Bicyclic heteroaryl derivatives

Patent metadata

Field	Value
Publication number	US-12084461-B2
Application number	US-201917273278-A
Country	US
Kind code	B2
Filing date	Sep 2, 2019
Priority date	Sep 3, 2018
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

The invention provides new bicyclic heteroaryl compounds having the general formula (I) wherein R 1 , Ar, n and m are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (I),

wherein:
n is 1, 2 or 3;
each R 1 is independently selected from halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, and lower alkoxy substituted by halogen;
m is 1 or 2; and
Ar is a six membered heteroaryl group, selected from:

wherein:
R 2 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, or lower alkoxy; and
R 3 is hydrogen or halogen;

or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 , wherein the compound of formula (I) is a compound of formula (Ia):

wherein R 1 , m, n and Ar are as defined in claim 1 .

3. The compound of formula (I) according to claim 1 , wherein the compound of formula (I) is a compound of formula (Ib):

wherein R 1 , m, n and Ar are as defined in claim 1 .

4. The compound of formula (I) according to claim 1 , wherein R 1 is halogen.

5. The compound of formula (I) according to claim 1 , wherein R 1 is fluorine or chlorine.

6. The compound of formula (I) according to claim 1 , wherein n is 2 or 3.

7. The compound of formula (I) according to claim 1 , wherein Ar is a six membered heteroaryl group, selected from:

wherein:
R 2 is lower alkyl or lower alkoxy; and
R 3 is hydrogen.

8. The compound of formula (I) according to claim 1 , wherein Ar is a six membered heteroaryl group, selected from:

wherein:
R 2 is methyl or methoxy; and
R 3 is hydrogen.

9. The compound of formula (I) according to claim 1 , wherein:
R 1 is halogen;
n is 2 or 3;
Ar is a six membered heteroaryl group, selected from:

wherein:
R 2 is lower alkyl or lower alkoxy; and
R 3 is hydrogen.

10. The compound of formula (I) according to claim 1 , wherein:
R 1 is fluorine or chlorine;
n is 2 or 3; and
Ar is a six membered heteroaryl group, selected from:

wherein:
R 2 is methyl or methoxy;
R 3 is hydrogen.

11. A compound according to claim 1 , selected from:
(9R)-9-(2,3-difluorophenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(2,3-difluorophenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)-9-(2,4-difluorophenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(2,4-difluorophenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)-9-(2,3-difluorophenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(2,3-difluorophenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)-9-(3,5-difluorophenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(3,5-difluorophenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)-9-(2,4-difluorophenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(2,4-difluorophenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)-9-(3,5-difluorophenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(3,5-difluorophenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)—N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-9-(2,3,4-trifluorophenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)—N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-9-(2,3,4-trifluorophenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)—N-[(1R,5S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-9-(2,3,4-trifluorophenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)—N-[(1R,5S)-3-(6-methylpyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-9-(2,3,4-trifluorophenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(9S)-9-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-c][1,4]oxazepin-2-amine;
(8R)-8-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine;
(8S)-8-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine;
(8R)—N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-8-(2,3,4-trifluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine;
(8S)—N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-8-(2,3,4-trifluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine;
(8R)-8-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine;
(8S)-8-(3-chloro-5-fluoro-phenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine;
(8R)—N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-8-(2,3,4-trifluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,4]oxazin-2-amine;
(8S)—N-[(1R,5S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-8-(2,3,4-trifluorophenyl)-6,8-dihydro-5H-[1,2,4]triazolo[5,1-c][1,

Assignees

• Hoffmann La Roche

Inventors

• Ratni Hasane
• Carter Jennifer Louise

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D519/00 Primary

  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

• C07D498/04 Primary

  Ortho-condensed systems · CPC title