Aza-pyridone compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10208045-B2
Application number	US-201615065627-A
Country	US
Kind code	B2
Filing date	Mar 9, 2016
Priority date	Mar 11, 2015
Publication date	Feb 19, 2019
Grant date	Feb 19, 2019

Abstract

Disclosed herein are aza-pyridone compounds, pharmaceutical compositions that include one or more aza-pyridone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an orthomyxovirus infection, with an aza-pyridone compound. Examples of an orthomyxovirus viral infection include an influenza infection.

First claim

What is claimed is:

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

wherein:
R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-4 alkyl, an optionally substituted heterocyclyl, —C(═O)Y 1 , —C(═O)—O—Y 1 , —(CH 2 )—O—C(═O)—Y 1 , —(CH 2 )—O—C(═O)—O—Y 1 , —(CHCH 3 )—O—C(═O)—Y 1 and —(CHCH 3 )—O—C(═O)—O—Y 1 ;
R 2 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 heterocyclyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl);
R 3a and R 3b are independently hydrogen or an optionally substituted C 1-4 alkyl;
R 4 is selected from the group consisting of:

R 6A and R 6B are each hydrogen, each fluoro or each chloro; or
R 6A and R 6B are independently hydrogen, an unsubstituted C 1-4 alkyl or an unsubstituted C 2-4 alkynyl, provided that at least one of R 6A and R 6B is an unsubstituted C 1-4 alkyl or an unsubstituted C 2-4 alkynyl;
R 6C is an optionally substituted aryl or an optionally substituted heteroaryl;
R 6D is an optionally substituted heteroaryl;
R 6E and R 6F are each hydrogen or each fluoro;
R 6G and R 6H are each fluoro or each chloro;
R 5 is selected from the group consisting of hydrogen, halogen, —CN, an optionally substituted C 1-6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —CH 2 OH, —CH(Y 2 )(OH) and —C(O)Y 2 ;
Y 1 and Y 2 are independently selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, a mono-substituted amino group, a di-substituted amino and —C(R 7 ) 2 NHR 8 ; and
each R 7 and R 8 are independently hydrogen or an optionally substituted C 1-4 alkyl; and
provided that:
when R 4 is

wherein R 6A and R 6B are each hydrogen, and R 2 is hydrogen, CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CF 3 , —CH 2 —(C 3 -cyclopropyl), tetrahydro-2H-pyran, —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 or —C(CH 3 ) 2 CH 2 OCH 3 ; then R 1 is not hydrogen, —C(═O)CH 3 , —C(═O)CH(CH 3 ) 2 , —C(═O)CH 2 CH(CH 3 ) 2 , —C(═O)—(C 5-6 -cycloalkyl), —C(═O)-(tetrahydro-2H-pyran), —C(═O)—O—CH(CH 3 ) 2 , —C(═O)—O—CH 2 CH(CH 3 ) 2 , —CH 2 —O—C(═O)CH(CH 3 )(NH 2 ), —CH 2 —O—C(═O)CH(CH(CH 3 ) 2 )(NH 2 ) or —CH 2 —O—C(═O)C((CH 3 ) 2 )(NH 2 );
when R 4 is

wherein R 6A and R 6B are each fluoro, and R 2 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 —(C 3 -cyclopropyl), -unsubstituted benzyl, —CH 2 CH 2 OH or —CH 2 CH 2 OCH 3 ; then R 1 is not hydrogen, —CH 2 CH 3 , —C(═O)CH 3 , —C(═O)CH(CH 3 ) 2 , —CH 2 —O—C(═O)—O-(phenyl substituted with methyl and nitro), —CH 2 —O—C(═O)—NH—CH 2 CH 2 -(morpholine), —CH 2 —O—C(═O)CH(CH(CH 3 ) 2 )(NH 2 ) or —CH 2 —O—C(═O)NH(CH 3 );
when R 4 is

wherein R 6A and R 6B are each chloro, and R 2 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 —(C 3 -cyclopropyl), —CH 2 CH 2 OH or —CH 2 CH 2 OCH 3 ; then R 1 is not hydrogen or —C(═O)CH(CH 3 ) 2 ;
when R 4 is

wherein one of R 6A and R 6B is an unsubstituted C 1-4 alkyl; then R 1 is not hydrogen;
when R 4 is

wherein R 6E and R 6F are each hydrogen, and R 2 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 —(C 3 -cyclopropyl), an unsubstituted benzyl, —CH(CH 3 )CF 3 , —CH 2 CH 2 OH or —CH 2 CH 2 OCH 3 ; then R 1 is not hydrogen or —C(═O)CH(CH 3 ) 2 ;
when R 4 is

wherein R 6E and R 6F are each fluoro, and R 2 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 —(C 3 -cyclopropyl), —CH 2 CH 2 OH or —CH 2 CH 2 OCH 3 ; then R 1 is not hydrogen or —C(═O)CH(CH 3 ) 2 ;
when R 4 is

wherein R 6C is pyrazolyl and R 6D is unsubstituted phenyl; then R 6C is a di-substituted pyrazolyl;
wherein when R 4 is

wherein R 6C is an optionally substituted imidazolyl or an optionally substituted pyridinyl; then R 6D is not an optionally substituted phenyl; and
when R 4 is

wherein R 6G and R 6H are each fluoro or each chloro, and R 2 is —CH 3 ; then R 1 is not hydrogen.

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

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6A and R 6B are each hydrogen.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6A and R 6B are each fluoro or each chloro.

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein one of R 6A and R 6B is an unsubstituted C 1-4 alkyl or an unsubstituted C 2-4 alkynyl.

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

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 6C is an optionally substituted aryl or an optionally substituted heteroaryl.

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 6D is an optionally substituted heteroaryl.

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

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 6E and R 6F are each hydrogen.

11. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 6E and R 6F are each fluoro.

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

Assignees

• Alios Biopharma Inc

Inventors

• Hendricks Robert Than
• Beigelman Leonid
• Smith David Bernard
• Stoycheva Antitsa Dimitrova

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61K31/215

  of carboxylic acids · CPC title

• C07H17/02

  Heterocyclic radicals containing only nitrogen as ring hetero atoms · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title