Orally-bioavailable nucleoside analogs

Patent metadata

Field	Value
Publication number	US-11638715-B2
Application number	US-202217842402-A
Country	US
Kind code	B2
Filing date	Jun 16, 2022
Priority date	Jun 14, 2021
Publication date	May 2, 2023
Grant date	May 2, 2023

Abstract

Described herein are orally-bioavailable nucleoside analogs and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of coronavirus infections, including SARS-CoV-2 infection.

First claim

What is claimed is:

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

wherein:
X is hydrogen or —CN;
G is

R 11 is hydrogen, —C(═O)R 21 , —C(═O)OR 21 , or C 1 -C 6 alkyl optionally substituted with one or more R 11a ;
each R 11a is independently halogen, —CN, —OH, —OR a , —NR c R d , cycloalkyl, or heterocycloalkyl;
or two R 11a on the same atom are taken together to form an oxo;
R 21 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 21a ;
each R 21a is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;
or two R 21a on the same atom are taken together to form an oxo;
or two R 21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
R 12 is hydrogen, —C(═O)R 22 , —C(═O)OR 22 , or C 1 -C 6 alkyl optionally substituted with one or more R 12a ;
each R 12a is independently halogen, —CN, —OH, —OR a , —NR c R d , cycloalkyl, or heterocycloalkyl;
or two R 12a on the same atom are taken together to form an oxo;
R 22 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a ;
each R 22a is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;
or two R 22a on the same atom are taken together to form an oxo;
or two R 22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
R 13 is hydrogen or C 1 -C 6 alkyl;
R 14 is —OH or fluoro;
R 15 is hydrogen, —C(═O)R 25 , —C(═O)OR 25 , —CH 2 —O—C(═O)R 25 , —CH 2 —O—C(═O)OR 25 , or C 1 -C 6 alkyl optionally substituted with one or more R 15a ;
each R 15a is independently halogen, —CN, —OH, —OR a , —NR c R d , cycloalkyl, or heterocycloalkyl;
or two R 15a on the same atom are taken together to form an oxo;
R 25 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 25a ;
each R 25a is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;
or two R 25a on the same atom are taken together to form an oxo;
or two R 25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
R 16 is —C(═O)R 26 , —C(═O)OR 26 , —CH 2 —O—C(═O)R 26 , or —CH 2 —O—C(═O)OR 26 ;
R 26 is C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 26a ;
each R 26a is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R 26a on the same atom are taken together to form an oxo;
or two R 26a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 ,

Assignees

• Venatorx Pharmaceuticals Inc

Inventors

• Burns Christopher J
• Coburn Glen
• Chu Guo-Hua
• Condon Stephen M
• Boyd Steven A
• Pevear Daniel C

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K9/4858

  Organic compounds · CPC title

• C07H19/173

  with 2-deoxyribosyl as the saccharide radical · CPC title

• C07H15/06

  being a hydroxyalkyl group esterified by a fatty acid · CPC title