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

Patent metadata

Field	Value
Publication number	US-9428456-B2
Application number	US-201314410426-A
Country	US
Kind code	B2
Filing date	Jun 21, 2013
Priority date	Jun 22, 2012
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

The present invention relates to 1-[m-carboxamido(hetero)aryl-methyl]-heterocycyl-carboxamide compounds of formula (I)

wherein X, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 5a , R 5b 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.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
Ar 1 represents a phenylene group or a 5- or 6-membered heteroarylene group, wherein the —CHR 4 — group and the —NH—CO—X—R 3 group are attached in meta arrangement to ring carbon atoms of Ar 1 ; 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 (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
X represents a
direct bond between R 3 and the carbonyl group;
(C 1-4 )alkylene which is unsubstituted, or mono-substituted with hydroxy;
(C 3-6 )cycloalkylene-;
CH 2 —O—, wherein the oxygen is linked to the R 3 group; or
—CH═CH—;

R 3 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 (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; halogen; cyano; (C 3-6 )cycloalkyl; —CO—(C 1-4 )alkoxy; —SO 2 —(C 1-4 )alkyl; and NR 6 R 7 , wherein R 6 and R 7 independently represent hydrogen or (C 1-3 )alkyl, or R 6 and R 7 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 (C 1-4 )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, R 3 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 (C 1-4 )alkyl or halogen; or
(C 3-8 )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, R 3 may in addition represent (C 2-6 )alkyl;
or, in case X is —CH═CH—, R 3 may in addition represent hydrogen, (C 1-4 )alkyl, or (dimethylamino)methyl;

R 1 represents
(C 1-6 )alkyl which is unsubstituted, or mono-substituted with (C 1-4 )alkoxy or hydroxy;
(C 2-3 )fluoroalkyl;
(C 3-8 )cycloalkyl or (C 3-8 )cycloalkyl-(C 1-3 )alkyl; wherein the respective (C 3-8 )cycloalkyl groups may optionally contain a ring oxygen atom; wherein the (C 3-8 )cycloalkyl or (C 3-8 )cycloalkyl (C 1-3 )alkyl independently is unsubstituted, or substituted as follows:
the (C 3-8 )cycloalkyl group is mono- or di-substituted wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, fluoro, hydroxy-methyl, hydroxy, and cyano; or
the (C 1-3 )alkyl group is mono-substituted with hydroxy;

aryl-(C 1-4 )alkyl-, or 5- or 6-membered heteroaryl-(C 1-4 )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 (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy; or
a 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 R 2 represents hydrogen, or (C 1-3 )alkyl; or
R 1 and R 2 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;
R 4 represents hydrogen, or (C 1-3 )alkyl; and
R 5a represents hydrogen, methyl, or fluorine; R 5b represents hydrogen; and p represents the integer 0, 1 or 2; or
R 5a represents hydrogen; R 5b 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.

2. The compound according to claim 1 ; wherein Ar 1 represents a phenylene group, wherein the —CHR 4 — group and the —NH—CO—X—R 3 group are attached in meta arrangement to said phenylene group; wherein said phenylene is unsubstituted or mono-substituted, wherein the substituent is selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 ; wherein
X represents a direct bond; —(C 1-4 )alkylene- which is unsubstituted, or mono-substituted with hydroxy; —(C 3-6 )cycloalkylene-; or —CH 2 —O, wherein the oxygen is linked to the R 3 group; and R 3 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 (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; halogen; cyano; (C 3-6 )cycloalkyl; and NR 6 R 7 , wherein R 6 and R 7 independently represent hydrogen or (C 1-3 )alkyl, or R 6 and R 7 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 (C 1-4 )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
X represents a direct bond or methylene; and R 3 represents 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 (C 1-4 )alkyl or halogen; or
X represents a direct bond or methylene; and R 3 represents (C 3-8 )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
X represents a direct bond; and R 3 represents (C 2-6 )alkyl;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 ; wherein
X represents a direct bond; methylene; ethylene; ethane-1,1-diyl; propane-2,2-diyl; 2-methyl-propan-1,1-diyl; —CH(OH)—; cyclopropylene; or —CH 2 —O—, wherein the oxygen is linked to the R 3 group; and
R 3 represents aryl which is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; halogen; and cyano; or
R 3 represents 5- to 10-membered heteroaryl; which is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; halogen; (C 3-6 )cycloalkyl; and NR 6 R 7 , wherein R 6 and R 7 independently represent hydrogen or (C 1-3 )alkyl, or R 6 and R 7 together with the n

Assignees

• Actelion Pharmaceuticals Ltd
• Actelion Pharmaceuticals Ltd

Inventors

• Fretz Heinz
• Gude Markus
• Guerry Philippe
• Kimmerlin Thierry
• Lehembre Francois
• Pfeifer Thomas
• Valdenaire Anja

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title