Substituted imidazo[1,5-a]pyrazines for the treatment of hepatitis B

Patent metadata

Field	Value
Publication number	US-11845752-B2
Application number	US-202117450808-A
Country	US
Kind code	B2
Filing date	Oct 13, 2021
Priority date	Oct 15, 2020
Publication date	Dec 19, 2023
Grant date	Dec 19, 2023

Abstract

Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A compound of Formula (I) having the structure:

or a pharmaceutically acceptable salt or a stereoisomer thereof,
wherein:
R 1 is a 3,4-disubstituted phenyl, wherein the 3,4-disubstituted phenyl is substituted with 2 substituents independently selected from the group consisting of —F, —Cl, —Br, —CHF 2 , —CF 3 , —CH 3 , —CN and —C≡CH, or a trisubstituted phenyl, wherein the trisubstituted phenyl is substituted with 3 substituents independently selected from the group consisting of —F, —Cl, —Br, —CHF 2 , —CF 3 , —CH 3 , —CN and —C≡CH;
R 2 is —C(═O) R 5 ;
R 3 is selected from the group consisting of a substituted phenyl, a substituted monocyclic heteroaryl a substituted bicyclic heteroaryl and

wherein the phenyl, the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with one or more substituents selected from the group consisting of halogen; hydroxy; —NH 2 ; —NH (an unsubstituted C 1-4 alkyl); —N(an unsubstituted C 1-4 alkyl) 2 ; an unsubstituted C 1-4 alkyl; an unsubstituted methoxy; an unsubstituted ethoxy; an unsubstituted n-propoxy; an unsubstituted isopropoxy; an unsubstituted n-butoxy; an unsubstituted iso-butoxy; an unsubstituted sec-butoxy; an unsubstituted tert-butoxy; an unsubstituted cyclopropoxy; an unsubstituted cyclobutoxy; an unsubstituted C 1-4 haloalkyl; an unsubstituted C 1-4 haloalkoxy; hydroxy-substituted methoxy; hydroxy-substituted ethoxy; hydroxy-substituted n-propoxy; hydroxy-substituted isopropoxy; hydroxy-substituted n-butoxy; hydroxy-substituted iso-butoxy; hydroxy-substituted sec-butoxy; hydroxy-substituted tert-butoxy; hydroxy-substituted cyclopropoxy; hydroxy-substituted cyclobutoxy; methoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); ethoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); n-propoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); isopropoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); n-butoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); iso-butoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); sec-butoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); tert-butoxy substituted by an amine-mono(an unsubstituted C 1-4 alkyl); methoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); ethoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); n-propoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); isopropoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); n-butoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); iso-butoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); sec-butoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); tert-butoxy substituted by an amine-di(an unsubstituted C 1-4 alkyl); methoxy substituted by a monocyclic heterocyclyl; ethoxy substituted by a monocyclic heterocyclyl; n-propoxy substituted by a monocyclic heterocyclyl; isopropoxy substituted by a monocyclic heterocyclyl; n-butoxy substituted by a monocyclic heterocyclyl; iso-butoxy substituted by a monocyclic heterocyclyl; sec-butoxy substituted by a monocyclic heterocyclyl; tert-butoxy substituted by a monocyclic heterocyclyl; an unsubstituted C 1-4 hydroxyalkyl; C 1-4 alkyl substituted by hydroxy and halogen; G methoxy substituted by hydroxy and halogen; ethoxy substituted by hydroxy and halogen; n-propoxy substituted by hydroxy and halogen; isopropoxy substituted by hydroxy and halogen; n-butoxy substituted by hydroxy and halogen; iso-butoxy substituted by hydroxy and halogen; tert-butoxy substituted by hydroxy and halogen; cyclopropoxy substituted by hydroxy and halogen; cyclobutoxy substituted by hydroxy and halogen; methoxy substituted by hydroxy and —NR Z1 R Z2 ethoxy substituted by hydroxy and —NR Z1 R Z2 ; n-propoxy substituted by hydroxy and —NR Z1 R Z2 ; isopropoxy substituted by hydroxy and —NR Z1 R Z2 ; n-butoxy; substituted by hydroxy and —NR Z1 R Z2 ; iso-butoxy substituted by hydroxy and —NR Z1 R Z2 ; tert-butoxy substituted by hydroxy and —NR Z1 R Z2 ; cyclopropoxy substituted by hydroxy and —NR Z1 R Z2 ; cyclobutoxy substituted by hydroxy and —NR Z1 R Z2 ; —O—CH 2 —C(═O)-(an unsubstituted C 1-4 alkyl); an unsubstituted monocyclic heterocyclyl; a substituted monocyclic heterocyclyl substituted by 1, 2 or 3 moieties selected from the group consisting of halogen, hydroxy, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 haloalkyl; an unsubstituted fused-bicyclic heterocyclyl; a substituted fused-bicyclic heterocyclyl substituted by 1, 2 or 3 moieties selected from the group consisting of halogen, hydroxy, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 haloalkyl; an unsubstituted sprio-bicyclic heterocyclyl; a substituted sprio-bicyclic heterocyclyl substituted by 1, 2 or 3 moieties selected from the group consisting of halogen, hydroxy, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 haloalkyl; an unsubstituted monocyclic heteroaryl; a substituted monocyclic heteroaryl substituted by 1, 2 or 3 moieties selected from the group consisting of halogen, hydroxy, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 haloalkyl; an unsubstituted bicyclic heteroaryl and a substituted bicyclic heteroaryl substituted by 1, 2 or 3 moieties selected from the group consisting of halogen, hydroxy, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 haloalkyl; and wherein each R Z1 and each R Z2 are independently H or an unsubstituted C 1-4 alkyl; or wherein each R Z1 and each R Z2 are taken together along with the N to which each R Z1 and each R Z2 are attached to form a monocyclic heterocyclyl;
R 4 is selected from the group consisting of —CHF 2 , —CH 3 , -cyclopropyl, —(CH 2 ) 1-4 -(hydroxy), —CH 2 —O—CH 2 -(an unsubstituted phenyl) and —CH 2 -(an unsubstituted heterocyclyl), wherein the unsubstituted heterocyclyl of the —CH 2 -(an unsubstituted heterocyclyl) is an unsubstituted monocyclic heterocyclyl;
(i) R 5 is

R 6 is an unsubstituted 5- or 6-membered monocyclic heteroaryl or a substituted 5- or 6-membered monocyclic heteroaryl,
wherein the unsubstituted monocyclic heteroaryl contains 1, 2 or 3 N (nitrogens, and optionally 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen and sulfur; and
wherein the substituted 5- or 6-membered monocyclic heteroaryl contains 1, 2 or 3 N (nitrogen), and optionally 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen and sulfur, and is substituted with one or more substituents independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted methoxy, an unsubstituted ethoxy, an unsubstituted n-propoxy, an unsubstituted isopropoxy, an unsubstituted n-butoxy, an unsubstituted iso-butoxy, an unsubstituted sec-butoxy, an unsubstituted tert-butoxy, —NH 2 and —NH (an unsubstituted C 1-6 alkyl);
R 7 is selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted methoxy, an unsubstituted ethoxy, an unsubstituted n-propoxy, an unsubstituted isopropoxy, an unsubstituted n-butoxy, an unsubstituted iso-butoxy, an unsubstituted sec-butoxy and an unsubstituted tert-butoxy; and
n is 0 or 1; or
(ii) R 5 is

R 6 is halogen;
R 7 is halogen; and
n is 1; and
provided t

Assignees

• Aligos Therapeutics Inc

Inventors

• Vendeville Sandrine
• Debing Yannick
• Stoycheva Antitsa Dimitrova
• Raboisson Pierre Jean-Marie Bernard

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

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

• A61P31/20

  for DNA viruses · CPC title