Macrocyclic compounds

Patent metadata

Field	Value
Publication number	US-9963464-B2
Application number	US-201515303212-A
Country	US
Kind code	B2
Filing date	Apr 8, 2015
Priority date	Apr 11, 2014
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

The present invention relates to novel macrocyclic compounds of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
A is a bivalent group selected from the group consisting of —S—, —S(═O)—, —S(═O) 2 —, and —S(═O)(═NR 5 )—;
L is a C 2 -C 6 -alkylene group,
wherein said group is optionally substituted with
(i) one substituent selected from the group consisting of hydroxy, C 2 -C 3 -alkenyl, C 2 -C 3 -alkynyl, C 3 -C 4 -cycloalkyl, hydroxy-C 1 -C 3 -alkyl, and —(CH 2 )NR 6 R 7 , and/or
(ii) one or two or three substituents, identically or differently, selected from the group consisting of halogen and C 1 -C 3 -alkyl,
with the proviso that a C 2 -alkylene group is not substituted with a hydroxy group,

or wherein
one carbon atom of said C 2 -C 6 -alkylene group forms a three- or four-membered ring together with a bivalent group to which it is attached, wherein said bivalent group is selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, and —CH 2 OCH 2 —;

X and Y are CH or N with the proviso that one of X and Y is CH and one of X and Y is N;
R 1 is a group selected from the group consisting of C 1 -C 6 -alkyl-, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, phenyl-C 1 -C 3 -alkyl- and heteroaryl-C 1 -C 3 -alkyl-,
wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C 1 -C 6 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 6 -alkoxy-, C 1 -C 3 -fluoroalkoxy-, —NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, —OP(═O)(OH) 2 , —C(═O)OH, and —C(═O)NH 2 ;

R 2 is a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 3 and R 4 are independently a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 5 is a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R 8 , —C(═O)OR 8 , —S(═O) 2 R 8 , —C(═O)NR 6 R 7 , C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, and heteroaryl,
wherein said C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;

R 6 and R 7 are independently a group selected from the group consisting of a hydrogen atom, C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
wherein said C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-, or

R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a cyclic amine; and
R 8 is a group selected from the group consisting of C 1 -C 6 -alkyl-, halo-C 1 -C 3 -alkyl-, C 3 -C 7 -cycloalkyl-, heterocyclyl-, phenyl, benzyl and heteroaryl,
wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-,

or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

2. The compound of formula (I) according to claim 1 , wherein
A is a bivalent group selected from the group consisting of —S—, —S(═O)—, —S(═O) 2 —, and —S(═O)(═NR 5 )—;
L is a C 2 -C 4 -alkylene group,
wherein said group is optionally substituted with one substituent selected from the group consisting hydroxy, C 3 -C 4 -cycloalkyl, hydroxy-C 1 -C 3 -alkyl, and —(CH 2 )NR 6 R 7 ,
and optionally substituted with one or two or three additional substituents, identically or differently, selected from the group consisting of halogen and C 1 -C 3 -alkyl,
with the proviso that a C 2 -alkylene group is not substituted with a hydroxy group;

X and Y are CH or N with the proviso that one of X and Y is CH and one of X and Y is N;
R 1 is a group selected from the group consisting of C 1 -C 6 -alkyl-, C 3 -C 5 -cycloalkyl-, phenyl and phenyl-C 1 -C 3 -alkyl-,
wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, C 1 -C 3 -alkyl-, fluoro-C 1 -C 2 -alkyl-, C 1 -C 3 -alkoxy-, C 1 -C 2 -fluoroalkoxy-, —NH 2 , alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH) 2 , —C(═O)OH, and —C(═O)NH 2 ;

R 2 is a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, C 1 -C 2 -alkyl-, C 1 -C 2 -alkoxy-, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;
R 3 and R 4 are independently a group selected from the group consisting of a hydrogen atom, a fluoro atom, a chloro atom, a bromo atom, cyano, C 1 -C 2 -alkyl-, C 1 -C 2 -alkoxy-, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;
R 5 is a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R 8 , —C(═O)OR 8 , —S(═O) 2 R 8 , —C(═O)NR 6 R 7 , C 1 -C 6 -alkyl-, C 3 -C 5 -cycloalkyl-, and phenyl,
wherein said C 1 -C 6 -alkyl, C 3 -C 5 -cycloalkyl- or phenyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, cyclic amines, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;

R 6 and R 7 are independently a group selected from the group consisting of a hydrogen atom, C 1 -C 6 -alkyl-, C 3 -C 5 -cycloalkyl-, phenyl and benzyl,
wherein said C 1 -C 6 -alkyl-, C 3 -C 5 -cycloalkyl-, phenyl or benzyl group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, cyclic amines, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-, or

R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a cyclic amine; and
R 8 is a group selected from the group consisting of C 1 -C 6 -alkyl-, fluoro-C 1 -C 3 -alkyl-, C 3 -C 5 -cycloalkyl-, phenyl and benzyl,
wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, cyclic amines, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-,

or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

3. The compound of formula (I) according to claim 1 , wherein
A is a bivalent group selected from the group consisting of —S—, —S(═O)—, —S(═O) 2 —, and —S(═O)(═NR 5 )—;
L is a C 2 -C 4 -alkylene group,
wherein said group is optionally substitu

Assignees

• Bayer Pharma AG

Inventors

• Lücking Ulrich
• Wasnaire Pierre
• Scholz Arne
• Lienau Philip
• Siemeister Gerhard
• Stegmann Christian
• Bömer Ulf
• Zheng Kunzeng
• Gao Ping
• Chen Gang
• Xi Jiajun

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/12

  Antivirals · CPC title