The structures of the set of pyrazoles of are contained

The structures of the set of pyrazoles of are contained in the supplied with this manuscript. Acknowledgments
Prostaglandin D (PGD) is known to bind with high affinity to two G protein-coupled seven-transmembrane receptors DP1 and DP2. The latter receptor, also known as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), is responsible for the chemoattractant effects of PGD on eosinophils, basophils and Th2-cells., The receptor also induces eosinophils shape change and degranulation, the production of proinflammatory cytokines in Th2 cells, and enhances the release of histamine from basophils. The combined pharmacological action of such biological events plays a key role in late phase allergic inflammation. CRTH2 is thus pursued as a target for respiratory diseases such as TAPI-1 and COPD. We recently reported the identification of a potent and selective CRTH2 antagonist (). As Phase I clinical trials were in progress, our main focus was to develop a potential backup for MK-7246 which would have an improved off-target activity profile. Our lead compound had a propensity to undergo moderate covalent binding on hepatic cells and showed micromolar activity on CYP2C9. Consequently, efforts in a new series were undertaken. One of the preferred approaches was to synthesize close analogs of the lead compound where the indole core would be replaced by an azaindole. This Letter reports the synthesis of all four possible regioisomers () as well as their structure–activity relationship. In view of increasing structural diversity of the newly born series and potentially avoiding allergic-reaction-type adverse effects related to the sulfonamide moiety, an amido-azaindole series was also explored and is reported. The original lengthy synthesis of MK-7246 proved to be incompatible with azaindoles as starting material. The key Dieckmann condensation could not be applied to that system and as a result a new synthetic route was devised. Efforts in other series had led to the development of a new route taking advantage of the multi-nucleophilic nature of the indole (). The use of an electrophilic aziridine bearing all of the carbons necessary for the construction of the carbocycle as well as the stereogenic center required in the final product, dramatically reduced the synthetic efforts needed to pursue SAR in that series. The number of linear steps fell from 18 to only eight steps. The synthesis of the aziridine () started with -aspartic acid as chiral building block. Methylation of the carboxylic acids followed by the introduction of the required sulfonamide yields the diester . The diester was then reduced to reveal diol which underwent selective intramolecular Mitsunobu reaction with the vicinal sulfonamide. The resulting alcohol bearing aziridine could then be protected with a TBS group and used for rapid construction of our inhibitors. The synthesis began with the addition of the aziridine onto the azaindole core with sodium hydride in DMF. Simple synthetic transformations then allowed the formation of an electrophilic aldehyde (). Although, this aldehyde was known to cyclize in high yield to generate the corresponding tricyclic compound with the indole core, the same reactivity was not observed with all azaindole regioisomers. Indeed, most regioisomers cyclized with low yields except 7-azaindoles and (). The 4-azaindole failed to condense under normal reaction condition (PPTS, toluene, reflux). Only when the solvent was switched to NMP, a low yield cyclization was observed. 4-Azaindole and 6-azaindole cyclizations failed in all conditions attempted. Cyclization was observed in low yield only when a chlorine substituent was incorporated onto the azaindole core (i.e., and . Next, the reduction of the condensation double bond and the carbon–chlorine bonds was investigated (for condensation products of compounds and ). Condensation product of compound was singularly hydrogenated using Monsanto catalyst to avoid dehalogenation of chlorine.