Substituted dihydroindene-4-carboxamides and analogs thereof, and methods using same

Patent metadata

Field	Value
Publication number	US-11098010-B2
Application number	US-201816495794-A
Country	US
Kind code	B2
Filing date	Mar 20, 2018
Priority date	Mar 21, 2017
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention includes novel substituted bicyclic compounds, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) infections in a patient. In certain embodiments, the compounds and compositions of the invention are capsid inhibitors.

First claim

What is claimed is:

1. A compound of formula (Is), or a salt, solvate, prodrug, stereoisomer, tautomer, or isotopically labelled derivative thereof, or any mixtures thereof:

wherein:
R 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, and optionally substituted heteroaryl;
each occurrence of R 2 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
R 3 is selected from the group consisting of —N(R 2 )C(═O)OR 6 , —OH, —OR 6 , —NH 2 , —NHR 6 , —NR 6 R 6 , —OC(═O)OR 6 , —OC(═O)N(R 2 )R 6 , —NR 7 C(═O)N(R 6 )(R 7 ), —N(R 2 )C(═O)R 6 , —NR 2 S(═O) 1-2 R 6 , optionally substituted aryl, optionally substituted heteroaryl, —CH 2 C(═O)OH, —CH 2 C(═O)NR 6 R 6 , —N(R 2 )C(═O)(CH 2 ) 1-2 R 6 , NR 2 S(═O) 2 N(R 6 )(R 7 ), and —NR 2 C(═O)C(═O)N(R 6 )(R 7 );
R 4 is H or C 1 -C 6 alkyl, or
R 3 and R 4 combine to form ═O or —C(═O)NR 6a —C(═O)—NR 6a —;

R 5a is selected from the group consisting of H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;
R 5b is selected from the group consisting of H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;
R 5c is independently selected from the group consisting of H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;
each occurrence of R 6 is independently selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted phenyl, and optionally substituted hetereoaryl;
each occurrence of R 6a is independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted phenyl, and optionally substituted hetereoaryl;
each occurrence of R 7 is independently selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl;
or, if R 6 and R 7 are bound to the same N atom, R 6 and R 7 optionally combine with the N atom to which both are bound to form optionally substituted 3-7 membered heterocyclyl; and

R 8 is selected from the group consisting of H and C 1 -C 6 alkyl.

2. The compound of claim 1 , wherein each occurrence of R 6 or R 6a is independently selected from the group consisting of —(CH 2 ) 1-3 -(optionally substituted heteroaryl), —(CH 2 ) 1-3 -(optionally substituted heterocyclyl), and —(CH 2 ) 1-3 -(optionally substituted aryl).

3. The compound of claim 1 , wherein each occurrence of optionally substituted alkyl, optionally substituted heterocyclyl, or optionally substituted cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkyl, halo, —OR a , optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —N(R a )C(═O)R a , —C(═O)NR a R a , and —N(R a )(R a ), wherein each occurrence of R a is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R a groups combine with the N to which they are bound to form a heterocycle.

4. The compound of claim 1 , wherein each occurrence of optionally substituted aryl or optionally substituted heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, —CN, —OR b , —N(R b )(R b ), —NO 2 , —S(═O) 2 N(R b )(R b ), acyl, and C 1 -C 6 alkoxycarbonyl, wherein each occurrence of R b is independently H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.

5. The compound of claim 1 , wherein each occurrence of optionally substituted aryl or optionally substituted heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, —CN, —OR c , —N(R c )(R c ), and C 1 -C 6 alkoxycarbonyl, wherein each occurrence of R c is independently H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.

6. The compound of claim 1 , wherein R 1 is selected from the group consisting of optionally substituted phenyl and optionally substituted benzyl, wherein the phenyl or benzyl is optionally substituted with at least one selected from the group consisting of C 1 -C 6 alkyl, halo, C 1 -C 3 haloalkyl, and —CN.

7. The compound of claim 1 , wherein R 1 is selected from the group consisting of 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 4-chloro-3-methoxyphenyl, 3-chloro-4-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 3-fluoro-4-methoxyphenyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethyl-4-fluorophenyl, 4-trifluoromethyl-3-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-cyano-4-fluorophenyl, 4-cyano-3-fluorophenyl, 3-difluoromethyl-4-fluorophenyl, 4-difluoromethyl-3-fluorophenyl, benzo[d][1,3]dioxol-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 3-pyridyl, 2-methyl-3-pyridyl, 3-methyl-3-pyridyl, 4-pyridyl, 2-methyl-4-pyridyl, and 6-methyl-4-pyridyl.

8. The compound of claim 1 , wherein each occurrence of R 2 is independently selected from the group consisting of H and methyl.

9. The compound of claim 1 , wherein R 3 is selected from the group consisting of: —NH 2 ; —OH; —NH(pyridinyl); —NH(pyrimidinyl); —NH(piridinyl-pyrimidinyl); —NH(pyrrolo[2,3-d]pyrimidinyl); —NHS(═O) 2 (C 1 -C 6 alkyl); —NHS(═O) 2 (C 3 -C 6 cycloalkyl); —NHS(═O) 2 (CH 2 ) 0-3 pyridinyl; —NHS(═O) 2 (benzyl); —NHS(═O) 2 (pyrazolyl); —NHS(═O) 2 (morpholinyl); —NHS(═O) 2 NH(C 1 -C 6 alkyl); —NHS(═O) 2 NH(C 3 -C 6 cycloalkyl); —NHS(═O) 2 NH(CH 2 ) 0-3 pyridinyl; —NHS(═O) 2 NH(benzyl); —NHS(═O) 2 NH(pyrazolyl); —NHS(═O) 2 NH(morpholinyl); —NHC(═O)(C 1 -C 6 alkyl); —NHC(═O)(C 3 -C 8 cycloalkyl); —NHC(═O)(C 1 -C 6 haloalkyl); —NHC(═O)(pyrazolyl); —NHC(═O)(thiazolyl); —NHC(═O)(oxazolyl); —NHC(═O)(pyridinyl); —NHC(═O)(CH 2 ) 1-3 (pyridinyl); —NHC(═O)(CH 2 ) 1-3 (pyrazinyl); —NHC(═O)(CH 2 ) 1-3 (pyrimidinyl); —NHC(═O)(CH 2 ) 1-3 (quinolinyl); —NHC(═O)(CH 2 ) 1-3 (isoxazolyl); —NHC(═O)(CH 2 ) 1-3 (oxazolyl); —NHC(═O)(CH 2 ) 1-3 (oxadiazolyl); —NHC(═O)(CH 2 ) 1-3 (triazolyl); —NHC(═O)(CH 2 ) 1-3 (thiazolyl); —NHC(═O)(CH 2 ) 1-3 (imidazolyl); —NHC(═O)(CH 2 ) 1-3 (pyrazolyl); —NHC(═O)(CH 2 ) 1-3 (piperidinyl); —NHC(═O)(CH 2 ) 1-3 (oxopiperidinyl); —NHC(═O)(CH 2 ) 1-3 (pyrrolidinyl); —NHC(═O)(CH 2 ) 1-3 (oxopyrrolidinyl); —NHC(═O)(CH 2 ) 1-3 (tetrahydrofuryl); —NHC(═O)(CH 2 ) 1-3 (tetrahydropyranyl); —NHC(═O)(CH 2 ) 1-3 (2-oxooxazolidinyl); —NHC(═O)(CH 2 ) 1-3 (morpholinyl); —NHC(═O)(CH 2 ) 1-3 (thiomorpholinyl); —NHC(═O)(CH 2 ) 1-3 (1-oxido-thiomorpholinyl); —NHC(═O)(CH 2 ) 1-3 (1,1-dioxido-thiomorpholinyl); —NHC(═O)(CH 2 ) 1-3 (oxoazetidinyl); —NHC(═O)(CH 2 ) 1-3 (imidazo[1,2-a]pyridin-2-yl); —NHC(═O)(CH 2 ) 1-3 C(═O)-(pyrrolidin-1-yl); —NHC(═O)O(C 1 -C 6 alkyl); —NHC(═O)O(C 3 -C 8 cycloalkyl); —NHC(═O)O(C 1 -C 6 haloalkyl); —NHC(═O)O(CH 2 ) 1-3 (pyridinyl); —NHC(═O)O(CH 2 ) 1-3 (pyrazinyl); —NHC(═O)O(CH 2 ) 1-3 (pyrimidinyl); —NHC(═O)O(CH 2 ) 1-3 (quinolinyl); —NHC(═O)O(CH 2

Assignees

• Arbutus Biopharma Corp

Inventors

• Cole Andrew G
• Dorsey Bruce D
• Kakarla Ramesh
• Kultgen Steven
• Quintero Jorge

Classifications

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C07D265/30

  not condensed with other rings · CPC title

• C07D205/08 Primary

  with one oxygen atom directly attached in position 2, e.g. beta-lactams · CPC title

• C07D249/08

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title