1-(tert-butyloxy)carbonyl-5'-cyano-2'-oxo-spiro[piperidine-4,3'-(2H)-indole] | 1159094-07-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-(tert-butyloxy)carbonyl-5'-cyano-2'-oxo-spiro[piperidine-4,3'-(2H)-indole]
• 英文别名: tert-Butyl 5-cyano-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate；tert-butyl 5-cyano-2-oxospiro[1H-indole-3,4'-piperidine]-1'-carboxylate
• CAS: 1159094-07-1
• 化学式: C₁₈H₂₁N₃O₃
• 分子量: 327.383
• InChiKey: LRDUPDBXEIPGBP-UHFFFAOYSA-N

物化性质

• 沸点：
  525.8±50.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  82.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(tert-butyloxy)carbonyl-5'-cyano-2'-oxo-spiro[piperidine-4,3'-(2H)-indole] 在 盐酸 、 copper(l) iodide 、 三乙酰氧基硼氢化钠 、 potassium carbonate 、 N,N'-二甲基乙二胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 生成 1-([1,1'-biphenyl]-4-yl)-1'-((3-methylpyridin-2-yl)methyl)-2-oxospiro[indoline-3,4'-piperidine]-5-carbonitrile 2,2,2-trifluoroacetate
  参考文献：
  名称：

  1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia

  摘要：

  The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.

  DOI：

  10.1021/jm201542d
• 作为产物：
  描述：

  1-(tert-butyloxy)carbonyl-5'-cyano-2'-oxo-1'-(4-methoxybenzyl)-spiro[piperidine-4,3'-(2H)-indole] 在 ceric ammonium nitrate 作用下， 以 水 、 乙腈 为溶剂， 反应 2.0h， 以15%的产率得到1-(tert-butyloxy)carbonyl-5'-cyano-2'-oxo-spiro[piperidine-4,3'-(2H)-indole]
  参考文献：
  名称：

  [EN] SPIROPIPERIDINES FOR USE AS TRYPTASE INHIBITORS
  [FR] SPIROPIPÉRIDINES UTILISABLES EN TANT QU'INHIBITEURS DE LA TRYPTASE

  摘要：

  本发明涉及一种化合物，其化学式为（I）：（I）或其形式，其中X1、X2、X3、X4、R1、R2和R3如本文所定义，可用作色氨酸蛋白酶抑制剂。

  公开号：

  WO2009067202A1

文献信息

• SPIROPIPERIDINES FOR USE AS TRYPTASE INHIBITORS
  申请人：Costanzo Michael J.

  公开号：US20120165327A1

  公开（公告）日：2012-06-28

  The present invention is directed to a compound of Formula (I): or a form thereof, wherein X 1 , X 2 , X 3 , X 4 , R 1 , R 2 and R 3 are as defined herein, useful as tryptase inhibitors.

  本发明涉及一个公式(I)的化合物或其形式，其中X1，X2，X3，X4，R1，R2和R3如本文所定义，可用作组胺酶抑制剂。
• Spiropiperidines for use as tryptase inhibitors
  申请人：Costanzo Michael J.

  公开号：US20090163527A1

  公开（公告）日：2009-06-25

  The present invention is directed to a compound of Formula (I): or a form thereof, wherein X 1 , X 2 , X 3 , X 4 , R 1 , R 2 and R 3 are as defined herein, useful as tryptase inhibitors.

  本发明涉及一种化合物，其化学式为(I)或其形式，其中X1、X2、X3、X4、R1、R2和R3的定义如本文所述，用作胰蛋白酶抑制剂。
• US8158792B2
  申请人：——

  公开号：US8158792B2

  公开（公告）日：2012-04-17
• US8536189B2
  申请人：——

  公开号：US8536189B2

  公开（公告）日：2013-09-17
• [EN] APOL1 INHIBITORS AND METHODS OF USE<br/>[FR] INHIBITEURS D'APOL1 ET MÉTHODES D'UTILISATION
  申请人：[en]MAZE THERAPEUTICS, INC.

  公开号：WO2023141432A2

  公开（公告）日：2023-07-27

  Provided herein are compounds of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, whereinm, n, p, R1, R2, R3, L1, L2, L3, R4, X1, X2, X3, and X4are as defined herein. Also provided are methods of preparing compounds of formula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided are methods of inhibiting APOL1 and methods of treating an APOL1 -mediated disease, disorder, or condition in an individual.