3-(4-(2-(aminomethyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile | 1034769-08-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 3-(4-(2-(aminomethyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile
• 英文别名: 3-[4-[2-(aminomethyl)morpholin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile
• CAS: 1034769-08-8
• 化学式: C₁₈H₁₈N₆O
• 分子量: 334.381
• InChiKey: GQCAEIXYYAWGMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-溴-4-氯-7H-吡咯并[2,3-d]嘧啶 在 四(三苯基膦)钯 、 四丁基氟化铵 、 sodium hydride 、 sodium carbonate 、 乙二胺 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 、 正丁醇 为溶剂， 反应 15.08h， 生成 3-(4-(2-(aminomethyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile
  参考文献：
  名称：

  Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

  摘要：

  Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.

  DOI：

  10.1021/jm2007326

文献信息

• [EN] MORPHOLINO-SUBSTITUTED BICYCLOHETEROARYL COMPOUNDS AND THEIR USE AS ANTI CANCER AGENTS<br/>[FR] COMPOSÉ BICYCLOHÉTÉROARYLÉS SUBSTITUÉ PAR MORPHOLINO ET LEUR UTILISATION EN TANT QU'AGENTS ANTI-CANCER
  申请人：CANCER REC TECH LTD

  公开号：WO2008075007A1

  公开（公告）日：2008-06-26

  [EN] The present invention pertains generally to the field of therapeutic compounds, and mor specifically to certain morpholino-substituted bicydoheteroaryl compounds (referred to herein as MBHA compounds), of the following formula: and especially certain morpholino-substituted 7H- pyrrolo[2,3-dlpyrimidine and mofholino-substituted 1H-pyrazolo[3.4-b]pyridine compounds, which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) 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 CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.
  [FR] La présente invention appartient d'une manière générale au domaine des composés thérapeutiques, et, plus spécifiquement, à certains composés bicyclohétéroarylés substitués par morpholino (désignés ci-après comme étant des composés MBHA), de la formule suivante : et notamment certains composés de 7H-pyrrolo[2,3-d]pyrimidine substitués par morpholino et 1H-pyrazolo[3,4-b]pyridine substitués par morpholino, qui, entre autres, inhibent la fonction kinase de la Kinase 1 de point de contrôle (CHK1). La présente invention concerne également des compositions pharmaceutiques comprenant de tels composés, et l'utilisation de tels composés et de telles compositions, à la fois in vitro et in vivo pour inhiber la fonction de kinase CHK1, et dans le traitement de maladies et d'états médiés par CHK1 améliorés par l'inhibition de la fonction de kinase CHK1, etc., comprenant des états prolifératifs tels que le cancer, etc., facultativement en combinaison avec un autre agent, par exemple, (a) un inhibiteur de l'ADN topoisomérase I ou II, (b) un agent endommageant l'ADN ; (c) un antimétabolite ou inhibiteur de TS ; (d) un agent ciblé sur les microtubules ; et (e) un rayonnement ionisant
• Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing
  作者：John C. Reader、Thomas P. Matthews、Suki Klair、Kwai-Ming J. Cheung、Jane Scanlon、Nicolas Proisy、Glynn Addison、John Ellard、Nelly Piton、Suzanne Taylor、Michael Cherry、Martin Fisher、Kathy Boxall、Samantha Burns、Michael I. Walton、Isaac M. Westwood、Angela Hayes、Paul Eve、Melanie Valenti、Alexis de Haven Brandon、Gary Box、Rob L. M. van Montfort、David H. Williams、G. Wynne Aherne、Florence I. Raynaud、Suzanne A. Eccles、Michelle D. Garrett、Ian Collins

  DOI：10.1021/jm2007326

  日期：2011.12.22

  Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.