HCV inhibiting macrocyclic phenylcarbamates

1. A compound of the formula (I):

wherein

A is —C(═O)OR 1 , —C(═O)—NH—SO 2 —R 2 , —C(═O)C(═O)NR 3a R 3b , —C(═O)—NH—SO 2 —NR 3a R 3b , —C(═O)NH—P(═O)(OR 4a )(R 4b ), or —P(═O)(OR 4a )(R 4b )

wherein;

R 1 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 with Het;

R 2 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 with Het;

R 3a and R 3b each independently are hydrogen; C 1-6 alkyl optionally substituted with C 1-6 alkoxy, hydroxy, halo, C 3-7 cycloalkyl, aryl, or with Het; aryl; C 2-6 alkenyl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or R 3a and R 3b together with the nitrogen atom to which they are attached form a group Het 1 ; and R 3a may also be C 1-6 alkoxy;

R 4a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, aryl, or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl or aryl;

R 4b is R 4b′ , OR 4b′ or NHR 4b′ ;

R 4b′ is C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, aryl, or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl or with aryl;

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

E is NR 5 , or when X is N then E is NR 5 or CR 6a R 6b ;

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

R 6a and R 6b are independently hydrogen or C 1-6 alkyl, or R 6a and R 6b together with the carbon atom to which they are attached form C 3-7 cycloalkyl;

n is 3, 4, 5 or 6;

each dotted line - - - independently represents an optional double bond;

R 7 is hydrogen, or where X is C or CH, R 7 may also be C 1-6 alkyl;

R 8 is a radical of formula

R 8a and R 9a each independently are hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy, halo, polyhaloC 1-6 alkyl, cyano, amino, mono- or C 1-6 dialkylamino;

each R 9 independently is C 1-6 alkyl optionally substituted with C 1-6 alkoxy, hydroxy, or halo; C 3-7 cycloalkyl; C 2-6 alkenyl; C 1-6 alkoxy; C 3-7 cycloalkyloxy; aryloxy; Het-O—; hydroxy; cyano; polyhaloC 1-6 alkyl; mono- or C 1-6 dialkylamino;

each R 10 independently is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy, halo, polyhaloC 1-6 alkyl, cyano, amino, mono- or C 1-6 dialkylamino;

each aryl independently is phenyl optionally substituted with one, two or three substituents selected from 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 diC 1-6 alkyl-amino, azido, mercapto, C 1-6 alkylthio, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl, and Het 1 ;

each Het independently is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally substituted with one, two or three substituents each independently selected from 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 diC 1-6 alkylamino, azido, mercapto, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl, Het 1 ;

each Het 1 independently is pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkyl-piperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl and wherein the morpholinyl and piperidinyl groups may optionally substituted with one or two C 1-6 alkyl radicals;

or an N-oxide, a stereoisomer, a pharmaceutically acceptable addition salt, or pharmaceutically acceptable solvate thereof.

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

3. A compound according to claim 1 , wherein ----- adjacent the —(CH 2 ) n — moiety is a double bond.

4. A compound according to claim 1 , wherein ----- in the five membered ring having X is a single bond and R 7 is hydrogen.

5. A compound according to claim 1 , wherein E is NR 5 .

6. A compound according to claim 1 , wherein X is N.

7. A compound according to claim 1 , wherein R 8 is a radical of formula:

8. A compound according to claim 1 , wherein R 8 is a radical of formula:

9. A compound according to claim 7 , wherein R 9 is C 1-6 alkyl; C 1-6 alkoxy; aryloxy; Het-O—; cyano; or R 9 is C 1-6 alkoxy or aryloxy.

10. A compound according to claim 7 , wherein R 10 is hydrogen; C 1-6 alkyl; C 1-6 alkoxy; or cyano.

11. A compound according to claim 1 , wherein the group

has the structure:

12. A compound according to claim 11 , wherein the group

has the structure:

13. A compound according to claim 11 , wherein R 8 , R 8a , R 9 are hydrogen.

14. A compound according to claim 1 , wherein aryl is phenyl optionally substituted with C 1-6 alkoxy and Het is pyridyl or pyrimidinyl.

15. A compound according to claim 1 , wherein A is —C(═O)—NH—SO 2 R 2 , in particular wherein R 2 is C 3-7 cycloalkyl, phenyl or a group Het, e.g. thiazolyl or pyridyl, either of which is optionally substituted with one or more, such as one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, and halo, or in particular with one or two substituents selected from methyl, fluoro and chloro; or A is C(═O)OR 1 wherein R 1 is hydrogen or C 1 -C 6 alkyl, such as methyl.

16. A pharmaceutical composition comprising said compound of formula (I) of claim 1 and a carrier.

17. A method for treating an HCV viral infection comprising administering the effective amount of the pharmaceutical composition of claim 16 to a subject in need thereof.

18. A pharmaceutical composition comprising a compound of formula (I) of claim 1 and an antiviral compound.

19. The composition of claim 18 , wherein said antiviral compound is an anti-HCV compound.