Pyrimidine substituted macrocyclic HCV inhibitors
View Patent ↗Compounds of the formula I: including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.
1. A compound of the formula I:
wherein:
A is —C(═O)OR 1 , —C(═O)—NH—SO 2 —R 2 , wherein;
R 1 is hydrogen; or C 1-6 alkyl;
R 2 is C 3-7 cycloalkyl, phenyl; or thiazolyl or pyridyl, any of which is optionally substituted with one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, and halo;
X is N, CH and when X bears a double bond it is C;
R q is hydrogen, or where X is C or CH, R q may also be C 1-6 alkyl;
E is NR 5 ;
R 5 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl;
n is 3, 4, 5 or 6;
each dotted line ----- independently represents an optional double bond;
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 alkylamino, 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;
wherein the pyrimidinyl radical
wherein R 7 and R 8 independently are phenyl or C 1-6 alkoxy;
R 9 is hydrogen or C 1-6 alkyl;
each R 8a or R 8b independently is hydrogen, C 1-6 alkoxy
or a stereoisomer, N-oxide or pharmaceutically acceptable addition salt thereof.
2. A compound of claim 1 , wherein n is 4 or 5.
3. A compound of claim 1 or 2 , wherein ----- adjacent the —(CH 2 ) n — moiety is a double bond.
4. A compound of claim 1 or 2 , wherein ----- in the five membered ring having X is a single bond and R q is hydrogen.
5. A compound of claim 1 , wherein X is N.
6. A compound of claim 1 , wherein A is —C(═O)—NH—SO 2 R 2 ; and R 2 is C 3-7 cycloalkyl, phenyl; or thiazolyl or pyridyl, either of which is optionally substituted with one or two substituents selected from C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, and halo.
7. A compound of claim 1 , wherein A is C(═O)OR 1 wherein R 1 is hydrogen or methyl.
8. A composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.
9. A method of treating hepatitis C virus infections comprising administering to a human in need of such treatment, a compound of claim 1 .
10. The composition of claim 8 having another antiviral compound.
11. A composition according to claim 10 wherein the other antiviral compound is an anti-HCV compound.
12. A compound according to claim 1 , wherein C 1-6 alkyl is methyl, C 1-6 alkoxy is methoxy, and halo is fluoro or chloro.
13. A compound according to claim 6 , wherein C 1-6 alkyl is methyl and halo is fluoro or chloro.