Macrocylic inhibitors of hepatitis C virus

1. A compound of the formula I:

and N-oxides, salts, and stereoisomers thereof

wherein

A is OR 1 , NHS(═O) p R 2 ; wherein;

R 1 is hydrogen, C 1 -C 6 alkyl, C 0 -C 3 alkylenecarbocyclyl, C 0 -C 3 alkyleneheterocyclyl;

R 2 is C 1 -C 6 alkyl, C 0 -C 3 alkylenecarbocyclyl, C 0 -C 3 alkyleneheterocyclyl;

p is independently 1 or 2;

n is 3, 4, 5 or 6;

denotes an optional double bond;

L is N or CRz;

Rz is H or forms a double bond with the asterisked carbon;

Rq is H or when L is CRz, Rq can also be C 1 -C 6 alkyl;

Rr is quinazolinyl, optionally substituted with one two or three substituents each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, halo, haloC 1 -C 6 alkyl, amino, mono- or dialkylamino, mono- or dialkylaminocarbonyl, C 1 -C 6 alkylcarbonylamino, C 0 -C 3 alkylenecarbocyclyl and C 0 -C 3 alkyleneheterocyclyl;

R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;

and wherein

each C 1 -C 6 alkyl, C 0 -C 3 alkylenecarbocycyl or C 0 -C 3 alkyleneheterocyclyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C 1 -C 6 alkyl, C 0 -C 3 alkylenecarbocyclyl, C 0 -C 3 alkyleneheterocyclyl, NH 2 C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHS(═O p )Rb, Y—S(═O) p Rb and Y—S(═O) p NRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb;

Y is independently a bond or C 1 -C 3 alkylene;

Ra is independently H, C 1 -C 6 alkoxy, C 1 -C 3 alkyl or;

Rb is independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 0 -C 3 alkylenecarbocyclyl or C 0 -C 3 alkyleneheterocyclyl;

or Ra and Rb together with the nitrogen to which they are attached join to form a heterocyclyl group.

2. A compound according to claim 1 , with the partial structure:

3. A compound according to claim 1 , wherein n is 4 or 5.

4. A compound according to claim 3 , wherein adjacent the cyclopropyl moiety is a double bond.

5. A compound according to claim 1 wherein R 5 is hydrogen or methyl.

6. A compound according to claim 1 , wherein A is —OH or —NHS(═O) 2 -cyclopropyl.

7. A compound according to claim 1 , wherein A is NHS(═O) 2 —C 1 -C 6 alkyl substituted cyclopropyl.

8. A compound according to claim 1 , with the formula:

where n, A, L, Rq and R 5 are as defined in claim 1 , and

R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 0 -C 3 alkylenecarbocyclyl, C 0 -C 3 alkylene-heterocyclyl, hydroxy, bromo, chloro or fluoro;

R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NRaRb, C 0 -C 3 alkylenecarbocyclyl, C 0 -C 3 alkyleneheterocyclyl; wherein said R 9 carbocyclyl or heterocyclyl is optionally substituted with R 10 ;

R 10 is C 1 -C 6 alkyl, C 0 -C 3 alkylenecycloalkyl, C 0 -C 3 alkyleneheterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkyl, amino, amido, azido, mercapto, cyano, sulfonyl, (C 1 -C 3 alkyl)sulfonyl, nitro, hydroxy, carboxy, mercapto, halo, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkyloxy;

Ra and Rb are as defined in claim 1 ;

R 11 is hydrogen or C 1 -C 6 alkoxy.

9. A compound according to claim 8 , wherein R 6 is C 1 -C 3 alkyl, chloro or fluoro, preferably bromo or hydrogen.

10. A compound according to claim 8 , wherein R 11 is hydrogen or methoxy.

11. A compound according to claim 8 , wherein R 9 is phenyl or heteroaryl, either being optionally substituted with one or two R 10 ; wherein

R 10 hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocyclyl, C 1 -C 6 alkoxy, halo, amino optionally mono- or di-substituted with C 1 -C 6 alkyl, or amido optionally mono- or di substituted with C 1 -C 6 alkyl.

12. A compound according to claim 11 , wherein R 9 is phenyl, pyridyl, thiazolyl, oxazolyl or pyrazolyl each of which is optionally substituted with R 10 as defined.

13. A compound according to claim 12 , wherein R 10 is hydrogen, fluoro, difluoro, methyl, ethyl, isopropyl, tert-butyl, C 1 -C 6 alkoxy, amino, mono- or diC 1 -C 6 alkylamino pyrrolidinyl, piperinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, or mono- or di-C 1 -C 6 alkylamido.

14. A compound according to claim 13 , wherein R 10 is hydrogen, fluoro or methoxy.

15. A compound according to claim 12 , wherein R 9 is selected from

16. A compound according to claim 12 , wherein it R 9 is selected from:

17. A compound having the formula

18. A compound having the formula:

19. A compound having the formula:

20. A compound having the formula:

21. A compound having the formula:

22. A compound having the formula:

23. A compound having the formula:

24. A compound having the formula:

25. A pharmaceutical composition comprising a compound according to claim 20 , and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition according to claim 25 , further comprising an additional HCV antiviral, selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin and interferon.

27. A method for treatment of HCV infection comprising the administration of an effective amount of a compound according to any one of claims 1 - 24 to an individual in need thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 - 24 , and a pharmaceutically acceptable carrier.