2,3-benzodiazepines

Patent metadata

Field	Value
Publication number	US-9890147-B2
Application number	US-201314421994-A
Country	US
Kind code	B2
Filing date	Aug 13, 2013
Priority date	Aug 16, 2012
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

What is described are BET protein-inhibitory, in particular BRD4-inhibitory 2,3-benzodiazepines of the general formula (I)

in which R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , A and X have the meanings given in the description, intermediates for preparing the compounds according to the invention, pharmaceutical compositions comprising the compounds according to the invention and their prophylactic and therapeutic use for hyperproliferative disorders, in particular for tumor disorders. Also described is the use of BET protein inhibitors for benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for the control of male fertility.

First claim

The invention claimed is:

1. A compound of formula I

in which
X represents an oxygen or sulphur atom, and
A represents a monocyclic heteroaryl ring which has 5 or 6 ring atoms or represents a phenyl ring, and
R 1a represents hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or
represents a C 1 -C 6 -alkoxy, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-C 2 -C 3 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, N-(heterocyclyl)-C 1 -C 6 -alkyl, N-(heterocyclyl)-C 1 -C 6 -alkoxy, hydroxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 1 -C 6 -alkylcarbonyl or C 1 -C 6 -alkoxycarbonyl radical, or
represents a monocyclic heterocyclyl radical which has 3 to 8 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, phenyl, halophenyl, phenyl-C 1 -C 6 -alkyl, pyridinyl, —NR 6 C(═O)—R 9 , —C(═O)—NR 6 R 7 , —C(═O)—R 8 , —S(═O) 2 —NR 6 R 7 , —S(═O)—R 9 , —S(═O) 2 —R 9 , —NH—S(═O) 2 —R 9 , and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or
represents a monocyclic heteroaryl radical which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxy, amino, cyano, nitro, carboxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, —C(═O)—NR 6 R 7 , —C(═O)—R 8 , —S(═O) 2 —NR 6 R 7 , —S(═O)—R 9 , —S(═O) 2 —R 9 , —NH—S(═O) 2 —R 9 , and/or by a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and/or by a monocyclic heteroaryl radical which has 5 or 6 ring atoms, and/or by a phenyl radical which for its part may optionally be mono- or polysubstituted by halogen, C 1 -C 3 -alkyl and/or C 1 -C 3 -alkoxy, or
represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, —C(═O)NR 6 R 7 , —C(═O)R 8 , C 1 -C 3 -alkylsulphinyl, C 1 -C 3 -alkylsulphonyl, —S(═O) 2 NH 2 , C 1 -C 3 -alkylsulphonylamino, C 1 -C 3 -alkylaminosulphonyl, C 3 -C 6 -cycloalkylaminosulphonyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, hydroxy-C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and/or a monocyclic heteroaryl radical which has 5 or 6 ring atoms and which for its part may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C 1 -C 3 -alkyl and C 1 -C 3 -alkoxy, and

R 1b and R 1c independently of one another represent hydrogen, halogen, hydroxy, cyano, nitro and/or represent a C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl radical and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and
R 2 represents a C 1 -C 3 -alkyl or trifluoromethyl or a C 3 - or C 4 -cycloalkyl radical, and
R 3 represents cyclopropyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, amino, cyclopropylamino or C 1 -C 3 -alkylamino, and
R 4 and R 5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulphonyl, or
represent C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or C 1 -C 6 -alkylaminosulphonyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, monocyclic heterocyclyl which has 3 to 8 ring atoms and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C 1 -C 3 -alkyl, or
represent C 3 -C 10 -cycloalkyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or
represent monocyclic heteroaryl which has 5 or 6 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 3 -C 10 -cycloalkyl, —C(═O)R 8 , —S(═O) 2 R 9 , —NR 6 R 7 , and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or
represent monocyclic heterocyclyl which has 3 to 8 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 3 -C 10 -Cycloalkyl, —C(═O)R 8 , —S(═O) 2 R 9 , —NR 6 R 7 , and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or
represent phenyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 6 -alkylaminosulphonyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, C 3 -C 10 -Cycloalkyl and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and

R 6 and R 7 independently of one another represent hydrogen, C 1 -C 3 -alkyl, cyclopropyl, di-C 1 -C 3 -alkyl-amino-C 1 -C 3 -alkyl or fluoropyridyl, and
R 8 represents hydroxy, C 1 -C 6 -alkyl, halo-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, monocyclic heterocyclyl which has 3 to 8 ring atoms or monocyclic heteroaryl which has 5 or 6 ring atoms, where phenyl, heteroaryl and heterocyclyl may optionally be mono- or disubstituted by halogen, C 1 -C 3 -alkoxy or C 1 -C 3 -alkyl, and
R 9 represents hydrogen, C 1 -C 6 -alkyl or C 1 -C 4 -alkoxy,
or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof, with the proviso that,
if A represents a phenyl ring and R 4 and R 5 independ

Assignees

• Bayer Pharma AG
• Bayer Pharma Aktiengesellshaft

Inventors

• Siegel Stephan
• Baeurle Stefan
• Cleve Arwed
• Haendler Bernard
• Fernandez Montalvan Amaury Ernesto
• Moenning Ursula
• Krause Sabine
• Lejeune Pascale
• Schmees Norbert
• Busemann Matthias
• Holton Simon
• Kuhnke Joachim

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• 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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title