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A mild and regioselective N-alkylation reaction of 2-pyridones in water has been developed. Tween 20 (2% w/ w) was added to create a micellar system for improved solubility of starting materials, which leads to enhanced reaction rates. The protocol demonstrated a wide substrate scope with good isolated yields (40−94%) for all of the 24 examples evaluated. High regioselectivity favoring N-alkylation over O-alkylation was observed for benzyl halides (>5:1), primary alkyl halides (>6:1), and bulky and less reactive secondary alkyl halides (>2.4:1).N-Alkylated 2-pyridones and close analogues are important components both in natural products 1−4 and in many active pharmaceuticals. 5 Due to their ambident nucleophilic nature, regioselective control of N-versus O-alkylation of 2-pyridones has intrigued chemists for over half a century. 6 Even though impressive progress has been made in the development of new methodologies (vide inf ra) to induce regioselectivity for Nalkylated 2-pyridones as well as in the mechanistic understanding of these alkylations, 7 there are no reports of a general and straightforward method on selective N-alkylation of 2-pyridones, especially with bulky secondary alkyl groups.Alkylation has been traditionally performed by treating alkyl halides with metal salts of 2-pyridones, either preformed or formed in situ. 8 The regioselectivity of N-versus O-alkylation depends on a variety of factors including the nature of the metals, the structure of the alkyl halides, substituents on the 2-pyridone ring, solvents, 9 and temperature. Modifications of the reaction conditions have been developed to improve the conversion and regioselectivity of these alkylations.

Structure-activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key compound 22 showed efficacy in a cuprizone-induced demyelination model with twice daily oral administration, thereby supporting CXCR2 to be a potential therapeutic target for the treatment of demyelinating diseases such as multiple sclerosis.

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CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue.