Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1.

布鲁顿酪氨酸激酶（Btk）是Tec激酶家族的成员，在造血谱系细胞（例如B细胞，巨噬细胞，单核细胞和肥大细胞）中表达。靶向ATP结合口袋中的Cys481的小分子共价不可逆Btk抑制剂已用于治疗B细胞恶性肿瘤。从一个片段开始，我们发现了一系列新的有效的共价不可逆Btk抑制剂，这些抑制剂带有N-连接基团，这些基团占据Btk激酶域活性位点的溶剂可及口袋（SAP）。但是，在Caco-2分析中，命中分子显示出高P-gp介导的流出比（ER）和不良的AB渗透性。通过降低tPSA，安装位阻并调节clogP，一个最重要的分子9被发现，与命中分子1相比，它的流出率降低了99％，AB渗透率提高了90倍。