Substituted pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidines as HIV integrase inhibitors
The present invention is directed to a class of substituted pyrido[1′2′:4,5]pyrazino[1,2-a]-pyrimidines useful as intermediates in the production of anti-HIV agents. The compounds have the formula (I-24b): wherein R e is one or two halogen; R z is C 1-8 alkyl; R z is hydrogen, C 3-6 cycloalkyl, heterocyclyl, or C 1-8 alkyl optionally substituted with hydroxy, C 3-6 cycloalkyl, alkoxy, heterocyclyl, heteroaryl, C 6-14 aryl, or amino, wherein said amino may be optionally substituted with —C(O)C 1-8 alkyl or C 1-8 alkyl; and P 1 is C 6-14 arylC 1-8 alkyl; or a pharmaceutically acceptable salt thereof.
1. A compound of formula (I-24b)
wherein:
R e is one or two halogen;
R z is C 1-8 alkyl;
R z1 is hydrogen, C 3-6 cycloalkyl, heterocyclyl, or C 1-8 alkyl optionally substituted with hydroxy, C 3-6 cycloalkyl, alkoxy, heterocyclyl, heteroaryl, C 6-14 aryl, or amino, wherein said amino may be optionally substituted with —C(O)C 1-8 alkyl or C 1-8 alkyl; and
P 1 is C 6-14 arylC 1-8 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R e is one or two fluorine.
3. The compound of claim 1 , wherein R z is methyl.
4. The compound of claim 1 , wherein R z1 is C 3-6 cycloalkyl.
5. The compound of claim 1 , wherein R z1 is C 3 cycloalkyl.
6. A compound which is:
7. A process for the preparation of a compound of formula (I-24b)
wherein
R e is one or two halogen;
R z is C 1-8 alkyl;
R z1 is hydrogen, C 3-6 cycloalkyl, heterocyclyl, or C 1-8 alkyl optionally substituted with hydroxy, C 3-6 cycloalkyl, alkoxy, heterocyclyl, heteroaryl, C 6-14 aryl, or amino, wherein said amino may be optionally substituted with —C(O)C 1-8 alkyl or C 1-8 alkyl; and
P 1 is C 6-14 arylC 1-8 alkyl;
comprising condensing a compound of the formula
wherein R e is one or two halogen;
R 50 is C 1-8 alkyl; and
P 1 is C 6-14 arylC 1-8 alkyl;
with a compound of the formula
wherein
R z is C 1-8 alkyl;
R z1 is hydrogen, C 3-6 cycloalkyl, heterocyclyl, or C 1-8 alkyl optionally substituted with hydroxy, C 3-6 cycloalkyl, alkoxy, heterocyclyl, heteroaryl, C 6-14 aryl, or amino, wherein said amino may be optionally substituted with —C(O)C 1-8 alkyl or C 1-8 alkyl; to form a compound of the formula (I-24b).
8. The process of claim 7 , further comprising a step of replacing the C 6-14 arylC 1-8 alkyl of P 1 with hydrogen.