N-(5-(2-amino-4-methylthiazol-5-yl)-2-chloropyridin-3-yl)benzenesulfonamide | 887308-98-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(5-(2-amino-4-methylthiazol-5-yl)-2-chloropyridin-3-yl)benzenesulfonamide
• 英文别名: N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chlorpyridin-3-yl]benzenesulfonamide；N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide
• CAS: 887308-98-7
• 化学式: C₁₅H₁₃ClN₄O₂S₂
• 分子量: 380.879
• InChiKey: FRLSZLLBLAZTKP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(5-(2-amino-4-methylthiazol-5-yl)-2-chloropyridin-3-yl)benzenesulfonamide 在 盐酸 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 2-amino-N-(5-(6-chloro-5-(phenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-2-methylpropanamide
  参考文献：
  名称：

  Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor

  摘要：

  PI3K delta, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3K delta inhibitors. Among them compound 151 (CHMFL-PI3K delta-317) displays an IC50 of 6 nM against PI3K delta in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3K delta mediated phosphorylation of Akt T308 but not PI3K delta, beta, gamma mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 mu M. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3K delta armory. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.07.036
• 作为产物：
  描述：

  2-氯-3-氨基-5-溴吡啶 在 吡啶 、 盐酸 、 三叔丁基膦 、 palladium diacetate 、 caesium carbonate 作用下， 以 乙醇 、 水 为溶剂， 反应 22.0h， 生成 N-(5-(2-amino-4-methylthiazol-5-yl)-2-chloropyridin-3-yl)benzenesulfonamide
  参考文献：
  名称：

  Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor

  摘要：

  PI3K delta, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3K delta inhibitors. Among them compound 151 (CHMFL-PI3K delta-317) displays an IC50 of 6 nM against PI3K delta in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3K delta mediated phosphorylation of Akt T308 but not PI3K delta, beta, gamma mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 mu M. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3K delta armory. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.07.036

文献信息

• 5-Heteroaryl Thiazoles And Their Use As PI3K Inhibitors
  申请人：Bengtsson Malena

  公开号：US20080132502A1

  公开（公告）日：2008-06-05

  The invention provides thiazole derivatives of formula (I), or pharmaceutically acceptable salts thereof in which Ring A, R 1 , R 2 and R 3 are as defined in the specification; a processes for their preparation; pharmaceutical compositions containing them; and their use in therapy, for example in the treatment of disease mediated by a PI3K enzyme and/or a mTOR kinase.

  本发明提供式(I)的噻唑衍生物或其药学上可接受的盐，其中环A、R1、R2和R3如说明书中所定义；一种制备它们的方法；含有它们的制药组合物；以及它们在治疗中的用途，例如用于治疗由PI3K酶和/或mTOR激酶介导的疾病。
• 5-heteroaryl thiazoles and their use as PI3K inhibitors
  申请人：AstraZeneca AB

  公开号：US07868188B2

  公开（公告）日：2011-01-11

  The invention provides thiazole derivatives of formula (I), or pharmaceutically acceptable salts thereof in which Ring A, R1, R2 and R3 are as defined in the specification; a processes for their preparation; pharmaceutical compositions containing them; and their use in therapy, for example in the treatment of disease mediated by a PI3K enzyme and/or a mTOR kinase.

  本发明提供了式(I)的噻唑衍生物或其药学上可接受的盐，其中环A、R1、R2和R3如规范中所定义；它们的制备方法；含有它们的药物组合物；以及它们在治疗中的用途，例如用于治疗由PI3K酶和/或mTOR激酶介导的疾病。
• [EN] NEW PI3K KINASE INHIBITOR<br/>[FR] NOUVEL INHIBITEUR DE LA KINASE PI3K<br/>[ZH] 一种新型的PI3K激酶抑制剂
  申请人：HEFEI INST PHYSICAL SCI CAS

  公开号：WO2016101553A1

  公开（公告）日：2016-06-30

  本发明涉及一种PI3K激酶抑制剂，其包括式I的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，其中Y、W、Z、R1、R2、R3、R4如说明书所定义。本发明还涉及包括式I化合物的药物组合物及其在制备用于治疗由PI3K激酶活化介导的病症的药物中的用途。
• WO2006/51270
  申请人：——

  公开号：——

  公开（公告）日：——
• 5-HETEROARYL THIAZOLES AND THEIR USE AS PI3K INHIBITORS
  申请人：AstraZeneca AB

  公开号：EP1841763B1

  公开（公告）日：2010-06-30