benzyl [(3S,4S)-4-fluoropyrrolidin-3-yl]carbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl [(3S,4S)-4-fluoropyrrolidin-3-yl]carbamate
• 英文别名: trans-3-(Cbz-amino)-4-fluoropyrrolidine；benzyl N-[(3S,4S)-4-fluoropyrrolidin-3-yl]carbamate
• 化学式: C₁₂H₁₅FN₂O₂
• 分子量: 238.262
• InChiKey: KZWUUEWPRQZDNF-QWRGUYRKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  50.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  tert-butyl (3S,4S)-3-{[(benzyloxy)carbonyl]amino}-4-fluoropyrrolidine-1-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以96%的产率得到benzyl [(3S,4S)-4-fluoropyrrolidin-3-yl]carbamate
  参考文献：
  名称：

  Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR

  摘要：

  Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.(1) Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.

  DOI：

  10.1021/acs.jmedchem.6b01894

文献信息

• PURINE DERIVATIVES
  申请人：PFIZER INC.

  公开号：US20150141402A1

  公开（公告）日：2015-05-21

  The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

  本发明涉及式(I)的化合物或其药用盐，其中Q、G、环A、环B、R1、R2、R3、R4、R5、R5a、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和m在此定义。这些新颖的嘌呤衍生物在治疗哺乳动物中的异常细胞生长，如癌症方面具有用途。另外，还涉及含有这些化合物的药物组合物，以及在治疗哺乳动物中的异常细胞生长方面使用这些化合物和组合物的方法。
• 2,6-SUBSTITUTED PURINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PROLIFERATIVE DISORDERS
  申请人：Pfizer Inc.

  公开号：EP3071570B1

  公开（公告）日：2018-06-20
• US9290496B2
  申请人：——

  公开号：US9290496B2

  公开（公告）日：2016-03-22
• [EN] 2,6-SUBSTITUTED PURINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PROLIFERATIVE DISORDERS<br/>[FR] DÉRIVÉS DE PURINE SUBSTITUÉS EN POSITIONS 2 ET 6, ET LEUR UTILISATION DANS LE TRAITEMENT DES DÉSORDRES PROLIFÉRATIFS
  申请人：PFIZER

  公开号：WO2015075598A1

  公开（公告）日：2015-05-28

  The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
• Discovery of <i>N</i>-((3<i>R</i>,4<i>R</i>)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1<i>H</i>-pyrazol-4-yl)amino)-9-methyl-9<i>H</i>-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR
  作者：Simon Planken、Douglas C. Behenna、Sajiv K. Nair、Theodore O. Johnson、Asako Nagata、Chau Almaden、Simon Bailey、T. Eric Ballard、Louise Bernier、Hengmiao Cheng、Sujin Cho-Schultz、Deepak Dalvie、Judith G. Deal、Dac M. Dinh、Martin P. Edwards、Rose Ann Ferre、Ketan S. Gajiwala、Michelle Hemkens、Robert S. Kania、John C. Kath、Jean Matthews、Brion W. Murray、Sherry Niessen、Suvi T. M. Orr、Mason Pairish、Neal W. Sach、Hong Shen、Manli Shi、James Solowiej、Khanh Tran、Elaine Tseng、Paolo Vicini、Yuli Wang、Scott L. Weinrich、Ru Zhou、Michael Zientek、Longqing Liu、Yiqin Luo、Shuibo Xin、Chengyi Zhang、Jennifer Lafontaine

  DOI：10.1021/acs.jmedchem.6b01894

  日期：2017.4.13

  Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.(1) Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.