br Conclusions br Acknowledgments This work was financially

Conclusions
Acknowledgments This work was financially supported partly by Shanghai Pujiang Talent Project (No.: 08PJ14017), the National Natural Science Foundation of China (Nos.: 20771029 and 91013001) and Shanghai Leading Academic Discipline Project (No. B108).
Soluble guanylate cyclase (sGC) is the only proven receptor for the ubiquitous biological messenger nitric oxide (NO). Stimulation of the enzyme by NO facilitates the conversion of guanosine-5′-triphosphate (GTP) to the intracellular second messenger cyclic guanosine-3′,5′-monophosphate (cGMP), which regulates various cGMP-specific effector systems such as PDEs, ion channels, and protein kinases. Thus, the NO/cGMP pathway is important in many physiological processes including vasodilatation, neurotransmission, and platelet aggregation. Since the emergence of sGC as a therapeutic target for cardiovascular and pulmonary disease, two AZD8186 of molecules have been developed: NO-independent but heme-dependent sGC stimulators and NO- and heme-independent sGC activators., The first reported direct stimulator of sGC is YC-1, followed by the discovery of more potent compounds such as BAY 41-8543 and the advanced clinical candidate riociguat (BAY 63-2521) by Bayer (). Riociguat is currently in phase III clinical trials for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). These compounds have a dual mode of action: they sensitize sGC to the body’s own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. It is postulated that they bind to an allosteric binding site within the catalytic domain and stabilize the nitrosyl-haem complex to keep sGC in its active conformation. To further improve physicochemical and pharmacokinetic properties, we envisaged to synthesize weakly acidic compounds instead of weakly basic aminopyrimidine congeners. A similar approach was published recently by Roberts et al. (Pfizer, example 25), yielding acidic triazoles. As a starting point we reinvestigated the acidic tetrazole congener (), which has been reported earlier. Tetrazole was found to have an excellent physicochemical and DMPK profile (), but its potency was insufficient. Thus, we synthesized a series of other heterocyclic carboxylic acid isosteres, with the aim to improve potency (), while maintaining the favorable physico chemical and pharmacokinetic profile. Compounds , , and were synthesized from the intermediate , which was built up in four linear steps () in analogy to our work on 7-azaindoles. 2-Fluoropyridine () was converted to the pyrazolopyridine in two steps. Upon lithiation at the 3-position it reacted with ethyl trifluoroacetate to give the corresponding trifluoroketone. Subsequent reaction with hydrazine hydrate provided . The trifluoromethyl group in pyrazolopyridine was anionically activated and underwent aminolysis via a methine intermediate and thus furnished nitrile . Regioselective benzylation in the presence of cesium carbonate gave intermediate . The nitrile was elaborated further to hydroxyamidine . Treating with 1,1′-thiocarbonyldiimidazole (TCDI) under either basic (DBU) or acidic (boron trifluoride etherate) conditions yielded 1,2,4-oxadiazol-5-thione and 1,2,4-thiadiazol-5-one , respectively. Upon treatment with 2-ethylhexyl carbonochloridate followed by cyclization in refluxing xylenes, was converted into the 1,2,4-oxadiazol-5-one . Starting from key intermediate , which has been described earlier,, compounds – were synthesized as outlined in . The ester was converted to hydrazide upon treatment with hydrazine hydrate. Cyclization with 1,1′-carbonyldiimidazole provided 1,3,4-oxadiazol-2-one . Further elaboration of hydrazide to the DMB-protected 1,2,4-triazole-3-one was performed via reaction with 2,4-dimethoxybenzyl isocyanate followed by alkaline cyclization. N-Alkylation and acidic deprotection yielded the target 1,2,4-triazole-3-ones , , and . In case of compound the alkylation step was omitted.