Derivatives of uridine 5'-cyclophosphate useful to treat hepatitis c viral infections

Patent metadata

Field	Value
Publication number	US-2016347783-A1
Application number	US-201415034757-A
Country	US
Kind code	A1
Filing date	Nov 19, 2014
Priority date	Nov 22, 2013
Publication date	Dec 1, 2016
Grant date	—

Abstract

Some embodiments of the present invention include nucleoside 5′-monophosphate derivative compounds, their preparation and their uses. In some embodiments, such compounds are useful to treat hepatitis C viral infections.

First claim

1 . A compound of Formula I:

and pharmaceutically acceptable salts thereof,
wherein:
R is an optionally substituted phenyl or an optionally substituted pyridyl; and
R 1 is selected from the group consisting of a C 1 -C 8 alkyl, and a C 1 -C 8 heteroalkyl, each optionally substituted with one or more halo; provided that R 1 is not propionyl.

2 . The compound of claim 1 , wherein R is selected from the group consisting of:

3 . The compound of claim 1 , wherein R is selected from the group consisting of

4 . The compound of claim 1 , wherein R 1 is selected from the group of a C 1 -C 6 haloalkyl, a C 1 -C 6 acyl, a C 1 -C 6 haloacyl, a C 1 -C 6 heteroacyl, and a C 1 -C 6 haloheteroacyl.

5 . (canceled)

6 . (canceled)

7 . The compound of claim 1 , wherein R 1 is selected from the group consisting of —C(═O)C(NH 2 )R 2 , —CH 2 R 3 , and —C(═O)OCH 2 CH 3 , wherein R 2 is alkyl; R 3 is selected from —OH, —CH 3 , or —O—C(═O)CH 3 .

8 . The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 1 having the structure of Formula I-A:

and pharmaceutically acceptable salts thereof,
wherein:
R 1A is C 1 -C 8 alkyl optionally substituted with one or more R 1AA ;
each R 1AA is independently hydroxy, halo, or —O—C(═O)R 1AB ; and
R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

10 . The compound of claim 9 , wherein R 1A is C 1 -C 8 alkyl substituted with one or more R 1AA ;
each R 1AA is independently hydroxy, or halo; and R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

11 . The compound of claim 9 , wherein R 1A is C 1 -C 8 alkyl substituted with one or more R 1AA ;
each R 1AA is independently —O—C(═O)R 1AB ; and R 1AB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

12 . The compound of claim 1 having the structure of Formula I-B:

and pharmaceutically acceptable salts thereof,
wherein:
R 1B is C 1 -C 8 alkyl or C 1 -C 8 alkoxy each optionally subsitituted with one or more R 1BA , or R 1B is —N(R 1C ) 2 ;
each R 1C is independently hydrogen or C 1 -C 8 alkyl;
each R 1BA is independently hydroxy, halo, —N(R 1CC ) 2 or —OR BB ;
R 1BB is C 1 -C 8 alkyl or C 1 C 8 haloalkyl; and
each R 1CC is independently hydrogen or C 1 -C 8 alkyl.

13 . The compound of claim 12 , wherein R 1B is C 1 -C 8 alkyl or C 1 -C 8 alkoxy each optionally substituted with one or more R 1BA ;
each R 1BA is independently hydroxy, halo, —N(R 1CC ) 2 or —OR 1BB ; R 1BB is C 1 -C 8 alkyl or C 1 -C 8 haloalkyl; and each R 1CC is independently hydrogen or C 1 -C 6 alkyl.

14 . The compound of claim 12 , wherein R 1B is —N(R 1C ) 2 ;
each R 1C is independently hydrogen or C 1 -C 6 alkyl.

15 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

16 . A method of treating a viral infection in a subject comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

17 . The method of claim 16 , further comprising administering an effective amount of an additional therapeutic agent to the subject wherein the additional therapeutic agent is selected from the group consisting of thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, an inhibitor of HCV helicase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, ribavirin, interferon-α, and pegylated interferon-α.

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . (canceled)

22 . The method of claim 16 , wherein the viral infection comprises hepatitis C (HCV).

23 . (canceled)

24 . (canceled)

25 . A method of inhibiting viral replication in a cell comprising contacting the cell with the compound of claim 1 .

26 . The method of claim 25 , wherein the viral replication is RNA-dependent.

27 . (canceled)

28 . The method of claim 25 , further comprising contacting the cell with an additional antiviral agent(s) selected from the group consisting of ribavirin, thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, ribavirin, interferon-α, and pegylated interferon-α.

29 . (canceled)

30 . (canceled)

31 . (canceled)

32 . (canceled)

33 . The method of claim 25 , wherein the cell is a hepatocyte.

34 - 53 . (canceled)

Assignees

• Ligand Pharm Inc

Inventors

• Zhi Lin

Classifications

• A61P31/14

  for RNA viruses · CPC title

• C07H19/10 Primary

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

• C07H19/11

  containing cyclic phosphate · CPC title