Inhibitors of human immunodeficiency virus replication
Compounds of formula I: wherein c, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are defined herein, are useful as inhibitors of HIV replication.
1. A compound of the formula (I)
wherein
R 2 is selected from:
a) (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, aryl, Het, halo, nitro or cyano;
b) —C(═O)—R 11 , —C(═O)—O—R 11 , —S—R 11 , —SO—R 11 , —SO 2 —R 11 , —(C 1-6 )alkylene-R 11 , —(C 1-6 )alkylene-C(═O)—R 11 , —(C 1-6 )alkylene-C(═O)—O—R 11 , —(C 1-6 )alkylene-O—R 11 , —(C 1-6 )alkylene-S—R 11 , —(C 1-6 )alkylene-SO—R 11 or —(C 1-6 )alkylene-SO 2 —R 11 ;
wherein R 11 is in each instance independently selected from H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, aryl and Het; and
wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from:
i) halo, oxo, thioxo, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, —OH, —O(C 1-6 )alkyl, —O(C 1-6 )haloalkyl, —SH, —S(C 1-6 )alkyl, —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 )alkyl, —C(═O)—N((C 1-4 )alkyl) 2 , —C(═O)-aryl, —C(═O)—Het, NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ;
ii) (C 1-6 )alkyl optionally substituted with —OH, —O—(C 1-6 )haloalkyl, or —O—(C 1-6 )alkyl; and
iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo, (C 1-6 )alkyl or COOH; and
c) —O—R 8a
wherein R 8a is selected from H, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, aryl and Het;
d) —N(R 9 )R 10 , —C(═O)—N(R 9 )R 10 , —O—C(═O)—N(R 9 )R 10 , —SO 2 —N(R 9 )R 10 , —(C 1-6 )alkylene-N(R 9 )R 10 , —(C 1-6 )alkylene-C(═O)—N(R 9 )R 10 , —(C 1-6 )alkylene-O—C(═O)—N(R 9 )R 10 , or —(C 1-6 )alkylene-SO 2 —N(R 9 )R 10 wherein
R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3-7 )cycloalkyl; and
R 10 is in each instance independently selected from R 11 , —(C 1-6 )alkylene-R 11 , —SO 2 —R 11 , —C(═O)—R 11 , —C(═O)OR 11 and —C(═O)N(R 9 )R 11 ; wherein R 11 and R 9 are as defined above; or
R 2 may also be H, (C 1-6 )alkyl or —O—(C 1-6 )alkyl when one of R 5 or R 8 is other than H or when one of R 6 or R 7 is other than H, halo, (C 1-6 )alkyl or (C 1-6 )haloalkyl,
R 5 and R 8 are each independently selected from:
a) halo, nitro or cyano;
b) R 11 , —C(═O)—R 11 , —C(═O)—O—R 11 , —O—R 11 , —S—R 11 , —SO—R 11 , —SO 2 —R 11 , —(C 1-6 )alkylene-R 11 , —(C 1-6 )alkylene-C(═O)—R 11 , —(C 1-6 )alkylene-C(═O)—O—R 11 , —(C 1-6 )alkylene-O—R 11 , —(C 1-6 )alkylene-S—R 11 , —(C 1-6 )alkylene-SO—R 11 or —(C 1-6 )alkylene-SO 2 —R 11 ;
wherein R 11 is in each instance independently selected from H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, aryl and Het; and
wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from:
i) halo, oxo, thioxo, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, —OH, —O(C 1-6 )alkyl, —O(C 1-6 )haloalkyl, —SH, —S(C 1-6 )alkyl, —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 )alkyl, —C(═O)—N((C 1-4 )alkyl) 2 , —C(═O)-aryl, —C(═O)—Het, NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ;
ii) (C 1-6 )alkyl optionally substituted with —OH, —O—(C 1-6 )haloalkyl, or —O—(C 1-6 )alkyl; and
iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo, (C 1-6 )alkyl or COOH; and
c) —N(R 9 )R 10 , —C(═O)—N(R 9 )R 10 , —O—C(═O)—N(R 9 )R 10 , —SO 2 —N(R 9 )R 10 , —(C 1-6 )alkylene-N(R 9 )R 10 , —(C 1-6 )alkylene-C(═O)—N(R 9 )R 10 , —(C 1-6 )alkylene-O—C(═O)—N(R 9 )R 10 , or —(C 1-6 )alkylene-SO 2 —N(R 9 )R 10 wherein
R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3-7 )cycloalkyl; and
R 10 is in each instance independently selected from R 11 , —(C 1-6 )alkylene-R 11 , —SO 2 —R 11 , —C(═O)—R 11 , —C(═O)OR 11 and —C(═O)N(R 9 )R 11 ; wherein R 11 and R 9 are as defined above;
R 6 is selected from:
a) (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl, nitro, cyano, aryl and Het;
b) —C(═O)—R 11 , —C(═O)—O—R 11 , —O—R 11 , —S—R 11 , —SO—R 11 , —SO 2 —R 11 , —(C 1-6 )alkylene-R 11 , —(C 1-6 )alkylene-C(═O)—R 11 , —(C 1-6 )alkylene-C(═O)—O—R 11 , —(C 1-6 )alkylene-O—R 11 , —(C 1-6 )alkylene-S—R 11 , —(C 1-6 )alkylene-SO—R 11 or —(C 1-6 )alkylene-SO 2 —R 11 ;
wherein R 11 is in each instance independently selected from H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, aryl and Het; and
c) —N(R 9 )R 10 , —C(═O)—N(R 9 )R 10 , —O—C(═O)—N(R 9 )R 10 , —SO 2 —N(R 9 )R 10 , —(C 1-6 )alkylene-N(R 9 )R 10 , —(C 1-6 )alkylene-C(═O)—N(R 9 )R 10 , —(C 1-6 )alkylene-O—C(═O)—N(R 9 )R 10 , or —(C 1-6 )alkylene-SO 2 —N(R 9 )R 10 wherein
R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3-7 )cycloalkyl; and
R 10 is in each instance independently selected from R 11 , —(C 1-6 )alkylene-R 11 , —SO 2 —R 11 , —C(═O)—R 11 , —C(═O)OR 11 and —C(═O)N(R 9 )R 11 ; wherein R 11 and R 9 are as defined above;
wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from:
i) halo, oxo, thioxo, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, —OH, —O(C 1-6 )alkyl, —O(C 1-6 )haloalkyl, —SH, —S(C 1-6 )alkyl, —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ;
ii) (C 1-6 )alkyl optionally substituted with —OH, —O—(C 1-6 )haloalkyl, or —O—(C 1-6 )alkyl; and
iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo, (C 1-6 )alkyl or COOH; and
R 6 may also be H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl when at least one of R 5 or R 8 is other than H or when R 7 is other than H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl or when R 2 is other than H, (C 1-6 )alkyl, or —O—(C 1-6 )alkyl;
R 7 is selected from:
a) (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl, nitro, cyano, aryl and Het;
b) —C(═O)—R 11 , —C(═O)—O—R 11 , —O—R 11 , —S—R 11 , —SO—R 11 , —SO 2 —R 11 , —(C 1-6 )alkylene-R 11 , —(C 1-6 )alkylene-C(═O)—R 11 , —(C 1-6 )alkylene-C(═O)—O—R 11 , —(C 1-6 )alkylene-O—R 11 , —(C 1-6 )alkylene-S—R 11 , —(C 1-6 )alkylene-SO—R 11 or —(C 1-6 )alkylene-SO 2 —R 11 ;
wherein R 11 is in each instance independently selected from H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, aryl and Het; and
c) —N(R 9 )R 10 , —C(═O)—N(R 9 )R 10 , —O—C(═O)—N(R 9 )R 10 , —SO 2 —N(R 9 )R 10 , —(C 1-6 )alkylene-N(R 9 )R 10 , —(C 1-6 )alkylene-C(═O)—N(R 9 )R 10 , —(C 1-6 )alkylene-O—C(═O)—N(R 9 )R 10 , or —(C 1-6 )alkylene-SO 2 —N(R 9 )R 10 wherein
R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3-7 )cycloalkyl; and
R 10 is in each instance independently selected from R 11 , —(C 1-6 )alkylene-R 11 , —SO 2 —R 11 , —C(═O)—R 11 , —C(═O)OR 11 and —C(═O)N(R 9 )R 11 ; wherein R 11 and R 9 are as defined above;
wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from:
i) halo, oxo, thioxo, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, —OH, —O(C 1-6 )alkyl, —O(C 1-6 )haloalkyl, —SH, —S(C 1-6 )alkyl, —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ;
ii) (C 1-6 )alkyl optionally substituted with —OH, —O—(C 1-6 )haloalkyl, or —O—(C 1-6 )alkyl; and
iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo, (C 1-6 )alkyl or COOH; and
R 7 may also be H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl when at least one of R 5 or R 8 is other than H or when R 6 is other than H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl or when R 2 is other than H, (C 1-6 )alkyl, or —O—(C 1-6 )alkyl;
or R 5 and R 6 , together with the C to which they are attached, R 6 and R 7 , together with the C to which they are attached, or R 7 and R 8 , together with the C to which they are attached; may be linked to form a 5- or 6-membered carbocycle or a 4- to 7-membered heterocycle optionally further containing 1 to 3 heteroatoms each independently selected from N, O and S, wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 ;
wherein the carbocycle or heterocycle is optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-6 )alkyl, —SH, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ;
R 3 is (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl-, Het-(C 1-6 )alkyl- or —Y—R 31 , and bond c is a single bond; or
R 3 is (C 1-6 )alkylidene and bond c is a double bond;
wherein Y is O or S and R 31 is (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl, aryl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl- or Het-(C 1-6 )alkyl-;
wherein each of the (C 1-6 )alkylidene, (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl-, Het-(C 1-6 )alkyl- and —Y—R 31 is optionally substituted with 1 to 3 substituents each independently selected from (C 1-6 ) alkyl, halo, cyano, oxo and —O(C 1-6 )alkyl;
R 4 is aryl or Het, wherein each of the aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-6 )alkyl, —SH, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 ) alkyl and —N((C 1-6 )alkyl) 2 ; wherein the (C 1-6 )alkyl is optionally substituted with hydroxy, —O(C 1-6 )alkyl, cyano or oxo;
wherein Het is a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S; wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 ;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 of the formula (Ib),
wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, (C 1-6 )alkyl or —O—(C 1-6 )alkyl when one of R 5 or R 8 is other than H or when one of R 6 or R 7 is other than H, halo, (C 1-6 )alkyl or (C 1-6 )haloalkyl.
4. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from —O(C 1-6 )alkyl, —O—(C 1-6 )haloalkyl, —O(C 2-6 )alkenyl, —O(C 2-6 )alkynyl or —O—(C 3-7 )cycloalkyl;
wherein each of the —O(C 1-6 )alkyl and —O—(C 3-7 )cycloalkyl is optionally substituted with 1 to 3 substituents each independently selected from (C 1-3 )alkyl, cyano, oxo and —O(C 1-6 ) alkyl; and bond c is a single bond.
5. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from phenyl optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-4 )alkyl and (C 1-4 )haloalkyl.
6. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is Het optionally substituted with 1 to 3 substituents each independently selected from halo and (C 1-6 )alkyl;
wherein the Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9- or 10-membered heteropolycycle having 1 to 3 heteroatoms each independently selected from N, O and S.
7. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, halo, (C 1-6 )alkyl, (C 1-6 )haloalkyl or —O(C 1-6 ) alkyl.
8. A compound according to any claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H when at least one of R 5 or R 8 is other than H or when R 7 is other than H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl or when R 2 is other than H, (C 1-6 )alkyl, or —O—(C 1-6 )alkyl.
9. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from:
a) (C 2-6 )alkenyl, (C 3-7 )cycloalkyl, nitro, cyano, aryl and Het;
b) —(C 1-6 )alkylene-R 11 ,
wherein R 11 is in each instance independently selected from H, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, aryl and Het; and
c) —N(R 9 )R 10 , —C(═O)—N(R 9 )R 10 , wherein
R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3-7 )cycloalkyl; and
R 10 is in each instance independently selected from R 11 , —(C 1-6 )alkylene-R 11 , —SO 2 —R 11 , —C(═O)—R 11 , —C(═O)OR 11 and —C(═O)N(R 9 )R 11 ; wherein R 11 and R 9 are as defined above;
wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from:
i) halo, oxo, thioxo, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, —OH, —O(C 1-6 )alkyl, —O(C 1-6 )haloalkyl, —SH, —S(C 1-6 )alkyl, —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ;
ii) (C 1-6 )alkyl optionally substituted with —OH, —O—(C 1-6 )haloalkyl, or —O—(C 1-6 )alkyl; and
iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo, (C 1-6 )alkyl or COOH;
R 7 may also be H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl when at least one of R 5 or R 8 is other than H or when R 6 is other than H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl or when R 2 is other than H, (C 1-6 )alkyl, or —O—(C 1-6 )alkyl.
10. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, when at least one of R 5 or R 8 is other than H or when R 6 is other than H, halo, (C 1-6 )alkyl, or (C 1-6 )haloalkyl or when R 2 is other than H, (C 1-6 )alkyl, or —O—(C 1-6 )alkyl.
11. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from:
a) F, Cl, Br; and
b) H, (C 1-3 )alkyl, —O—(C 1-3 )haloalkyl, phenyl and Het, —(C 1-3 )alkylene-phenyl, —(C 1-3 )alkylene-Het;
wherein each of the aryl and Het is optionally substituted with 1 to 2 substituents each independently selected from:
i) oxo, thioxo, —O(C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 )alkyl, —C(═O)—N((C 1-4 )alkyl) 2 , —C(═O)-aryl, —C(═O)-Het; and
ii) (C 1-6 )alkyl.
12. A pharmaceutical composition comprising a therapeutically a compound according to claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method for treating HIV in a host infected by HIV which method comprises administering to such host a therapeutically effective amount of a compound according to claim 2 , or a pharmaceutically acceptable salt thereof.