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Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.

Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structure–activity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC50 = 12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme.

This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration.

In addition to the total synthesis of the thiomethyl thiazole side chain analogue of epothilone B ( 3 ), a series of related trans -12,13-cyclopropyl epothilone B analogues ( 6 , 8 , 10 , 12 – 14 ) was accomplished. While the synthesis of the epothilone B analogue ( 3 ) proceeded through a Stille coupling of a vinyl iodide substrate containing the epothilone macrocycle with the appropriate side chain stannane, that of the cyclopropyl analogues ( 6 , 8 , 10 , 12 – 14 ) involved a convergent strategy in which a Nozaki–Hiyama–Kishi coupling as a means of introducing the side chains prior to Yamaguchi macrolactonization and final elaboration to the target molecules. The synthesized analogues were subjected to biological evaluation involving in vitro tubulin polymerization, affinity for the microtubule Taxol ® binding site and cell cytotoxicity assays. The results identified the methylthio thiazole side chain as a potency enhancing moiety for the epothilones and shed further light on the structure–activity relationships within this important class of chemotherapeutic agents.

A safe, practical, and scalable continuous flow protocol for the in situ generation of dimethylamine from DMF followed by nucleophilic aromatic substitution of a broad range of aromatic and heteroaromatic halides is reported.

In addition to the total synthesis of the thiomethyl thiazole side chain analogue of epothilone B ( 3 ), a series of related trans -12,13-cyclopropyl epothilone B analogues ( 6 , 8 , 10 , 12 – 14 ) was accomplished. While the synthesis of the epothilone B analogue ( 3 ) proceeded through a Stille coupling of a vinyl iodide substrate containing the epothilone macrocycle with the appropriate side chain stannane, that of the cyclopropyl analogues ( 6 , 8 , 10 , 12 – 14 ) involved a convergent strategy in which a Nozaki–Hiyama–Kishi coupling as a means of introducing the side chains prior to Yamaguchi macrolactonization and final elaboration to the target molecules. The synthesized analogues were subjected to biological evaluation involving in vitro tubulin polymerization, affinity for the microtubule Taxol ® binding site and cell cytotoxicity assays. The results identified the methylthio thiazole side chain as a potency enhancing moiety for the epothilones and shed further light on the structure–activity relationships within this important class of chemotherapeutic agents.