US 9,802,927 B2Granted

Oxadiazine compounds and methods of use thereof

AssigneeDenali Therapeutics Inc.

InventorsRaksha Acharya, Duane A. Burnett, Matthew Gregory Bursavich, Andrew Simon Cook, Bryce Alden Harrison, Andrew J. McRiner

Life of this patent

Estimating the term…

Abstract

The present disclosure relates to oxadiazine compounds, pharmaceutical compositions comprising an effective amount of an oxadiazine compound and methods for using an oxadiazine compound in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of an oxadiazine compound.

Claims19

Dependent claims

A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
R1 is —C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C4 alkylene-C3-C8 monocyclic cycloalkyl, phenyl, 5- to 6-membered aromatic heterocycle, 3- to 7-membered monocyclic heterocycle, 8- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —CN, —C1-C4 alkyl, —C3-C8 monocyclic cycloalkyl, halo-substituted C1-C4 alkyl, —C1-C4 alkoxy, halo-substituted C1-C4 alkoxy and oxo;
R2 is hydrogen or —C1-C4 alkyl;
Y is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —CN and —OH;
and
Z is nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —C1-C4 alkoxy and —OCF3.

4 more elements

A compound selected from the group consisting of:

(R)-5-(benzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5, 6-dihydro-4H-1,2,4-oxadiazine;
3-(6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(7-methylbenzofuran-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(R)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(5-methylbenzofuran-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(R)-5-(benzo[b]thiophen-2-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(3-methylbenzofuran-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(R)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(4-methylbenzofuran-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(R)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(6-methylbenzofuran-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-5-(7-methylbenzofuran-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(5-(4-chloro-1H-imidazol-1-yl)-6-methoxypyridin-2-yl)-5-(7-methylbenzofuran-2-yl)-5, 6-dihydro-4H-1,2,4-oxadiazine;
5-(4-chloro-2-methylphenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-4-methyl-5,6-dihydro-4H-1,2,4-oxadiazine;
3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-4-methyl-5-(3-(trifluoromethyl) phenyl)-5, 6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methoxy-1H-imidazol-1-yl)pyridin-2-yl)-5-(7-methylbenzofuran-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-phenyl-5,6-dihydro-4H-1,2,4-oxadiazine;
5-(benzofuran-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
5-(4-fluorophenyl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
5-(4-chlorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
5-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
5-(1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3, 4-dichlorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(6-fluorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(4-methoxyphenyl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(5-chlorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(4-(trifluoromethyl) phenyl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-cyclohexyl-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(7-chlorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(3-methylbenzo [b] thiophen-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(benzo [b] thiophen-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(4-(trifluoromethoxy) phenyl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(5-chloro-1-ethyl-6-fluoro-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(5-chloro-1-ethyl-6-fluoro-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3,4-difluorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(6-chlorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3,5-difluorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(5-fluorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(4-chloro-3-methylphenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(7-fluorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(3,4,5-trifluorophenyl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(4-(difluoromethoxy) phenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(4-chlorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(4-fluorobenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(5-fluoro-3-methylbenzofuran-2-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(6-fluoro-1-methyl-5-(trifluoromethyl)-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(6-fluoro-1-methyl-5-(trifluoromethyl)-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(4-chloro-3-fluorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3-chloro-4-fluorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3-chloro-5-fluorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(3-(trifluoromethyl) phenyl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(4-cyclopropylphenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3,5-dichlorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3-fluoro-4-(trifluoromethyl) phenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(1-methyl-1H-indazol-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(3-cyclopropylphenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
5-(2,4-difluorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(o-tolyl)-5,6-dihydro-4H-1,2,4-oxadiazine;
5-(2-chlorophenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine:
(+)-5-(4, 4-difluorocyclohexyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl) benzonitrile;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(3-methoxyphenyl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(tert-butyl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-isobutyl-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-cyclopentyl-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(1-methyl-1H-indol-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(1-methyl-1H-indol-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(5-fluoro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(4-fluoro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(4-fluoro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(6-fluoro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(6-fluoro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(5-chloro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(5-chloro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(6-chloro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(6-chloro-1-methyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(1-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-5-(4-fluoro-1-isopropyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-5-(4-fluoro-1-isopropyl-1H-indol-3-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(1-methyl-6-(trifluoromethyl)-1H-indol-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(−)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(1-methyl-6-(trifluoromethyl)-1H-indol-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-5-(1-methyl-1H-indol-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-2-(3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazin-5-yl)benzo[d]oxazole;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5-(1-methyl-1H-indol-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
(+)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl) pyridin-2-yl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrrolo [2,3-b] pyridin-3-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
and
(+)-5-(benzo[d]thiazol-2-yl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine;
or a pharmaceutically acceptable salt thereof.

81 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/178,626Filed 10 Jun 2016 · us provisional application
Priority: 10 Jun 2015
Published: US 2017/0066753 A19 Mar 2017
Granted: 31 Oct 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
A61K 31/535
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with at least one nitrogen and one oxygen as the…
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
C07D 247/02
Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00…

Family

Application62/173,723Us provisional application · filed 10 Jun 2015
Application62/279,384Us provisional application · filed 15 Jan 2016
US 2017/0066753 A1Pre-grant publication · published 9 Mar 2017
US 9,802,927 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

Facts

Application

15/178,626Filed 10 Jun 2016 · us provisional application

Priority

10 Jun 2015

Published

US 2017/0066753 A19 Mar 2017

Granted

31 Oct 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
A61K 31/535
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with at least one nitrogen and one oxygen as the…
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
C07D 247/02
Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00…