5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• 英文别名: 5-(2,3-dihydro-1H-indol-5-yl)-7-methylpyrrolo[2,3-d]pyrimidin-4-amine
• 化学式: C₁₅H₁₅N₅
• 分子量: 265.318
• InChiKey: CXRNQXFFWARLSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  68.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 、 4-吡啶乙酸盐酸盐 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以94%的产率得到7-methyl-5-[1-(4-pyridinylacetyl)-2,3-dihydro-1H-indol-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  参考文献：
  名称：

  Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

  摘要：

  We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasrnic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

  DOI：

  10.1021/ml400228e
• 作为产物：
  描述：

  N-BOC-5-溴吲哚啉 在 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 caesium carbonate 、 三环己基膦 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 46.0h， 生成 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  参考文献：
  名称：

  5-（2,3-二氢-1 H-吲哚-5-基）-7 H-吡咯并[2,3- d ]嘧啶-4-胺衍生物作为新型的受体相互作用蛋白激酶1（ RIPK1）抑制剂，在肿瘤转移模型中显示有效活性

  摘要：

  我们在这里报告了5-（2,3-dihydro-1 H-吲哚-5-基）-7 H-吡咯并[2,3- d ]嘧啶-4-胺衍生物的结构优化和构效关系研究。新型的受体相互作用蛋白激酶1（RIPK1）抑制剂。在所有获得的RIPK1抑制剂中，1-（5- {4-氨基-7-乙基-7 H-吡咯并[2,3- d ]嘧啶-5-基} -2,3-二氢-1 H-吲哚-1 -基）-2- [3-（三氟甲氧基）苯基]乙-1-酮（22b）是最活跃的。该化合物以0.004μM的结合亲和力（K D）和酶促IC 50有效抑制RIPK1值为0.011μM，并且还显示出良好的激酶选择性。它可以有效地保护细胞免于坏死性坏死，并减轻肿瘤细胞在体外和体内诱导的血管内皮细胞的坏死细胞死亡。重要的是，化合物22b在实验性B16黑色素瘤肺转移模型中显示出优异的抗转移活性。它还显示出良好的药代动力学性质。总体而言，22b可能是预防肿瘤转移的有前途的药物。

  DOI：

  10.1021/acs.jmedchem.8b01652

文献信息

• CHEMICAL COMPOUNDS
  申请人：Axten Jeffrey Michael

  公开号：US20120077828A1

  公开（公告）日：2012-03-29

  The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R 1 , R 2 , and R 3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代的吲哚啉衍生物。具体而言，本发明涉及按式I所示的化合物：其中R1、R2和R3在此定义。本发明的化合物是PERK的抑制剂，可用于治疗癌症、眼部疾病和与激活的未折叠蛋白质应答途径相关的疾病，如阿尔茨海默病、中风、1型糖尿病帕金森病、亨廷顿病、肌萎缩性侧索硬化、心肌梗死、心血管疾病、动脉硬化和心律失常，更具体地，乳腺癌、结肠癌、胰腺癌和肺癌。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还涉及使用本发明化合物或包含本发明化合物的药物组合物抑制PERK活性和治疗相关疾病的方法。
• Chemical compounds
  申请人：Axten Jeffrey Michael

  公开号：US08598156B2

  公开（公告）日：2013-12-03

  The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1, R2, and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代的吲哚啉衍生物。具体而言，本发明涉及符合公式I的化合物：其中R1，R2和R3在此定义。本发明的化合物是PERK的抑制剂，可用于治疗癌症、眼部疾病以及与激活的未折叠蛋白质反应途径相关的疾病，例如阿尔茨海默病、中风、1型糖尿病、帕金森病、亨廷顿病、肌萎缩侧索硬化、心肌梗死、心血管疾病、动脉粥样硬化和心律失常，更具体地是乳腺癌、结肠癌、胰腺癌和肺癌。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还涉及使用本发明化合物或包含本发明化合物的药物组合物来抑制PERK活性和治疗与其相关的疾病的方法。
• US8598156B2
  申请人：——

  公开号：US8598156B2

  公开（公告）日：2013-12-03
• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSÉS CHIMIQUES
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2011119663A1

  公开（公告）日：2011-09-29

  The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
• Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development
  作者：Jeffrey M. Axten、Stuart P. Romeril、Arthur Shu、Jeffrey Ralph、Jesús R. Medina、Yanhong Feng、William Hoi Hong Li、Seth W. Grant、Dirk A. Heerding、Elisabeth Minthorn、Thomas Mencken、Nathan Gaul、Aaron Goetz、Thomas Stanley、Annie M. Hassell、Robert T. Gampe、Charity Atkins、Rakesh Kumar

  DOI：10.1021/ml400228e

  日期：2013.10.10

  We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasrnic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.