Quinoxalinones and dihydroquinoxalinones as respiratory syncytial virus antiviral agents
Quinoxalinones and dihydroquinoxalinones having inhibitory activity on RSV replication and having the formula I including addition salts, and stereochemically isomeric forms thereof; compositions containing these compounds as active ingredient and processes for preparing these compounds and compositions.
1. A compound of formula I
or a stereochemically isomeric or tautomeric form thereof wherein:
Y is N or N—R 4 ;
Z 1 is N or C—R 6 ;
Z 2 is N or C—R 3 ;
R 1 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl;
R 2 is —(CR 7 R 8 ) n —R 9 ;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, CF 3 and halogen;
R 4 is selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl;
R 6 is selected from the group consisting of H, halogen, aryl and heteroaryl, wherein each of aryl or heteroaryl is optionally substituted with one or more R 10 ;
R 7 and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl;
n is an integer selected from the range of 1 to 6;
R 9 is selected from the group consisting of H, halogen, SO 2 R 7 , C 1 -C 6 alkyl, CONR 7 R 8 , COOR 7 , OH, CN, F, CFH 2 , CF 2 H and CF 3 ;
R 10 is selected from the group consisting of H, OH, CN, halogen, CFH 2 , CF 2 H, CF 3 , CONR 7 R 8 , COOR 7 and C 1 -C 6 alkyl, wherein each of R 10 is optionally substituted with one or more substituents selected from the group comprising NR 7 R 8 , CF 3 , CH 3 , OCH 3 , OCF 3 , morpholinyl and halogen;
or an addition salt or solvate thereof.
2. A compound according to claim 1 , wherein R 1 is halogen.
3. A compound according to claim 1 , wherein R 2 is —(CR 7 R 8 ) n —R 9 , R 7 and R 8 are each independently hydrogen or CH 3 , n is an integer of 3 or 4, R 9 is selected from the group consisting of halogen, CF 3 and SO 2 R 7 , and R 7 is CH 3 .
4. A compound according to claim 1 , wherein R 6 is selected from the group consisting of H, halogen, phenyl, pyridinyl, thiophenyl, pyrimidinyl, pyrazolyl, pyrrolyl, thiazolyl, each R 6 is optionally substituted with one or more R 10 .
5. A compound according to claim 1 , wherein R 10 is selected from the group consisting of halogen and C 1 -C 3 alkyl, wherein each R 10 is optionally substituted with one or more substituents selected from the group consisting of NR 7 R 8 , CF 3 , morpholinyl and halogen.
6. A compound according to claim 1 , wherein R 6 is selected from the group consisting of phenyl, pyridinyl, thiophenyl, pyrimidinyl, pyrazolyl, pyrrolyl, and thiazolyl, each R 6 is optionally substituted with halogen.
7. A compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl optionally substituted with one or more of F or SO 2 -Me.
8. A compound according to claim 1 , wherein R 4 is cyclopropyl or H.
9. A compound of claim 1 , wherein the compound is selected from the group consisting of:
10. A compound according to claim 1 , wherein R 2 is (CR 7 R 8 ) n —R 9 , R 7 and R 8 are each independently hydrogen or CH 3 , n is an integer of 3 or 4, R 9 is selected from the group consisting of halogen, CF 3 and SO 2 R 7 , and R 7 is H.
11. A compound according to claim 1 , wherein R 3 is halogen.
12. A compound according to claim 1 , wherein R 6 is H.
13. A compound according to claim 1 , wherein R 7 and R 8 are H.
14. A compound according to claim 1 , wherein R 9 is halogen.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a compound of claim 1 .
16. A process for preparing a pharmaceutical composition, said process comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of claim 1 .
17. A method of treating an RSV infection in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
18. A method of inhibiting RSV replication in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .