5-chloro-3-[(2-chloroacetimidoyl)amino]benzo[b]thiophene-2-carboxylic acid methyl ester hydrochloride | 1194097-43-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 英文名称: 5-chloro-3-[(2-chloroacetimidoyl)amino]benzo[b]thiophene-2-carboxylic acid methyl ester hydrochloride
• CAS: 1194097-43-2
• 化学式: C₁₂H₁₀Cl₂N₂O₂S*ClH
• 分子量: 353.657
• InChiKey: RCXTZAUUUNZXLG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.99
• 重原子数：
  20.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  64.68
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  5-chloro-3-[(2-chloroacetimidoyl)amino]benzo[b]thiophene-2-carboxylic acid methyl ester hydrochloride 生成 8-chloro-2-(chloromethyl)-3H-[1]benzothiolo[3,2-d]pyrimidin-4-one
  参考文献：
  名称：

  Discovery of 3H-Benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM) Kinases

  摘要：

  Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been Found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K-i values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC50 values. For example, compound 14j inhibited the growth of K562 cells with an EC50 value of 1.7 mu M and showed K-i values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein bin-ling, and no CYP inhibition below 20 mu M concentration.

  DOI：

  10.1021/jm900943h
• 作为产物：
  描述：

  氯乙腈 、 3-amino-5-chlorobenzo[b]thiophene-2-carboxylic acid methyl ester 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 生成 5-chloro-3-[(2-chloroacetimidoyl)amino]benzo[b]thiophene-2-carboxylic acid methyl ester hydrochloride
  参考文献：
  名称：

  Discovery of 3H-Benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM) Kinases

  摘要：

  Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been Found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K-i values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC50 values. For example, compound 14j inhibited the growth of K562 cells with an EC50 value of 1.7 mu M and showed K-i values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein bin-ling, and no CYP inhibition below 20 mu M concentration.

  DOI：

  10.1021/jm900943h