2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)isoindoline-1,3-dione | 1194097-64-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)isoindoline-1,3-dione
• 英文别名: 2-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propyl]isoindole-1,3-dione
• CAS: 1194097-64-7
• 化学式: C₂₃H₂₆BNO₅
• 分子量: 407.274
• InChiKey: CCZMLZKSKIDUHJ-UHFFFAOYSA-N

物化性质

• 沸点：
  554.2±35.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.05
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  65.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[(dimethylamino)methyl]-8-bromo[1]benzothieno[3,2-d]pyrimidin-4(3H)-one 、 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)isoindoline-1,3-dione 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 乙醇 、 水 为溶剂， 反应 0.17h， 生成 8-[4-(3-aminopropoxy)phenyl]-2-[(dimethylamino)methyl][1]benzothieno[3,2-d]pyrimidin-4(3H)-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：

  N-(3-溴丙基)苯二胺 、 4-羟基苯硼酸频哪醇酯 在 potassium carbonate 作用下， 以 乙二醇二甲醚 为溶剂， 反应 28.0h， 生成 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)isoindoline-1,3-dione
  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

文献信息

• Discovery of 3<i>H</i>-Benzo[4,5]thieno[3,2-<i>d</i>]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
  作者：Zhi-Fu Tao、Lisa A. Hasvold、Joel D. Leverson、Edward K. Han、Ran Guan、Eric F. Johnson、Vincent S. Stoll、Kent D. Stewart、Geoff Stamper、Nirupama Soni、Jennifer J. Bouska、Yan Luo、Thomas J. Sowin、Nan-Horng Lin、Vincent S. Giranda、Saul H. Rosenberg、Thomas D. Penning

  DOI：10.1021/jm900943h

  日期：2009.11.12

  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.