A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC₅₀ value of 0.013 μM in a kinase assay and with IC₅₀ values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (C_max) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.

中文翻译：

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N-（（4-（[1,2,4] triazolo [1,5-a] pyridin-6-yl）-5-（6-methylpyridin-2-yl）-1H-咪唑-2-yl的发现）甲基）-2-氟苯胺（EW-7197）：作为癌症免疫治疗/抗纤维化剂的TGF-βI型受体激酶的高效，选择性和口服生物利用度抑制剂。

合成了一系列2-取代的4-（[1,2,4]三唑并[1,5 - a ]吡啶-6-基）-5-（6-甲基吡啶-2-基）咪唑并对其进行了评估以优化TGF-βI型受体激酶（ALK5）的原型抑制剂，6。更换的喹喔啉-6-基结构部分的组合6与[1,2,4]三唑并[1,5一]吡啶-6-基部分，亚甲基氨基接头的插入，并且一个ö -F取代基在苯环显着提高了ALK5抑制活性，激酶选择性和口服生物利用度。的12B（EW-7197）抑制ALK5与IC ₅₀在激酶测定，并与IC 0.013μM的值₅₀在萤光素酶测定中，HaCaT（3TP-luc）稳定细胞和4T1（3TP-luc）稳定细胞中的0.0165和0.0121μM的值分别为 使用一组320种蛋白激酶对12b进行选择性分析，结果表明它是一种高度选择性的ALK5 / ALK4抑制剂。在大鼠中用12b ·HCl进行的药代动力学研究显示，口服生物利用度为51％，高全身暴露（AUC）为1426 ng×h / mL，最大血浆浓度（C _max）为1620 ng / mL。6的合理优化导致鉴定出高效，选择性和口服生物利用度高的ALK5抑制剂12b。