N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine | 1428336-01-9

• 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: N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
• 英文别名: N-[(4-methoxyphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
• CAS: 1428336-01-9
• 化学式: C₁₉H₂₅BN₂O₃
• 分子量: 340.23
• InChiKey: QEELMHOMTXOSJR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.0
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  52.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 、 6-bromo-N-(2-morpholinobenzo[d]oxazol-6-yl)picolinamide 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium carbonate 、 三氟乙酸 作用下， 以 水 、 乙腈 为溶剂， 以5%的产率得到6-(6-aminopyridin-3-yl)-N-(2-morpholin-4-yl-1,3-benzoxazol-6-yl)pyridine-2-carboxamide
  参考文献：
  名称：

  [EN] BICYCLIC HETEROCYCLES AS IRAK4 INHIBITORS
  [FR] HÉTÉROCYCLES BICYCLIQUES CONVENANT COMME INHIBITEURS DE L'IRAK4

  摘要：

  本发明提供了公式（I）的双环杂环化酶抑制剂化合物，可能在治疗中作为激酶抑制剂具有治疗作用，更具体地是IRAK4抑制剂。其中 A、R、R1、R2、m、n 和 p 的含义如规范中所给出，并且其在治疗和预防疾病或紊乱方面是有用的，特别是在需要抑制激酶酶有优势的疾病或紊乱中，更具体地是IRAK4酶的使用。本发明还提供了包含至少一种公式（I）的激酶抑制剂化合物的药物配方，以及其与药用载体、稀释剂或赋形剂一起使用。

  公开号：

  WO2013042137A1

文献信息

• Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies
  作者：Venkateshwar Rao Gummadi、Anima Boruah、Bharathi Raja Ainan、Brahma Reddy Vare、Srinivas Manda、Hari Prakash Gondle、Shiva Nagendra Kumar、Subhendu Mukherjee、Suraj T. Gore、Narasimha Rao Krishnamurthy、Sivapriya Marappan、Shilpa S. Nayak、Kavitha Nellore、Wesley Roy Balasubramanian、Archana Bhumireddy、Sanjeev Giri、Sreevalsam Gopinath、Dodheri S. Samiulla、Girish Daginakatte、Aravind Basavaraju、Shekar Chelur、Rajesh Eswarappa、Charamanna Belliappa、Hosahalli S. Subramanya、Robert N. Booher、Murali Ramachandra、Susanta Samajdar

  DOI：10.1021/acsmedchemlett.0c00255

  日期：2020.12.10

  Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.