4'-FLUORO-2'-METHYL SUBSTITUTED NUCLEOSIDE DERIVATIVES AS INHIBITORS OF HCV RNA REPLICATION

• US 20140341847A1
• Filed: 05/15/2014
• Published: 11/20/2014
• Est. Priority Date: 05/16/2013
• Status: Active Grant

• Current Assignee: Riboscience LLC
• Original Assignee: Riboscience LLC
• Inventors: Smith, Mark, Klumpp, Klaus G.
• Granted Patent: US 9,895,442 B2
• Time in Patent Office: Days
• US Class Current: 424/85.4
• 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 31/12 Antivirals
• 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
• CPC Class Codes: C07H 19/11 containing cyclic phosphate

Abstract

The present disclosure relates to the compound of Formula I:

Also disclosed are pharmaceutical compositions comprising the compound of Formula I, methods of using the compound of Formula I and/or compositions comprising the compound of Formula I for the treatment of HCV.

Claims

1. A compound of Formula I

2. The compound of claim 1, wherein R⁴ is H.

3. The compound of claim 2, wherein R⁶ is H or halo.

4. The compound of claim 3, wherein R¹ is naphthyl or phenyl.

5. The compound of claim 4, wherein R^2a is H.

6. The compound of claim 5, wherein R^2b is methyl.

7. The compound of claim 6, wherein R³ is isopropyl.

8. The compound of claim 7, wherein R⁵ is H.

9. The compound of claim 1, wherein R and R⁵ together form a bond.

10. The compound of claim 9, wherein R⁶ is OH.

11. The compound of claim 10, wherein R′

is —

OR³ and R³ is isopropyl.

12. The compound of claim 1, wherein X is S.

13. The compound of claim 1, wherein Base is uracil or cytosine.

15. A method for treating a Hepatitis C Virus (HCV) infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

16. The method of claim 15, further comprising administering an immune system modulator or an antiviral agent that inhibits replication of HCV, or a combination thereof.

17. The method of claim 16, wherein the immune system modulator is an interferon or chemically derivatized interferon.

18. The method of claim 16, wherein the antiviral agent is selected from the group consisting of a HCV protease inhibitor, a HCV polymerase inhibitor, a HCV helicase inhibitor, a HCV primase inhibitor, a HCV fusion inhibitor, and a combination thereof.

19. A method for inhibiting replication of HCV in a cell comprising administering a compound of claim 1.

20. A composition comprising the compound of claim 1, admixed with at least one carrier, diluent or excipient.

14. A compound selected from the group consisting of:

2′

-Deoxy-2′

,4′

-difluoro-2′

-methyluridine-5′

-(O-phenyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methyluridine-5′

-(O-2-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methyluridine-5′

-(O-1-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate

2′

-Deoxy-2′

,4′

-difluoro-2′

-methycytidine-5′

-(O-phenyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methylcytidine-5′

-(O-1-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methylcytidine-5′

-(O-2-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiosphosphoramidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methyluridine-3′

,5′

-cyclic phosphoric acid isopropyl ester;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methylcytidine-3′

,5′

-cyclic phosphoric acid isopropyl ester;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methyluridine-3′

,5′

-cyclic thiophosphoric acid isopropyl ester;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methylcytidine-3′

,5′

-cyclic thiophosphoric acid isopropyl ester;

4′

-Fluoro-2′

-methyluridine-5′

-(O-phenyl-N—

(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′

-Fluoro-2′

-methyluridine-5′

-(O-1-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′

-Fluoro-2′

-methyluridine-5′

-(O-1-naphthyl-N—

(S)-2-(isopropoxycarbonyl)ethyl phosphoramidate;

4′

-Fluoro-2′

-methylcytidine-5′

-(O-phenyl-N—

(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′

-Fluoro-2′

-cytidine-5′

-(O-1-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl phosphoramidate;

4′

-Fluoro-2′

-methylcytidine-5′

-(O-1-naphthyl-N—

(S)-2-(isopropoxycarbonyl)ethyl phosphoramidate;

4′

-Fluoro-2′

-methyluridine-5′

-(O-phenyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate;

4′

-Fluoro-2′

-methyluridine-5′

-(O-1-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate;

4′

-Fluoro-2′

-methyluridine-5′

-(O-1-naphthyl-N—

(S)-2-(isopropoxycarbonyl)ethyl thiophosphoramidate;

4′

-Fluoro-2′

-methylcytidine-5′

-(O-phenyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiophsphoramidate;

4′

-Fluoro-2′

-methylcytidine-5′

-(O-1-naphthyl-N—

(S)-1-(isopropoxycarbonyl)ethyl thiophosphoramidate;

4′

-Fluoro-2′

-methylcytidine-5′

-(O-1-naphthyl-N—

(S)-2-(isopropoxycarbonyl)ethyl thiophosphoramidate;

4′

-Fluoro-2′

-methyluridine-3′

,5′

-cyclic phosphoric acid isopropyl ester;

4′

-Fluoro-2′

-methylcytidine-3′

,5′

-cyclic phosphoric acid isopropyl ester;

4′

-Fluoro-2′

-methyluridine-3′

,5′

-cyclic thiophosphoric acid isopropyl ester;

4′

-Fluoro-2′

-methylcytidine-3′

,5′

-cyclic thiophosphoric acid isopropyl ester;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methyluridine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methylcytidine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methyluridine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate;

2′

-Deoxy-2′

,4′

-difluoro-2′

-methylcytidine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate;

4′

-Fluoro-2′

-methyluridine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate;

4′

-Fluoro-2′

-methylcytidine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]phosphorodiamidate;

4′

-Fluoro-2′

-methyluridine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate; and

4′

-Fluoro-2′

-methylcytidine-5′

-{N,N′

-bis[(S)-1-(isopropoxylcarbonyl)ethyl]thiophosphorodiamidate.