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;
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 [2.2]-cyclophane, each 2 atom linker of the [2.2]-cyclophane optionally contains a heteroatom selected from N, O, or S and is optionally substituted with 1 oxo group, and one or more substituents independently chosen from halogen, hydroxy, amino, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.
2. A compound or salt of claim 1 , wherein A is
3. A compound or salt of claim 1 , wherein A is
4. A compound or salt of claim 1 , of the formula
T-R-J 1 -W-A-W-J 1 -R-T or
T-R-J 2 -A-J 2 -R-T.
5. 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.
6. A compound or salt of claim 1 , wherein J 1 is
7. 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.
8. 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.
9. A compound or salt of claim 8 wherein R is independently chosen from
10. A compound or salt of claim 1 wherein T is independently chosen from C 2 -C 6 alkanoyl substituted with mono- or di-C 1 -C 6 alkylcarbamate, each of which T is optionally substituted with (C 1 -C 4 thioalkyl)C 0 -C 4 alkyl.
11. A 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.
12. A compound or pharmaceutically acceptable salt thereof, wherein the compound is
13. A compound of claim 12 of the formula
or a pharmaceutically acceptable salt thereof.
14. A compound of claim 12 of the formula
or a pharmaceutically acceptable salt thereof.
15. A compound of claim 12 of the formula
or a pharmaceutically acceptable salt thereof.
16. A compound of claim 12 of the formula
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound or salt of claim 12 together with a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17 , wherein the composition comprises a therapeutically effective amount of an additional compound, wherein the additional compound is a therapeutic active agent.
19. A pharmaceutical composition comprising a compound or salt of claim 13 together with a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising a compound or salt of claim 14 together with a pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising a compound or salt of claim 15 together with a pharmaceutically acceptable carrier.
22. A pharmaceutical composition comprising a compound or salt of claim 16 together with a pharmaceutically acceptable carrier.
23. The pharmaceutical composition of claim 18 , wherein the therapeutic active agent is a NS3a protease inhibitor.
24. The pharmaceutical composition of claim 19 , comprising an additional compound, wherein the additional compound is a therapeutic active agent or a salt thereof of the formula
25. The pharmaceutical composition of claim 20 , comprising an additional active agent, wherein the additional active agent is a compound or a salt thereof of the formula
26. The pharmaceutical composition of claim 21 , comprising an additional active agent, wherein the additional active agent is a compound or a salt thereof of the formula
27. The pharmaceutical composition of claim 22 , comprising an additional active agent, wherein the additional active agent is a compound or a salt thereof of the formula
28. A method of therapeutically treating hepatitis C infection in a patient, comprising providing a therapeutically effective amount of one or more compounds or salts thereof of claim 1 to the patient.
29. A method of therapeutically treating hepatitis C infection in a patient having a hepatitis C infection, comprising providing a therapeutically effective amount of a compound or salt thereof of claim 13 to the patient.
30. A method of therapeutically treating hepatitis C infection in a patient having a hepatitis C infection, comprising providing a therapeutically effective amount of a compound or salt thereof of claim 14 to the patient.
31. A method of therapeutically treating hepatitis C infection in a patient having a hepatitis C infection, comprising providing a therapeutically effective amount of a compound or salt thereof of claim 15 to the patient.
32. A method of therapeutically treating hepatitis C infection in a patient having a hepatitis C infection, comprising providing a therapeutically effective amount of a compound or salt thereof of claim 16 to the patient.