5-substituted 2-(morpholin-4-yl)-1,7-naphthyridines

Patent metadata

Field	Value
Publication number	US-10729680-B2
Application number	US-201716067830-A
Country	US
Kind code	B2
Filing date	Jan 6, 2017
Priority date	Jan 14, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

The present invention relates to 5-substituted 2-(morpholin-4-yl)-1,7-naphthyridine compounds of general formula (I) or (Ib), to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative disease as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is a group selected from:

wherein * indicates the point of attachment of said group with the rest of the molecule;

R 2 is hydrogen, —NR 7 R 8 , CN, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, 3- to 10-membered heterocycloalkoxy, C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, 3- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl, heteroaryl, —(CO)OR 7 , —(CO)NR 7 R 8 , —(SO 2 )R 9 , —(SO)R 9 , —SR 9 , —(SO 2 )NR 7 R 8 , —NR 7 (SO 2 )R 9 , —((SO)═NR 11 )R 10 , —N═(SO)R 9 R 10 , —SiR 10 R 11 R 12 , —(PO)(OR 7 ) 2 , —(PO)(OR 7 )R 10 or —(PO)(R 10 ) 2 ,
wherein each C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, 3- to 10-membered heterocycloalkoxy, C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, —CN, —NR 7 R 8 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 4 -hydroxyalkyl, phenyl-C 1 -C 4 -alkyl, (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl)-, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, —(CO)OR 7 , —(CO)NR 7 R 8 , —NR 7 (CO)R 10 , —NR 8 (CO)OR 7 , —NR 8 (CO) NR 7 R 8 , —(SO 2 )R 9 , —(SO)R 9 , —SR 9 , —(SO 2 )NR 7 R 8 , —NR 7 (SO 2 )R 9 , —((SO)═NR 11 )R 10 , —N═(SO)R 9 R 10 , —(PO)(OR 7 ) 2 , —(PO)(OR 7 )R 10 , —(PO)(R 10 ) 2 , with a heteroaryl group which is optionally substituted one or more times with C 1 -C 4 -alkyl, or
wherein two substituents of said phenyl group attached to two adjacent phenyl ring atoms are linked to one another to jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy or trimethyleneoxy group;
wherein each 4- to 10-membered heterocycloalkenyl is optionally substituted, one or more times, independently from each other, with C 1 -C 4 -alkyl;

R 3 and R 4 are independently hydrogen or methyl;
R 5 is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkoxy;
R 7 and R 8 are independently hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl or phenyl-CH 2 —, which phenyl is optionally substituted, one or more times, with halogen; or
R 7 and R 8 together represent a 4-, 5-, 6- or 7-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, said 4-, 5-, 6- or 7-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S;
R 9 is C 1 -C 4 -alkyl or phenyl, wherein each C 1 -C 4 -alkyl or phenyl is optionally substituted, one or more times, independently from each other, with R 13 ;
R 10 is C 1 -C 4 -alkyl; or
R 9 and R 10 together, in case of —N═(SO)R 9 R 10 group, represent a 5- to 8-membered heterocycloalkyl group;
R 11 is hydrogen, C 1 -C 4 -alkyl, —(CO)OR 7 , —(CO)NR 7 R 8 or CN;
R 12 is hydrogen or C 1 -C 4 -alkyl; and
R 13 is halogen, OH, —NR 7 R 8 , CN, NO 2 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, —(CO)OR 7 or —(CO)NR 7 R 8 ,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound of formula (I) according to claim 1 , wherein:
R 1 is a group:

wherein * indicates the point of attachment of said group with the rest of the molecule;

R 2 is hydrogen, —NR 7 R 8 , CN, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, 3- to 6-membered heterocycloalkoxy, C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, 3- to 6-membered heterocycloalkyl, phenyl, heteroaryl, —(CO)OR 7 , —(CO)NR 7 R 8 , —(SO 2 )R 9 , —(SO)R 9 , —SR 9 , —(SO 2 )NR 7 R 8 , —NR 7 (SO 2 )R 9 , —((SO)═NR 11 )R 10 , —N═(SO)R 9 R 10 , —(PO)(OR 7 ) 2 , —(PO)(OR 7 )R 10 or —(PO)(R 10 ) 2 ,
wherein each C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, 3- to 6-membered heterocycloalkoxy, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, —CN, —NR 7 R 8 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -hydroxyalkyl, phenyl-C 1 -C 2 -alkyl, (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl)-, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, —(CO)OR 7 , —(CO)NR 7 R 8 , —NR 7 (CO)R 10 , —NR 8 (CO)OR 7 , —NR 8 (CO) NR 7 R 8 , —(SO 2 )R 9 , —(SO)R 9 , —SR 9 , —(SO 2 )NR 7 R 8 , —NR 7 (SO 2 )R 9 , —((SO)═NR 11 )R 10 , —N═(SO)R 9 R 10 , with a heteroaryl group which is optionally substituted one or more times with C 1 -C 4 -alkyl, or
wherein two substituents of said phenyl group attached to two adjacent phenyl ring atoms are linked to one another to jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy or trimethyleneoxy group;

R 3 and R 4 are independently hydrogen or methyl;
R 5 is C 1 -C 4 -alkyl;
R 7 and R 8 are independently hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, phenyl or phenyl-CH 2 —, which phenyl is optionally substituted, one or more times, with halogen; or
R 7 and R 8 together represent a 5- or 6-membered cyclic amine group, which is optionally substituted, one or more times, independently from each other, with a substituent selected from C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, said 5- or 6-membered cyclic amine group optionally containing one further heteroatom selected from the group consisting of O, N and S;
R 9 is C 1 -C 4 -alkyl;
R 10 is C 1 -C 4 -alkyl; or
R 9 and R 10 together, in case of —N═(SO)R 9 R 10 group, represent a 5- to 6-membered heterocycloalkyl group; and
R 11 is hydrogen or C 1 -C 4 -alkyl,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (Ib)

wherein:
R 1 is a group:

wherein * indicates the point of attachment of said group with the rest of the molecule;

R 2 is NR 7 R 8 , C 1 -C 4 -alkoxy, C 4 -C 6 -cycloalkenyl, 6-membered heterocycloalkyl, phenyl, heteroaryl, —(CO)OR 7 , —N═(SO)R 9 R 10 , —(PO)(OR 7 )R 10 or —(PO)(R 10 ) 2 ,
wherein each C 1 -C 4 -alkoxy, 6-membered heterocycloalkyl, phenyl or heteroaryl is optionally substituted, one or more times, independently from each other, with halogen, OH, —CN, —NR 7 R 8 , C 1 -C 4 -alkyl, hydroxymethyl, phenyl-CH 2 —, methoxymethyl, C 1 -C 4 -alkoxy, 6-membered heterocycloalkyl, —(CO)OR 7 , —(CO)NR 7 R 8 , —(SO 2 )R 9 , —(SO)R 9 , —SR 9 , —NR 7 (SO 2 )R 9 , or
wherein two substituents of said phenyl group attached to two adjacent phenyl ring atoms are linked to one another to jointly form an ethylenedioxy group;

R 4 is methyl;
R 5 is methyl;
R 7 and R 8 are independently hydrogen, C 1 -C 6 -alkyl, cyclopropyl, phenyl or phenyl-CH 2 —, which phenyl is optionally substituted, one or more times, with halogen; or
R 7 and R 8 together represent a 5-membered cyclic amine group;
R 9 is methyl or ethyl; and
R 10 is methyl or ethyl; or
R 9 and R 10 together, in case of —N═(SO)R 9 R 10 group, represent a 5-membered heterocycl

Assignees

• Bayer Pharma AG

Inventors

• Lücking Ulrich
• Koppitz Marcus
• Lefranc Julien
• Wortmann Lars
• Wengner Antje Margret
• Siemeister Gerhard
• Bömer Ulf
• Bader Benjamin
• Lienau Philip
• Schick Hans

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4375 Primary

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title