Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines

Abstract

A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 μM concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUC of 5.2 μM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.

Keywords: Cancer; PI3K inhibitors; indazole; morpholinotriazine.

Figure 1

PI3Kα IC₅₀ of identified hit 3, compared to literature leads 1 and 2.

Scheme 1

Reagents and conditions: (a) morpholine, acetone/water (4:1), 0 °C, 3 h; (b) amino acid/ester, acetone/NaHCO₃ aq. (1:1), RT, 16 h; (c) aryl borate, Pd(PPh₃)₄, Na₂CO₃, DME/water (4:1), 120 °C, 20 min, MW.

Scheme 2

Reagents and conditions: (b) glycine amide, acetone/NaHCO₃ (aq.) (1:1), RT, 16 h; (c) aryl borate, Pd(PPh₃)₄, Na₂CO₃, DME/water (4:1), 120 °C, 20 min, MW.

Scheme 3

Reagents and conditions: (d) benzyl mercaptan, DIPEA, morpholine, THF, 0 °C, 5 h; (e) aryl borate, Pd(PPh₃)₄, Na₂CO₃, DME/water (4:1), 90 °C, 18 h; (f) oxone, THF/water (1:1), 0 °C–RT, 25 h; (g) RX, DMF, K₂CO₃, RT, 24 h; (h) methanesulfonic acid, methanol/water (2:1), 55 °C, 1 h.

Figure 2

Effect of 26 on mice bodyweight when dosed at 30mpk BID oral for 5 days.