Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H -pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.

中文翻译：

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发现1-（4-甲氧基苯基）-7-氧代-6-（4-（2-氧代哌啶-1-基）苯基）-4,5,6,7-四氢-1H-吡唑并[3,4-c ] pyridine-3-carboxamide（apixaban，BMS-562247），一种高度有效，选择性，有效和口服可利用的凝血因子Xa抑制剂。

确定对razaxaban（化合物4）合适的后续化合物的工作集中在修饰羧酰胺基接头上，以消除潜在的体内水解为伯胺的能力。羧酰胺连接子环化到新型的双环四氢吡唑并吡啶并酮支架上保留了有效的fXa结合活性。该系列药物的出色功效促使人们对中性P1部分进行了研究，从而鉴定了对甲氧基苯基P1，该对甲氧基苯基P1保留了Xa因子的结合亲和力和良好的口服生物利用度。C-3吡唑位置的进一步优化和中性杂环取代末端P4环的最终结果是发现了1-（4-甲氧基苯基）-7-氧代-6-（4-（2-氧代哌啶-1-基） ）苯基）-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-甲酰胺（阿哌沙班，化合物40）。