Azetidine amide derivatives as orexin receptor antagonists

Patent metadata

Field	Value
Publication number	US-9403813-B2
Application number	US-201414775474-A
Country	US
Kind code	B2
Filing date	Mar 11, 2014
Priority date	Mar 12, 2013
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The present invention relates to azetidine amide derivatives derivatives of formula (I)

wherein rings A 1 A 2 and A 3 are as described in the description, to pharmaceutically acceptable salts thereof, to their preparation, to pharmaceutical compositions containing one or more compounds of formula (I), and to their use as pharmaceuticals, especially to their use as orexin receptor antagonists.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein the carbon atom at position 2 of the azetidine ring is in absolute (S)-configuration;
ring A 3 represents a meta di-substituted 5-membered heteroarylene ring containing one, two or three heteroatoms; wherein at least one of said heteroatoms is nitrogen, and the remaining is/are independently selected from oxygen, sulfur and nitrogen;
ring A 2 represents phenyl or 6-membered heteroaryl; wherein said phenyl or 6-membered heteroaryl is independently unsubstituted, or mono-, di-, or tri-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and (C 3-6 )cycloalkyl-oxy-;
ring A 1 represents phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein
one of said substituents is attached in ortho-position to the point of attachment of A 1 to the rest of the molecule; wherein said substituent is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
and the other of said substituents, if present, is/are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy and dimethylamino;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 ; wherein the ring A 3 is a meta di-substituted 5-membered heteroarylene ring selected from oxadiazol-diyl, triazol-diyl, isoxazol-diyl, oxazol-diyl, thiazol-diyl, pyrazol-diyl, imidazol-diyl, isothiazol-diyl, and thiadiazol-diyl;
or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 ; wherein the ring A 3 represents

wherein the asterisks indicate the bond that is linked to the azetidin-2-yl moiety of the molecule;
or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 ; wherein ring A 2 represents
phenyl which is mono- or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkoxy; or
6-membered heteroaryl containing one or two ring nitrogen atoms; wherein said heteroaryl is mono-substituted; wherein the substituent is selected from (C 1-4 )alkoxy and (C 3-6 )cycloalkyl-oxy-;
or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 ; wherein the group A 3 -A 2 represents a group independently selected from the following groups A, B and C:
A: [1,2,4]oxadiazol-3,5-diyl groups selected from the groups:
A.1

A.2

A.3

B: [1,2,4]oxadiazol-3,5-diyl groups selected from the groups:
B.1

B.2

B.3

C: [1,2,4]triazol-3,5-diyl groups selected from the groups:
C.1

C.2

C.3

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 ; wherein one or both of the following characteristics are present:
in case ring A 1 represents a 5-membered heteroaryl group, such group is an oxazolyl or a thiazolyl group; and/or
in case ring A 1 represents a 6-membered heteroaryl group, such group is a pyridinyl, a pyrazinyl, or a pyrimidinyl group;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 ; wherein one or more of the following characteristics are present:
in case said ortho substituent of ring A 1 represents a 5-membered heteroaryl group, such group is an unsubstituted [1,2,3]triazol-2-yl] group; and/or
in case said ortho substituent of ring A 1 represents a 6-membered heteroaryl group, such group is an unsubstituted pyrimidin-2-yl group; and/or
in case said ortho substituent of ring A 1 represents a phenyl group, such group is an unsubstituted or mono-substituted phenyl group wherein the substituent is selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen;

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 ; wherein ring A 1 represents a group

wherein
(R x ) m represents one or two substituents independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy; and
Ar 4 represents unsubstituted or mono-substituted phenyl wherein the substituent is selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen; unsubstituted [1,2,3]triazol-2-yl; unsubstituted pyrazol-1-yl; unsubstituted pyridin-2-yl; or unsubstituted pyrimidin-2-yl;
or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 ; wherein the ring A 1 represents a group selected from the following groups A and B:
A: substituted phenyl groups selected from the groups:
A.1

A.2

A.3

B: substituted 5-membered heteroaryl groups selected from the groups:
B.1

B.2

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 selected from:
(5-Methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(S)-2-(3-o-tolyl-[1,2,4]oxadiazol-5-yl)-azetidin-1-yl]-methanone;
{(S)-2-[3-(3-Fluoro-2-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-azetidin-1-yl}-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone;
{(S)-2[3-(2-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-azetidin-1-yl}-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone;
{(S)-2[3-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-azetidin-1-yl}-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone;
{(S)-2-[3-(3-Chloro-2-methyl-phenyl)-[1,2,4]oxadiazol-5-yl]-azetidin-1-yl}-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone;
{(S)-2-[3-(2-Ethoxy-3-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-azetidin-1-yl}-(5-methyl-2-[1,2,3]t

Assignees

• Actelion Pharmaceuticals Ltd
• Actelion Pharmaceuticals Ltd

Inventors

• Bolli Martin
• Boss Christoph
• Brotschi Christine
• Heidmann Bibia
• Sifferlen Thierry
• Williams Jodi T

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title