Modified macrocyclic compounds

Patent metadata

Field	Value
Publication number	US-10214542-B2
Application number	US-201615764289-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	Oct 8, 2015
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The present invention relates to novel modified 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 moiety selected from the group consisting of —S—, —S(═O)—, —S(═O) 2 —, and —S(═O)(═NR 5 )—;
G and E are independently a bivalent moiety selected from the group consisting of —O—, —N(R A )—, —CH 2 —, —CH(C 1 -C 6 -alkyl)-, —C(C 1 -C 6 -alkyl) 2 -, —S—, —S(═O)—, and —S(═O) 2 —,
with the proviso that at least one of said bivalent moieties G and E is different from —O—;

L is a C 2 -C 8 -alkylene moiety,
wherein said moiety is optionally substituted with
(i) one substituent selected from the group consisting of hydroxy, —NR 6 R 7 , 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 or four substituents independently selected from the group consisting of halogen and C 1 -C 3 -alkyl-,
or wherein
one carbon atom of said C 2 -C 8 -alkylene moiety forms a three- or four-membered ring together with a bivalent moiety to which it is attached, wherein said bivalent moiety 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 independently 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 fluorine atom, a chlorine atom, a bromine 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 fluorine atom, a chlorine atom, a bromine 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 independently 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 independently 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;
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 independently 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-; and

R A is a hydrogen atom or a C 1 -C 6 -alkyl-group,
or an enantiomer, a diastereomer, a salt, or a solvate thereof, or a salt of said solvate.

2. The compound of formula (I) according to claim 1 , wherein:
A is a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O) 2 —, and —S(═O)(═NR 5 )—;
G and E are independently a bivalent moiety selected from the group consisting of —O—, —N(R A )—, —CH 2 —, —CH(C 1 -C 3 -alkyl)-, —S—, and —S(═O) 2 —, with the proviso that at least one of said bivalent moieties G and E is different from —O—;
L is a C 2 -C 5 -alkylene moiety,
wherein said moiety is optionally substituted with
(i) one substituent selected from the group consisting of hydroxy, 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 additional substituents independently selected from the group consisting of a fluorine atom and a C 1 -C 3 -alkyl-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- and C 3 -C 5 -cycloalkyl-,
wherein said group is optionally substituted with one or two or three substituents independently 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 fluorine atom, a chlorine atom, cyano, C 1 -C 2 -alkyl-, C 1 -C 2 -alkoxy-, and fluoro-C 1 -C 2 -alkyl-;
R 3 and R 4 are independently a group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine 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 independently 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 from each other, 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 independently 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;
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 independently 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-; and

R A is a hydrogen atom or a

Assignees

• Bayer Pharma AG

Inventors

• Lücking Ulrich
• Hog Daniel
• Geisler Jens
• Scholz Arne
• Petersen Kirstin
• Lienau Philip
• Stegmann Christian
• Andres Dorothee
• Siemeister Gerhard
• Werbeck Nicolas

Classifications

• C07D498/08

  Bridged systems · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D515/08

  Bridged systems · CPC title

• A61K31/529

  forming part of bridged ring systems · CPC title