tert-butyl 4-(8-methyl-6-(2-methyl-5-(3-(trifluoromethyl)-benzamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidin-2-ylamino)piperidine-1-carboxylate

• 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: tert-butyl 4-(8-methyl-6-(2-methyl-5-(3-(trifluoromethyl)-benzamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidin-2-ylamino)piperidine-1-carboxylate
• 英文别名: tert-butyl 4-[[1-methyl-3-[2-methyl-5-[[3-(trifluoromethyl)benzoyl]amino]phenyl]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-7-yl]amino]piperidine-1-carboxylate
• 化学式: C₃₂H₃₆F₃N₇O₄
• 分子量: 639.678
• InChiKey: BNKXWNJRHXGFLI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  46
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(8-methyl-6-(2-methyl-5-(3-(trifluoromethyl)-benzamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidin-2-ylamino)piperidine-1-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.5h， 以96%的产率得到N-(4-methyl-3-(1-methyl-2-oxo-7-(piperidin-4-ylamino)-1,2-dihydropyrimido[4,5-d]pyr imidin-3(4H)-yl)phenyl )-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

  摘要：

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

  DOI：

  10.1021/acs.jmedchem.5b01618
• 作为产物：
  描述：

  N-(4-methyl-3-(((4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methyl)amino)phenyl)-3-(trifluoromethyl)benzamide 在 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 49.0h， 生成 tert-butyl 4-(8-methyl-6-(2-methyl-5-(3-(trifluoromethyl)-benzamido)phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidin-2-ylamino)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

  摘要：

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

  DOI：

  10.1021/acs.jmedchem.5b01618

文献信息

• Discovery of 2-((3-Amino-4-methylphenyl)amino)-<i>N</i>-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia
  作者：Xiaofei Liang、Xiaochuan Liu、Beilei Wang、Fengming Zou、Aoli Wang、Shuang Qi、Cheng Chen、Zheng Zhao、Wenchao Wang、Ziping Qi、Fengchao Lv、Zhenquan Hu、Li Wang、Shanchun Zhang、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.5b01618

  日期：2016.3.10

  Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream Mediators such as STATS, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI(50) = 14 nM), KU812 (GI(50) = 25 nM), and MEG-01 (GI(50) = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.