Pyrazolopyridine inhibitors of B-RafV600E. Part 3: An increase in aqueous

solubility via the disruption of crystal packing

S. Wenglowsky et al. / Bioorg. Med. Chem. Lett. 22 (2012) 912–915

吡唑嘧啶类化合物1,2 的缺点在于溶解性偏低，结晶表明形成head-to-tail的双聚体，为破坏晶体堆积能，需要引入大基团取代破坏堆积，降低熔点，从而提高溶解度logS = 0.5 - 0.01(MP - 25) – logP。得到高溶解度的化合物6,8