The monomeric building blocks 1 and 2a-e were prepared according to our previously published protocol. Subsequently, the designed tripyrimidonamides 5a-d were synthesized using a modular approach. Briefly, a COMU-mediated amide coupling of the lithium carboxylate 2e with 5-aminopyrimidone 1 afforded the benzoyl-protected dimer 3 in 75% yield. Deprotection of the benzoylgroup by treatment of 3 with sodium hydroxide in methanol at 80 °C afforded the unprotected dimer 4 (77% yield). Additional coupling reactions of 4 with the respective lithium salts 2a-d in the presence of COMU furnished the tripyrimidonamides 5a-d in 39-76% yield. Compound 6 with an N-unsubstituted N-terminal pyrimidone ring was synthesized by treating the corresponding 4-methoxybenzyl-substituted derivative 5b with BBr 3 in DCM (Scheme 1). Finally, the trispyrimidonamides 7a and 7b with free phenolic groups were prepared by catalytic hydrogenation of their respective O-benzyl-protected precursors 5c and 5d (40 and 87% yield). shown in surface and cartoon representation. For one of the Hsp90 monomers, the Nterminal domain (NTD) is colored in red, the middle domain in beige, and the C-terminal domain (CTD) in blue. Above and below the protein structure, the structures of Hsp90i and their potential binding sites (see ref.