1-[m-carboxamido(hetero)aryl-methyl]-heterocyclyl-carboxamide derivatives

摘要

The present invention relates to 1-[m-carboxamido(hetero)aryl-methyl]-heterocycyl-carboxamide compounds of formula (I);wherein X, Ar1, R1, R2, R3, R4, R5a, R5b and p are as described in the description, to 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.

主权项

1. A compound of formula (I) wherein Ar1 represents a phenylene group or a 5- or 6-membered heteroarylene group, wherein the —CHR4— group and the —NH—CO—X—R3 group are attached in meta arrangement to ring carbon atoms of Ar1; wherein said phenylene or 5- or 6-membered heteroarylene independently is unsubstituted or mono-substituted, wherein the substituent is selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; X represents a
direct bond between R3 and the carbonyl group;(C1-4)alkylene which is unsubstituted, or mono-substituted with hydroxy;(C3-6)cycloalkylene-;CH2—O—, wherein the oxygen is linked to the R3 group; or—CH═CH—; R3 represents
aryl or 5- to 10-membered heteroaryl; wherein said aryl or 5- to 10-membered heteroaryl independently is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl; (C1-4)alkoxy; (C1-3)fluoroalkyl; (C1-3)fluoroalkoxy; halogen; cyano; (C3-6)cycloalkyl; —CO—(C1-4)alkoxy; —SO2—(C1-4)alkyl; and NR6R7, wherein R6 and R7 independently represent hydrogen or (C1-3)alkyl, or R6 and R7 together with the nitrogen atom to which they are attached to form a 5- or 6-membered ring selected from pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl optionally substituted at the vacant nitrogen atom with (C1-4)alkyl; wherein in case said 5- to 10-membered heteroaryl is pyridine, such pyridine may additionally be present in form of the respective N-oxide;or, in case X is a direct bond or a methylene group, R3 may in addition represent
a partially aromatic bicyclic ring system consisting of a phenyl ring which is fused to a 4- to 6-membered saturated carbocyclic ring optionally containing one or two heteroatoms independently selected from nitrogen and oxygen; wherein said ring system is optionally mono-, or di-substituted with (C1-4)alkyl or halogen; or(C3-8)cycloalkyl, wherein the cycloalkyl may optionally contain a ring oxygen atom, and wherein said cycloalkyl is optionally substituted with up to four methyl groups;or, in case X is a direct bond, R3 may in addition represent (C2-6)alkyl;or, in case X is —CH═CH—, R3 may in addition represent hydrogen, (C1-4)alkyl, or (dimethylamino)methyl; R1 represents
(C1-6)alkyl which is unsubstituted, or mono-substituted with (C1-4)alkoxy or hydroxy;(C2-3)fluoroalkyl;(C3-8)cycloalkyl or (C3-8)cycloalkyl-(C1-3)alkyl; wherein the respective (C3-8)cycloalkyl groups may optionally contain a ring oxygen atom; wherein the (C3-8)cycloalkyl or (C3-8)cycloalkyl (C1-3)alkyl independently is unsubstituted, or substituted as follows:
the (C3-8)cycloalkyl group is mono- or di-substituted wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, fluoro, hydroxy-methyl, hydroxy, and cyano; orthe (C1-3)alkyl group is mono-substituted with hydroxy;aryl-(C1-4)alkyl-, or 5- or 6-membered heteroaryl-(C1-4)alkyl-, wherein the aryl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; ora 1,2,3,4-tetrahydronaphthalenyl or an indanyl group, which groups are attached to the rest of the molecule through a carbon atom that is part of the non-aromatic ring; and R2 represents hydrogen, or (C1-3)alkyl; or R1 and R2 together with the nitrogen atom to which they are attached to represent an azetidine, pyrrolidine, piperidine, morpholine, or azepane ring, wherein said rings independently are unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of fluorine and methyl; R4 represents hydrogen, or (C1-3)alkyl; and
R5a represents hydrogen, methyl, or fluorine; R5b represents hydrogen; and p represents the integer 0, 1 or 2; orR5a represents hydrogen; R5b represents methyl; and p represents the integer 1; or a pharmaceutically acceptable salt thereof; wherein said compound of formula (I) is not: 1-[1-[3-(benzoylamino)phenyl]ethyl]-N-[(4-fluorophenyl)methyl]-4-piperidinecarboxamide; or N-[3-[1-[4-(1-pyrrolidinylcarbonyl)-1-piperidinyl]ethyl]phenyl]-benzamide.