Substituted nucleosides, nucleotides and analogs thereof

Patent metadata

Field	Value
Publication number	US-9598457-B2
Application number	US-201314654360-A
Country	US
Kind code	B2
Filing date	Dec 19, 2013
Priority date	Dec 21, 2012
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.

First claim

What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

wherein:
B 1 is an optionally substituted

an optionally substituted

or an

R 1 is selected from the group consisting of an unsubstituted C 1-6 alkyl, an unsubstituted C 2-6 alkenyl, an unsubstituted C 2-6 alkynyl, an unsubstituted C 3-6 cycloalkyl and an unsubstituted C 1-6 haloalkyl;
R 2 is halo, —OR 9A or —N(R 9B R 9C );
R 3 is

R 4A is selected from the group consisting of O − , OH, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
R 4B is selected from the group consisting of O − , OH, an —O-optionally substituted phenyl, an —O-optionally substituted heteroaryl and an —O-optionally substituted heterocyclyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted C 3-6 alkenyl, an unsubstituted C 3-6 alkynyl and an unsubstituted C 3-6 cycloalkyl;
R 7 is NHR 13 ;
R 8 is NHR 14 ;
R 9A is hydrogen or —C(═O)R 15 ;
R 9B and R 9C are independently hydrogen or an optionally substituted C 1-6 alkyl;
R 13 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 alkenyl, an optionally substituted C 3-6 cycloalkyl, —C(═O)R A1 and —C(═O)OR A2 ;
R 14 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 alkenyl, an optionally substituted C 3-6 cycloalkyl, —C(═O)R A3 and —C(═O)OR A4 ;
R 15 is an optionally substituted C 1-6 alkyl or an optionally substituted C 3-6 cycloalkyl;
X 1 is N or —CR 16 ,
R 16 is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl and an optionally substituted C 2-6 alkynyl;
R A1 , R A2 , R A3 and R A4 are independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, heteroaryl, heteroalicyclyl, aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl) and heteroalicyclyl(C 1-6 alkyl);
Z 1 is O or S; and
provided that when R 3 is

and R 4A is O − or OH, then R 4B is O − or OH; and
when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

2. The compound of claim 1 , wherein R 4A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; and R 4B is an —O-optionally substituted phenyl.

3. The compound of claim 2 , wherein R 4B is an —O-unsubstituted phenyl.

4. The compound of claim 2 , wherein R 4B is an —O-substituted phenyl.

5. The compound of claim 2 , wherein R 4A is an optionally substituted N-linked amino acid ester derivative.

6. The compound of claim 5 , wherein R 4A is an optionally substituted C 1-5 alkyl ester, an optionally substituted C 3-6 cycloalkyl ester, an optionally substituted phenyl ester or an optionally substituted benzyl ester of an N-linked amino acid selected from the group consisting of N-linked alanine, N-linked glycine, N-linked leucine or N-linked valine.

7. The compound of claim 5 , wherein R 4A is an optionally substituted C 1-5 alkyl ester, an optionally substituted C 3-6 cycloalkyl ester, an optionally substituted phenyl ester or an optionally substituted benzyl ester of N-linked alanine.

8. The compound of claim 5 , wherein R 4A is an optionally substituted C 1-5 alkyl ester or an optionally substituted C 3-6 cycloalkyl ester of N-linked alanine.

9. The compound of claim 1 , wherein R 4B is O − or OH; and R 4A is O − or OH.

10. The compound of claim 1 , wherein B 1 is

11. The compound of claim 1 , wherein B 1 is

12. The compound of claim 11 , wherein R 6 is an unsubstituted C 1-6 alkyl.

13. The compound of claim 12 , wherein the unsubstituted C 1-6 alkyl is ethyl.

14. The compound of claim 11 , wherein R 6 is an unsubstituted C 3-6 cycloalkyl.

15. The compound of claim 1 , wherein R 2 is —OH.

16. The compound of claim 1 , wherein R 1 is an unsubstituted C 1-6 alkyl.

17. The compound of claim 16 , wherein R 1 is methyl.

18. The compound of claim 1 , wherein Z 1 is O.

19. The compound of claim 1 , wherein Z 1 is S.

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

or a pharmaceutically acceptable salt of the foregoing.

Assignees

• Alios Biopharma Inc

Inventors

• Smith David Bernard
• Beigelman Leonid
• Wang Guangyi
• Welch Michael Hunter

Classifications

• C07H19/16

  Purine radicals · CPC title

• C07H19/207 Primary

  the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide · CPC title

• C07H19/20

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

• A61P31/14

  for RNA viruses · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title