N-(4-methyl-3-(1-methyl-2-oxo-7-(phenylamino)-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(trifluoromethyl)benzamide | 839708-13-3

• 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: N-(4-methyl-3-(1-methyl-2-oxo-7-(phenylamino)-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(trifluoromethyl)benzamide
• 英文别名: GNF-8；N-(4-Methyl-3-(1-methyl-2-oxo-7-(phenylamino)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide；N-[3-(7-anilino-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide
• CAS: 839708-13-3
• 化学式: C₂₈H₂₃F₃N₆O₂
• 分子量: 532.525
• InChiKey: JWXZQEPPXRGVKZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  90.5
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,4-二氯-5-(氯甲基)嘧啶 在 tris-(dibenzylideneacetone)dipalladium(0) 、 铁粉 、 potassium carbonate 、 氯化铵 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium iodide 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 丙酮 、 仲丁醇 为溶剂， 反应 16.5h， 生成 N-(4-methyl-3-(1-methyl-2-oxo-7-(phenylamino)-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia

  摘要：

  GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound lli is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.

  DOI：

  10.1021/acs.jmedchem.8b00882

文献信息

• A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl
  作者：Hwan Geun Choi、Pingda Ren、Francisco Adrian、Fangxian Sun、Hyun Soo Lee、Xia Wang、Qiang Ding、Guobao Zhang、Yongping Xie、Jianming Zhang、Yi Liu、Tove Tuntland、Markus Warmuth、Paul W. Manley、Jürgen Mestan、Nathanael S. Gray、Taebo Sim

  DOI：10.1021/jm901808w

  日期：2010.8.12

  The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I “gatekeeper” mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant

  为克服伊马替尼耐药而开发的第二代 Bcr-Abl 抑制剂尼罗替尼、达沙替尼和博舒替尼对 T315I“看门人”突变没有活性。在这里，我们描述了一种 II 型 T315I 抑制剂2 ( GNF - 7 )，基于 3,4-二氢嘧啶并[4,5- d ]嘧啶-2(1 H )-一个支架，能够有效抑制野生型和 T315I Bcr-Abl 以及其他临床相关的 Bcr-Abl 突变体，如 G250E、Q252H、Y253H、E255K、E255V、F317L 和 M351T，用于生化和细胞检测。此外，化合物2使用具有稳定荧光素酶表达的转化 T315I-Bcr-Abl-Ba/F3 细胞系，在生物发光异种移植小鼠模型中显示出针对 T315I-Bcr-Abl 的显着体内功效，而没有明显的毒性。化合物2是第一批能够抑制T315I的II型抑制剂之一，将作为设计第三代Bcr-Abl激酶抑制剂的重要线索。
• THERAPEUTIC AGENT OF ACUTE MYELOID LEUKEMIA CONTAINING 1,3,7-TRISUBSTITUTED 3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDINE-2(1H)-ONE DERIVATIVES
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US20180065969A1

  公开（公告）日：2018-03-08

  The present invention provides a therapeutic agent of acute myeloid leukemia containing a 1,3,7-trisubstituted 3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one compound as an active ingredient, which has proliferation inhibitory activity for a human acute myeloid leukemia cell line OCI-AML3 having a NRAS mutant gene while having low inhibitory activity for wild type NRAS and has activity of inhibiting GCK and ACK1 protein kinases at the same time.

  本发明提供了一种急性髓样白血病的治疗剂，含有1,3,7-三取代3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮化合物作为活性成分，对携带NRAS突变基因的人类急性髓样白血病细胞系OCI-AML3具有增殖抑制活性，同时对野生型NRAS的抑制活性较低，并具有同时抑制GCK和ACK1蛋白激酶的活性。
• Compounds and compositions as protein kinase inhibitors
  申请人：Sim Taebo

  公开号：US20050222177A1

  公开（公告）日：2005-10-06

  The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, BCR-Abl, Bmx, c-Raf, Csk, Fes, FGFR, Flt3, Ikk, IR, JNK, Lck, Mkk, PKC, PKD, Rsk, SAPK, Syk, Trk, BTK, Src, EGFR, IGF, Mek, Ros and Tie2 kinases.

  本发明提供了一类新型化合物，包括这些化合物的药物组合物和使用这些化合物治疗或预防与异常或非调节激酶活性相关的疾病或紊乱，尤其是涉及Abl，BCR-Abl，Bmx，c-Raf，Csk，Fes，FGFR，Flt3，Ikk，IR，JNK，Lck，Mkk，PKC，PKD，Rsk，SAPK，Syk，Trk，BTK，Src，EGFR，IGF，Mek，Ros和Tie2激酶异常激活的疾病或紊乱的方法。
• COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
  申请人：Sim Taebo

  公开号：US20080221098A1

  公开（公告）日：2008-09-11

  The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, BCR-Abl, Bmx, c-Raf, Csk, Fes, FGFR, Flt3, Ikk, IR, JNK, Lck, Mkk, PKC, PKD, Rsk, SAPK, Syk, Trk, BTK, Src, EGFR, IGF, Mek, Ros and Tie2 kinases.

  本发明提供了一类新型化合物，包括这些化合物的药物组合物以及使用这些化合物治疗或预防与异常或非调控激酶活性相关的疾病或疾病的方法，特别是涉及Abl、BCR-Abl、Bmx、c-Raf、Csk、Fes、FGFR、Flt3、Ikk、IR、JNK、Lck、Mkk、PKC、PKD、Rsk、SAPK、Syk、Trk、BTK、Src、EGFR、IGF、Mek、Ros和Tie2激酶异常活化的疾病或疾病。
• Therapeutic agent of acute myeloid leukemia containing 1,3,7-trisubstituted 3,4-dihydropyrimido[4,5-D]pyrimidine-2(1H)-one derivatives
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US10155767B2

  公开（公告）日：2018-12-18

  The present invention provides a therapeutic agent of acute myeloid leukemia containing a 1,3,7-trisubstituted 3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one compound as an active ingredient, which has proliferation inhibitory activity for a human acute myeloid leukemia cell line OCI-AML3 having a NRAS mutant gene while having low inhibitory activity for wild type NRAS and has activity of inhibiting GCK and ACK1 protein kinases at the same time.

  本发明提供了一种急性髓性白血病治疗剂，其活性成分为1,3,7-三取代的3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮化合物、它对具有 NRAS 突变基因的人类急性髓性白血病细胞系 OCI-AML3 具有增殖抑制活性，而对野生型 NRAS 的抑制活性较低，并同时具有抑制 GCK 和 ACK1 蛋白激酶的活性。