Background: Nowadays, in course of the drug design and discovery much attention is paid to the physicochemical parameters of a drug candidate, in addition to their biological activity. Disadvantageous physicochemical parameters can hinder the success of a drug candidate.

Objective: Lovering et al. introduced the Fsp3 character as a measure of carbon bond saturation, which is related to the physicochemical paramethers of the drug. The pharmaceutical research focuses on the synthesis of compounds with high Fsp3 character.

Methods: To improve the physicochemical properties (clogP, solubility, more advantageous ADME profile, etc.) of drug-candidate molecules one possibility is the replacement of all-carbon aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen atom containing systems, such as pyridines and pyridazines, etc. The other option is to increase the Fsp3 character of the drug candidates. Both of these aspects were considered in the design the new spiro[cycloalkanepyridazinones], the synthesis of which is described in the present study.

Results: Starting from 2-oxaspiro[4.5]decane-1,3-dione or 2-oxaspiro[4.4]nonane-1,3-dione, the corresponding ketocarboxylic acids were obtained by Friedel-Crafts reaction with anisole or veratrole. The ketocarboxylic acids were treated by hydrazine, methylhydrazine or phenylhydrazine to form the pyridazinone ring. N-Alkylation reaction of the pyridazinones resulted in the formation of further derivatives with high Fsp3 character.

Conclusion: A small compound library was obtained incorporating compounds with high Fsp3 characters, which predicts advantageous physico-chemical parameters (LogP, ClogP and TPSA) for potential applications in medicinal chemistry.

背景：如今，在药物设计和发现过程中，除其候选药物的生物活性外，还非常关注候选药物的理化参数。不利的理化参数会阻碍候选药物的成功。

目标：Lovering等。介绍了Fsp3特性作为碳键饱和度的量度，该特性与药物的理化副弹药有关。药物研究集中于合成具有高Fsp3特性的化合物。

方法：为了改善候选药物分子的物理化学性质（clogP，溶解度，更有利的ADME谱等），一种可能性是用生物等排杂芳族部分（例如用一个或两个含氮原子的系统）代替全碳芳族系统例如吡啶和哒嗪等。另一种选择是增加候选药物的Fsp3特性。设计新的螺环化合物时考虑了这两个方面，在本研究中描述了其合成方法。

结果：从2-氧杂螺[4.5]癸烷-1,3-二酮或2-氧杂螺[4.4]壬烷-1,3-二酮开始，通过与苯甲醚或四氢呋喃的Friedel-Crafts反应获得了相应的酮羧酸。用肼，甲基肼或苯肼处理酮羧酸，形成哒嗪酮环。哒嗪酮的N-烷基化反应导致形成具有高Fsp3特征的其他衍生物。

结论：获得了一个小的化合物文库，其中包含具有高Fsp3特征的化合物，它预测了有利的理化参数（LogP，ClogP和TPSA）在药物化学中的潜在应用。