4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication

• US 10,682,369 B2
• Filed: 09/21/2018
• Issued: 06/16/2020
• Est. Priority Date: 09/21/2017
• Status: Active Grant

• Current Assignee: Riboscience LLC
• Original Assignee: Riboscience LLC
• Inventors: Smith, Mark, Klumpp, Klaus G.
• Primary Examiner(s): Berry, Layla D
• Application Number:
  US16/138,698
• Publication Number:
  US 20190231804A1
• Time in Patent Office: 634 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Cytidine nucleoside analogues of Formula I, wherein the variables are as described herein, in combination with uridine nucleoside analogues of Formula II, wherein the variables are as described herein,

produce a synergistic effect on the inhibition of HCV polymerase.

Claims

1. A method of treatment of HCV comprising administering to a patient in need thereof, a combination of a compound of Formula I and a compound of Formula II:

2. The method of claim 1 wherein:

each R³ in Formula I or Formula II is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl;

or a pharmacologically acceptable salt thereof.

3. The method of claim 1, wherein wherein the compound of Formula I is selected from the group consisting of:

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

cyclohexyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

pentan-3-yl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

diisopropyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

dicyclohexyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl diphenyl phosphate;

diisopropyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

cyclohexyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

dicyclohexyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

pentan-3-yl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methyl diphenyl phosphate;

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

cyclohexyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

pentan-3-yl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

cyclohexyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

pentan-3-yl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; and

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

or

a mixture of S_P and R_P epimers thereof;

or

a pharmaceutically acceptable salt thereof of each of the foregoing compounds.

4. The method of claim 2, wherein the compound of Formula I is:

5. The method of claim 2, wherein the compound of Formula I is:

6. The method of claim 2, wherein the compound of Formula I is:

7. The method of claim 2, wherein the compound of Formula II is:

8. The method of claim 2, wherein the compound of Formula II is:

9. The method of claim 2, wherein the compound of Formula II is:

10. The method of claim 2, wherein the compound of Formula I and the compound of Formula II are, respectively,

11. The method of claim 2, wherein the compound of Formula I and the compound of Formula II are, respectively,

12. The method of claim 2, wherein the compound of Formula I and the compound of Formula II are, respectively,

13. The method of claim 2, wherein the compound of Formula I and the compound of Formula II are, respectively,

14. The method of claim 2, wherein the compound of Formula I and the compound of Formula II are, respectively,

15. The method of claim 2, wherein the combination of a compound of Formula I and a compound of Formula II further comprises one or more of ribavirin, peginterferon-α

, simeprevir, ledipasvir, daclatasvir, and velpatasvir.

16. A composition comprising a compound of Formula I and a compound of Formula II, admixed with at least one carrier, diluent or excipient

17. The composition of claim 16 wherein each R³ in Formula I or Formula II is independently H, lower alkyl, lower haloalkyl, phenyl or phenyl lower alkyl.

18. A method of treatment of HCV by administering to a patient in need thereof a compound of Formula I and a compound of Formula II, further in combination with a NS3A HCV protease inhibitor

19. The method of claim 18 wherein each R³ in Formula I or Formula II is independently H, lower alkyl, lower haloalkyl, cycloalkyl, phenyl or phenyl lower alkyl.

20. A method of treatment of HCV by administering to a patient in need thereof a compound of Formula I and a compound of Formula II, further in combination with an additional NS5B HCV polymerase inhibitor

21. The method of claim 20 wherein each R³ in Formula I or Formula II is independently H, lower alkyl, lower haloalkyl, cycloalkyl, phenyl or phenyl lower alkyl.

22. The method of claim 20, wherein the compound of Formula I is selected from the group consisting of:

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

cyclohexyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

pentan-3-yl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

diisopropyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

dicyclohexyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl diphenyl phosphate;

diisopropyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

cyclohexyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

dicyclohexyl ((((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)((amino)phosphoryl)-L-alaninate;

pentan-3-yl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methyl diphenyl phosphate;

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

isopropyl ((S)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

cyclohexyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

pentan-3-yl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,4-difluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

cyclohexyl ((R)-((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1-(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

pentan-3-yl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; and

isopropyl ((R)-(((2S,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate;

or

a mixture of S_P and R_P epimers thereof;

or

a pharmaceutically acceptable salt thereof of each of the foregoing compounds.