2-(3-amino-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide | 1808288-52-9

• 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: 2-(3-amino-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide
• 英文别名: 2-[(3-Amino-4-methylphenyl)amino]-N-[5-[(1,3-benzodioxol-5-ylcarbonyl)amino]-2-methylphenyl]-4-(methylamino)-5-pyrimidinecarboxamide；2-(3-amino-4-methylanilino)-N-[5-(1,3-benzodioxole-5-carbonylamino)-2-methylphenyl]-4-(methylamino)pyrimidine-5-carboxamide
• CAS: 1808288-52-9
• 化学式: C₂₈H₂₇N₇O₄
• 分子量: 525.567
• InChiKey: QAOAHNZKSXUBSE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  153
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-(3-amino-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide 、 丙烯酰氯 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以70%的产率得到2-(3-acrylamido-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide
  参考文献：
  名称：

  Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chromosome (BMX) Kinase Inhibitor

  摘要：

  BMX is a member of TEC family nonreceptor tyrosine kinase and is involved in a variety of critical physiological and pathological processes. Through combination of irreversible inhibitor design and type II inhibitor design approaches, we have discovered a highly selective and potent type II irreversible BMX kinase inhibitor compound 41 (CHMFL-BMX-078), which exhibited an IC50 of 11 nM by formation of a covalent bond with cysteine 496 residue in the DFG-out inactive conformation of BMX. It displayed a high selectivity profile (S score(1) = 0.01) against the 468 kinases/mutants in the KINOMEscan evaluation and achieved at least 40-fold selectivity over BTK kinase. Given the fact that BMX mediated signaling pathway is still not fully understood, compound 41 would serve as a useful pharmacological tool to elucidate the detailed mechanism of BMX mediated signaling pathways.

  DOI：

  10.1021/acs.jmedchem.6b01413
• 作为产物：
  描述：

  (3-氨基-4-甲基苯基)-氨基甲酸叔丁酯 在 盐酸 、 tin(II) chloride dihdyrate 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 62.0h， 生成 2-(3-amino-4-methylphenylamino)-N-(5-(benzo[d][1,3]dioxole-5-carboxamido)-2-methylphenyl)-4-(methylamino)pyrimidine-5-carboxamide
  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

• [EN] NOVEL BCR-ABL KINASE INHIBITOR<br/>[FR] NOUVEL INHIBITEUR DE KINASE BCR-ABL<br/>[ZH] 一种新型的BCR-ABL激酶抑制剂
  申请人：[en]HEFEI INSTITUTES OF PHYSICAL SCIENCE, CHINESE ACADEMY OF SCIENCES;[zh]中国科学院合肥物质科学研究院

  公开号：WO2016165205A1

  公开（公告）日：2016-10-20

  本发明公开了一种BCR-ABL激酶抑制剂，其包括式I的化合物或其药学上可接受的盐，溶剂化物、酯、酸、代谢物或前药，其中R1、R2、R3、R4、R5、R6如说明书所定义。本发明还公开了包括式I化合物的药物组合物及本发明化合物在制备用于治疗由BCR-ABL激酶活化介导的病症的药物中的用途。