Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group

Abstract

A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.

Keywords: HIV; MK-8718; inhibitor; protease.

Figure 1

Pyrrolidine based inhibitor 1 and proposed morpholine based inhibitor 2.

Scheme 1

Reagents and conditions: (a) (i) Ph₃P=CHCHO, THF, 50 °C; (ii) Pd/C, 30 psi H₂, EtOAc, RT; (b) BnNH₂, NaBH₄, THF/MeOH, RT; (ii) Pd/C, 50 psi H₂, MeOH, RT; (c) NaHCO₃, THF/H₂O, 0 °C; (d) TFA, Et₃SiH, CH₂Cl₂, RT.

Figure 2

Overlay of the enzyme bound conformations of 2 (green) and 8 (magenta). The flaps have been cut away for optimum viewing. The 5-position is marked with an *.

Scheme 2

Reagents and conditions: (a) (R)-epichlorohydrin, LiClO₄, NaOMe, toluene/MeOH, RT; (b) (i) Pd(OH)₂, Boc₂O, NEt₃, 45 psi H₂, RT; (ii) oxalyl chloride, NEt₃, DMSO, CH₂Cl₂, −78 °C; (c) (i) K₂CO₃, 18-crown-6, (2-nitrobenzyl)triphenylphosphonium bromide, DME, RT; (ii) Pd/C, 50 psi H₂, EtOH, RT; (d) (S)-2-((methoxycarbonyl)amino)-3,3-diphenylpropanoic acid, HATU, 2,6-lutidine, DMF, RT; (e) TBAF, THF, RT; (f) (i) benzylisocyanate, DCM, RT; (ii) TFA, DCM, 0 °C.

Scheme 3

Reagents and conditions: (a) K₂CO₃, 18-crown-6, (2-fluoro-6-nitrobenzyl)triphenylphosphonium bromide, DME, RT; (b) HCl, MeOH, RT; (c) (i) 2,2,2-trifluoroethylamine, CDI, pyridine, RT; (ii) Pd(OH)₂, 50 psi H₂, CF₃CH₂OH, RT.

Scheme 4

Reagents and conditions: (a) dimethyl (1-diazo-2-oxopropyl)phosphonate, K₂CO₃, MeOH, RT; (b) (i) 5-fluoro-4-iodopyridin-3-amine, 7% (PPh₃)₂PdCl₂, 10% CuI, Et₃N, CH₃CN, 70 °C; (ii) 50% PtO₂, 50 psi H₂, CF₃CF₂OH, RT; (c) (i) Cbz-Cl, pyridine, 0 °C; (ii) TBAF, THF, RT; (d) (i) 2,2,2-trifluoroethylamine, CDI, pyridine, 60 °C; (ii) Pd/C, 1 atm H₂, EtOH, RT.

Scheme 5

Reagents and conditions: (a) ⁿBuLi, (S)-4-phenyloxazolidin-2-one, THF, −78 °C; (b) (3-Fluorophenyl)magnesium bromide, CuBr.SMe₂, THF, −20 °C; (c) NaHMDS, trisyl azide, THF, −78 °C; (d) H₂O₂, LiOH, NaHCO₃, THF/H₂O, 0 °C.

Scheme 6

Reagents and conditions: (a) ⁿBuLi, (R)-4-phenyloxazolidin-2-one, THF, −78 °C; (b) (4-fluoro or chlorophenyl)magnesium bromide, CuBr·SMe₂, THF, −20 °C; (c) H₂O₂, LiOH, NaHCO₃, THF/H₂O, 0 °C; (d) SOCl₂, CH₂Cl₂, reflux; (d) ⁿBuLi, (S)-4-phenyloxazolidin-2-one, THF, −78 °C; (d) NaHMDS, trisyl azide, THF, −78 °C; (d) H₂O₂, LiOH, NaHCO₃, THF/H₂O, 0 °C.

Scheme 7

Reagents and conditions: (a) (i) (S)-2-((methoxycarbonyl)amino)-3,3-diphenylpropa-noic acid or (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropanoic acid, POCl₃, pyridine, 0 °C; (ii) 4 M HCl, dioxane, RT; (b) (i) 30, 39, or 40, POCl₃, pyridine, 0 °C; (ii) Pd/C, 1 atm H₂, MeOH, RT, or PPh₃, THF/H₂O, reflux; (iii) 4 M HCl, dioxane, RT.