PTEFb inhibiting macrocyclic compounds

Patent metadata

Field	Value
Publication number	US-11254690-B2
Application number	US-201816498662-A
Country	US
Kind code	B2
Filing date	Mar 22, 2018
Priority date	Mar 28, 2017
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

Abstract

The present invention relates to novel modified macrocyclic compounds with improved tolerability 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 general formula (I)

wherein
A represents a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O) 2 —, —S(═O)(═NR 5 )—, and —S(═NR 6 )(═NR 7 )—;
Z represents a hydrogen atom or a fluorine atom;
L represents a C 3 -C 8 -alkylene moiety,
wherein said moiety is optionally substituted with
(i) one substituent selected from hydroxy, —NR 8 R 9 , 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 8 R 9 , and/or
(ii) one or two or three or four substituents, identically or differently, selected from halogen and C 1 -C 3 -alkyl-,
or wherein one carbon atom of said C 3 -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 —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, and —CH 2 OCH 2 —;

X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
R 1 represents a group selected from C 1 -C 6 -alkyl-, C 3 -C 6 -alkenyl-, C 3 -C 7 -cycloalkyl-, and heterocyclyl-,
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 amine, —OP(═O)(OH) 2 , —C(═O)OH, and —C(═O)NH 2 ;
R 2 represents a group selected from 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 represent, independently from each other, a group selected from 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 represents a group selected from a hydrogen atom, cyano, —C(═O)R 10 , —C(═O)OR 10 , —S(═O 2 ) R 10 , —C(═O)NR 8 R 9 , C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, and heterocyclyl-,
wherein said C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl- and heterocyclyl-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 amine, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;

R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom, cyano, —C(═O)R 10 , —C(═O)OR 10 , —S(═O) 2 R 10 , —C(═O)NR 8 R 9 , C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl-, and heterocyclyl-,
wherein said C 1 -C 6 -alkyl-, C 3 -C 7 -cycloalkyl- or heterocyclyl-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 amine, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;

R 8 and R 9 represent, independently from each other, a group selected from 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- and 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 amine, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-, or

R 8 and R 9 , together with the nitrogen atom they are attached to, form a cyclic amine;
R 10 represents a group selected from 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 amine, 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 general formula (I) according to claim 1 , wherein A represents a bivalent moiety selected from the group consisting of —S—, —S(═O)—, —S(═O) 2 —, —S(═O)(═NR 5 )—, and —S(═NR 6 )(═NR 7 )—;
Z represents a hydrogen atom or a fluorine atom;
L represents a C 3 -C 5 -alkylene moiety,
wherein said moiety is optionally substituted with
i) one substituent selected from hydroxy, C 3 -C 4 -cycloalkyl-, hydroxy-C 1 -C 3 -alkyl-, and —(CH 2 )NR 8 R 9 , and/or
ii) one or two or three substituents, identically or differently, selected from halogen and C 1 -C 3 -alkyl-;

X, Y represent CH or N with the proviso that one of X and Y represents CH and one of X and Y represents N;
R 1 represents a group selected from C 1 -C 6 -alkyl- and C 3 -C 5 -cycloalkyl-,
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 amine, —OP(═O)(OH) 2 , —C(═O)OH, and —C(═O)NH 2 ;

R 2 represents a group selected from 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 3 and R 4 represent, independently from each other, a group selected from 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 represents a group selected from a hydrogen atom, cyano, —C(═O)R 10 , —C(═O)OR 10 , —S(═O) 2 R 10 , —C(═O)NR 8 R 9 , C 1 -C 6 -alkyl-, and C 3 -C 5 -cycloalkyl-,
wherein said C 1 -C 6 -alkyl- and C 3 -C 5 -cycloalkyl-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 amine, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;

R 6 and R 7 represent, independently from each other, a group selected from a hydrogen atom, cyano, —C(═O)R 10 , —C(═O)OR 10 , —S(═O) 2 R 10 , —C(═O)NR 8 R 9 , C 1 -C 6 -alkyl-, and C 3 -C 5 -cycloalkyl-,
wherein said C 1 -C 6 -alkyl- and C 3 -C 5 -cycloalkyl-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 amine, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;

R 8 and R 9 represent, independently from each other, a group selected from 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- and 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 amine, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-, or
R 8 and R 9 , together with the nitrogen atom they are attached to, form a cyclic amine;
R 10 represents a group selected from C 1 -C 6 -alkyl-, fluoro-C 1 -C

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Lücking Ulrich
• Hog Daniel
• Christ Clara
• Sack Ulrike
• Siegel Franziska
• Lienau Philip
• Werbeck Nicolas

Classifications

• C07D498/18 Primary

  Bridged systems · CPC title

• C07D239/30

  Halogen atoms or nitro radicals · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title