Substituted nucleosides, nucleotides and analogs thereof

Patent metadata

Field	Value
Publication number	US-9073960-B2
Application number	US-201213721988-A
Country	US
Kind code	B2
Filing date	Dec 20, 2012
Priority date	Dec 22, 2011
Publication date	Jul 7, 2015
Grant date	Jul 7, 2015

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 selected from Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
B 1A is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;
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, a sulfenyl substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted —O—C 1-6 alkyl, an optionally substituted —O—C 3-6 alkenyl, an optionally substituted —O—C 3-6 alkynyl and cyano;
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 or chloro;
R 5A is hydrogen or halogen;
R 6A , R 7A and R 8A are independently selected from the group consisting of absent, 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,

or
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 9A is independently selected from the group consisting of 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, 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 independently absent or hydrogen;
each R 15A , each R 16A , each R 17A and each R 18A are independently hydrogen, an optionally substituted C 1-24 alkyl or alkoxy;
R 19A , R 20A , R 22A and R 23A are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 21A and R 24A are independently 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 independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 26A and R 27A are independently —C≡N or an optionally substituted substituent selected from the group consisting of C 2-8 organylcarbonyl, C 2-8 alkoxycarbonyl and C 2-8 organylaminocarbonyl;
R 28A is 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 and an optionally substituted C 3-6 cycloalkenyl;
R 30A and R 31A are 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 and an optionally substituted C 3-6 cycloalkenyl;
R″ A is an optionally substituted C 1-24 -alkyl;
m is 0 or 1;
p and q are independently selected from the group consisting of 1, 2 and 3;
r is 1 or 2;
Z 1A , Z 2A , Z 3A and Z 4A are independently O or S; and
provided that when R 1A is

wherein R 8A is an unsubstituted C 1-4 alkyl or phenyl optionally para-substituted with a halogen or methyl and R 9A is methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tryptophan, methionine and proline; R 3A is OH; R 4A is fluoro; R 5A is fluoro or hydrogen; and B 1A is an unsubstituted uracil; then R 2A cannot be —OCH 3 ;
provided that when R 1A is H; R 3A is OH; R 4A is fluoro; R 5A is fluoro; and B 1A is an unsubstituted cytosine; then R 2A cannot be allenyl; and
provided that when R 1A is H; R 3A is OH; R 4A is fluoro; R 5A is fluoro; and B 1A is an unsubstituted cytosine; then R 2A cannot be ethynyl.

2. The compound of claim 1 , wherein R 1A is

is

; and R 7A is absent or hydrogen.

3. The compound of claim 1 , wherein R 1A is an optionally substituted acyl.

4. The compound of claim 1 , wherein R 1A is H.

5. The compound of claim 1 , wherein R 1A is an optionally substituted O-linked amino acid.

6. The compound of claim 1 , wherein R 1A is

7. The compound of claim 6 , wherein both R 6A and R 7A are independently selected from the group consisting of 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 and an optionally substituted aryl(C 1-6 alkyl).

8. The compound of claim 6 , wherein both R 6A and R 7A are independently selected from the group consisting of

9. The compound of claim 6 , wherein R 6A and R 7A are both

*—(CR 15A R 16A ) p —O—C 1-24 alkyl or *—(CR 17A R 18A ) q —O—C 2-24 alkenyl; or wherein R 6A and R 7A can be taken together to form a moiety selected from the group consisting of an optionally substituted

Assignees

• Alios Biopharma Inc

Inventors

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

Classifications

• C07D405/04

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

• C12N9/127

  RNA-directed RNA polymerase (2.7.7.48), i.e. RNA replicase · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07H19/14

  Pyrrolo-pyrimidine radicals · CPC title

• A61K45/06

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