Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2. Tricyclic Pyridobenzoxazepinones and Dibenzoxazepinones

Abstract

Dibenz[b,f][1,4]oxazepin-11(10H)-ones (III), pyrido[2,3-b] [1,4]benzoxazepin-6(5fl)-ones (IV), and pyrido[2,3-b]-[1,5]benzoxazepin-5(6H)-ones (V) were found to inhibit human immunodeficiency virus type 1 reverse transcriptase with IC50 values as low as 19 nM. A-ring substitution has a profound effect on activity, with appropriate substituents at the positions ortho and para to the lactam nitrogen providing dramatically enhanced potency. Substitution in the C-ring is generally neutral or detrimental to activity. Although a C-ring amino substituent at the position meta to the lactam carbonyl is generally beneficial to activity, it has essentially no effect when the A-ring is optimally substituted. Like the dipyridodiazepinone nevirapine, compounds III-V are specific for HIV-1 RT, exhibiting no inhibitory activity against HIV-2 RT or other virial reverse transcriptase enzymes. © 1992, American Chemical Society. All rights reserved.