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

Patent metadata

Field	Value
Publication number	US-9549932-B2
Application number	US-201615159548-A
Country	US
Kind code	B2
Filing date	May 19, 2016
Priority date	Aug 4, 2014
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The present invention relates to 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)

in which:
R 1 represents a group selected from:

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

R 2 represents hydrogen, halogen, —NR 7 R 8 , CN, C 1 -C 5 -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, 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, —NR 7 R 8 , C 1 -C 5 -alkyl optionally substituted with hydroxyl or phenyl, C 1 -C 6 -haloalkyl, 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 or with a heteroaryl group which is optionally substituted, one or more times, with C 1 -C 4 -alkyl;
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 , R 4 represent, independently from each other, hydrogen or methyl;
R 7 , R 8 represent, independently from each other, hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl or phenyl, 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 and 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 represents 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 represents 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 represents hydrogen, C 1 -C 4 -alkyl, —(CO)OR 7 , —(CO)NR 7 R 8 or CN;
R 12 represents hydrogen or C 1 -C 4 -alkyl; and
R 13 represents 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, or a salt thereof, or a mixture of the same.

2. The compound according to claim 1 , in which
R 1 represents a group selected from:

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

R 2 represents hydrogen, halogen, —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, 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, —NR 7 R 8 , C 1 -C 6 -alkyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkenyl 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 or with a heteroaryl group which is optionally substituted, one or more times, with C 1 -C 4 -alkyl;
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 , R 4 represent, independently from each other, hydrogen or methyl;
R 7 , R 8 represent, independently from each other, hydrogen or C 1 -C 6 -alkyl; 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 and 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 represents 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 represents 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 represents hydrogen, C 1 -C 4 -alkyl, —(CO)OR 7 , —(CO)NR 7 R 8 or CN;
R 12 represents hydrogen or C 1 -C 4 -alkyl; and
R 13 represents 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 -cycloaI kyl, —(CO)O R 7 or —(CO) NR 7 R 8 .

3. The compound according to claim 1 , which is selected from the group consisting of:
4-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]-naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide,
4-[(2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximide,
4-[6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,
4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine,
4-[4-(N,S-dimethylsulfonimidoyl)phenyl]-2-[morpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,
4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,
4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]-naphthyridine,
4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine hydrochloride,
dimethyl {4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}phosphonate,
4-isopropenyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine,
2-(morpholin-4-yl)-4-phenyl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine,
4-[4-(S-ethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,
3-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide,
4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,
4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine,
4-[5-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthy

Assignees

• Bayer Pharma AG

Inventors

• Wortmann Lars
• Lücking Ulrich
• Lefranc Julien
• Briem Hans
• Von Nussbaum Franz
• Bader Benjamin
• Siemeister Gerhard
• Bone Wilhelm
• Lienau Philip
• Moosmayer Dieter
• Eberspächer Uwe
• Schick Hans
• Eis Knut
• Koppitz Marcus
• Wengner Antje Margret
• Grudzinska-Goebel Joanna

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title