Compunds and methods for treating HIV
Inhibitors of HIV-1 protease and compositions containing them are described. Use of the inhibitors and compositions containing them to treat HIV, AIDS, and AIDS-related diseases is described.
1. A compound of the formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
A is a group of the formula
wherein (*) indicates the point of attachment; and wherein
one of Y 1 and Y 2 is methylene, and the other of Y 1 and Y 2 is oxygen; and R h represents one or more optional substituents, each of which is independently selected in each instance from hydrogen, hydroxy, alkylamino, cycloalkylamino, arylalkylamino, alkoxy, cycloalkoxy, cycloalkylalkoxy, and arylalkoxy, each of which is itself optionally substituted;
Q is oxygen;
W is oxygen or sulfur;
R 1 is hydrogen;
X is C(R a R b ) n , where n is 1, 2, or 3, and each of R a and R b is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
m is an integer selected from 0, 1, 2 or 3;
R 2 is optionally substituted aryl;
R 3 is hydrogen;
R 4 is optionally substituted alkyl;
Z is S(O) 2 ; and
R 5 is optionally substituted benzothiazole.
2. The compound or salt of claim 1 wherein R 2 is phenyl substituted with one or more methoxy, hydroxymethyl, fluoro or 2-(morpholino)ethoxy groups.
3. The compound or salt of claim 1 wherein R 4 is 2-fluoro-2-methylpropyl.
4. The compound or salt of claim 1 wherein R 5 is
wherein (*) indicates the point of attachment; in which X 5 is S; and R Y is (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl or NHR X or NR X R Z and each of R X and R Z is independently methyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, cyclohexyl, 4-piperidinyl or 1-cyclopentylpiperidin-4-yl, or the group NR X R Z is optionally substituted pyrrolidino, piperidino or piperazino.
5. The compound or salt of claim 4 wherein R Y is NHR X ; and R X is isopropyl or cyclopropyl.
6. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
A is a group of the formula
wherein a is 1; and R A is hydrogen, hydroxy, amino, OR B , or NHR B in which R B is alkyl, alkylcarbonyl, alkylsulfonyl or heteroalkyl or is optionally substituted benzyl or is an optionally substituted 5- or 6-membered aryl or heteroaryl;
R 2 is phenyl substituted with one or more methoxy, isopropoxy, hydroxymethyl, methoxymethyl, methoxyethyl, fluoro or 2-(morpholino)ethoxy groups;
R 4 is isobutyl or 2-fluoro-2-methylpropyl; and
R 5 is a group of the formula
in which X 5 is S; and R Y is (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl or NHR X or NR X R Z and each of R X and R Z is independently methyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, cyclohexyl, 4-piperidinyl or 1-cyclopentylpiperidin-4-yl, or the group NR X R Z is optionally substituted pyrrolidino, piperidino or piperazino;
or R 2 is phenyl and R 4 is 2-fluoro-2-methylpropyl;
or R 2 is phenyl and R A is not hydrogen.
7. The compound or salt of claim 6 wherein R 2 is 3-methoxyphenyl, 4-methoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 3-hydroxymethylphenyl, 3-hydroxymethylphenyl, 3-methoxymethylphenyl, 4-methoxymethylphenyl, 3-methoxyethylphenyl, 4-methoxyethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-[2-(morpholino)ethoxy]phenyl, or 4-[2-(morpholino)ethoxy]phenyl.
8. The compound or salt of claim 6 wherein R B is methyl, ethyl or isopropyl.
9. The compound or salt of claim 6 wherein R 4 is 2-fluoro-2-methylpropyl.
10. The compound or salt of claim 6 wherein R 5 is
in which X 5 is S; and R Y is NHR X or NR X R Z and each of R X and R Z is isopropyl or cyclopropyl or the group NR X R Z is optionally substituted pyrrolidino, piperidino or piperazino.
11. The compound or salt of claim 1 wherein R 5 is
in which X 5 is S; and R Y is NHR X ; and R X is isopropyl or cyclopropyl.
12. A pharmaceutical composition comprising one or more compounds of claim 1 and one or more carriers, diluents, or excipients, or a combination thereof.
13. A method for treating a patient in need of relief from an HIV infection, the method comprising the step of administering to a patient in need of relief from the HIV infection a therapeutically effective amount of one or more compounds of claim 1 .
14. A pharmaceutical composition comprising one or more compounds of claim 6 and one or more carriers, diluents, or excipients, or a combination thereof.
15. A method for treating a patient in need of relief from an HIV infection, the method comprising the step of administering to a patient in need of relief from the HIV infection a therapeutically effective amount of one or more compounds of claim 6 .