Macrocylic inhibitors of hepatitis C virus

1. A compound of formula (I):

an N-oxide, pharmaceutically acceptable salt, or stereoisomer thereof, wherein

each dashed line (represented by - - - ), represents an optional double bond;

X is N, CH and where X bears a double bond it is C;

R 1 is —OR 7 or —NH—SO 2 R 8 ;

R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl;

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

R 4 is aryl or Het;

n is 3, 4, 5, or 6;

R 5 is halo, C 1-6 alkyl, hydroxy, polyhaloC 1-6 alkyl, phenyl, or Het;

R 6 is C 1-6 alkoxy or dimethylamino;

R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or Het;

R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or Het;

aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents that is halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylcarbonyl, amino, mono- or di-C 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonylpiperazinyl, or morpholinyl; wherein the morpholinyl and piperidinyl groups are optionally substituted with one or with two C 1-6 alkyl radicals;

Het as a group or part of a group is a 5- or 6-membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from the group consisting of nitrogen, oxygen and sulfur, said heterocyclic ring being optionally connected with a benzene ring; and wherein said Het as a whole is optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl,

C 1-6 alkylcarbonyl, amino, mono- or di-C 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonylpiperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups are optionally substituted with one or with two C 1-6 alkyl radicals.

2. The compound according to claim 1 , wherein the compound has the formula (I-c), (I-d), or (I-e):

3. The compound according to claim 1 , wherein R 4 is phenyl, pyridin-4-yl,

wherein R 4a is hydrogen, halo, C 1-6 alkyl, amino, or mono- or di-C 1-6 alkylamino.

4. The compound according to claim 1 , wherein R 5 is methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or bromo; and R 6 is methoxy.

5. The compound according to claim 1 , wherein

R 1 is —OR 7 , wherein R 7 is C 1-6 alkyl or hydrogen.

6. The compound according to claim 1 , wherein

R 1 is —NHS(═O) 2 R 8 , wherein R 8 is methyl, cyclopropyl, or phenyl.

7. The compound according to claim 1 , wherein

R 1 is —NHS(═O) 2 R 8 , wherein R 8 is cyclopropyl substituted with methyl.

8. The compound according to claim 1 , wherein n is 4 or 5.

9. The compound according to claim 1 , wherein n is 4.

10. The compound according to claim 1 , wherein R 3 is hydrogen or C 1-6 alkyl.

11. The compound according to claim 10 , wherein R 3 , is hydrogen or methyl.

12. The compound according to claim 1 , wherein R 4 is

wherein, when possible, a nitrogen optionally bears an R 4a substituent or a link to the remainder of the molecule; and each R 4a in any of the R 4 substituents is Het.

13. The compound according to claim 1 , wherein R 4 is:

wherein each R 4a is hydrogen, halo, C 1-6 alkyl, amino, or mono- or di-C 1-6 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or 4-C 1-6 alkylpiperazinyl; and wherein the morpholinyl and piperidinyl groups are optionally substituted with one or two C 1-6 alkyl radicals.

14. The compound according to claim 13 , wherein in radicals (q-1), (q-2), (q-3), or (q-4), each R 4a is independently hydrogen, halo, C 1-6 alkyl, amino, or mono- or di-C 1-6 alkylamino.

15. The compound according to claim 1 , wherein R 6 is methoxy.

16. The compound according to claim 1 wherein the compound of formula (I) is:

17. The compound according to claim 16 , wherein R 2 is hydrogen and a double bond is present between carbon atoms 7 and 8.

18. The compound according to claim 1 wherein the compound of formula (I) is:

19. The compound according to claim 1 wherein the compound of formula (I) is:

20. The compound according to claim 1 wherein the compound of formula (I) is:

21. The compound according to claim 1 other than an N-oxide, or salt.

22. The compound according to claim 1 other than an N-oxide.

23. A combination comprising

(a) a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof; and

(b) ritonavir, or a pharmaceutically acceptable salt thereof.

24. A combination comprising

(a) a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof; and

(b) interferon-α, pegylated interferon-α, and/or ribavirin.

25. A pharmaceutical composition comprising a carrier, and as active ingredient, an anti-virally effective amount of a compound as claimed in claim 1 .

26. A pharmaceutical composition comprising a carrier, and as active ingredient, an anti-virally effective amount of a combination according to claim 23 or claim 24 .

27. A method of inhibiting HCV replication comprising administering to a patient in need thereof, a compound according to claim 1 .

28. A method of inhibiting HCV replication comprising administering to a patient in need thereof, a combination according to claim 23 or 24 .

29. A process for preparing a compound according to claim 1 comprising:

(a) preparing a compound of formula (I) wherein the bond between C 7 and C 9 is a double bond, which is a compound of formula (I-i), by forming a double bond between C 7 and C 8 with concomitant cyclization to the macrocycle as outlined in the following reaction scheme:

wherein in the above and following reaction schemes R 9 is:

(b) converting the compound of formula (I-i) to a compound, of formula (I-j) wherein the link between C7 and C8 in the macrocycle is a single bond:

by reducing the C7-C8 double bond in the compound of formula (I-j);

(c) preparing a compound of formula (I) wherein R 1 is —NHSO 2 R 8 , said compounds represented by formula (I-k-1), by forming an amide bond between an intermediate (2a) and an sulfonylamine (2b), or preparing a compound of formula (I) wherein R 1 represents —OR 7 , said compounds represented by formula (I-k-2), by forming an ester bond between an intermediate (2a) and an alcohol (2c) as outlined in the following scheme wherein G represents a group:

(d) preparing a compound of formula (I) wherein R 3 is hydrogen, said compound represented by (I-1), from a corresponding nitrogen-protected intermediate (3a), wherein PG represents a nitrogen protecting group:

(e) reacting an intermediate (4a) with intermediate (4b) as outlined in the following reaction scheme:

wherein Y in (4b) represents hydroxy or a leaving group; and where Y represents hydroxy the reaction of (4a) with (4b) is a Mitsunobu reaction; and where Y represents a leaving group the reaction of (4a) with (4b) is a substitution reaction;

(f) converting compounds of formula (I) into each other by a functional group transformation reaction; or

(g) preparing a salt form by reacting the free form of a compound of formula (I) with an acid or a base.

30. The process of claim 29 , wherein the formation of the double bond between C 7 and C 8 with concomitant cyclization to the macrocycle of step (a) is via an olefin metathesis reaction.