Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV
Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 2′-cyano, azido or amino nucleosides according to Formula 1001 or 2001: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R 1 and R 2 are as described herein.
1. A compound according to Formula I:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
Base is a nucleobase;
R 1 is cyano, azido or amino; and
R 2 is hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 7 cycloalkyl.
2. The compound of claim 1 according to Formula Ia or Ib:
3. The compound of claim 1 according to Formula II:
4. The compound of claim 3 according to Formula IIa or IIb:
5. The compound of claim 1 according to Formula III:
6. The compound of claim 5 according to Formula IIIa or IIIb:
7. The compound of claim 1 according to Formula IV:
8. The compound of claim 3 according to Formula IVa or IVb:
9. The compound of claim 1 wherein:
Base is
or a tautomer thereof;
R 4 is hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl, amino or alkoxy;
R 5 is hydrogen, halogen or methyl; and
R 6 is hydrogen, amino, or halo.
10. The compound of claim 9 according to any of Formulas (V)-(XVI):
11. The compound of claim 1 , wherein R 2 is hydrogen, methyl, or halo.
12. The compound of claim 1 according to any of Formulas 1-3:
13. The compound of claim 1 , wherein:
Base is
or a tautomer thereof;
R 1 is cyano, azido, or —NR 1′ R 2′ ;
R 2 is hydrogen, chloro, bromo, fluoro, iodo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 7 cycloalkyl;
R 4 is hydrogen, hydroxyl, hydroxylamine, chloro, bromo, fluoro, iodo, sulfanyl, —NR 1′ R 2′ , or —OR′;
R 5 is hydrogen, halogen, or methyl;
R 6 is hydrogen, —NR 1′ R 2′ , chloro, bromo, fluoro, or iodo;
R′ is C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl; and
R 1′ and R 2′ are each independently hydrogen, C 1 to C 10 alkyl, or C 3 to C 10 cycloalkyl.
14. The compound of claim 1 according to Formula 4:
15. The compound of claim 1 according to Formula 7:
16. The compound of claim 1 according to Formula 8:
17. A compound according to Formula 4001:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
Base is a nucleobase;
W is O or S;
R 1 is cyano, azido, or amino;
R 11 is hydrogen, alkyl, cycloalkyl, or aryl;
R 12 is alkyl; and
R 13 is hydrogen, alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or heteroaryl.
18. The compound of claim 17 according to Formula 4001a or 4001b:
19. The compound of claim 17 according to Formula 4002:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
20. The compound of claim 17 according to Formula 4003:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
21. The compound of claim 17 according to Formula 4004:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
22. The compound of claim 17 according to any of Formulas 1005-1012:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
23. The compound of claim 17 selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof.
24. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.
25. The pharmaceutical composition of claim 24 , wherein the composition is an oral formulation.
26. A method for the treatment of a host infected with a hepatitis C virus, comprising the administering of an effective treatment amount of a compound of claim 1 .
27. The method of claim 26 , wherein the host is a human.
28. The method of claim 26 , wherein the administering directs a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host.
29. The method of claim 26 , further comprising administering the compound or composition in combination or alternation with a second anti-viral agent, wherein the second antiviral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof.
30. A method of inhibiting the activity of a polymerase, comprising contacting the polymerase with a compound according to Formula I:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
Base is a nucleobase;
R 1 is cyano, azido or amino; and
R 2 is hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 7 cycloalkyl.
31. A method of treating a host infected with a pestivirus, comprising the administering of an effective treatment amount of a compound according to Formula I:
or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
Base is a nucleobase;
R 1 is cyano, azido or amino; and
R 2 is hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 7 cycloalkyl.