Azido nucleosides and nucleotide analogs

Patent metadata

Field	Value
Publication number	US-9346848-B2
Application number	US-201414531552-A
Country	US
Kind code	B2
Filing date	Nov 3, 2014
Priority date	Sep 22, 2010
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

Disclosed herein are 4′-azido-substituted nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of 4′-azido-substituted 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 4′-azido-substituted nucleoside, a nucleotide and/or an analog thereof. Examples of viral infections include a respiratory syncytial viral (RSV) and influenza infection.

First claim

What is claimed is:

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

wherein:
B 1 is selected from the group consisting of:

R 1 is selected from the group consisting of hydrogen,

n is 0, 1 or 2;
R 2 and R 3 are independently selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl;
R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR 18 and —OC(═O)R 19 ;
R 5 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl and —OR 20 ;
R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl and —OR 22 ;
or R 5 and R 6 are both oxygen atoms and linked together by a carbonyl group;

R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR 24 and —OC(═O)R 25 ;
R 8 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl;
R 9 , R 10 , each R 11 , R 12 and R 13 are independently absent or hydrogen;
R 14 is selected from the group consisting of an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl and an —O-optionally substituted heterocyclyl, and R 15 is

 or
R 14 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R 15 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or
R 14 is O − , hydroxy or an —O-optionally substituted C 1-6 alkyl, and R 15 and R 5 together are O;
R 16 is selected from the group consisting of an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl and an —O-optionally substituted heterocyclyl, and R 17 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or
R 16 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R 17 is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or
R 16 is O − , hydroxy or an —O-optionally substituted C 1-6 alkyl, and R 17 and R 5 together are O;
R 18 , R 20 , R 22 and R 24 are independently selected from the group consisting of hydrogen and an optionally substituted C 1-6 alkyl;
R 19 and R 25 are independently selected from the group consisting of an optionally substituted C 1-6 alkyl and an optionally substituted C 3-6 cycloalkyl;
R 26 is hydrogen or an optionally substituted C 1-4 -alkyl;
R 27 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 1-6 haloalkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 6 aryl, an optionally substituted C 10 aryl and an optionally substituted aryl(C 1-6 alkyl); and
R 28 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6 alkyl) and an optionally substituted haloalkyl,
or R 26 and R 27 are taken together to form an optionally substituted C 3-6 cycloalkyl;
R A2 is selected from the group consisting of hydrogen, halogen and NHR J2 , wherein R J2 is selected from the group consisting of hydrogen, —C(═O)R K2 and —C(═O)OR L2 ;
R B2 is halogen or NHR W2 , wherein R W2 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 3-8 cycloalkyl, —C(═O)R M2 and —C(═O)OR N2 ;
R D2 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 E2 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-8 cycloalkyl, —C(═O)R R2 and C(═O)OR S2 ;
R F2 is hydrogen;
Y 2 is N or CR I2 , wherein R I2 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 G2 is an optionally substituted C 1-6 alkyl;
R H2 is hydrogen or NHR T2 , wherein R T2 is independently selected from the group consisting of hydrogen, —C(═O)R U2 and C(═O)OR V2 ,
R O2 is selected from the group consisting of hydrogen, —C(═O)R P2 and —C(═O)OR Q2 ;
R Y2 is hydrogen or NHR Z2 , wherein R Z2 is selected from the group consisting of hydrogen, —C(═O)R AA2 and C(═O)OR BB2 ;
R K2 R L2 , R M2 , R N2 , R P2 , R Q2 , R R2 , R S2 , R U2 , R V2 , R AA2 and R BB2 are independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 3-6 cycloalkynyl, C 6-10 aryl, heteroaryl, heteroalicyclyl, aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl) and heteroalicyclyl(C 1-6 alkyl);
wherein each “optionally substituted” moiety is either unsubstituted or substituted, and wherein each substituted moiety is substituted with one or more substituents individually and independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocycanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amio, a mono-substituted amino group and a di-substituted amino group;
provided that when R 2 , R 3 , R 4 , and R 8 are all hydrogen, R 1 cannot be hydrogen;
provided that when R 2 and R 3 are both hydrogen, R 5 is hydroxy, R 4 and R 6 are both hydrogen, R 7 is halogen, R 8 is hydrogen, and B 1 is

 then R 1 cannot be

 wherein n is 0 or 2; and R 9 , R 1 ° and R 11 are hydrogen;
provided that when R 1 is

 R 2 and R 3 are both hydrogen, R 4 is hydrogen, R 5 is OH, R 6 is selected from the group consisting of halogen, hydrogen, and hydroxy, R 7 is selected from the group consisting of halogen, hydrogen, methyl, and hydroxy, R 8 is hydrogen, B 1 is selected from the group consisting of

 R 14 is an —O-optionally substituted aryl, then R 1

Assignees

• Alios Biopharma Inc

Inventors

• Beigelman Leonid
• Deval Jerome
• Smith David Bernard
• Wang Guangyi
• Rajwanshi Vivek Kumar

Classifications

• A61K31/7076

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

• C07H19/067 Primary

  with ribosyl as the saccharide radical · CPC title

• C07H19/167

  with ribosyl as the saccharide radical · CPC title

• A61P31/12

  Antivirals · CPC title

• C07H19/10

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