Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV

Patent metadata

Field	Value
Publication number	US-10231986-B2
Application number	US-201514866759-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Mar 13, 2013
Publication date	Mar 19, 2019
Grant date	Mar 19, 2019

Abstract

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.

First claim

What is claimed is:

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 adminis

Assignees

• Centre Nat Rech Scient
• Univ Montpellier 2 Sciences Et Techniques
• Idenix Pharmaceuticals Llc

Inventors

• Dukhan David
• Parsy Christophe Claude
• Gosselin Gilles
• Griffon Jean-François
• Brandt Guillaume
• Dousson Cyril B
• Moussa Adel M
• Mayes Benjamin Alexander
• Stewart Alistar James

Classifications

• C07H19/173

  with 2-deoxyribosyl as the saccharide radical · CPC title

• C07H19/073

  with 2-deoxyribosyl as the saccharide radical · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07H19/20

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title