1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester | 865443-82-9

• 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: 1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester
• 英文别名: Methyl 3-methyl-2-oxo-1-propan-2-ylbenzimidazole-5-carboxylate
• CAS: 865443-82-9
• 化学式: C₁₃H₁₆N₂O₃
• 分子量: 248.282
• InChiKey: HHNSAXWHGNJCSP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester 在 四丁基氯化铵 、 碳酸氢钠 2,2,6,6-tetramethyl-piperidine-N-oxyl 、 N-氯代丁二酰亚胺 、 锂硼氢 、 sodium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 36.0h， 生成 1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde
  参考文献：
  名称：

  Theoretical and Experimental Design of Atypical Kinase Inhibitors:  Application to p38 MAP Kinase

  摘要：

  Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.

  DOI：

  10.1021/jm050346q
• 作为产物：
  描述：

  4-异丙基氨基-3-硝基苯甲酸甲酯 在 palladium 10% on activated carbon 、 氢气 、 sodium hydride 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester
  参考文献：
  名称：

  [EN] CDK2 INHIBITORS AND METHODS OF USING THE SAME
  [FR] INHIBITEURS DE CDK2 ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  本公开涉及抑制Cyclin-dependent kinase 2（CDK2）活性的化学化合物及其在抑制CDK2活性方面的用途。本公开还提供了包含所披露化合物的药学上可接受的组合物以及使用上述化合物和组合物在治疗与CDK2活性相关的各种疾病方面的方法。

  公开号：

  WO2022272106A1

文献信息

• [EN] CDK2 INHIBITORS AND METHODS OF USING THE SAME<br/>[FR] INHIBITEURS DE CDK2 ET LEURS PROCÉDÉS D'UTILISATION
  申请人：CEDILLA THERAPEUTICS INC

  公开号：WO2022272106A1

  公开（公告）日：2022-12-29

  The present disclosure relates generally to Cyclin-dependent kinase 2 (CDK2) inhibiting chemical compounds and uses thereof in the inhibition of the activity of CDK2. The disclosure also provides pharmaceutically acceptable compositions comprising compounds disclosed herein and methods of using said compounds and compositions in the treatment of various disorders related to CDK2 activity.

  本公开涉及抑制Cyclin-dependent kinase 2（CDK2）活性的化学化合物及其在抑制CDK2活性方面的用途。本公开还提供了包含所披露化合物的药学上可接受的组合物以及使用上述化合物和组合物在治疗与CDK2活性相关的各种疾病方面的方法。
• Synthesis and bioevaluation of pyrazole-benzimidazolone hybrids as novel human 4-Hydroxyphenylpyruvate dioxygenase inhibitors
  作者：Yu-Ling Xu、Hong-Yan Lin、Xu Ruan、Sheng-Gang Yang、Ge-Fei Hao、Wen-Chao Yang、Guang-Fu Yang

  DOI：10.1016/j.ejmech.2015.01.018

  日期：2015.3

  4-Hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in tyrosine catabolism, is an important target for treating type I tyrosinemia. Inhibition of HPPD can effectively alleviate the symptoms of type I tyrosinemia. However, only one commercial HPPD inhibitor, 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC), has been available for clinical use so far. In the present study, a series of novel pyrazole-benzimidazolone hybrids were designed, synthesized and evaluated as potent human HPPD inhibitors. Most of the new compounds displayed significant inhibitory activity against the recombinant human HPPD. Moreover, compound 91 was identified as the most potent candidate with IC50 value of 0.021 mu M against recombinant human HPPD, about 3-fold more potent than NTBC. Thus the pyrazole-benzimidazolone hybrid has great potential to be further developed for the treatment of type I tyrosinemia. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Theoretical and Experimental Design of Atypical Kinase Inhibitors:  Application to p38 MAP Kinase
  作者：Kim F. McClure、Yuriy A. Abramov、Ellen R. Laird、John T. Barberia、Weiling Cai、Thomas J. Carty、Santo R. Cortina、Dennis E. Danley、Alan J. Dipesa、Kathleen M. Donahue、Mark A. Dombroski、Nancy C. Elliott、Christopher A. Gabel、Seungil Han、Thomas R. Hynes、Peter K. LeMotte、Mahmoud N. Mansour、Eric S. Marr、Michael A. Letavic、Jayvardhan Pandit、David B. Ripin、Francis J. Sweeney、Douglas Tan、Yong Tao

  DOI：10.1021/jm050346q

  日期：2005.9.1

  Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.