Discovery of a Novel Series of Potent SHP2 Allosteric Inhibitors

Abstract

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is the first reported nonreceptor oncogenic tyrosine phosphatase connecting multiple signal transduction cascades and exerting immunoinhibitory function through the PD-1 checkpoint receptor. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives bearing an original bicyclo[3.1.0]hexane basic moiety on the left-hand side region of the molecule were identified. We report herein the discovery process, the in vitro pharmacological profile, and the early developability features of compound 25, one of the most potent members of the series.

Figure 1

Chemical structures of some SHP2 inhibitors.

Figure 2

Imidazopyrazine derivatives.

Figure 3

3D overlay of compound 1 (green) and bicyclo[4.1.0]heptane derivative 5 (gray).

Scheme 1. Synthesis of the Final Compounds

Reagents and conditions: (a) NaH, DMF or DME, 0 °C to r.t., 30 min; (b) NaBH₄, CoCl₂, MeOH, 12 h or BH₃·SMe₂, THF, 50 °C, 3 h, then EtOH, 70 °C, 3 h; (c) benzyl chloroformate, TEA, 0 °C, 30 min or phthalic anhydride, toluene, 100 °C, 8 h; (d) 10% H₂SO₄, 120 °C, 12 h; (e) Boc₂O, THF, r.t., 2 h; (f) BH₃·SMe₂, THF, 50 °C, 3 h, then MeOH, r.t., 30 min; (g) NaH, ZnCl₂, THF, 50 °C; (h) DIAD, PPh₃, PTA, THF, r.t., 1 h; (i) diphenylphosphoryl azide, DIPEA, toluene, benzyl alcohol, 100 °C, 30 min, then 130 °C, 20 h; (j) 4 N HCl in 1,4-dioxane, CH₂Cl₂, r.t., 1.5 h; (k) D, DMSO, DIPEA, 120 °C, 4 h; (l) E, DMSO, DIPEA, 120 °C, 2 h; (m) F, DIPEA, DMF, 120 °C, 12 h; (n) 37% HCl, r.t., 12 h or N₂H₄·H₂O, MeOH, r.t., 18 h; (o) ArB(OH)₂, PdCl₂(dppf), K₃PO₄, 9:1 1,4-dioxane/H₂O, reflux, 1 h.

Figure 4

X-ray crystallographic analysis of 17a and SHP2 (PDB entry 8CBH).

Figure 5

Optimization of the RHS moiety.

Figure 6

Mean plasma concentrations of compound 25 at a dose of 1 mg/kg po in different formulations.