Oxadiazine compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9802927-B2
Application number	US-201615178626-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Jun 10, 2015
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

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.

First claim

We claim:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, —C 1 -C 4 alkylene-C 3 -C 8 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, —C 1 -C 4 alkyl, —C 3 -C 8 monocyclic cycloalkyl, halo-substituted C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy and oxo;
R 2 is hydrogen or —C 1 -C 4 alkyl;
Y is pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy, —C 1 -C 4 alkyl, halo-substituted C 1 -C 4 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, —C 1 -C 4 alkyl, halo-substituted C 1 -C 4 alkyl, —C 1 -C 4 alkoxy and —OCF 3 .

2. A compound of claim 1 , wherein R 1 is —C 1 -C 6 alkyl, —C 3 -C 8 monocyclic cycloalkyl, phenyl, 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, —C 1 -C 4 alkyl, —C 3 -C 8 monocyclic cycloalkyl, halo-substituted C 1 -C 4 alkyl, —C 1 -C 4 alkoxy and halo-substituted C 1 -C 4 alkoxy; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , wherein R 1 is —C 3 -C 8 monocyclic cycloalkyl, phenyl, 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, —C 1 -C 4 alkyl, —C 3 -C 8 monocyclic cycloalkyl, halo-substituted C 1 -C 4 alkyl, and halo-substituted C 1 -C 4 alkoxy; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 , wherein R 1 is 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, —C 1 -C 4 alkyl, and halo-substituted C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 , wherein R 1 is phenyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —CN, —C 1 -C 4 alkyl, —C 3 -C 8 monocyclic cycloalkyl, halo-substituted C 1 -C 4 alkyl, —C 1 -C 4 alkoxy and halo-substituted C 1 -C 4 alkoxy; or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 , wherein R 1 is —C 1 -C 6 alkyl which is unsubstituted; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 , wherein R 1 is —C 3 -C 8 monocyclic cycloalkyl, each of which is unsubstituted or substituted with one or more -halo; or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 , wherein R 1 is —C 3 -C 8 monocyclic cycloalkyl which is unsubstituted; or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 , wherein Y is pyridinyl which is unsubstituted or substituted with one or more —C 1 -C 4 alkoxy, halo-substituted C 1 -C 4 alkoxy; or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 , wherein Z is nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more —C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 , wherein Z is imidazolyl which is unsubstituted or substituted with one methyl; or a pharmaceutically acceptable salt thereof.

12. A compound of claim 1 , wherein:
R 1 is

each of which is optionally further substituted with -halo, —CF 3 or —C 1 -C 4 alkyl; and
Z is

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , wherein Y is

wherein the left most radical is connected to the Z group in Formula (I); or a pharmaceutically acceptable salt thereof.

14. 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-i

Assignees

• Denali Therapeutics Inc

Inventors

• Acharya Raksha
• Burnett Duane A
• Bursavich Matthew Gregory
• Cook Andrew Simon
• Harrison Bryce Alden
• Mcriner Andrew J

Classifications

• C07D273/04

  Six-membered rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D273/02

  having two nitrogen atoms and only one oxygen atom · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/535

  having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines · CPC title