(R)-2-chloro-4-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

• 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: (R)-2-chloro-4-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile
• 英文别名: 2-chloranyl-4-[[1-methyl-3-[(3~{R})-3-oxidanylbutyl]-2-oxidanylidene-benzimidazol-5-yl]amino]pyridine-3-carbonitrile；2-chloro-4-[[3-[(3R)-3-hydroxybutyl]-1-methyl-2-oxobenzimidazol-5-yl]amino]pyridine-3-carbonitrile
• 化学式: C₁₈H₁₈ClN₅O₂
• 分子量: 371.826
• InChiKey: YEBUIPXITBJLFQ-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  92.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,4-二氯-3-氰基吡啶 在 caesium carbonate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.75h， 生成 (R)-2-chloro-4-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile
  参考文献：
  名称：

  Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders

  摘要：

  Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,SS)-4,4-difluoro-3,5-dimethylpiperi din-1-yl) pyrimidin-4-yl) amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

  DOI：

  10.1021/acs.jmedchem.9b02076

文献信息

• [EN] BENZIMIDAZOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE BENZIMIDAZOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215801A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of Formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity: wherein X1, X2, R1, R2 and R3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的Formula I化合物：其中X1、X2、R1、R2和R3如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及BCL6活性有所涉及的其他疾病或病况中的用途。
• BENZIMIDAZOLONE DERIVED INHIBITORS OF BCL6
  申请人：Cancer Research Technology Limited

  公开号：EP3630291A1

  公开（公告）日：2020-04-08
• CHEMICALLY INDUCIBLE POLYPEPTIDE POLYMERIZATION
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：EP4061834A1

  公开（公告）日：2022-09-28
• [EN] CHEMICALLY INDUCIBLE POLYPEPTIDE POLYMERIZATION<br/>[FR] POLYMÉRISATION DE POLYPEPTIDE INDUCTIBLE CHIMIQUEMENT
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2021102283A1

  公开（公告）日：2021-05-27

  The invention features methods for characterizing a cancer as sensitive or resistant to Bcl6 therapies, as well as compositions and methods for inducing the degradation or polymerization of a polypeptide of interest.
• Achieving <i>In Vivo</i> Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders
  作者：Benjamin R. Bellenie、Kwai-Ming J. Cheung、Ana Varela、Olivier A. Pierrat、Gavin W. Collie、Gary M. Box、Michael D. Bright、Sharon Gowan、Angela Hayes、Matthew J. Rodrigues、Kartika N. Shetty、Michael Carter、Owen A. Davis、Alan T. Henley、Paolo Innocenti、Louise D. Johnson、Manjuan Liu、Selby de Klerk、Yann-Vaï Le Bihan、Matthew G. Lloyd、P. Craig McAndrew、Erald Shehu、Rachel Talbot、Hannah L. Woodward、Rosemary Burke、Vladimir Kirkin、Rob L. M. van Montfort、Florence I. Raynaud、Olivia W. Rossanese、Swen Hoelder

  DOI：10.1021/acs.jmedchem.9b02076

  日期：2020.4.23

  Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,SS)-4,4-difluoro-3,5-dimethylpiperi din-1-yl) pyrimidin-4-yl) amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.