N'-(2-fluoro-5-(4-fluoro-1H-pyrazol-1-yl)-3-methylbenzoyl)benzenesulfonohydrazide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N'-(2-fluoro-5-(4-fluoro-1H-pyrazol-1-yl)-3-methylbenzoyl)benzenesulfonohydrazide
• 英文别名: N'-(benzenesulfonyl)-2-fluoro-5-(4-fluoropyrazol-1-yl)-3-methylbenzohydrazide
• 化学式: C₁₇H₁₄F₂N₄O₃S
• 分子量: 392.386
• InChiKey: AAJDCAXJINQPQE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  5-溴-3-氟-2-甲基苯甲酸 在 trans-N,N'-dimethyl-1,2-cyclohexyldiamine 、 copper(l) iodide 、 N-羟基-7-氮杂苯并三氮唑 、 potassium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 N'-(2-fluoro-5-(4-fluoro-1H-pyrazol-1-yl)-3-methylbenzoyl)benzenesulfonohydrazide
  参考文献：
  名称：

  Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents

  摘要：

  A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 mu M. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; K-D = 0.002 mu M), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

  DOI：

  10.1021/acs.jmedchem.9b02071

文献信息

• Aryl sulfonohydrazides
  申请人：MONASH UNIVERSITY

  公开号：US10829446B2

  公开（公告）日：2020-11-10

  Compound of formula I: wherein: A is selected from: (i) where RF1 is H or F; (ii) (iii) a N-containing C6 heteroaryl group; and B is where X1 is either CRF2 or N, where RF2 is H or F; X2 is either CR3 or N, where R3 is selected from H, Me, Cl, F OMe; X3 is either CH or N; X4 is either CRF3 or N, where RF3 is H or F; where only one or two of X1, X2, X3 and X4 may be N; and R4 is selected from I, optionally substituted phenyl, optionally substituted C5-6 heteroaryl; optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, which are useful in the treatment of a condition ameliorated by the inhibition of MOZ.

  式 I 的化合物： 其中 A 选自 (i) 其中 RF1 为 H 或 F； (ii) (iii) 含 N 的 C6 杂芳基；以及 B 是 其中 X1 是 CRF2 或 N，其中 RF2 是 H 或 F；X2 是 CR3 或 N，其中 R3 选自 H、Me、Cl、F OMe；X3 是 CH 或 N；X4 是 CRF3 或 N，其中 RF3 是 H 或 F；其中 X1、X2、X3 和 X4 中只有一个或两个可以是 N；以及 R4 选自 I、任选取代的苯基、任选取代的 C5-6 杂芳基、任选取代的 C1-6 烷基和任选取代的 C1-6 烷氧基，它们可用于治疗通过抑制 MOZ 而改善的病症。
• ARYL SULFONOHYDRAZIDES
  申请人：MONASH UNIVERSITY

  公开号：US20180222857A1

  公开（公告）日：2018-08-09

  Compound of formula I: wherein: A is selected from: (i) where R F1 is H or F; (ii) (iii) a N-containing C 6 heteroaryl group; and B is where X 1 is either CR F2 or N, where R F2 is H or F; X 2 is either CR 3 or N, where R 3 is selected from H, Me, Cl, F OMe; X 3 is either CH or N; X 4 is either CR F3 or N, where R F3 is H or F; where only one or two of X 1 , X 2 , X 3 and X 4 may be N; and R 4 is selected from I, optionally substituted phenyl, optionally substituted C 5-6 heteroaryl; optionally substituted C 1-6 alkyl and optionally substituted C 1-6 alkoxy, which are useful in the treatment of a condition ameliorated by the inhibition of MOZ.
• Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents
  作者：Daniel L. Priebbenow、David J. Leaver、Nghi Nguyen、Benjamin Cleary、H. Rachel Lagiakos、Julie Sanchez、Lian Xue、Fei Huang、Yuxin Sun、Prashant Mujumdar、Ramesh Mudududdla、Swapna Varghese、Silvia Teguh、Susan A. Charman、Karen L. White、David M. Shackleford、Kasiram Katneni、Matthew Cuellar、Jessica M. Strasser、Jayme L. Dahlin、Michael A. Walters、Ian P. Street、Brendon J. Monahan、Kate E. Jarman、Helene Jousset Sabroux、Hendrik Falk、Matthew C. Chung、Stefan J. Hermans、Natalie L. Downer、Michael W. Parker、Anne K. Voss、Tim Thomas、Jonathan B. Baell

  DOI：10.1021/acs.jmedchem.9b02071

  日期：2020.5.14

  A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 mu M. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; K-D = 0.002 mu M), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.