Substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes useful for treating HCV infections
The present disclosure provides substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes, of Formula I D-M-D (Formula I) useful as antiviral agents. In certain embodiments disclosed herein M is a group —P-A-P— where A is Certain substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. Pharmaceutical compositions/and combinations containing one or more substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes and a pharmaceutically acceptable carrier are also provided by this disclosure. Methods for treating viral infections, including Hepatitis C viral infections are provided by the disclosure.
1. A compound of the formula
T-R-J 1 -W-A-W-J 1 -R-T;
T-R-J 1 -A-J 1 -R-T;
T-R-J 2 -A-J 2 -R-T; or
T-R-J 1 -W-A-J 1 -R-T;
or a pharmaceutically acceptable salt thereof; wherein
T is independently chosen at each occurrence and is T k where k is an integer from 1 to 2;
T 1 is —Y—Z, where Y is covalently bound to R and Y is a bond or C 1 -C 4 alkylene optionally substituted with oxo; and Z is a 5 or 6-membered heterocyclic group, each of which T 1 is substituted with (i) at least one substituent selected from —(C═O)OH, —(C═O)NH 2 , —(C═O)H, —C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, C 1 -C 4 alkylester, C 1 -C 4 alkenylester, and mono- and di-C 1 -C 4 alkylcarboxamide and (ii) optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
T 2 is independently chosen at each occurrence from C 2 -C 6 alkanoyl, C 1 -C 6 alkylester, C 1 -C 6 alkenylester, C 1 -C 6 alkylsulfonamide, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkanoyl substituted with mono- or di-C 1 -C 6 hydrocarbylcarbamate, C 2 -C 6 alkanoyl substituted with urea or mono- or di- C 1 -C 6 alkylurea, and C 2 -C 6 alkanoyl substituted with mono- or di-C 1 -C 6 alkylcarboxamide, each of which T 2 is optionally substituted with 1 or more substituents independently chosen from amino, cyano, hydroxyl, halogen, (C 1 -C 4 alkoxy)C 0 -C 4 alkyl, (mono- and di- C 1 -C 4 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkyl, (C 1 -C 4 thioalkyl)C 0 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R is independently chosen at each occurrence from 4- to 6-membered rings containing one or two nitrogen atoms with remaining ring atoms being carbon, which R is saturated or contains 1 unsaturated bond and is optionally bridged with an methylene or ethylene bridge, or fused to a phenyl or 5- to 6-membered heteroaryl ring; and
6- to 10-membered fused or spiro bicyclic ring systems containing one or two nitrogen atoms with remaining ring atoms being carbon, which 6- to 10-membered bicyclic ring is saturated or contains 1 unsaturated bond;
each R is optionally substituted with one or more substituents independently chosen from cyano, hydroxyl, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkylene, and C 1 -C 2 alkylsulfonyl;
J 1 is phenyl or a
group, where each J 1 is optionally substituted with one or more substituents independently chosen from amino, cyano, hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di- C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
J 2 is a benzimidazole group, wherein J 2 is optionally substituted with one or more substituents independently chosen from amino, cyano, hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di- C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
W is independently chosen at each occurrence and is a phenyl, pyridyl or alkynyl group, optionally substituted with one or more substituents independently chosen from amino, cyano, hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di- C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and
A is a group of the formula
wherein Q is a neutral or cationic metal.
2. A compound or salt of claim 1 , wherein A is
3. A compound or salt of claim 1 , of the formula
T-R-J 1 -A-J 1 -R-T; or
T-R-J 2 -A-J 2 -R-T.
4. A compound or salt of claim 1 wherein
W is phenyl, optionally substituted with one or more substituents independently chosen from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.
5. A compound or salt of claim 1 , wherein J 1 is
6. A compound or salt of claim 1 wherein
J 2 is a benzimidazole group, optionally substituted with one or more substituents independently chosen from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.
7. A compound or salt of claim 1 wherein each R is independently chosen from
each of which is optionally substituted with one or more substituents independently chosen from halogen, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy.
8. A compound or salt of claim 7 wherein each R is independently chosen from
9. A compound or salt of claim 1 wherein T is independently chosen from C 2 -C 6 alkanoyl substituted with mono- and di-C 1 -C 6 alkylcarbamate, each of which T is optionally substituted with (C 1 -C 4 thioalkyl)C 0 -C 4 alkyl.
10. compound or salt of claim 1 , of the formula
T-R-J 2 -A-J 2 -R-T; where
A is
Each R is an independently chosen 8- to 10-membered bicyclic ring systems containing one or two nitrogen atoms with remaining ring atoms being carbon, which 8- to 10-membered bicyclic ring is saturated or contains 1 unsaturated bond;
each R is optionally substituted with one or more substituents independently chosen from cyano, hydroxyl, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkylene, and C 1 -C 2 alkylsulfonyl; and
T 2 is independently chosen at each occurrence from C 2 -C 6 alkanoyl, C 1 -C 6 alkylester, C 1 -C 6 alkenylester, C 1 -C 6 alkylsulfonamide, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkanoyl substituted with mono- or di-C 1 -C 6 hydrocarbylcarbamate, C 2 -C 6 alkanoyl substituted with urea or mono- or di- C 1 -C 6 alkylurea, and C 2 -C 6 alkanoyl substituted with mono- or di-C 1 -C 6 alkylcarboxamide, each of which T 2 is optionally substituted with 1 or more substituents independently chosen from amino, cyano, hydroxyl, halogen, (C 1 -C 4 alkoxy)C 0 -C 4 alkyl, (mono- and di- C 1 -C 4 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkyl, (C 1 -C 4 thioalkyl)C 0 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.
11. A compound or salt thereof of claim 1 , wherein the compound is
12. A compound or salt thereof of claim 1 , wherein the compound is
13. A compound or salt thereof of claim 1 , wherein the compound is
14. A compound or salt thereof of claim 1 , wherein the compound is
15. A pharmaceutical composition comprising a compound or salt of claim 1 together with a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15 , wherein the composition comprises a therapeutically effective amount of an additional active compound, wherein the additional active compound is a therapeutically active agent.
17. A method of therapeutically treating hepatitis C infection in a patient, comprising providing a therapeutically effective amount of one or more compounds of claim 1 to a patient in need thereof.