CXCR7 receptor modulators

Patent metadata

Field	Value
Publication number	US-9920010-B2
Application number	US-201414892959-A
Country	US
Kind code	B2
Filing date	May 28, 2014
Priority date	May 30, 2013
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

The present invention relates to derivatives of formula (I)

wherein (R 1 ) n , R 2a , R 2b , R 3a , R 3b , R 4 , L 1 , L 2 , X, Y and Ar 1 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
X represents NR 5 , and Y represents CHR Y wherein R Y represents hydrogen, or (C 1-3 )alkyl; and
R 3a and R 3b together with the carbon atom to which they are attached to form a carbonyl group, or
two of R 2a , R 2b , R 3a and R 3b independently represent hydrogen, or (C 1-3 )alkyl; and the remaining of R 2 a, R 2b , R 3 a and R 3b represent hydrogen; or

X represents CHR X wherein R X represents hydrogen, or (C 1-3 )alkyl, and Y represents NR 5 ; and
R 2a and R 2b together with the carbon atom to which they are attached to form a carbonyl group, or
two of R 2a , R 2b , R 3a and R 3b independently represent hydrogen, or (C 1-3 )alkyl; and the remaining of R 2a , R 2b , R 3a and R 3b represent hydrogen; or

X represents NR 5 and Y represents a direct bond; R 2a and R 2b both represent hydrogen; and R 3a and R 3b both represent hydrogen; or
X represents NR 5 , Y represents —C(O)—; and R 2a , R 2b , R 3a and R 3b all represent hydrogen; or
X represents —C(O)—; Y represents NR 5 , and R 2a , R 2b , R 3a and R 3b all represent hydrogen;

R 5 represents
(C 1-6 )alkyl;
(C 1-4 )alkyl mono-substituted with (C 1-3 )alkoxy, cyano, vinyl; ethynyl, or (C 1-3 )alkoxy-carbonyl;
—CO—R 10 wherein R 10 represents (C 1-5 )alkyl; (C 1-5 )alkoxy; phenyl; phenyl-oxy-; phenyl-(C 1-3 )alkyl-; phenyl-(C 1-3 )-alkyl-oxy-; (C 3-6 )cycloalkyl-(C 1-3 )alkyl; (C 3-4 )alkenoxy; (C 3-4 )alkynoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; (C 1-3 )alkoxy-(C 2-3 )alkoxy; (C 1-3 )alkoxy-(C 1-3 )alkyl; (C 3-6 )cycloalkyl optionally having one ring oxygen atom, wherein said cycloalkyl is optionally mono- or di-substituted wherein the substituents independently are fluoro or (C 1 )fluoroalkyl; unsubstituted 5-membered heteroaryl; or —NR 10a R 10b wherein R 10a and R 10b independently represent hydrogen, (C 1-4 )alkyl or (C 3-6 )cycloalkyl, or R 10a and R 10b together with the nitrogen to which they are attached to form a 5- to 7-membered saturated ring;
—SO 2 —R 11 wherein R 11 represents (C 1-5 )alkyl or phenyl;
(C 2-4 )fluroroalkyl;
(C 3-6 )cycloalkyl optionally having one ring oxygen atom;
(C 3-6 )cycloalkyl-(C 1-3 )alkyl, wherein the (C 3-6 )cycloalkyl group optionally has one ring oxygen atom; wherein said cycloalkyl is optionally substituted with one or two methyl substituents;
phenyl-(C 0-3 )alkyl-, or 5- or 6-membered heteroaryl-(C 0-3 )alkyl-, 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, (C 1-3 )fluoroalkoxy, or cyano;

(R 1 ) n represents one or two optional substituents independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, or cyano;
L 1 represents a one- or two-membered linker group selected from —NH—CH 2 —*; —NR 16a —CH 2 —* wherein R 16a represents (C 1-3 )alkyl; —NH—CHR 16b —* wherein R 16b represents (C 1-3 )alkyl; —NH—CR 16c R 16d —* wherein R 16c and R 16d together with the carbon to which they are attached to form a (C 3-6 )cycloalkyl ring; —CH 2 —NH—*; —O—CH 2 —*; —O—CHR 17a —* wherein R 17a represents (C 1-3 )alkyl; —O—CR 17b R 17c —* wherein R 17b and R 17c together with the carbon to which they are attached to form a (C 3-6 )cycloalkyl ring; —CH 2 —; —CH 2 CH 2 —; —CH═CH—; and —CH═C(CH 3 )—*; wherein the asterisks indicate the bond with which the group L 1 is attached to the carbonyl group;
L 2 represents —(C 1-4 )alkylene- or —(C 3-4 )alkenylene-;
Ar 1 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; halogen; cyano; or NR 18a R 18b wherein R 18a and R 18b independently represent hydrogen or (C 1-3 )alkyl; and
R 4 represents
(C 2-6 )alkyl;
(C 2-5 )alkyl which is mono-substituted with (C 1-4 )alkoxy, benzyloxy, cyano, or hydroxy; or disubstituted wherein the substituents are independently selected from (C 1-3 )alkoxy, or hydroxy
(C 2-3 )fluoroalkyl which is optionally further substituted with one hydroxy;
—(C 2-4 )alkylene-NR 6 R 7 , wherein R 6 and R 7 independently represent hydrogen; (C 1-4 )alkyl; —CO—(C 1-4 )alkoxy; (C 3-5 )alkenyl; (C 3-4 )alkynyl; benzyl; —SO 2 —(C 1-3 )alkyl; (C 2-3 )fluoroalkyl; or (C 3-6 )cycloalkyl or (C 3-6 )cycloalkyl-(C 1-3 )alkyl, wherein in the above groups the (C 3-6 )cycloalkyl group optionally contains one ring oxygen atom, and wherein said (C 3-6 )cycloalkyl group is optionally substituted with methyl;
—(C 1-3 )alkylene-CO—R 8 , wherein R 8 represents (C 1-4 )alkoxy; or R 8 represents NR 81 R 82 wherein R 81 and R 82 independently represent hydrogen or (C 1-4 )alkyl, or R 81 and R 82 together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally substituted with two fluoro substituents;

—(C 1-3 )alkylene-SO 2 —R 9 wherein R 9 represents (C 1-3 )alkyl, or amino;
(C 3-6 )cycloalkyl or (C 3-6 )cycloalkyl-(C 1-3 )alkyl, wherein the cycloalkyl group is optionally mono-substituted with —CO—(C 1-4 )alkoxy or hydroxy;
(C 4-7 )heterocyclyl or (C 4-7 )heterocyclyl-(C 1-3 )alkyl, wherein in the above groups the (C 4-7 )heterocyclyl independently has one or two ring heteroatoms independently selected from nitrogen, sulfur or oxygen; wherein in the above groups said (C 4-7 )heterocyclyl independently is unsubstituted, or mono-, di-, or tri-substituted wherein the substituents are independently selected from:
one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen; and/or
two methyl substituents attached to a ring carbon atom in alpha position to a ring nitrogen atom; and/or
two oxo substituents at a ring sulfur ring atom; and/or
(C 1-4 )alkyl or —CO—(C 1-4 )alkoxy attached to a ring nitrogen atom having a free valency; and/or
two fluoro substituents attached to a ring carbon atom; and/or
in case of a (C 4-7 )heterocyclyl-(C 1-3 )alkyl group, methyl attached to a ring carbon atom which is attached to the linking (C 1-3 )alkyl group;

2-oxo-2,3-dihydropyridin-4-yl-(C 1-2 )alkyl;
phenyl-(C 1-3 )alkyl-, or 5- or 6-membered heteroaryl-(C 1-3 )alkyl-, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, or di-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, or cyano;
or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 , wherein
X represents NR 5 and:
Y represents CH 2 ; and R 2a , R 2b , R 3a and R 3b represent hydrogen; or
Y represents CHR Y wherein R Y represents (C 1-3 )alkyl; and R 2a , R 2b , R 3a and R 3 b represent hydrogen; or
Y represents CH 2 ; R 2a and R 2b both represent (C 1-3 )alkyl; and R 3a and R 3b both represent hydrogen; or
Y represents CH 2 ; R 2a and R 2b both represent hydrogen; one of R 3a and R 3b represents (C 1-3 )alkyl, and the remaining of R 3a and R 3b represents hydrogen;

or Y represents NR 5 and:
X represents CH 2 ; and R 2a , R 2b , R 3a and R 3b represent hydrogen; or
X represents CHR X wherein Rx represents (C 1-3 )alkyl; and R 2a , R 2b , R 3a and R 3b represent hydrogen; or
X represents CH 2 ; R 3a and R 3b both represent (C 1-3 )alkyl; and R 2a and R 2b both represent hydrogen; or
X represents CH 2 ; R 3a and R 3b both represent hydrogen; one of

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Fretz Heinz
• Guerry Philippe
• Kimmerlin Thierry
• Lehembre Francois
• Pothier Julien
• Siendt Hervé
• Valdenaire Anja

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

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

• A61P43/00

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