N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine | 1236670-88-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶唑类
• 英文名称: N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine
• 英文别名: 5-[[5-Methyl-2-[[3-(methylsulfonyl)phenyl]amino]-4-pyrimidinyl]amino]-2(3H)-benzoxazolone；5-[[5-methyl-2-(3-methylsulfonylanilino)pyrimidin-4-yl]amino]-3H-1,3-benzoxazol-2-one
• CAS: 1236670-88-4
• 化学式: C₁₉H₁₇N₅O₄S
• 分子量: 411.441
• InChiKey: MEPRAIGNNALDJA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  131
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  5-硝基-3H-1,3-苯并恶唑-2-酮 在 palladium 10% on activated carbon 、 氢气 、 碳酸氢钠 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 水 、 异丙醇 为溶剂， 35.0~100.0 ℃ 、275.8 kPa 条件下， 反应 2.0h， 生成 N4-(benzo[d]oxazol-2(3H)-on-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine
  参考文献：
  名称：

  作为有效 JAK1 抑制剂的嘧啶化合物的优化以及作为临床候选药物的 R507 的发现

  摘要：

  Janus 激酶 (JAK) 在介导免疫反应和细胞生长的 JAK/信号转导器和转录激活剂 (STAT) 信号通路中发挥着关键作用。从高通量筛选 (HTS) 命中到先导化合物优化，一系列嘧啶化合物被发现是有效的 JAK1 抑制剂，其选择性优于 JAK2。基于细胞的测定被用作评估效力和选择性的主要筛选方法，结果通过先导分子的生化和其他细胞测定进一步评估和确认。还讨论了 NADPH 存在下三氟甲基与 CYP3A4 抑制之间的独特相关性，NADPH 的活性随着氟原子的减少而成功降低，IC 50从 0.5 μM 增加至 >10 μM。开发新型且可扩展的氨基苯基中间体合成路线对于发现后期先导分子（包括临床候选药物 R507）至关重要 ( 33 )。在临床前研究中，33通过抑制 IL-2 诱导的 IFNγ 表达在小鼠研究中以及在大鼠胶原诱导的关节炎疾病模型中表现出巨大的功效。

  DOI：

  10.1021/acsmedchemlett.2c00411

文献信息

• Compounds and method for treating autoimmune diseases
  申请人：Rigel Pharmaceuticals, Inc.

  公开号：US10414758B2

  公开（公告）日：2019-09-17

  Compounds and embodiments of a method for treating and/or preventing autoimmune diseases are disclosed. The method includes administering to a subject having an autoimmune disease, such as an inflammatory bowel disease, a therapeutically effective amount of a compound according to formula I wherein X and Y independently are O or NR1; each R1 is independently H or C1-C6 alkyl; ring A is aryl; each R2 independently is H, alkyl, alkoxy, amide, cyano, halo, haloalkyl, hydroxyalkyl, heteroalkyl, heterocyclyl, sulfonyl, sulfonamide, or two R2 groups, taken together with the atom or atoms to which they are attached, combine to form a 4-10 membered ring system; p is 0, 1, 2, 3, or 4; R3 and R4 independently are H or C1-C6 alkyl; and R5 is halo, cyano, or C1-C6 alkyl.

  本发明公开了用于治疗和/或预防自身免疫性疾病的化合物和方法的实施方案。该方法包括向患有自身免疫性疾病（如炎症性肠病）的受试者施用治疗有效量的符合式 I 的化合物 其中X和Y独立地为O或NR1；每个R1独立地为H或C1-C6烷基；环A为芳基；每个R2独立地为H、烷基、烷氧基、酰胺、氰基、卤代、卤代烷基、羟基烷基、杂烷基、杂环烷基、磺酰基、磺酰胺，或两个R2基团与其所连接的原子结合形成4-10个成员的环系统；p 为 0、1、2、3 或 4；R3 和 R4 独立地为 H 或 C1-C6 烷基；R5 为卤代、氰基或 C1-C6 烷基。
• COMPOUNDS AND METHOD FOR TREATING AUTOIMMUNE DISEASES
  申请人：Rigel Pharmaceuticals, Inc.

  公开号：US20140213555A1

  公开（公告）日：2014-07-31

  Compounds and embodiments of a method for treating and/or preventing autoimmune diseases are disclosed. The method includes administering to a subject having an autoimmune disease, such as an inflammatory bowel disease, a therapeutically effective amount of a compound according to formula I wherein X and Y independently are O or NR 1 ; each R 1 is independently H or C 1 -C 6 alkyl; ring A is aryl; each R 2 independently is H, alkyl, alkoxy, amide, cyano, halo, haloalkyl, hydroxyalkyl, heteroalkyl, heterocyclyl, sulfonyl, sulfonamide, or two R 2 groups, taken together with the atom or atoms to which they are attached, combine to form a 4-10 membered ring system; p is 0, 1, 2, 3, or 4; R 3 and R 4 independently are H or C 1 -C 6 alkyl; and R 5 is halo, cyano, or C 1 -C 6 alkyl.
• US9890144B2
  申请人：——

  公开号：US9890144B2

  公开（公告）日：2018-02-13
• [EN] COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY BOWEL DISEASES<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR TRAITER DES SYNDROMES ABDOMINAUX INFLAMMATOIRES
  申请人：RIGEL PHARMACEUTICALS INC

  公开号：WO2014116973A1

  公开（公告）日：2014-07-31

  Compounds and embodiments of a method for treating and/or preventing autoimmune diseases are disclosed. The method includes administering to a subject having an autoimmune disease, such as an inflammatory bowel disease, a therapeutically effective amount of a compound according to formula I wherein X and Y independently are O or NR1; each R1 is independently H or C1-C6 alkyl; ring A is aryl; each R2 independently is H, alkyl, alkoxy, amide, cyano, halo, haloalkyl, hydroxyalkyl, heteroalkyl, heterocyclyl, sulfonyl, sulfonamide, or two R2 groups, taken together with the atom or atoms to which they are attached, combine to form a 4-10 membered ring system; p is 0, 1, 2, 3, or 4; R3 and R4 independently are H or C1-C6 alkyl; and R5 is halo, cyano, or C1-C6 alkyl.
• [EN] A COMBINATION FOR IMMUNE MEDIATED CANCER TREATMENT<br/>[FR] COMBINAISON À MÉDIATION IMMUNITAIRE POUR LE TRAITEMENT DU CANCER
  申请人：RIGEL PHARMACEUTICALS INC

  公开号：WO2017007658A1

  公开（公告）日：2017-01-12

  Disclosed embodiments concern a combination comprising a JAK inhibitor and an immunooncology agent. The immunooncology agent may comprise an anti-PD- 1 antibody, anti- PD-L1 antibody, PI3K inhibitor, indole dioxygenase inhibitor or a combination thereof. The JAK inhibitor may be a pyrimidin-2-amine, 2,4-pyrimidinediamine, or a combination thereof. Also disclosed are embodiments of a method for using the combination to treat a subject, particularly a subject having a cell proliferative disorder. The method may further comprise administering one or more therapeutic agents in addition to the JAK inhibitor and immunooncology agent. Kits comprising the combination are also disclosed.