Substituted pyridobenzodiazepinone-derivatives and use thereof

Patent metadata

Field	Value
Publication number	US-10047096-B2
Application number	US-201515529043-A
Country	US
Kind code	B2
Filing date	Nov 23, 2015
Priority date	Nov 25, 2014
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

The present application relates to novel (3-hydroxyphenyl)amino-substituted pyrido[2,3-b][1,5]benzodiazepin-5-one derivatives, to processes for preparation thereof, to the use thereof alone or in combination for treatment and/or prevention of diseases and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially of angiogenic disorders and hyperproliferative disorders in which neovascularization plays a role, for example ophthalmological disorders and cancers and tumours. Such treatments can be effected as monotherapy or else in combination with other medicaments or further therapeutic measures.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R 1 is hydrogen, halogen, hydroxyl, (C 1 -C 4 )-alkyl, —NH—C(═O)—R 4 , —NH—C(═O)—O—R 5 or —NH—SO 2 —R 6 ,
wherein
R 4 is hydrogen or (C 1 -C 4 )-alkyl;
R 5 is (C 1 -C 4 )-alkyl; and
R 6 is (C 1 -C 4 )-alkyl or phenyl;

R 2 is hydrogen, fluorine, chlorine, methyl or methoxy;
R 3 is hydrogen, fluorine, chlorine or methyl;
and
G is cyano, hydroxycarbonyl, —C(═O)—NR 7A R 7B or —CH 2 —NR 8A R 8B ,
wherein
R 7A is hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl, (C 1 -C 4 )-alkoxy or up to trisubstituted by fluorine;
R 7B is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl, 4- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl;
wherein (C 1 -C 6 )-alkyl is optionally up to hexasubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 9 , —O—(CH 2 CH 2 O) n —R 10 , —SR 11 , —NR 12A R 12B , —C(═O)—NR 13A R 13B , (C 3 -C 6 )-cycloalkyl, (C 4 -C 6 )-cycloalkenyl, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl;
and wherein
(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and (C 1 -C 4 )-alkoxy carbonyl;
(ii) the phenyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;
(iii) the heterocyclyl groups are optionally up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, oxo, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl; and
(iv) the heteroaryl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;
and wherein
R 9 is hydrogen or (C 1 -C 4 )-alkyl optionally substituted by 4- to 6-membered heterocyclyl;
R 10 is hydrogen or (C 1 -C 4 )-alkyl;
R 11 is (C 1 -C 4 )-alkyl;
R 12A , R 12B , R 13A and R 13B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl;
and
n is an integer from 1 to 10;

or
R 7A and R 7B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycle which optionally contains up to 2 further ring heteroatoms selected from the group consisting of N, O and S, and which is optionally up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, oxo, —OR 14 , —NR 15A R 15B , —C(═O)—NR 16A R 16B and phenyl;
wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxy or up to three times by fluorine;
and wherein
R 14 is hydrogen, (C 1 -C 4 )-alkyl or phenyl;
wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxyl, —C(═O)—NR 17A R 17B , (C 3 -C 6 )-cycloalkyl or up to trisubstituted by fluorine;

and
R 15A , R 15B , R 16A , R 16B , R 17A and R 17B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl;

R 8A is hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl, (C 1 -C 4 )-alkoxy or up to trisubstituted by fluorine;
and
R 8B is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl, 4- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl;
wherein (C 1 -C 6 )-alkyl is optionally up to hexasubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 18 , —O—(CH 2 CH 2 O) p —R 19 , —SR 20 , —NR 21A R 21B , —C(═O)—NR 22A R 22B , (C 3 -C 6 )-cycloalkyl, (C 4 -C 6 )-cycloalkenyl, phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl;
and wherein
(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl;
(ii) the phenyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;
(iii) the heterocyclyl groups are optionally up to trisubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, hydroxyl, oxo, hydroxycarbonyl and (C 1 -C 4 )-alkoxycarbonyl; and
(iv) the heteroaryl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy;
and wherein
R 18 is hydrogen or (C 1 -C 4 )-alky optionally substituted by 4- to 6-membered heterocyclyl;
R 19 is hydrogen or (C 1 -C 4 )-alkyl;
R 20 is (C 1 -C 4 )-alkyl;
R 21A , R 21B , R 22A and R 22B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl;
and
p is an integer from 1 to 10;

or
R 8A and R 8B are joined to one another and, together with the nitrogen atom to which they are bonded, form a 4- to 10-membered heterocycle which optionally contains up to 2 further ring heteroatoms selected from the group consisting of N, O and S, and which is optionally up to tetrasubstituted, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 )-alkyl, oxo, —OR 23 , —NR 24A R 24B , —C(═O)—NR 25A R 25B and phenyl;
wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxy or up to three times by fluorine;
and wherein
R 23 is hydrogen, (C 1 -C 4 )-alkyl or phenyl;
wherein (C 1 -C 4 )-alkyl is optionally substituted by hydroxyl, —C(═O)—NR 26A R 26B , (C 3 -C 6 )-cycloalkyl or up to trisubstituted by fluorine;

and
R 24A , R 24B , R 25A , R 25B , R 26A and R 26B are independently hydrogen or (C 1 -C 4 )-alkyl optionally substituted by hydroxyl,

or a salt, a solvate or a solvate of a salt thereof.

2. The compound of formula (I) according to claim 1 , wherein:
R 1 is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or —NH—SO 2 —R 6 ,
wherein
R 6 is (C 1 -C 4 )-alkyl or phenyl;

R 2 is hydrogen, fluorine, chlorine or methyl;
R 3 is hydrogen, fluorine, chlorine or methyl;
and
G is cyano, —C(═O)—NR 7A R 7B or —CH 2 —NR 8A R 8B ,
wherein
R 7A is hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl or 2-ethoxyethyl;
wherein methyl and ethyl are optionally up to trisubstituted by fluorine;

R 7B is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl;
wherein (C 1 -C 4 )-alkyl is optionally up to trisubstituted by fluorine and up to disubstituted, identically or differently, by a radical selected from the group consisting of —OR 9 , —SR 11 , —NR 12A R 12B , (C 3 -C 6 )-cycloalkyl and phenyl;
and wherein
(i) the cycloalkyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, methyl, ethyl, hydroxyl, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl; and
(ii) the phenyl groups are optionally up to disubstituted, identically or differently, by a radical selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxy and ethoxy;
and wherein
R 9 is hydrogen, methyl or ethyl;
R 11 is methyl or ethyl;
and
R 12A and R 12B are independently hydrogen, methyl, ethyl or 2-hydroxyethyl;

or
R 7A and R 7B are joined to one another and, together with the nitrogen atom to which t

Assignees

• Bayer Pharma AG
• Heinrich Keldenich Petra

Inventors

• Schall Andreas
• Klar Jürgen
• Lobell Mario
• Schirok Hartmut
• Telser Joachim
• Müller Steffen
• Brohm Dirk
• Briem Hans
• Jörissen Hannah
• Keldenich Joerg
• Böttger Michael
• Von Degenfeld Georges
• Schlange Thomas
• Bömer Ulf
• Lindner Niels
• Eilken Hanna
• Hristodorov Dmitrij
• Wasnaire Pierre
• Gericke Kersten Matthias
• Bärfacker Lars

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title