Macrocyclic inhibitors of hepatitis C virus
View Patent ↗Inhibitors of HCV replication of formula (I) and the salts and stereoisomers 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 , —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, C 3-7 cycloalkyl; n is 3, 4, 5, or 6; R 4 is C 1-6 alkyl or C 3-7 cycloalkyl; R 5 is hydrogen, halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, polyhaloC 1-6 alkyl; R 6 is hydrogen, C 1-6 alkoxy, mono- or diC 1-6 alkylamino; or R 5 and R 6 may form a 5- or 6-membered unsaturated or partially unsaturated ring, optionally comprising one or two selected from O, N and S; R 7 is hydrogen; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl; R 8 is C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl; or —NR 8a R 8b ; R 8a and R 8b are C 1-6 alkyl, or both may form a 5- or 6-membered saturated heterocyclic ring; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I).
1. A compound having the formula
and the salts and stereoisomers thereof, wherein
each dashed line (represented by independently represents an optional double bond;
X is N, CH and where X bears a double bond it is C;
R 1 is —OR 7 ;
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, C 3-7 cycloalkyl;
n is 3, 4, 5, or 6;
R 4 is C 1-6 alkyl or C 3-7 cycloalkyl;
R 5 represents hydrogen, halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, polyhaloC 1-6 alkyl;
R 6 represents hydrogen, C 1-6 alkoxy, mono- or diC 1-6 alkylamino; or
R 5 and R 6 may optionally, together with the carbon atoms to which they are attached, form a 5- or 6-membered unsaturated or partially unsaturated ring, and wherein said ring may optionally comprise one or two heteroatoms selected from 0, N and S;
R 7 is hydrogen; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl.
2. A compound according to claim 1 , wherein the compound has the formula (I-c) or (I-d):
3. A compound according to claim 1 , wherein
R 1 is —OR 7 , wherein R 7 is C 1-6 alkyl or hydrogen.
4. A compound according to claim 1 , wherein n is 4 or 5.
5. A compound according to claim 1 , wherein R 3 is hydrogen or C 1-6 alkyl.
6. A compound according to claim 1 , wherein R 5 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, or trifluoromethyl.
7. A compound according to claim 1 , wherein R 6 is hydrogen or methoxy.
8. A compound having the formula
and the salts and stereoisomers thereof, wherein
each dashed line (represented by independently represents an optional double bond;
X is N, CH and where X bears a double bond it is C;
R 1 is —NH—SO 2 R8;
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, C 3-7 cycloalkyl;
n is 3, 4, 5, or 6;
R 4 is C 1-6 alkyl or C 3-7 cycloalkyl;
R 5 represents hydrogen, halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, polyhaloC 1-6 alkyl;
R 6 represents hydrogen, C 1-6 alkoxy, mono- or diC 1-6 alkylamino; or
R 5 and R 6 may optionally, together with the carbon atoms to which they are attached, form a 5- or 6-membered unsaturated or partially unsaturated ring, and wherein said ring may optionally comprise one or two heteroatoms selected from O, N and S;
R 7 is hydrogen; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl;
R 8 is C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl; or —NR 8a R 8b , wherein R 8a and R 8b are, each independently, C 1-6 alkyl, or R 8a and R 8b together with the nitrogen to which they are attached form a 5- or 6-membered saturated heterocyclic ring.
9. A compound according to claim 8 , wherein R 8 is methyl, cyclopropyl; or cyclopropyl substituted with methyl.
10. A compound according to claim 8 , wherein n is 4 or 5.
11. A compound according to claim 8 , wherein R 3 is hydrogen or C 1-6 alkyl.
12. A compound according to claim 8 , wherein R 5 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo, or trifluoromethyl.
13. A compound according to claim 8 , wherein R 6 is hydrogen or methoxy.