We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.

中文翻译：

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新型的转化生长因子-βI型受体激酶域的芳基和杂芳基取代的5,6-二氢-4H-吡咯并[1,2-b]吡唑抑制剂的合成及活性。

我们已经扩展了我们先前报道的一系列基于TGF-βI型受体激酶域（TbetaR-I）的吡唑类抑制剂，现在包括新的5,6-二氢-4H-吡咯并[1,2-b]吡唑类似物。在基于酶和细胞的体外分析中对这一新系列的SAR进行了有限的检查，结果表明，取决于二氢吡咯并吡唑环上“战斗部”基团的性质，p38 MAP激酶（p38 MAPK）的选择性差异。与我们最初的吡唑系列一样，与取代基喹啉-4-基组成的取代基相比，取代基趋于对p38 MAPK表现出更大的选择性。我们还实现了化合物3和15的共结晶和X射线分析，这是该新系列的两个有效实例，具有TbetaR-1受体激酶域。