Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries

Abstract

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.

Figure 1

(A) Synthesis of 2-cyano azetidines from β-amino alcohols and (B) representative CNS-active agents containing phenylethylamine motif.

Figure 2

Representative library members synthesized for in vitro analysis.

Figure 3

Multi-fusion similarity (MFS) map, ECFP_4 fingerprints (Test set = azetidine scaffolds and derivatives (n = 64), Reference set = CNS drugs (n = 70).

Figure 4

CNS MPO score for the Spirocyclic Azetidine library members (n = 1976). were plotted from low to high CNS MPO score along the x-axis.

Scheme 1

Synthesis of azetidine-based templates 5a–d

Scheme 2

Synthesis of Azetidine Scaffolds 8, 10 and 12

Scheme 3

Synthesis of Spirocyclic Azetidine Scaffold 15

Scheme 4

Synthesis of Scaffolds 24 and 25

Scheme 5

Solid-phase library synthesis on SynPhase Lanterns