PTEFb inhibiting macrocyclic compounds

Patent metadata

Field	Value
Publication number	US-11242356-B2
Application number	US-201816497578-A
Country	US
Kind code	B2
Filing date	Mar 22, 2018
Priority date	Mar 28, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 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 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 )—;
G, E represent, independently from each other, 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 -, and —S—,
 with the proviso that at least one of said bivalent moieties G and E is different from —O—;
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 the group consisting of 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 the group consisting of 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 the group consisting of —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 the group consisting of 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-, a cyclic amine, —OP(═O)(OH) 2 , —C(═O)OH, and —C(═O)NH 2 ;
R 2 represents 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 , R 4 represent, independently from each other, 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 represents a group selected from the group consisting of 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-, a cyclic amine, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 6 , 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-, a cyclic amine, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-;
R 8 , R 9 represent, independently from each other, 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-, a 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 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 6 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, a cyclic amine, halo-C 1 -C 3 -alkyl-, and C 1 -C 3 -fluoroalkoxy-; and
R A represents a hydrogen atom or a C 1 -C 6 -alkyl- group;
or an enantiomer, diastereomer, salt, solvate or salt of solvate thereof.

2. The compound of 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 )—;
G, E each represent, independently from each other, a bivalent moiety selected from the group consisting of —O—, —N(R A )—, —CH 2 —, —CH(C 1 -C 3 -alkyl)-, and —S—,
 with the proviso that at least one of said bivalent moieties G and E is different from —O—;
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 the group consisting of 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 the group consisting of 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 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, 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-, a cyclic amine, —OP(═O)(OH) 2 , —C(═O)OH, and —C(═O)NH 2 ;
R 2 represents 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 3 , R 4 represent, independently from each other, 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 represents a group selected from the group consisting of 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-, a cyclic amine, fluoro-C 1 -C 2 -alkyl-, and C 1 -C 2 -fluoroalkoxy-;
R 6 , R 7 represent, independently from each other, a group selected from the group consisting of a hydrogen atom, cyano, —C(═O)R 10 , —C(═O)OR 10 , —S(═O) 2 R 10 , —

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

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

Classifications

• C07D239/30

  Halogen atoms or nitro radicals · CPC title

• C07D213/61

  Halogen atoms or nitro radicals · CPC title

• C07D498/08 Primary

  Bridged systems · CPC title

• C07D498/18 Primary

  Bridged systems · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title