methyl (R)-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate | 360793-11-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: methyl (R)-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate
• 英文别名: methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
• CAS: 360793-11-9
• 化学式: C₁₈H₁₂BrClF₃N₃O₂
• 分子量: 474.664
• InChiKey: OJPNWZPZCNQHMN-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl (R)-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate 、 (S)-吗啉-3-羧酸盐酸盐 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 (S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-2-(3,5-difluoro-pyridin-2-yl)-5-methoxycarbonyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
  参考文献：
  名称：

  Discovery and Pre-Clinical Characterization of Third-Generation 4-H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors

  摘要：

  Described herein are the discovery and structure activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of.analogue 12 (HAP_iR01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen' onding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further devehipffientas oral anti-HBV infection agent.

  DOI：

  10.1021/acs.jmedchem.7b00083
• 作为产物：
  描述：

  Bay 41-4109 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 四氯化碳 为溶剂， 反应 1.0h， 生成 methyl (R)-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate
  参考文献：
  名称：

  Discovery and Pre-Clinical Characterization of Third-Generation 4-H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors

  摘要：

  Described herein are the discovery and structure activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of.analogue 12 (HAP_iR01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen' onding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further devehipffientas oral anti-HBV infection agent.

  DOI：

  10.1021/acs.jmedchem.7b00083

文献信息

• [EN] HETEROARYLDIHYDROPYRIMIDINE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS<br/>[FR] DÉRIVÉS D'HÉTÉROARYLDIHYDROPYRIMIDINE ET PROCÉDÉS DE TRAITEMENT D'INFECTIONS PAR LE VIRUS DE L'HÉPATITE B
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2021121363A1

  公开（公告）日：2021-06-24

  Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

  本文提供了一些对需要治疗HBV感染的受试者有用的化合物，以及它们的药物组成和抑制、抑制或预防受试者HBV感染的方法。
• Medicaments against viral diseases
  申请人：——

  公开号：US20030232842A1

  公开（公告）日：2003-12-18

  Novel dihydropyrimidines and combinations thereof with other antiviral agents, suitable for combating HBV infections.

  新型二氢嘧啶和其他抗病毒药物的组合，适用于对抗HBV感染。
• [EN] NOVEL 6-FUSED AND 2-HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION<br/>[FR] NOUVELLES 2-HÉTÉROARYLDIHYDROPYRIMIDINES FUSIONNÉES EN POSITION 6 POUR LE TRAITEMENT ET LA PROPHYLAXIE DE L'INFECTION PAR LE VIRUS DE L'HÉPATITE B
  申请人：HOFFMANN LA ROCHE

  公开号：WO2017064156A1

  公开（公告）日：2017-04-20

  The present invention relates to novel 6-fused and 2-heteroaryldihydropyrimidines having pharmaceutical activity, their manufacture, pharmaceutical compositions containing them and their potential use as medicaments. The present invention relates to compounds of formula (I), wherein R1 to R7 are as described above, or to pharmaceutically acceptable salts, or to enantiomers or diastereomers thereof.
• Discovery and Pre-Clinical Characterization of Third-Generation 4-H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors
  作者：Zongxing Qiu、Xianfeng Lin、Weixing Zhang、Mingwei Zhou、Lei Guo、Buelent Kocer、Guolong Wu、Zhisen Zhang、Haixia Liu、Houguang Shi、Buyu Kou、Taishan Hu、Yimin Hu、Mengwei Huang、S. Frank Yan、Zhiheng Xu、Zheng Zhou、Ning Qin、Yue Fen Wang、Shuang Ren、Hongxia Qiu、Yuxia Zhang、Yi Zhang、Xiaoyue Wu、Kai Sun、Sheng Zhong、Jianxun Xie、Giorgio Ottaviani、Yuan Zhou、Lina Zhu、Xiaojun Tian、Liping Shi、Fang Shen、Yi Mao、Xue Zhou、Lu Gao、John A. T. Young、Jim Zhen Wu、Guang Yang、Alexander V. Mayweg、Hong C. Shen、Guozhi Tang、Wei Zhu

  DOI：10.1021/acs.jmedchem.7b00083

  日期：2017.4.27

  Described herein are the discovery and structure activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of.analogue 12 (HAP_iR01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen' onding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further devehipffientas oral anti-HBV infection agent.