Substituted pyrrolizine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10836769-B2
Application number	US-201916284812-A
Country	US
Kind code	B2
Filing date	Feb 25, 2019
Priority date	Feb 26, 2018
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

This application relates generally to certain substituted pyrrolizine compounds, and pharmaceutical compositions which inhibit HBV replication, and methods of making and using them.

First claim

What is claimed is:

1. A compound of Formula

or a pharmaceutically acceptable salt thereof,

wherein:
R 1 is C 1-6 alkyl optionally substituted with 1 to 3 R 1A , C 3-8 cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ;
each R 1A is independently halogen, —OH, —CN, C 1-2 haloalkyl, —C(O)NR X R Y , C 6-10 aryl optionally substituted with 1 to 3 R m , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R m , provided no more than 1 R 1A is C 6-10 aryl optionally substituted with 1 to 3 R m or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1B is independently —CN, halogen, C 1-6 alkyl optionally substituted with 1 to 3 —OH or —NR a R b , C 2-4 alkynyl, C 1-4 alkoxy, C 1-2 haloalkyl, C 3-6 cycloalkyl, —C(O)NR X R Y , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R m , provided no more than 1 R 1B is C 3-6 cycloalkyl or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1C is independently C 1-6 alkyl, oxo, C 1-4 haloalkyl, —C(O)H, —C(O)C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C(O)NR X R Y , or a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R m , provided no more than 1 R 1C is a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R X is independently —H, C 3-6 cycloalkyl, C 1-6 alkyl optionally substituted with 1 to 3 R Z , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R Y is independently —H or C 1-6 alkyl optionally substituted with 1 to 3 R Z ;
or R X and R Y are taken together to form a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
wherein each R Z is independently halogen, methyl, ethyl, oxo, —OH, —S(O) 2 C 1-3 alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
each R a is —H, C 1-3 alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R b is —H or C 1-3 alkyl; or
R a and R b taken together form a 3 to 8 membered monocyclic or bicyclic heterocycle optionally substituted with 1 to 3 R Z ;
the moiety

is a pyrrolidine or a 5-7 membered bicyclic heterocycle having one nitrogen, optionally substituted with 1 to 6 R 2 groups;
wherein each R 2 is independently halogen, C 1-3 alkyl, —OH, or —OC 1-3 alkyl;
R 3 is —H, halogen, or C 1-4 alkyl;
R 4 is C 6-10 aryl optionally substituted with 1 to 5 R 4A , or 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 4 R 4B ; and
each R 1D , R 4A , and R 4B are independently —CN, halogen, C 1-4 alkyl optionally substituted with —Si(C 1-4 alkyl) 3 , —OC 1-4 alkyl, —OC 1-4 haloalkyl, or C 1-4 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (II):

wherein
R 1 is C 1-6 alkyl optionally substituted with 1 to 3 R 1A , C 3-8 cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ;
each R 1A is independently halogen, —OH, —CN, C 1-2 haloalkyl, —C(O)NR X R Y , C 6-10 aryl optionally substituted with 1 to 3 R m , or a 5 to 43-8_membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R m , provided no more than 1 R 1A is C 6-10 aryl optionally substituted with 1 to 3 R m or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R m ;
each R 1B is independently halogen, C 1-6 alkyl optionally substituted with 1 to 3 —OH or —NR a R b , C 1-4 alkoxy, C 1-2 haloalkyl, C 2-6 alkyne, —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1B is 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1C is independently C 1-6 alkyl, oxo, C 1-4 haloalkyl, —C(O)H, —C(O)C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D ;
each R X is independently —H, C 3-6 cycloalkyl, C 1-6 alkyl optionally substituted with 1 to 3 R Z , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R Y is independently —H or C 1-6 alkyl optionally substituted with 1 to 3 R Z ;
or R X and R Y are taken together to form a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
wherein each R Z is independently halogen, methyl, ethyl, oxo, —OH, —S(O) 2 C 1-3 alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
each R a is —H, C 1-3 alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R b is —H or C 1-3 alkyl; or
R a and R b taken together form a 3 to 8 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1 to 3 R Z ;
each of R 2A , R 2B , R 2C , R 2D , R 2E , and R 2F are independently —H, halogen, C 1-3 alkyl, —OH, or —OC 1-3 alkyl, or R 2C or R 2D may be taken together with R 2A or R 2B or with R 2E or R 2F to form a cyclopropyl group;
R 3 is halogen or methyl;
R 4 is phenyl optionally substituted with 1 to 5 R 4A , or pyridinyl, optionally substituted with 1 to 4 R 4B ; and
each R 1D , R 4A , and R 4B are independently —CN, halogen, C 1-4 alkyl optionally substituted with-Si(C 1-4 alkyl) 3 , —OC 1-4 alkyl, —OC 1-4 haloalkyl, or C 1-4 haloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (II):

wherein
R 1 is C 3-6 cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 6 membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ;
each R 1B is independently halogen, C 1-6 alkyl optionally substituted with 1 —OH, C 2-6 alkyne, —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R m , provided no more than 1 R 1B is 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1C is independently —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R m ;
each R 1D is independently C 1-4 alkyl optiona

Assignees

• Gilead Sciences Inc

Inventors

• Gutierrez David Alan
• Kobayashi Tetsuya
• Lazerwith Scott E
• Lee Rick Andrew
• Morganelli Philip Anthony
• Pyun Hyung-Jung

Classifications

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61K45/06

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title