(S)-tert-butyl 3-(5-bromo-2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate | 1146159-74-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (S)-tert-butyl 3-(5-bromo-2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate
• 英文别名: tert-butyl (3S)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]pyrrolidine-1-carboxylate
• CAS: 1146159-74-1
• 化学式: C₁₃H₁₈BrClN₄O₂
• 分子量: 377.669
• InChiKey: IEMKRFYWNPSNEY-QMMMGPOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  67.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl 3-(5-bromo-2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate 在 二(氰基苯)二氯化钯 、 溴 、 sodium acetate 、 N,N-二异丙基乙胺 、 三(邻甲基苯基)磷 、 三氟乙酸 作用下， 以 四氢呋喃 、 溶剂黄146 、 仲丁醇 为溶剂， 反应 88.0h， 生成
  参考文献：
  名称：

  Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR^{L858R/T790M/C797S})

  摘要：

  Tertiary EGFRc797s mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR(L858R/T790M/C797S) inhibitors. A representative compound, 8r-B, exhibited an ICso of 27.5 nM against the EGFR(L858R/T790M/C797S) mutant, while being a significantly less potent for EGFRwr (IC50 > 1.0 NM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

  DOI：

  10.1021/acs.jmedchem.9b00576
• 作为产物：
  描述：

  5-溴-2,4-二氯嘧啶 、 (s)-(-)-N-叔丁氧羰基-3-氨基吡咯烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 (S)-tert-butyl 3-(5-bromo-2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  作为共价L858R / T790M突变体选择性表皮生长因子受体（EGFR）抑制剂的氧嘧啶并[2,3-d]嘧啶-7-个衍生物的合成及生物学评价

  摘要：

  背景：无小细胞癌（NSCLC）是全球最常见的癌症之一。现在已证明第一代EGFR-TKI（如吉非替尼和厄洛替尼）在具有EGFR激活突变的NSCLC患者中PFS延长。然而，在连续治疗后，大多数情况下患者会因CEE T790M突变而产生耐药性。第二代共价EGFR抑制剂（如afatinib）在临床前模型中对EGFRT790M具有中等程度的抑制作用，但由于T790M突变而在临床上缺乏疗效，原因是第三代EGFR抑制剂具有克服EGFRT790M耐药性突变并降低EGFRWT驱动的毒性的潜力，目前正在积极研究中。 方法：我们以化合物6为主要化合物。我们着重于AMG亲水侧链，接头和Micheal加成受体部分周围的结构修饰。设计并合成了一系列新的草酰吡啶并[2,3-d]嘧啶-7-酮衍生物。通过ELISA测定法测试了它们对EGFRWT和EGFRL858R / T790M的激酶抑制活性。SRB试验用于细胞抗增殖评估。

  DOI：

  10.2174/1570180815666180523090558

文献信息

• [EN] THERAPEUTIC OXY-PHENYL-ARYL COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS OXY-PHÉNYL-ARYLES THÉRAPEUTIQUES ET LEUR UTILISATION
  申请人：CANCER REC TECH LTD

  公开号：WO2009053694A1

  公开（公告）日：2009-04-30

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain oxy phenyl aryl compounds (referred to herein as OPA compounds), as described herein, which, inter alia, inhibit Checkpoint Kinase 2 (CHK2) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK2, that are ameliorated by the inhibition of CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明总体涉及治疗化合物领域，更具体地涉及如本文所述的某些氧基苯基芳基化合物（以下简称OPA化合物），其中，抑制检查点激酶2（CHK2）激酶功能。本发明还涉及包含此类化合物的药物组合物，以及使用此类化合物和组合物，在体内外抑制CHK2激酶功能，以及治疗由CHK2介导的疾病和状况，包括通过抑制CHK2激酶功能而改善的疾病和状况，等等，包括诸如癌症等增殖性疾病，可选地与另一剂联合使用，例如，（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或TS抑制剂；（d）针对微管的药剂；（e）电离辐射。
• Synthesis and Biological Evaluation of Oxopyrido[2,3-d] Pyrimidine-7- ones Derivatives as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
  作者：Ao Niu、Yang Wang、Yushe Yang、Jianhai Wei、Jian Ding、Yi Chen、Linjiang Tong、Hua Xie

  DOI：10.2174/1570180815666180523090558

  日期：2019.8.8

  compound 7k showed comparable activity in kinase inhibition assay and cell growth inhibition assay with our lead compound 6. Higher activity and selectivity over EGFRWT were observed in the in vitro antitumour assay comparing compound 7k to AZD-9291. Compound 7a exhibited higher selectivity over EGFRWT in kinase inhibition assay, but poor cell inhibition to NCI-1975 cell line. The in vivo pharmacokinetic

  背景：无小细胞癌（NSCLC）是全球最常见的癌症之一。现在已证明第一代EGFR-TKI（如吉非替尼和厄洛替尼）在具有EGFR激活突变的NSCLC患者中PFS延长。然而，在连续治疗后，大多数情况下患者会因CEE T790M突变而产生耐药性。第二代共价EGFR抑制剂（如afatinib）在临床前模型中对EGFRT790M具有中等程度的抑制作用，但由于T790M突变而在临床上缺乏疗效，原因是第三代EGFR抑制剂具有克服EGFRT790M耐药性突变并降低EGFRWT驱动的毒性的潜力，目前正在积极研究中。 方法：我们以化合物6为主要化合物。我们着重于AMG亲水侧链，接头和Micheal加成受体部分周围的结构修饰。设计并合成了一系列新的草酰吡啶并[2,3-d]嘧啶-7-酮衍生物。通过ELISA测定法测试了它们对EGFRWT和EGFRL858R / T790M的激酶抑制活性。SRB试验用于细胞抗增殖评估。
• Therapeutic Oxy-Phenyl-Aryl Compounds and Their Use
  申请人：Collins Ian

  公开号：US20110201592A1

  公开（公告）日：2011-08-18

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain oxy phenyl aryl compounds (referred to herein as OPA compounds), as described herein, which, inter alia, inhibit Checkpoint Kinase 2 (CHK2) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK2, that are ameliorated by the inhibition of CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明涉及治疗化合物领域，更具体地涉及某些氧苯基芳基化合物（以下简称OPA化合物），如本文所述，该化合物在其中抑制检查点激酶2（CHK2）激酶功能。本发明还涉及包含这种化合物的制药组合物，以及在体外和体内使用这种化合物和组合物来抑制CHK2激酶功能，并治疗由CHK2介导，通过抑制CHK2激酶功能改善的疾病和病况，包括增殖性疾病，如癌症等，可选择与另一种药物一起使用，例如（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或TS抑制剂；（d）微管靶向药物；和（e）电离辐射。
• Therapeutic oxy-phenyl-aryl compounds and their use
  申请人：Cancer Research Technology Limited

  公开号：US08324226B2

  公开（公告）日：2012-12-04

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain oxy phenyl aryl compounds (referred to herein as OPA compounds), as described herein, which, inter alia, inhibit Checkpoint Kinase 2 (CHK2) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK2, that are ameliorated by the inhibition of CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明涉及治疗化合物领域，更具体地涉及某些氧代苯基芳基化合物（以下简称OPA化合物），如本文所述，它们可以抑制检查点激酶2（CHK2）激酶功能。本发明还涉及包含这些化合物的制药组合物，以及在体内外使用这些化合物和组合物来抑制CHK2激酶功能，并用于治疗由CHK2介导的疾病和病情，通过抑制CHK2激酶功能而改善的疾病和病情，包括增生性疾病如癌症等，可选择与另一种药物联合使用，例如：（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或TS抑制剂；（d）微管靶向剂；和（e）电离辐射。
• A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790M mutant with improved pharmacokinetic properties
  作者：Lei Yu、Minhao Huang、Tianfeng Xu、Linjiang Tong、Xiao-e Yan、Zhang Zhang、Yong Xu、Caihong Yun、Hua Xie、Ke Ding、Xiaoyun Lu

  DOI：10.1016/j.ejmech.2016.12.006

  日期：2017.1

  Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR(T790M) inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR(L858R/T790M) kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERIC in NCI-H1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients. (C) 2016 Published by Elsevier Masson SAS.