Substituted nucleosides, nucleotides and analogs thereof

Patent metadata

Field	Value
Publication number	US-10307439-B2
Application number	US-201715423270-A
Country	US
Kind code	B2
Filing date	Feb 2, 2017
Priority date	Jun 24, 2014
Publication date	Jun 4, 2019
Grant date	Jun 4, 2019

Abstract

Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.

First claim

What is claimed is:

1. A method for ameliorating or treating a betacoronavirus infection comprising contacting a cell infected with the betacoronavirus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:

wherein:
B 1A is

 wherein R G2 is an unsubstituted C 1-6 alkyl;
R 3A is halo, OH, —OC(═O)R″ A or an unsubstituted O-linked α-amino acid;
R 4A is OH or halo;
R a1 and R a2 are independently hydrogen or deuterium;
R A is hydrogen or deuterium;
R 1A is selected from the group consisting of hydrogen,

R 2A is halo or —(CH 2 ) 1-6 halogen;
R 5A is selected from the group consisting of an unsubstituted C 1-6 alkyl, an unsubstituted C 2-6 alkenyl and an unsubstituted C 2-6 alkynyl;
R 6A and R 7A are independently selected from the group consisting of absent, hydrogen and

 or
R 6A is

 and R 7A is absent or hydrogen;
R 8A is an absent, hydrogen, an optionally substituted phenyl or an optionally substituted naphthyl;
R 9A is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
R 10A and R 11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
R 12A and R 13A are independently absent or hydrogen;
R 14A is O − or OH;
R 22A and R 23A are each hydrogen;
R 24A is selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted —O—C 1-24 alkyl;
m is 0 or 1;
s is 0, 1, 2 or 3; and
Z 1A , Z 2A , Z 3A and Z 4A are each O; and
wherein 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, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, -thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

2. The method of claim 1 , wherein the cell is in a human subject.

3. The method of claim 1 , wherein the betacoronavirus is MERS-CoV.

4. The method of claim 1 , wherein the betacoronavirus is SARS-CoV.

5. The method of claim 1 , wherein R 2A is F.

6. The method of claim 1 , wherein R 2A is —(CH 2 ) 1-6 F.

7. The method of claim 6 , wherein R 2A is —CH 2 ) F.

8. The method of claim 1 , wherein R 3A is OH.

9. The method of claim 1 , wherein R 3A is F.

10. The method of claim 1 , wherein R 4A is OH.

11. The method of claim 1 , wherein R 4A is F.

12. The method of claim 1 , wherein R 5A is methyl.

13. The method of claim 1 , wherein R 5A is ethynyl.

14. The method of claim 1 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F or CH 2 F; R 3A is OH or F; R 4A is OH or F; and R 5A is methyl or ethynyl.

15. The method of claim 1 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F; R 3A is OH; R 4A is F; and R 5A is methyl.

16. The method of claim 1 , wherein B 1A is

wherein R G2 is CH 2 CH 3 ; R a1 and R a2 are each hydrogen; R A is hydrogen; R 2A is F; R 3A is F; R 4A is OH; and R 5A is methyl.

17. The method of claim 1 , wherein R 1A is hydrogen.

18. The method of claim 1 , wherein R 1A is

19. The method of claim 18 , wherein R 6A is absent or hydrogen; and R 7A is absent or hydrogen.

20. The method of claim 18 , wherein R 6A and R 7A are independently

s is 0; and R 24A is an unsubstituted C 1-4 alkyl or an unsubstituted —O—C 1-4 alkyl.

21. The method of claim 18 , wherein R 6A is

m is 0, and R 7A , R 12A and R 13A are independently absent or hydrogen.

22. The method of claim 18 , wherein R 6A is

m is 1,R 7A , R 12A and R 13A are independently absent or hydrogen; and R 14A is O − or OH.

23. The method of claim 1 , wherein R 1A is

24. The method of claim 23 , wherein R 8A is an optionally substituted phenyl or an optionally substituted naphthyl; and R 9A is an optionally substituted N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the N-linked α-amino acid is selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, and the ester is selected from the group consisting of alkyl ester, cycloalkyl ester, an optionally substituted phenyl ester and an optionally substituted benzyl ester.

25. The method of claim 24 , wherein R 8A is an optionally substituted phenyl or an optionally substituted naphthyl; and R 9A is selected from the group consisting of N-linked alanine, N-linked alanine isopropyl ester, N-linked alanine cyclohexyl ester and N-linked alanine neopentyl ester.

26. The method of claim 1 , wherein B 1A is

27. The method of claim 1 , wherein B 1A is

wherein R G2 is —CH 2 CH 3 .

28. The method of claim 1

Assignees

• Alios Biopharma Inc

Inventors

• Blatt Lawrence M
• Beigelman Leonid
• Symons Julian Alexander
• Smith David Bernard

Classifications

• A61K31/708 Primary

  having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K45/06

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