2-amino-N-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-amino-N-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide
• 英文别名: Somcl-12-81；2-amino-N-[3-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]phenyl]acetamide
• 化学式: C₂₁H₂₃ClN₆O₃S
• 分子量: 474.971
• InChiKey: BDVGHJLTQZVVPA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-amino-N-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide 在 N-羟基-7-氮杂苯并三氮唑 、 三氯化硼 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 N-(2-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino) phenyl)amino)-2-oxoethyl)-2,4-dihydroxy-5-isopropylbenzamide
  参考文献：
  名称：

  Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

  摘要：

  To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diary-laminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors. (C) 2017 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2017.12.060
• 作为产物：
  描述：

  2-(异丙基磺酰基)苯胺 在 D(+)-10-樟脑磺酸 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 1.0h， 生成 2-amino-N-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide
  参考文献：
  名称：

  Discovery of Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases

  摘要：

  We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound 15 possessing IC50 values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model.

  DOI：

  10.1021/jm5005144

文献信息

• 抗肿瘤新药的合成方法及其药用盐和固体制剂
  申请人：北京淦航医药科技有限公司

  公开号：CN108383799A

  公开（公告）日：2018-08-10

  本发明的公开了一种抗肿瘤药的合成方法，化学名称为5‑氯‑N2‑(3‑氨基乙酰基氨基苯基)‑N4‑(2‑异丙砜基苯基)嘧啶‑2,4‑二胺。同时，对其盐型、晶型进行研究，筛选出了适合进一步作为制剂开发的马来酸盐、酒石酸盐和琥珀酸盐及其对应的晶型。本发明还提供了一种以上述抗肿瘤药为活性成分的固体制剂，其中添加有一种或多种酸性剂。本发明固体制剂的溶出性能以及稳定性优良，具有临床应用前景。
• 2,4-二胺基嘧啶化合物、其制备方法、药物组 合物及用途
  申请人：中国科学院上海药物研究所

  公开号：CN107586278B

  公开（公告）日：2020-01-10

  本发明公开了一类如以下通式I所示的含苯酚片段的2,4‑二胺基嘧啶化合物、其药学上可接受的盐或药学上可接受的溶剂合物，其制备方法，包含该类化合物的药物组合物，以及这类化合物在制备用于预防或治疗生物体内与间变性淋巴瘤酶相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病，以及与血管新生或癌转移相关的疾病的药物，尤其是用于治疗或预防肿瘤生长与转移的药物中的用途。
• Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs
  作者：Kaijun Geng、Hongchun Liu、Zilan Song、Chi Zhang、Minmin Zhang、Hong Yang、Jingchen Cao、Meiyu Geng、Aijun Shen、Ao Zhang

  DOI：10.1016/j.ejmech.2018.04.019

  日期：2018.5

  Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (173 vs 9.8 nM) and Hsp90 alpha (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALK(L1196M). Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AICT, and up-regulation of the chaperone protein Hsp70 in H3122 cells. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation
  作者：Kaijun Geng、Zongjun Xia、Yinchun Ji、Ruisi (Ruthy) Zhang、Deqiao Sun、Jing Ai、Zilan Song、Meiyu Geng、Ao Zhang

  DOI：10.1016/j.ejmech.2017.12.060

  日期：2018.1

  To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diary-laminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors. (C) 2017 Published by Elsevier Masson SAS.
• Discovery of Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases
  作者：Zilan Song、Yanhong Yang、Zhiqing Liu、Xia Peng、Junfeng Guo、Xinying Yang、Kui Wu、Jing Ai、Jian Ding、Meiyu Geng、Ao Zhang

  DOI：10.1021/jm5005144

  日期：2015.1.8

  We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound 15 possessing IC50 values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model.