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US 2019/0169180 A1Published application
Piperdine cxcr7 receptor modulators
AssigneeIdorsia Pharmaceuticals Ltd
InventorsHamed AISSAOUI, Philippe GUERRY, Francois LEHEMBRE, Julien POTHIER, Laetitia POUZOL, Sylvia RICHARD-BILDSTEIN, Shuguang YUAN
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Abstract
The present invention relates to piperidine derivatives of formula (I) wherein Ar1, Ar2, RAr1, R1, R2 and R3 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.
Claims23
A compound of formula (IA)
- wherein
- the two substituents of the piperidine ring:
- R1—CO— and —NH—CO—Ar1—Ar2, are in relative trans-configuration;
- Ar1 represents a 5-membered heteroarylene group selected from oxazol-diyl,
- isoxazol-diyl, oxadiazol-diyl, or triazol-diyl, wherein the —NH—CO— group and Ar2 are attached in meta arrangement to ring atoms of Ar1;
- wherein said 5-membered heteroarylene is unsubstituted, or mono-substituted with RAr1;
- wherein RAr1 represents methyl, methoxy, fluorine, chlorine, trifluormethyl, or trifluoromethoxy;
- Ar2 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 (C1)fluoroalkyl;
- R1 represents RN1RN2N_, wherein
- RN1 represents
- hydrogen;
- (C1-6)alkyl;
- (C1-6)alkyl which is mono-substituted with
- hydroxy;
- (C1-3)alkoxy;
- 2-hydroxy-ethoxy;
- —CO—NH2;
- —SO2—(C1-3)alkyl;
- cyano;
- (C1-3)fluoroalkoxy;
- —NRN3RN4, wherein RN3 and RN4 independently represent hydrogen or (C1-4)alkyl;
- (C2-6)alkynyl;
- (C2-5)fluoroalkyl;
- (C1-4)alkoxy;
- 2-(2-oxo-pyrrolidin-1-yl)-ethyl;
- a group -L1-Cy1;
- wherein
- L1 represents a direct bond, —(C1-3)alkylene-, or —(C3-5)cycloalkylene-;
- and
- Cy1 represents (C3-6)cycloalkyl, wherein said (C3-6)cycloalkyl optionally contains one ring oxygen atom;
- wherein said (C3-6)cycloalkyl independently is unsubstituted;
- or mono-substituted with fluoro, methyl, or hydroxy, —CO—(C1-4)alkoxy, or cyano;
- or di-substituted with fluoro, or tri-substituted with methyl and two fluoro;
- a group -L2-Ar3, wherein
- L2 represents a direct bond, —(C1-4)alkylene-;
- *—(C3-5)cycloalkylene-(C0-2)alkylene- wherein said (C3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar3 is attached;
- *—(C1-2)alkylene-(C3-5)cycloalkylene- wherein said (C3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar3 is attached;
- or —(C1-3)alkylene- which is mono-substituted with hydroxy, trifluoromethyl, or —CO—(C1-4)alkoxy;
- and
- Ar3 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 (C1-4)alkyl, (C1-4)alkoxy, halogen, hydroxy, (C1-3)fluoroalkyl, or (C1-3)fluoroalkoxy;
- wherein, in case Ar3 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 RN2 independently represents hydrogen, (C1-4)alkyl, or (C2-3)fluoroalkyl;
- or RN1 and RN2 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 Ar4, wherein Ar4 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 (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, or (C1-3)fluoroalkoxy;
- or
- morpholinyl;
- R2 represents
- hydrogen;
- (C1-6)alkyl;
- (C2-6)alkyl which is mono-substituted with (C1-3)alkoxy, or hydroxy;
- (C3-5)alkenyl (especially allyl);
- cyano-methyl;
- (C2-3)fluoroalkyl;
- (C3-8)cycloalkyl-(C0-3)alkyl;
- wherein the (C3-8)cycloalkyl is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C1-3)alkyl, fluoro, hydroxy, hydroxy-(C1-3)alkyl, (C1-3)alkoxy, or (C1-3)fluoroalkyl;
- thietan-3-yl;
- (C3-8)cycloalkenyl-(C1-3)alkyl;
- or
- Ar5—CH2-wherein Ar5 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 (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, or (C1-3)fluoroalkoxy;
- and
- R3 represents hydrogen, or methyl;
- or a pharmaceutically acceptable salt thereof.
69 more elements
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A compound of formula (Ib)
- wherein
- the two substituents of the piperidine ring:
- R1—CO— and —NH—CO—Ar1—Ar2, are in relative trans-configuration;
- Ar1 represents an unsubstituted 5-membered heteroarylene group containing one sulfur ring atom and one or two nitrogen ring atoms, wherein the —NH—CO— group and Ar2 are attached in meta arrangement to ring atoms of Ar1;
- Ar2 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 (C1)fluoroalkyl;
- R1 represents RN1RN2N—, wherein
- RN1 represents
- hydrogen;
- (C1-6)alkyl;
- (C1-6)alkyl which is mono-substituted with
- hydroxy;
- (C1-3)alkoxy;
- 2-hydroxy-ethoxy;
- —CO—NH2;
- SO2—(C1-3)alkyl;
- cyano;
- (C1-3)fluoroalkoxy;
- NRN3RN4, wherein RN3 and RN4 independently represent hydrogen or (C1-4)alkyl;
- (C2-6)alkynyl;
- (C2-5)fluoroalkyl;
- (C1-4)alkoxy;
- 2-(2-oxo-pyrrolidin-1-yl)-ethyl;
- a group -L1-Cy1;
- wherein
- L1 represents a direct bond, —(C1-3)alkylene-, or —(C3-5)cycloalkylene-;
- and
- Cy1 represents (C3-6)cycloalkyl, wherein said (C3-6)cycloalkyl optionally contains one ring oxygen atom;
- wherein said (C3-6)cycloalkyl independently is unsubstituted;
- or mono-substituted with fluoro, methyl, or hydroxy, —CO—(C1-4)alkoxy, or cyano;
- or di-substituted with fluoro, or tri-substituted with methyl and two fluoro;
- a group -L2-Ar3, wherein
- L2 represents a direct bond, —(C1-4)alkylene-;
- *—(C3-5)cycloalkylene-(C0-2)alkylene- wherein said (C3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar3 is attached;
- *—(C1-2)alkylene-(C3-5)cycloalkylene- wherein said (C3-5)cycloalkylene optionally contains one ring oxygen atom, wherein the asterisk indicates the bond to which Ar3 is attached;
- or —(C1-3)alkylene- which is mono-substituted with hydroxy, trifluoromethyl, or —CO—(C1-4)alkoxy;
- and
- Ar3 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 (C1-4)alkyl, (C1-4)alkoxy, halogen, hydroxy, (C1-3)fluoroalkyl, or (C1-3)fluoroalkoxy;
- wherein, in case Ar3 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 RN2 independently represents hydrogen, (C1-4)alkyl, or (C2-3)fluoroalkyl;
- or RN1 and RN2 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 Ar4, wherein Ar4 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 (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, or (C1-3)fluoroalkoxy;
- or
- morpholinyl;
- R2 represents
- hydrogen;
- (C1-6)alkyl;
- (C2-6)alkyl which is mono-substituted with (C1-3)alkoxy, or hydroxy;
- (C3-5)alkenyl (especially allyl);
- cyano-methyl;
- (C2-3)fluoroalkyl;
- (C3-8)cycloalkyl-(C0-3)alkyl;
- wherein the (C3-8)cycloalkyl is unsubstituted, or mono- or di-substituted wherein the substituents are independently selected from (C1-3)alkyl, fluoro, hydroxy, hydroxy-(C1-3)alkyl, (C1-3)alkoxy, or (C1-3)fluoroalkyl;
- thietan-3-yl;
- (C3-8)cycloalkenyl-(C1-3)alkyl;
- or
- Ar5—CH2— wherein Ar5 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 (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, or (C1-3)fluoroalkoxy;
- and
- R3 represents hydrogen, or methyl;
- or a pharmaceutically acceptable salt thereof.
66 more elements
Dependencies are inferred from the claim text.