(S)-methyl 6-bromo-4-(1H-indazole-7-carboxamido)spiro[chroman-2,4'-piperidine]-1'-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (S)-methyl 6-bromo-4-(1H-indazole-7-carboxamido)spiro[chroman-2,4'-piperidine]-1'-carboxylate
• 英文别名: methyl (S)-6-bromo-4-(1H-indazole-7-carboxamido)spiro[chromane-2,4'-piperidine]-1'-carboxylate；methyl (4S)-6-bromo-4-(1H-indazole-7-carbonylamino)spiro[3,4-dihydrochromene-2,4'-piperidine]-1'-carboxylate
• 化学式: C₂₃H₂₃BrN₄O₄
• 分子量: 499.364
• InChiKey: UTFIEXBNGOPQEA-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  32
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  96.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-methyl 6-bromo-4-(1H-indazole-7-carboxamido)spiro[chroman-2,4'-piperidine]-1'-carboxylate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 反应 16.0h， 以46%的产率得到methyl (S)-4-(1H-indazole-7-carboxamido)spiro[chromane-2,4'-piperidine]-1'-carboxylate
  参考文献：
  名称：

  [EN] MODULATORS OF INDOLEAMINE 2,3-DIOXYGENASE
  [FR] MODULATEURS D'INDOLAMINE 2,3-DIOXYGÉNASE

  摘要：

  提供了公式I的IDO抑制剂化合物及其药用盐，它们的药物组合物，它们的制备方法，以及它们在预防和/或治疗疾病中的使用方法。公式（I）:

  公开号：

  WO2019003148A1
• 作为产物：
  描述：

  4-氧代哌啶-1-羧酸甲酯 在 四氢吡咯 、 盐酸 、 titanium(IV) tetraethanolate 、 sodium tetrahydroborate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 69.5h， 生成 (S)-methyl 6-bromo-4-(1H-indazole-7-carboxamido)spiro[chroman-2,4'-piperidine]-1'-carboxylate
  参考文献：
  名称：

  DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors

  摘要：

  We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.

  DOI：

  10.1021/acs.jmedchem.9b01799

文献信息

• Modulators of indoleamine 2,3-dioxygenase
  申请人：GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED

  公开号：US10906924B2

  公开（公告）日：2021-02-02

  Provided are IDO inhibitor compounds of Formula I and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and methods for their use in the prevention and/or treatment of diseases.

  本文提供了式 I 的 IDO 抑制剂化合物及其药学上可接受的盐、它们的药物组合物、它们的制备方法以及它们用于预防和/或治疗疾病的方法。
• MODULATORS OF INDOLEAMINE 2,3-DIOXYGENASE
  申请人：GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED

  公开号：US20200165280A1

  公开（公告）日：2020-05-28

  Provided are IDO inhibitor compounds of Formula I and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and methods for their use in the prevention and/or treatment of diseases.
• [EN] MODULATORS OF INDOLEAMINE 2,3-DIOXYGENASE<br/>[FR] MODULATEURS D'INDOLAMINE 2,3-DIOXYGÉNASE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2019003148A1

  公开（公告）日：2019-01-03

  Provided are IDO inhibitor compounds of Formula I and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and methods for their use in the prevention and/or treatment of diseases. Formula (I):

  提供了公式I的IDO抑制剂化合物及其药用盐，它们的药物组合物，它们的制备方法，以及它们在预防和/或治疗疾病中的使用方法。公式（I）:
• DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors
  作者：Wieslaw M. Kazmierski、Bing Xia、John Miller、Martha De la Rosa、David Favre、Richard M. Dunham、Yoshiaki Washio、Zhengrong Zhu、Feng Wang、Makda Mebrahtu、Hongfeng Deng、Jonathan Basilla、Liping Wang、Ghotas Evindar、Lijun Fan、Alison Olszewski、Ninad Prabhu、Christopher Davie、Jeffrey A. Messer、Vicente Samano

  DOI：10.1021/acs.jmedchem.9b01799

  日期：2020.4.9

  We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.