5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine | 1421372-44-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine
• CAS: 1421372-44-2
• 化学式: C₁₉H₁₃ClFN₅O₃
• 分子量: 413.795
• InChiKey: PNYYRBPFTYDAGC-UHFFFAOYSA-N

物化性质

• 沸点：
  658.2±65.0 °C(Predicted)
• 密度：
  1.523±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine 在 铁粉 、 氯化铵 、 1-丙基磷酸酐 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 乙酸乙酯 为溶剂， 反应 7.5h， 生成
  参考文献：
  名称：

  Selective Covalent Targeting of Mutated EGFR(T790M) with Chlorofluoroacetamide-Pyrimidines

  摘要：

  Covalent modification of disease-associated proteins with small molecules is a powerful approach for achieving an increased and sustained pharmacological effect. To reduce the potential risk of nonselective covalent modification, molecular design of covalent inhibitors is critically important. We report herein the development of a targeted covalent inhibitor for mutated epidermal growth factor receptor (EGFR) (L858R/T790M) using alpha-chlorofluoroacetamide (CFA) as the reactive group. The chemically tuned weak reactivity of CFA was suitable for the design of third-generation EGFR inhibitors that possess the pyrimidine scaffold. The structure-activity relationship study revealed that CFA inhibitor 18 (NSP-037) possessed higher inhibition selectivity to the mutated EGFR over wild-type EGFR when compared to clinically approved osimertinib. Mass-based chemical proteomics analyses further revealed that 18 displayed high covalent modification selectivity for the mutated EGFR in living cells. These findings highlight the utility of CFA as a warhead of targeted covalent inhibitors and the potential application of the CFA-pyrimidines for treatment of non-small-cell lung cancer.

  DOI：

  10.1021/acsmedchemlett.9b00574
• 作为产物：
  描述：

  吲哚 在 甲基溴化镁 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 2-甲基四氢呋喃 为溶剂， 反应 21.17h， 生成 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine
  参考文献：
  名称：

  [EN] 2 - (2, 4, 5 - SUBSTITUTED -ANILINO) PYRIMIDINE DERIVATIVES AS EGFR MODULATORS USEFUL FOR TREATING CANCER
  [FR] DÉRIVÉS DE 2-(ANILINO 2,4,5-SUBSTITUÉ)PYRIMIDINE UTILISÉS COMME MODULATEURS DE L'EGFR UTILES POUR LE TRAITEMENT D'UN CANCER

  摘要：

  本发明涉及某些2-(2,4,5-取代苯胺基)嘧啶化合物及其药学上可接受的盐，这些化合物可能在治疗或预防通过某些突变形式的表皮生长因子受体介导的疾病或医疗状况中有用（例如L858R激活突变体、Exonl9缺失激活突变体和T790M耐药突变体）。这些化合物及其盐可能在治疗或预防多种不同癌症方面有用。该发明还涉及包含所述化合物和盐的药物组合物，特别是这些化合物和盐的有用多形式，用于制造所述化合物的中间体，以及使用所述化合物和盐治疗通过各种不同形式的EGFR介导的疾病的方法。

  公开号：

  WO2013014448A1

文献信息

• [EN] 2 - (2, 4, 5 - SUBSTITUTED -ANILINO) PYRIMIDINE DERIVATIVES AS EGFR MODULATORS USEFUL FOR TREATING CANCER<br/>[FR] DÉRIVÉS DE 2-(ANILINO 2,4,5-SUBSTITUÉ)PYRIMIDINE UTILISÉS COMME MODULATEURS DE L'EGFR UTILES POUR LE TRAITEMENT D'UN CANCER
  申请人：ASTRAZENECA AB

  公开号：WO2013014448A1

  公开（公告）日：2013-01-31

  The present invention relates to certain 2-(2,4,5-substituted-anilino) pyrimidine compounds and pharmaceutically acceptable salts thereof which may be useful in the treatment or prevention of a disease or medical condition mediated through certain mutated forms of epidermal growth factor receptor (for example the L858R activating mutant, the Exonl9 deletion activating mutant and the T790M resistance mutant). Such compounds and salts thereof may be useful in the treatment or prevention of a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, especially useful polymorphic forms of these compounds and salts, intermediates useful in the manufacture of said compounds and to methods of treatment of diseases mediated by various different forms of EGFR using said compounds and salts thereof.

  本发明涉及某些2-(2,4,5-取代苯胺基)嘧啶化合物及其药学上可接受的盐，这些化合物可能在治疗或预防通过某些突变形式的表皮生长因子受体介导的疾病或医疗状况中有用（例如L858R激活突变体、Exonl9缺失激活突变体和T790M耐药突变体）。这些化合物及其盐可能在治疗或预防多种不同癌症方面有用。该发明还涉及包含所述化合物和盐的药物组合物，特别是这些化合物和盐的有用多形式，用于制造所述化合物的中间体，以及使用所述化合物和盐治疗通过各种不同形式的EGFR介导的疾病的方法。
• [EN] HETEROARYL COMPOUNDS FOR KINASE INHIBITION<br/>[FR] COMPOSÉS HÉTÉROARYLE D'INHIBITION DE LA KINASE
  申请人：ARIAD PHARMA INC

  公开号：WO2015195228A1

  公开（公告）日：2015-12-23

  Compounds and pharmaceutical compositions that modulate kinase activity, including mutant EGFR and mutant HER2 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mutant EGFRand mutant HER2 activity, are described herein.

  调节激酶活性的化合物和药物组合物，包括突变的EGFR和突变的HER2激酶活性，以及与激酶活性相关的疾病和病况的治疗方法、化合物、药物组合物，包括突变的EGFR和突变的HER2活性，均在本文中描述。
• Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
  作者：M. Raymond V. Finlay、Mark Anderton、Susan Ashton、Peter Ballard、Paul A. Bethel、Matthew R. Box、Robert H. Bradbury、Simon J. Brown、Sam Butterworth、Andrew Campbell、Christopher Chorley、Nicola Colclough、Darren A. E. Cross、Gordon S. Currie、Matthew Grist、Lorraine Hassall、George B. Hill、Daniel James、Michael James、Paul Kemmitt、Teresa Klinowska、Gillian Lamont、Scott G. Lamont、Nathaniel Martin、Heather L. McFarland、Martine J. Mellor、Jonathon P. Orme、David Perkins、Paula Perkins、Graham Richmond、Peter Smith、Richard A. Ward、Michael J. Waring、David Whittaker、Stuart Wells、Gail L. Wrigley

  DOI：10.1021/jm500973a

  日期：2014.10.23

  receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild

  表皮生长因子受体（EGFR）抑制剂已在临床上用于治疗具有致敏（或激活）突变的非小细胞肺癌（NSCLC）患者，已有多年历史。尽管这些药物具有令人鼓舞的临床疗效，但在许多患者中，耐药性仍在发展，导致疾病进展。在大多数情况下，这种抗性是T790M突变的形式。另外，这些试剂固有的EGFR野生型受体抑制作用可导致皮疹和腹泻的剂量限制性毒性。我们在本文中描述了早期突变选择性导致临床候选药物AZD9291的进化，它是EGFR致敏（EGFRm +）和T790M抗性突变的不可逆抑制剂，对受体的野生型具有选择性。
• [EN] EGFR INHIBITOR, AND PREPARATION AND APPLICATION THEREOF<br/>[FR] INHIBITEUR D'EGFR, ET PRÉPARATION ET APPLICATION ASSOCIÉES<br/>[ZH] EGFR抑制剂及其制备和应用
  申请人：SHANGHAI HANSOH BIOMEDICAL CO LTD

  公开号：WO2016054987A1

  公开（公告）日：2016-04-14

  一种如式(I)所示的4-取代-2-(N-(5-取代烯丙酰胺基)苯基)氨基)嘧啶衍生物以及其作为EGFR抑制剂的制备和应用，该化合物具有抑制L858R EGFR突变体、T790M EGFR突变体和外显子19缺失激活突变体的活性，可以用来治疗单独或部分地由EGFR突变体活性介导疾病，在预防与治疗癌症尤其是非小细胞肺癌药物中的具有广泛应用。
• 2-(2,4,5-SUBSTITUTED-ANILINO) PYRIMIDINE COMPOUNDS
  申请人：BUTTERWORTH Sam

  公开号：US20130053409A1

  公开（公告）日：2013-02-28

  The present invention relates to certain 2-(2,4,5-substituted-anilino)pyrimidine compounds and pharmaceutically acceptable salts thereof which may be useful in the treatment or prevention of a disease or medical condition mediated through certain mutated forms of epidermal growth factor receptor (for example the L858R activating mutant, the Exon19 deletion activating mutant and the T790M resistance mutant). Such compounds and salts thereof may be useful in the treatment or prevention of a number of different cancers. The invention also relates to pharmaceutical compositions comprising said compounds and salts thereof, especially useful polymorphic forms of these compounds and salts, intermediates useful in the manufacture of said compounds and to methods of treatment of diseases mediated by various different forms of EGFR using said compounds and salts thereof.

  本发明涉及某些2-(2,4,5-取代苯胺基)嘧啶化合物及其药学上可接受的盐，这些化合物可能对通过某些突变表皮生长因子受体介导的疾病或医疗状况（例如L858R激活突变体、Exon19缺失激活突变体和T790M耐药突变体）的治疗或预防有用。这些化合物及其盐可能对多种不同的癌症的治疗或预防有用。本发明还涉及包含这些化合物及其盐的药物组合物，特别是这些化合物及其盐的有用多形式，以及用于制造这些化合物的中间体和使用这些化合物及其盐治疗通过不同形式的EGFR介导的疾病的方法。