BICYCLO 2,3-BENZODIAZEPINES AND SPIROCYCLICALLY SUBSTITUTED 2,3-BENZODIAZEPINES

摘要

BET-protein-inhibitory, in particular BRD4-inhibitory bicyclo- and spirocyclically substituted 2,3-benzodiazepines of the general formula (I),;;pharmaceutical compositions comprising the compounds according to the invention, and the prophylactic and therapeutic use thereof for hyperproliferative disorders, especially for tumour disorders, are described. Furthermore, the use of BET protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control is described.

主权项

1. Compounds of the general formula (I)
in which X represents an oxygen or sulphur atom, A represents a monocyclic heteroaryl ring having 5 or 6 ring atoms,
orrepresents a phenyl ring, R1a represents a spirocycloalkyl, heterospirocycloalkyl, bicycloalkyl, heterobicycloalkyl radical, a bridged cycloalkyl radical or a bridged heterocycloalkyl radical, a naphthyl radical or a bicyclic heteroaryl radical, or a partially saturated bicyclic aryl or heteroaryl radical, where the radicals mentioned may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl-, phenyl-, halophenyl-, phenyl-C1-C6-alkyl-, phenoxy-, pyridinyl-, —C(═O)—NR6R7, —C(═O)—R8, —S(═O)2—NR6R7, —S(═O)—R9, —S(═O)2—R9, —NH—S(═O)2—R9 and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, n represents 0, 1 or 2, R1b represents halogen, hydroxy, cyano, nitro or represents a C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl radical or a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R2 represents a C1-C3-alkyl or trifluoromethyl or a C3- or C4-cycloalkyl radical, R3 represents cyclopropyl-, C1-C3-alkyl-, C1-C3-alkoxy-, amino-, cyclopropylamino- or C1-C3-alkylamino-, R4 and R5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl-, fluorine, chlorine or bromine,
orrepresent C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkylamino-, C1-C6-alkylcarbonylamino-, C1-C6-alkylaminocarbonyl- or C1-C6-alkylaminosulphonyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxy, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkylamino-, amino-C1-C6-alkyl-, monocyclic heterocyclyl- having 3 to 8 ring atoms and monocyclic heteroaryl- having 5 or 6 ring atoms where the monocyclic heterocyclyl and heteroaryl radicals mentioned may for their part optionally be monosubstituted by C1-C3-alkyl,orrepresent C3-C10-cycloalkyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy- and a monocyclic heterocyclyl radical having 3 to 8 ring atoms,orrepresent monocyclic heteroaryl- having 5 or 6 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, C1-C6-alkylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl and a monocyclic heterocyclyl radical having 3 to 8 ring atoms,orrepresent monocyclic heterocyclyl- having 3 to 8 ring atoms which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkylamino-, amino-C1-C6-alkyl-, C1-C6-alkylamino-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl- and a monocyclic heterocyclyl radical having 3 to 8 ring atoms,orrepresents phenyl- which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxy, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-alkoxy-C1-C6-alkyl-, C1-C6-alkylamino-, amino-C1-C6-alkyl-, C1-C6-alkylaminocarbonyl-, C1-C6-alkylaminosulphonyl-, C1-C6-alkylamino-C1-C6-alkyl-, hydroxy-C1-C6-alkyl-, halo-C1-C6-alkyl-, halo-C1-C6-alkoxy-, C3-C10-cycloalkyl- and a monocyclic heterocyclyl radical having 3 to 8 ring atoms, R6 and R7 independently of one another represent hydrogen, C1-C3-alkyl-, cyclopropyl- or di-C1-C3-alkylamino-C1-C3-alkyl-, R8 are presents hydroxy, C1-C6-alkyl-, C1-C6-alkoxy-, halo-C1-C3-alkyl-, hydroxy-C1-C3-alkyl-, C1-C3-alkoxy-C1-C3-alkyl-, C3-C6-cycloalkyl-, phenyl-, monocyclic heterocyclyl- having 3 to 8 ring atoms or monocyclic heteroaryl- having 5 or 6 ring atoms, where phenyl-, heteroaryl- and heterocyclyl- may optionally be mono- or disubstituted by halogen, C1-C3-alkoxy- or C1-C3-alkyl-, R9 represents C1-C6-alkyl-, and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates.