US 5,874,430 A · 4,4-disubstitued-1,4-dihydro-2H-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

Abstract

The present invention relates to benzoxazinones of formula I: ##STR1## or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as an assay standard or reagent, and intermediates and processes for making the same.

A compound of formula (I):

##STR47## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is O or S;
W is N or CR.sup.3 ;
X is N or CR.sup.4 ;
Y is N or CR.sup.5 ;
Z is N or CR.sup.6 ;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
also, provided that if X is CR.sup.4 and R.sup.4 is F, Cl, Br, or I, then:
(a) at least one of W, Y, and Z is other than CH;
(b) R.sup.2 is --OCHR.sup.7 R.sup.8 or --NHCHR.sup.7 R.sup.8 ;
(c) if R.sup.2 is --C.tbd.C--R.sup.8, then R.sup.8 is C.sub.3-7 cycloalkyl substituted with 1 R.sup.9 ;
or
(d) any combination of (a), (b), and (c);
R.sup.1 is selected from CF.sub.3, CF.sub.2 H, C.sub.2 F.sub.5, C.sub.1-4 alkyl, C.sub.3-5 cycloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl;
R.sup.2 is selected from --QCHR.sup.7 R.sup.8, --QCHR.sup.7 C.tbd.C--R.sup.8, --QCHR.sup.7 C.dbd.C--R.sup.8, --Q(CH.sub.2).sub.p CHR.sup.7 R.sup.8, --C.tbd.C--R.sub.8, --CH.dbd.CR.sup.7 R.sup.8, --(CH.sub.2).sub.p CHR.sup.7 R.sup.8, --CHR.sup.7 C.tbd.C--R.sup.8, --CHR.sup.7 CH.dbd.CHR.sup.8, and CH.dbd.CHCHR.sup.7 R.sub.8 ;
provided that when R.sup.1 is C.sub.1-4 alkyl, then R.sup.2 is --C.tbd.C--R.sup.8 ;
provided that when R.sup.2 is --(CH.sub.2).sub.p CHR.sup.7 R.sup.8 and R.sup.8 is H or C.sub.1-6 alkyl, then R.sup.1 is other than cycloalkyl:
R.sup.3 is selected from H, F, Cl, Br, I, C.sub.1-3 alkoxy, and C.sub.1-3 alkyl;
R.sup.4 is selected from H, F, Cl, Br, I, C.sub.1-3 alkyl substituted with 0-3 R.sup.11, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, C.sub.1-3 alkoxy, OCF.sub.3, --CN, NO.sub.2, CHO, C(O)CH.sub.3, C(O)CF.sub.3, C(O)NH.sub.2, C(O)NHCH.sub.3, NR.sup.7 R.sup.7a, NR.sup.7 C(O)OR.sup.7a, C(O)OR.sup.7, S(O).sub.p R.sup.7, SO.sub.2 NHR.sup.7, NR.sup.7 SO.sub.2 R.sup.7b, phenyl substituted with 0-2 R.sup.10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R.sup.10 ;
alternatively, R.sup.3 and R.sup.4 together form --OCH.sub.2 O--;
R.sup.5 is selected from H, F, Cl, Br, and I;
alternatively, R.sup.4 and R.sup.5 together form --OCH.sub.2 O--or a fused benzo ring;
R.sup.6 is selected from H, OH, C.sub.1-3 alkoxy, --CN, F, Cl, Br, I, NO.sub.2, CF.sub.3, CHO, C.sub.1-3 alkyl, and C(O)NH.sub.2 ;
R.sup.7 is selected from H and C.sub.1-3 alkyl;
R.sup.7a is selected from H and C.sub.1-3 alkyl;
R.sup.7b is C.sub.1-3 alkyl;
R.sup.8 is selected from H, C.sub.1-6 alkyl substituted with 0-3 R.sup.11, CH(--OCH.sub.2 CH.sub.2 O--), C.sub.2-6 alkenyl, C.sub.3-7 cycloalkyl substituted with 0-2 R.sup.9, phenyl substituted with 0-2 R.sup.10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R.sup.10 ;
R.sup.9 is selected from .sup.2 H, OH, C.sub.1-3 alkoxy, C.sub.1-3 alkyl, and F;
R.sup.10 is selected from OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, F, Cl, Br, I, CN, NR.sup.7 R.sup.7a, and C(O)CH.sub.3 ;
R.sup.11 is selected from OR.sup.7, CN, F, Cl, Br, I, NO.sub.2, NR.sup.7 R.sup.7a, CHO, C(O)CH.sub.3, C(O)NH.sub.2 ;
Q is selected from O, S and NH;
and,
p is selected from 0, 1, and 2.

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4,4-disubstitued-1,4-dihydro-2H-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

Life of this patent

4,4-disubstitued-1,4-dihydro-2H-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

Life of this patent

Abstract

Claims22