Substituted nucleosides, nucleotides and analogs thereof

Patent metadata

Field	Value
Publication number	US-10464965-B2
Application number	US-201514790645-A
Country	US
Kind code	B2
Filing date	Jul 2, 2015
Priority date	Dec 22, 2011
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.

First claim

What is claimed is:

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

wherein:
B 1A is an optionally substituted purine base or an optionally substituted pyrimidine base;
R 1A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid,

the dashed line (------) is absent;
R 2A is selected from the group consisting of an unsubstituted C 1-6 alkyl, a halogen-substituted C 1-6 alkyl, a hydroxy-substituted C 1-6 alkyl, an alkoxy-substituted C 1-6 alkyl and a sulfenyl-substituted C 1-6 alkyl;
R 3A is selected from the group consisting of OH, OC(═O)R″ A and an optionally substituted O-linked amino acid;
R 4A is fluoro;
R 5A is hydrogen;
R 6A and R 7A are each absent or independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C 1-6 alkyl), an optionally substituted *—(CR 15A R 16A ) p —O—C 1-24 alkyl, an optionally substituted *—(CR 17A R 18A ) q —O—C 1-24 alkenyl,

R 6A is

and R 7A is absent or hydrogen; or
R 6A and R 7A are taken together to form a moiety selected from the group consisting of an optionally substituted

and an optionally substituted

wherein the oxygens connected to R 6A and R 7A , the phosphorus and the moiety form a six-membered to ten-membered ring system;
R 8A is selected from the group consisting of absent, hydrogen, an optionally substituted aryl and an optionally substituted heteroaryl;
R 9A is selected from the group consisting of NR 30A R 31A , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
R 10A and R 11A are independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
R 12A , R 13A and R 14A are each independently absent or hydrogen;
each R 15A , each R 16A , each R 17A and each R 18A are each independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and alkoxy;
R 22A and R 23A are each independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 24A is selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C 1-24 alkyl and an optionally substituted —O-aryl;
R 25A and R 29A are each independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R″ A is an optionally substituted C 1-24 -alkyl;
m is 0 or 1;
p and q are each independently selected from the group consisting of 1, 2 and 3; and
Z 1A , Z 2A , Z 3A , Z 4A are each O.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A is

R 6A is absent or hydrogen; and R 7A is absent or hydrogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A is an unsubstituted acyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A is

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein both R 6A and R 7A are

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B 1A is

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2A is a halogen-substituted C 1-6 alkyl.

8. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

9. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A is

R 6A is

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

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1A is

R 6A is

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

12. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the unsubstituted acyl is —C(═O)R 39A wherein R 39A is selected from the group consisting of an unsubstituted C 1-12 alkyl, an unsubstituted C 2-12 alkenyl, an unsubstituted C 2-12 alkynyl, an unsubstituted C 3-8 cycloalkyl, an unsubstituted C 5-8 cycloalkenyl, an unsubstituted C 6-10 aryl, an unsubstituted heteroaryl, an unsubstituted heterocyclyl, an unsubstituted aryl(C 1-6 alkyl), an unsubstituted heteroaryl(C 1-6 alkyl) and an unsubstituted heterocyclyl(C 1-6 alkyl).

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 39A is an unsubstituted C 1-12 alkyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B 1A is an optionally substituted purine base.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B 1A is an optionally substituted pyrimidine base.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B 1A is

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B 1A is

Assignees

• Alios Biopharma Inc

Inventors

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

Classifications

• C07D493/04

  Ortho-condensed systems · CPC title

• C07H19/20

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

• C07H19/06 Primary

  Pyrimidine radicals · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07H19/207

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