Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors

Abstract

Protein tyrosine phosphatase SHP2 is an oncogenic protein that can regulate different cytokine receptor and receptor tyrosine kinase signaling pathways. We report here the identification of a novel series of SHP2 allosteric inhibitors having an imidazopyrazine 6,5-fused heterocyclic system as the central scaffold that displays good potency in enzymatic and cellular assays. SAR studies led to the identification of compound 8, a highly potent SHP2 allosteric inhibitor. X-ray studies showed novel stabilizing interactions with respect to known SHP2 inhibitors. Subsequent optimization allowed us to identify analogue 10, which possesses excellent potency and a promising PK profile in rodents.

Figure 1

Examples of known SHP2 allosteric inhibitors are endowed with diverse central cores.

Figure 2

Key pharmacophoric features of the SHP2 allosteric inhibitors. X-ray structure of compound SHP099 bound to SHP2 (PDB: 5EHR).

Figure 3

X-ray determined the 3D structure of 8 bound to SHP2 (PDB: 8B5Y).

Scheme 1. General Synthesis of Imidazopyrazines

Reagents and conditions: (a) CDI, THF, 60 °C, 96 h; (b) TCDI, dioxane, 50 °C, 16 h; (c) 2-(trifluoromethyl) pyridine-3-thiol, Pd₂ (dba)₃, Xantphos, DIPEA, dioxane, 110 °C, 1 h; (d) POCl₃, 110 °C, 10 h; (e) amine, dioxane, 100 °C; (f) TFA, DCM, rt, 1 h; (g) MeI, NaH, DMF, rt, 2 h; (h) m-CPBA, DCM, rt, 3 h; (i) RSH, Pd₂ (dba)₃, Xantphos, DIPEA, dioxane, 100 °C, 4 h; (j) SEMCl, NaH, DMF, 0 °C, 1 h; (k) 2-ethylhexyl 3-mercaptopropanoate, Pd₂ (dba)₃, Xantphos, DIPEA, dioxane, 110 °C, 1 h; (l) RBr, Pd₂ (dba)₃, Xantphos, t BuOK, DIPEA, dioxane, 110 °C, 1 h; (m) TFA, DCM, rt, 1 h; HCl (1.25 M in MeOH), MeOH, rt, 4 h.