6-Bromo-3-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1H-quinolin-2-one | 916429-35-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-Bromo-3-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1H-quinolin-2-one
• 英文别名: 6-bromo-3-(5-(piperidin-1-ylmethyl)-1H-indol-2-yl)quinolin-2(1H)-one；6-bromo-3-[5-(piperidin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one
• CAS: 916429-35-1
• 化学式: C₂₃H₂₂BrN₃O
• 分子量: 436.351
• InChiKey: LZHCRWLAJUPZKK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  48.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-Bromo-3-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1H-quinolin-2-one 、 3-羟基苯硼酸 在 四(三苯基膦)钯 、 sodium carbonate 、 lithium chloride 作用下， 以 1,4-二氧六环 为溶剂， 以60%的产率得到6-(3-Hydroxy-phenyl)-3-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1H-quinolin-2-one
  参考文献：
  名称：

  Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors

  摘要：

  Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.

  DOI：

  10.1016/j.bmcl.2006.08.053
• 作为产物：
  描述：

  4 -溴- 2 - 碘苯甲胺 在 N-甲基吡咯烷酮 、 palladium diacetate 、 四(三苯基膦)钯 、 三正丁胺 、 三乙酰氧基硼氢化钠 、 sodium carbonate 、 戴斯-马丁氧化剂 、 溶剂黄146 、 triethylamine tris(hydrogen fluoride) 、 三氟乙酸 、 lithium chloride 、 lithium diisopropyl amide 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙二醇 、 乙腈 为溶剂， 反应 0.33h， 生成 6-Bromo-3-(5-piperidin-1-ylmethyl-1H-indol-2-yl)-1H-quinolin-2-one
  参考文献：
  名称：

  Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors

  摘要：

  Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.

  DOI：

  10.1016/j.bmcl.2006.08.053

文献信息

• [EN] INHIBITORS OF CHECKPOINT KINASES<br/>[FR] INHIBITEURS DES KINASES DU POINT DE CONTROLE
  申请人：MERCK & CO INC

  公开号：WO2007084135A9

  公开（公告）日：2007-10-11

  [EN] The instant invention provides for compounds which comprise substituted quinolinones that inhibit CHK1 activity. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting CHK1 activity by administering the compound to a patient in need of treatment of cancer.
  [FR] La présente invention concerne des composés qui comprennent des quinolinones substituées capables d'inhiber l'activité CHK1. L'invention concerne également des compositions qui comprennent de tels composés inhibiteurs et des procédés destinés à inhiber l'activité CHK1 par l'administration du composé à un patient qui a besoin d'un traitement anticancéreux.
• Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors
  作者：Shaei Huang、Robert M. Garbaccio、Mark E. Fraley、Justin Steen、Constantine Kreatsoulas、George Hartman、Steve Stirdivant、Bob Drakas、Keith Rickert、Eileen Walsh、Kelly Hamilton、Carolyn A. Buser、James Hardwick、Xianzhi Mao、Marc Abrams、Steve Beck、Weikang Tao、Rob Lobell、Laura Sepp-Lorenzino、Youwei Yan、Mari Ikuta、Joan Zugay Murphy、Vinod Sardana、Sanjeev Munshi、Lawrence Kuo、Michael Reilly、Elizabeth Mahan

  DOI：10.1016/j.bmcl.2006.08.053

  日期：2006.11

  Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.