Scheme 1. Synthetic Route for Compound 4a and its Derivatives^a.

^aReagents and conditions: (a) R₁O₂CCl, NaOH, H₂O, rt, 5 h, or (Boc)₂O, K₂CO₃, THF/H₂O, rt, 7 h; (b) (i) ClCO₂Et, NEt₃, rt, 12 h, (ii) n-BuLi, i-Pr₂NH, THF, –78 °C, 1 h, MeI, THF, 5 h; (c) (i) 2 M NaOH, (ii) CDI, THF, 4 h, KO₂CCH₂CO₂Et, MgCl₂, DMAP, THF/CH₃CN, overnight; (d) (i) DCM, microwave, 100 °C, (ii) N₂H₄·HCl, H₂O, EtOH, 80 °C, 8 h; (e₁) AcOH, reflux, 120 °C, overnight; (e₂) EtOH, TFA, reflux, 85 °C, 48 h; (f) TFA, DCM, 0 °C, 2 h; (g) DMF, HOBt, HBTU, DIPEA, rt, overnight.