Substituted nucleosides, nucleotides and analogs thereof

Patent metadata

Field	Value
Publication number	US-10370401-B2
Application number	US-201715790764-A
Country	US
Kind code	B2
Filing date	Oct 23, 2017
Priority date	Oct 11, 2013
Publication date	Aug 6, 2019
Grant date	Aug 6, 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 Picornavirus and/or Flaviviridae infection with one or more nucleosides, nucleotides and nucleotide analogs.

First claim

What is claimed is:

1. A method for ameliorating or treating a Picornaviridae viral infection comprising contacting a cell infected with the Picornaviridae virus 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 selected from the group consisting of OH, OC(═O)R″ A and an unsubstituted O-linked α-amino acid;
R 4A is selected from the group consisting of OH and 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;
R 5A is selected from the group consisting of an unsubstituted C 1-6 alkyl and an unsubstituted C 2-6 alkenyl;
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; or
R 8A is absent, hydrogen, an optionally substituted phenyl or an optionally substituted naphthyl;
R 9A is an optionally substituted N-linked amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the optionally substituted N-linked α-amino acid ester derivative is an unsubstituted C 1-6 alkyl ester, an optionally substituted C 3-6 cycloalkyl ester, an optionally substituted C 6 aryl ester, an optionally substituted C 10 aryl ester or an optionally substituted benzyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine;
R 10A and R 11A are independently an optionally substituted N-linked amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the optionally substituted N-linked α-amino acid ester derivative is an unsubstituted C 1-6 alkyl ester, an optionally substituted C 3-6 cycloalkyl ester, an optionally substituted C 6 aryl ester, an optionally substituted Cm aryl ester or an optionally substituted benzyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine;
R 12A and R 13A are independently absent or hydrogen;
R 14A is O − , OH or methyl;
R 22A and R 23A are each hydrogen;
R 24A is selected from the group consisting of hydrogen, an unsubstituted C 1-24 alkyl, and an unsubstituted —O—C 1-24 alkyl;
R″ A is an unsubstituted 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.

2. The method of claim 1 , wherein the virus is an Enterovirus.

3. The method of claim 1 , wherein the virus is a Rhinovirus.

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

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

wherein R G2 is ethyl.

6. The method of claim 1 , wherein R 2A is fluoro.

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

8. The method of claim 1 , wherein R 3A is —OC(═O)R″ A , wherein R″ A is an unsubstituted C 1-4 alkyl.

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

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

11. The method of claim 10 , wherein R 4A is fluoro.

12. The method of claim 1 , wherein R 5A is an unsubstituted C 1-6 alkyl.

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

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

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

16. The method of claim 15 , wherein R 6A is

R 7A , R 12A and R 13A are independently absent or hydrogen; R 14A is O − and OH; and m is 0 or 1.

17. The method of claim 16 , wherein m is 1.

18. The method of claim 1 , wherein R a1 and R a2 are each hydrogen.

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

20. The method of claim 15 , wherein R 6A and R 7A are independently absent or hydrogen.

21. The method of claim 15 , wherein R 6A and R 7A are each

wherein s is 0.

22. The method of claim 15 , wherein R 6A and R 7A are each isopropyloxycarbonyloxymethyl.

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

24. The method of claim 23 , wherein R 8A is an optionally substituted phenyl.

25. The method of claim 24 , wherein R 8A is an unsubstituted phenyl.

26. The method of claim 25 , wherein R 9A is an unsubstituted C 1-6 alkyl ester or an unsubstituted C 3-6 cycloalkyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked isoleucine, N-linked leucine and N-linked valine.

27. The method of claim 25 , wherein R 9A is selected from the group consisting of

28. Th

Assignees

• Alios Biopharma Inc
• Janssen Biopharma Inc

Inventors

• Beigelman Leonid
• Wang Guangyi
• Smith David Bernard
• Prhavc Marija
• Jekle Christian Andreas
• Deval Jerome

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61K31/708

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

• A61K31/7052

  having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides · CPC title

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title