8-[(2S)-1-(4-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide | 1403458-45-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 8-[(2S)-1-(4-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
• 英文别名: 8-[(2S)-1-(4-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide
• CAS: 1403458-45-6
• 化学式: C₂₆H₂₈FN₃O₄
• 分子量: 465.524
• InChiKey: JJISBRLBXMGCRF-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  62.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  tert-butyl 2-(6-(dimethylcarbamoyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate 在 盐酸 、 5% rhodium on activated aluminium oxide 、 氢气 、 palladium diacetate 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 20.0~100.0 ℃ 、6.08 MPa 条件下， 反应 29.5h， 生成 8-[(2S)-1-(4-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide 、 8-[(2R)-1-(4-fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
  参考文献：
  名称：

  Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-one as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours

  摘要：

  Attempts to lock the active conformation of compound 4, a PI3K beta/delta inhibitor (PI3K beta cell IC50 0.015 mu M), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-y1)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3K beta/delta inhibitors. Compound 10 proved exquisitely potent and selective: PI3K beta cell IC50 0.0011 mu M in PTEN null MDA-MB-468 cell and PI3K delta cell IC50 0.014 mu M in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AILS phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3K beta/delta preclinical candidates. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.03.027

文献信息

• [EN] CHROMENONE COMPOUNDS AS PI 3 -KINASE INHIBITORS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS DE CHROMÉNOME EN TANT QU'INHIBITEURS DE PI3-KINASE DESTINÉS AU TRAITEMENT DU CANCER
  申请人：ASTRAZENECA AB

  公开号：WO2012140419A1

  公开（公告）日：2012-10-18

  The invention concerns chromenone compounds of Formula I; or pharmaceutically-acceptable salts thereof, wherein each of R1, R2, R3, R4, R5, n and R6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

  这项发明涉及公式I的香豆素酮化合物；或其药用可接受的盐，其中R1、R2、R3、R4、R5、n和R6中的每一个具有在描述中先前定义的任何含义；它们的制备方法，含有它们的药物组合物以及它们在制造用于治疗细胞增殖紊乱的药物的药物中的使用。
• CHROMENONE DERIVATIVES
  申请人：BARLAAM Bernard Christophe

  公开号：US20120264731A1

  公开（公告）日：2012-10-18

  The invention concerns chromenone compounds of Formula I; or pharmaceutically-acceptable salts thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , n and R 6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

  这项发明涉及公式I的香豆素酮化合物；或其药用盐，其中R1、R2、R3、R4、R5、n和R6中的每一个具有在描述中先前定义的任何含义；它们的制备方法，含有它们的药物组合物以及它们在制造用于治疗细胞增殖紊乱的药物的药物中的使用。
• Chromenone Derivatives
  申请人：Astrazeneca AB

  公开号：US20140038937A1

  公开（公告）日：2014-02-06

  The invention concerns chromenone compounds of Formula I; or pharmaceutically-acceptable salts thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , n and R 6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

  本发明涉及公式I的香豆素化合物；或其药学上可接受的盐，其中R1、R2、R3、R4、R5、n和R6中的每一个具有本说明书中定义的任何含义；制备它们的过程，含有它们的药物组成物以及它们在制造用于治疗细胞增殖性疾病的药物的过程中的使用。
• CHROMENONE COMPOUNDS AS PI 3 -KINASE INHIBITORS FOR THE TREATMENT OF CANCER
  申请人：AstraZeneca AB

  公开号：EP2697220A1

  公开（公告）日：2014-02-19
• CHROMENONE COMPOUNDS AS PI 3-KINASE INHIBITORS FOR THE TREATMENT OF CANCER
  申请人：AstraZeneca AB

  公开号：EP2697220B1

  公开（公告）日：2016-01-13