BET-PROTEIN-INHIBITING DIHYDROPYRIDOPYRAZINONES

摘要

The present invention relates to BET protein-inhibitory, especially BRD4-inhibitory, dihydropyridopyrazinones of the general formula (I);;in which A, X, R1, R2, R3, R4, R4, R6, R7 and n have the meanings given in the description, to intermediates for preparation of the compounds according to the invention, to pharmaceutical compositions comprising the compounds according to the invention, and to the prophylactic and therapeutic use thereof in the case of hyperproliferative disorders, especially in the case of neoplastic disorders.;This invention further relates to the use of BET protein inhibitors in viral infections, in neurodegenerative disorders, in inflammation diseases, in atherosclerotic disorders and in male fertility control.

主权项

1. A compound of the general formula (I) in which A represents —NH— or —O—, X represents —N—, n represents 0 or 1, R1 represents —C(═O)NR8R9 or represents —S(═O)2NR8R9,
or represents oxazolin-2-yl which may optionally be mono- or disubstituted by identical or different C1-C3-alkyl substituents, R2 represents hydrogen, halogen, cyano, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, halo-C1-C4-alkyl-, C1-C4-alkoxy-, C1-C4-alkoxy-C1-C4-alkyl-, halo-C1-C4-alkoxy-, C1-C4-alkylthio-, halo-C1-C4-alkylthio- or —NR10R11, R3 represents halogen, C1-C3-alkyl, C1-C3-alkoxy-, C1-C4-alkoxy-C1-C4-alkyl-, trifluoromethyl- or cyano and may be attached to any of the still-unoccupied positions in the aromatic system, R4 represents methyl or ethyl, R5 represents hydrogen or C1-C3-alkyl, R6 represents hydrogen or C1-C3-alkyl,
or R5 and R6 together represent C2-C5-alkylene, R7 represents C1-C6-alkyl, C3-C8-cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl or phenyl-C1-C3-alkyl,
in which C1-C6-alkyl may optionally be mono-, di- or trisubstituted by identical or different substituents from the group consisting of fluorine, oxo, cyano, hydroxy, C1-C3-alkoxy- and —NR10R11,and in which the phenyl radical may in each case optionally be mono-, di- or trisubstituted by identical or different substituents from the group consisting of halogen, cyano, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy-, halo-C1-C4-alkyl- and halo-C1-C4-alkoxy-,and in which 4- to 8-membered heterocycloalkyl may optionally be mono- or disubstituted by identical or different substituents from the group consisting of oxo, fluorine, cyano, C1-C4-alkyl, C1-C4-alkoxy-, C1-C4-alkylcarbonyl- and C1-C4-alkoxycarbonyl-, R8 represents C1-C6-alkyl which may optionally be mono-, di- or trisubstituted by identical or different substituents from the group consisting of hydroxy, oxo, fluorine, cyano, C1-C4-alkoxy-, halo-C1-C4-alkoxy-, —NR10R11, C3-C8-cycloalkyl, C4-C8-cycloalkenyl, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C11-spirocycloalkyl, C5-C11-heterospirocycloalkyl, bridged C6-C12-cycloalkyl, bridged C6-C12-heterocycloalkyl, C6-C12-bicycloalkyl, C6-C12-heterobicycloalkyl, phenyl or 5- to 6-membered heteroaryl,
in which C3-C8-cycloalkyl, C4-C8-cycloalkenyl, 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C11-spirocycloalkyl, C5-C11-heterospirocycloalkyl, bridged C6-C12-cycloalkyl, bridged C6-C12-heterocycloalkyl, C6-C12-bicycloalkyl, C6-C12-heterobicycloalkyl may in each case optionally be monosubstituted by oxo, C1-C4-alkyl or C1-C4-alkoxycarbonyl-,and in which phenyl and 5- to 6-membered heteroaryl may optionally be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, trifluoromethyl-, C1-C3-alkyl and C1-C3-alkoxy-,or represents C3-C6-alkenyl or C3-C6-alkynyl,or represents C3-C8-cycloalkyl, C4-C8-cycloalkenyl, C5-C11-spirocycloalkyl-, bridged C6-C12-cycloalkyl- or C6-C12-bicycloalkyl-which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of hydroxy, oxo, cyano, fluorine, C1-C3-alkyl-, C1-C3-alkoxy-, trifluoromethyl-, —NR10R11 and 4- to 8-membered heterocycloalkyl,or represents 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C11-heterospirocycloalkyl, bridged C6-C12-heterocycloalkyl or C6-C12-heterobicycloalkyl which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of hydroxy, oxo, cyano, fluorine, C1-C3-alkyl, C1-C3-alkoxy-, trifluoromethyl-, —NR10R11, C1-C4-alkylcarbonyl- and C1-C4-alkoxycarbonyl-,or represents hydrogen, R9 represents hydrogen or C1-C3-alkyl,
or R8 and R9 together with the nitrogen atom to which they are attached represent 4- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkenyl, C5-C11-heterospirocycloalkyl, bridged C6-C12-heterocycloalkyl or C6-C12-heterobicycloalkyl which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of hydroxy, oxo, cyano, fluorine, C1-C3-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy-, trifluoromethyl-, —NR10R11, C1-C4-alkylcarbonyl- or C1-C4-alkoxycarbonyl-, R10 and R11 independently of one another represent hydrogen or represent C1-C6-alkyl which is optionally mono-, di- or trisubstituted by identical or different substituents from the group consisting of hydroxy, oxo and fluorine,
or represent C1-C4-alkylcarbonyl- or C1-C4-alkoxycarbonyl-,or R10 and R11 together with the nitrogen atom to which they are attached represent 4- to 8-membered heterocycloalkyl which may optionally be mono- or disubstituted by identical or different substituents from the group consisting of hydroxy, oxo, cyano, fluorine, C1-C3-alkyl, halo-C1-C4-alkyl-, C3-C6-cycloalkyl-, C3-C6-cycloalkyl-C1-C3-alkyl-, benzyl or C1-C4-alkoxycarbonyl-, or a diastereomer or physiologically acceptable salt thereof.