{1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetic acid | 1429500-45-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: {1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetic acid
• 英文别名: 1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl-acetic acid；2-[1-oxo-7-[3-(trifluoromethyl)phenyl]-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-4-yl]acetic acid
• CAS: 1429500-45-7
• 化学式: C₁₆H₁₃F₃N₂O₃
• 分子量: 338.286
• InChiKey: QYVVZONPQURWOK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  71.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-氟苄胺 、 {1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetic acid 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 6.25h， 以9%的产率得到N-(3-fluorobenzyl)-2-{1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetamide
  参考文献：
  名称：

  Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

  摘要：

  A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.054
• 作为产物：
  描述：

  ethyl {1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetate 在 水 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 16.0h， 以97%的产率得到{1-oxo-7-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}acetic acid
  参考文献：
  名称：

  Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

  摘要：

  A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.054

文献信息

• [EN] 4-ALKYL SUBSTITUTED 3,4-DIHYDROPYRROLO[1,2-a]PYRAZIN-1(2H)-ONE DERIVATIVES AS KINASES INHIBITORS<br/>[FR] DÉRIVÉS 3,4-DIHYDROPYRROLO[1,2-A]PYRAZIN-1(2H)-ONE SUBSTITUÉ PAR 4-ALKYLE EN TANT QU'INHIBITEURS DE KINASES
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2013050448A1

  公开（公告）日：2013-04-11

  The present invention relates to 4-alkyl substituted 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them.

  本发明涉及4-烷基取代的3,4-二氢吡咯并[1,2-a]吡嗪-1(2H)-酮衍生物，其调节蛋白激酶的活性，因此在治疗由失调的蛋白激酶活性引起的疾病方面具有用途。本发明还提供了制备这些化合物的方法，包括这些化合物的药物组合物，以及利用这些化合物或含有它们的药物组合物治疗疾病的方法。
• 4-ALKYL SUBSTITUTED 3,4-DIHYDROPYRROLO[1,2-a]PYRAZIN-1(2H)-ONE DERIVATIVES AS KINASES INHIBITORS
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US20140249146A1

  公开（公告）日：2014-09-04

  The present invention relates to 4-alkyl substituted 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them.

  本发明涉及调节蛋白激酶活性的4-烷基取代的3,4-二氢吡咯并[1,2-a]吡嗪-1(2H)-酮衍生物，因此在治疗由蛋白激酶活性失调引起的疾病方面具有用途。本发明还提供了制备这些化合物的方法，包括这些化合物的药物组合物，以及利用这些化合物或含有它们的药物组合物治疗疾病的方法。
• US9181258B2
  申请人：——

  公开号：US9181258B2

  公开（公告）日：2015-11-10
• Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases
  作者：Francesco Casuscelli、Elena Ardini、Nilla Avanzi、Elena Casale、Giovanni Cervi、Matteo D’Anello、Daniele Donati、Daniela Faiardi、Ronald D. Ferguson、Gianpaolo Fogliatto、Arturo Galvani、Aurelio Marsiglio、Danilo G. Mirizzi、Marisa Montemartini、Christian Orrenius、Gianluca Papeo、Claudia Piutti、Barbara Salom、Eduard R. Felder

  DOI：10.1016/j.bmc.2013.09.054

  日期：2013.12

  A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described. (C) 2013 Elsevier Ltd. All rights reserved.