Piperdine CXCR7 receptor modulators

Patent metadata

Field	Value
Publication number	US-10752620-B2
Application number	US-201716320906-A
Country	US
Kind code	B2
Filing date	Jul 27, 2017
Priority date	Jul 28, 2016
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

The present invention relates to piperidine derivatives of formula (I)

wherein Ar 1 , Ar 2 , R Ar1 , R 1 , R 2 and R 3 are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as CXCR7 receptor modulators.

First claim

The invention claimed is:

1. A compound of formula (Ia)

wherein
the two substituents of the piperidine ring: R 1 —CO— and —NH—CO—Ar 1 —Ar 2 , are in relative trans-configuration;
Ar 1 represents a 5-membered heteroarylene group selected from oxazol-diyl, isoxazol-diyl, oxadiazol-diyl, or triazol-diyl, wherein the —NH—CO— group and Ar 2 are attached in meta arrangement to ring atoms of Ar 1 ; wherein said 5-membered heteroarylene is unsubstituted, or mono-substituted with R Ar1 ; wherein R Ar1 represents methyl, methoxy, fluorine, chlorine, trifluoromethyl, or trifluoromethoxy;
Ar 2 represents phenyl, or 6-membered heteroaryl; wherein said phenyl or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from fluoro, chloro, methyl, cyano, methoxy, or (C 1 )fluoroalkyl;
R 1 represents R N1 R N2 N—, wherein
R N represents
hydrogen;
(C 1-6 )alkyl;
(C 1-6 )alkyl which is mono-substituted with
hydroxy;
(C 1-3 )alkoxy;
2-hydroxy-ethoxy;
CO—NH 2 ;
SO 2 —(C 1-3 )alkyl;
cyano;
(C 1-3 )fluoroalkoxy;
NR N3 R N4 , wherein R N3 and R N4 independently represent hydrogen or (C 1-4 )alkyl;

(C 2-6 )alkynyl;
(C 2-5 )fluoroalkyl;
(C 1-4 )alkoxy;
2-(2-oxo-pyrrolidin-1-yl)-ethyl;
a group -L 1 -Cy 1 ; wherein
L 1 represents a direct bond, —(C 1-3 )alkylene-, or —(C 3-5 )cycloalkylene-; and
Cy 1 represents (C 3-6 )cycloalkyl, wherein said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl independently is unsubstituted; or mono-substituted with fluoro, methyl, or hydroxy, —CO—(C 1-4 )alkoxy, or cyano; or di-substituted with fluoro, or tri-substituted with methyl and two fluoro;

a group -L 2 -Ar 3 , wherein
L 2 represents a direct bond, —(C 1-4 )alkylene-; *—(C 3-5 )cycloalkylene-(C 0-2 )alkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached; *—(C 1-2 )alkylene-(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached; or —(C 1-3 )alkylene- which is mono-substituted with hydroxy, trifluoromethyl, or —CO—(C 1-4 )alkoxy; and
Ar 3 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, hydroxy, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherein, in case Ar 3 represents 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in form of the respective N-oxide;

and R N2 independently represents hydrogen, (C 1-4 )alkyl, or (C 2-3 )fluoroalkyl;
or R N and R N2 together with the nitrogen atom to which they are attached to form a 4- to 6-membered ring selected from
azetidinyl, pyrrolidinyl or piperidinyl; each independently
unsubstituted;
or mono-substituted with fluoro, methyl, or hydroxy;
or di-substituted with fluoro;
or mono-substituted with Ar 4 , wherein Ar 4 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; or

morpholinyl;

R 2 represents
hydrogen;
(C 1-6 )alkyl;
(C 2-6 )alkyl which is mono-substituted with (C 1-3 )alkoxy, or hydroxy;
(C 3-5 )alkenyl;
cyano-methyl;
(C 2-3 )fluoroalkyl;
(C 3-8 )cycloalkyl-(C 0-3 )alkyl; wherein the (C 3-8 )cycloalkyl is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C 1-3 )alkyl, fluoro, hydroxy, hydroxy-(C 1-3 )alkyl, (C 1-3 )alkoxy, or (C 1-3 )fluoroalkyl;
thietan-3-yl;
(C 3-8 )cycloalkenyl-(C 1-3 )alkyl; or
Ar 5 —CH 2 — wherein Ar 5 represents phenyl, or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; and

R 3 represents hydrogen, or methyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of formula (Ia) as defined in claim 1 which are also compounds of Formula (Ia S ), wherein the two substituents of the piperidine ring: R 1 —CO— and —NH—CO—Ar 1 —Ar 2 , are in relative trans-configuration, wherein the absolute configuration of the two chiral carbon atoms in position 3 and 4 of the piperidine ring is (3S,4S):

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 ; wherein R 3 represents hydrogen;
or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 ; wherein Ar 1 represents oxazol-2,5-diyl, oxazol-2,4-diyl, isoxazol-3,5-diyl, [1,3,4]oxadiazol-2,5-diyl, [1,2,4]oxadiazol-3,5-diyl, or 1H-[1,2,3]triazol-1,4-diyl; wherein said 5-membered heteroarylene is unsubstituted;
or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 ; wherein Ar 2 represents phenyl which is mono-, di- or tri-substituted; wherein one or two of said substituents is/are independently selected from fluoro, chloro, or methyl, and the remaining, if present, is/are fluoro;
or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 ; wherein R 1 represents R N1 R N2 N—, wherein
R N1 represents
(C 1-6 )alkyl;
(C 1-6 )alkyl which is mono-substituted with
hydroxy;
(C 1-3 )alkoxy;
2-hydroxy-ethoxy;
CO—NH 2 ;
SO 2 —(C 1-3 )alkyl;
cyano;
(C 1-3 )fluoroalkoxy;
NR N3 R N4 , wherein R N3 and R N4 independently represent hydrogen or (C 1-4 )alkyl;

(C 2-6 )alkynyl;
(C 2-5 )fluoroalkyl;
2-(2-oxo-pyrrolidin-1-yl)-ethyl;
a group -L 1 -Cy 1 ; wherein
L 1 represents a direct bond, —(C 1-3 )alkylene-, or —(C 3-5 )cycloalkylene-; and
Cy 1 represents (C 3-6 )cycloalkyl, wherein said (C 3-6 )cycloalkyl optionally contains one ring oxygen atom; wherein said (C 3-6 )cycloalkyl independently is unsubstituted: or mono-substituted with fluoro, methyl, hydroxy, CO—(C 1-4 )alkoxy, or cyano; or di-substituted with fluoro, or tri-substituted with methyl and two fluoro;

a group -L 2 -Ar 3 , wherein
L 2 represents a —(C 1-4 )alkylene-; —(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom; *—(C 3-5 )cycloalkylene-(C 1-2 )alkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached; *—(C 1-2 )alkylene-(C 3-5 )cycloalkylene- wherein said (C 3-5 )cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar 3 is attached; or —(C 1-3 )alkylene- which is mono-substituted with hydroxy or trifluoromethyl; and
Ar 3 represents phenyl, or 5-membered heteroaryl containing one oxygen atom and one or two nitrogen atoms, or 6-membered heteroaryl containing one or two nitrogen atoms; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, or (C 1-3 )fluoroalkoxy; wherei

Assignees

• Idorsia Pharmaceuticals Ltd
• Idorsia Pharmaceuticals Ltd

Inventors

• Aissaoui Hamed
• Guerry Philippe
• Lehembre Francois
• Pothier Julien
• Pouzol Laetitia
• Richard-Bildstein Sylvia
• Yuan Shuguang

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title