ethyl 2-(6-(4-methyl-1, 4-diazepan-1-yl)-1H-benzo[d]imidazol-2-yl)acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: ethyl 2-(6-(4-methyl-1, 4-diazepan-1-yl)-1H-benzo[d]imidazol-2-yl)acetate
• 英文别名: ethyl 2-[6-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]acetate
• 化学式: C₁₇H₂₄N₄O₂
• 分子量: 316.403
• InChiKey: PUIZGOIOQOMBGT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  61.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 2-(6-(4-methyl-1, 4-diazepan-1-yl)-1H-benzo[d]imidazol-2-yl)acetate 、 2-氨基苯甲腈 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 以5%的产率得到4-amino-3-[5-(4-methyl(1,4-diazaperhydroepinyl))benzimidazol-2-yl]hydroquinolin-2-one
  参考文献：
  名称：

  Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

  摘要：

  The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TK1258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFR beta with IC50 values <0.1 mu M. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

  DOI：

  10.1021/jm800790t
• 作为产物：
  描述：

  N-甲基高哌嗪 在 potassium carbonate 、 一水合肼 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 22.67h， 生成 ethyl 2-(6-(4-methyl-1, 4-diazepan-1-yl)-1H-benzo[d]imidazol-2-yl)acetate
  参考文献：
  名称：

  [EN] HPK1 INHIBITORS AND METHODS OF USING SAME
  [FR] INHIBITEURS DE HPK1 ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  Thienopyridinone化合物的化学式（I）及其药用盐已被描述。在这些化合物中，X1、X2和X3中的一个是S，另外两个分别是独立的CR，其中R和所有其他变量如本文所定义。已证明这些化合物能抑制HPK1激酶活性并具有体内抗肿瘤活性。这些化合物可以有效地与药用载体以及其他免疫调节方法结合使用，例如检查点抑制或色氨酸氧化抑制剂。化学式（I）。

  公开号：

  WO2016205942A1

文献信息

• [EN] HPK1 INHIBITORS AND METHODS OF USING SAME<br/>[FR] INHIBITEURS DE HPK1 ET LEURS PROCÉDÉS D'UTILISATION
  申请人：UNIV HEALTH NETWORK

  公开号：WO2016205942A1

  公开（公告）日：2016-12-29

  Thienopyridinone compounds of Formula (I) and pharmaceutically acceptable salts thereof are described. In these compounds, one of X1; X2, and X3 is S and the other two are each independently CR, wherein R and all other variables are as defined herein. The compounds are shown to inhibit HPK1 kinase activity and to have in vivo antitumor activity. The compounds can be effectively combined with pharmaceutically acceptable carriers and also with other immunomodulatory approaches, such as checkpoint inhibition or inhibitors of tryptophan oxidation. Formula (I).

  Thienopyridinone化合物的化学式（I）及其药用盐已被描述。在这些化合物中，X1、X2和X3中的一个是S，另外两个分别是独立的CR，其中R和所有其他变量如本文所定义。已证明这些化合物能抑制HPK1激酶活性并具有体内抗肿瘤活性。这些化合物可以有效地与药用载体以及其他免疫调节方法结合使用，例如检查点抑制或色氨酸氧化抑制剂。化学式（I）。
• HPK1 inhibitors and methods of using same
  申请人：University Health Network

  公开号：US11059832B2

  公开（公告）日：2021-07-13

  Thienopyridinone compounds of Formula (I) and pharmaceutically acceptable salts thereof are described. In these compounds, one of X1; X2, and X3 is S and the other two are each independently CR, wherein R and all other variables are as defined herein. The compounds are shown to inhibit HPK1 kinase activity and to have in vivo antitumor activity. The compounds can be effectively combined with pharmaceutically acceptable carriers and also with other immunomodulatory approaches, such as checkpoint inhibition or inhibitors of tryptophan oxidation. Formula (I).

  描述了式 (I) 的噻吩并吡啶酮化合物及其药学上可接受的盐类。在这些化合物中，X1、X2 和 X3 中的一个为 S，另外两个各自独立地为 CR，其中 R 和所有其他变量如本文所定义。研究表明，这些化合物可抑制 HPK1 激酶活性，并具有体内抗肿瘤活性。这些化合物可与药学上可接受的载体有效结合，也可与其他免疫调节方法结合，如检查点抑制或色氨酸氧化抑制剂。式 (I).
• HPK1 INHIBITORS AND METHODS OF USING SAME
  申请人：University Health Network

  公开号：EP3322711B1

  公开（公告）日：2021-03-10
• Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors
  作者：Paul A. Renhowe、Sabina Pecchi、Cynthia M. Shafer、Timothy D. Machajewski、Elisa M. Jazan、Clarke Taylor、William Antonios-McCrea、Christopher M. McBride、Kelly Frazier、Marion Wiesmann、Gena R. Lapointe、Paul H. Feucht、Robert L. Warne、Carla C. Heise、Daniel Menezes、Kimberly Aardalen、Helen Ye、Molly He、Vincent Le、Jayesh Vora、Johanna M. Jansen、Mary Ellen Wernette-Hammond、Alex L. Harris

  DOI：10.1021/jm800790t

  日期：2009.1.22

  The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TK1258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFR beta with IC50 values <0.1 mu M. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
• [EN] FUSED HETEROCYCLIC DERIVATIVE AND USE THEREOF IN MEDICINE<br/>[FR] DÉRIVÉ HÉTÉROCYCLIQUE FUSIONNÉ ET SON UTILISATION EN MÉDECINE<br/>[ZH] 一种并环杂环衍生物及其在医药上的应用
  申请人：[en]HAISCO PHARMACEUTICAL GROUP CO., LTD.;[zh]海思科医药集团股份有限公司

  公开号：WO2023109902A1

  公开（公告）日：2023-06-22

  本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与HPK1激酶活性或表达量相关疾病的药物中的应用。