4-bromo-2-(4-chloroquinazolin-2-yl)phenol | 421581-49-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 4-bromo-2-(4-chloroquinazolin-2-yl)phenol
• CAS: 421581-49-9
• 化学式: C₁₄H₈BrClN₂O
• 分子量: 335.587
• InChiKey: ZHFPZUZQFCKPAR-UHFFFAOYSA-N

物化性质

• 沸点：
  384.1±42.0 °C(Predicted)
• 密度：
  1.662±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  46
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-bromo-2-(4-chloroquinazolin-2-yl)phenol 在 盐酸 、 potassium phosphate 、 四(三苯基膦)钯 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基乙酰胺 、 水 为溶剂， 反应 16.17h， 生成 (S)-4-(1H-pyrazol-4-yl)-2-(4-(pyrrolidin-3-ylamino)quinazolin-2-yl)phenol
  参考文献：
  名称：

  Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

  摘要：

  Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

  DOI：

  10.1021/jm101150b
• 作为产物：
  描述：

  5-bromo-2-methoxybenzoyl chloride 在 双氧水 、 三溴化硼 、 N,N-二异丙基乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 氯仿 、 水 为溶剂， 反应 80.0h， 生成 4-bromo-2-(4-chloroquinazolin-2-yl)phenol
  参考文献：
  名称：

  Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

  摘要：

  Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

  DOI：

  10.1021/jm101150b

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。
• Design, Synthesis and Biological Evaluation of the Quinazoline Derivatives as L858R/T790M/C797S Triple Mutant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
  作者：Mingguang Zhang、Yunyun Wang、Jia Wang、Zhaogang Liu、Jingmiao Shi、Mingxin Li、Yongqiang Zhu、Shifa Wang

  DOI：10.1248/cpb.c20-00411

  日期：2020.10.1

  Inhibition of the epidermal growth factor receptor (EGFR) has been proved to be one of the most promising strategies for the treatment of non-small cell lung cancers. A series of 2-aryl-4-amino substituted quinazoline derivatives were designed and synthesized with the purpose to overcome L858R/T790M/C797S (CTL) triple mutant drug resistance and the biological activity for inhibition of CTL kinases and EGFR

  事实证明，抑制表皮生长因子受体（EGFR）是治疗非小细胞肺癌的最有希望的策略之一。设计并合成了一系列2-芳基-4-氨基取代的喹唑啉衍生物，旨在克服L858R / T790M / C797S（CTL）三突变体耐药性以及抑制CTL激酶和EGFR野生型（WT）的生物学活性。被评估。三种化合物（20，24和27）表现出优异的抑制活性针对EGFR激酶三重突变体CTL（IC 50  <1μM）和高选择性（IC 50：WT / CTL> 10000）。细胞株评估表明，最有效的化合物27对H1975-EGFR L858R / T790M（IC 50  = 3.3 µM）和H1975-EGFR L858R / T790M / C797S（IC 50  = 1.2 µM）具有显着的抗性。化合物27在人，大鼠和小鼠肝脏中也表现出良好的微粒体稳定性，但生物利用度较低。这项工作对于发现新的喹唑啉衍生物作为靶向三重突变体L858R
• 2-芳胺-4-胺基喹唑啉化合物、其制备方法及用途
  申请人：江苏正大丰海制药有限公司

  公开号：CN113248448A

  公开（公告）日：2021-08-13

  本发明提供一种2‑芳胺‑4‑胺基喹唑啉化合物及其制备方法，所述2‑芳胺‑4‑胺基喹唑啉化合物如式I所示，本发明中的式I化合物对EGFR L858R/T790M/C797S激酶具有较好的抑制活性，可用于制备治疗肿瘤有关的疾病或病症的药物；
• 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：EP2227460A1

  公开（公告）日：2010-09-15