020172932A1/zh
Priority to IL285852A priority patent/IL285852A/en
Priority to CONC2021/0012375A priority patent/CO2021012375A2/es

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Abstract

本发明公开了一种WDR5蛋白-蛋白相互作用抑制剂，包含结构如通式(I)所示的化合物。实验表明该抑制剂作用于WDR5蛋白与其相互作用蛋白包括但不局限于MLL，选择性抑制白血病细胞的增殖，在细胞水平上抑制H3K4的甲基化和下游Hox/Meis-1基因的表达。本发明还公开了该抑制剂的制备方法以及在制备治疗急性白血病等相关疾病药物中的应用。

Description

苯胺类WDR5蛋白-蛋白相互作用抑制剂及其制法和用途 技术领域
本发明涉及药物化学的一种苯胺类化合物及其制法和用途，该化合物作为WDR5蛋白-蛋白相互作用抑制剂，在细胞水平抑制组蛋白的甲基转移酶的水平和下游造血基因的表达，在动物水平上抑制裸鼠移植瘤的生长，可应用于治疗急性白血病等疾病。
背景技术
WDR5蛋白由334个氨基酸组成，包含7个WD40重复的结构域。结构学研究表明WD40重复结构形成7叶螺旋桨结构，每一叶桨又含有4个反向平行的链，这样的结构特征使WDR5与许多其他蛋白相互作用WDR5-MLL1，WDR5-MYC，WDR5-MOF/HAT。WDR5还可以与H3K4me2相结合。研究表明WDR5可以稳定或组装病毒诱导的信号调节(VISA)相关复合物，在I型干扰素和抗病毒先天免疫应答中起着重要作用。WDR5蛋白在膀胱癌中也高表达，通过激活H3K4me3的表达，促进膀胱癌细胞的增殖，自我更新和化疗。WDR5作为重要的辅因子参与N-Myc-调节的转录激活和肿瘤生成。抑制WDR5蛋白作为治疗MYCN-放大的神经母细胞瘤的新型靶点。
组蛋白甲基化修饰在许多生物学过程中起到了关键作用，是表观遗传调控领域的重要研究内容。MLL1是一种组蛋白H3的4位赖氨酸(H3K4)甲基转移酶。MLL1基因易位重排形成融合基因进而表达具有致癌作用的MLL融合蛋白，从而诱发混合系白血病(mixed lineage leukemia，MLL1，急性骨髓性白血病和急性淋巴性白血病)。MLL异常引起的白血病的治疗常规化疗不理想，预后不良，目前尚无靶向药物，所以迫切需要针对该疾病的生物学性质开发新的治疗药物。
MLL1的染色体易位只发生在单等位基因上，还存在着一个野生型的MLL1。野生型的MLL1和其融合蛋白共同参与混合系白血病的发生与发展，其中野生型MLL1的酶催化活性对MLL1融合蛋白诱发白血病生成是至关重要的。因此特异性地抑制野生型MLL1的酶催化活性能达到治疗白血病的作用。
单独存在的MLL1的催化活性很差，并且仅能催化H3K4单甲基化；当MLL1与形成WDR5、RbBP5、Ash2L和DPY30，形成核心复合物后酶催化活性大大提升，尤其是对H3K4me2的催化活性。其中WDR5作为连接MLL1C-端WIN motif部分与其他蛋白的连接桥梁，对复合物的形成起着至关重要的作用。因此，利用小分子抑制剂干扰WDR5的蛋白-蛋白相互作用是抑制MLL1的酶催化活性、从而抑制下游Hox和Meis-1基因表达、进而阻断白血病进展的一种有效手段。
发明内容
发明目的：本发明的目的在于提供一种WDR5蛋白-蛋白相互作用抑制剂，在细胞水平抑制组蛋白的甲基转移酶的水平和下游造血基因的表达，在动物水平上抑制裸鼠移植瘤的生长，在治疗与MLL酶功能有关适应症药物中的应用，可应用于治疗急性白血病等疾病。
技术方案：本发明公开了一种可以干扰WDR5蛋白-蛋白相互作用的小分子化合物，其通过干扰WDR5蛋白-蛋白相互作用，抑制MLL1的甲基转移催化活性，下调Hox和Meis-1基因表达水平，从而诱导白血病细胞的凋亡，用于治疗急性白血病。本发明化合物结构如下：
Figure PCTCN2019079160-appb-000001
其中X代表CH或N；
Y代表C或N；
R 1、R 2和R 3彼此相同或不同，各自独立选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷氧基取代的C 1-C 6烷基、硝基、卤素、氰基、醛基、羟基、-NR 7R 8，或者R 2、R 3连接形成的
Figure PCTCN2019079160-appb-000002
其中R 7、R 8彼此相同或不同，各自独立代表氢或C 1-C 4烷基或者R 7、R 8连接形成的3-7元含氮杂环；
R 4代表吗啉基、哌嗪基、4-取代哌嗪基，4-取代高哌嗪基，3-取代哌嗪基或2-取代哌嗪基，取代基为C 1-C 4烷基，3-7元环烷基，羟烷基，苯基；
R 5代表硝基、氨基、苯基、取代苯基、含氧或氮的5-6元芳杂环、取代的含氧或氮的5-6元芳杂环、-NHCOR 9；其中R 9代表羟基、C 1～C 6烷氧基、苯基、取代苯基、含氧或氮的5-6元芳杂环、取代的含氧或氮的5-6元芳杂环，取代基是C 1-C 4烷基、C 1-C 4烷氧基、卤素、氰基、-NHCOR 10、-CONR 11R 12或-COOR 10，其中R 10代表氢、C 1-C 6烷基、C 1-C 6氨基取代烷基、3～7元环烷基、含氮或含氧的3～7元杂环、苯基；R 11、R 12独立代表氢、C 1-C 6烷基、苯基或取代苯基、取代的或未取代的含氮或含氧3～7元杂环或R 11、R 12连接形成含氮或含氧的3～7元杂环；
R 6代表氢、卤素、甲基、三氟甲基、氨基、取代氨基，取代基是C 1-C 4烷基、烯丙基；
R 1、R 2和R 3彼此相同或不同，各自独立优选自氢、卤素、甲基、硝基、氰基、醛基、甲氧基、-NR 7R 8,或者R 2、R 3连接形成的
Figure PCTCN2019079160-appb-000003
其中R 7、R 8彼此相同或不同，各自独立代表氢或C 1-C 4烷基或者R 7、R 8连接形成的3-5元含氮杂环；
R 4优选吗啉基、哌嗪基、4-取代哌嗪基、取代基是甲基、乙基、环丙基、羟乙基、苯基；
R 5优选硝基、氨基、-NHCO R 9、呋喃基、嘧啶基、吡啶基、取代三氮唑、取代苯基，取代基为单或双取代的卤素、-NHCOR 10、-CONR 11R 12或-COOR 10；R 9代表苯基；R 10代表氢、C 1-C 6烷基、C 1-C 6氨基取代烷基、3～7元环烷基、含氮或含氧的3～7元杂环、苯基；R 11、R 12独立代表氢、C 1-C 6烷基、苯基或取代苯基、取代的或未取代的含氮或含氧3～7元杂环或R 11、R 12连接形成含氮或含氧的3～7元杂环。
本发明同时包括化合物(I)的药学上可接受的盐，及其溶剂化物，都与化合物(I)有同样的药理功效。
本发明公开了一种药物组合物，其包含化合物(I)或其可药用盐，或溶剂合物，以及一种或多种可药用载体、稀释剂和赋形剂。
本发明还提供式(I)化合物或其可药用盐或溶剂合物在制备用于通过抑制WDR5蛋白-蛋白相互作用来治疗该酶介导的疾病的药物中的用途，所述疾病如MLL基因融合型白血病，其可通过抑制MLL1的酶活性来治疗。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可以根据病情的轻重或剂型的不同偏离此范围。
在某些实施方案中，根据式(I)的化合物可含有足以形成盐的碱性官能团。代表性的盐包括药用无机酸盐，有盐酸盐、氢溴酸盐和硫酸盐；药用有机酸盐，优选乙酸盐、三氟乙酸盐、乳酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、甲磺酸盐、对苯甲酸盐和对苯甲磺酸盐。
同时本发明还公开了式(I)相关化合物的制备方法，所述制备方法包括如下方法：
Figure PCTCN2019079160-appb-000004
Figure PCTCN2019079160-appb-000005
有益效果：本发明的苯胺类化合物具有较强的WDR5蛋白-蛋白相互作用抑制活性，可以在细胞水平降低MLL1酶催化活性、下调Hox和Meis-1基因表达，治疗与WDR5酶功能有关适应症，有关适应症指血液性肿瘤，包括急性白血病等疾病。
附图说明
图1是Western-blot实验检测实施例72在细胞内对MLL1酶催化活性的影响；
图2是RT-PCR实验检测实施例72在细胞内对下调Hoxa9和Meis-1基因表达；
图3是MV4-11裸鼠移植瘤模型检测实施例72在动物水平对肿瘤的抑制水平。
具体实施方式
实施例1
Figure PCTCN2019079160-appb-000006
N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)喹唑啉-4-胺
步骤1：2-(4-甲基哌嗪-1-基)-5-硝基苯胺的制备
将2-氟-5-硝基苯胺(2g,12.8mmol)溶于DMF(20mL)中，加入DIPEA(3.3g,25.6mmol)和1-甲基哌嗪(25.6mmol)，100℃下搅拌反应8h。在反应液中加入100mL水，乙酸乙酯萃取(3×50mL)，合并有机层，并用无水Na 2SO 4干燥，减压蒸馏后得到粗品，用CH 3CN洗涤得到黄色固体，收率53.0％；m.p.200℃-202℃； 1H NMR(300MHz,DMSO-d 6)δ7.53(d,J＝2.4Hz,1H),7.42(dd,J＝8.8,2.4Hz,1H),7.04(d,J＝8.7Hz,1H),5.26(s,2H),3.11(s,4H),2.58(s,4H),2.24(s,3H).HRMS(ESI):calcd.for m/z C 11H 17N 4O 2,[M+H] +237.1316,found 237.1342.
步骤2：标题化合物N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)喹唑啉-4-胺的制备
将2-(4-甲基哌嗪-1-基)-5-硝基苯胺(0.2g,0.846mmol)溶于异丙醇(10mL)中，加入1mL浓HCl和4-氯喹唑啉(0.27g,1.69mmol)回流18h，减压蒸馏至有固体析出，冷却，抽滤，滤饼用异丙醇(5mL×3)洗涤，干燥得到黄色固体，收率63.5％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ9.57(s,1H),8.61(s,2H),8.43(s,1H),8.07(s,1H),7.86(d,J＝10.0Hz,2H),7.69(s,1H),7.30(s,J＝8.8Hz,1H),3.09(s,4H),2.32(s,4H),2.13(s,3H).HRMS(ESI):calcd.for m/z C 19H 20N 6O 2,[M+H] +365.1720,found 365.1722.HPLC(100％ MeOH):t R＝7.772min,99.16％.
实施例2
Figure PCTCN2019079160-appb-000007
6-氯-N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4-胺
按实施例1步骤2的方法，用4，6-二氯嘧啶(1.69mmol)替换4-氯喹唑啉得黄色固体，收率65.8％；m.p.169℃-171℃； 1H NMR(300MHz,DMSO-d 6)δ9.36(s,1H),8.48(s,1H),8.42(d,J＝2.7Hz,1H),8.02(dd,J＝8.9,2.8Hz,1H),7.23(d,J＝9.0Hz,1H),6.81(s,1H),3.04(t,J＝4.6Hz,4H),2.35(t,J＝4.7Hz,4H),2.16(s,3H).HRMS(ESI):calcd.for m/z C 15H 17ClN 6O 2,[M+H] +349.1174,found 349.1177.HPLC(100％MeOH):t R＝6.097min,96.84％.
实施例3
Figure PCTCN2019079160-appb-000008
N 4，N 4-二甲基-N 6-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4,6-二胺
将实施例2(0.35mmol)溶解在DMF(5mL)中，加入DIPEA(1.5mmol)和二甲基胺(1mmol),在120℃条件下反应4h,反应液用乙酸乙酯(20mL)稀释，水洗(10mL×3)，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，抽滤，旋干，粗品用硅胶柱层析(二氯甲烷:甲醇＝50:1)得到黄色固体。收率49.5％；m.p.152℃-154℃； 1H NMR(300MHz,CDCl 3)δ8.69(d,J＝2.7Hz,1H),8.28(s,1H),7.80(dd,J＝8.7,2.7Hz,1H),7.06(d,J＝8.8Hz,1H),6.94(s,1H),5.82(s,1H),3.03(s,6H),2.94(t,J＝4.8Hz,4H),2.65-2.48(m,4H),2.30(s,3H).HRMS(ESI):calcd.for m/z C 17H 23N 7O 2,[M+H] +358.1986,found 358.1992.HPLC(100％MeOH):t R＝4.709min,99.20％.
实施例4
Figure PCTCN2019079160-appb-000009
6-氯-2-甲基-N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4-胺
按照实施例1步骤2的方法，用4,6-二氯-2-甲基嘧啶替换4-氯喹唑啉得黄色固体，收率44.8％；m.p.196℃-198℃； 1H NMR(300MHz,CDCl 3)δ9.09(d,J＝2.6Hz,1H),7.97(dd,J＝8.8,2.7Hz,1H),7.55(s,1H),7.23(s,1H),6.59(s,1H),3.02(t,J＝4.8Hz,4H),2.65-2.61(m,7H),2.40(s,3H).HRMS(ESI):calcd.for m/z C 16H 19ClN 6O 2,[M+H] + 363.1331,found 363.1335.HPLC(100％MeOH):t R＝8.574min,97.99％.
实施例5
Figure PCTCN2019079160-appb-000010
6-氯-N 4-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-2,4-二胺
按照实施例1步骤2的制备方法，用4,6-二氯-2-氨基嘧啶替换4-氯喹唑啉得黄色固体，收率77.6％；m.p.248℃-251℃； 1H NMR(300MHz,CDCl 3)δ9.13(s,1H),7.94(dd,J＝8.7,2.6Hz,1H),7.41(s,1H),7.20(d,J＝2.6Hz,1H),5.16(s,2H),3.00(t,J＝4.8Hz,4H),2.64(s,4H),2.41(s,3H).HRMS(ESI):calcd.for m/z C 15H 18ClN 7O 2,[M+H] +364.1283,found 364.1289.HPLC(100％MeOH):t R＝5.850min,97.14％.
实施例6
Figure PCTCN2019079160-appb-000011
6-氯-5-甲基-N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4-胺
按照实施例1步骤2的制备方法，用4,6-二氯-5-甲基嘧啶替换4-氯喹唑啉得黄色固体,收率60.5％；m.p.259℃-261℃； 1H NMR(300MHz,CDCl 3)δ9.55(s,1H),8.57(s,1H),8.18(s,1H),7.95(dd,J＝8.7,2.7Hz,1H),7.27(s,1H),3.02(t,J＝4.8Hz,4H),2.66(s,4H),2.42(s,6H).HRMS(ESI):calcd.for m/z C 16H 19ClN 6O 2,[M+H] +363.1331,found 363.1349.HPLC(100％MeOH):t R＝7.673min,97.05％.
实施例7
Figure PCTCN2019079160-appb-000012
6-氯-N 4-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4,5-二胺
按照实施例1步骤2的制备方法，用4,6-二氯-5-氨基嘧啶替换4-氯喹唑啉得黄色固体，收率84.7％；m.p.185℃-187℃； 1H NMR(300MHz,DMSO-d 6)δ8.65(d,J＝2.6Hz,1H),8.22(s,1H),7.98-7.91(m,2H),7.27(d,J＝8.9Hz,1H),5.41(s,2H),2.91(br s,4H),2.47(br s,4H),2.20(s,3H).HRMS(ESI):calcd.for m/z C 15H 18ClN 7O 2,[M+H] +364.1283,found 364.1286.HPLC(100％MeOH):t R＝6.581min,98.22％.
实施例8
Figure PCTCN2019079160-appb-000013
6-氯-2-甲基-N  4-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4,5-二胺
按照实施例1步骤2的制备方法，用4,6-二氯2-甲基-5-氨基嘧啶替换4-氯喹唑啉得黄色固体，收率67.8％；m.p.248℃-250℃； 1H NMR(300MHz,DMSO-d 6)δ8.87(d,J＝2.8Hz,1H),8.22(s,1H),7.94(dd,J＝8.8,2.8Hz,1H),5.12(s,2H),2.98(t,J＝4.8Hz,4H),2.46(s,4H),2.32(s,3H),2.21(s,3H).HRMS(ESI):calcd.for m/z C 16H 20ClN 7O 2,[M+H] +378.1440,found 378.1440.HPLC(100％MeOH):t R＝6.251min,97.99％.
实施例9
Figure PCTCN2019079160-appb-000014
N 4-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4,5-二胺
按照实施例1步骤2的制备方法，用4-氯-5-氨基嘧啶替换4-氯喹唑啉得黄色固体，收率43.7％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.25(s,1H),7.82(dd,J＝7.4,1.9Hz,1H),7.81-7.77(m,2H),7.67(s,1H),7.04(d,J＝7.5Hz,1H),5.82(s,2H),3.20(t,J＝5.3Hz,4H),2.98(t,J＝5.3Hz,4H),2.60(s,3H).HRMS(ESI):calcd.for m/z C 15H 19N 7O 2,[M+H] +330.1673,found 330.1675.HPLC(100％MeOH):t R＝7.673min,97.05％
实施例10
Figure PCTCN2019079160-appb-000015
N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-2-胺
按照实施例1步骤2的制备方法，用2-溴嘧啶替换4-氯喹唑啉得黄色固体，收率57.5％；m.p.195℃-197℃； 1H NMR(300MHz,CDCl 3)δ9.47(s,1H),8.54(d,J＝3.0Hz,2H),8.03(s,1H),7.88(d,J＝3.0Hz,1H),7.22(d,J＝9.0Hz,1H),6.85(t,J＝9.0Hz,1H),3.04(t,J＝5.6Hz,4H),2.70(br s,4H),2.42(s,3H).HRMS(ESI):calcd.for m/z C 15H 18ClN 7O 2,[M+H] +315.1564,found 315.1566.HPLC(100％MeOH):t R＝16.340min,96.09％.
实施例11
Figure PCTCN2019079160-appb-000016
N 2-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-2,4-二胺
按照实施例1步骤2的制备方法，用2-氯嘧啶-4-胺替换4-氯喹唑啉得黄色固体，收率45.7％；m.p.210℃-212℃； 1H NMR(300MHz,DMSO-d 6)δ9.30(s,1H),7.94(d,J＝6.0 Hz,1H),7.80(dd,J＝8.7Hz,1H),7.63(s,1H),7.32(d,J＝8.8Hz,1H),6.81(br s,2H),6.03(d,J＝5.8Hz,1H),2.93(t,J＝4.7Hz,4H),2.54(br s,4H),2.26(s,3H).HRMS(ESI):calcd.for m/z C 15H 19N 7O 2,[M+H] +330.1673,found 330.1679.HPLC(100％MeOH):t R＝6.354min,96.85％.
实施例12
Figure PCTCN2019079160-appb-000017
N 2-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)吡啶-2,3-二胺
按照实施例1步骤2，用2-氯吡啶-3-胺替换4-氯喹唑啉得黄色固体，收率36.6％；m.p.210℃-212℃； 1H NMR(300MHz,DMSO-d 6)δ9.06(d,J＝2.8Hz,1H),7.77(dd,J＝8.8,2.8Hz,1H),7.68-7.59(m,2H),7.28(d,J＝8.8Hz,1H),7.77(dd,J＝7.6,1.7Hz,1H),6.75(dd,J＝7.6,1.7Hz,1H),4.94(s,2H),2.90(t,J＝4.8Hz,4H),2.54(s,4H),2.25(s,3H).HRMS(ESI):calcd.for m/z C 15H 20N 6O 2,[M+H] +329.1720,found 329.1722.HPLC(100％MeOH):t R＝4.151min,95.29％.
实施例13
Figure PCTCN2019079160-appb-000018
6-氯-N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)-5-硝基嘧啶-4-胺
按照实施例1步骤2的制备方法，用4,6-二氯-5-硝基嘧啶替换4-氯喹唑啉得黄色固体，收率53.2％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ10.20(s,1H),8.85(d,J＝6.5Hz,1H),8.16(d,J＝6.0Hz,2H),7.62(t,J＝9.5Hz,1H),3.52(br s,4H),2.42(br s,4H),2.22(s,3H).HRMS(ESI):calcd.for m/z C 15H 16ClN 7O 4,[M+H] +394.0671,found 394.0674.HPLC(100％MeOH):t R＝6.083min,97.01％.
实施例14
Figure PCTCN2019079160-appb-000019
4-氯-6-((2-(4-甲基哌嗪-1-基)-5-硝基苯基)氨基)嘧啶-5-甲腈
按照实施例1步骤2的制备方法，用4,6-二氯嘧啶-5-甲腈替换4-氯喹唑啉得黄色固体，收率82.7％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.39(d,J＝2.8Hz,1H),8.22(s,1H),8.06(dt,J＝9.0,3.1Hz,1H),7.32(d,J＝8.9Hz,1H),3.21(br s,4H),2.84(br s, 4H),2.47(s,3H).HRMS(ESI):calcd.for m/z C 16H 16ClN 7O 2,[M+H] +374.1133,found 374.1135.HPLC(100％MeOH):t R＝5.679min,98.83％.
实施例15
Figure PCTCN2019079160-appb-000020
4-氯-6-((2-(4-甲基哌嗪-1-基)-5-硝基苯基)氨基)嘧啶-5-甲醛
按照实施例1步骤2的制备方法，用4,6-二氯嘧啶-5-甲醛替换4-氯喹唑啉得黄色固体，收率：75.9％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ11.93(s,1H),10.05(s,1H),9.05(d,J＝2.6Hz,1H),8.36(d,J＝1.6Hz,1H),8.01(dt,J＝8.9,2.3Hz,1H),7.36(dd,J＝8.9,1.8Hz,1H),3.04-2.87(m,4H),2.56(t,J＝4.6Hz,4H),2.26(s,3H).HRMS(ESI):calcd.for m/z C 16H 17ClN 6O 3,[M+H] +377.1130,found 377.1132.HPLC(100％MeOH):t R＝6.472min,98.17％.
实施例16
Figure PCTCN2019079160-appb-000021
6-氯-5-甲氧基-N-(2-(4-甲基哌嗪-1-基)-5-硝基苯基)嘧啶-4-胺
按照实施例1步骤2的制备方法，用4,6-二氯嘧啶-5-甲醛替换4-氯喹唑啉得黄色固体，收率88.9％；m.p.>250℃； 1H NMR(300MHz,CDCl 3)δ9.59(d,J＝2.7Hz,1H),8.68(s,1H),8.45(d,J＝3.5Hz,1H),7.96(dd,J＝8.8,2.7Hz,1H),7.26(d,J＝2.1Hz,1H),4.06(s,1H),3.06-2.97(m,4H),2.67(br s,4H),2.42(s,3H).HRMS(ESI):calcd.for m/z C 16H 19ClN 6O 3,[M+H] +379.1280,found 379.1286.HPLC(100％MeOH):t R＝6.614min,95.68％.
实施例17
Figure PCTCN2019079160-appb-000022
6-氯-N 4-(5-硝基-2-(哌嗪-1-基)苯基)嘧啶-4,5-二胺
步骤1：6-氯-N 4-(2-氟-5-硝基苯基)嘧啶-4,5-二胺的制备
将2-氟-5-硝基苯胺(2g,12.8mmol)溶于异丙醇(50mL)中，加入2mL的浓硫酸和4,6-二氯-5-氨基嘧啶(25.6mmol)，回流18h，将反应液旋至有固体析出，冷却析出固体，抽滤，滤饼用异丙醇(5mL×3)洗涤，干燥得黄色固体。收率59.5％；m.p.209℃-211℃； 1H-NMR(300MHz,DMSO-d 6)δ9.14(s,1H),8.65-8.62(m,1H),8.06-8.03(m,1H),7.86(s, 1H),7.58-7.54(m,1H),5.54(s,2H).m/z(EI-MS):284.1[M] + .
步骤2：目标产物6-氯-N 4-(5-硝基-2-(哌嗪-1-基)苯基)嘧啶-4,5-二胺的制备
将6-氯-N 4-(2-氟-5-硝基苯基)嘧啶-4,5-二胺(0.35mmol)溶于5mL DMF中，加入DIPEA(1.5mmol)和叔丁基哌嗪-1-羧酸酯(1.0mmol)，在50℃下反应5h，反应液用乙酸乙酯(20mL)稀释,水洗(10mL×3)，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，旋干，得到的粗品溶于二氯甲烷中(20mL),滴加三氟醋酸(2mL),在室温下反应2h，反应液用饱和碳酸氢钠中和至不在有气泡产生，乙酸乙酯萃取，旋干得黄色固体，用CH 3CN洗涤，干燥，收率65.6％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ9.09(br s,1H),8.60(d,J＝2.7Hz,1H),8.33(s,1H),7.89(dd,J＝8.9,2.7Hz,1H),7.83(s,1H),7.23(d,J＝8.9Hz,1H),5.55(s,2H),3.21(s,4H),3.42(t,J＝6.0Hz,4H).HRMS(ESI):calcd.for m/z C 14H 17ClN 7O 2,[M+H] +350.1127,found 350.1131.HPLC(100％MeOH):t R＝4.069min,96.17％.
实施例18
Figure PCTCN2019079160-appb-000023
6-氯-N 4-(2-吗啉代-5-硝基苯基)嘧啶-4,5-二胺
将6-氯-N 4-(2-氟-5-硝基苯基)嘧啶-4,5-二胺(0.35mmol)溶于5mL DMF中，加入DIPEA(1.5mmol)和吗啉(1.0mmol)，在50℃下反应5h，反应液用乙酸乙酯(20mL)稀释,水洗(10mL×3)，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，旋干，得到的粗品，用CH 3CN洗涤，干燥，收率71.4％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.70(s,1H),8.32(s,1H),8.08-7.86(m,2H),7.29(d,J＝9.0Hz,1H),5.46(s,2H),3.73(s,4H),2.99(s,4H).HRMS(ESI):calcd.for m/z C 14H 16ClN 6O 3,[M+H] +351.0967,found 351.0967.HPLC(100％MeOH):t R＝7.041min,98.84％.
实施例19
Figure PCTCN2019079160-appb-000024
6-氯-N 4-(2-(4-乙基哌嗪-1-基)-5-硝基苯基)嘧啶-4,5-二胺
按照实施例18步骤2的制备方法，用1-乙基哌嗪替换吗啉的黄色固体，收率46.7％；m.p.185℃-187℃； 1H NMR(300MHz,CDCl 3)δ9.34(s,1H),8.32(s,1H),8.18(s,1H),7.93(dt,J＝8.8,2.7Hz,1H),7.27-7.20(m,1H),3.60(s,2H),3.08-2.93(m,4H),2.70(s,4H),2.53(qd,J＝7.2,2.7Hz,2H),1.16(td,J＝7.3,2.7Hz,3H).HRMS(ESI):calcd.for m/z  C 16H 21ClN 7O 2,[M+H] +378.1440,found 348.1449.HPLC(100％MeOH):t R＝4.542min,97.65％.
实施例20
Figure PCTCN2019079160-appb-000025
6-氯-N 4-(2-(4-环丙基哌嗪-1-基)-5-硝基苯基)嘧啶-4,5-二胺
按照实施例18步骤2的制备方法，用1-环丙基哌嗪替换吗啉的黄色固体，收率58.9％；m.p.223℃-225℃； 1H NMR(300MHz,CDCl 3)δ9.35(d,J＝2.7Hz,1H),8.32(s,1H),8.21(s,1H),7.92(dd,J＝8.7,2.7Hz,1H),3.62(s,2H),2.96(t,J＝4.7Hz,4H),2.87(s,4H),1.78-1.71(m,1H),0.56-0.51(m,2H),0.49-0.44(m,2H).HRMS(ESI):calcd.for m/z C 17H 21ClN 7O 2,[M+H] +390.1440,found 390.1446.HPLC(100％MeOH):t R＝4.811min,99.31％.
实施例21
Figure PCTCN2019079160-appb-000026
2-(4-(2-((5-氨基-6-氯嘧啶-4-基)氨基)-4-硝基苯基)哌嗪-1-基)乙-1-醇
按照实施例18步骤2的制备方法，用2-(哌嗪-1-基)乙-1-醇替换吗啉的黄色固体，收率76.4％；m.p.202℃-204℃； 1H NMR(300MHz,CDCl 3)δ9.33(s,1H),8.32(s,1H),8.15(s,1H),7.94(d,J＝8.7Hz,1H),7.27(s,1H),3.70(s,2H),3.64-2.46(m,2H),3.02(s,4H),2.78(s,4H),2.68(s,2H),2.57(s,1H).HRMS(ESI):calcd.for m/z C 16H 20ClN 7O 3,[M+H] +394.1389,found 394.1387.HPLC(100％MeOH):t R＝7.347min,96.12％.
实施例22
Figure PCTCN2019079160-appb-000027
6-氯-N 4-(5-硝基-2-(4-苯基哌嗪-1-基)苯基)嘧啶-4,5-二胺
按照实施例18步骤2的制备方法，用1-苯基哌嗪替换吗啉的黄色固体，收率76.4％；m.p.>250℃； 1H NMR(300MHz,CDCl 3)δ9.39(d,J＝2.7Hz,1H),8.35(s,1H),8.25(s,1H),7.97(dd,J＝8.9,2.6Hz,1H),7.39-7.28(m,3H),7.06-6.90(m,3H),3.54(s,2H),3.44(t,J＝4.9Hz,4H),3.16(t,J＝4.9Hz,4H).HRMS(ESI):calcd.for m/z C 20H 20ClN 7O 2,[M+H] +426.1440,found 426.1449.HPLC(100％MeOH):t R＝4.905min,95.52％.
实施例23
Figure PCTCN2019079160-appb-000028
(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)(吗啉代)甲酮
步骤1：4'-氟-3'-硝基-[1,1'-联苯基]-4-羧酸甲酯的制备
将4-溴-1-氟-2硝基苯(5.0g,22.8mmol)溶在1,4-二氧六环(100mL)中，加入(4-(甲氧基羰基)苯基)硼酸(27.3mmol)中，加入碳酸铯(14.8g,45.6mmol)和催化量的Pd(PPh 3) 2Cl 2，N 2保护下回流20h，过滤除掉催化剂和碳酸铯，旋干后的粗品柱层析(二氯甲烷：甲醇＝50:1)得白色固体，收率69.9％；m.p.145℃-147℃. 1H NMR(300MHz,CDCl 3)δ8.31-8.13(m,3H),7.88-7.59(m,1H),8.28(m,3H),7.42-7.36(m,1H),3.94(s,3H).m/z(EI-MS):276.2[M] +.
步骤2：4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-羧酸甲酯的制备
按照实施例1步骤1的制备方法，将2-F-5-硝基苯胺替换成4'-氟-3'-硝基-[1,1'-联苯基]-4-羧酸甲酯得黄色固体，收率93.8％；m.p.130℃-132℃； 1H NMR(300MHz,CDCl 3)δ8.11(dd,J＝6.8,1.9Hz,2H),8.05(d,J＝2.3Hz,1H),7.44(dd,J＝8.6,2.3Hz,1H),7.68-7.61(m,2H),7.21(d,J＝8.6Hz,1H),3.95(s,3H),3.16(t,J＝4.7Hz,4H),2.61(t,J＝4.7Hz,4H),2.38(s,3H).m/z(EI-MS):356.2[M] +.
步骤3：3'-氨基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯的制备
将4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-羧酸甲酯(12.9mmol)溶于甲醇中，加入催化量的Pd/C,H 2保护下室温搅拌2h，过滤旋干得灰白色固体。收率90.4％；m.p.229℃-231℃； 1H NMR(300MHz,CDCl 3)δ8.07(d,J＝8.5Hz,2H),7.61((dd,J＝6.7,1.8Hz,2H),7.09(d,J＝8.5Hz,1H),7.03(m,2H),4.06(s,2H),3.93(s,3H),3.01(t,J＝4.4Hz,4H),2.61(s,4H),2.38(s,3H).m/z(EI-MS):326.2[M] +.
步骤4：3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯的制备
将4,6-二氯-5-硝基嘧啶(7.40g,38.11mmol)溶于四氢呋喃(50mL)中，加入三乙胺(3.17mL,22.86mmol)，0℃下滴加3'-氨基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯的四氢呋喃溶液，升至室温搅拌6h，旋干，粗品硅胶柱层析(二氯甲烷：甲醇＝100:1)分离得黄色固体，继续溶于乙酸乙酯中，加入SnCl 2(3倍当量)回流4h,用饱和碳酸氢钠调节至不再有气泡产生，抽滤，滤饼用乙酸乙酯洗涤(4×20mL)，滤液用乙酸乙酯萃取(4×50mL)，合并有机层，干燥，旋干得到米白色固体，收率45.7％；m.p.209℃-210℃； 1H NMR(300MHz,DMSO-d 6)δ8.53-8.42(m,1H),8.23(s,1H),7.96-7.90 (m,3H),7.70(d,J＝8.4Hz,2H),7.46-7.42(m,1H),7.26(d,J＝8.3Hz,1H),5.36(s,2H),3.93(s,3H),3.57(t,J＝4.6Hz,4H),2.87(t,J＝4.7Hz,4H),2.24(s,3H).m/z(EI-MS):453.2[M] +.
步骤5:3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸的制备
将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯溶于甲醇(50mL)中，加入氢氧化锂(1M,10mL)，室温搅拌2h，用1M HCl调节至有大量固体析出，抽滤，干燥得白色固体，收率80.0％；m p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.33-8.28(m,2H),8.10(s,1H),7.86-7.84(m,2H),7.80(s,1H),7.13-7.11(m,2H),6.88(d,J＝2.0Hz,1H),5.42(s,2H),3.54(t,J＝4.6Hz,4H),2.35(t,J＝4.7Hz,4H),2.24(s,3H).m/z(EI-MS):439.3[M] +
步骤6：目标产物:(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)(吗啉代)甲酮的制备
将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯(0.1g,0.26mmol)溶于DMF(10mL)中，加入缩合剂BOP(0.22g,0.49mmol)和三乙胺(0.12mL,0.88mmol)，室温搅拌30min后加入吗啉(0.39mmol)，室温搅拌12h后，将反应液倒入水中(50mL),乙酸乙酯萃取(3×50mL)，有机层用无水硫酸钠干燥，过滤，旋干，柱层析分离纯化(二氯甲烷：甲醇＝50:1)得白色固体，收率67.8％；m.p.225℃-227℃； 1H NMR(300MHz,DMSO-d 6)δ8.45(d,J＝13.6Hz,2H),7.90(s,1H),7.69(d,J＝7.9Hz,2H),7.49(d,J＝7.7Hz,2H),7.42(d,J＝8.4Hz,1H),7.27(d,J＝8.2Hz,1H),5.39(s,2H),3.61(s,4H),3.35(s,4H),2.98-2.90(s,4H),2.64(s,4H),2.34(s,3H).HRMS(ESI):calcd.for m/z C 26H 30ClN 7O 2,[M+H] +508.2222,found 508.2223.HPLC(80％methanol in water):t R＝3.507min,98.81％.
实施例24
Figure PCTCN2019079160-appb-000029
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-N-(2-吗啉代乙基)-[1,1'-联苯]-唑-4-甲酰胺
按照实施例23步骤6的制备方法，用2-吗啉乙基-1-胺替换吗啉得白色固体，收率55.8％；m.p.230℃-232℃； 1H NMR(300MHz,DMSO-d 6)δ8.45(s,1H),8.27-8.22(m,2H),7.92-7.90(m,3H),7.71(d,J＝8.0Hz,2H),7.45(d,J＝8.2Hz,1H),7.26(d,J＝8.4Hz,1H),5.39(s,2H),3.58(s,4H),3.40-3.34(m,4H),2.90(s,4H),2.61(s,4H),2.44(s,4H),2.31(s, 3H).HRMS(ESI):calcd.for m/z C 28H 35ClN 8O 2,[M+H] +551.2644,found 551.2639.HPLC(80％methanol in water):t R＝3.196min,98.91％.
实施例25
Figure PCTCN2019079160-appb-000030
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-N-(3-吗啉代丙基)-[1,1'-联苯]-唑-4-甲酰胺
按照实施例23步骤6的制备方法，用3-吗啉丙基-1-胺替换吗啉得白色固体，收率48.9％；m.p.210℃-212℃； 1H NMR(300MHz,DMSO-d 6)δ8.53-8.42(m,1H),8.28(d,J＝2.8Hz,1H),8.23(s,1H),7.96-7.90(m,3H),7.70(d,J＝8.4Hz,2H),7.46-7.42(m,1H),7.26(d,J＝8.3Hz,1H),5.36(s,2H),3.57(t,J＝4.6Hz,4H),3.32-3.30(m,2H),2.87(t,J＝4.7Hz,4H),2.51-2.49(m,4H),2.37-2.32(m,6H),2.24(s,3H).HRMS(ESI):calcd.for m/z C 29H 31ClN 8O 2,[M+H] +565.2801,found 565.2801.HPLC(80％methanol in water):t R＝3.974min,96.00％.
实施例26
Figure PCTCN2019079160-appb-000031
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-N，N-二甲基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺
按照实施例23步骤6的制备方法，用二甲基胺替换吗啉得白色固体，收率78.9％；m.p.142℃-145℃； 1H NMR(300MHz,DMSO-d 6)δ8.24(s,1H),7.70(s,2H),7.56-7.41(m,5H),7.02(s,1H),5.57(s,2H),3.19-3.97(m,10H),2.75(s,4H),2.43(s,3H).HRMS(ESI):calcd.for m/z C 24H 28ClN 7O,[M+H] +466.2117,found 466.2121.HPLC(80％methanol in water):t R＝2.489min,95.56％.
实施例27
Figure PCTCN2019079160-appb-000032
(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)(4-甲基哌嗪-1-基)甲酮
按照实施例23步骤6的制备方法，用1-甲基哌嗪替换吗啉得白色固体，收率56.9％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.54(d,J＝13.6Hz,2H),7.90(s, 1H),7.68(d,J＝7.9Hz,2H),7.45(d,J＝7.7Hz,2H),7.39(d,J＝8.4Hz,1H),7.27(d,J＝8.1Hz,1H),5.35(s,2H),3.61(s,4H),3.35(s,4H),2.98-2.90(s,4H),2.64(s,4H),2.34(s,3H),2.30(s,3H).HRMS(ESI):calcd.for m/z C 27H 33ClN 8O,[M+H] +521.2937,found 521.2937.HPLC(80％methanol in water):t R＝4.094min,98.10％.
实施例28
Figure PCTCN2019079160-appb-000033
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-N-(3-(二甲基氨基)丙基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺
按照实施例23步骤6的制备方法，用N 1，N 1-二甲基-1,3-二胺替换吗啉得白色固体，收率38.9％；m.p.232℃-234℃； 1H NMR(300MHz,DMSO-d 6)δ8.66(s,1H),8.26-8.20(m,2H),7.93-7.88(m,3H),7.73(d,J＝9.8Hz,2H),7.47(s,1H),7.29(s,1H),5.44(s,2H),3.08-2.90(m,8H),2.77(s,6H),2.50(s,4H),1.90(s,4H),1.28-1.23(m,2H).HRMS(ESI):calcd.for m/z C 27H 36ClN 8O,[M+H] +523.2695,found 523.2695.HPLC(90％methanol in water):t R＝3.409min,98.88％.
实施例29
Figure PCTCN2019079160-appb-000034
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-N-(2-(吡咯烷-1-基)乙基)-[11,1'-联苯基]-4-甲酰胺
按照实施例23步骤6的制备方法，用2-(吡咯烷-1-基)乙-1-胺替换吗啉得白色固体，收率37.8％；m.p.241℃-243℃； 1H NMR(300MHz,DMSO-d 6)δ8.67(s,1H),8.25-8.22(m,2H),7.93-7.88(m,3H),7.73(d,J＝9.8Hz,2H),7.47(s,1H),7.29(s,1H),5.64(s,2H),3.64-3.62(m,2H),3.38-3.34(m,6H),3.12(s,4H),2.54(s,2H),2.48(s,2H),2.36(s,3H),1.93(s,4H).HRMS(ESI):calcd.for m/z C 28H 35ClN 8O,[M+H] +535.2695,found 535.2690.HPLC(100％methanol):t R＝7.516min,98.64％.
实施例30
Figure PCTCN2019079160-appb-000035
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-N-(3-羟基丙基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-唑-4-甲酰胺
按照实施例23步骤6的制备方法，用3-氨基丙-1-醇替换吗啉得白色固体，收率50.7％；m.p.189℃-192℃； 1H NMR(300MHz,DMSO-d 6)δ8.45(d,J＝7.2Hz,1H),8.30-8.19(m,2H),7.93-7.90(m,3H),7.72-7.69(m,2H),7.43(d,J＝8.4Hz,1H),7.26(d,J＝8.4Hz,1H),5.37(s,2H),4.49-4.47(m,1H),3.51-3.45(m,4H),2.88(s,4H),2.52-2.50(m,4H),2.27(s,3H),1.74-1.64(m,2H).HRMS(ESI):calcd.for m/z C 25H 31ClN 7O 2,[M+H] +496.2222,found 496.2217.HPLC(80％methanol in water):t R＝2.384min,96.63％
实施例31
Figure PCTCN2019079160-appb-000036
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-N-异丙基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺
按照实施例23步骤6的制备方法，用丙-2-胺替换吗啉得白色固体，收率63.8％；m.p.184℃-186℃； 1H NMR(300MHz,DMSO-d 6)δ8.27-8.22(m,2H),7.91(d,J＝8.1Hz,2H),7.71(s,1H),7.59(d,J＝8.0Hz,2H),7.43-7.30(m,2H),7.04(d,J＝8.2Hz,1H),5.54(s,2H),4.12(s,1H),3.33(s,4H),3.07(s,4H),2.82(s,3H),1.18(s,6H).HRMS(ESI):calcd.for m/z C 25H 30ClN 7O,[M+H] +480.2279,found 480.2276.HPLC(80％methanol in water):t R＝3.601min,96.77％.
实施例32
Figure PCTCN2019079160-appb-000037
步骤1：1-(4-溴-2-硝基苯基)-4-甲基哌嗪的制备
将2-氟-5-溴硝基苯(10.0g,45.4mmol)溶在DMF(20mL)中，加入DIPEA(9.5mL,54.6mmol)和1-甲基哌嗪(6.6mL,54.6mmol)，80℃搅拌8h后，将反应液倒入100mL水中，乙酸乙酯萃取(3×100mL)，有机层用无水硫酸钠干燥，过滤，旋干得黄色固体，收率95.0％； 1H NMR(300MHz,CDCl 3)δ7.91(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.4Hz,1H),7.04(d,J＝8.8Hz,1H),3.08(t,J＝4.9Hz,4H),2.58(t,J＝4.9Hz,4H),2.37(s,3H).m/z(EI-MS):300.0[M] +.
步骤2：5-溴-2-(4-甲基哌嗪-1-基)苯胺的制备
将1-(4-溴-2-硝基苯基)-4-甲基哌嗪(12.9g,43.14mmol)溶于甲醇(100mL)中，加入催化量的Pd/C,氢气保护下，室温反应2h，过滤，旋干得黄色固体，收率89％；m.p.165-167℃； 1H NMR(300MHz,CDCl 3)δ6.84-6.79(m,3H),4.01(s,2H),2.89(s,4H),2.45(s,4H),2.35(s,3H).m/z(EI-MS):270.0[M] +.
步骤3：N 4-(5-溴-2-(4-甲基哌嗪-1-基)苯基)-6-氯嘧啶-4,5-二胺的制备
按照实施例23步骤4的制备方法，将3'-氨基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯替换成5-溴-2-(4-甲基哌嗪-1-基)苯胺，得白色固体。收率72.5％；m.p.196-198℃； 1H NMR(300MHz,CDCl 3)δ8.26(s,1H),6.84-6.79(m,3H),8.10(s,1H),5.34(s,2H),2.89(s,4H),2.45(s,4H),2.34(s,3H).m/z(EI-MS):397.1[M] +.
步骤4：目标产物N 4-(4'-氨基-4-(4-甲基哌嗪-1-基)-[1,1'-联苯]-3-基)-6-氯嘧啶-e-4,5-二胺的制备
将N 4-(5-溴-2-(4-甲基哌嗪-1-基)苯基)-6-氯嘧啶-4,5-二胺(1.0g,2.5mmol)溶于1,4-二氧六环(30mL)中，加入4-氨基苯硼酸(2.9mmol)和碳酸铯(1.6g,5mmol)和催化量的Pd(PPh 3) 2Cl 2，氮气保护下回流20h，过滤除去催化剂和碳酸铯，旋干滤液，柱层析分离纯化(二氯甲烷：甲醇＝50:1)得到淡黄色固体，收率67.3％；m.p.212℃-214℃； 1H NMR(300MHz,DMSO-d 6)δ8.16(d,J＝8.1Hz,2H),7.90(s,1H),7.65(d,J＝8.2Hz,2H),7.55(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,1H),7.26(d,J＝8.2Hz,1H),5.43(s,2H),5.15(s,2H),3.17(s,4H),3.06(s,4H),2.75(s,3H).m/z(EI-MS):410.2[M] +.HPLC(100％methanol):t R＝7.489min,95.67％.
实施例33
Figure PCTCN2019079160-appb-000038
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)四氢-2H-吡喃-4-甲酰胺
将四氢-2H-吡喃-4-羧酸(0.35mmol)溶于DMF(8mL)中，加入BOP(0.26g,0.59mmol)和三乙胺(0.1mL,0.88mmol)，室温搅拌30min后加入实施例32(0.12g,0.29mmol)室温搅拌12h，将反应液倒入50mL水中，用乙酸乙酯(3×50mL)萃取，无水硫酸钠干燥，过滤，旋干，硅胶柱层析分离纯化(二氯甲烷：甲醇＝50:1)得白色固体，收率78.5％；m.p.207℃-209℃； 1H NMR(300MHz,DMSO-d 6)δ9.99(s,1H),8.21(s,1H),7.90(s,1H),7.68(dd,J＝8.4,5.9Hz,3H),7.57-7.54(m,2H),7.38-7.35(m,1H),5.38(s,2H),3.94-3.90(m,3H),3.37-3.35(m,2H),2.92(s,4H),2.76(s,4H),2.43(s,3H),1.72-1.69(m,4H).HRMS(ESI):calcd.for m/z C 27H 32ClN 7O 2,[M+H] +522.2379,found 522.2377.HPLC(80％methanol in water):t R＝4.280min,95.50％.
实施例34
Figure PCTCN2019079160-appb-000039
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)-1-甲基哌啶-4-甲酰胺
按照实施例33，将四氢-2H-吡喃-4-羧酸替换成1-甲基哌啶-4-羧酸,得到白色固体，收率63.6％；m.p.157℃-160℃； 1H NMR(300MHz,DMSO-d 6)δ10.19(s,1H),8.22-8.19(m,2H),7.95(s,1H),7.69(d,J＝8.4Hz,2H),7.57(d,J＝8.7Hz,2H),7.36(d,J＝8.4Hz,1H),7.24(d,J＝8.1Hz,1H),5.42(s,2H),2.99-2.90(m,5H),2.85(s,4H),2.73(s,3H),2.53(s,4H),2.49(s,3H),2.03-1.99(m,4H).HRMS(ESI):calcd.for m/z C 28H 36ClN 8O,[M+H] +535.2695,found 535.2710.HPLC(80％methanol in water):t R＝4.518min,98.25％.
实施例35
Figure PCTCN2019079160-appb-000040
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)环己烷甲酰胺
按照实施例33，将四氢-2H-吡喃-4-羧酸替换成环己烷羧酸,得到白色固体，收率80.1％；m.p.256℃-258℃； 1H NMR(300MHz,DMSO-d 6)δ9.91(s,1H),8.18(d,J＝8.2Hz,2H),7.90(s,1H),7.69(d,J＝8.3Hz,2H),7.55(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,1H),7.26(d,J＝8.2Hz,1H),5.43(s,2H),3.17(s,4H),3.06(s,4H),2.75(s,3H),2.34-2.30(m,1H),1.76(t,J＝12.5Hz,4H),1.42(t,J＝11.6Hz,2H),1.33-1.09(m,4H).HRMS(ESI):calcd.for m/z C 28H 34ClN 7O,[M+H] +520.2586,found 520.2584.HPLC(90％methanol in water):t R＝4.003min,97.87％.
实施例36
Figure PCTCN2019079160-appb-000041
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)丁酰胺
按照实施例33，将四氢-2H-吡喃-4-羧酸替换成正丁酸,得到白色固体，收率79.7％；m.p.196℃-198℃； 1H NMR(300MHz,DMSO-d 6)δ10.00(s,1H),8.21-8.16(m,2H),7.90(d,J＝6.0Hz,1H),7.71-7.69(m,2H),7.59-7.54(m,2H),7.38(d,J＝7.8Hz,1H),7.27(d,J＝8.2Hz,1H),5.44(s,2H),3.51-3.46(m,4H),3.27-3.16(m,4H),2.88(s,3H),2.32-2.27(m,2H),1.68-1.58(m,2H),0.96-0.89(m,3H).HRMS(ESI):calcd.for m/z C 25H 31ClN 7O,[M+H] +480.2273,found 480.2274.HPLC(80％methanol in water):t R＝4.696min,96.97％.
实施例37
Figure PCTCN2019079160-appb-000042
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)苯甲酰胺
按照实施例33，将四氢-2H-吡喃-4-羧酸替换成苯甲酸,得到白色固体，收率77.9％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ10.00(s,1H),8.21-8.16(m,2H),7.90(d,J＝6.0Hz,1H),7.71-7.69(m,2H),7.59-7.54(m,2H),7.38(d,J＝7.8Hz,1H),7.27(d,J＝8.2Hz,1H),5.44(s,2H),3.51-3.46(m,4H),3.27-3.16(m,4H),2.88(s,3H),2.32-2.27(m,2H),1.68-1.58(m,2H),0.96-0.89(m,3H).HRMS(ESI):calcd.for m/z C 28H 28ClN 7O,[M+H] +514.2117,found 514.2115.HPLC(90％methanol in water):t R＝3.889min,95.09％.
实施例38
Figure PCTCN2019079160-appb-000043
(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)(4-甲基哌嗪-1-基)甲酮
按照实施例32步骤4的制备方法，将4-氨基苯硼酸替换成2-F-4-羧基苯硼酸，得白色中间体，按照实施例23步骤6的制备方法，将吗啉替换成1-甲基哌嗪得白色固体，收率43.1％；m.p.182℃-184℃； 1H NMR(300MHz,DMSO-d 6)δ8.12(s,1H),7.80(s,1H),7.68-7.65(m,2H),7.60(dd,J＝7.5,2.0Hz,1H),7.10(dd,J＝7.5,2.0Hz,1H),6.93(d,J＝7.3Hz,1H),6.82(d,J＝2.0Hz,1H),5.36(s,2H),3.55(t,J＝5.1Hz,4H),3.30(t,J＝5.1Hz,4H),2.85(t,J＝4.7Hz,4H),2.53(s,4H),2.34(s,3H),2.32(s,3H).HRMS(ESI):calcd.for m/z C 27H 32ClFN 8O,[M+H] +539.2444,found 539.2443.HPLC(80％methanol in water):t R＝4.156min,95.21％.
实施例39
Figure PCTCN2019079160-appb-000044
N 4-(3'-氨基-4-(4-甲基哌嗪-1-基)-[1,1'-联苯]-3-基)-6-氯嘧啶电子-4,5-二胺
按照实施例32步骤4的制备方法，将4-氨基苯硼酸替换成3-氨基苯硼酸，制备得到白色固体，收率69.4％；m.p.215℃-217℃； 1H NMR(300MHz,DMSO-d 6)δ8.23(s,1H),8.17(s,1H),7.90(s,1H),7.23(d,J＝6.4Hz,2H),7.07(d,J＝7.7Hz,1H),6.80(s,1H),6.73 (d,J＝7.6Hz,1H),6.53(d,J＝8.0Hz,1H),5.36(s,2H),5.17(s,2H),2.85(s,4H),2.61(s,4H),2.25(s,3H).HRMS(ESI):calcd.for m/z C 21H 24ClN 7,[M+H] +410.1854,found 410.1852.HPLC(100％methanol):t R＝7.491min,95.66％.
实施例40
Figure PCTCN2019079160-appb-000045
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-3-基)四氢-2H-吡喃-4-甲酰胺
按照实施例33的制备方法，将实施例32替换成实施例39，得到白色固体，收率65.0％；m.p.212℃-214℃； 1H NMR(300MHz,DMSO-d 6)δ9.99(s,1H),8.24(s,1H),8.19(s,1H),7.89(s,2H),7.59(d,J＝8.0Hz,1H),7.44-7.19(m,4H),5.38(s,2H),3.91(d,J＝10.9Hz,2H),3.47-3.35(m,3H),2.86(s,4H),2.54(m,4H),2.24(s,3H),1.70(s,4H).HRMS(ESI):calcd.for m/z C 27H 32ClN 7O 2,[M+H] +522.2379,found 522.2368.HPLC(100％methanol):t R＝7.105min,98.72％.
实施例41
Figure PCTCN2019079160-appb-000046
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-3-基)-1-甲基哌啶-4-甲酰胺
按照实施例34的制备方法，将实施例32替换成实施例39，得到白色固体，收率56.9％；m.p.158℃-160℃； 1H NMR(300MHz,DMSO-d 6)δ9.95(s,1H),8.24(s,1H),8.18(s,1H),7.89(s,2H),7.59(d,J＝8.3Hz,1H),7.39-7.19(m,4H),5.38(s,2H),2.86-2.83(m,4H),2.80(s,1H),2.57-2.51(m,4H),2.22(s,3H),2.15(s,3H),1.89-1.82(m,2H),1.79-1.58(m,4H),1.22(s,2H).HRMS(ESI):calcd.for m/z C 28H 36ClN 8O,[M+H] +535.2695,found 535.2702.HPLC(100％methanol):t R＝7.252min,95.45％.
实施例42
Figure PCTCN2019079160-appb-000047
6-氯-N 4-(4'-甲氧基-4-(4-甲基哌嗪-1-基)-[1,1'-联苯]-3-基)嘧啶-4,5-二胺
按照实施例32步骤4的制备方法，将4-氨基苯硼酸替换成4-甲氧基苯硼酸，得到白色固体，收率59.9％；m.p.211℃-213℃； 1H NMR(300MHz,DMSO-d 6)δ8.24(s,2H), 7.90(s,1H),7.57(d,J＝7.9Hz,2H),7.40-7.35(m,3H),7.24(d,J＝8.3Hz,1H),5.37(s,2H),5.22(s,1H),4.52(s,2H),2.85(t,J＝4.5Hz,4H),2.53(s,4H),2.24(s,3H).m/z(EI-MS):425.2[M] +.HPLC(80％methanol in water):t R＝4.590min,99.44％.
实施例43
Figure PCTCN2019079160-appb-000048
6-氯-N 4-(5-(呋喃-3-基)-2-(4-甲基哌嗪-1-基)苯基)嘧啶-4,5-二胺
按照实施例32步骤4的制备方法，将4-氨基苯硼酸替换成3-呋喃苯硼酸，得到白色固体，收率70.1％；m.p.164℃-166℃； 1H NMR(300MHz,DMSO-d 6)δ8.23(s,1H),7.90(s,1H),7.54(d,J＝7.5Hz,1H),7.43(s,1H),7.07(d,J＝7.7Hz,1H),6.91(d,J＝7.4Hz,1H),6.82(s,1H),6.53(d,J＝8.0Hz,1H),5.36(s,2H),2.85(s,4H),2.61(s,4H),2.25(s,3H).HRMS(ESI):calcd.for m/z C 19H 22ClN 6O,[M+H] +385.1538,found 385.1538.HPLC(90％methanol in water):t R＝6.859min,96.26％.
实施例44
Figure PCTCN2019079160-appb-000049
6-氯-N 4-(2-(4-甲基哌嗪-1-基)-5-(嘧啶-5-基)苯基)嘧啶-4,5-二胺
按照实施例32步骤4的制备方法，将4-氨基苯硼酸替换成4-嘧啶苯硼酸，得到白色固体，收率45.8％；m.p.189℃-191℃； 1H NMR(300MHz,DMSO-d 6)δ9.17(s,1H),9.10(s,2H),8.57(s,1H),7.80(s,1H),7.10(dd,J＝7.5,2.0Hz,1H),6.99(d,J＝7.4Hz,1H),6.82(d,J＝2.0Hz,1H),5.32(s,2H),2.85(s,4H),2.54(s,4H),2.34(s,3H).HRMS(ESI):calcd.for m/z C 19H 22ClN 8,[M+H] +397.1651,found 397.1653.HPLC(80％methanol in water):t R＝3.973min,97.50％.
实施例45
Figure PCTCN2019079160-appb-000050
6-氯-N 4-(2-(4-甲基哌嗪-1-基)-5-(吡啶-4-基)苯基)嘧啶-4,5-二胺
按照实施例32步骤4的制备方法，将4-氨基苯硼酸替换成4-吡啶苯硼酸，得到白色固体，收率44.2％；m.p.202℃-204℃； 1H NMR(300MHz,DMSO-d 6)δ8.83(s,1H),8.69(d,J＝5.1Hz,2H),7.80(s,1H),7.75(s,2H),7.10(dd,J＝7.5,2.0Hz,1H),6.94(d,J＝7.5Hz,1H),6.82(s,1H),5.54(s,2H),3.30(t,J＝5.1Hz,4H),2.85(t,J＝4.7Hz,4H),2.54(s, 4H),2.34(s,3H),2.32(s,3H).m/z(EI-MS):411.1[M] +.HPLC(100％methanol):t R＝7.074min,96.00％.
实施例46
Figure PCTCN2019079160-appb-000051
1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸甲酯步骤1：4-(4-甲基哌嗪-1-基)-3-硝基苯胺的制备
将4-F-3-硝基苯胺(5g,32mmol)溶解在乙腈(50mL)中，加入DIPEA(7.9mL,47.8mmol)和1-甲基哌嗪(5.3mL,67.8mmol)，回流12h，将反应液旋干得红色固体粗品，用乙腈洗涤，抽滤，烘干，收率95.5％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ7.06(d,J＝8.6Hz,1H),6.76(s,1H),6.69(d,J＝8.5Hz,1H),5.34(s,2H),2.70(t,J＝4.4Hz,4H),2.27(s,4H),2.09(s,3H).m/z(EI-MS):237.1[M] +.
步骤2：1-(4-叠氮基-2-硝基苯基)-4-甲基哌嗪的制备
将4-(4-甲基哌嗪-1-基)-3-硝基苯胺(5.0g,21.25mmol)溶在2M的HCl中，冰浴条件下滴加NaNO 2(2.2g,31.8mmol)的水溶液(12mL)，在冰浴条件下搅拌30min，加入叠氮化钠(2.8g,42.5mmol)，升至室温搅拌2h，反应液用2M的NaOH调节至pH＝9～10至红棕色固体析出，过滤干燥，收率87.7％；m.p.88-91℃； 1H NMR(300MHz,DMSO-d 6)δ7.48(d,J＝2.2Hz,1H),7.34-7.20(m,2H),2.85(t,J＝4.7Hz,4H),2.31(t,J＝4.8Hz,4H),2.11(s,3H).m/z(EI-MS):262.1[M] +.
步骤3：1-(4-(4-甲基哌嗪-1-基)-3-硝基苯基)-1H-1,2,3-三唑-4-羧酸甲酯的制备
将1-(4-叠氮基-2-硝基苯基)-4-甲基哌嗪(2.0g,7.6mmol)溶解在甲醇(50mL)加入丙炔酸甲酯(1.8g,22.8mmol)，随后加入CuI(0.14g,0.76mmol)和DIPEA(1.2mL,7.6mmol)回流48h。过滤除去CuI，滤液旋干得粗品，用乙酸乙酯洗涤得红棕色固体。收率61.7％；m.p.159-161℃； 1H NMR(300MHz,DMSO-d 6)δ9.45(s,1H),8.36(d,J＝2.7Hz,1H),8.11-8.01(m,1H),7.42(d,J＝9.1Hz,1H),3.80(s,3H),2.99(t,J＝5.4Hz,4H),2.35(t,J＝5.2Hz,4H),2.13(s,3H).m/z(EI-MS):369.2[M+Na] +.
步骤4：1-(3-氨基-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸甲酯的制备
将1-(4-(4-甲基哌嗪-1-基)-3-硝基苯基)-1H-1,2,3-三唑-4-羧酸甲酯(1.7g,4.9mmol)溶在甲醇(50mL)中，加入催化量的Pd/C，氢气保护下室温搅拌6h，过滤除去Pd/C，滤液旋干得粉色固体。收率85.3％；m.p.194-197℃； 1H NMR(300MHz,DMSO-d 6)δ9.28(s,1H),7.28(d,J＝1.9Hz,1H),7.07(d,J＝1.9Hz,2H),5.15(s,2H),3.90(s,3H),2.87(t,J＝4.5Hz,4H),2.53(br s,4H),2.26(s,3H).m/z(EI-MS):317.2[M] +.
步骤5：目标产物1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸甲酯的制备
按照实施例23的步骤4的制备方法，将3'-氨基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯替换成1-(3-氨基-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸甲酯，得米白色固体，收率65.9％；m.p.231℃-233℃； 1H NMR(300MHz,DMSO-d 6)δ9.46(s,1H),8.62(s,1H),8.34(s,1H),7.95(s,1H),7.64(d,J＝8.6Hz,1H),7.37(d,J＝8.7Hz,1H),5.44(s,2H),3.89(s,3H),2.88(s,4H),2.51(s,4H),2.23(s,3H).HRMS(ESI):calcd.for m/z C 19H 22ClFN 9O 2,[M+H] +444.1657,found 444.1660.HPLC(90％methanol in water):t R＝3.775min,97.63％.
实施例47
Figure PCTCN2019079160-appb-000052
(1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-基)(吗啉代)甲酮
步骤1：1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸的制备
按照实施例23步骤5的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸甲酯，得米白色固体，收率87.6％；m.p.232℃-234℃； 1H NMR(300MHz,DMSO-d 6)δ12.20(s,1H),9.36(s,1H),8.62(s,1H),8.34(s,1H),7.95(s,1H),7.63(d,J＝8.7Hz,1H),7.38(d,J＝8.7Hz,1H),5.47(s,2H),2.90(s,4H),2.53(s,4H),2.34(s,3H).HRMS(ESI):calcd.for m/z C 18H 20ClFN 9O 2,[M+H] +430.1488,found 430.1492.HPLC(90％methanol in water):t R＝3.548min,99.16％.
步骤2：目标产物(1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-基)(吗啉代)甲酮的制备
按照实施例23步骤6的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸，得到米白色固体。收率68.3％；m.p.200℃-202℃； 1H NMR(300MHz,DMSO-d 6)δ9.20(s,1H),8.60(s,1H),8.53(t,J＝5.8Hz,1H),8.34(s,1H),7.94(s,1H),7.62(d,J＝8.7Hz,1H),7.37(d,J＝8.6Hz,1H),5.45(s,2H),3.58(t,J＝4.5Hz,4H),3.45-3.36(m,4H),2.91(t,J＝4.5Hz,4H),2.60(s,4H),2.44(s,4H),2.30(s,3H).HRMS(ESI):calcd.for m/z C 24H 32ClFN 11O 2,[M+H] +542.2502,found  542.2500.HPLC(80％methanol in water):t R＝4.612min,99.65％.
实施例48
Figure PCTCN2019079160-appb-000053
1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(3-吗啉代丙基)-1H-1,2,3-三唑-4-甲酰胺
按照实施例24的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸，得到米白色固体。收率65.9％；m.p.203℃-205℃； 1H NMR(300MHz,DMSO-d 6)δ9.19(s,1H),8.82(t,J＝5.6Hz,1H),8.59(s,1H),8.34(s,1H)7.94(s,1H),7.62(d,J＝8.7Hz,1H),7.36(d,J＝8.7Hz,1H),5.45(s,2H),3.61(s,4H),3.36-3.33(m,4H),2.90(s,4H),2.58(s,4H),2.40(s,4H),2.28(s,3H),1.73-1.68(m,2H).HRMS(ESI):calcd.for m/z C 25H 34ClFN 11O 2,[M+H] +556.2660,found 556.2662.HPLC(80％methanol in water):t R＝4.457min,98.27％.
实施例49
Figure PCTCN2019079160-appb-000054
(1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-基)(4-甲基哌嗪-1-基)甲酮
按照实施例25的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸，得到米白色固体。收率46.2％；m.p.225℃-228℃； 1H NMR(300MHz,DMSO-d 6)δ9.19(s,1H),8.72(s,1H),8.52(s,1H),8.34(s,1H)7.94(s,1H),7.62(d,J＝8.7Hz,1H),7.37(d,J＝8.7Hz,1H),5.45(s,2H),3.76(s,4H),3.39(s,4H),2.93(s,4H),2.68(s,4H)2.22(s,3H),2.15(s,3H).HRMS(ESI):calcd.for m/z C 23H 31ClFN 11O,[M+H] +512.2396,found 512.2397.HPLC(90％methanol in water):t R＝3.707min,98.00％.
实施例50
Figure PCTCN2019079160-appb-000055
1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-N,N-二甲基-1H-1,2,3-三唑 -4-甲酰胺
按照实施例27的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸，得到米白色固体。收率66.6％；m.p.215℃-217℃； 1H NMR(300MHz,DMSO-d 6)δ9.84(s,1H),9.18(s,1H),8.62(s,1H),8.27(s,1H)7.95(s,1H),7.68(s,1H),7.44(s,1H),5.52(s,2H),3.58(s,4H),3.30(s,6H),3.04(s,4H),2.88(s,3H).HRMS(ESI):calcd.for m/z C 20H 25ClFN 10O,[M+H] +457.1974,found 457.1966.HPLC(80％methanol in water):t R＝4.203min,98.52％.
实施例51
Figure PCTCN2019079160-appb-000056
1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-N,N-二甲基-1H-1,2,3-三唑-4-甲酰胺
按照实施例26的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸，得到米白色固体。收率66.6％；m.p.215℃-217℃； 1H NMR(300MHz,DMSO-d 6)δ9.84(s,1H),9.18(s,1H),8.62(s,1H),8.27(s,1H)7.95(s,1H),7.68(s,1H),7.44(s,1H),5.52(s,2H),3.58(s,4H),3.30(s,6H),3.04(s,4H),2.88(s,3H).HRMS(ESI):calcd.for m/z C 20H 25ClFN 10O,[M+H] +457.1974,found 457.1966.HPLC(80％methanol in water):t R＝4.203min,98.52％.
实施例52
Figure PCTCN2019079160-appb-000057
1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(2-(二甲基氨基)乙基)-1H-1,2,3-三唑-4-甲酰胺
按照实施例28的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸，得到米白色固体。收率39.9％；m.p.149℃-152℃； 1H NMR(300MHz,DMSO-d 6)δ9.84(s,1H),9.18(s,1H),8.62(s,1H),8.54(s,1H),7.95(s,1H),7.68(d,J＝8.7Hz,1H),7.44(d,J＝8.7Hz,1H),5.46(s,2H),3.08-2.90(m,6H),2.77(s,6H),2.50(s,4H),1.90(s,4H),1.28-1.23(m,2H).HRMS(ESI):calcd.for m/z  C 22H 30ClFN 11O,[M+H] +500.2402,found 500.2404.HPLC(80％methanol in water):t R＝4.157min,98.88％.
实施例53
Figure PCTCN2019079160-appb-000058
1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(2-(吡咯烷-1-基)乙基)-1H-1,2,3-三唑-4-甲酰胺
按照实施例29的制备方法，将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸替换成1-(3-((5-氨基-6-氯嘧啶-4-基)氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸，得到米白色固体。收率40.7％；m.p.172℃-175℃； 1H NMR(300MHz,DMSO-d 6)δ9.19(s,1H),8.72(s,1H),8.52(s,1H),8.34(s,1H)7.94(s,1H),7.62(d,J＝8.7Hz,1H),7.37(d,J＝8.7Hz,1H),5.45(s,2H),3.64-3.62(m,2H),3.38-3.34(m,6H),3.12(s,4H),2.54(s,2H),2.48(s,2H),2.36(s,3H),1.93(s,4H).HRMS(ESI):calcd.for m/z C 24H 32ClFN 11O,[M+H] +526.2553,found 526.2543.HPLC(80％methanol in water):t R＝4.211min,99.19％.
实施例54
Figure PCTCN2019079160-appb-000059
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-N，N-二甲基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺
步骤1：1-溴-2,4-二氟-3-硝基苯的制备：
在冰浴条件下制备硫酸(10mL)与三氟醋酸(50mL)的混合溶液,加入2,6-二氟硝基苯(5.0g,31.4mmol)，分批缓慢加入N-溴代丁二酰亚胺(6.15g,34.5mmol)，反应液在室温下搅拌18h，将反应液倒入冰水(100mL)，乙酸乙酯(3×50mL)萃取，有机层用2M氢氧化钠洗涤，无水硫酸钠干燥，过滤，旋干，得红色油状物(6.6g)，产率90.0％； 1H NMR(300MHz,CDCl 3)δ7.78(m,1H),7.28-7.16(m,1H).m/z(EI-MS):237.9[M] +
步骤2：2'，4'-二氟-3'-硝基-[1,1'-联苯]-4-羧酸甲酯的制备：
按照实施例23步骤1的制备方法将4-溴1-F硝基苯替换为1-溴-2,4-二氟-3-硝基苯。收率65.0％. 1H NMR(300MHz,CDCl 3)δ7.98-7.96(m,2H),7.91-7.87(m,1H),7.58-7.55(m,2H),7.19-7.15(m,1H),3.95(s,3H).m/z(EI-MS):294.1[M] +.
步骤3：2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯基]-4-羧基甲酸甲酯的制备：
按照实施例23步骤2的制备方法将4'-氟-3'-硝基-[1,1'-联苯基]-4-羧酸甲酯替换为2'，4'-二氟-3'-硝基-[1,1'-联苯]-4-羧酸甲酯。收率88.2％；m.p.112℃-115℃； 1H NMR(300MHz,DMSO-d 6)δ8.02-7.99(m,2H),7.69-7.62(m,3H),6.98(d,J＝8.6Hz,1H),3.95(s,3H),3.39(t,J＝4.7Hz,4H),2.54(t,J＝4.6Hz,4H),2.34(s,3H).m/z(EI-MS):374.1[M] +.
步骤4：3'-氨基-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯的制备：
按照实施例23步骤3的制备方法将4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-羧酸甲酯替换为2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯基]-4-羧基甲酸甲酯。收率73.5％；m.p.162℃-165℃； 1H NMR(300MHz,DMSO-d 6)δ8.01-7.99(m,2H),7.68-7.66(m,2H),6.75(dd,J＝7.5,5.7Hz,1H),6.58(d,J＝7.5Hz,1H),4.35(s,2H),3.95(s,3H),3.39(t,J＝4.7Hz,4H),2.54(t,J＝4.7Hz,4H),2.34(s,3H).m/z(EI-MS):344.2[M] +.
步骤5：3'-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯的制备：
按照实施例23步骤4的制备方法将3'-氨基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯替换为3'-氨基-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯。收率55.7％；m.p.222℃-225℃； 1H NMR(300MHz,DMSO-d 6)δ8.11(s,1H),8.01-7.99(m,2H),7.80(s,1H),7.62-7.60(m,2H),7.12(dd,J＝7.5,5.7Hz,1H),6.65(d,J＝7.5Hz,1H).5.35(s,2H),3.95(s,3H),3.34(t,J＝4.7Hz,4H),2.57(t,J＝4.7Hz,4H),2.39(s,3H).HRMS(ESI):calcd.for m/z C 23H 24ClFN 6O 2,[M+H] +471.1706,found 471.1707.HPLC(80％methanol in water):t R＝2.744min,99.52％.
步骤6：3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸的制备：
按照实施例23步骤5的制备方法将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯替换为3'-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯。两步收率80.4％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.11(dd,J＝5.3,2.2Hz,3H),7.80(s,1H),7.69-7.67(m,2H),7.12(dd,J＝7.5,5.7Hz,1H),6.66(d,J＝7.5Hz,1H),5.35(s,2H),3.93(s,3H),3.34(t,J＝4.7Hz,4H),2.57(s,4H),2.32(s,3H).m/z(EI-MS):457.2[M] +.
步骤7：目标产物3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-N，N-二甲基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺的制备：
按照实施例23步骤6类似的制备方法。收率77.5％；m.p.158℃-160℃； 1H NMR(300MHz,DMSO-d 6)δ8.03(s,1H),7.71(s,1H),7.60-7.46(m,4H),7.40(t,J＝8.5Hz,1H), 7.00(d,J＝8.6Hz,1H),5.49(s,2H),2.99-2.98(m,6H),2.87(s,4H),2.38(s,4H),2.18(s,3H).HRMS(ESI):calcd.for m/z C 24H 27ClFN 7O,[M+H] +484.2202,found 484.2203.HPLC(80％methanol in water):t R＝3.448min,95.30％.
实施例55：
Figure PCTCN2019079160-appb-000060
(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)(吗啉代)甲酮
按照实施例54的制备方法将二甲基胺替换为吗啉，收率84.7％；m.p.145℃-148℃； 1H NMR(300MHz,DMSO-d 6)δ8.05(s,1H),7.72(s,1H),7.54(dd,J＝8.5,5.4Hz,4H),7.41(t,J＝8.5Hz,1H),7.03(d,J＝8.6Hz,1H),5.48(s,2H),3.61(s,4H),3.34(s,4H),2.98(s,4H),2.65(s,4H),2.38(s,3H).HRMS(ESI):calcd.for m/z C 26H 29ClFN 7O 2,[M+H] +526.2128,found 526.2122.HPLC(80％methanol in water):t R＝3.560min,98.66％
实施例56
Figure PCTCN2019079160-appb-000061
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-N-(2-吗啉代乙基)-[1,11,1'-联苯基]-4-甲酰胺
按照实施例54的制备方法将二甲基胺替换为2-吗啉乙基-1-胺，收率74.9％；m.p.199℃-202℃； 1H NMR(300MHz,DMSO-d 6)δ8.48(t,J＝5.5Hz,1H),8.09(s,1H),7.90(d,J＝8.1Hz,2H),7.71(s,1H),7.59(d,J＝7.9Hz,2H),7.41(t,J＝8.5Hz,1H),7.00(d,J＝8.5Hz,1H),5.50(s,2H),3.57(s,4H),3.41-3.38(m,2H),2.91(s,4H),2.49(s,4H),2.42(s,6H),2.21(s,3H).HRMS(ESI):calcd.for m/z C 28H 34ClFN 8O 2,[M+H] +569.2550,found 569.2548.HPLC(80％methanol in water):t R＝3.634min,98.88％.
实施例57
Figure PCTCN2019079160-appb-000062
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-N-(3-吗啉代丙基)-[1,11,1'-联苯基]-4-甲酰胺
按照实施例54的制备方法将二甲基胺替换为3-吗啉丙基-1-胺，收率65.2％；m.p.202℃-205℃； 1H NMR(300MHz,DMSO-d 6)δ8.46(t,J＝5.7Hz,1H),7.96(s,1H),7.81 (d,J＝8.2Hz,2H),7.31(t,J＝8.6Hz,2H),6.90(d,J＝8.7Hz,1H),5.40(s,2H),3.47(t,J＝5.4Hz,4H),3.21-3.19(m,2H),2.80(s,4H),2.28-2.22(m,10H),2.09(s,3H),1.60(t,J＝7.1Hz,2H).HRMS(ESI):calcd.for m/z C 29H 37ClFN 8O 2,[M+H] +583.2706,found 583.2707.HPLC(80％methanol in water):t R＝3.601min,97.46％.
实施例58
Figure PCTCN2019079160-appb-000063
(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)(4-乙基哌嗪-1-基)甲酮
按照实施例54的制备方法将二甲基胺替换为1-乙基哌嗪，收率64.8％；m.p.229℃-232℃； 1H NMR(300MHz,DMSO-d 6)δ8.05(s,1H),7.71(s,1H),7.57(d,J＝8.2Hz,2H),7.47(d,J＝8.1Hz,2H),7.39(t,J＝8.5Hz,2H),7.00(d,J＝8.7Hz,1H),5.49(s,2H),3.61(s,2H),2.91(s,4H),2.38-2.34(m,10H),2.20(s,3H),1.17(t,J＝7.1Hz,2H),1.01(t,J＝7.1Hz,2H).HRMS(ESI):calcd.for m/z C 28H 34ClFN 8O,[M+H] +553.2587,found 553.2596.HPLC(80％methanol in water):t R＝3.794min,97.08％.
实施例59
Figure PCTCN2019079160-appb-000064
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]--4-基)四氢-2H-吡喃-4-甲酰胺
步骤1：2'，4'-二氟-3'-硝基[1,1'-联苯]-4-胺的制备
按照实施例23步骤1的制备方法将4-溴1-F硝基苯替换为1-溴-2,4-二氟-3-硝基苯，收率69.0％；m.p.136℃-138℃； 1H NMR(300MHz,DMSO-d 6)δ7.87-7.83(m,1H),7.24-7.22(m,2H),7.15(dd,J＝9.0,7.5Hz,1H),6.72-6.70(m,2H),5.24(s,2H).m/z(EI-MS):251.1[M] +.
步骤2：2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基[1,1'-联苯]-4-胺的制备
按照实施例23步骤2的制备方法将4'-氟-3'-硝基-[1,1'-联苯基]-4-羧酸甲酯替换为2'，4'-二氟-3'-硝基[1,1'-联苯]-4-胺，收率88.2％；m.p.145℃-147℃； 1H NMR(300MHz,DMSO-d 6)δδ7.60(dd,J＝7.4,5.8Hz,1H),7.25–7.18(m,2H),6.96(d,J＝7.5Hz,1H),6.77–6.71(m,2H),5.24(s,2H),3.20(t,J＝4.6Hz,4H),2.54(t,J＝4.6Hz,4H),2.34(s,3H).m/z(EI-MS):331.2[M] +.
步骤3：N-(2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基[1,1'-联苯]-4-基)四氢-2H-吡喃-4-甲酰胺的制备：
按照实施例33类似的制备方法，将N 4-(4'-氨基-4-(4-甲基哌嗪-1-基)-[1,1'-联苯]-3-基)-6-氯嘧啶-e-4,5-二胺替换为2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基[1,1'-联苯]-4-胺，收率88.2％；m.p.166℃-168℃； 1H NMR(300MHz,DMSO-d 6)δ9.52(s,1H),7.63(dd,J＝7.5,5.7Hz,1H),7.42-7.38(m,4H),6.99(d,J＝7.5Hz,1H),3.95-3.92(m,2H),3.53-3.50(m,2H),3.20(t,J＝4.7Hz,4H),2.54(t,J＝4.7Hz,4H),2.65-2.60(m,4H),2.08-2.01(m,2H),1.83-1.76(m,2H).m/z(EI-MS):443.2[M] +.
步骤4：目标产物N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]--4-基)四氢-2H-吡喃-4-甲酰胺的制备
按照实施例23步骤3和步骤4类似的制备方法，得到化合物59，三步收率36.6％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ9.56(s,1H),8.25(s,1H),7.80-7.77(m,3H),7.41-7.39(m,2H),7.07(dd,J＝7.5,5.7Hz,1H),6.68(d,J＝7.3Hz,1H),5.43(s,2H),3.52-3.49(m,4H),3.34(t,J＝4.6Hz,4H),2.70-2.67(m,1H),2.44(s,4H),2.22(s,3H),2.06-1.99(m,2H),1.85-1.78(m,2H)..HRMS(ESI):calcd.for m/z C 27H 31ClFN 7O 2,[M+H] +540.2285,found 540.2276.HPLC(90％methanol in water):t R＝3.656min,98.94％.
实施例60
Figure PCTCN2019079160-appb-000065
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-吡啶-4-基)-1-甲基哌啶-4-甲酰胺
步骤1：N-(2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基[1,1'-联苯]-4-基)-1-甲基哌啶-4-甲酰胺的制备
按照实施例59步骤3的制备方法，将四氢吡喃-4-甲酸替换成1-甲基哌嗪-4-甲酸，收率75.3％；m.p.170℃-172℃； 1H NMR(300MHz,DMSO-d 6)δ9.55(s,1H),7.63(dd,J＝7.5,5.7Hz,1H),7.40(s,4H),6.98(d,J＝7.5Hz,1H),3.22(t,J＝4.7Hz,4H),2.99-2.93(m,6H),2.64-2.58(m,4H),2.37(s,3H),2.29-2.24(m,2H),2.09-2.02(m,2H),1.71-1.64(m,2H).m/z(EI-MS):455.2[M] +.
步骤2：目标产物N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-吡啶-4-基)-1-甲基哌啶-4-甲酰胺的制备：
按照实施例23步骤3和步骤4类似的制备方法，得到化合物60，三步收率35.3％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ9.66(s,1H),8.18(s,1H),7.80(s,1H),7.63 (d,J＝7.5,2H),7.40(d,J＝7.6,2H),7.08-7.05(m,1H),6.61(d,J＝7.5Hz,1H),5.30(s,2H),3.20(t,J＝4.9Hz,4H),3.01-2.96(m,6H),2.63-2.60(m,4H),2.37(s,3H),2.21-2.18(m,4H),2.07-2.02(m,4H).HRMS(ESI):calcd.for m/z C 28H 34ClFN 8O,[M+H] +553.2607,found 553.2606.HPLC(80％methanol in water):t R＝3.168min,97.33％.
实施例61
Figure PCTCN2019079160-appb-000066
N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-哌啶-4-基)-2-(四氢-2H-吡喃-4-基)乙酰胺
步骤1：N-(2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基[1,1'-联苯]-4-基)-2-(四氢-2H-吡喃-4-基)乙酰胺的制备
按照实施例59步骤3，四氢吡喃-4-甲酸替换成四氢吡喃-4-乙酸，收率68.9％；m.p.148℃-150℃； 1H NMR(300MHz,DMSO-d 6)δ7.80-7.77(m,2H),7.70(s,1H),7.65-7.63(m,1H),7.39(d,J＝7.5Hz,2H),6.94(d,J＝7.5Hz,1H),3.90-3.87(m,2H),3.55-3.51(m,2H),3.24(t,J＝4.7Hz,4H),,2.60(s,3H),2.38(t,J＝4.7Hz,4H),2.15(d,J＝7.0Hz,2H),2.05-1.99(m,1H),1.20-1.17(m,4H).m/z(EI-MS):457.2[M] +.
步骤2：目标产物N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-哌啶-4-基)-2-(四氢-2H-吡喃-4-基)乙酰胺的制备
按照实施例23步骤3和步骤4类似的制备方法，得到化合物61，三步收率38.6％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.24(s,1H),8.11(s,1H),7.80(s,1H),7.40(s,4H),7.15-7.12(m,1H),6.73(d,J＝7.5Hz,1H),5.42(s,2H),3.55-3.50(m,4H),3.53(t,J＝4.6Hz,4H),2.48(s,4H),2.26(s,3H),2.15(d,J＝7.0Hz,2H),2.03-2.01(m,1H),1.70-1.64(m,4H).HRMS(ESI):calcd.for m/z C 28H 33ClFN 7O 2,[M+H] +554.2441,found 554.2440.HPLC(80％methanol in water):t R＝3.524min,99.10％.
实施例62
Figure PCTCN2019079160-appb-000067
2-氨基-N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'联苯基]-4-基)-3-甲基丁酰胺
步骤1：(1-((2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-基)氨基)-3-甲基叔丁基-1-氧代丁-2-基)氨基甲酸的制备
按照实施例59步骤3，将四氢吡喃-4-甲酸替换成(叔丁氧羰基)缬氨酸，收率69.0％；m.p.108℃-110℃； 1H NMR(300MHz,DMSO-d 6)δ9.63(s,1H),7.64-7.61(m,3H),7.44-7.42(m,2H),7.39(s,3H),6.98(d,J＝7.5Hz,1H),4.13-4.12(m,1H),3.75-3.72(m,2H),3.31-3.27(m,2H),2.79-2.77(m,2H),2.63-2.61(m,1H),2.60(s,3H),2.24-2.22(m,2H),1.44(s,9H),0.94-0.88(m,6H).m/z(EI-MS):530.3[M] +.
步骤2：目标产物2-氨基-N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'联苯基]-4-基)-3-甲基丁酰胺的制备
按照实施例23步骤3和步骤4类似的制备方法，得到化合物62，三步收率46.9％,m.p.189℃-192℃； 1H NMR(300MHz,DMSO-d 6)δ8.00(s,1H),7.74-7.71(m,3H),7.45(s,2H),7.33(t,J＝8.5Hz,1H),6.96(d,J＝7.2Hz,1H),5.47(s,2H),3.15-3.12(m,1H),2.86(s,4H),2.36(s,4H),2.16(s,3H),1.95(s,2H),1.17(s,1H),0.93(s,3H),0.86(s,3H).HRMS(ESI):calcd.for m/z C 26H 32ClFN 8O,[M+H] +527.2444,found 527.2449.HPLC(80％methanol in water):t R＝3.858min,99.62％.
实施例63
Figure PCTCN2019079160-appb-000068
2-氨基-N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'联苯基]-4-基)-4-甲基戊酰胺
步骤1：(1-((2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-基)氨基)-4-甲基叔丁基-1-氧代戊-2-基)氨基甲酸的制备
按照实施例59步骤3，将四氢吡喃-4-甲酸替换成(叔丁氧羰基)亮氨酸，收率67.2％；m.p.114℃-116℃； 1H NMR(300MHz,DMSO-d 6)δ9.46(s,1H),7.65-7.62(m,1H),7.45-7.42(m,4H),6.95(d,J＝7.5Hz,1H),6.24(s,1H),4.04-4.01(m,1H),3.87-3.82(m,2H),3.31-3.25(m,2H),2.79-2.74(m,2H),2.25-2.19(m,4H),1.98-1.92(m,2H),1.71-1.65(m,1H),1.44(s,9H),0.96-0.90(m,6H).m/z(EI-MS):544.3[M] +.
步骤2：目标产物2-氨基-N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'联苯基]-4-基)-4-甲基戊酰胺的制备
按照实施例23步骤3和步骤4类似的制备方法，得到化合物63，三步收率47.6％；m.p.182℃-185℃； 1H NMR(300MHz,DMSO-d 6)δ7.99(s,1H),7.73-7.71(m,3H),7.45(d,J＝8.1Hz,2H),7.33(t,J＝8.5Hz,2H),6.96(d,J＝8.6Hz,2H),5.45(s,2H),3.38-3.36(m,1H),2.87(s,4H),2.36(s,4H),2.17(s,3H),1.78-1.74(m,2H),1.52-1.47(m,2H),1.19-1.17(m,1H),0.90(t,J＝7.2Hz,6H).m/z(EI-MS):541.3[M] +.HPLC(80％methanol  in water):t R＝3.680min,98.32％.
实施例64
Figure PCTCN2019079160-appb-000069
2-氨基-N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'联苯基]-4-基)乙酰胺
步骤1：(2-((2'-氟-4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-基)氨基)-2-氧代乙基叔丁基)氨基甲酸酯的制备
按照实施例59步骤3，将四氢吡喃-4-甲酸替换成(叔丁氧羰基)甘氨酸，收率70.0％；m.p.112℃-114℃； 1H NMR(300MHz,DMSO-d 6)δ8.20(s,1H),7.63(dd,J＝7.5,5.7Hz,1H),7.49-7.47(m,2H),7.44-7.42(m,2H),6.94(d,J＝7.5Hz,1H),6.31(s,1H),3.89(s,2H),3.30(t,J＝4.7Hz,4H),2.44(s,4H),2.24(s,3H),1.44(s,9H).m/z(EI-MS):486.2[M] +.
步骤2：目标产物2-氨基-N-(3″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'联苯基]-4-基)乙酰胺的制备
按照实施例23步骤3和步骤4类似的制备方法，得到化合物64，三步收率50.9％；m.p.177℃-179℃； 1H NMR(300MHz,DMSO-d 6)δ7.88(s,1H),7.63-7.61(m,3H),7.36(d,J＝8.2Hz,2H),7.24(t,J＝8.5Hz,2H),6.87(d,J＝8.5Hz,2H),5.35(s,2H),4.00(s,1H),3.08(s,2H),2.77(t,J＝4.7Hz,4H),2.27(t,J＝4.6Hz,4H),2.07(s,3H).m/z(EI-MS):485.3[M] +.HPLC(80％methanol in water):t R＝3.595min,99.76％.
实施例65
Figure PCTCN2019079160-appb-000070
3″-((5-氨基-6-氯嘧啶-4-基)氨基)-N，N，2'-三甲基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺
步骤1:1-溴-4-氟-2-甲基-3-硝基苯的制备
按照实施例54步骤1的制备方法将2,6-二氟硝基苯替换为1-溴-2,4-二氟-3-硝基苯，收率86.7％；m.p.74℃-77℃； 1H NMR(300MHz,CDCl 3)δ7.72(d,J＝7.5,Hz,1H),7.03(d,J＝7.5Hz,1H),2.32(s,3H).m/z(EI-MS):233.9[M] +
步骤2：4'-氟-N，N，2'-三甲基-3'-硝基-[1,1'-联苯]-4-甲酰胺的制备
按照实施例54步骤2的制备方法，将(4-(甲氧基羰基)苯基)硼酸替换为(4-(二甲基氨基甲酰基)苯基)硼酸,收率76.9％； 1H NMR(300MHz,CDCl 3)δ7.89-7.86(m,2H),7.76(d,J＝7.5,Hz,1H),7.51-7.49(m,2H),7.26(d,J＝7.5Hz,1H),3.03(s,6H),2.30(s,3H).m/z (EI-MS):303.1[M] +.
步骤3：N，N，2'-三甲基-4'-(4-甲基哌嗪-1-基)-3'-硝基[1,1'-联苯]-4-甲酰胺的制备
按照实施例54步骤3的制备方法将4'-氟-3'-硝基-[1,1'-联苯基]-4-羧酸甲酯替换为4'-氟-N，N，2'-三甲基-3'-硝基-[1,1'-联苯]-4-甲酰胺。收率85.5％；m.p.110℃-112℃； 1H NMR(300MHz,DMSO-d 6)δ7.91(d,J＝5.7Hz,2H),7.60-7.57(m,3H),7.04(d,J＝5.6Hz,1H),3.39(t,J＝4.7Hz,4H),3.03(s,6H),2.54(t,J＝4.6Hz,4H),2.34(s,3H),2.17(s,3H).m/z(EI-MS):383.2[M] +.
步骤4：3'-氨基-N，N，2'-三甲基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺的制备：
按照实施例54步骤4的制备方法将4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-羧酸甲酯替换为N，N，2'-三甲基-4'-(4-甲基哌嗪-1-基)-3'-硝基[1,1'-联苯]-4-甲酰胺.收率80.5％；m.p.158℃-160℃； 1H NMR(300MHz,DMSO-d 6)δ7.91-7.89(m,2H),7.61-7.59(m,2H),6.68-6.64(m,2H),4.35(s,2H),3.39(t,J＝4.7Hz,4H),3.03(s,6H),2.54(s,4H),2.14(s,3H),2.09(s,3H).m/z(EI-MS):353.2[M] +.
步骤5：目标产物3″-((5-氨基-6-氯嘧啶-4-基)氨基)-N，N，2'-三甲基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺的制备
按照实施例54步骤5的制备方法，得到化合物65.收率44.5％；m.p.165℃-167℃； 1H NMR(300MHz,DMSO-d 6)δ8.09(s,1H),7.87-7.85(m,2H),7.80(s,1H),7.58(d,J＝7.4Hz,2H),7.10(d,J＝7.5Hz,1H),6.86(d,J＝7.5Hz,1H),.5.49(s,2H),3.01-2.98(m,6H),2.87(s,4H),2.38(s,4H),2.18(s,3H),2.09(s,3H).m/z(EI-MS):480.2[M] +.HPLC(80％methanol in water):t R＝3.543min,96.37％.
实施例66
Figure PCTCN2019079160-appb-000071
5'-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯步骤1：2'，4'-二氟-5'-硝基-[1,1'-联苯]-4-羧酸甲酯的制备
按照实施例23步骤1的制备方法将4-溴1-F硝基苯替换为1-溴-2,4-二氟-5-硝基苯,收率67.8％；m.p.134℃-136℃； 1H NMR(300MHz,CDCl 3)δ8.30(t,J＝5.7Hz,1H),7.97(d,J＝8.9Hz,2H),7.57(d,J＝5.8Hz,2H),7.24(t,J＝8.9Hz,1H),3.95(s,3H).m/z(EI-MS):294.1[M] +.
步骤2：2'-氟-4'-(4-甲基哌嗪-1-基)-5'-硝基-[1,1'-联苯]-4-羧酸甲酯的制备
按照实施例23步骤2的制备方法将4'-氟-3'-硝基-[1,1'-联苯基]-4-羧酸甲酯替换为2'，4'-二氟-5'-硝基-[1,1'-联苯]-4-羧酸甲酯。收率84.3％；m.p.137℃-140℃； 1H  NMR(300MHz,DMSO-d 6)δ8.02-7.99(m,3H),7.68-7.65(m,2H),6.79(d,J＝7.5Hz,1H),3.95(s,3H),3.39(t,J＝4.7Hz,4H),2.54(t,J＝4.6Hz,4H),2.14(s,3H).m/z(EI-MS):374.1[M] +.
步骤3：5'-氨基-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯的制备
按照实施例23步骤3的制备方法将4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-羧酸甲酯替换为2'-氟-4'-(4-甲基哌嗪-1-基)-5'-硝基-[1,1'-联苯]-4-羧酸甲酯.收率80.6％；m.p.162℃-165℃； 1H NMR(300MHz,DMSO-d 6)δ8.00(d,J＝8.9Hz,2H),7.68(d,J＝8.8Hz,2H),6.56(d,J＝5.7Hz,1H),6.39(d,J＝8.9Hz,1H),4.35(s,2H),4.35(s,2H),3.95(s,3H),3.39(t,J＝4.7Hz,4H),2.54(t,J＝4.7Hz,4H),2.17(s,3H).m/z(EI-MS):344.2[M] +.
步骤4：目标产物5'-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯的制备：
按照实施例23步骤4类似的制备方法，得到化合物66，收率57.4％；m.p.220℃-223℃； 1H NMR(300MHz,DMSO-d 6)δ8.14(s,1H),8.02-7.99(m,2H),7.80(s,1H),7.66-7.64(m,2H),6.80(d,J＝5.7Hz,1H),6.56(d,J＝8.9Hz,1H),5.35(s,2H),3.95(s,3H),3.34(t,J＝4.7Hz,4H),2.57(t,J＝4.7Hz,4H),2.19(s,3H).HRMS(ESI):calcd.for m/z C 23H 24ClFN 6O 2,[M+H] +471.1706,found 471.1706.HPLC(80％methanol in water):t R＝4.248min,98.83％.
实施例67
Figure PCTCN2019079160-appb-000072
(5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-基)(吗啉代)甲酮
步骤1：5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸的制备
按照实施例23步骤5制备方法将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯替换为5'-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯。收率82.7％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.14-8.10(m,3H),7.80(s,1H),7.73-7.70(m,2H),6.80(d,J＝5.7Hz,1H),6.57(d,J＝8.9Hz,1H),5.34(s,2H),3.93(s,3H),3.34(t,J＝4.7Hz,4H),2.57(s,4H),2.12(s,3H).m/z(EI-MS):457.2[M] +.
步骤2：目标产物(5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-[1,1'- 联苯]-4-基)(吗啉代)甲酮的制备
按照实施例23步骤6类似的制备方法，得到目标化合物67.收率78.4％；m.p.136℃-138℃； 1H NMR(300MHz,DMSO-d 6)δ8.09(s,1H),7.93(d,J＝8.7Hz,1H),7.82(s,1H),7.59(s,2H),7.51(d,J＝7.8Hz,2H),7.12(d,J＝8.6Hz,1H),5.40(s,2H),3.61(s,4H),2.97(s,4H),2.72(s,4H),2.54–2.51(m,4H),2.41(s,3H).HRMS(ESI):calcd.for m/z C 26H 29ClFN 7O 2,[M+H] +526.2128,found 526.2130.HPLC(80％methanol in water):t R＝4.046min,96.85％.
实施例68
Figure PCTCN2019079160-appb-000073
5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-N-(2-吗啉代乙基)-[1,11,1'-联苯基]-4-甲酰胺
按照实施例67类似的制备方法，将吗啉替换为1-乙基吗啉，得到目标化合物68。收率78.4％；m.p.199℃-202℃； 1H NMR(300MHz,DMSO-d 6)δ8.47(s,1H),8.09(s,1H),7.95-7.92(m,3H),7.81(s,1H),7.62(d,J＝7.9Hz,2H),7.11(d,J＝12.4Hz,1H),5.39(s,2H),3.58(t,J＝4.6Hz,4H),3.41-3.40(m,4H),2.92(s,4H),2.56(s,4H),2.45(s,4H),2.29(s,3H).HRMS(ESI):calcd.for m/z C 28H 34ClFN 8O 2,[M+H] +569.2550,found 569.2548.HPLC(80％methanol in water):t R＝4.049min,98.64％.
实施例69
Figure PCTCN2019079160-appb-000074
5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-N-(3-吗啉代丙基)-[1,11,1'-联苯基]-4-甲酰胺
按照实施例67类似的制备方法，将吗啉替换为1-丙基吗啉，得到目标化合物69。收率78.4％；m.p.204℃-206℃； 1H NMR(300MHz,DMSO-d 6)δ8.55(s,1H),8.09(s,1H),7.93-7.90(m,3H),7.81(s,1H),7.63-7.60(m,2H),7.11(d,J＝12.3Hz,1H),5.39(s,2H),3.59(s,4H),3.32(s,4H),2.92(s,4H),2.58(s,4H),2.41(s,4H),2.31(s,3H),1.72(s,2H).HRMS(ESI):calcd.for m/z C 29H 36ClFN 8O 2,[M+H] +583.2693,found 583.2699.HPLC(80％methanol in water):t R＝3.885min,99.38％.
实施例70
Figure PCTCN2019079160-appb-000075
5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-N-(4-羟基环己基)-4″-(4-甲基哌嗪-1-基)-[1,11,1'-联苯基]-4-甲酰胺
按照实施例67类似的制备方法，将吗啉替换为哌啶-4-醇，得到目标化合物70.收率65.2％；m.p.200℃-203℃； 1H NMR(300MHz,DMSO-d 6)δ9.67(s,1H),8.06(s,1H),7.92(d,J＝8.4Hz,1H),7.82(s,1H),7.58(d,J＝7.7Hz,2H),7.47(d,J＝7.9Hz,2H),7.21(d,J＝12.2Hz,1H),5.44(s,2H),4.82(s,1H),4.01(s,2H),3.52(s,2H),3.16(s,8H),2.78(s,3H),1.76(s,2H),1.36(s,2H).HRMS(ESI):calcd.for m/z C 27H 31ClFN 7O 2,[M+H] +554.2441,found 554.2442.HPLC(80％methanol in water):t R＝4.057min,98.48％.
实施例71：
Figure PCTCN2019079160-appb-000076
5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-4″-(4-甲基哌嗪-1-基)-N-((四氢-2H-吡喃-4-基)甲基)-[1,1'-联苯基]-4-甲酰胺
按照实施例67类似的制备方法，将吗啉替换为(四氢-2H-吡喃-4-基)甲胺，得到目标化合物71.收率75.2％；m.p.189℃-191℃； 1H NMR(300MHz,DMSO-d 6)δ8.54(s,1H),8.10(s,1H),7.94-7,91(m,3H),7.61(d,J＝8.0Hz,2H),7.11(d,J＝12.2Hz,1H),5.40(s,2H),3.87-3.83(m,2H),3.17(s,4H),2.92(s,4H),2.57(s,4H),2.30(s,3H),1.81(s,1H),1.23(s,4H).HRMS(ESI):calcd.for m/z C 28H 33ClFN 7O 2,[M+H] +540.2285,found 540.2284.HPLC(100％methanol):t R＝7.989min,99.16％.
实施例72
Figure PCTCN2019079160-appb-000077
5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-氟-N，N-二甲基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-甲酰胺
按照实施例67类似的制备方法，将吗啉替换为二甲基胺，得到目标化合物72.收率75.2％；m.p.157℃-159℃； 1H NMR(300MHz,DMSO-d 6)δ8.01(s,1H),7.83(dd,J＝8.7,3.7Hz,1H),7.72(d,J＝3.6Hz,1H),7.49(d,J＝7.1Hz,2H),7.45–7.36(m,2H),7.14–7.01(m,1H),5.35(s,2H),3.27-2.87(m,14H),2.40(s,3H).HRMS(ESI):calcd.for m/z  C 24H 27ClFN 7O,[M+H] +484.2022,found 484.2022.HPLC(80％methanol in water):t R＝4.751min,95.34％.
实施例73
Figure PCTCN2019079160-appb-000078
5'-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-甲基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯步骤1：4'-氟-2'-甲基-5'-硝基-[1,1'-联苯基]-4-羧酸甲酯的制备
按照实施例23步骤1的制备方法将4-溴1-F硝基苯替换为1-溴-4-氟-2-甲基-5-硝基苯。收率68.9％；m.p.133℃-134℃； 1H NMR(300MHz,DMSO-d 6)δ8.06(dd,J＝9.4,3.2Hz,2H),7.97(d,J＝7.7Hz,1H),7.62-7.57(m,3H),3.89(s,3H),2.33(s,3H).m/z(EI-MS):290.1[M] +.
步骤2：2'-甲基-4'-(4-甲基哌嗪-1-基)-5'-硝基-[1,1'-联苯]-4-羧酸甲酯的制备
按照实施例23步骤2的制备方法将4'-氟-3'-硝基-[1,1'-联苯基]-4-羧酸甲酯替换为4'-氟-2'-甲基-5'-硝基-[1,1'-联苯基]-4-羧酸甲酯。收率84.3％；m.p.153℃-155℃； 1H NMR(300MHz,DMSO-d 6)δ8.02-7.99(m,2H),7.84(s,1H),7.61-7.58(m,2H),7.09(s,1H),3.95(s,3H),3.39(t,J＝4.7Hz,4H),2.54(t,J＝4.6Hz,4H),2.32(d,J＝1.0Hz,3H),2.14(s,3H).m/z(EI-MS):370.1[M] +.
步骤3：5'-氨基-2'-甲基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯的制备
按照实施例23步骤3的制备方法将4'-(4-甲基哌嗪-1-基)-3'-硝基-[1,1'-联苯]-4-羧酸甲酯替换为2'-甲基-4'-(4-甲基哌嗪-1-基)-5'-硝基-[1,1'-联苯]-4-羧酸甲酯。收率78.5％；m.p.158℃-160℃； 1H NMR(300MHz,DMSO-d 6)δ8.00(d,J＝8.9Hz,2H),7.68(d,J＝8.8Hz,2H),6.56(d,J＝5.7Hz,1H),6.39(d,J＝8.9Hz,1H),4.35(s,2H),4.35(s,2H),3.95(s,3H),3.39(t,J＝4.7Hz,4H),2.54(t,J＝4.7Hz,4H),2.17(s,3H).m/z(EI-MS):340.2[M] +.
步骤4：目标化合物5'-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-甲基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯的制备
按照实施例23步骤4的制备方法将3'-氨基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯替换为5'-氨基-2'-甲基-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯，收率45.9％；m.p.225℃-228℃； 1H NMR(300MHz,DMSO-d 6)δ8.14(s,1H),8.00(d,J＝7.7Hz,2H),7.80(d,J＝4.4Hz,2H),7.50–7.47(m,2H),7.08(s,1H),5.30(s,2H),2.86(d,J＝5.5Hz,4H),2.47(s,4H),2.22(d,J＝8.0Hz,6H).HRMS(ESI):calcd.for m/z C 24H 27ClN 6O 2,[M+H] +467.1957,found 467.1953.HPLC(80％methanol in water):t R＝3.844min,97.34％.
实施例74
Figure PCTCN2019079160-appb-000079
5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-甲基-4″-(4-甲基哌嗪-1-基)-N-(3-吗啉代丙基)-[1,11,1'-联苯基]-4-甲酰胺
步骤1：5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-甲基-4″-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸的制备
按照实施例23步骤5的制备方法将3'-((5-氨基-6-氯嘧啶-4-基)氨基)-4'-(4-甲基哌嗪-1-基)-[1,1'-联苯基]-4-羧酸甲酯替换为5“-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-甲基-4”-(4-甲基哌嗪-1-基)-[1,1'-联苯]-4-羧酸甲酯。收率79.4％；m.p.>250℃； 1H NMR(300MHz,DMSO-d 6)δ8.13-8.10(m,3H),7.80(s,1H),7.66-7.62(m,2H),6.85(s,1H),6.77(s,1H),5.30(s,2H),2.98(d,J＝5.1Hz,4H),2.47(s,4H),2.24(d,J＝8.0Hz,6H).m/z(EI-MS):453.2[M] +.
步骤2：目标化合物5″-((5-氨基-6-氯嘧啶-4-基)氨基)-2'-甲基-4″-(4-甲基哌嗪-1-基)-N-(3-吗啉代丙基)-[1,11,1'-联苯基]-4-甲酰胺的制备
按照实施例67类似的制备方法，得到化合物74.收率78.4％；m.p.204℃-206℃； 1H NMR(300MHz,DMSO-d 6)δ8.65(s,1H),8.10(s,1H),7.93-7.90(m,3H),7.80(s,1H),7.66-7.62(m,2H),7.11(d,J＝12.3Hz,1H),5.39(s,2H),3.59(s,4H),3.32(s,4H),2.92(s,4H),2.58(s,4H),2.41(s,4H),2.31(s,6H),1.72(s,2H).HRMS(ESI):calcd.for m/z C 20H 39ClN 8O 2,[M+H] +579.2944,found 579.2950.HPLC(80％methanol in water):t R＝3.830min,98.82％.
测试实施例1：部分药效学试验及结果：
本发明基于与WDR5结合的一段MLL1肽段构造荧光分子探针，作为研究苯胺类化合物干扰WDR5蛋白-蛋白相互作用的方法，测定苯胺类化合物在不同浓度条件下的抑制率，进而计算IC 50值。具体实验步骤：在384孔板中分别加入20μL WDR5蛋白、20μL荧光探针、20μL不同浓度梯度的化合物，孵育0.5小时后，利用多功能酶标仪在激发波长485nm发射波长为535nm的条件下读取荧光，计算mP值，利用以下公式计算抑制率后，再利用GraphPad软件计算IC 50值，结果见表1。
Figure PCTCN2019079160-appb-000080
干扰WDR5的蛋白-蛋白相互作用将会影响MLL1的H3K4甲基转移酶活性，进而 调节Hox和Meis-1基因表达下调，抑制白血病细胞的增殖。
联苯类化合物DDO-2084是已经报道的能够抑制WDR5蛋白-蛋白相互作用、小分子抑制剂(Eur.J.Med.Chem.2016,124,480-489.)，本发明中DDO-2084作为阳性对照化合物。
表1.本发明化合物WDR5蛋白-蛋白相互作用抑制活性及甲基转移酶活性
Figure PCTCN2019079160-appb-000081
a化合物的结构见具体实施例； bDDO-2084的结构：
Figure PCTCN2019079160-appb-000082
未进行测试。
由表1可见，本发明的化合物具有较强的WDR5蛋白-蛋白相互作用抑制活性。表1中为本发明部分化合物是否具有抑制H3K4的甲基化水平作用的实验结果。实验结果表明本发明中对WDR5蛋白-蛋白相互作用具有抑制作用的化合物均能下调H3K4的甲基化水平。
本发明的部分化合物也进行了白血病细胞的抗增殖活性实验。表2为本发明的部分化合物评价抑制急性白血病细胞增殖活性的结果，其中MV4-11为人急性单核白血病细胞，Molm-13为人急性髓性白血病细胞。表2表明本发明的化合物具有明显抑制各种白血病细胞增殖的作用。
表2.本发明部分化合物对白血病细胞的抗增殖活性
Figure PCTCN2019079160-appb-000083
a化合物的结构见具体实施例； bND为未进行测试；
同时部分化合物也进行了蛋白免疫印迹试验(Western-blot)在细胞水平对MLL1的甲基转移酶功能的抑制作用结果见图1.通过图1可知，实施例72能够剂量依赖性的抑制MLL1的催化活性而降低H3K4me1/2/3的表达含量。
同时，本发明的部分化合物也进行了细胞水平的RT-PCR实验，部分化合物的细胞水平的对下游Hox和Meis-1基因表达水平抑制结果见图2，通过图2可知，实施例72能 够剂量依赖性的下调Hox和Meis-1基因表达水平。
另外本发明的部分化合物也进行了动物水平的抗肿瘤活性实验，选取白血病细胞MV4-11裸鼠移植瘤模型，进行口服给药，部分化合物对MV4-11肿瘤的抑制结果见图3，通过图3可知，实施例72能够在动物水平剂量依赖性抑制肿瘤的生长。

Claims (10)

  1. 一种苯胺类WDR5蛋白-蛋白相互作用抑制剂，其特征在于包含如通式(I)所示的化合物及其药学上可接受的盐、其前药及其水合物或溶剂合物：
    Figure PCTCN2019079160-appb-100001
    其中，X代表CH或N；
    Y代表C或N；
    Figure PCTCN2019079160-appb-100002
    代表氢或C 1-C 4烷基或者R 7、R 8连接形成的3-7元含氮杂环；
    R 4代表吗啉基、哌嗪基、4-取代哌嗪基，4-取代高哌嗪基，3-取代哌嗪基或2-取代哌嗪基，取代基为C 1-C 4烷基，3-7元环烷基，羟烷基，苯基；
    R 5代表硝基、氨基、苯基、取代苯基、含氧或氮的5-6元芳杂环、取代的含氧或氮的5-6元芳杂环、-NHCOR 9；其中R 9代表羟基、C 1～C 6烷氧基、苯基、取代苯基、含氧或氮的5-6元芳杂环、取代的含氧或氮的5-6元芳杂环，取代基是C 1-C 4烷基、C 1-C 4烷氧基、卤素、氰基、-NHCOR 10、-CONR 11R 12或-COOR 10，其中R 10代表氢、C 1-C 6烷基、C 1-C 6氨基取代烷基、3～7元环烷基、含氮或含氧的3～7元杂环、苯基；R 11、R 12代表氢、C 1-C 6烷基、苯基或取代苯基、取代的或未取代的含氮或含氧3～7元杂环或R 11、R 12连接形成含氮或含氧的3～7元杂环；
    R 6代表氢、卤素、甲基、三氟甲基、氨基、取代氨基，取代基是C 1-C 4烷基、烯丙基；
  2. 根据权利要求1所述的苯胺类WDR5蛋白-蛋白相互作用抑制剂，其特征在于X
    Figure PCTCN2019079160-appb-100003
    者R 7、R 8连接形成的3-5元含氮杂环；
  3. 根据权利要求1所述的苯胺类WDR5蛋白-蛋白相互作用抑制剂，其特征在于R 4代表吗啉基、哌嗪基、4-取代哌嗪基，取代基是甲基、乙基、环丙基、羟乙基、苯基；
  4. 根据权利要求1所述的苯胺类WDR5蛋白-蛋白相互作用抑制剂，其特征在于R 5代表硝基、氨基、-NHCOR 9、呋喃基、嘧啶基、吡啶基、取代三氮唑、取代苯基，取代基为单或双取代的卤素、-NHCOR 10、-CONR 11R 12或-COOR 10；R 9代表苯基，R 10 代表氢、C 1-C 6烷基、C 1-C 6氨基取代烷基、3～7元环烷基、含氮或含氧的3～7元杂环、苯基；R 11、R 12代表氢、C 1-C 6烷基、苯基或取代苯基、取代的或未取代的含氮或含氧3～7元杂环或R 11、R 12连接形成含氮或含氧的3～7元杂环；
  5. 根据权利要求1所述的苯胺类WDR5蛋白-蛋白相互作用抑制剂，其特征在于所述药学上可接受的盐是通式(I)的无机酸盐和有机酸盐；无机酸盐为盐酸盐、氢溴酸盐、硫酸盐；有机酸盐为乙酸盐、乳酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、甲磺酸盐或对苯甲磺酸盐。
  6. 一种权利要求1中通式(I)的制备方法，其特征在于包括如下反应步骤：
    Figure PCTCN2019079160-appb-100004
  7. 一种药物组合物，其特征在于包含权利要求1所述的苯胺类WDR5蛋白-蛋白相互作用抑制剂。
  8. 一种权利要求1所述的苯胺类WDR5蛋白-蛋白相互作用抑制剂在制备治疗与 WDR5酶功能有关适应症药物中的应用。
  9. 根据权利要求8所述的WDR5酶功能有关适应症，其特征在于有关适应症为血液性肿瘤。
  10. 根据权利要求9所述的WDR5酶功能有关适应症，其特征在于血液性肿瘤为急性白血病。
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