7-tert-butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-3H-quinazolin-4-one | 1147530-73-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7-tert-butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-3H-quinazolin-4-one
• 英文别名: 7-tert-Butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3H-quinazolin-4-one；7-tert-butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]quinazolin-4-one
• CAS: 1147530-73-1
• 化学式: C₂₅H₃₁BN₂O₃
• 分子量: 418.344
• InChiKey: XJLPPYQFPMAXDG-UHFFFAOYSA-N

物化性质

• 沸点：
  565.4±60.0 °C(Predicted)
• 密度：
  1.09±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.29
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  51.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-chloro-2-methyl-4-[5-(morpholine-4-carbonyl)pyridin-2-ylamino]-2H-pyridazin-3-one 、 7-tert-butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-3H-quinazolin-4-one 在 盐酸 、 四(三苯基膦)钯 、 sodium cyanoborohydride 、 sodium carbonate 作用下， 以 甲醇 、 乙二醇二甲醚 、 水 为溶剂， 反应 0.96h， 生成 7-tert-butyl-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridin-2-ylamino]-6-oxo-1,6-dihydropyridazin-3-yl}phenyl)-2,3-dihydro-1H-quinazolin-4-one
  参考文献：
  名称：

  Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis

  摘要：

  Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.

  DOI：

  10.1021/jm500305p
• 作为产物：
  描述：

  3-氨基-2-甲基苯硼酸频哪醇酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 41.5h， 生成 7-tert-butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-3H-quinazolin-4-one
  参考文献：
  名称：

  Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis

  摘要：

  Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.

  DOI：

  10.1021/jm500305p

文献信息

• BTK protein kinase inhibitors
  申请人：Dewdney Nolan James

  公开号：US20090105209A1

  公开（公告）日：2009-04-23

  This application discloses pyridine and pyrimidine compounds according to formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 1 and A are as described herein which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions containing compounds of formula I and at least one carrier, diluent or excipient.

  这个申请公开了根据公式I的吡啶和嘧啶化合物，其中R1、R2、R3、R4、R5、X1和A如本文所述，可抑制Btk。所公开的化合物有助于调节Btk的活性，并治疗与Btk活性过度相关的疾病。这些化合物进一步用于治疗与异常B细胞增殖相关的炎症和自身免疫疾病，如类风湿性关节炎。还公开了包含公式I化合物和至少一种载体、稀释剂或助剂的组合物。
• Inhibitors of Bruton's Tyrosine Kinase
  申请人：Dewdney Nolan James

  公开号：US20090318448A1

  公开（公告）日：2009-12-24

  This application discloses 5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one derivatives according to generic Formulae I-IV: wherein, variables R, X, Y 1 , Y 2 , Y 2 , Y 3 , Y 4 , n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions comprising compounds of Formulae I-IV and at least one carrier, diluent or excipient.

  本申请揭示了根据通用式I-IV制备的5-苯基-1H-吡啶-2-酮和6-苯基-2H-吡啶并[3,4-d]嘧啶-3-酮衍生物，其中变量R、X、Y1、Y2、Y2、Y3、Y4、n和m的定义如本文所述，这些衍生物能够抑制Btk。本文所披露的化合物有助于调节Btk的活性，并治疗与过度Btk活性相关的疾病。这些化合物还有助于治疗与异常B细胞增殖相关的炎症和自身免疫性疾病，例如类风湿性关节炎。此外，还披露了包含通用式I-IV化合物和至少一种载体、稀释剂或赋形剂的组合物。
• Inhibitors of bruton's tyrosine kinase
  申请人：Roche Palo Alto

  公开号：US07902194B2

  公开（公告）日：2011-03-08

  This application discloses 5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one derivatives according to generic Formulae I-IV: wherein, variables R, X, Y1, Y2, Y2, Y3, Y4, n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions comprising compounds of Formulae I-IV and at least one carrier, diluent or excipient.

  本申请公开了根据通用式I-IV公式披露的5-苯基-1H-吡啶-2-酮和6-苯基-2H-吡啶嗪-3-酮衍生物，其中变量R、X、Y1、Y2、Y2、Y3、Y4、n和m的定义如本文所述，其抑制Btk。本文所披露的化合物有助于调节Btk的活性并治疗与过度Btk活性相关的疾病。这些化合物进一步有助于治疗与异常B细胞增殖相关的炎症和自身免疫性疾病，例如类风湿性关节炎。还披露了包含通式I-IV化合物和至少一种载体、稀释剂或赋形剂的组合物。
• INHIBITORS OF BRUTON'S TYROSINE KINASE
  申请人：Roche Palo Alto LLC

  公开号：US20140194413A1

  公开（公告）日：2014-07-10

  This application discloses 5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one derivatives according to generic Formulae I-IV: wherein, variables R, X, Y 1 , Y 2 , Y 2′ , Y 3 , Y 4 , n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions comprising compounds of Formulae I-IV and at least one carrier, diluent or excipient.

  本申请公开了根据通用式I-IV所述的5-苯基-1H-吡啶-2-酮和6-苯基-2H-吡嗪-3-酮衍生物：其中，变量R、X、Y1、Y2、Y2'、Y3、Y4、n和m的定义如本文所述，这些衍生物抑制Btk。本文所披露的化合物有用于调节Btk活性并治疗与过度Btk活性相关的疾病。这些化合物进一步有助于治疗与异常B细胞增殖相关的炎症和自身免疫性疾病，如类风湿性关节炎。还公开了包含通用式I-IV化合物和至少一种载体、稀释剂或赋形剂的组合物。
• Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis
  作者：Yan Lou、Xiaochun Han、Andreas Kuglstatter、Rama K. Kondru、Zachary K. Sweeney、Michael Soth、Joel McIntosh、Renee Litman、Judy Suh、Buelent Kocer、Dana Davis、Jaehyeon Park、Sandra Frauchiger、Nolan Dewdney、Hasim Zecic、Joshua P. Taygerly、Keshab Sarma、Junbae Hong、Ronald J. Hill、Tobias Gabriel、David M. Goldstein、Timothy D. Owens

  DOI：10.1021/jm500305p

  日期：2015.1.8

  Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.