Substituted nucleosides, nucleotides and analogs thereof

Patent metadata

Field	Value
Publication number	US-9815864-B2
Application number	US-201414313043-A
Country	US
Kind code	B2
Filing date	Jun 24, 2014
Priority date	Jun 26, 2013
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

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, of the Formula (I).

Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a norovirus, with a nucleoside, a nucleotide and an analog thereof.

First claim

What is claimed is:

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

wherein:
B 1A is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;
R aa1 and R aa2 are independently hydrogen or deuterium;
R A is hydrogen, deuterium, an unsubstituted C 1-3 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 2-3 alkynyl or cyano;
R 1A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid,

R 2A is selected from the group consisting of halogen, azido, an optionally 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 halogen, OH, —OC(═O)R″ A and an optionally substituted O-linked amino acid;
R 4A is selected from the group consisting of hydrogen, halogen, OR 1D , an optionally substituted O-linked amino acid, azido and NR 2D R 3D ;
R 1D is hydrogen or —C(═O)R ″D ;
R 2D and R 3D are independently hydrogen or an optionally substituted C 1-6 alkyl;
R 5A 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 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 and the asterisks indicate the points og attachment in the R 1A moiety defined to include variables R 6A and R 7A ;
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, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-monocyclic heterocyclyl and

R 25A1 , R 25A2 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 alkylcarbonyl, C 2-8 alkoxycarbonyl and C 2-8 alkylaminocarbonyl;
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 and R ″D are independently an optionally substituted C 1-24 -alkyl;
h is 1 or 2;
w1 is 0 or 1;
w2 is 3, 4 or 5;
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; and
Z 1A , Z 2A , Z 3A and Z 4A are independently O or S.

2. The method of claim 1 , wherein R 1A is an optionally substituted acyl, an optionally substituted O-linked amino acid,

3. The method of claim 2 , wherein R 6A and R 7A are independently selected from the group consisting of hydrogen, absent, 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 aryl(C 1-6 alkyl), *—(CR 15A R 16A ) p —O—C 1-24 alkyl, *—(CR 17A R 18A ) q —O—C 2-24 alkenyl,

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.

4. The method of claim 2 , wherein R 8A is 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 and an optionally

Assignees

• Alios Biopharma Inc

Inventors

• Beigelman Leonid
• Deval Jerome
• Jin Zhinan

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• C07H19/11

  containing cyclic phosphate · CPC title

• C07H19/06

  Pyrimidine radicals · CPC title

• C07H19/20 Primary

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