Scheme 1. Synthesis of ADAMTS-4 Off-DNA Hits.

Reagents and conditions: (i) amine (1 equiv), EDCI (1.25 equiv), DMAP (0.2 equiv), CH₂Cl₂, 0 °C – rt; (ii) TFA (50% in CH₂Cl₂), room temperature, 20 min; (iii) amine (1 equiv), CH₃CN/H₂O (1/1), pH 9–10, 0 °C; (iv) amine (R²NH₂ or R³) (1 equiv), CH₃CN/H₂O (1/1), pH 9–10, room temperature overnight; (v) R³ = H: Pd/C, H₂, room temperature 1 h; R³ = OH/HCl (6 N, 10% v/v), CH₃CN/H₂O (1/1), 80 °C overnight; R³ = amines/amine (5–10 equiv), CH₃CN/H₂O (1/1), 80 °C; (vi) amine (1 equiv), DIEA (2.5 equiv), NMP, 0 °C; (vii) amine (5 equiv), NMP, 80 °C for 1 h; (viii) 1 N NaOH, room temperature overnight.