RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [Aversa, Biaryl amide compounds as kinase inhibitors and their preparation. WO 2014151616, 2014], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.

中文翻译：

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设计和的发现ñ - （2-甲基-5'-吗啉代-6' - （（四氢-2- ħ -2H-吡喃-4-基）氧基） - [3,3'-联吡啶] -5-基）-3- -（三氟甲基）苯甲酰胺（RAF709）：针对RAS突变癌的有效，选择性和有效的RAF抑制剂。

RAS致癌基因已涉及超过30％的人类癌症，均代表高度未满足的医疗需求。在基因工程小鼠模型和人类肿瘤细胞中已经建立了对KRAS突变肿瘤中对CRAF激酶的精确依赖性。迄今为止，许多针对CRAF的小分子方法正在研究中，但是激酶选择性抑制剂和细胞有效抑制剂的鉴定仍然具有挑战性。在此，我们描述14（RAF709）[Aversa，联芳酰胺化合物作为激酶抑制剂及其制备方法。WO 2014151616， [2014]，一种选择性的B / C RAF抑制剂，通过假设驱动的方法开发，该方法侧重于药物样特性。在药物化学研究中遇到的一个关键挑战是在KRAS突变肿瘤细胞系中保持良好的溶解度和有效的细胞活性（pMEK的抑制和增殖）之间的平衡。我们研究了铅分子7的小分子晶体结构，并假设破坏晶体堆积会提高溶解度，从而导致从N-甲基吡啶酮转变为四氢吡喃基氧基-吡啶衍生物。在KRAS突变异种移植模型中，有14种被证明是可溶的，激酶选择性的和有效的。