2-((4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(o-tolyl)quinazolin-4(3H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-((4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(o-tolyl)quinazolin-4(3H)-one
• 英文别名: 2-[[4-Amino-3-(3,4-dimethoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-fluoro-3-(2-methylphenyl)quinazolin-4-one；2-[[4-amino-3-(3,4-dimethoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-fluoro-3-(2-methylphenyl)quinazolin-4-one
• 化学式: C₂₉H₂₄FN₇O₃
• 分子量: 537.553
• InChiKey: KFESJNODSOOMQN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  40
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-氨基-6-氟苯甲酸 在 四(三苯基膦)钯 、 氯化亚砜 、 sodium carbonate 、 potassium carbonate 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 24.5h， 生成 2-((4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluoro-3-(o-tolyl)quinazolin-4(3H)-one
  参考文献：
  名称：

  Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors

  摘要：

  PI3K delta and PI3K gamma regulate immune cell signaling. Selective PI3K delta or PI3K gamma inhibitors and dual PI3K delta/gamma inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazoloI3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3K delta inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3K delta at the concentration of 1 mu M, with the 1050 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3K delta (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3K delta over beta and gamma, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3K delta/gamma inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3K delta and PI3K gamma, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3K delta over PI3K alpha and PI3K beta. In agreement with their remarkable PI3K delta inhibitory activity, compounds 10d and 10e showed high anti proliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3K delta/gamma inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.03.068

文献信息

• Discovery of novel quinazolinone derivatives as high potent and selective PI3Kδ and PI3Kδ/γ inhibitors
  作者：Chen-Chen Ma、Cheng-Mei Zhang、Long-Qian Tang、Zhao-Peng Liu

  DOI：10.1016/j.ejmech.2018.03.068

  日期：2018.5

  PI3K delta and PI3K gamma regulate immune cell signaling. Selective PI3K delta or PI3K gamma inhibitors and dual PI3K delta/gamma inhibitors have the potential for the treatment of immune cell-mediated diseases and hematological malignancies. Based on the quinazolinone pharmacophore, we used a pyrazoloI3,4-d]pyrimidin-4-amine portion as the hinge region binding moiety, an aromatic or a heteroaromatic substituent at the 3-position of the pyrazolo[3,4-d]pyrimidine core as the affinity element, and designed novel 2-tolyl and 2,6-dimethylphenyl quinazolinone derivatives as potential PI3K delta inhibitors. Most of these compounds displayed high inhibitory rates (89-97%) against PI3K delta at the concentration of 1 mu M, with the 1050 values of 8.4 nM-106 nM. Among the 3-(2,6-dimethylphenyl)quinazolinone series, the introduction of an indol-5yl substituent at the pyrazolo[3,4-d]pyrimidine 3-position led to a potent and selective PI3K delta (IC50 = 8.6 nM) inhibitor 10d, that was more than 3630-fold, 390-fold and 40-fold selective for PI3K delta over beta and gamma, while the substitution with a 3,4-dimethoxyphenyl resulted in a potent and selective dual PI3K delta/gamma inhibitor 10e with IC50 values of 8.4 nM and 62 nM against PI3K delta and PI3K gamma, respectively. Compound 10e was also more than 1400-fold, 820-fold selective for PI3K delta over PI3K alpha and PI3K beta. In agreement with their remarkable PI3K delta inhibitory activity, compounds 10d and 10e showed high anti proliferative activity against human B-cell SU-DHL-6 cells. Moreover, the dual PI3K delta/gamma inhibitor 10e had reasonable pharmacokinetic profiles with a good plasma exposure, low clearance, low volume distribution, and an acceptable oral bioavailability of 34.9%. (C) 2018 Elsevier Masson SAS. All rights reserved.