(S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
• 英文别名: (S)-1-(4-(7-(3-Hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one；1-[4-[7-(3-hydroxynaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one
• 化学式: C₃₀H₃₆N₆O₃
• 分子量: 528.654
• InChiKey: GQSSXKRUKAMOQS-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  39
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  85.3
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-甲基-L-脯氨醇 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 caesium carbonate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 5.0h， 生成 (S)-1-(4-(7-(3-hydroxynaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
  参考文献：
  名称：

  KRAS G12C INHIBITORS

  摘要：

  本发明涉及抑制KRas G12C的化合物。特别地，本发明涉及不可逆抑制KRas G12C活性的化合物、包含这些化合物的药物组合物及其使用方法。

  公开号：

  US20190144444A1

文献信息

• [EN] KRAS G12C INHIBITORS<br/>[FR] INHIBITEURS DE KRAS G12C
  申请人：MIRATI THERAPEUTICS INC

  公开号：WO2017201161A1

  公开（公告）日：2017-11-23

  The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

  本发明涉及抑制KRas G12C的化合物。特别是，本发明涉及不可逆地抑制KRas G12C活性的化合物，包括含有这些化合物的药物组合物及其使用方法。
• KRas G12C inhibitors
  申请人：Mirati Therapeutics, Inc.

  公开号：US10125134B2

  公开（公告）日：2018-11-13

  The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

  本发明涉及抑制 KRas G12C 的化合物。特别是，本发明涉及不可逆地抑制 KRas G12C 活性的化合物、包含该化合物的药物组合物及其使用方法。
• KRAS G12C inhibitors
  申请人：Mirati Therapeutics, Inc.

  公开号：US11267812B2

  公开（公告）日：2022-03-08

  The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

  本发明涉及抑制 KRas G12C 的化合物。特别是，本发明涉及不可逆地抑制 KRas G12C 活性的化合物、包含该化合物的药物组合物及其使用方法。
• Identification of the Clinical Development Candidate <b>MRTX849</b>, a Covalent KRAS^G12C Inhibitor for the Treatment of Cancer
  作者：Jay B. Fell、John P. Fischer、Brian R. Baer、James F. Blake、Karyn Bouhana、David M. Briere、Karin D. Brown、Laurence E. Burgess、Aaron C. Burns、Michael R. Burkard、Harrah Chiang、Mark J. Chicarelli、Adam W. Cook、John J. Gaudino、Jill Hallin、Lauren Hanson、Dylan P. Hartley、Erik J. Hicken、Gary P. Hingorani、Ronald J. Hinklin、Macedonio J. Mejia、Peter Olson、Jennifer N. Otten、Susan P. Rhodes、Martha E. Rodriguez、Pavel Savechenkov、Darin J. Smith、Niranjan Sudhakar、Francis X. Sullivan、Tony P. Tang、Guy P. Vigers、Lance Wollenberg、James G. Christensen、Matthew A. Marx

  DOI：10.1021/acs.jmedchem.9b02052

  日期：2020.7.9

  Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRAS(G12C) that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRAS(G12C) is described.
• Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity
  作者：Jay B. Fell、John P. Fischer、Brian R. Baer、Joshua Ballard、James F. Blake、Karyn Bouhana、Barbara J. Brandhuber、David M. Briere、Laurence E. Burgess、Michael R. Burkard、Harrah Chiang、Mark J. Chicarelli、Kevin Davidson、John J. Gaudino、Jill Hallin、Lauren Hanson、Kenneth Hee、Erik J. Hicken、Ronald J. Hinklin、Matthew A. Marx、Macedonio J. Mejia、Peter Olson、Pavel Savechenkov、Niranjan Sudhakar、Tony P. Tang、Guy P. Vigers、Henry Zecca、James G. Christensen

  DOI：10.1021/acsmedchemlett.8b00382

  日期：2018.12.13

  KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.